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Adapting a Meds-to-Beds Program to COVID-19 Impact of RDT And Biomarkers On Antimicrobial Stewardship: Deriving Their Optimal Benefit

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Where Do We Go From Here?

TREATMENT FOR NOSOCOMIAL PNEUMONIA HAS ARRIVED

In HABP/VABP and cUTI caused by susceptible Gram-negative microorganisms

OUTSMART RESISTANCE Fetroja outsmarts pathogens by using iron to gain cell entry, like a Trojan horse.1,2

Fetroja—the world’s only siderophore cephalosporin—overcomes Gram-negative antibacterial resistance1 INDICATIONS Fetroja® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.

Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens.

USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of Fetroja.

WARNINGS AND PRECAUTIONS Increase in All-Cause Mortality in Patients with CarbapenemResistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with Fetroja as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenemresistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin.

Stable in vitro against all known classes of ϐ-lactamases, including serine-carbapenemases (such as KPC and OXA) and metallo-ϐ-lactamases (such as VIM, IMP, and NDM)1 Active against pathogens with porin channel deletions and efflux pump up-regulation1,3,4 The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with Fetroja than in patients treated with BAT [25/101 (24.8%) vs 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with BAT through Day 49 [34/101 (33.7%) vs 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established.

Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in Fetroja-treated patients in clinical trials. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

Fetroja has an extensive Gram-negative spectrum that includes hard-to-treat pathogens1 Fetroja has demonstrated activity against the following Gram-negative bacteria, both in vitro and in HABP/VABP: Acinetobacter baumannii complex, Escherichia coli*, Enterobacter cloacae complex*, Klebsiella pneumoniae*, Pseudomonas aeruginosa*, Serratia marcescens *Also included in cUTI indication.

In a seriously ill patient population with HABP or VABP, Fetroja exhibited non-inferiority to extended-infusion, high-dose meropenem1

Fetroja is highly active in vitro vs Gramnegative carbapenem-NS pathogens5 In this study, susceptibility of >38,000 Gram-negative clinical isolates from multiple countries (2013-2018) was tested against Fetroja

• Study highlights:

In vitro activity does not necessarily correlate with clinical efficacy.

Enterobacteralesa Overall

Enterobacterales

a

carbapenem-non-susceptible

P aeruginosaa

(n=25,995)

100%

(n=814)

97%

– 60% of patients were ventilated, while approximately 33% had failed empiric treatment1,5

98%

– The top 5 baseline Gram-negative pathogens were K pneumoniae, P aeruginosa, A baumannii, E coli, and E cloacae5

(n=6213)

Overall

P aeruginosaa

95%

(n=1416)

carbapenem-non-susceptible

A baumannii complexa A baumannii complexa

(n=2274)

S maltophilia b

(n=1565)

carbapenem-non-susceptible

Overall

• At Day 14, all-cause mortality (primary endpoint) in the mITT population was 12.4% for Fetroja vs 12.2% for extended-infusion, high-dose meropenem (95% CI, -7.2, 7.7)1

90%

(n=4185)

Overall

85% 100%

(inherently carbapenem-resistant)5,7

0

– Meropenem was used as a comparator in the trial and was optimized (2 grams IV over 3 h q8h) for seriously ill patients with a multidrug-resistant Gram-negative infection in the ICU1

20

40

PERCENT

60

80

100

In a phylogenetic reclassification performed in 2016, the nomenclature of Enterobacterales was proposed, which includes formerly established Enterobacteriaceae family and other genera such as Proteus spp, Providencia spp, Photorhabdus spp, and Serratia spp.8

In vitro susceptibility study design Clinical isolates of Gram-negative bacteria were collected from 4 global surveillance studies (SIDERO-WT-2014, SIDERO-WT-2015, SIDERO-WT-2016, and SIDERO-WT-2018) that included Enterobacterales* and non-fermenter strains. The global surveillance study (Proteeae†) collected clinical isolates from 2013-2016, and were tested centrally (IHMA Inc., Schaumburg, IL, USA). Fetroja MICs were determined by microbroth dilution using irondepleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) as approved by the Clinical and Laboratory Standards Institute (CLSI) subcommittee on antimicrobial susceptibility testing in January 2016. FDA breakpoints were used for Enterobacterales MIC ≤4 μg/mL, P aeruginosa MIC ≤1 μg/mL, and A baumannii complex‡ MIC ≤1 μg/mL, whereas CLSI investigational breakpoint was used for S maltophilia MIC ≤4 μg/mL. Carbapenem-nonsusceptible strain was defined as meropenem MIC ≥2 μg/mL for Enterobacterales strains (including Proteeae) and MIC ≥4 μg/mL for P aeruginosa and A baumannii complex.5 a FDA breakpoints used for Enterobacterales MIC ≤4 μg/mL, P aeruginosa MIC ≤1 μg/mL, and A baumannii complex MIC ≤1 μg/mL. b CLSI investigational breakpoint used for S maltophilia MIC ≤4 μg/mL. *E coli, K pneumoniae, other Klebsiella spp, Enterobacter spp, Serratia spp, and Citrobacter spp. † Morganella morganii, P mirabilis, Proteus vulgaris, and Providencia rettgeri. ‡ A baumannii complex consists of A baumannii, A calcoaceticus, A dijkshoorniae, A nosocomialis, A pittii, and A seifertii.

IMPORTANT SAFETY INFORMATION (continued) WARNINGS AND PRECAUTIONS (continued) Hypersensitivity Reactions (continued) Before therapy with Fetroja is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue Fetroja if an allergic reaction occurs.

Clostridioides difficile-associated Diarrhea (CDAD) Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including Fetroja. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

• Fetroja exhibited comparable safety vs extended-infusion, high-dose meropenem in HABP/VABP1 Study Design Multicenter, double-blind, parallel-group, randomized, active-controlled Phase 3 study in approximately 300 adults with documented nosocomial pneumonia caused

by Gram-negative bacteria. Subjects were randomized (1:1) to either cefiderocol, 2 grams, administered IV over 3 hours every 8 hours (q8h) or extended-infusion, high-dose meropenem, 2 grams, administered IV over 3 hours q8h. Randomization was performed by the stratified randomization method using their infection diagnosis (HABP, VABP, and HCABP) and Acute Physiology And Chronic Health Evaluation II (APACHE II) score (≤15 and ≥16) as allocation factors. Linezolid was administered for at least 5 days to subjects in both arms to provide coverage for methicillin-resistant Staphylococcus aureus (MRSA), and to maintain the study blind.1,5 CI=confidence interval.

FOR MORE INFORMATION, VISIT

Fetroja.com Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including Fetroja, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust Fetroja dosing based on creatinine clearance. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether Fetroja should be discontinued.

Development of Drug-Resistant Bacteria Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

ADVERSE REACTIONS The most common adverse reactions occurring in (≥2%) of patients receiving Fetroja compared to imipenem/cilastatin in the cUTI trial were: diarrhea (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%). The most common adverse reactions occurring in (≥4%) of patients receiving Fetroja compared to meropenem in the HABP/VABP trial were: elevations in liver tests (16% vs 16%), hypokalemia (11% vs 15%), diarrhea (9% vs 9%), hypomagnesemia (5% vs <1%), and atrial fibrillation (5% vs 3%).

Please see a Brief Summary of Prescribing Information on following page.

References: 1. Fetroja (cefiderocol) [package insert]. Florham Park, NJ: Shionogi Inc.; 2020. 2. Zhanel GG, Golden AR, Zelenistky S, et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli. Drugs. 2019;79(3):271-289. 3. Iregui A, Khan Z, Landman D, Quale J. Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resist. 2020;26(7):1-5. 4. Iregui A, Khan Z, Landman D, Quale J. Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resist. 2020;26(7) (suppl):S1-S3. 5. Data on file. 6. Brooke JS. Stenotrophomonas maltophilia: an emerging global opportunistic pathogen. Clin Microbiol Rev. 2012;25(1):2-41. 7. Ruppé É, Woerther PL, Barbier F. Mechanisms of antimicrobial resistance in Gramnegative bacilli. Ann Intensive Care. 2015;5(1):61. doi:10.1186/s13613-015-0061-0. 8. Adeolu M, Alnajar S, Naushad S, Gupta RS. Genome-based phylogeny and taxonomy of the 'Enterobacteriales': proposal for Enterobacterales ord. nov. divided into the families Enterobacteriaceae, Erwiniaceae fam. nov., Pectobacteriaceae fam. nov., Yersiniaceae fam. nov., Hafniaceae fam. nov., Morganellaceae fam. nov., and Budviciaceae fam. nov. Int J Syst Evol Microbiol. 2016;66(12):5575-5599. © 2020 Shionogi Inc. Florham Park, NJ 07932. All Rights Reserved.

Fetroja is a registered trademark of Shionogi & Co., Ltd. Osaka, Japan. USFET-0209 09/20

FETROJA (cefiderocol) for injection, for intravenous use Initial U.S. Approval: 2019 BRIEF SUMMARY: Please see package insert for full prescribing information.

1 INDICATIONS AND USAGE 1.1 Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA® is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex [see Clinical Studies (14.1) in the full prescribing information].

1.2 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) FETROJA is indicated in patients 18 years of age or older for the treatment of hospitalacquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens [see Clinical Studies (14.2) in the full prescribing information].

1.3 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of FETROJA and other antibacterial drugs, FETROJA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

4 CONTRAINDICATIONS FETROJA is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of FETROJA [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

5 WARNINGS AND PRECAUTIONS 5.1 Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with FETROJA as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin.

The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with FETROJA than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with FETROJA than in patients treated with BAT through Day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established.

Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. 5.2 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs.

Hypersensitivity was observed in FETROJA-treated patients in clinical trials [see Adverse Reactions (6.1)]. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

5.4 Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including FETROJA, have been implicated in triggering seizures [see Adverse Reactions (6.1)]. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment.

Adjust FETROJA dosing based on creatinine clearance [see Dosage and Administration (2.2) in the full prescribing information]. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether FETROJA should be discontinued.

5.5 Development of Drug-Resistant Bacteria Prescribing FETROJA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage (1.3)].

6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in the Warnings and Precautions section: • Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections [see Warnings and Precautions (5.1)] • Hypersensitivity Reactions [see Warnings and Precautions (5.2)] • Clostridioides difficile-associated Diarrhea (CDAD) [see Warnings and Precautions (5.3)] • Seizures and Other Central Nervous System Adverse Reactions [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA was evaluated in an active-controlled, randomized clinical trial in patients with cUTI, including pyelonephritis (Trial 1). In this trial, 300 patients received FETROJA 2 grams every 8 hours infused over 1 hour (or a renally-adjusted dose), and 148 patients were treated with imipenem/cilastatin 1gram/1gram every 8 hours infused over 1 hour (or a renally-adjusted dose). The median age of treated patients across treatment arms was 65 years (range 18 to 93 years), with approximately 53% of patients aged greater than or equal to 65. Approximately 96% of patients were White, most were from Europe, and 55% were female. Patients across treatment arms received treatment for a median duration of 9 days.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 1, a total of 14/300 (4.7%) cUTI patients treated with FETROJA and 12/148 (8.1%) of cUTI patients treated with imipenem/cilastatin experienced serious adverse reactions. One death (0.3%) occurred in 300 patients treated with FETROJA as compared to none treated with imipenem/cilastatin. Discontinuation of treatment due to any adverse reaction occurred in 5/300 (1.7%) of patients treated with FETROJA and 3/148 (2.0%) of patients treated with imipenem/cilastatin. Specific adverse reactions leading to treatment discontinuation in patients who received FETROJA included diarrhea (0.3%), drug hypersensitivity (0.3%), and increased hepatic enzymes (0.3%).

Common Adverse Reactions Table 4 lists the most common selected adverse reactions occurring in ≥ 2% of cUTI patients receiving FETROJA in Trial 1.

Selected Adverse Reactions Occurring in ≥ 2% of cUTI Patients Receiving FETROJA in Trial 1 FETROJAa Imipenem/Cilastatinb Adverse Reaction (N = 300) (N = 148)

Table 4

Before therapy with FETROJA is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs.

Discontinue FETROJA if an allergic reaction occurs.

Diarrhea

4%

6%

Infusion site reactionsc

4%

5%

5.3 Clostridioides difficile-associated Diarrhea (CDAD) Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including FETROJA. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

Constipation

3%

4%

Rashd

3%

< 1%

Candidiasise

2%

3%

Cough

2%

< 1%

Elevations in liver testsf

2%

< 1%

Headache

2%

5%

Hypokalemiag

2%

3%

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.

(continued)

Table 4

Selected Adverse Reactions Occurring in ≥ 2% of cUTI Patients Receiving FETROJA in Trial 1 FETROJAa (N = 300)

Imipenem/Cilastatinb (N = 148)

Nausea

2%

4%

Vomiting

2%

1%

Adverse Reaction

cUTI = complicated urinary tract infection. a 2 grams IV over 1 hour every 8 hours (with dosing adjustment based on renal function). b 1 gram IV over 1 hour every 8 hours (with dosing adjustment based on renal function and body weight). c Infusion site reactions include infusion site erythema, inflammation, pain, pruritis, injection site pain, and phlebitis. d Rash includes rash macular, rash maculopapular, erythema, skin irritation. e Candidiasis includes oral or vulvovaginal candidiasis, candiduria. f Elevations in liver tests include alanine aminotransferase, aspartate aminotransferase, gammaglutamyl transferase, blood alkaline phosphatase, hepatic enzyme increased. g Hypokalemia includes blood potassium decreased.

Other Adverse Reactions of FETROJA in the cUTI Patients (Trial 1) The following selected adverse reactions were reported in FETROJA-treated cUTI patients at a rate of less than 2% in Trial 1: Blood and lymphatic disorders: thrombocytosis Cardiac disorders: congestive heart failure, bradycardia, atrial fibrillation Gastrointestinal disorders: abdominal pain, dry mouth, stomatitis General system disorders: pyrexia, peripheral edema Hepatobiliary disorders: cholelithiasis, cholecystitis, gallbladder pain Immune system disorders: drug hypersensitivity Infections and infestations: C. difficile infection Laboratory investigations: prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), red blood cells urine positive, creatine phosphokinase increase Metabolism and nutrition disorders: decreased appetite, hypocalcemia, fluid overload Nervous system disorders: dysgeusia, seizure Respiratory, thoracic, and mediastinal disorders: dyspnea, pleural effusion Skin and subcutaneous tissue disorders: pruritis Psychiatric disorders: insomnia, restlessness Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) FETROJA was evaluated in an active-controlled clinical trial in patients with HABP/VABP (Trial 2). In this trial, 148 patients received FETROJA 2 grams every 8 hours infused over 3 hours, and 150 patients received meropenem 2 grams every 8 hours infused over 3 hours. Doses of study treatments were adjusted based on renal function. The median age was 67 years, approximately 59% of patients were 65 years of age and older, 69% were male, and 68% were White. Overall, approximately 60% were ventilated at randomization, including 41% with VABP and 14% with ventilated HABP. The mean Acute Physiology And Chronic Health Evaluation (APACHE II) score was 16. All patients received empiric treatment for Gram-positive organisms with linezolid for at least 5 days.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 2, serious adverse reactions occurred in 54/148 (36.5%) HABP/VABP patients treated with FETROJA and 45/150 (30%) of HABP/VABP patients treated with meropenem. Adverse reactions leading to death were reported in 39/148 (26.4%) patients treated with FETROJA and 35/150 (23.3%) patients treated with meropenem.

Adverse reactions leading to discontinuation of treatment occurred in 12/148 (8.1%) of patients treated with FETROJA and 14/150 (9.3%) of patients treated with meropenem.

The most common adverse reactions leading to discontinuation in both treatment groups were elevated liver tests.

Common Adverse Reactions Table 5 lists the most common selected adverse reactions occurring in ≥ 4% of patients receiving FETROJA in the HABP/VABP trial.

Table 5

Selected Adverse Reactions Occurring in ≥ 4% of HABP/VABP Patients Receiving FETROJA in Trial 2 FETROJAa N = 148

Meropenemb N = 150

Elevations in liver testsc

16%

16%

Hypokalemiad

11%

15%

Diarrhea

9%

9%

Hypomagnesemia

5%

< 1%

Atrial fibrillation

5%

3%

Adverse Reaction

HABP/VABP = hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. a 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function). b 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function). c Elevations in liver tests include the following terms: aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyl transferase increased, liver function test increased, liver function test abnormal, hepatic enzyme increased, transaminases increased, hypertransaminesemia. d Hypokalemia includes blood potassium decreased.

Other Adverse Reactions of FETROJA in HABP/VABP Patients in Trial 2 The following selected adverse reactions were reported in FETROJA-treated HABP/VABP patients at a rate of less than 4% in Trial 2:

Blood and lymphatic disorders: thrombocytopenia, thrombocytosis Cardiac disorders: myocardial infarction, atrial flutter Gastrointestinal disorders: nausea, vomiting, abdominal pain Hepatobiliary disorders: cholecystitis, cholestasis Infections and infestations: C. difficile infection, oral candidiasis Laboratory investigations: prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT) Metabolism and nutrition disorders: hypocalcemia, hyperkalemia Nervous system disorders: seizure Renal and genitourinary disorders: acute interstitial nephritis Respiratory, thoracic, and mediastinal disorders: cough Skin and subcutaneous tissue disorders: rash including rash erythematous 7 DRUG INTERACTIONS 7.1 Drug/Laboratory Test Interactions Cefiderocol may result in false-positive results in dipstick tests (urine protein, ketones, or occult blood). Use alternate clinical laboratory methods of testing to confirm positive tests.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on FETROJA use in pregnant women to evaluate for a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Available data from published prospective cohort studies, case series, and case reports over several decades with cephalosporin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).

Developmental toxicity studies with cefiderocol administered during organogenesis to rats and mice showed no evidence of embryo-fetal toxicity, including drug-induced fetal malformations, at doses providing exposure levels 0.9 times (rats) or 1.3 times (mice) higher than the average observed in patients receiving the maximum recommended daily dose.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups.

Animal Data Developmental toxicity was not observed in rats at intravenous doses of up to 1000 mg/kg/day or mice at subcutaneous doses of up to 2000 mg/kg/day given during the period of organogenesis (gestation days 6-17 in rats and 6-15 in mice). No treatment-related malformations or reductions in fetal viability were observed. Mean plasma exposure (AUC) at these doses was approximately 0.9 times (rats) and 1.3 times (mice) the daily mean plasma exposure in patients that received 2 grams of cefiderocol infused intravenously every 8 hours.

In a pre- and postnatal development study, cefiderocol was administered intravenously at doses up to 1000 mg/kg/day to rats from Day 6 of pregnancy until weaning. No adverse effects on parturition, maternal function, or pre- and postnatal development and viability of the pups were observed.

In pregnant rats, cefiderocol-derived radioactivity was shown to cross the placenta, but the amount detected in fetuses was a small percentage (< 0.5%) of the dose.

8.2 Lactation Risk Summary It is not known whether cefiderocol is excreted into human milk; however, cefiderocolderived radioactivity was detected in the milk of lactating rats that received the drug intravenously. When a drug is present in animal milk, it is likely that the drug will be present in human milk. No information is available on the effects of FETROJA on the breastfed infant or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FETROJA and any potential adverse effects on the breastfed child from FETROJA or from the underlying maternal condition.

Data

Patients Receiving CRRT

Cefiderocol-derived radioactivity was detected in milk following intravenous administration to lactating rats. The peak level in rat milk was approximately 6% of the peak plasma level.

A total of 16 patients treated with FETROJA received CRRT in clinical trials. Dosage adjustment of FETROJA is required in patients receiving CRRT including CVVH, CVVHD, and CVVHDF. Dosage of FETROJA should be based on the effluent flow rate in patients receiving CRRT [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. While on CRRT, a patientâ&#x20AC;&#x2122;s residual renal function may change. Improvements or reductions in residual renal function may warrant a change in FETROJA dosage.

8.4 Pediatric Use Safety and effectiveness of FETROJA in pediatric patients younger than 18 years of age have not been established.

8.5 Geriatric Use cUTI Of the 300 patients treated with FETROJA in the cUTI trial, 158 (52.7%) were 65 years of age and older, and 67 (22.3%) were 75 years of age and older. No overall differences in safety or efficacy were observed between these patients and younger patients.

HABP/VABP Of the 148 patients treated with FETROJA in the HABP/VABP trial, 83 (56.1%) were 65 years of age and older, and 40 (27%) were 75 years of age and older.

The incidence of adverse reactions in patients treated with FETROJA was similar in patients under 65 years of age as compared to older patients (65 years of age and older and 75 years of age and older). The incidence of adverse reactions in older patients (65 years of age and older and 75 years of age and older) was also similar between treatment groups.

Clinical cure rates at the Test-of-Cure visit (TOC) in FETROJA-treated adult patients younger than 65 years of age, 65 years of age to younger than 75 years of age and 75 years of age and older were 60%, 77.5%, and 60%, respectively. In comparison, the clinical cure rates at the TOC visit in the meropenem-treated patients for each of these subgroups were 65.5%, 64.4%, and 70.5%, respectively. The observed all-cause mortality rates at Day 14 in the FETROJA-treated patients for each of these subgroups were 12.3%, 7.5%, and 17.5%, respectively. In comparison, in the meropenem-treated patients for each of these subgroups, they were 10.3%, 17.8%, and 9.1%, respectively.

Patients with CLcr 120 mL/min or Greater CLcr 120 mL/min or greater may be seen in seriously ill patients, who are receiving intravenous fluid resuscitation. Dosage adjustment of FETROJA is required in patients with CLcr 120 mL/min or greater [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy.

8.7 Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of cefiderocol have not been evaluated. Hepatic impairment is not expected to alter the elimination of cefiderocol as hepatic metabolism/excretion represents a minor pathway of elimination for cefiderocol.

Dosage adjustments are not necessary in patients with impaired hepatic function.

10 OVERDOSAGE There is no information on clinical signs and symptoms associated with an overdose of FETROJA. Patients who receive doses greater than the recommended dose regimen and have unexpected adverse reactions possibly associated with FETROJA should be carefully observed and given supportive treatment, and discontinuation or interruption of treatment should be considered.

Approximately 60% of cefiderocol is removed by a 3- to 4-hour hemodialysis session [see Clinical Pharmacology (12.3) in the full prescribing information].

cUTI and HABP/VABP FETROJA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required based on age. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) in the full prescribing information].

8.6 Renal Impairment Patients with CLcr 60 to 89 mL/min No dosage adjustment of FETROJA is recommended in patients with CLcr 60 to 89 mL/min.

Patients with CLcr Less Than 60 mL/min Including Patients Receiving Intermittent HD Dose adjustment is required in patients with CLcr less than 60 mL/min, and in patients who are receiving HD. In patients requiring HD, complete HD at the latest possible time before the start of cefiderocol dosing [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy.

Manufactured by Shionogi & Co., Ltd. Osaka 541-0045 Japan Manufactured for Shionogi Inc. Florham Park, NJ USA, 07932 FET-PI-02A USFET-0247 09/20

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TABLE OF

CONTENTS

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MCMAHON PUBLISHING GROUP

Adapting a Meds-to-Beds Program to COVID-19 Jennifer Hillman, MBA, PharmD

Impact of Rapid Diagnostic Testing And Biomarkers on Antimicrobial Stewardship: Deriving Their Optimal Benefit Karen Fong, PharmD, BCIDP, AAHIVP

Amid COVID-19, the Challenges Of DIY 503B Continue Gina Shaw

January to December 2019

Medication Errors: The Year in Review Institute for Safe Medication Practices

Parenteral Nutrition Therapy: Assessment Tools and Guidelines Jay M. Mirtallo, MS, RPh, FASHP, FASPEN, BCNSP

Practical Considerations for

Implementation of Biosimilars in Oncology Douglas Hackenyos, PharmD, BCOP

Vancomycin Dosing Guidelines: Where Do We Go From Here?

Nicholas Rebold, PharmD Dana Holger, PharmD Michael Rybak, PharmD, MPH, PhD, FCCP, FIDP, FIDSA

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Adapting a Meds-to-Beds Program to COVID-19

By Jennifer Hillman, MBA, PharmD Director of Pharmacy Department of Pharmacotherapy and Pharmacy Services University Hospital San Antonio, Texas

with other health-system pharmacies to ensure patient access to discharge medications despite the ongoing COVID-19 pandemic.

Strategic Location Introduction University Hospital, located in San Antonio, Texas, is a Level 1 trauma, academic medical center that serves 22 counties in the South Texas region. The hospital is licensed for approximately 700 beds and is comprised of 3 free-standing, high-rise towers. In 2018, the hospital initiated a meds-to-beds program that has proved extremely successful, increasing the monthly prescriptions dispensed from the discharge pharmacy from 3,000 to more than 15,000 per month. Since the COVID-19 pandemic began, several modifications have been made to allow staff to continue to serve patients in the program. This article shares these innovations

The meds-to-beds program was started using the discharge pharmacy located on the first floor in the south end of the hospital. This location is far from the main 10-story Sky tower on the north side of the hospital, where more than 50% of hospitalized patients are admitted.

At its farthest point, it can take up to 12 minutes for staff to travel from the pharmacy to the top floor of the Sky tower. To reduce the travel time between the discharge pharmacy and the patient bedside, the pharmacy opened a second meds-to-beds location in the main Sky tower. This new meds-to-beds, closed-door pharmacy is strategically positioned on and between the highest-volume discharging floors. The close proximity of the pharmacy to patients enables the medsto-beds technician to use either the elevators or stairs, thereby reducing travel between deliveries and increasing efficiency. The second location, focused exclusively on meds-to-beds patients, reduced phone calls and eliminated front counter distractions.

Because the meds-to-beds operation is a closed-door pharmacy, there is no risk for infection transmission from patient contact. The pharmacy department split the staff to keep a team of members who were unexposed to patients in the meds-to-beds operation. In the event of an outbreak of COVID-19 among the discharge pharmacy staff, a team of segregated pharmacy staff is available to keep the operation functioning.

