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A Randomized Study Comparing Levofloxacin, Omeprazole, Nitazoxanide, and Doxycycline Versus Triple Therapy for the Eradication O

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A Randomized Study Comparing Levofloxacin, Omeprazole, Nitazoxanide, and Doxycycline Versus Triple Therapy for the Eradication O 1970 ORIGINAL CONTRIBUTIONS nature publishing group see related editorial on page 1976 A Randomized Study Comparing Levofl oxacin, Omeprazole, Nitazoxanide, and Doxycycline versus Triple Therapy for the Eradication of Helicobacter pylori STOMACH STOMACH P. Patrick Basu , MD 1 , 2 , Krishna Rayapudi , MD 2 , Tommy Pacana , MD 2 , Niraj James Shah , MD 2 , Nithya Krishnaswamy , MD 2 and Molly Flynn , PharmD 3 OBJECTIVES: Resistance to standard Helicobacter pylori (HP) treatment regimens has led to unsatisfactory cure rates in HP-infected patients. This study was designed to evaluate a novel four-drug regimen (three antibiotics and a proton pump inhibitor (PPI)) for eradication of HP infection in treatment-naive patients. METHODS: Patients with a diagnosis of HP gastritis or peptic ulcer disease confi rmed using endoscopy and stool antigen testing were eligible for inclusion in this study. All patients underwent a washout period of 6 weeks from any prior antibiotic or PPI usage. Patients were then randomized to either levofl oxacin, omeprazole, nitazoxanide, and doxycycline (LOAD) therapy for 7 days (LOAD-7) or 10 days (LOAD- 10), including levofl oxacin 250 mg with breakfast, omeprazole 40 mg before breakfast, nitazoxanide (Alina) 500 mg twice daily with meals and doxycycline 100 mg at dinner, or lansoprozole, amoxicillin, and clarithromycin (LAC) therapy for 10 days, which included lansoprozole 30 mg, amoxicillin 1 g with breakfast and dinner, and clarithromycin 500 mg with breakfast and dinner. HP eradication was confi rmed by stool antigen testing at least 4 weeks after cessation of therapy. RESULTS: Intention-to-treat analysis revealed signifi cant differences ( P < 0.05) in the respective eradication rates of the LOAD therapies (88.9 % (80 / 90) LOAD-10, 90 % (81 / 90) LOAD-7, 89.4 % (161 / 180) for combined LOAD) compared with those receiving LAC, 73.3 % (66 / 90). There were no differences in adverse effects between the groups. CONCLUSION: This open-label, prospective trial demonstrates that LOAD is a highly active regimen for the treat- ment of HP in treatment-naive patients. A large randomized controlled trial is warranted to further evaluate the effi cacy of this regimen. Am J Gastroenterol 2011; 106:1970–1975; doi: 10.1038/ajg.2011.306; published online 11 October 2011 INTRODUCTION tetracycline) as a standard of care in the treatment of confi rmed Helicobacter pylori (HP) is a small, Gram-negative spirochete HP infections ( 4,7 ). However, a study by Rokkas et al. ( 8 ), based on inhabiting the mucous layer overlying the gastric epithelial cells in the Maastricht III guidelines, indicated that treatment with a PPI, humans. It is the most common chronic human bacterial infection amoxicillin, and clarithromycin regimen as fi rst-line therapy will and the most common cause of gastritis, with incidence rates as fail in ~ 30 % of patients on an intention-to-treat (ITT) basis, and high as 50 % worldwide ( 1 ). Furthermore, according to the World treatment with PPI, bismuth, metronidazole, and tetracycline as Health Organization, HP is classifi ed as a type 1 carcinogen and is second-line therapy will fail in another 30 % , leaving ~ 10 % of the the primary cause of peptic ulcer disease, gastric carcinoma, and total patient population in need of an alternative regimen. Patient mucosa-associated lymphoid tissue lymphomas ( 1 – 7 ). tolerability, adherence, and drug resistance rates play a major role Current guidelines from the American College of Gastroenter- in treatment selection and effi cacy. Drug resistance has the greatest ology and the European Helicobacter Study Group recommend impact on clarithromycin therapy, with HP resistance rates ranging either a clarithromycin-based triple therapy (a proton pump from 10 to 30 % ( 2,9 – 11 ), and actual cure rates for PPI, amoxicillin, inhibitor (PPI) plus amoxicillin and clarithromycin) or a bis- and clarithromycin triple therapy consistently falling below 80 % muth quadruple therapy (a PPI plus bismuth, metronidazole, and ( 5,6,8,10,12 ). In contrast, global resistance rates to metronidazole 1 Department of Gastroenterology, Hepatology and Liver Transplant, Columbia University, College of Physicians and Surgeons, New York , New York , USA ; 2 Department of Internal Medicine, Forest Hills Hospital , Forest Hills , New York, USA ; 3 University of Florida College of Pharmacy , Gainesville , Florida , USA . Correspondence: P. Patrick Basu, MD , North Shore University Hospital , 5 Station Square, Forest Hills , New York 11375 , USA . E-mail: [email protected] Received 11 April 2011; accepted 16 June 2011 The American