Risk factors for antibiotic-resistant Escherichia coli isolated from community-acquired urinary tract infections in Dakar, Senegal

Jacques Albert Dromigny1,*, Pierre Nabeth2, Ann Juergens-Behr2 and Jean David Perrier-Gros-Claude1

1 Laboratoire de Microbiologie, Institut Pasteur de Dakar, 36 Avenue Pasteur, BP 220, Dakar, Senegal; 2 Unité d'Epidémiologie, Institut Pasteur de Dakar, 36 Avenue Pasteur, BP 220, Dakar, Senegal


* Corresponding author. Tel: +221-839-92-31; Fax: +221-822-70-52; Email: dromigny{at}pasteur.sn

Received 18 February 2005; returned 11 March 2005; revised 13 April 2005; accepted 15 April 2005


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Objectives: To assess overall resistance rates and risk factors for resistance to ampicillin, co-amoxiclav, nalidixic acid, fluoroquinolones and trimethoprim/sulfamethoxazole in Escherichia coli strains isolated from outpatients with acute urinary tract infection in Dakar (Senegal).

Patients and methods: From June 2001 to June 2003, a prospective study was performed among Senegalese outpatients consulting at the Institut Pasteur of Dakar for urine analysis. Evaluated risk factors were: age, gender, prior hospitalization, antibiotic exposure, urinary tract infection and urinary catheter.

Results: A total of 398 non-duplicate, consecutive, biologically significant E. coli were isolated. The levels of antibiotic resistance in Dakar appeared dramatic and worrisome with resistance rates ranging from 18.6% for fluoroquinolones to 73.6% for ampicillin. With the exception of the presence of urinary catheter, the risk factors identified were consistent with data previously reported in developed countries.

Conclusions: We hope our results will assist medical authorities in the development of appropriate control strategies.

Keywords: antimicrobial resistance , multivariate analysis , Enterobacteriaceae


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Urinary tract infection is a common community-acquired bacterial disease which frequently affects female outpatients.1 Escherichia coli, the most common member of the family Enterobacteriaceae, accounts for 75–90% of all urinary tract infections in both inpatients and outpatients.2 Increasing rates of resistance among bacterial uropathogens has caused growing concern in both developed and developing countries.2 A limited number of studies conducted in developed countries have analysed demographic and epidemiological data in order to determine the risk factors associated with resistant isolates from urine cultures,1,3,4 but to our knowledge, no such research has been done in developing countries.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
To determine the risk factors for urinary tract infection due to E. coli strains that are resistant to commonly used antimicrobial agents, we performed a prospective study from June 2001 to June 2003 among Senegalese outpatients consulting at the Institut Pasteur of Dakar (Senegal) for urine analysis. The majority of these patients (~75%) were civil servants or middle class workers who were insured through a special agreement with the Senegalese government or through private health insurance. After obtaining informed consent, each study participant was asked to complete a brief questionnaire requesting demographic data and medical history. The risk factors for E. coli resistance to ampicillin, co-amoxiclav, nalidixic acid, fluoroquinolones and trimethoprim/sulfamethoxazole—the most commonly used antimicrobial agents in Dakar—were determined according to the following variables: age group (<15 years, between 15 and 45 years and >45 years), gender, hospitalization and antibiotic exposure during the previous 6 months, and urinary tract infection and presence of urinary catheter during the previous year. The biological criteria for inclusion were a pure bacterial culture with a colony count of ≥104 cfu/mL and a leucocyte count of ≥104 cells/mL. E. coli was biochemically identified using API 20E system (bioMérieux, Marcy l'Étoile, France). Susceptibility testing was performed by disc diffusion method as recommended by the Antibiogram Committee of the French Society for Microbiology.5 The antibiotics tested were supplied by Bio-Rad (Marne la Coquette, France) with respective quantities (µg/disc) of active compounds: ampicillin (10), co-amoxiclav (20/10), ticarcillin (75), cefazolin (30), cefoxitin (30), cefotaxime (30), imipenem (10), nalidixic acid (30), fluoroquinolones [including pefloxacin (5), norfloxacin (5) and ciprofloxacin (5)], gentamicin (15), tobramycin (10), amikacin (30), tetracycline (30), chloramphenicol (30) and trimethoprim/sulfamethoxazole (1.25/23.75). Extended-spectrum ß-lactamase (ESBL) strains were systematically detected by double disc synergy test with cefotaxime or ceftazidime and co-amoxiclav as recommended.5 Isolates producing an ESBL were classified as resistant to cephalosporins.5 Zones of inhibition were measured by an automatic reader (Sirscan I2A, Pérols, France) and classified according to criteria of the Antibiogram Committee of the French Society for Microbiology.5 Intermediate and resistant strains were grouped together and classified as resistant. Repeat isolates from the same patients with the same resistance pattern were excluded. E. coli isolates displaying resistance to one of the three fluoroquinolones tested were classified as fluoroquinolone-resistant. Appropriate ATCC control strains were used and tested weekly. Statistical analyses were performed using STATA software version 6.0. Risk factors predicting E. coli resistance were estimated by univariate analysis and tested where appropriate by {chi}2 or Fisher's exact test. Variables with P < 0.25 in the univariate analysis were then included in a multivariable logistic regression model. Variables with an adjusted odds ratio of P < 0.05 were considered risk factors.


