Nancy Siepman

Risk factors for Helicobacter pylori resistance in the United States: the surveillance of H. pylori antimicrobial resistance partnership (SHARP) study, 1993-1999.

BACKGROUND: Pretreatment antimicrobial resistance has an important impact on the efficacy of many Helicobacter pylori treatment regimens. OBJECTIVE: To estimate the prevalence of H. pylori resistance to antimicrobials in the United States, to characterize risk factors associated with H. pylori antimicrobial resistance, and to explore the association between drug utilization and antimicrobial resistance patterns over time. DESIGN: Meta-analysis using patient-level data. SETTING: 20 nationwide trials of H. pylori eradication. PATIENTS: 3624 men and women, each of whom contributed one isolate. MEASUREMENTS: Rates of H. pylori resistance to clarithromycin, metronidazole, and amoxicillin, according to geographic region, age, sex, study year, ethnicity, ulcer status, test method, and study. RESULTS: Overall resistance to clarithromycin, metronidazole, and amoxicillin was 10.1% (95% CI, 9.1% to 11.1% [360 of 3571 patients]), 36.9% (CI, 35.1% to 38.7% [1063 of 2883 patients]), and 1.4% (CI, 1.0% to 1.8% [48 of 3486 patients]), respectively. In multivariable analyses, multiple risk factors were associated with resistance to individual agents. Clarithromycin resistance was significantly associated with geographic region (P = 0.050), older age (P < 0.001), female sex (P < 0.001), inactive ulcer disease (P < 0.001), and study (P = 0.010). Metronidazole resistance was significantly associated with female sex (P < 0.001), earlier year of study enrollment (P = 0.036), Asian ethnicity (P < 0.001), use of an epsilometer test (P = 0.002), and study (P < 0.001). Amoxicillin resistance was low and was not significantly associated with any risk factor. In the 1990s, when rates for use of oral macrolides and metronidazole were relatively stable, clarithromycin resistance rates were stable and metronidazole resistance rates varied. CONCLUSIONS: Clinicians should consider risk factors for antimicrobial resistance when deciding which patients should have susceptibility testing and when choosing appropriate H. pylori treatments in the empirical setting.More than half of all days spent in an intensive care unit are incurred by patients older than 65 years of age, and the number of days per year spent in the intensive care unit (per 1000 person-years) is sevenfold higher for persons older than 75 years compared with persons younger than 65 years (1). The population of older persons and their respective proportion of health care expenditures are expected to double by 2030 (2), and some have suggested that we ration the care provided to older patients (3-5). Indeed, physicians in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT) withheld mechanical ventilation at higher rates in older patients, especially in patients 70 years of age or older (6-8). However, previous reports of older patients with respiratory failure from various causes have indicated that recovery and overall prognosis in this age group do not justify using age alone to determine treatment decisions (9-11). Instead, the decision to place older persons with acute lung injury on mechanical ventilation should incorporate several factors, including comorbid illnesses (12), patient preference or previously stated wishes, physician gestalt, and bedside judgment. The incidence of acute respiratory failure requiring mechanical ventilation increases 10-fold from the ages of 55 to 85 years (13), resulting in an increasing number of elderly patients receiving treatment in intensive care units (1, 11, 14). Therefore, health care professionals need to understand the effect of age on outcomes of acute lung injury and the acute respiratory distress syndrome (henceforth called acute lung injury) to guide their treatment decisions and prognostic discussions (15, 16). In most investigations, the mortality rate from acute lung injury has ranged from 40% to 50% (15, 17-21). Data from a large cohort followed from 1983 to 1993 revealed encouraging declines in acute lung injury-related mortality but showed that these improved outcomes were confined largely to patients younger than 60 years of age (22). We used data from an acute lung injury database sponsored by the National Heart, Lung, and Blood Institute (23, 24) to investigate the effect of age on the ability to recover from acute lung injuryinformation that could prove extremely important given the growing number of older persons at risk for acute lung injury (2-5, 16, 25). We hypothesized that age would independently affect acute lung injury outcomes, even after adjustment for severity of illness and other covariates. To investigate this hypothesis, we asked the following questions about age and acute lung injury: 1) How does age affect survival from acute lung injury? 2) Do physiologic recovery and successful liberation from the ventilator take longer in older patients? Methods Patients We examined data on 902 patients who participated in the National Heart, Lung, and Blood Institute multicenter, randomized trials of the Acute Respiratory Distress Syndrome (ARDS) Network between 18 March 1996 and 28 May 1999. Patients were enrolled from 24 hospitals associated with 10 U.S. medical centers. Included in this analysis were the 861 patients from a recently reported randomized trial of mechanical ventilation that compared lower with traditional tidal volume (6 mL/kg of ideal body weight vs. 12 mL/kg of ideal body weight) (24). After the early stopping of the ventilator trial by the data safety monitoring board for efficacy, the 41 additional patients in our analysis had received lisofylline or placebo with the lower tidal-volume strategy. (Lisofylline is a xanthine derivative that decreases the inflammatory response.) The institutional review boards of each participating medical center or hospital approved this study. Patients or their surrogate provided informed consent before enrollment. The study was conducted in accordance with the