Trimethoprim-sulfamethoxazole and fluoroquinolones Resistant Escherichia Coli in Community-Acquired and Nosocomial Urinary Tract Infections in Rio De Janeiro, Brazil

Julio César Delgado Correal; Lincoln de Oliveira Sant’Anna; Ana Fátima Coelho Carvalho; Claudia Patricia Alburquerque de Carvalho Seraphim; Gustavo Braga Mendes; Gabriela Higino de Souza; Suzimar da Silveira Rioja; Eduardo de Almeida Ribeiro Castro; Raphael Hirata Jr; Ana Cláudia de Paula Rosa; Ana Luíza Mattos-Guara

doi:10.4172/2332-0877.1000192

ISSN: 2332-0877

Journal of Infectious Diseases & Therapy

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Trimethoprim-sulfamethoxazole and fluoroquinolones Resistant Escherichia Coli in Community-Acquired and Nosocomial Urinary Tract Infections in Rio De Janeiro, Brazil

Julio César Delgado Correal¹, Lincoln de Oliveira Sant’Anna², Ana Fátima Coelho Carvalho¹, Claudia Patricia Alburquerque de Carvalho Seraphim², Gustavo Braga Mendes¹, Gabriela Higino de Souza¹, Suzimar da Silveira Rioja², Eduardo de Almeida Ribeiro Castro¹, Raphael Hirata Jr², Ana Cláudia de Paula Rosa², Ana Luíza Mattos-Guaraldi^2*, José Augusto Adler Pereira² and Paulo Vieira Damasco^1,3,4
¹State University of Rio de Janeiro, Medical Science Department, Brazil
²State University of Rio de Janeiro, Microbiology Department, Brazil
³Federal University of the State of Rio de Janeiro, Medicine School, UNIRIO, Brazil
⁴Pedro Ernesto University Hospital, Infection Control Committee, Brazil
Corresponding Author :	Ana Luiza de Mattos Guaraldi Laboratório de Difteria e Corinebactérias de Importância Clínica-LDCIC Disciplina de Microbiologia e Imunologia, Faculdade de Ciências Médicas Universidade do Estado do Rio de Janeiro - UERJ - Av. 28 de Setembro, 87 - Fundos, 3º andar. Vila Isabel, RJ, Brazil, CEP: 20 551-030 Tel: +55(21) 2868-8280 Fax: +55(21) 2868-8376 E-mail: aguaraldi@gmail.com
Received October 04, 2014; Accepted November 28, 2014; Published December 07, 2014
Citation: Correal JCD, Sant’Anna LO, Carvalho AFC, Seraphim CPAC, Mendes GB, et al. (2014) Trimethoprim-sulfamethoxazole and fluoroquinolones Resistant Escherichia Coli in Community-Acquired and Nosocomial Urinary Tract Infections in Rio De Janeiro, Brazil. J Infect Dis Ther 2:192. doi: 10.4172/2332-0877.1000192
Copyright: © 2014 Correal JCD, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract

To investigate the multidrug resistance (MDR) patterns of Escherichia coli causative of urinary tract infections (UTI) in patients attending a tertiary university hospital of Rio de Janeiro, Brazil. Antibiotic susceptibility testing was performed by the disk diffusion method. MDR, extensively-resistance (XDR) and pan-resistance (PDR) were defined by using recently described criteria. Retrospective analyses of clinical, microbiological and demographic features of outpatients and inpatients with UTI (n=416) were also performed. High antibiotic resistance rates for trimethoprimsulfamethoxazole - SXT-TMP (n=177; 46.7%) and fluoroquinolones - FQ [n=117; norfloxacin (27%) and ciprofloxacin (26.8%) – (FQ) were demonstrated for E. coli strains isolated from community and healthcare-onsets. Risk factors associated with UTIs due to MDR E. coli isolates included prior three-month hospitalization (OR: 2.4; CI 95%: 1.3-4.4; p<0.005), presence of neurogenic bladder (OR: 3.7; CI 95% :1.7-8.3; p<0.01 ) and kidney transplantation (OR: 3.1; CI 95%:1-0.5; p<0.04). A high prevalence of community-acquired and nosocomial urinary tract infections due SXT-TMP/ FQ resistant E. coli strains was observed in Rio de Janeiro metropolitan area, Brazil. According to IDSA Guidelines, initial empirical therapy for community-associated UTI with SXT-TMP and FQ should be avoided in Rio de Janeiro. Nitrofurantoin, amoxicillin/clavulanic, piperacillin/tazobactam or gentamicin associations were effective for the empiric therapy for community-acquired and healthcare-associated UTIs, respectively.

