Cefpodoxime Vs Ciprofloxacin For Short-Course Treatment of Acute Uncomplicated Cystitis

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JAMA. Author manuscript; available in PMC 2013 August 07.
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JAMA. 2012 February 8; 307(6): 583589. doi:10.1001/jama.2012.80.
Cefpodoxime vs Ciprofloxacin for Short-Course Treatment of

Acute Uncomplicated Cystitis:
A Randomized Trial
Thomas M. Hooton, MD, Pacita L. Roberts, MS, and Ann E. Stapleton, MD
Department of Medicine, School of Medicine, University of Miami, Miami, Florida (Dr Hooton); and
Department of Medicine, School of Medicine, University of Washington, Seattle (Ms Roberts and
Dr Stapleton).
Abstract
ContextAlthough fluoroquinolones remain the most reliable urinary antimicrobial, resistance
rates have increased and effective fluoroquinolone-sparing antimicrobials are needed.
ObjectiveTo determine whether cefpodoxime is noninferior to ciprofloxacin for treatment of

acute cystitis.
Design, Setting, and PatientsRandomized, double-blind trial of 300 women aged 18 to 55
years 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 in
Miami, Florida. The study was conducted from 2005 to 2009 and outcomes were assessed at 5 to 9
days and 28 to 30 days after completion of therapy. Intent-to-treat and per-protocol analyses were
performed; 15 women in the ciprofloxacin group and 17 women in the cefpodoxime group were
lost 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
(thooton@med.miami.edu).
Author Contributions: Dr Hooton had full access to all of the data in the study and takes responsibility for the integrity of the data
and 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 of
Interest. Dr Hooton reported that he has been a consultant for Pinnacle Pharmaceuticals, Pfizer Inc, and Alita Pharmaceuticals. No
other author reported disclosures.
Previous Presentations: Presented in part at the 47th Annual Meeting of the Infectious Diseases Society of America; October 29November 1, 2009; Philadelphia, Pennsylvania.
Additional Contributions: We greatly appreciate the involvement of Walter E. Stamm, MD (deceased) in discussions leading to the
conception, conduct, and completion of this study. We are greatly indebted to D. C. Dugdale, MD, medical director, and the staff at
Hall Health Primary Care Center (University of Washington, Seattle) for assistance with study enrollment; Niki Deshaw, MA, and
Ellen Cassen, ARNP, for participant enrollment and follow-up; Marsha Cox, BS, and Sheila Manuguid, BS, for laboratory assistance
at the University of Washington, Seattle; Wisvline Labrousse, PhD, ARNP, for participant enrollment and follow-up; and Nadege
Atis, BS, for laboratory assistance at the University of Miami, Miami, Florida. All of these individuals were salaried employees of
their respective institutions and no one received additional compensation for their efforts in this study.
Hooton et al.
Page 2
InterventionsPatients were given 250 mg of ciprofloxacin orally twice daily for 3 days or 100
mg of cefpodoxime proxetil orally twice daily for 3 days.
Main Outcome MeasuresOverall clinical cure (defined as not requiring antimicrobial

treatment during follow-up) at the 30-day follow-up visit. Secondary outcomes were clinical and
microbiological cure at the first follow-up visit and vaginal Escherichia coli colonization at each
follow-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, the
upper limit of the confidence interval would be <10%) was formulated prior to data collection.
ResultsThe overall clinical cure rate at the 30-day visit with the intent-to-treat approach in
which patients lost to follow-up were considered as having clinical cure was 93% (139/150) for
ciprofloxacin 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 as
having not responded to treatment, the clinical cure rate was 83% (124/150) for ciprofloxacin
compared with 71% (106/150) for cefpodoxime (difference of 12%; 95% CI, 3% 21%). The
microbiological cure rate was 96% (123/128) for ciprofloxacin compared with 81% (104/129) for
cefpodoxime (difference of 15%; 95% CI, 8% 23%). At first follow-up, 16% of women in the
ciprofloxacin group compared with 40% of women in the cefpodoxime group had vaginal E coli
colonization.
ConclusionsAmong women with uncomplicated cystitis, a 3-day regimen of cefpodoxime

