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1 ORIGINAL CONTRIBUTION Comparison of Ciprofloxacin (7 Days) and Trimethoprim-Sulfamethoxazole (14 Days) for Acute Uncomplicated Pyelonephritis in Women A Randomized Trial David A. Talan, MD Walter E. Stamm, MD Thomas M. Hooton, MD Gregory J. Moran, MD Thomas Burke, MD Abdollah Iravani, MD Jonathan Reuning-Scherer, PhD Deborah A. Church, MD IN THE UNITED STATES AT LEAST episodes of acute pyelonephritis occur annually among adult women, resulting in as many as hospitalizations. 1,2 However, the optimal antimicrobial regimen and duration of therapy for this infection have not been established. In contrast to the paucity of controlled treatment trials in women with pyelonephritis, recent studies of women with uncomplicated lower urinary tract infections have established that these infections can be treated effectively with antimicrobials for less than 7 to 14 days. 3-5 Three-day regimens of trimethoprim-sulfamethoxazole or fluoroquinolones appear to provide adequate cure rates, while being associated with lower cost and fewer adverse effects than longer regimens. The current standard duration of therapy for acute uncomplicated pyelonephritis is 14 days, but few studies of shorter-course therapy for this infection have been undertaken. Increasing antimicrobial re- See also Patient Page. Context The optimal antimicrobial regimen and treatment duration for acute uncomplicated pyelonephritis are unknown. Objective To compare the efficacy and safety of a 7-day ciprofloxacin regimen and a 14-day trimethoprim-sulfamethoxazole regimen for the treatment of acute pyelonephritis in women. Design Randomized, double-blind comparative trial conducted from October 1994 through January Setting Twenty-five outpatient centers in the United States. Patients Of 378 enrolled premenopausal women aged at least 18 years with clinical diagnosis of acute uncomplicated pyelonephritis, 255 were included in the analysis. Other individuals were excluded for no baseline causative organism, inadequate receipt of study drug, loss to follow-up, no appropriate cultures, and other reasons. Interventions Patients were randomized to oral ciprofloxacin, 500 mg twice per day for 7 days (with or without an initial 400-mg intravenous dose) followed by placebo for 7 days (n = 128 included in analysis) vs trimethoprim-sulfamethoxazole, 160/800 mg twice per day for 14 days (with or without intravenous ceftriaxone, 1 g) (n = 127 included in the analysis). Main Outcome Measure Continued bacteriologic and clinical cure, such that alternative antimicrobial drugs were not required, among evaluable patients through the 4- to 11-day posttherapy visit, compared by treatment group. Results At 4 to 11 days posttherapy, bacteriologic cure rates were 99% (112 of 113) for the ciprofloxacin regimen and 89% (90 of 101) for the trimethoprimsulfamethoxazole regimen (95% confidence interval [CI] for difference, ; P =.004). Clinical cure rates were 96% (109 of 113) for the ciprofloxacin regimen and 83% (92 of 111) for the trimethoprim-sulfamethoxazole regimen (95% CI, ; P =.002). Escherichia coli, which caused more than 90% of infections, was more frequently resistant to trimethoprim-sulfamethoxazole (18%) than to ciprofloxacin (0%; P.001). Among trimethoprim-sulfamethoxazole treated patients, drug resistance was associated with greater bacteriologic and clinical failure rates (P.001 for both). Drugrelated adverse events occurred in 24% of 191 ciprofloxacin-treated patients and in 33% of 187 trimethoprim-sulfamethoxazole treated patients, respectively (95% CI, to 0.2). Conclusions In our study of outpatient treatment of acute uncomplicated pyelonephritis in women, a 7-day ciprofloxacin regimen was associated with greater bacteriologic and clinical cure rates than a 14-day trimethoprim-sulfamethoxazole regimen, especially in patients infected with trimethoprim-sulfamethoxazole resistant strains. JAMA. 2000;283: Author Affiliations and Financial Disclosures are listed at the end of this article. Corresponding Author and Reprints: David A. Talan, MD, Olive View-UCLA Medical Center, Olive View Dr, North Annex, Sylmar, CA ( idnet@ucla.edu) American Medical Association. All rights reserved. JAMA, March 22/29, 2000 Vol 283, No

2 sistance and concomitant reduced clinical efficacy of amoxicillin and ampicillin for urinary tract infections have been observed for the last 2 decades, greatly limiting the use of these drugs for treatment of cystitis and pyelonephritis. 4 Recently, increasing in vitro resistance of uropathogens to trimethoprimsulfamethoxazole has been reported in the United States. 