Dataset Information

In Vitro Synergy of Colistin in Combination with Meropenem or Tigecycline against Carbapenem-Resistant Acinetobacter baumannii.

ABSTRACT: Acinetobacter baumannii is currently classified as one of six pathogens that contribute to increased patient mortality. Thus, exploratory studies navigating alternative treatment strategies are of supreme interest. Herein, we completed minimum inhibitory concentration (MIC) testing, and time-kill analyses (TKA) on 50 carbapenem-resistant Acinetobacterbaumannii isolates including 28 colistin-resistant isolates. Upon testing of MEM or TGC in the presence of sub-inhibitory COL against the 50 isolates, there was a median 2-fold reduction in MEM and TGC MICs. In the TKAs, the COL+MEM combination was synergistic in 45 (90%) isolates and bactericidal in 43 (86%) isolates at 24 hours, whereas the COL+TGC combination TKAs demonstrated synergy in 32 (64%) isolates and bactericidal activity was shown in 28 (56%) isolates. Additionally, sulbactam (SUL) and TGC were added to the COL+MEM dual therapy regimen to assess the possible utility of a triple therapy regimen against five non-responsive isolates. The COL+MEM+SUL and COL+MEM+TGC regimens effectively restored synergy in (5/5) 100% of the isolates. The results of this study demonstrate the potential utility of COL combinations in the treatment of carbapenem-resistant isolates.

SUBMITTER: Abdul-Mutakabbir JC

PROVIDER: S-EPMC8300792 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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In Vitro Synergy of Colistin in Combination with Meropenem or Tigecycline against Carbapenem-Resistant Acinetobacter baumannii.

Abdul-Mutakabbir Jacinda C JC Yim Juwon J Nguyen Logan L Maassen Philip T PT Stamper Kyle K Shiekh Zain Z Kebriaei Razieh R Shields Ryan K RK Castanheira Mariana M Kaye Keith S KS Rybak Michael J MJ

Antibiotics (Basel, Switzerland) 20210720 7

Acinetobacter baumannii is currently classified as one of six pathogens that contribute to increased patient mortality. Thus, exploratory studies navigating alternative treatment strategies are of supreme interest. Herein, we completed minimum inhibitory concentration (MIC) testing, and time-kill analyses (TKA) on 50 carbapenem-resistant Acinetobacterbaumannii isolates including 28 colistin-resistant isolates. Upon testing of MEM or TGC in the presence of sub-inhibitory COL ...[more]

PMID: 34356801

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Project description:BackgroundWith an increase in the use of colistin methansulfonate (CMS) to treat carbapenem-resistant Acinetobacter baumannii infections, colistin resistance is emerging.MethodsPatients with infection or colonization due to colistin-resistant A. baumannii were identified at a hospital system in Pennsylvania. Clinical data were collected from electronic medical records. Susceptibility testing, pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST) were performed. To investigate the mechanism of colistin resistance, lipid A was subjected to matrix-assisted laser desorption/ionization mass spectrometry.ResultsTwenty patients with colistin-resistant A. baumannii were identified. Ventilator-associated pneumonia was the most common type of infection. Nineteen patients had received intravenous and/or inhaled CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection prior to identification of colistin-resistant isolates. The 30-day all-cause mortality rate was 30%. The treatment regimen for colistin-resistant A. baumannii infection associated with the lowest mortality rate was a combination of CMS, a carbapenem, and ampicillin-sulbactam. The colistin-susceptible and -resistant isolates from the same patients were highly related by PFGE, but isolates from different patients were not, suggesting evolution of resistance during CMS therapy. By MLST, all isolates belonged to the international clone II, the lineage that is epidemic worldwide. Phosphoethanolamine modification of lipid A was present in all colistin-resistant A. baumannii isolates.ConclusionsColistin-resistant A. baumannii occurred almost exclusively among patients who had received CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection. Lipid A modification by the addition of phosphoethanolamine accounted for colistin resistance. Susceptibility testing for colistin should be considered for A. baumannii identified from CMS-experienced patients.

Project description:Carbapenem-resistant Acinetobacter baumannii (CRAB) is a Priority 1 (Critical) pathogen urgently requiring new antibiotics. Polymyxins are a last-line option against CRAB-associated infections. This transcriptomic study utilized a CRAB strain to investigate mechanisms of bacterial killing with polymyxin B, colistin, colistin B and colistin/sulbactam combination therapy. After 4 h of 2 mg/L polymyxin monotherapy, all polymyxins exhibited common modes of action which primarily involved disruption to amino acid and fatty acid metabolism. Of the three monotherapies, polymyxin B induced the greatest number of differentially expressed genes (DEGs), including for genes involved with fatty acid metabolism. Gene disturbances with colistin and colistin B were highly similar (89% common genes for colistin B), though effects on gene expression were generally lower (0-1.5-fold in most cases) with colistin B. Colistin alone (2 mg/L) or combined with sulbactam (64 mg/L) resulted in rapid membrane disruption as early as 1 h. Transcriptomic analysis of this combination revealed the effects were driven by colistin and included disturbances in fatty acid synthesis and catabolism and inhibition of nutrient uptake. Combination therapy produced substantially higher fold changes in 72% of DEGs shared with monotherapy, resulting in substantially greater reductions in fatty acid biosynthesis and increases in biofilm, cell wall and phospholipid synthesis. This indicates synergistic bacterial killing with the colistin/sulbactam combination results from a systematic increase in perturbation of many genes associated with bacterial metabolism. These mechanistic insights enhance our understanding of bacterial responses to polymyxin mono- and combination therapy and will assist to optimize polymyxin use in patients. Carbapenem-resistant Acinetobacter baumannii (CRAB) is a Priority 1 (Critical) pathogen urgently requiring new antibiotics. Polymyxins are a last-line option against CRAB-associated infections. This transcriptomic study utilized a CRAB strain to investigate mechanisms of bacterial killing with polymyxin B, colistin, colistin B and colistin/sulbactam combination therapy. After 4 h of 2 mg/L polymyxin monotherapy, all polymyxins exhibited common modes of action which primarily involved disruption to amino acid and fatty acid metabolism. Of the three monotherapies, polymyxin B induced the greatest number of differentially expressed genes (DEGs), including for genes involved with fatty acid metabolism. Gene disturbances with colistin and colistin B were highly similar (89% common genes for colistin B), though effects on gene expression were generally lower (0-1.5-fold in most cases) with colistin B. Colistin alone (2 mg/L) or combined with sulbactam (64 mg/L) resulted in rapid membrane disruption as early as 1 h. Transcriptomic analysis of this combination revealed the effects were driven by colistin and included disturbances in fatty acid synthesis and catabolism and inhibition of nutrient uptake. Combination therapy produced substantially higher fold changes in 72% of DEGs shared with monotherapy, resulting in substantially greater reductions in fatty acid biosynthesis and increases in biofilm, cell wall and phospholipid synthesis. This indicates synergistic bacterial killing with the colistin/sulbactam combination results from a systematic increase in perturbation of many genes associated with bacterial metabolism. These mechanistic insights enhance our understanding of bacterial responses to polymyxin mono- and combination therapy and will assist to optimize polymyxin use in patients.

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.

Dataset Information

In Vitro Synergy of Colistin in Combination with Meropenem or Tigecycline against Carbapenem-Resistant Acinetobacter baumannii.

Publications

In Vitro Synergy of Colistin in Combination with Meropenem or Tigecycline against Carbapenem-Resistant <i>Acinetobacter baumannii</i>.

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