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Biomedical subjects

A H Groll

Publications and source records attributed to A H Groll.

49 records · Page 3Linked to original sources
PubMed1998

Invasive pulmonary aspergillosis in a critically ill neonate: case report and review of invasive aspergillosis during the first 3 months of life.

We report a fatal case of invasive pulmonary aspergillosis in a severely ill neonate and review 43 additional cases of invasive aspergillosis reported from 1955 through 1996 that occurred during the first 3 months of life. Eleven of the 44 patients had primary cutaneous aspergillosis, 10 had invasive pulmonary aspergillosis, and 14 had disseminated disease. Most infections were nosocomial in origin. Prematurity (43%); proven chronic granulomatous disease (14%); and a complex of diarrhea, dehydration, malnutrition, and invasive bacterial infections (23%) accounted for the majority of underlying conditions. At least 41% of the patients had received corticosteroid therapy before diagnosis, but only one patient had been neutropenic. Among patients who received medical and/or surgical treatment, outcome was relatively favorable, with an overall survival rate of 73%. Invasive aspergillosis may occur in neonates and young infants and warrants consideration under certain circumstances. Current therapeutic approaches consist of high-dose amphotericin B and appropriate surgical interventions.

Amphotericin B↗
PubMed1998

Compartmental pharmacokinetics and tissue drug distribution of the pradimicin derivative BMS 181184 in rabbits.

The pharmacokinetics of the antifungal pradimicin derivative BMS 181184 in plasma of normal, catheterized rabbits were characterized after single and multiple daily intravenous administrations of dosages of 10, 25, 50, or 150 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of BMS 181184 were determined by a validated high-performance liquid chromatography method, and plasma data were modeled into a two-compartment open model. Across the investigated dosage range, BMS 181184 demonstrated nonlinear, dose-dependent kinetics with enhanced clearance, reciprocal shortening of elimination half-life, and an apparently expanding volume of distribution with increasing dosage. After single-dose administration, the mean peak plasma BMS 181184 concentration (Cmax) ranged from 120 microg/ml at 10 mg/kg to 648 microg/ml at 150 mg/kg; the area under the concentration-time curve from 0 to 24 h (AUC0-24) ranged from 726 to 2,130 microg . h/ml, the volume of distribution ranged from 0.397 to 0.799 liter/kg, and the terminal half-life ranged from 4.99 to 2.31 h, respectively (P < 0.005 to P < 0.001). No drug accumulation in plasma occurred after multiple daily dosing at 10, 25, or 50 mg/kg over 15 days, although mean elimination half-lives were slightly longer. Multiple daily dosing at 150 mg/kg was associated with enhanced total clearance and a significant decrease in AUC0-24 below the values obtained at 50 mg/kg (P < 0.01) and after single-dose administration of the same dosage (P < 0.05). Assessment of tissue BMS 181184 concentrations after multiple dosing over 16 days revealed substantial uptake in the lungs, liver, and spleen and, most notably, dose-dependent accumulation of the drug within the kidneys. These findings are indicative of dose- and time-dependent elimination of BMS 181184 from plasma and renal accumulation of the compound after multiple dosing.

Animals↗
PubMed1998

Antifungal efficacy, safety, and single-dose pharmacokinetics of LY303366, a novel echinocandin B, in experimental pulmonary aspergillosis in persistently neutropenic rabbits.

LY303366 is a novel semisynthetic derivative of echinocandin B and a potent inhibitor of fungal (1,3)-beta-D-glucan synthase. The antifungal efficacy and safety of LY303366 were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Treatment study groups were either not treated (controls) or treated with amphotericin B (AmB) at 1 mg/kg of body weight per day or with LY303366 at 1, 5, 10, and 20 mg/kg/day. In rabbits treated with LY303366, there was a significant improvement in survival and a reduction in organism-mediated pulmonary injury measured by the number of infarcts, total lung weight, and ultrafast computerized tomography scan pulmonary lesion score. Rabbits receiving prophylactic LY303366 also demonstrated significant improvement in survival and reduction in organism-mediated pulmonary injury. AmB and LY303366 had comparable therapeutic efficacies by all parameters with the exception of reduction in tissue burden of A. fumigatus, where AmB was superior to LY303366. LY303366 demonstrated a dose-dependent effect on hyphal injury with progressive truncation, swelling, and vacuolization. LY303366 administered in single doses of 1, 5, 10, and 20 mg/kg demonstrated dose-proportional increases in the maximum concentration of drug in plasma and the area under the concentration-time curve from 0 to 72 h with no changes in plasma drug clearance. The 1-mg/kg dosage maintained plasma drug levels above the MIC for 18 h, and dosages of >/=5 mg/kg maintained plasma drug levels above the MIC for the entire 24-h dosing interval. There was no significant elevation of the concentrations of hepatic transaminases or creatinine in serum in LY303366-treated rabbits. In summary, LY303366 improved survival and decreased pulmonary injury with no apparent toxicity in the treatment and prevention of invasive pulmonary aspergillosis in persistently neutropenic rabbits.

Amphotericin B↗
PubMed1998

Antifungal activity of the pradimicin derivative BMS 181184 in the treatment of experimental pulmonary aspergillosis in persistently neutropenic rabbits.

