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GASTROENTEROLOGY 2012;143:55–61

CLINICAL—ALIMENTARY TRACT

Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy inEradication of Helicobacter pylori Infection

ALESSANDRO FEDERICO,* GERARDO NARDONE,‡ ANTONIETTA G. GRAVINA,* MARIA ROSARIA IOVENE,§

AGNESE MIRANDA,* DEBORA COMPARE,‡ PAOLA A. PILLONI,§ ALBA ROCCO,‡ LUIGI RICCIARDIELLO,�

RICCARDO MARMO,¶ CARMELINA LOGUERCIO,* and MARCO ROMANO*

Dipartimento Medico Chirurgico di Internistica Clinica e Sperimentale ed UOC di *Gastroenterologia e, §Microbiologia Clinica, Azienda Ospedaliera Universitaria,econda Università di Napoli, Napoli; ‡Dipartimento di Medicina Clinica e Sperimentale-Area Funzionale di Gastroenterologia, Università Federico II, Napoli;

�Dipartimento di Medicina Clinica-Gastroenterologia, Università di Bologna, Bologna; and ¶Unità Operativa di Gastroenterologia, A.O. Salerno, Presidio Ospedalieroolla (SA), Italy

This article has an accompanying continuing medical education activity on page e13. Learning Objective: Uponcompletion of the CME activity, successful learners will be able to formulate an appropriate treatment schedule

for eradication of Helicobacter pylori infection in infected patients naive to treatment.

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See Covering the Cover synopsis on page 1;editorial on page 10.

BACKGROUND & AIMS: Helicobacter pylori have be-ome resistant to antimicrobial agents, reducing eradica-ion rates. A 10-day sequential regimen that containsevofloxacin was efficient, safe, and cost saving in eradi-ating H pylori infection in an area with high prevalence oflarithromycin resistance. We performed a noninferiorityandomized trial to determine whether a 5-day levofloxa-in-containing quadruple concomitant regimen was asafe and effective as the 10-day sequential regimen inradicating H pylori in previously untreated patients.

ETHODS: We randomly assigned patients with H pylorinfection to groups that were given 5 days of concomitantherapy (esomeprazole 40 mg twice daily, amoxicillin 1 gwice daily, levofloxacin 500 mg twice daily, and tinidazole00 mg twice daily; n � 90) or 10 days of sequentialherapy (esomeprazole 40 mg twice daily, amoxicillin 1gwice daily for 5 days followed by esomeprazole 40 mgwice daily, levofloxacin 500 mg twice daily, and tinidazole00 mg twice daily for 5 more days; n � 90). Antimicro-ial resistance was assessed by the E-test. Efficacy, adversevents, and costs were determined. RESULTS: Intention-o-treat analysis showed similar eradication rates foroncomitant (92.2%; 95% confidence interval [CI], 84.0%–5.8%) and sequential therapies (93.3%; 95% CI, 86.9%–7.3%). Per-protocol eradication results were 96.5% (95%I, 91%–99%) for concomitant therapy and 95.5% for

equential therapy (95% CI, 89.6%–98.5%). The differencesetween sequential and concomitant treatments were.1% in the intention-to-treat study (95% CI; �7.6% to.8%) and �1.0% in the per-protocol analysis (95% CI;

8.0% to 5.9%). The prevalence of antimicrobial resistance

nd incidence of adverse events were comparable betweenroups. Concomitant therapy cost $9 less than sequentialherapy. CONCLUSIONS: Five days of levofloxacin-ontaining quadruple concomitant therapy is as effec-ive and safe, and less expensive, in eradicating Hylori infection than 10 days of levofloxacin-contain-ng sequential therapy.

eywords: Bacterial Infection; Fluoroquinolone; Antibioticlinical Trial.

