Pharmacodynamic Effects of Sulbactam/Meropenem/Polymyxin-B Combination Against Extremely Drug Resistant Acinetobacter baumannii Using Checkerboard Information.

Aim: The aims of the study are to evaluate the activity of sulbactam, meropenem, and polymyxin B alone and in combination against six isolates of extremely drug resistant Acinetobacter baumannii and to determine dosing regimens that achieve a sufficient joint probability of target attainment (PTA) based on combination antimicrobial pharmacodynamics. Materials and Methods: The combinations were evaluated by the checkerboard method and were considered synergistic when the fractional inhibitory concentration index (FICI) ≤0.5. Pharmacodynamic analyses were carried out by evaluating dosing regimens that achieve ≥90% joint PTA at the percentage of time over a 24-h period wherein the free drug concentration is above the minimum inhibitory concentration (%fT> MIC) of 40% and 60% for meropenem and sulbactam, respectively, and 20 for the ratio of the area under the free drug concentration-time curve over MIC (fAUC/MIC) for polymyxin B. Results: For both polymyxin B-resistant and susceptible isolates, the addition of sulbactam in combination with meropenem and subinhibitory concentration of polymyxin B showed important synergistic activity (five isolates; FICI ≤0.281); the recommended dosing regimens were 2/4 g meropenem/sulbactam q8 hours and 0.5 mg/kg polymyxin B q12 hours. Conclusion: This in vitro study showed that sulbactam can significantly improve the action of meropenem and polymyxin B in OXA-producing A. baumannii isolates, especially when there are no new treatment options available for infections caused by these microorganisms.

Synergistic activity of polymyxin B combined with vancomycin against carbapenem-resistant and polymyxin-resistant Acinetobacter baumannii: first in vitro study.

PURPOSE: The effect of a combination of polymyxin B (PMB) and vancomycin (VAN) was assessed against six Acinetobacter baumannii clinical isolates belonging to six different clusters (three PMB-susceptible and three PMB-resistant). METHODOLOGY: The synergistic effect of the PMB-VAN combination was determined with the checkerboard, time-kill, disk-diffusion and M.I.C.Evaluator assays. PMB-resistance was investigated with mcr-1 gene amplification and a mutant frequency assay. RESULTS: In the checkerboard assay, all PMB-resistant isolates showed a synergistic effect. The time-kill assay demonstrated that the PMB-VAN combination had a bactericidal effect at 24 h against isolates with a high mutant rate for PMB, suggesting that this combination may block the hypermutation of some isolates. No antagonism was detected. All PMB-resistant isolates also showed synergism in the disk-diffusion test, and a significant decrease in VAN MICs in the M.I.C.Evaluator assay. CONCLUSION: Our findings indicate that the PMB-VAN combination has a synergistic effect on A. baumannii, especially against PMB-resistant isolates.

What does the susceptible-dose dependent interpretive category for cefepime in ESBL-producing bacteria?

In this study, we investigated the frequency of isolates included in the susceptible-dose dependent (SDD) category, according to the Clinical and Laboratory Standards Institute guidelines, carrying blaTEM, blaSHV and blaCTX genes among 92 Klebsiella pneumoniae and 80 Enterobacter cloacae clinical isolates. The presence of one or more extended-spectrum ß-lactamases (ESBLs) genes was observed in 64% K. pneumoniae and 69% E. cloacae isolates. Nineteen isolates were included in SDD interpretive category criteria, of which 15 carried ESBL genes (seven K. pneumoniae and eight E. cloacae). Considering the high proportion of ESBL gene-containing isolates included in the SDD category (79%), we recommend that physicians exercise caution in the use of cefepime for treatment of infections caused by these isolates, reducing possible therapeutic failure, particularly in cases of ESBL-producing bacterial strains.

Strategies for the treatment of polymyxin B-resistant Acinetobacter baumannii infections.

