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Diarrhea vs. Death: You Decide
Abstract & Commentary
By Barbara A. Phillips, MD, MSPH, Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington. Dr. Phillips is a consultant for Cephalon, and serves on the speakers bureaus for Resmed and Respironics. This article originally appeared in the June 29, 2010 issue of Internal Medicine Alert. It was edited by Stephen A. Brunton, MD, and peer reviewed by Gerald Roberts, MD. Dr. Brunton is Adjunct Clinical Professor, University of North Carolina, Chapel Hill, and Dr. Roberts is Assistant Clinical Professor of Medicine, Albert Einstein College of Medicine, New York, NY. Dr. Brunton serves on the advisory boards of Amylin, Kowa, Novo Nordisk, and serves on the speaker's bureau for Boehringer Ingelheim and Novo Nordisk. Dr. Roberts reports no financial relationships relevant to this field of study.
Synopsis: Early antibiotic administration was associated with reduced likelihood of death, mechanical ventilation, and readmission (but increased risk of Clostridium difficile infection) among patients hospitalized for acute exacerbations of COPD.
Source: Rothberg MB, et al. Antibiotic therapy and treatment failure in patients hospitalized for acute exacerbations of chronic obstructive pulmonary disease. JAMA 2010;303:2035-2042.
This report is the result of a retrospective, nonrandomized chart review of 312 hospitals over a two-year period. The hypothesis was probably that use of antibiotics in patients who were hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations would improve outcomes.
Participating hospitals were primarily small- to medium-sized nonteaching hospitals located in urban areas. The investigators were able to collect and review extensive data for the patients included in this study, including age, sex, race, marital and insurance status, principal diagnosis, comorbidities, self-reported race, and specialty of the attending physician. In addition, they were able to determine which tests and treatments patients received. They were also able to distinguish between those elements of patient management that were guideline-recommended and those that were not. Patients were included if they were at least 40 years of age and had a principal diagnosis of an acute exacerbation of COPD or emphysema, or if they had respiratory failure coupled with a secondary diagnosis of COPD exacerbation. Patients were excluded if they had another indication for antibiotics, a length of stay shorter than two days, a secondary diagnosis of pulmonary embolism or pneumothorax, a recent hospital discharge, or an attending physician who was not an internist, family physician, hospitalist, pulmonologist, or intensivist.
Antibiotic treatment was defined as a minimum of two consecutive days of an antibiotic, initiated on hospital day 1 or 2, including time spent in the emergency department. Antibiotics that were "counted," included first-, second-, and third-generation cephalosporins, quinolones, macrolides, tetracyclines, trimethoprim-sulfamethoxazole, and amoxicillin with or without clavulanic acid. Patients receiving other classes of antibiotics, or who received only a single day of treatment on hospital day 1 or 2, were excluded from the analysis. For the analysis, all antibiotics were considered equivalent, regardless of class, dose, duration, or route of administration. Patients whose antibiotic treatment started later than hospital day 2 were grouped with those who were not treated. The primary outcome was a composite measure of treatment failure, defined as the initiation of mechanical ventilation after hospital day 2, in-hospital mortality, or readmission for COPD within 30 days of discharge. Secondary outcomes included hospital costs and length of stay, as well as allergic reactions, diarrhea, and antibiotic-associated diarrhea, defined as treatment with either metronidazole or oral vancomycin initiated after hospital day 3 or readmission within 30 days for diarrhea and Clostridium difficile.
The sample used for the analysis included 84,621 patients whose median age was 69 years; 61% were women and 71% were white. Ninety percent of patients had a principal diagnosis of obstructive chronic bronchitis with acute exacerbation and 10% had respiratory failure. The most common comorbid conditions were hypertension, diabetes mellitus, and congestive heart failure. Twenty-eight percent had been admitted at least once in the preceding 12 months. In-hospital mortality was 1.2%, while 10% of patients experienced the composite measure of treatment failure (initiation of mechanical ventilation after hospital day 2, in-hospital mortality, or readmission for COPD within 30 days of discharge). Mean length of stay was 4.8 days.
