Colistin for multidrug-resistant Acinetobacter baumannii from Thailand

textMultidrug-resistant (MDR) Acinetobacter baumannii have caused nosocomial infections worldwide. Nowadays, there are no effective regimens to treat MDR- A. baumannii. Therefore, this study’s objective was to find out an effective antimicrobial combination against MDR-A. baumannii. This project consisted of four parts. Part 1 was an in vitro antimicrobial susceptibility test of MDR-A. baumannii collected from Thailand. Minimum inhibitory concentrations (MICs) were performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines using a broth microdilution technique. This study found that colistin was the most active against MDR-A. baumannii (MIC50 0.5µg/mL, MIC90 1µg/mL). In addition, 77% of MBL -producing A. baumannii were reported using the MBL Etest strips. This prevalence was higher than previously reported. Part 2 was conducted to compare antimicrobial susceptibility profiles of pre- and post-colistin exposure A. baumannii isolates. After colistin exposure, A. baumannii isolates became resistant to colistin but more susceptible to cefepime, doxycycline, meropenem and rifampicin. These findings suggested the potential of a synergistic activity of colistin combinations. Part 3 was a time-kill study that compared activity of colistin alone and in combination against MDR-A. baumannii. Time-kill assays were performed using a standard inoculum. Colistin monotherapy was rapidly bactericidal against these isolates; however, regrowth occurred at 24 hrs. On the other hand, colistin in combination with cefepime, doxycycline, meropenem or rifampicin demonstrated synergy and maintained bactericidal activity over 24 hrs (100%). Part 4 was designed to optimize meropenem dosing regimens using a PK-PD model. Three MDR-A. baumannii with colistin MICs (0.5-1µg/mL) and meropenem MICs (32-128µg/mL) were tested. The antimicrobial regimens alone and in combination evaluated were: colistin 2.5mg/kg every 12 hrs, meropenem 3g and 6g continuously infused (CI) over 24 hrs. Colistin monotherapy was rapidly bactericidal but regrowth did occur. Both combinations express synergy (100%). Nevertheless, colistin and high dose meropenem (6g CI over 24 hrs) was bactericidal and prevented regrowth over 24 hrs. In conclusion, MBL-producing A. baumannii is more prevalent than previously thought and colistin combined with a high dose meropenem (6g/day) has good potential to overcome multidrug- and carbapenem-resistant A. baumannii. These findings should be further evaluated in animal models and clinical practices.Pharmac

In Vitro Synergy of Polymyxins and Carbapenems: Systematic Review and Meta Analysis.

ObjectivesTo examine the evidence on in-vitro synergy of polymyxin-carbapenem combination therapy against Gram-negative bacteria (GNB)MethodsSystematic review and meta-analysis. All studies examining in-vitro interactions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB. A broad search was conducted with no language, date or publication status restrictions. Synergy rates, defined as fractional inhibitory concentration index 2log colony forming unit reduction, were pooled separately for time-kill, checkerboard, and E-test in a mixed-effects meta-analysis of rates. We examined whether synergy rate depended on testing method, type of antibiotic, bacteria and resistance to carbapenems. Pooled rates with 95% confidence intervals are shown.Results39 published studies and 15 conference proceeding were included, reporting on 246 different tests on 1054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI 64-87) for Acinetobacter baumannii, 44% (95% CI 30-59%) for Klebsiella pneumoniae and 50% (95% CI 30-69%) for Pseudomonas aeruginosa with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. For A. baumannii, meropenem was more synergistic than imipenem, whereas for P. aeruginosa the opposite was true. Checkerboard and Etest studies generally reported lower synergy rates than time-kill. Use of combination therapy led to less resistance development in-vitro.ConclusionsThe combination of a carbapenem with a polymyxin against GNB, especially A. baumannii, is supported in-vitro by high synergy rates, with low antagonism and less resistance development. These findings should be examined in clinical studies