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.
The epidemiology of pseudallescheriasis complicating transplantation: nosocomial and community-acquired infection.
The epidemiology of two cases of pseudallescheriasis in organ transplant patients are described and the disease in that population is reviewed. Disseminated hospital-acquired infection occurred in a liver transplant recipient and was fatal despite therapy with miconazole. A heart transplant recipient developed localized disease following soil contamination of soft tissue trauma which was cured with surgical resection and miconazole therapy. Itraconazole showed in vitro activity against Pseudallescheria boydii and should be evaluated in pseudallescheriasis. P. boydii infections are important complications of transplantation and should be considered in the differential diagnosis of community-acquired as well as nosocomial fungal infections in this population.
Current concepts in cryptococcosis.
Cryptococcus neoformans has become an increasingly important pathogen. Cryptococcosis is an important cause of morbidity and mortality in immunocompromised hosts and is the second most common fungal infection complicating AIDS. In recent years, research has focused on the host defenses against Cryptococcus and has led to an improved understanding of the capsular virulence of the organism, the mechanisms of T-cell defenses, and the role of phagocytic cells in the fungistasis and killing of cryptocci. Amphotericin B with or without flucytosine has clearly improved treatment of cryptococcosis, but therapy is associated with significant toxicity. Current investigation is focused on the triazoles, which may offer improved therapy for cryptococcosis. In this report, we review recent developments in the understanding of the host defenses against Cryptococcocus and discuss current recommendations for the management of cryptococcosis.
Treatment of experimental invasive aspergillosis with novel amphotericin B/cholesterol-sulfate complexes.
An immunosuppressed rabbit model of invasive aspergillosis was used to evaluate a novel micellar preparation of cholesterol sulfate complexed to amphotericin B. The acute LD50 of amphotericin B-deoxycholate was 5.1 mg/kg versus 20 mg/kg for the amphotericin/cholesterol-sulfate complexes. Amphotericin B-deoxycholate given iv at a dose of 1.5 mg/kg was more effective in sterilizing liver and kidney than the amphotericin/cholesterol-sulfate complexes given iv at 1.5-4.5 mg/kg, but infection persisted in the lungs of all rabbits treated with those doses. Infection persisted even when the rabbits were given a lethal dose of amphotericin B-deoxycholate (4.5 mg/kg), but a dose of 15 mg/kg of the amphotericin/cholesterol-sulfate complexes sterilized tissues and was associated with no acute lethality. Equivalent doses of the amphotericin/cholesterol-sulfate complexes were less effective than amphotericin B-deoxycholate, but a fourfold decrease in acute lethality improved the therapeutic index of amphotericin B. The amphotericin/cholesterol-sulfate complexes appear to be an improved means of amphotericin B delivery and may improve therapy for invasive aspergillosis.
Evaluation of restriction endonuclease analysis as an epidemiologic typing system for Branhamella catarrhalis.
Restriction endonuclease analysis (REA) was evaluated as an epidemiologic typing tool to distinguish Branhamella catarrhalis strains. Fourteen beta-lactamase-producing strains were collected over a 16-month period at a hospital where a nosocomial outbreak of this organism was previously documented by REA. REA produced 12 distinct patterns which correlated with epidemiologic data. Chromosomal REA appears to be a useful technique for distinguishing B. catarrhalis strains.
Assuring safe travel for today's elderly.
The increased availability of time and resources has made travel attractive to many elderly patients. Both healthy and chronically ill geriatric patients can travel safely and without medical complications in many circumstances. Many of these patients, however, have special health needs that call for specific advice from practitioners. Patients with medical problems, such as chronic obstructive pulmonary disease, cardiovascular disease, thrombotic disease, sinus conditions, or diabetes, should be aware of possible complications involved in travel. In addition, medical advice regarding vaccinations, traveler's diarrhea, jet lag, and malaria prophylaxis should be tailored to this population. Such a prescribed regimen may make travel safe and feasible for many geriatric patients.
The role of liposomal amphotericin B in the treatment of systemic fungal infections.