Most (79%) patients received at least two consecutive days of antibiotic treatment beginning on day 1 or 2 of hospitalization, usually with a quinolone (60%), a cephalosporin (37%), or a macrolide (38%). Compared with patients not receiving antibiotics in the first two days, antibiotic-treated patients were less likely to receive mechanical ventilation after the second hospital day (1.07% vs. 1.80%), had lower inpatient mortality (1.04% vs. 1.59%), had a lower incidence of treatment failure (9.77% vs. 11.75%), had lower costs, and subsequently had lower rates of readmission for acute exacerbations of COPD (7.91% vs. 8.79%). Although antibiotic-treated patients had somewhat fewer allergic reactions (0.13% vs. 0.20%), they had a higher incidence of readmissions for C. difficile diarrhea (0.19% vs. 0.09%). After adjustment for the severity of illness, the beneficial effects of antibiotics were still evident. Buried in the fine print, however, was the revelation that the antibiotic group had higher costs than the non-antibiotic group, after adjustment.
Most hospitals had rates of antibiotic prescribing between 65% and 95%. When individual patients were assigned a probability of initial treatment with antibiotics equal to the hospital rate where they received care, each 10% increase in the hospital rate of treatment (e.g., from 70% to 80%) was associated with a 5% reduction in the odds of treatment failure, and this relationship was strengthened by removing patients with asthma plus COPD with acute exacerbation from the calculation.
There were some differences between those patients whose physicians ordered early antibiotics and those who did not in this nonrandomized trial. Compared with patients who did not receive initial treatment with an antibiotic, treated patients were younger and had fewer comorbidities and prior recent admissions. They were more likely to have private insurance and to be white. They were also more likely to be from hospitals that were smaller, southern, rural, and nonteaching.
In general, those patients who received early antibiotics were more likely to be treated according to published guidelines, including receiving steroids and bronchodilators. They were also, however, more likely to receive some treatments not recommended by guidelines, such as methylxanthine and mucolytic agents and chest physiotherapy. They were less likely to receive loop diuretics, morphine, and non-invasive positive pressure ventilation. The authors determined several factors that increased the propensity for antibiotic use early on; after adjustment for the "propensity score" of antibiotic prescription, those who were prescribed antibiotics early on were still more likely to be white, rural, insured by Medicare, and to have heart failure, diabetes, or renal failure. They also were more likely to receive methylxanthines, bronchodilators, steroids, morphine, and diuretics. They also underwent more diagnostic testing, but the differences were small.
Although its prevalence has begun to fall as tobacco consumption falls, COPD remains prevalent, and is the fourth leading cause of death in the United States.1 COPD exacerbations drive much of the cost of care for COPD patients, and are responsible for more than 600,000 hospitalizations annually, resulting in direct costs of more than $20 billion.2 Respiratory infections are probably the most common cause of COPD exacerbation,3 and several COPD treatment guidelines recommend antibiotic treatment for patients with purulent sputum and either an increase in sputum production or an increase in dyspnea.2,4,5 As is true for many expert guidelines, these recommendations are largely based on older (albeit randomized) trials. The current report, while retrospective and nonrandomized, comes from a large national sample of hospitals, and assessed outcomes in addition to mortality and respiratory failure. In this sample, fewer than 80% of patients received antibiotics in the first two days of hospitalization, perhaps because current guidelines recommend antibiotics only for patients with purulent or increased sputum production. What is new here is that the results of this analysis do not support restriction of antibiotics to COPD patients (experiencing exacerbation) with purulent sputum, increased sputum production, or dyspnea. The authors conclude that since "... all patient groups seemed to benefit from therapy and that harms were minimal ... all patients hospitalized with acute exacerbations of COPD should be prescribed antibiotics." Compared to lots of other things we do for patients who have a very high probability of winding up in the ICU, this does not seem to be such a far-fetched conclusion.
1. National, Heart, Lung, and Blood Institute. Take the first step to breathing better. Learn more about COPD. Available at: www.nhlbi.nih.gov/health/public/lung/copd. Accessed June 7, 2010.
2. Snow V, et al; Joint Expert Panel on Chronic Obstructive Pulmonary Disease of the American College of Chest Physicians and the American College of Physicians-American Society of Internal Medicine. Evidence base for management of acute exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 2001;134:595-599.
3. Rosell A, et al. Microbiologic determinants of exacerbation in chronic obstructive pulmonary disease. Arch Intern Med. 2005;165:891-897.
4. Celli BR, MacNee W; ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS Task Force. Eur Respir J. 2004;23:932-946.
5. Rabe KF, et al; Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care. Med 2007;176:532-555.