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T J Walsh

Publications and source records attributed to T J Walsh.

At least 91 records · Page 5Linked to original sources
PubMed1999

Current approaches to diagnosis and treatment of fungal infections in children infected with human immuno deficiency virus.

UNLABELLED: The prolonged survival of profoundly immunocompromised patients has revealed mucosal and invasive fungal infections to be major causes of morbidity and mortality in advanced HIV disease in children of all age groups. Antifungal resistance has become a clinically relevant problem. Paediatricians caring for HIV-infected children need to be aware of these increasingly frequent and often life-threatening infectious complications. This article reviews what is currently known about epidemiology, clinical presentation, diagnosis and treatment of mucosal and invasive fungal infections in children and adolescents with HIV disease. Candida spp. have become a leading bloodstream isolate in hospitalised patients; mucosal candidiasis is the most prevalent opportunistic infection in HIV-infected patients, and in both invasive and superficial infections, non Candida albicans spp. are on the increase. Invasive pulmonary aspergillosis has surfaced as an HIV-associated complication and previously uncommon fungi are more frequently encountered. HIV-infected individuals are particularly susceptible to Peumocystis carinii, Cryptococcus neoformans and infections by endemic fungi, such as Histoplasma capsulatum, Coccidioides immitis, Penicillium marneffei, and others. Newer immunological and molecular-based methods provide early and rapid diagnosis and monitoring. Potent and broad-spectrum third generation triazoles and novel fungicidal lipopeptides of the echinocandin class of antifungal antibiotics have entered clinical trials. Immunmodulation by recombinant cytokines and antifungal vaccines are very actively pursued inroads to adjunctive and preventive immunotherapy. CONCLUSION: Mucosal and invasive fungal infections will remain important complications in HIV-infected children of all age groups. Interventional studies and well documented case series are needed to improve the molecular diagnosis, treatment and prevention of invasive fungal infections in the paediatric HIV-infected population.

AIDS-Related Opportunistic Infections↗
PubMed1999

Increased adherence of fluconazole-resistant isolates of Candida species to explanted esophageal mucosa.

The adherence of fluconazole-resistant and fluconazole-susceptible isolates of Candida albicans to explanted rabbit esophageal mucosa was examined in vivo. Among six Candida albicans isolates collected from HIV-infected patients, three fluconazole-resistant (MIC > 64 microg/ml) isolates attached more avidly than three fluconazole-susceptible strains (MIC < or = 0.5 microg/ml) to esophageal mucosa (P < or = 0.05). When three strains each of six different Candida spp. were compared, the more inherently fluconazole-resistant isolates adhered more avidly in the following order: Candida glabrata>Candida krusei>Candida albicans fluconazole-sensitive>Candida tropicalis>Candida parapsilosis. Nonetheless, fluconazole-resistant Candida albicans demonstrated the greatest degree of adherence in comparison to all fluconazole-susceptible Candida albicans (P<0.001) and to all Candida spp. tested (P<0.001). Thus, the refractoriness of esophageal candidiasis in patients infected with fluconazole-resistant isolates may be related to both in vitro drug resistance and increased mucosal adherence.

Animals↗
PubMed1999

Safety and toxicokinetics of intravenous liposomal amphotericin B (AmBisome) in beagle dogs.

PURPOSE: Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses. METHODS: Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1, 4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology. RESULTS: Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable. CONCLUSIONS: AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18-94 microg/mL.

Amphotericin B↗
PubMed1999

Emerging fungal pathogens: evolving challenges to immunocompromised patients for the twenty-first century.