Keywords
Escherichia coli; Healthcare-associated infections; Kidney transplantation trimethoprim-sulfamethoxazole resistance; Fluoroquinolones resistance; Urinary tract infection
Introduction
Urinary tract infection (UTI) is one of the most important causes of healthcare-associated infections in many clinical onsets worldwide, including Brazil [1,2]. UTI brings considerable risk on morbidity and mortality to patients, especially in catheter associated urinary tract infections (CAUTI) which prolonged the length of stay in intensive care units (ICU) and increased the risk of death [3]. Several epidemiological studies have shown increasing trends on multidrug resistant (MDR) Escherichia coli in UTI and bloodstream infections within the community as well as in hospitals and long-term care facilities [4-10]. Nowadays, the emergence of antimicrobial resistance among uropathogenic E.coli is one of the most impacting factors in UTI management. Recent published guidelines for the management of uncomplicated UTI [11] and CAUTI [12] have several limitations on antibiotic choices related to the regional epidemiologic variations of E. coli drug resistance. Therefore, periodically surveillance of antibiotic resistance patterns is a strategic tool to guide empiric antibiotic therapy in UTI, especially of patients presenting structural disturbs of urinary tract and/or submitted to prior hospitalization or kidney transplantation.
The aims of this study were to characterize the antibiotic susceptibility profiles of E. coli isolates recovered from community and healthcare-associated UTIs and to correlate these findings with risk factors and clinical features of patients attending a tertiary teaching 600-beds hospital in Rio de Janeiro metropolitan area, Brazil.
Methodology
Microbiological, clinical and demographic characteristics of patients with UTI
Urine cultures records from outpatients and inpatients (n=419) with E. coli growth in a recount higher than 10⁵ colony-forming unit (CFU) (n=437) were retrospectively analyzed. Bacterial isolation and identification procedures were performed following institutional protocols and using biochemical tests described elsewhere [13]. Definition of community and healthcare-associated E. coli infection was based on the classification of the Centers for Disease Control and Prevention-CDC (USA) [14]. Community-associated E. coli isolates were considered when recovered from patients with 48 hours or less of hospitalization. Only one positive-culture by patient during a threemonth period was selected for this survey. Urine samples presenting more than one microorganism isolated in cultures were excluded from this study.
A retrospective analysis of the antibiotic susceptibility profiles of E. coli isolates recovered from community and healthcare-associated UTIs and the possible risk factors and clinical features of patients attending the Pedro Ernesto University Hospital, Rio de Janeiro, Brazil (a tertiary teaching 600-beds urban hospital, 5-intensive care units) was conducted in this descriptive serial study. Microbiological data were obtained from the records of the Laboratory of Microbiology at the HUPE/FCM/UERJ – RJ, Brazil and from clinical record of each patient.
The following clinical and epidemiological aspects of cases of UTI due to E. coli were analyzed in this study: age, gender, hospitalization setting and time, prior hospitalization, use of antimicrobial agents and surgical procedures, co-morbidities (i.e., diabetes mellitus, renal chronic insufficiency), immunosuppressive conditions, kidney transplantation and structural or functional anomalies of urinary tract (bladder dysfunction) (Table 1).
Antimicrobial susceptibility profiles. The sensitivity to antimicrobial agents (Oxoid, Hampshire, United Kingdom) amikacin (30 μg), amoxicillin (30 μg), amoxicillin plus clavulanic acid (30 μg), ampicillin (30 μg), ampicillin plus sulbactam (10/10 μg), cefepime (30 μg), ceftazidime (30 μg), cefotaxime (30 μg), ceftriaxone (30 μg), ciprofloxacin (5μg), norfloxacin (10μg), gentamicin (10 μg), imipenem (10μg), meropenem (10μg), nitrofurantoin (10 μg), piperacillin plus tazobactam (100/10 μg), and trimethoprim-sulfamethoxazole (SXTTMP) (1.25/23.75 μg) was determined by the disk diffusion method in accordance with the Clinical Laboratory Standards Institute-CLSI (2013) guidelines [15]. MDR E. coli was defined as acquired nonsusceptibility to at least one agent in three or more antimicrobial categories [16].
The presence of extended-spectrum beta-lactamase (ESBL) was determined by the double–disk synergy test. A zone of inhibition between any one of the disk containing beta–lactams and the disk containing clavulanic acid indicated the presence of ESBL [17].
Statistical Analysis