compared with ciprofloxacin did not meet criteria for noninferiority for achieving clinical cure.
These findings, along with concerns about possible adverse ecological effects associated with
other broad-spectrum -lactams, do not support the use of cefpodoxime as a first-line
fluoroquinolone-sparing antimicrobial for acute uncomplicated cystitis.
Antimicrobial resistance among uropathogens causing uncomplicated cystitis has increased
over the past decade and there is greater appreciation of the importance of the ecological
adverse effects of antimicrobial therapy.1 Fluoroquinolones have high rates of efficacy, high
rates 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 than
trimethoprim-sulfamethoxazole for uncomplicated UTI in women in the United States.2,3
However, increasing rates of fluoroquinolone-resistant Escherichia coli are being reported

worldwide, including areas within the United States and Canada, even among young women
with uncomplicated cystitis.47 To prevent further emergence of fluoroquinolone resistance,
there are calls for restricting fluoroquinolones to those specific instances of uncomplicated
cystitis when other UTI antimicrobials are not suitable.8 Although fluoroquinolones are
highly efficacious and thus preferred in some circumstances, recently published guidelines
from the Infectious Diseases Society of America for the treatment of uncomplicated cystitis
recommend limiting their use because of the risk of propagating resistance and concerns
about adverse ecological effects.1
Although most studies demonstrate that -lactam antimicrobials are generally inferior in
cure rates to trimethoprim-sulfamethoxazole and the fluoroquinolones for the treatment of
cystitis,911 there is a paucity of data on the use of cefpodoxime proxetil, an oral thirdgeneration cephalosporin, for the treatment of uncomplicated cystitis. Cefpodoxime, with its
broad spectrum of antimicrobial activity, would provide a useful alternative to
fluoroquinolones for the treatment of cystitis if demonstrated to be similar in efficacy to
fluoroquinolones and without adverse ecological effects (such as the selection of drugresistant organisms).12
Hooton et al.
Page 3
Thus, we conducted a noninferiority trial of a 3-day course of cefpodoxime compared with a

standard 3-day regimen of ciprofloxacin for the treatment of acute uncomplicated cystitis to
assess whether cefpodoxime would have clinically acceptable efficacy and tolerance
compared with ciprofloxacin. A noninferiority margin of 10% was considered to be
clinically acceptable. We also evaluated the effects of both antimicrobials on vaginal E coli
colonization because the inferior ability of -lactam antimicrobials to eradicate E coli from
the vagina has been postulated to explain their poorer clinical activity in the treatment of
UTI.11 We also assessed the effects of antimicrobial resistance on efficacy.
METHODS
Study Population
The study was conducted at the Hall Health Primary Care Center, an outpatient clinic that
offers care to students, faculty, and staff at the University of Washington and to the general
public 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 general
health, had acute cystitis as defined by typical symptoms (dysuria, frequency, and/or
urgency) and pyuria (white blood cell count 8 cells/mm3), and received antimicrobial
treatment. 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 the
urinary tract, known allergy to the study drugs, exposure to an oral or parenteral
antimicrobial (including prophylactic antimicrobials) in the last 2 weeks, or were pregnant,
lactating, or not consistently using contraceptives. Race and ethnicity were self-reported on
the enrollment questionnaire (options were defined by the investigators). We collect such
data routinely in our studies because many of them are funded by the National Institutes of
Health, which requires self-reporting of ethnicity. The human subjects review committees of
the University of Washington and the University of Miami approved the study, and all
patients gave written informed consent.
Study Procedures
Flyers and discussions with other local clinicians were the main methods of recruitment.
Interested women were screened via a checklist of inclusion and exclusion criteria, and
eligible patients signed written informed consent. At the initial visit, patients underwent a
directed history and physical examination, an interview using a standardized study
questionnaire, a midstream urine specimen collection to evaluate bacteriuria and pyuria, and
a vaginal swab specimen collection to evaluate bacterial colonization.
Patients were randomized in a double-blind fashion to treatment with 250 mg of

