Short-Course Nitrofurantoin for the Treatment of Acute Uncomplicated Cystitis in Women

ORIGINAL INVESTIGATION Short-Course Nitrofurantoin for the Treatment of Acute Uncomplicated Cystitis in Women

Kalpana Gupta, MD, MPH; Thomas M. Hooton, MD; Pacita L. Roberts, MS; Walter E. Stamm, MD

Background: There is a paucity of data on the efficacy methoprim-sulfamethoxazole group and in 84% of the of nitrofurantoin for the treatment of acute uncompli- nitrofurantoin group, for a difference of −5% (95% con- cated cystitis in regimens shorter than 7 days. Evidence- fidence interval, −13% to 4%). Clinical and microbio- based use of this drug is increasingly important as tri- logical cure rates at the first follow-up visit were also methoprim-sulfamethoxazole resistance among equivalent between the 2 groups. In the trimethoprim- uropathogens increases. sulfamethoxazole arm, 7 of 17 women (41%) with a trimethoprim-sulfamethoxazole–nonsusceptible isolate had Methods: To assess the efficacy of nitrofurantoin vs tri- a clinical cure compared with 84% of women with a trimethoprim-sulfamethoxazole, 338 women aged 18 to 45 methoprim-sulfamethoxazole–susceptible isolate years with acute uncomplicated cystitis were random- (PϽ.001). ized to open-label treatment with either trimethoprim- sulfamethoxazole, 1 double-strength tablet twice daily for Conclusion: A 5-day course of nitrofurantoin is equiva- 3 days, or nitrofurantoin, 100 mg twice daily for 5 days. lent clinically and microbiologically to a 3-day course of Clinical cure 30 days after therapy was the main out- trimethoprim-sulfamethoxazole and should be consid- come measure. Secondary outcomes included clinical and ered an effective fluoroquinolone-sparing alternative for microbiological cure rates 5 to 9 days after therapy and, the treatment of acute cystitis in women. for trimethoprim-sulfamethoxazole–treated women, clinical cure stratified by the trimethoprim-sulfamethoxa- Trial Registration: clinicaltrials.gov Identifier: zole susceptibility of the uropathogen. NCT00391651

Results: Clinical cure was achieved in 79% of the tri- Arch Intern Med. 2007;167(20):2207-2212

RIMETHOPRIM-SULFAMETH- suspicion of a trimethoprim-sulfamethoxa- oxazole is the recom- zole–resistant infection based on indi- mended drug of choice in vidual patient factors.2,3 Fluoroquinolones the United States for the are a popular alternative to trimethoprim- treatment of acute uncom- sulfamethoxazole and have very high rates plicatedT cystitis in women. Evidence- of efficacy, high rates of susceptibility among based guidelines published by the Infec- pathogens that cause uncomplicated uri- tious Diseases Society of America concluded nary tract infection (UTI), and minimal ad- that a 3-day course of trimethoprim- verse effects when used in a 3-day regimen sulfamethoxazole was the preferred regi- as recommended. A recent survey found that men because of its high efficacy (micro- fluoroquinolones have replaced trimetho- biological cure rate) and minimal adverse prim-sulfamethoxazole as the most com- events. On the basis of the large body of lit- mon class of antibiotic prescribed in the erature supporting this regimen, it was also United States for uncomplicated UTI in recommended as the standard compara- women.4 However, increasing rates of fluo- tor for evaluation of any new drug or dos- roquinolone-resistant Ecoliare being re- ing schedule for the treatment of uncom- ported worldwide, including in some areas plicated cystitis in women.1 in the United States.5-7 To prevent further emergence of fluoroquinolone resistance, See also page 2201 many experts recommend limiting their use Author Affiliations: to more serious infections, preferring in- Departments of Medicine and Alternatives to trimethoprim-sulfa- stead fluoroquinolone-sparing agents as sec- Schools of Medicine, Yale methoxazole need to be considered in a va- ond-line therapy for UTI when trimetho- University, New Haven, riety of clinical settings, including the pres- prim-sulfamethoxazole cannot be used.2 Connecticut (Dr Gupta); ence of a history of allergy to sulfa drugs, a Such agents include nitrofurantoin, fosfo- University of Miami, Miami, ␤ Florida (Dr Hooton); and known high prevalence of antimicrobial re- mycin, and -lactams. Fosfomycin has the University of Washington, sistance to trimethoprim-sulfamethoxa- advantage of single-dose therapy but has Seattle (Ms Roberts and zole among outpatient Escherichia coli iso- relatively low efficacy.1,2 Although some Dr Stamm). lates in the community, and a high clinical ␤-lactams, such as extended-spectrum

