Influence of carbapenem resistance on mortality of patients with Pseudomonas aeruginosa infection: a meta-analysis.
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SUBMITTER: Liu Q
PROVIDER: S-EPMC4479982 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Whether carbapenem resistance is associated with mortality in patients with Pseudomonas aeruginosa bacteremia is controversial. To address this issue, we conducted a systematic review and meta-analysis based on cohort studies. We searched PubMed and Embase databases to identify articles (up to April 2015). The DerSimonian and Laird random-effect model was used to generate a summary estimate of effect. Associations were evaluated in subgroups based on different patient characteristics and study quality criteria. Seven studies with a total of 1613 patients were finally included, of which 1 study had a prospective design, and the other 6 were retrospective. Our meta-analysis showed patients with carbapenem-resistant P. aeruginosa bacteremia were at a higher risk of death compared with those with carbapenem-susceptible P. aeruginosa bloodstream infections (pooled odds ratio (OR) from three studies reporting adjusted ORs: 3.07, 95% confidence interval (CI), 1.60-5.89; pooled OR from 4 studies only reporting crude ORs: 1.46, 95% CI, 1.10-1.94). The results were robust across a number of stratified analyses and a sensitivity analysis. We also calculated that 8%-18.4% of deaths were attributable to carbapenem resistance in four studies assessing the outcome with 30-day mortality, and these were 3% and 14.6%, respectively, in two studies using 7-day mortality or mortality during bacteremia as an outcome of interest. Carbapenem resistance had a deleterious impact on the mortality of P. aeruginosa bacteremia; however, the results should be interpreted cautiously because only three studies reporting adjusted ORs were included. More large-scale, well-designed prospective cohorts, as well as mechanistic studies, are urgently needed in the future.
| S-EPMC4820673 | biostudies-literature
Project description:This study established the in vitro activity of ceftolozane/tazobactam (C/T) and its genotypic resistance mechanisms by whole-genome sequencing (WGS) in 195 carbapenem-nonsusceptible Pseudomonas aeruginosa (CNSPA) clinical isolates recovered from Singapore between 2009 and 2020. C/T susceptibility rates were low, at 37.9%. Cross-resistance to ceftazidime/avibactam was observed, although susceptibility to the agent was slightly higher, at 41.0%. Whole-genome sequencing revealed that C/T resistance was largely mediated by the presence of horizontally acquired ?-lactamases, especially metallo-?-lactamases. These were primarily disseminated in well-recognized high-risk clones belonging to sequence types (ST) 235, 308, and 179. C/T resistance was also observed in several non-carbapenemase-producing isolates, in which resistance was likely mediated by ?-lactamases and, to a smaller extent, mutations in AmpC-related genes. There was no obvious mechanism of resistance observed in five isolates. The high C/T resistance highlights the limited utility of the agent as an empirical agent in our setting. Knowledge of local molecular epidemiology is crucial in determining the potential of therapy with novel agents.IMPORTANCE Pseudomonas aeruginosa infection is one of the most difficult health care-associated infections to treat due to the ability of the organism to acquire a multitude of resistance mechanisms and express the multidrug resistance phenotype. Ceftolozane/tazobactam (C/T), a novel ?-lactam/?-lactamase inhibitor combination, addresses an unmet medical need in patients with these multidrug-resistant P. aeruginosa infections. Our findings demonstrate geographical variation in C/T susceptibility owing to the distinct local molecular epidemiology. This study adds on to the growing knowledge of C/T resistance, particularly mutational resistance, and will aid in the design of future ?-lactams and ?-lactamase inhibitors. WGS proved to be a useful tool to understand the P. aeruginosa resistome and its contribution to emerging resistance in novel antimicrobial agents.