Patient Consent

A pharmacist works at University Hospital’s new Sky tower location, which features a closed-door pharmacy meds-to-beds model.

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Meds-to-beds programs require patients to voluntarily fill prescriptions using the hospital pharmacy. Pharmacy staff explain the basic components of the program to patients in their hospital rooms. If the patient is interested, technicians obtain the patient’s consenting signature.

Since the pandemic began, admitted patients who were designated as COVID-19-positive or under investigation for possible COVID-19 are asked to participate in the meds-to-beds program using a revised method. Technicians still approach the patient room; however, instead of entering, the technicians stop at the observation window. They call the patient’s hospital room telephone from their cleanable mobile phone. The observation window allows the patient to see the pharmacy technician

necessitated removal of over half the chairs to create at least 6 feet of distance between each patient.

Social distancing floor demarcations were installed in the lobby and the exterior hallway leading to the lobby, directing patients to physically distance themselves in a safe manner. Hand-sanitizing stations were mounted in the pharmacy lobby, and clear plexiglass barriers were installed in prescription dropoff and pick-up areas.

Pharmacy staff monitor the pharmacy lobby and proactively intervene if the lobby becomes noticeably full. Staff members triage patients in line. If prescriptions are not urgent, staff ask the patient if they would accept prescriptions by mail or same-day courier. This strategy has been effective in reducing the number of patients congregating in a small space.

Alternate Delivery Methods

while maintaining a safe barrier. Technicians sign the consent form on behalf of the patient and note “verbal approval obtained COVID.” Using this adapted method, the department has been able to maintain enrollment rates. A secondary benefit of this modified approach is the conservation of personal protective equipment, which at times has been a limited resource.

Prescription Transmissions Before COVID-19, prescription submission to the medsto-beds program was accomplished primarily through printed paper prescriptions. Paper prescriptions were picked up several times per day on the hospital floors by the meds-to-beds technicians and hand delivered to the discharge pharmacy. With the onset of COVID-19, the health system encouraged providers to use the electronic prescription submission functionality. As a result, electronic prescription rates increased to the current rate of 90%. Electronic prescriptions have reduced staff exposure to potential infection via time spent on the floors and touch contamination.

The pharmacy department has requested that discharge prescription transmission occur as early as possible, including up to a day before anticipated discharge.

The purpose of the request is to expedite prescription processing, with the goal of preventing patients from remaining on the hospital floor to wait for their medications or relocating to the hospital transitional unit, pharmacy lobby or hospital lobby to wait. If providers are not certain about a particular medication for discharge but are sure about others, the pharmacy will fill 100% of the confirmed prescriptions and hold processing those that are being reconciled until final discharge. Filled prescriptions awaiting delivery are kept in the medsto-beds pharmacy until the discharge is confirmed.

The emergency department (ED) is serviced by the meds-to-beds program. This area is known to have a higher percentage of suspected and confirmed COVID-19 patients. To minimize the risk for exposure to the virus, the meds-to-beds program has elected to use the pneumatic tube system to deliver medications to the ED instead of hand delivering to the bedside. A single tube station within the ED is designated for discharge medications. The nurse providing care to the patient retrieves the medicines from the designated pneumatic tube system and dispenses them to the patient.

Payment Transactions Patients retrieving prescriptions at the discharge pharmacy pay at the front counter. To reduce the transaction time at the pharmacy window and touch contamination, patients are allowed to request a prescription bill be sent to their residence.

Refills The majority of discharge prescriptions are not written with refills. For prescriptions that do have refills, the discharge pharmacy team coordinates them ahead of time, contacting the patients by telephone and arranging for mail or home delivery. This change has averted patients from traveling to the hospital to request and/or pick up refills.

Conclusion COVID-19 has dramatically changed the way outpatient care is delivered. New practices aimed at reducing exposure for both patients and staff continue to evolve. The alternate pathways developed

by University Hospital’s meds-to-beds program have proven successful, as shown by the consistent number of discharge prescriptions dispensed to patients’ in the pre- and post-COVID-19 environments.

Pharmacy Lobby Modifications The discharge pharmacy lobby originally was designed with densely packed seating. The pandemic

Hillman reported no relevant financial relationships.

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Impact of Rapid Diagnostic Testing and Biomarkers on Antimicrobial Stewardship Deriving Their Optimal Benefit KAREN FONG, PHARMD, BCIDP, AAHIVP Clinical Pharmacist Infectious Diseases and Antimicrobial Stewardship Department of Pharmacy University of Utah Health Salt Lake City, Utah

R

apid diagnostic tests (RDTs) represent an exciting advancement in the clinical microbiology laboratory, with the potential to transform the management of infectious diseases by

allowing for more rapid and robust microbiological diagnoses.

These technological advances can guide early clinical decision making in the management of bacterial, viral, and fungal infections and have the potential to significantly affect clinical outcomes, antimicrobial use, and cost savings.1-3 Although RDTs are not yet a replacement for bacterial and fungal cultures with antimicrobial susceptibility testing, they add valuable knowledge to the clinical presentation, allowing clinicians to determine antimicrobial coverage by predicting susceptibility patterns based on local antibiograms.

When implementing RDTs, much consideration is required to ensure results are actionable and addressed promptly to improve clinical outcomes and reduce unnecessary antimicrobial use. Antimicrobial stewardship programs (ASPs) can facilitate correct interpretation and rapid communication of results, directing clinicians to appropriately adjust antimicrobial therapy.4 ASPs have demonstrated their immense value by improving clinical outcomes and mitigating adverse events through the optimization of antimicrobial use.5,6 Studies have shown that hospital ASPs improve rates of infection cures and combat challenges with Clostridioides difficile infections, antimicrobial resistance, adverse effects, length of stay (LOS), and costs.6-8 RDTs combined with ASP intervention have been revolutionary in improving antimicrobial optimization and

patient outcomes, particularly for bloodstream infections (BSIs).1,2 In addition, rapid testing for broad panels of respiratory viruses has been deemed by ASP guidelines as an important intervention to reduce the inappropriate use of antibiotics.9 RDTs are complex interventions and their impact is influenced by clinical context, patient flow, access, and timing; thus, their benefit should be maximized through use of efficient evidence-based ASP interventions.2,10,11 Messacar et al summarize key considerations and potential ASP strategies in the RDT implementation process (Table).4 Although RDTs provide a promising level of diagnostic accuracy, to observe translational outcomes they need to be combined with routine ASP efforts, as shown with BSIs.2,12-14 Evaluations in the clinical efficacy of RDTs beyond BSIs are still evolving and may benefit from evaluation of the context of a hierarchical model of efficacy. Fryback et al describe a hierarchical 6-tiered model of efficacy in diagnostic imaging that can be applied to nearly all diagnostic technologies, including RDTs (Figure).15 This model emphasizes the assessment of diagnostic technologies beyond their quality or accuracy and considers the ultimate value or benefit resulting from such technologies.15 Level 2 addresses diagnostic accuracy efficacy, which is characterized by measures associated with interpretation

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T E C H N I C A L E FFI C ACY • Resource constraints • Turnaround time

DI AGNOSTIC ACC U R ACY E FFI C ACY • Specificity and sensitivity • Positive and negative predictive values

DI AGNOSTIC T H I N K I N G E FFI C ACY • Facilitates diagnosis

TH ERAP E UTIC E FFI C ACY • Therapy change • Procedure change

PATIE NT OU TCOME E FFI C ACY • Morbidity and procedures avoided • Patient improvement with test

SO CIETAL EFF I C ACY • Cost-effectiveness

Figure. Efficacy hierarchy of microbiology diagnostics.

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of tests, such as positive predictive value, negative predictive value (NPV), sensitivity, and specificity.15 These measures highlight the important concept that diagnostic accuracy efficacy is a joint function of the test and an observer who controls both the specificity in the clinical practice environment and the sensitivity to the extent that it varies with the spectrum of disease.15 In addition, asymmetry in relationships exists between adjacent levels in the continuum of efficacy. For efficacy to be observed at a higher level in this hierarchy, efficacy must be observed at lower levels, but the reverse is not true.15 Perhaps this model alludes to the performance variability of RDTs: outcomes observed at levels 4 to 6 usually are suboptimal without consistent ASP intervention.2,12-14 This model has been endorsed by the Infectious Diseases Society of America (IDSA) Diagnostics Committee and can inform discussion of novel RDTs, including respiratory panels, biomarker and sepsis diagnostics, and advances in blood culture testing, as well as the prospects of outpatient pointof-care testing and the performance of RDTs with current diagnostic stewardship practices.10

Respiratory PROCALCITONIN

AND

RESPIRATORY VIRAL PANELS

In the United States, pneumonia has been a major contributor of morbidity and mortality, resulting in an estimated 63,000 deaths and 1.2 million hospitalizations annually.16,17 The American Thoracic Society (ATS)/IDSA recommendations for empiric antimicrobial therapy in community-acquired pneumonia (CAP) are based on selection of agents targeted against the major treatable respiratory bacterial pathogens.18 Unfortunately, overuse of antibiotics is common in lower respiratory tract infections (LRTIs) because there is difficulty in distinguishing between bacterial and viral etiologies.19 Antibiotic therapy could be withheld safely in patients with isolated viral pneumonia if these infections easily could be distinguished from those with bacterial etiology.20 Procalcitonin (PCT) is a component of the innate proinflammatory response that is released in response to bacterial challenge, allowing discrimination between viral and bacterial infections.21 The ATS/IDSA guidelines for the diagnosis and treatment of adults with CAP were updated in 2019 and included recommendations for the use of PCT. Initial empiric antibiotic therapy is recommended in adults with clinically suspected and radiographically confirmed CAP, regardless of initial serum PCT level.18 This recommendation acknowledges the findings of a recently updated Cochrane review assessing the safety and efficacy of using PCT for initiating or discontinuing antibiotics among a variety of patients with varying severity of acute respiratory infections (ARIs) from different clinical settings.

The analysis included 32 randomized controlled trials of adults with ARIs who received antibiotic treatment based on either a PCT-guided antibiotic stewardship algorithm or usual care. In the majority

Table. Key Antimicrobial Stewardship Considerations For Implementation of Rapid Infectious Disease Diagnostics Goal

Key Question

Key Considerations and Potential Strategies • Result reporting language

Right interpretation

Will the clinician understand the test result?

• Selective reporting of relevant results • Prospective audit and feedback • Real-time decision support • Clinical practice guidelines

Right antimicrobial

Will the clinician appropriately modify antimicrobials based on the test result?

• Electronic health record–based decision support with result reporting • Prospective audit and feedback • Real-time decision support • Reporting in electronic health record

Right time

Will the clinician act upon the test result promptly?

• Results called with read-back reporting • Prospective audit and feedback • Real-time decision support

of cases, the PCT algorithm used levels of less than 0.1 mg/L to indicate a high likelihood of viral infection, whereas levels above 0.25 mg/L indicated a high likelihood of bacterial pneumonia. Mortality was significantly lower with PCT guidance compared with usual care (8.6% vs 10.0%; adjusted odds ratio [OR], 0.83; 95% CI, 0.700.99; P=0.037).22 PCT guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 vs 8.1 days; 95% CI, –2.71 to –2.15; P<0.001) and lower risk for adverse effects related to antibiotic use (16.3% vs 22.1%; adjusted OR, 0.68; 95% CI, 0.57-0.82; P<0.001).22 Results were similar among different types of ARIs and clinical settings, supporting syndrome-specific PCT utilization with antimicrobial stewardship.

However, Self et al evaluated the association between serum PCT concentration with pneumonia etiology in a multicenter prospective surveillance study of adults hospitalized with CAP.23 The authors were unable to identify a PCT threshold that allowed perfect discrimination between viral and bacterial infection, a challenging goal. Although the results established that there was a lower frequency of bacterial pathogens in patients with PCT below both the 0.1-ng/mL (6%) and 0.25-ng/mL (8%) thresholds, this also underlines that clinicians cannot solely rely on PCT to guide antibiotic treatment decisions.

This was further supported by a recent meta-analysis of 12 studies including 2,408 patients with CAP demonstrating that the PCT sensitivity and specificity were too low and variable at 0.55 (95% CI, 0.37-0.71; I2=95.5%) and 0.76 (95% CI, 0.62-0.86; I2=94.1%), respectively.

Thus, PCT is unlikely to provide reliable evidence that will enable clinicians to confidently address whether the infection is bacterial and antibiotics need to be administered or it is viral and antibiotics may

be withheld.24 Furthermore, in a multicenter, randomized controlled trial, Huang et al did not demonstrate a reduction in mean antibiotic-days using PCT compared with usual care in patients with LRTIs.19 Outcomes may have been limited by subpar adherence with the PCT antibiotic prescribing guideline and lack of real-time prospective audit and feedback. Therefore, implementation may have failed to demonstrate benefit in the absence of ASP intervention.

Given the mixed results of PCT efficacy, a respiratory viral polymerase chain reaction (PCR) assay—the FilmArray respiratory panel (BioFire Diagnostics) or eSensor respiratory viral panel (GenMark Diagnostics)— may be a useful adjunct to RDT. This combination may be more likely to exclude bacterial coinfection with confidence in a meaningful period.10 Moradi et al explored the use of an respiratory PCR assay combined with PCT and an automated antimicrobial stewardship provider alert in a multicenter quasi-experimental study.25 If 3 criteria were met—PCT less than 0.25 ng/mL, virus detected on PCR, and active use of systemic antibiotics—the automated alert would prompt de-escalation by communicating “antimicrobial stewardship alert: your patient has a positive viral PCR + negative PCT + one or more antibiotics ordered.

These results suggest viral infection—please reassess necessity of antibiotics as indicated.” Antibiotic-days of therapy were significantly reduced in the intervention group by a mean of 2.2 days (5.8 vs 8.0 days; P<0.001).

In addition, significantly more patients had antibiotics discontinued within 24 hours of initiation (37.8% vs 18.6%; P<0.001) and fewer patients were discharged on antibiotics (20.0% vs 47.8%; P<0.001).

In the absence of ASP intervention, previous evidence observed low rates of antibiotic discontinuation

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in patients with negative PCT and a positive respiratory PCR.26 The findings from this study emphasize the importance of its real-world implementation strategy by leveraging indirect ASP intervention through an automated alert, which may be especially worthwhile in settings with minimal resources.25,27 Similarly, Lee et al examined the clinical effect of combining an respiratory viral panel with PCT in older adults with severe ARIs through a prospective multicenter observational study.28 Outcomes were compared between the interventional group and a propensity scoreâ&#x20AC;&#x201C;matched historical cohort. Patients in the intervention group had significantly more antibiotic deescalation (21.9% vs 13.2%; P=0.007), shorter duration of IV antibiotic use (median, 10.0 days; interquartile range [IQR], 5.3-14.6 days vs 14.5 days; IQR, 7.2-22.0 days; P<0.001), and a shorter hospital LOS (median, 14.0 days; IQR, 5.0-20.5 days vs 16.1 days; IQR, 6.0-24.5 days; P=0.030). The authors did not incorporate formal ASP in their study, but a study nurse promoted antibiotic stewardship by communicating the tests results and reminding physicians of the antibiotic treatment recommendations based on different testing results. Reduction in antibiotic-days of therapy observed with PCT and respiratory viral panel combination with a varying level of ASP intervention appears to be similar if not greater and more consistent compared with use of either PCT or viral panel with ASP intervention, but more robust head-to-head comparisons are needed to confirm this.19,22,25,28,29

LRTI PANELS Multiple syndromic molecular testing panels for LRTIs have been cleared by the FDA, including the BioFire FilmArray pneumonia panel and Curetis Unyvero lower respiratory tract (LRT) panel. These panels offer increased sensitivity compared with clinical cultures. In addition, the panels may offer benefit over conventional microbiology cultures by detecting the presence of resistance markers within as little as 1 to 5 hours from specimen collection and testing. The BioFire panel offers detection of 8 viruses, 8 resistance genes, 3 atypical bacteria using qualitative targets, and 15 bacterial targets with semiquantitative analysis, which can assist in evaluating colonization versus infection. The Curetis Unyvero LRT panel can detect 29 bacterial pathogens and 19 resistance genes. Both panels can be used with multiple specimen types (sputum, endotracheal aspirates, bronchoalveolar lavage fluid).

Although semiquantitative analysis may improve the clinical specificity, neither molecular testing panels nor culture separate airway colonizers from invasive pathogens. The possibility of a downstream effect of paradoxically increasing antimicrobial use should be a concern. These panels may be most useful in situations in which patients have new or worsening lung infiltrates, are moderately to severely ill, have received empiric antibiotics before cultures are obtained, and/or there is concern about multidrug-resistant bacteria or

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a polymicrobial infection.10 Buchan et al examined the impact of the BioFire FilmArray pneumonia panel in as study of 259 adult patients submitting bronchoalveolar lavage specimens for laboratory analysis; they demonstrated positive percent agreement (PPA) and negative percent agreement (NPA) at 98.1% and 96.2%, respectively, for the identification of bacterial targets compared with culture.30 The panel results had the potential for antibiotic adjustment in 70.7% of patients, including antibiotic discontinuation or de-escalation in 48.2% of patients, leading to an average savings of 6.2 antibiotic-days per patient.

Similarly, Webber et al observed a high overall agreement of 99.2% (95% CI, 98.4%-99.6%) and 96.8% (95% CI, 96.1%-97.4%) for viral and bacterial detection, respectively, between the BioFire FilmArray pneumonia panel and culture.31 Yoo et al were able to accurately detect resistance genes using the BioFire FilmArray pneumonia panel, showing concordant results for the resistant organisms identified by culture.32 However, the genetic markers of antimicrobial resistance, particularly CTX-M and carbapenemase genes, could not be linked definitively to the microorganisms detected. Thus, panel results should be used with cultures results to confirm susceptibility or resistance.

A retrospective multicenter study observed antimicrobial de-escalation in 63 of 159 (40%) and escalation in 35 (22%) of hospitalized pneumonia patients based on BioFire FilmArray pneumonia panel results, reinforcing its potential to reduce unnecessary antimicrobial exposure and increase the appropriateness of empiric antibiotic therapy.33 The Curetis Unyvero LRT panel also has been shown to have robust diagnostic accuracy. In an evaluation by Collins et al, the PPA and NPA for the bacterial targets were 96.5% and 99.6%, respectively.34 For the resistance targets, interpretation challenges were observed because not all genes could be attributed to an organism, highlighting that current culture methods with antimicrobial susceptibility testing must be maintained while consistency in technological advances is pursued.

In a prospective study of ventilated patients with pneumonia, the Curetis Unyvero LRT panel was associated with earlier initiation of effective antibiotic therapy in 20 of 95 patients (21%) and de-escalation in 37 patients (39%).35 Challenges with interpretation of newer respiratory viral panels, especially with resistance genes, are of concern but may be potentially mitigated by ASP intervention; this requires further exploration.

CLINICAL UTILITY OF SURVEILLANCE SCREENING MRSA NASAL PCR Methicillin-resistant Staphylococcus aureus (MRSA) nasal screens, such as the Cepheid GeneXpert SA Nasal, have evolved beyond use for infection prevention and control practice to have clinical utility for routine use in de-escalations of MRSA therapy, predominantly in patients with suspected or confirmed pneumonia.

Robust evidence has reflected a more than 95% NPV for the test in ruling out MRSA pneumonia.36 Therefore, the ATS/IDSA guidelines endorsed the routine use of MRSA nasal PCR screening for the de-escalation of MRSA coverage.18 ASP implementation of this approach has been associated with a median decrease of 2.1 days of vancomycin (P<0.01).37 Nasal screening for vancomycin avoidance in suspected or confirmed pneumonia among ICU patients also has been associated with $108 per patient in cost avoidance based on the cost of surveillance testing, vancomycin, and vancomycin therapeutic drug monitoring levels.38 Reviews of implementation considerations suggest fidelity of the nasal testing for 7 days after results and lack of impact of vancomycin exposure in affecting the results of testing.39,40 A systematic review and meta-analysis also have supported the use of the screen for the NPV beyond pneumonia, such as in skin and soft tissue infections.41 A national study from the Veterans Affairs system. with the largest cohort to date including clinical cultures (N=561,325), supports this concept.42 These data showed a high overall NPV for all infection types (96.5%) and among specific infections, including BSIs (96.5%), intraabdominal infections (98.6%), respiratory infections (96.1%), wound cultures (93.1%), and urinary tract infections (99.2%). In contrast, although the surveillance of gram-negative resistance using rectal swab testing (eg, Streck ARM-D resistance detections kits) may be standard in some settings, the clinical utility of these tests in directing therapy has yet to be confirmed.43,44

Biomarkers and Sepsis Diagnostics Candidemia, one of the most common hospitalacquired BSIs in the United States, is associated with up to 47% attributable mortality; the number is even higher among patients who develop septic shock. Prompt initiation of appropriate antifungal therapy and source control has been associated with as much as a 50% reduction in mortality. However, this is often delayed due to blood culture insensitivity, prolonged turnaround time needed to yield growth (median time to positivity, 2-3 days; range, 1 to ≥7 days), and the possibility of negative growth with invasive abdominal candidiasis.45 These limitations promote overuse of empiric antifungal therapy for suspected invasive candidiasis, which is a practice of unproven clinical value.46 Nonculture diagnostic tests, such as the Fungitell beta-D-glucan (BDG) detection assay (ViraCor) and the T2Candida panel (T2 Biosystems), have a much shorter turnaround time (8-12 hours) and entered clinical practice as adjuncts to cultures.45,47 BDG is a component of the cell wall in Candida species, Aspergillus species, and Pneumocystis jiroveci. Therefore, true-positive results have limited specificity for candidemia due to cross-reactivity with other organisms. Another concern is false positivity, which may be caused by physiologic changes, certain antimicrobials, hemodialysis, albumin or immunoglobulin therapy, or use of surgical material

Several rapid diagnostics have been cleared to improve diagnosis of lower respiratory tract infections.

containing glucan.45 A few studies exploring the use of BDG in patients with suspected candidemia showed deescalation of antifungal therapy through avoidance and reduction, but they were limited by sample size and did not incorporate active ASP intervention.48,49 Rautemaa-Richardson et al developed a local ASPdriven guideline for the diagnosis and management of suspected or proven invasive candidiasis in non-neutropenic adults.50 BDG was used as a rule-out test to guide the discontinuation of therapy in the absence of other microbiological evidence at 48 to 96 hours. The authors retrospectively evaluated ICU compliance with the invasive candidiasis guideline, the effect of the ASP on mortality, and antifungal consumption using data from patients initiated on micafungin during a 4-month audit periods in 2014 (with active ASP intervention) and 2016 (without ASP intervention). They found significant changes between 2014 and 2016 in patients categorized as “proven or probable invasive candidiasis,” “appropriately suspected but candidiasis excluded,” and “inappropriately suspected” (P=0.01). A 90% reduction in inappropriately initiated antifungal courses was observed between 2014 and 2016. All-cause mortality due to proven or probable invasive candidiasis decreased to 19% from 45% in the study period compared with the historical cohort in 2003-2007. Furthermore, a 49% decrease in micafungin consumption was observed. Although reduction of micafungin consumption was likely attributed to BDG, improvements in inappropriate initiation of antifungals and mortality were

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more likely influenced by assessment of risk factors, source removal, and further workup of invasive candidiasis as recommended by the guideline. Of note, there was improvement with guideline compliance and micafungin utilization from 2014, even though active ASP intervention was withdrawn in 2016.

Ito-Takeichi et al observed mixed results in their single-center prospective cohort study evaluating the impact of implementing antifungal daily reviews by ASP through prospective audit and feedback combined with BDG (Fujifilm Wako Pure Chemical Corp) monitoring on antifungal consumption and clinical outcomes of patients with candidiasis.51 The ASP recommended stopping antifungal therapy in cases with negative BDG, but testing appeared to be at physician discretion. Overall antifungal use was not significantly decreased after intervention, but there was a significant reduction in the 60-day clinical failure rate (80.0% vs 36.4%; P<0.001) and 60-day mortality (42.9% vs 18.2%; P=0.004) in patients with proven candidiasis. This was likely due to most ASP interventions being based on the choice of antifungal (104/223; 47%) followed by dosage adjustment (77/223; 35%). There were minimal interventions on BDG guidance and de-escalation (8/223; 4%).

Although false-negative BDG results are considered scarce, a retrospective study of 148 adult patients with proven candidemia found 26 (17.6%) patients with persistently negative BDG tests. In multivariable analysis, persistently negative BDG tests were independently associated with better prognoses (OR, 0.12; 95% CI, 0.03-0.49; P=0.003), probably due to lower systemic fungal burden.52 These findings challenge the testâ&#x20AC;&#x2122;s frequent use in the early discontinuation of empiric antifungal therapy.

Molecular Candida platforms, such as the T2 Biosystems T2Candida panel and Karius Test detecting Candida species DNA from whole blood, also have emerged. While sensitivity and specificity seem to be much more promising compared with blood cultures, the role of these technologies in the early diagnosis and management of candidemia remains unclear.45 Patch et al evaluated the impact of the T2Candida panel combined with active ASP intervention through positive culture review in a 2-phase retrospective analysis on timing of appropriate antifungal initiation for patients with candidemia and micafungin duration of therapy in patients without microbiological evidence of invasive candidiasis.53 The authors observed a significant decrease in time to appropriate therapy in the post-T2Candida group (34 vs 6 hours; P=0.0147).

Despite a lack of mycological evidence in the preT2Candida group, in the post-T2Candida group average duration of therapy was 6.7 days compared with 2.4 days in patients with negative T2Candida results without mycological evidence. This resulted in a total antifungal cost savings of $48,440 (or $280 per tested patient). Of concern, discordance was observed in 3 patients with unpaired positive blood cultures and negative T2Candida results.