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 cephalosporins, may have good activity against UTI patho- pending on the organism and its susceptibility profile. Patients gens, the expected efficacy with this class of drugs has also, with a uropathogen that was not susceptible to the drug to which in general, been low.1,8,9 Nitrofurantoin has been used for they were randomized continued taking the initial agent unless more than 5 decades for the treatment of uncomplicated they had persistent symptoms, in which case they were discon- cystitis and remains active against most uropathogens, but tinued from the study and were retreated with an agent active against the causative uropathogen. its popularity is hampered by a recommended 7-day dosing regimen and concerns about efficacy and toler- LABORATORY PROCEDURES ance.1,3,8 Few studies have evaluated the efficacy and toler- Urine samples were refrigerated and transported to the labo- ance of nitrofurantoin, especially in a regimen shorter than ratory within 24 hours of collection. Standard urine culture and 7 days, as is now more commonly preferred for the susceptibility testing were performed using the standards of the treatment of UTI.1,2 The purpose of this study was thus Clinical and Laboratory Standards Institute (formerly the Na- to assess the efficacy and tolerance of a 5-day course of tional Committee for Clinical Laboratory Standards).10 Esch- nitrofurantoin compared with a standard 3-day regi- erichia coli isolates found to be resistant to trimethoprim- men of trimethoprim-sulfamethoxazole for the treat- sulfamethoxazole were further tested for minimum inhibitory ment of acute uncomplicated cystitis. The effects of tri- concentration (MIC) by means of broth dilution. methoprim-sulfamethoxazole resistance on efficacy were also assessed. SAMPLE SIZE The sample size was based on the hypothesis that the clinical METHODS cure rate with nitrofurantoin would be equivalent to that with trimethoprim-sulfamethoxazole within a 10% margin, with the STUDY POPULATION expected cure rate for trimethoprim-sulfamethoxazole being 90%. Using the method proposed by Blackwelder11 as imple- This study was conducted at the Hall Health Primary Care Cen- mented using UnifyPow,12 and aiming for a significance level ter, an outpatient clinic that offers care to students, faculty, and of 5% and power of 80%, a sample size estimate was set for 143 staff at the University of Washington and to the general public of patients per treatment group. The target enrollment was in- Seattle. Women 18 to 45 years of age who were not pregnant, who flated to 160 patients per group to allow for an anticipated 10% were in good general health, and who had symptoms of acute cys- dropout or unevaluable rate among enrollees. titis (dysuria, frequency, and/or urgency) and a urine culture with at least 102 CFU/mL of a uropathogen were eligible for partici- MAIN OUTCOME MEASURES pation. Women who were pregnant, lactating, or not regularly using contraception or who had diabetes mellitus, known ana- The clinical cure rate at the end of the entire study period (30 tomical abnormalities of the urinary tract, allergy to any of the days after therapy) was the primary outcome of interest. Women study drugs, or recent (Ͻ2 weeks) exposure to an oral or paren- who required antimicrobial drug treatment for lack of resolu- teral antimicrobial agent or who were currently using prophy- tion of initial UTI symptoms or for new UTI symptoms of dys- lactic antibiotic drugs were not eligible. uria, frequency, and/or urgency or signs of pyelonephritis (cos- tovertebral angle tenderness—with or without fever) during STUDY PROCEDURES follow-up were defined as having a clinical failure. All others were designated a clinical cure. The clinical and microbiologi- Flyers and newspaper advertisements were the main methods of cal cure rates at the early follow-up visit (5-9 days after therapy) recruitment. Interested women were screened via a checklist of were secondary outcomes. In addition, the primary outcome inclusion and exclusion criteria. Eligible individuals signed writ- was stratified by the antimicrobial susceptibility of the ini- ten informed consent forms and then completed a baseline ques- tially infecting strains. tionnaire and provided a clean-catch midstream urine sample for In asymptomatic women, microbiological cure was defined 5 urinalysis and culture. Participants were then randomized to open- as having less than 10 CFU/mL of all uropathogens and at least label treatment with trimethoprim-sulfamethoxazole, 1 double- a 1-log decrease in colony count of the causative uropathogen com- strength tablet twice daily for 3 days, or nitrofurantoin (Macro- pared with the urine culture at enrollment. In women who had bid; Procter & Gamble Pharmaceuticals, Cincinnati, Ohio), 100 persistent or recurrent symptoms of UTI, microbiological cure 2 mg twice daily for 5 days. Treatment assignments were gener- was defined as having less than 10 CFU/mL of a uropathogen. ated by the study statistician (P.L.R.) using a computerized ran- Possible uropathogens included enteric gram-negative rods, dom-number generator and were placed in individual, sequen- Staphylococcus saprophyticus, enterococci, and group B strepto- ␣ tially numbered opaque envelopes to be opened by study personnel cocci. Coagulase-negative staphylococci, -hemolytic strepto- at the time of enrollment. cocci, lactobacilli, diphtheroids, and mixed gram-positive flora Participants were contacted by telephone or e-mail on day 3 were categorized as nonuropathogens. If more than 1 organism of therapy to assess clinical cure. Women randomized to the ni- was identified, the predominant organism (highest colony count) trofurantoin arm also collected a midstream urine specimen af- was considered the causative pathogen. Multiple pathogens pre- ter taking their sixth dose (after 3 days of therapy). All the par- sent in equal quantities were considered copathogens unless more ticipants were scheduled for follow-up visits at 5 to 9 and 28 to than 3 pathogens were present, in which case the culture was con- 30 days after completion of therapy. At each follow-up visit a ques- sidered contaminated and not eligible for analysis. tionnaire regarding UTI symptoms was administered, and urine specimens for urinalysis and culture were collected. Patients who STATISTICAL ANALYSIS returned to the clinic at any time during the study period with recurrence of symptoms (recurrent UTI) or without resolution A case-available analysis was performed on all participants who of symptoms (persistent UTI) had another urinalysis and cul- attended at least 1 follow-up visit. The 95% confidence inter- ture performed and were treated with an alternative agent de- vals were constructed about the difference in binomial out-

