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Antibiotic Breakpoints: How Redefining Susceptibility Preserves Efficacy and Improves Patient Care
Guiliano and colleagues1 provided an excellent overview in the April 2019 issue of P&T on how to interpret culture and susceptibility results from the microbiology laboratory. A critical lesson described in their article is the application of susceptibility data to daily clinical practice. As P&T readers are aware, antibiotic resistance is a global health crisis. Consequently, The Joint Commission mandated standards (standard MM.09.01.01) on antibiotic stewardship programs (ASP) on January 1, 2017, published as the New Antimicrobial Stewardship Standard, applicable to acute care hospitals and critical access hospitals for use in managing resistance.2,3 An important component of ASP is the provision of timely antibiograms. These data sets are frequently used to construct empiric antibiotic selection guidelines, which enable clinicians to prescribe antibiotics appropriately. The development of antibiograms is dependent on accurate and reproducible susceptibility testing using current antibiotic breakpoints established by the Clinical and Laboratory Standards Institute (CLSI).4 Because antibiograms reflect susceptibility data acquired from large populations, generalizations should be used cautiously when developing institution-specific, empiric antibiotic guidelines. More narrowly, the individual patient pathology report informs clinicians of potential choices in drug selection. Accurate susceptibility information relies on laboratory utilization of appropriate antibiotic breakpoints for both the broader antibiogram and patient-specific reports.
The recognition of new bacterial resistance mechanisms within the Enterobacterales (formerly, Enterobacteriaceae) family, such as Klebsiella pneumoniae, represented a signal suggesting that the original breakpoints and susceptibility categories for carbapenems no longer met clinical needs. For example, Patel and colleagues5 found that a group of patients infected by an organism within the Enterobacterales family, with carbapenem minimum inhibitory concentrations (MICs) of 2 mg/Liter to 8 mg/Liter, had a significantly higher 30-day mortality than the group with carbapenem MICs of ≤ 1 mg/Liter (38.9% vs. 5.6%, P = 0.04). At the time of this study, the FDA susceptible breakpoint for meropenem was 4 mg/Liter. From 2009 to 2010, CLSI carried out an investigation to determine whether breakpoint revisions were in order. Because little clinical evidence was available to reassess carbapenem breakpoints, pharmacokinetic–pharmacodynamic (PK/PD) analyses were conducted. These focused on determining whether FDA-approved dosage regimens of carbapenems would be expected to provide target drug exposures that are associated with bacterial killing in vivo with MICs that are at and below a susceptibility breakpoint. The resulting analysis showed that a breakpoint of 1 mg/Liter provided a consistent target level of exposure in humans and excluded bacterial isolates with MICs greater than this new breakpoint. The overall effect of the two-dilution lowering of imipenem and meropenem breakpoints was to prevent interpreting isolates with “carbapenem-resistance mechanisms” as “susceptible.”6 The historic (pre-2010) and revised breakpoints are shown in
Laboratories that use revised carbapenem breakpoints detect significantly more carbapenem-resistant Enterobacterales than laboratories that use historical breakpoints. The studies in
Significantly, there are several major consequences of failing to update breakpoints that are relevant to the clinical microbiology laboratory, consequences that can have significant implications. First, the quality of data emanating from the laboratory is compromised. As errors in susceptibility interpretation originate within the microbiology department, quality improvements must be addressed by experts in the institution’s laboratories. McKinnell and colleagues conducted a survey of 128 laboratories and discovered that only 72% of laboratories employed current CLSI carbapenem breakpoints and that time to implementation varied from 0 to 68 months (mean, 41 months; median, 55 months).11 Implementing those changes is time-consuming, and it may not be feasible for some laboratories due to the interruption of workflow, lack of test strains, and lack of adequate resources needed to verify the new breakpoints. Validation of the new carbapenem breakpoints should be immediate, given the time that has elapsed since the 2010 revisions. In addition, the ASP team and infectious disease practitioners should liaise with their laboratory regarding breakpoint changes, and update the antibiogram issued to prescribers to guide empiric therapy.
