NIH Public Access Pacita L. Roberts, MS, and Ann E ...acute cystitis. Design, Setting, and Patients—Randomized, double-blind trial of 300 women aged 18 to 55 years with acute uncomplicated

Cefpodoxime vs Ciprofloxacin for Short-Course Treatment ofAcute Uncomplicated Cystitis:A Randomized Trial

Thomas M. Hooton, MD, Pacita L. Roberts, MS, and Ann E. Stapleton, MDDepartment of Medicine, School of Medicine, University of Miami, Miami, Florida (Dr Hooton); andDepartment of Medicine, School of Medicine, University of Washington, Seattle (Ms Roberts andDr Stapleton).

AbstractContext—Although fluoroquinolones remain the most reliable urinary antimicrobial, resistancerates have increased and effective fluoroquinolone-sparing antimicrobials are needed.

Objective—To determine whether cefpodoxime is noninferior to ciprofloxacin for treatment ofacute cystitis.

Design, Setting, and Patients—Randomized, double-blind trial of 300 women aged 18 to 55years with acute uncomplicated cystitis comparing ciprofloxacin (n=150) with cefpodoxime(n=150); patients were from a student health center in Seattle, Washington, and a referral center inMiami, Florida. The study was conducted from 2005 to 2009 and outcomes were assessed at 5 to 9days and 28 to 30 days after completion of therapy. Intent-to-treat and per-protocol analyses wereperformed; 15 women in the ciprofloxacin group and 17 women in the cefpodoxime group werelost to follow-up.

© 2012 American Medical Association. All rights reserved.

Corresponding Author: Thomas M. Hooton, MD, Clinical Research Bldg, 1120 NW 14th St, Ste 310G, Miami, FL 33136([email protected]).

Author Contributions: Dr Hooton had full access to all of the data in the study and takes responsibility for the integrity of the dataand the accuracy of the data analysis.Study concept and design: Hooton, Roberts, Stapleton.Acquisition of data: Hooton, Stapleton.Analysis and interpretation of data: Hooton, Roberts, Stapleton.Drafting of the manuscript: Hooton, Roberts, Stapleton.Critical revision of the manuscript for important intellectual content: Hooton, Roberts, Stapleton.Statistical analysis: Roberts.Obtained funding: Hooton, Stapleton.Administrative, technical, or material support: Hooton, Stapleton.Study supervision: Hooton, Stapleton.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts ofInterest. Dr Hooton reported that he has been a consultant for Pinnacle Pharmaceuticals, Pfizer Inc, and Alita Pharmaceuticals. Noother author reported disclosures.

Previous Presentations: Presented in part at the 47th Annual Meeting of the Infectious Diseases Society of America; October 29-November 1, 2009; Philadelphia, Pennsylvania.

Additional Contributions: We greatly appreciate the involvement of Walter E. Stamm, MD (deceased) in discussions leading to theconception, conduct, and completion of this study. We are greatly indebted to D. C. Dugdale, MD, medical director, and the staff atHall Health Primary Care Center (University of Washington, Seattle) for assistance with study enrollment; Niki Deshaw, MA, andEllen Cassen, ARNP, for participant enrollment and follow-up; Marsha Cox, BS, and Sheila Manuguid, BS, for laboratory assistanceat the University of Washington, Seattle; Wisvline Labrousse, PhD, ARNP, for participant enrollment and follow-up; and NadegeAtis, BS, for laboratory assistance at the University of Miami, Miami, Florida. All of these individuals were salaried employees oftheir respective institutions and no one received additional compensation for their efforts in this study.

NIH Public AccessAuthor ManuscriptJAMA. Author manuscript; available in PMC 2013 August 07.

Published in final edited form as:JAMA. 2012 February 8; 307(6): 583–589. doi:10.1001/jama.2012.80.

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-PA Author Manuscript

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Interventions—Patients were given 250 mg of ciprofloxacin orally twice daily for 3 days or 100mg of cefpodoxime proxetil orally twice daily for 3 days.

