Michael F. Luther

Stroke in infective endocarditis.

We reviewed 212 consecutive episodes of infective endocarditis in 203 patients at six hospitals between 1978 and 1986 and found that 21% were complicated by stroke. Of 133 episodes involving native mitral and/or aortic valves, brain ischemia occurred in 19%, brain hemorrhage in 7%, and non-central nervous system emboli in 11%; vegetations were identified in 56% of 113 adequate echocardiograms and did not correlate with risk of embolism. In native-valve endocarditis, most (74%) ischemic strokes had occurred by the time of presentation and an additional 13% occurred less than or equal to 48 hours after diagnosis; the incidence of brain ischemia was 13% on presentation, 3% during the first 48 hours of hospitalization, and 2%-5% during the remainder of the acute course. Stroke recurred at a rate of 0.5%/day, often heralding relapse/uncontrolled infection. Only 9% of ischemic infarcts were large (all in patients with Staphylococcus aureus infection), while 8% were small and subcortical. Brain hemorrhage occurred primarily at the time of presentation, particularly in intravenous drug abusers, and was associated with uncontrolled S. aureus infection with pyogenic arteritis. Ischemic and hemorrhagic stroke continue to be frequent and important in patients with infective endocarditis and are clustered during uncontrolled infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation between Antifungal Susceptibilities of Coccidioides immitis In Vitro and Antifungal Treatment with Caspofungin in a Mouse Model

ABSTRACT Caspofungin (Merck Pharmaceuticals) was tested in vitro against 25 clinical isolates of Coccidoides immitis. In vitro susceptibility testing was performed in accordance with the National Committee for Clinical Laboratory Standards document M38-P guidelines. Two C. immitis isolates for which the caspofungin MICs were different were selected for determination of the minimum effective concentration (MEC), and these same strains were used for animal studies. Survival and tissue burdens of the spleens, livers, and lungs were used as antifungal response markers. Mice infected with strain 98-449 (48-h MIC, 8 μg/ml; 48-h MEC, 0.125 μg/ml) showed 100% survival to day 50 when treated with caspofungin at ≥1 mg/kg. Mice infected with strain 98-571 (48-h MIC, 64 μg/ml; 48-h MEC, 0.125 μg/ml) displayed ≥80% survival when the treatment was caspofungin at ≥5 mg/kg. Treatment with caspofungin at 0.5, 1, 5, or 10 mg/kg was effective in reducing the tissue fungal burdens of mice infected with either isolate. When tissue fungal burden study results were compared between strains, caspofungin showed no statistically significant difference in efficacy in the organs of the mice treated with both strains. A better in vitro-in vivo correlation was noted when we used the MEC instead of the MIC as the endpoint for antifungal susceptibility testing. Caspofungin may have a role in the treatment of coccidioidomycosis.

Fluconazole, D0870, and flucytosine treatment of disseminated Candida tropicalis infections in mice.

D0870 is a recently developed triazole with characteristics of a broad spectrum of activity and slow clearance by nonrenal mechanisms. Herein we have evaluated the efficacy of D0870, alone and combined with flucytosine, in a murine model of disseminated Candida tropicalis infection. Four isolates of C. tropicalis were evaluated. Two were highly susceptible in vitro to fluconazole, and two were resistant to fluconazole. All were highly susceptible to flucytosine and D0870. Animals were pretreated with 5-fluorouracil 1 day before infection because C. tropicalis has reduced virulence in immunocompetent mice. This was done to render them neutropenic for > 10 days. Mice were infected intravenously and treated orally with D0870 or fluconazole, alone or combined with flucytosine. Survival and tissue burden of the spleen and kidneys were used to evaluate the efficacy of antifungal therapy. Fluconazole was less effective for treatment of resistant C. tropicalis than susceptible C. tropicalis. D0870 was more potent than fluconazole and was effective in fluconazole-resistant isolates. Flucytosine was consistently effective when used alone but did not consistently add to the benefit of D0870 or fluconazole. D0870 has potential in treatment of candidiasis caused by C. tropicalis, including fluconazole-resistant isolates.