established ethical standards of the medical centers and with the principles of the Declaration of Helsinki (26). We analyzed age as a binary category and according to decade. To assess the varying effect of age on outcomes, we also used age, coded as a series of indicator variables for decade of age, in multivariable analysis. In keeping with our prospectively defined analysis plan, we decided a priori to report these data as a comparison of the patients younger than 70 years of age (n = 729) with the patients 70 years of age or older (n = 173). In the absence of any clearly defined age cutoff designating patients as elderly, we chose these binary age categories on the basis of data from the SUPPORT studies suggesting that physicians most often used 70 to 75 years of age as a decision-making cut point affecting intensity of care and threshold for withholding mechanical ventilation (6-8). However, additional analyses defining older persons at lower (65 years of age) and higher (80 years of age) cutoffs have yielded similar results. Details of inclusion and exclusion criteria for the ARDS network trials have been reported previously (23, 24). Briefly, patients were eligible if they required mechanical ventilation for acute lung injury, with a partial Po 2 divided by fraction of inspired oxygen of 300 or less, bilateral pulmonary infiltrates consistent with pulmonary edema, and no clinical evidence of left atrial hypertension. If measured, the pulmonary capillary wedge pressure was required to be 18 mm Hg or less (27). The major reasons for exclusion were as follows: more than 36 hours elapsed since the inclusion criteria were met, age younger than 18 years, participation in other acute lung injury trials in the past 30 days, pregnancy, increased intracranial pressure, neuromuscular disease that could impair spontaneous breathing, sickle-cell disease, severe chronic respiratory disease (as previously described [23, 24]), massive obesity, burns covering more than 30% of body surface, comorbid conditions with an estimated 6-month mortality rate greater than 50%, bone marrow or lung transplantation, chronic liver disease (as defined by Child-Pugh Class C [28]), inability to consent, and attending physician refusal or unwillingness to commit full life support. The patients surrogate and managing physician determined whether to withdraw mechanical ventilation, and we analyzed all patient data on an intention-to-treat basis. Protocol for Mechanical Ventilator Management Mechanical ventilation was performed in strict accordance with the ARDS network study protocol (24). Weaning was done according to a protocol that included a daily weaning screen followed by pressure support ventilation and a 2-hour spontaneous breathing trial. The Daily Weaning Screen and Spontaneous Breathing Trials Patients were followed daily to determine when they passed the following weaning screens, which were based on data from previous investigations (29-31): oxygen saturation of at least 0.88 on positive end-expiratory pressure of 8 cm H2O or less and a fraction of inspired oxygen of 0.40 or less, systolic blood pressure of 90 mm Hg or more without vasopressor support, and demonstration of spontaneous inspiratory efforts (initiating breaths above the rate of the ventilator setting). After meeting these daily weaning screen criteria, patients were given a 5-minute trial of spontaneous breathing with continuous positive airway pressure of 5 cm H2O. If the respiratory rate remained 35 breaths/min or less, the patient entered a pressure support weaning protocol and then a 2-hour spontaneous breathing trial on a T-piece or continuous positive airway pressure of 5 cm H2O without pressure support ventilation, as described previously (www.ardsnet.org). The spontaneous breathing trial was terminated if any of the following predetermined conditions were met: respiratory rate greater than 35 breaths/min for more than 5 minutes, sustained arterial oxygen saturation less than 0.90, heart rate that had increased by 20% or more compared with the rate at 0600 hours (6 a.m.), marked use of accessory respiratory muscles, abdominal paradox, marked subjective dyspnea, or diaphoresis. If any of these criteria were met, then the ventilator was set at the patients previously used settings and the patient was weaned by using the pressure-support protocol until the following day, at which time the daily weaning screen would be performed again. Patients passed the spontaneous breathing trial if none of the above conditions were met. After passing the 2-hour spontaneous breathing trial, patients graduated to unassisted breathing, meaning that they were extubated, continued receiving a T-piece, or received continuous positive airway pressure of 5 cm water without pressure support ventilation. Definitions of Recovery Landmarks To determine the rate of recovery of older compared with younger patients, the earliest time at which patients had successfully passed four clearly defined recovery landmarks was recorded: 1) the daily weaning screen, 2) the 2-hour spontaneous breathing trial, 3) the date on which the patient began a period of unassisted breathing that lasted 48 hours or more, and 4) discharge from the intensive care unit alive and with no mechanical ventilation. Severity of Illness Classification and Organ or System Failure Baseline severity of illness was recorded at enrollment by using the Acute Physiology, Age, and Chronic Health Evaluation III (APACHE III) score (32). During analysis, we used a modified APACHE III score that excluded age so that age would remain an independent factor of outcome. Nonpulmonary organ system failures were also recorded by using definitions based on the following objective criteria (24, 33-35): for circulatory failure, a systolic blood pressure of 90 mm Hg or less or the need for treatment with any vasopressor; for coagulation failure, a platelet count of 80 109 cells/L or less; for central nervous system failure, a Glasgow coma scale rating less than 12; for hepatic failure, a serum bilirubin concentration

