Cephalosporin
No Match for Standard Antimicrobial in Cystitis
Clinical
Context
Fluoroquinolones
are preferred antibiotics because of their high rate of efficacy and low
adverse effect profile. However, the widespread use of fluoroquinolones may be
promoting the spread of resistant bacteria such as methicillin-resistant Staphylococcus aureus
(MRSA). In a study by Madaras-Kelly and colleagues, which was published in the
February 2006 issue of Infection
Control and Hospital Epidemiology, researchers examined the effects
of limiting fluoroquinolone use on the rate of nosocomial infection in a single
center. They found that their program reduced fluoroquinolone use by 34%, which
was in turn associated with a reduction in the prevalence of MRSA by more than
half. Although rates of infection with Enterococcus also declined with the
study intervention, rates of infection with gram-negative organisms increased.
The
routine use of fluoroquinolones for more limited infections, such as
uncomplicated cystitis, can substantially contribute to the selection of
resistant organisms. Therefore, the current study by Hooton and colleagues
compares cefpodoxime, a broad-spectrum cephalosporin, vs ciprofloxacin among
women with uncomplicated cystitis.
Study
Synopsis and Perspective
Three
days of cefpodoxime failed to measure up to 3 days of ciprofloxacin in the
treatment of women with acute uncomplicated cystitis, according
to an article published in the February 8 issue of JAMA. Thomas Hooton, MD,
from the Department of Medicine at the School of Medicine of the University of
Miami in Florida, and colleagues in Washington state report that 100 mg of
cefpodoxime orally twice daily (n = 150) did not meet criteria for
noninferiority when compared with 250 mg of ciprofloxacin orally twice daily (n
= 150) in a randomized, double-blind, noninferiority trial.
The
investigators conducted the trial because of the need to find a
fluoroquinolone-sparing regimen to treat acute uncomplicated cystitis in the
face of increasing fluoroquinolone resistance. Cefpodoxime has a broad spectrum
of antimicrobial activity, but there is a paucity of data on its use in this
setting.
The
researchers recruited study participants between the ages of 18 and 55 years
from a student health center in Seattle, Washington, and a referral center in
Miami. Exclusion criteria included diabetes mellitus or exposure to
antimicrobial agents in the previous 2 weeks. Fifteen women in the
ciprofloxacin group and 17 women in the cefpodoxime group were lost to
follow-up.
At
baseline, the 2 groups had similar characteristics except that more women in
the cefpodoxime group had a history of urinary tract infections and
pyelonephritis, and fewer women had fewer than 105 colony forming
units of a uropathogen per milliliter. The majority of infections (75%) were
caused by Escherichia coli
alone or in combination with another uropathogen (2%).
In
an intent-to-treat analysis, regardless of whether women lost to follow-up were
considered as cured or as treatment failures, cefpodoxime did not meet criteria
of noninferiority for achieving overall clinical cure. The predefined criterion
for noninferiority of cefpodoxime was a cure rate within a 10% margin of
ciprofloxacin (ie, for the difference in the cure rate for ciprofloxacin minus
the rate for cefpodoxime, the upper limit of the confidence interval had to be
<10%). An overall clinical cure was defined as not requiring antimicrobial
treatment at a 30-day visit.
Table.
Cure Rates at 30-Day Visit
Ciprofloxacin | Cefpodoxime | Difference | 95% | |
Clinical | ||||
Considering | 93% | 82% | 11% | 3% |
Considering | 83% | 71% | 12% | 3% |
Microbiological | 96% | 81% | 15% | 8% |
ITT,
intent-to-treat approach.
At a
first follow-up visit at 5 to 9 days after the start of therapy, 16% of women
taking ciprofloxacin and 40% of women taking cefpodoxime had vaginal
colonization with E coli.
The inferior activity of cefpodoxime to eliminate E coli may help to explain its poorer
clinical activity in treating cystitis.
The
test for noninferiority was not statistically significant (P = .57). Therefore, the
investigators concluded that these findings "do not support the use of
cefpodoxime as a first-line fluoroquinolone-sparing antimicrobial for acute
uncomplicated cystitis."
The
authors note that strengths of the study are its double-blind design, large
sample size, low drop-out rate, and high rate of medication adherence (98% -
99% of the women reported taking all 6 doses of the drugs). However, these
strengths are also a limitation, in that the results with these highly
compliant, mainly white students may not be generalizable to other patient
populations with different characteristics.
James
Johnson, MD, professor of medicine in the Division of Infectious Diseases at
the University of Minnesota in Minneapolis, told Medscape Medical News that he thinks the
study was well done, using 2 well-defined, randomized groups that were
followed-up appropriately to investigate all the relevant endpoints.
"I
think it's a lovely and very convincing study that pretty definitively shows
that the 2 treatments cannot be regarded as equal," said Dr. Johnson, who
was not involved in the study. "Still, the difference was not all that
big, and I think this is really valuable because there have not been good
studies previously of this drug, cefpodoxime. So now we have a pretty good
benchmark for how it performs for treating uncomplicated bladder infections.
This is going to be very useful when we run into organisms that are resistant
to our other options," or when a patient cannot tolerate another drug of
choice.
"We
have an epidemic of resistance to ciprofloxacin and similar drugs
(fluoroquinolones) right now. So it's important to think about how to avoid
using fluoroquinolones by using effective alternative agents," Dr. Johnson
pointed out. There is also resistance to an older standard drug,
trimethoprim-sulfamethoxazole.