Helicobacter pylori is a transmissible human pathogenthat causes symptomatic diseases, including adeno-

carcinoma of the distal stomach, in approximately 20% ofinfected subjects.1,2 Therefore, this infection should beured whenever it is diagnosed.3 Although H pylori is

susceptible to a number of antimicrobials, H pylori infec-tion has proven challenging to cure because the preva-lence of bacterial strains resistant to the most commonlyused antimicrobials, in particular clarithromycin (CLA),increases.4 – 6 As a result, currently recommended first-lineherapies both in the United States and Europe achieve a5%– 80% eradication rate, which is not acceptable.7,8 Be-

cause of this, the Maastricht III9 and Maastricht IV (Dralfertheiner, personal communication, May 2011) Con-

ensus Conferences recommended bismuth-containinguadruple therapy (ie, proton pump inhibitor [PPI] plus

Abbreviations used in this paper: AMO, amoxicillin; CI, confidenceinterval; CLA, clarithromycin; 5d-QCT, 5-day quadruple concomitanttherapy; ITT, intention-to-treat; LEV, levofloxacin; MET, metronidazole;PP, per-protocol; PPI, proton pump inhibitor; ST, sequential therapy;10d-ST, 10-day sequential therapy; TET, tetracycline; TIN, tinidazole;UBT, urea breath test.

© 2012 by the AGA Institute0016-5085/$36.00

http://dx.doi.org/10.1053/j.gastro.2012.03.043

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56 FEDERICO ET AL GASTROENTEROLOGY Vol. 143, No. 1

bismuth, tetracycline [TET], and metronidazole [MET]) asa first-line strategy in areas with a high (ie, �15%) preva-lence of CLA resistance, even though compliance with thisregimen is low.

A novel 10-day sequential therapy (ST) consisting of5-day dual therapy (PPI standard dose twice daily plusamoxicillin [AMO] 1 g twice daily) followed by 5-day tripletherapy (PPI standard dose twice daily plus CLA 500 mgtwice daily plus tinidazole [TIN] 500 mg twice daily) hasshown good eradication rates,10,11 even when there isvidence of CLA resistance.12 However, most recent stud-es have shown lower than expected efficacy with CLA-ontaining sequential regimens, thus raising the questions to whether this therapy should be recommended as anmpiric first-line regimen.13 In this regard, we have re-

cently shown that in an area of high prevalence (ie, �15%)of CLA and dual (ie, CLA plus MET) resistance, a levo-floxacin (LEV)-containing ST is more effective than aCLA-containing ST regimen, achieving eradication rateshigher than 95%.14 Among the alternative regimens to

LA-containing therapies, a novel bismuth-containinguadruple therapy using a single 3-in-1 capsule contain-

ng bismuth subcitrate, MET, and TET has recently beenroposed to decrease the pill burden and improve patientompliance.15 In a randomized clinical trial, this single-

capsule bismuth-containing 10-day treatment showed anintention-to-treat (ITT) cure rate of 80% and a per-proto-col (PP) cure rate of 93%.15

ST is actually a quadruple therapy with 3 antimicrobi-als (ie, AMO, a macrolide/quinolone, and an imidazole)and an acid suppressive agent given in sequence over a10-day period. Based on the hypothesis that the use of 3antimicrobials rather than the sequential scheme of drugadministration plays a major role in the efficacy of ST, wedesigned a study to assess whether the concomitant ad-ministration of a PPI, AMO, LEV, and TIN for 5 daysmight be as effective as the 10-day sequential administra-tion of the same drugs at the same total dose of antimi-crobials in H pylori–infected patients naïve to treatment.

econdary end points were to assess the influence ofntimicrobial resistance on the outcome of eradicationreatments, the incidence of adverse events, and the costs

related to either regimen.

