Combination Therapy for Carbapenem-resistant Gram-negative Bacteria

Alexandre P Zavascki; Jurgen B Bulitta; Cornelia B Landersdorfer


Expert Rev Anti Infect Ther. 2013;11(12):1333-1353. 

In This Article

Abstract and Introduction


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.


Carbapenems are potent broad spectrum β-lactam antibiotics that have been used as the last resort treatment for many Gram-negative bacteria (GNB) causing serious nosocomial infections.[1] Prior to 2000, only relatively few clinical isolates were carbapenem resistant, mostly Pseudomonas aeruginosa and some Acinetobacter baumannii, due to the combination of high-level β-lactamase expression coupled with decreased permeability of the outer membrane and/or hyperexpression of efflux pumps.[2] Therefore, carbapenem resistance was not a major clinical problem before 2000,[3] but has since then become a major, global health concern. With imipenem having been US FDA-approved in 1985 and meropenem in 1996, this means that carbapenem resistance became a major clinical challenge within 15–20 years after approval of the first carbapenem. A similar relationship has been observed for other antibiotic classes.[4]

The emergence of acquired carbapenem-hydrolyzing β-lactamases (carbapenemases) at the end of the past century and their worldwide dissemination is a major global threat to the antibiotic era and to all the clinical procedures that rely on effective antibiotic therapy.[5–11] The carbapenemases were initially described in a few organisms and restricted to specific geographic areas, but they have become a global concern by the middle of the past decade.[5–11] Some enzymes determining broad-spectrum β-lactam resistance in major nosocomial bacteria such as P. aeruginosa, A. baumannii and Enterobacteriaceae isolates have disseminated through the continents and completely changed the scenario of antibiotic resistance in GNB.

Unequivocally, the emergence of metallo-β-lactamases VIM, IMP and NDM (molecular class B), OXA-48 and its derivatives (molecular class D), and Klebsiella pneumoniae carbapenemases (KPCs, molecular class A) has rapidly caused several paradigm shifts in antibiotic therapy against GNB. This would not be a major concern if the discovery and development of new antimicrobials had evolved as quickly and effectively as the ability of these GNB to become resistant to antibiotics. However, the discovery and development pipeline of new antibiotics against GNB has dried out since several years.[12] Consequently, physicians are now compelled to restore 'old' antibiotics as the last resort therapy against infections they had been used to successfully treat with broad spectrum β-lactam antibiotics, especially the carbapenems.[13–17]

The global epidemics of carbapenem-resistant (CR) GNB and carbapenemases have been very dynamic and a detailed revision of this issue is beyond the scope of this article. Interested readers are invited to read thoughtful reviews published elsewhere [5–11,18]. Similarly, the reasons for the paucity of new antibiotics against GNB have also been extensively discussed previously[19,20] and will not be described here. Finally, GNB isolates with intrinsic resistance to carbapenems, such as Stenotrophomonas maltophilia,[21] will also not be reviewed here. This review focuses on clinically available antibiotics and does not cover antibiotics currently under development.

In the past few years, antibiotic combinations against CR GNB have been proposed as the best practice in the management of infections by these organisms. In this report, we will review recent pharmacokinetic (PK) and PK/pharmacodynamic (PD) findings for the most often used antibiotics against major GNB with acquired resistance to carbapenems. Additionally, relevant pre-clinical and clinical data that may contribute to the choice of optimal combination regimens against these pathogens are summarized.