Investigation of Colistin Heteroresistance and Some Factors Affecting Heteroresistance in Carbapenem-Resistant A. baumannii Strains

Introduction: Colistin can be used in patients infected with carbapenem-resistant Acinetobacter baumannii complex (CR-ABC), but recently resistance to colistin and heteroresistance have been reported. In this study we aimed to investigate the colistin heteroresistance rates and the effects of colistin and its combinations on colistin heteroresistance/resistance development in CR-ABC strains in our hospital. Materials and Methods: Heteroresistance analysis was performed on CR-ABC isolates and standard ABC strain [American Type Culture Collection (ATCC) 19606)] strain. To investigate hidden heteroresistance, the isolates were exposed to colistin at sub-inhibitory concentrations. ‘Time-kill’ study was performed on the standard strain and a clinical strain for colistin. Serial passage test was performed to investigate the effects of drug combinations on heteroresistance/resistance development. Results: In the first heteroresistance analysis test, all strains were found to be non-heteroresistant. However, after sub-inhibitory exposure to colistin, colistin heteroresistance/resistance developed in all isolates. In serial passages, colistin-rifampicin and colistin-tigecycline (Col+Tig) combinations were found to be effective and prevented growth of colistin-resistant sub-populations even at sub-inhibitory doses. Colistin-gentamicin (Col+Gen) combination was not found to be effective against the clinical isolate while it was effective on ATCC strain. Colistin-fluconazole combination was found to be ineffective at all concentrations. Conclusion: In our study, it was shown that the strains which were detected to be non-heteroresistant could easily transform to heteroresistant/resistant forms after exposure to colistin. Colistin-rifampicin and Col+Tig combinations were found to be effective and prevented the emergence of heteroresistance/resistance to colistin even at low concentrations. At low concentrations, Col+Gen combination was ineffective against the clinical ABC isolate. Colistin-fluconazole combination failed to inhibit the emergence of resistant bacteria. Heteroresistance or resistance to colistin may easily develop because of inappropriate use of this antibiotic. To prevent this condition, colistin should be administrated at appropriate doses and in combination with the suggested antibiotics