6 However, the extent of this resistance and its clinical implications are unclear. Furthermore, the current shift to outpatient management and emphasis on cost-saving strategies make it timely to evaluate critically treatment regimens for acute, uncomplicated pyelonephritis. We conducted a multicenter, randomized,double-blind,outpatienttrialtocompare the efficacy, safety, and relative costs of oral ciprofloxacin, 500 mg twice per day for 7 days, and oral trimethoprimsulfamethoxazole, 160/800 mg twice per day for 14 days (with or without an initial intravenous dose of ciprofloxacin or ceftriaxoneineachgroup) inwomenwith acute uncomplicated pyelonephritis. We hypothesized that the 7-day ciprofloxacin regimen would have equivalent efficacy to the 14-day trimethoprimsulfamethoxazole regimen and in vitro resistanceoftheinfectingpathogenwould be associated with decreased efficacy. METHODS Study Population Premenopausal women aged at least 18 years with a clinical diagnosis of acute uncomplicated pyelonephritis were enrolled at 25 outpatient centers (ie, emergency departments, clinics, and offices) throughout the United States between October 1994 and January The study was approved by each institutional review board. Eligible patients had flank pain and/or costovertebral angle tenderness; a temperature higher than 38.0 C, orally, or higher than 38.6 C, rectally; and pyuria ( 8 leukocytes per microliter by hemocytometer or 5 leukocytes per high-power field by the sediment examination method). Exclusion criteria were: severe sepsis; immunocompromised condition; diabetes; urologic abnormality; serum creatinine level of more than 229 µmol/l (2.6 mg/dl) or creatinine clearance level of less than 30 ml/min (0.50 ml/s); persistent vomiting; hospital admission; fluoroquinolone, sulfaonamide, penicillin, or cephalosporin allergy; pregnancy or lactation; a systemic antimicrobial within the previous 72 hours; investigational drug administration within 30 days; and previous enrollment in this study. Study Procedures Subjects had a medical history and physical examination performed, including a pelvic examination. Those who met entry criteria and provided written informed consent had pretherapy blood cultures (2 sets) and urine specimens (collected by midstream clean catch or bladder catheterization) obtained for culture and susceptibility testing. Initial stratification to decide whether the initial dose of antimicrobial would be given intravenously or orally was made by the treating physician. Subjects were then randomly assigned to receive 500-mg tablets of ciprofloxacin (Cipro, Bayer Corporation Pharmaceutical Division, West Haven, Conn) or 160/800-mg tablets of trimethoprimsulfamethoxazole (Bactrim, Roche Laboratories, Nutley, NJ). Subjects receiving an initial intravenous dose were administered 400 mg of ciprofloxacin (ciprofloxacin group) or 1 g of ceftriaxone (trimethoprim-sulfamethoxazole group, Rocephin, Roche Laboratories) over 60 minutes. Antimicrobial infusions were identical and oral medications were encapsulated in opaque gelatin capsules (#000) for blinding purposes. Patients who were unable to tolerate oral medications after up to 12 hours of observation were discontinued from the study. All patients received 1 capsule twice per day for 14 days; ciprofloxacin-treated subjects received placebo twice per day for the last 7 days. Compliance was evaluated by conducting pill counts from blister packets at each follow-up evaluation. Microbiological Methods All patients had a quantitative urine culture collected before the start of therapy, at days 3 to 5 during therapy, and at days 4 to 11 and 22 to 48 posttherapy (ie, following the end of the initial 14-day regimen for each treatment group). Organisms present in a concentration of 10 3 colony-forming units/ml or more were identified using standard microbiological techniques. Antimicrobial susceptibility testing was performed according to National Committee for Clinical Laboratory Standards laboratory procedures using the modified Kirby-Bauer procedure or by microdilution. 7,8 Pretherapy blood cultures, if positive, were repeated within 72 hours. Main Outcome Measures Primary study outcomes were study drug efficacy based on continued bacteriologic and clinical cure (such that no alternative antimicrobial therapy for urinary tract infection was prescribed) through the 4- to 11-day posttherapy visit among all enrolled patients who were evaluable for efficacy analyses (efficacyvalid group). Criteria for efficacy evaluation were: (1) enrollment criteria for acute uncomplicated pyelonephritis, (2) pretherapy growth of uropathogens of 10 4 colony-forming units/ml or more (midstream clean catch) or of 10 3 colonyforming units/ml or more (catheterization); (3) study drug received 5 full days or more (unless clinical or bacteriologic failure occurred requiring another antimicrobial); (4) no other systemic antimicrobial use; and (5) 1 or more posttherapy follow-up visits including repeat urine culture and measurement of pyuria. Patients remained in the study whether the pretherapy blood or urine isolate was subsequently found to be resistant to either or both study drugs. Continued bacteriologic cure was defined as pathogen growth of less than 10 4 (clean catch) or less than 10 3 (catheterized) colony-forming units/ml through the posttherapy follow-up visits. Bacteriologic failure through the 4- to 11- day posttherapy visit was classified as superinfection with a new uropathogen or persistence of the original uropathogen (based on standard microbiological identification techniques). Continued clinical cure was defined as absence 1584 JAMA, March 22/29, 2000 Vol 283, No American Medical Association. All rights reserved.

