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Stenotrophomonas maltophilia is a life-threatening nosocomial pathogen with profound multidrug-resistant attributes. It is associated with high mortality, particularly in immunocompromised patients. Data on therapy for S. maltophilia infections are scarce, especially in children hospitalized in intensive care settings (pediatric intensive care unit).A retrospective chart review of pediatric patients with isolates of S. maltophilia hospitalized over a 5-year period in 2 pediatric intensive care units.Thirty-one patients and 91 isolates from blood, respiratory secretions and soft tissues were identified and reviewed. The overall incidence of S. maltophilia infections increased during the study period (P = 0.003). The all-cause crude mortality was 61%, and the attributed mortality was approximately 16%. Risk factors associated with mortality included longer hospitalization before infection (P = 0.002), septic shock (P = 0.003), mechanical ventilation (P = 0.004), an indwelling central vein catheter (P = 0.03) and prior use of steroids (P = 0.04) and carbapenems (P = 0.004). On multivariate analysis, mortality was associated with mechanical ventilation (P = 0.02) and preinfection hospitalization days (P = 0.01). Combination treatment of trimethoprim and sulfamethoxazole, ciprofloxacin and/or minocycline significantly extended survival time (P < 0.001). The method of treatment did not significantly affect the interval between S. maltophilia isolation to resolution of infection (P = 0.200).Combinations of trimethoprim and sulfamethoxazole, ciprofloxacin and minocycline are proposed for pediatric intensive care unit patients harboring S. maltophilia. Meticulous evaluation of central vascular access and prior treatment with carbapenems are indicated, especially for mechanically ventilated and septic children.