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In vitro activity of antibiotic combinations against multidrug-resistant strains of Acinetobacter baumannii and the effects of their antibiotic resistance determinants.

ABSTRACT: Various combinations of antibiotics are reported to show synergy in treating nosocomial infections with multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii). Here, we studied hospital-acquired outbreak strains of MDR A. baumannii to evaluate optimal combinations of antibiotics. One hundred and twenty-one strains were grouped into one major and one minor clonal group based on repetitive PCR amplification. Twenty representative strains were tested for antibiotic synergy using Etest(®). Five strains were further analyzed by analytical isoelectric focusing and PCR to identify ?-lactamase genes or other antibiotic resistance determinants. Our investigation showed that the outbreak strains of MDR A. baumannii belonged to two dominant clones. A combination of colistin and doxycycline showed the best result, being additive or synergistic against 70% of tested strains. Antibiotic additivity was observed more frequently than synergy. Strains possessing the same clonality did not necessarily demonstrate the same response to antibiotic combinations in vitro. We conclude that the effect of antibiotic combinations on our outbreak strains of MDR A. baumannii seemed strain-specific. The bacterial response to antibiotic combinations is probably a result of complex interactions between multiple concomitant antibiotic resistance determinants in each strain.

SUBMITTER: Miyasaki Y

PROVIDER: S-EPMC3280091 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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In vitro activity of antibiotic combinations against multidrug-resistant strains of Acinetobacter baumannii and the effects of their antibiotic resistance determinants.

Miyasaki Yoko Y Morgan Margie A MA Chan Raymond C RC Nichols W Stephen WS Hujer Kristine M KM Bonomo Robert A RA Murthy A Rekha AR

FEMS microbiology letters 20120106 1

Various combinations of antibiotics are reported to show synergy in treating nosocomial infections with multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii). Here, we studied hospital-acquired outbreak strains of MDR A. baumannii to evaluate optimal combinations of antibiotics. One hundred and twenty-one strains were grouped into one major and one minor clonal group based on repetitive PCR amplification. Twenty representative strains were tested for antibiotic synergy using Etest(®). ...[more]

PMID: 22151035

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Project description:Background and Objectives: Developing effective treatment outcomes for multidrug-resistant Acinetobacter baumannii (MRAB) infections, with colistin and tigecycline the current frontline therapies, is challenging, because of the risk of renal toxicity and low blood concentrations of active ingredients when administered intravenously. This study aimed to identify the effect of combination therapy using conventional antimicrobial agents that are used for treating drug-resistant bacteria and the additional synergistic effect of four probiotic culture extracts isolated from the human body and Lactobacillus preparations. Materials and Methods: The antimicrobial combination and synergistic effect of adding Lactobacillus extract against 33 strains of A. baumannii isolated from pus, urine, and other specimens submitted to the Department of Laboratory Medicine of a university hospital, located in Gyeonggi-do, Korea, was investigated over a 3-year period between January 2017 and December 2019. Results: Antimicrobial susceptibility tests on bacteria isolated in clinical practice demonstrated that 26 strains (79%) were MRAB, while multi-locus sequence typing indicated that ST191 was the predominant type (45%; n = 15). Checkerboard test results demonstrated that combination therapy using meropenem and colistin had the highest synergistic effect (fractional inhibitory concentration index = 0.5), while the time-kill assay test using Lactobacillus spp. culture extract exhibited an inhibitory effect within 1 h and complete inhibition of MRAB within 3 h. Lactobacillus paracasei exhibited the fastest antimicrobial reactivity and longest sustained antimicrobial activity. Conclusion: These findings provide useful foundational data for an appropriate combination of colistin with other antimicrobial agents for treating MRAB infection in clinical settings, and the use of various probiotic culture extracts to reduce the required dosage, and therefore toxicity of colistin.

