Cefetamet pivoxil in the treatment of acute urinary tract infections in children

CURRENT THERAPEUTIC RESEARCH VOL. 55, NO. 10, OCTOBER 1994

CEFETAMET PIVOXIL IN THE TREATMENT OF ACUTE URINARY TRACT INFECTIONS IN CHILDREN ANTOINE BOURILLON, 1 GIUSEPPE ROBERTO BURGIO, 2 LUDWIG STEFFENS, 3 ALOIS KRANZ, 4 MATTHIAS NOACK, 5 GERALD WEIPPL, 6 KATHARINA MALAKA-ZAFIRIU, 7 MAGDALENE GATZOLA, s MOHAMADOU FALL, 9 E K O E T E T A N Y E , 1° J U L I O T O P O R O V S K I , 11 L U I Z F E L I P E D E A R A U J O V I E I R A L V E S , 12 A N D M A R G O T K I S S L I N G 13

1H6pital Robert Debrd, Paris, France, 2Policlinico S. Matteo, Pavia, Italy, 3St-Antonius Hospital, Eschweiler, Germany, 4St-Elisabeth Hospital, Iserlohn, Germany, 5Private Practice, Simmerath, Germany, 6Wilhelminenspital, Vienna, Austria, 7Hospital Agia Sofia, Thessaloniki, Greece, SHospital AHEPA (University Clinic), Thessaloniki, Greece, 9HOpital Le Dantec, Dakar, Senegal, l°H6pital Central, Yaoundd, Cameroun, llFaculdade de Ci~ncias M~dicas da Santa Casa de Sdo Paulo, Sdo Paulo, Brazil, ~2Clinica Uroginecologista Assoc. Ltda, Rio de Janeiro, Brazil, and 13F. Hoffmann-La Roche Ltd., Basel, Switzerland ABSTRACT

The data from this multicenter comparison of oral cefetamet pivoxil (CAT) (10 and 20 mg/kg twice daily) and amoxicillin plus clavulanic acid (30 to 50 mg/kg/d, in three divided doses) in the treatment of acute (recurrent) urinary tract infections (UTIs) in children are reported. A total of 421 children (aged 2 months to 15 years) were treated for 7 to 10 days. At follow-up (day 28), there was bacteriologic success (eradication or reinfection) in 97% of those treated with CAT and in 93% of those treated with amoxicillin plus clavulanic acid. The overall cure rate was 97% for CAT and 93% for amoxicillin plus clavulanic acid. There was no difference in outcome between the two CAT dosages. With both drugs adverse events were gastrointestinal in nature. CAT is an appropriate drug for the treatment of acute UTIs in children, being at least as effective as amoxicillin plus clavulanic acid. INTRODUCTION

Urinary tract infections (UTIs), a common source of morbidity, are among the conditions frequently diagnosed by general practitioners and pediatricians. Treatment is often initiated before the bacteriologic findings and sensitivity pattern of the urinary pathogens are known. In these circumstances, the choice of antibacterial agent should be based on knowledge of the prevailing sensitivity pattern of the common urinary pathogens. In UTIs, gram-negative fermenting rods (Enterobacteriaceae) are the predominant causative organisms. Cefetamet pivoxil (CAT) is an oral third-generation cephalosporin with a broad spectrum of antibacterial activity and a favorable pharmacokinetic profile, making it particularly suitable for the treatment of a Address correspondence to: Dr. M. Kissling, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, CH-4002 Basel, Switzerland. Received for publication on July 19, 1994. Printed in the U.S.A. Reproduction in whole or part is not permitted. 1161

