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Thomas S Harrison

Publications and source records attributed to Thomas S Harrison.

10 recordsLinked to original sources
PubMed2005

Baseline correlation and comparative kinetics of cerebrospinal fluid colony-forming unit counts and antigen titers in cryptococcal meningitis.

Cerebrospinal fluid (CSF) cryptococcal colony-forming unit counts and CSF cryptococcal antigen titers serve as alternative measures of organism load in cryptococcal meningitis. For these measures, we correlated baseline values and rates of decline during the first 2 weeks of therapy in 68 human immunodeficiency virus--seropositive patients with cryptococcal meningitis. At baseline, there was a strong correlation between CSF cryptococcal colony-forming unit counts and CSF cryptococcal antigen titers. During the first 2 weeks of therapy, CSF cryptococcal colony-forming unit counts decreased by >5 logs, and CSF cryptococcal antigen titers decreased by 1.5 dilutions. In individual patients, there was no correlation between the rate of decline in CSF cryptococcal colony-forming unit counts and that in CSF cryptococcal antigen titers.

Antifungal Agents↗
PubMed2005

Cryptococcal meningitis.

Cryptococcal meningitis is a common opportunistic infection in AIDS patients, particularly in Southeast Asia and Africa. Cases also occur in patients with other forms of immunosupression and in apparently immunocompetent individuals. Mortality from HIV-associated cryptococcal meningitis remains high (10-30%), even in developed countries, because of the inadequacy of current antifungal drugs and the complication of raised intracranial pressure. In cohorts of HIV-infected patients from sub-Saharan Africa, cryptococcosis has accounted for 13-44% of all deaths. Optimal current therapy is with amphotericin B 0.7-1 mg/kg/day plus flucytosine 100 mg/kg/day for 2 weeks, followed by fluconazole 400 mg/day for 8 weeks and 200 mg/day thereafter. Saline loading reduces amphotericin B nephrotoxicity. If there is no contraindication on CT head scan, repeat lumbar puncture with drainage of cerebrospinal fluid (CSF) is recommended for patients with very raised CSF opening pressure. Expansion of antiretroviral programmes raises the prospect of transforming the long-term prognosis of these patients, provided that they survive the acute phase of the illness. Studies are needed to define more fungicidal drug regimens and to improve the treatment of raised intracranial pressure.

AIDS-Related Opportunistic Infections↗
PubMed2005

IFN-gamma at the site of infection determines rate of clearance of infection in cryptococcal meningitis.

In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-gamma, TNF-alpha, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-alpha, IFN-gamma, and IL-6 levels and baseline cryptococcal CFU. Log IFN-gamma, G-CSF, TNF-alpha, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-gamma remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-gamma secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-gamma in the treatment of refractory HIV-associated cryptococcosis.

Cryptococcus neoformans↗
PubMed2005

Lumbar drainage for control of raised cerebrospinal fluid pressure in cryptococcal meningitis: case report and review.

Raised intracranial pressure in the absence of ventricular dilatation is common in cryptococcal meningitis and associated with increased mortality. We report the case of a patient with HIV-associated cryptococcal meningitis, who developed increasing CSF pressure and visual impairment on therapy despite serial lumbar punctures. Insertion of a temporary lumbar drain controlled the opening pressure and resulted in full visual recovery. The advantages and necessary precautions with this approach are reviewed, and alternative protocols for the use of lumbar drains discussed.

AIDS-Related Opportunistic Infections↗
PubMed2005

Correspondence of in vitro and in vivo fluconazole dose-response curves for Cryptococcus neoformans.

We conducted in vitro experiments to evaluate the susceptibility of a clinical isolate of Cryptococcus neoformans to a wide range of concentrations of fluconazole. In vitro susceptibility was tested using broth macrodilution methods modified to provide a numeric count of viable organisms. The association between the quantitative in vitro response and fluconazole drug concentrations was estimated using local nonparametric regression. Regression analysis was used to assess the correspondence between the in vitro fluconazole concentration-response curve and the murine dose-response curve observed in our previously reported murine model. The regression model was then used to predict the murine response. There was a strong correspondence between in vitro measures of response to fluconazole alone and the previously reported biologic effects seen in the mouse. In vitro antifungal drug susceptibility testing can reliably predict the murine response to fluconazole.

