Safety and clinical outcomes when utilizing high-dose (> or =8 mg/kg) daptomycin therapy.

BACKGROUND: Daptomycin is approved for the treatment of skin and skin-structure infections (4 mg/kg) and Staphylococcus aureus bacteremia, including right-sided endocarditis (6 mg/kg). In vitro and animal studies have reported increased activity with increased daptomycin doses. There are limited clinical data on use of daptomycin at doses greater than 6 mg/kg. OBJECTIVE: To evaluate the safety and efficacy of higher doses (> or =8 mg/kg) of daptomycin when administered for a variety of gram-positive infections. METHODS: Data were collected retrospectively as part of an ongoing registry (the Cubicin Outcomes Registry and Experience database) for the 2005-2007 program years. For the purpose of this study, the safety and efficacy of daptomycin were evaluated in patients who received doses of 8 mg/kg or higher. RESULTS: Ninety-four (2.6%) of 3617 patients received daptomycin doses of 8 mg/kg or higher; 18 (19%) of those patients received doses of 10 mg/kg or higher. The most common infections were bacteremia (30/94), skin and skin-structure infections (22/94), and endocarditis (15/94). The most common pathogens were Enterococcus spp. (37/94; 57% vancomycin-resistant) and S. aureus (28/94; 68% methicillin-resistant). Fifty-one percent of the patients were male, 39% were aged 66 years or older, 27% had an initial creatinine clearance less than 30 mL/min, and 17% were on dialysis. The median duration of daptomycin therapy was 15 days (minimum 1, maximum 90). Six (6.4%) of the 94 patients experienced 1 or more adverse events or abnormal laboratory value changes possibly related to daptomycin; in 2 (2.1%) of the 94 patients, daptomycin was discontinued due to treatment-related adverse events. Seventy-four (79%) patients were considered evaluable for efficacy. The overall clinical success rate was 89% (bacteremia, 91%; skin and skin-structure infections, 88%; endocarditis, 67%). CONCLUSIONS: Daptomycin was well tolerated and effective at doses of 8 mg/kg or higher in patients with gram-positive infections. Further prospective and comparative studies of daptomycin at doses greater than 6 mg/kg are warranted.

Adverse reactions to trimethoprim/sulfamethoxazole in AIDS.

OBJECTIVE: To report the case of a woman with AIDS who developed tremor, acute pancreatitis, and elevated serum creatinine levels while receiving trimethoprim/sulfamethoxazole (TMP/SMX). CASE SUMMARY: A 37-year-old Puerto Rican woman with AIDS, HIV nephropathy, and a recent history of disseminated histoplasmosis presented with fever, nonproductive cough, pancytopenia, and elevated transaminase and alkaline phosphatase levels. Serum creatinine was near her baseline level of 2.9 mg/dL. Treatment was started with amphotericin B lipid complex for histoplasmosis and intravenous TMP/SMX for presumed Pneumocystis carinii pneumonia. Two days later, the patient developed a high-frequency tremor and severe abdominal pain, and serum creatinine increased to 5.6 mg/dL. TMP/SMX was discontinued, after which the patient's symptoms resolved within 72 hours and serum creatinine returned to baseline levels. DISCUSSION: A high incidence of adverse reactions to TMP/SMX has been reported among HIV-infected persons. Toxic sulfamethoxazole metabolites may elicit hypersensitivity reactions. Trimethoprim can inhibit renal creatinine secretion, leading to high serum creatinine levels. Trimethoprim also inhibits dihydrofolate reductase, causing decreased dopamine production, which may lead to parkinsonian symptoms. Use of the Naranjo probability scale indicated a probable relationship between the adverse effect and TMP/SMX. CONCLUSIONS: The high frequency and wide range of potential adverse effects associated with the use of TMP/SMX in HIV-infected persons require that clinicians consider drug toxicity as a cause of new symptoms in patients receiving this medication.