The effect of statins on mortality in patients with bacteremia.

The statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, act to regulate the biosynthesis of cholesterol. Statins also deplete nonsterol cholesterol precursors, the isoprenoids, which are necessary for prenylation of critical membrane proteins that regulate cellular communication, including the inflammatory response. In a retrospective review of 388 bacteremic infections due to aerobic gram-negative bacilli and Staphylococcus aureus, there was a significant reduction in both overall (6% vs. 28%; P=.002) and attributable (3% vs. 20%; P=.010) mortality among patients taking statins compared with patients not taking statins. This reduction in mortality persisted in a multivariate analysis (odds ratio, 7.6; 95% confidence interval, 1.01-57.5). Among the statin group, diabetes, hypertension, and coronary artery disease were more prevalent (P<.001), and there were more skin and soft tissue infections identified as sources of bacteremia (P=.008). These data suggest a potential clinical role of statins in bacteremic infection; however, the mechanism by which mortality is reduced remains undefined.

Practice guidelines for diseases caused by Aspergillus. Infectious Diseases Society of America.

Aspergillosis comprises a variety of manifestations of infection. These guidelines are directed to 3 principal entities: invasive aspergillosis, involving several organ systems (particularly pulmonary disease); pulmonary aspergilloma; and allergic bronchopulmonary aspergillosis. The recommendations are distilled in this summary, but the reader is encouraged to review the more extensive discussions in subsequent sections, which show the strength of the recommendations and the quality of the evidence, and the original publications cited in detail. Invasive aspergillosis. Because it is highly lethal in the immunocompromised host, even in the face of therapy, work-up must be prompt and aggressive, and therapy may need to be initiated upon suspicion of the diagnosis, without definitive proof (BIII). Intravenous therapy should be used initially in rapidly progressing disease (BIII). The largest therapeutic experience is with amphotericin B deoxycholate, which should be given at maximum tolerated doses (e.g., 1-1.5 mg/kg/d) and should be continued, despite modest increases in serum creatinine levels (BIII). Lipid formulations of amphotericin are indicated for the patient who has impaired renal function or who develops nephrotoxicity while receiving deoxycholate amphotericin (AII). Oral itraconazole is an alternative for patients who can take oral medication, are likely to be adherent, can be demonstrated (by serum level monitoring) to absorb the drug, and lack the potential for interaction with other drugs (BII). Oral itraconazole is attractive for continuing therapy in the patient who responds to initial iv therapy (CIII). Therapy should be prolonged beyond resolution of disease and reversible underlying predispositions (BIII). Adjunctive therapy (particularly surgery and combination chemotherapy, also immunotherapy), may be useful in certain situations (CIII). Aspergilloma. The optimal treatment strategy for aspergilloma is unknown. Therapy is predominantly directed at preventing life-threatening hemoptysis. Surgical removal of aspergilloma is definitive treatment, but because of significant morbidity and mortality it should be reserved for high-risk patients such as those with episodes of life-threatening hemoptysis, and considered for patients with underlying sarcoidosis, immunocompromised patients, and those with increasing Aspergillus-specific IgG titers (CIII). Surgical candidates would need to have adequate pulmonary function to undergo the operation. Bronchial artery embolization rarely produces a permanent success, but may be useful as a temporizing procedure in patients with life-threatening hemoptysis. Endobronchial and intracavitary instillation of antifungals or oral itraconazole may be useful for this condition. Since the majority of aspergillomas do not cause life-threatening hemoptysis, the morbidity and cost of treatment must be weighed against the clinical benefit. Allergic bronchopulmonary aspergillosis (APBA). Although no well-designed studies have been carried out, the available data support the use of corticosteroids for acute exacerbations of ABPA (AII). Neither the optimal corticosteroid dose nor the duration of therapy has been standardized, but limited data suggest the starting dose should be approximately 0.5 mg/kg/d of prednisone. The decision to taper corticosteroids should be made on an individual basis, depending on the clinical course (BIII). The available data suggest that clinical symptoms alone are inadequate to make such decisions, since significant lung damage may occur in asymptomatic patients. Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and worsening spirometry suggest that corticosteroids should be used (BII). Multiple asthmatic exacerbations in a patient with ABPA suggest that chronic corticosteroid therapy should be used (BIII). Itraconazole appears useful as a corticosteroid sparing agent (BII). (ABSTRACT TRUNCATED)

Enhanced oxidative killing of azole-resistant Candida glabrata strains with ERG11 deletion.

The susceptibility of genetically defined Candida glabrata strains to killing by H2O2 and neutrophils was assessed. Fluconazole-susceptible L5L and L5D strains demonstrated survival rates higher than those of two fluconazole-resistant strains lacking the ERG11 gene coding for 14 alpha-demethylase. Fluconazole resistance can occur by mechanisms which increase fungal susceptibility to oxidative killing by H2O2 and neutrophils.

Polymerase chain reaction for the diagnosis of candidemia.

