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During an 18-month period, antibiotic prophylaxis in 120 patients undergoing closed tube thoracostomy was evaluated by a prospective, randomized double-blind technique. Forty-six subjects had sustained penetrating chest trauma. Either placebo (n = 60) or 1 gm/6 hours cefamandole (n = 60) was begun intravenously at the time of tube insertion and was continued intravenously or intramuscularly until the second day following tube removal. Cultures were taken of the pleural drainage, usually blood, at tube insertion, on tube removal, and on several occasions between those times. Antibiotic concentrations were determined biologically on the same specimens of pleural fluid as well as selectively on concomitant venous blood samples. Cultures were also obtained from all subsequent foci of infection, including the wound, any empyema, bronchial secretions, urine, or infected intravenous sites. Aerobic and anaerobic isolation and identification were carried out according to standard laboratory procedures with sensitivity testing (disc and tube dilution) only of the aerobes. Results demonstrated that infection of the lung and/or pleural space was eight times more common in the placebo group (13.3%) than in the group receiving cefamandole (1.7%) (p <0.01). In addition, the single infection that developed despite use of the antibiotic was due to a susceptible organism. No major adverse drug reactions were noted.