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Original Investigation |

Clinical Outcome and Influencing Factors of a New Short-term Quadruple Therapy for Helicobacter pylori Eradication A Randomized Controlled Trial (MACLOR Study) FREE

Gerhard Treiber, MD; Joachim Wittig, MD; Susanne Ammon, MD; Siegfried Walker, MD; Leen-Jan van Doorn, PhD; Ulrich Klotz, PhD
[+] Author Affiliations

From the Department of Gastroenterology, Robert Bosch Hospital, Stuttgart, Germany (Dr Treiber); Department of Gastroenterology, Hospital of Bietigheim, Bietigheim, Germany (Drs Wittig and Walker); Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart (Drs Ammon and Klotz); and Delft Diagnostic Centre R.deGraaf Group (SSDZ), Delft, the Netherlands (Dr van Doorn). Dr Treiber is now with the Department of Gastroenterology/Hepatology, University Hospital of Magdeburg, Magdeburg, Germany.


Arch Intern Med. 2002;162(2):153-160. doi:10.1001/archinte.162.2.153.
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Background  Short-term therapies for eradicating Helicobacter pylori in selected patients might offer advantages in terms of costs, compliance, and adverse effects in contrast to standard 1-week triple therapy.

Methods  To determine eradication success and influencing factors in a new short-term quadruple therapy, a total of 243 patients positive for H pylori were randomly assigned to 1 of 3 regimens according to age, smoking status, and diagnosis: a 5-day treatment with 3 antibiotics (amoxicillin, 1 g twice daily [bid]; clarithromycin, 250 mg bid; and metronidazole, 400 mg bid) and lansoprazole (30 mg bid [L5; reference treatment]) or ranitidine hydrochloride (300 mg bid [R5]), or the same 3-day antibiotic-lansoprazole combination (L3) with a 2-day pretreatment with lansoprazole.

Results  A total of 234 patients completed the study. On an intention-to-treat basis, overall eradication of H pylori was confirmed in 86.4%: 89.2% in the L5 group vs 81.2% in the L3 group vs 88.8% in the R5 group; differences were not significant. Multiple logistic regression analysis showed that younger age (<55 years; P = .03), history of peptic ulcer disease (P = .04), smoking (P = .03), metronidazole resistance (P = .003), low ranitidine trough serum concentrations (P = .005), cytotoxin-associated gene A–negative strains in peptic ulcer disease (P = .04), and outer inflammatory protein A–positive strains (P = .02) were associated with eradication failure.

Conclusions  This new quadruple H pylori eradication regimen is efficacious, safe, well tolerated, and cost saving, and may be a treatment option for patients older than 55 years with no history of peptic ulcer disease. Furthermore, strains that are sensitive to all antibiotics, cytotoxin-associated gene A–positive, and outer inflammatory protein A–negative could be suitable for short-term quadruple therapy. Patients with an unfavorable combination of characteristics should be treated for a minimum of 7 days.

MORE THAN 10 years after the rediscovery of Helicobacter pylori, H pylori eradication therapy is well established for peptic ulcer disease (PUD) in terms of ulcer healing and prevention of recurrence,1,2 but the impact on nonulcer dyspepsia remains a matter of debate.3 However, there may be a small subgroup of patients with nonulcer dyspepsia who receive a long-lasting benefit from H pylori eradication.4 The relationship between H pylori and gastric cancer has become increasingly convincing.5,6

Numerous reviews and meta-analyses have tried to identify the value of specific treatment combinations in eradication of H pylori, and several guidelines have been published.715 The so-called standard triple regimen, composed of 2 antibiotics and an acid-suppressive drug, is recommended for 1 week as first-line therapy by the Maastricht Consensus conferences13 or for up to 2 weeks by the American College of Gastroenterology.15 Nevertheless, these and other guidelines differ substantially concerning treatment duration and drug dosage. This complex situation can be explained, at least in part, by different health care resources, country-specific drug availability, and package size. Most people would probably agree that the optimal treatment recommendation for H pylori infection has not been established. Further progress may be achieved with new drugs or drug combinations, a vaccine, or a shorter treatment with a more convenient application schedule. Several groups have focused on cost-effectiveness, mainly by decreasing the duration of treatment; thus, patients may benefit by increased compliance and fewer adverse effects. In addition, substantial savings in drug prescription costs (of up to 30%-40%) as compared with standard triple therapy may be achievable by either replacing a proton pump inhibitor (PPI) with an H2-receptor antagonist or by treating for less than 7 days.

In 1998, our group16 described a successful 5-day regimen by combining all 3 antibiotics generally used for standard triple therapy with a PPI. In the present study, we tried to expand on this short-term concept by additionally identifying factors that influence clinical outcome and subjective improvement of symptoms.

STUDY DESIGN

This open-label controlled study involved 2 centers in southwest Germany and was conducted from April 1, 1997, to March 31, 1999. The study protocol was approved by the local ethics committee and regulating government authorities, and all patients gave their written informed consent before study entry. All patients were prospectively randomized centrally by a computer-generated predefined list. We used stratified randomization (blocks of 6 patients within strata) according to age (≥55 years or <55 years), smoking habits (smoker or nonsmoker), and actual endoscopic diagnosis, classified as PUD (duodenal ulcer or gastric ulcer) or non–peptic ulcer disease (NPUD) (characterized by either erosive gastritis with macroscopic lesions <5 mm in diameter or no visible lesions [nonulcer dyspepsia]), to assign patients to 1 of 3 treatment arms within 48 hours after endoscopic investigation. Patients then received amoxicillin (1 g twice daily [bid]), metronidazole (400 mg bid), and clarithromycin (250 mg bid) for 5 days together with either lansoprazole (30 mg bid) (designated L5) or ranitidine hydrochloride (300 mg bid) (R5) for 5 days, or the same antibiotics for only 3 days (L3; days 3-5) with a 2-day lansoprazole pretreatment (days 1-5). This design was used primarily to answer the following questions: Are L3 and R5 inferior to the previously evaluated reference arm L5? Are there factors that influence treatment success?