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Steuber et al retrospectively evaluated 628 T2Candida panel results at a large community hospital, with prospective audit and feedback typically performed on negative results within 24 hours.54 An antifungal was ordered in 265 (42.4%) of cases, and appropriate deescalation/optimization (ie, discontinuation) of therapy occurred in 143 (54%) of the cases. In 120 of 225 negative results (53.3%), antifungal therapy was not discontinued within 48 hours, despite being negative. In the regression model, ICU LOS was predictive of failure to discontinue antifungal therapy within 48 hours of negative results (OR, 0.96; 95% CI, 0.94-0.99; P=0.002).

Patients with negative results had significantly fewer days of antifungal therapy compared with those with positive tests (4.9Âą6.3 vs 10Âą10 days, respectively; P=0.03). Antifungal discontinuation with negative tests was unexpectedly low, even with antimicrobial stewardship intervention. Further study is warranted to assess whether negative results would provide any additional value to patients already at substantially high risk for fungal infections.

In patients without microbiological evidence of candidemia, negative T2Candida results were compared with negative BDG, along with active ASP intervention in both groups, in a retrospective quasi-experimental study on their facilitation in antifungal discontinuation.47 During the study period, there was a systemwide guideline on the standard of care for invasive candidiasis, which included either BDG or T2Candida as RDT. Negative results for either prompted a suggestion to discontinue echinocandin therapy. In addition, the ASP reviewed BDG and T2Candida results for patients on anidulafungin (Eraxis, Pfizer) during both periods.

Among 206 ICU patients, the median duration of therapy was 2 days (1-5 days) compared with 1 day (1-2 days) in the BDG and T2Candida group (P<0.001). Moreover, T2Candida was the only independent predictor of early anidulafungin discontinuation (adjusted OR, 3.0; 95% CI, 1.7-5.6; P<0.001).

Gill et al conducted the first active comparison between distinct RDT-based antifungal stewardship strategies, reinforcing the potential advantage of T2Candida use in minimizing unnecessary antifungal exposure with the presence of active ASP intervention.47 The T2Bacteria panel made its debut detecting bacteria DNA by T2 magnetic resonance from whole blood to improve early initiation of appropriate antibiotic therapy in BSIs. Paired with a single set of blood cultures, T2Bacteria sensitivity and specificity in diagnosing BSIs caused by Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli were 90% (95% CI, 76%-96%) and 90% (95% CI, 88%91%), respectively.55 NPV was 99.7%. Limited to only 5 bacteria, sensitivity and specificity for any organism was 43% (95% CI, 32%-54%) and 89% (95% CI, 87%-91%).

Time from initiation of testing to detection and identification of pathogens was shorter for T2Bacteria (mean, 7.70 [SD 1.38] hours) than for blood cultures (mean, 71.7 [SD 39.3] hours). However, a 10% false-positive rate was

The focus on stewardship is expanding into the outpatient setting.

observed for its targeted organisms.

Voigt et al examined 137 emergency department patients from 2 centers in a prospective noninterventional T2Bacteria panel clinical study.56 Relative to blood culture, T2Bacteria showed 100% PPA and 98.4% NPA. The T2Bacteria assay detected 25% more positive results associated with evidence of infection and identified bacteria on average 56.6 hours faster compared with blood culture. T2Bacteria could have potentially de-escalated therapy in 8 patients, reduced time to species-directed therapy in 4 patients, and reduced time to effective therapy in 4 patients. Further prospective, ideally interventional, studies are needed to justify its role along with ASPs in patient care.57 The Karius Test is a potential new tool in the antimicrobial stewardship testing armamentarium. This novel metagenomic microbiological diagnostic test uses plasma microbial cell-free DNA sequencing, which is able to identify 1,250 bacteria, fungi, parasites, and viruses.58,59 Although clinical data are fairly limited, this new technology has shown promise in diagnosing and identifying causative infectious etiologies for pneumonia, bacteremia, and general sepsis. Its role may be useful in immunocompromised hosts in whom a broader range of pathogens may be associated with illness. In a small cohort of 10 immunocompromised hosts with febrile neutropenia, pneumonia, or intraabdominal infection, the Karius Test demonstrated a positive agreement with conventional diagnostic laboratory methods in 7 (70%) cases, including proven/ probable invasive aspergillosis, P. jirovecii pneumonia, Stenotrophomonas maltophilia bacteremia, and cytomegalovirus and adenovirus viremia.60 Larger studies are needed to validate these findings.

RDT for Blood Culture Testing Molecular RDT has fundamentally changed the management of BSIs and blood culture contaminants

(eg, coagulase-negative Staphylococcus) by providing actionable information much earlier in the course of treatment than conventional microbiology cultures.

Implementation of PCR-based technologies (eg, BioFire FilmArray blood culture identification panel [BCID], GenMark ePlex BCID), nanoparticle probe technology (eg, VERIGENE gram-positive and gram-negative blood culture test, Luminex), or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (eg, bioMĂŠrieux, BD Bruker) have been associated with decreases in time to effective therapy, hospital LOS, and mortality when associated with ASP interventions.2 Similar to the clinical impacts observed, cost-effectiveness analysis also has reflected benefits of molecular RDTs in BSIs.12 These data also highlight the strong synergy of stewardship and RDT: RDT has an 80% chance of cost-effectiveness with an ASP, but only 41.1% without it.

Further potential changes in the management of BSIs have developed with the introduction of automated rapid phenotypic testing systems such as the Accelerate Pheno system (Accelerate Diagnostics). This system can yield organism identification, minimum inhibitory concentration (MIC), and susceptibility interpretation with a turnaround time of approximately 7 hours after positive blood culture.

Several studies have explored the Accelerate Pheno system coupled with ASP intervention. Results of 448 patients with gram-negative BSIs in a randomized controlled trial with prospective audit and feedback in both arms reflected significantly faster antibiotic changes (median decrease of approximately 25 hours for gramnegative antibiotics; P<0.001) with the Accelerate Pheno system compared with culture-based methods. Antibiotic escalation also was significantly faster with the Accelerate Pheno system relative to culture-based methods for antimicrobial-resistant BSIs (median decrease

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of approximately 43 hours; P=0.01). There were no differences between arms in patient outcomes, including mortality and LOS.61 Two quasi-experimental before-andafter observational studies analyzed integration of the Accelerate Pheno system with ASP intervention, with variable results in patient outcomes.62,63 Dare et al included 496 bacteremic episodes at a single center with routine prospective audit and feedback on positive blood cultures.63 Median LOS was significantly shorter (6.3 days and 6.7 days vs 8.1 days; P=0.001) with the Accelerate Pheno system with or without realtime notification compared with the historical cohort of culture-based methods. Median antimicrobial duration of therapy was significantly shorter in both intervention arms compared with the historical cohort (6 days each vs 7 days; P=0.011). Although LOS and duration of therapy significantly improved after Accelerate Pheno implementation, the addition of real-time notification did not demonstrate further improvement in the setting of active ASP, suggesting integration may omit resources to include real-time notification. Ehren et al observed in 204 patients that median time from Gram stain to optimal therapy (7 vs 11 hours; P=0.024) and step-down antimicrobial therapy (12 vs 27.8 hours; P=0.019) was significantly shorter with the Accelerate Pheno system with bedside ASP intervention compared with conventional diagnostics with or without bedside ASP intervention.62 However, groups did not differ in duration of antimicrobial therapy or LOS. Future studies on a larger scale with ASP intervention are needed to assess its impact on clinical outcomes.

Although susceptibility interpretation associated with MIC testing may be variable,64 rapid phenotypic testing may be of particular importance to ASPs treating critically ill patients based on its ability to help optimize therapeutic dosing to maximize pharmacokinetic and pharmacodynamics (PK/PD) parameters in the setting of a known MIC. Optimal drug exposures have been associated with achievement of enhanced PK/PD targets.65 Prospective evaluations of critically ill patients have shown that underdosing for PK/PD targets is common.66 Therefore, the use of rapid phenotypic technologies, such as the Accelerate Pheno system, combined with therapeutic drug monitoring in critically ill patients likely has the potential to significantly affect patient outcomes.

Outpatient Antimicrobial Prescribing And Diagnostic Potential The focus of antimicrobial stewardship on the outpatient setting has developed relatively recently. Population database evaluations of antimicrobial prescribing in the United States suggest that at least one-third of prescribing is inappropriate, the majority attributed to respiratory infections.67 Following this finding, the CDC released its Core Elements of Outpatient Antibiotic Stewardship, which recommends a variety of interventions such as commitment posters to decrease inappropriate antibiotic prescribing.68 A systematic review on

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interventions to influence prescriber behavior in ARIs in primary care reflected C-reactive protein testing, shared decision making, and PCT-guided management have promise for decreasing inappropriate use of antibiotics.69 In contrast, conclusions could not be made on the utility of respiratory diagnostics because there were few studies or those available were of very low quality.

Respiratory RDTs in outpatient settings are evolving. Although influenza testing using digital lateral flow immunoassays, such as the BD Veritor Plus, are widely available in the primary care setting, the use of pointof-care molecular testing has been limited by regulations on who and where testing can be performed (Clinical Laboratory Improvement Amendment [CLIA] waivers) and logistical issues of achieving turnaround time during clinic visits. The first CLIA-waived nucleic acid amplification test, Alere i influenza A&B test, was approved in 2015. In 2016, the BioFire FilmArray respiratory panel EZ (RP EZ), a CLIA-waived respiratory panel, became available to allow for multiplex respiratory inclinic testing. These advances in technologies have the potential to change outpatient health care.

In a recent study, investigators evaluated the BioFire FilmArray RP EZ in 430 patients in 2 pediatric clinics. In clinic A, the RP EZ was routinely used at provider discretion, while in clinic B, if antigen testing was performed for influenza or respiratory syncytial virus, samples also were tested using the FilmArray, with results blinded to patients and providers. In clinic A, at least 1 organism was detected in 70.4% of patients, leading to appropriate treatment in 93.6% of patients compared with 87.9% of patients in clinic B without the panel (P=0.0445).70 Significant increases in neuraminidase inhibitor use (75% vs 31.6%; P<0.01) occurred among patients in clinic A compared with clinic B, although this may have been related to differences in patient presentations and related indications for therapy. The RP EZ was associated with a decrease in clinic appointment duration (mean check-in to checkout time, 48 vs 55 minutes; P<0.01). Although promising, these results are very likely limited by the turnaround time of the CLIA-waived test of approximately 1 hour.

The importance of turnaround time in yielding clinically actionable information in the outpatient setting cannot be overstated. Post hoc analysis of randomized controlled trial data on the use of respiratory viral panels for patients presenting to EDs with respiratory symptoms has shown that faster turnaround times are associated with improved patient management.71 As mean office visit times for respiratory tract infections are often 15 minutes, the logistics of primary care require technologies that can accommodate these time constraints.72 With the development of such technologies, it will need to be determined what patient population to target, which targets provide clinical utility (antibiotic avoidance, antiviral use, lab and imaging utilization, subsequent health care utilization), and the optimal implementation strategies of these panels.73 Utilization of clinical decision support may be of benefit

in directing front-line clinicians in the optimal use of RDT results, particularly as the resources for prospective audit and feedback from antimicrobial stewardship in the outpatient setting may be limited.27

13. Bookstaver PB, Nimmich EB, Smith TJ 3rd, et al. Cumulative effect of an antimicrobial stewardship and rapid diagnostic testing bundle on early streamlining of antimicrobial therapy in gramnegative bloodstream infections. Antimicrob Agents Chemother.

2017;61(9):e00189-17.

Conclusion

14. Avdic E, Wang R, Li DX, et al. Sustained impact of a rapid microarray-based assay with antimicrobial stewardship interventions on optimizing therapy in patients with gram-positive bacteraemia. J Antimicrob Chemother. 2017;72(11):3191-3198.

A multitude of advances are occurring in technologies available for the management of BSIs, severe respiratory infections, sepsis, candidiasis, PK/PD optimization opportunities, and outpatient respiratory infections. Many of these technologies along with implementation of efficient evidence-based ASP interventions show promise in their potential to have positive effects on patient care. However, efficacy evaluations of these technologies are critically important and should be approached with considerable contemplation to ensure they are not only improving the accuracy and speed of diagnosis but also influencing clinicians’ diagnostic thinking, changing clinical management, affecting patient outcomes, and yielding overall cost-effectiveness.

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50. Rautemaa-Richardson R, Rautemaa V, Al-Wathiqi F, et al. Impact of a diagnostics-driven antifungal stewardship programme in a UK tertiary referral teaching hospital. J Antimicrob Chemother.

2018;73(12):3488-3495.

51. Ito-Takeichi S, Niwa T, Fujibayashi A, et al. The impact of implementing an antifungal stewardship with monitoring of 1-3, beta-D-glucan values on antifungal consumption and clinical outcomes. J Clin Pharm Ther. 2019;44(3):454-462.

52. Agnelli C, Bouza E, Del Carmen Martinez-Jimenez M, et al. Clinical relevance and prognostic value of persistently negative (1,3)-betaD-glucan in adults with candidemia: a 5-year experience in a tertiary hospital. Clin Infect Dis. 2020;70(9):1925-1932.

53. Patch ME, Weisz E, Cubillos A, et al. Impact of rapid, culture-independent diagnosis of candidaemia and invasive candidiasis in a community health system. J Antimicrob Chemother. 2018;73(suppl 4):iv27-iv30.

54. Steuber TD, Tucker-Heard G, Edwards J, et al. Utilization and impact of a rapid Candida panel on antifungal stewardship

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69. Tonkin-Crine SK, Tan PS, van Hecke O, et al. Clinician-targeted interventions to influence antibiotic prescribing behaviour for acute respiratory infections in primary care: an overview of systematic reviews. Cochrane Database Syst Rev. 2017;9:CD012252.

70. Beal SG, Posa M, Gaffar M, et al. Performance and impact of a CLIA-waived, point-of-care respiratory PCR panel in a pediatric clinic. Pediatr Infect Dis J. 2020;39(3):188-191.

71. Brendish NJ, Malachira AK, Beard KR, Ewings S, Clark TW. Impact of turnaround time on outcome with point-of-care testing for respiratory viruses: a post hoc analysis from a randomised controlled trial. Eur Respir J. 2018;52(2):1800555. doi: 10.1183/13993003.00555-2018 72. Linder JA, Singer DE, Stafford RS. Association between antibiotic prescribing and visit duration in adults with upper respiratory tract infections. Clin Ther. 2003;25(9):2419-2430.

73. Kozel TR, Burnham-Marusich AR. Point-of-care testing for infectious diseases: past, present, and future. J Clin Microbiol.

2017;55(8):2313-2320.

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Amid COVID-19, the Challenges Of DIY 503B Continue

I

n retrospect, Vanderbilt University Medical Center hit “pause” on creating its own in-house 503B compounding facility at just the right time.

As 2019 drew to a close, the medical center’s Department of Pharmaceutical Services determined that, before moving forward, it would take the time to put key products through the enhanced stability testing required for meeting the extended beyonduse dating (BUD) standards that are part of the FDA’s current good manufacturing practice requirements for 503B compounding outsourcing facilities.

“We wanted to send all of our products through that level of testing just as a measure of preparedness for the future,” Deidra Dickerson, PharmD, the manager of sterile and nonsterile compounding at the Nashville, Tenn., institution, told Pharmacy Practice News. “So at the end of 2019, we made the decision to start using a 503B outsourcing facility while pulling back from our own internal program, planning to ramp back up later once the results started trickling in.”

After meeting with several outsourcing facilities, Vanderbilt settled on QuVa, which has compounding facilities in Sugar Land, Texas, and Bloomsbury, N.J., serving more than 2,200 hospital customers with over 280 product SKUs. “We placed our first order with QuVa in January, right before the pandemic hit the United States,” Dickerson said. “By March and April, they were experiencing such demand that they were

‘In these critical [pandemic] situations, I cannot underscore enough the importance of having these [outsourcing] relationships, and even multiple relationships for redundancy.’

—Deidra Dickerson, PharmD no longer able to bring on new customers because of the need to properly serve existing customers.”

Vanderbilt initially outsourced only a handful of products to QuVa, including ephedrine, epinephrine and phenylephrine syringes, and phenylephrine and midazolam IV bags. But as the pandemic continued, more were added. “Fentanyl was an item that became challenging early on, and we were having difficulties procuring any of the vials for infusion we typically get from our standard wholesaler,” Dickerson said. “QuVa was able to step in then, which took a stressor off of us during that time.”

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Hospitals Rethinking 503Bs Before the pandemic, many hospitals and health systems, like Vanderbilt, were putting significant investments into pharmacy as one of their profit centers. However, with COVID-19 decimating the bottom line for many institutions, the availability of capital for major new investments, such as a 503B compounding facility, has dried up. “Of the CEOs and chief pharmacy officers I’ve spoken with, most of them say that prospectively trying to get into 503Bs probably isn’t in the works for at least another couple of years, financially speaking,” said Michael Souza, the CEO of New England Life Care (NELC), whose Advanced Compounding Solutions (ACS) 503B outsourcing facility is jointly owned by its 50-plus member hospitals (most in the Northeast).

‘[It] costs, by conservative estimates, $5 [million] to $15 million and three years to open your [503B] doors.

It’s not a quick fix, not just <797> on steroids.’

—Eric Kastango, MBA, BSPharm “We are experiencing an uptick in interest based on our model, so much so that we’ve created a joint venture with another system-owned 503B facility in Minnesota, and we are combining our efforts both to market to a broader base and provide more capacity for the increased demand we’re seeing,” said Keith Thomasset, PharmD, ACS’ vice president of clinical solutions and chief pharmacy officer. “I would say that this is at least partially attributable to pressures from the pandemic, especially for those hospitals that were considering developing their own 503Bs. But even pre-pandemic, the capital investment and operating expenses associated with opening a 503B can get pretty scary if you’re going it alone.”

Fagron Sterile Services US, another leading 503B outsourcing company, found early in the pandemic that it had to modify its production planning. “We had a significant increase, approximately 20%, in demand from our customers, with hospitals requiring new and different products or much greater quantities of existing products for needs such as supporting high numbers of patients going on ventilators,” said Jason McGuire, who oversees operational and quality areas of Fagron Sterile Services US. “They needed high quantities of narcotics like fentanyl and hydromorphone to sedate patients, and they just didn’t have the support within their facilities to provide the dosage forms and volumes they needed. Every day, there was something new that would pop up from health systems, and some of these products, quite frankly, we didn’t have immediately available,” McGuire said.

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“But we [were] still able to respond fairly quickly with something that would work and yet maintain a high level of quality.”

A Pioneer Partners Up The midwestern hospital system SSM Health, which operates more than two dozen hospitals and health centers in Wisconsin, Illinois, Oklahoma and Missouri, was the first health system to register as a 503B sterile compounder in 2014, and remains one of only a handful of such systems in the country. SSM Health currently produces about nine products in-house. Because operating rooms closed to elective surgeries during the height of the pandemic, SSM Health pharmacy director Kristina Bryowsky, PharmD, said her facility shifted production toward bags for the ICU and away from OR syringes. “We saw a reduction in volume overall because of the ORs, so we shifted the days we would have produced other products to make sure we stocked up heavily on IV products for the ICUs, so we never had a shortage of those bags. That was a big relief for our ICU team,” said Bryowsky.

In December 2019, SSM Health had started its first round of testing to add fentanyl to its list of compounded products, but after the pandemic began, the system was unable to access active pharmaceutical ingredients (API) to complete the next two rounds of testing. Bryowsky said they will complete that testing before the end of the year, but in the meantime, to accommodate the high volume of fentanyl needed at the system’s larger hospitals, they use either an outsourcer or compound in-house under 503A’s internal <797> seven-day BUD limits.

“Some of our bigger centers had allocations with larger outsourcers, but if you didn’t have that already, you weren’t going to get it during COVID-19,” Bryowsky said.

“Because our ORs were closed and care had shifted to patients who were incredibly acute, the volume wasn’t as high. So we were able to spend the extra time to make internal batches of 300 bags with 2- or 5-mL vials, which is not something an outsourcer will do anyway.”

Because of the shutdown of elective surgeries in both hospital ORs and ambulatory surgery centers, compounders such as Fagron also were able to free up some of their capacity and shift it to meet hospitals’ ICU needs.

“It was still a bit of a challenge, especially as it relates to narcotics—you have to go to the Drug Enforcement Administration [DEA] and request access for more than your original quote,” McGuire said. “Fortunately, the DEA was very responsive and helpful, as was the FDA. For example, if there was a product that we had never created before within our facility, we might not have performed the full stability testing or validation around it.

So we were permitted to leverage our partner laboratories’ data available via R&D or the published literature, and then, using FDA guidance, get something out there, even though it might have more limited dating. They were really trying to find ways for outsourcing facilities to be flexible during this extraordinary time, to meet patient needs while still maintaining our responsibility for the

Flexibility From the FDA

D

uring the COVID-19 pandemic, the FDA provided some flexibility for both 503B outsourcing facilities that produce large batches of product with or without prescriptions while adhering to current good manufacturing practices (CGMPs), as well as 503A entities, which are traditional compounding pharmacies that compound in accordance with patient-specific prescriptions and comply with U.S. Pharmacopeia (USP) standards.

In April, the agency issued two guidance documents establishing temporary policies regarding the compounding of certain drugs. For 503Bs, the FDA said that under the current state of supply disruption, it would not take action against an outsourcing facility for compounding a drug that is considered essentially a copy of an approved drug, or for using bulk substances not on the FDA’s approved Bulks List if those drug products are used to treat COVID-19 for hospitalized patients. The agency also would not pursue enforcement against 503Bs

for not meeting CGMP requirements for product stability testing and establishment of an expiration date, provided the outsourcer used shorter default beyond-use dates (BUD)s as specified by the FDA. Furthermore, in an unprecedented move, 503As would be temporarily permitted to compound drugs in short supply for hospital patients with COVID-19 without a patient prescription.

“They’ve flexed pharmacy,” said Eric Kastango, MBA, BSPharm, the vice president and managing partner at Kastango Consulting Group.

“The 503Bs have capacity limits: There are only so many doses they can make and they only have so much ability to ramp up production to meet demand. With the COVID crisis and the number of patients who needed emergency medications, they could not keep up.

So, the agency published a guidance of when a 503A can do compounding that is typically limited to a 503B, identifying half a dozen mostly critical care, anesthesia and

high quality of the products we produce.”

The February closure of PharMedium, AmerisourceBergen’s compounding business, was a double whammy for hospitals in the Northeast, noted Stuart Hinchen, the co-founder and chief executive officer of QuVa. “The initial wave of COVID hit the Northeast particularly hard, and that was also an area where PharMedium had been very strong,” Hinchen said. “So a lot of hospitals were really cut short, and we were getting four times the regular demand for certain products, particularly in critical care.

We had to give preferential treatment to COVID-related

pain management agents.”

Still unknown: the question of when and how the FDA will ultimately implement its draft “one mile” rule, which allows 503A compounding hospital pharmacies to distribute compounded drugs to health care facilities owned and controlled by the same entity as the pharmacy, as long as they are located within a one-mile radius of the pharmacy. The rule, first released in draft form as part of the agency’s 2016 compounding guidance, is based on the reasoning that a central pharmacy sending compounded drugs beyond the one-mile limit would be operating like a 503B pharmacy but not regulated like one.

In its April 2020 guidance, the agency made it clear that the rule was still in draft and would not be enforced at present. “The FDA has been saying for well over a year now that the new version is coming, and that they are considering all of the comments they’ve received,” said Mike Koch, the senior vice president of professional services for Central Admixture Pharmacy Services, a national network of outsourcing pharmacies. “They have also previously hinted that they may alter the one-mile radius, either by making it time dependent, in terms of beyond-use dating, or by extending the radius. But it’s all just rumors right now, and I wouldn’t begin to hazard a guess on what they will ultimately say or their timing.”

—G.S.

products wherever we could. We looked at other inventory we had on the shelves, and where we had adequate reserves, slots that would have gone to that inventory were reallocated to COVID-related products. Throughout March and April, every day was a major production effort and there really was no playbook.”

As changes in the pandemic have rippled throughout the country, along with reopenings of elective procedures, outsourcers have worked to keep up with shifting demand.

“COVID-19 became less frantic in May, but then elective surgeries started to open up in June, so we went through

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‘We still do have outsourcing partnerships and always will.

[Outsourcers] can have a portfolio of 50 items or more, but for smaller [in-house 503B] operations like ours, it doesn’t make sense to have all those products, especially if only one or two of our sites use them or the volumes are really low. There’s a place for both.’

—Kristina Bryowsky, PharmD an oscillation as the health networks were extremely keen to get those going again,” Hinchen said. “Then in the summer, COVID-19 cases spiked in the Sun Belt and we had dual pressures of both COVID-19 and elective surgeries.”

QuVa, NELC/ACS and Fagron all have increased capacity to meet the changing demand. QuVa has added more than 100 people to its labor force this year, with more staffing planned in the immediate future. “We put on a third shift in our Sugar Land site, which handles the bulk of our compounding work, and five days a week we are running 24/7 with stopgap work over the weekend,” Hinchen said. The company’s 75,000-square-foot facility in New Jersey will double in size over the next 12 months, and a lease on a new facility in Sugar Land also will double the company’s current 75,000-square-foot footprint in Texas. Similarly, NELC/ACS has added weekend shifts and filled all its hoods on the weekday second shift.

A Need to Pivot Quickly Although NELC/ACS, like its non-hospital-owned competitors, experienced an early increase in demand for some supplies at the height of the pandemic, particularly products for patients on mechanical ventilation, Thomasset said there was never significant concern that they would not be able to meet demand. “We tend to keep at least three to four months’ worth of API on our shelves, so API shortages that affected some hospitals were not affecting us. The FDA had also provided guidance that we could compound sterile preparations from sterile API with a small extension beyond the current USP <797> BUD without requiring studies. That gave us upwards of about a month’s worth of expiration.” (See sidebar.)