Main Outcome Measures—Overall clinical cure (defined as not requiring antimicrobialtreatment during follow-up) at the 30-day follow-up visit. Secondary outcomes were clinical andmicrobiological cure at the first follow-up visit and vaginal Escherichia coli colonization at eachfollow-up visit. The hypothesis that cefpodoxime would be noninferior to ciprofloxacin by a 10%margin (ie, for the difference in the primary outcome for ciprofloxacin minus cefpodoxime, theupper limit of the confidence interval would be <10%) was formulated prior to data collection.

Results—The overall clinical cure rate at the 30-day visit with the intent-to-treat approach inwhich patients lost to follow-up were considered as having clinical cure was 93% (139/150) forciprofloxacin compared with 82% (123/150) for cefpodoxime (difference of11%; 95% CI, 3% –18%); and for the intent-to-treat approach in which patients lost to follow-up were considered ashaving not responded to treatment, the clinical cure rate was 83% (124/150) for ciprofloxacincompared with 71% (106/150) for cefpodoxime (difference of 12%; 95% CI, 3% – 21%). Themicrobiological cure rate was 96% (123/128) for ciprofloxacin compared with 81% (104/129) forcefpodoxime (difference of 15%; 95% CI, 8% – 23%). At first follow-up, 16% of women in theciprofloxacin group compared with 40% of women in the cefpodoxime group had vaginal E colicolonization.

Conclusions—Among women with uncomplicated cystitis, a 3-day regimen of cefpodoximecompared with ciprofloxacin did not meet criteria for noninferiority for achieving clinical cure.These findings, along with concerns about possible adverse ecological effects associated withother broad-spectrum β-lactams, do not support the use of cefpodoxime as a first-linefluoroquinolone-sparing antimicrobial for acute uncomplicated cystitis.

Antimicrobial resistance among uropathogens causing uncomplicated cystitis has increasedover the past decade and there is greater appreciation of the importance of the ecologicaladverse effects of antimicrobial therapy.1 Fluoroquinolones have high rates of efficacy, highrates of susceptibility among pathogens causing uncomplicated urinary tract infection (UTI),and minimal adverse drug reactions when used in a 3-day regimen as recommended. Indeed,recent surveys have found that fluoroquinolones are more commonly used thantrimethoprim-sulfamethoxazole for uncomplicated UTI in women in the United States.2,3

However, increasing rates of fluoroquinolone-resistant Escherichia coli are being reportedworldwide, including areas within the United States and Canada, even among young womenwith uncomplicated cystitis.4–7 To prevent further emergence of fluoroquinolone resistance,there are calls for restricting fluoroquinolones to those specific instances of uncomplicatedcystitis when other UTI antimicrobials are not suitable.8 Although fluoroquinolones arehighly efficacious and thus preferred in some circumstances, recently published guidelinesfrom the Infectious Diseases Society of America for the treatment of uncomplicated cystitisrecommend limiting their use because of the risk of propagating resistance and concernsabout adverse ecological effects.1

Although most studies demonstrate that β-lactam antimicrobials are generally inferior incure rates to trimethoprim-sulfamethoxazole and the fluoroquinolones for the treatment ofcystitis,9–11 there is a paucity of data on the use of cefpodoxime proxetil, an oral third-generation cephalosporin, for the treatment of uncomplicated cystitis. Cefpodoxime, with itsbroad spectrum of antimicrobial activity, would provide a useful alternative tofluoroquinolones for the treatment of cystitis if demonstrated to be similar in efficacy tofluoroquinolones and without adverse ecological effects (such as the selection of drug-resistant organisms).12

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Thus, we conducted a noninferiority trial of a 3-day course of cefpodoxime compared with astandard 3-day regimen of ciprofloxacin for the treatment of acute uncomplicated cystitis toassess whether cefpodoxime would have clinically acceptable efficacy and tolerancecompared with ciprofloxacin. A noninferiority margin of 10% was considered to beclinically acceptable. We also evaluated the effects of both antimicrobials on vaginal E colicolonization because the inferior ability of β-lactam antimicrobials to eradicate E coli fromthe vagina has been postulated to explain their poorer clinical activity in the treatment ofUTI.11 We also assessed the effects of antimicrobial resistance on efficacy.

