Pediatr Nephrol (2002) 17:173176

IPNA 2002

O R I G I N A L A RT I C L E

Noemia P. Goldraich Anglica Manfroi

Febrile urinary tract infection: Escherichia coli susceptibility to oral antimicrobials

Received: 20 December 2000 / Revised: 26 November 2001 / Accepted: 27 November 2001

Abstract Empirical treatment is indicated for young children with febrile urinary tract infection (UTI). In this clinical setting, oral antibiotics are as safe and effective as intravenous therapy. The aim of this study was to investigate in children with febrile UTI whether there were longitudinal changes in the prevalence of bacteria and in the pattern of Escherichia coli susceptibility to oral antimicrobial agents. Two hundred and eighty-seven positive urine cultures from children (1 month to 12 years) with febrile UTI collected over three periods (19861989, 19901991, and 1997) were studied. E. coli was the most-prevalent microorganism in all three study-periods (n=228). The susceptibility pattern of E. coli to nitrofurantoin (92%, 95%, 94%) and nalidixic acid (85%, 92%, 95%) did not present any statistically significant differences (P>0.05) over time. There was a significant increase (P<0.05) in E. coli susceptibility to cephalexin (65%, 54%, 81%). The E. coli susceptibility to trimethoprim-sulfamethoxazole (40%, 85%, 40%) behaved differently. Initially there was a significant rise (P<0.05), followed by a significant decrease (P<0.05). Empirical oral treatment with nitrofurantoin or nalidixic acid can safely be started in children with febrile UTI seen in the Emergency Department, Hospital de Clnicas de Porto Alegre, Brazil. Keywords Urinary tract infection Escherichia coli susceptibility Escherichia coli resistance Antimicrobial agents Oral treatment

Introduction
Urinary tract infection (UTI) is one of the most-common infections in children, and its prevalence is higher in the first 2 years of life. Goldraich et al. [1] found UTI in 10.9% of febrile children aged 124 months seen in the pediatric emergency department at a university hospital. When the group aged 112 months was analyzed separately, the prevalence of UTI was 15%. The microorganisms responsible for UTI present different susceptibility patterns to antimicrobial agents, which vary according to the place where the study is performed and also over time. Susceptibility patterns to antimicrobials depend on the minimum inhibitory concentration (MIC), the time that the concentration remains above the MIC, and the dose of the antimicrobial agent required to reach the MIC at the desired site of action. In clinical practice, the antimicrobial must reach a concentration above the MIC, in a non-toxic dose, be easy to administer, and have a low cost. The frequent use of one antimicrobial drug may result in the selection of resistant strains of bacteria causing therapeutic failure. The mostimportant factor in the emergence of antimicrobial resistance continues to be excess and inappropriate antimicrobial use [2, 3]. Although most children with UTI present a good prognosis, there is a group at risk of developing progressive kidney disease, i.e., children aged 05 years with febrile UTI [4, 5]. In these and in children that present with clinically severe infection at any age, UTI must be treated immediately, even before the urine culture result is available [5]. More recently, it has been shown that oral antibiotics are as safe and effective as intravenous therapy for patients aged 124 months with febrile UTI [6, 7, 8]. To start empirical treatment of UTI in these children it is important that the selection of the antimicrobial is influenced not only by the most likely pathogen but also by its local updated susceptibility pattern [3]. The aim of this study was to investigate in children with febrile UTI whether there are longitudinal changes in the prevalence of bacteria and their susceptibility pat-

N.P. Goldraich A. Manfroi Pediatric Nephrology Unit, Hospital de Clnicas de Porto Alegre, Porto Alegre, RS, Brazil N.P. Goldraich () Rua Quintino Bocaiva 1234 ap 701, 90440-050 Porto Alegre RS, Brazil e-mail: noemia.goldraich@terra.com.br Tel.: +55-51-33326781, Fax: +55-51-33329180

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terns to oral antimicrobial agents. Based on these data an appropriate oral empirical therapy can be suggested.

