Comparison of cotrimoxazole vs. second-generation cephalosporins for prevention of urinary tract infections in children

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1 Pediatr Nephrol (2016) 31: DOI /s ORIGINAL ARTICLE Comparison of cotrimoxazole vs. second-generation cephalosporins for prevention of urinary tract infections in children Charalampos Antachopoulos 1 & Maria Ioannidou 1 & Athanasios Tratselas 1 & Elias Iosifidis 1 & Aspasia Katragkou 1 & Paschalis Kadiltzoglou 1 & Konstantinos Kollios 1 & Emmanuel Roilides 1 Received: 1 February 2016 /Revised: 17 July 2016 /Accepted: 19 July 2016 /Published online: 15 August 2016 # IPNA 2016 Abstract Background Antimicrobial prophylaxis is recommended for the prevention of urinary tract infections (UTI) in high-risk children. However, there is growing concern about the use of β-lactams as prophylaxis and subsequent development of antibiotic resistance. Methods In this prospective, randomized, crossover controlled trial we compared cotrimoxazole (SXT) and second-generation cephalosporins (2GC) as UTI prophylaxis in children ranging in age from 1 to 60 months. Eligible patients were 1:1 randomized to receive either SXT or 2GC for the initial 6-month period (1 course), then switched to the other antimicrobial agent class for the subsequent course, with switching continuing after each course until the end of the study. Urethral orifice cultures (UOCs) were obtained at the time of switching antimicrobial prophylaxis. Results Among 97 children (mean age 13.6 months) on prophylaxis, breakthrough UTIs occurred during 13.3 % (10/75) of SXT courses and 10.3 % (8/78) of 2GC courses (p = 0.62). 2GC failed earlier than SXT (mean ± standard error: 0.81 ± 0.1 vs ± 0.36 months, respectively; p = 0.028). Pseudomonas aeruginosa and Enterococcus spp. were more frequently isolated after 2GC courses than after SXT courses [22.6 vs. 4.8 % (p = 0.02) and 20.7 vs. 4.8 % (p = 0.035), respectively]. Prophylaxis with 2GC significantly increased resistance to both 2GC and SXT, while SXT prophylaxis did not affect susceptibility to 2GC. * Emmanuel Roilides roilides@med.auth.gr 1 3rd Department of Pediatrics, Hippokration General Hospital, Aristotle University School of Medicine, Konstantinoupoleos 49, Thessaloniki, Greece Conclusions While SXT and 2GC appear to be equally efficacious as UTI prophylaxis in children, the latter exert a broader effect on patients flora and development of bacterial resistance, suggesting that SXT may be more appropriate for UTI prophylaxis than 2GC. Keywords Urinary tract infection. Children. Antimicrobial prophylaxis. Bacterial resistance. Cephalosporins. Cotrimoxazole Introduction The benefits and side effects of antimicrobial prophylaxis for the prevention of recurrent urinary tract infections (UTIs) in children and renal scarring have been a focus for scientific study over the last 15 years. A number of well-designed clinical trials have been conducted and published on these subjects, the latest of which is the RIVUR study [1 5]. While the results of these studies are still the subject of much discussion, clinicians have become decidedly more cautious with regard to prescribing prophylaxis and choosing which of their patients are likely to benefit from prophylaxis. However, there will always be patients for whom prophylaxis may ultimately be prescribed, such as those with recurrent febrile UTIs, with serious anatomical abnormalities of the urogenital tract or with neurogenic bladder. A subject much less studied is the type of antimicrobial agent that should be used for prophylaxis. Trimethoprim sulfamethoxazole (cotrimoxazole; SXT) and nitrofurantoin have long been considered to be the most appropriate prophylactic agents, and these agents were used in most of the above-mentioned clinical trials. However, evidence is accumulating that β-lactam antimicrobial agents, such as cephalosporins and amoxicillin/

2 2272 Pediatr Nephrol (2016) 31: clavulanate, are commonly used as prophylaxis in pediatric patients. In a nationwide Israeli survey, cephalosporins were used prophylactically by % of responding physicians [6], and in the guidelines published in 2012 by the Italian Society of Pediatric Nephrology, both amoxicillin clavulanic acid and SXT are mentioned as agents that can be used for prophylaxis [7]. Cephalexin is listed among the agents suggested for prophylaxis in recent review papers and books from the USA [8, 9]. In the Swedish Reflux Trial in Children, cefadroxil was among the agents prescribed for children who were randomly assigned to receive prophylaxis [1]. Evidence for prophylactic use of cephadroxil, cephalexin, cefradine, cefaclor, cefprozil and cefixime also comes from a number of published studies around the world [10 15]. However, very little is known about the comparative prophylactic