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


Although it may seem paradoxical at first sight, carbapenems have been commonly prescribed against CR GNB, particularly for KPC-producing Enterobacteriaceae infections, either as an adjuvant or even as the cornerstone drug.[8,46–48] This is mainly due to the fact that many carbapenemase-producing Enterobacteriaceae isolates present carbapenem MICs near to or even at the current susceptibility breakpoints, that is, 1–4 mg/l; this occurs especially for meropenem and doripenem. Numerous studies have shown that higher doses and optimal modes of administration, either by extended or continuous infusion of the drugs,[122–125] can lead to an acceptable probability of attaining the PK/PD target (i.e., time of free drug during the dose interval above the MIC >40%) for pathogens with carbapenem MICs between 1 and 8 mg/l, even in critically ill patients.[126] Combination therapy may provide further benefits (Figure 1) for the use of carbapenems in these CR GNB isolates with borderline susceptibility. These PK/PD data have been corroborated by the analysis of many case series and some cohort studies demonstrating lower mortality rates among patients treated with a carbapenem-containing regimen for infections caused by CR K. pneumoniae with MICs below 8 mg/l, and particularly below 4 mg/l.[8,46–48,127]

In contrast to Enterobacteriaceae, carbapenem MICs in CR non-fermentative organisms are often very high (>32 mg/l), either because more potent carbapenemases are involved or other resistance mechanisms are additionally present.[2] This fact along with the lack of clinical data supporting the use a carbapenem in combination therapy against CR P. aeruginosa or A. baumannii may discourage the use of carbapenem-containing regimens against such pathogens at this time. However, as described earlier, many preclinical studies have demonstrated potential benefits, particularly for combinations of carbapenems with a polymyxin or an aminoglycoside. This is caused by synergistic killing and resistance prevention, as carbapenems are not subject to the same resistance mechanisms as polymyxins and aminoglycosides.

Another recently proposed approach for treating KPC-producing Enterobacteriaceae is the double-carbapenem combination therapy.[128,129] Specifically, the rationale is using a carbapenem with increased affinity for KPC, that is, ertapenem, to act as a 'suicidal' drug in order to improve the action of another carbapenem, especially doripenem, with increased stability against the hydrolyzing activity of KPC.[128,129] Indeed, experimental data simulating high dose doripenem regimens (2 g every 8 h infused over 3 or 4 h) plus ertapenem (1 g daily) have shown enhanced microbiologic efficacy of this combination over doripenem in monotherapy and this effect has been attributed to the interaction between ertapenem and the carbapenemase enzyme.[128,129] Anecdotal case reports have shown clinical success with combinations of high dose doripenem or meropenem plus ertapenem in the treatment of PDR Enterobacteriaceae,[130,131] and double-carbapenem therapy may be a promising alternative against pathogens with such a resistance profile, particularly in combination with a third drug. However, non-carbapenemase-mediated resistance to carbapenems also occurs among CR GNB and combining carbapenems is expected to be ineffective against such isolates. Thus, such a strategy may be potentially useful against carbapenemase-producing strains, but more clinical data are needed to routinely recommend such practice.

Finally, there is some pre-clinical evidence that carbapenems may present higher microbiological efficacy against non-carbapenemase-producing CR K. pneumoniae in comparison with KPC-producing isolates.[132] Additionally, one study reported higher microbiological activity of carbapenems against NDM-1-producing compared with KPC-2-producing isolates.[133] Thus, although clinical support is still lacking, carbapenems may be especially attractive as the mainstream agents against non-KPC-producing K. pneumoniae isolates with MIC ≤ 4 mg/l and offer an excellent safety profile.