Patients and MethodsDesign OverviewThis was a prospective, randomized, controlled study. At

baseline, patients were evaluated for inclusion and exclusioncriteria and provided written informed consent. Patients werethen randomly assigned to a treatment group and had a fol-low-up evaluation to assess the eradication rate of H pyloriinfection and adverse events. The study was performed accord-ing to Good Clinical Practice and the Declaration of Helsinkiand was approved by the institutional ethical committee. Allpatients who had not been eradicated of the infection wereoffered a second gastroenterology consultation, a rescue therapy,

and retesting. d

A total of 468 consecutive patients with dyspepsia who werereferred to our gastroenterology units for consultation betweenJanuary and December 2011 were asked to participate in thestudy. H pylori–infected patients who were at least 18 years of ageand who had never received H pylori eradication treatment wereincluded in the study. Diagnosis of H pylori infection was basedon positivity to 13C urea breath test (13C-UBT) or on positivity to

oth rapid urease test and histology in those patients whonderwent endoscopy because of age older than 45 years and/orresence of alarm symptoms. In patients undergoing endoscopy,biopsy (2 antrum, 2 body, and 1 angulus) specimens were

aken for histologic assessment according to the Sydney systemnd 2 more specimens (1 from the antrum and 1 from the body)ere taken for rapid urease test. Two additional biopsy samplesere obtained from the antrum for bacterial culture and anti-icrobial susceptibility testing. Biopsy samples were sent to ouricrobiology laboratory within 24 hours and stored at �70°C.

solated strains were tested for in vitro susceptibility to AMO,ET, CLA, LEV, and MET by E-test as described previously.16 –18

H pylori strains with a minimal inhibitory concentration value�0.25 mg/L, �1 mg/L, �0.5 mg/L, �2 mg/L, and �8 mg/L

ere considered to be resistant to AMO, TET, CLA, LEV, andET, respectively. Exclusion criteria were previous treatment forpylori infection; use of inhibitors of acid secretion and/or

ntibiotics during the 6 weeks before the study; gastrointestinalalignancy; previous gastroesophageal surgery; severe concom-

tant cardiovascular, respiratory, or endocrine diseases; clinicallyignificant renal or hepatic disease; hematologic disorders; anyther clinically significant medical condition that could increaseisk; history of allergy to any of the drugs used in the study;regnancy or lactation; alcohol abuse; drug addiction; severeeurologic or psychiatric disorders; and long-term use of corti-osteroids or anti-inflammatory drugs.

Patients were enrolled by the medical personnel of the GInit after assessment of appropriate indication and ruling out

ny contraindication to the treatments. Patients were randomlyllocated to receive one of the 2 treatment regimens using aentralized computer-generated random number list with blockize of 3, 6, 9, and 12. An independent medical staff memberssigned subjects to the 2 schedules. In each block there wereerially numbered, sealed, opaque envelopes. Each patient re-eived the next pack stored in the center following ascendingrder of labels. Patients were interviewed at completion of ther-py to assess adherence to the therapeutic regimen and adversevents by medical personnel blinded to the eradication regimenf each patient. In particular, first open-ended questions ondverse effects and then specific questions on anticipated ad-erse events were asked. To assess whether the infection hadeen eradicated, H pylori status was reevaluated by 13C-UBT

performed by nonmedical personnel unaware of the eradicationregimen of each patient at 6 and 10 weeks after completion oftherapy. Infection was considered eradicated if patients had anegative test result on both occasions.13C-UBT was performedafter an overnight fast. A baseline breath sample was obtained,and 100 mg of 13C urea with citric acid (1.4 g) was administered

s an aqueous solution (Expirobacter; SOFAR, Milano, Italy).nother breath sample was collected 30 minutes later. The test

esult was considered positive if the difference between theaseline sample and the 30-minute sample exceeded 5.0 parts/000 of 13CO2. All breath tests were analyzed at the same labo-atory by using a single gas isotope ratio mass spectrometerABCA, Europe Scientific, Crewe, England). All treated patients

iscontinued treatment with PPIs at least 2 weeks before under-

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July 2012 VASCULAR EFFECTS OF CIRRHOTIC MICROPARTICLES 57

going 13C-UBT. Inclusion and posttreatment 13C-UBT were al-ways performed in the same laboratory with the same methodsand cutoff point.