efficacy of cephalosporins and SXT as well as their effect on alteration of the host s bacterial flora. In the study reported here we prospectively compared SXT and second-generation cephalosporins (2GC) as prophylaxis for UTI in children in terms of efficacy, changes induced in patients flora and development of bacterial resistance. Patients and Methods Study design The study was a prospective, randomized, crossover trial which was conducted in the pediatric department of Hippokration hospital, a tertiary care general hospital, in Thessaloniki, Greece. Patients included in the study were children aged from 1 month to 5 years who were hospitalized for their first episode of febrile UTI and considered to be eligible for prophylaxis by the treating physicians. Common indications for initiating prophylaxis included vesicoureteral reflux, anatomical abnormalities of the urinary tract and neurogenic bladder. None of the authors were involved in the decision-making process to place or not place these children on prophylaxis. Exclusion criteria for the study were glucose- 6-phosphate dehydrogenase deficiency, history of allergy to SXT or 2GC, congenital or acquired immunodeficiency and/ or already on prophylactic antimicrobial treatment for any reason. Children recruited were randomized at a 1:1 ratio to receive either SXT or 2GC (cefuroxime axetil, cefprozil or cefaclor) as prophylaxis for UTI. All patients received both antimicrobial classes interchangeably for periods (Bcourses^) of 6 months. More specifically, patients initially assigned to receive SXT prophylaxis were switched after 6 months of treatment to 2GC and vice versa. Patients were followed until prophylaxis was discontinued (based on their treating physician s decision) or until their first episode of breakthrough UTI. Urethral orifice cultures (UOCs) of each patient were obtained at the time of switching antimicrobial prophylaxis (i.e. at 6-month intervals) as well as at the end of study period; the species and susceptibility of the microorganisms isolated from the UOCs were recorded. SXT and 2GC were compared in terms of efficacy (prevalence of breakthrough UTIs during each of the 6-month courses as well as time to first breakthrough UTI) and their effect on patient s flora (as indicated by bacterial species isolated from UOCs and their antimicrobial susceptibility). Diagnosis of UTI The diagnosis of UTI was based on the finding of significant bacteriuria [growth of 10 5 colonyforming units (CFU)/mL of only one bacterial species in a clean catch specimen or 10 4 CFU/mL in specimens collected via catheterization of the bladder or any growth in specimens collected via suprapubic aspiration) together with any of signs or symptoms compatible with UTI, such as fever (axillary temperature 38 C), lethargy, irritability, poor feeding, vomiting, failure to thrive, increased frequency of urination, dysuria, abdominal pain and loin tenderness. UTI prophylactic chemotherapy Antimicrobial agents used for prophylaxis were administered once daily, in the evening, at doses of 2 mg/kg of trimethoprim for SXT, 10 mg/kg for cefuroxime axetil, 10 mg/kg for cefprozil and 15 mg/kg for cefaclor. Compliance was assessed by regularly (monthly) questioning the parents. UOCs, species identification and susceptibility testing A swab was taken from the urethral orifice of each enrolled child at the end of each 6-month prophylaxis course as well as at the end of the study period; there was no temporary withdrawal of the prophylactic antimicrobial agent before these cultures were taken. The swab was placed into Stuart transport medium and immediately transferred to the Microbiology Laboratory for culture. Species identification and susceptibility testing were performed using the VITEK 2 automated system (biomérieux, Marcy l Étoile, France). Resistance to cefuroxime was indicative of resistance to all 2GC used in this study (cefuroxime, cefprozil, cefaclor). When more than one bacterial isolate was recovered from an UOC, all isolates were identified to species level, tested for susceptibility and included in the analysis. Outcomes and data analysis The prevalence of breakthrough UTIs, time to first breakthrough UTI, bacterial species isolated from UOCs at the end of each prophylaxis course and percentage resistance to SXT and 2GC of these isolates were compared among SXT and 2GC courses. The primary endpoint was the prevalence of breakthrough UTIs; secondary endpoints were time to first breakthrough UTI, species isolated from UOCs and percentage resistance to SXT/2GC. The Fisher s exact test or Student s t test were used to test for differences between courses according to the variables. SPSS Statistics 20.0 software (IBM Corp., Armonk, NY) was used for statistical analysis, and p values of <0.05 were considered to be significant.

