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. 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. 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). 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, but the ratio of AUC/MIC, an exposure-dependent metric, has also been correlated with a reduction in bacterial counts. 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. 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) 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.
Expert Rev Anti Infect Ther. 2013;11(12):1333-1353. © 2013 Expert Reviews Ltd.