METHODSStudy Population

The study was conducted at the Hall Health Primary Care Center, an outpatient clinic thatoffers care to students, faculty, and staff at the University of Washington and to the generalpublic of Seattle, Washington, and at the Clinical Research Unit at the University of Miami,in Miami, Florida. Women were eligible if they were aged 18 to 55 years, in good generalhealth, had acute cystitis as defined by typical symptoms (dysuria, frequency, and/orurgency) and pyuria (white blood cell count ≥8 cells/mm3), and received antimicrobialtreatment. A positive urine culture was defined as 102 or more colony-forming units (CFU)per milliliter of a uropathogen.

Women were not eligible if they had diabetes mellitus, known anatomic abnormalities of theurinary tract, known allergy to the study drugs, exposure to an oral or parenteralantimicrobial (including prophylactic antimicrobials) in the last 2 weeks, or were pregnant,lactating, or not consistently using contraceptives. Race and ethnicity were self-reported onthe enrollment questionnaire (options were defined by the investigators). We collect suchdata routinely in our studies because many of them are funded by the National Institutes ofHealth, which requires self-reporting of ethnicity. The human subjects review committees ofthe University of Washington and the University of Miami approved the study, and allpatients gave written informed consent.

Study ProceduresFlyers and discussions with other local clinicians were the main methods of recruitment.Interested women were screened via a checklist of inclusion and exclusion criteria, andeligible patients signed written informed consent. At the initial visit, patients underwent adirected history and physical examination, an interview using a standardized studyquestionnaire, a midstream urine specimen collection to evaluate bacteriuria and pyuria, anda vaginal swab specimen collection to evaluate bacterial colonization.

Patients were randomized in a double-blind fashion to treatment with 250 mg ofciprofloxacin twice daily for 3 days or 100 mg of cefpodoxime proxetil twice daily for 3days. Treatment assignments were generated by the study statistician using a computerized,random-number generator that was given to the pharmacy where the study medications wereencapsulated in indistinguishable gelatin capsules, allocated according to treatmentassignment, and packaged by study identifier number. Randomized treatments wereassigned in blocks of 10 and clinic and laboratory personnel were kept naive to the treatmentdrug. Treatment assignment was unblinded only after the study had been completed andoutcomes had been determined.

Patients were scheduled for follow-up visits at 5 to 9 days and 28 to 30 days aftercompletion of therapy and were asked to return to the clinic if their cystitis symptoms didnot resolve or if they had recurrent symptoms of acute cystitis. At each return visit, aquestionnaire regarding UTI symptoms was administered and urine and vaginal specimens



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were collected using the same methods as in the initial visit. At symptomatic return visits, anantimicrobial treatment was instituted if patients met criteria for diagnosis of acute cystitis.If the infecting microbiological isolate at enrollment was susceptible, treatment was withtrimethoprim-sulfamethoxazole, but if not, treatment was with nitrofurantoin. At the firstfollow-up visit (days 5–9), participants were asked how many study pills they had taken as ameasure of compliance.

Laboratory ProceduresMethods for collecting urine and vaginal specimens and isolating, identifying, andquantifying urine and vaginal uropathogens have been previously described.13,14 Urine andvaginal samples were refrigerated and transported to the laboratory within 24 hours ofcollection. Standard urine culture and susceptibility testing was performed using themethods of the Clinical and Laboratory Standards Institute.15 Pyuria was assessed inundiluted urine using a hemocytometer. Vaginal cultures were considered positive for E coliif there was growth of 1 or greater on a semi-quantitative scale ranging from 1 to 4.