3 Pediatr Nephrol (2016) 31: Study approval The study was approved by the hospital Ethics Committee. Written informed consent was obtained from parents. Results A total of 97 children (44 % female) with a mean age of 13.6 months (range 1 month 4.5 years) met the inclusion criteria and were entered into the study. These children received a total of month courses of prophylaxis, of which 75 were SXT and 78 were 2GC courses. More specifically, 69 children received one course of antimicrobial prophylaxis, 15 received two courses, seven received three courses and six received four or more courses. Breakthrough UTIs occurred in 13.3 % (10/75) and 10.3 % (8/78) of children on SXT and 2GC prophylaxis course, respectively (p = 0.62). In all but one child breakthrough UTI occurred during the first 6-month course. 2GC failures occurred earlier than SXT failures (mean ± standard error: 0.81 ± 0.1 vs ± 0.36 months, respectively; p = 0.028). UOCs were positiveattheendof34(45.3%)sxtcoursesand40(51.2%) 2GC courses (p = 0.1); a total of 41 and 53 bacterial isolates were recovered after SXT and 2GC courses, respectively. Escherichia coli was isolated more frequently after SXT courses than after 2GC courses (43.9 vs %, respectively; p = 0.001), as shown in Table 1. When all Enterobacteriaceae isolates were grouped together, they were isolated after 90.2 % of SXT courses but only after 52.8 % of 2GC courses (p < ). In contrast, Pseudomonas aeruginosa and Enterococcus spp. were more frequently isolated after 2GC than after SXT courses [22.6 vs. 4.8 % (p = 0.02) and 20.7 vs. 4.8 % (p = 0.035), respectively] (Table 1). At the end of the SXT courses 38 (92.6 %) isolates were resistant to SXT, while at the end of the 2GC courses 49 (92.4 %) isolates were resistant to 2GC. Based on comparison of the susceptibility patterns of microorganisms isolated before (urine culture confirming UTI) and after the first 6-month prophylaxis course (UOC), the administration of SXT significantly increased resistance to SXT (p = ) but not to 2GC (p = 0.35), whereas administration of 2GC significantly increased resistance to both SXT (p = 0.027) and 2GC (p = ) (Fig. 1). In children receiving at least two consecutive courses, loss of resistance to the previous antimicrobial agent occurred during 44 % (4/9) of SXT courses and during 31 % (4/13) of 2GC courses (p =0.66). Discussion In this randomized, crossover study, we found that while SXT and 2GC appear to be equally efficacious in terms of the number of breakthrough UTI episodes which occurred during Table 1 Microorganisms isolated from urethral orifice cultures at the end of cotrimoxazole and second-generation cephalosporin prophylaxis courses Microorganisms SXT 2GC p Enterobacteriaceae 37 (90.2) 28 (52.8) < Escherichia coli 18 (43.9) 7 (13.2) Klebsiella spp 8 (19.5) 4 (7.5) 0.12 Enterobacter cloacae 7 (17.0) 3 (5.6) 0.10 Proteus spp. 2 (4.8) 8 (15.0) 0.18 Morganella spp. 2 (4.8) 5 (9.4) 0.46 Serratia marcescens 0 (0) 1 (1.8) 1.00 Pseudomonas aeruginosa 2 (4.8) 12 (22.6) 0.02 Enterococcus spp. 2 (4.8) 11 (20.7) Staphylococcus haemolyticus 0 (0) 2 (3.7) 0.50 Total no. of bacterial isolates 41 (100) 53 (100) Values are presented as the absolute numbers of isolates, with the percentages over the total numbers of isolates given in parentheses SXT, Cotrimoxazole; 2GC, second-generation cephalosporins the respective courses, the failures of 2GC prophylaxis occurred earlier than those of SXT prophylaxis. It should be noted that 2GC exerted a broader adverse effect on patients colonizing flora and the development of bacterial resistance, suggesting that SXT may be the more appropriate antimicrobial agent for UTI prophylaxis. When prophylaxis is prescribed for UTI in children, the choice of antimicrobial agent should combine efficacy in preventing infections with minimal effects on a patient s flora in order to minimize the development of bacterial resistance. The latter could significantly complicate the treatment of breakthrough UTIs and also result in the spread of resistant strains in the community. In our study we prospectively compared SXT with 2GC as prophylaxis for UTI in children, with the aim to evaluate both of the above aspects of prophylaxis i.e. efficacy in the prevention of infections but also induction of changes in patients colonizing flora. To our knowledge, there is only one prospective randomized study published to date which has compared SXT with cephalosporins (cephadroxil and cefprozil) as prophylaxis for UTI in children [11]; however, this study focused only on efficacy and did not include effects of the cephalosporins on bacterial flora and resistance. The latter were investigated more recently by a retrospective non-randomized study by Cheng et al. [16], who also found a tendency of cephalosporin prophylaxis to be followed by increased resistance. We decided to use 2GC for comparison with SXT as the resistance rates of community E. coli isolates to cephalothin in northern Greece at the beginning of the study approximated 40 % [17], making first-generation cephalosporins inappropriate for UTI prophylaxis. As susceptibility patterns of the three 2GC (cefuroxime axetil, cefprozil and cefaclor) are similar, children receiving any one of these cephalosporins were