| S-EPMC7885320 | biostudies-literature
Project description:ImportanceTreatment of patients with infections due to Pseudomonas aeruginosa has been complicated by increased antibiotic resistance rates, which contribute to delayed appropriate treatment and deleterious outcomes.ObjectiveTo develop 2 clinical risk scores based on variables available at clinical presentation to estimate the risk of carbapenem resistance (CR) or extensive ?-lactam resistance (EBR) among hospitalized, adult patients with P aeruginosa infections.Design, setting, and participantsThis retrospective cohort study included adult (age, ?18 years) members of Kaiser Permanente Southern California (KPSC) with a P aeruginosa infection during hospitalization from September 1, 2011, through August 31, 2016, who received antibiotic therapy within 2 days of the culture date. Data were analyzed from July 2, 2017, through August 15, 2018.ExposuresDemographic, clinical, and laboratory covariates 1 year before the index culture date were evaluated.Main outcomes and measuresPseudomonas aeruginosa was categorized as antibiotic susceptible, CR, or EBR (nonsusceptibility to carbapenems, ceftazidime, and combined piperacillin sodium and tazobactam sodium). Patients were randomly split (1:1) into training and validation data sets. The training data set was used to develop 2 prediction models using high-performance logistic regression with variable selection by Schwarz-Bayesian criterion. The models were translated into risk scores, with risk score points equaling the weighted sums of regression coefficients from the prediction model. The patient's risk was estimated as the inverse logit of the risk score.ResultsOf the 7775 patients with 11?502 P aeruginosa infections included in the analysis, most were male (4308 [55.4%]) and non-Hispanic white (3927 [50.5%]). The mean (SD) age was 70.3 (15.5) years. Among 11?502 P aeruginosa infections, 2324 (20.2%) were CR, 9178 (79.8%) were non-CR, 1033 (9.0%) were EBR, and 10?469 were non-EBR (91.0%). The strongest predictors of resistance in the CR and EBR models were history of CR P aeruginosa infection (odds ratios [ORs],?8.80 [95% CI, 6.74-11.49] and?5.04 [95% CI, 3.88-6.54], respectively), tracheostomy (ORs,?3.49 [95% CI, 2.92-4.16] and?3.13 [95% CI, 2.50-3.91], respectively), and carbapenem use in the prior 30 days (ORs,?4.18 [95% CI, 3.29-5.31] and 2.26 [95% CI, 1.74-2.93], respectively). The models for CR and EBR performed well, with areas under the receiver operating characteristics curve of 0.81 or greater for the training and validation data sets.Conclusions and relevanceThe findings of this study suggest that parsimonious risk scores can aid physicians in appropriate treatment selection during the critical period when P aeruginosa infection is suspected but antibiotic susceptibility results are not yet available.
| S-EPMC6324445 | biostudies-literature
Project description:The emergence of carbapenem-resistant Pseudomonas aeruginosa represents a worldwide problem. To understand the carbapenem-resistance mechanisms and their spreading among P. aeruginosa strains, whole genome sequences were determined of two extensively drug-resistant strains that are endemic in Dutch hospitals. Strain Carb01 63 is of O-antigen serotype O12 and of sequence type ST111, whilst S04 90 is a serotype O11 strain of ST446. Both strains carry a gene for metallo-?-lactamase VIM-2 flanked by two aacA29 genes encoding aminoglycoside acetyltransferases on a class 1 integron. The integron is located on the chromosome in strain Carb01 63 and on a plasmid in strain S04 90. The backbone of the 159-kb plasmid, designated pS04 90, is similar to a previously described plasmid, pND6-2, from Pseudomonas putida. Analysis of the context of the integron showed that it is present in both strains on a ?30-kb mosaic DNA segment composed of four different transposons that can presumably act together as a novel, active, composite transposon. Apart from the presence of a 1237-bp insertion sequence element in the composite transposon on pS04 90, these transposons show > 99% sequence identity indicating that transposition between plasmid and chromosome could have occurred only very recently. The pS04 90 plasmid could be transferred by conjugation to a susceptible P. aeruginosa strain. A second class 1 integron containing a gene for a CARB-2 ?-lactamase flanked by an aacA4'-8 and an aadA2 gene, encoding an aminoglycoside acetyltransferase and adenylyltransferase, respectively, was present only in strain Carb01 63. This integron is located also on a composite transposon that is inserted in an integrative and conjugative element on the chromosome. Additionally, this strain contains a frameshift mutation in the oprD gene encoding a porin involved in the transport of carbapenems across the outer membrane. Together, the results demonstrate that integron-encoded carbapenem and carbapenicillin resistance can easily be disseminated by transposition and conjugation among Pseudomonas aeruginosa strains.