0011-393x/94/$3.50

CEFETAMET PIVOXIL IN ACUTE UTIs IN CHILDREN

wide range of infectious diseases. The pivoxil ester is absorbed and hydrolyzed to the active compound, cefetamet, before reaching the systemic circulation. The antibacterial activity of CAT against gram-negative fermenting rods is generally comparable to that of cefixime and cefpodoxime proxetil but superior to that of cefuroxime, cefaclor, and the combination of amoxicillin plus clavulanic acid. 1 CAT appears to be as active as other recently developed, orally active cephalosporins but somewhat less active than cefotaxime.1 CAT is also active against gram-positive bacteria; however, like cefixime, CAT is not active against staphylococci. CAT has been shown to be effective in infections of many body sites, such as lower respiratory tract infections (including community-acquired pneumonia); ear, nose, and throat infections; and UTIs (including acute, uncomplicated pyelonephritis). The positive results obtained in adults with complicated UTIs 2-4 led to a program of studies of CAT in children with acute UTIs. While a number of these studies have been presented during congresses, MalakaZafiriu et al 5 and Toporovski et al 6 published the data from their studies of a total of 87 children with acute UTIs (>105 colony forming units per milliliter [CFU/mL] urine) due to susceptible pathogens. The children were treated with either CAT (10 to 20 mg/kg twice daily) or amoxicillin plus clavulanic acid (30 to 50 mg/kg/d, in three divided doses). The overall success rate was 100% for CAT and 94% for amoxicillin plus clavulanic acid. This paper presents a summary of the data we obtained in this multicenter study comparing CAT and amoxicillin plus clavulanic acid in the treatment of acute UTIs in pediatric patients. PATIENTS AND METHODS

In this comparative multicenter study, a total of 421 patients with UTIs was assessed. The same basic protocol was used at each of the 12 centers; the data from those centers were combined. Children aged <1 to 15 years, with acute (recurrent) UTI or acute uncomplicated pyelonephritis due to susceptible organisms, who had significant bacteriuria (two colony counts of at least 105 CFUs/mL), were eligible. Informed consent was provided by the patient; parent, or guardian, as appropriate, and ethics committee approval was obtained for the study. In the majority of the centers, two doses of CAT syrup, 10 mg/kg twice daily and 20 mg/kg twice daily were compared with amoxicillin plus clavulanic acid suspension, 30 to 50 mg/kg/d, given in three divided doses. In one study, which included 10 patients in each group, CAT tablets, 500 mg twice daily, were compared with amoxicillin plus clavulanic acid, as above. All treatments were given for 7 to 10 days. Two formulations of CAT syrup were used. A preliminary formulation was supplied as dried syrup to be dissolved in tap water; the second for1162

A. BOURILLON ET AL.

mulation consisted of sachets of flavored pellets to be reconstituted with a bottle of syrup. The preliminary formulation was abandoned, since it was found to be unpalatable. The data from all centers have been combined. The overall outcome for each patient was categorized as cure (clinical and bacteriologic findings subsided within 4 - 1 days, with no clinical or bacteriologic evidence of infection at treatment end or at the follow-up evaluation on day 28 - 7), improvement (pathogen eradicated and clinical signs subsided but the patient was reinfected with a new pathogen during follow-up), failure (no apparent response to therapy), or not assessable. The definitions used for bacteriologic evaluations were as follows: (1) cure--the initially susceptible pathogens (i>105 CFU/mL urine) were reduced to ~<10a CFU/mL urine during therapy and follow-up; (2) superinfection/reinfection--initial bacteriologic response followed by growth of t>105 CFU/mL urine of a new pathogen during treatment (superinfection) or follow-up (reinfection); (3) relapse--recurrence of significant bacteriuria of original pathogen after transient elimination during follow-up; or (4) failure--persistence of significant counts of the original pathogen. The combined study population was sufficiently large for equivalence between the two treatments to be detected with a statistical power of 80%, equivalence being defined as a difference of less than 10% in success rates. RESULTS

Data from 421 patients were analyzed. Of these, 139 patients received CAT at 10 mg/kg twice daily, 135 received CAT at 20 mg/kg twice daily, and 147 received amoxicillin plus clavulanic acid. Demographic characteristics of the study patients, details of the diagnosis, and duration of disease are shown in Table I. The majority of patients (78%) were female; their ages ranged from 2 months to 15 years. The most common diagnoses were uncomplicated UTI or recurrent uncomplicated UTI; in approximately half the patients, the duration of the disease was less than 1 week. Few children were receiving concomitant medications: 21 were taking analgesics and 10 antipyretics. Four children took antiepileptic medication and the other treatments (antihistamines, corticosteroids, and expectorants) were t a k e n by only one or two children each. Clinical signs and symptoms are summarized in Table II. Dysuria and urgency were the most common symptoms at baseline. All patients treated with CAT were symptom free at the end of treatment and few had symptoms at follow-up. Similar results were obtained with amoxicillin plus clavulanic acid. The majority of assessable cases were cured, as shown in Table III, with 22 patients being unassessable. Treatment was withdrawn prematurely for 3 patients in the CAT 10-mg/kg twice daily group (1 due to nausea and diarrhea and 2 due to the unpalatable syrup) and 5 patients in 1163