Outcome MeasuresThe primary study outcome was clinical cure at the 30-day follow-up visit (overall clinicalcure). Women who did not require further antimicrobial treatment for acute cystitis duringfollow-up were defined as cured, whereas those who required further antimicrobialtreatment were defined as not responding to treatment. In addition, the main outcome wasstratified by patients’ prior UTI history.

Secondary study outcomes were clinical and microbiological cure at the first follow-up visitand vaginal E coli colonization at each follow-up visit. Microbiological cure was defined ashaving (in women who did not require treatment a second time) less than 105 CFU/mL of alluropathogens and at least a 10-fold decrease in colony count of the causative uropathogencompared with the urine culture at enrollment. In women who were treated a second timewith an antimicrobial for persistent or recurrent UTI at or before the first follow-up visit,microbiological cure was defined as having less than 102 CFU/mL of a uropathogen at thetime of the second treatment.

We evaluated associations between antimicrobial susceptibility of the initially infectinguropathogen and clinical and microbiological outcomes. Uropathogens included entericgram-negative rods, Staphylococcus saprophyticus, enterococci, and group B streptococci.Enterococci and group B streptococci were considered causative uropathogens only if theyoccurred without other uropathogens or at quantities of 105 CFU/mL or greater. Coagulase-negative staphylococci, α-hemolytic streptococci, lactobacilli, diphtheroids, and mixed–grampositive flora were categorized as nonuropathogens.

Sample SizeBased on published cure rates of trimethoprim-sulfamethoxazole and ciprofloxacin, weassumed a reasonable and acceptable cure rate for the standard treatment group(ciprofloxacin) to be between 85% and 95%.11,16–19 Using a noninferiority margin of 10%for the experimental treatment (cefpodoxime), and setting significance at 5%, a sample sizeof 113 to 140 evaluable patients per treatment group would be necessary to achieve a levelof power of 80% to 85%. The targeted enrollment was set at 300 women (150 in each studygroup) to aim for approximately 250 evaluable patients for comparison.

Statistical AnalysisAn intent-to-treat approach was used to determine the sample for primary and secondaryoutcomes. All women who were enrolled and randomized were included in the main



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analysis. Patients without any follow-up visits were imputed as clinical cures given that weprovided 24-hour availability of a study investigator for questions, immediate appointmentsto the study clinic during weekday hours, and no charge for clinic visits or antimicrobials.Additional analyses imputing those lost to follow-up as having not responded to treatmentalso were performed. For the secondary outcome of early microbiological cure, a per-protocol approach was used and women with positive urine cultures at enrollment and withfollow-up urine culture information were evaluated.

A 2-sided 95% confidence interval was constructed regarding the difference in binomialoutcomes between the 2 treatment groups for evaluation of the hypothesis of noninferiorityof cefpodoxime. The difference was constructed using the outcome for the standardtreatment minus the experimental treatment (ie, ciprofloxacin minus cefpodoxime). A valueof less than 10% in the upper limit of this confidence interval would be interpreted assupporting the hypothesis that cefpodoxime is noninferior to ciprofloxacin. The hypothesisof noninferiority was also tested using the Wald statistic,20 using a 1-sided alternativehypothesis. A Kaplan-Meier curve depicting time to treatment nonresponse was constructedto display the timing of the nonresponses by treatment assignment using the per-protocolanalysis sample. Data management and statistical analyses were performed using SASversion 9.2 (SAS Institute Inc).

RESULTSAll patient enrollment and follow-up took place between 2005 and 2009. Three hundredwomen were enrolled and randomized to receive either ciprofloxacin (n=150) orcefpodoxime (n=150) (Figure 1). Two otherwise eligible individuals who were approachedrefused participation. Thirty-three women had negative cultures at enrollment, 17 in theciprofloxacin group and 16 in the cefpodoxime group. Fifteen women in the ciprofloxacingroup and 17 in the cefpodoxime group were lost to follow-up by the 30-day visit.

