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Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Rat Pneumonia Model.

ABSTRACT: Minocycline is currently approved in the United States for the treatment of infections caused by susceptible isolates of Acinetobacter spp. The objective of these studies was to determine the minocycline exposures associated with an antibacterial effect against Acinetobacter baumannii in a rat pneumonia model. Rats received minocycline doses as 30-min intravenous infusions. In the rat pneumonia model, six clinical isolates of A. baumannii with MICs ranging from 0.03 to 4?mg/liter were studied. In this model, minocycline produced a bacteriostatic effect with a free 24-h area under the concentration-time curve (AUC)/MIC ratio of 10 to 16 and produced 1 log of bacterial killing with a free 24-h AUC/MIC of 13 to 24. These exposures can be achieved with the current FDA-approved dosage regimens of intravenous minocycline.

SUBMITTER: Tarazi Z

PROVIDER: S-EPMC6355566 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Rat Pneumonia Model.

Tarazi Ziad Z Sabet Mojgan M Dudley Michael N MN Griffith David C DC

Antimicrobial agents and chemotherapy 20190129 2

Minocycline is currently approved in the United States for the treatment of infections caused by susceptible isolates of Acinetobacter spp. The objective of these studies was to determine the minocycline exposures associated with an antibacterial effect against Acinetobacter baumannii in a rat pneumonia model. Rats received minocycline doses as 30-min intravenous infusions. In the rat pneumonia model, six clinical isolates of A. baumannii with MICs ranging from 0.03 to 4 mg/ ...[more]

PMID: 30397059

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Project description:Minocycline-based combination therapy has been suggested to be a possible choice for the treatment of infections caused by minocycline-susceptible Acinetobacter baumannii, but its use for the treatment of infections caused by minocycline-resistant A. baumannii is not well established. In this study, we compared the efficacy of minocycline-based combination therapy (with colistin, cefoperazone-sulbactam, or meropenem) to that of colistin in combination with meropenem for the treatment of minocycline-resistant A. baumannii infection. From 2006 to 2010, 191 (17.6%) of 1,083 A. baumannii complex isolates not susceptible to minocycline from the Taiwan Surveillance of Antimicrobial Resistance program were collected. Four representative A. baumannii isolates resistant to minocycline, amikacin, ampicillin-sulbactam, ceftazidime, ciprofloxacin, cefepime, gentamicin, imipenem, levofloxacin, meropenem, and piperacillin-tazobactam were selected on the basis of the diversity of their pulsotypes, collection years, health care setting origins, and geographic areas of origination. All four isolates had tetB and overexpressed adeABC, as revealed by quantitative reverse transcription-PCR. Among all minocycline-based regimens, only the combination with colistin produced a fractional inhibitory concentration index comparable to that achieved with meropenem combined with colistin. Minocycline (4 or 16 ?g/ml) in combination with colistin (0.5 ?g/ml) also synergistically killed minocycline-resistant isolates in time-kill studies. Minocycline (50 mg/kg of body weight) in combination with colistin (10 mg/kg) significantly improved the survival of mice and reduced the number of bacteria present in the lungs of mice compared to the results of monotherapy. However, minocycline (16 ?g/ml)-based therapy was not effective at reducing biofilm-associated bacteria at 24 or 48 h when its effectiveness was compared to that of colistin (0.5 ?g/ml) and meropenem (8 ?g/ml). The clinical use of minocycline in combination with colistin for the treatment of minocycline-resistant A. baumannii may warrant further investigation.

Project description:BACKGROUND:Acinetobacter baumannii is an opportunistic pathogen that causes serious nosocomial infection in intensive care units. In particular, carbapenem-resistant A. baumannii (CRAB) strains have been increasing in the past decade, and they have caused major medical problems worldwide. In this study, a novel A. baumannii lytic phage, the YMC 13/03/R2096 ABA BP (phage Βϕ-R2096), which specifically causes the lysis of CRAB strains, was characterized in detail in vitro and in silico, and the in vivo effectiveness of phage therapy was evaluated using Galleria mellonella and a mouse model of acute pneumonia. RESULTS:The A. baumannii phage Βϕ-R2096 was isolated from sewage water using CRAB clinical strains selected from patients at a university hospital in South Korea. The complete genome of the phage Βϕ-R2096, which belongs to the Myoviridae family, was analyzed. Phage Βϕ-R2096 inhibited bacterial growth in a dose-dependent manner and exhibited high bacteriolytic activity at MOI = 10. In the evaluation of its therapeutic potential against CRAB clinical isolates using two in vivo models, phage Βϕ-R2096 increased the survival rates of both G. mellonella larvae (from 0 to 50% at 24 h) and mice (from 30% with MOI = 0.1 to 100% with MOI = 10 for 12 days) in post-infection of CRAB. In particular, phage Βϕ-R2096 strongly ameliorated histologic damage to infected lungs, with bacterial clearance in the lungs observed on day 3 postinfection in the mouse acute pneumonia model. Moreover, in vivo studies revealed no mortality or serious side effects in phage-treated groups. CONCLUSION:The results of this study strongly suggest that phage Βϕ-R2096, a novel A. baumannii lytic phage, could be an alternative antibacterial agent to control CRAB infections. This study is the first report to compare in vivo evaluations (G. mellonella larvae and a mouse acute pneumonia model) of the therapeutic efficacy of a phage against CRAB infections.

Dataset Information

Pharmacodynamics of Minocycline against Acinetobacter baumannii in a Rat Pneumonia Model.

Publications

Pharmacodynamics of Minocycline against <i>Acinetobacter baumannii</i> in a Rat Pneumonia Model.

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