McGuire said the biggest lesson for 503B compounders from the COVID-19 pandemic has been understanding how to pivot very quickly. “You need to have a culture in your business where people are willing to do whatever it takes to meet patients’ needs,” he said. “It was amazing to see how folks rallied around each other and made sure we did everything possible to get medicine out the door to wherever the needs were.”

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MCMAHON PUBLISHING GROUP

Vanderbilt is still in discussions about creating its own 503B facility—a conversation that Dickerson said will likely take several years—and does plenty of its own 503A compounding, with only about 10 products outsourced. But regardless of what happens with those plans, the medical center still will continue relationships with 503B compounding outsourcers. “Even aside from the pandemic, we know there are still some products that it doesn’t make financial sense for us to make in-house,” she said. “Some institutions still have fears associated with 503Bs, and frustrations with them because the consistency of product availability may not always be what people would hope. But in these critical situations, I cannot underscore enough the importance of having these [outsourcing] relationships, and even multiple relationships for redundancy.”

Bryowsky agreed. “We still have outsourcing partnerships and always will. [Outsourcers] can have a portfolio of 50 items or more, but for smaller operations like ours, it doesn’t make sense to have all those products, especially if only one or two of our sites use them or the volumes are really low. There’s a place for both.”

Eric Kastango, MBA, BSPharm, the vice president and managing partner at Kastango Consulting Group, cited cost as perhaps the biggest barrier to taking a DIY approach to 503B compounding. “[It] costs, by conservative estimates, $5 [million] to $15 million and three years to open your doors,” he said. “It’s not a quick fix, not just <797> on steroids.

“Most of the people I have spoken with are going to multiple sources and have created relationships with more than one 503B,” Kastango added. “Most people can’t get by using just one 503B vendor, because they don’t all make the same products, or they are looking for supply redundancy. This pandemic has given us a new appreciation for just how important this unsexy part of pharmacy—compounding and distribution—really is.”

—Gina Shaw The sources reported no relevant financial relationships beyond their stated employment.

FOR PATIENTS WHO NEED

Vancomycin Hydrochloride for Oral Solution USP

(Generic equivalent to Vancocin® for Oral Solution) 250 mg per 5 mL*

Single bottle storage ~ Simple reconstitution ~ Mixed Berry taste DYE-FREE ~ Tapering options ~ Refrigeration required How supplied (250 mg per 5 mL*): Reconstitution Volume

Total Content ‡

National Drug Code (NDC)

Common Use

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62559-830-80

Tapering or post hospital discharge

150 mL

7,500 mg

62559-830-55

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300 mL

15,000 mg

62559-830-03

For patients needing 14-day therapy

For additional information, please call 1-800-434-1121 or visit www.anipharmaceuticals.com.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. * When prepared as directed, each 5 mL of solution contains vancomycin hydrochloride equivalent to approximately 250 mg of vancomycin. ‡ Content of vancomycin per bottle.

Vancocin® is a registered trademark of ANI Pharmaceuticals, Inc.

Copyright © 2020 ANI Pharmaceuticals, Inc. All rights reserved.

Please see Brief Summary of Prescribing Information on adjacent page.

Vancomycin Hydrochloride for Oral Solution USP Indications and Usage: Vancomycin Hydrochloride for Oral Solution is a prescription medication administered orally for treatment of enterocolitis caused

by Staphylococcus aureus (including methicillin-resistant strains) and antibiotic-associated pseudomembranous colitis caused

by Clostridium difficile. Parenteral administration of vancomycin is not effective for the above indications; therefore, Vancomycin Hydrochloride for Oral Solution must be given orally for these infections. Orally administered Vancomycin Hydrochloride for Oral Solution is not effective for other types of infection.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Vancomycin Hydrochloride for Oral Solution and other antibacterial drugs, Vancomycin Hydrochloride for Oral Solution should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Important Safety Information

Contraindications Vancomycin Hydrochloride for Oral Solution is contraindicated in patients with known hypersensitivity to vancomycin.

Warnings and Precautions • Significant systemic absorption has been reported in some patients (e.g., patients with renal insufficiency and/or colitis) who have taken multiple oral doses of vancomycin hydrochloride for C. difficile-associated diarrhea. In these patients, serum vancomycin concentrations reached therapeutic levels for the treatment of systemic infections. Some patients with inflammatory disorders of the intestinal mucosa also may have significant systemic absorption of vancomycin. These patients may be at risk for the development of adverse reactions associated with higher doses of vancomycin oral solution; therefore, monitoring of serum concentrations of vancomycin may be appropriate in some instances, e.g., in patients with renal insufficiency and/or colitis or in those receiving concomitant therapy with an aminoglycoside antibacterial drug.

• Nephrotoxicity (e.g. reports of renal failure, renal impairment, blood creatinine increased) has occurred following oral vancomycin hydrochloride therapy in randomized controlled clinical trials, and can occur either during or after completion of therapy. The risk of nephrotoxicity is increased in patients over 65 years of age. In patients over 65 years of age, including those with normal renal function prior to treatment, renal function should be monitored during and following treatment with vancomycin oral solution to detect potential vancomycin induced nephrotoxicity.

• Ototoxicity has occurred in patients receiving vancomycin. It may be transient or permanent. It has been reported mostly in patients who have been given excessive intravenous doses, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent, such as an aminoglycoside. Serial tests of auditory function may be helpful in order to minimize the risk of ototoxicity.

• Use of vancomycin may result in the overgrowth of non-susceptible bacteria. If superinfection occurs during therapy, appropriate measures should be taken.

• Prescribing vancomycin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug resistant bacteria.

• Hemorrhagic occlusive retinal vasculitis, including permanent loss of vision, occurred in patients receiving intracameral or intravitreal administration of vancomycin during or after cataract surgery. The safety and efficacy of vancomycin administered by the intracameral or intravitreal route have not been established by adequate and well-controlled studies. Vancomycin is not indicated for prophylaxis of endophthalmitis.

Adverse Reactions The most common adverse reactions include C. difficile colitis, nausea, vomiting, hypokalemia, and nephrotoxicity. This is not a complete list of side effects and others may occur. Please see the full Prescribing Information for a complete list of adverse reactions.

To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800-308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

This Important Safety Information does not include all the information needed to use Vancomycin Hydrochloride for Oral Solution USP safely and effectively. See full Prescribing Information for Vancomycin Hydrochloride for Oral Solution USP. For additional information, please call 1-800-434-1121 or visit www.anipharmaceuticals.com.

Copyright © 2020 ANI Pharmaceuticals, Inc. All rights reserved.

10239 Rev 10/20

PRINTER-FRIENDLY VERSION AVAILABLE AT PHARMACYPRACTICENEWS.COM

January to December 2019

Medication Errors: The Year in Review

P

reventing medication errors is an essential component of caring for patients and must be a core mission of every

pharmacy. For medication error–prevention efforts to be effective, they must be a priority.

Horsham, Pennsylvania

An error reduction program begins by establishing a multidisciplinary medication safety team to improve medication use. To be effective, the team must be given reasonable time and resources to assess medication safety and implement systemwide changes that make it difficult or impossible for practitioners to make mistakes that endanger patients. This multidisciplinary team should accept ownership of the medication-use process and enthusiastically embrace the opportunity to improve medication safety. Effective results depend on understanding the entire medication-use process through varied perspectives and disciplines.

The goals of the team should include the following: • Promote a culture of safety to reduce harm from medication errors.

• Increase detection and reporting of medication errors and potentially hazardous drug–use situations.

• Explore and understand the root causes of and factors that contribute to medication errors.

• Educate practitioners about the system-based causes of errors and their prevention.

• Recommend methods to facilitate the implementation of organization-wide, system-based changes to prevent medication errors.

• Respond to potentially hazardous situations before errors occur.

• Learn from errors occurring in other organizations through the ISMP Medication Safety Alert! and other published reports of medication errors, and proactively take measures to prevent similar errors.

The Institute for Safe Medication Practices (ISMP) is a nonprofit organization that works closely with health care practitioners and institutions, regulatory agencies, professional organizations, and the pharmaceutical industry to provide education about medication errors and their prevention. ISMP independently reviews medication errors that practitioners and patients have submitted voluntarily to the ISMP National Medication Error Reporting Program (ISMP MERP). ISMP is an accessible resource for any pharmacist or organization interested in implementing the actions recommended Text continues on page 41

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Table 1. Safety Issues Related to Labeling, Packaging, and Nomenclature Title

Problem/Discussion Point

Recommendation

Tech

Bupivacaine 0.25% mistaken as bupivacaine with EPINEPHrine after package insert on top of packaging was misread

• A pharmacy technician nearly placed a package of bupivacaine vials into a bin containing vials of bupivacaine with EPINEPHrine, but the error was caught during barcode scanning of the product.

• The package insert displayed on the packing carton listed both plain bupivacaine and bupivacaine with EPINEPHrine (FDA allows a single package insert for both products).

• Require barcode scanning of these products during storage and administration.

• Warn pharmacy staff members about the risk for a mix-up and remind them to look at the side panels of the packing carton for the official product label, not the package insert visible on the top.

2,4,6

“Insulin” should be easier to distinguish on Myxredlin (Baxter) labels

• MYXREDLIN (insulin, human) 100 units per 100 mL is a new premixed insulin IV infusion bag.

• Myxredlin would benefit from improved product labeling (Figure 1).

• ISMP has received reports of concerns about confusion with other Baxter minibags, but no incidents have been reported.

• The nonproprietary name (insulin human) should be easier to distinguish on the label.

• Consider adding an auxiliary warning, such as “contains insulin,” to help identify Myxredlin.

• Storing the product in its carton will help ensure correct product identification.

• As always, barcode scanning of the bag or carton at the bedside can help prevent container mix-ups.

2

Look-alike labeling on various Alvogen product vials

• Look-alike labeling can cause mix-ups between Alvogen injectable products (eg, deferoxamine mesylate, dexrazoxane, ketorolac, labetalol, metoprolol tartrate, midazolam, rocuronium, tranexamic acid, vancomycin).

• Carton and vial labels have the same mustard yellow background, and a color band highlighting the strength distracts one’s eyes away from the drug name.

• When possible, purchase these products from different manufacturers so the labels are dissimilar.

• Separate the storage of all Alvogen products.

• Use barcode scanning before drug preparation and administration to detect drug mix-ups.

2,6

Look-alike vials of bupivacaine and pantoprazole from AuroMedics

• Vials of bupivacaine and pantoprazole are the same size with similar light blue labels.

• If the vials are stored near each other in areas such as the emergency department or perioperative area, mix-ups could result in inadvertent IV administration of bupivacaine, which is cardiotoxic.

• Consider purchasing these products from different manufacturers.

• Use barcode scanning before drug preparation and administration to detect drug mix-ups.

• Wherever IV bupivacaine is stored, make lipid emulsion readily available for reversal of inadvertent IV bupivacaine administration.

2,6

Mix-up between concentrations of Dr. Reddy’s levETIRAcetam premixed bags

• Dr. Reddy’s premixed bags of levetiracetam 1,000 mg per 100 mL (10 mg/mL) and 500 mg per 100 mL (5 mg/mL) were erroneously mixed together in the pharmacy storage bins.

• The different-strength bags look nearly identical, and concentrations appear in very small print.

• Purchase premixed bags of levetiracetam from different manufacturers with better labeling.

• If you use multiple Dr. Reddy’s products in your facility: - store the bags apart from each other; - place prominent warning labels in the storage areas; - affix auxiliary labels; and - use barcode scanning before dispensing and administration.

2

Mix-up between insulin and tranexamic acid

• 2 cases of mix-ups between 100-mL bags of insulin and tranexamic acid were reported in the OR, where barcode scanning was not used.

• The bags had similar white pharmacy labels with very small text.

• The wrong product was administered to both patients, who recovered after receiving IV dextrose.

• Barcode scanning in the pharmacy before dispensing and in the OR before administration could prevent these errors.

• Consider applying auxiliary labels to pharmacy-prepared IV bags that look similar to help identify their contents.

2,6

See KEY on page 39.

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MCMAHON PUBLISHING GROUP

Table 1. Safety Issues Related to Labeling, Packaging, and Nomenclature Title

Problem/Discussion Point

Recommendation

Tech

Mix-up between look-alike bottles of phenol and flexible collodion (from Medisca) leads to phenol-related burns

• A surgeon was accidentally handed a bottle of liquified phenol (89%) that was stored near the requested bottle of flexible collodion skin adhesive needed to close a surgical wound.

• Both 100-mL bottles are dark amber with white caps and have almost identical-looking green and white labels.

• The surgeon applied phenol to the wound, which resulted in burns that required extensive irrigation.

• If phenol is stored in your facility, determine why it is being used and whether alternatives are plausible (eg, prepackaged phenol applicators, which contain a small amount of phenol for procedures).

• If bulk bottles of liquid phenol must be used, store them in the pharmacy and repackage liquid phenol in small applicator bottles with auxiliary label warnings for dispensing to areas outside of the pharmacy.

Mix-up between methotrexate and metOLazone

• A patient died after receiving daily methotrexate for a month instead of metolazone.

• A common cause of drug name mix-ups is searching by just the first few letter characters, which presents multiple look-alike drug names on the screen.

• In this case, the first 3 letters are the same (M-E-T), and both are available in 2.5- and 5-mg tablet strengths.

• Use at least 5 letters (see ISMP Guidelines for Safe Electronic Communication of Medication Information, www.ismp.org/node/1322) to reduce the number of different drugs that appear on a screen during a search.

• Employ a hard stop in order entry systems to avoid daily methotrexate without an appropriate cancer indication.

• Use tall man letters for metolazone.

1,4,5

Mix-up between mitoMYcin and mitoXANTRONE

• A patient underwent intraperitoneal administration of mitoXANTRONE after the pharmacy dispensed the product in a brown overwrap, believing it was light-sensitive mitoMYcin. The overwrap made it difficult to see the drug’s blue color.

• The pharmacy workflow system displayed an “invalid route” warning when mitoXANTRONE (approved for IV use) was scanned.

• The system was bypassed because a “wrong drug” alert did not occur.

• The error was noticed later due to blue staining of the peritoneal tissues.

• Address any change in the expected appearance of the drug and any unexpected workflow system error messages because they can be important clues for detecting medication errors.

• Perform manual quality checks in situations where pharmacy workflow system controls are bypassed.

6

Spinal administration of tranexamic acid instead of bupivacaine or ropivacaine

• 2 recent cases of inadvertent spinal administration of tranexamic acid were reported to ISMP. • A recent review article identified 21 additional cases.

• This error has a mortality rate of 50%, and can result in other patient harm, including paraplegia.

• Tranexamic acid, bupivacaine, and ropivacaine come in vials with blue caps that are often stored upright, making labels difficult to read.

• These agents typically are used in areas where barcode scanning is not used (eg, OR, labor and delivery).

• Purchase these products from various manufacturers to help differentiate vial appearance.

• Employ barcode scanning before dispensing or administering these products.

• Avoid upright storage to ensure labels are always visible.

• Store tranexamic acid vials separately.

• Add an auxiliary label to tranexamic acid containers to note the route of administration.

2,4,6

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Table 2. Safety Issues Associated With Order Communication and Documentation Title

Problem/Discussion Point

Recommendation

Tech

Dosing levothyroxine in mg continues to cause overdoses

• During 2 hospitalizations, a patient was prescribed 0.5 mg of oral levothyroxine (500 mcg instead of 50 mcg).

• A prescriber modified the selected dose of “25” mcg to “0.5” and changed the dosing unit from “mcg” to “mg.”

• Decimal point confusion has also led to errors between 0.025 and 0.25 mg.

• Consider adding an order entry warning with a hard stop for doses that exceed 200 mcg.

• Require all levothyroxine doses to be prescribed in mcg (as expressed on levothyroxine containers).

• Ensure the dosing unit (mcg) cannot be modified during order entry.

1,5

Finalized guidelines for electronic communication of medication information

• Electronic forms of communication are widely used in health care.

• If the conventions used to communicate medication information electronically are not carefully considered, these technologies may contribute to medication errors rather than mitigate risks.

• Health care organizations and vendors of electronic health information technology should apply the principles in ISMP’s updated Guidelines for Safe Electronic Communication of Medication Information (www.ismp.org/node/1322) when information about medications is communicated in electronic formats.

1,5

Mix-up between pralidoxime and pyridoxine due to sound-alike drug names

• A poison control center recommended a pralidoxime loading dose and infusion to treat organophosphate poisoning.

• The physician heard “pyridoxine” and repeated it back without recognition of the error.

• The patient received a bolus dose and part of the pyridoxine infusion before the error was detected.

• Spelling the drug name instead of just repeating it back can catch misheard oral communication of sound-alike drug names.

• Poison control center staff should consider sending an immediate confirmation email/fax of their recommendations for verification.

5

Mix-ups with rifAMPin and rifAXIMin

• During a telephone consultation, a physician misheard rifAXIMin and prescribed rifAMPin (550 mg IV).

• Due to the unusual dose, a pharmacist questioned the order, but the physician confirmed it.

• The next day, the pharmacist learned the patient had hepatic encephalopathy and that the intended drug was rifaximin.

• Brand- and generic-name mix-ups are possible with all the rifamycin antibiotics.

• Practitioners should familiarize themselves with various dosing parameters and indications for all rifamycin antibiotics.

• Pharmacists should persist in clarifying unusual orders that do not match the usual indications or doses.

5

Mix-up between ZEMPLAR (paricalcitol, AbbVie) and ZEMURON (a former brand of rocuronium) due to look-alike names

• A nurse received a telephone order for Zemplar from a physician in the hospital.

• When the nurse entered the drug into the order entry system, Zemplar appeared with a nonformulary warning, and Zemuron appeared below it in the drug picklist.

• The nurse selected Zemuron instead of Zemplar, but the verifying pharmacist caught the potentially fatal error.

• Avoid displaying the Zemuron brand name for rocuronium, which is no longer manufactured using that brand name, in drug picklists.

• Only display the generic name, rocuronium.

• Only allow verbal/telephone orders to be used in an emergency or when the provider is working in a sterile environment.

1,4,5

Unintentional 1,000-fold zinc overdose when transposing mcg and mg dosing units

• When prescribing PN for a child, a physician ordered 700 mg instead of 700 mcg of zinc.

• The PN template defaulted to mg dosing units, which could not be changed to mcg if the physician noticed the error.

• 2 pharmacists verified the order but failed to notice the error.

• A dose warning was issued when the order was transmitted to an outsourcer, but it was overlooked.

• A pharmacist noticed the error while compounding the PN.

• Ensure that a warning with a hard stop for critical zinc overdoses (eg, >250 mcg/kg) appears in order entry systems.

• Default to mcg dosing units for zinc in pediatric PN templates and ensure that this corresponds to the way orders are entered in automated compounders.

• Conduct effective order verification processes in the pharmacy.

• Validate the competencies of staff who order, transcribe, verify, and compound PN.

1,5,6

See KEY on page 39.

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Table 3. Problems Involving Drug Information, Patient Information, Patient Education, and Staff Education Title

Problem/Discussion Point

Recommendation

Tech

Confusion between FIASP and NOVOLOG (both formulations of insulin aspart

by Novo Nordisk), which have different onsets of action

• NovoLOG and Fiasp are both formulations of insulin aspart, but they are not substitutable.

• Fiasp contains niacinamide to increase the speed of absorption and is given at the start of a meal or within 20 minutes afterward.

• NovoLOG is given 5-10 minutes before a meal.

• Confusion has led to dispensing errors if the brand name is not on the prescription.

• In one case, a physician selected Fiasp, but the system sent an insulin aspart prescription to the pharmacy and NovoLOG was dispensed.

• If Fiasp is intended, prescribers should include the brand name on the prescription.

• Electronic order systems should communicate the brand name if the prescriber selects it instead of only including the generic name.

• Practitioners, particularly pharmacists, should confirm the brand name if it isn’t specified on the prescription.

• Patients should be made aware of the intended product and check the drug they receive from a retail pharmacy.

Include 4-letter suffixes when expressing biosimilar drugs, as required by the FDA

• The FDA requires the use of a random 4-letter suffix attached by a hyphen to the end of the generic name of biosimilar drugs, unless approved before the new naming convention.

• Versions of the same biological drug may not be an exact copy of the same molecule.

• The suffix will identify the specific product if it is associated with an AE.

• When a biological nonproprietary drug name is used, include the full name along with the suffix, on all labels, in EHRs, and in AE reporting systems.

• ISMP encourages use of the brand and nonproprietary names together to provide redundancy and avoid name confusion.

Medical residents’ electronic medication prescribing errors

• A large study that analyzed medical residents’ medication e-prescribing found that pharmacists identified an error in 4% of the medication orders, particularly antimicrobial and anticoagulant orders (www.ismp.org/ext/153).

• Errors were most frequent in August and September and among first- and third-year residents.

• The errors were most often associated with a failure to adjust dosing for renal impairment (40%), unclear or incomplete orders (27%), and duplicate therapy (25%).

• Increase resident supervision for the first 3 months of training, not just July.

• Educate residents about the specific kinds of errors that are common when ordering antimicrobials and anticoagulants.

• Ensure third-year residents consult with other health care professionals when caring for complex patients or ordering drugs that are prescribed infrequently.

• Establish a reliable plan for renal dose adjustments.

Mix-ups between dexAMETHasone and dexMEDEtomidine (PRECEDEX)

• Mix-ups between dexmedetomidine and dexamethasone injection have been reported.

• Pharmacy staff have selected the wrong drug when preparing an IV admixture or when restocking an ADC. • Nurses have removed the wrong drug from ADCs by overriding the system.

• Nurses have programmed dexmedetomidine as dexamethasone in smart infusion pumps.

• Use premixed dexmedetomidine when it is available.

• Employ barcode scanning before IV admixture or when selecting and stocking vials in ADCs. • Do not store these drugs near each other in the pharmacy.

• Consider using tall man letters (dexMEDEtomidine, dexAMETHasone) if you carry both products.

Patient education needed for use of disposable standard pen needles

• Errors with home use of standard pen needles continue to occur.

• In the latest case, a patient failed to remove the inner needle cover on an insulin pen for more than a year.

• When he realized his mistake, he injected himself correctly but at a dose that had been repeatedly increased during the past year, leading to hospitalization due to hypoglycemia.

• Contact pen needle manufacturers for demonstration devices to show patients which covers to remove before administration.

• If a patient’s blood glucose level remains elevated after insulin administration, suspect pen or needle misuse before increasing the dose.

• Ask the patient to demonstrate the administration process if improper use is suspected.

Refills prescribed for ELIQUIS (apixaban, Bristol-Myers Squibb) starter pack

• When prescribing an Eliquis starter pack, a provider modified the default setting of zero refills and sent the prescription to an outpatient pharmacy with refills.

• Several months of refills were dispensed.

• Investigation revealed other instances in which the starter pack had been prescribed with refills.

• Set the default for refills of all drug starter packs to zero without the ability to modify this field.

• If prescriptions for both the starter pack and maintenance dose are sent together to the pharmacy, instruct the pharmacist to put the maintenance prescription on hold until the starter pack has been completed.

• Patient education should be provided.

2,4,6

1,5

Table continues on following page

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Table 3. Problems Involving Drug Information, Patient Information, Patient Education, and Staff Education cont’d Title

Problem/Discussion Point

Recommendation

Tech

Subcutaneousonly HERCEPTIN HYLECTA (trastuzumab and hyaluronidase-oysk, Genentech) may accidentally be administered IV

• Herceptin Hylecta is administered subcutaneously, whereas HERCEPTIN (trastuzumab) is administered as an IV infusion.

• While the volume of a typical subcutaneous injection is 2 mL or less, the Herceptin Hylecta dose is 5 mL, which may lead practitioners to believe it should be administered IV.

• Use barcode technology to avoid mix-ups between IV and subcutaneous forms.

• Also affix a prominent auxiliary label that states, “Administer subcutaneously in the thigh,” on syringes of Herceptin Hylecta or use the peel-off sticker provided on the vial to label the syringe.

2

Subcutaneous-only RITUXAN HYCELA (riTUXimab and hyaluronidase, Genentech) confused with IV-only RITUXAN (riTUXimab, Genentech)

• Rituxan Hycela has been administered IV instead of subcutaneously.

• Practitioners have mistakenly believed the drug should be administered IV because the volume of the dose (either 11.7 or 13.4 mL) is larger than a typical subcutaneous dose.

• Name similarities also can contribute to mix-ups and confusion.

• Store Rituxan Hycela and Rituxan in a way that indicates that they are different formulations.

• Employ barcode scanning to verify storage and administration.

• Educate oncologists and nurses about the risk for wrong route errors.

• Include an auxiliary warning on Rituxan Hycela syringes, “Administer subcutaneously in the abdomen.”

1,4,5

Use independent double checks judiciously and properly

• Manual independent double checks have long been disputed, discounted, and misused in health care.

• The process is time-consuming and often associated with practical problems in implementation.

• Although studies confirm that independent double checks can detect up to 95% of errors when they are conducted properly, failed checking processes can be linked to: - inconsistent use; - variability in how the checks are performed; - “cosigning” with little real appraisal; - deference to authority that constrains questions; - excessive trust in the work of others; and - distractions and interruptions of staff.

• Evaluate whether independent double checks are being used judiciously and properly.

• Consider what you are trying to verify or catch, the necessary steps to achieve this goal, and whether an independent double check is the best strategy and/or if other more effective risk reduction strategies should be used.

• Fewer, strategically placed independent double checks will be more effective than excessive independent double checks.

• If an independent double check is needed (ISMP does not recommend this for all high-alert medications), design and implement the strategy as outlined in www.ismp.org/node/8884.