ciprofloxacin twice daily for 3 days or 100 mg of cefpodoxime proxetil twice daily for 3
days. Treatment assignments were generated by the study statistician using a computerized,
random-number generator that was given to the pharmacy where the study medications were
encapsulated in indistinguishable gelatin capsules, allocated according to treatment
assignment, and packaged by study identifier number. Randomized treatments were
assigned in blocks of 10 and clinic and laboratory personnel were kept naive to the treatment
drug. Treatment assignment was unblinded only after the study had been completed and
outcomes had been determined.
Patients were scheduled for follow-up visits at 5 to 9 days and 28 to 30 days after
completion of therapy and were asked to return to the clinic if their cystitis symptoms did
not resolve or if they had recurrent symptoms of acute cystitis. At each return visit, a
questionnaire regarding UTI symptoms was administered and urine and vaginal specimens
Hooton et al.
Page 4
were collected using the same methods as in the initial visit. At symptomatic return visits, an
antimicrobial treatment was instituted if patients met criteria for diagnosis of acute cystitis.
If the infecting microbiological isolate at enrollment was susceptible, treatment was with
trimethoprim-sulfamethoxazole, but if not, treatment was with nitrofurantoin. At the first
follow-up visit (days 59), participants were asked how many study pills they had taken as a
measure of compliance.
Laboratory Procedures
Methods for collecting urine and vaginal specimens and isolating, identifying, and
quantifying urine and vaginal uropathogens have been previously described.13,14 Urine and
vaginal samples were refrigerated and transported to the laboratory within 24 hours of
collection. Standard urine culture and susceptibility testing was performed using the
methods of the Clinical and Laboratory Standards Institute.15 Pyuria was assessed in
undiluted urine using a hemocytometer. Vaginal cultures were considered positive for E coli
if there was growth of 1 or greater on a semi-quantitative scale ranging from 1 to 4.
Outcome Measures
The primary study outcome was clinical cure at the 30-day follow-up visit (overall clinical
cure). Women who did not require further antimicrobial treatment for acute cystitis during
follow-up were defined as cured, whereas those who required further antimicrobial
treatment were defined as not responding to treatment. In addition, the main outcome was
stratified by patients prior UTI history.
Secondary study outcomes were clinical and microbiological cure at the first follow-up visit
and vaginal E coli colonization at each follow-up visit. Microbiological cure was defined as
having (in women who did not require treatment a second time) less than 105 CFU/mL of all
uropathogens and at least a 10-fold decrease in colony count of the causative uropathogen
compared with the urine culture at enrollment. In women who were treated a second time
with 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 the
time of the second treatment.
We evaluated associations between antimicrobial susceptibility of the initially infecting

