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Is de-escalation an effective ABx stewardship strategy?
Is De-Escalation an Effective Stewardship Strategy?
By David Wild
While a number of organizations recommend narrowing the spectrum of antibiotic therapy in hospitalized patients in light of laboratory findings, some are questioning the primacy of the practice, including one expert who said there are no convincing data concerning spectrum de-escalation to judge whether it improves outcomes.
“I would question whether it really should be the standard of practice based on the available data,” said Meghan Jeffres, PharmD, an associate professor in the Department of Clinical Pharmacy at Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, in Aurora.
Transitioning from a broad-spectrum antibiotic to that of a narrower spectrum based on culture results is one form of antibiotic de-escalation, a broader term encompassing, for example, discontinuing redundant or unnecessary antibiotics or switching from IV to oral antibiotics.
While Dr. Jeffres said she does not dispute that use drives antibiotic resistance, she said the data behind “spectrum de-escalation” have not convinced her that it is necessary to pursue this measure to prevent resistance. For example, a single-center retrospective study of 7,118 patients with severe sepsis or septic shock showed that each additional day of treatment with anti-pseudomonal betalactams increased the chances of developing new resistance by 4% (Pharmacotherapy 2019;39[3]:261-270), and a follow-up analysis of those data found resistance to these broad-spectrum agents increased from around 2% during the first three days to roughly 10% between 10 and 18 days, rising slightly more between 19 and 21 days (Infect Control Hosp Epidemiol 2020;41[4]:484-485).
“While the authors’ theory is that resistance continues to increase with prolonged duration of these broad-spectrum agents, I would suggest the same phenomenon would be present if they looked at a different narrower spectrum antibiotic,” Dr. Jeffres asserted. “Why would we assume this relationship to be unique to the antipseudomonal beta-lactams?”
Other studies supporting the practice of spectrum de-escalation may not have adequately accounted for possible confounding variables, she said, pointing to findings that show administering antipseudomonal beta-lactams for longer than 48 hours in patients with Enterobacteriaceaebloodstream infections leads to a higher risk for Clostridioides difficile infection (CDI) within 90 days (7% for >48 hours vs. 1.8% for ≤48 hours) (Clin Infect Dis 2019;69[3]:414-420).
In this case, Dr. Jeffres said, the risk factors for longer treatment—such as older age, female sex, more comorbidities and bacteremia, and longer lengths of hospital stays prior to bloodstream infections—are some of the same established risk variables for CDI.
“Arguably, this study does not support the early discontinuation of antipseudomonal beta-lactams in decreasing CDI risk,” Dr. Jeffres said.
Other data are “at best, indifferent to the idea that spectrum de-escalation is important,” she said.
For example, a trial of 116 patients with severe sepsis who received empiric treatment and were then randomly assigned to undergo spectrum deescalation or continue with this treatment found that ICU stays were longer among the de-escalation group (median 3.4 days longer), that de-escalation was associated with more days of antibiotic use (14 vs. 10 days) and that the practice was linked with higher rates of superinfections (27% vs. 11%; P=0.03) (Intensive Care Med 2014;40[10]:1399-1408). The authors’ finding that 44% of those who underwent de-escalation and had a superinfection developed resistance to the index pathogen, compared with 67% of those who continued empiric treatment, provides insight into the mechanism behind these results, she said.
“It looks like when you de-escalate and expose patients to a second antibiotic, you may raise the risk of developing resistance to additional pathogens,” said Dr. Jeffres, noting the study’s small size and that results need to be validated in larger trials.
Shorten Duration
Rather than focusing on spectrum de-escalation efforts, Dr. Jeffres suggested implementing other stewardship interventions, such as shortening the duration of antibiotic exposure.
“We know that shortening the length of antibiotic administration is arguably the highest-impact measure we can take to prevent antibiotic resistance and improve patient outcomes,” she said.
