In Vitro Synergy of Colistin in Combination with Meropenem or Tigecycline against Carbapenem-Resistant Acinetobacter baumannii.
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SUBMITTER: Abdul-Mutakabbir JC
PROVIDER: S-EPMC8300792 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Acinetobacter baumannii complex is an increasingly important cause of osteomyelitis. It is considered a difficult to treat agent, due to increasing antimicrobial resistance and few available therapeutic options. Objective: To compare effectiveness and tolerability of tigecycline and colistin in patients with osteomyelitis caused by carbapenem-resistant A. baumannii complex (CRABC). Methods: This retrospective review included all patients admitted to a 150-bed tertiary hospital from 2007 to 2015 with microbiologically confirmed CRABC osteomyelitis for which they received tigecycline or colistin. Data on demographic and clinical characteristics, adverse events, and outcomes 12 months after the end of antimicrobial treatment were analysed and stratified according to the antimicrobial used. Results: 65 patients were included, 34 treated with colistin and 31 with tigecycline. There were significantly more men (P = 0.028) in the colistin group, and more smokers (P = 0.021) and greater occurrence of chronic osteomyelitis (P = 0.036) in the tigecycline treatment group. Median duration of therapy was 42.5 days for colistin and 42 days for tigecycline, with no significant difference. Overall incidence of adverse events was higher in the colistin group (P = 0.047). In particular, incidence of renal impairment was also higher in this group (P = 0.003). Nausea and vomiting were more frequent with tigecycline (P = 0.046). There were no significant differences between groups in relapse, amputation, or death. Conclusions: Tigecycline had a better safety profile than colistin in the treatment of osteomyelitis due to CRABC, with no significant difference in outcomes after 12 months of follow-up.
| S-EPMC7242406 | biostudies-literature
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.
| S-EPMC4462660 | biostudies-literature
Project description:We assessed the activity of tigecycline (TGC) combined with colistin (COL) against carbapenem-resistant enterobacteria. Synergy occurred in vitro against the majority of isolates, with the exception of Serratia marcescens. In a simple animal model (Galleria mellonella), TGC-COL was superior (P < 0.01) in treating Escherichia coli, Klebsiella pneumoniae, and Enterobacter infections, including those with TGC-COL resistance. Clinical studies are needed to determine whether TGC-COL regimens may be a viable option.
| S-EPMC4068506 | biostudies-literature
Project description:Few effective therapeutic options are available for treating severe infections caused by extensively drug-resistant Acinetobacter baumannii (XDR-AB). Using a murine thigh-infection model, we examined the in vivo efficacy of colistin in combination with meropenem, tigecycline, fosfomycin, fusidic acid, rifampin, or sulbactam against 12 XDR-AB strains. Colistin, tigecycline, rifampin, and sulbactam monotherapy significantly decreased bacterial counts in murine thigh infections compared with those observed in control mice receiving no treatment. Colistin was the most effective agent tested, displaying bactericidal activity against 91.7% of strains at 48 h post-treatment. With strains showing a relatively low minimum inhibitory concentration (MIC) for meropenem (MIC ≤ 32 mg/L), combination therapy with colistin plus meropenem caused synergistic inhibition at both 24 h and 48 h post-treatment. However, when the meropenem MIC was ≥64 mg/L, meropenem did not significantly alter the efficacy of colistin. The addition of rifampin and fusidic acid significantly improved the efficacy of colistin, showing a synergistic effect in 100% and 58.3% of strains after 24 h of treatment, respectively, while the addition of tigecycline, fosfomycin, or sulbactam did not show obvious synergistic activity. No clear differences in activities were observed between colistin-rifampin and colistin-fusidic acid combination therapy with most strains. Overall, our in vivo study showed that administering colistin in combination with rifampin or fusidic acid is more efficacious in treating XDR-AB infections than other combinations. The colistin-meropenem combination may be another appropriate option if the MIC is ≤32 mg/L. Further clinical studies are urgently needed to confirm the relevance of these findings.
| S-EPMC4912081 | biostudies-literature
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.