Triple versus dual therapy for eradicating Helicobacter pylori and preventing ulcer recurrence: a randomized, double-blind, multicenter study of lansoprazole, clarithromycin, and/or amoxicillin in different dosing regimens.

Objective:The efficacy and safety of dual and triple therapies with a proton pump inhibitor and antibiotic(s) for therapy of Helicobacter pylori-associated duodenal ulcer disease have been compared using results from independent studies using different methods and regimens, making interpretation difficult. In a large, double-blind, multicenter study conducted in the United States, we compared a triple therapy regimen with four dual therapy and one monotherapy regimens in the eradication of H. pylori and the prevention of ulcer recurrence.Methods:Patients with active duodenal ulcer disease or history of duodenal ulcer disease within the past year and H. pylori infection were randomized to receive one of six 14-day treatment regimens: lansoprazole 30 mg, clarithromycin 500 mg, and amoxicillin 1 gm b.i.d.; lansoprazole 30 mg b.i.d. and either clarithromycin 500 mg b.i.d. or t.i.d.; lansoprazole 30 mg b.i.d. or t.i.d. with amoxicillin 1 gm t.i.d.; or lansoprazole 30 mg t.i.d. alone. No additional acid suppression therapy followed eradication therapy. Primary efficacy endpoints were eradication of H. pylori and ulcer recurrence.Results:Of 396 patients enrolled in the study, 352 met the entry criteria for duodenal ulcer status and H. pylori positivity. At 4–6 wk after the end of therapy, H. pylori was eradicated from 94% (44 of 47) of patients receiving lansoprazole, clarithromycin, and amoxicillin triple therapy, 77% (39 of 51) of those receiving lansoprazole t.i.d./amoxicillin t.i.d., 75% (36 of 48) of those receiving lansoprazole b.i.d./clarithromycin t.i.d., 57% (28 of 49) of those receiving lansoprazole b.i.d./clarithromycin b.i.d., 53% (26 of 49) of those receiving lansoprazole b.i.d./amoxicillin t.i.d., and 2% (1 of 53) of those receiving lansoprazole monotherapy (p≤ 0.05, triple therapy vs each dual therapy and each dual therapy vs monotherapy). Of those patients who were documented as free of ulcer at 4–6 wk after treatment, ulcers recurred within 6 months in 7% of patients receiving triple therapy, as compared with 13–23% of patients receiving dual therapy, and 69% of patients receiving lansoprazole monotherapy. Patients who were H. pylori negative at 4–6 wk after treatment were less likely to have an ulcer recurrence than were patients who were H. pylori positive (11% [10 of 95] vs 47% [20 of 43], respectively, across treatment groups). For triple therapy and dual therapy, a similar proportion of patients reported a drug-related adverse event (23%vs 17–33%, respectively). Conclusions: In patients with active or a recent history of duodenal ulcer, a 14-day course of lansoprazole-based triple therapy without additional acid suppression therapy is highly effective in the eradication of H. pylori and in preventing ulcer recurrence. Among the dual therapies, higher eradication rates occurred when lansoprazole (with amoxicillin) or clarithromycin (with lansoprazole) was administered t.i.d. vsb.i.d., but the rates were still significantly lower than with lansoprazole triple therapy with all three drugs administered b.i.d.