CEFETAMET PIVOXIL IN ACUTE UTIs IN CHILDREN

Table I. Demographiccharacteristics, diagnosis, and duration of disease. Treatment Group CAT (10 mg/kg BID)

CAT (20 mg/kg BID)

28 111

34 101

Sex Male Female Age (y) Mean Median (range) Weight (kg) Mean Median (range) Diagnosis Uncomplicated UTI Complicated UTI Recurrent uncomplicated UTI Recurrent complicated UTI Acute uncomplicated pyelonephritis Duration of disease <1 week 1-2 weeks 3-12 weeks 3-6 months >6 months Acute exacerbation lasting >6 months

6.74 6.0 (0.2-14)

Amoxicillin Plus Clavulanic Acid (30-50 mg/kg) 31 116

5.97 6.5 (0.5--15)

6.49 7.0 (1--14)

23.6 21.0 (6-55)

20,0 18.5 (8-57)

24.5 25.0 (12-45)

65 2 39 11 22

57 3 39 18 18

74 3 42 11 17

64 27 11 12 25

66 28 3 2 9 27

70 30 12 5 12 18

CAT = cefetamet pivoxil; BID = twice daily; UTI = urinary tract infection.

th e 20-mg/kg twice daily group (1 with hepatitis A as an i n t e r c u r r e n t illness, 3 due to the unpalatable syrup, and 1 refused to take the tablets). Resistant organisms at baseline were found for 1 patient in each group; in both CAT groups t he organism was Pseudomonas aeruginosa and in the amoxicillin plus clavulanic acid group it was Streptococcus faecalis. No culture was performed at baseline in an additional 2 patients per group. One p a t i e n t in each CAT group was lost to follow-up, as were 3 patients in th e amoxicillin plus clavulanic acid group. Table II. Clinical signs and symptoms of urinary tract infection. CAT (10 mg/kg BID) Sign or Symplom Dysuria Flank tenderness Urgency Lower abdominal pain/cramps

Baseline End

Amoxicillin Plus Clavulanio Acid (30-50 mg/kg)

CAT (20 mg/kg BID)

Followup

Baseline End

Followup

Baseline End

Followup

102 22 96

-

1 1

109 18 93

-

3

112 17 98

2 2 -

2 2 6

54

-

-

71

-

2

68

1

1

CAT = cefetarnet pivoxil; BID = twice daily; End = end of treatment.

1164

A. BOURILLON ET AL.

Table III. Overall outcome of treatment.

Treatment Group

Outcome No. of patients No. of assessablepatients Cure No. of patients (%) 95% confidence interval Improvement Failure Not assessable

CAT (10 mg/kg BID)

CAT (20 mg/kg BID)

Amoxicillin Plus Clavulanic Acid (30-50 mg/kg)

139 132

135 126

147 141

129 (97.7) 95-100 2 1 7

121(96.0) 93-99 3 2 9

131(92.9) 89-97 6 4 6

CAT = cefetamet pivoxil; BID = twice daily.

