Dataset Information

Evaluation of Aminoglycoside and Carbapenem Resistance in a Collection of Drug-Resistant Pseudomonas aeruginosa Clinical Isolates.

ABSTRACT: Pseudomonas aeruginosa, a Gram-negative bacterium, is a member of the ESKAPE pathogens and one of the leading causes of healthcare-associated infections worldwide. Aminoglycosides (AGs) are recognized for their efficacy against P. aeruginosa. The most common resistance mechanism against AGs is the acquisition of AG-modifying enzymes (AMEs) by the bacteria, including AG N-acetyltransferases (AACs), AG O-phosphotransferases (APHs), and AG O-nucleotidyltransferases (ANTs). In this study, we obtained 122 multidrug-resistant P. aeruginosa clinical isolates and evaluated the antibacterial effects of six AGs and two carbapenems alone against all clinical isolates, and in combination against eight selected strains. We further probed for four representatives of the most common AME genes [aac(6')-Ib, aac(3)-IV, ant(2")-Ia, and aph(3')-Ia] by polymerase chain reaction (PCR) and compared the AME patterns of these 122 clinical isolates to their antibiotic resistance profile. Among the diverse antibiotics resistance profile displayed by these clinical isolates, we found correlations between the resistance to various AGs as well as between the resistance to one AG and the resistance to carbapenems. PCR results revealed that the presence of aac(6')-Ib renders these isolates more resistant to a variety of antibiotics. The correlation between resistance to various AGs and carbapenems partially reflects the complex resistance strategies adapted in these pathogens and encourages the development of strategic treatment for each P. aeruginosa infection by considering the genetic information of each isolated bacteria.

SUBMITTER: Holbrook SYL

PROVIDER: S-EPMC6154764 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Evaluation of Aminoglycoside and Carbapenem Resistance in a Collection of Drug-Resistant Pseudomonas aeruginosa Clinical Isolates.

Holbrook Selina Y L SYL Garneau-Tsodikova Sylvie S

Microbial drug resistance (Larchmont, N.Y.) 20171220 7

Pseudomonas aeruginosa, a Gram-negative bacterium, is a member of the ESKAPE pathogens and one of the leading causes of healthcare-associated infections worldwide. Aminoglycosides (AGs) are recognized for their efficacy against P. aeruginosa. The most common resistance mechanism against AGs is the acquisition of AG-modifying enzymes (AMEs) by the bacteria, including AG N-acetyltransferases (AACs), AG O-phosphotransferases (APHs), and AG O-nucleotidyltransferases (ANTs). In this study, we obtaine ...[more]

PMID: 29261405

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Project description:Optimizing antibiotic combinations is promising to combat multidrug-resistant Pseudomonas aeruginosa This study aimed to systematically evaluate synergistic bacterial killing and prevention of resistance by carbapenem and aminoglycoside combinations and to rationally optimize combination dosage regimens via a mechanism-based mathematical model (MBM). We studied monotherapies and combinations of imipenem with tobramycin or amikacin against three difficult-to-treat double-resistant clinical P. aeruginosa isolates. Viable-count profiles of total and resistant populations were quantified in 48-h static-concentration time-kill studies (inoculum, 107.5 CFU/ml). We rationally optimized combination dosage regimens via MBM and Monte Carlo simulations against isolate FADDI-PA088 (MIC of imipenem [MICimipenem] of 16 mg/liter and MICtobramycin of 32 mg/liter, i.e., both 98th percentiles according to the EUCAST database). Against this isolate, imipenem (1.5× MIC) combined with 1 to 2 mg/liter tobramycin (MIC, 32 mg/liter) or amikacin (MIC, 4 mg/liter) yielded ≥2-log10 more killing than the most active monotherapy at 48 h and prevented resistance. For all three strains, synergistic killing without resistance was achieved by ≥0.88× MICimipenem in combination with a median of 0.75× MICtobramycin (range, 0.032× to 2.0× MICtobramycin) or 0.50× MICamikacin (range, 0.25× to 0.50× MICamikacin). The MBM indicated that aminoglycosides significantly enhanced the imipenem target site concentration up to 3-fold; achieving 50% of this synergistic effect required aminoglycoside concentrations of 1.34 mg/liter (if the aminoglycoside MIC was 4 mg/liter) and 4.88 mg/liter (for MICs of 8 to 32 mg/liter). An optimized combination regimen (continuous infusion of imipenem at 5 g/day plus a 0.5-h infusion with 7 mg/kg of body weight tobramycin) was predicted to achieve >2.0-log10 killing and prevent regrowth at 48 h in 90.3% of patients (median bacterial killing, >4.0 log10 CFU/ml) against double-resistant isolate FADDI-PA088 and therefore was highly promising.

