Colistin and Fusidic Acid, a Novel Potent Synergistic Combination for Treatment of Multidrug-Resistant Acinetobacter baumannii Infections

Abstract

bThe spread of multidrug-resistant Acinetobacter baumannii (MDRAB) has led to the renaissance of colistin (COL), often the only agent to which MDRAB remains susceptible. Effective therapy with COL is beset with problems due to unpredictable pharmacokinetics, toxicity, and the rapid selection of resistance. Here, we describe a potent synergistic interaction when COL was combined with fusidic acid (FD) against A. baumannii. Synergy in vitro was assessed against 11 MDRAB isolates using disc diffusion, checkerboard methodology (fractional inhibitory concentration index [FICI] of < 0.5, susceptibility breakpoint index [SBPI] of >2), and time-kill methodology (>2 log 10 CFU/ml reduction). The ability of FD to limit the emergence of COL resistance was assessed in the presence and absence of each drug alone and in combination. Synergy was demonstrated against all strains, with an average FICI and SBPI of 0.064 and 78.85, respectively. In time-kill assays, COL-FD was synergistic and rapidly bactericidal, including against COL-resistant strains. Fusidic acid prevented the emergence of COL resistance, which was readily selected with COL alone. This is the first description of a novel COL-FD regimen for the treatment of MDRAB. The combination was effective at low concentrations, which should be therapeutically achievable while limiting toxicity. Further studies are warranted to determine the mechanism underlying the interaction and the suitability of COL-FD as an unorthodox therapy for the treatment of multidrug-resistant Gram-negative infections. Infections due to the Gram-negative bacterium Acinetobacter baumannii are increasingly challenging to treat and control. The organism has emerged worldwide as a major nosocomial pathogen in critical care units responsible for bloodstream, respiratory, skin and soft tissue, and device-related infections (1). Clinical isolates are often resistant to multiple antimicrobial drugs and belong to successful epidemiologically defined clones that, once established, are extremely difficult to eradicate from the hospital environment (2). As a result, outbreaks are common, typically last for months, and may cost institutions in excess of $500,000 to curtail (3). Treatment of infected individuals is equally hampered by a seemingly endless capacity of the organism to acquire and maintain large numbers of antimicrobial resistance genes (4). Carbapenems, once considered the treatment of choice, are increasingly found to be ineffective, leaving polymyxins (polymyxin B and colistin [COL]) as the treatment of last resort (5).Although polymyxins have been widely employed in the treatment of A. baumannii infections, there are still concerns about their efficacy and safety. These include the unreliable methods for performing susceptibility testing, inadequate population pharmacokinetic data, uncertainties around appropriate dosing regimens, and the availability of the licensed formulations of colistin only as the inactive prodrug colistimethate sodium (6).Despite this, polymyxins have frequently been s...

Host defense antimicrobial peptides as antibiotics: design and application strategies

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Fusidic Acid: A Bacterial Elongation Factor Inhibitor for the Oral Treatment of Acute and Chronic Staphylococcal Infections

“…The recent spread of multi-drug-resistant Gram-negative pathogens and the inability to treat these infections even with colistin has led to testing fusidic acid in combination with colistin (Phee et al 2015). Fusidic acid is synergistic with colistin against Acinetobacter baumannii in vitro and the combination prevented resistance selection to both agents.…”

Sulbactam enhances the in�vitro activity of sitafloxacin against extensively‑drug resistant Acinetobacter baumannii

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