INCLUSION AND EXCLUSION CRITERIA

Patients were regarded eligible for study entry if they were between 18 and 85 years of age; if treatment was indicated because of either macroscopic abnormalities on upper gastrointestinal tract endoscopy or persistent upper gastrointestinal tract symptoms during the previous 3 months; and if H pylori status was positive, as assessed by rapid urease test and serologic testing as well as facultatively by histologic testing and/or culture. In a few cases, rapid urease testing (if not performed) was replaced by a urea breath test (UBT). Exclusion criteria were the following: severe illnesses with a life expectancy of less than 1 year, present viral disease, known allergy against the intended medication, pregnancy and lactation, severe renal and/or liver dysfunction (creatinine clearance of <30 mL/min or liver cirrhosis, Child-Pugh classification stage B or C), cognitive impairment or mental illness, and relevant disorders of the central or peripheral nervous system. Patients were excluded from the study if they had been previously (<4 weeks before study entry) treated with bismuth salts or antibiotics; had had PPI pretreatment longer than 1 week; and/or had received more than once-daily dosing of the equivalent of omeprazole, 20 mg/d.

ASSESSED DATA

At entry, age, body mass index and weight changes, smoking status (smoker, nonsmoker, or abstinence for at least 6 months), alcohol intake (not relevant if <20 g/d), concomitant use of aspirin or nonsteroidal anti-inflammatory drugs, history of peptic ulcer disease, and actual endoscopic diagnosis were recorded. The subjective measures (reported symptoms) nausea, vomiting, epigastric pain, distention, heartburn, diarrhea, and loss of appetite were monitored by means of visual analog scales (0-10 cm, with higher numbers indicating more severe symptoms).

In addition to routine laboratory variables, we assessed serum gastrin levels with an upper normal limit of 100 pg/mL (Gastrin-RIA; DPC Biermann, Bad Nauheim, Germany) and pepsinogen I and II (PEPSI-I K and PEPSI-II K; DiaSorin, Saluggia, Italy) by radioimmunoassay under fasting conditions. We assumed the presence of gastric atrophy17 if the values of pepsinogen I were less than 60 ng/mL or if the pepsinogen ratio (pepsinogen I–pepsinogen II) was less than 3.5. Immunoblot (Helicoblot 2.0; Genelabs Diagnostics Pte Ltd, Singapore) was used for outer inflammatory protein A (oip-A) (35-kd band) as well as cytotoxin-associated gene A (cag-A) and vacuolating cytotoxin A (vac-A) status (phenotyping) and compared in several patients (n = 47) by a polymerase chain reaction–based assay (genotyping).18,19 When cultures were available (n = 56), we determined the resistance status for amoxicillin, clarithromycin, and metronidazole by means of the Etest (AB Biodisk, Solna, Sweden) with cutoff values of 4, 2, and 8 µg/mL, respectively. Creatinine clearance was calculated from serum creatinine level, age, and body weight by means of the equation of Cockcroft and Gault.20 Finally, IgA and IgG serologic testing (Pyloriset EIA-A plus EIA-G; Orion Corporation Orion Diagnostica, Espoo, Finland) was performed. If available (n = 120), histologic findings of biopsy specimens from the antrum and corpus were classified according to the upgraded Sydney system, where gastritis activity was 0 (none) and 3 (maximum presence). The same system was applied for presence or absence of metaplasia and atrophy.

For all patients, weight changes and reported symptoms were recorded using visual analog scales at the end of treatment and after 1 and 3 months (patients with NPUD were also seen at 6 months). In addition, follow-up evaluation for the patient responses was performed concomitantly by questionnaire: change in symptoms ("Do you now experience other symptoms than at the beginning of treatment?"), constant symptoms ("Do you now experience the same symptoms as at the beginning of treatment?"), improvement of symptoms ("Has an improvement in symptoms occurred since the beginning of therapy?"), tolerability of therapy ("Was this treatment tolerable for you?"), reparticipation ("Would you participate again in this therapy?"), and additional treatment ("Did you need additional treatment from your general practitioner or self-medication since study entry?") were assessed.

Adverse effects, such as metallic and other taste disturbances, diarrhea, and rash or allergy, were assessed (any event) and patients were asked if these effects had interfered with normal daily activities (major event). Adverse effects were assumed to be therapy related if they first appeared during treatment or if pretherapeutic symptoms (eg, diarrhea) worsened during therapy. Routine laboratory measures were determined after treatment to detect any abnormalities induced by treatment. Serum levels of the administered drugs were measured in all patients during the last dosing interval under steady-state conditions to test for compliance and to correlate the results with eradication failure.

Eradication success was determined by a UBT device (FanCi2; Fischer ANalysen Instrumente GmbH, Leipzig, Germany) before and 30 minutes after ingestion of 100 mg of urea labeled with carbon 13 (n = 223), assuming a delta over baseline value of 2 or less. Only if both UBTs (performed 1 and 3 months after treatment end) were negative, patients were classified as H pylori negative. Alternatively, at 3 months in 11 patients (4.7%), 1 negative UBT and a titer decline of more than 30% compared with baseline was accepted in defining treatment success. This UBT device had previously been validated against mass spectroscopy in-house, with 95% concordant results. The rapid urease test and UBT had been compared in a previous study16 and obtained 98% concordant results. Thus, testing was performed in accordance with actual official guidelines.21

DATA EVALUATION

Calculations were performed on the following variables by means of commercially available statistical programs (Prism 2.01; GraphPad Software, Inc, San Diego, Calif; and SPSS 9.0; SPSS Inc, Chicago, Ill) according to a prespecified order of significance: treatment success according to regimen, factors influencing treatment success, outcome of subjective symptoms, and adverse events. For differences among patient groups, Fisher exact test was applied. For comparison of metric data in multiple groups, 1-way analysis of variance (the so-called post testing using the Bonferroni method) was used, and for analysis of influencing factors, multiple logistic or linear regression analysis with and without adjustment for putative confounding factors was used. The results are shown as mean or median values with corresponding 95% confidence intervals (CIs) or SD. P<.05 (2-sided) was regarded as significant. As precalculated by a statistical program (StatMate; GraphPad Software, Inc), the study was designed to detect a clinically relevant and significant (P<.05) difference of more than 10% between the reference arm (L5, with a presumed mean success rate of 90%) and the 2 other treatment arms by including 80 patients per treatment arm, assuming a power of 80%. To be considered equivalent to the same prevalidated 5-day quadruple therapy,16 the 95% CI (per-protocol [PP] analysis) of all regimens should be within the predefined range of 90%± 10% therapeutic success rate.

