International Journal of Antimicrobial Agents 21 (2003) 79 /81 www.isochem.

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Letter
Antimicrobial resistance in Escherichia coli causing urinary tract infections in Costa Rica: a clinical dilemma Urinary tract infection (UTI) is one of the most common illnesses for which patients seek medical attention worldwide. It is estimated that there are up to 8 million outpatient visits due to UTI each year in the United States, with upwards of $1 billion in associated health care costs for cystitis alone [1 /3]. Escherichia coli is the most commonly isolated organism, accounting for 60 /85% of positive urine cultures [4]. In recent years, emerging antimicrobial resistance in E . coli isolates has increasingly complicated the management of UTI [5]. The rising prevalence of resistance to trimethoprim/ sulphamethoxazole (TMP/SMZ) has been addressed by the Infectious Diseases Society of America (IDSA) in guidelines for the management of uncomplicated acute cystitis and pyelonephritis in women [6]. These guidelines recommend that first-line empirical therapy for uncomplicated cystitis should be 3 days of TMP/SMZ, unless the local prevalence of resistance to TMP/SMZ among uropathogens exceeds 10/20%, in which case a 3-day course of a fluoroquinolone should be used instead [6]. In this report, we describe the treatment dilemma that has developed in San Jose, Costa Rica, where resistance among E . coli isolates from outpatient urine cultures to both TMP/SMZ and ciprofloxacin has reached prevalence levels beyond those addressed by the IDSA guidelines. San Juan de Dios Hospital is a 700-bed academic tertiary care centre in central Costa Rica in the capital city of San Jose. Results for all urine cultures received from June 1, 2000, through December 31, 2000, from the outpatient clinics or the emergency department at San Juan de Dios Hospital were reviewed and were compared with results for concurrent urine cultures from the hospitals general medical wards and intensive care unit (ICU). Cultures were processed in the hospitals Dr Clodomiro Picado Clinical Laboratory. Isolates were identified using standard microbiological techniques and were defined as significant based on species and concentration criteria according to the laboratorys established protocols (not shown). Antimicrobial susceptibility was determined for all significant isolates by using a standard broth microdilution method on the Vitek NC4 system (bio Merieux Inc., Hazelwood, MO). Results were interpreted according to criteria as proposed by the National Committee for Clinical Laboratory Standards (NCCLS). Clinical data regarding the source patients were not collected. A x2-test for linear trend was used to assess the differences in prevalence of antimicrobial resistance among outpatient, hospital ward, and ICU urine isolates. From the outpatient urine cultures processed during the 7 month study period, 273 significant organisms were isolated. Among these isolates, E . coli was the most prevalent organism, accounting for 63% of isolates. The next four most prevalent organisms, which collectively accounted for 22% of the isolates, were Klebsiella pneumoniae , Proteus mirabilis , Enterococcus species, and Pseudomonas aeruginosa . The remaining 41 isolates (/15% of the total) included diverse species, with seven or fewer isolates per species (data not shown). Aggregate antimicrobial susceptibility profiles to TMP/SMZ, ciprofloxacin, and nitrofurantoin are shown in Fig. 1. Of note, of the outpatient E . coli urine isolates tested, only 60% were susceptible to TMP/SMZ, 89% to ciprofloxacin and 92% to nitrofurantoin (Fig. 1a). Similarly, considering all outpatient urine isolates, only 64% were susceptible to TMP/SMZ, 87% to ciprofloxacin, and 81% to nitrofurantoin (Fig. 1b). Comparative antimicrobial susceptibility profiles for the same three antibiotics among significant inpatient urine isolates from the hospitals general medical wards and ICU also are shown in Fig. 1. For each agent, a progressive decline in susceptibility is evident from outpatient, to ward, to ICU, with both E . coli (Fig. 1a) and all organisms (Fig. 1b). This trend was highly statistically significant by x2-test for linear trend for all comparisons (for nitrofurantoin and E . coli , P /0.003; for all others, P B/0.001). There were even unacceptable levels of resistance to ciprofloxacin among hospital ward and ICU isolates, and none of the agents were active against !/67% of hospital ward isolates, or !/53% of ICU isolates (Fig. 1b). We demonstrate in this report that resistance to TMP/ SMZ among E . coli and other urine organisms is a significant problem at a major urban hospital in Costa Rica. This problem appears to be shared by a number of institutions in Latin America [2,7,8]. Of even greater concern is that increasing resistance is eroding the utility of second-line agents, ciprofloxacin and nitrofurantoin, as reliable alternatives for the management of UTI in this locale. Current IDSA guidelines do not address the treatment dilemma facing Costa Rican physicians [6]. These

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Letter to the Editor

Fig. 1. Susceptibility proles of signicant urine isolates to TMP/SMZ, ciprooxacin and nitrofurantoin (1a, E . coli . 1b, all urine isolates). Note the linear trend in declining susceptibility from outpatient, to hospital ward, to ICU for all drug/organism comparisons (for the nitrofurantoin/E . coli comparison, P 0/0.003; for all other comparisons, P B/0.001).

guidelines were based on the premise that once the prevalence of resistance to TMP/SMZ exceeded 20%, the fall-back alternative would be fluoroquinolone therapy [6]. This strategy assumes a high level of susceptibility and effectiveness for fluoroquinolone agents in treating bacterial cystitis. In central Costa Rica, the validity of that assumption diminishes as the

prevalence of fluoroquinolone resistance among outpatient urine isolates rises. Moreover, ciprofloxacin resistance levels of 35% among hospital ward urine isolates and 65% among ICU urine isolates is an ominous harbinger of future developments in the outpatient setting, where the range of alternative therapies is limited.