Materials and methods

Study design and materials Two hundred and eighty-seven positive urine cultures and antibiograms from patients with febrile UTI seen at the Pediatric Emergency Department, Hospital de Clnicas de Porto Alegre, Porto Alegre, RS, Brazil were studied; 179 urine cultures were from infants (aged 124 months), 74 were from pre-school children (25 years), and 34 were from school-aged children (512 years). All urine samples were collected by suprapubic bladder aspiration. E. coli susceptibility pattern was analyzed in 228 urine cultures in which this organism grew. Study periods Data were collected over three periods: 1. Period I: September 1986 to March 1989: 104 urine cultures (22 males, 82 females), 58 from infants, 28 from pre-school children, 18 from school-aged children; 79 positive urine cultures with E. coli 2. Period II: March 1990 to February 1991: 78 urine cultures (21 males, 57 females), 41 from infants, 22 from pre-school children, 15 from school-aged children); 64 positive urine cultures with E. coli 3. Period III: January to December 1997: 105 urine cultures (34 males, 71 females), 80 from infants, 24 from pre-school children, 1 from a school-aged child); 85 positive urine cultures with E. coli Methods Febrile UTI was defined as a positive urine culture in a child seen at the emergency department presenting with fever (>38C) in whom a urine culture was part of the work-up. Table 1 Prevalence of etiological agents causing febrile urinary tract infections during the three periods (n=287) Bacteria Escherichia coli Proteus sp Klebsiella sp Others 19861989 (n=104) 76% 13% 8% 3% 19901991 (n=78) 82% 13% 1% 4% 1997 (n=105) 81% 6% 7% 6%

Search of the records from the emergency department identified the patients in whom a febrile UTI was diagnosed, regardless of whether the child was admitted to the hospital or treated at home. Following this, in each period the urine culture records were searched. For each patient, only the first positive urine culture was included. Laboratory procedures In the microbiology unit, the urine cultures were immediately performed by the streak plates method with an appropriate agar identifying medium. The bacterial growth was assessed after 2448 h of incubation when indicated. The bacterial identification procedures with conventional biochemical tests were performed according to National Committee for Clinical Laboratory Standards (NCCLS) standard tests [9]. The urine culture was considered positive when there was growth of any number of colonies. The susceptibility test to antimicrobials was performed using the disk diffusion method, modified from the Kirby-Bauer method [9]. The reading zone sizes were determined according to the standards provided by the NCCLS [9]. Oral antimicrobial agents The oral antimicrobial agents usually indicated for the treatment of UTI in children, nitrofurantoin, nalidixic acid, cephalexin, and trimethoprim-sulfamethoxazole, were analyzed individually over the three study-periods. All are easy to administer and this, together with their cost, provides even stronger reasons for their use. Due to lack of availability of the antimicrobial disks during period III, only 63 of 85 (79%) E. coli isolates were tested for cephalexin. Statistics Significant tests for trends in resistance over time were performed using the chi-squared test. Statistical significance was considered for P<0.05. SPSS for Windows Student Version was used.

Results
E. coli was the most-prevalent microorganism isolated from children with febrile UTI in all three study-periods: 76% in period I, 82% in period II, and 81% in period III. These variations were not statistically significant (P>0.05) (Table 1). The susceptibility patterns of E. coli to antimicrobial oral agents are presented in Table 2. No statistically significant differences (P>0.05) were found over time in its susceptibility to nitrofurantoin and nali-

Table 2 E. coli susceptibility to antimicrobial agents during the three study-periods Antimicrobial agents 19861989 Susceptibility N Nitrofurantoin Nalidixic acid Cephalexin Trimethoprim-sulfamethoxazole 79 79 79 79 n 73 67 52 32 % 92 85 65 40 19901991 Susceptibility N 64 64 64 64 n 61 59 35 54 % 95 92 54 85 1997 Susceptibility N 82 85 63 84 n 77 81 51 34 % 94 95 81 40 0.993 0.06 0.007 0.001 P*

*Chi-squared test N=total number of E. coli tested for each antimicrobial; n=total number of E. coli susceptible to each antimicrobial; %=percentage of E. coli susceptible to each antimicrobial

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dixic acid. However, the susceptibility patterns of E. coli to cephalexin and trimethoprim-sulfatomethoxazole showed statistically significant variations (P<0.05) in the three study-periods.

