Emergence of Tigecycline and Colistin Resistance inAcinetobacterSpecies Isolated from Patients in Kuwait Hospitals
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AbstractThe development of resistance is a compelling reason for reviewing administration of antibiotics. Recently, most Acinetobacter infections are caused by multidrug-resistant (MDR) strains which have necessitated the use of tigecycline or colistin. This study was undertaken to determine the susceptibility of Acinetobacter spp. To these and other drugs. A total of 250 Acinetobacter isolates were collected from the 8 government hospitals over a period of 6 months. Susceptibility to 18 antibiotics, including tigecycline and colistin, was investigated by determining their minimum inhibitory concentrations using e test. Of the 250 isolates, 13.6% and 12% were resistant to tigecycline and colistin. A total of 25.2% and 37.2% were resistant to imipenem and meropenem, respectively. Of the 250 isolates 88.4% were MDR. This relatively high prevalence of tigecycline and colistin-resistant isolates indicates an emerging therapeutic problem which may severely compromise the treatment of MDR Acinetobacter spp. infections in Kuwait.Keywords: Acinetobacter sppresistancetigecyclinecolistinKuwaitKeywords:
Tigecycline
Colistin
Carbapenemase-producing Enterobacterales have become a severe public health concern because of their rapidly transmissible resistance elements and limited treatment options. The most effective antimicrobial combinations against carbapenemase-producing Enterobacterales are currently unclear. Here, we aimed to assess the therapeutic effects of seven antimicrobial combinations (colistin-meropenem, colistin-tigecycline, colistin-rifampicin, colistin-erythromycin, meropenem-tigecycline, meropenem-rifampicin, and meropenem-tigecycline-colistin) against twenty-four carbapenem-producing Enterobacterales (producing blaKPC, blaNDM, coexisting blaNDM and blaIMP, and coexisting mcr-1/8/9 and blaNDM genes) and one carbapenem-susceptible Enterobacterales using the checkerboard assay, time-kill curves, and scanning electron microscopy. None of the combinations were antagonistic. The combination of colistin-rifampicin showed the highest synergistic effect of 76% (19/25), followed by colistin-erythromycin at 60% (15/25), meropenem-rifampicin at 24% (6/25), colistin-meropenem at 20% (5/25), colistin-tigecycline at 20% (5/25), and meropenem-tigecycline at 4% (1/25). The triple antimicrobial combinations of meropenem-tigecycline-colistin had a synergistic effect of 100%. Most double antimicrobial combinations were ineffective on isolates with coexisting blaNDM and blaIMP genes. Meropenem with tigecycline showed no synergistic effect on isolates that produced different carbapenemase genes and were highly resistant to meropenem (92% meropenem MIC ≥ 16 mg/mL). Colistin-tigecycline showed no synergistic effect on Escherichia coli producing blaNDM-1 and Serratia marcescens. Time-kill curves showed that antimicrobial combinations achieved an eradication effect (≥ 3 log10 decreases in colony counts) within 24 h without regrowth, based on 1 × MIC of each drug. The synergistic mechanism of colistin-rifampicin may involve the colistin-mediated disruption of bacterial membranes, leading to severe alterations in their permeability, then causes more rifampicin to enter the cell and induces cell death. In conclusion, the antimicrobial combinations evaluated in this study may facilitate the successful treatment of patients infected with carbapenemase-producing pathogens.
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Carbapenem
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Infections due to carbapenem-resistant NDM-producing Escherichia coli represent a major therapeutic challenge, especially in situations of pre-existing colistin resistance. The aim of this study was to investigate combinatorial pharmacodynamics of colistin and tigecycline against E. coli harboring blaNDM-5 and mcr-1, with possible mechanisms explored as well. Colistin disrupted the bacterial outer-membrane and facilitated tigecycline uptake largely independent of mcr-1 expression, which allowed a potentiation of the tigecycline-colistin combination. A concentration-dependent decrease in colistin MIC and EC50 was observed with increasing tigecycline levels. Clinically relevant concentrations of colistin and tigecycline combination significantly decreased bacterial density of colistin-resistant E. coli by 3.9 to 6.1-log10 cfu/mL over 48 h at both inoculums of 106 and 108 cfu/mL, and were more active than each drug alone (P < 0.01). Importantly, colistin and tigecycline combination therapy was efficacious in the murine thigh infection model at clinically relevant doses, resulting in >2.0-log10cfu/thigh reduction in bacterial density compared to each monotherapy. These data suggest that the use of colistin and tigecycline combination can provide a therapeutic alternative for infection caused by multidrug-resistant E. coli that harbored both blaNDM-5 and mcr-1.