Therapeutic RegimensEach group consisted of 90 patients. One group was

treated with a 5-day quadruple concomitant therapy (5d-QCT)(ie, esomeprazole 40 mg twice daily plus AMO 1 g twice dailyplus LEV 500 mg twice daily plus TIN 500 mg twice daily for 5consecutive days). The second group was treated with 10-daysequential therapy (10d-ST) (ie, esomeprazole 40 mg twice dailyplus AMO 1 g twice daily for 5 days followed by esomeprazole 40mg twice daily plus LEV 500 mg twice daily plus TIN 500 mgtwice daily for 5 more days). Patients who failed to eradicate theinfection were re-treated with a quadruple therapy consisting ofesomeprazole 40 mg twice daily plus MET 500 mg 3 times dailyplus TET 500 mg 4 times a day plus bismuth subcitrate 240 mgtwice daily and underwent a new 13C-UBT after 6 weeks.

Objective and OutcomesThe objective of the trial was to compare a 5-day con-

comitant and a 10-day sequential administration of a non–bismuth-containing, LEV-containing, 4-drug treatment regimenfor the eradication of H pylori infection in patients naïve totreatment. The trial was designed as a noninferiority trial. Theprimary outcome was the ITT H pylori eradication rates for the2 treatments. The secondary outcomes were the PP eradicationrates and the role of antimicrobial resistance in the response totreatments. Finally, we evaluated the frequency of adverse eventsand costs of either regimen.

Statistical AnalysisBoth ITT and PP analyses were used for the assessment

of the eradication rates of H pylori infection in the 2 groups. Theignificance level was set at P � .05. The 95% confidence intervalsCIs) were constructed by normal approximation. The descrip-ive data, endoscopic diagnosis between subjects in the 2 treat-

ent arm groups, and incidence of adverse events were com-ared by �2 test or Fisher exact test as appropriate. The

difference in patients’ age in the 2 groups was examined usingStudent t test. A 2-sided P value of �.05 was considered statis-tically significant. Eradication rates achieved with the 2 thera-peutic regimens were compared by �2 test, and a 1-sided (ie,

oninferiority) P value of �.05 was considered statistically sig-ificant. The data were analyzed using the Stata statistical pack-ge (version 11.1; StataCorp LP, College Station, TX); all P valuesere 1 sided. Sample size was calculated with StudySize 2.0

CreoStat HB, Frolunda, Sweden).The study was designed to show the noninferiority efficacy of

he concomitant therapy versus the sequential treatment. With aoint estimate of 95% in the reference standard,14,19 we calcu-

lated the sample size considering a noninferiority margin (ie, �)of 10%, upper and lower CIs varying from �10% to �1%, a powerof 0.80, and a significance level of .05 (1-sided � level of .05). Thevalue of � indicates how much the efficacy of the active controlie, 10d-ST) can exceed the efficacy of the new treatment (ie,d-QCT), with the new treatment still considered noninferior tohe active control. Our choice of a � of 10% was based on current

recommendation of several regulatory agencies, including the

Food and Drug Administration, for anti-infective trials, regard-less of the specific type or severity of infection.20,21 Also, follow-ng the recommendation of the Food and Drug Administrationo use the best comparator to avoid biocreep (ie, the phenome-on that can occur when a slightly inferior treatment becomeshe active control for the next generation of noninferiority trialsnd so on until the active controls become no better than alacebo), we chose 10d-ST (which has an efficacy close to 95%) ashe active control. Based on this, a sample size of 80 patients perreatment group was calculated to be sufficient; however, weecided to increase the number to 90 patients per treatmentroup to compensate for a potential 10% loss at follow-up.ecause we assumed that the 5d-QCT was not inferior to the0d-ST, comparison between costs related to either regimen waserformed by a cost minimization analysis.

ResultsPatientsThe flow of patients through the study is shown in

Supplementary Figure 1. Of the 468 patients who partic-ipated in the first visit, 270 were excluded because theywere not infected with H pylori. Of the remaining 198patients, 2 were excluded because of gastric cancer, 1 wasexcluded because of gastric mucosa-associated lymphoidtissue (MALT) lymphoma, and 15 withdrew consent. Ofthe 180 randomly assigned patients, 4 in the 5d-QCTgroup and 2 in the 10d-ST group discontinued therapybecause of severe adverse events. The demographic andclinical characteristics of patients were comparable in the2 groups (Table 1).