    Results and discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
During the study period, 8221 urine samples were analysed by the microbiology unit of the clinical laboratory. Of 695 uropathogen strains collected, a total of 398 non-duplicate, consecutive, biologically significant E. coli were isolated from 282 female and 116 male patients with a mean age of 39.1 years (95% CI: 38.2–42.1). The majority of our patients (72.9%) were uncomplicated urinary tract infections and 39% admitted to have taken an antibiotic treatment during the last 6 months. Table 1 shows the rates of resistance by year to selected antimicrobial agents. Resistance to trimethoprim/sulfamethoxazole, ampicillin and tetracycline—the most commonly used drugs in Senegal—was highest, with respective resistance rates of 67.8%, 73.6% and 75.9%. Among ß-lactams, imipenem and cefotaxime appeared to be the most effective drugs, with resistance rates of 0% and 6.5%, respectively. Resistance rates to nalidixic acid and fluoroquinolones were ~20%. Compared with the other classes of drugs, aminoglycosides were the most effective, and in particular, the rate of resistance to amikacin was less than 1%. During the study, 25 ESBL-producing strains were isolated. Among the five antimicrobial agents most commonly used for the treatment of urinary tract infections (ampicillin, co-amoxiclav, trimethoprim/sulfamethoxazole, nalidixic acid and fluoroquinolones), resistance phenotype rates to ampicillin + trimethoprim/sulfamethoxazole, ampicillin + co-amoxiclav + trimethoprim/sulfamethoxazole, ampicillin + co-amoxiclav + trimethoprim/sulfamethoxazole + nalidixic acid and ampicillin + co-amoxiclav + trimethoprim/sulfamethoxazole + nalidixic acid + fluoroquinolones were 60%, 47%, 15% and 12%, respectively. Only 10.6% of the E. coli isolates were susceptible to all of the tested antibiotics prescribed either for short course therapy (trimethoprim/sulfamethoxazole and fluoroquinolones for 3 days) or for a 7 day course (ampicillin, co-amoxiclav).


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Table 1. Rate of resistance of E. coli isolated from urinary tract infection by antibiotic and year of study

 
Following univariate analysis, age groups for ampicillin and co-amoxiclav and prior urinary catheter for ampicillin and trimethoprim/sulfamethoxazole were not entered into the logistic regression model. According to multivariate analysis (Table 2), prior antibiotic exposure was identified as a significant risk factor for resistance to ampicillin, co-amoxiclav, nalidixic acid and trimethoprim/sulfamethoxazole. Prior urinary tract infection was also identified as a risk factor for resistance to nalidixic acid and fluoroquinolones. E. coli strains were statistically more resistant to ampicillin amongst men than amongst women. Age >45 years was associated with E. coli resistance to nalidixic acid and fluoroquinolones. Prior urinary catheter and prior hospitalization were not found to be significant risk factors.


View this table:
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Table 2. Multivariate analysis of independent risk factors for E. coli resistance to ampicillin, co-amoxiclav, nalidixic acid, fluoroquinolones and trimethoprim/sulfamethoxazole

 
The majority of urinary tract infections are treated empirically especially in developing countries where patients often cannot afford to consult a physician or to conduct laboratory analysis. Consequently, when urine samples are collected in a laboratory setting, there may be an overrepresentation of microorganisms that do not respond to treatment and of patients with complicated clinical courses, repeat infections, or underlying diseases. Despite this possible bias due to recruitment of patients in a laboratory setting, our study allows us to provide information about risk factors for urinary tract infection due to E. coli strains that are resistant to commonly used antimicrobial agents in a developing country.

Consistent with previous reports, women represented the majority of patients consulting with urinary tract infection and E. coli was the uropathogen most frequently isolated.2 Rates of resistance to the antimicrobial agents studied appeared much higher than those usually published for community-acquired urinary tract infection,6 and seemed more consistent with data from hospitalized patients.7 These levels of resistance can be explained by widespread and easy access to first-line antimicrobials in pharmacies and open-air markets in Dakar.8 Consequently, antimicrobials such as ampicillin, co-amoxiclav, trimethoprim/sulfamethoxazole and first-generation cephalosporins can no longer be recommended as initial empirical therapies. In addition, first-generation quinolones and fluoroquinolones also seem to be threatened as second-line therapies given that rates of E. coli resistance to these drugs are ~20%.

