Paradoxical Effect of Polymyxin B: High Drug Exposure Amplifies Resistance in Acinetobacter baumannii

Abstract

f Administering polymyxin antibiotics in a traditional fashion may be ineffective against Gram-negative ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. Here, we explored increasing the dose intensity of polymyxin B against two strains of Acinetobacter baumannii in the hollow-fiber infection model. The following dosage regimens were simulated for polymyxin B (t 1/2 ‫؍‬ 8 h): nonloading dose (1.43 mg/kg of body weight every 12 h [q12h]), loading dose (2.22 mg/kg q12h for 1 dose and then 1.43 mg/kg q12h), front-loading dose (3.33 mg/kg q12h for 1 dose followed by 1.43 mg/kg q12h), burst (5.53 mg/kg for 1 dose), and supraburst (18.4 mg/kg for 1 dose). Against both A. baumannii isolates, a rapid initial decline in the total population was observed within the first 6 h of polymyxin exposure, whereby greater polymyxin B exposure resulted in greater maximal killing of ؊1.25, ؊1.43, ؊2.84, ؊2.84, and ؊3.40 log 10 CFU/ml within the first 6 h. Unexpectedly, we observed a paradoxical effect whereby higher polymyxin B exposures dramatically increased resistant subpopulations that grew on agar containing up to 10 mg/liter of polymyxin B over 336 h. High drug exposure also proliferated polymyxin-dependent growth. A cost-benefit pharmacokinetic/pharmacodynamic relationship between 24-h killing and 336-h resistance was explored. The intersecting point, where the benefit of bacterial killing was equal to the cost of resistance, was an fAUC 0 -24 (area under the concentration-time curve from 0 to 24 h for the free, unbound fraction of drug) of 38.5 mg · h/liter for polymyxin B. Increasing the dose intensity of polymyxin B resulted in amplification of resistance, highlighting the need to utilize polymyxins as part of a combination against high-bacterial-density A. baumannii infections.T he polymyxin antibiotics have emerged as a last line of defense for the treatment of Gram-negative strains resistant to all other currently available antibiotics (1-3). Polymyxin B and colistin are often the only available agents with activity against these Gram-negative superbugs (4, 5). Even more worrisome is the first report of plasmid-mediated polymyxin resistance in Escherichia coli, which could be transferred to other Gram-negative strains (6). Furthermore, current dosage regimens for both polymyxin B and colistin result in polymyxin plasma concentrations that are suboptimal in a significant proportion of patients (7-10). In vitro and animal studies clearly demonstrate that antibiotic resistance is amplified during exposure to suboptimal polymyxin concentrations, especially against polymyxin-heteroresistant strains that are frequently isolated in Acinetobacter baumannii (11)(12)(13)(14).Administering nontraditional, high-intensity polymyxin regimens may be a strategy to maximize bacterial killing while minimizing resistance and potential toxicity. We have previously determined that front-loading colistin resulted in greater bacteri...

Colistin Dosage without Loading Dose Is Efficacious when Treating Carbapenem-Resistant Acinetobacter baumannii Ventilator-Associated Pneumonia Caused by Strains with High Susceptibility to Colistin

“…With this strategy, the main concern would be if low dosages might select more easily resistant strains. However, this drawback seems to be ruled out by recent in vitro models, in which the emergence of resistant strains was paradoxically increased with higher colistin concentrations [37–38]. …”

New Polymyxin B Dosing Strategies To Fortify Old Allies in the War against KPC-2-Producing Klebsiella pneumoniae

“…The polymyxins are among the only remaining classes of antibiotics that consistently maintain activity against KPC-Kp, with susceptibility rates of Ͼ85% (5). Despite sustained in vitro activity, treatment with polymyxin monotherapy frequently results in clinical failure, probably due to rapid proliferation of resistant subpopulations (6,7). Polymyxin-carbapenem combination regimens have been associated with improved clinical outcomes and reduced mortality in KPC-Kp infections, providing a viable alternative to polymyxin monotherapy (8,9).…”

“…Population analysis profiles (PAPs) were also determined during the HFIM by plating a 50-l aliquot of a bacterial sample onto an agar plate embedded with polymyxin B (0.5, 1, 4, or 10 mg/liter) or meropenem (4, 16, or 64 mg/liter) to simultaneously track the polymyxin-and meropenemheteroresistant subpopulations that are often present in K. pneumoniae (25,26). HFIM polymyxin B dosage regimens were based on the population pharmacokinetic model described by Sandri et al from 24 critically ill patients who received intravenous polymyxin B doses ranging from 0.45 to 3.38 mg/kg of body weight/day (7,21). The following polymyxin B (half-life [t 1/2 ] ϭ 8 h), meropenem (t 1/2 ϭ 2.5 h), and rifampin (t 1/2 ϭ 2.5 h) regimens were simulated using each drug alone or in double or triple combinations in the HFIM based on human pharmacokinetic data in critically ill patients (22-24):…”

Comparative pharmacodynamics of four different carbapenems in combination with polymyxin B against carbapenem-resistant Acinetobacter baumannii

“…A previous hollow-fibre infection analysis of PMB alone against A. baumannii with susceptible PMB MICs also failed to eradicate the pathogen in vitro [17]. Despite rapid initial killing, polymyxin-resistant subpopulations amplified by over 5 log 10 CFU/mL within 24 h of PMB exposure to allow for continued growth in the presence of PMB.…”