uropathogen and clinical and microbiological outcomes. Uropathogens included enteric
gram-negative rods, Staphylococcus saprophyticus, enterococci, and group B streptococci.
Enterococci and group B streptococci were considered causative uropathogens only if they
occurred without other uropathogens or at quantities of 105 CFU/mL or greater. Coagulasenegative staphylococci, -hemolytic streptococci, lactobacilli, diphtheroids, and mixed
grampositive flora were categorized as nonuropathogens.
Sample Size
Based on published cure rates of trimethoprim-sulfamethoxazole and ciprofloxacin, we
assumed a reasonable and acceptable cure rate for the standard treatment group
(ciprofloxacin) to be between 85% and 95%.11,1619 Using a noninferiority margin of 10%
for the experimental treatment (cefpodoxime), and setting significance at 5%, a sample size
of 113 to 140 evaluable patients per treatment group would be necessary to achieve a level
of power of 80% to 85%. The targeted enrollment was set at 300 women (150 in each study
group) to aim for approximately 250 evaluable patients for comparison.
Statistical Analysis
An intent-to-treat approach was used to determine the sample for primary and secondary
outcomes. All women who were enrolled and randomized were included in the main
Hooton et al.
Page 5
analysis. Patients without any follow-up visits were imputed as clinical cures given that we
provided 24-hour availability of a study investigator for questions, immediate appointments
to 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 treatment
also were performed. For the secondary outcome of early microbiological cure, a perprotocol approach was used and women with positive urine cultures at enrollment and with
follow-up urine culture information were evaluated.
A 2-sided 95% confidence interval was constructed regarding the difference in binomial
outcomes between the 2 treatment groups for evaluation of the hypothesis of noninferiority
of cefpodoxime. The difference was constructed using the outcome for the standard
treatment minus the experimental treatment (ie, ciprofloxacin minus cefpodoxime). A value
of less than 10% in the upper limit of this confidence interval would be interpreted as
supporting the hypothesis that cefpodoxime is noninferior to ciprofloxacin. The hypothesis
of noninferiority was also tested using the Wald statistic,20 using a 1-sided alternative
hypothesis. A Kaplan-Meier curve depicting time to treatment nonresponse was constructed
to display the timing of the nonresponses by treatment assignment using the per-protocol
analysis sample. Data management and statistical analyses were performed using SAS
version 9.2 (SAS Institute Inc).
RESULTS
All patient enrollment and follow-up took place between 2005 and 2009. Three hundred
women were enrolled and randomized to receive either ciprofloxacin (n=150) or
cefpodoxime (n=150) (Figure 1). Two otherwise eligible individuals who were approached
refused participation. Thirty-three women had negative cultures at enrollment, 17 in the
ciprofloxacin group and 16 in the cefpodoxime group. Fifteen women in the ciprofloxacin
group 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 in
the 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 were
caused by E coli alone (75%) or in combination with another uropathogen (2%). The
remaining enrollment UTIs were caused by S saprophyticus (3%) or by enterococci,
Klebsiella species, Proteus mirabilis, or group B streptococci (1%3% each). Overall, 4% of
isolates (4% of E coli and 8% of nonE coli) were nonsusceptible to ciprofloxacin and 8%
(4% of E coli and 36% of nonE coli) were nonsusceptible to cefpodoxime.
The number of E coli strains was 119 (79%) for ciprofloxacin compared with 114 (76%) for
cefpodoxime (P = .49). The number of uropathogens susceptible to ciprofoxacin was 131
(96%) for ciprofloxacin compared with 129 (96%) for cefpodoxime (P = .98). The number
of uropathogens susceptible to cefpodoxime was 125 (92%) for ciprofloxacin compared with
122 (91%) for cefpodoxime (P = .80).
Primary Outcome
The overall clinical cure rate with the intent-to-treat approach in which patients lost to
follow-up were imputed as having clinical cure was 93% (139/150) for ciprofloxacin
compared 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 exceeded
10%, the results were inconsistent with a finding of noninferiority for cefpodoxime. The test
of noninferiority was not statistically significant (P = .57). The per-protocol analysis yielded
similar results with a clinical cure rate of 92% (124/135) in the ciprofloxacin group
compared with 80% (106/133) in the cefpodoxime group (difference of 12%; 95% CI, 4%
Hooton et al.
Page 6
20%). In an alternative intent-to-treat analysis in which patients who were lost to follow-up
were 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 of
12%; 95% CI, 3%21%).
Among women who reported no previous UTI in the past year before enrollment, the overall
clinical 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 among
women 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 were
susceptible to the study antibiotic, the overall clinical cure rates were 94% (117/125) for
ciprofloxacin and 82% (97/119) for cefpodoxime (difference of 12%; 95% CI, 4%20%).
Among those infected with strains nonsusceptible to the treatment antibiotic, the overall
clinical 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 E
coli susceptible to the assigned treatment drug. Information on the pyelonephritis strains was
available only for the woman treated with cefpodoxime who had E coli susceptible to all
antibiotics tested, including cefazolin, cefuroxime, and ceftriaxone; however, it was not
tested against cefpodoxime.
Secondary Clinical Outcome
The 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 of
5%; 95% CI, 1% to 12%) (Table 2). The clinical cure rates over the duration of the study
are shown in Figure 2, in which the Kaplan-Meier curves demonstrate the similarity in
outcome during the first week of follow-up, after which the curves diverge due to further
nonresponse to treatment in the cefpodoxime group.
Among patients with available urine culture data, E coli was the causative uropathogen in
38% (3/8) of nonresponders to treatment for ciprofloxacin (5 had no growth) compared with
64% (16/25) for cefpodoxime (4 had no growth). Two women in the ciprofloxacin group
with treatment nonresponse caused by E coli had a ciprofloxacin-resistant E coli strain at
both enrollment and at the time of recurrent UTI and 1 had a susceptible strain at enrollment
but a resistant strain causing the recurrent UTI. Thirteen of 16 women in the cefpodoxime
group with treatment nonresponse caused by E coli had cefpodoxime-susceptible strains at
enrollment and during the recurrent UTI, 2 had resistant strains at both enrollment and
recurrent UTI, and 1 had a resistant strain at enrollment, but a susceptible strain during the
recurrent UTI.
Secondary Microbiological Outcomes
The microbiological cure rate at the first follow-up visit (mean, 5 days after treatment) was
96% (123/128) for ciprofloxacin compared with 81% (104/129) for cefpodoxime (difference
of 15%; 95% CI, 8%23%). Among those women infected with strains that were susceptible
to the study antibiotic, the microbiological cure rates were 97% (117/120) for ciprofloxacin
and 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. By
the first follow-up visit, however, 16% (21/132) of the women in the ciprofloxacin group
compared with 40% (54/136) in the cefpodoxime group had vaginal E coli colonization. The
difference persisted to a lesser extent at the 30-day follow-up visit (29% for ciprofloxacin vs
Hooton et al.
Page 7
40% for cefpodoxime). The development of subsequent UTI did not correlate with the
presence of vaginal E coli colonization at the first follow-up visit.
Tolerance and Adherence

