Short CommunicationComparative pharmacodynamics of four different carbapenems in combination with polymyxin B against carbapenem-resistant Acinetobacter baumannii
Introduction
Acinetobacter baumannii is an invasive, opportunistic, Gram-negative pathogen responsible for an alarming rate of morbidity and mortality in the intensive care population [1]. Historically, carbapenems have been the most reliable treatment option for serious nosocomial A. baumannii infections. However, identification of the ideal carbapenem for combatting multidrug-resistant A. baumannii has been confounded by conflicting reports of minimum inhibitory concentration (MIC) testing and in vitro kill assessments. Whilst ertapenem reportedly possesses the least intrinsic activity [2], opposing studies have suggested that either doripenem [2], meropenem [3] or imipenem [4] is the most active against multidrug-resistant A. baumannii. Unfortunately, acquisition of carbapenem resistance mechanisms has further obscured the ideal treatment of A. baumannii.
To counter the increasing prevalence of carbapenem-resistant A. baumannii, clinicians are now forced to utilise a polymyxin [colistin or polymyxin B (PMB)] as a drug of last resort [5]. However, the emergence of colistin heteroresistance and the increasing frequency of polymyxin resistance have precipitated the search for polymyxin combinations that elicit greater bacterial killing than is possible with a polymyxin alone [6]. Enhanced activity against A. baumannii has been observed when a polymyxin is paired with a carbapenem in vitro [7], and successful use of carbapenem/polymyxin combinations has been reported clinically [8]. Although a meta-analysis of in vitro carbapenem/polymyxin killing identified meropenem and doripenem as the most likely candidates for enhancing polymyxin activity, the study results were based on rates of synergy and did not examine the rate and extent of killing for each combination [9]. It is also unknown whether the density of the A. baumannii inoculum influences selection of the optimal carbapenem. In the present study, we sought to characterise the comparative pharmacodynamics of each carbapenem in combination with PMB against carbapenem-resistant A. baumannii utilising time–kill experiments conducted at two different starting inocula.
Section snippets
Materials and methods
Two polymyxin-susceptible A. baumannii strains (N16870 and 03-149-1) were utilised in this study. Time–kill experiments were conducted over 48 h at starting inocula of 106 CFU/mL and 108 CFU/mL in cation-adjusted Mueller–Hinton broth as detailed previously [10]. Solutions of ertapenem, doripenem, meropenem and imipenem (Sigma Chemical Co., St Louis, MO) were freshly prepared on the day of each experiment. An array of five antibiotic concentrations was prepared for each carbapenem. The highest
Results
The results of the time–kill experiments at the 106 CFU/mL inoculum are displayed in Fig. 1. For strain 03-149-1, all four carbapenems were able to achieve a ≥3 log10 CFU/mL reduction by 6 h [Fig. 1(A1–A4)]. Ertapenem combinations displayed the least activity, with bacterial counts that began to recover by 8 h independent of the ertapenem concentration used in the combination (mean standard deviation 0.4 log10 CFU/mL). The majority of doripenem combinations also resulted in regrowth by 8 h,
Discussion
The ability of A. baumannii to acquire resistance mechanisms to commonly used antibiotics has made the pathogen particularly troubling in the nosocomial environment [1]. Here we sought to characterise the pharmacodynamics of four different carbapenems in combination with PMB at two different inocula to better understand the killing of antimicrobial combinations against carbapenem-resistant A. baumannii. Regardless of the inoculum, a PMB concentration of 1.5 mg/L was unable to achieve sustained
Conclusions
During A. baumannii time–kill experiments, ertapenem was the least active carbapenem in combination with PMB, whilst doripenem, meropenem and imipenem combinations displayed slight differences in their activities that were influenced by the A. baumannii strain and bacterial burden. Individual carbapenem MICs were also poorly predictive of how each carbapenem performed when in combination with PMB. Given the similar activities of doripenem, meropenem and imipenem when paired with PMB, the
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These two authors contributed equally to this work.