Baseline characteristics were similar between the 2 study groups except that more women inthe cefpodoxime group had previous UTIs and pyelonephritis and fewer had less than 105

CFU/mL of a uropathogen at enrollment (Table 1). The majority of enrollment UTIs werecaused by E coli alone (75%) or in combination with another uropathogen (2%). Theremaining enrollment UTIs were caused by S saprophyticus (3%) or by enterococci,Klebsiella species, Proteus mirabilis, or group B streptococci (1%–3% each). Overall, 4% ofisolates (4% of E coli and 8% of non−E coli) were nonsusceptible to ciprofloxacin and 8%(4% of E coli and 36% of non–E coli) were nonsusceptible to cefpodoxime.

The number of E coli strains was 119 (79%) for ciprofloxacin compared with 114 (76%) forcefpodoxime (P = .49). The number of uropathogens susceptible to ciprofoxacin was 131(96%) for ciprofloxacin compared with 129 (96%) for cefpodoxime (P = .98). The numberof uropathogens susceptible to cefpodoxime was 125 (92%) for ciprofloxacin compared with122 (91%) for cefpodoxime (P = .80).

Primary OutcomeThe overall clinical cure rate with the intent-to-treat approach in which patients lost tofollow-up were imputed as having clinical cure was 93% (139/150) for ciprofloxacincompared with 82% (123/150) for cefpodoxime (difference of 11%; 95% CI, 3% – 18%)(Table 2). Because the upper limit of the 95% confidence interval of the difference exceeded10%, the results were inconsistent with a finding of noninferiority for cefpodoxime. The testof noninferiority was not statistically significant (P = .57). The per-protocol analysis yieldedsimilar results with a clinical cure rate of 92% (124/135) in the ciprofloxacin groupcompared with 80% (106/133) in the cefpodoxime group (difference of 12%; 95% CI, 4%–



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20%). In an alternative intent-to-treat analysis in which patients who were lost to follow-upwere considered to have not responded to treatment, the clinical cure rate was 83%(124/150) for ciprofloxacin compared with 71% (106/150) for cefpodoxime (difference of12%; 95% CI, 3%–21%).

Among women who reported no previous UTI in the past year before enrollment, the overallclinical cure rate was 96% (113/118) for ciprofloxacin and 83% (83/100) for cefpodoxime(difference of 13%; 95% CI, 5%–21%). This magnitude of difference was not seen amongwomen who reported 1 or more UTIs in the past year before enrollment (ciprofloxacin: 84%[26/31]; cefpodoxime: 80% [40/50]). Among women infected with strains that weresusceptible to the study antibiotic, the overall clinical cure rates were 94% (117/125) forciprofloxacin and 82% (97/119) for cefpodoxime (difference of 12%; 95% CI, 4%–20%).Among those infected with strains nonsusceptible to the treatment antibiotic, the overallclinical cure rate was 50% (3/6) for ciprofloxacin and 67% (8/12) for cefpodoxime.

Two women, 1 from each treatment group, were diagnosed with pyelonephritis at day 2(ciprofloxacin) and day 28 (cefpodoxime) following enrollment. At enrollment, both had Ecoli susceptible to the assigned treatment drug. Information on the pyelonephritis strains wasavailable only for the woman treated with cefpodoxime who had E coli susceptible to allantibiotics tested, including cefazolin, cefuroxime, and ceftriaxone; however, it was nottested against cefpodoxime.

Secondary Clinical OutcomeThe clinical cure rate at the first follow-up visit (mean, 5 days after treatment) was 93%(140/150) for ciprofloxacin compared with 88% (132/150) for cefpodoxime (difference of5%; 95% CI, −1% to 12%) (Table 2). The clinical cure rates over the duration of the studyare shown in Figure 2, in which the Kaplan-Meier curves demonstrate the similarity inoutcome during the first week of follow-up, after which the curves diverge due to furthernonresponse to treatment in the cefpodoxime group.