Table 4. Safety Issues Related to Medical Devices and Equipment Title

Problem/Discussion Point

Recommendation

• 42 reports of enoxaparin prefilled syringe failures and inadvertent activation of the needle safety mechanism have been received involving both brand-name and generic products.

• Reports indicated that needlesticks, underdoses, missed doses, and embedded needles occurred.

• Most reports indicated the following: - Syringes broke apart when engaging the safety mechanism.

- Safety mechanisms did not engage, were difficult to engage, or engaged too soon.

• FDA and Sanofi are looking into these complaints.

• In the meantime, advise practitioners handling these syringes to always point the needle end away from themselves and others, including the patient, until the moment of injection as well as after injection when activating the safety mechanism.

• If these syringes are dispensed for use in the home, patients should be educated about proper use.

Legacy feeding tubes, administration sets, and transition adapters going away

• GEDSA has announced that manufacturers will begin phasing out legacy feeding tubes starting July 1, 2020, and will discontinue transition adapters (whether sold singly or attached to ENFit feeding sets) on January 1, 2021 (Figures 2 and 3).

• These moves will force the adoption of ENFit to reduce the risk for misconnections involving use of other connector types.

• Ensure that this information is communicated to the broader health care community in your organization, including purchasers and clinical personnel (pharmacists, nurses, physicians, etc).

• For additional information, check the GEDSA Stay Connected website (http://gedsa.org/).

Ring that remains after removing tamper-evident cap may fall off

• Some pharmacies use tamper-evident caps for medication syringes (Figures 4-6).

• When the caps are removed, a plastic ring remains on the end of the syringe.

• The ring can fall off or be a choking hazard if left at the bedside.

• During an abdominal procedure, the plastic ring from a ceFAZolin syringe fell off into an irrigation solution but was noticed before intraabdominal irrigation.

• The cap manufacturer, International Medical Industries, recommends discarding the ring after removing the cap and before administering the medication.

• Remind nurses and other providers who use these products about the hazards of a fallen ring and to remove and properly dispose of the ring before using/administering syringe contents.

Enoxaparin (LOVENOX, sanofi-aventis) syringe failures

See KEY on page 39.

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Tech

Table 5. Other Discussion Items Title

Problem/Discussion Point

Recommendation

Tech

Designing effective warnings

• Warnings generally are less reliable than design strategies that eliminate hazards altogether, prevent hazards from touching targets, or detect errors before they reach patients.

• Well-designed warnings can reduce the risk for errors.

• If warnings do not reach the target audience, capture attention, and cause the recipient to understand the warning and required response, they will not be effective.

• Print visual warnings in big, bold font using mixed-case letters, and ensure warnings are clinically important.

• Use correct signal words (caution or warning for injuries that might occur; danger for serious hazards that will occur) and color to draw attention to the warnings.

• Use affirmative wording when possible (eg, avoid “not for IV use;” state “for oral use only”), and embed pictorials.

• The most effective warning requires the recipient to interact with it to continue.

Distribute FREE Nurse AdviseERR to all nurses

• Front-line nurses need to be aware of significant medication errors that are happening across the nation and ways to avoid them.

• Nurse AdviseERR is a free ISMP newsletter that can help accomplish this goal.

• We are worried that many US hospitals are not distributing this resource to their nurses, thus missing a key opportunity.

• Find out if nurses are currently receiving Nurse AdviseERR, and if they are not, forward this subscription link: www.ismp.org/node/138.

• ISMP encourages a coordinator from each facility to subscribe and then redistribute the newsletter to other facility nurses.

• If a nurse is having difficulty subscribing to the newsletter without a fee, they can use the code NURSE2019 at checkout.

“Fuzzy matching” during electronic searches can lead to errors

• An Epic upgrade incorporates fuzzy matching, which creates a list of “near hits” based on what the system “thinks” you are searching for with patient names, medications, and other orders.

• However, the near hits may lead to selection of the wrong drug if the drug names look alike, particularly if the drug name is misspelled (eg, cycloSERINE misspelled as “cyclosorine” creates a list containing cycloSPORINE).

• The use of fuzzy matching is a risk not worth taking and is unsafe for medication ordering.

• Fuzzy matching can be disabled for all search options, but not for drugs alone.

• Although Epic recently revised the algorithms, which eliminated some of the problems, similar-looking drug names still are presented to users during searches, so the functionality should be disabled.

Hepatitis C vial contamination despite using sterile needles and syringes

• A study in Anesthesiology (2019;131[8]:305-314) shows that practitioners inadvertently can contaminate a drug vial diaphragm, and subsequent access with sterile needles and syringes can transfer hepatitis C virus into the drug, where it remains stable for at least 72 h, in sufficient quantities to infect subsequent patients.

• Wiping the diaphragm with an alcohol swab was not sufficient to eliminate hepatitis C virus infectivity, whether or not alcohol was allowed to dry before vial access.

• Eliminating the use of multidose vials for more than 1 patient would eliminate this risk.

• According to the CDC, practitioners using multidose vials for more than 1 patient should withdraw patient-specific doses “in a centralized medication area and [should] not bring the multidose vial into the immediate patient treatment area” (eg, the OR).

• Given that a remote medication preparation area does not always exist in the OR, consider eliminating multidose vials and using pharmacy-prepared, single-dose syringes.

• Frequent hand hygiene, better environmental cleaning between cases, and removal of all used syringes and vials from the OR at the end of a case are additional strategies.

IV push GAT helps uncover national priorities for safe injection practices

• Results from ISMP’s IV push GAT (www.ismp.org/ node/1188) reveal low scores for many of the best practices in the ISMP Safe Practice Guidelines for Adult IV Push Medications (www.ismp.org/node/97), including: - dispensing IV push medications in a ready-toadminister form; - not diluting or reconstituting IV push medications in a saline flush syringe; - permitting emergency administration of rescue agents per protocols/orders; - administering IV push medications and flushes at the recommended rate; and - barcode scanning of flush syringes.

• Review the results of the IV push GAT, particularly the 10 national priorities for safe injection practices related to the lowest scoring best practices (www.ismp.org/ node/11496).

• Assess your organization’s compliance with these practices and determine an actionable plan to address any gaps in the safe use of IV push medications in your organization.

1,4

2,3

Table continues on following page

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Table 5. Other Discussion Items

cont’d

Title

Problem/Discussion Point

Recommendation

Patientcontrolled analgesia (PCA) pump keys available online

• Pump keys for CADD-Solis (Smiths Medical) and Care-Fusion Alaris Medley PCA syringe pumps still can be purchased online, threatening the security of medications in the pumps.

• Lockboxes for various PCA pumps also can be accessed with common items.

• Follow the manufacturer’s directions and use other security features that may be available with PCA pumps, such as a software code to activate the locking mechanism, rather than using just a manual key lock.

Unsafe storage of vecuronium and vancomycin

• When checking a prepared IV admixture, a pharmacist noticed that vecuronium had been used instead of vancomycin.

• Investigation found that vecuronium was stocked next to vancomycin in the IV area in an unlidded bin (the lid had broken off) (Figure 7).

• The label that warned about respiratory paralysis and arrest on the vecuronium bin was curled and could not be fully read.

• Segregate and sequester neuromuscular blocking agents from other medications (eg, place in a lidded bin or rapid sequence intubation kit).

• Scan barcodes for IV admixtures using IV workflow technology.

• If warning labels are used, inspect them regularly and replace them as soon as signs of wear are recognized.

Tech

6

Table 6. ISMP’s Targeted Medication Safety Best Practices for Hospitals Title

Problem/Discussion Point

Recommendation

Error associated with the use of sterile water

• Sterile water for inhalation was inadvertently administered IV to a young woman at an outpatient surgery center.

• Bags of sterile water for inhalation, IV normal saline, lactated Ringer’s solution, and other common IV fluids were stored on the same shelf.

• The error was discovered when the nurse was about to administer a second liter of IV fluid before the patient was discharged.

• However, an entire liter of sterile water had been infused, and the patient developed hemolysis, became anuric, and now requires dialysis.

• Eliminate all 1,000-mL bags of sterile water for injection, irrigation, or inhalation from all areas outside of the pharmacy (www.ismp.org/node/160, ISMP Targeted Medication Safety Best Practice #10).

• Use product containers of alternative sizes and/or shapes.

• Establish a policy to ensure that 1,000-mL bags of sterile water can be ordered only by a pharmacy purchaser for pharmacy compounding purposes, not for storage in clinical locations.

• If sterile water (irrigation, inhalation) must be available in a clinical location, purchase the pour bottler or other plastic containers with distinct appearance from other IV fluids.

• Establish guidelines regarding the safe provision of large volumes of sterile water to surgery/the OR when they are needed.

Fatal error due to PAXIL (PARoxetine) and TREXALL (methotrexate) sound-alike names

• A prescription for Paxil (10 mg daily) was called into a pharmacy.

• Pharmacy staff likely misheard the drug name and dispensed Trexall (10-mg tablets), with directions to take 1 tablet daily.

• The patient thought Trexall (on the pharmacy label) was the new antidepressant she was expecting.

• Seven days later, she was hospitalized and died.

• Order entry systems should default to a weekly oral methotrexate dose; any daily orders should cause a hard stop (www.ismp.org/node/160, ISMP Targeted Medication Safety Best Practice #2).

• All patients filling methotrexate prescriptions should be counseled.

• ISMP offers a free consumer education guide about oral methotrexate (www.ismp.org/ext/290).

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Tech

1,5

KEY Identified issue involves a medication listed on ISMP’s List of High-Alert Medications in Acute Care Settings (www.ismp.org/Tools/institutionalhighAlert.asp). High-alert medications are associated with a heightened risk for causing significant patient harm when they are used in error.

ADC, automated dispensing cabinet; AE, adverse event; CPOE, computerized prescriber order entry; EHR, electronic health record; GAT, gap analysis tool; GEDSA, Global Enteral Device Supplier Association; IV, intravenous; OR, operating room; MAR, medication administration record; PN, parenteral nutrition

TECHNOLOGY (TECH) KEY

1

A fully integrated CPOE system includes the capability to build medication safety alerts and clinical decision rules. It should directly interface with the laboratory system and pharmacy, list drug–drug and drug–disease interactions, and offer clinical decision support.

4

ADCs are robust, point-of-use dispensing systems. ADCs should

2

Barcode-enabled point-of-care systems are designed to detect medication errors during medication distribution and/or administration. Using a barcode scanner to scan barcodes on a medication and a patient’s wristband, users can verify and record all drugs administered to the patient.

5

A “robust” pharmacy order entry system is fully interfaced with a

3

“Smart” infusion pump systems allow users to enter drug infusion

6

IV workflow technology combines software and automated pharmacy workflow technology for compounding sterile products. It receives dose information from health IT systems and uses robotics, gravimetric analysis, and barcode scanning with video technology or digital images. Some systems can generate drug-specific administration notes and labels for point-of-care scanning by nurses.

protocols into a drug library with predefined dose limits. If a dose is programmed outside established limits or clinical parameters, the pump halts or sounds an alarm. Some pumps can integrate patient monitoring and other patient parameters.

be integrated with the health care facility’s information system and directly interface with the pharmacy system. In addition, ADCs must be able to use barcoding technology for the restocking process to prevent medication errors.

CPOE system and must be able to produce medication safety alerts, directly interface with a health care facility’s information systems, and generate a computerized MAR to be used by nurses while they administer medications.

Figure 1. Commercially available premixed insulin (Myxredlin, 100 units per 100 mL) is available from Baxter.

To prevent confusion with other 100-mL minibags, the generic name, insulin, needs to be more prominently displayed on this product.

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Figure 2. ENFit feeding set used for enteral feedings.

Note the white transition adapter that fits legacy feeding tubes. The adapter, removed in this photo, now accompanies feeding sets but will not after 2021.

Figure 3. Transition adapter on ENFit administration set fits legacy gastrojejunostomy feeding tube.

After July 1, 2020, these and other legacy feeding tubes will no longer be manufactured, and they will be replaced by tubing with ENFit connectors.

Figure 4. Example of white tamperevident cap on syringe.

In the case described, the caps were red.

Figure 5. Outer cap removed with clear inner stopper intact and white plastic ring retained.

Figure 6. Plastic ring can easily fall off.

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Text continued from page 31

Figure 7. Unsafe storage of vecuronium and vancomycin next to each other.

Also, warnings on the vecuronium container are worn and difficult to read.

herein. Among the many products and services ISMP offers is ISMP Medication Safety Alert! Acute Care, a biweekly newsletter that provides timely information related to error prevention. It identifies errors that have been reported by organizations and offers recommendations to prevent those errors from occurring.

The information in the tables of this review summarizes many of the significant error-prevention strategies recommended in the ISMP Medication Safety Alert!

Acute Care newsletter from January through December 2019. The errors presented in the tables are actual or potential errors reported to ISMP. Each table consists of 4 columns. The first column lists the involved medications, devices, or other problematic issues. The second column describes the specific error or problem. The third column contains ISMPâ&#x20AC;&#x2122;s recommendations to proactively address similar errors and prevent them from reoccurring. The fourth column lists technology that may help prevent or detect such errors. Technology can be a powerful tool in the fight against medication errors but only when it is used appropriately within a welldesigned medication-use system.

The technology key summarizes the technology addressed in the tables and specific criteria that ISMP believes should be included.

ISMP and FDA/ISMP Safe Medication Management Fellows. 2018-2019: Avani Bhalodia, PharmD; Samantha Burton, PharmD; Barbrakaryne Fobi, PharmD, MPH; Mona Hammam, PharmD; Farzana Samad, PharmD; and Alexander Shilman, PharmD. 2019-2020: Benedicta Asamoah, PharmD; Allison Hanson, PharmD, BCPS; Neha Kumar, PharmD; Yashar Rafi, PharmD; and Nistha Shah, PharmD.

Suggested Reading Cohen MR, ed. Medication Errors. 2nd ed. Washington, DC: American Pharmacists Association; 2007.

Institute for Safe Medication Practices. ISMP Medication Safety Alert!

Acute Care newsletters 2019. Accessed January 30, 2020. www.ismp. org/newsletters/default.asp Institute for Safe Medication Practices website. Accessed January 30, 2020. www.ismp.org

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PRINTER-FRIENDLY VERSION AVAILABLE AT PHARMACYPRACTICENEWS.COM

Parenteral Nutrition Therapy: Assessment Tools and Guidelines JAY M. MIRTALLO, MS, RPH, FASHP, FASPEN, BCNSP Clinical Practice Specialist The American Society for Parenteral and Enteral Nutrition Professor Emeritus The Ohio State University College of Pharmacy Columbus, Ohio

M

alnutrition is associated with an increased frequency of treatment-related complications, longer ICU and hospital

lengths of stay, and increased costs of medical care.1 Patients at high risk for malnutrition should be identified and evaluated for nutrition support.2 To improve patient outcomes, it is important to choose the appropriate route of nutrition support for patients at risk for malnutrition.3

In patients with a functioning gastrointestinal (GI) tract, enteral nutrition (EN) can improve outcomes.4 EN has been shown to improve nutritional status and reduce ICU length of stay, and it is associated with fewer infectious complications than parenteral nutrition (PN).4-6 The major limitation of EN is the need to gain enteral (post-pyloric) access so that the nutrient infusion is tolerated and serious complications, such as aspiration pneumonia, are avoided.4,7 Techniques are available to facilitate access to the GI tract to allow safe administration of enteral tube feedings.4 For patients who have nonfunctioning GI tracts, PN is an alternate method of nutrition support.4 PN is essential for patients who are severely malnourished and have GI tract problems that are not expected to resolve within 7 days.4,8 PN is complex and has been associated with a unique set of complications, some of which can be serious or even life-threatening.8,9 Although a few older published reports could not demonstrate that PN had a consistently favorable effect on patient outcomes,10,11 new evidence using contemporary doses and approaches to PN therapy has shown

beneficial effects that are comparable to those of enteral nutrition support.12 Other reports found beneficial effects on body composition and quality of life.13,14 This new evidence shows PN has evolved from a therapy to avoid to an effective alternative to prevent and treat malnutrition in patients in whom the GI tract is not functioning or who cannot tolerate adequate EN.4,8 This review discusses nutritional assessment, nutritional requirements, PN formulation design, medication compatibility with PN, and guidelines for special diseases, as well as provides an overview of evidencebased guidelines and PN practices published by the American Society for Parenteral and Enteral Nutrition (ASPEN).3,4,15-18

Nutrition Assessment The purpose of nutrition assessment is to identify the degree to which a patient’s current or future nutritional status will influence his or her outcomes. Nutritional status is determined by several factors, including the patient’s weight and how it compares with ideal and usual weights (Table 1)19,20; the duration of any weight P H A R M AC Y P R AC T I C E N E WS S P E C I A L E D I T I O N • 2 0 2 0

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loss; laboratory values indicative of fluid, electrolyte, and nutritional deficits; clinical condition; and whether the patient can be nourished by oral, enteral, or parenteral means.19,21 Inflammation due to underlying disease has evolved as a potentially important factor in the development of and recovery from malnutrition.21 Malnutrition may occur as the result of decreased nutrient intake or as a response to inflammatory mediators that decrease

Table 1. Classification of Malnutrition Mild

Moderate

Severe

Ideal body weight, %

80-90

70-80

<70

Usual body weight, %

85-95

75-84

<74

Weight loss in 1 wk, %

—

1-2

>2-5

Weight loss in 1 mo, %

—

5

>5-7.5

Weight loss in 3 mo, % —

7.5

>7.5-10

Weight loss in 6 mo, % —

10

>10

Weight

Recent Weight Loss

Based on references 19 and 20.

appetite, increase nutrient requirements, or interfere with incorporation of nutrients into lean body mass.21 Malnutrition is defined as an acute, subacute, or chronic state associated with varying degrees of over- or undernutrition, with or without inflammatory activity that leads to a change in body composition and functional impairments.22 Contemporary recommendations for diagnosing malnutrition involve assessment for 6 characteristics: diminished energy (nutrient) intake, unintentional weight loss, diminished muscle or fat mass, edema, and objective measures of diminished functional status (eg, handgrip strength).23 The presence of 2 or more of the characteristics is required for a diagnosis of malnutrition. The etiology-based diagnosis of malnutrition falls into 3 categories: acute disease related, chronic disease related, and starvation (also described as social or environmental).21,23 Malnutrition also is classified as either moderate or severe based on the amount and duration of weight loss and diminished energy intake. For example, weight loss in a patient with acute disease–related malnutrition is defined as severe if it represents greater than 5% of their body weight and lasts longer than 1 month. Severe weight loss of greater than 10% lasting longer than 6 months is defined as starvation.23 A useful algorithm for determining the appropriate indications for PN is presented in Figure 1. Clinicians should consider PN if a trial of enteral feedings has

Nutrition assessment Decision to initiate nutrition support

Functional GI tract?

Yes

• Aggressive attempt to obtain enteral access • Feedings may be more appropriate distal to the pylorus for patients with high gastric residuals, critical illness, gastroparesis, or pancreatitis

EN

No

Inconclusive

EN trial

PN

Yes

EN tolerated?

No

No

PN only if EN contraindicateda

PN

Yes

Continue EN

(Aspiration, abdominal distention, diarrhea, high gastric residuals)

Status of GI function Nonfunctional Continue PN

Functional Transition to EN

Figure 1. Algorithm for the administration of nutrition support. a

Obstruction, peritonitis, paralytic ileus, mesenteric ischemia, short bowel syndrome, enterocutaneous fistula, and malabsorption.

EN, enteral nutrition; GI, gastrointestinal; PN, parenteral nutrition

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failed, if the enteral route is contraindicated, or if the GI tract has severely diminished function because of underlying disease or treatment and GI function is not expected to return within 7 days.4,8 Contraindications to PN include a functional GI tract; an inability to achieve appropriate venous access; an unstable clinical condition; and terminal disease, critical illness, or metabolic derangement for which a favorable response to therapy is not feasible or the risk for complications is too high.18 In these conditions, the metabolic profile is such that exogenous nutrients are poorly used and frequently cause complications that require prolonged mechanical ventilation, intensive care, or hospitalization.18,19 Metabolic derangements, such as azotemia and hyperchloremic metabolic acidosis necessitate cautious use of PN until the patient’s condition improves (Table 2).19,24 In malnourished patients with chronic kidney disease requiring hemodialysis, intradialytic PN should not be used as the sole nutrition; it may be considered in malnourished patients unable to ingest or absorb adequate oral nutrition or EN.18 A nutrition consultation form that incorporates the aforementioned concepts can improve use of PN.25 Such a form also documents the need for nutrition support, and, with the nutritional assessment, can include a recommendation for route and dose of nutrients to be provided.

Table 2. Metabolic Derangements Requiring Caution in Use of PN Metabolic Derangement

Abnormality to Be Corrected

Azotemia

Blood urea nitrogen >100 mg/dL

Hemodynamic instability

Fluid deficits, perfusion pressures

Hyperchloremic metabolic acidosis

Serum Cl >110 mEq/L

Hyperglycemia

Serum glucose >100-200 mg/dL

Hyponatremia

Serum sodium <130 mEq/L

Hypernatremia

Serum sodium >150 mEq/L

Hyperosmolality

Serum osmolality >350 mOsm/kg

Hypochloremic metabolic alkalosis

Serum Cl <85 mEq/L

Hypokalemia

Serum potassium <3 mEq/L

Hypophosphatemia

Serum phosphorus <2 mg/dL

Cl, chloride; PN, parenteral nutrition

Nutritional Requirements Over the past several years, there has been continual refinement of PN, focusing on the delivery of the safest, most effective doses. Guidelines provide a framework for nutrient doses in patients with a variety of disease states.4,26 In general, there has been a decline in recommended caloric doses; a liberalization of protein doses, especially for renal and liver failure; and more specific recommendations for injectable lipid emulsion (ILE) doses (Table 3).4,8,26-30 The guidelines list 2 specific purposes for fat: nonprotein calories and prevention of essential fatty acid deficiency. The market introduction of new ILEs—Smoflipid (Fresenius Kabi) and Clinolipid (Baxter)—provides alternatives that significantly lower the soybean oil (linoleic acid) dose.31,32 Obesity (body mass index [BMI] >30 kg/m2) is prevalent and needs to be considered in dosing of PN. Hypocaloric PN has been reported to be beneficial in obese patients, resulting in the achievement of positive nitrogen balance and weight loss.33 However, with newer classifications of obesity, class I patients (BMI 30-35 kg/m2) may be required to maintain their weight during PN; if so, they should receive a more normal amount of calories.

Overfeeding of calories and protein can have serious consequences in patients receiving PN and has led to the specific recommendations provided in Table 3.4,8,26-30 When maximum doses of macronutrients are exceeded, the consequences outlined in Figure 2 frequently are reported.8,34,35 Micronutrients—electrolytes, trace elements, and vitamins—are essential for the incorporation of macronu-

Based on references 19 and 24.

trients into the body cell mass.26 The content of micronutrients in the body fluctuates on the basis of cellular needs and deficits occurring during periods of low or no intake or losses; these fluctuations often occur in patients with nonfunctional GI tracts. Daily monitoring of serum electrolytes and periodic (initially and every 2-3 weeks) assessment of vitamin and trace element status are essential for a patient requiring PN.36 Monitoring for micronutrient deficiencies also should be increased during periods of PN product shortages.36 Guidelines for dosing of micronutrients in PN are outlined in Table 4.26,29 Formulations of PN are extremely complex products intended for IV use.16 Careful consideration of nutrient dose and avoidance of unstable or incompatible ingredients are necessary. Inconsistent compounding practices have led to serious harm in patients receiving PN.26,37 To provide consistent, specific guidelines for PN, the National Advisory Group on Standards and Practice Guidelines for Parenteral Nutrition published “Safe Practices for Parenteral Nutrition.” These guidelines provide recommendations for the PN label and order, as well as for PN compounding, compatibility, stability, and administration.26 They call for a standardized PN label format to promote correct interpretation of PN contents across all health care environments; describe the pharmacist’s duty to review the PN formula to ensure it is complete and balanced and will be stable and compatible upon admixture; and include P H A R M AC Y P R AC T I C E N E WS S P E C I A L E D I T I O N • 2 0 2 0

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Table 3. Macronutrients: PN Dosing Guidelines Normal Range

Usual Doses

Maximum

Special Considerations

Calories

20-35 kcal/kg/d

20-30 kcal/kg/d

Glucose

70%-85% of nonprotein calories

Stable: 4-5 mcg/kg/min Critical illness: <4 mcg/kg/min

7 g/kg/d; 4-5 mcg/kg/min

• Maintaining blood glucose at 150-180 mg/dL is recommended for the general patient population.

Fat

15%-30% of nonprotein calories

SO ILE: 1 g/kg/d or for critically ill, <1 g/kg/d OO, SO ILE: 1-1.5 g/kg/d SO, OO, MCT, FO ILE: 1-2 g/kg/d

2.5 g/kg/d

• When administered separately from PN, infusion should be completed within 12 h.

• Safest when administered continuously over 24 h.

• Withhold or limit SO emulsion during the first week of PN in critically ill patients.

• Consider OO, SO ILE or SO, OO, MCT, FO ILE with lower SO content.

Protein

0.8-2 g/kg/d

Stable: 0.8-1.5 g/kg/d Critical illness: 1.2-2.5 g/kg/d

2 g/kg/d

• Provided as high biologic value (ie, content high in essential AAs).

• Should be dosed to achieve positive nitrogen balance or normal AA profile for renal disease.

• See reference 29 for more specific recommendations.

Fat (lipids)

Prevention of essential fatty acid deficiency

2%-4% of caloric dose as linoleic acid and 0.25%-0.5% of caloric dose as alpha-linolenic acid

• Obesity: Hypocaloric doses have been used (75% of estimated needs).

• Measurement of energy expenditure is advised.