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 comes between the 2 treatment groups for evaluation of the hy- potheses of equivalence in major outcomes. An absolute value 338 Women less than 10% in the upper bound was considered equivalent. A Kaplan-Meier curve depicting time to clinical failure was con- 23 (9 taking nitrofurantoin and 14 structed to display clinical outcomes by treatment assignment taking TMP–SMX) were and antibiotic susceptibility (for the trimethoprim- culture-negative sulfamethoxazole group only). A log-rank test was used to evaluate differences in time to clinical failure.13 315 Women

RESULTS

162 Women were assigned to 153 Women were assigned to All participant enrollment and follow-up took place be- 5–day nitrofurantonion treatment 3–day TMP–SMX treatment tween January 1, 2002, and December 31, 2005. A total of 338 women were enrolled and randomized to receive 2 Women were not evaluable 5 Women were not evaluable either trimethoprim-sulfamethoxazole (n=167) or ni- (no follow-up data) (no follow-up data) trofurantoin (n=171) (Figure 1). After randomiza- tion, 23 women (14 taking trimethoprim-sulfameth- 160 Were included in analyses 148 Were included in analyses oxazole and 9 taking nitrofurantoin) were deemed ineligible for the study based on negative urine culture results. An additional 7 women (5 taking trimethoprim- Figure 1. Flow diagram of women enrolled, randomized, and included in this case-available analysis. TMP-SMX indicates trimethoprim-sulfamethoxazole. sulfamethoxazole and 2 taking nitrofurantoin) did not attend any follow-up visits, leaving 308 women (148 taking trimethoprim-sulfamethoxazole and 160 taking ni- Table 1. Demographic Characteristics of 308 Women trofurantoin) available for analyses. The demographics, With Acute UTI by Treatment Group UTI history, and sexual history were similar between the 2 treatment groups (Table 1). Approximately 30% of Trimethoprim- Nitrofurantoin the women in each group had less than 105 CFU/mL but Sulfamethoxazole Group at least 102 CFU/mL of a uropathogen at enrollment. Most Characteristic Group (n = 148) (n = 160) enrollment UTIs were caused by E coli alone (82%) or Age, median (range), y 21 (18-40) 21 (18-41) in combination with another uropathogen (4%). The re- Never married, No. (%) 128 (86) 131 (82) maining enrollment UTIs were caused by S saprophyti- Race, No. (%) cus (8%) or by enterococci, Klebsiella species, Proteus mi- White 109 (74) 115 (72) rabilis, Enterobacter species, or group B streptococci Asian 27 (18) 29 (18) African American 2 (1) 0 (1%-3% each). The susceptibility profiles of the infect- Other 10 (7) 16 (10) ing uropathogens are given in Table 2. Overall, 14% of Hispanic ethnicity, No. (%) 4 (3) 7 (4) isolates (12% of E coli and 23% of non–E coli isolates) Ն3 Lifetime UTIs, No. (%) 38 (26) 39 (24) were intermediate or resistant to trimethoprim- Sexually active in past month, No. (%) 144 (97) 149 (93) sulfamethoxazole. Of the 13 resistant E coli isolates avail- Spermicide use in past month, No. (%) 36 (24) 33 (21) able for MIC testing to trimethoprim-sulfamethoxazole, all had an MIC greater than 160/3040 µg/mL. Abbreviation: UTI, urinary tract infection.