Among patients with available urine culture data, E coli was the causative uropathogen in38% (3/8) of nonresponders to treatment for ciprofloxacin (5 had no growth) compared with64% (16/25) for cefpodoxime (4 had no growth). Two women in the ciprofloxacin groupwith treatment nonresponse caused by E coli had a ciprofloxacin-resistant E coli strain atboth enrollment and at the time of recurrent UTI and 1 had a susceptible strain at enrollmentbut a resistant strain causing the recurrent UTI. Thirteen of 16 women in the cefpodoximegroup with treatment nonresponse caused by E coli had cefpodoxime-susceptible strains atenrollment and during the recurrent UTI, 2 had resistant strains at both enrollment andrecurrent UTI, and 1 had a resistant strain at enrollment, but a susceptible strain during therecurrent UTI.

Secondary Microbiological OutcomesThe microbiological cure rate at the first follow-up visit (mean, 5 days after treatment) was96% (123/128) for ciprofloxacin compared with 81% (104/129) for cefpodoxime (differenceof 15%; 95% CI, 8%–23%). Among those women infected with strains that were susceptibleto the study antibiotic, the microbiological cure rates were 97% (117/120) for ciprofloxacinand 81% (94/116) for cefpodoxime (difference of 16%; 95% CI, 9%–24%).

Vaginal E coli colonization was present at enrollment in 82% of women in both groups. Bythe first follow-up visit, however, 16% (21/132) of the women in the ciprofloxacin groupcompared with 40% (54/136) in the cefpodoxime group had vaginal E coli colonization. Thedifference persisted to a lesser extent at the 30-day follow-up visit (29% for ciprofloxacin vs



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40% for cefpodoxime). The development of subsequent UTI did not correlate with thepresence of vaginal E coli colonization at the first follow-up visit.

Tolerance and AdherenceAmong women with follow-up, 99% of the ciprofloxacin group and 98% of thecefpodoxime group reported taking all 6 treatment doses. In response to an open-endedquestion, 20% of women in the ciprofloxacin group and 23% in the cefpodoxime groupreported an adverse effect related to the study medication, whereas 30% and 27%,respectively, reported at least 1 adverse effect when asked about specific symptoms. Themajority of adverse effects were nausea, diarrhea, headache, lightheadedness, or vaginaldiscomfort. Interruption of study medication due to adverse effects occurred in1%ofwomenin the ciprofloxacin group and 0% in the cefpodoxime group. Seven women in theciprofloxacin group compared with 3 in the cefpodoxime group required treatment(primarily over-the-counter medication) for adverse effects.

COMMENTThe updated guideline on the management of uncomplicated UTI by the Infectious DiseasesSociety of America noted that the choice of a therapeutic agent should consider efficacy,risk of adverse effects, local resistance rates, propensity to cause adverse ecologicaleffects,12 cost and availability of the drug, and clinician threshold for failure.1 The guidelinepanel also indicated that none of the antimicrobials currently available outweighs the othersin terms of optimizing each of these factors for the treatment of acute cystitis.

The panel recommended that the fluoroquinolones, while highly efficacious, should bereserved for important uses other than acute cystitis, and thus should be consideredalternative antimicrobials for acute cystitis. The main concern regarding fluoroquinolone usefor acute cystitis is the possible promotion of fluoroquinolone resistance, not only amonguropathogens but also other organisms causing more serious and difficult-to-treat infectionsat other sites. There also is concern about the association between fluoroquinolone use andincreased rates of methicillin-resistant Staphylococcus aureus.12,21–23

This study is, to our knowledge, the first comparison of a 3-day regimen of ciprofloxacinwith a 3-day regimen of cefpodoxime for the treatment of acute uncomplicated cystitis inwomen. Our study failed to demonstrate clinical noninferiority for 100 mg of cefpodoximetwice daily for 3 days compared with 250 mg of ciprofloxacin twice daily for 3 days (curerate, 82% vs 93%, respectively) (difference of 11%; 95% CI, 3%– 18%). This finding wasconsistent with those in the per-protocol analysis and in microbiological cure anderadication of vaginal E coli colonization at the early follow-up visit. Study outcomes weresimilarly different when patients lost to follow-up were considered to have not responded totreatment. Ciprofloxacin’s clinical advantage was diminished in women with a history ofUTI or infected with a nonsusceptible uropathogen.

