Making Lemonade Out of Lemons: The Effect of Mandatory Infectious Diseases Consultation on Carbapenem Use after Drug Shortages

Carbapenems, or “big guns” and “gorillacillins” to many infectious diseases faculty, are one of the biggest targets of antimicrobial stewardship programs (ASP). Use of these agents, both optimal and suboptimal, has led to the development of carbapenem-resistant Pseudomonas spp., Acinetobacter spp., and Enterobacterales. While rates of carbapenem-resistant organisms have decreased or remained stable over the past decade, rates of extended-spectrum beta-lactamase (ESBL) producing Enterobacterales continue to increase.¹ This trend may cause carbapenem use to increase as well, given the scarcity of evidence or failure of other carbapenem-sparing treatment strategies for serious ESBL infections.² Consequently, judicious use of carbapenems is critically important to prevent further worsening of antibiotic resistance.

The purpose of ASPs is to optimize antimicrobial use to appropriately treat infections, reduce antimicrobial-related adverse effects, and reduce the development of antimicrobial resistance.3 Several stewardship strategies effectively reduce suboptimal antimicrobial use, rates of resistance, and healthcare costs. The most effective of these strategies are preauthorization and prospective audit and feedback (PAF).^3,4 While preauthorization is effective in optimizing antimicrobial use, it reduces physician autonomy and requires more ASP resources than is feasible for many institutions. Conversely, PAF preserves physician autonomy and is logistically easier to perform, but it does not address suboptimal or unnecessary empiric antibiotic use.

Mani and colleagues performed a retrospective, longitudinal, pre-post study of a new policy to address a severe meropenem shortage of mandatory infectious diseases consultation for all meropenem and imipenem orders active for >72 hours combined with PAF implementation. While the shortage resolved within 6 months, the policy remained in effect for stewardship purposes. The study took place at a tertiary/quaternary care facility and acute care hospital from January 1, 2013 to November 14, 2015 for the pre-period and from November 15, 2015 to October 31, 2019 for the post-period. All inpatients were included except for those in the neonatal intensive care unit or with cystic fibrosis, as the policy excluded these populations.

The intervention consisted of daily or thrice weekly reviews of all inpatients receiving meropenem and imipenem, depending on the facility. An ASP pharmacist contacted the primary team with de-escalation recommendations, as appropriate, and a reminder of the mandatory consultation policy for use beyond 72 hours. Additionally, an electronic alert displayed on meropenem and imipenem orders, informing ordering providers of the mandatory consultation policy and offering an option to select an alternative antibiotic. In the pre-period, carbapenem use was unrestricted and not systematically reviewed by an ASP member.

The primary outcome was meropenem and imipenem days of therapy per 1000 patient days (DOT). Ertapenem DOT served as a control group, as use was not restricted in the post-period. Secondary outcomes included carbapenem initiation, duration of therapy, annual 30-day mortality and length of stay (LOS) in patients with gram-negative rod bacteremia at one of the facilities, and use trends for cefepime, ceftriaxone, and piperacillin-tazobactam. Only one instance of empiric use per month was included per patient per hospitalization, and only the first episode of bacteremia was included. The statistical analysis was performed as an interrupted time series. Each facility was modeled separately due to differing patient populations and initial DOT rates. Mortality and LOS were evaluated with logistic regression and a proportional subdistribution hazards regression model, respectively, adjusting for age and sex.

A total of 4,066 patients were analyzed in the pre-period, and 2,552 in the post-period with similar baseline characteristics between groups. Post-intervention, immediate meropenem and imipenem DOT decreased by 43.6% (95% CI, 20.7 – 59.9) and 72.1% (95% CI, 66.9 – 76.6) at each facility, respectively. This decrease remained stable over the following four years with a -1.19% change per month (95% CI, -1.96 to -0.41) in one facility and 0.51% (95% CI, 0.1 – 0.92) in the other. Conversely, ertapenem DOT did not significantly change in the pre- or post-periods. Meropenem and imipenem initiation also decreased significantly in the post-period by 64.9% (95% CI, 58.7 – 70.2) and 44.7% (95% CI, 28.1 – 57.4) at each facility, respectively, and meropenem duration decreased from 4 days to 3 days (P <.001). No differences in 30-day mortality or hospital LOS were observed between periods. Cefepime, ceftriaxone, and piperacillin-tazobactam use did not differ significantly between the pre- and post-periods.

Like many others, this study highlights the positive effect of ASPs on antimicrobial use. Despite the known benefits of ASPs, however, resources remain scarce for some institutions and countries. This study adds an effective, resource-efficient stewardship intervention to the ASP toolkit and uniquely combines the effects of preauthorization and PAF. While the retrospective nature of the study limits conclusions of causality, the interrupted time series design and inclusion of ertapenem use as a control strengthens the relationship between the intervention and sustained decreases in carbapenem use at the included facilities. In the absence of a carbapenem shortage, which was the cause for the new policy in this case, mandatory infectious diseases consultation may be difficult to pitch to institutional leadership and providers. Additionally, while less resource intensive than other stewardship interventions, this policy still requires dedicated technological resources and ASP personnel, which may not be available at all institutions. However, for institutions with moderately sized ASPs and a favorable institutional culture, the intervention presented in this study may provide a simple and sustainable strategy to reduce antimicrobial use.

Highlighted study: Mani NS, Lan KF, Jain R, et al. Post-prescription review with threat of infectious disease consultation and sustained reduction in meropenem use over four years. Clin Infect Dis. 2020; ciaa1279. https://doi.org/10.1093/cid/ciaa1279.

Britt is a Pharmacy Clinical Practice Specialist in Infectious Diseases at UTMB Health in Galveston, Texas.

References

1. ^{CDC. Antibiotic Resistance Threats in the United States, 2019. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2019.}
2. ^{Harris PN, Tambya PA, Lye DC, et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA. 2018;320(10): 984-994. doi: 10.1001/jama.2018.12163.}
3. ^{CDC. Core Elements of Hospital Antibiotic Stewardship Programs. Atlanta, GA: US Department of Health and Human Services, CDC; 2019. Available at https://www.cdc.gov/antibiotic-use/core-elements/hospital.html.}
4. ^{Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62(10):51-77.}