Urinary tract infection is one of the most common bacterial diseases of childhood, with a reported prevalence in one study of 8.4% in girls by the age of 7 years [1]. Short term therapy advantages are based on increased patient compliance, with decreased adverse effects, decreased costs, and decreased rates of resistance development among the gut and vaginal flora [2]. However, the increasing rate of TMP- SMX resistance in the community world wide [3] as well as adverse effects of TMP-SMX [4] are causes of concern. Thus, alternative short–course antimicrobial regimens are required. Unfortunately, amoxicillin and cephalosporin are effective only when they are administered for 5 days.While nitrofurantoin requires at least 7 days of therapy [5].

Cefpodoxime is an orally administered prodrug which is absorbed and deesterified by the intestinal mucosa to release the advanced cephalosporin cefpodoxime, which has approximately 50% systemic bioavailability[6]. Cefpodoxime absorption is significantly increased by food, whereas it is reduced by agents that elevate the gastric PH.[7] It has a broad spectrum of anti bacterial activity encompassing both gram-negative and gram- positive bacteria and is stable against the most commonly found plasmid – mediated beta-lactomases including the TEM-2 and SHV-1 enzymes [8]. However, cefpodoxime is hydrolyzed by SHV-2, which is produced by some klebsiella pneumonia and Escherichia coli strains and is also susceptible to hydrolyses by species–specific chromosomally mediated inducible cephelosporinases produced by strains of pseudomonas aeruginoses, Morganella morganii, serratia mercescens and enterobacter SPP [9]. The extended half life of cefpodoxime in plasma, which ranges from 1.9 to 3.7 hours, permits twice daily administration, while its elimination, primarily by renal excretion, renders cefpodoxime a promising candidate for therapy of UTI [10] The aim of the present study was to evaluate the efficacy and safety of 3 days regimen of cefpodoxime and to compare it with the established short course 3 day regimen of oral TMP-SMX for the treatment of girls with acute uncomplicated cystitis.

This prospective, open, randomized study was performed at Aljahra hospital in Kuwait. Girls between the ages of 3 and 12 years who were referred to the Nephrology clinic because of symptoms compatible with acute cystitis were eligible for participation in the study. The diagnosis of uncomplicated cystitis was based upon clinical symptoms (i.e. dysuria, frequency, urgency, and burning pain on urination) as well as the absence of fever (temperature 37.5 c) or flank pain, laboratory findings (i.e., pyuria in uncentrifuged urine of 8 leukocytes per mm3) and a positive urine culture yielding 10 cfu/m) within 48 hr before initiation of treatment [11]. Exclusion criteria were as follows: serum creatinine concentration of 88 Uml/L, the presence of a permanent indwelling urinary catheter, diabetes or any immuno suppressive disease, a history or evidence of a functionally or anatomically abnormal urinary tract,a symptomatic bacteriuria , known hypersensivity to B-lactamas or TMP-SMX and any contraindication to the use of TMP-SMX (i.e., glucose-6-phosphate dehydrogenase deficiency), symptoms and signs of upper UTI, a history of acute pyelonephritis, previous UTI episodes with TMP-SMX treatment failure in the previous month or symptoms of lower UTI for longer than 3 days prior to presentation, any antimicrobial therapy within the previous 72 hours or therapy with any antimicrobial except in the study drugs during the trial, suspicion of non compliance, and the presence of urinary pathogens resistant to one of the agents used in the study.

Clean, voided midstream urine samples were collected subjected to urinalysis, and cultured by conventional methods. Treatment was given on an open randomized basis. Patients were assigned to receive either cefpodoxime (5 mg/kg b.i.d) or TMP-SMX (TMP 6 mg/kg, SMX 30 mg/kg B.I.D) for 3 days. Each patient was monitored clinically and bacteriologically at the baseline visit as well as at 4 to 7 and 28 days after the discontinuation of therapy. Before therapy and at the second follow–up visit, a clinical assessment and urinalysis were performed, urine was obtained for culture, and a blood sample was obtained for routine hematology and serum chemistry, while at the first follow-up visit, only the clinical evaluation and urinalysis were performed and urine was obtained for culture. Only patients who returned for at least the first follow-up visit were eligible for the study.

The effectiveness of the study drugs was evaluated as follows[12]. The patients were considered to be clinically cured when all symptoms had subsided and to have treatment failure when symptoms persisted during therapy or relapsed after the discontinuation of therapy.

Bacteriological cure was defined as eradication of the causative pathogen, with sterile urine at both follow–ups while isolation of any microorganism in urine cultures, as determined below, was considered bacteriological failure. Persistent was defined as the presence of the initial causative organisms at the first follow–up visit, super infection was defined as the isolation of a new pathogen from the cultures of urine obtained at first follow-up, relapse was defined as the presence of the initial causative pathogen at the second follow-up visit with sterile urine at the first follow-up visit, and re-infection was defined as the isolation of a new microorganism at the second follow-up visit with sterile urine at the first follow-up visit. For bacteriological evaluation and whenever symptoms of a lower UTI were present, bacteriological failure was considered a cut off of 10000 cfu/ml , whereas in the case of asymptomatic bacteriuria, a cut off of 100000 cfu/ml was necessary. In the case of treatment failure, the patients were subjected to ultrasound of the urinary tract.