Eradication of H pylori Infection and AdverseEventsThe efficacy of the 2 eradication regimens is shown

in Table 2. In particular, in the ITT analysis, eradicationrates were 83/90 (92.2%; 95% CI, 84.0%–95.8%) with 5d-QCT and 84/90 (93.3%; 95% CI, 86.9%–97.3%) with 10d-ST. In the PP analysis, eradication rates were 83/86 (96.5%;95% CI, 91.0%–99.0%) with 5d-QCT and 84/88 (95.5%;95% CI, 89.6%–98.5%) with 10d-ST. The noninferioritycomparisons of the 2 treatments both in the ITT and PP

Table 1. Baseline Characteristics of Patients

Variable5d-QCT

(n � 90)10d-ST

(n � 90)P

value

Age range, (median), y 22–77 (50) 28–78 (53) .102Male/female 35/55 42/48 .216Upper endoscopy 47/90 (52.2) 52/90 (57.7) .976Peptic ulcer 3/47 (6.3) 3/52 (5.8) .898Mild mixed gastritis 38/47 (80.9) 41/52 (78.8) .804Antrum-predominant

gastritis6/47 (12.8) 8/52 (15.4) .709

Corpus-predominantgastritis

3/47 (6.3) 3/52 (5.8) .898

Intestinal metaplasia 9/47 (19.1) 12/52 (23.0) .633

NOTE. Values are given as n (%) unless otherwise indicated.

analyses did not show any significant difference (Table 2).

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Patients with unsuccessful first-line therapy were treatedwith bismuth-containing quadruple therapy, which led toeradication of the infection in the 3 patients who had notbeen eradicated of the infection with 5d-QCT and in the4 patients who had not been eradicated of the infectionfollowing 10d-ST (data not shown). The 4 patients whodiscontinued therapy because of severe adverse eventswith 5d-QCT were tested by 13C-UBT, and 2 of 4 wereeradicated of the infection. Also, the 2 patients who dis-continued therapy in the 10d-ST group underwent 13C-UBT, and both tested positive.

The incidence of adverse events was comparable in the2 groups (Table 3). Adverse events were so severe as tocause discontinuation of therapy in 4 patients (4.4%) inthe 5d-QCT group and 2 patients (2.2%) in the 10d-STgroup. Symptoms that caused discontinuation of therapywere skin rash and itching in 2 patients after 2 days oftreatment and diarrhea, nausea, and vomiting after 3 daysof treatment in 2 more patients in the 5d-QCT group;diarrhea and epigastric pain at the third day of the firstperiod caused discontinuation of therapy in 2 patients inthe 10d-ST group. The most frequently reported adverseevent was bad taste/taste alteration, which was experi-enced by more than 25% of patients in both groups. Allpatients reported an unpleasant feeling of a bitter tasteimmediately following the ingestion of TIN. However, it isimpossible from this to extrapolate that the alteration oftaste was due to TIN.

Table 2. Eradication Rates of 5d-QCT and 10d-ST andNoninferiority Comparisons

ITT PP

5d-QCT 83/90 (92.2) 83/86 (96.5)95% CI 84%–95.8% 91%–99%

10d-ST 84/90 (93.3) 84/88 (95.5)95% CI 86.9%–97.3% 89.6%–98.5%

Absolute difference 1.1% �1.0%95% CI �7.6 to 9.8 �8.0 to 5.9P value .774 .769

NOTE. Values are given as n (%) unless otherwise indicated.