ERADICATION AND ADVERSE EFFECTS

Two hundred forty-six patients fulfilled the entry criteria and were regarded as eligible. Three patients withdrew their consent before randomization and receiving the first dose; thus, 243 remained (intention-to-treat [ITT] basis). Of these 243 randomized patients, 9 had to be excluded from final analysis for the following reasons: 2 patients died of non–study-related diseases (acute myocardial infarction [L3] and acute colonic ileus from previously unrecognized malignancy [L3]), 2 stopped treatment because of drug-related adverse effects (diarrhea [L5] and allergic reaction to amoxicillin [L5]), 1 patient had gastric malignancy diagnosed 2 weeks after study inclusion (L3), 1 patient was noncompliant without adverse events (L3), and 3 were unavailable for follow-up [2 in L5 and 1 in R5].

The characteristics of the remaining 234 patients (PP basis) without trial rule violation are shown in Table 1. The groups were comparable for all characteristics evaluated at baseline. The outcome according to the regimens applied is summarized in Table 2. No significant differences were observed between the 2 participating centers. The overall eradication rate (ITT) averaged 86.4%. All treatments fulfilled the proposed Food and Drug Administration criteria of efficacy for H pylori eradication, ie, the lower limit of the 95% CI exceeded 70%. The reference arm (L5) was equivalent to previous experience with 5-day quadruple therapy16 (93.7 vs 94.1% on a PP basis) and not superior over the 2 other treatments. However, equivalence to L5 could be noted only for the R5 but not for the L3 treatment arm: the upper limit of the 95% CI of the difference between proportions for L3 and L5 is 18.8% and therefore above the proposed criterion of 10% given by the Committee for Proprietary Medicinal Products of the European Drug Agency or of 15% by the Food and Drug Administration.22 In addition, for L3, the 95% CI crosses below the predefined lower margin of 80%.

Table Graphic Jump LocationTable 1 Characteristics of Patients Entering the Prospective Randomized Controlled Study*
Table Graphic Jump LocationTable 2 Eradication Results for the 3 Regimens, Calculated on ITT and PP Basis*

Adverse effects (any event, including major events interfering with daily activities) are listed in Table 3. All were reversible at the end of treatment except for mucosal candidiasis in 2 patients, which had to be treated topically. By quantifying any event according to the regimen used, the most common one was diarrhea, appearing frequently in the R5 group (56.4% vs 36.9% with L5 [P = .056] and 36.3% with L3 [P = .08]). However, this regimen caused fewer nonmetallic taste disturbances (1.3% vs 9.5% with L5 [P = .06] and 11.3% with L3 [P = .02]) but more often induced a new loss of appetite (9.0% vs 1.2% with L5; P = .03) and nonspecific, nonallergic erythemas (9.0% vs 1.3% with L3; P = .06). Interestingly, 5 patients reported nonmetallic taste disturbances beyond the end of treatment. No clinically relevant changes of routine laboratory measures were noticed. Compliance, as assessed by monitoring of drug levels, exceeded 95%.

Table Graphic Jump LocationTable 3 Incidence of Adverse Events Independent of the Applied Regimen at the End of Therapy
FACTORS AFFECTING ERADICATION SUCCESS

Multiple regression analysis identified several single factors that had a significant impact on treatment outcome (Table 4): age, smoking status, history of peptic ulcer, and strain properties (metronidazole resistance; presence or absence of oip-A). The effect of smoking was no longer significant (P = .11) when controlled for age. History of peptic ulcer was independent of other factors. Taking 2 clinical variables (age and history of PUD) into account, the best eradication rate was achieved in older patients (≥55 years) without a history of PUD (Table 5), resulting in an important 20% difference between the best- and worst-case scenario (P = .002).

Table Graphic Jump LocationTable 4 Multiple Logistic Regression Analysis for Factors Influencing Treatment Outcome Without Adjustment for Confounding Factors*
Table Graphic Jump LocationTable 5 Eradication Results According to Clinical Factors (n = 234) and Selected Strain Properties (n = 231)*

Cultures were obtained in 56 patients for determination of resistance background. Pretherapeutic resistances were 0% for amoxicillin, 7.3% for clarithromycin, and 29.1% for metronidazole. During the study period, we obtained cultures from 205 additional patients who could not be included in the study. The corresponding resistance rates of this (control) population were 0% for amoxicillin, 9.3% for clarithromycin, and 34.6% for metronidazole. Thus, in terms of resistance, the studied patients can be regarded as representative of our 2 centers. Metronidazole resistance had the greatest impact on H pylori eradication failure (Table 6). However, if the serum trough steady-state value of metronidazole was above the strain's minimum inhibitory concentration for metronidazole, therapeutic outcome was improved regardless of whether this strain had been classified "minimum inhibitory concentration resistant." This finding did not hold true for clarithromycin (Table 7).

Table Graphic Jump LocationTable 6 Influence of Primary Resistance on Treatment Success
Table Graphic Jump LocationTable 7 Association Between Drug Levels and Strain Susceptibility

In 47 patients, we were able to genotype the strains, which was confirmed in 96% of cases by the immunoblot expression for cag-A (119-kd band); for vac-A, the signal(s) type s1 compared with 89-kd band, only 50% conformity was observed. Overall, cag-A status did not correlate with the initial diagnosis or the posttherapeutic H pylori status as indicated by immunoblot. However, a subgroup of patients with peptic ulcer on endoscopy and a cag-A–positive strain were more likely to respond to therapy than patients with the cag-A–negative one (93.1% vs 76.5%; P = .04). The absence of oip-A was independent of clinical factors and significantly (P = .02) associated with an improved outcome of treatment (Table 4 and Table 5). No direct correlation was seen between treatment outcome and presence of elevated gastrin level or reduced pepsinogen ratio, which could have indicated mucosal atrophy.

Serum trough steady-state values of ranitidine were significantly (P = .005) and positively related to a negative posttherapeutic H pylori status, while there was only a slight positive trend for lansoprazole and no difference for the antibiotics used (Table 8).

