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


Rifampicin is a derivative of rifamycin with intra-cellular anti-bacterial activity determined by the suppression of RNA synthesis initiation by inhibiting DNA-dependent RNA polymerase.[188] It has a broad spectrum of activity including Gram-positive and -negative pathogens, although it is not recommended as a single therapeutic agent because of rapid emergence of high-level resistance in vitro and in vivo.[188] Apart from its use against some Staphylococcus aureus infections, rifampicin has been used in combination with polymyxins against CR GNB, most notably against A. baumannii.[189,190] This use is based on pre-clinical studies indicating synergism of such combinations, but it has not been corroborated by clinical evidence of benefit according to two recent RCTs.[23,24] As described earlier, PK/PD approaches based on pre-clinical data show a strong benefit of colistin plus rifampicin combination therapy compared with monotherapy.

Indeed, neither CLSI nor EUCAST have defined breakpoints of rifampicin for Gram-negative organisms. The susceptibility breakpoint proposed for S. aureus and Enterococcus spp. is ≤1 mg/l.[301,302] The French Society for Microbiology has established a rifampicin breakpoint for A. baumannii based on MIC distributions (susceptible, ≤4 mg/l; intermediate, 8–16 mg/l and resistant, >16 mg/l).[191] Nonetheless, the PK/PD index that best correlates with anti-bacterial activity has not been elucidated so far. It is known that it has a Cmax/MIC related activity with a potent post-antibiotic effect against M. tuberculosis,[192] but the ratio of AUC/MIC, an exposure-dependent metric, has also been correlated with a reduction in bacterial counts.[193] Also the long post-antibiotic effect may not translate to other more rapidly replicating bacteria.

The administration of 600 mg rifampicin orally resulted in peak serum concentrations of 7–10 mg/l, and following intravenous administration of 300 or 600 mg over 30 min peak concentrations of 9 or 17.5 mg/l are reached.[188] However, considering an 80% protein binding,[188,194] it is unlikely that unbound rifampicin concentrations will either reach peak concentrations able to achieve a Cmax/MIC, which has been associated with best anti-bacterial activity (8–10)[195] or appropriate fAUC/MIC,[194,195] considering the MICs of rifampicin against most CR A. baumannii.[23,195] Thus, any activity of this drug most likely relies on its potential synergistic proprieties rather than on an anti-bacterial activity per se. Finally, although doses as high as 600 mg every 8 h have been administered to some patients, the safety of these dosages should be further evaluated and therefore they cannot be routinely recommended.[196]