• Contraindicated in patients with pancreatitis induced by hyperlipidemia.

• Withhold doses for triglyceride levels >400 mg/dL. • Administer using DEHP-free tubing and use a 1.2-micron filter.

AA, amino acid; DEHP, di-2-ethylhexyl phthalate; FO, fish oil; ILE, injectable lipid emulsion; MCT, medium chain triglycerides; OO, olive oil; PN, parenteral nutrition; SO, soybean oil Based on references 4, 8, and 26-30.

admixture processes and quality control requirements that foster safe and accurate compounding of PN formulas (Table 5).26 However, since these PN practices were developed, PN errors have continued to be reported and characterized.38,39 Shortages of PN products also have contributed to aberrations in procurement, stability, compatibility, compounding, and administration of the therapy.40,41 During shortages, it is persistently difficult to provide adequate doses, or even PN therapy at all, to people in need. With these continued issues, ASPEN held a PN Safety Summit in 2011, which focused on discussing processes for improving PN safety, from order to administration.42 The results of the summit guided the development of PN safety consensus recommendations (Table 6).43-45 As health care becomes more complex and the diversity of clinicians who order PN increases, the competency of personnel involved in the PN process must be ensured. ASPEN recommends that a standardized process to determine competency of those who prescribe, review orders, and compound PN be in place at all facilities providing PN therapy.46,47 Renewed interest in standard PN formulations prompted ASPEN to create a “Statement on Parenteral Nutrition Standardization.”44 This evidence-based analy-

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sis of the literature resulted in the recommendations provided in Table 7.44 This statement recommends a standardized PN process, recognizes the need for clinicians with PN expertise to be involved with the process, and addresses the patient with complex needs for whom a customized PN formulation may be necessary.44

Medication Compatibility With PN Patients receiving PN usually need their medications to be administered intravenously. Multiple-lumen central venous catheters have alleviated some problems associated with coadministration of drugs with PN.48 Although it is recommended that the catheter or port for PN administration be used solely for PN, this is not always possible in patients with limited venous access. Administration of medications with PN may be unavoidable. In these situations, compatibility concerns are relevant.

FAT CONTENT

AN IMPORTANT

CONSIDERATION

The pharmacist’s objective is to ensure the safe, compatible, and effective provision of both pharmacologic therapy and nutrition support. In reviewing a patient’s regimen for compatibility, it is important to consider whether the PN contains fat emulsion. Studies have shown differences in compatibility based on the

Excess protein

PN formulation used. Table 8 was developed to provide consistent, reliable, and up-to-date information on the compatibility of drugs administered via Y-site injection with PN.49-74 Of note, 3-in-1 admixture and ILE compatibility is specific to the soybean oil emulsion, Intralipid (Baxter). Drug compatibility with Smoflipid and Clinolipid should be determined by contacting the manufacturer. It is not appropriate to assume that drug compatibility for Intralipid represents compatibility for all ILEs. If no compatibility data exist, the medication should not be administered parenterally.

There is a distinction between Y-site administration and direct admixture of the drug with PN. Adequate assessment of specific pharmacotherapeutic criteria for direct admixture of drugs (eg, ranitidine or famotidine) in PN is required.48 These criteria may be summarized as follows48: • Stability and compatibility of the drug with the specific PN admixture over a 24-hour period must be determined before the medication is added.

• The medication must have appropriate pharmacokinetics and proven efficacy for continuous infusion.

• The medication dose must have remained constant throughout the previous 24-hour period before admixture in PN. • There must be a stable PN infusion rate for at least 24 hours before the medication is added.

• PN must include appropriate labeling to avoid pharmacotherapeutic problems associated with abrupt discontinuation.

In general, only histamine-2 antagonists and insulin have been admixed in 3-in-1 admixtures. These drugs also may be admixed with 2-in-1 solutions. Other drugs that have been shown to be stable and efficacious in 2-in-1 solutions are heparin, aminophylline, hydromorphone, hydrochloric acid (maximum concentration, 100 mEq/L), and iron dextran.

Not all issues with medications and PN are due to incompatibility during admixture or administration.

An FDA Safety Alert issued in 2007 for ceftriaxone (Rocephin, Roche) warned clinicians about the potential precipitation of calcium and ceftriaxone in vital organs, leading to complications and death, when these agents are administered within 48 hours of each other.75 This reaction is possible even when the PN and ceftriaxone are administered via separate infusion catheters. Thus, use of calcium in PN concurrently with ceftriaxone should be avoided; calcium administration can be resumed 48 hours after ceftriaxone therapy is completed.

hyperglycemia, >150 mg/dL).79 Glucose control in PN patients has been addressed in recent guidelines and practice reviews.3,4,8 A reasonable target level for blood glucose is between 140 and 180 mg/dL.4 Use of insulin in PN to control glucose has been advocated, beginning with a dose of 0.1 units per gram of dextrose (15 U/150 g).8 Glucose should be monitored every 4 to 6 hours when insulin is added to PN. If the patient’s glucose level exceeds this goal, supplemental insulin should be administered every 4 to 6 hours, and the subsequent PN dose should be adjusted based on the previous day’s sliding-scale insulin use. It is recommended that the dose does not exceed approximately 0.2 units of insulin per gram of dextrose.8

Glucose Control

PN Guidelines 76

Hyperglycemia is associated with poor outcomes.

Aggressive use of insulin to manage hyperglycemia predisposes to hypoglycemic events.77 Problems with glucose control have been related to the lack of adequate targets for serum glucose in PN patients.78 The frequency of hyperglycemia ranges from 44% (criterion for hyperglycemia, >200 mg/dL) to 90% (criterion for

• Renal solute load • Azotemia • Impaired renal function • Acidosis

Excess fat • Serum triglycerides • Impaired pulmonary alveolar function • Altered immunologic function • Hepatobiliary disease

Excess dextrose Hyperglycemia • Serum glucose >200 mg/dL • Hyperinsulinemia • Impaired phagocytosis and neutrophil chemotaxis

Excess total calories Liver • Fatty infiltration • Aspartate aminotransferase • Alanine aminotransferase • Alkaline phosphatase • Hepatomegaly • Cholestasis

Pulmonary function • CO2 production and minute ventilation • Respiratory failure in patients with limited reserve • Prolonged mechanical ventilation

Figure 2. Consequences of protein-calorie overfeeding.

CO2, carbon dioxide Based on references 8,34, and 35.

Guidelines for PN in cancer and critically ill patients initially were published in 2009.15,17 In cancer patients, nutrition support should not be used routinely. However, when it is indicated, EN is preferred over PN.15,80 In most instances, a standard diet is preferred over PN, except in severely malnourished patients undergoing surgery. These patients may benefit from PN therapy if P H A R M AC Y P R AC T I C E N E WS S P E C I A L E D I T I O N • 2 0 2 0

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Trace Elements

Vitamins

Electrolytes

Table 4. Micronutrients: PN Dosing Guidelines Normal Daily Requirements

Usual Daily Doses

Na, K

1-2 mEq/kg

• Variable; individualize

Cl, acetate

As needed for acid–base balance

• Equal amounts as Na or K salt

Phosphorus

20-40 mmol

Calcium

10-15 mEq

Magnesium

8-20 mEq

Thiamine (B1)

6 mg

Riboflavin (B2)

3.6 mg

Niacin (B3)

40 mg

Folic acid

600 mcg

Pantothenic acid

15 mg

Pyridoxine (B6)

6 mg

Cyanocobalamin (B12)

5 mcg

Biotin

60 mcg

Ascorbic acid

200 mg

Vitamin A

3,300 IU

Vitamin D

200 IU

Vitamin E

10 IU

Vitamin K

150 mcg

Chromium

10-15 mcg

Copper

0.3-0.5 mg

Manganese

60-100 mcg

Zinc

2.5-5.0 mg

Selenium

20-60 mcg

Iron

Not routinely added

• Gluconate salt preferred for PN; stability limited by concentration of calcium and phosphorus

• Provided by addition of multiple vitamin injection product • FDA-mandated reformulation of vitamin products to increase thiamine, folic acid, pyridoxine, and ascorbic acid • Monitor warfarin carefully during transition to products with vitamin K • Prescribe full daily dose of multivitamins unless patient is able to ingest and/or absorb orally or enterally

• Use manganese with caution in patients with elevated bilirubin (accumulation may result in neurologic toxicity) • Zinc requirements increase with high GI output • Selenium is indicated for long-term care and critically ill patients • Patients on long-term PN are prone to iron deficiency; iron status should be assessed initially and every 3 mo in these patients

Cl, chloride; GI, gastrointestinal; K, potassium; Na, sodium; PN, parenteral nutrition Based on references 26 and 29.

it is administered 7 to 14 days before surgery, as long as the potential medical risks associated with delaying surgery are acceptable.15 As noted earlier, perioperative PN was found by Klek et al to deliver comparable results to EN in malnourished cancer patients.12 Additionally, Pelzer et al found improvements in body composition in advanced pancreatic cancer patients with cachexia.13 These positive results suggest that PN in cancer patients may be beneficial when used to treat malnutrition.

In critically ill patients, EN is superior to PN.4 If EN is not feasible and the patient is at low nutrition risk before the critical illness, it is prudent to withhold PN over the first 7 days.4 PN should be used if EN is contraindicated and the patient is malnourished or at high

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nutrition risk before critical illness. New approaches to PN are presented in the revised critical care guidelines. The use of supplemental PN is suggested if less than 60% of estimated requirements are met after 7 to 10 days of EN.4 Also, a role of hypocaloric (<20 kcal/kg or <80% of estimated requirements) PN during the first week of ICU stay is described.4 To improve efficiency and reduce complications, protocols and a nutrition support team are recommended.4 Glucose control in critical care was described earlier.

The last important aspect of the critical care guideline is the use of ILEs.4 The use of soybean oil–based emulsions should be withheld or limited during the first week of PN.4 A dose of 100 g per week, usually in divided

Table 5. ASPEN Safe Practice Guidelines Practice Guidelines Ordering PN 1. Standardized order forms should be used.

2. PN formula is assessed to determine whether the contents are appropriate for the patient’s condition (adult or pediatric) or the patient’s disease state warrants a dose outside the standard range.

3. Nutrients are indicated as total daily dose.

4. Percent concentration should not be used on the order form.

5. Avoid potentially dangerous abbreviations.

6. All components of the PN order are rewritten when PN is reordered.

Labeling PN Formulations 1. Labels for PN admixtures should be standardized: • The amount per day is required.

• Quantity per liter also may be used.

• Dosing weight is required on the label.

2. Auxiliary labels may be used, especially when orders are written in a different format from the label.

3. Patient transfer between health care environments such as hospital to home requires pharmacist-to-pharmacist communication of the PN prescription.

4. The PN label should be compared with the order, and the beyond-use date should be checked before administration.

Standard Nutrient Requirements 1. The pharmacist should assess the PN contents to ensure that the dose of all nutrients is appropriate to the patient’s needs.

2. ILE should be provided to adult and pediatric patients to avoid essential fatty acid deficiency when fat is not included in the base formula.

3. All PN patients should receive a parenteral vitamin preparation daily.

4. PN products should be chosen with the lowest aluminum content when possible.

5. Parenteral iron should not be used routinely in PN therapy.

Compounding of PN Formulations Screening 1. Review of PN contents is required to ensure that a balanced and complete formulation is provided.

2. Each PN component is assessed for adequacy of dose and potential for a compatibility or stability problem.

3. Any dose outside the accepted range not explained by a specific patient condition should be clarified before compounding PN. PN Compounding 1. The additive sequence is optimized and validated as a safe, efficacious method.

2. A review of the compounding method is recommended if PN is compounded manually or if there has been a change in commercial source of PN products.

3. Manufacturers of automated methods of PN compounding should provide the additive sequence that ensures the safety of the compounding device based on the nutrient products used at the institution.

4. Each PN formulation compounded must be inspected for signs of particulate contamination and/or phase separation of TNA. Quality Assurance 1. Gravimetric analysis of PN formulations can be applied, focusing on the most dangerous additives tolerating the least margin of error (eg, potassium salts).

2. Chemical analysis can be incorporated into the PN compounding operations of the pharmacy.

3. Refractometric analysis is an alternative but is limited to formulations that do not contain fat.

4. Daily in-process or end-product testing of PN formulations is recommended.

5. Compounding accuracy of PN prepared by automated compounding devices should be verified by end-product testing.

6. Aseptic extemporaneous preparation of PN formulations should adhere to the USP <797> Pharmaceutical Compounding—Sterile Preparations.

(continued on next page)

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Table 5. ASPEN Safe Practice Guidelines

(continued)

Practice Guidelines PN Administration Venous Catheters 1.

2.

3.

4.

Central PN should be administered via CVC with distal tip in SVC adjacent to the right atrium.

Avoid use of femoral catheters for PN administration.

Proper CVC placement should be confirmed before initiating PN and when signs/symptoms of malposition are present.

Care for CVC according to published standards.

Equipment 1. A 0.2-micron filter should be used for 2-in-1 formulations, and a 1.2- to 5-micron filter should be used for TNAs. 2. Alternatively, a 1.2-micron filter may be used for all PN formulations to remove larger particles. The FDA requires a 1.2-micron filter for TNA and a 0.2-micron filter for 2-in-1 formulations.

3. A filter that clogs during administration may be replaced but never removed entirely.

4. Use containers and sets free of DEHP if ILE is used.

5. Change administration sets for ILE given separately from PN after use, or at least every 24 h if it is administered as a continuous infusion.

6. Change TNA administration sets every 24 h.

7. Change 2-in-1 administration sets every 72 h.

8. PN infusion pumps should have adequate “free-flow” protection.

9. Medical devices should be selected that protect the user from needlesticks and exposure to bloodborne pathogens.

Administration 1. The label should be used to verify the patient identity before administration.

2. The PN should be inspected before setup and not used if its integrity appears to be compromised (precipitate, color change, or cracked emulsion).

3. The PN infusion should be completed within 24 h of its initiation.

4. The PN patient should be monitored for PN efficacy, complications, and change in clinical condition, and to document clinical outcomes.

5. Policies and procedures should be in place to deal with PN compounded by an outside facility.

Stability and Compatibility of PN Formulations 1.

2.

3.

4.

All PN processes are confirmed to ensure that all components are stable and compatible.

The pharmacist ensures that the coinfusion of medications with PN admixtures is safe, stable, and compatible.

If no information exists about a medication’s compatibility with PN, it should be administered separately from PN. Compatibility information should be evaluated according to the concentration of medication and whether the PN formulation is a 2-in-1 or TNA. 5. Insulin use in PN should be consistent throughout the health system.

6. Decisions are made based on the most recent evidence from the literature or from the manufacturer.

7. Use of 2-in-1 formulas with separate administration of ILE is recommended for neonatal/infant patients.

CVC, central venous catheter; DEHP, di-2-ethylhexyl phthalate; ILE, injectable lipid emulsion; PN, parenteral nutrition; SVC, superior vena cava; TNA, total nutrient admixture Adapted from reference 26.

American Society for Parenteral and Enteral Nutrition (ASPEN) does not endorse this material in any form other than in its entirety.

doses, is suggested when there is a concern for essential fatty acid deficiency.4 It is recommended to consider the use of an alternative ILE (Smoflipid: soybean, mediumchain triglycerides, and olive and fish oils; Clinolipid: olive and soybean oils) when available in your institution as a means to reduce the load of linoleic acid in PN patients.4 The PN guidelines provide some useful information for pharmacists. A few concepts from the guidelines are outlined below16: • Education of health care professionals will improve PN ordering and reduce errors.

• The maximum osmolarity of PN should be 900 mOsm/L.

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• Commercial premade (“premixed”) multichamber PN formulations can be considered an available PN option along with the option for customization.

• There is no difference in infectious risk between 2-in-1 and 3-in-1 formulations. In home infusion, 3-in-1 formulations may have an increased risk for catheter occlusion.

• Suggested dosing limits for macronutrients to maintain stability in 3-in-1 admixtures are as follows: at least 4% amino acids, at least 10% dextrose, and at least 2% ILE. • Heparin should not be used in PN admixtures to reduce the incidence of central venous thrombosis.

Table 6. ASPEN PN Safety Consensus Recommendations Section or Process

Safety Discussion

Prescribing and communicating the order

• Use a standardized process to improve clarity and reduce PN errors • Describe the essential elements of a PN order necessary to prevent errors • Improvements in the physical environment to improve the PN order and safe use • Methods to educate non–nutrition support specialists to improve PN prescribing

Order review and verification process

• Describe the essential components or attributes of the PN transmission process of PN orders for pharmacist review and verification • Are there improvements in the PN review and verification process that will enhance PN safety?

• Improvement in the PN label and labeling system • Processes recommended to improve safety of PN therapy during product shortages

Compounding

• Describe errors caused by deficits in knowledge, training, competency, and proficiency • Use of soft and hard limits in automated compounding devices to avoid PN errors • The role of USP Chapter <797> in preventing PN errors

PN administration

• System-based measures to enhance the safety of PN administration • Strategies to prevent errors in the verification node of PN administration • Practices to safely administer PN

PN, parenteral nutrition Adapted from references 43-45.

American Society for Parenteral and Enteral Nutrition (ASPEN) does not endorse this material in any form other than in its entirety.

Table 7. ASPEN Recommendations For PN Standardization 1. A standardized process for PN management is advocated. This may include use of standardized PN formulations and pertains to the ordering, labeling, screening, and administration of PN. 2. Evidence on patient safety does not support the general use of standardized PN formulations across health care organizations.

3. Evidence suggests that the use of standardized PN formulations may be more efficient, economical, and clinically appropriate compared with individualized PN formulations in selected patient populations.

4. When implementing standardized PN formulations, a mechanism should be established to provide customized PN formulations for individuals who have complex requirements secondary to disease or underlying illness or when warranted by routine monitoring of electrolytes, organ function, growth, and development.

5. A standardized process must include clinicians with expertise in nutrition support.

6. PN compounding practices should adhere to recommendations promulgated by national professional organizations.

PN, parenteral nutrition Based on reference 44.

American Society for Parenteral and Enteral Nutrition (ASPEN) does not endorse this material in any form other than in its entirety.

Withholding and Withdrawing PN The decision to use PN can be difficult when a patient is unresponsive to therapy or in the terminal stages of disease. The decision to withhold or withdraw PN should be discussed with the medical staff and the patient or a designee. The discussion should elucidate the patient’s preferences, goals, and values—including religious beliefs—and include a detailed list of the possible benefits and burdens of therapy. If the benefit versus risk is not easy to predict, a time-related trial period to evaluate effectiveness, benefits, and burdens should be considered. Chermesh et al showed that incurable cancer patients had a higher rate of complications from PN than noncancer PN patients; however, if a Karnofsky Performance Status score greater than 50 was achieved, PN was associated with longer survival.81 The process of withholding or withdrawing PN requires an understanding of ethical issues concerning nutrition support.82 When necessary, a bioethics committee should be consulted.

Conclusion PN can be effective in treating malnutrition. Its properties, however, confer a unique set of complications that may adversely affect patient outcomes.

Optimal use of PN requires careful consideration of the patient’s clinical condition and nutritional state, and the physical and chemical characteristics of the admixture.

Additionally, use of evolving guidelines for determining the proper indication, dose, and mode of administration of PN facilitates the provision of the most appropriate nutritional therapy.

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Table 8. Y-Site Injection Compatibility of IV Medications With PNa Admixture Type Medication

2-in-1 3-in-1

Admixture Type

ILE

Medication

2-in-1 3-in-1

ILE

Acetazolamide

I

—

—

Droperidol

C

I

I

Acyclovir

I

I

I

Enalaprilat

C

C

C

Amikacin sulfate Aminophylline Amphotericin B Ampicillin sodium

C

C/I

C/I

Epinephrine HCI

C

—

—

C/I

C

C

Epoetin alfa

C

—

—

I

I

I

Erythromycin lactobionate

C

C

C

C/I

C

C

Famotidine

C

C

C

Ampicillin sodium–sulbactam sodium

C

C

C

Fentanyl citrate

C

C

C

Atracurium besylate

C

—

—

Fluconazole

C

C

C

Aztreonam

C

C

C

5-Fluorouracil

C/I

C/I

—

Bumetanide

C

C

C

Foscarnet

C

—

—

Buprenorphine HCl

C

C

C

Furosemide

C/I

C

C

Butorphanol tartrate

C

C

C

Gallium nitrate

C

C

C

Caffeine

C

—

—

Ganciclovir sodium

I/C

I

I

Calcium gluconate

C

C

C

Gentamicin sulfate

C

C

C

Carboplatin

C

C

C

Granisetron HCl

C

C

C

C/I

C

C

Heparin sodium

C

I

I

Cefazolin sodium

b

Cefepime

C

—

—

Hydrochloric acid

C

—

—

Cefoperazone sodium

C

C

C

Hydrocortisone sodium phosphatec

C

C

C

Cefotaxime sodium

C

C

C

Hydromorphone HCl

C

I/C

—

Cefotetan disodium

C

C

C

Ifosfamide

C

C

C

Cefoxitin sodium

C

C

C

Imipenem-cilastatin sodium

C

C

C

Ceftazidime sodium

C

C

C

Immune globulin

—/C

—

—

Ceftizoxime sodium

C

C

C

Indomethacin sodium trihydrate

I

—

—

Ceftriaxone sodium

I

I

I

Insulin, regular

C

C

C

Cefuroxime sodium

C

C

C

Iron dextran

C/I

I/C

—

Chloramphenicol sodium succinate

C

—

C

Isoproterenol HCl

C

C

C

Chlorpromazine HCl

C

C

C

Kanamycin sulfate

C

C

C

Cimetidine

C

C

C

Leucovorin calcium

C

C

C

Ciprofloxacin lactate

I

C

C

Levorphanol tartrate

C

I

—

Cisplatin

I

C

C

Lidocaine HCl

C

C

C

Clindamycin phosphate

C

C

C

Linezolid

C

—

—

Cyclophosphamide

C

C

C

Lorazepam

C

I

I

C/I

C/I

C/I

Magnesium sulfate

C

C

C

Cytarabine

I

C

C

Mannitol

C

C

C

Dexamethasone sodium phosphate

C

C

C

Meperidine HCl

C

C

C

Digoxin

C

C

C

Meropenem

—

C

C

Diphenhydramine HCl

C

C

C

Mesna

C

C

C

Dobutamine HCl

C

C

C

Methotrexate

I

C

C

Dopamine HCl

C

C/I

C/I

Methyldopate HCl

C

C/I

C/I

Doxorubicin HCl

I

I

—

Methylprednisolone sodium succinate

Doxycycline hyclate

C

I

I

Metoclopramide HCl

Cyclosporine

52

MCMAHON PUBLISHING GROUP

C

C

C

I/C

C

C

Table 8. Y-Site Injection Compatibility of IV Medications With PNa Admixture Type Medication

2-in-1 3-in-1

ILE

Medication

2-in-1 3-in-1

ILE

Metronidazole

C

C

C

Potassium chloride

C

C

C

Miconazole

C

C

C

Potassium phosphate

I

I

I

C

C

C

C/I

C

C

Midazolam HCl

I/C

I

I

Prochlorperazine edisylate

Milrinone lactate

C

—

—

Promethazine HCl

Mitoxantrone HCl

I

C

C

Propofol

C

—

—

Morphine sulfate

C

C/Id

C/I

Ranitidine HCl

C

C

C

Nafcillin sodium

C

C

C

Sargramostim

C

—

—

Nalbuphine HCl

C

I

—

Sodium bicarbonate

I/C

C

C

Nitroglycerin

C

C

C

Norepinephrine bitartrate

C

C

C

Sodium nitroprusside

C

C

C

Octreotide acetate

C

C

C

Sodium phosphate

I

I

—

Tacrolimus

C

C

C

Ondansetron HCl

C

I

I

Oxacillin sodium

C

C

C

Ticarcillin disodium

C

C

C

Paclitaxel

C

C

C

Ticarcillin disodium–clavulanate potassium

C

C

C

Penicillin G potassium

C

C

C

Penicillin G sodium

C

—

—

Pentobarbital sodium

C

I

I

Phenobarbital sodium

C

I

I

Phenytoin sodium

I

—

—

Piperacillin sodium–tazobactam sodium

C

C

C

a

During simulated studies of compatibility, a 1:1 volume ratio of drug mixture with PN is used. For example, 1 mL of drug solution is combined with 1 mL of test PN admixture for a period consistent with that usually observed in practice during Y-site administration of the drug with PN.

b

Hydrochloric acid: not to exceed a concentration of 100 mEq/L. Maintain pH of final solution >3.0.

c

Available only as part of Hydrocortone, Merck.

d

Morphine sulfate incompatible at concentration of 15 mg/mL, compatible at concentration of 1 mg/mL.

—, compatibility data not available; C, compatibility has been demonstrated. When Y-site compatibility was not available, medications compatible in-solution for 24 hours were assumed to be Y-sitecompatible; C/I, conflicting compatibility has been demonstrated

References 1.

Admixture Type

Lim SL, Ong KC, Chan YH, et al. Clin Nutr. 2012;31(3):345-350.

2. Mueller CM, Comper C, Druen ME, A.S.P.E.N. Board of Directors.

JPEN J Parenter Enteral Nutr. 2011;35(1):16-24.

3. Mirtallo JM, Forbes A, McClave SA, et al. JPEN J Parenter Enteral Nutr.

2012;36(3):284-291.