CLINICAL AND MICROBIOLOGICAL OUTCOMES was achieved in 127 of 130 women (98%) who were The overall clinical cure rate (the percentage of women tested. not having a persistent or recurrent UTI throughout the Among women treated with trimethoprim-sulfa- study period) was 79% (117/148) in the trimethoprim- methoxazole, there was a statistically significant de- sulfamethoxazole arm and 84% (134/160) in the nitro- crease in clinical cure in women who had a trimethoprim- furantoin arm, for a nonsignificant difference of −5% (95% sulfamethoxazole–nonsusceptible (intermediate or confidence interval, −13% to 4%). All of the women with resistant) uropathogen compared with women who had clinical failure had symptoms of cystitis except 2 women a susceptible isolate (Figure 2B). Overall, 110 of 131 tri- in the trimethoprim-sulfamethoxazole group who were methoprim-sulfamethoxazole–treated women (84%) with diagnosed as having pyelonephritis. An intention-to- a trimethoprim-sulfamethoxazole–susceptible uropatho- treat approach assigning clinical failure to any woman gen had a clinical cure compared with 7 of 17 women without outcome data (including women who had nega- (41%) with a trimethoprim-sulfamethoxazole–non- tive urine culture results at enrollment and women who susceptible uropathogen (PϽ.001, log-rank test). Mi- did not attend any follow-up visits) also demonstrated crobiological cure was achieved in 123 of 127 trimeth- that the 2 drugs were equivalent within the prespecified oprim-sulfamethoxazole–treated women with a margin of 10%. The clinical cure rate for the duration of trimethoprim-sulfamethoxazole–susceptible isolate (97%) the study is shown in Figure 2A(P=.25, log-rank test). vs 11 of 17 women with a trimethoprim-sulfamethoxa- Clinical and microbiological cure rates at the early fol- zole–nonsusceptible isolate (65%) (PϽ.001, ␹2 test). low-up visit were also statistically equivalent (Table 3). Only 3 women in the nitrofurantoin arm had a nitro- Microbiological cure on day 3 of nitrofurantoin therapy furantoin-nonsusceptible isolate; 2 of these women (67%)

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 Table 2. Susceptibility of Uropathogens in Women With Acute UTIa

Trimethoprim- Amoxicillin- Nitrofurantoin Sulfamethoxazole Ciprofloxacin Clavulanate Cefotaxime Escherichia coli, % (n = 276) Susceptible 99.6 88 99.6 82 100b Intermediate 0 0 0 13 0b Resistant 0.4 12 0.4 6 0 Non–E coli, %(n=61) Susceptible 90 77 76 98 100 Intermediate 4 2 22 2 0 Resistant 6 21 2 0 0

Abbreviation: UTI, urinary tract infection. a There were 337 isolates from 308 women with UTI. b Percentage has been rounded.