Project description:BackgroundInfections sustained by multidrug-resistant (MDR) and pan-resistant Acinetobacter baumannii have become a challenging problem in Intensive Care Units. Tigecycline provided new hope for the treatment of MDR A. baumannii infections, but isolates showing reduced susceptibility have emerged in many countries, further limiting the therapeutic options. Empirical combination therapy has become a common practice to treat patients infected with MDR A. baumannii, in spite of the limited microbiological and clinical evidence supporting its efficacy. Here, the in vitro interaction of tigecycline with seven commonly used anti-Acinetobacter drugs has been assessed.MethodsTwenty-two MDR A. baumannii isolates from Intensive Care Unit (ICU) patients and two reference strains for the European clonal lineages I and II (including 3, 15 and 6 isolates that were resistant, intermediate and susceptible to tigecycline, respectively) were tested. Antimicrobial agents were: tigecycline, levofloxacin, piperacillin-tazobactam, amikacin, imipenem, rifampicin, ampicillin-sulbactam, and colistin. MICs were determined by the broth microdilution method. Antibiotic interactions were determined by chequerboard and time-kill assays. Only antibiotic combinations showing synergism or antagonism in both chequerboard and time-kill assays were accepted as authentic synergistic or antagonistic interactions, respectively.ResultsConsidering all antimicrobials in combination with tigecycline, chequerboard analysis showed 5.9% synergy, 85.7% indifference, and 8.3% antagonism. Tigecycline showed synergism with levofloxacin (4 strains; 16.6%), amikacin (2 strains; 8.3%), imipenem (2 strains; 8.3%) and colistin (2 strains; 8.3%). Antagonism was observed for the tigecycline/piperacillin-tazobactam combination (8 strains; 33.3%). Synergism was detected only among tigecycline non-susceptible strains. Time-kill assays confirmed the synergistic interaction between tigecycline and levofloxacin, amikacin, imipenem and colistin for 5 of 7 selected isolates. No antagonism was confirmed by time-kill assays.ConclusionThis study demonstrates the in vitro synergistic activity of tigecycline in combination with colistin, levofloxacin, amikacin and imipenem against five tigecycline non-susceptible A. baumannii strains, opening the way to a more rationale clinical assessment of novel combination therapies to combat infections caused by MDR and pan-resistant A. baumannii.

Project description:ObjectivesWidespread antimicrobial resistance often limits the availability of therapeutic options to only a few last-resort drugs that are themselves challenged by emerging resistance and adverse side effects. Apramycin, an aminoglycoside antibiotic, has a unique chemical structure that evades almost all resistance mechanisms including the RNA methyltransferases frequently encountered in carbapenemase-producing clinical isolates. This study evaluates the in vitro activity of apramycin against multidrug-, carbapenem- and aminoglycoside-resistant Enterobacteriaceae and Acinetobacter baumannii, and provides a rationale for its superior antibacterial activity in the presence of aminoglycoside resistance determinants.MethodsA thorough antibacterial assessment of apramycin with 1232 clinical isolates from Europe, Asia, Africa and South America was performed by standard CLSI broth microdilution testing. WGS and susceptibility testing with an engineered panel of aminoglycoside resistance-conferring determinants were used to provide a mechanistic rationale for the breadth of apramycin activity.ResultsMIC distributions and MIC90 values demonstrated broad antibacterial activity of apramycin against Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Morganella morganii, Citrobacter freundii, Providencia spp., Proteus mirabilis, Serratia marcescens and A. baumannii. Genotypic analysis revealed the variety of aminoglycoside-modifying enzymes and rRNA methyltransferases that rendered a remarkable proportion of clinical isolates resistant to standard-of-care aminoglycosides, but not to apramycin. Screening a panel of engineered strains each with a single well-defined resistance mechanism further demonstrated a lack of cross-resistance to gentamicin, amikacin, tobramycin and plazomicin.ConclusionsIts superior breadth of activity renders apramycin a promising drug candidate for the treatment of systemic Gram-negative infections that are resistant to treatment with other aminoglycoside antibiotics.

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In vitro activity of antibiotic combinations against multidrug-resistant strains of Acinetobacter baumannii and the effects of their antibiotic resistance determinants.

Publications

In vitro activity of antibiotic combinations against multidrug-resistant strains of Acinetobacter baumannii and the effects of their antibiotic resistance determinants.

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