Volume 9 • Number 3 • 2004

Efficacy of Two Rabeprazole/Gatifloxacin-Based Triple Therapies
for Helicobacter pylori
Ala I. Sharara,* Hani F. Chaar,‡ Eddy Racoubian,† Oussayma Moukhachen,‡ Kassem A. Barada,* Fadi H. Mourad* and George F. Araj† *Departments of Internal Medicine; †Pathology and Laboratory Medicine, American University of Beirut Medical Center; ‡School of Pharmacy, Lebanese American University, Beirut, Lebanon A B S T R A C T
Objectives. To evaluate the efficacy of two novel
and intention-to-treat analysis: 83%; 95% CI: 72– treatment regimens consisting of gatifloxacin (400 mg 93%) and in 48 of 52 patients in the RAG40 group daily), amoxicillin (1 g twice daily), and rabeprazole (both per-protocol and intention-to-treat analysis: 20 mg once (RAG20) or twice daily (RAG40) given 92%; 95% CI: 85–99%). Seven patients in the RAG40 for 7 days in the eradication of Helicobacter pylori.
group who had previously failed one or more treat- Methods. Eligible patients undergoing endoscopy
ment regimens for H. pylori were cured. No significant and having a positive rapid urease assay for H. pylori adverse effects were reported. All 50 recovered H. pylori were enrolled in this open-label trial. Gastric biopsies strains were susceptible to amoxicillin and gatifloxacin from a random cohort of patients were cultured for H. pylori and in vitro susceptibility to gatifloxacin and Conclusions. A 7-day regimen of gatifloxacin-
amoxicillin was performed using the E-test. Compliance rabeprazole-amoxicillin is effective eradication and side-effects were evaluated by phone calls. 14C-urea therapy for H. pylori. The use of rabeprazole twice breath tests were performed a minimum of 4 weeks after daily results in superior eradication rates including therapy and 3 weeks after any acid suppressive therapy.
cases of failed primary therapy. This new regimen is Results. A total of 104 patients, 52 in each group (40
simple, well-tolerated, and may lead to higher females and 64 males; mean age 45.7 years) were enrolled sequentially. Eradication occurred in 43 out Keywords. gastritis, peptic ulcer, fluoroquinolones,
of 52 patients in RAG20 group (both per-protocol Helicobacter pylori is an established cause of 79–83% by intention-to-treat analyses [2]. The histological gastritis, peptic ulcer disease, duration of therapy remains controversial and gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma [1]. Although ade- improved eradication rate of up to 9% over the quate therapeutic regimens are currently avail- 7-day regimen [3]. However, limited compliance able, the determination of the optimal treatment with longer therapy duration can contribute to remains an active area of investigation. The most primary treatment failure as well as to the devel- widely used regimen consists of a proton pump opment of resistant strains. Primary resistance to inhibitor and two antibiotics, most commonly clarithromycin remains relatively low, albeit on clarithromycin in combination with either met- the rise. Importantly, primary resistance of ronidazole or amoxicillin and gives cure rates of H. pylori to clarithromycin appears to have sig-nificant clinical downfalls with eradication ratesof 8–50% [4–6].
Recipient of the ACG Presidential Poster Award at the 68thAnnual Scientific Meeting of the American College of Gas- troenterology, October 11–15, 2003, Baltimore, MD, USA.
Reprint requests to: Ala Sharara, MD, FACP, Associate Pro- of H. pylori. Using a 7-day regimen of moxi- fessor of Medicine, Head, Division of Gastroenterology, floxacin, clarithromycin and lansoprazole, Di American University of Beirut Medical Center, PO Box 11- Caro et al. reported a 90% eradication rate [7].
0236/16-B Beirut, Lebanon. Tel.: + 961-1-350000 Ext. 5351;Fax: + 961-1-370814; E-mail: [email protected] This combination, however, retained the use of 2004 Blackwell Publishing Ltd, Helicobacter, 9, 255– 261
clarithromycin and hence did not offer a new alcoholism, drug addiction, or history of poor alternative. Cammarota et al. showed that a 7-day treatment consisting of rabeprazole, levofloxacinand tinidazole or amoxicillin results in an erad-ication rate of 90 and 92%, respectively [8]. The combination was safe, simple, and well-tolerated.