The results of the bacteriologic evaluation are shown in Table IV. The most common infecting organism at baseline was Escherichia coli, being identified in 336 (84%) of the 399 assessable patients. At follow-up, in those treated with CAT, there were 2 cases of failure, 5 relapses, and 1 reinfection, giving a bacteriologic success rate (eradication + reinfection) of 97% (251/258). In those treated with amoxicillin plus clavulanic acid, there were 9 cases of reinfection and 10 relapses, giving a bacteriologic success rate of 93% (131/141). There were both radiologic and bacteriologic findings for 27 patients in the CAT 10-mg/kg twice daily group, for 27 in the CAT 20-mg/kg twice daily group, and 24 in the amoxicillin plus clavulanic acid group. Two patients in the CAT 10-mg/kg twice daily group with an initial group A beta-hemolytic streptococcal (GABHS) infection were found to have relapsed at follow-up, and a third, who had initially been infected with E coli, was found at follow-up to have been reinfected with GABHS. In the CAT 20-mg/kg twice daily group, one patient with an initial E coli infection was found to have been reinfected with Streptococcus faecalis at the end of the treatment period. Another patient with an E coli infection had relapsed at follow-up. Of those taking amoxicillin plus clavulanic acid, three patients with E coli infections were found at follow-up to have relapsed and a fourth was reinfected with Proteus mirabilis. Another patient in this group, who had GABHS at the start of the study, was found to have an infection with P mirabilis at follow-up. The adverse events reported for patients receiving the improved syrup or tablets are shown in Table V. The overall incidence of adverse events was slightly higher with CAT than with amoxicillin plus clavulanic acid. With all treatments the adverse events were gastrointestinal in nature. Vomiting occurred in 5 of the 11 children who reported adverse events while receiving CAT. The patient with diarrhea and nausea receiving CAT 1165

-

. .

1 1 1 .

Mixed infections

.

.

. .

.

.

-

.

. .

1 relapse

.

1 relapse -

1 failure 1*

1 reinf

.

.

Follow-up

. .

.

.

1

-

.

2

3 2

8

.

110

Baseline

CAT = cefetamet pivoxil; BID = twice daily; End = end of treatment; r e i n = reinfection. * Patient received antibiotic treatment 10 days after end of treatment with CAT.

.

-

. 1

.

-

2

. -

1

1 relapse

4

13

Proteus mirabilis

-

End

CAT

(10 mg/kg BID)

Proteus vulgaris Klebsiella pneumoniae Klebsiella sp Enterobacter sp Morganella morganii Citrobacter sp Streptococcus hemolyticus, Group A Staphylococcus saprophyticus Streptococcus liquefaciens Staphylococcus epidermidis

108

Baseline

Escherichia coli

Pathogen

Table IV. Bacteriologic evaluation.

.

.

.

.

-

.

.

1 reinf -

-

2 reinf 1 failure

End

CAT

.

.

(20 mg/kg BID)

.

.

-

-

-

.

.

1 failure 3 relapse

.

.

Follow-up

.

.

3

1

1 1

1 1 2

13

118

.

.

Baseline 2 3 1 1

-

-

-

-

reinf relapse failure relapse

End

-

-

1 reinf 1 reinf

1 reinf 1 relapse

2 reinf 2 relapse

4 reinf 7 relapse

Follow-up

Amoxicillin Plus Clavulanic Acid (30-50 mg/kg)

A. B O U R I L L O N ET

AL.

Table V. Adverse events while receiving tablets and the improved syrup.

Adverse Event Nausea Nausea and vomiting Vomiting Diarrhea Diarrhea and nausea Total no. (%) of patients with adverse event

CAT (10 mg/kg BID) (n = 75)

CAT (20 mg/kg BID) (n = 81)

Amoxicillin Plus Clavulanic Acid (n = 83)

1 1 2 1

0 2 3 1 -

0 0 2 2 -

5 (6,7%)

6 (7.4%)

4 (4.8%)

CAT = cefetamet pivoxil; BID = twice daily.

10 mg/kg twice daily and two of the three children experiencing vomiting receiving 20 mg/kg twice daily were withdrawn from treatment. The third child withdrew because of hepatitis A, which was not related to the study drug. Among the 118 children taking the preliminary form of syrup, 19 experienced adverse events that were gastrointestinal in nature (mainly vomiting); this was due to the unpalatability of the preliminary syrup. DISCUSSION AND CONCLUSION