were clinically and microbiologically cured (1 with E coli drug.14 The latter issue is important in a clinical setting where and 1 with P mirabilis). The third woman had a P mira- treatment is chosen empirically (either without a urine cul- bilis UTI and met the criteria for clinical and microbio- ture or before the infecting pathogen and its susceptibility logical failure. are known if a urine culture is performed). Despite rec- ommendations for a 3-day course of therapy with trimeth- TOLERANCE AND COMPLIANCE oprim-sulfamethoxazole for uncomplicated cystitis, many health care professionals still prescribe a 5-day course of Similar proportions of women in the trimethoprim- this drug.4,15 This study provides evidence of an addi- sulfamethoxazole and nitrofurantoin arms (31% and 28%, tional treatment choice using the same duration in set- respectively) reported an adverse effect related to the study tings in which trimethoprim-sulfamethoxazole cannot be medication in response to an open-ended question. On di- used, which has the potential to result in decreased use of rect questioning about specific symptoms, 41% of women fluoroquinolones for the treatment of acute uncompli- in the trimethoprim-sulfamethoxazole group and 39% in cated cystitis. the nitrofurantoin group reported at least 1 adverse effect. Although the study was not designed to specifically Most adverse effects were related to the gastrointestinal sys- evaluate a 3-day regimen of nitrofurantoin, it does dem- tem (nausea or diarrhea), central nervous system (head- onstrate that most women (98%) had microbiological cure ache or lightheadedness), and urogenital system (vaginal by 3 days of therapy. This is in contrast to a study16 per- itching). Discontinuation of the study due to adverse ef- formed in a similar population in which a 3-day course of fects occurred in 1% and 2% of women in the trimethoprim- macrocrystalline nitrofurantoin (Macrodantin; Procter & sulfamethoxazole and nitrofurantoin groups, respec- Gamble Pharmaceuticals) resulted in early microbiologi- tively. Fewer women in the nitrofurantoin group (6%) than cal cure in only 32 of 38 women (84%) and overall cure in in the trimethoprim-sulfamethoxazole group (11%) re- only 22 of 36 women (61%). A smaller sample size, a dif- quired treatment (primarily over-the-counter medica- ferent formulation of nitrofurantoin requiring 4 daily doses, tions) for adverse effects. a low rate of trimethoprim-sulfamethoxazole resistance Excluding women who stopped taking their study drug (5%), and a different composite outcome combining bac- early because of a clinical failure requiring repeated treat- terial and clinical response may account for some of the ment with another agent (2 taking trimethoprim- discrepancies between the earlier study and the present data. sulfamethoxazole and 3 taking nitrofurantoin), 100% of Nonetheless, a well-powered randomized trial specifically women in the trimethoprim-sulfamethoxazole arm re- aimed at evaluating a 3-day course of nitrofurantoin is ported taking all 6 doses of the drug and 97% of women needed, and we do not recommend use of a 3-day regi- in the nitrofurantoin arm reported taking all 10 doses of men until such efficacy data are available. A recent phar- their drug. All the women in the nitrofurantoin arm took macy database study17 found that a 3-day course of nitro- at least 6 of the prescribed 10 doses. furantoin was frequently used (presumably for uncomplicated UTI) and resulted in another antibiotic pre- COMMENT scription more often than longer courses. Most previous clinical trials of nitrofurantoin have evalu- This is one of the largest studies evaluating the efficacy and ated a 7-day course of a twice-daily regimen. One of the tolerance of a 5-day regimen of nitrofurantoin for the treat- largest studies is a randomized trial of ciprofloxacin, 100 ment of acute uncomplicated cystitis in adult women. Aside mg twice daily for 3 days, vs nitrofurantoin or trimethoprim- from the adequacy of the sample size to establish equiva- sulfamethoxazole for 7 days.18 The primary efficacy mea- lence as outlined by CONSORT (Consolidated Standards sure, microbiological cure 4 to 10 days after therapy, was of Reporting Trials) guidelines, this study has the added similar among the 3 treatment groups and was achieved advantage of evaluating outcomes stratified by suscepti- in 86% of 177 evaluable women treated with nitrofuran- bility of the original infecting pathogen to the treatment toin. Clinical cure rates with the 7-day regimen of nitro-

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 a A Table 3. Treatment Outcomes by Treatment Group