4 2274 Pediatr Nephrol (2016) 31: Resistant isolates Resistant isolates 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% SXT prophylaxis SXT p = (a) p =0.35 b-lactams 2GC prophylaxis p =0.027 SXT (b) p = b-lactams Pre-course Post-course Pre-course Post-course Fig. 1 a Bacterial resistance (%) to cotrimoxazole (SXT) and secondgeneration cephalosporins (2GC), pre- and post-sxt courses, b bacterial resistance (%) to SXT and 2GC, pre- and post-2gc courses eligible for entry into the study. The crossover study design was employed to minimize the influence of confounding factors that could affect outcome (such as gender, circumcision, degree of reflux, anatomical abnormalities, dysfunctional voiding habits, among others) and increase statistical power [18]. Moreover, this design would potentially allow the study of sequential effects of different agents (SXT, 2GC) in a patient s flora, such as possible restoration of susceptibility to the agent administered over the previous 6-month period. We also performed UOCs as a means to obtain more information on the sequential changes induced in patients colonizing flora and potential uropathogens, as data from breakthrough UTIs were expected to be significantly more limited: colonizing flora is only partially reduced and not eradicated by antimicrobial prophylaxis [19]. Our results did not reveal a significant difference between SXT and 2GC in terms of their efficacy to prevent breakthrough UTIs, although the latter occurred significantly earlier during the administration of 2GC than during the administration of SXT. The comparable number of breakthrough UTIs does not exactly parallel the somewhat increased in vitro resistance of common uropathogens in Greece to SXT compared to 2GC [17, 20]. In their prospective study, Belet et al. randomly divided children eligible for UTI prophylaxis into three groups, with each group receiving either cotrimoxazole, cephadroxil or cefprozil. The frequency of symptomatic breakthrough UTIs was not statistically different among groups, in accordance with our findings [11]. Cheng et al. found that the recurrence rate of breakthrough UTIs in one of the two hospitals participating in their study was significantly higher in children receiving cotrimoxazole prophylaxis (1.73 cases/100 treatment-months) than in those receiving cephalexin (0.90 cases/100 treatment-months) or cefaclor prophylaxis (1.38 cases/100 treatment-months). However, at the other hospital participating in the study, where only cotrimoxazole was prescribed for prophylaxis, the recurrence rate was 1.25 cases/100 treatment-months, which was comparable to that recorded for cefaclor prophylaxis [16]. An important question which needs to be answered is whether the occurrence of breakthrough UTIs observed in this study was related to the development of bacterial resistance to the antimicrobial agent (SXT or 2GC) administered prophylactically. We retrospectively searched for susceptibility data on breakthrough uropathogens and were able to retrieve results for 11 of 18 breakthrough infections, seven of which occurred following SXT prophylaxis and four following 2GC prophylaxis. Resistance to SXT was observed in 28.5 % (2/7) of these cases andresistanceto2gcwasobservedin25%(1/4).intotal, resistance to the administered prophylactic agent was observed in 27.2 % (3/11) of breakthrough infections. These findings suggest that bacterial resistance to the administered prophylactic agent was not the main cause for prophylaxis failure in this study. The relatively low percentage of resistant isolates could probably be explained by the short time interval until first breakthrough UTI (mean duration: 0.81 and 2.37 months for 2GC and SXT prophylaxis, respectively). The yield of UOCs obtained in this study (45.3 and 51.2 % positive after SXT and 2GC courses, respectively) was comparable to that (37 %) previously reported for uncircumcised boys receiving antimicrobial prophylaxis for vesicoureteral reflux [19]. SXT and 2GC prophylaxis appeared to exert differential effects on children s colonizing flora at the species level: E. coli and generally Enterobacteriaceae were isolated more frequently from those receiving SXT while P. aeruginosa and Enterococcus spp. were isolated more frequently from those on 2GC prophylaxis. Our results are in agreement with those of Cheng et al., who found that children receiving cephalexin or cefaclor prophylaxis were more likely to have breakthrough UTIs by pathogens other than E. coli than those receiving cotrimoxazole [16]. These authors also found that P. aeruginosa was isolated more frequently from

