BERKELEY, CA (UroToday.com) - E. coli is responsible for the vast majority of febrile urinary tract infections (FUTI) in men.
It has been demonstrated that the prostate is the organ most frequently involved in males with FUTI and most of these infections are acute bacterial prostatitis (ABP).
Quinolones, mainly fluoroquinolones (FQ), reach high concentrations in the prostatic tissue and are considered to be the first therapeutic choice in males with FUTI. The widespread use of FQ has led to an increasing resistance to these agents. As quinolones are the optimal treatment of FUTI in men, identification of risk factors for QR would improve the selection of which males with FUTI could receive quinolones empirically.
The objective of this study was to evaluate the clinical factors associated to QR among E. coli strains isolated from males with FUTI. This was an ambispective cross-sectional study in which we evaluated 153 males with a community FUTI caused by E. coli. A structured questionnaire was completed for each patient. Positive urine cultures were defined by bacterial growth ≥103 colony forming units/mL. Antimicrobial susceptibility was tested by agar disk diffusion method. Intermediate and resistant E. coli strains to either of the antimicrobials tested were grouped together for data analysis.
Among the 153 FUTI episodes, 52 (34%) were due to QR E. coli strains. QR E. coli strains were more frequently resistant to other antibiotics including a higher frequency of extended-spectrum β-lactamase (ESBL) production. In the univariate analysis, males with FUTI caused by QR E. coli strains were more likely to be older, to have a HA-UTI, dementia, and higher Charlson scores. They also had a higher frequency of previous UTI, urinary tract abnormalities, and antibiotic use in the previous month.
We performed 3 multivariate models. In each model we included those variables with a P value ≤0.1 in the univariate analysis. In the first model we included HA-UTI and previous antibiotic use but not their individual components. The independent risk factors for a QR E. coli FUTI selected in this model were to have a HA-UTI (OR, 3.82, 95% CI, 1.3-11.24; P 0.015) and use of antimicrobials in the previous month (OR, 5.82, 95% CI, 2.3-14.88; P <0.001).
In the second model we introduced the different components included in the HA-UTI definition with a P value ≤0.1 in the univariate analysis, instead of HA-UTI, and the same variables as in the first model. In this model, none of the variables included in the definition of HA-UTI that resulted significantly in the univariate analysis reached statistical significance. In the third model we introduced FQ use, as this was the only antimicrobial with a P value ≤0.1 in the univariate analysis, and the same variables as in the first mode. In this final model, prior treatment with FQ was associated to QR E. coli FUTI (OR, 13.97, 95% CI, 2.73-71.53; P 0.002).
In our study, 34% of the E. coli strains isolated from men with community FUTI were QR. In this study, despite the fact that several variables were more prevalent in patients with an infection related to a QR E. coli strain, in the multivariate analysis, only a health-care related acquisition of the UTI and the use of FQ in the preceding month remained associated to QR E. coli.
Regarding HA-UTI, one of the main problems when analyzing this variable is that its diagnostic criteria have not been properly defined. Despite this limitation, the association of HA-UTI with QR suggests that the health care setting serves as a reservoir for QR and that patients acquire these QR E. coli resistant strains after establishing contact with it.
Another interesting observation of our study was that QR E. coli strains were more frequently resistant to other antimicrobials. Resistance to quinolones in E. coli arises as a result of mutations in genes encoding the quinolone targets or in those affecting either the expression of porins or efflux pumps. Mutations that lead to an increased expression of multidrug efflux pumps may explain the higher frequency of resistance to other antimicrobials found in QR E. coli strains. Resistance to FQ can also be transmitted through plasmids. Strains that possess the quinolone plasmids encoded resistance are frequently associated with enzymes that inactivate third generation cephalosporins - which may partially explain the frequent association, as observed in our study, between QR and ESBL production in Enterobacteriaceae.
The other variable that was associated to QR in the multivariate analysis was having received antibiotic treatment, particularly FQ, in the preceding month. Prior antibiotic use with quinolones has widely been recognised as a factor related to QR in E. coli strains causing community UTI. Interestingly nearly 40% of the patients included in the study referred a history of previous UTI, which rose to 60% in the group of FUTI caused by QR E. coli strains. Recurrent UTI in men are frequently associated with the existence of a subjacent chronic bacterial prostatitis (CBP). It has been demonstrated that E. coli strains isolated from patients with CBP frequently produce biofilm. Patients with CBP usually receive long and recurrent antimicrobial courses, frequently involving the administration of FQ. We suggest that the administration of repeated courses of FQ could expose E. coli strains present in the deep biofilm layers to sub-inhibitory concentrations of FQ, which could lead to the selection of QR strains that could cause subsequent episodes of UTI.
The present study has some limitations. First of all we have used a definition of HA-UTI that has not been supported by prospective studies. Second, we included as QR not only those E. coli strains resistant to ciprofloxacin but also those resistant to pipemidic acid and susceptible to ciprofloxacin. Most E. coli isolates that are resistant to nalidixic acid carry a mutation in one of the quinolone targets. E. coli strains that already have a mutation in one of these targets can easily develop a second mechanism of resistance and acquire higher levels of resistance in presence of quinolones. The clinical importance of treating with FQ infections caused by nalidixic resistant microorganism has been demonstrated in typhoid fever caused by nalidixic resistant S. typhy strains but not in UTI caused by nalidixic resistant E. coli strains. The third consideration is that we have analyzed an apparent miscellaneous group of patients with FUTI. This approach could be questioned but as stated in the Guidelines on urological infections from the European Association of Urology, most men with FUTI have a concomitant infection of the prostate and should be considered as ABP.
The importance of this study is that it not only confirms the significance of previously known risk factors for QR in males, mainly the existence of a previous exposure to FQ, but also highlights the relevance of new risk factors such as having had a recent health contact. These risk factors should be taken into consideration before initiating empirical treatment with quinolones.
Alex Smithson, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
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