3 of all signs and symptoms of illness through the posttherapy follow-up visits. Clinical failure was defined as deterioration, persistence of signs and symptoms of the initial infection after 3 days of antimicrobial treatment, or recurrence of signs and symptoms after initial cure or improvement. According to the study protocol, patients with bacteriologic or clinical failure discontinued taking the study antimicrobial and were prescribed alternative antimicrobial therapy. Secondary study outcomes included bacteriologic and clinical responses through the 22- to 48-day posttherapy visit for the efficacy-valid group. For all patients receiving at least 1 dose of study drug, intent-to-treat analyses were done. Adverse drug events, evaluated by questioning patients at each follow-up visit, were calculated for all enrolled patients. Continued bacteriologic and clinical cure rates were calculated for all enrolled patients who had a pretherapy and at least 1 posttherapy evaluation, using the last posttherapy visit. Health resource use and cost-per-cure analyses were done for all enrolled patients with cure determined by clinical status at the last visit, regardless of whether the patient received alternative antimicrobial therapy. Patients without follow-up or with inconclusive follow-up were classified as having clinical failure. Patients were withdrawn from the study if they were either classified as a clinical or bacteriologic failure, or if they experienced a serious adverse drug event. At this time, patients were also evaluated for bacteriologic and/or clinical outcome. Unblinding of study drug assignment was discouraged, occurred after study withdrawal, and excluded subjects from the efficacy-valid group. An attempt was made to follow patients (including those who discontinued taking the study drug) through the 22- to 48-day posttherapy visit. Health Resource Use and Cost Analyses All health care resources used were prospectively collected. Additional resources were defined as those associated with clinical or bacteriologic failure, or adverse drug events. The perspective of the cost analysis was that of the third-party payer. Direct medical costs were assigned retrospectively and were reported in 1997 dollars. 9,10 Total costs were calculated based on the sum of the costs associated with the following: the initial visit, including site of care (ie, office or emergency department), antimicrobial, urinalysis, and urine culture; a single follow-up visit (if there was at least 1 follow-up visit) with urinalysis and urine culture; and additional resources used associated with failures and adverse drug events including subsequent nonstudy-required medical visits, laboratory and radiology tests, hospitalizations, therapeutic adjuncts, and other antimicrobials, through the patient s last visit. Costs of hospitalizations, office visits, laboratory tests, and other procedures were estimated by multiplying relative value units by an estimate of the average cost per relative value unit (TABLE 1) Cost per cure was calculated based on the total costs for all patients divided by the number of cured patients in each treatment group. Statistical Methods It was originally estimated that 180 efficacy-valid patients needed to be enrolled to have an 80% power to demonstrate equivalence in cure rates at 5- to 9-day and 25- to 45-day posttherapy visits using a 1-sided 95% confidence interval (CI) around the difference in bacteriologic and clinical responses for the efficacy-valid group. During the study, new US Food and Drug Administration guidelines were issued recommending 2-sided 95% CIs. 16 Thus, for the primary efficacy variables, 2-sided 95% CIs weighted by stratum using a Cochran- Mantel-Haenszel procedure were constructed around the difference in success rates. The 2 treatments were considered equivalent at the 5% significance level if the lower bound of the 95% CI around the difference in success rates was 10% or more. Based on these changes, the estimated sample size was increased (ie, 250 efficacy-valid patients) and enrollment was extended, but the number of efficacy-valid patients was lower Table 1. Examples of Cost Assumptions Used in Health Economics Analysis Variable Cost, $ Study drugs Oral ciprofloxacin, 500 mg Intravenous ciprofloxacin, 400 mg Oral trimethoprimsulfamethoxazole, /800 mg 9 Intravenous ceftriaxone, 1 g Medical care service Outpatient clinic or office visit 12, Emergency department visit 12, Hospitalization (per day) 10, Medical test Urinalysis 14, Urine culture 14, Diagnostic and imaging test Ultrasound (renal) 12, Excretory urogram 12, than anticipated, in part because of variable times of patient follow-up. Consequently, prior to data analysis and unblinding, follow-up evaluation intervals were extended to 4 to 11 days and 22 to 48 days, resulting in 27 (15 ciprofloxacin, 12 trimethoprim-sulfamethoxazole) and 12 (7 ciprofloxacin, 5 trimethoprim-sulfamethoxazole) additional efficacy-valid patients, respectively. Baseline medical variables were analyzed using contingency table analysis, adjusting for a possible stratum effect. For continuous variables, a 2-way analysis of variance model was fitted with stratum and treatment as factors to compare the 2 treatment groups. The 95% CIs around the differences in rates for secondary variables were constructed using a normal approximation of the binomial distribution with continuity correction. RESULTS Study Population A total of 378 patients were enrolled and followed up for a median of 45 days after study entry (range, 0-98 days). Numbers of patients assigned to treatment groups, who were evaluable for study drug efficacy and assessed at follow-up visits, and reasons for nonevaluability are summarized in FIGURE 1. Evaluable subjects in the 2 treatment groups were well matched with respect to demographic characteristics and symptom severity on study entry (TABLE 2). No evaluable patient missed more than 2 doses of her prescription American Medical Association. All rights reserved. JAMA, March 22/29, 2000 Vol 283, No

