Aminoglycosides against carbapenem-resistant Enterobacteriaceae in the critically ill: the pitfalls of aminoglycoside susceptibility.

INTRODUCTION: The emergence of carbapenem-resistant Enterobacteriaceae (CRE) has brought aminoglycosides to the frontline since an aminoglycoside may be the only antimicrobial to which CRE isolates show in vitro susceptibility. The appropriateness of aminoglycoside-based therapies for severe infections by CRE is discussed considering the current breakpoints and recent pharmacokinetic (PK) studies in critically ill patients. Areas covered: Many aminoglycoside-susceptible CRE isolates present minimal inhibitory concentrations (MICs) at or slightly below the breakpoint of amikacin or gentamicin. However, recent PK studies with these aminoglycosides in critically ill have invariably shown that the PK/pharmacodynamic (PD) target is very unlikely attained even when high doses are administered, if the MICs are near the breakpoint. Expert commentary: While new antimicrobials are not widely available, the authors forecast an increasing use of aminoglycosides as backbone antibiotics against CRE isolates. However, the altered PK of aminoglycosides in critically ill patients severely impairs their predicted efficacy in these patients. Aminoglycoside breakpoints may hide 'aminoglycoside-susceptible' CRE isolates for that aminoglycosides will unlikely be effective if used in monotherapy. Therefore, these breakpoints may need to be revised due to the increasing use of aminoglycosides as backbone antibiotics to treat severe infections by CRE isolates in critically ill patients.

Combination therapy for carbapenem-resistant Gram-negative bacteria.

The emergence of resistant to carbapenems Gram-negative bacteria (CR GNB) has severely challenged antimicrobial therapy. Many CR GNB isolates are only susceptible to polymyxins; however, therapy with polymyxins and other potentially active antibiotics presents some drawbacks, which have discouraged their use in monotherapy. In this context, along with strong pre-clinical evidence of benefit in combining antimicrobials against CR GNB, the clinical use of combination therapy has been raised as an interesting strategy to overcome these potential limitations of a single agent. Polymyxins, tigecycline and even carbapenems are usually the cornerstone agents in combination schemes. Optimization of the probability to attain the pharmacokinetic/pharmacodynamic targets by both cornerstone drug and adjuvant drug is of paramount importance to achieve better clinical and microbiological outcomes. Clinical evidence of the major drugs utilized in combination schemes and how they should be prescribed considering pharmacokinetic/pharmacodynamic characteristics against CR GNB will be reviewed in this article.