A descriptive analysis of the variables analyzed was performed. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for categorical variables and the χ² test was also used (the Fisher exact test was used if an expected value was less than 5). Logistic regression was used to examine potential associations between variables, and a multivariate analysis was performed to identify risk factors independently associated with mortality. Variables with a p value>0.05 were excluded from the final model. STATA™ version 9.1 (Statacorp, Texas, USA. 2006) was used for all data analyses, and a p value ≤ 0.05 was considered statistically significant.
Results
Results of the analysis of demographic and clinical records from cases of UTI due to E. coli are shown in Table 1. Most of the patients were female (77.8%) with a mean age of 53.6 years-old (range 0-91). From a total of 437 UTI episodes, 375 were in the communityonset (85.7%): 116 (26.4%) healthcare-associated and 259 (59.2%) community-associated.
A number of 139 patients had 3-month prior hospitalization (31.8%); 32.5% of them were from internal medicine or related specialties. There were also patients from the nephrology (21%) and the urology (20%) settings, including a total of forty-four (10%) kidneytransplanted patients in the community (n=43) and hospital-onset (n=1).
Antimicrobial susceptibility profiles of E. coli strains associated with UTI are shown in Table 2. A total of 130 (29.7%) E. coli strains associated with UTI were MDR. In the transplanted group, one third of E. coli isolates were classified as MDR (38.2%); Microorganisms showed resistance to most of the antibiotics tested, especially to nitrofurantoin and fluoroquinolones.
Differences were observed between the E.coli isolated from community and healthcare-onsets. MDR, ESBL-producing cefotaxime and cefuroxime-resistant E.coli isolates were found more prevalent in the healthcare-onset (p<0.05). Generally, E. coli strains from UTI cases showed high resistance rates to norfloxacin (27%), ciprofloxacin (26.8%) and SXT-TMP (46.7%).
Results of multivariate analysis and the respective odds ratios (OR) and 95% confidence interval (CI) performed in order to examine possible associations between the clinic and demographic characteristics of the patients and the presence of MDR E. coli isolates in UTI are shown in Tables 3 and 4. The risk factors associated with the presence of MDR E. coli isolates in UTI were: prior 3-month antibiotic use, presence of neurogenic bladder and previous kidney transplantation. In a separated multivariate analysis of the community-onset, the presence of MDR isolates were associated with aging (65 years-old and older), renal chronic insufficiency, prior 3-month hospitalization and antibiotic use.
A proposal of an antibiotic guidance to initial empiric therapy in urinary tract infections (UTI) due to Escherichia coli based on profiles of antibiotic resistance < 10% is displayed in Table 5.
Discussion
UTIs due to E. coli are the most prevalent infectious diseases in the general population. They cause a substantial financial burden in the community and are associated with significant morbidity and mortality, particularly in hospitalized patients or patients with comorbidities. An optimal antimicrobial therapy should be based on local antimicrobial resistance patterns, specific risk factors of the patients, pharmacokinetic and pharmacodynamic principles and costs.
Regional studies of UTI in community and healthcare-onsets in order to evaluate the periodically modifications on the resistance patterns of E. coli, especially to fluoroquinolones, SXT-TMP, cephalosporins and carbapenems remain necessary. Presently, we found high rates of resistance to classes of antimicrobial agents recommended for treatment of UTI by the United States and European guidelines [11,12]. Interestingly, only two E. coli strains isolated from ITU showed resistance to carbapenems.
MDR E. coli strains are included among other MDR Gram-negative bacilli highly endemic in healthcare-onsets in Brazil, particularly critical settings, such as Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter spp [18]. The increase of resistance can be related to dissemination of MDR E.coli clones verified in others countries. Specifically, the E. coli clone O25b:H4-ST131 has recently emerged globally as a leading MDR pathogen causing UTI and bloodstream infections in hospitals and in the community [19]. This clone is the major contributors to what is known as ‘the CTX-M pandemic; a recent worldwide increase in E. coli uropathogens that produce CTX-M type extended spectrum β-lactamases (ESBLs) [20]. E. coli ST131 are commonly identified among E. coli producing CTX-M-15; currently the most widespread CTX-M extended-spectrum β-lactamases (ESBL) enzyme [5,21]. Additionally, this clone is frequently resistant to fluoroquinolones [6]. Nowadays, is widely recognized the transference of pathogenicity islands containing resistance genes to E. coli (in vitro and in vivo) from others species and this is particularly true for ESBL, ampC and ultimately carbapenemases [22-24]. Consequently, further studies remain necessary in order to define predominant MDR E. coli clones related with UTI in our environment.
