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PubMed2006

Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii.

Multidrug-resistant Acinetobacter baumannii has emerged as a significant clinical problem worldwide and colistin is being used increasingly as "salvage" therapy. MICs of colistin against A. baumannii indicate its significant activity. However, resistance to colistin in A. baumannii has been reported recently. Clonotypes of 16 clinical A. baumannii isolates and ATCC 19606 were determined by pulsed-field gel electrophoresis (PFGE), and colistin MICs were measured. The time-kill kinetics of colistin against A. baumannii ATCC 19606 and clinical isolate 6 were investigated, and population analysis profiles (PAPs) were conducted. Resistance development was investigated by serial passaging with or without exposure to colistin. Five different PFGE banding patterns were found in the clinical isolates. MICs of colistin against all isolates were within 0.25 to 2 microg/ml. Colistin showed early concentration-dependent killing, but bacterial regrowth was observed at 24 h. PAPs revealed that heteroresistance to colistin occurred in 15 of the 16 clinical isolates. Subpopulations (<0.1% from inocula of 10(8) to 10(9) CFU/ml) of ATCC 19606, and most clinical isolates grew in the presence of colistin 3 to 10 microg/ml. Four successive passages of ATCC 19606 in broth containing colistin (up to 200 microg/ml) substantially increased the proportion of the resistant subpopulations able to grow in the presence of colistin at 10 microg/ml from 0.000023 to 100%; even after 16 passages in colistin-free broth, the proportion only decreased to 2.1%. This represents the first demonstration of heterogeneous colistin-resistant A. baumannii in "colistin-susceptible" clinical isolates. Our findings give a strong warning that colistin-resistant A. baumannii may be observed more frequently due to potential suboptimal dosage regimens recommended in the product information of some products of colistin methanesulfonate.

Acinetobacter Infections↗
PubMed2026

Investigation of pmrCAB and mcr associated resistance in colistin-resistant A. baumannii isolates.

BACKGROUND & OBJECTIVES: Colistin is one of the last-resort antibiotics for multidrug-resistant Acinetobacter baumannii. Increasing resistance to colistin limits treatment options, particularly in intensive care units (ICUs). The aim of this study was to compare the expression levels of pmrC, pmrA, and pmrB, among colistin-resistant and colistin-susceptible clinical A. baumannii isolates, to investigate the presence of plasmid-mediated mcr-1-5 genes, and to determine clonal relationships among colistin-resistant isolates. METHODS: A total of 110 A. baumannii isolates recovered from ICU patients in 2020 were included. Colistin minimum inhibitory concentrations were determined using the broth microdilution method. Expression levels of pmrC, pmrA, and pmrB were analyzed by RT-qPCR and compared with the reference strain A. baumannii ATCC 19606. Colistin-resistant isolates (Group 1) were compared with 10 randomly selected colistin-susceptible isolates (Group 2). Detection of mcr-1-5 genes was performed by in-house multiplex PCR. Clonal relationships among resistant isolates were assessed by PFGE. RESULTS: Colistin resistance was detected in 15.45% (17/110) of isolates. The median relative expression levels of pmrC, pmrB, and pmrA in colistin-resistant isolates were 47.84-fold (IQR: 19.29-67.18), 14.72-fold (IQR: 10.13-16.68), and 8.57-fold (IQR: 5.17-12.82), respectively. In colistin-susceptible isolates, the corresponding median expression levels were 5.32-fold (IQR: 3.60-7.97), 3.29-fold (IQR: 0.85-5.95), and 3.31-fold (IQR: 2.58-6.55). Expression levels were significantly higher in colistin-resistant isolates for pmrC (p < 0.001), pmrB (p = 0.002), and pmrA (p = 0.024). None of the resistant isolates carried mcr-1-5 genes. PFGE analysis revealed 12 distinct genotypes among 17 resistant isolates. INTERPRETATION & CONCLUSIONS: Colistin-resistant A. baumannii isolates exhibited significantly higher expression levels of the pmrC, pmrA, and pmrB genes compared to colistin-susceptible isolates. Among the genes evaluated, pmrC showed the largest effect size and the strongest association with the colistin-resistant phenotype. No changes were found in the mcr-1-5 genes among the isolates studied. Further studies, including genomic and functional analyses, are needed to elucidate the underlying mechanisms of these expression changes and their contribution to colistin resistance.

Journal Article↗
PubMed1985

Binding and neutralization of bacterial lipopolysaccharide by colistin nonapeptide.

