In Vitro Pharmacodynamics of Polymyxin B and Tigecycline Alone and in Combination against Carbapenem-Resistant Acinetobacter baumannii

Abstract

b Carbapenem-resistant Acinetobacter baumannii is increasing in prevalence. Polymyxin B and tigecycline are among the most active antibiotics used against this pathogen in vitro. Past in vitro studies, however, neglected the importance of simulating exposures observed in humans to determine their antibacterial effects. In this study, four carbapenem-resistant A. baumannii isolates were evaluated using an in vitro pharmacodynamic model. Free-drug exposures using 1 mg/kg of body weight of polymyxin B every 12 h (q12h), 100 and 200 mg tigecycline q12h, and the combination of these regimens were simulated. The microbiological responses to these treatments were measured by the change in log 10 CFU/ml over 24 h and the area under the bacterial killing and regrowth curve (AUBC). Resistance was assessed by a population analysis profile (PAP) conducted after 24 h of treatment. Polymyxin B achieved a reduction on the order of ؊2.05 ؎ 0.68 log 10 CFU/ml against these A. baumannii isolates, while all isolates grew to control levels with tigecycline monotherapy. Combination therapy with polymyxin B plus 200 mg tigecycline q12h achieved a greater reduction in bacterial density than did therapy with polymyxin B alone (؊3.31 ؎ 0.71 versus ؊2.05 ؎ 0.68 log 10 CFU/ml, P < 0.001) but not significantly different than combination therapy with 100 mg tigecycline q12h (؊2.45 ؎ 1.00 log 10 CFU/ml, P ‫؍‬ 0.370). Likewise, combination therapy with polymyxin B plus 200 mg tigecycline q12h significantly reduced the AUBC compared to that with polymyxin B alone (62.8 ؎ 8.9 versus 79.4 ؎ 10.5 log 10 CFU/ml, P < 0.05). No changes in the PAP from baseline were observed for either antibiotic alone. In this study, combination therapy with simulated exposures of polymyxin B and tigecycline at an aggressive dose of 200 mg q12h produced synergistic or additive effects on humans against these multidrug-resistant A. baumannii strains.

Combination of polymyxin B and meropenem eradicates persister cells from Acinetobacter baumannii strains in exponential growth

“…Although the standard antimicrobial scheme against A. baumannii infections has not been fully established, evidence supports the fact that combination therapies including polymyxin B are more effective than polymyxin B monotherapies. Moreover, polymyxin B combined with a second antimicrobial agent was able to reduce hospital mortality rates, and has been widely recommended due to resistance emerging in some A. baumannii strains during treatments [2][3][4]. Nevertheless, antimicrobial therapy failure has been reported, especially in recalcitrance of chronic infections, which may be due to the tolerance mediated by persister cells [5,6] -a microbial subpopulation able to survive to normally lethal concentrations of bactericidal antimicrobials [7], as has been previously described in Acinetobacter spp.…”

Untitled

“…In-vitro system: One-compartment dilution system: The in-vitro modeling of the FDC was done using a single-compartment chemostat infection system as described previously 10,11 . Briefly, the chemostat system assembly consisted of a 500 mL glass central reservoir chamber with ports for the addition and removal of media via silicone tubes connected to peristaltic pumps, injection of drug (antibiotic combination) solution, and removal of medium samples.…”

Antibiotic Resistance Profiles and Genotypes of <i>Acinetobacter baumannii</i> Isolates and <i>In Vitro</i> Interactions of Various Antibiotics in Combination with Tigecycline and Colistin

“…6 As a result of this increasing carbapenem resistance, alternative antibiotic classes have become part of treatment. 1 Of these alternative classes, polymyxin and tigecycline (TGC) remain the most active treatments in vitro against MDR A. baumannii but resistance against these antibiotics is also reported. 4,6,7,8 Combination therapy is often used in the treatment of MDR A. baumannii infections to prevent the emergence of resistance and obtain a synergistic effect.…”

“…1,2,3 Before the 1970s, A. baumannii was susceptible to most traditional antibiotics such as broad spectrum beta-lactams, cephalosporins and tetracyclines. In recent years Acinetobacter related infections have been eradicated with difficulty in general by using single antimicrobial agent because of the ability of the bacteria to develop resistance.…”

“…4,6,7,8 Combination therapy is often used in the treatment of MDR A. baumannii infections to prevent the emergence of resistance and obtain a synergistic effect. 1,3,8 The aim of this study was to determine the antimicrobial resistance profile, clonal relation and efficacy of antimicrobial combinations on nosocomial MDR A. baumannii. …”