International Journal of Infectious Diseases

International Journal of Infectious Diseases 14 (2010) e770 e774 Contents lists available at ScienceDirect International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid Increasing resistance in community-acquired urinary tract infections in Latin America, five years after the implementation of national therapeutic guidelines P.H.A. Bours a,1, *, R. Polak a,1, A.I.M. Hoepelman a, E. Delgado b, A. Jarquin b, A.J. Matute b a Department of Internal Medicine and Infectious Diseases, University Medical Center, PO Box 85500, Room F.02.126, 3508 GA Utrecht, the Netherlands b Department of Medicine, University Hospital, Universidad Nacional Autónoma de Nicaragua (UNAN), León, Nicaragua ARTICLE INFO SUMMARY Article history: Received 3 October 2009 Accepted 25 February 2010 Corresponding Editor: William Cameron, Ottawa, Canada Keywords: Urinary tract infections Resistance Antibiotics Extended-spectrum beta-lactamase Epidemiology Background: The worldwide increasing resistance to antibiotics has complicated antimicrobial treatment of urinary tract infections (UTIs), especially in Latin America. This study aimed to report the present etiology and antimicrobial susceptibility of UTIs, and the effects of the national guidelines for UTIs introduced in 2003. Methods: Urine samples were collected from 304 patients with a clinical suspicion of UTI at the university hospital and primary health centers of León, Nicaragua. When bacterial growth was reported, antimicrobial susceptibility tests for nine frequently used antibiotics were performed. Results: Ninety-one (29.9%) patients had a positive urine culture. The most frequently isolated microorganisms were Escherichia coli (n = 44), Serratia spp (n = 11), and Escherichia fergusonii (n = 10). High resistance rates were observed in E. coli to ampicillin (61.4%), cefalothin (45.5%), trimethoprim sulfamethoxazole (38.6%), ciprofloxacin (31.8%), and ceftriaxone (20.5%). Amikacin and nitrofurantoin were the only drugs to which >90% of E. coli were susceptible. E. fergusonii and Serratia spp showed comparable high resistance patterns. Thirteen strains (29.5%) of E. coli were suspected to produce extended-spectrum beta-lactamase (ESBL). Conclusions: Resistance rates in community-acquired UTIs in Nicaragua are increasing. The introduction of therapeutic guidelines with ceftriaxone recommended for upper UTIs and nitrofurantoin for lower UTIs, has led to increasing resistance against both antibiotics. The emergence of ESBL-producing E. coli is worrisome, along with the appearance of Serratia spp in the population. ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. 1. Introduction A high prevalence of symptomatic urinary tract infections (UTIs) combined with high resistance rates to fluoroquinolones and beta-lactam antibiotics is one of the greatest problems in the health systems of Latin American countries. 1 3 In the USA, epidemiological research estimates an incidence of 8 million cases of UTI per year. Annually, this corresponds to a 10.8% risk of a UTI for women aged 18 years and over. Consequently, women have a lifetime risk of almost 50% of suffering a UTI, for which antimicrobial therapy is needed. In Latin American countries this problem appears to be even more severe. 1 3 Escherichia coli is the most frequently isolated uropathogen in symptomatic UTIs worldwide. The prevalence of other isolated uropathogens, such as Staphylococcus saprophyticus, Klebsiella spp, Proteus mirabilis, Serratia spp, and Enterobacter spp, varies between * Corresponding author. Tel.: +31 338501281. E-mail address: pha.bours@gmail.com (P.H.A. Bours). 1 P.H.A. Bours and R. Polak contributed equally to this work. regions and studies. 1 7 In 2003 Matute et al., in the first large national prevalence study concerning patients with a symptomatic UTI, showed that E. coli (56%), Klebsiella spp, (18%) and Enterobacter spp (11%) were the most commonly isolated uropathogens in Nicaragua. Globally, the clinical management of UTIs has been hampered by increasing resistance rates to frequently used antibiotics. 5 7 In particular, in Latin American countries where unregulated prescription of antibiotics is more likely, the resistance patterns of frequently observed uropathogens are alarming. 1 3 Considering these patterns of high resistance, well chosen antibiotic prescription and usage will reduce the disease burden of UTIs and thereby lower its consequences and costs. 8,9 The main objective of this study was to gain an insight into the present situation regarding the etiology and antimicrobial susceptibility of uropathogens in Nicaragua. The secondary objective was to analyze the effects of the implementation of national guidelines in 2003. 1 These national guidelines were introduced to manage symptomatic UTIs in primary and secondary care units in León. 1201-9712/$36.00 see front matter ß 2010 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2010.02.2264

