Talan DA, Stamm WE, Hooton TM, Moran GJ, Burke T, Iravani A, Reuning-Scherer J, Church DA. Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis in women.
Overall Study Question
This study was a prospective, multicentre, randomized, double-blind trial designed to compare the safety, efficacy and relative costs of oral ciprofloxacin for 7 days or oral trimethoprim-sulfamethoxazole for 14 days in women with acute uncomplicated pyelonephritis. Premenopausal women at least 18 years of age with a clinical diagnosis of acute uncomplicated pyelonephritis were enrolled in 25 outpatient centers. Eligible patients had flank pain and/or costovertebral angle tenderness; a temperature higher than 38.0C orally, or higher than 38.6C rectally; and pyuria. The primary study endpoints were continued bacteriologic and clinical cure through the 4-11 day posttherapy visit. Secondary endpoints included bacteriologic and clinical responses through the 22-48 day posttherapy visit. Adverse drug events, and health resource use and cost-per-cure analysis from the perspective of the third-party payer were also completed for all enrolled patients.
Are the Results of the Study Valid?
Was assignment of patients randomized?
Yes. Initial stratification to decide whether an initial dose of antimicrobial would be given intravenously or orally was made by the treating physician. Patients receiving an initial intravenous dose were administered 400 mg (IV) of ciprofloxacin or 1 g (IV) of ceftriaxone. Eligible patients were then randomly assigned to receive ciprofloxacin 500 mg or trimethoprim- sulfamethoxazole 160/800 mg tablets (PO) twice daily for 14 days. Ciprofloxacin-treated patients received placebo (PO) twice daily for the final 7 days.
Were all patients who entered the trial properly accounted for and attributed at its conclusion?
Yes. A total of 378 patients were enrolled and randomized; however, 123 patients were discontinued from the study for reasons including a lack of baseline organisms, inadequate administration of study drug, patient lost to follow-up, inappropriate cultures, inadvertent unblinding, patient being given another antibiotic for unrelated infection and other protocol violations. Thus, 255 patients were considered evaluable for efficacy analysis (128 in the ciprofloxacin group and 127 in the placebo group).
Were patients, their clinicians, and study personnel ‘blind’ to treatment?
Yes. Antimicrobial infusions were identical and oral medications were encapsulated in opaque gelatin capsules for blinding purposes.
Were the groups similar at the start of the trial?
Yes. Evaluable patients in the treatment groups were well matched with respect to demographic characteristics and symptom severity on study entry.
Aside from the experimental intervention, were the groups treated equally?
Overall, are the results of the study valid?
What were the Results?
How large was the treatment effect?
The primary endpoint of bacteriological cure at 4-11 days posttherapy for efficacy-valid patients was achieved in 99% of ciprofloxacin-treated patients compared to 89% for those treated with trimethoprim-sulfamethoxazole, absolute risk reduction (ARR) 10%, number needed to treat (NNT) 10; (95% confidence interval [CI] 0.04-0.16, p=0.004). Clinical cure at 4-11 days posttherapy was achieved in 96% of ciprofloxacin-treated patients compared to 83% for those treated with trimethoprim- sulfamethoxazole, ARR 13%, NNT 8; (95% CI 0.06-0.22, p=0.002). These results did not change when evaluated using intention-to-treat analysis for both bacteriologic and clinical cure. Bacteriological cure at the 22-48 days posttherapy was achieved in 85% of ciprofloxacin-treated patients compared to 74% for those treated with trimethoprim- sulfamethoxazole (95% CI 0.00-0.21, p=0.08). Clinical cure at 22-48 days posttherapy was achieved in 91% of ciprofloxacin-treated patients compared to 77% for those treated with trimethoprim-sulfamethoxazole, ARR 14%, NNT 8; (95% CI 0.03-0.23, p=0.02).
Forty-seven (18.4%) of all uropathogens (44 E. coli, 2. E. aerogenes and 1 P. mirabilis) were resistant to trimethoprim-sulfamethoxazole, while only one strain (P. mirabilis) was resistant to ciprofloxacin (0.4%, p<0.001). Among trimethoprim-sulfamethoxazole treated patients bacteriological and clinical cure was 50% (7 of 14) and 35% (6 of 17), respectively, as compared to 96% (73 of 76) and 92% (76 of 83) success rates for infections involving susceptible strains.
Adverse effects occurred in 33% of trimethoprim-sulfamethoxazole treated patients compared to 24% for those treated with ciprofloxacin resulting in study discontinuation in 11% and 6%, respectively. Gastrointestinal events (16% vs. 9%), headache (10% vs. 5%) and rash (7% vs. 2%) occurred more frequently in the trimethoprim-sulfamethoxazole group.
Health care resources for hospital stay, return medical visits or telephone consultation, laboratory tests including cultures were all higher in the trimethoprim-sulfamethoxazole-treated patients. The mean total cost per patient was $687 (US) for the trimethoprim-sulfamethoxazole group and $531 (US) for the ciprofloxacin group, a difference of $156 (US) (95% CI -$118-$443 (US)). The mean cost per cure was also higher in the trimethoprim-sulfamethoxazole group as compared to ciprofloxacin at $770 (US) and $615 (US), a difference of $155 (95% CI $102-$207 (US)).
How precise was the estimate of the treatment effect?
The 95% CI for the primary endpoint of continued bacteriologic and clinical cure at days 4-11 did not cross zero indicating statistical significance.
Will the Results Help Me in Caring for My Patients?
Can the results be applied to my patient care?
It would appear that the use of ciprofloxacin 500 mg orally twice daily for 7 days achieves improved bacteriologic and clinical cure compared to trimethoprim-sulfamethoxazole 160-800 mg orally twice daily for 14 days for the treatment of uncomplicated pyelonephritis in women. These results should not be extrapolated to patients with complicated pyelonephritis or those with severe sepsis.
Were all clinically important outcomes considered?
Yes. As with any infectious disease-related study, bacteriologic and clinical cure rate and safety assessment are necessary to interpret the impact of each intervention. This was provided. Although not powered to demonstrate a difference between groups, this trial also provided an economic analysis of health resources from the perspective of the third-party payer. This affords clinicians an additional parameter for which to determine the appropriateness of prescribing a more costly agent (i.e. ciprofloxacin) with improved outcomes and the associated reductions in resource consumption that are associated with treatment failures and adverse effects.
Are the likely treatment benefits worth the potential harms and costs?
Yes. The improved efficacy of ciprofloxacin was also associated with a reduction in adverse effects and treatment-associated costs.
The management of uncomplicated pyelonephritis has not been clearly defined in many clinical trials. In addition, attempts have been made to determine the proper duration of therapy and previous studies suggest that an abbreviated course of therapy may be appropriate. This trial was able to demonstrate that a 7-day course of oral ciprofloxacin was more effective than a 14-day course of trimethoprim-sulfamethoxazole with improved patient tolerance and lower utilization of health resources. Much of the improved benefit of ciprofloxacin could be attributed to the presence of trimethoprim-sulfamethoxazole-resistant strains of E-coli. Although the reason for improved outcome with ciprofloxacin appears obvious, the use of an abbreviated oral regimen with fewer adverse effects and a lower cost is an attractive option in women with uncomplicated pyelonephritis.