Opportunistic fungi have emerged during the past decade as important causes of morbidity and mortality in immunocompromised patients. Candida species constitute the third to fourth most common causes of nosocomial blood stream infections, and Aspergillus species have emerged as the most common infectious cause of pneumonic mortality in bone marrow/stem cell transplant recipients. Among HIV-infected patients, meningoencephalitis due to Cryptococcus neoformans ranks among the most common AIDS-defining infections. Hyaline septated filamentous fungi, such as Fusarium species, Acremonium species, Paecilomyces species, and Trichoderma species, are increasingly reported as causing invasive mycoses refractory to conventional therapy. Dematiaceous septated filamentous fungi, such as Pseudallescheria boydii, Bipolaris species, and Cladophialophora bantiana cause pneumonia, sinusitis, and CNS infection unresponsive to current therapy. An increasing number of different members of the class of Zygomycetes are reported as causing lethal infections, despite aggressive medical and surgical interventions. Yet the treatment for zygomycosis has not changed in approximately 40 years. The prevalence of the endemic mycoses, such as those due to Penicillium marneffei, Coccidioides immitis, and Histoplasma capsulatum, has been reported to expand rapidly in response to environmental exposures and increased numbers of vulnerable hosts in endemic regions of the world. Dermatophytoses are occurring with increasing prevalence and morbidity in elderly and immunocompromised patients. As we enter the next millennium, we may anticipate that emergent fungal infections will continue to develop in the settings of permissive environmental conditions, selective antifungal pressure, and an expanding population of immunocompromised hosts.

AIDS-Related Opportunistic Infections↗
PubMed1999

Adherence of Candida albicans to bladder mucosa: development and application of a tissue explant assay.

In order to study the interactions between Candida species and uroepithelial tissue, a tissue explant assay was developed using bladder mucosa harvested from New Zealand white rabbits. Blastoconidia of Candida albicans, Candida tropicalis and Candida glabrata attached to the uroepithelial tissue in similar quantities. However, there was significantly more adherence to the uroepithelium by pre-germinated C. albicans compared with C. albicans blastoconidia. Furthermore, the amount of uroepithelial tissue injury was directly related to the length of exposure of the tissue to Candida. Thus, this tissue explant assay may provide a useful method for investigating properties related to fungal adherence to transitional uroepithelium and organism-mediated tissue injury.

Animals↗
PubMed1999

Decrease of glial fibrillary acidic protein in rat frontal cortex following aluminum treatment.

Aluminum lactate was injected either intraperitoneally or stereotactically into the lateral cerebral ventricles of rats. Rats were killed at various times after treatment, and frontal cortex, hippocampus, and striatum were dissected out. Microtiter plate-based sandwich ELISA and immunohistochemistry were used to measure the glial fibrillary acidic protein (GFAP) concentration. GFAP levels were significantly decreased in frontal cortex 7 days after a single lateral ventricular injection of aluminum lactate and 14 days following systemic treatment. In contrast, neither hippocampus nor striatum exhibited any significant changes in the content of this astrocytic intermediate filament protein after aluminum treatment. Levels of a predominantly astroglial enzyme, glutamine synthetase, were also selectively reduced in the frontal cortex following intraventricular injection of aluminum. This depression exhibited a regional and temporal specificity similar to that found for GFAP. These results suggest a selective and progressive diminution of astrocytic responsivity in frontal cortex following either systemic or intraventricular aluminum dosing. The depression of GFAP levels reported here, which was found in the rat cerebral cortex 7-14 days after aluminum treatment in a species that does not form neurofilamentous aggregates, may reflect extended impairment of astrocytic function and suggests that these cells may be the primary targets of aluminum neurotoxicity.

Aluminum Compounds↗
PubMed1999

Liposomal nystatin against experimental pulmonary aspergillosis in persistently neutropenic rabbits: efficacy, safety and non-compartmental pharmacokinetics.

The activity of liposomal nystatin against invasive pulmonary aspergillosis was investigated in persistently neutropenic rabbits. Treatment groups included liposomal nystatin at dosages of 1, 2 and 4 mg/kg/day intravenously, or amphotericin B deoxycholate 1 mg/kg/day administered intravenously after normal saline loading. As compared with untreated controls, liposomal nystatin administered at 2 and 4 mg/kg/day prolonged survival and reduced fungus-mediated tissue injury and excess lung weight at post-mortem in a similar manner to amphotericin B. Although amphotericin B was superior in clearing infected lung tissue, treatment with all regimens of liposomal nystatin led to a significant reduction in pulmonary fungal tissue burden. During treatment, ultrafast CT-scan demonstrated ongoing resolution of pulmonary lesions at 2 and 4 mg/kg/day, but not at 1 mg/kg/day. With the exception of mild increases in blood urea nitrogen (BUN) and serum creatinine values during treatment at 2 and 4 mg/kg/day, which were similar to those found in amphotericin B-treated rabbits, liposomal nystatin was well tolerated. Preliminary pharmacokinetic studies in non-infected animals established linear drug disposition of liposomal nystatin in plasma over the investigated dosage range and peak plasma levels above the MIC for the test strain after multiple daily dosing for 7 days. Liposomal nystatin increased survival and provided reduced tissue injury, effective microbiological clearance and tolerable side effects in experimental pulmonary aspergillosis in persistently neutropenic rabbits, thus providing a rational basis for further investigations in clinical trials.