Project description:BACKGROUND: Carbapenemase genes are one of the most frequent mechanisms reported in carbapenem-resistant P. aeruginosa; however, description of P. aeruginosa co-harbouring two or more carbapenemases is unusual. METHODS: In this study we evaluated the presence of carbapenemase genes and the clonality of P. aeruginosa isolates obtained from a hospital over a 12-year period. A total of 127 isolates of carbapenem-resistant P. aeruginosa recovered from 109 patients feces (four samples), rectal swab (three samples), nasal swab (one sample) and anal abscess (one sample), were evaluated. Minimum inhibitory concentrations of the following antibiotics imipenem, meropenem and polymyxin E were determined by broth microdilution. The molecular profile of isolates was evaluated by pulsed field gel electrophoresis (PFGE). PCR for the following carbapenemase genes blaIMP;blaSPM;blaVIM;blaSIM;blaNDM;blaKPC;blaGES and nucleotide sequencing to confirm the enzyme gene types were performed and compared with the database available on the Internet (BLAST-http://www.ncbi.nlm.nhi.gov/blast/). RESULTS: All isolates were carbapenem-resistant, their MIC50 and MIC90 were respectively 64 ?g/mL and 256 ?g/mL to imipenem and 32 ?g/mL and 256 ?g/mL to meropenem, all isolates except one (MIC = 8 mg/L) were susceptible to polymyxin E. The most frequent carbapenemase genes identified were blaSPM identified in 41 isolates (32%), followed by 10 with blakpc and 5 with blaVIM (3.9%). All belonged to the class SPM-1 and VIM-2. In 2011, one isolate harbouring three carbapenemase genes (SPM-1, VIM-2 and KPC-2) that belonged to a new clone was identified in a hematopoietic stem cell transplanted patient. Then, 19 carbapenem-resistant P. aeruginosa were identified in an outbreak that occurred in the bone marrow transplant unit, all positive for SPM-1 gene, and 9 (47.3%) harbored both SPM-1 and KPC. CONCLUSION: Our findings showed that PCR for KPC gene should be performed to evaluate carbapenem resistance in P. aeruginosa and that this agent can harbor more than one carbapenemase gene. Attention should be focused on the possible rapid spread of KPC in P. aeruginosa isolates and for the fact that P. aeruginosa may become a reservoir of this transmissible resistance mechanism.

Project description:All (236) Pseudomonas aeruginosa isolates resistant to imipenem and/or meropenem collected during a multicenter (127-hospital) study in Spain were analyzed. Carbapenem-resistant isolates were found to be more frequently resistant to all beta-lactams and non-beta-lactam antibiotics than carbapenem-susceptible isolates (P < 0.001), and up to 46% of the carbapenem-resistant isolates met the criteria used to define multidrug resistance (MDR). Pulsed-field gel electrophoresis revealed remarkable clonal diversity (165 different clones were identified), and with few exceptions, the levels of intra- and interhospital dissemination of clones were found to be low. Carbapenem resistance was driven mainly by the mutational inactivation of OprD, accompanied or not by the hyperexpression of AmpC or MexAB-OprM. Class B carbapenemases (metallo-beta-lactamases [MBLs]) were detected in a single isolate, although interestingly, this isolate belonged to one of the few epidemic clones documented. The MBL-encoding gene (bla(VIM-2)), along with the aminoglycoside resistance determinants, was transferred to strain PAO1 by electroporation, demonstrating its plasmid location. The class 1 integron harboring bla(VIM-2) was characterized as well, and two interesting features were revealed: intI1 was found to be disrupted by a 1.1-kb insertion sequence, and a previously undescribed aminoglycoside acetyltransferase-encoding gene [designated aac(6')-32] preceded bla(VIM-2). AAC(6')-32 showed 80% identity to AAC(6')-Ib' and the recently described AAC(6')-31, and when aac(6')-32 was cloned into Escherichia coli, it conferred resistance to tobramycin and reduced susceptibility to gentamicin and amikacin. Despite the currently low prevalence of epidemic clones with MDR, active surveillance is needed to detect and prevent the dissemination of these clones, particularly those producing integron- and plasmid-encoded MBLs, given their additional capacity for the intra- and interspecies spread of MDR.

Dataset Information

Evaluation of Aminoglycoside and Carbapenem Resistance in a Collection of Drug-Resistant Pseudomonas aeruginosa Clinical Isolates.

Publications

Evaluation of Aminoglycoside and Carbapenem Resistance in a Collection of Drug-Resistant Pseudomonas aeruginosa Clinical Isolates.

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