Urinary
tract infections (UTIs) are common and are increasingly difficult to treat
because of mounting resistance in the bacteria. He said the investigators chose
to test a drug for which there had not been much experience in cystitis and
that was a reasonable drug to consider based on its activity against the usual
causative organisms of UTIs.
A
secondary endpoint in the trial was how well the drugs eliminated organisms in
the vagina. "It's known that the bugs that cause bladder infections often
come from there and reside there, and unless they are eliminated from there,
there's a risk for reinfection," Dr. Johnson noted. "Although there
was a difference in [how] the drugs performed there, it's not clear that that
explained their result."
To
spare fluoroquinolones, he said recent guidelines have suggested using nitrofurantoin, which needs to be given
for at least 5 days and may not work as well as ciprofloxacin. Another option
is fosfomycin, which does not have
cross-resistance with fluoroquinolones, trimethoprim-sulfamethoxazole,
or cephalosporins. "It works pretty well, but not
quite as well as the ciprofloxacin and trimethoprim-sulfa[methoxazole],"
Dr. Johnson said. In addition, it is given as a single, large dose and may
cause some stomach upset. Finally, there is also amoxicillin-clavulanate.
"We're
in sort of an unhappy place," Dr. Johnson said. "We have these
various non-ciprofloxacin-type options, and they're great for avoiding using
cipro[floxacin], but they maybe don't work quite as well," and that is why
physicians like to use ciprofloxacin.
However,
Dr. Johnson warned that the use of fluoroquinolones is a balancing act between
what is best today for a particular patient and what will preserve the
antimicrobial activity of current drugs into the future. "That's where the
recommendation for using nitrofurantoin comes from, and I think it's a sensible
recommendation," he advised.
Dr.
Hooton has been a consultant for Pinnacle Pharmaceuticals, Pfizer, Inc, and
Alita Pharmaceuticals. The other authors have disclosed no relevant financial
relationships. Dr. Johnson has received research support from Merck, Rochester
Medical, and Syntiron.
JAMA. 2012;307:583-589.
Study
Highlights
- Women
eligible for study participation received treatment in study centers in
Florida and Washington and were between the ages of 18 and 55 years. All
participants had typical symptoms of acute cystitis as well as pyuria on
urine testing. A urine culture result was considered positive if it grew
at least 102 colony-forming units of a uropathogen. - Women
with diabetes mellitus, known abnormalities of the urinary tract, or
recent exposure to antimicrobials were excluded from study analysis. - Participants
were randomly assigned to receive either ciprofloxacin 250 mg twice daily
for 3 days, or cefpodoxime 100 mg twice daily for 3 days. Study treatment
was double blinded. - Participants
completed follow-up visits at 5 to 9 days and 28 to 30 days after
completion of therapy, or earlier if they experienced problems. - Urine
specimens were collected at each study visit, as were vaginal specimens to
evaluate for colonization with uropathogens. - The
main study outcome was clinical cure, which was defined as the absence of
need for additional antimicrobial therapy for 30 days after study
treatment. Secondary study outcomes included clinical and microbiological
cure at the first follow-up visit and rates of vaginal colonization with E coli. - The
study was designed to test noninferiority of cefpodoxime vs ciprofloxacin. - The
study was completed between 2005 and 2009. A total of 300 women enrolled
in the trial, and the mean age of participants was 23 years. Most women
had contracted cystitis before the study date, and women receiving
cefpodoxime had higher rates of cystitis during the past year. - Women
receiving cefpodoxime were also more likely to have growth of at least 105
colony-forming units on urine culture. - 75%
of cases of cystitis were because of E
coli. Rates of antimicrobial sensitivity to ciprofloxacin and
cefpodoxime were 96% for each drug. - The
primary cure rates associated with treatment with ciprofloxacin and
cefpodoxime were 93% and 82%, respectively. Cefpodoxime failed to
demonstrate noninferiority to ciprofloxacin in this outcome in both
intent-to-treat and per-protocol analyses. - Ciprofloxacin
was superior to cefpodoxime in subgroup analyses based on a first-ever
episode of cystitis and urine cultures with pathogens susceptible to the
study drug. - The
clinical cure rates at 5 days in the ciprofloxacin and cefpodoxime groups
were 93% and 88%, a result suggesting noninferiority of cefpodoxime. The
response to therapy was greater after the first week in the ciprofloxacin
group. - Nonresponse
to therapy was more common among women with E coli infections treated with
cefpodoxime vs ciprofloxacin. - The
respective microbiological cure rates at 5 days with ciprofloxacin and
cefpodoxime were 96% and 81%. - 82%
of women had vaginal E
coli colonization at enrollment. By study day 5, these rates
had decreased to 16% and 40% in the ciprofloxacin and cefpodoxime groups,
respectively. - Adverse
events associated with study treatment were generally mild and were
similar in the ciprofloxacin and cefpodoxime groups.
Clinical
Implications
- Previous
research by Madaras-Kelly and colleagues suggests that reducing the use of
fluoroquinolones can reduce the prevalence of infection with MRSA and
Enterococcus, but there is an increased risk for infection with
gram-negative organisms. - The
current study by Hooton and colleagues demonstrates that ciprofloxacin vs
cefpodoxime is associated with improved rates of clinical and
microbiologic cure for uncomplicated cystitis among women.
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