Side effects were recorded after each patient was asked at the follow-up visit about the appearance of any symptoms during the previous week(s) and specifically of symptoms related to the drug treatment, such as abdominal pain, nausea , vomiting, rash, and fever.

Statistical analysis was performed by chi-square test, and a value of 0.05 was considered statistically significant [13].

A total of 82 girls entered the study. Of these girls, 41 received cefpodoxime and 41 received TMP-SMX. However, 15 patients were excluded: 6 patients in the cefpodoxime arm were excluded because pre-treatment urine cultures were negative, and one patient in the cefpodoxime arm was excluded because of unstable neurogenic bladder, whereas 4 patients in the TMP-SMX arm were excluded because the pre-treatment urine culture was negative and 4 patients, in the TMP-SMX arm were excluded because the isolated microorganisms were resistant to the drug tested.

The demographic and clinical characteristics of the evaluable patients in both treatment groups were similar (Table 1) clinical and bacteriological results, are listed tables (II+III). There were no statistically significant differences in either the clinical or bacteriological efficacies of the two drugs ( p=0.54). Compared to those who were cured, all patients in the two treatment groups who failed bacteriologically had histories of two or more episodes of lower UTI, per year (p0.001).

Among the three cefpodoxime recipients who failed bacteriologically, E.coli persisted in one patient and in two patients a re-infection caused by enterococcus facalis was observed. Thirteen patients, in TMP-SMX arm were considered bacteriological failures (all at the second follow-up visit). Among those thirteen patients, eleven
had relapses caused by E.coli, one had a relapse caused by staphylococcus saprophyticus, and one was reinfected with E.fecalis. No super infection was observed in any of the individuals participating in the study (Table 2). It should be mentioned that all patients, who failed bacteriologically, had symptoms compatible with a lower UTI.

Both drugs were well tolerated. In the cefpodoxime arm, one patient experienced an allergic maculopapular rash, but it did not discontinue therapy, whereas two patients, in the TMP-SMX arm stopped treatment because of intense epigastric pain and vomiting.

TMP-SMX is one of the most widely used antibacterial agents for short-term treatment of acute uncomplicated UTI in children [14]. However, hypersensivity reactions and the emergence of resistant isolates worldwide necessitates the search for other short-term treatment options [15]. The recent advent of oral quinolones has provided physicians with a valuable weapon against gram-negative infection. Its use has been somewhat limited in the pediatric population because of its reported adverse effects on cartilage development in various animal studies [16]. This necessitated the evaluation of short term regimens with advanced cephalosporin. A 5-day treatment regimen with older B-lactamas such as amoxicillin and narrow–spectrum cephalosporins had efficacy superior to that of 3-day regimen and there was an even greater risk of treatment failure with single day regimens [17].

In a multi center study, 3-day regimen of cefuroxime proved to be as effective as 3-day regimen of ofloxicin for the treatment of uncomplicated UTI, in 163 women [18]. In the latter study, clinical cure and improvement were registered in 84.8 and 95.2% of the patients, respectively, at 7 to 9 days post therapy, where as bacteriuria (10/ml) was eliminated from 80.3 and 89.1% of the evaluable patients, receiving cefuroxime and ofloxicin, respectively, with no statistically significant difference between treatment groups. On the other hand in a double–blind randomized study, a three day regimen of 400 mg of cefixime once daily was as effective as a 3-day regimen of 200 mg of ofloxicin twice a day for the treatment of 99 women with uncomplicated cystitis[19]. In the latter study, the respective clinical cure rates were 89% of 92% at early follow-up and 81% and 84% at last follow-up with bacteriological cure rate of 83% and 86%, respectively 7 days after the discontinuation of therapy and 77 and 80% respectively, 4 weeks after the discontinuation of therapy [19].

In the present study, cefpodoxime at a dose of 5 mg/kg has been shown to be more effective than TMP/SMX at dose 6/30 mg/kg when both regimens are given twice daily for 3 days. At 28 days after discontinuation of therapy, clinical cure was observed in 87.3% and 53.5% of the patients, in the cefpodoxime and TMP-SMX arms, respectively.

The fact that in this study short-term therapy with cefpodoxime was more effective than TMP-SMX could be, probably based on the slower elimination of cefpodoxime from urine because of its prolonged half life. Surveillance cultures for vaginal reservoir flora, which were not performed in the present study, could also offer another explanation for the low bacteriological failure rates observed in the cefpodoxime arm [12].

The tolerance of both antimicrobials was satisfactory. Only one patient in the cefpodoxime arm reported mild adverse events, whereas two patients in the TMP-SMX arm discontinued therapy because of gastrointestinal side effects. Hematological and biochemical results, did not show any important difference pre- and post therapy.

This study has reported for the first time in the available literature that a short 3-day course of therapy with cefpodoxime is more effective than TMP-SMX for treatment of acute uncomplicated UTI in girls.

Click here to view Table 3