| S-EPMC6133989 | biostudies-literature
Project description:IntroductionAvailable evidence from observational studies and meta-analyses has highlighted an increased mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infections (BSI) compared with their carbapenem-susceptible (CSKP) counterparts, but the exact reasons for this outcome difference are still to be determined.MethodsWe updated the search of a previous meta-analysis through four databases up to April 2018. A two-stage individual-patient data (IPD) meta-analysis was conducted, building an adjusting model to account for age, comorbidities and activity of empirical and targeted antimicrobial therapy. The protocol was registered on PROSPERO (identifier: CRD42018104256).ResultsIPD data were obtained from 14 out of 28 eligible observational studies. A total of 1952 patients were investigated: 1093 in the CRKP group and 859 in the CSKP group. Patients with CRKP-BSI had a twofold risk of death compared with CSKP-infected patients [adjusted odds ratio (aOR) 2.17; 95% confidence interval (CI) 1.56-3.04; I2 = 44.1%]. Mortality was higher in patients with CRKP BSI, in both the subgroup of absent/inactive (aOR 1.75; 95% CI 1.24-2.47; I2 = 0) and of active initial therapy (aOR 2.66; 95% CI 1.70-4.16; I2 = 16%) as well as in case of active targeted therapy (aOR 2.21; 95% CI 1.36-3.59; I2 = 58%).ConclusionResistance to carbapenem is associated with worse outcome in patients with BSI by Klebsiella pneumoniae even adjusting for comorbidities and treatment appropriateness according to in vitro activity of empirical and targeted therapy. This applies to a scenario dominated by colistin-based therapies for CRKP. Further studies are needed to compare the mortality difference between CRKP and CSKP cases in the light of new anti-CRKP antimicrobials.
| S-EPMC7954918 | biostudies-literature
Project description:BackgroundPseudomonas aeruginosa is a clinically important pathogen that causes opportunistic infections and nosocomial outbreaks. Recently, the type III secretion system (TTSS) has been shown to play an important role in the virulence of P. aeruginosa. ExoU, in particular, has the greatest impact on disease severity. We examined the relationship among the TTSS effector genotype (exoS and exoU), fluoroquinolone resistance, and target site mutations in 66 carbapenem-resistant P. aeruginosa strains.MethodsSixty-six carbapenem-resistant P. aeruginosa strains were collected from patients in a university hospital in Daejeon, Korea, from January 2008 to May 2012. Minimum inhibitory concentrations (MICs) of fluoroquinolones (ciprofloxacin and levofloxacin) were determined by using the agar dilution method. We used PCR and sequencing to determine the TTSS effector genotype and quinolone resistance-determining regions (QRDRs) of the respective target genes gyrA, gyrB, parC, and parE.ResultsA higher proportion of exoU+ strains were fluoroquinolone-resistant than exoS+ strains (93.2%, 41/44 vs. 45.0%, 9/20; P≤0.0001). Additionally, exoU+ strains were more likely to carry combined mutations than exoS+ strains (97.6%, 40/41 vs. 70%, 7/10; P=0.021), and MIC increased as the number of active mutations increased.ConclusionsThe recent overuse of fluoroquinolone has led to both increased resistance and enhanced virulence of carbapenem-resistant P. aeruginosa. These data indicate a specific relationship among exoU genotype, fluoroquinolone resistance, and resistance-conferring mutations.
| S-EPMC4071185 | biostudies-literature
Project description:It is well established that antibiotic treatment selects for resistance, but the dynamics of this process during infections are poorly understood. Here we map the responses of Pseudomonas aeruginosa to treatment in high definition during a lung infection of a single ICU patient. Host immunity and antibiotic therapy with meropenem suppressed P. aeruginosa, but a second wave of infection emerged due to the growth of oprD and wbpM meropenem resistant mutants that evolved in situ. Selection then led to a loss of resistance by decreasing the prevalence of low fitness oprD mutants, increasing the frequency of high fitness mutants lacking the MexAB-OprM efflux pump, and decreasing the copy number of a multidrug resistance plasmid. Ultimately, host immunity suppressed wbpM mutants with high meropenem resistance and fitness. Our study highlights how natural selection and host immunity interact to drive both the rapid rise, and fall, of resistance during infection.