—Meghan Jeffres, PharmD
By Milena Murray, PharmD, MSc, BCIDP, AAHIVP, FCCP
The treatment of HIV has dramatically advanced over the past 40 years. Clear data show a decreased occurrence of AIDS and an increased life expectancy.1,2 However, a small percentage of the overall population with HIV cannot achieve treatment goals. People with HIV who are highly treatment-experienced (HTE) may have limited antiretroviral therapy (ART) options due to resistance or tolerability issues. This population may have problems with virologic suppression, immune function, toxicities, and drug–drug interactions. These challenges may lead to an overall decrease in health-related quality of life (HRQOL).3 HTE people with HIV need novel ART options and classes with improved tolerability and no cross-resistance to current ART classes. Both transmitted and acquired resistance must be considered in the HIV treatment discussion. In a World Health Organization survey report, there was more than 10% resistance to nevirapine or efavirenz in people with HIV initiating therapy.4 This global prevalence of resistance to the nonnucleoside reverse transcriptase inhibitors emphasizes the need to use ART with long-term efficacy and durability.4 There is also a need to retain these patients in care and encourage adherence. Global access to HIV RNA testing is needed to ensure that ART is effective and to rapidly identify cases of virologic failure.4
Overall resistance rates to 4 ART classes are thought to be low; however, reported prevalence rates to 3 and 4 ART classes are estimated to be 5% to 10% in Europe and less than 3% in North America.1,5 In the United States, approximately 12,000 people with multidrug-resistant HIV need novel agents.2,6 When HIV RNA undetectability cannot be achieved, a secondary goal is to reduce the HIV RNA levels as much as possible and maintain immunologic function.7 Entry inhibitors are second-line agents that prevent HIV-1 cellular entry by binding a cellular target.1 Enfuvirtide (Fuzeon, Genentech) and maraviroc were the first agents in this class; however, there are several disadvantages to these agents, including the route of administration, pill burden, and lower virologic efficacy compared with other ART options.1 The newest agents in the entry inhibitor class are fostemsavir (Rukobia, ViiV) and ibalizumab-uiyk (Trogarzo, Theratechnologies).
Fostemsavir is an HIV-1 attachment inhibitor that binds the gp120 envelope glycoprotein and prevents viral connection to CD4 T cells. The drug was approved in July 2020 and has no apparent cross-resistance to other ART classes.3 Within the same drug class, there is no cross-resistance with ibalizumab-uiyk or maraviroc.8,9 Fostemsavir is dosed as 600-mg tablets orally twice daily without regard to food.1 One concern with twice-daily administration is that nonadherence may have led to virologic failure, and adhering to a twice-daily regimen may
see HIV OPTIONS, page 14
STEWARDSHIP
continued from page 10
Jonathan Ryder, MD, a fellow in the Division of Infectious Diseases at the University of Nebraska Medical Center, in Omaha, said the evidence supporting use of spectrum de-escalation is hampered by design limitations, such as small sample sizes and observational research that has yielded conflicting results, but well-designed randomized controlled trials are underway. “For now, physicians should know that antibiotic spectrum de-escalation has an important role in clinical practice and antimicrobial stewardship programs, although many questions persist in how best to incorporate this efficiently in antimicrobial stewardship programs and what the broader ecologic consequences are,” Dr. Ryder said.
Dominic Chan, PharmD, an infectious diseases specialist and the director of pharmacy at Legacy Emanuel Medical Center, in Portland, Ore., said evidence on the practice of spectrum de-escalation is lacking, specifically on “the outcomes we care about: mortality, notable resistance rates and long-term consequences of microbiota disruption.”
Additionally, he said, there are cases where spectrum de-escalation following use of a broad-spectrum antibiotic does not significantly alleviate the antibiotic pressure on the microbiota.
“For example, the difference in bacterial spectrum of activity between meropenem and ceftriaxonemetronidazole may be large, but the collateral damage that ceftriaxone-metronidazole has on commensal bacteria is still tremendous,” Dr. Chan said.
“The questions we likely should be asking are, ‘Does this patient need any antibiotics, or are they on the correct, most valuable, antibiotic,’ rather than ‘Should we decrease the spectrum of the antibiotics?’” he said.
Vancomycin Diagnostic Stewardship Initiative Is a Winner
By David Wild
Asuccessful stewardship initiative requires robust planning, needs buy-in from stakeholders and should demonstrate its impact after implementation. According to one stewardship expert, data should be at the center of every stewardship project.
“There are a million ways to improve patient care and only so much time during the day, and I’m a firm believer in letting the data drive what you do,” said Erin McCreary, PharmD, an infectious diseases pharmacist at UPMC, a clinical assistant professor of medicine at the University of Pittsburgh School of Medicine and the director of director of Stewardship Innovation for Infectious nfectious Disease Connect, in Pittsburgh. gh.
In the midst of the COVID-19 pan-19 pandemic in June 2020, Dr. McCreary and Creary and her colleagues still managed to impled to implement several diagnostic stewardship iniwardship initiatives. These were targeted toward d toward decreasing vancomycin usage ge in light of data gathered over a er a 16-month pre-pandemic period iod showing the duration of vancomycomycin treatment was “through the the roof” and that 31% of vancomycin mycin recipients experienced acute kide kidney injury because they received eived a high dose or underwent treateatment for too long, for example. ple.