After documentation of the H. pylori infection, The newer fluoroquinolones are effective in the patients were assigned sequentially to the vitro against H. pylori with the most effect seen following treatment regimens, both given for with gatifloxacin, clinafloxacin and trovafloxacin 7 days. Patients 1–52 received rabeprazole 20 mg [9]. Gatifloxacin is well absorbed from the gas- daily (Pariet®, Janssen-Cilag, Tokyo, Japan) trointestinal tract after oral administration and is plus gatifloxacin 400 mg daily (Tequin®, Bristol- widely distributed throughout the body into many Myers-Squibb, Princeton, New Jersey, USA) body tissues and fluids. Rapid distribution of and amoxicillin (Amoximex®, Cimex, Liesburg, gatifloxacin into tissues results in higher concen- Switzerland) 1 g twice daily (RAG20 group).
trations in most target tissues than in serum [10].
Patients 53–104 received gatifloxacin 400 mg Drug-related adverse effects are rare and include daily plus rabeprazole 20 mg and amoxicillin 1 g, nausea, diarrhea, and headache (all < 5%) [11].
both given twice daily (RAG40 group). Addi- tional use of acid suppressive therapy beyond pump (H+,K+-ATPase) inhibitor with a rapid the treatment period was left to the discretion of onset of action (as a result of its pKa of 5.4) resulting in rapid and potent acid inhibition.
These properties lead to an improved directbactericidal activity against H. pylori [12] and a Patient Instructions, Side-Effects and Follow-Up theoretical rapid effect on antibiotic bioavail- Patients were provided with the oral medications ability and stability, hence a more rapid kill of at no expense, and counseled on the appropriate the organism. Moreover, a recent meta-analysis drug intake. Compliance and potential side- of 13 studies involving 2391 patients showed an effects were evaluated by phone calls over the improved cure rate with triple therapies using a period of treatment. A minimum of 4 weeks standard double dose when compared to single after completion of therapy, patients underwent an office-based 14C-urea breath test according Based on the above, we studied a new combi- to standard protocol using the office-based nation therapy consisting of a 7-day single-dose vs. double-dose rabeprazole, in combination Sweden) [14]. All patients had to have been off with gatifloxacin and amoxicillin in patients with any acid-suppressive therapy for a minimum of peptic ulcers and/or H. pylori-related gastritis.
Materials and Methods
Isolation and Identification of H. pylori Over a 1-year period, 104 patients with dyspep- Fresh gastric biopsy specimens obtained during sia undergoing gastroscopy and with a positive gastroscopy from a random cohort of patients rapid urease assay (Pronto-Dry®, Medical with a positive rapid urease assay were trans- Instruments Corp., Brignais, France) document- ported to the laboratory in sterile physiologic ing H. pylori infection were enrolled in this saline and processed within 4 hours. Biopsy prospective, open-label trial. The study was approved by the Institutional Research Board physiological sterile saline (0.5 ml) then plated and all patients gave their informed consent.
immediately on two plate media to increase Exclusion criteria included age under 18 years, yield: the first medium was brucella agar supple- allergies to any of the drugs used, recent anti- mented with 7% horse blood and the second was biotic therapy (within 2 weeks of enrolment), gastric perforation or obstruction, use of quini- blood. Both plates contained Dent’s supplement dine, procainamide, or amiodarone, previous (Oxoid, Unipath Ltd, Basingstoke, UK). The gastrectomy, gastric cancer, pregnancy or lacta- plates were then incubated in a microaerophilic tion and severe concomitant disease or condition making the treatment unlikely to be effective (i.e.
(Oxoid) at 37°C for a maximum of 10 days.
2004 Blackwell Publishing Ltd, Helicobacter, 9, 255– 261
Gatifloxacin-Based Therapy of H. pylori Suspected isolates were identified as H. pylori by conventional methods using Gram stain, ure- ase, catalase and oxidase activities and by the API Campy commercial identification system (bio Merieux, Marcy l’Etoile, France). Once identi- fied as H. pylori, colonies were subcultured on blood until heavy growth was secured, usually Two antimicrobial agents (amoxicillin and NSAID = nonsteroidal anti-inflammatory drugs.
gatifloxacin) were tested against each H. pyloriisolate using the epsilometer test (Etest, ABBiodisk, Solna, Sweden). Briefly, a heavy inocu- patients in the RAG20 group became H. pylori- lum from a fresh subculture was made equivalent negative (83% by both per-protocol and inten- to 4–6 McFarland and streaked using a cotton tion-to-treat analyses; 95% CI: 72–93%), and swab on brucella agar containing 7% sheep nine patients of 52 (17%) failed to eradicate blood. The antibiotic strips were added and then H. pylori. In the RAG40 group, 48 of 52 patients the plates were incubated at 37 °C in a micro- became H. pylori-negative (92% by both per- aerobic environment using Campy Pak system protocol and intention-to-treat analyses; 95% for 3–4 days before reading the minimum inhibi- CI: 85–99%), while four (8%) were still positive.
