Correlation of Checkerboard Synergy Testing with Time-Kill Analysis and Clinical Outcomes of Extensively Drug-Resistant Acinetobacter baumannii Respiratory Infections

Abstract

We tested 76 extensively drug-resistant (XDR) Acinetobacter baumannii isolates by the checkerboard method using only wells containing serum-achievable concentrations (SACs) of drugs. Checkerboard results were correlated by time-kill assay and clinical outcomes. Minocycline-colistin was the best combination in vitro, as it inhibited growth in one or more SAC wells in all isolates. Patients who received a combination that inhibited growth in one or more SAC wells demonstrated better microbiological clearance than those who did not (88% versus 30%; P ‫؍‬ 0.025). The checkerboard platform may have clinical utility for XDR A. baumannii infections.A mong Gram-negative organisms, extensively drug-resistant (XDR) Acinetobacter baumannii is considered a serious threat to public health. As A. baumannii infections are associated with significant morbidity and mortality, the timely administration of effective broad-spectrum antibiotics is imperative (1). In recent years, increasing resistance among A. baumannii isolates has limited many therapy options, requiring the administration of empirical combination therapy for serious A. baumannii infections (2). In an attempt to select the most effective empirical antibiotic therapy, antimicrobial stewardship programs (ASPs) annually evaluate susceptibility based on institutional, unit-specific, or combination antibiograms. However, antibiograms are simply based on percent susceptibility and do not provide clinicians with additional aspects, including synergy or antagonism between agents. This presents significant limitations for ASPs in selecting optimal combination therapy for the treatment of A. baumannii infections.The comparison of specific antibiotic combinations identified in the literature provides ASPs with more definitive conclusions but does not address the heterogeneity of synergistic interactions of a specific combination against all isolates (3-6). Therefore, it may be more beneficial for ASPs to evaluate potential synergistic interactions in real time, particularly in critically ill patients infected with XDR A. baumannii. This study evaluated the use of a checkerboard platform to determine antibiotic combinations that are synergistic against XDR A. baumannii and compared the results to both time-kill assay results and clinical outcomes.We selected 76 unique XDR A. baumannii clinical isolates from our center between January 2009 and October 2013. Isolates were stored at Ϫ70°C and subcultured twice prior to testing. For the checkerboard assay, we identified the susceptibilities to amikacin (Crescent Chemical, Islandia, NY), colistin (MP Biomedical, Solon, OH), doripenem (TSZChem, Framingham, MA), minocycline (EMD Millipore, Darmstadt, Germany), and tigecycline (TSZChem, Framingham, MA) by microbroth dilution. Other susceptibilities were determined by the MicroScan system (Beckman Coulter, CA). The susceptibilities (percent) to the antibiotics tested were as follows: amikacin, 2/76 (3%); ampicillin-sulbactam, 2/76 (3%); cefepime, 0/76 (0%); ciprofloxacin, 0/76 (0%); do...

Pharmacodynamic Attainment of the Synergism of Meropenem and Fosfomycin Combination against Pseudomonas aeruginosa Producing Metallo-β-Lactamase

“…Although the methods of evaluation of synergism in vitro sometimes present controversial clinical reproducibility, Jean et al, evaluating the combination of tigecycline and imipenem-cilastatin in 28 patients with ventilator-associated pneumonia due to extensively drug-resistant (XDR) Acinetobacter baumannii, demonstrated a good correlation between the results of the checkerboard test and the lowest 30-day mortality for the patients treated with this combination (45). Comparing the synergistic action of antimicrobial combinations against extended-drug-resistant A. baumannii, Bremmer et al also demonstrated by the checkerboard method and a clinical study that the combination consisting of minocycline with colistin was superior to meropenem with colistin, with microbiological eradication being achieved in 88% and 30% of the patients (P ϭ 0.025), respectively (46). These studies support the use of information from the checkboard method in the PTA determination to optimize combination dosing regimens in clinical settings where no monotherapy option is available for MDR infections.…”

Humanized Exposures of a β-Lactam-β-Lactamase Inhibitor, Tazobactam, versus Non-β-Lactam-β-Lactamase Inhibitor, Avibactam, with or without Colistin, against <b><i>Acinetobacter baumannii</i></b> in Murine Thigh and Lung Infection Models

“…In vitro, colistin has demonstrated synergy against A. baumannii with various antibiotics, such as rifampin, aztreonam, meropenem, vancomycin, and minocycline [24][25][26], albeit findings with colistin and sulbactam are mixed, thereby demonstrating minimal synergy against colistin-resistant A. baumannii and antagonism against MDR A. baumannii [14,24,27]. Conversely, a meta-analysis of 7 studies involving polymyxins combined with sulbactam or ampicillin/sulbactam yielded synergy rates of 56.0 and 54.1%, respectively, against 70 A. baumannii isolates [28].…”

<p>Small Molecule Adjuvants Potentiate Colistin Activity and Attenuate Resistance Development in <em>Escherichia coli</em> by Affecting <em>pmr</em>AB System</p>

“…The fractional inhibitory concentrations (FICs) of SMs in combination with antibiotics were determined as described previously. 37 Synergistic, indifferent, and antagonistic activities were defined by FICs of 0.5, 0.51 to 4.0, and >4.0, respectively. Four SMs (SM2, SM3, SM5, and SM7) that showed synergism with most of the antibiotics tested were selected for further study.…”