4. McClave SA, Taylor BE, Martindale RG, et al. JPEN J Parenter Enteral Nutr. 2016;40(2):159-211.

5. Braunschweig CL, Levy P, Sheean PM, et al. Am J Clin Nutr. 2001; 74(4):534-542.

Tobramycin sulfate

C

C

C

Trimethoprim-sulfamethoxazole

C

C

C

Vancomycin HCl

C

C

C

Vecuronium bromide

C

—

—

Vitamin K1 phytonadione

C

C

—

Zidovudine

C

C

C

and strength of the evidence supports compatible; I, Incompatibility has been demonstrated; I/C, conflicting compatibility has been demonstrated and strength of evidence supports incompatible; HCl, hydrochloride; ILE, injectable lipid emulsion; PN, parenteral nutrition; all forms of IV nutrition including 3-in-1 and 2-in-1 admixtures or IV fat emulsions (also known as parenteral nutrient solution); Y-site injection, drug administration via piggyback, IV push, or other IV methods at the Y-site injection port or other access port (ie, stopcock), between the PN solution and the central venous catheter; 2-in-1, traditional parenteral nutrient admixtures containing dextrose and amino acids with a yellow appearance similar to that of IV solutions containing multivitamins (also known as dextrose–amino acid solution); 3-in-1, combination of dextrose, amino acids, and fat in 1 final container, resulting in an IV fluid having a milky white appearance (also referred to as a total nutrient admixture) Based on references 49-74.

8. Mundi MS, Nystrom EM, Hurley DL, et al. JPEN J Parenter Enteral Nutr.

2017;41(4):535-549.

9. Knowles JB, Cusson G, Smith M, et al. JPEN J Parenter Enteral Nutr.

1989;13(2):209-213.

10. Heslin MJ, Latkany L, Leung D, et al. Ann Surg. 1997;226(4): 567-577.

11. Detsky AS, Baker JP, O’Rourke K, et al. Ann Intern Med. 1987;107(2):195-203.

12. Klek S, Sierzega M, Szybinski P, et al. Clin Nutr. 2011;30(6):708-713.

13. Pelzer U, Arnold D, Govercin M, et al. BMC Cancer. 2010:10:86-91.

6. Kudsk KA, Croce MA, Fabian TC, et al. Ann Surg. 1992;215(5):503-511.

14. Vashi PG, Dahik S, Popiel B, et al. BMC Cancer. 2014;14:593-602.

7.

15. August DA, Hahmann MB. JPEN J Parenter Enteral Nutr.

2009;33(5):472-500.

Ukleja A, Sanchez-Fermin M. Curr Gastroenterol Rep. 2007; 9(4):309-316.

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Evolution of PN

tion use. October 1, 2010. Accessed August 11, 2020. www.uspnf.com/ sites/default/files/usp_pdf/EN/USPNF/c1066.pdf 46. Guenter P, Boullata JI, Ayers P, et al. Nutr Clin Pract. 2015;30(4):570-576.

1. Specific recommendations for a team approach/ interdisciplinary PN 2. PN as a system of care with a focus on safety

47. Boullata JI, Holcombe B, Sacks G, et al. Nutr Clin Pract.

2016;31(4):548-555.

48. Driscoll DF, Baptista RJ, Mitrano FP, et al. Ann Pharmacother.

1991;25(3):276-283.

49. Veltri M, Lee CK. Am J Health Syst Pharm. 1996;53(21):2611-2613.

3. New data published subsequent to cancer guidelines demonstrate comparable efficacy of PN to EN; positive impact of PN on body composition in cancer; and performance measures as a parameter of benefit of PN in incurable cancer patients

50. Trissel LA, Gilbert DL, Martinez JF, et al. Am J Health Syst Pharm.

1997;54(11):1295-1300.

51. Miranda TMM, Ferraresi AA. Einstein (Sao Paulo). 2012;14(1):52-55.

52. Watson D. JPEN J Parenter Enteral Nutr. 1985;9(2):220-224.

53. Gilbar PJ, Groves CF. Aust J Hosp Pharm. 1994;24:167-170.

54. Nahata MC, Zingarelli J, Durrell DE. J Clin Pharm Ther. 1989;14(1):53-55.

EN, enteral nutrition; PN, parenteral nutrition

16. Boullata JI, Gilbert K, Sacks G, et al. JPEN J Parenter Enteral Nutr.

2014;38(3):334-377.

17. McClave SA, Martindale RG, Vanek VW, et al. JPEN J Parenter Enteral Nutr. 2009;33(3):277-316.

18. Worthington P, Balint J, Bechtold M, et al. JPEN J Parenter Enteral Nutr.

2017;41(3):324-377.

19. A.S.P.E.N. Board of Directors. JPEN J Parenter Enteral Nutr. 1995;10(1):1-3.

20. Blackburn GL, Bistrian BR, Maini BS, et al. JPEN J Parenter Enteral Nutr. 1977;1(1):11-22.

21. Jensen GL, Mirtallo J, Compher C, et al. JPEN J Parenter Enteral Nutr.

2010;34(2):156-159.

22. Soeters PB, Schols AM. Curr Opin Clin Nutr Metab Care.

2009;12(5):487-494.

23. White JV, Guenter P, Jensen G, et al. JPEN J Parenter Enter Nutr.

2012;36(3):275-283.

24. Morrison G. Clinical Methods: the History, Physical, and Laboratory Examinations. 3rd ed. Butterworths; 1990.

56. Trissel LA, Gilbert DL, Martinez JF, et al. JPEN J Parenter Enteral Nutr.

1999;23(2):67-74.

57. Baptista RJ, Dumas GJ, Bistrian BR, et al. Am J Hosp Pharm.

1985;42(4):777-778.

58. Ohls RK, Christensen RD. Ann Pharmacother. 1996;30(5):466-468.

59. Baltz JK, Kennedy P, Minor JR, et al. Am J Hosp Pharm. 1990;47(9):20752077.

60. Bullock L, Clark JH, Fitzgerald JF, et al. JPEN J Parenter Enteral Nutr.

1989;13(5):505-509.

61. Mirtallo JM, Rogers KR, Johnson JA, et al. Am J Hosp Pharm.

1981;38(11):1729-1731.

62. Lindsay CA, Dang K, Adams JM, et al. Ann Pharmacother.

1994;28(9):1014-1017.

63. Ishisaka DY, Van Vleet J, Marquardt E. Am J Hosp Pharm.

1991;48(11):2442-2443.

64. Mayhew SL, Quick MW. Am J Health Syst Pharm. 1997;54(5):570-571.

65. Vaughn LM, Small C, Plunkett V. Am J Hosp Pharm. 1990;47(8):1745-1746.

25. Mirtallo JM, Hawksworth K, Payne B. Nutr Clin Pract.

2009;24(4):447-458.

66. Tu YH, Knox NL, Biringer JM, et al. Am J Hosp Pharm.

1992;49(9):2233-2235.

26. Mirtallo J, Canada T, Johnson D, et al. JPEN J Parenter Enteral Nutr.

2004;28(6 suppl):S39-S70.

67. Athanikar N, Boyer B, Deamer R, et al. Am J Hosp Pharm.

1979;36(4):511-513.

27. Choban P, Dickerson R, Malone A, et al. JPEN J Parenter Enteral Nutr.

2013;37(6):714-744.

68. Baptista RJ, Lawrence RW. Am J Hosp Pharm. 1985;42(2):362-363.

28. Delafosse B, Viale JP, Tissot S, et al. Am J Physiol. 1994;267(5 pt 1):E775-E780.

29. ASPEN. Appropriate dosing for parenteral nutrition: ASPEN recommendations. January 2019. Accessed August 11, 2020. www.nutritioncare.org/ PNDosing 30. Mirtallo JM, Ayers P, Boullata JB, et al. Nutr Clin Pract. 2020;35(5):769782.

31. Smoflipid [prescribing information]. Fresenius Kabi; 2016.

32. Clinolipid [prescribing information]. Baxter Healthcare Corporation; 2016.

33. Choban PS, Dickerson RN. Nutr Clin Pract. 2005;20(4):480-487.

34. Btaiche IF, Khalidi N. Am J Health Syst Pharm. 2004;61(19):2050-2057.

35. Mirtallo JM, Dasta JF, Kleinschmidt KC, et al. Ann Pharmacother.

2010;44(4):688-700.

69. Trissel LA, Williams KY, Gilbert DL. J Am Pharm Assoc.

2000;40(4):516-519.

70. Bhatt-Mehta V, Rosen DA, King RS, et al. Am J Hosp Pharm.

1993;50(2):285-288.

71. Akkerman SR, Zhang H, Mullins RE, et al. Am J Health Syst Pharm.

1999;56(1):63-68.

72. Bhatt-Mehta V, Paglia RE, Rosen DA. Am J Health Syst Pharm.

1995;52(2):192-196.

73. Trissel LA, Bready BB, Kwan JW, et al. Am J Hosp Pharm.

1992;49(2):402-406.

74. Dahl GB, Svensson L, Kinnander NG, et al. JPEN J Parenter Enteral Nutr.

1994;18(7):234-239.

75. FDA Safety Alert. Accessed August 11, 2020. goo.gl/szRKWf

36. Mirtallo JM. Nutr Clin Pract. 2015;30(1):86-91.

76. Pasquel FJ, Spiegelman R, McCauley M, et al. Diabetes Care.

2010;33(4):739-741.

37. Gupta N, Hocevar SN, Moulton-Meissner HA, et al. Clin Infect Dis. 2014;59(1):1-8.

77. Smith WD, Winterstein AG, Johns T, et al. Am J Health Syst Pharm.

2005;62(7):714-719.

38. Sacks GS. JPEN J Parenter Enteral Nutr. 2012;36(2 suppl):20S-22S.

78. Mirtallo JM. JPEN J Parenter Enteral Nutr. 2013;37(2):181-189.

39. Storey MA, Weber RJ, Besco K, et al. Nutr Clin Pract. 2016;31(2):211-217.

79. Pleva M, Mirtallo JM, Steinberg SM. Nutr Clin Pract. 2009;24(5):626-634.

40. ISMP Medication Safety Alert! Accessed August 11, 2020. www.ismp.org/ newsletters/acutecare/articles/20100923.asp 41. Mirtallo JM, Holcombe B, Kochevar M, et al. Nutr Clin Pract.

2012;27(3):385-391.

42. Mirtallo JM, Guenter P. JPEN J Parenter Enteral Nutr. 2012;36:7S-9S. 43. Ayers P, Adams S, Boullata J, et al. JPEN J Parenter Enteral Nutr.

2014;38(3):296-333.

44. Kochevar M, Guenter P, Holcombe B, et al. JPEN J Parenter Enteral Nutr.

2007;31(5):441-448.

45. USP. Chapter <1066> - physical environments that promote safe medica-

54

55. Bouchoud L, Fonzo-Christe C, Klingmuller M, et al. JPEN J Parenter Enteral Nutr. 2012;37(3):416-424.

MCMAHON PUBLISHING GROUP

80. Braga M, Gianotti K, Gentilini O, et al. Crit Care Med. 2001;29(2):242-248.

81. Chermesh I, Mashiach T, Amit A, et al. Med Oncol. 2011;28(1):83-88.

82. A.S.P.E.N. Ethics Position Paper Task Force, Barrocus A, Geppert C, et al. Nutr Clin Pract. 2010;25(6):672-679.

Suggested Reading The ASPEN website includes information related to PN safety, including tool kits to assist in implementing organizational changes. For more information, visit www.nutritioncare.org/PNResources.

PRINTER-FRIENDLY VERSION AVAILABLE AT PHARMACYPRACTICENEWS.COM

Practical Considerations for

Implementation of Biosimilars in Oncology DOUGLAS HACKENYOS, PHARMD, BCOP Oncology Pharmacy Clinical Coordinator Department of Pharmacy UConn Health Farmington, Connecticut

T

he FDA approval of filgrastim-sndz (Zarxio, Sandoz) in March 2015 marked a major milestone in drug development—the first agent approved under the Biologics Price Competition and Innovation Act

of 2009.1,2 Since then, 27 more biosimilars have reached the US market.2,3

Although the introduction of additional biosimilars in oncology comes with the hope of significant health care savings, individual institutions are faced with growing challenges related to formulary management.

This article focuses on the practical management and uptake of biosimilars in oncology practice, covering factors related to product selection, information technology (IT) integration and the role of pharmacist in educating providers and patients about these agents.

Selecting a Preferred Product An immediate issue facing any institution looking to implement use of biosimilars is the selection of appropriate preferred products. Product selection is complicated by the availability of competing biosimilars for any given reference product (Table 1).4-15 Two key processes are involved in evaluating biosimilar products: clinical review and comparison and pharmacoeconomic evaluation.

CLINICAL REVIEW

AND

COMPARISON

As with any agent being considered for formulary addition, a thorough review of safety and efficacy data is a necessary first step. A unique aspect in reviewing and deciding between biosimilar products is the potential for varying levels of supporting data for each agent. Biosimilars—defined as biologics that are highly similar to and have no clinically meaningful differences from a previously approved reference product in terms of safety, purity, and potency—receive FDA approval based on analytical studies of structure and function, animal studies, and clinical studies to compare pharmacokinetics, pharmacodynamics, safety, and efficacy end points.16 Depending on the data provided, the FDA may allow

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Table 1. Approved Antineoplastic Biosimilars and Reference Products Reference Product

Biosimilar

FDA Approval Date

Bevacizumab (Avastin, Genentech)

Bevacizumab-awwb (Mvasi, Amgen)

September 2017

Bevacizumab-bvzr (Zirabev, Pfizer)

June 2019

Trastuzumab-dkst (Ogivri, Mylan)

December 2017

Trastuzumab-pkrb (Herzuma, Celltrion)

December 2018

Trastuzumab-dttb (Ontruzant, Samsung Bioepis)

January 2019

Trastuzumab-qyyp (Trazimera, Pfizer)

March 2019

Trastuzumab-anns (Kanjinti, Amgen)

June 2019

Rituximab-abbs (Truxima, Celltrion)

November 2018

Rituximab-pvvr (Ruxience, Pfizer)

July 2019

Trastuzumab (Herceptin, Genentech)

Rituximab (Rituxan, Genentech)

Based on references 4-15.

extrapolation and approval of indications without additional clinical studies. Although the FDA approval process for biosimilars helps to reduce significant clinical differences between products, pharmacy and therapeutics committees ultimately must choose between products and establish any restrictions on use. In evaluating indications for rituximab products, for example, rituximab (Rituxan, Genentech) and rituximab-abbs (Truxima, Celltrion) carry FDA approvals for rheumatoid arthritis whereas rituximabpvvr (Ruxience, Pfizer) does not.4-6 It is important to consider the patient populations seen at an institution when deciding between products, given potential coverage issues resulting from different approved indications. Additional factors to weigh include the reliability of manufacturers with respect to product quality and availability.

PHARMACOECONOMIC EVALUATION In tandem with any clinical review is the necessary pharmacoeconomic evaluation of available biosimilars.

Historically, average wholesale price is approximately 20% to 30% lower for biosimilars compared with reference products.17 Additional savings may be realized through participation in group purchasing organizations (GPOs). A further benefit of many GPOs is their ability to provide ongoing evaluation of biosimilars and coverage considerations, thus shifting some of this process from individual institutions.

Reimbursement factors largely into any biosimilar formulary decision, given that the majority of their use occurs in the outpatient setting. Familiarity with an institutionâ&#x20AC;&#x2122;s payor mix and the formulary preferences of major commercial payors should be weighed heavily in biosimilar implementation decisions. The

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Centers for Medicare & Medicaid Services (CMS) also has rules to provide financial incentives for use of biosimilars, and many recently approved biosimilars benefit from higher reimbursement than reference products due to 340B pass-through status.18,19 Manufacturer rebates may incentivize some payors to continue to prefer reference products; however, increased market competition with additional biosimilars likely will help increase their uptake.17

IMPLEMENTING BIOSIMILAR USE After selecting a formulary preferred product, full implementation involves IT integration as well as significant provider and patient education. The overall approach to implementation may involve use only in newly started patients or may include conversion of patients already receiving a reference product. Either way, careful coordination with care team members and prior authorization staff is necessary.

MANAGING EXCEPTIONS

AND

CHANGES

The ever-changing landscape of biosimilar approvals and insurance formularies makes it nearly impossible for most institutions to select a single biosimilar to replace any given reference product.

Making preferred product selection clear across systems may help minimize inappropriate orders and support prior authorization requests; however, a successful biosimilar implementation process will allow conversion to a reference product or non-preferred biosimilar in cases of insurmountable insurance restrictions or rare clinical exceptions. Additional patient-specific exceptions may be required for clinical trials and medications supplied by mail order or specialty pharmacy.

Table 2. Reference Products and Innovative Subcutaneous Formulations That Add Competition to Biosimilar Market Intravenous Reference Product

Novel Subcutaneous Formulation

Rituximab (Rituxan, Genentech)

Rituximab and hyaluronidase (Rituxan Hycela, Genentech)

FDA Approval Date

Indication(s)

June 2017

• Chronic lymphocytic leukemia • Diffuse large B-cell lymphoma • Follicular lymphoma

Trastuzumab (Herceptin, Genentech)

Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta, Genentech)

February 2019 • HER2-positive breast cancer, early adjuvant • HER2-positive breast cancer, metastatic

Pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo, Genentech)

June 2020

• HER2-positive breast cancer, early adjuvant or neoadjuvant • HER2-positive breast cancer, metastatic

Based on references 10, 16, and 20-22.

INNOVATION

IN

REFERENCE PRODUCT LINES

Competition breeds innovation, and this can be seen in additional non-biosimilar products that are poised to draw away from biosimilar use (Table 2).10,16,20-22 Monoclonal antibodies with hyaluronidase intended for faster, more convenient subcutaneous administration are attractive treatment options compared with existing intravenous reference products and biosimilars.23 These agents have the potential to further complicate inventory management and treatment decisions, but insurance authorization hurdles, site of care issues, and narrower FDA-approved indications hamper widespread use at this time. As more innovative formulations reach the market and lists of approved indications grow, competition with biosimilars undoubtedly will increase.

Biosimilar IT Integration ELECTRONIC HEALTH RECORD BUILD Successful incorporation of biosimilars into the electronic health record (EHR) begins with well-constructed building blocks: electronic prescriptions or medication records. It is important to recognize that biosimilar products have distinct National Drug Codes (NDCs), billing codes, and names that will not allow them to be interchanged the way conventional brandname and generic medications are. Biosimilar electronic medication records (eMARs) should include the unique NDC, HCPCS J code, generic name (with 4-letter suffix), and brand name associated with each unique product. Comprehensive biosimilar builds minimize look-alike/sound-alike (LASA) errors that may arise with order entry, verification, preparation, and administration (Table 3). LASA warnings also may

be added to each build so they appear on the eMAR and drug labels.

BIOSIMILAR ORDER SETS In addition to their many other benefits, electronic order sets and oncology treatment pathways can aid biosimilar uptake substantially. A preferred formulary biosimilar may be set as the default agent in a plan to bolster use and prevent provider confusion at order entry. Statements added to treatment plans and electronic consent forms can be used to further highlight formulary preferences and promote patient education related to biosimilars. Defaulted treatment plans also may assist in streamlining the prior authorization referral process and make the preferred biosimilar selection clear to authorization staff.

Default selection of a preferred formulary product within a treatment plan also must be balanced with a need for flexibility. Ideally, plans should be designed to accommodate third-party payor preferences and nonpreferred products supplied by specialty pharmacies or manufacturer assistance programs. Sophisticated EHRs may allow for “toggling” between biosimilars and reference products within a treatment plan to allow pharmacist substitution of the required product. Efforts to minimize or avoid use of brand names in oncology treatment pathway titles, plan parameters, and other order set fields outside of the specific medication order may make future substitutions or product conversions more efficient.

DISPENSING TECHNOLOGY Technology within the pharmacy can drastically improve an institution’s ability to incorporate biosimilars into practice. Inventory management systems with

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Table 3. Tips for Minimizing Look-Alike/Sound-Alike Medication Errors With Biosimilars Order Entry

• Discrete medication records for each biosimilar with full generic name, 4-letter suffix, and brand name • Default order sets/treatment pathways to formulary product preference

Verification

• Discrete medication records for each biosimilar with full generic name, 4-letter suffix, and brand name • Minimize need for substitution upon verification

Preparation

• Barcode scanning • Segregated inventory locations for reference, biosimilar, and subcutaneous product formulations

Administration

• Barcode scanning • Discrete medication records for each biosimilar with full generic name, 4-letter suffix, and brand name • Segregated inventory locations in automated dispensing cabinets

electronic barcode scanning can help pharmacy staff differentiate between biosimilars and reference products as soon as medications enter the pharmacy. Biosimilar products may be assigned segregated locations using inventory management technology to avoid confusion during stocking and picking of physical inventory. Barcode scanning, image capturing, and dose compounding verification technology also can minimize preparation errors that may result from LASA biosimilar products. Dose preparation and verification technology also may help prevent preparation errors that may result from differences in the preparation of specific products. For example, vial sizes, reconstitution instructions, and the need for sterile water for injection (SWFI) versus bacteriostatic SWFI vary between single- and multidose trastuzumab products.15,20 Inventory management and dose preparation may be further complicated by the need to stock multiple biosimilars as well as subcutaneous formulations for any given reference product; barcoding technology is essential to avoid errors in such scenarios.

MEDICATION ADMINISTRATION TECHNOLOGY Technology greatly facilitates safe administration of all medications including biosimilars. The use of barcode scanning and smart infusion pumps can reduce errors that may come with multiple product options.

Many institutions are opting to minimize build and maintenance work for their smart pump libraries by using a single entry under a generic name to address both reference and biosimilar products with identical administration instructions. Some eMARs also may allow the addition of intranet links to drug information and patient education resources for biosimilar products for easy access at the point of care.

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The Role of Pharmacists In Biosimilar Education The continued development and approval of biosimilar agents bring both opportunities and challenges to health care. Biosimilars stand to provide price competition and cost savings sorely needed in cancer care.

Unfortunately, significant knowledge gaps have been identified that add to the challenge of implementing biosimilar use.

BECOMING INFORMED

AS A

PHARMACIST

The rapid introduction of multiple biosimilar agents has challenged all clinicians, including pharmacists, to stay informed. In a 2019 survey conducted by the International Society of Oncology Pharmacy Practitioners, respondents identified 3 key areas that required more training: biosimilar comparative efficacy to innovator products (74%), practical guidance for managing biosimilar conversions (74%), and biosimilar medication safety, including immunogenicity (74%).24 Pharmacists must have a fundamental understanding of biosimilars to be in a position to implement them and educate providers and patients about their use. Numerous review articles, including publications geared specifically toward oncology pharmacists, discuss biosimilars.25,26 Pharmacists also can stay abreast of the most recent biosimilar approvals through resources such as FDA Alerts and weekly FDA briefings from the Hematology/Oncology Pharmacy Association (HOPA).27,28

EDUCATING CLINICIANS Several studies have identified areas for improvement in oncology clinicians’ understanding of biosimilars, and pharmacists may play a key role closing

Table 4. Key Patient Counseling Points for Biosimilar Agents What are biosimilars?

• These biologic agents are highly similar to a reference product and are safe and effective.

• Biosimilars are tested and compared with reference products before FDA approval.

• These agents are not generic versions. As biologics, they are large, complicated molecules made by living cells that can’t be copied exactly.

Why use biosimilars?

• These agents provide more treatment options.

• They enhance competition and increase cost savings in health care.

• Biosimilars improve access to care.

• Insurance coverage may require use of biosimilars.

Is it safe to switch to a biosimilar?

• There are no meaningful differences in effectiveness or side effects of biosimilars compared with reference products.

• The function, purity, potency, and immunogenicity of biosimilars are similar to those of reference products.

• Biosimilars use the same dosage and administration as reference products and are produced in FDA-licensed facilities.

• Safety tracking continues after the biosimilar has been approved and reaches the market.

these knowledge gaps.29,30 Position statements and resources from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), HOPA, and Oncology Nursing Society (ONS) can be very helpful in supporting pharmacistled education of clinicians and, ultimately, increasing acceptance of biosimilars.31-34 Educational efforts and identification of a physician to champion biosimilar use can be critical for successful biosimilar implementation.

In addition to clinician education, support staff should be informed about new considerations related to the addition of biosimilars. Pharmacists can facilitate the education of staff involved in patient access and prior authorization by explaining care plan changes, emphasizing changes in preferred products, and providing clinical rationales for biosimilar prior authorizations. Pharmacy technicians also should be educated to minimize the risk for LASA errors in compounding and dispensing.

EDUCATING PATIENTS Patient education remains a vital component of cancer treatment using antineoplastic biosimilars.

The education of patients newly taking biosimilars is comparable to that of other patients initiating treatment with a biologic. Given the growing potential for changing payor and institutional formularies based on cost savings, it may be appropriate to introduce the patient to the term biosimilar and explain key concepts of biosimilar switching, safety, immunogenicity, and production (Table 4).

The massive amount of information that patients must process at the start of a new regimen necessitates

succinct, patient-friendly written information. Biosimilar manufacturers often provide helpful explanations and easily interpreted figures, and these aids can help if branded patient educational materials are permitted at your institution. In addition, the FDA has a host of nonbranded materials with infographics that quickly explain key concepts related to biosimilars in patientfriendly terms.35 Education at the time of conversion from an antineoplastic reference product to a biosimilar is an important, sensitive step to maintain a respectful patient–provider relationship during implementation.

Conversions may be driven by institutional cost-savings opportunities or insurance formulary preferences; in either case, it is important to be open about the general motivation for increasing biosimilar use.

In the outpatient setting, education must be coordinated in advance of order conversion, prior authorization, and eventual treatment with the biosimilar.

An example conversion time line may include patient education about the biosimilar in person or via telephone at the time of their treatment with a reference product, prior authorization between treatments, order conversion, and follow-up at the first biosimilar infusion.

Whether patients need to re-consent when converted to an antineoplastic biosimilar is a frequently asked question. Pharmacists can review institution-specific consenting policies and consult in-house legal counsel (if available) to help determine the most appropriate course of action. Either way, it may be appropriate to update consent forms or policies to contain broader wording (eg, “treatment with: X drug and similar products”) to allow for future conversions.