To shorten duration of therapy rapy in patients receiving vancomymycin for pneumonia, Dr. McCreary’s eary’s team proposed moving from m chromogenic agar–based methethicillin-resistant Staphylococcus cus aureus nares testing to polymerase chain reaction (PCR) test) testing, which would reduce the turnaround time from 48 hours urs to one hour and increase testing sting sensitivity from 65.7% to 91.8%. 8%. However, it would also raise the cost per test from $5/$6 to $25/$35.
“We launched the project as a small-scale pilot to see if outcomes would justify the increase in testing expenditures,” she said. They collaborated with infection prevention staff to create a unique pharmacy-placed order for the rapid diagnostic test, and provided education and tracked outcomes.
The initiative proved successful, as data gathered over a six-month period after implementation in June 2020 showed. Vancomycin was discontinued for nearly all patients with a negative test, and 15% were able to avoid vancomycin altogether because able to avoid va of the fast turnaround of PCR testing. Of of the fast turn note, the median number of days on vanconote, the med mycin fell from three to one, Dr. McCreary mycin fell from said. said. “This led to a drop in demand for vanco“This led to a mycin monitoring, less lab time due to less mycin monitorin vancomycin levels being sent, less pharmacy vancomycin leve time spent on pharmacokinetics consults, time spent o fewer instances of acute kidney injury, fewer inst and it decreased the overall cost of and it de patient care,” Dr. McCreary said. She patient did not share cost data but said the did not program’s success has led to the program intervention being implemented at interve other sites across UPMC. other s Dr. McCreary noted that educatDr. M ing stakeholders about the stewarding stak ship initiative was “really challenging, ship ini especially at a larger center like ours especia where you have to keep making where y adjustments to your protocol. adjustm “But over time, all providers have “But embraced the policy of PCR testembrac ing when initiating vancomycin in ing wh patients with pneumonia,” she said. patient Dr. McCreary reported serving on the Dr. M advisory boards for AbbVie, Cidara, ad Entasis, Ferring, MeMed, Merck, Shionogi and Summit.
HIV OPTIONS
continued from page 12
be an issue for some people with HIV.6 Common adverse reactions with fostemsavir include nausea, diarrhea, headache, abdominal pain, dyspepsia, fatigue, rash, and sleep disturbances.6 Fostemsavir was studied in people with HIV who failed to respond to their current ART, and this agent also may be used for tolerability issues.10 This drug, combined with optimized background therapy, showed robust and sustained virologic and immunologic responses.11 Patient-reported outcomes from the BRIGHTE trial showed improved HRQOL outcomes.3 These improved outcomes are thought to increase overall adherence to ART, leading to better health outcomes. A case report of the use of fostemsavir to overcome a drug–drug interaction issue also has been published.12
Ibalizumab-uiyk is a long-acting post-attachment inhibitor.13 It is a humanized immunoglobulin G4 (IgG4) monoclonal antibody targeting CD4 receptors of T cells to interfere with the binding of HIV-1 gp120.1 The medication was approved in March 2018 and is given as a twice-monthly parenteral infusion (2,000-mg loading dose, followed by subsequent doses of 800 mg every 2 weeks).2 The most common adverse reactions reported in trials were diarrhea, dizziness, nausea, and rash. Monotherapy with ibalizumabuiyk is not recommended due to the development of resistance in 1 to 2 weeks.2 The parenteral administration of ibalizumab-uiyk presents logistical barriers to patient care implementation. Adherence may be an issue when clinic visits or home infusions are needed every 2 weeks.2 Missed infusions may lead to resistance.
Several clinical trials reported a decrease in HIV RNA and virologic suppression after therapy with ibalizumabuiyk.2,14 Pharmacoeconomic studies have reported that ibalizumab-uiyk represents a cost-effective and affordable option for HTE people due to an increase in quality-adjusted lifeyears.13,15 Successful treatment of panresistant HIV has been described with ibalizumab-uiyk used as an “induction treatment” followed by an optimized “maintenance treatment.”5 A case report of a switch to ibalizumab as a “bridge therapy” due to a drug–drug interaction with chemotherapy showed an alternative use when other ART options are not available.16
Another novel therapy is lenacapavir (Gilead) in the newest ART class of capsid inhibitors, which works by disrupting the functioning of the HIV capsid across multiple steps in the viral life cycle.17 Lenacapavir is an investigational agent and can be administered orally, either daily or weekly, and subcutaneously up to every 6 months.17 It is being investigated in both HTE and treatment-naive people with HIV. No overlapping resistance with other classes or preexisting resistance mechanisms is known; however, emergent resistance during treatment has been reported.17,18 Results from the CAPELLA and CALIBRATE studies reported a rapid reduction in HIV RNA and no serious adverse events.17 After submission to the FDA, the manufacturer received a complete response letter in March 2022 detailing chemistry, manufacturing, and controls concerns relating to the compatibility of lenacapavir with the proposed borosilicate glass vial.19 Gilead is working with the FDA to resolve the issues.19
Transmitted and acquired resistance leading to virologic failure remain a global issue in the treatment of HIV. Recently approved agents represent a step forward toward virologic control for all people with HIV, including those who are HTE. However, there is still a need for more options in novel classes to overcome resistance, tolerability, and drug–drug interaction issues.
