Pharmacy Guided Procalcitonin Ordering

Pharmacy Guided Procalcitonin Ordering in Adult Inpatients with Lower Respiratory Tract Infections

By: Dr. Katie Dircksen, Dr. Riley Bowers, Dr. Dustin Bryan, Ms. Emily Woodfield, and Dr. Serina Tart

Introduction

Lower respiratory tract infections are among the most common diagnoses for antibiotic prescriptions; however, a study by the Center for Disease Control (CDC) found that 86% of patients presenting with pneumonia had either a viral infection or lacked an identifiable pathogen. 1,2 Lower respiratory tract infections (LRTI) can be diagnosed via microbiologic testing, but culture results can take days and often do not identify the causative organism(s). Consequently, the diagnosis of LRTI in the emergency department (ED) is based on symptoms and clinical history. Symptoms of LRTI include cough, sputum production, dyspnea, tachypnea, pleuritic pain, rales, crepitation, and signs of infection (core body temperature >38.0°C, leukocyte count >10,000/µL or <4000/µL). 3 With these symptoms being of low specificity, it is easy to misdiagnose a patient with LRTI when they truly have another diagnosis, such as an exacerbation of chronic obstructive lung disease (COPD), heart failure (HF), or asthma. 4

Procalcitonin (PCT) is an inflammatory marker that can indicate the presence of a bacterial infection. 5 In patients without an acute bacterial infection, this lab value is typically undetectable (<0.07 mcg/L). Triggers that cause inflammation specific to bacterial infections include microbial toxins (i.e., endotoxins) and cytokines (tumor necrosis factor (TFN)-alpha, interleukin-1 beta, and interleukin-6). In contrast, viral infections lack PCT synthesis due to cytokines released by the virus that inhibit TNF-alpha production and thus prevent inflammation. 5 PCT concentration elevations secondary to bacterial infections typically rise within 2-4 hours of an inflammatory trigger and reach their peak at approximately 24- 48 hours. Peak concentrations may be higher depending on the severity of the infection and decline quickly at a predictable rate with the resolution of inflammation. 1

Due to the specificity for bacterial infection, a high PCT level has a positive predictive value indicating that antibiotics are necessary. If the PCT level is low, a non-bacterial cause for the patient’s symptoms should be considered. 6 In 2012 a Cochrane review showed that an initial assessment of PCT levels resulted in the reduction in antibiotic use by 60-70% in patients with low-severity respiratory tract infections. 7 The same Cochrane

review found that trending PCT values in patients with community-acquired pneumonia resulted in a 40% reduction in the duration of the antibiotic treatment without increasing morbidity or mortality. 7 In the ProREAL study, the authors showed that the duration of antibiotic therapy was significantly shorter if a PCT algorithm was followed compared with when it was overruled (5.9 days vs 7.4 days; 95% CI -2.04 to -0.98; p<0.001). 8

When patients present with LRTI at our institution, PCT levels are currently obtained at the discretion of the provider and there is no established protocol for PCT monitoring or follow-up. The purpose of this quality-initiative pilot sought to determine if a pharmacist-guided PCT ordering protocol and algorithm for patients presenting with a primary diagnosis of LRTI reduced the duration of antibiotic therapy.

Methods

This study was a single-center, quasi-experimental, quality-improvement initiative conducted from November 1, 2019, to January 31, 2020, in compliance with the pharmacist guided PCT pilot protocol (Appendix I), which was approved by the institution’s Pharmacy and Therapeutics Committee. The retrospective control group consisted of patients admitted with LRTI from November 1, 2018, to January 31, 2019. The study protocol was granted exempt status by the Institutional Review Board of the study site.

The primary objective of this study was to compare the total duration of all antibiotic therapy (DOT) prescribed during the inpatient stay and at discharge for adult inpatients with LRTI before and after the intervention of pharmacy guided PCT ordering. The secondary objectives were to compare time, in days, to antibiotic de-escalation from IV to PO antibiotics in adult inpatients with LRTI who did and did not have pharmacist ordered PCT levels to guide therapy, to assess prescriber acceptance of pharmacist recommendations after protocol introduction, and to compare the number of PCT levels ordered before and after protocol introduction.

Patients were included if they were ³ 18 years old and admitted to the institution between November 1, 2018, to January 31, 2019 (control group) or November 1, 2019, to January 31, 2020 (intervention group). Patients were required to have a suspected or diagnosed bacterial LRTI defined as a principal diagnosis upon admission, which was identified from a generated list of diagnosis codes. Diagnosis codes were generated through Midas, which is an integrated, care management, data, workflow, and reporting tool. Patients had to be reviewed by either the antimicrobial stewardship (AMS) pharmacist, internal medicine (IM) pharmacist, or a pharmacy resident to be included in the study.