Table 3. Number of Patients With Adverse Events DuringTherapy

Adverse event5d-QCT

(n � 90)10d-ST

(n � 90) P value

Diarrhea 9 (10.0) 7 (7.8) .600Epigastric pain 6 (6.7) 7 (7.8) .773Nausea 6 (6.6) 5 (5.6) .756Vomiting 5 (5.6) 3 (3.3) .469Glossitis 7 (7.8) 6 (6.7) .773Bad taste/taste alteration 25 (27.8) 24 (26.6) .867Headache 4 (4.4) 4 (4.4) 1Itching 5 (5.6) 3 (3.3) .469Skin rash 5 (5.5) 2 (2.2) .247

evere adverse eventsa 4 (4.4) 2 (2.2) .406

OTE. Values are given as n (%) unless otherwise indicated.

aEvents that caused discontinuation of therapy.

Role of Primary Resistance in the Eradicationof H pylori InfectionBacterial culture was performed in those patients

who had undergone endoscopy and was successful inapproximately 90% of patients. Data of antimicrobial re-sistance were therefore available in 42 of 47 (89.3%) and47 of 52 (90.4%) subjects in the 5d-QCT and 10d-STgroups, respectively. No resistance to AMO and TET wasdetected in any patient (Table 3). The overall prevalence ofresistance to CLA, MET, LEV, and CLA plus MET was18/89 (20.2%), 21/89 (23.6%), 7/89 (7.9%), and 6/89 (6.7%),respectively, and no significant differences in antimicro-bial resistance were observed between groups (Table 4).

5d-QCT eradicated the infection in 8 of 8 patients(100%) with isolated resistance to CLA and in 9 of 10patients (90.0%) with isolated MET resistance, whereas10d-ST was 100% effective in patients with CLA-resistantstrains and eradicated the infection in 10 of 11 patients(90.9%) with MET-resistant strains (Table 5). Both regi-mens were 100% effective in eradicating the infection inthe patients (3 per each group) with dual (ie, CLA plusMET) resistant strains. Finally, 2 of 3 patients (66.7%),both in the 5d-QCT and 10d-ST groups, infected withLEV-resistant strains had eradicated infections (Table 5).

Table 4. Prevalence of Antimicrobial Resistance in the 5d-QCT Group (n � 42) and in the 10d-ST Group(n � 47)

Antimicrobial Overall 5d-QCT 10d-STP

value

AMO 0/89 0/42 0/47 NATET 0/89 0/42 0/47 NACLA 18/89 (20.2) 8/42 (19) 10/47 (21.3) .794MET 21/89 (23.6) 10/42 (23.8) 11/47 (23.4) .964LEV 7/89 (7.9) 3/42 (7.1) 4/47 (8.5) .908CLA � MET 6/89 (6.7) 3/42 (7.1) 3/47 (6.4) .887

NOTE. Values are given as n (%) unless otherwise indicated.NA, not available.

Table 5. Effect of CLA, MET, Dual (ie, CLA � MET), and LEVResistance on H pylori Eradication Rates in the 2Study Groups

Antimicrobial5d-QCT

(n � 42)10d-ST

(n � 47) P value

CLA resistant 8/8 (100) 10/10 (100) NACLA susceptible 29/31 (93.5) 31/33 (93.9) .949MET resistant 9/10 (90) 10/11 (90.9) .943MET susceptible 28/29 (96.5) 31/32 (96.9) .944CLA � MET

resistant3/3 (100) 4/4 (100) NA

CLA � METsusceptible

20/21 (95.2) 21/22 (95.5) .973

LEV resistant 2/3 (66.7) 2/3 (66.7) 1LEV susceptible 38/39 (97.4) 43/44 (97.7) .931

NOTE. Values are given as n (%) unless otherwise indicated.

NA, not available.

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July 2012 VASCULAR EFFECTS OF CIRRHOTIC MICROPARTICLES 59

Cost of Eradication RegimensThe cost of 5d-QCT, according to the Italian Na-

tional Health System, was €33.5 ($43.50), whereas the costf the 10d-ST was €40.2 ($52.30). Therefore, the cost ofd-QCT was approximately €7 ($9) less compared withhe cost of 10d-ST. This difference was accounted for byhe lower amount of esomeprazole used in the 2 regimensie, 2 tablets/day for 5 days for a total of 10 tablets in thed-QCT group and 2 tablets/day for 10 days for a total of0 tablets in the 10d-ST group).