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OBJECTIVES: To determine in vitro antimicrobial susceptibility and synergistic activity of colistin in combination with tigecycline against clinical strains of carbapenem- resistant Acinetobacter baumannii (CRAB).
MATERIAL AND METHODS: Colistin and tigecycline minimum inhibitory concentrations (MICs) of 12-clinical CRAB isolates were determined by broth microdilution. Checkerboard testing was performed to assess the interaction of the colistin-tigecycline combination. Fractional inhibitory concentration indexes (ΣFIC) in the range of 0.5 to 1.0, > 1.0 to < 4.0 and ≥ 4.0 are considered as additive, indifferent, and antagonistic effects, respectively.
RESULTS: All CRAB isolates were susceptible to colistin. Three out of 12 CRABs were susceptible to tigecycline based on a pharmacokinetic-pharmacodynamics (PK-PD) breakpoint (MICs ≤ 0.25 μg/mL). The MIC of both antimicrobials was decreased in most of the CRAB isolates in the checkerboard synergy testing. The interaction of colistin and tigecycline combination revealed both additive and indifferent effects in five and seven of the 12-CRAB isolates, respectively. Neither synergism nor antagonism of colistin and tigecycline combination was demonstrated.
CONCLUSION: No synergistic effect between colistin and tigecycline against CRAB isolates was detected. However, the combination of these two drugs is likely to result in a decrease in the MIC of both drugs. Further studies with a larger sample to determine the in vitro synergistic activity of colistin and tigecycline combination are required.
Keywords: in vitro, synergism, tigecycline, colistin, checkerboard method
DOI: 10.31524/bkkmedj.2019.02.005
Tigecycline
Acinetobacter baumannii
Colistin
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An alarming increase in the resistance rates of tigecycline and colistin among carbapenemase-producing Acinetobacter baumannii recovered from a Greek hospital over a 3-year period (2011-2013) was investigated. The antimicrobial resistance profiles and carbapenemase gene content were determined for a collection of colistin- and/or tigecycline-resistant carbapenemase-producing A. baumannii isolates (n = 42), which were recovered consecutively during the study period. A gradual increase in the incidence of blaOXA-23 producers was observed from 2011 to 2013. A cluster of 21 isolates comprised tigecycline-resistant blaOXA-23 producers displayed a single antimicrobial resistance pattern. The emergence of two blaOXA-23 producers resistant to both tigecycline and colistin was documented. Furthermore, determination of the mechanisms of colistin and tigecycline resistance and molecular typing by the tri-locus sequence typing (3LST) scheme for nine isolates recovered from bloodstream infections were performed. Out of nine isolates, five tigecycline- and two colistin-resistant isolates were blaOXA-23 producers of 3LST ST101 corresponding to the international clone II recovered during 2012-2013. All nine isolates were positive for the presence of the adeB gene of the AdeABC efflux pump. Three colistin-resistant isolates possessed novel substitutions in PmrB, which may be implicated in colistin resistance. To the best of our knowledge, this is the first report of the acquisition of tigecycline and colistin resistance among blaOXA-23-producing A. baumannii of 3LST ST101 in Greece; thus, continuous surveillance and molecular characterization, prudent use of antibiotics and implementation of infection control measures for A. baumannii are urgent.
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Acinetobacter baumannii
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OBJECTIVES: To determine in vitro antimicrobial susceptibility and synergistic activity of colistin in combination with tigecycline against clinical strains of carbapenem- resistant Acinetobacter baumannii (CRAB).MATERIAL AND METHODS: Colistin and tigecycline minimum inhibitory concentrations (MICs) of 12-clinical CRAB isolates were determined by broth microdilution. Checkerboard testing was performed to assess the interaction of the colistin-tigecycline combination. Fractional inhibitory concentration indexes (ΣFIC) in the range of 0.5 to 1.0, > 1.0 to < 4.0 and ≥ 4.0 are considered as additive, indifferent, and antagonistic effects, respectively.RESULTS: All CRAB isolates were susceptible to colistin. Three out of 12 CRABs were susceptible to tigecycline based on a pharmacokinetic-pharmacodynamics (PK-PD) breakpoint (MICs ≤ 0.25 μg/mL). The MIC of both antimicrobials was decreased in most of the CRAB isolates in the checkerboard synergy testing. The interaction of colistin and tigecycline combination revealed both additive and indifferent effects in five and seven of the 12-CRAB isolates, respectively. Neither synergism nor antagonism of colistin and tigecycline combination was demonstrated.CONCLUSION: No synergistic effect between colistin and tigecycline against CRAB isolates was detected. However, the combination of these two drugs is likely to result in a decrease in the MIC of both drugs. Further studies with a larger sample to determine the in vitro synergistic activity of colistin and tigecycline combination are required.
