Transcript Slide 1

Efficacy of 5-Day LevofloxacinContaining Concomitant Therapy
in Eradication of Helicobacter
pylori Infection
Gastroenterology, Volume 143, Issue 1, July 2012, Pages 10-12
Alessandro Federico et al
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Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of
Helicobacter pylori Infection
• Helicobacter pylori is a transmissible human pathogen that
causes symptomatic diseases, including adenocarcinoma
of the distal stomach, in approximately 20% of infected
subjects. Therefore, this infection should be cured
whenever it is diagnosed.
• H pylori infection has proven challenging to cure because
the prevalence of bacterial strains resistant to the most
commonly used antimicrobials, in particular clarithromycin
(CLA), increases.
Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of
Helicobacter pylori Infection
• As a result, currently recommended first-line therapies
both in the United States and Europe achieve a 75%–
80% eradication rate, which is not acceptable.
• Because of this, the Maastricht III and Maastricht IV
Consensus Conferences recommended bismuthcontaining quadruple therapy (ie, proton pump inhibitor
[PPI] plus bismuth, tetracycline [TET], and metronidazole
[MET]) as a first-line strategy in areas with a high (ie,
>15%) prevalence of CLA resistance, even though
compliance with this regimen is low.
Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of
Helicobacter pylori Infection
• We have recently shown that in an area of high prevalence
(ie, >15%) of CLA and dual (ie, CLA plus MET) resistance,
a levofloxacin (LEV)-containing ST is more effective than a
CLA-containing ST regimen, achieving eradication rates
higher than 95%.
• ST is actually a quadruple therapy with 3 antimicrobials (ie,
AMO, a macrolide/quinolone, and an imidazole) and an acid
suppressive agent given in sequence over a 10-day period.
Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of
Helicobacter pylori Infection
• Based on the hypothesis that the use of 3 antimicrobials
rather than the sequential scheme of drug administration
plays a major role in the efficacy of ST, we designed a
study to assess whether the concomitant administration
of a PPI, AMO, LEV, and TIN for 5 days might be as
effective as the 10-day sequential administration of the
same drugs at the same total dose of antimicrobials in H
pylori–infected patients naïve to treatment.
• Secondary end points were to assess the influence of
antimicrobial resistance on the outcome of eradication
treatments, the incidence of adverse events, and the
costs related to either regimen.
Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of
Helicobacter pylori Infection
Methods
• A total of 468 consecutive patients with dyspepsia who
were referred to our gastroenterology units for
consultation between January and December 2011 were
asked to participate in the study.
• H pylori–infected patients who were at least 18 years of
age .
• Diagnosis of H pylori infection was based on positivity to
13C urea breath test (13C-UBT) or on positivity to both
rapid urease test and histology in those patients who
underwent endoscopy because of age older than 45
years and/or presence of alarm symptoms.
Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of
Helicobacter pylori Infection
• In patients undergoing endoscopy, 5 biopsy specimens
were taken for histologic assessment according to the
Sydney system and 2 more specimens (1 from the antrum
and 1 from the body) were taken for rapid urease test.
• Two additional biopsy samples were obtained from the
antrum for bacterial culture and antimicrobial susceptibility
testing. Biopsy samples were sent to our microbiology
laboratory within 24 hours and stored at −70°C.
• Isolated strains were tested for in vitro susceptibility to
AMO, TET, CLA, LEV, and MET by E-test .
Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of
Helicobacter pylori Infection
• Exclusion criteria : previous treatment for H pylori
infection; use of inhibitors of acid secretion and/or
antibiotics during the 6 weeks before the study;
gastrointestinal malignancy; previous gastroesophageal
surgery; severe concomitant diseases; hematologic
disorders; history of allergy to any of the drugs used in
the study; pregnancy or lactation; alcohol abuse; drug
addiction; severe neurologic or psychiatric disorders; and
long-term use of corticosteroids or anti-inflammatory
drugs.
• To assess whether the infection had been eradicated, H
pylori status was reevaluated by 13C-UBT performed by
nonmedical personnel unaware of the eradication
regimen of each patient at 6 and 10 weeks after
completion of therapy.
• Infection was considered eradicated if patients had a
negative test result on both occasions.
• 13C-UBT was performed after an overnight fast. A
baseline breath sample was obtained, and 100 mg of
13C urea with citric acid (1.4 g) was administered as an
aqueous solution .Another breath sample was collected
30 minutes later.
• The test result was considered positive if the difference
between the baseline sample and the 30-minute sample
exceeded 5.0 parts/1000 of 13co2.
• All treated patients discontinued treatment with PPIs at
least 2 weeks before undergoing 13C-UBT.
Therapeutic Regimens
• Each group consisted of 90 patients. One group was
treated with a 5-day quadruple concomitant therapy (5dQCT) (ie, esomeprazole 40 mg twice daily plus AMO 1 g
twice daily plus LEV 500 mg twice daily plus TIN 500 mg
twice daily for 5 consecutive days).
• The second group was treated with 10-day sequential
therapy (10d-ST) (ie, esomeprazole 40 mg twice daily
plus AMO 1 g twice daily for 5 days followed by
esomeprazole 40 mg twice daily plus LEV 500 mg twice
daily plus TIN 500 mg twice daily for 5 more days).