Granulocyte colony stimulating factor therapy of experimental cryptococcal meningitis

Cryptococcal meningitis was induced in mice using intracerebral injection of Cryptococcus neoformans. Beginning either 3 days before or 1 day after infection, mice were treated with human recombinant granulocyte colony stimulating factor (hGCSF). In high doses hGCSF reduced the brain tissue burden of C. neoformans but had no effect on survival. The effect of hGCSF was dependent on size of the infecting dose and time of administration. A large innocula of C. neoformans, or when hGCSF was initiated after infection, there was no added benefit. Some groups of mice also received low doses of fluconazole beginning 1 day after infection. Fluconazole both prolonged survival and reduced brain tissue counts of C. neoformans. Combined cytokine/fluconazole therapy was superior to either agent given alone. These studies suggest that hGCSF can add to the efficacy of fluconazole therapy in murine cryptococcosis, and suggest that polymorphonuclear leucocytes contribute to host defence in cryptococcal meningitis. The relative potency of fluconazole appears greater than hGCSF.

Variation in fluconazole efficacy for Candida albicans strains sequentially isolated from oral cavities of patients with AIDS in an experimental murine candidiasis model.

Four strains of Candida albicans, isolated from two patients with AIDS who had undergone prolonged fluconazole therapy for oral candidiasis, were studied in a model of disseminated murine candidiasis. Pre- and posttreatment isolates from each patient were genetically related, and the fluconazole MICs for the strains had increased significantly, from 0.25 to 32 micrograms/ml for the strains isolated from patient 1 and from 1.0 to 16 micrograms/ml for the strains isolated from patient 2. Mice were infected intravenously and were treated orally with fluconazole. For survival studies, mice were treated from day 1 to day 10 postinfection and were observed through day 30. The fluconazole dosages were as follows: 0.25, 0.5, 1.0, and 5.0 mg/kg of body weight twice a day. For tissue burden studies, two groups of mice (each group received fluconazole at 0.25 or 5.0 mg/kg) were treated from day 1 to day 7 and were sacrificed 1 day later for quantitative tissue cultures of the spleen and both kidneys. For pretreatment isolates from both patients, all fluconazole dosing regimens were effective at prolonging survival compared with the survival of the control groups. For posttreatment isolates, only fluconazole at 5.0 mg/kg was effective at prolonging survival. Both fluconazole dosing regimens used in the tissue burden studies significantly reduced the counts of the pretreatment isolate from patient 1 in the spleen and kidney, while fluconazole at 5.0 mg/kg was effective at reducing the counts of the posttreatment isolate. For both isolates from patient 2, only fluconazole at 5.0 mg/kg was effective at reducing the counts in the spleen and kidney. The study indicates that C. albicans mutation to resistance to fluconazole may play a critical role in fluconazole-refractory oral candidiasis in AIDS patients.

Efficiency of lower threshold criteria for the diagnosis of gestational diabetes

Objectives To determine the incidence of adverse outcome in normal untreated gravidas with minimal hyperglycemia, classified as having gestational diabetes mellitus (GDM) by threshold criteria lower than current standards; to determine how efficient the different criteria are in identifying infants at risk for morbidity; and to explore the pathophysiology of minimal hyperglycemia using the glucose tolerance test (GTT) periodicity concept. Methods Seven hundred eight subjects considered nondiabetic by current ACOG criteria were reclassified by the criteria of Coustan (fasting 95, 1 hour 180, 2 hours 155, and 5 hours 140 mg/dL), Sacks (96, 172, 152, and 131 mg/dL), or Langer (at least one abnormal ACOG value). Glucose tolerance test periodicity, the incidence of large for gestational age (LGA) neonates, and macrosomia were then determined for each gravida diagnosed as having GDM by these criteria. Results Both Coustan and Langer criteria identified a significantly greater incidence of LGA infants compared with non-GDM (23.6 and 25.3%, respectively, versus 14%, P < .05), and identified them as efficiently as current criteria, approximately one LGA infant for every four GDM subjects treated. The incidence of LGA did not differ between the Sacks GDM and non-GDM groups. Glucose tolerance test periodicity for newly diagnosed GDM gravidas was significantly longer than non-GDM for Coustan and Langer criteria (3.9 and 4.06 versus 3.3 hours, P < .01) but not for the Sacks criteria. Conclusion Using lower threshold criteria to diagnose GDM identified morbidity at an incidence and efficiency comparable to current standards. These newly diagnosed GDM gravidas had abnormal GTT characteristics, with each group exceeding the 3.5-hour GTT periodicity limit previously found for nondiabetic gravidas. Sackss conversion of existing standards may be too low to efficiently identify pregnant subjects at risk for increased morbidity.