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Colistin
Acinetobacter baumannii
Broth microdilution
Checkerboard
Carbapenem
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In order to compare the In Vitro killing activity of meropenem and imipenem against multiresistant P.aeruginosa 14 strains were used. All nosocomial isolates were susceptible to meropenem and imipenem minimum inhibitory concentration (MIC ≤ 4 μg/ml) and resistant to at least two other antimicrobial agents of diverse chemical class with antipseudomonal activity. Forty-two killing curves were performed by exposing a 5 X 105 CFU/ml log-phase inoculum to 1x minimum bactericidal concentration (MBC) of each carbapenem. Meropenem was found to possess a slower killing rate than imipenem over the first 5 hours of P.aeruginosa exposure, but to be equally effective as imipenem after 24 hours of incubation. Forty percent and 11.1% of P.aeruginosa strains developed resistance to imipenem and meropenem respectively after a 24-hour exposure to carbapenem. The authors speculate about the underlying mechanisms explaining the higher rate of resistance development to imipenem than to meropenem.
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DX-8739 is a new dehydropeptidase I-stable carbapenem. In order to evaluate its activity in comparison with those of meropenem and imipenem, 147 multiresistant Pseudomonas aeruginosa isolates acquired nosocomially were simultaneously exposed to the actions of the three carbapenems in vitro, whereas to compare their killing effects on 14 strains, 56 killing curve studies were performed. Overall DX-8739 was found to possess inhibitory activity as well as bactericidal activity statistically superior to those of meropenem and imipenem. At a concentration of 4 micrograms/ml, 106 strains (72.1%) were found to be imipenem resistant; 33 and 27.4% of these strains were inhibited by DX-8739 and meropenem, respectively, a statistically significant difference (P < 0.05). DX-8739 was also shown to possess intrinsic activity in vitro superior to those of meropenem and imipenem against the imipenem-susceptible population of strains. However, no statistically significant difference regarding the comparative killing activities of the three studied carbapenems was observed. Following exposure to carbapenem for 24 h, 33.3, 44.4, and 70% of the strains which survived became resistant to DX-8739, meropenem, and imipenem, respectively. The reported results demonstrate the significant activity of DX-8739 against multiresistant P. aeruginosa strains acquired nosocomially. The mechanism of action of DX-8739 on P. aeruginosa is unknown, and various hypotheses that might explain its in vitro superiority over meropenem and imipenem are proposed.
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The aim of the study is to determine in-vitro effects of imipenem–tigecycline, imipenem–colistin and tigecycline–colistin against carbapenem-resistant Enterobacteriaceae (CRE) isolates. A total of 25 CRE isolates were included to the study. The minimum inhibition concentrations of imipenem, colistin-sulphate and tigecycline were determined with broth dilution method. Synergistic effects of imipenem–tigecycline, imipenem–colistin and tigecycline–colistin were investigated by microdilution checkerboard technique. All of the isolates were resistant to imipenem, whereas 25% of the isolates were resistant to colistin and tigecycline. Imipenem–colistin, imipenem–tigecycline and tigecycline–colistin combinations were synergistic against 40% (10/25), 24% (6/25), and 36% (9/25) of the isolates, respectively. Antagonism was observed in 8% (2/25) of the isolates in tigecycline–colistin combination. Tigecycline–colistin was the most effective (70% synergy) combination in Klebsiella spp. strains; whereas imipenem–colistin was the most effective (75% synergy) combination in Escherichia coli strains. Synergistic effect was variable and strain-depended against CRE isolates that have been tested.
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Colistin
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Acinetobacter baumannii
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