Patients were excluded if they had CKD stage 4 or 5 (eGFR <30 mL/min) on hemodialysis (HD) or were susceptible to increased inflammation (Table 1). Patients were also excluded if they had chronic infection or concurrent infection necessitating antibiotic treatment. Pregnant patients were excluded, as well as patients who were directly admitted (transfers) from other facilities, had antibiotics present at the admission medication reconciliation, or had been admitted for >24 hours without an initial PCT level drawn.

An AMS or IM pharmacist reviewed each patient admitted with LRTI and determined if the patient met inclusion criteria. If the patient was included in the study, the pharmacist would follow the pilot protocol for ordering and monitoring PCT levels (Appendix I). Documentation of the pharmacist’s recommendations after protocol introduction was completed in Epic via iVents by the reviewing pharmacist.

Using a preset alpha of 0.05 and two-sided 95% confidence interval with an anticipated decrease of 20% in total antibiotic duration, we estimated a required sample size of 129 patients per group to reach 80% power; therefore, we targeted approximately 160 patients per group for inclusion in the study. For the primary objective, we conducted an unpaired student t-test with 95% confidence intervals to compare means of antibiotic duration in DOT. The secondary analysis of time to antibiotic de-escalation in DOT was also compared using an unpaired student t-test with 95% confidence intervals. The remaining secondary objectives were analyzed using descriptive statistics.

Results

tified for the control group, and 319 patients identified for the intervention group using LRTI diagnosis codes. Of the 208 patients in the control group, 75 patients met inclusion criteria (36.1%) compared to only 41 patients meeting inclusion criteria in the intervention group (12.9%) (Figure 1). The baseline characteristics of the two groups also varied (Table 2). The average age for patients in the control group was 66.6 years old, compared to 58.1 years in the intervention group. Most patients in the control group were women (57%), whereas men were the majority of patients in the intervention group (54%). There were 45 patients in the control group (60%) that had at least one or more co-existing illnesses, compared to 19 patients in the intervention group (46.3%). Lastly, the intervention group had more signs of infection at presentation, with a higher mean temperature (37.3°C vs 36.8°C) and a higher WBC count (12.4 vs 11.8). Both groups had relatively low numbers of positive sputum cultures.

The primary objective of total antibiotic duration in DOT was not found to be statistically significant when comparing the control group to the intervention group, 10.8 days vs 10.0 days, respectively (95% CI -2.49-0.86; p=0.34). Our secondary objective of time to antibiotic de-escalation in DOT was also not statistically significant when comparing the control group to the intervention group, 4.8 vs 4.8 days, respectively (95% CI -1.09-1.26; p=0.89).

When assessing prescriber acceptance to pharmacist-guided PCT monitoring, prescribers were more likely to accept recommendations to de-escalate antibiotics than they were to accept recommendations to discontinue antibiotics (Table 3). The number of PCTs ordered during the intervention group time frame (88) was more than the number of those ordered during the control group time frame (29).

Discussion

Implementing a pharmacist guided PCT algorithm failed to produce a statistically significant reduction in total antibiotic duration. Even though there was no statistical difference seen in DOT, there was a trend towards decreased DOT in the intervention group; however, the study did not meet the calculated power needed to show significance.

The difference in time to antibiotic de-escalation in DOT was not statistically significant between the control group and the intervention group. It is also important to note that patient length of stay (LOS) in the institution was approximately five days in both groups. The lack of statistical significance for time to antibiotic de-escalation could be due to de-escalating antibiotics at discharge.

Prescriber acceptance of recommendations was low when pharmacists recommended discontinuing antibiotics, with only 33% accepted. This could be due to the lack of prescriber understanding of PCT values, the patient’s infection worsening, or the prescriber’s reluctance to discontinue antibiotics. Prescriber acceptance of antibiotic de-escalation recommendations was higher at 86%. The willingness to accept de-escalation recommendations compared to discontinuation recommendations supports the idea of prescriber reluctance to discontinue antibiotics despite guideline recommendations. While our time to antibiotic de-escalation in the control group compared to the intervention group was not statistically significant, the prescriber acceptance rate of recommendations points to a potential place in practice where pharmacy could have an impact.

Under the pilot PCT protocol, 88 PCT levels were ordered. Each test is $25, totaling $2,200. Comparatively, 29 PCT levels were ordered during the control group time period, which totaled $725. Our pharmacists found that unnecessary PCT levels had to be ordered per our protocol. Considering the lack of statistical significance for our objectives and the difference in costs, future protocols should include pharmacist’s clinical decision whether or not additional PCT levels are justified.

The major strength of our study was that we decreased confounding variables as much as possible by having an extensive set of exclusion criteria. While this limits our patient population size, it allows us to confidently assess that the study was not influenced by confounding variables.