Table Graphic Jump LocationTable 8 Minimal Steady-state Serum Concentrations (Css) of the Applied Drugs According to Posttherapeutic Helicobacter pylori Status

A history of peptic ulcers was marginally related to a positive cag-A status (P = .08). Age was significantly associated with other factors: the presence of gastric atrophy (r = 0.19, P<.003; atrophy itself was associated with a positive cagA–status, P = .06) and parietal cell mass, which is reflected by serum gastrin levels (r = 0.15, P = .04). Other factors positively related to age were elevated titers of IgA (r = 0.28, P<.001) and IgG (r = 0.17, P = .005). Age was still significantly associated with eradication success after adjusting for sex, history of peptic ulcer, cag-A status, gastrin, and pepsinogen ratio (P = .05).

Finally, forward Wald logistic stepwise regression analysis at an entry P<.01 identified the absence of a history of peptic ulcer disease (odds ratio, 0.38; 95% CI, 0.16-0.93) and of oip-A (odds ratio, 0.37; 95% CI, 0.15-0.89) as the factors best predicting H pylori eradication success (P = .007).

OUTCOME ACCORDING TO SYMPTOMS

During a 6-month follow-up, various symptoms were recorded, but only the score on a visual analog scale for epigastric pain discriminated patients according to their H pylori status (positive vs negative) at month 3 (1.3 vs 0.7; P<.001) and month 6 (2.0 vs 0.7; P<.001) compared with prestudy levels (3.5 vs 2.8; P = .20). Since a substantial number of patients were asymptomatic at onset, we also calculated the proportion of symptomatic patients at any monitored time point and analyzed the results according to diagnosis (PUD and NPUD) and posttherapeutic H pylori status, which was different in H pylori–positive vs –negative patients with NPUD at month 3 (53.3% vs 26.4%; P = .04) and at month 6 (58.3% vs 16.0%; P = .003), whereas patients with PUD did not differ. The same observation in favor of H pylori eradication held true for overall symptom improvement at 3 months (NPUD with 71.4% vs 93.3% [P = .03], PUD with 71.4% vs 98.6% [P = .02]) and at 6 months (75.0% vs 95.3%) (P = .04). In symptomatic patients, we found a nonsignificant trend (because of the small number of treatment failures) toward an almost 2-fold increase of recurrence of identical symptoms associated with eradication failure involving PUD and NPUD. At the end of treatment, 21.7% of H pylori–positive patients and 30.5% of H pylori–negative patients complained about the same persisting symptoms, compared with 45.5% vs 26.0% at month 3 and 58.3% vs 23.8% at month 6. Patients with and without successful eradication showed no difference during follow-up in terms of abdominal distention, nausea, loss of appetite, diarrhea, vomiting and heartburn, tolerability of therapy, and consent for reparticipation. Only patients with successful eradication showed a significant (P<.001) weight gain (mean, 1.2 kg at month 6). In addition, the percentage of patients needing further medication (antacids, prokinetics, H2-receptor antagonists prescribed by their general practitioner or self-medicated) for symptom relief was significantly higher at month 3 (33.3% vs 9.3%; P = .002) and month 6 (33.3% vs 10.6%; P = .05) if H pylori infection persisted.

In 1998, our group introduced a 5-day quadruple therapy for H pylori eradication, consisting of 3 antibiotics (amoxicillin, clarithromycin, and metronidazole) and a PPI. We compared it with 1-week standard triple therapy, and equivalence was noted in terms of eradication (ITT: 90.1% vs 90.5%; PP: 94.1% vs 92.7%) and adverse effects.16 This is in accordance with the latest data published for triple therapy (macrolide plus either amoxicillin or metronidazole), with an ITT rate ranging from 81% to 86%.10,11,23 We have now reproduced these success rates, with an ITT rate ranging from 81.2% to 89.2% (dependent on the regimen used), thus concluding that our present and previously evaluated control arm (5-day PPI-based quadruple regimen) is again comparable with standard triple therapy, although this therapy was actually not included again. Although this study was not designed as an equivalence trial, the replacement of a PPI by an H2-receptor antagonist in a 5-day regimen seems to be possible, whereas shortening the treatment duration to 3 days should be regarded with caution, even if the fraction difference to the reference treatment may be below 10% (7.9%, ITT) and thus clinically not important. These results were confirmed by a well-conducted and controlled study by Neville et al,24 who demonstrated that the same 5-day quadruple regimen was significantly more effective than a 5-day triple regimen containing amoxicillin and clarithromycin (ITT: 88% vs 59%; P<.001) but not than the 5-day combination of metronidazole and clarithomycin (ITT: 88% vs 81%; P = .38). Resistance to metronidazole had some impact on the efficacy of the triple therapy with clarithromycin and metronidazole. Interestingly, age was a predicting factor for treatment success in that English study. In an uncontrolled trial, Okada et al25 reported an eradication rate of 92% (ITT) with a similar but 1-week quadruple therapy. Their prevalence of metronidazole resistance (16%) was much lower than in the English study (52%)24 or in our present study (29%). Two recently published studies26,27 had less power and did not report resistance data; they compared either a 5-day regimen of rabeprazole sodium, amoxicillin, and clarithromycin with vs without metronidazole, which achieved 94.5% vs 80% cure (ITT, P<.05), or a 3-day regimen of omeprazole, amoxicillin, and clarithromycin with metronidazole vs the same regimen without metronidazole but given for 10 days, which achieved 89.3% vs 81.8% cure (ITT, P = .29). In summary, the mean success rates of all of these quadruple regimens are consistently around 90% and appear to be influenced less by the local pattern of metronidazole resistance. As highlighted in a recent review,23 these 4 studies and others provide strong evidence that the amoxicillin-clarithromycin combination in triple therapy is clearly inferior to the actual quadruple therapy in a short-term (<7 days) setting.