tory concentrations (MIC). The MIC was deter- The difference in the success rate of the two mined based on the inhibition intersection.
study groups was not statistically significant( p = .14). Notably, all seven patients who hadfailed prior eradication therapy were cured. Com- pliance with the prescribed treatment was excel- We used the χ2 statistic with correction for con- lent and four patients in each group (7.7%) tinuity (categorical variables) and Student’s t-test experienced slight or mild side-effects consist- (continuous variables) to test for significant ing of nausea, headache and mild diarrhea not differences in characteristics between the two necessitating discontinuation of therapy.
patient groups. The rates of successful eradica- Fifty isolates of H. pylori were recovered tion between the two treatment arms were com- from gastric biopsies collected in a random pared using hypothesis testing of the difference cohort of study subjects. All cultured H. pylori between the two populations’ proportions.
strains were sensitive to amoxicillin (median Significance was drawn at p = .05 and the 95% confidence intervals were calculated accordingly.
Both per-protocol and intention-to-treat analy-ses were performed.
Triple therapies, including a combination of an antisecretory agent and two antimicrobials for One hundred and four patients were enrolled 7–14 days, are first-line therapies in treating and all completed the study. Table 1 shows the H. pylori infection [15,16]. The most commonly demographic and endoscopic data for these patients. The baseline characteristics and endo- clarithromycin and the nitroimidazoles.
scopic findings were not statistically different Clarithromycin-based regimens are considered amongst the two groups except that all 52 the current gold standard and large randomized patients in the RAG20 group were treatment- trials have confirmed the efficacy of such regi- naïve whereas seven out of 52 patients in the mens when given for 7 days, with rates of cure of RAG40 group had previously failed to eradicate 79–83% according to intention-to-treat analyses H. pylori following one or more treatment regi- [15,17–19]. Failures of eradication are felt to mens (Table 2). At the end of treatment, 43 of 52 occur in individuals who are noncompliant, 2004 Blackwell Publishing Ltd, Helicobacter, 9, 255– 261
Outcome of patients who had previously failed Helicobacter pylori eradication therapy A = Amoxicillin; C = Clarithromycin; L = Lansoprazole; Lv = Levofloxacin; M = Metronidazole; P = Pantoprazole; R = Rabeprazole.
those with resistant organisms, and the so- important to note that secondary resistance to called constitutional group, in whom failure is clarithromycin occurs in up to 62.5% of isolates but in only 9% for ciprofloxacin after failed Antimicrobial resistance plays an important eradication therapy [40,41], suggesting that role in these failures [4,20,21]. Primary resistance fluoroquinolone-based therapy may be effective to amoxicillin and tetracycline remains low, and although the frequency of clarithromycin resist- ance is low in Lebanon (4%) [22], it is reported safety of two 1-week rabeprazole/gatifloxacin- to be as high as 15% in the USA and Japan and based regimens in the eradication of H. pylori up to 28% in Europe [23–28]. Furthermore, lon- infection. Cure rates obtained with the double- gitudinal studies have shown that such primary dose rabeprazole appear to be superior (92%) resistance increases with time [23,29–32], likely and are in line with the results of a recent meta- as a result of the wider use of clarithromycin for analysis showing that triple therapies containing a variety of infections such as otitis media and a standard double dose of proton pump inhibitor respiratory infections in children. In fact, studies are associated with an increase of 6–8% in erad- in pediatric patients have documented an alarm- ication rates over those containing a single dose ing rate of primary clarithromycin resistance of [13]. Furthermore, our study suggests that this 23–43% [30,33–35]. This primary resistance to regimen may be promising in patients who have clarithromycin results in significant clinical failed primary conventional eradication thera- downfall with eradication rates of less than 60% pies. Perri et al. have recently reported an despite an increase in the dose of clarithromycin unacceptable eradication rate of 68% using a 7- or proton pump inhibitor [5,24]. As clarithro- day regimen of pantoprazole, levofloxacin and mycin resistance is expected to continue to rise, amoxicillin [42]. However, Zullo et al. showed the identification of an alternative agent to clar- an 88% eradication rate using a 10-day triple ithromycin becomes increasingly important.