DiscussionOver the past decade, a steady decline was observed

in the rate of H pylori eradication following triple thera-pies, thus requiring a search for novel therapeutic ap-proaches to cure H pylori infection.22,23 This randomizedlinical trial involving 180 patients from 2 university hos-itals shows that in an area of high prevalence (ie, �15%)f CLA-resistant H pylori strains, a 5-day LEV-containinguadruple concomitant therapy produced ITT eradicationates �90% and was safe and well tolerated by mostatients. The regimen is easy to follow for the patientsnd also results in a substantial saving in costs because ofhe lower amount of PPI used (ie, 5 days rather than 10ays). Our results are in agreement with a recent study byu et al showing that concomitant and sequential ther-

pies were equally effective in the eradication of H pylorinfection in patients naïve to treatment.24 However, unlike

our study, both treatments lasted for 10 days, and there-fore patients in the concomitant arm of treatment re-ceived twice as much of antimicrobials compared withthose in the sequential arm.

Several randomized controlled trials and one meta-analysis25 have shown that nonbismuth quadruple (con-omitant) therapy is more effective than and as equallyolerated as standard triple therapy. The efficacy of non-ismuth quadruple (concomitant) therapy has recentlyeen critically reviewed in a meta-analysis of 15 studies

nvolving 1723 patients by Gisbert and Calvet, who foundmean H pylori cure rate (ITT analysis) of 90% for non-

ismuth quadruple therapy with a tendency toward betteresults with longer treatments (ie, 7–10 days).26 In ourtudy, we obtained comparable eradication rates with ahorter duration of the eradication therapy (ie, 5 days),hich increases patients’ compliance and reduces costs.In a subset of patients who underwent endoscopy, we

erformed in vitro antimicrobial susceptibility testing,hich confirmed the high prevalence of CLA-, MET-, andual-resistant H pylori strains together with an approxi-ately 8% prevalence of LEV resistance. As expected, CLA

esistance did not affect the efficacy of therapy and 100%f patients infected with CLA-resistant strains were erad-

cated of the infection. Nine of 10 (90%) and 10 of 1190.9%) patients infected with a MET-resistant strain erad-cated the infection in the 5d-QCT group and 10d-STroup, respectively. Interestingly, in patients infected with

n LEV-resistant strain, eradication was achieved in 2 of 3

ubjects (66.7%) in both groups. However, the number isoo limited to draw conclusions on the efficacy of thisradication regimen in the face of LEV resistance.

Fluoroquinolones such as LEV have been used success-ully in combination with PPI and AMO in the treatmentf H pylori infection both as first-line27 and second-

ine28,29 therapy. In a recent study by Molina–Infante et al,10-day LEV-containing sequential regimen, while show-

ng higher efficacy compared with a 10-day CLA-contain-ng sequential regimen, achieved ITT eradication rates ofpproximately 85%, which is lower than that reported inur study (ie, 93%).30 The lower efficacy of LEV-ST com-ared with our study might be related to a higher preva-

ence of LEV-resistant H pylori strains in Spain comparedwith our geographical area.31 In this respect, one mustkeep in mind that the main disadvantage with use ofLEV-containing therapies is the rapid emergence of resis-tance to this antimicrobial.32 This might represent a lim-tation in the future of our eradication regimen and ofhose containing LEV in general.

A �95% efficient empiric eradication regimen is still farrom being available. There are not many antimicrobialsurrently used to cure the infection, and unfortunatelyhe rate of resistance to all of them is increasing. Oneption is to search for a novel scheme of treatments tovercome the antimicrobial resistance. An example of thispproach is hybrid therapy (ie, PPI and AMO for 14 daysith CLA and MET added for the final 5 days), which has

ecently shown promising results with ITT eradicationates of 97.4%.33 Another approach is to use only a com-

bination of drugs that is known to be successful in thelocal population of H pylori–infected subjects; to this end,it is crucial to continuously monitor the prevalence ofantimicrobial resistance in the areas in which we prac-tice.34 Finally, agents other than antimicrobials capable ofreating an hostile environment to H pylori without caus-ng the emergence of any further resistance should beearched for and might represent a valid strategy in theuture.