Second, patient morbidity and mortality can be affected by reporting incorrect susceptibility results. Antibiotics that are selected for specifically chosen therapy based on an individual patient culture and susceptibility report might be inappropriate and could lead to clinical failure. It has been shown that such inappropriate antibiotic therapy increases morbidity and mortality, as demonstrated by longer lengths of hospitalization and intensive care unit (ICU) days, a greater number of days on antibiotics, and higher costs of therapy.12 Competition for resources such as ventilators, non-antibiotic medications, and IV pumps may increase. Furthermore, inappropriate antibiotic usage leads to the necessity for additional therapeutic agents, prolongs the number of days of therapy, and increases potential exposure to nephrotoxic agents.13 Sequelae of prolonged antibiotic use include an increased risk for infection and colonization by opportunistic and invasive pathogens, such as Clostridium difficile infection, vancomycin-resistant enterococci, and Candida spp., which exert a significant cost burden.14
Finally, and what is often overlooked, is the potential for the spread of resistant pathogens when infection-control specialists cannot identify emerging resistance trends. Reliance on the accurate identification of carbapenemase-producers is necessary to institute appropriate management strategies that will address the potential for intra-hospital spread. For example, using a simulation model, Bartsch and colleagues15 found that a 32-month delay in changing carbapenem-resistant Enterobacteriaceae (CRE) breakpoints resulted in 1,821 additional carriers in Orange County, California––an outcome that could have been avoided by identifying CRE and initiating the appropriate isolation or contact precautions. The authors suggest that a policy aimed at minimizing delay in the adoption of new breakpoints for antimicrobials against emerging pathogens should be implemented when the containment of spread is paramount. A delay of no more than 1.5 years would have the most impact in slowing the spread of carbapenemase-producing Enterobacterales. Failure to identify resistant pathogens can result in their dissemination throughout the hospital environment, leading to colonization and infections in other patients.
The story for carbapenem breakpoints is now being repeated for drugs within the fluoroquinolone class, specifically levofloxacin and ciprofloxacin, against members of Enterobacterales and Pseudomonas aeruginosa. Fluoroquinolone resistance can arise through mutations in defined regions of DNA gyrase or topoisomerase IV––termed the Quinolone-Resistance Determining Regions (QRDRs)––decreased outer-membrane permeability, dysregulation of efflux pumps, and plasmid-mediated resistance mechanisms.16 Revised breakpoints were published in January 2019 by CLSI.4 Following a similar process for carbapenems––rising resistance to fluoroquinolones––PK/PD analyses provided the basis for lower breakpoints for ciprofloxacin and levofloxacin. As the infectious disease community is gaining experience in antibiotic susceptibility breakpoint adjustments, two recently published reports provide laboratory staff and clinicians guidance in validating these new fluoroquinolone breakpoints.17,18
In summary, ASP practices require an understanding of the interplay between mechanisms of antibiotic resistance, MICs, breakpoints defining susceptibility, and PK/PD––important components that synergize to optimize the chances for positive clinical success. The consequences of failing to adopt revised breakpoints include the following:
Carbapenems are primary therapeutic agents for the treatment of infections caused by multidrug-resistant bacterial pathogens. To maintain their efficacy and to control the emergence of further resistance, breakpoints corresponding to recommended doses that provide appropriate PK/PD target attainment are essential. The implementation of revised breakpoints is vital to the practice of diagnostic stewardship and leads to improved patient care.
CLSI/FDA Carbapenem Breakpoints (mg/Liter) for Enterobacterales
|Antimicrobial agent||Historical (pre-2010)||Current (2010 and later)|
|Ertapenem||≤ 2||4||≥ 8||≤ 0.5||1||≥ 2|
|Imipenem||≤ 4||8||≥ 16||≤ 1||2||≥ 4|
|Meropenem||≤ 4||8||≥ 16||≤ 1||2||≥ 4|
CLSI = Clinical and Laboratory Standards Institute; FDA = Food and Drug Administration Current FDA and CLSI breakpoints are listed on the FDA Susceptibility Test Interpretive Criteria (STIC) website:
Effect of a Two-Dilution Decrease in Meropenem MIC Breakpoint in Two Large Surveillance Studies of Carbapenem-Resistant Enterobacterales
|Study||Cumulative susceptibility to meropenem of clinical enterobacterales isolates||Decrease in cumulative % susceptibility between pre-2010 and current breakpoints|
|MIC ≤ 1 mg/Liter||MIC ≤ 4 mg/Liter|
n = 265 (8)
n = 991 (9)
CRE = carbapenem-resistant Enterobacteriaceae; KPC =
- Guiliano C, Patel CR, Kale-Pradham PB. A guide to bacterial culture identification and results interpretation. P T 2019;44;(4):
- Joint Commission Perspectives July 2016;36;(7): Available at: https://www.jointcommission.org/assets/1/6/New_Antimicrobial_Stewardship_Standard.pdf. Accessed August 8, 2019
- Centers for Disease Control and Prevention. Core elements of hospital antibiotic stewardship programs May 7, 2015; Available at: https://www.cdc.gov/antibiotic-use/healthcare/implementation/core-elements.html. Accessed August 8, 2019
- Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing
29th ed.CLSI supplement M100 July 2019; Available at: https://clsi.org/standards/products/microbiology/documents/m100/. Accessed August 8, 2019
- Patel TS, Nagel JL. Clinical outcomes of Enterobacteriaceae infections stratified by carbapenem MICs [published online November 5, 2014]. J Clin Microbiol 2015;53;(1):201–205.