Polymyxin nonapeptides, proteolytic derivatives of polymyxin antibiotics, are less toxic than their parent compounds but retain some of their antibacterial activities. To confirm and expand observations that polymyxin nonapeptides have anti-endotoxin activity, we studied the ability of colistin nonapeptide to bind to bacterial lipopolysaccharide (LPS) and to inhibit the effects of LPS on Limulus amoebocyte lysate and lymphocyte mitogenicity. Colistin nonapeptide was purified by high-pressure liquid chromatography and was demonstrated to bind to LPS by equilibrium dialysis. The ability of colistin nonapeptide to render E. coli ATCC 25922 cells sensitive to erythromycin was abrogated by 50% after incubation with E. coli O18 LPS in a ratio by weight of LPS to colistin nonapeptide of 3.9:1. The presence of 4 micrograms of colistin nonapeptide or colistin per ml increased by 130- and 800-fold, respectively, the concentration of E. coli O113 LPS required to produce 50% gelation of Limulus amoebocyte lysate as measured by a spectrophotometric assay. Neutralization of LPS by colistin nonapeptide was time and concentration dependent. In contrast to the neutralization seen with LPS derived from a colistin-sensitive organism, colistin nonapeptide neutralized very little LPS extracted from a strain of Serratia marcescens that was resistant to colistin. Colistin nonapeptide also inhibited LPS-induced [3H]thymidine uptake by splenic lymphocytes, but its activity was less than 1/10 that of colistin. We conclude that colistin nonapeptide binds to LPS and possesses antiendotoxin activity. However, the anti-endotoxin activity of the nonapeptide is considerably less than that of its parent compound, colistin.

Chromatography, High Pressure Liquid↗
PubMed2025

Molecular characterization of colistin resistance in carbapenem-resistant Klebsiella pneumoniae from a tertiary hospital in China.

Colistin resistance in carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a significant global health challenge, as colistin remains the last-resort antibiotic for treating multidrug-resistant K. pneumoniae infections. This study aimed to investigate the prevalence and molecular mechanisms underlying colistin resistance in CRKP (Colr-CRKP) isolates in Henan, China, from 2021 to 2024. The minimum inhibitory concentrations of colistin for 134 K. pneumoniae isolates were determined using the broth microdilution method. Whole-genome sequencing was performed using the Illumina platform to identify carbapenemase genes and sequence types (STs). Colistin resistance mechanisms were investigated, including mutations in two-component systems (pmrA/pmrB, phoP/phoQ), inactivation of the mgrB gene, and the presence of plasmid-mediated mcr genes. Most isolates were collected from intensive care units (99/134, 73.9%), with 48.5% (59/134) of patients having no documented colistin exposure history. Notably, ST11 was the predominant sequence type among Colr-CRKP isolates (113/134, 84.3%), all of which carried blaKPC-2 as the sole carbapenemase determinant. In contrast, seven non-carbapenemase-producing isolates exhibited phenotypic resistance to carbapenems. Genomic analysis revealed inactivation or loss of the mgrB gene in 53.7% (72/134) of isolates, predominantly due to insertion mutations (54/72). Although 32.8% (44/134) of isolates carried mutations in two-component systems, these alterations did not exhibit pathway-specific clustering. Intriguingly, plasmid-mediated mcr genes were detected in only 1.5% (2/134) of cases (mcr-8.2 and mcr-1.1), while 22.4% (30/134) of colistin-resistant strains lacked identifiable resistance determinants based on current detection methods. Our findings indicate that disruption of the mgrB gene is the primary mechanism of colistin resistance in ST11 CRKP clones. The emergence of resistance in 48.5% of patients without prior colistin exposure, combined with low mcr gene prevalence (1.5%) and unexplained resistance in 22.4% of isolates, suggests complex selective pressures beyond direct antimicrobial use. These findings underscore the urgent need for strengthened antimicrobial stewardship and the development of alternative therapeutic strategies to combat this high-risk pathogen.IMPORTANCEThe global rise of colistin-resistant Klebsiella pneumoniae, particularly in carbapenem-resistant Klebsiella pneumoniae (CRKP) strains, has severely restricted treatment options for multidrug-resistant infections. Our study provides the first comprehensive molecular characterization of colistin resistance in CRKP in a large tertiary hospital in central China. We identified mgrB disruption as the predominant resistance mechanism, while plasmid-mediated mcr genes were rare. Notably, nearly half of the resistant isolates occurred in patients without prior colistin exposure, suggesting alternative selective pressures driving resistance. These findings highlight the complex dynamics of colistin resistance in CRKP and underscore the need for enhanced genomic surveillance and stewardship interventions to limit further dissemination.

Colistin↗
PubMed1999

In vitro assessment of colistin's antipseudomonal antimicrobial interactions with other antibiotics.