4 Figure 1. Patient Assignment and Follow-up Assessments 191 Assigned to Ciprofloxacin Group 66 Patients Received Initial Dose Intravenously 125 Patients Received Initial Dose Orally 63 Discontinued Study 17 Did Not Have Baseline Causative Organism 16 Inadequately Received Study Drug 13 Were Lost to Follow-up 8 Did Not Have Appropriate Cultures 7 Had Other Protocol Violations 2 Had Blind Broken Bacteriologic Outcome, 4-11 Days After Therapy 113 Were Evaluable 15 Did Not Have a Bacteriologic Bacteriologic Outcome, Days After Therapy 111 Were Evaluable 17 Did Not Have a Bacteriologic 378 Patients Enrolled and Randomized Clinical Outcome, 4-11 Days After Therapy 113 Were Evaluable 15 Did Not Have a Clinical Clinical Outcome, Days After Therapy 106 Were Evaluable 22 Did Not Have a Clinical 187 Assigned to Trimethoprim-Sulfamethoxazole Group 61 Patients Received Initial Dose Intravenously 126 Patients Received Initial Dose Orally 60 Discontinued Study 23 Did Not Have Baseline Causative Organism 13 Inadequately Received Study Drug 6 Were Lost to Follow-up 7 Did Not Have Appropriate Cultures 7 Had Other Protocol Violations 2 Had Blind Broken 2 Were Given Another Antibiotic for Another Infection 128 Were Evaluable for Efficacy Analyses 127 Were Evaluable for Efficacy Analyses Bacteriologic Outcome, 4-11 Days After Therapy 101 Were Evaluable 26 Did Not Have a Bacteriologic Bacteriologic Outcome, Days After Therapy 108 Were Evaluable 19 Did Not Have a Bacteriologic Clinical Outcome, 4-11 Days After Therapy 111 Were Evaluable 16 Did Not Have a Clinical Clinical Outcome, Days After Therapy 106 Were Evaluable 21 Did Not Have a Clinical The ciprofloxacin group was given oral ciprofloxacin, 500 mg twice per day for 7 days (with or without initial 400-mg intravenous dose) followed by placebo for 7 days. The trimethoprim-sulfamethoxazole group was given oral trimethoprim-sulfamethoxazole, 160/800 mg twice per day for 14 days (with or without initial intravenous ceftriaxone, 1 g). Table 2. Demographic and Clinical Characteristics of Women in the Efficacy-Valid Group* Variable Ciprofloxacin Group (n = 128) Trimethoprim-Sulfamethoxazole Group (n = 127) Age, median (range), y 25 (18-53) 23 (18-58) White 74 (58) 61 (48) Excellent or good health status 126 (99) 124 (98) Pyelonephritis in last year 13 (10) 12 (10) Duration of illness, median (range), d 3 (1-28) 3 (1-30) Severe flank pain 45 (35) 48 (38) Vomiting 38 (30) 38 (30) Temperature 39.0 C 30 (23) 30 (24) Bacteremia 4 (3) 10 (8) *Values are expressed as number (percentage) unless otherwise indicated. Given oral ciprofloxacin, 500 mg twice per day for 7 days (with or without an initial 400-mg intravenous dose). Given trimethoprim-sulfamethoxazole, 160/800 mg twice per day for 14 days (with or without intravenous ceftriaxone, 1 g). Defined as intense and debilitating. of Bacteriologic and Clinical Outcomes Causative Uropathogens and Their Antimicrobial Resistance. For the efficacyvalid group, 117 (91%) ciprofloxacin and 119 (94%) trimethoprim-sulfamethoxazole treated subjects had Escherichia coli isolated from their baseline urine specimens. Other less-frequently isolated uropathogens included: Enterobacter aerogenes (5 ciprofloxacin, 4 trimethoprimsulfamethoxazole); Staphylococcus saprophyticus (2 ciprofloxacin, 3 trimethoprim-sulfamethoxazole); Klebsiella pneumoniae (1 ciprofloxacin, 2 trimethoprim-sulfamethoxazole); Citrobacter (1 ciprofloxacin, 1 trimethoprim-sulfamethoxazole); Proteus mirabilis (2 ciprofloxacin, 1 trimethoprim-sulfamethoxazole); and Enterobacter agglomerans (1 ciprofloxacin). Four patients had 2 uropathogens isolated. Forty-seven (18.4%) of all uropathogens (44 E coli,2e aerogenes, and 1 P mirabilis) were resistant to trimethoprim-sulfamethoxazole, while 1 strain (P mirabilis) was resistant to ciprofloxacin (0.4%; P.001). Among all E coli strains, trimethoprim-sulfamethoxazole resistance was 7% at Eastern US centers, 14% in the Midwest, and 32% in Western states (range [per center], 0%-46%). Ceftriaxone resistance was reported for 1 E coli isolate. Fourteen subjects (5.5%) had bacteremia pretherapy, all with E coli. All E coli blood isolates were susceptible to ciprofloxacin, whereas 4 (29%) were resistant to trimethoprim-sulfamethoxazole. Bacteriologic Outcome. For the efficacy-valid group, 112 (99%) of 113 subjects given oral ciprofloxacin for 7 days with or without an initial intravenous dose of ciprofloxacin and 90 (89%) of 101 subjects given oral trimethoprimsulfamethoxazole for 14 days with or without an initial intravenous dose of ceftriaxone had continued bacteriologic cure through the 4- to 11-day posttherapy visit (95% CI, for the difference; P =.004; FIGURE 2). In this interval, all failures were due to persistence except for 2 trimethoprim-sulfamethoxazole treated subjects who had superinfection caused by Staphylococcus aureus and Citrobacter freundii, re JAMA, March 22/29, 2000 Vol 283, No American Medical Association. All rights reserved.

