Comparison of the physicochemical, antifungal, and toxic properties of two liposomal amphotericin B products.

Small unilamellar amphotericin B liposomes can reduce the toxicity of amphotericin B. In this study, we compared the physical, antifungal, pharmocokinetic, and toxic properties of two liposomal amphotericin B products, AmBisome and Anfogen, that have the same chemical composition but are manufactured differently. In vitro tests included determinations of the MICs and the concentrations causing the release of 50% of the intracellular potassium from red blood cells (K50 values) to assess toxicity. The 50% lethal dose (LD50) was evaluated by using uninfected C57BL/6 mice and single intravenous (i.v.) doses of 1 to 100 mg/kg of body weight. Multiple i.v. dosing over 18 days was performed with 0.5, 1.0, or 5.0 mg of Anfogen/kg or 1.0, 5.0, or 25 mg of AmBisome/kg to evaluate chronic toxicity. DBA/2 mice were infected intranasally with 2.5 x 10(6) Aspergillus fumigatus conidia, treated for 3 or 4 days with 3.0, 5.0, or 7.5 mg of Anfogen/kg or 3, 5, 7.5, or 15 mg of AmBisome/kg, and evaluated to assess the toxicity of the drugs to the kidneys (by measurement of blood urea nitrogen and creatinine levels and histopathology) and the drug efficacy. The median particle size was 77.8 nm for AmBisome and 111.5 nm for Anfogen. In vitro K(50) values were significantly lower for Anfogen (0.9 mug/ml) than for AmBisome (20 microg/ml), and the LD50 of AmBisome was >100 mg/kg, versus 10 mg of Anfogen/kg. There was significant renal tubular necrosis in uninfected and infected mice given Anfogen but no tubular necrosis in AmBisome-treated mice. AmBisome at 7.5 or 15 mg/kg was also more efficacious than 7.5 mg of Anfogen/kg for the treatment of pulmonary aspergillosis, based on survival and weight loss data and numbers of CFU per gram of lung. In conclusion, the efficacy and toxicity of these two liposomal amphotericin B products were significantly different, and thus, the products were not comparable.

Immunomodulation with interferon-gamma and colony-stimulating factors for refractory fungal infections in patients with leukemia.

BACKGROUND: Invasive fungal infections (IFI) in immunocompromised patients are associated with significant morbidity and mortality, despite appropriate antifungal treatment and recovery from neutropenia. The outcome of these infections depends significantly on the overall state of immunosuppression, including mainly the phagocytic system (neutrophils and macrophages). Interferon-gamma (IFN-gamma), granulocyte-colony--stimulating factor (G-CSF) and granulocyte-macrophage-colony--stimulating factor (GM-CSF) are cytokines that enhance the activity of neutrophils and macrophages. METHODS: The authors reported 4 patients with leukemia and refractory invasive candidiasis or trichosporonosis despite 1-13 months of appropriate antifungal treatment. RESULTS: Cytokines were administered for 1.5-5 months without significant toxicity. For each patient, initiation of interferon-gamma plus a colony-stimulating factor resulted in a clinical response. The contribution of cytokines to control the fungal infection in these 4 patients was suggested by the strong inflammatory reaction observed in the 2 patients who had an immediate response (within 7 days of initiation of cytokine therapy) and by the good outcome in the 2 other patients in whom antifungal agents were discontinued at the start of cytokine therapy. CONCLUSIONS: These data suggested a potential role for immunomodulation in patients with leukemia with refractory invasive fungal infections.

Stenotrophomonas maltophilia infections.

Stenotrophomonas maltophilia is a ubiquitous, gram-negative organism that causes hospital-acquired infections. Persons often come in contact with S. maltophilia through environmental water sources, including hospital tap water or faucets, and it has been associated with nosocomial outbreaks of infection. S. maltophilia often infects debilitated persons and those with underlying medical conditions, including immunosuppression. Manifestations of infection include pneumonia, often in mechanically ventilated patients, bacteremia, skin and soft tissue infection, urinary tract infection, and endocarditis. Treatment of S. maltophilia infection is difficult because the organism is resistant to a number of agents typically used for hospital-acquired infections. In vitro and clinical data indicate that trimethoprim-sulfamethoxazole is the agent of choice. Beta-lactamase inhibitors such as clavulanate are also active, and combination therapy may be indicated for certain serious infections due to S. maltophilia.

