In vitro and in vivo assessment of the antibacterial activity of colistin alone and in combination with other antibiotics against Acinetobacter baumannii and Escherichia coli.
OBJECTIVES
Limited therapeutic options exist for treating severe infections caused by multidrug-resistant (MDR) and extensively drug-resistant Gram-negative bacteria (GNB). In this study, the activity of colistin (COL) as monotherapy and in combination with other antibiotics against Acinetobacter baumannii in vitro was investigated. In addition, the efficacy of intravenous colistimethate sodium (CMS) was evaluated in a murine model of urinary tract infection (UTI) induced by MDR Escherichia coli.


METHODS
Minimum inhibitory concentration (MIC), Monte Carlo simulation, fractional inhibitory concentration index (FICI), time-kill study and erythrocyte lysis assay were applied to evaluate the effect and cytotoxicity of COL, meropenem, imipenem, doripenem (DOR) and sulbactam alone and in combination. For the in vivo experiment, determination of the bacterial burden and histopathological examination were performed to evaluate the efficacy of CMS against UTI.


RESULTS
Of 106 A. baumannii isolates, 104 (98.1%) were susceptible to COL. In the chequerboard assay, COL + DOR showed the highest rate of synergism (60%). No antagonism or cytotoxicity was observed. All COL-based combinations were able to inhibit or slow bacterial re-growth in a time-kill assay. In an in vivo activity study, intravenous CMS reduced not only the bacterial load but also inflammation and maintained structural integrity of infected bladders and kidneys.


CONCLUSION
The effectiveness of COL alone in vitro and in vivo suggested that intravenous CMS will be an effective and available therapeutic strategy for UTI due to MDR-GNB. In-depth in vitro tests demonstrated that COL + DOR could be an attractive option, especially when the COL MIC is ≥1 μg/mL.
['Wang|Yale|Y|', 'Li|He|H|', 'Xie|Xiaoqian|X|', 'Wu|XiaoHan|X|', 'Li|Xinxin|X|', 'Zhao|Zeyue|Z|', 'Luo|Shasha|S|', 'Wan|Zhijie|Z|', 'Liu|Jingjing|J|', 'Fu|Lei|L|', 'Li|Xiaotian|X|']
D040981:Acinetobacter baumannii D061605:Administration, Intravenous D000818:Animals D000900:Anti-Bacterial Agents D018441:Biofilms D003091:Colistin D004195:Disease Models, Animal D000077726:Doripenem D024901:Drug Resistance, Multiple, Bacterial D004357:Drug Synergism D004359:Drug Therapy, Combination D004926:Escherichia coli D004927:Escherichia coli Infections D005260:Female D006801:Humans D015378:Imipenem D000077731:Meropenem D051379:Mice D008826:Microbial Sensitivity Tests D009010:Monte Carlo Method D013407:Sulbactam D016896:Treatment Outcome D014552:Urinary Tract Infections
Antibacterial activity Colistin Multidrug-resistant Extensively drug-resistant Gram-negative bacteria Urinary tract infection