Discussion
Febrile UTI is a very common disease in childhood. E. coli is the most-prevalent organism identified in these children. In the literature there is evidence that it may be harmful to wait for the results of urine culture before starting treatment of children with febrile UTI [5]. Early empirical treatment is indicated for young children with febrile UTI due to the difficulty in early diagnostic documentation of the UTI (urine culture results can take up to 48 h) in order to minimize renal scarring that results from acute pyelonephritis [5, 8]. In this clinical setting, oral antibiotics are as safe and effective as intravenous therapy [6, 7, 8]. Current data regarding the prevalence of microorganisms and their susceptibility to antimicrobial agents, as well as their variations over time are important. Inappropriate use of antibiotics must be avoided to prevent bacterial resistance from occurring. We investigated the susceptibility of E. coli to oral antibiotics isolated from children with febrile UTI. There is little information on this subject, at least in Brazil. UTI comprise a broad spectrum of entities: asymptomatic bacteriuria, cystitis, and febrile UTI that require different treatment and have different consequences. Our study includes a well-defined population of outpatient children with febrile UTI seen at the emergency department of a main teaching hospital. All urine samples were collected by suprapubic bladder aspiration, which is the gold-standard for urine collection for culture [8]. It is superior to bladder catheterization, because it avoids contamination from bacteria that are present in healthy children in the distal urethra, as well the need for a cutoff point for bacterial growth to establish the diagnosis of UTI [10, 11]. There were no significant changes in the prevalence of the microorganisms causing febrile UTI in children during the three study-periods (Table 1). E. coli remained the most-prevalent pathogen, in accordance with the literature. In our study, the susceptibility patterns of E. coli isolated from children with febrile UTI to oral antimicrobial agents presented variations over time. There was no change in the susceptibility patterns to nitrofurantoin, as reported by Dyer et al. [12] and Gupta et al. [13] who studied E. coli isolates from adult women with UTI over the periods 199119941997 and 19921996, respectively. Our results showed that there were no significant differences (P>0.05) in E. coli susceptibility patterns to nalidixic acid, which remained high with time, indicating that this antimicrobial drug is an excellent therapeutic option in children with febrile UTI.

Susceptibility of E. coli to cephalexin varied from 65% in period I, 54% in period II, and 81% in period III. We observed a significant modification (P<0.05) in the susceptibility pattern of E. coli to cephalexin, as reported in adults by Dyer et al. [12] and Gupta et al. [13]. The E. coli susceptibility pattern to trimethoprimsulfamethoxazole behaved differently. There was a significant rise (P<0.05) during period II and a significant decrease (P<0.05) during period III. Gur et al. [14] studied the prevalence of pathogens responsible for UTI in children and their susceptibility patterns to several antimicrobial agents. They reported that the susceptibility to trimethoprim-sulfamethoxazole was 48% when all microorganisms were considered. The prevalence of E. coli was 67%. Their results are similar to ours in periods I and III, when the susceptibility to trimethoprim-sulfamethoxazole was also decreased (40% in these periods). Dyer et al. [12] reported that E. coli susceptibilities to trimethoprim-sulfamethoxazole were 85.4%, 68.1%, and 84.6% during 199119941997, respectively. Maartens and Oliver [15] studied adult men and women and found that the susceptibility pattern of E. coli to trimethoprim-sulfamethoxazole varied from 60% to 37% between 1985 and 1991. Gupta et al. [13] reported an increase in resistance from 9% in 1992 to 18% in 1996 among E. coli isolated from women with acute cystitis. These three studies included a different population from ours (adults), but the findings confirm the tendency of E. coli to develop resistance to sulfamethoxazole-trimetoprim. Berdichevski et al. [16], in a study performed at another university hospital in Porto Alegre in 1996 (July to December) and in 1997 (January) that can be superimposed on our period III, showed E. coli susceptibility to trimethoprim-sulfamethoxazole to vary between 60% and 65%. These values are significantly different from ours (40%) during the same period (1997). It is important to point out that despite the fact that the study of Berdichevski et al. [16] and ours were performed in the same city and during the same period, the E. coli susceptibility patterns to sulfamethoxazole-trimetoprim were different. This difference could be due to the peculiar characteristics of each of the populations seen at both hospitals, which further reinforces the need for each unit to have its own data available for pediatric and adult patients. We looked at the availability of this antimicrobial drug at the National Health Service Authority in Porto Alegre during the three study-periods. Its widespread availability (period I) resulted in an increased resistance of E. coli. When its availability was restricted (period II), resistant strains stopped being selected, allowing an increase in susceptibility. During period III, it was probably widely used again, as reflected in the low percentage of sensitive organisms. It can be speculated that the variations observed in the susceptibility patterns to trimethoprim-sulfamethoxazole are the result of changes in the prescription of this antimicrobial, although we do not have reliable data on this. It could be suggested that its use should be restricted again, so that this antimicrobial

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agent again becomes another therapeutic option for the treatment of UTI in children. Considering the evidence accumulated so far [5], it is necessary to begin empirical treatment of pediatric patients (especially infants and pre-school children) with febrile UTI, even before the results of the urine culture and antibiogram are obtained. Empirical oral treatment with nitrofurantoin or nalidixic acid can be started in children with febrile UTI seen in the emergency department at our hospital. Since these data cannot apply to other institutions, each unit must have updated longitudinal data concerning the prevalence of microorganisms and their susceptibility patterns to antimicrobial agents.
Acknowlegements This work received a grant from Fundao de Amparo Pesquisa do Estado do Rio Grande do Sul (FAPERGS). We would like to thank Dr. Afonso Lus Barth, Chief of Research, Clinical Laboratory of Hospital de Clnicas de Porto Alegre for reviewing this manuscript.

References
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