therapy comprising of rabeprazole, levofloxacin A range of different antibacterial agents, such and amoxicillin in 30 patients with persistent as macrolides, new fluoroquinolones, furazo- H. pylori infection [43]. It is important to note lidone and rifabutin, is currently under investi- that the improved in vitro activity of gatifloxacin gation. The new generation fluoroquinolones over levofloxacin against H. pylori [9], and the may arguably offer the best alternative. In vitro theoretical beneficial effect of rabeprazole on studies show excellent susceptibility of H. pylori antibiotic bioavailability and stability, may sup- to newer quinolones [9,36] and although the port the use of this regimen preferentially over prevalence of primary resistance of H. pylori to those containing levofloxacin or other proton some of these newer quinolones is unclear, pump inhibitors. A larger study is needed, how- limited studies suggest a low rate of 8% for cipro- ever, to confirm the efficacy of this regimen in floxacin [37] and 4.7% to trovafloxacin [38]. Our the secondary treatment of H. pylori after failure in vitro susceptibility studies did not show any resistance to gatifloxacin in 50 H. pylori isolates.
In conclusion, we believe the results of this Resistance to quinolones appears to be primarily study support the use of rabeprazole/gati- a result of alterations in the gyrA gene and hence floxacin/amoxicillin in the treatment of H. pylori could theoretically confer cross-resistance infection. The low prevalence of primary resist- across various quinolones [39]. However, it is ance to gatifloxacin, its safety, and once-daily 2004 Blackwell Publishing Ltd, Helicobacter, 9, 255– 261
Gatifloxacin-Based Therapy of H. pylori Estimated retail price in US dollars of the on outcome of Helicobacter pylori therapy: a meta- rabeprazole-gatifloxacin-amoxicillin regimen (RAG40) in analytical approach. Dig Dis Sci 2000;45:68–76.
comparison to commonly used triple therapies for the 5 Murakami K, Sato R, Okimoto T, et al. Eradication eradication of Helicobacter pylori (data compiled from rates of clarithromycin-resistant Helicobacter pylori using either rabeprazole or lansoprazole plus amoxicillin and clarithromycin. AlimentPharmacol Ther 2002;16:1933–8.
6 Tankovic J, Lamarque D, Lascols C, Soussy CJ, Delchier JC. Impact of Helicobacter pylori resist- ance to clarithromycin on the efficacy of the omeprazole-amoxicillin-clarithromycin therapy.
A = Amoxicillin; C = Clarithromycin; E = Esomeprazole; Aliment Pharmacol Ther 2001;15:707–13.
G = Gatifloxacin; L = Lansoprazole; O = Omeprazole; 7 Di Caro S, Ojetti V, Zocco MA, et al. Mono, dual and triple moxifloxacin-based therapies forHelicobacter pylori eradication. Aliment PharmacolTher 2002;16:527–32.
dosing make it an acceptable alternative to 8 Cammarota G, Cianci R, Cannizzaro O, et al. Effi- clarithromycin-based therapies. Similarly, the cacy of two one-week rabeprazole/levofloxacin- existing low incidence of secondary H. pylori based triple therapies for Helicobacter pylori resistance to fluoroquinolones makes them infection. Aliment Pharmacol Ther 2000;14:1339– suitable for extended time of use in the future.
9 Bauernfeind A. Comparison of the antibacterial Table 3 lists the current estimated costs of activities of the quinolones Bay 12-8039, gati- conventional triple therapies compared with the floxacin (AM 1155), trovafloxacin, clinafloxacin, regimen used in this study. The comparative levofloxacin and ciprofloxacin. J Antimicrob pharmacoeconomics, or cost effectiveness, of these regimens is unclear but the simplicity and 10 Grasela DM. Clinical pharmacology of gati- tolerability of our regimen may arguably lead to floxacin, a new fluoroquinolone. Clin Infect Dis higher compliance and reduced direct as well as indirect costs currently associated with failure of 11 Casillas JL, Rico G, Rodriguez-Parga D, Mas- conventional therapies [44]. Larger studies are, careno A, Rangel-Frausto S. Multicenter evalua- however, needed to determine the broad appli- tion of the efficacy and safety of gatifloxacin in cability of this eradication regimen and its cost- Mexican adult outpatients with respiratory tractinfections. Adv Ther 2000;17:263–71.
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