In this study, the activity of meropenem (MEM), fosfomycin (FOF) and polymyxin B (PMB), alone and in combination, was analysed. In addition, optimisation of the pharmacodynamic index of MEM and FOF against six isolates of OXA-23-producing Acinetobacter baumannii (including three resistant to PMB) that were not clonally related was assessed. Antimicrobial combinations were evaluated by chequerboard analysis and were considered synergistic when the fractional inhibitory concentration index (FICI) was ≤0.5. Pharmacodynamic analyses of the MEM and FOF dosing schemes were performed by Monte Carlo simulation. The target pharmacodynamic index (%ƒT>MIC) for MEM and FOF was ≥40% and ≥70%, respectively, and a probability of target attainment (PTA) ≥0.9 was considered adequate. Among the PMB-resistant isolates, combinations of PMB+MEM and PMB+FOF+MEM showed the highest synergistic activity (FICI ≤0.125); isolates that were previously PMB-resistant were included in the susceptible category using CLSI interpretive criteria. Pharmacodynamic evaluation found that for a FOF minimum inhibitory concentration (MIC) of ≤16µg/mL, treatment both by bolus dosing and prolonged infusion achieved adequate PTA, whilst for MIC=32µg/mL only infusion achieved adequate PTA. For a MEM MIC of 4µg/mL, only the bolus treatment scheme with 1.5g q6h and the infusion schemes with 1.0g q8h, 1.5g q6h and 2.0g q8h achieved PTA ≥0.9. Results of antimicrobial and pharmacodynamic analyses can assist in treating infections caused by multidrug-resistant A. baumannii. However, in vivo clinical studies are essential to evaluate the true role of these compounds, including intravenous antimicrobial FOF therapy.

ISAba1/blaOXA-23: A serious obstacle to controlling the spread and treatment of Acinetobacter baumannii strains.

This study demonstrated a direct correlation between Acinetobacter baumannii clusters carrying the ISAba1/blaOXA-23 gene and increased minimal inhibitory concentrations for carbapenems and greater clonal diversity. Our findings showed that clusters carrying ISAba1 are widely distributed in our hospital, further complicating the treatment and control of infections caused by A baumannii.

A rapid and simple method to detect ESBL in Enterobacter cloacae based on MIC of cefepime.

INTRODUCTION: The aim of this study was to identify a rapid and simple phenotypic method for extended-spectrum ß-lactamase (ESBL) detection in Enterobacter cloacae. METHODS: A total of 79 consecutive, non-repeated samples of E. cloacae were evaluated. Four phenotypic methods were applied for ESBL detection, results were compared to multiplex polymerase chain reaction (PCR) as the gold standard reference method: 1) ceftazidime and cefotaxime disks with and without clavulanate, both with boronic acid added; 2) disk approximation using cefepime and amoxicillin/clavulanate; 3) ESBL screening by minimum inhibitory concentration (MIC) ≥ 16µg/mL and 4) by MIC ≥ 2µg/mL for cefepime. RESULTS: Method 4 showed the best combination of sensitivity (100%) and specificity (94%). CONCLUSIONS: MIC ≥ 2µg/mL for cefepime would be very useful for the phenotypic detection of ESBL in samples of E. cloacae.

Can ampicillin/sulbactam resistance in Acinetobacter baumannii be predicted accurately by disk diffusion?

The objective of this study was to compare the performance of disk diffusion and agar dilution for the determination of susceptibility to ampicillin/sulbactam (SAM), ceftazidime, cefepime, imipenem, meropenem, polymyxin B and tigecycline of 121 Acinetobacter baumannii clinical isolates. The antimicrobial susceptibility testing methods were performed as recommended by the Clinical and Laboratory Standards Institute (CLSI). For SAM, in addition the Etest method was performed according to the manufacturer's instructions. The error rates for the antimicrobial agents for 121 isolates tested were within the acceptable ranges established by the CLSI, with the exception of SAM and polymyxin B. For polymyxin B, there were 1.7% very major errors and for SAM there were 15% comparing disk diffusion with agar dilution. The very major error rate of SAM comparing the Etest with agar dilution was 10%. These high observed rates of very major error cast doubt on the disk diffusion and Etest techniques as appropriate methods for detecting resistance to SAM.