This overview of the results of studies at 12 centers comparing CAT and amoxicillin plus clavulanic acid in the treatment of children with acute UTIs indicates a high degree of efficacy for both compounds. The proportion of assessable patients with an overall cure ranged from 93% with amoxicillin plus clavulanic acid to 98% with CAT 10 mg/kg twice daily. At baseline, resistant organisms were found for only one patient in each group (P aeruginosa for CAT and S faecalis for amoxicillin plus clavulanic acid). The bacteriologic evaluation also demonstrated cure for the majority of patients, although the proportion of patients with reinfection or relapse at follow-up was somewhat higher with amoxicillin plus clavulanic acid than with CAT (13% and 3%, respectively). Other studies of the efficacy of amoxicillin plus clavulanic acid in the treatment of UTIs in children have found a similar degree of efficacy to that reported here. A1 Roomi et al 7 described a clinical and bacteriologic cure rate of 80%, Contardi et al s reported an 80% cure rate, and Jeffries et al 9 had a bacteriologic cure rate of 88%. As expected, we found the predominant causative organism of UTIs in children to be E coli, with similar findings having been reported in other studies. 1,7,S,10 We found the overall incidence of adverse events with amoxicillin plus clavulanic acid to be just below 5%, although other reports 7'9 have described up to a 25% incidence of adverse events. With both CAT and amoxicillin plus clavulanic acid, adverse events were gastrointestinal in nature. The combined incidence of adverse events with the new 1167

CEFETAMETPIVOXILINACUTEUTIsIN CHILDREN

syrup and the tablet formulations of CAT was lower than the overall incidence of 10.9% previously reported in children. 1 An incidence of 8.5% for gastrointestinal disturbances with CAT was also cited in the same review. 1 The most common adverse effect of CAT we found was vomiting with or without nausea. In children, the most frequently reported gastrointestinal disturbance is nausea with or without vomiting, whereas in adults diarrhea is more common. 1 In conclusion, both doses at CAT were effective and well tolerated in the pediatric study population. The efficacy was at least equal to that of amoxicillin plus clavulanic acid. CAT is an appropriate choice for the treatment of acute UTIs in children encountered in general practice.

Acknowledgment This study was supported by an educational grant from F. Hoffmann-La Roche Ltd., Basel, Switzerland. References:

1. Cullman W, Edwards DJ, Kissling M, et al. Cefetamet pivoxih A review of its microbiology, toxicology, pharmacokinetic and clinical efficacy. Int J Antimicrob Agents. 1992; 1:175-192. 2. Sourander L, Becq-Giraudon B, Bernstein-Habn L, et al. Cefetamet pivoxil in geriatric patients with complicated urinary tract infection. Drug Invest. 1989;1:34-39. 3. Sourander L, Kissling M. Efficacy and tolerability of cefetamet pivoxil in diabetic patients with urinary tract infections. Curr Med Res Opin. 1991;12:304-308. 4. Stathakis CH, Roulleau N, Libert M, et al. Cefetamet pivoxil in acute pyelonephritis: An open study. Curr Med Res Opin. 1990;12:43-50. 5. Malaka-Zafiriu K, Papachristou F, Augoustidou-Savvopoulou P, Eleftheriadou E. Oral cefetamet pivoxil compared to amoxicillin-clavulanicacid in the treatment of urinary tract infections (UTI) in children. Proceedings of the 16th International Congress of Chemotherapy; June 11-16, 1989; Jerusalem, Israel. In: Rubenstein E, Adam D, eds. Recent Advances in Chemotherapy, Antimicrobial Section 1. E. Levin Epstein Ltd: 1990:95.1-95.2. 6. Toporovski J, Steffens L, Noack M, et al. Effectiveness of cefetamet pivoxil in the treatment of pyelonephritis in children. J Int Med Res. 1992;20:87-93. 7. A1 Roomi LG, Sutton AM, Cockburn F, McAllister TA. Amoxycillin and clavulanic acid in the treatment of urinary infection. Arch Dis Child. 1984;59:256-259. 8. Contardi I, Nastri A, Frigerio D. Treatment of urinary tract infections (UTI) in children. A comparative study. Proceedings of the 17th International Congress of Chemotherapy; June 23-27, 1991; Berlin. In: Adam D, Lode H, Rubinstein E, eds. Recent Advances in Chemotherapy, Antimicrobial Section 2. Munich: Futuramed Publishers; 1991:14441445. 9. Jeffries MG, Rose AJ, Williams HN. An initial assessment of Augmentin for the treatment of paediatric infections in general practice. Br J Clin Pract. 1983;37:61-66. 10. Pitt WR, Gray S, Heathcote B, et al. Augmentin therapy in childhood urinary tract infection. Aust Pediatric J. 1986;22:254-259. 1168