Although extended-spectrum cephalosporins such as cefpodoxime have good activityagainst UTI pathogens, the expected efficacy with β-lactam drugs has in general been lowcompared with trimethoprim-sulfamethoxazole or fluoroquinolones.9–11 We have speculatedthat the lower clinical response with β-lactams compared with other first-line antimicrobialsmay be due to their poorer activity in eradicating the uropathogen from the vaginalflora.11,24 In this regard, cefpodoxime demonstrated significantly poorer activity thanciprofloxacin in eradicating E coli from the vaginal flora in this study.



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In a smaller published trial of cefpodoxime for treatment for uncomplicated cystitis,cefpodoxime yielded high rates of clinical and microbiological cure similar to thecomparator agent, trimethoprim-sulfamethoxazole.18

In addition to its poor performance compared with ciprofloxacin, another concern aboutcefpodoxime for uncomplicated cystitis is whether this agent promotes emergence of gram-negative extended-spectrum β-lactamase (ESBL) resistance. Although we are not aware ofdata suggesting that cefpodoxime is associated with ESBL resistance, parenteral broad-spectrum cephalosporins have been associated with promotion of ESBL resistance amonggram-negative bacteria.12 None of the 16 E coli strains causing recurrent UTI among womentreated with cefpodoxime appeared to be ESBL strains by susceptibility patterns.

This study adheres to the guidelines for clinical trials designed to test noninferiority recentlypublished by the Consolidated Standards of Reporting Trials (CONSORT) group.25 Ourstudy is one of the few double-blind randomized trials comparing antimicrobial drugs fortreatment of acute uncomplicated cystitis. Strengths of this study include its double-blindstudy design, large sample size, well-defined study population, low dropout rate, and highrate of medication adherence. The participants in our trial were primarily a highly compliant,white student population and thus our findings may not be generalizable to settings in whichthese characteristics differ.

We chose to compare 3-day regimens of ciprofloxacin and cefpodoxime for the treatment ofacute uncomplicated cystitis because of the need for safe and effective fluoroquinolone-sparing antimicrobials, the broad-spectrum coverage of cefpodoxime, and the absence of alarge trial comparing 3-day regimens of cefpodoxime with current standard therapy. Boththe intention-to-treat and per-protocol analyses produced consistent results showing that,among women with acute uncomplicated cystitis, a 3-day regimen of cefpodoximecompared with ciprofloxacin did not meet criteria for noninferiority in achieving clinicalcure.

Our findings in this study and concerns about possible adverse ecological effects that havebeen associated with parenteral broad-spectrum cephalosporins do not support the use ofcefpodoxime as a first-line fluoroquinolone-sparing antimicrobial for acute uncomplicatedcystitis. As recommended in recently published guidelines, nitrofurantoin, trimethoprim-sulfamethoxazole (except in areas where the resistance prevalence is known to be high),fosfomycin, and pivmecillinam (not available in the United States) should be consideredbefore fluoroquinolones and β-lactams such as cefpodoxime for patients with uncomplicatedcystitis.1

AcknowledgmentsFunding/Support: This work was supported by grants P01 DK053369 and SCOR P50 DK64540 from the NationalInstitute of Diabetes and Digestive and Kidney Diseases.

Role of the Sponsors: The funding source did not play any role in the design and conduct of the study; in thecollection, management, analysis, or interpretation of the data; or in the preparation, review, or approval of themanuscript.