However, it must be emphasized that the type of culture, the methods of resistance testing (Etest vs disk diffusion), and smoking status influence the rates of metronidazole resistance.28,29 Another considerable factor is the serum drug levels achieved. As postulated in a previous review9 and confirmed by our direct measurements, the serum concentrations of metronidazole in contrast to clarithromycin do not always exceed the strain's minimum inhibitory concentration in patients with "sensitive" strains, indicating that higher doses might be more effective and could overcome "clinical" metronidazole resistance. Since metronidazole plays a key role in the success of all treatments for less than 7 days,23 this observation appears to be important. However, as with all short-term multidrug regimens, loss of clinical efficacy due to induced bacterial resistances after treatment failure is of major concern. Two studies attenuated this fear by showing decreased secondary resistance rates for clarithromycin if amoxicillin was used as comedication.30,31 This observation may further justify the addition of amoxicillin to a metronidazole and macrolide-containing triple therapy even in the absence of antibiotic resistance. With mostly sensitive strains to metronidazole and clarithromycin, eradication rates do not significantly benefit from the addition of amoxicillin16,24; however, the opposite could be true for primarily resistant strains to 1 of these 2 antibiotics. New methods of detecting clarithromycin resistance32,33 may allow more individualized therapy in the near future. Until then, it is important to be aware of the antibiotic resistance pattern in the general population.

The quadruple therapy used was safe and generally as well tolerated as triple therapy. Although the rate of any event may appear as high, we noted only 2 drug-related dropouts, and the incidence of adverse effects interfering with daily activities appeared as low as in other studies.16,2427 These observations were confirmed by the results of our questionnaire, demonstrating that, even immediately after the end of treatment, 90% of all patients would participate again in such a treatment. Finally, it is noteworthy that our patients were exposed to drugs and related adverse events for 2 to 4 days less than with standard 1-week triple therapy.

In the past, several factors were thought responsible for influencing clinical outcome.28,3437 This study may be one of the largest to systematically investigate this issue. For interpretation of our results, it must be emphasized that the 3 study groups were well-balanced for a variety of predictive factors.

Age, as suggested by previous studies,26,37 again appeared to have a major impact on success of eradication. Although in H pylori–positive patients several pathophysiologic changes (eg, atrophy, acid secretion) are affected by age,26,38 none of these assessed variables directly influenced eradication success. Apart from this, age directly and indirectly influences drug disposition.26,39 Smoking must be regarded as a confounding factor for age. Surprisingly, the absence of peptic ulcer history, independent of present ulcer status, was closely associated with eradication success, perhaps because of an association with a low likelihood of previous antibacterial treatments (and induced resistance) for H pylori. This factor was independent of all others except cag-A. In accordance with other studies,26,35 cag-A status influenced eradication outcome in this study, solely in patients with PUD. Of all other specific strain markers, only the presence of oip-A was associated with eradication failure, which, to our knowledge, is the first such report in the literature. The characteristics of oip-A have been described recently,26,40 but it was noted earlier to be a good marker for peptic ulceration by inducing interleukin 8 secretion.41,42

In the past, research focused on the influence of acid suppression on successful eradication.36,37,4345 We, therefore, compared a PPI with an H2-receptor antagonist in a higher acid-suppressing dose. Although clinical results for both acid-suppressive drugs did not differ, higher steady-state trough levels of ranitidine significantly correlated with eradication success. This trend was also seen with lansoprazole. Thus, it can be concluded that a certain extent of acid suppression is necessary even in a multidrug regimen. Derived from these results, the substitution of ranitidine for a PPI in patients with NPUD could lead to further cost savings while eradication results are comparable with those of triple regimens.4648

Evaluation of symptoms was not a primary objective in the present study. However, for important clinical features (abdominal pain, overall symptom improvement, persistence of identical symptoms, and need for additional medical treatment), we observed that patients with NPUD with eradication success felt better on a long-term basis than those with treatment failures, underlined by an objective response (weight gain).

In summary, this short-term quadruple therapy (regardless of the drug used for acid suppression) represents an efficacious, safe, well-tolerated, and cost-saving treatment for H pylori eradication. Especially the 5-day regimens may be a first-line treatment option for older patients without a history of peptic ulcer. This population is easily defined and might profit from fewer adverse events compared with 1-week standard triple therapy because of a decreased treatment duration. Based on our results, patients with unfavorable clinical characteristics, a metronidazole-resistant strain, and/or a strain that does not express cag-A but does express oip-A may otherwise benefit from a prolonged treatment duration23,49 with or without a higher metronidazole dose.9,50 Future trials should prospectively investigate this hypothesis.

Accepted for publication April 18, 2001.

This study was supported in full by the Robert Bosch Foundation, Stuttgart, Germany, and in part by a grant from Takeda Pharma, Aachen, Germany.

We thank Frieder Kees, MD, Department of Pharmacology, University of Regensburg, Regensburg, Germany, for his help in drug analysis and Marita Schwabe, Biologische Analysen System Company, Lich, Germany, for her support concerning immunoblot analysis. The technical assistance of Erika Schneider and secretarial help of Heidi Köhler are highly appreciated.

Corresponding author and reprints: Gerhard Treiber, MD, Department of Gastroenterology/Hepatology, University Hospital of Magdeburg, Leipziger Str 44, D-39120 Magdeburg, Germany (e-mail: gerhard.treiber@medizin.uni-magdeburg.de).

