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Clinical Predictive Model of Multidrug Resistance in Neutropenic Cancer Patients with Bloodstream Infection Due to Pseudomonas aeruginosa.

ABSTRACT: We aimed to assess the rate and predictive factors of bloodstream infection (BSI) due to multidrug-resistant (MDR) Pseudomonas aeruginosa in neutropenic cancer patients. We performed a multicenter, retrospective cohort study including oncohematological neutropenic patients with BSI due to P. aeruginosa conducted across 34 centers in 12 countries from January 2006 to May 2018. A mixed logistic regression model was used to estimate a model to predict the multidrug resistance of the causative pathogens. Of a total of 1,217 episodes of BSI due to P. aeruginosa, 309 episodes (25.4%) were caused by MDR strains. The rate of multidrug resistance increased significantly over the study period (P?=?0.033). Predictors of MDR P. aeruginosa BSI were prior therapy with piperacillin-tazobactam (odds ratio [OR], 3.48; 95% confidence interval [CI], 2.29 to 5.30), prior antipseudomonal carbapenem use (OR, 2.53; 95% CI, 1.65 to 3.87), fluoroquinolone prophylaxis (OR, 2.99; 95% CI, 1.92 to 4.64), underlying hematological disease (OR, 2.09; 95% CI, 1.26 to 3.44), and the presence of a urinary catheter (OR, 2.54; 95% CI, 1.65 to 3.91), whereas older age (OR, 0.98; 95% CI, 0.97 to 0.99) was found to be protective. Our prediction model achieves good discrimination and calibration, thereby identifying neutropenic patients at higher risk of BSI due to MDR P. aeruginosa The application of this model using a web-based calculator may be a simple strategy to identify high-risk patients who may benefit from the early administration of broad-spectrum antibiotic coverage against MDR strains according to the local susceptibility patterns, thus avoiding the use of broad-spectrum antibiotics in patients at a low risk of resistance development.

SUBMITTER: Gudiol C

PROVIDER: S-EPMC7179320 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Clinical Predictive Model of Multidrug Resistance in Neutropenic Cancer Patients with Bloodstream Infection Due to Pseudomonas aeruginosa.

Gudiol C C Albasanz-Puig A A Laporte-Amargós J J Pallarès N N Mussetti A A Ruiz-Camps I I Puerta-Alcalde P P Abdala E E Oltolini C C Akova M M Montejo M M Mikulska M M Martín-Dávila P P Herrera F F Gasch O O Drgona L L Paz Morales H H Brunel A-S AS García E E Isler B B Kern W V WV Morales I I Maestro-de la Calle G G Montero M M Kanj S S SS Sipahi O R OR Calik S S Márquez-Gómez I I Marin J I JI Gomes M Z R MZR Hemmatti P P Araos R R Peghin M M Del Pozo J L JL Yáñez L L Tilley R R Manzur A A Novo A A Carratalà J J

Antimicrobial agents and chemotherapy 20200324 4

We aimed to assess the rate and predictive factors of bloodstream infection (BSI) due to multidrug-resistant (MDR) <i>Pseudomonas aeruginosa</i> in neutropenic cancer patients. We performed a multicenter, retrospective cohort study including oncohematological neutropenic patients with BSI due to <i>P. aeruginosa</i> conducted across 34 centers in 12 countries from January 2006 to May 2018. A mixed logistic regression model was used to estimate a model to predict the multidrug resistance of the c ...[more]

PMID: 32015035

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Project description:BackgroundBloodstream infections (BSIs) caused by multidrug-resistant (MDR)-Pseudomonas aeruginosa are associated with poor clinical outcomes, at least partly due to delayed appropriate antimicrobial therapy. The characteristics of MDR-P. aeruginosa bloodstream isolates have not been evaluated in Qatar. Our study aimed to examine in vitro susceptibility, clinical and molecular characteristics, and mechanisms of resistance of MDR-P. aeruginosa bloodstream isolates from Qatar.Materials and methodsWe included all MDR-P. aeruginosa isolated from blood cultures taken between October 2014 and September 2017. Blood cultures were processed using BD BACTEC™ FX automated system. BD Phoenix™ was used for identification, Liofilchem® MIC Test Strips for MIC determination. Whole-genome sequencing was performed using the Illumina-HiSeq-2000.ResultsOut of 362 P. aeruginosa bloodstream isolates, 16 (4.4%) were MDR. The median patient age was 55 years (range 43-81) and all patients presented with septic shock. Most patients received meropenem (12/16) and/or colistin (10/16). Clinical response was achieved in eight patients, and five patients died within 30-days. MDR-P. aeruginosa isolates belonged to 13 different sequence types. All isolates were non-susceptible to cefepime and ciprofloxacin. The most active agents were colistin (16/16) and aztreonam (10/16). Seven isolates produced blaVIM, and four possessed genes encoding extended-spectrum β-lactamases. Aminoglycoside modifying enzymes were present in 15/16, transferable qnr-mediated quinolone resistance gene was detected in 3/16, and the novel ciprofloxacin modifying enzyme CrpP-encoding gene in one isolate.ConclusionMDR-P. aeruginosa BSIs are relatively uncommon in Qatar but are highly resistant, harbour multiple resistance genes, and are commonly associated with unfavourable clinical outcomes. Colistin was the only agent with consistent activity against the study isolates.Key messagesMDR-P. aeruginosa constituted <5% of P. aeruginosa blood isolates over three years.Typical risk factors for MDR infections were highly prevalent in the study population and overall clinical outcomes are consistent with those previously reported.Colistin was the only agent with consistent antibacterial activity against the study isolates.