P.H.A. Bours et al. / International Journal of Infectious Diseases 14 (2010) e770 e774 e771 2. Patients and methods 2.1. Study design The authors conducted a cross-sectional study between August 2007 and September 2008 in which 304 patients attending the university hospital (Hospital Escuela Oscar Danilo Rosales Argüello; HEODRA) and the primary health centers (PHC) of León, Nicaragua were included. Symptomatic patients were included if they had at least two of the following inclusion criteria: dysuria, urgency, frequency, fever, chills, flank pain, nausea or vomiting, suprapubic sensitivity, use of a Foley catheter, and fever without apparent focus. Patients who had used antibiotics within the last 7 days were excluded. Recruitment of patients was carried out at four PHCs throughout the urban region of León and from the gynecology, pediatrics, and internal medicine wards and the emergency rooms of HEODRA. UTIs were classified as complicated or uncomplicated according to a modification of the Infectious Diseases Society of America (IDSA) guidelines. An uncomplicated form of UTI occurs in women with a normal renal tract and function, who are not in the menopause, and who are over 12 years of age. Complicated UTIs are those in pregnant women, male patients, and patients with an abnormal renal tract, impaired renal function, impaired host defenses, or a catheter. 4,10,11 Based upon the anatomy of the urinary tract, infections were classified as lower (cystitis and urethritis) or upper (pyelonephritis) UTIs. 2.2. Measurements All patients with a suspected UTI completed a questionnaire on clinical symptoms and potential risk factors (e.g., diabetes mellitus, chronic obstructive pulmonary disease (COPD), chronic renal insufficiency, cancer, congenital abnormalities of the urinary tract, nephrolithiasis, pregnancy, use of a Foley catheter in the last 3 days, and previous UTI) and demographic data (e.g., age, gender, Table 1 Patient characteristics (N = 304) No UTI (n = 213) UTI (n = 91) Age, mean (SD) years 20.81 (22.14) 31.81 (29.88) Age groups, years <12 117 (54.9) 35 (38.5) 13 50 63 (29.6) 23 (25.3) >51 30 (14.1) 30 (33.0) Females 139 (65.3) 69 (75.8) Hospitalization >48 h 15 (7.0) 8 (8.8) Location of recruitment Wards 70 (32.9) 40 (44.0) Emergency room 106 (49.8) 37 (40.7) Primary health centers (PHCs) 37 (17.4) 14 (15.4) Underlying diseases COPD 7 (3.3) 0 (0) Renal failure 8 (3.8) 5 (5.5) Liver cirrhosis 1 (0.5) 4 (4.4) Diabetes mellitus 14 (6.6) 12 (13.2) Insulin dependent 2 (0.9) 2 (2.2) Predisposing factors Previous UTI 50 (23.5) 27 (29.7) Catheter 4 (1.9) 12 (13.2) Pregnant 15 (7.0) 5 (5.5) Renal stones 4 (1.9) 5 (5.5) Malformation urinary tract 0 (0) 0 (0) Prostatic hypertrophy 1 (0.5) 1 (1.1) Pelvic inflammatory disease 3 (1.4) 4 (4.4) Results are n (%) unless otherwise stated. UTI, urinary tract infection; SD, standard deviation; COPD, chronic obstructive pulmonary disease. and area of residence). Additionally, a physical examination was performed. All included patients provided a midstream urine sample which was cultivated at 36 8C for 18 24 h on blood and MacConkey agars. When bacterial growth of a uropathogen occurred, disk diffusion tests were performed using the Kirby Bauer method and the Clinical and Laboratory Standards Institute (CLSI) criteria. 12,13 Significant bacterial infection was defined as the growth of 10 5 colony forming units (CFU)/ml of a single species cultured from urine 12. Resistance rates to the following antibiotics were examined: ampicillin, amoxicillin clavulanate, cefalothin, ciprofloxacin, ceftriaxone, gentamicin, trimethoprim sulfamethoxazole (TMP SMX), nitrofurantoin, and amikacin. Resistance tests for uropathogens other than Enterobacteriaceae were performed according to CLSI guidelines 13. Non-susceptibility to the thirdgeneration cephalosporin ceftriaxone was used as an indicator of extended-spectrum beta-lactamase (ESBL) production 13. 