2023-07-01 | GSE218219 | GEO
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.
| S-EPMC2693502 | biostudies-literature
Project description:The spread of carbapenem-non-susceptible Klebsiella pneumoniae strains bearing different resistance determinants is a rising problem worldwide. Especially infections with KPC (Klebsiella pneumoniae carbapenemase) - producers are associated with high mortality rates due to limited treatment options. Recent clinical studies of KPC-blood stream infections revealed that colistin-based combination therapy with a carbapenem and/or tigecycline was associated with significantly decreased mortality rates when compared to colistin monotherapy. However, it remains unclear if these observations can be transferred to K. pneumoniae harboring other mechanisms of carbapenem resistance. A three-dimensional synergy analysis was performed to evaluate the benefits of a triple combination with meropenem, tigecycline and colistin against 20 K. pneumoniae isolates harboring different β-lactamases. To examine the mechanism behind the clinically observed synergistic effect, efflux properties and outer membrane porin (Omp) genes (ompK35 and ompK36) were also analyzed. Synergism was found for colistin-based double combinations for strains exhibiting high minimal inhibition concentrations against all of the three antibiotics. Adding a third antibiotic did not result in further increased synergistic effect in these strains. Antagonism did not occur. These results support the idea that colistin-based double combinations might be sufficient and the most effective combination partner for colistin should be chosen according to its MIC.
| S-EPMC4465894 | biostudies-literature
Project description:Multidrug-resistant Acinetobacter baumannii (MDRAB) presents an increasing challenge to health care. Although colistin has been used as a treatment of last resort, there is concern regarding its potential for toxicity and the emergence of resistance. The mechanism of action of colistin, however, raises the possibility of synergy with compounds that are normally inactive against Gram-negative organisms by virtue of the impermeability of the bacterial outer membrane. This study evaluated the effect of colistin combined with vancomycin on 5 previously characterized epidemic strains and 34 MDRAB clinical isolates by using time-kill assay, microdilution, and Etest methods. For all the isolates, significant synergy was demonstrated by at least one method, with reductions in the MIC of vancomycin from >256 μg/ml to ≤48 μg/ml for all strains after exposure to 0.5 μg/ml colistin. This raises the possibility of the clinical use of this combination for infections due to MDRAB, with the potential for doses lower than those currently used.
| S-EPMC2981237 | biostudies-literature
Project description:The emergence of carbapenem-resistant Acinetobacter baumannii (CRAB) has been increasingly reported, leading to greater challenges in treating infections. With the development of phage therapy and phage-antibiotic combinations, it is promising to improve the treatment of bacterial infections. In the present study, a novel vB_AbaP_WU2001 (vWU2001) phage-specific CRAB with a genome of 40,792 bp was isolated. Genomic analysis disclosed that it belongs to the Autographiviridae family of the order Caudovirales. Phage vWU2001 had a broad host range with a high adsorption rate, short latent period, large burst size and good stability. The phage could reduce preformed biofilms and inhibit biofilm formation. The combination of phage vWU2001 and colistin had significantly higher bacterial growth inhibition activity than that of phage, or colistin alone. The efficacy of the combined treatment was also evaluated in Galleria mellonella. Evaluation of its therapeutic potential showed that the combination of phage and colistin resulted in a significantly greater increase in G. mellonella survival and in bacterial clearance, as compared with that of phage or colistin alone, indicating that the combination was synergistic against CRAB. The results demonstrated that phage vWU2001 has the potential to be developed as an antibacterial agent.
| S-EPMC8850435 | biostudies-literature
Project description:Carbapenem-resistant Acinetobacter baumannii (CRAB) strains are prevalent worldwide and represent a major threat to public health. However, treatment options for infections caused by CRAB are very limited as they are resistant to most of the commonly used antibiotics. Consequently, understanding the mechanisms underlying carbapenem resistance and restoring bacterial susceptibility to carbapenems hold immense importance. The present study used gas chromatography-mass spectrometry (GC-MS)-based metabolomics to investigate the metabolic mechanisms of antibiotic resistance in clinically isolated CRAB. Inactivation of the pyruvate cycle and purine metabolism is the most typical characteristic of CRAB. The CRAB exhibited a reduction in the activity of enzymes involved in the pyruvate cycle, proton motive force, and ATP levels. This decline in central carbon metabolism resulted in a decrease in the metabolic flux of the α-ketoglutarate-glutamate-glutamine pathway toward purine metabolism, ultimately leading to a decline in adenine nucleotide interconversion. Exogenous adenosine monophosphate (AMP) and adenosine triphosphate (ATP) enhance the killing efficacy of Meropenem against CRAB. The combination of ATP and Meropenem also has a synergistic effect on eliminating CRAB persisters and the biofilm, as well as protecting mice against peritonitis-sepsis. This study presents a novel therapeutic modality to treat infections caused by CRAB based on the metabolism reprogramming strategy.
| S-EPMC10788854 | biostudies-literature