Pathogenic molds (including Aspergillus species) in hospital water distribution systems: a 3-year prospective study and clinical implications for patients with hematologic malignancies.

The incidence of mold infections in patients with hematologic malignancies continues to increase despite the widespread use of air filtration systems, suggesting the presence of other hospital sources for these molds. Water sources are known to harbor pathogenic molds. We examined samples from water, water surfaces, air, and other environment sources from a bone marrow transplantation unit with optimal air precautions. Molds (Aspergillus species, others) were recovered in 70% of 398 water samples, in 22% of 1311 swabs from plumbing structures and environmental surfaces, and in 83% of 274 indoor air samples. Microscopic examination of the water plumbing lines revealed hyphal forms compatible with molds. Four findings suggest that indoor airborne molds were aerosolized from the water: (1) higher mean airborne concentrations of molds in bathrooms (16.1 colony-forming units [CFU]/m(3)) than in patient rooms (7 CFU/m(3)) and hallways (8.6 CFU/m(3); P =.00005); (2) a strong type and rank correlation between molds isolated from hospital water and those recovered from indoor hospital; (3) lack of seasonal correlation between the airborne mold concentration in outdoor and indoor air; and (4) molecular relatedness between a clinical strain and a water-related strain (previously reported). Hospital water distribution systems may serve as a potential indoor reservoir of Aspergillus and other molds leading to aerosolization of fungal spores and potential exposure for patients.

The hospital water supply as a source of nosocomial infections: a plea for action.

BACKGROUND: Microbiologically contaminated drinking water is a cause of community-acquired infection, and guidelines for prevention of such infections have been established. Microbes in hospital water can also cause nosocomial infection, yet guidelines for preventing such infections do not exist. The purpose of this review is to assess the magnitude of the problem caused by waterborne nosocomial infections and to plea for immediate action for their prevention. METHODS: We conducted a MEDLINE search of the literature published between January 1, 1966, and December 31, 2001. STUDY SELECTION AND DATA EXTRACTION: Investigations in which microorganisms (other than Legionella species) caused waterborne nosocomial infections and public health agency recommendations for drinking water. RESULTS: Forty-three outbreaks of waterborne nosocomial infections have been reported, and an estimated 1400 deaths occur each year in the United States as a result of waterborne nosocomial pneumonias caused by Pseudomonas aeruginosa alone. Despite the availability of effective control measures, no clear guidelines exist for the prevention of these infections. By contrast, guidelines for the prevention of community-acquired waterborne infections are now routinely used. Hospitals caring for patients at high risk for infection do not enforce the standards of water quality recommended by US and United Kingdom public health agencies for the patients' community counterparts. CONCLUSION: Because of the seriousness of these nosocomial waterborne infections and the availability, low cost, and proven effectiveness of sterile water, we recommend that hospitalized patients at high risk for infection avoid exposure to hospital water and use sterile water instead.

Pathogenic Aspergillus species recovered from a hospital water system: a 3-year prospective study.

Nosocomial aspergillosis, a life-threatening infection in immunocompromised patients, is thought to be caused primarily by Aspergillus organisms in the air. A 3-year prospective study of the air, environmental surfaces, and water distribution system of a hospital in which there were known cases of aspergillosis was conducted to determine other possible sources of infection. Aspergillus species were found in the hospital water system. Significantly higher concentrations of airborne aspergillus propagules were found in bathrooms, where water use was highest (2.95 colony-forming units [cfu]/m(3)) than in patient rooms (0.78 cfu/m(3); P=.05) and in hallways (0.61 cfu/m(3); P=.03). A correlation was found between the rank orders of Aspergillus species recovered from hospital water and air. Water from tanks yielded higher counts of colony-forming units than did municipal water. An isolate of Aspergillus fumigatus recovered from a patient with aspergillosis was genotypically identical to an isolate recovered from the shower wall in the patient's room. In addition to the air, hospital water systems may be a source of nosocomial aspergillosis.