Journal of GASTROENTEROLOGY VOLUME 106 | NOVEMBER 2011 www.amjgastro.com LOAD Therapy for Helicobacter pylori 1971 have been reported to range from 25 to 66 % , but some investiga- meeting the defi nition of a “ cure ” (HP-negative by stool antigen at tors believe resistance might be overcome with increased doses of least 4 weeks aft er the cessation of therapy) was performed. Th ese metronidazole ( 2,4,9 – 13 ). Unfortunately, this increase in dosage patients were asked to return to the clinic approximately 1 year can lead to the potential for intolerable side eff ects and pill burden, later to test for HP recurrence (recrudescence or reinfection). thus aff ecting treatment tolerability and adherence ( 4 ). In response to increasing rates of resistance with the aforemen- Outcome assessments tioned three- and four-drug regimens, newer treatment regimens Th e primary effi cacy outcome was measured as relative eradica- aimed at eradicating the organism more eff ectively are increasing tion rates between the three regimens, at least 4 weeks aft er the in popularity ( 1,3,5 – 10,12 ). Th is study evaluates a novel four-drug cessation of therapy, with patient tolerability and compliance STOMACH STOMACH regimen, three antibiotics and a PPI, for the eradication of HP addressed as secondary end points. At the cessation of HP therapy, infection in treatment-naive patients. all anti-secretory agents were discontinued and stool antigen test- ing for HP was performed at least 4 weeks aft er therapy to evalu- ate for complete eradication. Usage of a monoclonal antibody METHODS stool antigen test to assess HP eradication has been validated in a Study patients large meta-analysis and was approved by the United States Food Consecutive patients with dyspeptic symptoms undergoing and Drug Administration ( 14,15 ). During the course of therapy, upper endoscopy were recruited for study participation. To be all patients were contacted by phone at least four times to assess included in the study, patients must have had HP-induced gas- for side eff ects and adherence. Helicobacter pylori recrudescence tritis confi rmed by endoscopy (four-quadrant stomach biopsy or reinfection was assessed using a 13 C – urea breath test (OAPI (antro – corpus – incisura); Caris Life Sciences, Irving, TX) and BreathTeK Otsuka Pharmaceutical, Rockville, MD) and stool monoclonal stool antigen testing (Premier Platinum HPsA PLUS, antigen testing as previously described. Patients were instructed Meridian Bioscience, Cincinnati, OH). Exclusion criteria were as to discontinue any anti-secretory agent at least 2 weeks before fol- follows: partial gastrectomy or gastric malignancy; active bleed- low-up testing. ing; age < 20 years; pregnancy; prior HP treatment or infection; Th e study protocol was approved by the institutional review recent history and treatment for Clostridium diffi cile infection; board at Long Island Jewish Hospital-Forest Hills, and performed current use of a PPI, H2 receptor antagonist, antacid, anticoagu- in accordance with the Declaration of Helsinki, the International lant, or misoprostol; recent use of antibiotics (within 6 weeks), or Conference on Harmonisation Good Clinical Practice Guidelines, allergy to any medication used in the study. and applicable local laws and regulations. Signed informed con- sent was obtained from each patient before study enrollment. Study design A randomized, open-label trial was conducted to compare the tol- erability and effi cacy of a novel four-drug regimen in eradicating RESULTS HP gastritis. Th e study compared the LOAD regimen ( l evofl oxacin Clinical outcomes (Levaquin ®; Ortho-McNeil-Janssen Pharmaceuticals, Raritan, NJ), In total, 653 patients ( N = 653) were evaluated from a commu- o meprazole (Prilosec® ; AstraZeneca Pharmaceuticals LP, Wilm- nity referral base between February 2008 and January 2010. ington, DE), nitazoxanide ( A linia ®; Romark Laboratories, LC, Th ese patients reported symptoms of dyspepsia ( n = 439, 67.2 % ), Tampa, FL), and d oxycycline (Vibramycin ®; Pfi zer, New York, NY)) abdominal pain (n = 114, 17.5 % ), gastroesophageal refl ux with the current standard of care as represented by the LAC regi- ( n = 89, 13.6 % ), early satiety ( n = 8, 1.2 % ), and loss of appe- men (l ansoprazole (Prevacid ®; Takeda Pharmaceuticals North tite ( n = 3, 0.5 % ). Of these patients, 270 (41.3 % ) were enrolled America, Deerfi eld, IL), a moxicillin (Amoxil ®; GlaxoSmithKline, with confi rmed HP gastritis or non-bleeding peptic ulcers as Research Triangle Park, NC), and c larithromycin (Biaxin ®; Abbott documented by endoscopy (four-quadrant stomach biopsies) Laboratories, Abbott Park, IL)). Before randomization, patients and stool antigen testing. Overall, 278 patients (42.6 % ) were underwent a washout period of 6 weeks from any antibiotic or PPI excluded because of recent or ongoing usage of PPI, H2 recep- use, and provided written
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