Seven‐Day Triple Therapy with Lansoprazole, Clarithromycin, and Metronidazole for the Cure of Helicobacter pylori Infection: A Short Report

BackgroundTo refine our understanding of anti‐Helicobacter pylori treatment regimens further, we evaluated the efficacy and safety of lansoprazole given in combination with clarithromycin and metronidazole for 7 days in an open‐label, multicenter study.

Double-blind, multicenter evaluation of lansoprazole and amoxicillin dual therapy for the cure of Helicobacter pylori infection

BackgroundTreatment with amoxicillin plus omeprazole results in disappointing cure rates of Helicobacter pylori infection. The minimal inhibitory concentration of lansoprazole for H. pylori in vitro is lower than that for omeprazole, prompting interest in treatment with amoxicillin plus lansoprazole.

Proton Pump Inhibitors: Effective First-Line Treatment for Management of Dyspepsia

The aim of this study was to evaluate the reasons for trial exclusion among dyspeptic patients and estimate the proportion that may have benefited from proton pump inhibitor (PPI) therapy. Stringent inclusion criteria for enrollment in two multicenter functional dyspepsia trials included dyspepsia (predominant persistent/recurrent upper abdominal discomfort [UAD] during the prior 3 months) of at least moderate intensity during ≥30% of days during the prior 2 to 3 weeks. Exclusion criteria were mild/infrequent UAD; heartburn and UAD of equal frequency; predominant heartburn with UAD; endoscopic evidence of erosive esophagitis or Barrett’s or gastric and/or duodenal erosions (>5) or ulcers; irritable bowel syndrome (IBS); other gastrointestinal diagnoses; or other “non-categorized” disorders. Of 2,588 screened patients, 1,667 were excluded. Excluded patients by category had mild/infrequent UAD (12.5%, n=324), heartburn and UAD of equal frequency (1.1%, n=29), predominant heartburn with UAD (11.6%, n=300), endoscopic evidence of erosive esophagitis or Barretts (6.2%, n=160), gastric and/or duodenal erosions (1.4%, n=36), gastric and/or duodenal ulcers (2.0%, n=53), IBS (7%, n=180), “other” gastrointestinal diagnoses (2.8%, n=73), or other “non-categorized” disorders (19.8%, n=512). Fifty-four percent of patients (902/1,667) had symptoms/diagnoses that would be expected to improve with PPI therapy. Individuals with IBS, “other,” or “non-categorized” disorders were considered to have symptoms unlikely to respond to PPI treatment. Empiric PPI treatment would be expected to provide symptom relief to the majority of dyspepsia sufferer who present in clinical practice. PPIs represent the best currently available therapy for acid-related disorders and should be considered the first-line management approach in patients with uninvestigated dyspepsia.

Triple Therapy with Lansoprazole, Clarithromycin, and Amoxicillin for the Cure of Helicobacter pylori Infection: A Short Report

BackgroundGiven the therapeutic potential of proton pump inhibitor‐based triple therapy for successful cure of Helicobacter pylori infection, we evaluated the efficacy and safety of lansoprazole with clarithromycin and amoxicillin in an open‐label, single‐center study.

Helicobacter pylori and Early Duodenal Ulcer Status Post-Treatment: a Review

Data submitted to the FDA were reviewed to analyze the relationship between Helicobacter pylori infection and the incidence of early duodenal ulcers, within 6 weeks, following treatment.

Evaluation of risk factors in the surveillance of heucobacter pywri antimicrobial resistance partnership (SHARP) in the united states from 1993–1999

EVALUATION OF RISK FACTORS IN THE SURVEILLANCE OF HEUCOBACTER PYWRI ANTIMICROBIAL RESISTANCE PARTNERSHIP (SHARP) IN THE UNITED STATES FROM 19931999. Joette M. Meyer, Karen M. Higgins, Wenjin Wang, Nancy Y. Siepman, Jennifer E. Sugg, David Morris, Jie Zhang, Helen Bhattacharya, Eileen C. King, Robert 1. Hopkins, U S Food and Drug Admin, Rockville, MD; Wyeth-Ayerst Research, Philadelphia, PA; TAP Holdings, Inc, Deerfield, IL; AstraZeneca LP, Wayne, PA; Abbott Lab, Abbott Park, IL; Pfizer Pharmaceuticals, New York, NY; Procter & Gamble, Mason, OH.