Animals↗
PubMed2004

Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial.

BACKGROUND: It frequently takes more than 2 weeks for drug treatments for cryptococcal meningitis to sterilise cerebrospinal fluid (CSF). In-vitro and animal studies lend support to the use of combinations of amphotericin B, flucytosine, and fluconazole for treatment of cryptococcosis. We compared the fungicidal activity of combinations of these drugs for initial treatment of patients with cryptococcal meningitis. METHODS: 64 patients with a first episode of HIV-associated cryptococcal meningitis were randomised to initial treatment with: amphotericin B (0.7 mg/kg daily); amphotericin B plus flucytosine (100 mg/kg daily); amphotericin B plus fluconazole (400 mg daily); or triple therapy with amphotericin B, flucytosine, and fluconazole. Our primary endpoint was fungicidal activity, measured by the rate of reduction in CSF cryptococcal colony-forming units (CFU) from serial quantitative CSF cultures on days 3, 7, and 14 of treatment. FINDINGS: Baseline CSF CFU counts were an important prognostic factor. Clearance of cryptococci from the CSF was exponential and was significantly faster with amphotericin B plus flucytosine than with amphotericin B alone (p=0.0006), amphotericin B plus fluconazole ( p=0.02), or triple therapy (p=0.02). INTERPRETATION: At these doses, amphotericin B plus flucytosine is the most rapidly fungicidal regimen. Quantification of CSF cultures provides a powerful new means to accurately assess the fungicidal activity of new treatment regimens for cryptococcal meningitis.

AIDS-Related Opportunistic Infections↗
PubMed2003

Dengue hemorrhagic fever with fulminant hepatic failure in an immigrant returning to Bangladesh.

An immigrant from Bangladesh living in the United Kingdom presented with a nonspecific febrile illness after visiting his homeland and subsequently developed fulminant hepatic failure accompanied by hypotension, ascites, a generalized coagulopathy, and thrombocytopenia. Serology and detection of dengue virus serotype 3 by PCR established a postmortem diagnosis of hepatic failure secondary to dengue hemorrhagic fever.

Ascites↗
PubMed2003

Superoxide dismutase influences the virulence of Cryptococcus neoformans by affecting growth within macrophages.

Superoxide dismutase (SOD) is an enzyme that converts superoxide radicals into hydrogen peroxide and molecular oxygen and has been shown to contribute to the virulence of many human-pathogenic bacteria through its ability to neutralize toxic levels of reactive oxygen species generated by the host. SOD has also been speculated to be important in the pathogenesis of fungal infections, but the role of this enzyme has not been rigorously investigated. To examine the contribution of SOD to the pathogenesis of fungal infections, we cloned the Cu,Zn SOD-encoding gene (SOD1) from the human-pathogenic yeast Cryptococcus neoformans and made mutants via targeted disruption. The sod1 mutant strains had marked decreases in SOD activity and were strikingly more susceptible to reactive oxygen species in vitro. A sod1 mutant was significantly less virulent than the wild-type strain and two independent reconstituted strains, as measured by cumulative survival in the mouse inhalational model. In vitro studies established that the sod1 strain had attenuated growth compared to the growth of the wild type and a reconstituted strain inside macrophages producing reduced amounts of nitric oxide. These findings demonstrate that (i) the Cu,Zn SOD contributes to virulence but is not required for pathogenicity in C. neoformans; (ii) the decreased virulence of the sod1 strain may be due to increased susceptibility to oxygen radicals within macrophages; and (iii) other antioxidant defense systems in C. neoformans can compensate for the loss of the Cu,Zn SOD in vivo.

Animals↗