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Huang  J-QHunt  RH The importance of clarithromycin dose in the management of Helicobacter pylori infection: a meta-analysis of triple therapies with a proton pump inhibitor, clarithromycin and amoxicillin or metronidazole. Aliment Pharmacol Ther. 1999;13719- 729
Link to Article
Pipkin  GAWilliamson  RWood  JR One-week clarithromycin triple therapy regimens for eradication of Helicobacter pyloriAliment Pharmacol Ther. 1998;12823- 837
Link to Article
Houben  MVanDeBeek  DHensen  ECraen  ARauws  EATytgat  GN A systematic review of Helicobacter pylori eradication therapy: the impact of antimicrobial resistance on eradication rates. Aliment Pharmacol Ther. 1999;131047- 1055
Link to Article
Laheij  RVanRossum  LJansen  JStraatman  HVerbeek  AL Evaluation of treatment regimens to cure Helicobacter pylori infection: a meta-analysis. Aliment Pharmacol Ther. 1999;13857- 864
Link to Article
Malfertheiner  PMegraud  FO'Morain  C  et al. for the European Helicobacter Pylori Study Group (EHPSG), Current European concepts in the management of Helicobacter pylori infection: the Maastricht Consensus Report. Gut. 1997;418- 13
Link to Article
National Institutes of Health, Consensus conference: Helicobacter pylori in peptic ulcer disease. JAMA. 1994;27265- 69
Link to Article
Howden  CWHunt  RH Guidelines for the management of Helicobacter pylori infection. Am J Gastroenterol. 1998;932330- 2338
Link to Article
Treiber  GAmmon  SSchneider  EKlotz  U Amoxicillin/metronidazole/omeprazole/clarithromycin: a new, short quadruple therapy for Helicobacter pylori eradication. Helicobacter. 1998;354- 58
Link to Article
Oksanen  ASipponen  PKarttunen  R  et al.  Atrophic gastritis and Helicobacter pylori infection in outpatients referred for gastroscopy. Gut. 2000;46460- 463
Link to Article
van Doorn  LJFigueiredo  CSanna  R  et al.  Expanding allelic diversity of Helicobacter pylori vacA. J Clin Microbiol. 1998;362597- 2603
van Doorn  LJFigueiredo  CSanna  R  et al.  Clinical relevance of the cagA, vacA, and iceA status of Helicobacter pyloriGastroenterology. 1998;11558- 66
Link to Article
Cockcroft  DWGault  MH Prediction of creatinine clearance from serum creatinine. Nephron. 1976;1631- 41
Link to Article
Working Party of the European Helicobacter Pylori Study Group, Guidelines for clinical trials in Helicobacter pylori infection. Gut. 1997;41 ((suppl 2)) S1- S23
Link to Article
Roehmel  J Therapeutic equivalence investigations: statistical considerations. Stat Med. 1998;171703- 1714
Link to Article
Treiber  G Treating Helicobacter pylori shorter than one week: a real future perspective? Z Gastroenterol. 2000;38807- 812
Link to Article
Neville  PMEverett  SLangworthy  H  et al.  The optimal antibiotic combination in a 5-day Helicobacter pylori eradication regimen. Aliment Pharmacol Ther. 1999;13497- 501
Link to Article
Okada  MNishimura  HKawashima  M  et al.  A new quadruple therapy for Helicobacter pylori: influence of resistant strains on treatment outcome. Aliment Pharmacol Ther. 1999;13769- 774
Link to Article
Nagahara  AMiwa  HOgawa  K  et al.  Addition of metronidazole to rabeprazole-amoxicillin-clarithromycin regimen for Helicobacter pylori infection provides an excellent cure rate with five-day therapy. Helicobacter. 2000;588- 93
Link to Article
Catalano  FBranciforte  GCatanzaro  RCipolla  RBentivegna  CBrogna  A Helicobacter pylori–positive duodenal ulcer: three-day antibiotic eradication regimen. Aliment Pharmacol Ther. 2000;141329- 1334
Link to Article
Tytgat  GNJ Treatments that impact favourably upon the eradication of Helicobacter pylori and ulcer recurrence. Aliment Pharmacol Ther. 1994;8359- 368
Link to Article
Megraud  F Epidemiology and mechanism of antibiotic resistance in Helicobacter pyloriGastroenterology. 1998;1151278- 1282
Link to Article
Laine  LSuchower  LFrantz  JConnors  ANeil  G Low rate of emergence of clarithromycin-resistant Helicobacter pylori with amoxycillin co-therapy. Aliment Pharmacol Ther. 1998;12887- 892
Link to Article
Svensson  MSörberg  MNilsson  M  et al.  Do combinations with nitroimidazoles or amoxicillin prevent development of clarithromycin resistance in Helicobacter pylori [abstract]? Gut. 1999;43 ((suppl)) A8
Trebesius  KPanthel  KStrobel  S  et al.  Rapid and specific detection of Helicobacter pylori macrolide resistance genes in gastric tissue by fluorescent in situ hybridization. Gut. 2000;46608- 614
Link to Article
Marais  AMonteiro  LOcchialini  APina  MLamouliatte  HMegraud  E Direct detection of Helicobacter pylori resistance to macrolides by a polymerase chain reaction DNA enzyme immunoassay in gastric biopsy specimens. Gut. 1999;44463- 467
Link to Article
Cutler  AFSchubert  TT Patient factors affecting Helicobacter pylori eradication with triple therapy. Am J Gastroenterol. 1993;88505- 509
Treiber  G Negative cag-A status is a risk factor for Helicobacter pylori eradication failure [abstract]. Gut. 2000;47 ((suppl 1)) A27
Labenz  JLeverkus  FBörsch  G Omeprazole plus amoxicillin for cure of Helicobacter pylori infection: factors influencing the treatment success. Scand J Gastroenterol. 1994;291070- 1075
Link to Article
Treiber  GAmmon  SKlotz  U Age-dependent eradication of Helicobacter pylori with dual therapy. Aliment Pharmacol Ther. 1997;11711- 718
Link to Article
Haruma  KKamada  TKawaguchi  H  et al.  Effect of age and Helicobacter pylori infection on gastric acid secretion. J Gastroenterol Hepatol. 2000;15277- 283
Link to Article
Ammon  STreiber  GKees  FKlotz  U Influence of age on the steady state disposition of drugs commonly used for the eradication of Helicobacter pyloriAliment Pharmacol Ther. 2000;14759- 766
Link to Article
Yamaoka  YKwon  DHGraham  DY A M(r) 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pyloriProc Natl Acad Sci U S A. 2000;977533- 7538
Link to Article
Aucher  PPetit  MMannant  PPecennec  LBabin  PFauchere  J Use of immunoblot assay to define serum antibody patterns associated with Helicobacter pylori infection and with Helicobacter pylori–related ulcers. J Clin Microbiol. 1998;36931- 936
Yamaoka  YKodama  TGraham  DY  et al.  Search for putative virulence factors of Helicobacter pylori: the low-molecular-weight (33-35 K) antigen. Dig Dis Sci. 1998;431482- 1487
Link to Article
Klotz  U Pharmacokinetic considerations in the eradication of Helicobacter pyloriClin Pharmacokinet. 2000;38243- 270
Link to Article
Gustavson  LEKaiser  JFEdmonds  ALLocke  CSDeBartolo  MLSchneck  DW Effect of omeprazole on concentrations of clarithromycin in plasma and gastric tissue at steady state. Antimicrob Agents Chemother. 1995;392078- 2083
Link to Article
Goddard  AFJessa  MJBerret  DAShaw  PNSpiller  RC Effect of omeprazole on the distribution of metronidazole, amoxicillin, and clarithromycin in human gastric juice. Gastroenterology. 1996;111358- 367
Link to Article
Kihira  KSatoh  KSaifuku  K  et al.  Comparison of ranitidine and lansoprazole in short-term low-dose triple therapy for Helicobacter pylori infection. Aliment Pharmacol Ther. 1997;11511- 514
Link to Article
Spadaccini  Ade Fanis  CSciampa  G  et al.  Omeprazole versus ranitidine: short-term triple therapy in patients with Helicobacter pylori–positive duodenal ulcers. Aliment Pharmacol Ther. 1996;10829- 831
Link to Article
Gschwantler  MDragosics  BSchütze  K  et al.  Famotidine versus omeprazole in combination with clarithromycin and metronidazole for eradication of Helicobacter pyloriAliment Pharmacol Ther. 1999;131063- 1069
Link to Article
Calvet  XGarcia  NLopez  TGisbert  JPGene  ERoque  M A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and either metronidazole or amoxicillin for treating Helicobacter pylori infection. Aliment Pharmacol Ther. 2000;14603- 609
Link to Article
Graham  DY Therapy of Helicobacter pylori: current status and issues. Gastroenterology. 2000;118 ((suppl 1)) S2- S8
Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1 Characteristics of Patients Entering the Prospective Randomized Controlled Study*
Table Graphic Jump LocationTable 2 Eradication Results for the 3 Regimens, Calculated on ITT and PP Basis*
Table Graphic Jump LocationTable 3 Incidence of Adverse Events Independent of the Applied Regimen at the End of Therapy
Table Graphic Jump LocationTable 4 Multiple Logistic Regression Analysis for Factors Influencing Treatment Outcome Without Adjustment for Confounding Factors*
Table Graphic Jump LocationTable 5 Eradication Results According to Clinical Factors (n = 234) and Selected Strain Properties (n = 231)*
Table Graphic Jump LocationTable 6 Influence of Primary Resistance on Treatment Success
Table Graphic Jump LocationTable 7 Association Between Drug Levels and Strain Susceptibility
Table Graphic Jump LocationTable 8 Minimal Steady-state Serum Concentrations (Css) of the Applied Drugs According to Posttherapeutic Helicobacter pylori Status