5 Pediatr Nephrol (2016) 31: children on cephalexin/cefaclor prophylaxis than from those receiving cotrimoxazole, but that there was no significant difference between the groups in terms of the frequency of Enterococcus spp. [16]. In another non-comparative study evaluating cefaclor as UTI prophylaxis, 11 children developed breakthrough UTIs; in four of these children UTIs were caused by Enterococcus spp. and in one child it was caused by Pseudomonas spp. [21]. The increased possibility of isolating P. aeruginosa and Enterococcus spp. in children receiving 2GC prophylaxis is likely to have clinical implications: these organisms are not susceptible to many of the antibacterial agents administered as empirical treatment for UTI and, consequently, effective treatment may be delayed. In addition, there are only a limited number of oral antibiotics which are active against P. aeruginosa and Enterococcus spp., and therefore outpatient treatment of these breakthrough infections may be problematic. Long-term antimicrobial administration is complicated by the development of bacterial resistance due to natural selection of resistant strains. This was confirmed in our study, where the administration of either SXT or 2GC prophylaxis resulted in loss of in vitro susceptibility of colonizing flora to the administered agent at the end of corresponding courses, an effect which was observed to a similar degree (>90 %) for both agents. Cheng et al. also reported a marked loss of susceptibility to the administered prophylactic agent to a comparable level for both cotrimoxazole and cephalosporins [16]. However, the development of bacterial resistance seems to be a time-dependent phenomenon: when separately analyzing UOCs obtained at the time of first breakthrough UTIs (a total of 6 isolates grown from 18 UOCs), we found that resistance to the administered prophylactic agent was observed in only 33.3 % (2/6) of isolates. This low resistance rate is comparable to that observed in breakthrough uropathogens (27.2 %) mentioned above and could be due to the early occurrence of first breakthrough UTIs. We also found that while SXT prophylaxis promoted resistance only to SXT and not to 2GC 2GC prophylaxis significantly induced resistant strains to both antimicrobial agents. Thus, a greater Becological damage^ and a broader development of bacterial resistance appear to be associated with 2GC prophylaxis; the latter may be complicated by difficult to treat breakthrough infections, as many of the commonly administered oral agents (SXT, first- and second-generation cephalosporins) are likely to be ineffective. Narchi et al., analyzing uropathogen resistance during breakthrough infections in children receiving UTI prophylaxis, found that multidrug-resistant strains were isolated more frequently with cephalosporin prophylaxis than with cotrimoxazole prophylaxis [13]. Cheng et al. also found that cephalexin or cefaclor prophylaxis was associated with reduced susceptibility of breakthrough isolates to cotrimoxazole, while cotrimoxazole prophylaxis did not significantly affect susceptibility to cefuroxime [16]. In conclusion, we found no difference between SXT and 2GC in terms of their efficacy to prevent UTIs in children. However, compared to SXT prophylaxis, 2GC prophylaxis was associated with earlier breakthrough infections and major changes in patients colonizing flora, resulting in the more frequent isolation of P. aeruginosa and Enterococcus spp. instead of Enterobacteriaceae and a broader development of bacterial resistance. These data provide evidence supporting the use of SXT instead of 2GC as prophylaxis against UTIs in children. Acknowledgments The investigators wish to thank their colleagues from the Third Department of Pediatrics, Aristotle University of Thessaloniki, for referring potentially eligible patients for this study. They also wish to thank all children and their parents who participated in the study. Contribution of each co-author C. Antachopoulos conducted the study and wrote the first draft of the manuscript. M. Ioannidou conducted the study and reviewed the manuscript. A. Tratselas conducted the study and reviewed the manuscript. E. Iosifidis analyzed data and reviewed the manuscript. A. Katragkou conducted the study and reviewed the manuscript. P. Kadiltzoglou conducted the study and reviewed the manuscript. K. Kollios conducted the study and reviewed the manuscript. E. Roilides designed the protocol and reviewed the manuscript Compliance with Ethical Standards Funding This study was not funded by any source. Conflict of interest of interest. All of the authors declare that they have no conflict Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all individual participants included in the study. References 1. Brandstrom P, Esbjorner E, Herthelius M, Swerkersson S, Jodal U, Hansson S (2010) The Swedish reflux trial in children: III. 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