1.0 Patients, No./Total No. (%)

TMP-SMX Nitrofurantoin 0.8 Group Group Difference Outcome (n = 148) (n = 160) (95% CI), % Primary outcome 0.6 Overall clinical cure 117/148 (79) 134/160 (84) −5 (−13 to 4) Secondary outcomes Early clinical cure 133/148 (90) 144/160 (90) −0.1 (−7 to 7) Early microbiological 131/144 (91) 141/154 (92) −1 (−7 to 6) 0.4 cure Proportion Clinically Cured Abbreviations: CI, confidence interval; TMP-SMX, trimethoprim- 0.2 sulfamethoxazole. Nitrofurantoin treatment a TMP-SMX treatment All outcomes were statistically equivalent between groups. See the “Main Outcome Measures” subsection for definitions of the outcomes.

0 0 10 20 30 Time to Persistent or Recurrent UTI, d bial agents used to treat UTI. Although previous studies B have evaluated the clinical and bacterial cure rates with 1.0 trimethoprim-sulfamethoxazole stratified by trimethoprim- sulfamethoxazole susceptibility, few of these have pro- spectively studied a 3-day regimen of trimethoprim- 0.8 sulfamethoxazole in a large cohort and also measured MICs of the resistant organisms.21-23 We found that all of the trimethoprim-sulfamethoxazole–resistant isolates tested had 0.6 MICs greater than the achievable concentration of trimethoprim-sulfamethoxazole in the urine. Given this finding, it is not surprising that the clinical failure rate in women 0.4 with a trimethoprim-sulfamethoxazole–resistant organ- 23 Proportion Clinically Cured ism was very high (59%). A previous prospective study in Israel found a 50% clinical failure rate with a 5-day regi- 0.2 men of trimethoprim-sulfamethoxazole in women with a Nonsusceptible isolate trimethoprim-sulfamethoxazole–resistant E coli UTI but Susceptible isolate did not report MIC data. A clinical failure rate of 50% 0 to 60% dictates that alternative agents need to be used 0 10 20 30 when a uropathogen with high-level trimethoprim-sulfa- Time to Persistent or Recurrent UTI, d methoxazole resistance is suspected. This study adheres to many of the guidelines for clini- Figure 2. Clinical outcomes in women treated with trimethoprim- cal trials designed to test equivalence recently pub- sulfamethoxazole (TMP-SMX) vs nitrofurantoin (A) and in women with a lished by the CONSORT group.14 One exception to the TMP-SMX–susceptible vs TMP-SMX–nonsusceptible isolate (TMP-SMX treatment group only) (B). Kaplan-Meier survival curves demonstrate guideline is that this was an unblinded study, and it is equivalent rates of clinical cure between nitrofurantoin- and possible that open-label therapy led to a bias in the evalu- TMP-SMX–treated women (A) and significantly lower clinical cure rates for ation of clinical response to therapy. However, because TMP-SMX–treated women who had a TMP-SMX–nonsusceptible isolate compared with those who had a susceptible isolate (B) (PϽ.001, log-rank trimethoprim-sulfamethoxazole is the gold standard regi- test). UTI indicates urinary tract infection. men and the one expected to have higher efficacy based on previous studies, it would be more likely that any bias would favor finding clinical failures in nitrofurantoin- furantoin (93%) were similar to what we report herein with treated participants. In addition, the secondary out- a 5-day regimen (90%). A more recent randomized trial19 come of microbiological cure is objective and thus is un- comparing nitrofurantoin, 100 mg twice daily for 7 days, likely to be affected by the lack of masking. Although some with single-dose fosfomycin for uncomplicated cystitis experts may consider a case-available analysis rather than found a microbiological cure rate of 81% 5 to 11 days after an intention-to-treat analysis to be a limitation, it is re- nitrofurantoin therapy. Another study20 of a 7-day regi- assuring that both methods produced consistent re- men of nitrofurantoin found an 82% microbiological cure sults.14 Finally, the participants were primarily a highly rate with a twice daily formulation and an 83% microbio- compliant, white student population, and therefore, these logical cure rate with trimethoprim-sulfamethoxazole, both findings may not be generalizable to settings where these lower than those reported herein. characteristics differ. The impact of antimicrobial resistance has been postu- An important question raised by this study is whether lated as being of lesser significance in UTI because of the demonstration of efficacy with a 5-day regimen of nitro- high urinary concentrations achieved by most antimicro- furantoin will provide enough impetus for health care pro-

