Colistin for multidrug-resistant Acinetobacter baumannii from Thailand

Abstract

Multidrug-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.