Amphotericin B↗
PubMed1999

Effects of feeding program and crude protein intake during rearing on fertility of broiler breeder females.

Arbor Acres broiler breeder pullets were grown from hatch to 24 wk on one of four feeding programs that achieved similar cumulative intakes of ME and CP at 24 wk, but not 20 wk (photostimulation), in Experiment 1. Graphing the four programs in terms of feed per bird per day by week of age gave the general shapes of linear, convex, concave, and deeply concave with respect to 0 and 24 wk reference points. The linear program, which achieved 1,192 g CP at 20 wk (photostimulation), as compared to < 1,150 g CP for the two concave programs, exhibited the best fertility. Although the pullets reared on the convex program consumed 1,255 g CP, fertility was poor, probably due to the reduced rate of increase in feed allocation late in rearing that delayed oviduct development. In Experiment 2, pullets were fed to the same cumulative ME intake at 20 wk using either a concave or convex feeding program with respect to 0 and 20 wk reference points with two levels of dietary protein. The higher level of CP intake (1,363 vs 1,212 g) produced higher fertility. A significant feeding program by dietary protein interaction was found. Level of CP intake at photostimulation had no effect on fertility with the concave feeding program but the convex program decreased fertility at the lower CP intake as in Experiment 1.

Animal Husbandry↗
PubMed1999

Amphotericin B lipid complex in pediatric patients with invasive fungal infections.

BACKGROUND: Lipid formulations of amphotericin B have been recently introduced for treatment of invasive fungal infections. However, little is known about their role in pediatric populations. METHODS: We studied the safety and antifungal efficacy of amphotericin B lipid complex (ABLC, Abelcet) in 111 treatment episodes in pediatric patients through an open label, emergency use multicenter study. Patients with invasive fungal infections were enrolled if they had mycoses refractory to conventional antifungal therapy, if they were intolerant of previous systemic antifungal agents or concomitant nephrotoxic drugs or if they had preexisting renal disease. RESULTS: All 111 treatment episodes were evaluable for safety and 54 were evaluable for efficacy. The mean serum creatinine for the study population did not significantly change between baseline (1.23 +/- 0.11 mg/dl) and cessation of ABLC therapy (1.32 +/- 0.12 mg/dl) during 6 weeks. There were no significant differences observed between initial and end-of-therapy levels of serum potassium, magnesium, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and hemoglobin. However, there was an increase in mean total bilirubin (3.66 +/- 0.73 to 5.31 +/- 1.09 mg/dl) at the end of therapy (P = 0.054). Among 54 cases fulfilling criteria for evaluation of antifungal efficacy, a complete or partial therapeutic response was obtained in 38 patients (70%) after ABLC therapy. Complete or partial therapeutic response was documented in 56% of cases with aspergillosis (n = 25) and in 81% (n = 27) with candidiasis. Among premature infants (n = 8) and allogeneic marrow recipients (n = 14), response rates were 88 and 57%, respectively. Response was similar in those patients enrolled because of intolerance to previous antifungal therapy or because of progressive infection. CONCLUSIONS: These data support the use of ABLC for treatment of invasive fungal infections in pediatric patients who are intolerant of or refractory to conventional antifungal therapy.

Adolescent↗
PubMed1999

Safety and efficacy of multilamellar liposomal nystatin against disseminated candidiasis in persistently neutropenic rabbits.