5 spectively. Continued bacteriologic cure rates through the 22- to 48-day posttherapy visit were 94 (85%) of 111 ciprofloxacin-treated patients and 80 (74%) of 108 trimethoprim-sulfamethoxazole treated patients (95% CI, ; P =.08; Figure 2). Among women receiving ciprofloxacin, bacteriologic cure rates were similar regardless of whether the initial dose was given intravenously (TABLE 3). Among women receiving trimethoprimsulfamethoxazole, an initial intravenous dose of ceftriaxone was associated with a greater bacterial cure rate at days 4 to 11, but not at 22 to 48 days posttherapy, compared with that seen for women receiving only oral trimethoprim-sulfamethoxazole (Table 3). Intentto-treat analysis of continued bacteriologic cure for the ciprofloxacin group was 84% (128 of 153 patients) compared with 74% (112 of 152 patients) for the trimethoprim-sulfamethoxazole regimen (95% CI, ). Of the 14 patients with E coli bacteremia, 2 (20%) of 10 trimethoprim-sulfamethoxazole treated subjects had urinary bacterologic persistence. All 4 ciprofloxacin-treated subjects achieved bacterologic cure. Clinical Outcome. For the efficacyvalid group, 109 (96%) of the 113 subjects given oral ciprofloxacin for 7 days with or without an initial intravenous dose of ciprofloxacin and 92 (83%) of 111 subjects given oral trimethoprimsulfamethoxazole for 14 days with or without an initial intravenous dose of ceftriaxone had continued clinical cure through the 4- to 11-day posttherapy visit (95% CI, ; P =.002; Figure 2). Of the clinical failures, 1 (25%) of the ciprofloxacin-treated patients and 8 (42%) of the trimethoprim-sulfamethoxazole treated patients failed within the first 4 days of treatment. Continued clinical cure rates through the 22- to 48-day posttherapy visit were 96 (91%) of 106 ciprofloxacin-treated patients and 82 (77%) of 106 trimethoprimsulfamethoxazole treated patients (95% CI, ; P =.02; Figure 2). For both treatment groups, clinical cure rates were similar regardless of whether an initial dose of antimicrobial was given intravenously (Table 3). Intent-to-treat analysis of continued clinical cure rates for the ciprofloxacin group were 82% (137 of 167 patients) compared with 72% (124 of 172 patients) for the trimethoprim-sulfamethoxazole group (95% CI, ). Of the 14 subjects with E coli bacteremia, 1 of 10 trimethoprimsulfamethoxazole treated subjects was considered a clinical failure; the remaining subjects were clinical cures. Effect of Trimethoprim-Sulfamethoxazole Resistance on Bacteriologic and Clinical Outcomes. Continued bacteriologic cure rates through the 4- to 11-day posttherapy visit among trimethoprim-sulfamethoxazole treated subjects were significantly higher among those infected with trimethoprimsulfamethoxazole susceptible as opposed to resistant E coli, 96% (73 of 76) vs 50% (7 of 14), respectively (95% CI, ; P.001). Corresponding continued clinical cure rates through the 4- to 11-day posttherapy visit among trimethoprim-sulfamethoxazole treated subjects infected with trimethoprimsulfamethoxazole susceptible vs resistant E coli were also significantly differ- Figure 2. Continued Bacteriologic and Clinical Cure Rates Through the 4- to 11-Day and 22- to 48-Day Posttherapy Visits for Women with Acute Uncomplicated Pyelonephritis Patients, % Bacterial Eradication P =.004 n = 113 n = Days After Therapy Ciprofloxacin P =.08 n = 111 n = Days After Therapy Trimethoprim-Sulfamethoxazole P =.002 n = 113 n = Days After Therapy Clinical Cure P =.02 n = 106 n = Days After Therapy The ciprofloxacin group was given an oral dose of ciprofloxacin, 500 mg twice per day for 7 days (with or without initial 400-mg intravenous dose) followed by placebo for 7 days. The trimethoprim-sulfamethoxazole group was given oral trimethoprim-sulfamethoxazole, 160/800 mg twice per day for 14 days (with or without initial intravenous ceftriaxone, 1 g). Table 3. Continued Bacteriologic and Clinical Cure Rates Stratified by Oral or Intravenous Administration of the First Dose of Antimicrobial* Response Bacteriologic cure through 4-11 days after therapy Bacteriologic cure through days after therapy Clinical cure through 4-11 days after therapy Clinical cure through days after therapy Ciprofloxacin Group Trimethoprim- Sulfamethoxazole Group Oral Intravenous Oral Intravenous 75 (100) 37 (97) 61 (85) 29 (100) 60 (83) 34 (87) 54 (72) 26 (63) 72 (96) 37 (98) 66 (85) 26 (79) 63 (89) 33 (94) 58 (78) 24 (75) *Includes patients with eradication of the initially infecting strain and absence of recurrent infection, or continued clinical cure, not requiring alternative antimicrobial therapy through the visits after therapy. Values are expressed as number (percentage). Given oral ciprofloxacin, 500 mg twice per day for 7 days (with or without an initial 400-mg intravenous dose). Given trimethoprim-sulfamethoxazole, 160/800 mg twice per day for 14 days (with or without intravenous ceftriaxone, 1 g) American Medical Association. All rights reserved. JAMA, March 22/29, 2000 Vol 283, No