A limitation to 100% efficiency of eradication regimenss compliance to treatment, mainly due to drug-relateddverse events. In our study, patients were instructed noto suspend therapy arbitrarily and to contact us in thease of the occurrence of adverse effects. Nearly all adversevents were numerically slightly higher in the 5d-QCTrm compared with the 10d-ST arm, as was the number ofatients who discontinued therapy because of severe ad-erse events. However, this did not reach statistical signif-cance. Further studies are needed to assess whether this

ight represent a potential limitation of 5d-QCT. Weerformed 13C-UBT in all patients who interrupted ther-

apy. All of them were still infected, with the exception of2 patients in the 5d-QCT group who were eradicated ofthe infection despite discontinuing therapy after 3 daysof treatment. This once again confirms that adherence totherapy is crucial to achieve cure of the infection.

Cost is an important consideration for any therapy. In

our study, because of the reduced amount of esomepra-

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zole used (ie, 40 mg twice daily for 5 days vs 40 mg twicedaily for 10 days), 5d-QCT was approximately €7 ($9) lessexpensive than 10d-ST. Therefore, 5d-QCT is as effectiveas 10d-ST but at a reduced cost. It is important to pointout that in our study we used an expensive PPI at a highdose. Therefore, by using less expensive PPIs or a lowerdose of PPI, the difference in cost between the 2 regimenswould be smaller. One may argue that $9 may not repre-sent a significant saving. However, if we consider the highprevalence of the infection and the high number of pa-tients who need treatment, we believe that even a smallsaving per patient translates into a significant saving forthe public health system on a larger scale.

A limitation of the study is that only 55% of the par-ticipants underwent endoscopy and had assessment of H

ylori status at entry by 2 tests on biopsy specimens asequired by the Working Party of the European Helico-acter pylori Study Group for clinical trials.35 In theemaining 45%, H pylori status at entry was assessed withsingle 13C-UBT. A misclassification due to the inclusion

of patients who are falsely positive for H pylori would errtoward the null and might be a bias. However, one mustkeep in mind that 13C-UBT is an excellent test to use inlinical practice with sensitivity and specificity higherhan 95%, and therefore scheduling only this single testefore inclusion might be considered an acceptable ap-roach.36

In conclusion, this randomized trial showed that in anarea of high (ie, �15%) prevalence of CLA-resistant H.pylori strains, a 5-day LEV-containing, nonbismuth, qua-druple concomitant therapy is highly effective in the treat-ment of H pylori infection with an ITT eradication rate of92% and a PP eradication rate of 96%. Also, this eradica-tion regimen is easy to follow for the patient and welltolerated. Therefore, this regimen may represent an ef-fective, reduced cost, and safe first-line therapeutic alter-native in areas where the efficacy of triple therapy isunacceptably low.

Supplementary Material

Note: To access the supplementary materialaccompanying this article, visit the online version ofGastroenterology at www.gastrojournal.org, and at http://dx.doi.org.10.1053/j.gastro.2012.03.043.

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Received January 27, 2012. Accepted March 26, 2012.

Reprint requestsAddress requests for reprints to: Marco Romano, MD, c/o II

Policlinico, Edifico 3, IV piano, Via Pansini 5, 80131 Napoli, Italy.e-mail: marco.romano@unina2.it; fax: (39) 0815666714.

AcknowledgmentsA.F., G.N., and A.G.G. contributed equally to this manuscript.

Conflicts of interestThe authors disclose no conflicts.

FundingSupported in part by institutional research funding from the

Second University Medical School of Naples, Italy.

1. Flow diagram of the study.

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Supplementary Figure