2.3. Statistical analysis Differences between groups were tested using the Chi-square test (or Fisher s exact test when expected frequencies were too low), with the assumed level of statistical significance at a p-value of <0.05. Data analysis was performed with SPSS version 15.0 for Windows (SPSS Inc., Chicago, IL, USA). 3. Results 3.1. Study population In total we acquired valid data for 304 study subjects (Table 1). Ninety-one patients (29.9%) had a positive urine culture. The majority of the positive samples (75.8%) were collected from female patients. Sixteen percent of the patients with a demonstrated UTI had signs and symptoms of pyelonephritis. The most frequently isolated microorganisms for uncomplicated and complicated UTI were successively E. coli (n = 44; 48.8%), Serratia spp (n = 11; 12.1%), and Escherichia fergusonii (n = 10; 11.0%) (Table 2). Seventy-five (80.2%) patients with a positive culture were classified as having a complicated UTI. 10 Of those with positive urine cultures, only eight (8.8%) patients were hospitalized more than 48 h before urine sampling. The following pathogens were cultured from these eight patients: four E. coli, two Cedecea davisae, one Acinetobacter spp, and one Enterobacter spp. 3.2. Antimicrobial resistance E. coli (n = 44) showed high resistance rates against ampicillin (61.4%), amoxicillin clavulanate (18.6%), ceftriaxone (20.5%), gentamicin (25.0%), TMP SMX (38.6%), ciprofloxacin (31.8%), and cefalothin (45.5%). The only drugs against E. coli to which Table 2 Uropathogens Pathogens No. of samples (%) Escherichia coli 44 (48.4) Serratia spp 11 (12.1) Escherichia fergusonii 10 (11.0) Enterobacter spp 6 (6.6) Cedecea davisae 4 (4.4) Klebsiella spp 3 (3.3) Staphylococcus aureus 3 (3.3) Kluyvera spp 3 (3.3) Proteus mirabilis 2 (2.2) Other pathogens 5 (5.5) Total 91 (100)

e772 P.H.A. Bours et al. / International Journal of Infectious Diseases 14 (2010) e770 e774 Table 3 Antibiotic resistance % Susceptible 2008 % Resistant 2008 % Resistant 2003 Difference (p-value) b Escherichia coli (n = 44) (n = 44) (n = 35) Ampicillin a 31.8 61.4 74.0 0.34 Amoxicillin clavulanate a 69.8 18.6 34.0 0.12 Ceftriaxone 72.7 20.5 0 0.04 Gentamicin 72.7 25.0 11.0 0.16 Trimethoprim sulfamethoxazole a 59.1 38.6 63.0 0.04 Nitrofurantoin a 93.0 7.0 0 0.25 Ciprofloxacin a 68.2 31.8 30.0 1.0 Cefalothin 45.5 45.5 58.0 0.37 Amikacin 95.3 2.3 0 1.0 Escherichia fergusonii (n = 10) (n = 10) (n = 0) Ampicillin a 10.0 90.0 Amoxicillin clavulanate a 90.0 0 Ceftriaxone 90.0 0 Gentamicin 50.0 40.0 Trimethoprim sulfamethoxazole a 40.0 50.0 Nitrofurantoin a 100 0 Ciprofloxacin a 90.0 10.0 Cefalothin 80.0 20.0 Amikacin 87.5 0 Serratia spp (n = 11) (n = 11) (n =0) Ampicillin a 0 90.9 Amoxicillin clavulanate a 63.3 9.1 Ceftriaxone 81.8 18.2 Gentamicin 90.9 9.1 Trimethoprim sulfamethoxazole a 72.7 27.3 Nitrofurantoin a 81.8 18.2 Ciprofloxacin a 72.7 27.3 Cefalothin 27.3 63.6 Amikacin 100 0 Enterobacter spp (n =6) (n =6) (n =7) Ampicillin a 0 100 100 1.0 Amoxicillin clavulanate a 50.0 33.3 86.6 0.103 Ceftriaxone 66.7 33.3 29.0 1.0 Gentamicin 66.7 33.3 29.0 1.0 Trimethoprim sulfamethoxazole a 66.7 33.3 29.0 1.0 Nitrofurantoin a 83.8 0 Ciprofloxacin a 50.0 50.0 0 0.070 Cefalothin 40.0 60.0 86.0 0.559 Amikacin 66.7 16.7 Resistance rates were determined according to Clinical and Laboratory Standards Institute guidelines. a Orally administered antibiotics. b Chi-square test or Fisher s exact test. the susceptibility rate was higher than 80% were nitrofurantoin (93.0%) and amikacin (95.3%). E. fergusonii (n = 10) showed relatively high susceptibility rates (Table 3). For Serratia spp (n = 11), high resistance rates against ampicillin (90.9%), TMP SMX (27.3%) and ciprofloxacin (27.3%) were observed. Serratia spp were susceptible to amikacin and gentamicin (>90%) and to nitrofurantoin and ceftriaxone (>80%). Enterobacter spp (n = 6) were only susceptible to nitrofurantoin (83.8%) and had high resistance to beta-lactam agents as well as ciprofloxacin (Table 3). Resistance rates between pathogens causing uncomplicated and complicated UTIs were not significantly different. Inclusion or exclusion of the >48 h hospitalized patients did not reveal significant differences between overall resistance rates. 