6 ent: 92% (76 of 83) and 35% (6 of 17), respectively(95%ci, ;p.001). Oftrimethoprim-sulfamethoxazole treated women with resistant strains, 6 of 7 who had bacteriologic failure also had clinical failure. Among ciprofloxacintreated women who were infected with trimethoprim-sulfamethoxazole resistantstrains, bacteriologicandclinicalcure ratesthroughthe4- to11-dayposttherapy visit were 100% (18 of 18) and 95% (18 of 19), respectively. Among women infected with trimethoprim-sulfamethoxazole resistant E coli, continued bacteriologic cure through the 4- to 11-day posttherapy visit occurred more frequently among those receiving an initial intravenous dose of ceftriaxone than those only treated with oral trimethoprim-sulfamethoxazole (5 of 5 Table 4. Rates of Adverse Drug Events Among Women* patients vs 2 of 9 patients, respectively). However, continued clinical cure rates were similar (4 of 7 patients vs 2 of 10 patients, respectively). The 1 patient with a ciprofloxacin-resistant P mirabilis strain was treated with ciprofloxacin and achieved bacteriologic and clinical cure. of Safety, Health Resource Use, and Costs Safety, healthresourceuse, andcostswere evaluatedforall378enrolledpatients. Adversedrugeventsoccurredin24%of191 ciprofloxacin-treated patients and in 33% of 187 trimethoprim-sulfamethoxazole treated patients, respectively (95% CI, to 0.2) (TABLE 4). Gastrointestinal events, headache, and rash tended to occur more frequently in the trimethoprim-sulfamethoxazole group. Adverse Body System Ciprofloxacin Group (n = 191) Trimethoprim-Sulfamethoxazole Group (n = 187) Any event 46 (24) 62 (33) Events causing study antimicrobial discontinuation 11 (6) 21 (11) Any digestive 17 (9) 29 (16) Nausea 10 (5) 14 (7) Vomiting 8 (4) 10 (5) Diarrhea 6 (3) 6 (3) Any central nervous system 12 (6) 25 (13) Headache 9 (5) 19 (10) Dizziness 3 (2) 6 (3) Rash 4 (2) 14 (7) *Values are expressed as number (percentage). Given oral ciprofloxacin, 500 mg twice per day for 7 days (with or without an initial 400-mg intravenous dose). Given trimethoprim-sulfamethoxazole, 160/800 mg twice per day for 14 days (with or without intravenous ceftriaxone, 1 g). Table 5. Additional Medical Resource Use for Women by Treatment Group* Resource Ciprofloxacin Group (n = 191) Trimethroprim-Sulfamethoxazole Group (n = 187) Hospital stay, d Medical visits/telephone consultations Radiological procedures Other therapeutic procedures Laboratory tests Cultures Antimicrobial prescriptions *Values are rates per 100 intent-to-treat subjects for additional resources associated with failures and adverse drug events (ie, excluding resources required for initial management and follow-up visits after therapy for patients without earlier treatment failure). Given oral ciprofloxacin, 500 mg twice per day for 7 days (with or without an initial 400-mg intravenous dose). Given trimethoprim-sulfamethoxazole, 160/800 mg twice per day for 14 days (with or without intravenous ceftriaxone, 1 g). Such as intravenous fluids, bladder catheterization, or cystoscopy. Such as urinalysis, complete blood cell count, or serum chemistry. Includes all topical and systemic antimicrobials (including antibacterial and antifungal agents). events causing study drug discontinuationoccurredin11(6%)oftheciprofloxacin-treated patients and 21 (11%) trimethoprim-sulfamethoxazole treated patients. Additional health resource use (ie, excluding resources required for initial management, and posttherapy follow-up visits for patients without earlier treatment failure) was higher in all categories for patients treated with trimethoprim-sulfamethoxazole than ciprofloxacin, with the exception of radiological procedures (TABLE 5). Since more trimethoprim-sulfamethoxazole treated patients had clinical failures and accrued high costs, the mean total cost per patient was greater for trimethoprimsulfamethoxazole treated patients ($687) than for ciprofloxacin-treated patients ($531) by 29% or $156 (95% CI, $118 to $443). By the last follow-up visit, clinical cure occurred in 86.4% and 89.3% of ciprofloxacin and trimethoprim-sulfamethoxazole treated patients, respectively (95% CI, to 0.037). Seventeen ciprofloxacin and 10 trimethoprim-sulfamethoxazole treated patients had inconclusive follow-up and were classified as failures. Since trimethoprim-sulfamethoxazole treated patients ultimately required more interventions and new antimicrobial prescriptions to achieve cure, the mean cost per cure was higher for trimethoprimsulfamethoxazole ($770) than ciprofloxacin-treated patients ($615) by 25% or $155 (range of difference based on upper and lower bounds of the 95% CI in cure rates, $102-$207). COMMENT Although acute uncomplicated pyelonephritis is a relatively common and potentially serious infection in young women, few controlled treatment trials have been conducted to define optimal therapy. 17 Previous studies suggest that ampicillin should no longer be used since at least 30% of causative E coli strains are ampicillin-resistant. 4,18,19 In addition, these and other studies demonstrate that treatment of acute uncomplicated pyelonephritis in the outpatient setting is safe and effective in appropriately se JAMA, March 22/29, 2000 Vol 283, No American Medical Association. All rights reserved.