The activity of liposomal nystatin (L-Nys) against subacute disseminated candidiasis was investigated in persistently neutropenic rabbits. Antifungal therapy was administered for 10 days starting 24 h after intravenous inoculation of 10(3) blastoconidia of Candida albicans. Responses to treatment were assessed by the quantitative clearance of the organism from blood and tissues. Treatments consisted of L-Nys at dosages of 2 and 4 mg/kg of body weight/day (L-Nys2 and L-Nys4, respectively) amphotericin B deoxycholate at 1 mg/kg/day (D-AmB), and fluconazole at 10 mg/kg/day (Flu). All treatments were given intravenously once daily. Compared to the results for untreated but infected control animals, treatment with L-Nys2, L-Nys4, D-AmB, and Flu resulted in a significant clearance of the residual burden of C. albicans from the kidney, liver, spleen, lung, and brain (P < 0.0001 by analysis of variance). When the proportion of animals infected at at least one of the five tissue sites studied was evaluated, a dose-dependent response to treatment with L-Nys was found (P < 0.05). Compared to D-AmB-treated rabbits, mean serum creatinine and blood urea nitrogen levels at the end of therapy were significantly lower in animals treated with L-Nys2 (P < 0.001) and L-Nys4 (P < 0.001 and P < 0.01, respectively). L-Nys was less nephrotoxic than conventional amphotericin B and had dose-dependent activity comparable to that of amphotericin B for the early treatment of subacute disseminated candidiasis in persistently neutropenic rabbits.

Amphotericin B↗
PubMed1999

Fungal lethality, binding, and cytotoxicity of syringomycin-E.

Syringomycin-E (SE) was significantly lethal to Aspergillus and Fusarium species at between 1.9 and 7.8 micrograms/ml. SE complexed with the following fungal wall constituents (in order of binding): beta-1,3-glucan > chitin > mannan > ergosterol = cholesterol. Cytotoxicity in HeLa cells was proportional to the SE concentration, while the amount required for cytotoxicity was 3 to 20 times that needed to kill 95% of the fungi tested.

Antifungal Agents↗
PubMed1999

Pharmacokinetics of oral zidovudine entrapped in biodegradable nanospheres in rabbits.

The pharmacokinetic profile of oral zidovudine entrapped in a 50:50 polyactide-coglycolide matrix (nanospheres) was compared to those of standard oral and parenteral zidovudine formulations in rabbits. The bioavailability of zidovudine nanospheres at 50 mg/kg of body weight was 76%, and this dose achieved prolonged exposure to zidovudine compared to standard formulations without an increase in the drug's peak concentration.

Animals↗
PubMed1999

Antifungal activity of LY303366, a novel echinocandin B, in experimental disseminated candidiasis in rabbits.

The safety and antifungal activity of LY303366 (LY), a new broad-spectrum semisynthetic echinocandin, were studied against disseminated candidiasis in persistently neutropenic rabbits. In vitro time-kill assays demonstrated that LY has concentration-dependent fungicidal activity. The pharmacokinetics of LY in the plasma of nonneutropenic rabbits suggested a linear relationship between dose and area under the curve (AUC). The times spent above the MIC during the experimental dosing interval of 24 h were 4 h for LY at 0.1 mg/kg of body weight/day (LY0.1), 8 h for LY at 0.25 mg/kg/day (LY0.25), 12 h for LY at 0.5 mg/kg/day (LY0.5), and 20 h for LY at 1 mg/kg/day (LY1). Antifungal therapy was administered to infected rabbits for 10 days starting 24 h after the intravenous (i.v.) inoculation of 10(3) Candida albicans blastoconidia. Study groups consisted of untreated controls (UCs) and animals treated with amphotericin B (AmB; 1 mg/kg/day i.v.), fluconazole (FLU; 10 mg/kg/day i.v.), and LY0.1, LY0.25, LY0.5, or LY1 i.v. Rabbits treated with LY0.5, LY1, AmB, and FLU had similarly significant clearance of C. albicans from the liver, spleen, kidney, lung, vena cava, and brain in comparison to that for UCs. There was a dose-dependent clearance of C. albicans from tissues in response to LY. Among rabbits treated with LY0.1 there was a significant reduction of C. albicans only in the spleen. In animals treated with LY0.25 there was a significant reduction in all tissues but the brain. By comparison, LY0.5 and LY1 cleared all tissues, including the brain, of C. albicans. These in vivo findings were consistent with the results of in vitro time-kill assays. A dose-dependent effect of altered cell wall morphology was observed among UCs and animals treated with LY0.1, and LY0.25, with a progressive transition from hyphal structure to disrupted yeast forms. Serum creatinine levels were higher and serum potassium levels were lower in AmB-treated rabbits than in UCs and LY- and FLU-treated rabbits. LY0.5 and LY1 were well tolerated, displayed predictable pharmacokinetics in plasma, and had activities comparable to those of AmB and FLU in the treatment of disseminated candidiasis in persistently neutropenic rabbits.