Project description:Purpose: Recently we have characterize 43 clinical isolates of Pseudomonas aeruginosa overproducing the efflux pump MexEF-OprN. About 45% of these strains did not display mutations in any of the regulators known to control mexEF-oprN expression. Here we identified a novel regulator of the efflux operon mexEF-oprN that we named CmrA by characterizing in vitro selected mutants from the strain PA14. Methods: MexEF-OprN overproducing spontaneous mutants were selected in vitro using the reference strain PA14 in presence of chloramphenicol. Selected mutants (PJ mutants) were characterized using different criteria such as antibiotic susceptibility and production of virulence traits. Gene expression was evaluated by RT-qPCR. Whole genome sequencing of selected mutants (PJ mutants) was performed using IonTorrent technology. Knock-out mutants were constructed by overlapping PCR and homologous recombination. Finally, a transcriptomic analysis by RNAseq was performed to identify the genes depending on CmrA. Results: Characterization of the 4 selected PJ mutants showed that these strains have resistance and virulence profiles slightly differentent from those typically observed in MexEF-OprN overproducing strains (mexS- NfxC strains). The cmrA+ strains (here called NfxC2) showed moderate resistance to MexEF-OprN antibiotic substrates (ciprofloxacin, chloramphenicol and trimethoprim from 8- to 32-fold compared to PA14) and showed a less compromised capacity to produce some virulence traits (rhamnolipids, elastase, biofilm and pyocyanin) as well as the swarming motility. Whole genome sequencing of PJ mutants led to the identification of SNPs in the gene PA14_38040 (PA14_RS15465 after 2015 genome annotation uptdate). The gene PA14_RS15465 codes for an unknown transcriptional activator and was named cmrA for chlormaphenicol resistance activator. Aminoacid substitutions in CmrA found in PJ mutants were shown to constantly activate this regulator. Further characterization by gene inactivation showed that cmrA is responsible for the activation of the expression of the mexEF-oprN operon in PJ mutants. The locus cmrA was characterized and the complete sequence, including regulatory sequeces, was submitted to GenBank (accession number KX274690). Further analysis showed that the CmrA-activating pathway was dependent on mexS and mexT, both genes are known to affect mexEF-oprN expression. Finally, the transcriptomic analysis of the PJ01 mutant (compared to PA14 and to PJ01∆mexT) revealed that CmrA significally activate the expression of 11 genes most of them coding for enzymes involved in redox regulation. Conclusions: The discovery of cmrA opens the posibility to give an explanation to those clinical strains overproducing the efflux pump MexEF-OprN for unknown reasons. Our data shows that this regulator can activate the efflux pump in a way that the strain is capable to tolerate the antibiotics substrates of the pump and to mantain its capacity to produce some virulence traits. CmrA seems to have a role in the activation of regulatory pathways involved in redox homeostasis as shown by the transcriptomic analysis. The fact that the MexEF-OprN pump is activated at the same time that a redox system let us think that this pump could be related to intracellular detoxification of molecules altering the intracellular homeostasis as it has been previously proposed. We are currently analyzing the transcriptome of CmrA to describe the whole activation pathway of this regulator.

Dataset Information

Clinical Predictive Model of Multidrug Resistance in Neutropenic Cancer Patients with Bloodstream Infection Due to Pseudomonas aeruginosa.

Publications

Clinical Predictive Model of Multidrug Resistance in Neutropenic Cancer Patients with Bloodstream Infection Due to Pseudomonas aeruginosa.

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