Consistent with previous reports, our logistic regression model showed that prior antibiotic treatment was the most frequent risk factor for resistance to antimicrobials commonly used for treatment of urinary tract infection (ampicillin, co-amoxiclav, nalidixic acid and trimethoprim/sulfamethoxazole).9 Although prior urinary tract infection is probably associated with previous antimicrobial treatment, this variable was only linked with resistance to nalidixic acid and fluoroquinolones in our multivariate analysis. The risk factors identified most probably reflect the frequent and uncontrolled use of antimicrobials in Dakar. In addition, patients frequently do not complete the full course of medication because of lack of resources, facilitating a selection of mutant isolates. Contrary to previously published data, prior urinary catheter was not identified as a significant risk factor for resistance to any of the antibiotics tested.3 This could be explained by our relatively weak sample size. However, consistent with previous reports, prior hospitalization was not significantly associated with E. coli resistance.3,4 Male patients had a significantly higher risk of urinary tract infections caused by E. coli resistant to ampicillin than female patients,10 and age greater than 45 years was associated with urinary tract infection caused by nalidixic acid and fluoroquinolone-resistant E. coli.3,4

Our study is the first to provide information from a developing country concerning risk factors for urinary tract infection due to E. coli strains that are resistant to commonly used antimicrobial agents. Despite a possible bias due to the recruitment of patients in a laboratory setting, the overall resistance rates of E. coli in Dakar appeared notably high with the confirmation of the emergence of multidrug-resistant strains. Multivariate analysis showed that previous antibiotic treatment and prior urinary tract infection were the strongest determinants of urinary tract infection due to resistant E. coli. We hope that our results will contribute to the development of strategies aimed at limiting the evolution of antimicrobial resistance in Dakar. Possible strategies include a better control of the distribution of antimicrobial drugs in pharmacies and among street sellers, the reinforcement of therapeutic guidelines and infection control strategies, the distribution of information about antibiotic use and drug resistance and the continued support of large antimicrobial susceptibility studies.


    Acknowledgements
 
We are extremely grateful to Fatou Kine Loum, Rokhaya Mbaye and Laetitia Novak for their technical assistance.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
1. Allen UD, MacDonald N, Fuite L et al. Risk factors for resistance to ‘first-line’ antimicrobials among urinary tract isolates of Escherichia coli in children. Can Med Assoc J 1999; 160: 1436–40.[Abstract/Free Full Text]

2. Gupta K. Addressing antibiotic resistance. Am J Med 2002; 113 Suppl 1A: 29S–34S.[CrossRef][ISI][Medline]

3. Ena J, Amador C, Martinez C et al. Risk factors for acquisition of urinary tract infections caused by ciprofloxacin resistant Escherichia coli. J Urol 1995; 53: 117–20.[CrossRef]

4. Sotto A, De Boever CM, Fabbro-Peray P et al. Risk factors for antibiotic-resistant Escherichia coli isolated from hospitalized patients with urinary tract infections: a prospective study. J Clin Microbiol 2001; 39: 438–44.[Abstract/Free Full Text]

5. Comité de l'Antibiogramme de la Société Française de Microbiologie, Communiqué. Pathol Biol 1999; 47: 845–72.[ISI][Medline]

6. Kahlmeter G. The ECO.SENS Project: a prospective, multinational, multicentre epidemiological survey of the prevalence and antimicrobial susceptibility of urinary tract pathogens—interim report. J Antimicrob Chemother 2000; 46 Suppl 1: 15–22.[Abstract/Free Full Text]

7. Gordon KA, Jones RN. SENTRY Participant Groups (Europe, Latin America, North America). Susceptibility patterns of orally administered antimicrobials among urinary tract infection pathogens from hospitalized patients in North America: comparison report to Europe and Latin America. Results from the SENTRY Antimicrobial Surveillance Program (2000). Diagn Microbiol Infect Dis 2003; 45: 295–301.[CrossRef][ISI][Medline]

8. Fassin D. Illicit sale of pharmaceuticals in Africa: sellers and clients in the suburbs of Dakar. Trop Geogr Med 1988; 40: 166–70.[ISI][Medline]

9. Garau J, Xercavins M, Rodriguez-Carballeira M et al. Emergence and dissemination of quinolone-resistant Escherichia coli in the community. Antimicrob Agents Chemother 1999; 43: 2736–41.[Abstract/Free Full Text]

10. Sahm DF, Thornsberry C, Mayfield DC et al. Multidrug-resistant urinary tract isolates of Escherichia coli: prevalence and patient demographics in the United States in 2000. Antimicrob Agents Chemother 2001; 45: 1402–6.[Abstract/Free Full Text]





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