OBJECTIVE: To study the interactions of colistin (MIC 2 mg/L) at concentrations of 0.5 and 5 mg/L with ceftazidime (1 and 75 mg/L, MIC 0.5 mg/L), aztreonam (1 and 30 mg/L, MIC 0.12 mg/L), meropenem (1 and 25 mg/L, MIC 0.03 mg/L), gentamicin (1 and 10 mg/L, MIC 2 mg/L), piperacillin (5 and 100 mg/L, MIC 4 mg/L) and ciprofloxacin (0.25 and 4 mg/L, MIC 1 mg/L) using a representative strain of Pseudomonas aeruginosa isolated from a cystic fibrosis patient. METHODS: The method used was a bacterial time kill curve with single agents and combinations. Using inocula of 106 CFU/mL, multiple sampling was performed over 6 h and in triplicate. The AUBKC of the time versus viable count curve, with single agents and combinations of agents, was taken as the endpoint for comparison. RESULTS: For colistin plus ceftazidime, colistin plus aztreonam, colistin plus meropenem and colistin plus ciprofloxacin, the pattern was for all the combinations (high or low concentrations) to produce smaller AUBKCs than single agents. In experiments using a bacteriostatic agent such as ceftazidime, the AUBKCs (log CFU/µL per h) for colistin 0.5 mg/L or 5 mg/L alone were 32.3±0.8 or 12.7±0.5, and for ceftazidime 1 mg/L or 75 mg/L alone they were 24.3±1.5 or 20.9±2.7. Combinations of colistin 0.5 mg/L plus either ceftazidime 1 mg/L or 75 mg/L produced AUBKCs of 23.8±1.8 or 16.1 mg/L. Combinations of colistin 5 mg/L plus ceftazidime 1 mg/L or 75 mg/L produced AUBKCs of 12.2±0.8 or 8.7±1.0. The AUBKCs for colistin 5 mg/L plus 75 mg/L are significantly smaller than those for the single agents, indicating synergy. In experiments using the bactericidal agent ciprofloxacin, the AUBKCs (log CFU/mL per h) for colistin 0.5 mg/L or 5 mg/L alone were 33.6±1.9 or 11.2±2.4, and for ciprofloxacin 0.25 mg/L or 4 mg/L alone they were 32.8±1.3 or 5.0±0.7. Combinations of colistin 0.5 mg/L plus either ciprofloxacin 0.25 mg/L or 4 mg/L produced AUBKCs of 32.2±0.9 or 4.3±1.4. Combinations of colistin 5 mg/L plus ciprofloxacin 0.25 mg/L or 4 mg/L produced AUBKCs of 10.7±1.5 or 4.2±0.6. Although combination AUBKCs were smaller than those for single agents, in no case did this reach statistical significance (p<0.05). CONCLUSIONS: These studies indicate that addition of colistin to other antipseudomonal drugs tends to produce smaller AUBKCs and hence greater killing of Pseudomonas aeruginosa than monotherapy.

Journal Article↗
PubMed2002

Synergy of colistin with rifampin and trimethoprim/sulfamethoxazole on multidrug-resistant Stenotrophomonas maltophilia.

Stenotrophomonas maltophilia is characterized by intrinsic resistance to a variety of antimicrobials. Therapeutic options are often limited particularly after the emergence of isolates resistant to trimethoprim/sulfamethoxazole. The application of colistin for infections caused by multidrug-resistant Gram-negative pathogens is limited due to its toxicity. In order to evaluate the activity of the interaction of colistin with rifampin or trimethoprim/sulfamethoxazole on S. maltophilia, 24 different isolates resistant to trimethoprim/sulfamethoxazole were in vitro exposed over-time to the combination of 1x and 4 x MIC of colistin with 2 microg/ml of rifampin or 2/38 microg/ml of trimethoprim/sulfamethoxazole. The applied concentrations for rifampin and trimethoprim/sulfamethoxazole reflect their mean serum levels. Synergy of colistin and rifampin was documented after the first two hours of bacterial growth for approximately 60% of isolates and it occurred with both applied concentrations of colistin. The interaction of colistin and rifampin prevented regrowth observed when single colistin was applied. Synergy of colistin and trimethoprim/sulfamethoxazole was mainly found when colistin was applied at a concentration of 4 x MIC involving 41.7% of isolates after 24 h of growth. In the presence of trimethoprim/sulfamethoxazole bacterial regrowth, observed when single colistin was applied, was prevented. It is concluded that growth of multidrug-resistant S. maltophilia is significantly inhibited by the interaction of colistin and rifampin and to a lesser extent of colistin and trimethoprim/sulfamethoxazole. These results merit further study in both the animal model and the clinical setting.

Anti-Bacterial Agents↗