7 lected women Unfortunately, most previous trials have not assessed patients with causative organisms resistant to the study antimicrobials, thus precluding evaluation of the effects of in vitro resistance on clinical outcome. In general, existing studies of treatment duration in acute uncomplicated pyelonephritis have been uncontrolled, small, and underpowered, or have included patients with complicated infections. 17,23-26 In 1 randomized trial comparing 2 vs 6 weeks of oral therapy with trimethoprim-sulfamethoxazole or ampicillin for women with acute uncomplicated pyelonephritis, 2-week therapy was as effective as 6-week therapy with either drug and resulted in fewer adverse effects, less frequent selection of resistant strains, and lower costs. 19 Whether a duration of therapy even less than 14 days is effective is unclear. In a small trial of hospitalized men and women with complicated and uncomplicated pyelonephritis, who were given parenteral netilmicin or ciprofloxacin, Bailey et al 23 demonstrated that 5 days of treatment resulted in short-term bacteriologic cure rates of approximately 90%. However, late recurrence was observed in some patients. 23 A trial among menand women with acute complicated and uncomplicated pyelonephritis, conducted by Jernelius et al, 24 demonstrated that a 7-day oral regimen of pivampicillin-pivmecillinam resulted in significantly fewer bacteriologic cures compared with a 14-day regimen (9 [28%] of 32 patients vs 20 [69%] of 29 patients, respectively). In contrast, our data demonstrate bacteriologic and clinical cure rates exceeding 90% with a 7-day course of ciprofloxacin for women with acute uncomplicated pyelonephritis. The difference in bacteriologic outcomes in these studies may be due to multiple factors, including differences in the drugs used and patient inclusion criteria. 24 Our data demonstrate an unexpectedly high prevalence of in vitro resistance to trimethoprim-sulfamethoxazole among E coli strains causing acute uncomplicated pyelonephritis. In 1994, prior to beginning the study, resistance rates to trimethoprim-sulfamethoxazole among uropathogens associated with acute uncomplicated pyelonephritis were generally less than 10% at investigative sites. However, increasing rates of trimethoprim-sulfamethoxazole resistance have been reported among urinary E coli isolates. 6,27-30 Significantly, in vitro resistance to trimethoprim-sulfamethoxazole was strongly associated with bacteriologic and clinical failure in our patients. In vitro resistance, which is correlated with achievable serum antimicrobial levels, would not necessarily be expected to predict clinical outcome in urinary tract infections since urine antimicrobial levels are many times greater than serum levels for most antimicrobial agents. Indeed, for cystitis, bacteriologic eradicationcanfrequentlybeachieveddespite in vitro resistance of the uropathogen to the treatment antimicrobial. 5 Pyelonephritis appears to be a deep tissue infection for which adequate serum antimicrobial levels are important. We also observed that trimethoprimsulfamethoxazole resistance was not uniform among E coli causing acute uncomplicated pyelonephritis in the United States, with much higher rates seen in the Western states. These data suggest that trimethoprim-sulfamethoxazole may no longer be appropriate as an empiric therapy in certain geographic areas. In these areas, initial empiric outpatient therapy with a fluoroquinolone should be strongly considered. Patients treated with trimethoprim-sulfamethoxazole should be followed up carefully until susceptibility results are available. A frequent practice in emergency departments is to administer the first antimicrobial dose intravenously to sicker patients with pyelonephritis, particularly those with nausea and vomiting. 22 To mimic clinical practice and include patients with greater illness severity in the current trial, physicians were allowed to give the first dose of ciprofloxacin intravenously prior to an oral ciprofloxacin regimen, or ceftriaxone prior to an oral trimethoprim-sulfamethoxazole regimen. Ceftriaxone was chosen as most representative of emergency department practice at that time based on an informal survey. Administration of the first antimicrobial dose intravenously did not generally appear to enhance cure rates compared with those observed in patients receiving only oral regimens. However, patients were not randomized to these treatment strategies and, therefore, no conclusions can be made as to their relative therapeutic benefit. We also evaluated the use of health care resources by women presumptively treated for acute pyelonephritis with the 2 antimicrobial regimens. This trial was not powered to show statistical significance in the economic differences between treatment groups for health care resource use. However, resource use did appear to be higher in all categories among trimethoprimsulfamethoxazole treated patients, with the exception of radiological procedures. Although the prescription cost of the ciprofloxacin regimen was greater than that of the trimethoprim-sulfamethoxazole regimen, patients treated with the trimethoprim-sulfamethoxazole regimen tended to have greater overall costs, particularly those related to subsequent hospitalizations, office visits, and laboratory tests. It should be noted that, because these results were derived from a clinical trial, they may not accurately reflect actual or optimal practice. For example, whereas some physicians may routinely change antimicrobial drug therapy for an improved patient whose urine isolate is subsequently found to demonstrate in vitro resistance to their treatment drug, this was not mandated in our protocol. Also, since the cost analysis was conducted from the perspective of the third-party payer, our results did not capture indirect or intangible costs (eg, missed work or school, diminished health-related quality of life). The current investigation was designed to address many of the limitations of previous studies and to conform to the Infectious Diseases Society of America s recommendations for conducting clinical trials by limiting the study population to a homogeneous group of young women with acute uncomplicated pyelonephritis; by employing a randomized blinded design; by treating all women, including those later found to have resistant strains with the assigned regimen; by fol American Medical Association. All rights reserved. JAMA, March 22/29, 2000 Vol 283, No