References

Treiber  GLambert  JR The impact of Helicobacter pylori eradication on peptic ulcer healing. Am J Gastroenterol. 1998;931080- 1084
Link to Article
Penston  G Clinical aspects of Helicobacter pylori eradication therapy in peptic ulcer disease. Aliment Pharmacol Ther. 1996;10469- 486
Link to Article
Talley  NJAxon  ABytzer  PHoltmann  GLam  SKVan Zanten  S Management of uninvestigated and functional dyspepsia: a working party report for the World Congresses of Gastroenterology 1998. Aliment Pharmacol Ther. 1999;131135- 1148
Link to Article
Moayyedi  PSoo  SDeeks  J  et al.  Systematic review and economic evaluation of Helicobacter pylori eradication treatment for non-ulcer dyspepsia. BMJ. 2000;321659- 664
Link to Article
Huang  JQSridhar  SChen  YHunt  RH Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology. 1998;1141169- 1179
Link to Article
Watanabe  TTada  MNagai  HSasaki  SNakao  M Helicobacter pylori infection induces gastric cancer in mongolian gerbils. Gastroenterology. 1998;115642- 648
Link to Article
Penston  JGMcColl  KEL Eradication of Helicobacter pylori: an objective assessment of current therapies. Br J Clin Pharmacol. 1997;43223- 243
Link to Article
Treiber  G The influence of drug dosage on Helicobacter pylori eradication: a cost-effectiveness analysis. Am J Gastroenterol. 1996;91246- 257
Huang  J-QHunt  RH The importance of clarithromycin dose in the management of Helicobacter pylori infection: a meta-analysis of triple therapies with a proton pump inhibitor, clarithromycin and amoxicillin or metronidazole. Aliment Pharmacol Ther. 1999;13719- 729
Link to Article
Pipkin  GAWilliamson  RWood  JR One-week clarithromycin triple therapy regimens for eradication of Helicobacter pyloriAliment Pharmacol Ther. 1998;12823- 837
Link to Article
Houben  MVanDeBeek  DHensen  ECraen  ARauws  EATytgat  GN A systematic review of Helicobacter pylori eradication therapy: the impact of antimicrobial resistance on eradication rates. Aliment Pharmacol Ther. 1999;131047- 1055
Link to Article
Laheij  RVanRossum  LJansen  JStraatman  HVerbeek  AL Evaluation of treatment regimens to cure Helicobacter pylori infection: a meta-analysis. Aliment Pharmacol Ther. 1999;13857- 864
Link to Article
Malfertheiner  PMegraud  FO'Morain  C  et al. for the European Helicobacter Pylori Study Group (EHPSG), Current European concepts in the management of Helicobacter pylori infection: the Maastricht Consensus Report. Gut. 1997;418- 13
Link to Article
National Institutes of Health, Consensus conference: Helicobacter pylori in peptic ulcer disease. JAMA. 1994;27265- 69
Link to Article
Howden  CWHunt  RH Guidelines for the management of Helicobacter pylori infection. Am J Gastroenterol. 1998;932330- 2338
Link to Article
Treiber  GAmmon  SSchneider  EKlotz  U Amoxicillin/metronidazole/omeprazole/clarithromycin: a new, short quadruple therapy for Helicobacter pylori eradication. Helicobacter. 1998;354- 58
Link to Article
Oksanen  ASipponen  PKarttunen  R  et al.  Atrophic gastritis and Helicobacter pylori infection in outpatients referred for gastroscopy. Gut. 2000;46460- 463
Link to Article
van Doorn  LJFigueiredo  CSanna  R  et al.  Expanding allelic diversity of Helicobacter pylori vacA. J Clin Microbiol. 1998;362597- 2603
van Doorn  LJFigueiredo  CSanna  R  et al.  Clinical relevance of the cagA, vacA, and iceA status of Helicobacter pyloriGastroenterology. 1998;11558- 66
Link to Article
Cockcroft  DWGault  MH Prediction of creatinine clearance from serum creatinine. Nephron. 1976;1631- 41
Link to Article
Working Party of the European Helicobacter Pylori Study Group, Guidelines for clinical trials in Helicobacter pylori infection. Gut. 1997;41 ((suppl 2)) S1- S23
Link to Article
Roehmel  J Therapeutic equivalence investigations: statistical considerations. Stat Med. 1998;171703- 1714
Link to Article
Treiber  G Treating Helicobacter pylori shorter than one week: a real future perspective? Z Gastroenterol. 2000;38807- 812
Link to Article
Neville  PMEverett  SLangworthy  H  et al.  The optimal antibiotic combination in a 5-day Helicobacter pylori eradication regimen. Aliment Pharmacol Ther. 1999;13497- 501
Link to Article
Okada  MNishimura  HKawashima  M  et al.  A new quadruple therapy for Helicobacter pylori: influence of resistant strains on treatment outcome. Aliment Pharmacol Ther. 1999;13769- 774
Link to Article
Nagahara  AMiwa  HOgawa  K  et al.  Addition of metronidazole to rabeprazole-amoxicillin-clarithromycin regimen for Helicobacter pylori infection provides an excellent cure rate with five-day therapy. Helicobacter. 2000;588- 93
Link to Article