A PCR assay was developed for the diagnosis of candidemia. Primers were selected to amplify a 158-bp segment from the Candida actin gene that was detected by hybridization with a 32P-labeled oligomer probe. The lower limit of detection was DNA extracted from 10 Candida yeasts/sample, or 25 fg of purified Candida albicans DNA. This PCR was specific for medically important Candida species. Circulating Candida DNA was detected by this PCR from plasma of mice with induced candidemia and from sera in 11 (79%) of 14 patients with blood cultures positive for Candida species. This PCR may offer a sensitive method for diagnosis of candidemia.

Comparative safety, tolerance, and pharmacokinetics of amphotericin B lipid complex and amphotericin B desoxycholate in healthy male volunteers.

Amphotericin B lipid complex (ABLC), a lipid complex formulation of amphotericin B, and amphotericin B desoxycholate (AB) were compared for safety, tolerance, and pharmacokinetics in two groups of eight healthy male volunteers. After a 1-mg test dose, study drug was infused at 0.1, 0.25, and 0.5 mg/kg; the 0.5-mg/kg dose was not given to subjects receiving AB. ABLC caused few acute adverse effects except for mild somnolence (drowsiness) in six volunteers. In addition, three of eight ABLC recipient had asymptomatic, transient serum transaminase elevations that resolved spontaneously. The AB recipients experienced more acute side effects, but only one had a mild shaking chill: three of eight also experienced sleepiness. No significant changes in vital signs, electrocardiogram, oximetry, pulmonary function, or clinical status were observed in either group. Due to its increased estimate volume of distribution and estimated clearance. ABLC yielded decreased amphotericin B levels and area under the serum concentration versus time curve relative to AB.

Beta 1,4-oligoglucosides inhibit the binding of Aspergillus fumigatus conidia to human monocytes.

The binding of Aspergillus fumigatus conidia to human monocytes is mediated by a barley beta-glucan-inhibitable receptor. The simplest linkages in this glucan are present in the disaccharides laminaribiose (beta 1,3) and cellobiose (beta 1,4). Although laminaribiose gave strong inhibition of conidial binding to monocytes, cellobiose and oligosaccharides with beta 1,4-linked glucose residues were more potent as specific inhibitors of this binding over similar concentrations. Increasing the number of beta 1,4-linked glucose residues led to greater inhibition of conidial binding by human monocytes.

Efficacies of four antifungal agents in experimental murine sporotrichosis.

Four antifungal agents, amphotericin B, SDZ 89-485, itraconazole, and terbinafine, were tested for efficacy in a murine model of systemic sporotrichosis. Survival in the groups treated with amphotericin B, SDZ 89-485, and itraconazole was significantly better than that of control infected mice. However, these agents did not wholly protect the infected mice, as tail and paw lesions, whole-body radiographs, and positive cultures from survivors showed evidence of dissemination. Terbinafine-treated mice had the same or poorer survival as control infected mice, despite documented drug absorption.

Lectin-like attachment sites on murine pulmonary alveolar macrophages bind Aspergillus fumigatus conidia.

Murine pulmonary alveolar macrophages bound Aspergillus fumigatus conidia in vitro at 4 C and 37 C in the absence of serum or opsonins. This attachment was dependent on calcium and was sensitive to mild trypsinization and paraformaldehyde pretreatment of the macrophage membrane. Chitotriose, N-acetylglucosamine, D-mannose, alpha-methyl-mannoside, and L-fucose, but not D-galactose, were effective inhibitors of conidial binding. This pattern of reduction of conidial binding was consistent with that for the mannosylfucosyl receptor. In addition, conidial binding may be mediated by another lectin on the macrophage membrane, one that recognizes chitin components, because N-acetylglucosamine and chitotriose exhibited greater inhibition than expected for the mannosyl-fucosyl lectin.

Bioassay for SF 86-327, a new antifungal agent.

A bioassay with Trichophyton mentagrophytes is described for SF 86-327, an allylamine antifungal agent. SF 86-327 serum concentrations were measured by bioassay in 117 serum sampler from five patients receiving 500 mg/day. The peak, trough, and area under the concentration-time curve were determined after the first dose and at steady state. Drug accumulation occurred with prolonged therapy.

Tolerance to cryptococcal polysaccharide in cured cryptococcosis patients: failure of antibody secretion in vitro.

Ten patients cured of cryptococcosis and 14 normal volunteers were immunized with subcutaneous injections of cryptococcal polysaccharide (CPS). Peripheral mononuclear cells cultured from the volunteers 7 days post-immunization secreted significant amounts of IgM, IgA and IgG antibody to CPS in vitro. In cell cultures obtained 7 days after immunization of patients, nine of 10 had neither IgM nor IgG antibody response to CPS, and eight lacked anti-CPS IgA. Depletion of T lymphocytes from patients' cell cultures did not promote specific antibody secretion to CPS by B cells. The intense, prolonged antigenaemia with CPS that accompanies cryptococcosis may be responsible for the failure of cured patients to have circulating anti-CPS-secreting cells after immunization.