Pharmacodynamics of Polymyxin B against Pseudomonas aeruginosa

Abstract

Despite limited data, polymyxin B (PB) is increasingly used clinically as the last therapeutic option for multidrug-resistant (MDR) gram-negative bacterial infections. We examined the in vitro pharmacodynamics of PB against four strains of Pseudomonas aeruginosa. Clonal relatedness of the strains was assessed by random amplification of polymorphic DNA. Time-kill studies over 24 h were performed with approximately 10 5 and 10 7 CFU/ml of bacteria, using PB at 0, 0.25, 0.5, 1, 2, 4, 8, and 16؋ MIC. Dose fractionation studies were performed using an in vitro hollow-fiber infection model (HFIM) against a wild-type and a MDR strain. Approximately 10 5 CFU/ml of bacteria were exposed to placebo and three regimens (every 8 h [q8h], q12h, and q24h) simulating the steady-state unbound PB pharmacokinetics resulting from a daily dose of 2.5 mg/kg of body weight and 20 mg/kg (8 times the clinical dose). Samples were obtained over 4 days to quantify PB concentrations, total bacterial population, and subpopulation with reduced PB susceptibility (>3؋ MIC). The bactericidal activity of PB was concentration dependent, but killing was significantly reduced with a high inoculum. In HFIM studies, a significant reduction in bacterial load was seen at 4 h in all active regimens, but selective amplification of the resistant subpopulation(s) was apparent at 24 h with the clinical dose (both strains). Regrowth was eventually observed in all dosing regimens with the MDR strain, but its occurrence was prevented in the wild-type strain by using 8 times the clinical dose (regardless of dosing intervals). Our results suggested that the bactericidal activity of PB was concentration dependent and appeared to be related to the ratio of the area under the concentration-time curve to the MIC.

Subinhibitory concentrations of the cationic antimicrobial peptide colistin induce the pseudomonas quinolone signal in Pseudomonas aeruginosa

“…Polymyxins are known to displace the calcium and magnesium bridges that stabilize the LPS (Evans et al, 1999;Hancock, 1997b;Hermsen et al, 2003;Tam et al, 2005). Both pmrHFIJKLM and PQS are induced in the exponential growth phase when P. aeruginosa is grown in magnesium-limiting media (Guina et al, 2003).…”

Polymyxin B in combination with doripenem against heteroresistant Acinetobacter baumannii : pharmacodynamics of new dosing strategies

“…Polymyxin showed rapid bactericidal activity in vitro and the PD of polymyxin B is most closely linked to the AUC/MIC ratio. 18 Based on our and previous time -kill studies, monotherapy with polymyxin B leads to rapid initial decline followed by extensive regrowth. Hence, the combination regimens with administration of polymyxin in a high-intensity fashion, based on the mechanism-based modelling, provided an effective way of addressing the subpopulations that are resistant to either polymyxin B or doripenem.…”

“…15,16 Previous in vitro studies have shown that polymyxin combinations with a carbapenem are highly bactericidal against A. baumannii 17 although the rapid bactericidal activity of this combination is followed by regrowth with the emergence of resistant subpopulations. 18 Therefore, this underscores the need to develop novel strategies to combat A. baumannii focused on polymyxin combinations to maximize bactericidal activity, minimize resistance and decrease drug exposure.…”

Polymyxins Revisited

“…Numerous studies have been performed in recent years using a pharmacodynamic model or standard time-kill studies of the effect of polymyxin B or colistin against strains of P. aeruginosa (19,59,67,93,107,166), A. baumannii (60,88,106,136,160,170), and K. pneumoniae (20). Nearly all studies demonstrated that the polymyxins produce concentration-dependent killing, with an initial kill followed by regrowth.…”