3.3. Effects of guideline implementation For five years, in accordance with the national guidelines, nitrofurantoin has been the recommended drug for uncomplicated lower UTIs. In the present study a non-significant increase in resistance to this drug was seen for E. coli (0% vs. 7% p = 0.25). Reduced usage of beta-lactam antibiotics over the last five years has resulted in a decline in resistance to ampicillin (61.4% vs. 74.0%; p = 0.34) and ampicillin clavulanate (18.6% vs. 34.0%; p = 0.12). Resistance to TMP SMX has declined significantly (38.6% vs. 63%; p = 0.04). Due to the use of ceftriaxone as the preferred drug for upper UTIs, as recommended in the guidelines, a significant increase in resistance has been seen in E. coli since 2003 (20.5% vs. 0%; p = 0.04). 3.4. Extended-spectrum beta-lactamases Thirteen (29.5%) strains of E. coli were suspected of ESBL production. Resistance rates in this group were significantly higher to ampicillin (84.6% vs. 51.6%; p = 0.050), amoxicillin clavulanate (46.2% vs. 6.5%; p = 0.005), cefalothin (84.6% vs. 29.0%; p = 0.001), ceftriaxone (69.2% vs. 0%; p = 0.000), and ciprofloxacin (61.5% vs. 19.4%; p = 0.012) compared to pathogens that did not produce ESBL 13. 4. Discussion This study reports the recent etiology of UTIs and antimicrobial susceptibility of uropathogens in León, a medium-sized Latin American city. The differences in outcome between this study and the study performed in 2003 provide an insight into the development of resistance patterns following the implementation of therapeutic guidelines in a country with overall high resistance rates. With the aim of including as many patients with communityacquired UTIs as possible, some changes were made between the

P.H.A. Bours et al. / International Journal of Infectious Diseases 14 (2010) e770 e774 e773 study designs of the investigations in 2003 and 2008. This prevalence study was performed not only in the secondary healthcare setting, but also in the primary healthcare setting. Furthermore, meropenem was replaced by amikacin to introduce another important antibiotic class (aminoglycosides). In daily practice the use of this drug is preferred for economic reasons. 4.1. Uropathogens In our study population, the most frequently isolated pathogens were E. coli, Serratia spp, and E. fergusonii. In the investigation of 2003 the latter two pathogens were absent in the study population. Serratia spp are known to be important causes of nosocomial UTIs throughout the world. 14,15 Because this study represents the community-acquired UTIs in León, Nicaragua, the high prevalence of Serratia spp came as a surprise. In our study population, no significant differences in patient characteristics and resistance rates were seen in those with Serratia spp strains compared to non- Serratia spp strains. However, recent studies have shown a low response of Serratia spp to frequently used antibiotics, indicating the potential danger of this pathogen. 14 16 E. fergusonii showed relatively low resistance rates compared to non-e. fergusonii pathogens. However, the development of resistance in E. fergusonii is unpredictable due to the low incidence of this pathogen worldwide, and to its recent appearance in the population of Nicaragua. 17,18 4.2. Extended-spectrum beta-lactamases Worldwide and especially in Latin America, the emerging problem of ESBL-producing pathogens is worrisome. Various investigators have shown a high prevalence of ESBL pathogens in Latin America, varying from 1.7% to 20.8% in E. coli. 2,3,16,19 This study supports the previously described high prevalence of ESBLproducing pathogens by reporting 29.5% of the E. coli strains as suspected for ESBL. Unfortunately, ESBL screening was only based on non-susceptibility to a third-generation cephalosporin, although susceptibility to this antibiotic has been described for ESBL-positive uropathogens. 13 ESBL confirmatory tests were not performed. Nevertheless, the prevalence of ESBL-producing pathogens in community-acquired UTIs is high in our study compared to other investigations in Latin America. 4.3. Antimicrobial resistance The international literature has alerted physicians all over the world to the problem of increasing resistance rates in uropathogens. 