Amphotericin B↗
PubMed1999

Effects of the hematoregulatory peptide SK&F 107647 alone and in combination with amphotericin B against disseminated candidiasis in persistently neutropenic rabbits.

The effects of the hematoregulatory peptide SK&F 107647 were examined in a persistently and profoundly neutropenic rabbit model of disseminated candidiasis in order to determine its potential to enhance resistance against infection and its role as an adjunct to conventional antifungal chemotherapy. In healthy animals, SK&F 107647 elicited a time-dependent increase in CD11b-positive monocytes and neutrophils. When administered to neutropenic rabbits infected with Candida albicans, no significant differences in the number of CFU per gram in any of the tissues tested compared with the number in untreated control rabbits were detected. However, when SK&F 107647 was administered in combination with low doses of amphotericin B, there was a significant reduction in organism burden in the lungs, liver, spleen, and kidneys compared with the burdens in the organs of untreated control animals and in the lungs and kidneys compared with the burdens in the lungs and kidneys of animals treated with amphotericin B alone. These data suggest a potential role for this peptide as adjunctive therapy in combination with conventional antifungal agents in the treatment of disseminated candidiasis in the setting of profound and persistent neutropenia.

Adjuvants, Immunologic↗
PubMed1999

Histatin 3-mediated killing of Candida albicans: effect of extracellular salt concentration on binding and internalization.

Human saliva contains histidine-rich proteins, histatins, which have antifungal activity in vitro. The mechanism by which histatins are able to kill Candida albicans may have clinical significance but is currently unknown. Using radiolabeled histatin 3, we show that the protein binds to C. albicans spheroplasts in a manner that is dependent on time and concentration. Binding to the spheroplasts was saturable and could be competed with unlabeled histatin 3. A single histatin 3 binding site with a K(d) = 5.1 microM was detected. Histatin 3 binding resulted in potassium and magnesium efflux, predominantly within the first 30 min of incubation. Studies with fluorescent histatin 3 demonstrate that the protein is internalized by C. albicans and that translocation of histatin inside the cell is closely associated with cell death. Histatin binding, internalization, and cell death are accelerated in low-ionic-strength conditions. Indeed, a low extracellular salt concentration was essential for cell death to occur, even when histatin 3 was already bound to the cell. The interaction of histatin 3 with C. albicans, and subsequent cell death, is inhibited at low temperature. These results demonstrate that the candidacidal activity of histatin 3 is not due exclusively to binding at the cell surface but also involves subsequent interactions with the cell.

Binding Sites↗
PubMed1999

Interleukin-12 enhances antifungal activity of human mononuclear phagocytes against Aspergillus fumigatus: implications for a gamma interferon-independent pathway.

The potential of recombinant human interleukin-12 (IL-12) to enhance the capacity of human monocytes (MNC) to elicit an oxidative burst and damage hyphae of Aspergillus fumigatus was investigated. Incubation of peripheral blood mononuclear cells (PBMC) from healthy adults with 10 to 100 ng of IL-12/ml at 37 degrees C for 2 to 3 days enhanced the production of superoxide anion (O2-) in response to phorbol myristate acetate (PMA) (P = 0.04) and unopsonized A. fumigatus hyphae (P = 0.03) and further enhanced hyphal damage (P = 0.009). Anti-gamma interferon (anti-IFN-gamma) blocked secretion of IFN-gamma by IL-12-treated PBMC but did not inhibit IL-12-induced O2- production by these cells in response to PMA. In addition, IL-12-treated elutriated MNC secreted no IFN-gamma or tumor necrosis factor alpha but exhibited enhanced O2- production compared to controls (P = 0.013). These findings demonstrate that IL-12 augments oxidative antifungal activities of MNC via an IFN-gamma-independent route, suggesting a novel pathway of IL-12 action in antifungal defense.

Adult↗