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.

Approach to the Treatment of Patients with Serious Multidrug‐Resistant Pseudomonas aeruginosa Infections

“…Ceftazidime 58 2 g q8h (3 hrs) Cefepime 58 2 g q8h (3 hrs) Meropenem 11 2 g q8h (3-4 hrs) Imipenem 11 1 g q8h ( resistance. Empiric use would seem most prudent in a patient with a documented history of MDR-PSA who is presenting with serious systemic infection, where use of another empiric agent would be inappropriate based on prior recent susceptibility patterns, clinical characteristics, or local hospital epidemiology.…”

“…Carbapenem resistance may result when combined with other mechanisms such as changes in porin or efflux pumps. 11 It is worth noting that imipenem, but not meropenem, is a strong inducer of AmpC production. 20 P. aeruginosa may also express a number of acquired b-lactamases in Ambler classes A, B, and D. Pseudomonas-specific enzymes (PSEs) are class A enzymes that hydrolyze narrow spectrum b-lactams, although they appear to have a limited effect on cephalosporins, carbapenems, or aztreonam.…”

“…8,10 The most well-characterized porin mutation for PSA is loss of OprD, which confers low-level resistance to carbapenems. 8,11 Imipenem appears to be most affected, followed by meropenem. Porin mutations may result in decreased carbapenem susceptibility alone (e.g., slight elevation in minimum inhibitory concentrations [MICs]), although frank resistance can occur with concurrent expression of other resistance mechanisms.…”

“…Porin mutations may result in decreased carbapenem susceptibility alone (e.g., slight elevation in minimum inhibitory concentrations [MICs]), although frank resistance can occur with concurrent expression of other resistance mechanisms. 8,11 P. aeruginosa can also alter the characteristics and polarity of the outer cellular membrane. 8,12 This is believed to contribute to nonsusceptibility of aminoglycosides and polymyxins, depending on the membrane alterations present.…”

“…Increased efflux pump expression affects a larger number of antipseudomonal antibiotics, although, similar to porins, this mechanism alone may not lead to frank resistance. 8,11 Exposure to antibiotics has been shown to upregulate several of these efflux pump systems while downregulating membrane porins (e.g., OprD), often leading to overt antibiotic resistance across multiple classes. 8,10,15 P. aeruginosa may express an array of b-lactamases.…”