- Dudley MN. Rationale for the 2010 Revised Susceptibility Breakpoints for Cephalosporins, Aztreonam, and Carbapenems for Enterobacteriaceae. J Pediatric Infect Dis Soc 2012;1;(2):166–168.
- Humphries RM, Abbott AN, Hindler JA. Understanding and addressing CLSI breakpoint revisions: a primer for clinical laboratories. J Clin Microbiol 2019;57;(6):e00203–19.
- Castanheira M, Huband MD, Mendes RE, Flamm RK. Meropenem-vaborbactam tested against contemporary Gram-negative isolates collected worldwide during 2014, including carbapenem-resistant, KPC-producing, multidrug-resistant, and extensively drug-resistant Enterobacteriaceae. Antimicrob Agents Chemother 2017;61;(9):e00567–17.
- Hackel MA, Lomovskaya O, Dudley MN, et al.
In vitroactivity of meropenem-vaborbactam against clinical isolates of KPC-positive Enterobacteriaceae. Antimicrob Agents Chemother 2017;62;(1):e01904–17. 10.1128/AAC.01904-17
- Humphries RM, Hindler JA, Epson E, et al. Carbapenem-resistant Enterobacteriaceae detection practices in California: what are we missing?. Clin Infect Dis 2018;66;(7):1061–1067.
- McKinnell JA, Bhaurla S, Marquez-Sung P, et al. Public health efforts can impact adoption of current susceptibility breakpoints, but closer attention from regulatory bodies is needed. J Clin Microbiol 2019;57;(3):e01488–18.
- Zilberberg MD, Nathanson BH, Sulham K, et al. Carbapenem resistance, inappropriate empiric treatment, and outcomes among patients hospitalized with Enterobacteriaceae urinary tract infection, pneumonia, and sepsis. BMC Infect Dis 2017;17;(1):279
- Nicasio AM, Eagye KJ, Kuti EL, et al. Length of stay and hospital costs associated with a pharmacodynamic-based clinical pathway for empiric antibiotic choice for ventilator-associated pneumonia. Pharmacotherapy 2010;30;(5):453–462.
- Safdar N, Maki DG. The commonality of risk factors for nosocomial colonization and infection with antimicrobial-resistant
Staphylococcus aureus, enterococcus, Gram-negative bacilli, Clostridium difficile, and Candida. Ann Intern Med 2002;136;(11):834–844. 10.7326/0003-4819-136-11-200206040-00013
- Bartsch SM, Huang SS, Wong KF, et al. Impact of delays between Clinical and Laboratory Standards Institute and Food and Drug Administration revisions of interpretive criteria for carbapenem-resistant Enterobacteriaceae [published online August 31, 2016]. J Clin Microbiol 2016;54;(11):2757–2762.
- Morgan-Linnell SK, Becnel Boyd L, Steffen D, Zechiedrich L. Mechanisms accounting for fluoroquinolone resistance in
Escherichia coliclinical isolates [published online October 6, 2008]. Antimicrob Agents Chemother 2009;53;(1):235–241. 10.1128/AAC.00665-08
- Humphries RM, Hindler JA, Shaffer K, et al. Evaluation of ciprofloxacin and levofloxacin disk diffusion and Etest using the 2019 Enterobacteriaceae CLSI breakpoints. J Clin Microbiol 2019;57;(3):e01797–18.
- Van TT, Minejima E, Chiu CA, et al. Don’t get wound up: revised fluoroquinolone breakpoints for
Enterobacteriaceaeand Pseudomonas aeruginosa. J Clin Microbiol 2019;57;(7):e02072–18. 10.1128/JCM.02072-18