8 lowing patients for approximately 4 to 6 weeks; and by enrolling an adequate sample size to ensure statistical power. 31 However, this trial does have methodological limitations as well. We intended the clinical response to be judged independently of bacteriologic outcome by the treating physician, but the physicians did have access to culture and susceptibility results. Therefore, assessment of the clinical outcome, and subsequent management, could have been influenced by this knowledge. In conclusion, for the outcomes of bacteriologic and clinical cure, we have demonstrated that the 7-day ciprofloxacin regimen is at least as efficacious as the 14-day trimethoprim-sulfamethoxazole regimen, and statistically, the ciprofloxacin regimen was superior. In practice, the shorter duration ciprofloxacin regimen, which was associated with fewer adverse effects, would be expected to lead to higher patient acceptance and medication compliance rates. The higher cost of the ciprofloxacin prescription would have to be weighed against the potential additional costs related to more treatment failures with trimethoprim-sulfamethoxazole, especially in geographic areas with high rates of E coli resistance to trimethoprimsulfamethoxazole. These findings should not be extrapolated to men, patients with complicated infections, or those with severe sepsis. Patients with acute uncomplicated pyelonephritis should have urine cultures obtained to both confirm the diagnosis and assess the antimicrobial susceptibility of the infecting uropathogen, so as to better predict bacteriologic and clinical outcome. Continued local and national surveillance of uropathogen antimicrobial-resistance patterns is essential to provide optimal care for women with acute uncomplicated pyelonephritis in an era of increasing antimicrobial resistance. Author Affiliations: Divisions of Emergency Medicine and Infectious Diseases, Department of Medicine, Olive View-UCLA Medical Center, University of California, Los Angeles (Drs Talan and Moran); Division of Infectious Diseases, Department of Medicine (Drs Stamm, Hooton, and Burke), Harborview Medical Center, University of Washington, Seattle (Drs Stamm and Hooton); Providence St Peter s Hospital, Olympia, Wash (Dr Burke); Central Florida Medical Research Center, Orlando (Dr Iravani); and Bayer Corporation Pharmaceutical Division, West Haven, Conn (Drs Reuning-Scherer and Church). Investigators: J. Plouffe, Ohio State University Hospital, Columbus; J. Johnson, University of Minnesota, Minneapolis; C. Cox, University of Tennessee, Memphis; S. Traub, Mercy Hospital, Springfield, Mass; G. Richard, University of Florida, Gainesville; R. Bessette, Fallon Clinic, Worcester, Mass; J. Dalovisio, Ochsner Clinic, New Orleans, La; R. Cooper, Madigan Army Medical Center, Tacoma, Wash; L. Payne, United States Air Force Medical Center, Lackland AFB, Texas; I. Klimberg, The Urology Center of Florida, Ocala; G. Wells, Alabama Urology Associations, Birmingham; R. Feldman, Urology Specialists, Waterbury, Conn; N. Ruiz, Henry M. Jackson Foundation, National Naval Medical Center, Bethesda, Md; F. Wenger, Jr, Albert Einstein Medical Center, Philadelphia, Pa; P. Vinson, Norwood Clinical Research Center, Birmingham, Ala; C. Terregino, Cooper Hospital, University Medical Center, Camden, NJ; M. Cancio, St Joseph s Comprehensive Research Institute, Tampa, Fla; R. Shesser, George Washington Clinic, Washington, DC; M. Sperling, Edinger Medical Group, Fountain Valley, Calif; L. A. Walker III, Vanderbilt University Medical Center, Nashville, Tenn; F. Harchelroad, Allegheny General Hospital, Pittsburgh, Pa; J. Linden, Boston City Hospital, Boston, Mass. Financial Disclosures: Drs Talan and Moran have received research support and lecture honoraria from Bayer Inc and lecture honoraria from Roche Laboratories. Drs Talan and Moran also have received research support from Pfizer Inc, Ortho-McNeil Pharmaceutical, and Eli Lilly Co, and have been paid speakers for Pfizer Inc and Ortho-McNeil Pharmaceutical. Dr Stamm has received honoraria and research support from Bayer Inc, Ortho-McNeil Pharmaceutical, and Proctor & Gamble. Dr Reuning-Scherer was an employee of Bayer Inc and is a statistical consultant for Bayer Inc. Dr Hooton has received research support and lecture honoraria from Bayer Inc. Dr Burke has received research support from Bayer Inc and Merck & Co Inc. Funding/Support: This work was supported by a research grant from Bayer Corporation, Pharmaceutical Division, West Haven, Conn. Previous Presentation: Presented in part at the Eighth International Congress on Infectious Diseases, Boston, Mass, May 15-18, 1998, and the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, Calif, September 24-27, Acknowledgment: We are indebted to Adrienne L. Block, PhD; Teresa Tartaglione, PharmD; Roberta Amore, RN; and Blair Robertson, PhD, for editorial and scientific contributions. REFERENCES 1. Stamm WE, Hooton TM, Johnson JR, et al. Urinary tract infections. J Infect Dis. 1989;15: McCarthy E. Inpatient Utilization of Short-Stay Hospitals, by Diagnosis: United States Hyattsville, Md: National Center for Health Statistics; DHHS publication Norrby SR. Short-term treatment of uncomplicated lower urinary tract infections in women. Rev Infect Dis. 1990;12: Stamm WE, Hooton TM. Management of urinary tract infections in adults. N Engl J Med. 1993;329: Hooton TM, Winter C, Tiu F, Stamm WE. 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