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Conclusion Successful implementation of antineoplastic biosimilars requires flexibility in a changing market. Evaluation of clinical data, cost, reimbursement, formulary preferences of major payors, and new innovative formulations is essential for appropriate decision making and product selection. IT systems must be leveraged to further support implementation; comprehensive eMAR builds and technology involved in dispensing and administration will enhance uptake and minimize errors related to biosimilar use. With third-party payor preference being a major factor in determining biosimilar product selection, it is also essential to maintain flexibility in eMAR and oncology treatment pathway design. In addition, the incorporation of biosimilars into oncology practice requires education such that everyone involved in the medication use process understands how and when biosimilars are appropriately used. Adequate patient counseling and support when a patient is newly initiated or converting to a biosimilar are critical. Pharmacists are uniquely positioned to provide clinician and patient education and will play a significant role in increasing adoption of biosimilars for cancer treatment.

References 1.

FDA. Drugs@FDA: FDA-Approved Drugs. Filgrastim-sndz.

Accessed August 11, 2020. www.accessdata.fda.gov/scripts/cder/ daf/index.cfm

2.

FDA. Biosimilar product information. Accessed October 28, 2020. www.fda.gov/drugs/biosimilars/biosimilar-product-information

3. FDA. Title VII—improving access to innovative medical therapies.

Subtitle A—Biologics Price Competition and Innovation. Accessed August 11, 2020. www.fda.gov/media/78946/download 4. Rituxan (rituximab) [package insert]. South San Francisco, CA: Genentech, Inc.; 2012.

5.

Truxima (rituximab-abbs) [package insert]. Incheon, South Korea: Celltrion, Inc.; 2020.

6. Ruxience (rituximab-pvvr) [package insert]. New York, NY: Pfizer, Inc.; 2019.

7.

Avastin (bevacizumab) [package insert]. South San Francisco, CA: Genentech, Inc; 2020.

8. Mvasi (bevacizumab-awwb) [package insert]. Thousand Oaks, CA: Amgen, Inc; 2019.

9. Zirabev (bevacizumab-bvzr) [package insert]. New York, NY: Pfizer, Inc; 2019.

10. Herceptin (trastuzumab) [package insert]. South San Francisco, CA: Genentech, Inc; 2018.

11. Ogivri (trastuzu-dkst) [package insert]. Zurich, Switzerland: Mylan; 2017.

17. Mulcahy AW, Hlavka JP, Case SR. Biosimilar cost savings in the United States: initial experience and future potential.

Rand Health Q. 2018;7(4):3.

18. Centers for Medicare & Medicaid Services. Fact sheet: Final policy, payment, and quality provisions in the Medicare physician fee schedule for calendar year 2018. Accessed August 11, 2020. www.cms.gov/newsroom/fact-sheets/ final-policy-payment-and-quality-provisions-medicare-physicianfee-schedule-calendar-year-2018 19. Centers for Medicare & Medicaid Services. Medicare program: changes to hospital outpatient prospective payment and ambulatory surgical center payment systems and quality reporting programs. Accessed August 11, 2020. www.federalregister.gov/documents/2018/11/21/2018-24243/ medicare-program-changes-to-hospital-outpatient-prospectivepayment-and-ambulatory-surgical-center 20. Herceptin Hylecta (trastuzumab and hyaluronidase-oysk) [package insert]. South San Francisco, CA: Genentech, Inc: 2019.

21. Phesgo (pertuzumab, trastuzumab, and hyaluronidase-zzxf) [package insert]. South San Francisco, CA: Genentech, Inc: 2020.

22. Rituxan Hycela (rituximab and hyaluronidase) [package insert].

South San Francisco, CA: Genentech, Inc: 2017.

23. Anderson KC, Landgren O, Arend RC, et al. Humanistic and economic impact of subcutaneous versus intravenous administration of oncology biologics. Future Oncol. 2019;15(28):3267-3281.

24. Chan A, Patel H, Siderov J, et al. Assessing biosimilar education needs among oncology pharmacy practitioners worldwide: an ISOPP membership survey. J Oncol Pharm Pract. 2020; 26(3 suppl):11-21.

25. Cuellar S, McBride A, Medina P. Pharmacist perspectives and considerations for implementation of therapeutic oncology biosimilars in practice. Am J Health Syst Pharm.

2019;76(21):1725-1738.

26. Foreman E, Chan A, Biosimilars Task Force. Biosimilar implementation in clinical practice: an ISOPP collection for oncology pharmacists. J Oncol Pharm Pract. 2020;26(3 suppl 2).

27. FDA. Get email updates. Accessed September 28, 2020. https://fda.gov/about-fda/contact-fda/get-email-updates 28. Hematology/Oncology Pharmacy Association. Drug updates.

Accessed September 28, 2020. https://www.hoparx.org/table/ resources/drug-updates-from-the-fda/ 29. Cook JW, McGrath MK, Dixon MD, et al. Academic oncology clinicians’ understanding of biosimilars and information needed before prescribing. Ther Adv Med Oncol. 2019; 11:1758835918818335. doi: 10.1177/1758835918818335 30. Williamson C, Berger L, Sullivan TP, et al. Addressing oncologists’ gaps in the use of biosimilar products. Am J Manag Care.

2019;25(6 Spec No.):SP188-SP191.

31. Zelenetz AD, Ahmed I, Braud EL, et al. NCCN Biosimilars White Paper: regulatory, scientific, and patient safety perspectives.

J Natl Compr Canc Netw. 2011;9(4 suppl):S1-S22.

32. Lyman GH, Balaban E, Diaz M, et al. American Society of Clinical Oncology statement: biosimilars in oncology. J Clin Oncol.

2018;36(12):1260-1265.

13. Ontruzant (trastuzumab-dttb) [package insert]. Incheon, South Korea: Samsung Bioepis Co, Ltd; 2019.

33. Hematology/Oncology Pharmacy Association. Biosimilars issue brief: an important new category of medications for cancer patients. Revised December 2015. Accessed September 28, 2020. http://www.hoparx.org/images/hopa/advocacy/Issue-Briefs/ HOPA_Biosimilars_Issue_Brief.pdf

14. Trazimera (trastuzumab-qyyp) [package insert]. New York, NY: Pfizer, Inc: 2019.

34. Vizgirda V, Jacobs I. Biosimilars: considerations for oncology nurses. Clin J Oncol Nurs. 2017;21(2):E54-E60.

15. Kanjinti (trastuzumab-anns) [package insert]. Thousand Oaks, CA: Amgen, Inc: 2019.

35. FDA. Patient materials: biosimilar basics for patients. Updated March 23, 2020. Accessed September 28, 2020. https://www.fda. gov/drugs/biosimilars/patient-materials

12. Herzuma (trastuzumab-pkrb) [package insert]. Incheon, South Korea: Celltrion, Inc; 2018.

16. FDA. Guidance document: scientific considerations in demonstrating biosimilarity to a reference product. Accessed August 11, 2020. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf

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Dr Hackenyos reported no relevant financial relationships.

PRINTER-FRIENDLY VERSION AVAILABLE AT PHARMACYPRACTICENEWS.COM

Vancomycin Dosing Guidelines: Where Do We Go From Here?

NICHOLAS REBOLD, PHARMD ID Outcomes Research Fellow Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit, Michigan

V

DANA HOLGER, PHARMD ID PK/PD Outcomes Research Fellow Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit, Michigan

MICHAEL RYBAK, PHARMD, MPH, PHD, FCCP, FIDP, FIDSA Professor of Pharmacy and Medicine Director, Anti-Infective Research Laboratory Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit, Michigan

ancomycin has been in clinical use for more than 60 years and remains one of the most widely used antimicrobials in the inpatient setting. Previously known as Mississippi

mud due to its brown color and impurities, vancomycin was developed to overcome Staphylococcus aureus resistance to penicillin. Today, it is used to treat methicillin-resistant S. aureus (MRSA), for which it has become the primary therapy worldwide.

The original dosing scheme for vancomycin in the 1960s was based on maintaining serum concentrations at least 4 to 5 times the minimum inhibitory concentration (MIC). During the 1980s and throughout the 1990s, vancomycin dosing and monitoring consisted of initial doses of 15 mg/kg based on actual body weight and target peak and trough serum concentrations of 30 to 40 and 5 to 10 mg/L, respectively.1-3 Monitoring was in place to ensure effective concentrations and prevent vancomycin toxicity. During these years, animal and in vitro experiments, and some limited human data, validated the area under the curve (AUC) over MIC (AUC/MIC) as the best predictor of vancomycin efficacy and toxicity. Despite these findings, monitoring during the 1990s up to

the publication of the 2009 vancomycin monitoring guidelines consisted primarily of trough monitoring, with dose adjustments accomplished by nomogram or dose-to-trough proportions.1 The 2009 vancomycin guidelines reinforced the AUC/MIC ratio as the pharmacokinetic/pharmacodynamic (PK/PD) predictive efficacy parameter for vancomycin. At the time, these guidelines endorsed targeting trough concentrations of 15 to 20 mg/L as a surrogate marker for an AUC/MIC value greater than 400 mg*hour/L.4 In the years following these recommendations, a number of studies described an avoidable risk for nephrotoxicity associated with maintaining trough levels greater than 15 mg/L. Maintaining troughs above this level often corresponded to doses exceeding 3 g per day, with

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Table 1. Vancomycin Guidelines Comparison by Year

a

2009 Guidelines

2020 Guidelines

Serum trough monitoring of 15-20 mg/L

AUC/MIC of 400-600 mg*h/L instead of trough monitoringa

Addresses vancomycin use for serious infections by MRSA, except SSTI and UTI

Addresses vancomycin use for serious infections caused by MRSA, except SSTIs, UTIs, and meningitis

Unclear whether elevated troughs are linked to nephrotoxicity

Clear link with increased exposureb leading to nephrotoxicity

LD: 25-30 mg/kg based on ABW

LD: 20-35 mg/kg based on ABW, with a 3 g dose cap

No specific dosing recommendations for subpopulations

Obesity—LD: 20-25 mg/kg based on ABW, with a 3 g dose cap Pediatrics—60-80 mg/kg/d in divided doses every 6 h Neonates (up to 3 mo)—10-20 mg/kg every 8-48 h depending on postmenstrual age, weight, and SCr

No continuous infusion recommendations

Continuous infusion can be used; targeting levels of 20-25 mg/L

No specific dosing recommendations for impaired renal function

Hemodialysis—target pre-dialysis concentrations of 15-20 mg/Lc Hybrid hemodialysis recommendations—LD, with maintenance dose of 15 mg/kg after dialysis CRRT dosing recommendations—LD, with empiric maintenance dose of 7.5-10 mg/kg every 12 h

Assumed MIC of 1 for staph infections. b Higher troughs, more aggressive dosing, and higher AUCs. c Limited to no data on AUC monitoring in hemodialysis.

ABW, actual body weight; AUC, area under the curve; CRRT, continuous renal replacement therapy; LD, loading dose; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; SCr, serum creatinine; SSTI, skin and soft tissue infection; UTI, urinary tract infection

elevated vancomycin AUC exposures often above 600 mg*hour/L.5,6 More recent studies have demonstrated that monitoring vancomycin by the AUC/MIC ratio reduces the likelihood of acute kidney injury (AKI) while maintaining its efficacy.7,8 Given the plethora of new data, guideline committee members were encouraged to revise the 2009 vancomycin guidelines; this brings us to another chapter in vancomycin’s story with the 2020 publication of revised vancomycin consensus guidelines that primarily focus on dosing vancomycin by the AUC/MIC ratio instead of trough monitoring.9 These updated guidelines further delineate appropriate vancomycin dosing for efficacy and safety. Thus, the eras of vancomycin can broadly be categorized as Mississippi mud, peak and trough monitoring, nomogram and trough monitoring, and now dosing and monitoring by the AUC/MIC ratio.

Revised Guidelines Address Gaps in Data The revised consensus guidelines for therapeutic monitoring of vancomycin were published online and in the March 2020 issue of the American Journal of Health-System Pharmacy,9 and they are approved by ASHP, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. Given consistent data regarding vancomycin-induced AKI, safety concerns with continued trough monitoring, and a proliferation of

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data on uses in special populations, a revised guideline update was necessary. The new guidelines address some of the gaps in data that existed in the first set of guidelines, namely the limited data for pediatric patients, vancomycin dose adjustments in morbidly obese patients, vancomycin dosing in patients undergoing renal replacement therapy, continuous infusion recommendations, large doses (>3 g/day) of vancomycin, and concerns with the safety and efficacy of targeted trough concentrations of 15 to 20 mg/L. The new guidelines outline improved efficacy and safety data supporting AUC/MIC monitoring for serious MRSA infections, and provide 2 methods of calculating the AUC/MIC ratio through 2-level calculated AUC or Bayesian methods. The primary differences between the 2009 and 2020 guidelines are summarized in Table 1.

However, these guidelines must be interpreted accurately, as they do not apply to MRSA infections with documented MICs greater than 1 mg/L. This is due to a predominance of MRSA strains (95.1%) found through large surveillance studies to have an MIC less than or equal to 1 mg/L, as well as limitations with available susceptibility testing methods in clinical practice.10,11 For example, the clinically used Etest method is likely to report higher vancomycin MIC values compared with gold standard broth microdilution (BMD) methods.12 However, if a true MIC of 2 mg/L is found by BMD, there

are limited data using AUC in this area, and alternative antibiotics (eg, daptomycin, linezolid, etc) could be considered to ensure effective treatment if the patient is not clinically improving. The guidelines also do not apply to non-MRSA pathogens such as methicillin-susceptible S. aureus, coagulase-negative Staphylococcus, and Streptococcus due to a lack of data on appropriate PD targets. These guidelines only apply to serious MRSA infections. They specifically exclude urinary tract infections and skin and soft tissue infections (SSTIs) as nonserious infections, and tacitly exclude infections with meningitis, given Streptococcus pneumoniae as the primary cause and lack of AUC data in this area (Figure 1).13 More data regarding monitoring the AUC/MIC ratio for SSTIs is emerging, with a new paper supporting dosing vancomycin with an AUC more than 435 mg*hour/L as a method to improve timely clinical success in SSTIs without any increase in AKI over the below-target group.14 However, more studies on SSTIs are needed to validate these AUC exposures.

Diving into the specific recommendations of the revised guidelines, the focus remains on the AUC/MIC ratio of greater than or equal to 400 mg*hour/L (with MIC determined by BMD). This is the current accepted critical PK/PD index for efficacy, as well as the primary method to avoid the development of resistance with S. aureus strains. More evidence suggests a link between vancomycin exposure and AKI that is highlighted in the new guidelines. Higher AUC/MIC values above 600 mg*hour/L and troughs above 15 mg/L have been shown in a meta-analysis and multiple analytical and even prospective AUC comparative studies to lead to a higher risk for AKI, with exposure showing a direct relationship.5-7,15-17 As a result, improved patient outcomes related to AKI development remain among the top reasons to switch to AUC dosing.

Loading doses have received general approval in the new guidelines, with a wider range of 20 to 35 mg/kg in the new guidelines compared with a recommendation of 25 to 30 mg/kg for a loading dose in the old guidelines.

These loading doses are recommended for any critically ill patient at rates of up to 1 g per hour using actual body weight when dosing but not exceeding a dose of 3 g.

The practice of using a wider loading dose range may be more palatable to clinicians who are concerned about administering a large dose up front to a patient with poor renal function. However, in seriously ill patients, it is vital to rapidly achieve target ranges of vancomycin in the blood to decrease the risk for slower therapeutic effect in the first few days of therapy. The guidelines recommend using actual body weight for loading doses, and this comes from research in obesity and vancomycin dosing, which has demonstrated that volume of distribution related to one’s weight (Vd) coefficient decreases with increasing weight. The average Vd coefficient ranges from 0.6 to 0.7 to 0.25 to 0.55 L/kg for obesity.18,19 Therefore, loading doses for obesity are recommended at 20 to 25 mg/kg using actual body weight, with the cap at 3 g per dose. Data in patient subpopulations like

Guideline-covered indications (AUC/MIC 400-600 mg*hour/L) • Bacteremia • Endocarditis • Bone/joint infections • Pneumonia • Necrotizing fasciitis • Febrile neutropenia • Sepsis, source unknown

Trough-based monitoring (15-20 mg/L) • Meningitis/CNS infection

Excluded indications • SSTI • UTI • Surgical prophylaxis

Figure 1. Indications for application of revised vancomycin dosing guidelines.

AUC, area under the curve; CNS, central nervous system; MIC, minimum inhibitory concentration; SSTI, skin and soft tissue infection; UTI, urinary tract infection

these are an important consideration of the new vancomycin guidelines, which extend to pediatrics, renal dysfunction, and even alternate methods of infusion.

PEDIATRIC GUIDELINES For pediatrics, data in the guidelines from a meta-analysis of 10 pediatric studies show that trough concentrations of 15 mg/L or more led to a 2.7-fold increase in AKI.20 One pediatric study with 680 patients also showed a more than 2.5-fold increase in AKI/nephrotoxicity with a vancomycin minimum blood plasma concentration of at least 15 mcg/mL and an AUC of at least 800 mg*hour/L.21 Therefore, pediatric and neonatal dosing should target a similar AUC/MIC ratio of at least 400, potentially up to 600 mg*hour/L, given retrospective data showing greater AKI from trough-based monitoring but no improved efficacy outcome from trough versus AUC monitoring.22-24 Given this AUC/MIC target, this leads to the recommendations of an empiric maintenance regimen of 60 to 80 mg/kg per day given in divided doses every 6 hours for children older than 3 months, and 60 to 70 mg/kg per day given in divided doses every 6 to 8 hours for children aged 12 years and older. This

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Table 2. Table of AUC Methods: Pros and Cons Bayesian Pros

Cons

• Can be modified to incorporate selected PK models

• High cost associated with software initially

• Ability to use pre– steady-state vancomycin concentrations

• Strong informatics component if integrating software into EHR

• Most accurate method when combined with 2 vancomycin levels and accurate Bayesian prior model.

• Lack of familiarity with Bayesian methods

• 1 level sufficient for AUC estimation

• Bayesian prior model affects predictions

• Reliance on online outside vendor system

• Incorporates real-time individual patient data and able to adapt and improve

2-Level Trapezoidal

is dosed in CRRT using dose by level. Close monitoring of renal replacement flow rates needs to be considered because it is the replacement for creatinine clearance in these patients, and regular vancomycin monitoring still should be paramount in this critically ill population.

Continuous infusion is a new area of the vancomycin guidelines, and specific ranges are given to this infrequent practice. Continuous infusion has a trend toward less frequent occurrence of nephrotoxicity. The calculation of AUC in this instance is simpler than other methods by targeting a concentration of 20 to 25 mg/L, which when multiplied by 24 hours equates to an area under the concentration–time curve from 0 to 24 hours (AUC0-24h)/MIC ratio of 480 to 600 mg*hour/L. Continuous infusion provides an option for patients who have difficulty achieving therapeutic concentrations or are receiving larger than expected vancomycin doses; however, this needs to be balanced against the need for a dedicated line specifically for vancomycin for the patient (Table 2).25

Pros

Cons

• Accurate patient-specific kinetics calculated for period of 2-level calculations

• Requires 2 levels

A Conundrum

• Only accurate for PK parameters after first dose or at steady state

One of the most important considerations in the new vancomycin guidelines is the method used to estimate a patient’s AUC0-24h/MIC ratio. There are 2 general methods: Bayesian methodology done by software, which the guidelines prefer, or 2-level AUC concentrations using analytic PK equations. Bayesian methodology has an a priori population of patients (Bayesian prior, before any drawn vancomycin level) that is used to calculate the probability of a specific patient’s Vd and clearance. These estimates are used to obtain the dose and dosing interval for the targeted AUC. When patient-specific vancomycin concentrations are drawn, the Bayesian prior probability compares the patient-specific levels drawn and calculates a revised probability distribution for the patient’s AUC, Vd, and clearance PK parameters (Bayesian conditional posterior). Although 2 levels are the most accurate in Bayesian methodology, this method is beneficial because it is possible to draw only 1 vancomycin level to determine a sufficient AUC estimation. On the other hand, the 2-level calculated trapezoidal method requires 2 levels (Table 2). However, in Bayesian methodology, the PK Bayesian prior model can distinctly affect a priori vancomycin predictions. One study comparing 32 Bayesian models found that estimates of relative bias and relative root-mean-square error could vary between a range of –122.8% to 68.0% and 44.3% to 136.8%, respectively; in addition, the 10th to 90th percentiles of median AUC0-24h were 215 to 383 mg*hour/L, respectively.26 The 2-level calculated method also uses prior PK population estimates for Vd and clearance, and applies traditional 1-compartment PK equations to get initial dosing and interval information for the targeted AUC. Both of

• Low up-front costs for pharmacy department • No software necessary • Formulas for determining the AUC are familiar to most pharmacists

• Uses trapezoidal approximations for AUC • Nonadaptive • Population PK prior estimates affects predictions

AUC, area under the curve; EHR, electronic health record; PK, pharmacokinetic

Based on reference 25.

guideline provides guidance for pharmacists and providers in pediatrics to use vancomycin dosed by the AUC, and it creates a strong impetus for many hospitals to change their pediatric dosing practices due to the harm revealed via trough-based monitoring.

RENAL REPLACEMENT THERAPY Regarding renal replacement therapy, the guidelines detail specific ways that intermittent hemodialysis, hybrid hemodialysis, and continuous renal replacement therapy (CRRT) affect dosing/monitoring. Changes include targeting pre-dialysis vancomycin concentrations of 15 to 20 mg/L, which likely would achieve the targeted AUC/ MIC ratio of 400 to 600 mg*hour/L, rather than previous higher targets such as 20 to 25 or 25 to 30 mg/L pre-dialysis. CRRT dosing recommendations now include low scheduled maintenance dosing at 7.5 to 10 mg/kg every 12 hours, which differ from how vancomycin often

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Trough monitoring

77%

Bayesian or population PK AUC

AUC monitoring

8%

23%

2-Level AUC

15%

Figure 2. Institutional survey of vancomycin dosing method.

Figure 3. Twitter poll on Bayesian vancomycin uptake. these methods underscore that the patientâ&#x20AC;&#x2122;s modeled PK parameters must be chosen accurately, whether with a representative Bayesian prior model or accurate chosen PK estimates for a specific population. Then, patient-specific Vd, elimination rate constant (Ke) and estimated AUC can be derived after levels are drawn to readjust the regimen to get the desired AUC. The 2 vancomycin levels in the trapezoidal method must either be consecutive, with at least a 4-hour gap between them, and after the first dose or at steady state. AUC levels at steady state do not need to be consecutive and in the same interval. However, levels drawn in the same interval are recommended because these would be the most accurate for determining the patient-specific PK. Table 2 compares the differences between Bayesian methodology, which is preferred by the guidelines, with 2-level calculated methods.

These 2 methods create a conundrum for pharmacists and hospitals, whether in transitioning away from troughbased monitoring for a Bayesian-based approach or a 2-level AUC-calculated approach. In a multicenter, crosssectional survey from May 2019, a total of 78 institutions completed the survey, and 18 of 78 (23.1%) of the institutions used vancomycin by any AUC method (Figure 2).

Breaking down the AUC method, 12 of 18 (66.7%) of the health care institutions performed 2-level calculated AUC, and the remainder performed either Bayesian- or population-based PK. Regarding the trough-only institutions

that only performed trough-based monitoring, 53 of 60 (88.3%) did not plan on or were unsure about transitioning to AUC-based methods within the next year. The primary reason among nonpracticing institutions (44/60; 73.3%) and the greatest barrier for AUC institutions (13/18; 72.2%) was pharmacist and/or provider unfamiliarity.25 In an updated informal poll, almost 20% of respondents were using Bayesian methods, which is somewhat consistent with previous literature but shows that AUC implementation across hospitals still is limited (Figure 3).

Analyzing different aspects of a health care institution, its electronic health records, budget, patients, and workflow can help the institution choose the best AUC calculation method and how to best apply these guidelines to their population. For instance, a hospital that has more difficulty with phlebotomy and lab drawing times or special patient populations (ie, pediatric patients) may not want to use the 2-level calculated AUC method. A hospital that has a tight pharmacy informatics budget may not be as amenable to Bayesian dosing software methods, even if Bayesian dosing calculations carry lower costs. Whichever method is used, the data are clear. We are in the era of dosing vancomycin by AUC. There likely is going to be further integration with informatics to dose patients more accurately, and hospitals will need to consider which option is best for them to care for their patients and improve patient outcomes.

References 1.

Levine DP. Vancomycin: a history. Clin Infect Dis. 2006; 42(suppl 1):S5-S12.

2.

Matzke GR, McGory RW, Halstenson CE, et al. Pharmacokinetics of vancomycin in patients with various degrees of renal function.

Antimicrob Agents Chemother. 1984;25(4):433-437.

3. Moellering RC, Krogstad DJ, Greeblatt DJ. Vancomycin therapy in patients with impaired renal function: a nomogram for dosage.

Ann Intern Med. 1981;94(3):343-346.

4. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009;66(1):82-98.

5.

Lodise TP, Patel N, Lomaestro BM, et al. Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients. Clin Infect Dis. 2009;49(4):507-514.

6. van Hal SJ, Paterson DL, Lodise TP. Systematic review and metaanalysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother. 2013;57(2):734-744.

7.

Finch NA, Zasowski EJ, Murray KP, et al. A quasi-experiment to study the impact of vancomycin area under the concentration-time curve-guided dosing on vancomycinassociated nephrotoxicity. Antimicrob Agents Chemother.

2017;61(12):e01293-17.

8. Aljefri DM, Avedissian SN, Rhodes NJ, et al. Vancomycin area under the curve and acute kidney injury: a meta-analysis.

Clin Infect Dis. 2019;69(11):1881-1887.

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