Amphotericin B remains the treatment of choice for systemic fungal infections, but amphotericin B is toxic and is often not effective in treating disseminated infections. Liposome intercalation of amphotericin B reduces the toxicity associated with amphotericin B and targets reticuloendothelial tissues most heavily involved in fungal infections. The targeted delivery and reduced toxicity of liposomal amphotericin B improves the therapeutic index of amphotericin B. Although liposomes have been shown to effectively treat a variety of experimental and human fungal infections, the optimal composition of liposomal amphotericin has not been established. Vesicle type, lipid content, size, and conditions of storage markedly affect toxicity, therapeutic efficacy, and tissue distribution. In vitro studies have been poor predictors of in vivo efficacy and toxicity. Animal models can be used to evaluate in vivo the optimal liposome preparation. Liposomal amphotericin B appears to be an improved means of amphotericin B delivery and may improve the treatment of patients with systemic fungal infections.
A nosocomial outbreak of Branhamella catarrhalis confirmed by restriction endonuclease analysis.
An outbreak of respiratory illness due to Branhamella catarrhalis occurred in the intermediate care unit of a Veterans Administration hospital and involved patients and staff members. Four patients had pneumonia and four had bronchitis. Infected patients were placed in a cohort separated from noninfected patients and were treated. Pharyngeal culture was used to survey prevalence in staff and all other patients on the unit; three of 18 staff members and two of 19 asymptomatic patients were positive for B. catarrhalis. A case-control study showed that respiratory therapy, steroid use, and location within the unit were significant risk factors for B. catarrhalis infection or colonization. Strains from five patients and two staff members had identical bacterial restriction endonuclease digestion patterns with three different enzymes; these patterns were distinct from those of control strains. This study is the first to document an outbreak of B. catarrhalis infection confirmed with a typing system and thus establishes B. catarrhalis as a nosocomial pathogen.
Activity of LY146032 in vitro and in experimental enterococcal pyelonephritis.
The efficacy of LY146032 (LY), a new lipopeptide antibiotic, was compared with that of vancomycin, ciprofloxacin, ceftriaxone, imipenem, and gentamicin and combinations of LY-ceftriaxone, LY-imipenem, and LY-gentamicin against 15 strains of Streptococcus (Enterococcus) faecalis by microtiter dilution and checkerboard techniques. LY was effective within a very narrow range of drug concentrations (from 0.125 to 2.0 micrograms/ml) and was more active than other agents tested against S. faecalis. Enhanced inhibition of S. faecalis was seen more frequently with combinations of either penicillin or ampicillin and an aminoglycoside than with combinations of LY and gentamicin, imipenem, or ceftriaxone. The in vivo efficacy of LY was compared with that of vancomycin and ampicillin alone and combinations of vancomycin-gentamicin, ampicillin-gentamicin, and LY-gentamicin in a rat model of chronic enterococcal pyelonephritis. At a dose of 10 mg/kg given twice daily, LY reduced the number of organisms per kidney significantly compared with that in infected untreated controls within 48 h after the initiation of therapy. At 20 mg/kg given once a day, LY was less effective but reduced colony counts significantly after 4 days of therapy, and its activity was comparable to that of vancomycin or vancomycin-gentamicin given twice daily. LY may be a promising agent for the treatment of enterococcal infections.
Efficacy of fluconazole in experimental invasive aspergillosis.
The efficacy of fluconazole against Aspergillus fumigatus was evaluated in an immunosuppressed, temporarily leukopenic rabbit model of invasive aspergillosis. Fluconazole was given at a dosage of 60 mg/kg twice daily and was compared with amphotericin B given intravenously at a dosage of 1.5 mg/(kg.d). Fluconazole reduced the tissue burden of Aspergillus from that in untreated controls by 10- to 100-fold in liver, kidney, and lung. However, at these doses amphotericin B was more effective in sterilizing tissues and in reducing the tissue burden of Aspergillus in those organs. Both fluconazole and amphotericin B decreased or eliminated circulating Aspergillus antigen and improved survival over that of untreated controls. Thus fluconazole shows activity in this rabbit model of invasive aspergillosis and should be further evaluated for use in the treatment of this disease.