1 7 High resistance rates against TMP SMX are seen as a worldwide problem because this antibiotic is used as a first-line treatment in uncomplicated UTIs. Studies from Latin America have not only shown high resistance rates to TMP SMX, but also to other common and inexpensive orally administered agents, such as ampicillin and ciprofloxacin. 1 3 In 2003, Matute et al. showed that resistance rates in Nicaragua were alarmingly high. The resistance of uropathogens in Nicaragua in 2008 is of even greater concern. High resistance rates were present against TMP SMX, but also against beta-lactam antibiotics, aminoglycoside antibiotics, and fluoroquinolones. Therefore, the risk of clinical failure when using these agents increases and thereby usage becomes clinically unacceptable. 20,21 This study has evaluated the effects of the therapeutic guidelines implemented in Nicaragua in 2003. Implementation led to a decrease in resistance against ampicillin and TMP SMX without clinical importance. Resistance against amoxicillin clavulanate decreased to 18.6%, which can therefore become an alternative to nitrofurantoin in the treatment of uncomplicated UTIs in the future. Then again, in the current situation susceptibility rates were too low for the effective use of amoxicillin clavulanate (susceptibility 69.8%). A limitation of this study is that the authors did not determine how often the guidelines were followed over the past five years. Resistance against nitrofurantoin, which is the first choice antibiotic in uncomplicated lower UTIs in Nicaragua, increased from 0 to 7%. Despite the fact that this increase demonstrates that frequent use of a certain antibiotic for a long period of time will elevate the resistance, this resistance is clinically acceptable (susceptibility >90%). 4,20 Usage of ceftriaxone, until now the preferred antibiotic for upper UTIs, is nowadays no longer clinically acceptable (susceptibility 72.2%). Therefore, the switch to another therapeutic regime is inevitable. 4.4. Conclusions and recommendations The situation we are facing in Nicaragua is challenging because of the increased overall resistance of uropathogens, resulting in a growing lack of therapeutic options for UTIs. The introduction of therapeutic guidelines, with ceftriaxone recommended in upper UTIs and nitrofurantoin in lower UTIs, has led to increasing resistance against both antibiotics. The emergence of ESBLproducing E. coli is worrisome, along with the appearance of Serratia spp in the population. Physicians facing comparable high resistance rates should avoid the risk of losing an effective antibiotic cure. Therefore, the choice of a sensible antibiotic regime is essential. In cases of uncomplicated lower UTIs, the authors recommend a 5-day course of nitrofurantoin as the empirical treatment of first choice, despite increasing resistance rates after implementation of the national guidelines. 22,23 In cases of complicated lower UTIs, experience has shown that the risk of clinical failure is higher. 4,24,25 Therefore, we recommend antibiogram assessment while starting with nitrofurantoin therapy in these cases. Special attention should be given to patients in this group who develop symptoms of tissue infiltration, i.e. signs of an upper UTI. For these patients, nitrofurantoin should not be a therapeutic option because of the poor tissue penetration of this drug. 4,26,27 In cases of upper UTI, therapeutic options are running out. Regarding resistance rates, parenteral use of amikacin in an inpatient setting should be the first choice therapy in all cases of upper UTI, complicated and uncomplicated. When an antibiogram has been assessed, the change to a susceptible oral antibiotic can be made. Conflict of interest: All authors state that there are no conflicts of interest, commercial affiliations, consultations, stock or equity interests present for this manuscript. No sources of funding were used for this research. References 1. Matute AJ, Hak E, Schurink CA, McArthur A, Alonso E, Paniagua M, et al. Resistance of uropathogens in symptomatic urinary tract infections in León, Nicaragua. Int J Antimicrob Agents 2004;23:506 9. 2. Gales AS, Sader HS, Jones RN, SENTRY Participants Group (Latin America). Urinary tract infection trends in Latin American hospitals: report from the SENTRY antimicrobial surveillance program (1997 2000). Diagn Microbiol Infect Dis 2002;44:289 99. 3. 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