Catalano  FBranciforte  GCatanzaro  RCipolla  RBentivegna  CBrogna  A Helicobacter pylori–positive duodenal ulcer: three-day antibiotic eradication regimen. Aliment Pharmacol Ther. 2000;141329- 1334
Link to Article
Tytgat  GNJ Treatments that impact favourably upon the eradication of Helicobacter pylori and ulcer recurrence. Aliment Pharmacol Ther. 1994;8359- 368
Link to Article
Megraud  F Epidemiology and mechanism of antibiotic resistance in Helicobacter pyloriGastroenterology. 1998;1151278- 1282
Link to Article
Laine  LSuchower  LFrantz  JConnors  ANeil  G Low rate of emergence of clarithromycin-resistant Helicobacter pylori with amoxycillin co-therapy. Aliment Pharmacol Ther. 1998;12887- 892
Link to Article
Svensson  MSörberg  MNilsson  M  et al.  Do combinations with nitroimidazoles or amoxicillin prevent development of clarithromycin resistance in Helicobacter pylori [abstract]? Gut. 1999;43 ((suppl)) A8
Trebesius  KPanthel  KStrobel  S  et al.  Rapid and specific detection of Helicobacter pylori macrolide resistance genes in gastric tissue by fluorescent in situ hybridization. Gut. 2000;46608- 614
Link to Article
Marais  AMonteiro  LOcchialini  APina  MLamouliatte  HMegraud  E Direct detection of Helicobacter pylori resistance to macrolides by a polymerase chain reaction DNA enzyme immunoassay in gastric biopsy specimens. Gut. 1999;44463- 467
Link to Article
Cutler  AFSchubert  TT Patient factors affecting Helicobacter pylori eradication with triple therapy. Am J Gastroenterol. 1993;88505- 509
Treiber  G Negative cag-A status is a risk factor for Helicobacter pylori eradication failure [abstract]. Gut. 2000;47 ((suppl 1)) A27
Labenz  JLeverkus  FBörsch  G Omeprazole plus amoxicillin for cure of Helicobacter pylori infection: factors influencing the treatment success. Scand J Gastroenterol. 1994;291070- 1075
Link to Article
Treiber  GAmmon  SKlotz  U Age-dependent eradication of Helicobacter pylori with dual therapy. Aliment Pharmacol Ther. 1997;11711- 718
Link to Article
Haruma  KKamada  TKawaguchi  H  et al.  Effect of age and Helicobacter pylori infection on gastric acid secretion. J Gastroenterol Hepatol. 2000;15277- 283
Link to Article
Ammon  STreiber  GKees  FKlotz  U Influence of age on the steady state disposition of drugs commonly used for the eradication of Helicobacter pyloriAliment Pharmacol Ther. 2000;14759- 766
Link to Article
Yamaoka  YKwon  DHGraham  DY A M(r) 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pyloriProc Natl Acad Sci U S A. 2000;977533- 7538
Link to Article
Aucher  PPetit  MMannant  PPecennec  LBabin  PFauchere  J Use of immunoblot assay to define serum antibody patterns associated with Helicobacter pylori infection and with Helicobacter pylori–related ulcers. J Clin Microbiol. 1998;36931- 936
Yamaoka  YKodama  TGraham  DY  et al.  Search for putative virulence factors of Helicobacter pylori: the low-molecular-weight (33-35 K) antigen. Dig Dis Sci. 1998;431482- 1487
Link to Article
Klotz  U Pharmacokinetic considerations in the eradication of Helicobacter pyloriClin Pharmacokinet. 2000;38243- 270
Link to Article
Gustavson  LEKaiser  JFEdmonds  ALLocke  CSDeBartolo  MLSchneck  DW Effect of omeprazole on concentrations of clarithromycin in plasma and gastric tissue at steady state. Antimicrob Agents Chemother. 1995;392078- 2083
Link to Article
Goddard  AFJessa  MJBerret  DAShaw  PNSpiller  RC Effect of omeprazole on the distribution of metronidazole, amoxicillin, and clarithromycin in human gastric juice. Gastroenterology. 1996;111358- 367
Link to Article
Kihira  KSatoh  KSaifuku  K  et al.  Comparison of ranitidine and lansoprazole in short-term low-dose triple therapy for Helicobacter pylori infection. Aliment Pharmacol Ther. 1997;11511- 514
Link to Article
Spadaccini  Ade Fanis  CSciampa  G  et al.  Omeprazole versus ranitidine: short-term triple therapy in patients with Helicobacter pylori–positive duodenal ulcers. Aliment Pharmacol Ther. 1996;10829- 831
Link to Article
Gschwantler  MDragosics  BSchütze  K  et al.  Famotidine versus omeprazole in combination with clarithromycin and metronidazole for eradication of Helicobacter pyloriAliment Pharmacol Ther. 1999;131063- 1069
Link to Article
Calvet  XGarcia  NLopez  TGisbert  JPGene  ERoque  M A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and either metronidazole or amoxicillin for treating Helicobacter pylori infection. Aliment Pharmacol Ther. 2000;14603- 609
Link to Article
Graham  DY Therapy of Helicobacter pylori: current status and issues. Gastroenterology. 2000;118 ((suppl 1)) S2- S8
Link to Article

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