Carbapenem susceptibility breakpoints, clinical implications with the moving target

ABSTRACT

Carbapenems are primary agents used to treat a variety of Gram-negative multi-drug resistant infections. In parallel with increasing use, increasing resistance to carbapenem agents has manifested as increased minimum inhibitory concentrations (MICs). To attempt to improve clinical outcomes with carbapenems, the Clinical Laboratory Standards Institute and the Food Drug Administration decreased susceptibility breakpoints. The European equivalent expert committee, the European Committee on Antimicrobial Susceptibility Testing, also utilizes lower MIC susceptibility breakpoints. This review focuses on the rationale for recent breakpoint changes and the associated clinical outcomes for patients treated with carbapenems for infections with varying MICs proximal to the breakpoint. Supporting pharmacokinetics and pharmacodynamics that underpin the breakpoints are also reviewed.

KEYWORDS:

• Carbapenem
• β-lactam
• resistance mechanisms
• breakpoint
• minimum inhibitory concentration

Financial and competing interests disclosure

M Scheetz has received funds for an investigator initiated study with Cubist Pharmaceuticals (now a wholly owned subsidiary of Merck) for an antimicrobial stewardship consumption study. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Around 90% of antibiotics used in human medicine are prescribed in primary care. At least half of these prescriptions are either unnecessary or inappropriate.

• Multifaceted interventions have proved useful in improving antibiotic prescribing, but they should be adapted to the context (‘One size does not fit all’ and ‘No magic bullet’ concepts). Behavior change theories are helpful for designing interventions that target healthcare professionals.

• Recent evidence related to various interventions targeting healthcare professionals are described here (Table 1): education, guidelines, clinical decision support systems, delayed prescribing, patient materials, public commitment, POC diagnostic tests, selective susceptibility reporting, quality indicators, audit and feedback, and restrictive prescribing measures.

• Interventions targeting the healthcare system have been overlooked so far, even though their impact can be large and sustained. Some examples are given here, including dispensing of antibiotics, financial incentives, and public reporting.

• Most published studies come from Europe or North America. We need studies from a much greater range of settings.

• Most interventions have focussed on GPs. In the future, all healthcare professionals should be targeted. Most studies have focussed on RTIs; we need to develop a better understanding of how much improvement is possible for other conditions and how well suited our current interventions are to achieving this.

• Patient-centered outcomes remain largely underdeveloped and underreported.

• Innovative strategies, including those targeting the system organization, should be tested.