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Network Analysis Reveals Sex- and Antibiotic Resistance-Associated Antivirulence Targets in Clinical Uropathogens.

ABSTRACT: Increasing antibiotic resistance among uropathogenic Escherichia coli (UPEC) is driving interest in therapeutic targeting of nonconserved virulence factor (VF) genes. The ability to formulate efficacious combinations of antivirulence agents requires an improved understanding of how UPEC deploy these genes. To identify clinically relevant VF combinations, we applied contemporary network analysis and biclustering algorithms to VF profiles from a large, previously characterized inpatient clinical cohort. These mathematical approaches identified four stereotypical VF combinations with distinctive relationships to antibiotic resistance and patient sex that are independent of traditional phylogenetic grouping. Targeting resistance- or sex-associated VFs based upon these contemporary mathematical approaches may facilitate individualized anti-infective therapies and identify synergistic VF combinations in bacterial pathogens.

SUBMITTER: Parker KS

PROVIDER: S-EPMC4788272 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Network Analysis Reveals Sex- and Antibiotic Resistance-Associated Antivirulence Targets in Clinical Uropathogens.

Parker Kaveri S KS Wilson James D JD Marschall Jonas J Mucha Peter J PJ Henderson Jeffrey P JP

ACS infectious diseases 20150724 11

Increasing antibiotic resistance among uropathogenic <i>Escherichia coli</i> (UPEC) is driving interest in therapeutic targeting of nonconserved virulence factor (VF) genes. The ability to formulate efficacious combinations of antivirulence agents requires an improved understanding of how UPEC deploy these genes. To identify clinically relevant VF combinations, we applied contemporary network analysis and biclustering algorithms to VF profiles from a large, previously characterized inpatient cli ...[more]

PMID: 26985454

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Project description:With the growing threat of antimicrobial resistance worldwide, uncovering the molecular epidemiology is critical for understanding what is driving this crisis. We aimed to evaluate the prevalence of plasmid-mediated-quinolone-resistance (PMQR) and extended-spectrum beta-lactamase- (ESBL) producing gram-negative organisms among primigravid women with bacteriuria. We collected urine specimens from primigravid women attending their first antenatal visit at Gandhi Hospital during October 1, 2015 to September 30, 2016. We determined antimicrobial susceptibility and ESBL and quinolone resistance using VITEK-2. We performed polymerase chain reaction amplification on resistant isolates for detection of ESBL-encoding genes (TEM, SHV, CTX-M) and PMQR genes (qnrA, qnrB, qnrD, qnrS, aac (6')-Ib-cr). Of 1,841 urine samples, 133 demonstrated significant bacterial growth with gram-negative bacilli accounting for 85% of isolates, including Escherichia coli (n = 79), Klebsiella pneumoniae (n = 29), Sphingomonas (n = 3), Enterobacter (n = 1), and Citrobacter (n = 1). We found 65% of E. coli isolates and 41% of K. pneumoniae isolates were ESBL positive. Of ESBL-positive isolates, the most common genes conferring resistance were TEM-1 (66.7%) followed by CTX-M-15 (33.3%). Fifty-seven percent of ESBL-positive E. coli also demonstrated resistance to quinolones with the most common PMQR genes being qnr-S (62.5%) and aac (6')-Ib-cr (37.5%). We did not find any resistance to quinolones among ESBL-positive K. pneumoniae isolates. Across different classes of antibiotics we found a strong clustering of multi-drug resistance in E. coli with over 45% of ESBL-positive isolates demonstrating resistance to at least three classes of antibiotics. This study emphasizes the high prevalence of plasmid-mediated ESBL and quinolone resistance in community-acquired urinary tract infections of primigravid women. The overall abundance of multi-drug-resistant isolates in this population is alarming and may present therapeutic challenges.

Project description:BackgroundWhile the resistance rates of commonly detected uropathogens are well described, those of less frequent Gram-negative uropathogenic bacteria have seldom been reported. The aim of this study was to examine the resistance rates of less frequent uropathogenic Gram-negatives in a population of patients treated in a Department of Urology of a tertiary referral centre in Central Europe over a period of 9 years.MethodsData on all positive urine samples from urological in- and out-patients were extracted form the Department of Clinical Microbiology database from 2011 to 2019. Numbers of susceptible and resistant isolates per year were calculated for these uropathogens: Acinetobacter spp. (n = 74), Citrobacter spp. (n = 60), Enterobacter spp. (n = 250), Morganella morganii (n = 194), Providencia spp. (n = 53), Serratia spp. (n = 82) and Stenotrophomonas maltophilia (n = 27). Antimicrobial agents selected for the survey included: ampicillin, amoxicillin/clavulanic acid, piperacillin/tazobactam; cefuroxime, cefotaxime, ceftazidime and cefepime; ciprofloxacin and ofloxacin; gentamicin and amikacin; ertapenem, meropenem and imipenem; trimethoprim-sulfamethoxazole (co-trimoxazole), nitrofurantoin and colistin.ResultsPenicillin derivatives have generally poor effect except piperacillin/tazobactam. Cefuroxime is not efficient unlike cefotaxime (except against Acinetobacter spp. and S. maltophilia). Susceptibility to fluoroquinolones is limited. Amikacin is somewhat more efficient than gentamicine but susceptibilities for both safely exceed 80%. Nitrofurantoin shows virtually no efficiency. Cotrimoxazole acts well against Citrobacter spp., Serratia spp. and it is the treatment of choice for S. maltophilia UTIs. Among carbapenems, ertapenem was less efficient than meropenem and imipenem except for S. maltophilia whose isolates were mostly not suceptible to any carbapenems.ConclusionsUropathogenic microorganisms covered in this report are noteworthy for their frequently multi-drug resistant phenotypes. Knowledge of resistance patterns helps clinicians choose the right empirical antibiotic treatment when the taxonomical assignment of the isolate is known but sensitivity results are pending.

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Network Analysis Reveals Sex- and Antibiotic Resistance-Associated Antivirulence Targets in Clinical Uropathogens.

Publications

Network Analysis Reveals Sex- and Antibiotic Resistance-Associated Antivirulence Targets in Clinical Uropathogens.

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