Elsevier

The Lancet

Volume 352, Issue 9127, 15 August 1998, Pages 522-527
The Lancet

Articles
Randomised comparison of ciprofloxacin suspension and pivmecillinam for childhood shigellosis

https://doi.org/10.1016/S0140-6736(97)11457-XGet rights and content

Summary

Background

Infections caused by multiply resistant Shigella species are a major cause of childhood morbidity and mortality in Third World countries. The fluoroquinolone agent ciprofloxacin is active in vitro against these strains of bacteria, but has not been routinely used to treat acute childhood infections because of concern that quinolones may cause arthropathy in children. We undertook a randomised double-blind study to test the effects of ciprofloxacin treatment in children with shigella dysentery.

Methods

We compared the efficacy and toxic effects of ciprofloxacin suspension (10 mg/kg every 12 h for 5 days, maximum individual dose 500 mg) with those of pivmecillinam tablets (15–20 mg/kg every 8 h for 5 days, maximum individual dose 300 mg). We enrolled 143 children aged 2–15 years with dysentery of 72 h or less duration. Patients stayed in hospital for 6 days, and were followed up 7, 30, and 180 days after hospital discharge. Joint symptoms and function were assessed daily for 6 days. Clinical success was defined as the absence of frank dysentery on day 3, and on day 5 no bloody-mucoid stools, one or no watery stool, six or fewer total stools, and no fever. If no shigella were isolated from faecal samples on day 3 or thereafter, treatment was judged bacteriologically successful.

Findings

13 patients were excluded since they did not meet eligibility criteria; 10 withdrew before day 5. Thus 120 patients (60 in each group) completed the study. Treatment was clinically successful in 48 (80%) of 60 patients who received ciprofloxacin and in 39 (65%) of 60 patients who received pivmecillinam (p=0·10). Treatment was bacteriologically successful in all of the patients receiving ciprofloxacin, and in 54 (90%) of the patients receiving pivmecillinam (p=0·03). Joint pain after treatment began in 13 (18%) of 71 patients who received ciprofloxacin and 16 (22%) of 72 patients who received pivmecillinam (p>0·2), and no patient had signs of arthritis.

Interpretation

In our trial, ciprofloxacin suspension and pivmecillinam had the same clinical efficacy. Ciprofloxacin had greater bacteriological efficacy and was not associated with the development of arthropathy. We conclude that ciprofloxacin is an effective and safe drug for use in multiply resistant childhood shigellosis.

Introduction

Fluoroquinolones are among the most commonly prescribed antimicrobial agents for adults.1 However, they cause arthropathy in juveniles of most animal species on which they have been tested,2 so they have been used sparingly in children. The quinolone agent nalidixic acid also causes arthropathy in juvenile animals,2 but that drug was approved for paediatric use before this toxic effect was known, and has not been associated with arthropathy in human beings.3, 4 Limited experience of fluoroquinolone use in children has shown that standard doses do not cause arthropathy.5 The fluoroquinolones are not available in liquid form, and their use in children has generally been restricted to those with chronic, potentially lethal disorders such as cystic fibrosis and malignant disorders,6, 7, 8 or with infections for which other antimicrobial treatments have not worked.9, 10

We assessed the efficacy of a suspension formulation of the fluoroquinolone agent ciprofloxacin to treat children with shigellosis. Although the fluoroquinolones are a mainstay of the treatment of enteric infections in adults,11, 12 studies of enteric infections in children have generally been small or poorly controlled.13, 14, 15 There is an increasing awareness of the need for systematic assessment of drugs in children, rather than extrapolation of the findings of studies in adults.16 Infections caused by shigella are a good choice of acute childhood infection on which to assess treatment with a fluoroquinolone,17 because they are potentially life-threatening,18 they are resistant to most available oral antimicrobial agents,19 and because the quinolone agent nalidixic acid was commonly used to treat them3 before shigella developed resistance to this drug.19

The study hypothesis was that ciprofloxacin would be equivalent to pivmecillinam in terms of efficacy and safety.

Section snippets

Patients

Our randomised, double-blind controlled trial enrolled patients from the Dhaka Diarrhoea Treatment Centre at the International Centre for Diarrhoeal Disease Research, Bangladesh, between August, 1995, and March, 1997. We used the same study methods as in our previous studies.3, 11, 20, 21, 22 Eligible patients were children aged 2–15 years who had dysentery, defined as passage of grossly bloody-mucoid stools for 72 h or less, but who had not received any suitable antimicrobial therapy, which we

Results

143 children were enrolled in the study (figure 1). 13 patients (six in the ciprofloxacin group and seven in the pivmecillinam group) were excluded from the analysis of clinical efficacy because they were not eligible: 12 had no shigella isolate, and one had received a dose of nalidixic acid before study entry and was infected with a nalidixic-acid-susceptible strain of shigella. Ten children, five in each group, withdrew from the study before the assessment of clinical outcome on day 5 (two on

Discussion

For children moderately to severely ill with shigellosis, we have shown that ciprofloxacin suspension is clinically as effective, and bacteriologically more effective, than pivmecillinam tablets. Though the clinical success with ciprofloxacin was greater than that with pivmecillinam, the 15% difference was not statistically significant. This study was designed only to demonstrate clinical equivalence; a study with a larger sample size might have shown a significant difference in clinical

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