There were limitations to the pilot protocol. The first one identified was the heavy workload that the protocol placed on select pharmacists. The AMS and IM pharmacists only reviewed patients during the first shift hours

Monday through Friday. This hindered our ability to include all patients with LRTI in the intervention group due to some meeting exclusion criteria by being admitted on the weekend. Another limitation would be the short LOS that we noticed retrospectively. While decreasing hospitalization for these patients is ideal, it impeded our ability to collect follow up PCT levels, and thus decreased our chances to make recommendations. The baseline characteristics varied between the control group and the intervention group. We hypothesize that this is due to changing electronic health record (EHR) systems between the control group time frame and the intervention group time frame. The control group EHR was more difficult to navigate and find pertinent patient information, while the intervention group EHR was more user friendly and easily accessible. Lastly, our patient population was small, and the study did not meet the calculated power needed to show significance.

Conclusion

Pharmacist guided PCT ordering and monitoring did not result in a decrease in total days of antibiotic therapy at our institution. Due to this and the increased workload it placed on our pharmacists, we determined this protocol could not be implemented to the entire department in its current state. Nevertheless, with the trend towards shorter antibiotic duration and high acceptance rates of pharmacist’s recommendations for antibiotic de-escalation, there may be a place in practice for pharmacist guided PCT ordering and monitoring in the future. An increase in prescriber awareness and additional pharmacist involvement will aid in making a standing protocol successful.

References

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7. Rhee C, Mansour M. (2019). Procalcitonin use in lower respiratory tract infections. Bond S (Ed), UpToDate. Retrieved August 20, 2019, from https://www. uptodate.com/contents/procalcitonin-use-in-lower-respiratory-tract-infections. Jain S, Self WH, Wunderink RG, Fakhran S, Balk R, Bramley AM, et al. Community acquired pneumonia requiring hospitalization among U.S. adults. N Engl J Med 2015; 373:415–27. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009;302(10):1059–66. Schuetz P, Briel M, Christ-Crain M, Stolz D, Bouadma L, Wolff M, Luyt CE, Chastre J, Tubach F, Kristoffersen KB, et al. Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis. Clin Infect Dis 2012;55(5):651–662. doi: 10.1093/cid/cis464. Lee H. Procalcitonin as a biomarker of infectious diseases. Korean J Intern Med 2013; 28(3):285-291. Sagar R, Kutz A, Mueller B, Scheutz P. Procalcitonin-guided diagnosis and antibiotic stewardship revisited. BMC Med 2017;15:15 Schuetz P, Muller B, Christ-Crain M, Stolz D, Tamm M, Bouadma L, Luyt CE, Wolff M, Chastre J, Tubach F, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract in8.

9. fections. Cochrane Database Syst Rev 2012; 9(9). Dusemund F, Bucher B, Meyer S, et al. Influence of procalcitonin on decision to start antibiotic treatment in patients with lower respiratory tract infection: insight from the observational multicentric ProREAL surveillance. Eur J Clin Microbiol Infect Dis 2013; 32(1):51-60. Schuetz P, Beishuizen A, Broyles M, et al. Procalcitonin-guided antibiotic stewardship: an international experts consensus on optimized clinical use. Clin Chem Lab Med 2019; 57(9): 1308-1318.

The authors have no disclosures to report.

Authors: Katie Dircksen, PharmD (Corresponding Author) is a PGY1 Pharmacy Resident, Acute Care Track at Cape Fear Valley Medical Center (CFVMC), kdirckse@gmail. com; Riley Bowers, PharmD, BCCP, BCPS, is the Associate Director of Graduate Pharmacy Education at CFVMC and Clinical Assistant Professor at Campbell University College of Pharmacy & Health Sciences (CPHS); Dustin Bryan, PharmD, BCPS is the PGY1 Pharmacy Residency Director at CFVMC; Ms. Emily Woodfield is a 2021 PharmD Candidate at CPHS; Serina Tart, PharmD is an Antimicrobial Stewardship Clinical Pharmacist at CFVMC.