Among women with follow-up, 99% of the ciprofloxacin group and 98% of the
cefpodoxime group reported taking all 6 treatment doses. In response to an open-ended
question, 20% of women in the ciprofloxacin group and 23% in the cefpodoxime group
reported an adverse effect related to the study medication, whereas 30% and 27%,
respectively, reported at least 1 adverse effect when asked about specific symptoms. The
majority of adverse effects were nausea, diarrhea, headache, lightheadedness, or vaginal
discomfort. Interruption of study medication due to adverse effects occurred in1%ofwomen
in the ciprofloxacin group and 0% in the cefpodoxime group. Seven women in the
ciprofloxacin group compared with 3 in the cefpodoxime group required treatment
(primarily over-the-counter medication) for adverse effects.
COMMENT
The updated guideline on the management of uncomplicated UTI by the Infectious Diseases
Society of America noted that the choice of a therapeutic agent should consider efficacy,
risk of adverse effects, local resistance rates, propensity to cause adverse ecological
effects,12 cost and availability of the drug, and clinician threshold for failure.1 The guideline
panel also indicated that none of the antimicrobials currently available outweighs the others
in terms of optimizing each of these factors for the treatment of acute cystitis.
The panel recommended that the fluoroquinolones, while highly efficacious, should be
reserved for important uses other than acute cystitis, and thus should be considered
alternative antimicrobials for acute cystitis. The main concern regarding fluoroquinolone use
for acute cystitis is the possible promotion of fluoroquinolone resistance, not only among
uropathogens but also other organisms causing more serious and difficult-to-treat infections
at other sites. There also is concern about the association between fluoroquinolone use and
increased rates of methicillin-resistant Staphylococcus aureus.12,2123
This study is, to our knowledge, the first comparison of a 3-day regimen of ciprofloxacin
with a 3-day regimen of cefpodoxime for the treatment of acute uncomplicated cystitis in
women. Our study failed to demonstrate clinical noninferiority for 100 mg of cefpodoxime
twice daily for 3 days compared with 250 mg of ciprofloxacin twice daily for 3 days (cure
rate, 82% vs 93%, respectively) (difference of 11%; 95% CI, 3% 18%). This finding was
consistent with those in the per-protocol analysis and in microbiological cure and
eradication of vaginal E coli colonization at the early follow-up visit. Study outcomes were
similarly different when patients lost to follow-up were considered to have not responded to
treatment. Ciprofloxacins clinical advantage was diminished in women with a history of
UTI or infected with a nonsusceptible uropathogen.
Although extended-spectrum cephalosporins such as cefpodoxime have good activity
against UTI pathogens, the expected efficacy with -lactam drugs has in general been low
compared with trimethoprim-sulfamethoxazole or fluoroquinolones.911 We have speculated
that the lower clinical response with -lactams compared with other first-line antimicrobials
may be due to their poorer activity in eradicating the uropathogen from the vaginal
flora.11,24 In this regard, cefpodoxime demonstrated significantly poorer activity than
ciprofloxacin in eradicating E coli from the vaginal flora in this study.
Hooton et al.
Page 8
In a smaller published trial of cefpodoxime for treatment for uncomplicated cystitis,