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18. Kavatha D, Giamarellou H, Alexiou Z, et al. Cefpodoxime-proxetil versus trimethoprim-sulfamethoxazole for short-term therapy of uncomplicated acute cystitis in women. AntimicrobAgents Chemother. 2003; 47(3):897–900. [PubMed: 12604518]

19. Naber KG, Allin DM, Clarysse L, et al. Gatifloxacin 400 mg as a single shot or 200 mg once dailyfor 3 days is as effective as ciprofloxacin 250 mg twice daily for the treatment of patients withuncomplicated urinary tract infections. Int J Antimicrob Agents. 2004; 23(6):596–605. [PubMed:15194131]



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20. Chow, SC.; Shao, J.; Wang, H. Sample Size Calculations in Clinical Research. Boca Raton, FL:CRC Press; 2003.

21. MacDougall C, Powell JP, Johnson CK, Edmond MB, Polk RE. Hospital and communityfluoroquinolone use and resistance in Staphylococcus aureus and Escherichia coli in 17 UShospitals. Clin Infect Dis. 2005; 41(4):435–440. [PubMed: 16028149]

22. Charbonneau P, Parienti JJ, Thibon P, et al. French Fluoroquinolone Free (3F) Study Group.Fluoroquinolone use and methicillin-resistant Staphylococcus aureus isolation rates in hospitalizedpatients: a quasi experimental study. Clin Infect Dis. 2006; 42(6):778–784. [PubMed: 16477553]

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Figure 1.Enrollment and Outcomes



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Figure 2.Time to Treatment Nonresponse in Women Treated With Ciprofloxacin vs Cefpodoxime



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Table 1

Description of Women at Enrollment

No. (%) of Womena

PValue

Ciprofloxacin(n = 150)

Cefpodoxime(n = 150)

Age, mean (SD), y 24 (6) 23 (5) .67

Never married 129 (86) 120 (80) .17

Race

White 94 (63) 103 (69)

.50

Asian 39 (26) 32 (21)

Black 2 (1) 4 (3)

Otherb 15 (10) 11 (7)

Ethnicity

Hispanic 6 (4) 13 (9) .10

History of UTI in lifetime

Any 85 (57) 104 (69) .02

≥3 40 (27) 62 (41) .007

History of pyelonephritis 6 (4) 13 (9) .09

UTI in past year 31 (21) 50 (33) .02

Sexual activity during past month

Sexually active 141 (94) 141 (94) .81

Vaginal intercourse episodes, median (range) 8 (0–40) 8 (0–40) .43

Spermicide exposurec (n = 116) 23 (20) (n = 113) 17 (15) .39

Uropathogen colony count

No growth 16 (11) 16 (11)

.42 102 to <105 CFU/mL 55 (37) 45 (30)

≥105 CFU/mL 78 (52) 89 (59)

Abbreviations: CFU, colony-forming units; UTI, urinary tract infection.

aUnless otherwise indicated.

bIncludes American Indians, Native Americans, and Alaskan Natives.

cIncludes use of diaphragm or spermicide-coated condom. If unknown for spermicide-coating, this was set to missing.


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Table 2

Treatment Outcomes by Study Groupa

No./Total (%)Difference

(95% CI), %Ciprofloxacin Cefpodoxime

Primary outcomes

Overall clinical cureb 139/150 (93) 123/150 (82) 11 (3 to 18)

Overall clinical curec 124/150 (83) 106/150 (71) 12 (3 to 21)

Per-protocol analysis 124/135 (92) 106/133 (80) 12 (4 to 20)

Secondary outcomes

Early clinical cured 140/150 (93) 132/150 (88) 5 (−1 to 12)

Early microbiological cured 123/128 (96) 104/129 (81) 15 (8 to 23)

aSee text for definitions.

bIntent-to-treat analysis, imputing values for patients without follow-up visits as having clinical cure.

cIntent-to-treat analysis, imputing values for patients without follow-up visits as not having responded to treatment.

dAt first follow-up visit.


Documents

NIH Public Access Pacita L. Roberts, MS, and Ann E ...acute cystitis. Design, Setting, and Patients—Randomized, double-blind trial of 300 women aged 18 to 55 years with acute uncomplicated