• Patients who failed to eradicate the infection were retreated with a quadruple therapy consisting of
esomeprazole 40 mg twice daily plus MET 500 mg 3
times daily plus TET 500 mg 4 times a day plus bismuth
subcitrate 240 mg twice daily and underwent a new 13CUBT after 6 weeks.
• The trial was designed as a noninferiority trial. The
primary outcome was the ITT H pylori eradication rates
for the 2 treatments.
• The secondary outcomes were the PP eradication rates
and the role of antimicrobial resistance in the response
to treatments. Finally, we evaluated the frequency of
adverse events and costs of either regimen.
Results
Results
• Patients with unsuccessful first-line therapy were treated
with bismuth-containing quadruple therapy, which led to
eradication of the infection in the 3 patients who had not
been eradicated of the infection with 5d-QCT and in the
4 patients who had not been eradicated of the infection
following 10d-ST.
• The 4 patients who discontinued therapy because of
severe adverse events with 5d-QCT were tested by 13CUBT, and 2 of 4 were eradicated of the infection.
• Also, the 2 patients who discontinued therapy in the 10dST group underwent 13C-UBT, and both tested positive.
• Symptoms that caused discontinuation of therapy were
skin rash and itching in 2 patients after 2 days of
treatment and diarrhea, nausea, and vomiting after 3 days
of treatment in 2 more patients in the 5d-QCT group;
diarrhea and epigastric pain at the third day of the first
period caused discontinuation of therapy in 2 patients in
the 10d-ST group.
• The cost of 5d-QCT, according to the Italian National
Health System, was €33.5 ($43.50), whereas the cost of
the 10d-ST was €40.2 ($52.30).
• Therefore, the cost of 5d-QCT was approximately €7
($9) less compared with the cost of 10d-ST. This
difference was accounted for by the lower amount of
esomeprazole used in the 2 regimens
Discussion
• Over the past decade, a steady decline was observed in the
rate of H pylori eradication following triple therapies, thus
requiring a search for novel therapeutic approaches to cure
H pylori infection.
• This randomized clinical trial involving 180 patients from 2
university hospitals shows that in an area of high
prevalence (ie, >15%) of CLA-resistant H pylori strains, a 5day LEV-containing quadruple concomitant therapy
produced ITT eradication rates >90% and was safe and well
tolerated by most patients.
• Our results are in agreement with a recent study by Wu
et al showing that concomitant and sequential therapies
were equally effective in the eradication of H pylori
infection in patients naïve to treatment. However, unlike
our study, both treatments lasted for 10 days, and
therefore patients in the concomitant arm of treatment
received twice as much of antimicrobials compared with
those in the sequential arm.
• Several randomized controlled trials and one metaanalysis have shown that nonbismuth quadruple
(concomitant) therapy is more effective than and as
equally tolerated as standard triple therapy.
• We performed in vitro antimicrobial susceptibility testing,
which confirmed the high prevalence of CLA-, MET-, and
dual-resistant H pylori strains together with an
approximately 8% prevalence of LEV resistance.
• As expected, CLA resistance did not affect the efficacy of
therapy and 100% of patients infected with CLA-resistant
strains were eradicated of the infection.
• Nine of 10 (90%) and 10 of 11 (90.9%) patients infected
with a MET-resistant strain eradicated the infection in the
5d-QCT group and 10d-ST group, respectively.
• In a recent study by Molina–Infante et al, a 10-day LEVcontaining sequential regimen, while showing higher
efficacy compared with a 10-day CLA-containing
sequential regimen, achieved ITT eradication rates of
approximately 85%, which is lower than that reported in
our study (ie, 93%).
• The lower efficacy of LEV-ST compared with our study
might be related to a higher prevalence of LEV-resistant
H pylori strains in Spain compared with our geographical
area. In this respect, one must keep in mind that the
main disadvantage with use of LEV-containing therapies
is the rapid emergence of resistance to this antimicrobial.
• A limitation to 100% efficiency of eradication regimens is
compliance to treatment, mainly due to drug-related
adverse events.
• In our study, patients were instructed not to suspend
therapy arbitrarily and to contact us in the case of the
occurrence of adverse effects. Nearly all adverse events
were numerically slightly higher in the 5d-QCT arm
compared with the 10d-ST arm.
• However, this did not reach statistical significance.
• A limitation of the study is that only 55% of the
participants underwent endoscopy and had assessment
of H pylori status at entry by 2 tests on biopsy specimens
• In the remaining 45%, H pylori status at entry was
assessed with a single 13C-UBT. However, one must
keep in mind that 13C-UBT is an excellent test to use in
clinical practice with sensitivity and specificity higher
than 95.
Conclusion
• In this randomized trial showed that in an area of high
(ie, >15%) prevalence of CLA-resistant H. pylori strains,
a 5-day LEV-containing, nonbismuth, quadruple
concomitant therapy is highly effective in the treatment of
H pylori infection with an ITT eradication rate of 92% and
a PP eradication rate of 96%. Also, this eradication
regimen is easy to follow for the patient and well
tolerated. Therefore, this regimen may represent an
effective, reduced cost, and safe first-line therapeutic
alternative in areas where the efficacy of triple therapy is
unacceptably low.
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