Biomedical subjects
T F Patterson
Publications and source records attributed to T F Patterson.
Animal models: usefulness for studies of fungal pathogenesis and drug efficacy in aspergillosis.
This review describes our experience during the past 8 years with an immunocompromised rabbit model of invasive aspergillosis. We have used the model to evaluate the efficacy of a variety of antifungal therapies, including amphotericin B-deoxycholate, a liposomal amphotericin B preparation, some of the newer azoles (i.e., fluconazole, saperconazole, and the experimental compound SCH 39304), and combination therapy with amphotericin B-deoxycholate plus fluconazole. The model provides a rigorous test of efficacy when animals receive a lethal challenge; permits studies of the kinetics of aspergillar antigenemia in response to therapy with each antifungal agent or regimen; allows comparison of the relation of antigenemia to the extent of disease in target organs; and is useful in correlating the timing of antifungal therapy with the success of treatment. These observations in our animal model may provide some insight into the treatment of invasive aspergillosis in humans.
IgA-containing immune complexes after challenge with food antigens in patients with IgA nephropathy.
The possibility that patients with IgA nephropathy (IgAN) might have abnormal IgA immune responses to immunogens commonly encountered at mucosal surfaces, resulting in the formation of circulating immune complexes (CIC), was examined. Since it is generally held that such increased IgA responses are characterized by detectable aberrancies in handling of IgA-containing CIC, IgAN patients and controls were given a large volume of bovine milk (after dietary deprivation of bovine antigens) and immune complex levels were measured over a period of 12 h. An assay based on binding of CIC containing C3 to solid-phase anti-C3 and subsequent development with isotype-specific antibody revealed no differences in responses of patients and controls with respect to IgG- and IgM-containing CIC. Although IgAN patients tended to have higher levels of IgA-containing CIC, there were no differences in response patterns when IgA CIC levels after ingestion of the milk stimulus were related to baseline levels. Polymorphonuclear leucocytes (PMNC), which bear surface receptors for IgA, were isolated from some subjects at the same times as the samples for CIC levels and examined by two-colour immunofluorescence for the coincident presence of IgA and milk antigens. In contrast to the data obtained in the CIC assays, these experiments revealed the simultaneous presence of IgA and two of three milk proteins in PMNC of IgAN patients but not controls. Follow-up experiments designed to assess more quantitatively the coincidental presence of IgA and milk antigens indicated no significant differences between patients and controls. However, milk proteins seemed to be more commonly associated with IgA in PMNC of IgAN patients, suggesting the presence of non-complement-fixing IgA/antigen CIC after mucosal challenge of some IgAN patients.
Saperconazole therapy in a rabbit model of invasive aspergillosis.
The efficacy of orally and intravenously administered saperconazole against Aspergillus fumigatus was assessed in an immunosuppressed temporarily leukopenic rabbit model of invasive aspergillosis and compared with that of amphotericin B. Oral saperconazole at dosages of 5, 10, and 15 mg/kg of body weight per day improved survival compared with that of controls. In addition, saperconazole at 10 and 15 mg/kg/day reduced the tissue burden and reduced levels of circulating antigen, which correlated with increasing dosages of saperconazole. Intravenous saperconazole produced levels in serum more than 10-fold that of oral therapy. Intravenous saperconazole not only improved survival and reduced antigen levels but also significantly eradicated A. fumigatus from tissues compared with those of controls and was as effective as amphotericin B in these studies. Saperconazole was effective in the treatment of experimental invasive aspergillosis and demonstrates the potential of the newer azoles in therapy for invasive aspergillosis.
Epidemiology, natural history, and management of urinary tract infections in pregnancy.
The urinary tract undergoes profound physiologic and anatomic changes during pregnancy that facilitate the development of symptomatic UTIs in women with bacteriuria. Although the adverse effects of asymptomatic bacteriuria on maternal and fetal health continue to be debated, it is clear that asymptomatic bacteriuria is the major risk factor for developing symptomatic UTI and that symptomatic infections are associated with significant maternal and fetal risks. Because the majority of symptomatic UTIs develop in women with bacteriuria earlier in pregnancy, treatment of bacteriuria is undertaken to prevent symptomatic infections. All women should be screened at the first antenatal visit, which is reliably and inexpensively done with a dipstick culture. Short-course therapy is as effective as prolonged therapy and should be followed with a repeat culture to document clearing of the bacteriuria. Failure to eliminate bacteriuria with repeated therapy or recurrence with the same organism is indicative of renal parenchymal infection or a structural abnormality. All women with persistent bacteriuria or recurrent infection should have follow-up cultures and a complete urologic evaluation after delivery.
The role of fluconazole in the early treatment and prophylaxis of experimental invasive aspergillosis.
The efficacy of fluconazole against Aspergillus fumigatus was assessed in an immunosuppressed temporarily leukopenic rabbit model of invasive aspergillosis. Therapy with fluconazole at 60 or 120 mg/kg/day was begun 24 h after lethal challenge and compared to that with amphotericin B at 1.5 mg/kg/day. Fluconazole reduced mortality compared with that in untreated controls and at 120 mg/kg/day reduced the tissue burden of A. fumigatus 10- to 100-fold in liver, kidney, and lung. However, amphotericin B was more effective in sterilizing tissues. Both fluconazole and amphotericin B dramatically decreased or eliminated circulating aspergillus antigen. Prophylaxis with fluconazole, begun 48 h before sublethal challenge, sterilized liver and kidney tissues and significantly reduced the tissue burden in lung. Early treatment with fluconazole reduced mortality and reduced antigenemia but did not sterilize tissues. Fluconazole prophylaxis at these doses prevented dissemination of invasive aspergillosis. Fluconazole was shown to have activity in the early treatment and prophylaxis of experimental invasive aspergillosis.
Efficacy of SCH 39304 in treatment of experimental invasive aspergillosis.
The efficacy of SCH 39304 (SCH) against Aspergillus fumigatus was assessed with an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis. Therapy with SCH at 10 or 15 mg/kg of body weight per day was begun 24 h after lethal challenge and compared with therapy with amphotericin B at 1.5 mg/kg/day. Compared with untreated controls, SCH reduced mortality and also reduced the tissue burden of A. fumigatus 100- to 1,000-fold in liver, kidney, and lung tissues. SCH at 15 mg/kg/day and amphotericin B eliminated A. fumigatus in liver, kidney, and lung tissues. In addition, both dosages of SCH significantly eliminated the organism from brain tissues, compared with controls. Both SCH and amphotericin B decreased or eliminated circulating aspergillus antigen. These results show that new azoles can be as effective as amphotericin B in eradicating the organism from tissues and offer promise in improving the treatment of invasive aspergillosis.