Patients Susceptible to Increased Inflammation

Admitted to intensive care unit Immediate postnatal period Receiving immunomodulatory agents (e.g., T-cell antibodies, alemtuzumab, interleukin-2, and granulocyte transfusions) Neuroendocrine tumors (medullary thyroid cancer) Pre-existing lung disease/lung cancer Severe immunosuppression Cystic fibrosis Active tuberculosis Severe physical trauma Recent surgery during current admission Cardiac arrest or circulatory shock during current admission Pancreatitis during current admission Intracranial hemorrhage during current admission Severe burns being treated during current admission

Table 2: Baseline Characteristics

Age (yrs) ± SD Male – n (%) Co-existing illness – n (%) COPD HF Asthma Infectious Signs on Admission Temperature (°C) ± SD WBC Count ± SD Positive Sputum Culture – n (%)

Control Group (n=75)

66.6 ± 16.8 32 (43)

29 (39) 21 (28) 8 (11)

36.8 ± 0.8 11.8 ± 5.2 5 (6.7)

Intervention Group (n=41)

58.1 ± 16.6 22 (54)

9 (22) 10 (24) 6 (15)

37.3 ± 0.9 12.4 ± 5.9 1 (2.4)

Table 3: Prescriber Acceptance of Recommendations

Prescriber acceptance of antibiotic discontinuation Prescriber acceptance of antibiotic de-escalation

Intervention Group (n=41)

5/15 (33%) 12/14 (86%)

Figure 1: Patient Population

Control Group

208 patients reviewed

133 (64%) patients were excluded from final analysis 55 (41%) had CKD III/IV or ESRD 34 (25%) susceptible to increased inflammation 22 (17%) required antibiotics for concurrent infection 14 (11%) were transfers 8 (6%) did not have LRTI as primary diagnosis

75 patients met inclusion criteria during November 1, 2018-January 31,2019 Intervention Group

319 patients reviewed

278 (87%) patients were excluded from final analysis 59 (21%) susceptible to increased inflammation 58 (21%) required antibiotics for concurrent infection 54 (20%) had CKD III/IV or ESRD 34 (12%) >24 hr admit w/o PCT 31 (11%) not followed 26 (9%) were transfers 16 (6%) discharged before any PCT levels returned

41 patients met inclusion criteria during November 1, 2019-January 31,2020

Appendix I:

PROCALCITONIN ALGORITHM

Immunocompetent patients only Patient with admission diagnosis of LRTI, pharmacist will: Order PCT level within 24 hours of admission, if not already completed, and per algorithm below

INITIAL PROCALCITONIN LEVEL

BACTERIAL INFECTION UNLIKELY BACTERIAL INFECTION LIKELY Appendix I:

< 0.1 mcg/L 0.1-0.25 mcg/L 0.26-0.5 mcg/L PROCALCITONIN ALGORITHM Immunocompetent patients only > 0.5 mcg/L Patient with admission diagnosis of LRTI, pharmacist will: Order PCT level within 24 hours of admission, if not already completed, and per algorithm below

ANTIBIOTIC USE

Strongly Discouraged Discouraged BACTERIAL INFECTION UNLIKELY INITIAL Encouraged PROCALCITONIN LEVEL Strongly Encouraged BACTERIAL INFECTION LIKELY

< 0.1 mcg/L 0.1-0.25 mcg/L 0.26-0.5 RECOMMENDATION mcg/L > 0.5 mcg/L

Repeat measurement within 24 hours if antibiotic ANTIBIOTIC USE started Consider alternative diagnosis if PCT remains low Pharmacist documents recommendation in progress note from iVent Discouraged Strongly Discouraged

- Continue empiric antibiotics - De-escalate as cultures indicate - Draw PCT levels every 48 hrs(72 hours if weekend overlaps) to assess duration of antibiotic Encouraged Strongly therapy Encouraged

FOLLOW UP PROCALCITONIN LEVEL RECOMMENDATION

Clinical judgment should supersede lab values Repeat measurement within 24 hours if antibiotic - Continue empiric antibiotics < 0.25 mcg/L OR80% decreasefrom initial started Consider alternative diagnosis if PCT remains low ≥0.5 mcg/LAND decreased by less than 80% - De-escalate as cultures indicate - Draw PCT levels every 48 hrs(72 hours if Recommend to Stop Antibiotics Document recommendation as progress note Pharmacist documents recommendation in progress note from iVent Continue Antibiotics and follow PCT for max of 4 levels total weekend overlaps) to assess duration of antibiotic therapy

RECOMMENDATION FOLLOW UP PROCALCITONIN LEVEL Clinical judgment should supersede lab values

Cessations of antibiotics encouraged if signs/symptoms have resolved. < 0.25 mcg/L OR80% decreasefrom initial

Consider continuation if clinically unstable or disease progress present Recommend to Stop Antibiotics Document recommendation as progress note

If PCT is increasing or not adequately ≥ decreasing, consider treatment failure. 0.5 mcg/LAND decreased by less than 80% Evaluate for expanding coverage or further diagnostic evaluation. Continue Antibiotics and follow PCT for max of 4 levels total

Cessations of antibiotics encouraged if signs/symptoms have resolved. Consider continuation if clinically unstable or disease progress present

RECOMMENDATION

If PCT is increasing or not adequately decreasing, consider treatment failure. Evaluate for expanding coverage or further diagnostic evaluation.