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 fessionals to switch from choosing a fluoroquinolone as the REFERENCES second-line (or first-line in some cases) agent for uncomplicated cystitis to nitrofurantoin. The efficacy, tolerabil- 1. Warren JW, Abrutyn E, Hebel JR, Johnson JR, Schaeffer AJ, Stamm WE. Guide- ity, and availability of once-daily dosing regimens are fac- lines for antimicrobial treatment of uncomplicated acute bacterial cystitis and tors that may still lead to preferred prescribing of acute pyelonephritis in women. Clin Infect Dis. 1999;29(4):745-758. fluoroquinolones. However, as the need for preservation 2. Hooton TM, Besser R, Foxman B, Fritsche TR, Nicolle LE. Acute uncomplicated of the fluoroquinolones is increasingly recognized, the cystitis in an era of increasing antibiotic resistance: a proposed approach to em- pirical therapy. Clin Infect Dis. 2004;39(1):75-80. strong evidence presented herein for excellent efficacy and 3. Gupta K, Hooton TM, Stamm WE. Increasing antimicrobial resistance and the tolerance of a 5-day regimen of nitrofurantoin may facili- management of uncomplicated community-acquired urinary tract infections. Ann tate prescribing that optimizes the care of patients with cys- Intern Med. 2001;135(1):41-50. titis while minimizing the propagation of resistance.2 4. Kallen AJ, Welch HG, Sirovich BE. Current antibiotic therapy for isolated urinary tract infections in women. Arch Intern Med. 2006;166(6):635-639. 5. Gupta K. Emerging antibiotic resistance in urinary tract pathogens. Infect Dis Clin Accepted for Publication: April 30, 2007. North Am. 2003;17(2):243-259. Correspondence: Kalpana Gupta, MD, MPH, Yale Uni- 6. Bolon MK, Wright SB, Gold HS, Carmeli Y. The magnitude of the association be- versity and VA Connecticut Healthcare System, 950 tween fluoroquinolone use and quinolone-resistant Escherichia coli and Klebsi- Campbell Ave, 11-ACSLG, West Haven, CT 06516 ella pneumoniae may be lower than previously reported. Antimicrob Agents ([email protected]). Chemother. 2004;48(6):1934-1940. 7. Goettsch W, van Pelt W, Nagelkerke N, et al. Increasing resistance to fluoro- Author Contributions: Dr Gupta had full access to all quinolones in Escherichia coli from urinary tract infections in the Netherlands. the data in the study and takes responsibility for the in- J Antimicrob Chemother. 2000;46(2):223-228. tegrity of the data and the accuracy of the data analysis. 8. Nicolle L, Anderson PA, Conly J, et al. Uncomplicated urinary tract infection in Study concept and design: Gupta, Hooton, and Stamm. Ac- women: current practice and the effect of antibiotic resistance on empiric treatment. quisition of data: Gupta and Stamm. Analysis and inter- Can Fam Physician. 2006;52:612-618. 9. Hooton TM, Scholes D, Gupta K, Stapleton AE, Roberts PL, Stamm WE. Amoxicillin- pretation of data: Gupta, Hooton, Roberts, and Stamm. clavulanate vs ciprofloxacin for the treatment of uncomplicated cystitis in wom- Drafting of the manuscript: Gupta, Hooton, Roberts, and en: a randomized trial. JAMA. 2005;293(8):949-955. Stamm. Critical revision of the manuscript for important 10. Clinical and Laboratory Standards Institute. Performance Standards for Antimi- intellectual content: Gupta, Hooton, and Stamm. Statis- crobial Susceptibility Testing: Fifteenth Informational Supplement (M100-S15). tical analysis: Roberts. Obtained funding: Gupta and Stamm. Wayne, PA: Clinical and Laboratory Standards Institute; 2005. 11. Blackwelder WC. “Proving the null hypothesis” in clinical trials. Control Clin Trials. Administrative, technical, and material support: Gupta and 1982;3(4):345-353. Stamm. Study supervision: Gupta, Hooton, and Stamm. 12. O’Brien RG. A tour of UnifyPow: a SAS module/macro for sample size analysis. Financial Disclosure: Dr Gupta has served as a consul- In: Proceedings of the 23rd SAS Users Group International Conference; 1998; tant for, received research support from, and received Cary, NC. speaking honoraria from Procter & Gamble Inc, Bayer 13. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. 2nd ed. New York, NY: John Wiley & Sons Inc; 2002. Pharmaceutical, and Ortho-McNeil. Dr Hooton has re- 14. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ. Reporting of nonin- ceived consulting and speaking honoraria from Bayer and feriority and equivalence randomized trials: an extension of the CONSORT speaking honoraria from Ortho-McNeil and Bristol- statement. JAMA. 2006;295(10):1152-1160. Meyers Squibb. Ms Roberts has received research sup- 15. Huang ES, Stafford RS. National patterns in the treatment of urinary tract infec- port from Procter & Gamble Inc. Dr Stamm has served tions in women by ambulatory care physicians. Arch Intern Med. 2002;162 (1):41-47. as a consultant for and has received research support and 16. Hooton TM, Winter C, Tiu F, Stamm WE. Randomized comparative trial and cost honoraria from Procter & Gamble Inc, Ortho-McNeil, analysis of 3-day antimicrobial regimens for treatment of acute cystitis in women. and Bayer Pharmaceutical. JAMA. 1995;273(1):41-45. Funding/Support: This study was supported in part by a 17. Goettsch WG, Janknegt R, Herings RM. Increased treatment failure after 3-days’ grant from Proctor & Gamble Inc and by grants DK 53369 courses of nitrofurantoin and trimethoprim for urinary tract infections in wom- and DK 02660 from the US Public Health Service. en: a population-based retrospective cohort study using the PHARMO database. Br J Clin Pharmacol. 2004;58(2):184-189. Role of the Sponsors: None of these funding sources 18. Iravani A, Klimberg I, Briefer C, Munera C, Kowalsky SF, Echols RM. A trial com- played any role in the design and conduct of the study; paring low-dose, short-course ciprofloxacin and standard 7 day therapy with co- in the collection, management, analysis, or interpreta- trimoxazole or nitrofurantoin in the treatment of uncomplicated urinary tract tion of the data; or in the preparation, review, or ap- infection. J Antimicrob Chemother. 1999;43(suppl A):67-75. 19. Stein GE. Comparison of single-dose fosfomycin and a 7-day course of nitrofu- proval of the manuscript. rantoin in female patients with uncomplicated urinary tract infection. Clin Ther. Previous Presentations: This study was presented in part 1999;21(11):1864-1872. at the 45th Interscience Conference of Antimicrobial 20. Spencer RC, Moseley DJ, Greensmith MJ. Nitrofurantoin modified release versus Agents and Chemotherapy; December 17, 2005; Wash- trimethoprim or co-trimoxazole in the treatment of uncomplicated urinary tract in- ington, DC; and at the 44th Annual Meeting of the In- fection in general practice. J Antimicrob Chemother. 1994;33(suppl A):121-129. 21. McNulty CA, Richards J, Livermore DM, et al. Clinical relevance of laboratory- fectious Diseases Society of America; October 13, 2006; reported antibiotic resistance in acute uncomplicated urinary tract infection in Toronto, Ontario, Canada. primary care. J Antimicrob Chemother. 2006;58(5):1000-1008. Additional Contributions: Ajit Limaye, MD, and Susan 22. Gupta K, Stamm WE. Outcomes associated with trimethoprim/sulphamethoxazole Swanzy, BS, RM, performed and interpreted the MIC tests; (TMP/SMX) therapy in TMP/SMX resistant community-acquired UTI. Int J Antimi- Marsha Cox, BS, and Sheila Manuguid, BS, performed mi- crob Agents. 2002;19(6):554-556. 23. Raz R, Chazan B, Kennes Y, et al. Empiric use of trimethoprim-sulfamethoxazole crobiological processing and testing; and Niki Deshaw, MA, (TMP-SMX) in the treatment of women with uncomplicated urinary tract infections, and Ellen Cassen, APRN, performed participant enroll- in a geographical area with a high prevalence of TMP-SMX-resistant uropathogens. ment and follow-up (all at the University of Washington). Clin Infect Dis. 2002;34(9):1165-1169.

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