cefpodoxime yielded high rates of clinical and microbiological cure similar to the
comparator agent, trimethoprim-sulfamethoxazole.18
In addition to its poor performance compared with ciprofloxacin, another concern about
cefpodoxime for uncomplicated cystitis is whether this agent promotes emergence of gramnegative extended-spectrum -lactamase (ESBL) resistance. Although we are not aware of
data suggesting that cefpodoxime is associated with ESBL resistance, parenteral broadspectrum cephalosporins have been associated with promotion of ESBL resistance among
gram-negative bacteria.12 None of the 16 E coli strains causing recurrent UTI among women
treated with cefpodoxime appeared to be ESBL strains by susceptibility patterns.
This study adheres to the guidelines for clinical trials designed to test noninferiority recently
published by the Consolidated Standards of Reporting Trials (CONSORT) group.25 Our
study is one of the few double-blind randomized trials comparing antimicrobial drugs for
treatment of acute uncomplicated cystitis. Strengths of this study include its double-blind
study design, large sample size, well-defined study population, low dropout rate, and high
rate 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 which
these characteristics differ.
We chose to compare 3-day regimens of ciprofloxacin and cefpodoxime for the treatment of
acute uncomplicated cystitis because of the need for safe and effective fluoroquinolonesparing antimicrobials, the broad-spectrum coverage of cefpodoxime, and the absence of a
large trial comparing 3-day regimens of cefpodoxime with current standard therapy. Both
the intention-to-treat and per-protocol analyses produced consistent results showing that,
among women with acute uncomplicated cystitis, a 3-day regimen of cefpodoxime
compared with ciprofloxacin did not meet criteria for noninferiority in achieving clinical
cure.
Our findings in this study and concerns about possible adverse ecological effects that have
been associated with parenteral broad-spectrum cephalosporins do not support the use of
cefpodoxime as a first-line fluoroquinolone-sparing antimicrobial for acute uncomplicated
cystitis. As recommended in recently published guidelines, nitrofurantoin, trimethoprimsulfamethoxazole (except in areas where the resistance prevalence is known to be high),
fosfomycin, and pivmecillinam (not available in the United States) should be considered
before fluoroquinolones and -lactams such as cefpodoxime for patients with uncomplicated
cystitis.1
Acknowledgments
Funding/Support: This work was supported by grants P01 DK053369 and SCOR P50 DK64540 from the National
Institute 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 the
collection, management, analysis, or interpretation of the data; or in the preparation, review, or approval of the
manuscript.
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Hooton et al.
Page 11

Figure 1.
Enrollment and Outcomes
Hooton et al.
Page 12

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

Hooton et al.
Page 13
Table 1
Description of Women at Enrollment
No. (%) of Womena

P
Value
Ciprofloxacin
(n = 150)
Cefpodoxime
(n = 150)
24 (6)
23 (5)
.67
129 (86)
120 (80)
.17
White
94 (63)
103 (69)
Asian
39 (26)
32 (21)
Black
2 (1)
4 (3)
Otherb
15 (10)
11 (7)
6 (4)
13 (9)
.10
Any
85 (57)
104 (69)
.02
40 (27)
62 (41)
.007
6 (4)
13 (9)
.09
31 (21)
50 (33)
.02
Sexually active
141 (94)
141 (94)
.81
Vaginal intercourse episodes, median (range)
8 (040)
8 (040)
.43
(n = 116) 23 (20)
(n = 113) 17 (15)
.39
No growth
16 (11)
16 (11)
102 to <105 CFU/mL
55 (37)
45 (30)
105 CFU/mL
78 (52)
89 (59)
Age, mean (SD), y

Never married
Race
.50
Ethnicity
Hispanic
History of UTI in lifetime
History of pyelonephritis
UTI in past year
Sexual activity during past month
Spermicide exposurec
Uropathogen colony count
.42
Abbreviations: CFU, colony-forming units; UTI, urinary tract infection.
Unless otherwise indicated.
Includes American Indians, Native Americans, and Alaskan Natives.
Includes use of diaphragm or spermicide-coated condom. If unknown for spermicide-coating, this was set to missing.
Hooton et al.
Page 14
Table 2
Treatment Outcomes by Study Groupa

No./Total (%)
Ciprofloxacin
Cefpodoxime
Difference
(95% CI), %
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)
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)
Primary outcomes
Secondary outcomes
See text for definitions.
Intent-to-treat analysis, imputing values for patients without follow-up visits as having clinical cure.
Intent-to-treat analysis, imputing values for patients without follow-up visits as not having responded to treatment.
At first follow-up visit.


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