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In the US TMP/SMZ resistance among E . coli urinary isolates is a well recognized and growing concern [5]. However, the fluoroquinolone resistance problem seen in Costa Rica is rarely encountered in the US in the outpatient setting, where the prevalence of resistance has been reported as usually less than 1% [5]. The Costa Rican situation is alarming because it may represent a paradigm that ultimately will be seen in the US and elsewhere. Already, prevalent fluoroquinolone resistance among E . coli has been described from several locales [9,10,12]. Increased prescribing of fluoroquinolones by physicians is an independent predictor of fluoroquinolone resistance among E . coli [10,11]. Multiple other factors likely play contributory roles, including over-the-counter sales of antibiotics without prescription, which was relatively common until recently in Costa Rica, and agricultural use of antibiotics, particularly in the poultry industry [9,12]. Reverting to older antimicrobial agents such as nitrofurantoin, which in this study was active against 92% of outpatient E . coli urine isolates, may temporarily relieve the Costa Rican therapeutic dilemma. Although for maximal efficacy in cystitis nitrofurantoin may require a more extended (e.g. 7 day) course of therapy, use of nitrofurantoin could have the added benefit of reducing the overall pressure towards worsening TMP/SMZ and ciprofloxacin resistance [6]. Unfortunately, the ICU data reported here show that the prevalence of resistance to nitrofurantoin among urinary E . coli isolates already exceeds 40%, which suggests that nitrofurantoin may be a short-lived therapeutic option in the outpatient setting. Other potential fluoroquinolone-sparing alternatives include fosfomycin [6]. However, avoidance of fluoroquinolones for UTI therapy may have a limited impact on the emergence of fluoroquinolone resistance, since UTI therapy is but one of many contributors to the total consumption of fluoroquinolones worldwide.

[2] Gales AC, Jones RN, Gordon KA, et al. Activity and spectrum of 22 antimicrobial agents tested against urinary tract infection pathogens in hospitalized patients in Latin America: report from the second year of the SENTRY antimicrobial surveillance program. J Antimicrob Chemother 2000;45:295 /303. [3] Gupta K, Hooton TM, Stamm WE. Increasing antimicrobial resistance and the management of uncomplicated communityacquired urinary tract infections. Ann Intern Med 2001;135:41 / 50. [4] Chomarat M. Resistance of bacteria in urinary tract infections. Int J Antimicrob Agents 2000;16:483 /7. [5] Gupta K, Scholes D, Stamm WE. Increasing prevalence of antimicrobial resistance among uropathogens causing acute uncomplicated cystitis in women. JAMA 1999;281:736 /8. [6] Warren JW, Abrutyn E, Hebel JR, Johnson JR, Schaeffer AJ, Stamm WE. Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Clin Infect Dis 1999;29:745 /58. [7] Felmingham D, Arakawa S. Resistance among urinary pathogens: experience outside the USA. Clin Drug Invest 2001;21(Supp. 1):7 /11. [8] Guzman-Blanco M, Casellas JM, Sader HS. Bacterial resistance to antimicrobial agents in Latin America: the giant is awakening. Infect Dis Clin North Am 2000;14(1):67 /81. [9] McDonald LC, Chen F, Lo H, et al. Emergence of reduced susceptibility and resistance to uoroquinolones in Escherichia coli in Taiwan and contributions of distinct selective pressures. Antimicrob Agents Chemother 2001;45:3084 /91. [10] Goettsch W, van Pelt W, Nagelkerke N, et al. Increasing resistance to uoroquinolones in Escherichia coli from urinary tract infections in the Netherlands. J Antimicrob Chemother 2000;46:223 /8. [11] Sefton AM. The impact of resistance on the management of urinary tract infections. Int J Antimicrob Agents 2000;16:489 /91. [12] 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(11):2736 /41.

David N. Williams, Mark R. Sannes, Alison A. Eckhoff, Phillip K. Peterson Department of Medicine, Hennepin County Medical Center, Minneapolis, MN, USA E-mail: msannes@pol.net, peter137@umn.edu James R. Johnson, Mark R. Sannes Veterans Affairs Medical Center and Department of Medicine, University of Minnesota, Minneapolis, MN, USA Marielos San Roman, Nury Mora Laboratorio Clnico Clodomiro Picado, San Juan de Dios Hospital, San Jose, Costa Rica Javier Moya Universidad de Ciencias Medicas, San Jose, Costa Rica

Acknowledgements This research was supported in part by an unrestricted educational grant from Merck, Inc. The authors also wish to thank Michael A. Kuskowski, Minneapolis VA Medical Center, for assistance with statistical analysis.

References
[1] Johnson JR, Stamm WE. Urinary tract infections in women; diagnosis and treatment. Ann Intern Med 1989;111:906 /17.