Adhering to a twice-daily regimen may be an issue for some people with HIV.
References
1. Berruti M, Pincino R, Taramasso L, et al.
Evaluating fostemsavir as a therapeutic option for patients with HIV. Expert Opin
Pharmacother. 2021;22(12):1539-1545. 2. Chahine EB, Durham SH. Ibalizumab: the first monoclonal antibody for the treatment of HIV-1 infection. Ann Pharmacother. 2021;55(2):230-239. 3. Anderson SJ, Murray M, Cella D, et al.
Patient-reported outcomes in the phase III
BRIGHTE trial of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals. Patient. 2022;15(1):131-143. 4. World Health Organization. HIV drug resistance. November 22, 2021. Accessed April 26, 2022. https://www.who.int/news-room/ fact-sheets/detail/hiv-drug-resistance 5. Canetti D, Muccini C, Spagnuolo V, et al.
Achieving virological control in panresistant HIV-1 infection: a case series.
EBioMedicine. 2022;77:103906. doi:10.1016/j. ebiom.2022.103906 6. Chahine EB. Fostemsavir: the first oral attachment inhibitor for treatment of
HIV-1 infection. Am J Health Syst Pharm. 2021;78(5):376-388. 7. Department of Health and Human Services.
Panel on Antiretroviral Guidelines for
Adults and Adolescents. Guidelines for the
Use of Antiretroviral Agents in Adults and
Adolescents With HIV. Updated January 20, 2022. Accessed April 26, 2022. https://bit.ly/38ybb0p-IDSE 8. Muccini C, Canetti D, Castagna A, et al.
Efficacy and safety profile of fostemsavir for the treatment of people with human immunodeficiency virus-1 (HIV-1): current evidence and place in therapy. Drug Des Devel
Ther. 2022;16:297-304. 9. Rose R, Gartland M, Li Z, et al. Clinical evidence for a lack of cross-resistance between temsavir and ibalizumab or maraviroc. AIDS. 2022;36(1):11-18. 10. Hiryak K, Koren DE. Fostemsavir: a novel attachment inhibitor for patients with multidrug-resistant HIV-1 infection.
Ann Pharmacother. 2021;55(6):792-797. 11. Ackerman P, Thompson M, Molina JM, et al.
Long-term efficacy and safety of fostemsavir among subgroups of heavily treatmentexperienced adults with HIV-1. AIDS. 2021;35(7):1061-1072. 12. Pecora Fulco P, Nixon D, Gomes DC. Novel use of fostemsavir for 2 multidrug-resistant persons with human immunodeficiency virus.
Ann Pharmacother. 2022;56(4):501-502. 13. Brogan AJ, Talbird SE, Davis AE, et al. The cost-effectiveness and budget impact of ibalizumab-uiyk for adults with multidrugresistant HIV-1 infection in the United States.
Pharmacoeconomics. 2021;39(4):421-432. 14. Gathe JC, Hardwicke RL, Garcia F, et al.
Efficacy, pharmacokinetics, and safety over 48 weeks with ibalizumab-based therapy in treatment-experienced adults infected with
HIV-1: a phase 2a study. J Acquir Immune
Defic Syndr. 2021;86(4):482-489. 15. Millham LRI, Scott JA, Sax PE, et al. Clinical and economic impact of ibalizumab for people with multidrug-resistant HIV in the
United States. J Acquir Immune Defic Syndr. 2020;83(2):148-156. 16. Dickter JK, Martin AL, Ho S, et al.
Ibalizumab-uiyk as a bridge therapy for a patient with drug-resistant HIV-1 infection receiving chemotherapy: a case report. J Clin
Pharm Ther. 2021;46($):1185-1187. 17. Dvory-Sobol H, Shaik N, Callebaut C, et al.
Lenacapavir: A first-in-class HIV-1 capsid inhibitor. Curr Opin HIV AIDS. 2022;17(1): 15-21. 18. Margot N, Vanderveen L, Naik V, et al.
Phenotypic resistance to lenacapavir and monotherapy efficacy in a proof-of-concept clinical study. J Antimicrob Chemother. 2022;77(4):989-995. 19. Gilead receives complete response letter from
U.S. FDA for investigational lenacapavir due to vial compatibility issues [press release].
Business Wire; March 1, 2022. Accessed April 26, 2022. https://bwnews.pr/3yWvaAi