| S-EPMC8080559 | biostudies-literature
Project description:Carbapenems, fluoroquinolones (FQs), and aminoglycosides (AGs) are key drugs for treating Pseudomonas aeruginosa infections, and accumulation of drug resistances make antibiotic therapy difficult.We evaluated 169 patients with imipenem (IPM)-resistant P. aeruginosa and compared patient background and microbiological characteristics between groups with or without FQ resistance. Similar analyses were performed for AG.Of the 169 IPM-resistant strains, 39.1% showed resistance to FQs and 7.1% to AGs. The frequency of exposure to FQs within 90 days previously was higher in the group with FQ resistance (45.5%) than in the group without FQ resistance (13.6%). Similarly, 33.3% of patients in the group with AG resistance had been previously administered AGs, higher than the 7.6% of patients without AG resistance. Frequencies of metallo-β-lactamase (MBL) production were higher in the group with FQ or AG resistance (16.7% or 33.3%) than in the group without FQ or AG resistance (2.9% or 6.4%). Multivariate analyses showed exposures to FQs or AGs were related to the respective resistances. MBL production was a common factor for resistance to FQs or AGs, in addition to IPM-resistant P. aeruginosa.As well as promoting appropriate use of antibiotics, MBL production should be detected as a target of intervention for infection control.
| S-EPMC5481610 | biostudies-other
Project description:BackgroundCarbapenem-resistant Pseudomonas aeruginosa (CRPA) isolates can frequently retain susceptibility to traditional antipseudomonal β-lactams including cefepime, ceftazidime and piperacillin/tazobactam.ObjectivesThis observational study aimed to determine the proportion of CRPA isolates that were susceptible to all tested other traditional antipseudomonal β-lactams (S-CRPA) and assess whether patients with S-CRPA had improved 30 day mortality compared with patients with NS-CRPA (non-susceptible to cefepime, ceftazidime or piperacillin/tazobactam).MethodsPatients with CRPA isolated from normally sterile sites, urine, lower respiratory tracts and wounds were identified using active population- and laboratory-based surveillance through the Georgia Emerging Infections Program from August 2016 to July 2018 in Atlanta, GA, USA. Only unique patients who were hospitalized at the time of, or within 1 week of, culture were included. We excluded patients with cystic fibrosis. Multivariable logistic regression estimated the association between S-CRPA and 30 day mortality.ResultsAmong 635 adults hospitalized with CRPA, 219 (34%) had S-CRPA. Patients with S-CRPA were more likely to be white (50% versus 38%, P = 0.01) and live in a private residence prior to culture (44% versus 28%, P < 0.01), and less likely to have required ICU care within the prior week (23% versus 36%, P < 0.01) compared with patients with NS-CRPA. Compared with those with NS-CRPA, patients with S-CRPA had an increased 30 day mortality (18% versus 15%, adjusted OR 1.9; 95% CI 1.2-3.1).ConclusionsS-CRPA was associated with higher 30 day mortality than NS-CRPA in hospitalized patients. The reason for this observed increase in mortality deserves further investigation.
| S-EPMC8678435 | biostudies-literature
Project description:Carbapenems are the most important therapeutic options that effect against serious infections caused by multidrug resistant Pseudomonas aeruginosa (MDR-PA) isolates. Carbapenems resistant isolates of P. aeruginosa are increasing worldwide. The aim of this study was to determine the carbapenem resistance mechanisms in clinical P. aeruginosa isolates from burn patients, in Tehran, Iran. A total of 53 non-duplicated isolates of carbapenem-resistant P. aeruginosa were collected from burn patients. The presence of carbapenemase genes were determined by PCR. AmpC overproducer isolates were detected by phenotypic method. The mutation and transcription level of oprD were determined by PCR-sequencing and quantitative Real-time PCR (RT-PCR), respectively. Twenty-seven (50.9%) isolates were positive for carbapenemase (blaVIM=25 and blaIMP=2) and showed high-level resistance to imipenem and meropenem. Twenty-eight isolates were AmpC overproducers. All isolates had a mutation in the oprD gene and down-regulation of oprD was found in 56.6% of MDR-PA isolates. Although the presence of carbapenemase is the common mechanism of resistant to carbapenem, but carbapenem resistance was found by oprD mutation-driven and the AmpC overproducing isolates in Tehran, Iran.
| S-EPMC7320450 | biostudies-literature