January 20, 2010 — Patients at risk for multidrug-resistant pathogens whose physicians followed guidelines from the American Thoracic Society and the Infectious Diseases Society of America to manage pneumonias with empirical antibiotic regimens had increased mortality compared with those patients receiving noncompliant therapy, new research suggests.
Daniel H. Kett, MD, from the University of Miami, Florida, and colleagues with the Improving Medicine through Pathway Assessment of Critical Therapy of Hospital-Acquired Pneumonia program published their findings online today in the Lancet Infectious Diseases.
In 2005, the American Thoracic Society and Infectious Diseases Society of America published updated guidelines for treating hospital-acquired pneumonia and related infections. These guidelines suggest that empirical treatment should be selected based on whether patients have recognized risk factors for multidrug-resistant pathogens.
The current study sought to evaluate the use of these guidelines and compare them with noncompliant treatment in 303 patients at 4 academic medical centers in the United States. All patients were in intensive care units and at risk for multidrug-resistant pneumonia.
Prescribed treatment was considered guideline compliant in 129 patients and noncompliant in 174 patients. Treatment was compliant if within 1 day of pneumonia recognition, therapy with a triple drug regimen as follows was implemented: cephalosporin, carbapenem, or β-lactam and β-lactamase inhibitor; an aminoglycoside or fluoroquinolone (in units with a high rate of carbapenem-resistant Acinetobacter spp, colistin was regarded as acceptable); and linezolid or vancomycin. Treatment not meeting these criteria was considered noncompliant.
Of the patients in the compliance group, 44 (34%) died before 28 days compared with only 35 (20%) in the noncompliance group. After adjusting for severity of illness and participants lost to follow-up, the estimated survival was significantly lower in the compliance group at 65% compared with 79% in the noncompliance group (P = .0042). Median length of stay and duration of mechanical ventilation were comparable between groups.
The most common reason for noncompliance was failure to use a secondary anti-Gram-negative drug (154 patients) and failure to empirically treat methicillin-resistant Staphylococcus aureus (MRSA) (24 patients). Another, less common, category of noncompliance was failure to use a primary anti-Gram-negative therapy.
"Despite our hopes to the contrary, we found that the use of guideline-compliant empirical treatment in patients in intensive-care units who were at risk for multidrug-resistant pathogens was associated with increased mortality," the authors conclude.
According to the researchers, the increased mortality associated with guideline-compliant empirical regimens may be explained by antibiotic-specific toxic effects. "Colistin and aminoglycoside use were associated with acute deterioration of renal function," they write. Neurotoxic effects have been described with aminoglycosides, colistin, and fluoroquinolones, and aminoglycosides contribute to critical illness polyneuropathy and myopathy. In addition, "prolongation of fluoroquinolone-induced QT interval can lead to life-threatening ventricular arrhythmias."
"[W]e suggest a comparison of regimens employing MRSA treatment and single versus dual Gram-negative coverage," the authors note.
Limitations include that the study was observational, lack of generalizability to inpatient wards, and incomplete information regarding prescribing practices.
In a related comment accompanying the article, Santiago Ewig, MD, from the Center for Thoracic Diseases of the Ruhrgebiet, Bochum, Germany, disputes the findings, although he agrees that the recommended triple approach is not supported by current evidence.
"All patients with septic shock, and probably severe sepsis, should receive dual coverage or triple coverage if MRSA is indicated," he writes. "Whether all haemodynamically stable patients with nosocomial pneumonia need such a wide coverage is questionable; at least, de-escalation [ie, monotherapy] treatment is mandatory, since it reduces selection pressure, organ toxic effects, and saves money. After all, de-escalation is what matters.
"The definition of non-adherence to American Thoracic Society guidelines should not read 'less than triple therapy' but rather 'less than long-term prognosis and risk-adjusted broad coverage and de-escalation according to culture and susceptibility results,' " he adds.
The study was supported by Pfizer. Dr. Kett and the other authors all have received financial support from or are employees of Pfizer. Several study authors have also declared financial relationships with the following institutions: Astellas, Cubist, Fallon Medica, GlaxoSmithKline, Johnson and Johnson, Madcat Healthcare, Merck, and Wyeth. Dr. Ewig has disclosed no relevant financial relationships.
Lancet Infect Dis. Published online January 20, 2011.
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