Interestingly, some co-morbidities, such as, diabetes mellitus, surgical procedures of abdominal-pelvic cavity or others chronic pathology of bladder different of a neurogenic bladder were not currently associated with the presence of MDR E. coli. In the community onset data showed association of UTI due to MDR E. coli with aging (65 years-old and older) of the patients, which may indicate obstructive pathologies of the urinary tract. Once MDR E. coli was more frequently found among patients with 3-month prior hospitalization and with previous use of antibiotics, a new category in the guidelines of management of UTI should be considered for this “community with risk patients”. Additionally, it should be recommended promptly antibiotic therapy directed to MDR microorganisms whenever menacing important programs such as kidney transplant or prosthetic advice use in urologic procedures. It is also necessary to seek for a more appropriate empirical scheme of treatment for UTI in those patients with prior hospitalization or contact with healthcare-onsets, especially in transplanted patients.
Unfortunately useful antibiotics such as fosfomycin are not tested routinely and there are not well established breakpoints for resistance isolates from the Clinical and Standard Laboratory Institute (CLSI) or the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations in complicate UTI [25]. Additionally, there are few studies correlating clinical responses of this antibiotic in UTI complicated and uncomplicated due to MDR E. coli. [26]. The new cephalosporins (ceftobiprole and ceftaroline) can select P. aeruginosa isolates worsening the prognosis of immunosuppressed patients. An issue of great concern it is the high resistance in E. coli isolates to fluoroquinolones, recognized inductors for MDR in methicillinresistant Staphylococcus aureus (MRSA), carbapenems-resistant Acinetobacter spp. and carbapenemase-producing K. pneumonia [27,28].
The use of fluoroquinolones in the healthcare-onset in many settings of Brazil may be questioned. Based in the proportion of antimicrobial resistance of E. coli isolates an antibiotic scheme for empirical therapy adapted to our local reality may be suggested. Despite the low rates of resistance to piperacillin/tazobactam E. coli isolates in both hospital and community-onsets, it is recommended in community-associated infections only in case of therapeutic failure with other agents in order to save this options for complicated UTI and avoid induction of resistance for other microorganisms (i.e., P. aeruginosa, Acinetobacter sp. and K. pneumoniae). Neither fluoroquinolones nor SXT-TMP was considered in this proposal due to the high rates of resistance observed. It should be only recommended in cases of positive cultures for susceptible microorganisms. In community-associated UTI, the use of cefepime may be recommended as a first choice in cases that intravenous therapy is required due to the benefits on final outcome and costs.
Whereas the lowest prevalence of resistance to oral antimicrobials for E. coli was 5.1%, 7.2% for nitrofurantoin and amoxicillin /clavulanic acid association respectively, these drugs may be considered as the best options for community-acquired UTI. On the other hand, 1.6% of E. coli isolates showed resistance for piperacillin/tazobactam and 3.3% to gentamicin in our hospital. The association piperacillin/ tazobactam or gentamicin seemed to be the best option for the empiric treatment of healthcare-associated UTIs considering that E. coli is still the main microorganism isolated in urine samples up to 30 days of hospitalization or bladder catheterization. Finally, it is important to reconsider the strategies recommended by laboratory procedure standardization international committees (i.e., CSLI and EUCAST) about the necessity of routinely testing antibiotics such as nalidixic acid or ampicillin in urine cultures showing increased resistance in E. coli (59.5 and 50.9% in our series). New prospective studies evaluating the proposed empirical scheme of antibiotic use in UTI should be done, including identification of specific E. coli clones disseminated locally in the community and healthcare-onsets.
Acknowledgements
This is work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Sub-Reitoria de Pós-Graduação e Pesquisa da Universidade do Estado do Rio de Janeiro (SR-2/UERJ).
Conflict of interests
On behalf of all authors, the corresponding author states that there is no conflict of interest. The authors disclose any financial and personal relationships with other people or organizations that could inappropriately influence their work. All authors declare that they have no competing interests.