The activity of the pradimicin derivative BMS 181184 was evaluated in a model of invasive pulmonary aspergillosis in persistently neutropenic rabbits and compared with that of amphotericin B deoxycholate. BMS 181184 at total daily doses of 50 and 150 mg/kg of body weight was at least as effective as amphotericin B at 1 mg/kg once a day in conferring survival and had comparable activity in reducing organism-mediated tissue injury and excess lung weight. Although treatment at all dosing regimens of BMS 181184 resulted in significant reductions in fungal tissue burden compared to untreated controls, equivalence to amphotericin B occurred only at the higher dosage level. Similar observations were made in bronchoalveolar lavage fluid cultures obtained postmortem. Monitoring of the animals through ultrafast computerized tomography scan revealed a marked resolution of pulmonary lesions during treatment with BMS 181184. The compound was well tolerated at all dosing regimens, and no toxicity was noted. Pharmacokinetic studies revealed nonlinear drug disposition with increased clearance at higher dosages and some evidence for extravascular drug accumulation. BMS 181184 had excellent activity in the treatment of experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits, thus underscoring the potential of pradimicin derivatives in therapy of invasive aspergillosis in the neutropenic host.

Animals↗
PubMed1997

Fluconazole versus nystatin in the prevention of candida infections in children and adolescents undergoing remission induction or consolidation chemotherapy for cancer.

An open, prospective, randomized pilot study was performed to assess the efficacy and safety of oral fluconazole 3 mg/kg once daily compared with oral nystatin 50,000 units/kg/day in four divided doses in preventing candida infections in 50 children undergoing remission induction or consolidation therapy for cancer. In 21 of 25 fluconazole-treated and 20 of 25 nystatin-treated patients the overall outcome of prophylaxis was clearly successful. Mild and transient oropharyngeal candidosis was observed in two and three patients in the fluconazole and nystatin groups respectively. One patient randomized to fluconazole and two patients randomized to nystatin required empirical treatment with amphotericin B and one patient assigned to fluconazole developed tissue-proven candida colitis. Initially non-colonized patients remained yeast-free throughout treatment with no differences between the two study arms. Initially colonized patients stayed colonized throughout treatment although at the end of the study, more patients randomized to nystatin were still harbouring yeasts (P = 0.05). Almost exclusively, Candida albicans (95%) was isolated. A change in species was observed in one patient in each arm of the study. Candida krusei or Candida glabrata were not encountered. Transient elevations of hepatic transaminases were more common in the fluconazole group, although not statistically significant (28% vs 12%, P = 0.15). Reversible grade I gastrointestinal and skin symptoms were observed in four patients randomized to fluconazole (16 vs 0%, P < 0.05). Fluconazole was as safe and effective as nystatin in controlling yeast colonization and in preventing superficial and invasive candida infections and the empirical use of amphotericin B in children and adolescents undergoing intensive chemotherapy for cancer.

Adolescent↗
PubMed1996

Trends in the postmortem epidemiology of invasive fungal infections at a university hospital.

BACKGROUND: Due to the lack of reliable diagnostic tools, clinical data on the significance of most invasive fungal infections are difficult to assess and information on frequency, disease pattern and prognostic impact still largely relies on autopsy data. METHODS AND RESULTS: To determine temporal trends in invasive fungal infections, we analyzed data from 8124 autopsies performed between 1978 and 1992 on patients who died at the University Hospital of Frankfurt/Main. During that period, a total of 278 invasive fungal infections were found. The prevalence rose from 2.2% (1978-82) and 3.2% (1983-87) to 5.1% in the most recent years (P < 0.001). Besides the emergence of mixed and unclassified infections, this was mainly due to a significant increase in Aspergillus infections (P < 0.001), whereas the prevalence of Candida infections was stable and even showed a declining trend within the last years. The highest infection rates were found in aplastic syndromes (68%), followed by AML (25%) and AIDS (19%). In the majority of cases (76%), invasive fungal infection was related to the immediate cause of death. However, the proportion of patients with endstage underlying conditions increased significantly over time from 53% to 80% (P < 0.001). Accordingly, the number of patients who were not considered terminally ill but had died from fungal infection dropped from 35% to 17% within the last years (P < 0.01). CONCLUSIONS: These observations document significant changes in frequency, aetiology and underlying disease processes in invasive fungal infections at autopsy and underscore the continuing need for more effective prevention, diagnosis, and treatment.

Adolescent↗
PubMedDate not supplied

New antifungal drugs and the pediatric cancer patient: current status of clinical development.

Invasive mycoses are important causes for treatment related morbidity and mortality in severely immunocompromised pediatric patients with hematological malignancies or hematopoietic stem cell transplantation. The past decade has witnessed a major expansion of antifungal drug research, which has resulted in the development of the novel class of echinocandin lipopeptides (anidulafungin, micafungin, caspofungin) and a new generation of antifungal triazoles with improved pharmacological properties (posaconazole, ravuconazole, voriconazole). Whereas caspofungin and voriconazole have been licensed in the European Union, the United States, Canada and several other countries throughout the world, posaconazole, ravuconazole, anidulafungin and micafungin are under regulatory review or in advanced stages of clinical development. Caspofungin and voriconazole are increasingly prescribed in pediatric patients, although pediatric dosage finding and safety evaluations have not been completed. This article reviews the clinical pharmacology of the new antifungal agents and the status of their clinical development in immunocompromised pediatric patients.

Adolescent↗
PubMedDate not supplied

Treatment of refractory CMV-infection following hematopoietic stem cell transplantation with the combination of foscarnet and leflunomide.

BACKGROUND: Treatment of cytomegalovirus (CMV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is limited by toxicities of current antiviral drugs and the occurrence of drug resistant strains. Leflunomide, an immunosuppressive agent used for treatment of rheumatoid arthritis, also has activity against CMV by impairing viral assembly. Here we report the control of refractory CMV disease by the combined use of foscarnet and leflunomide. PATIENTS AND RESULTS: A 1S-year-old boy with juvenile myelo-monocytic leukemia (JMML) received an allogeneic HSCT with bone marrow stem cells from a mismatched, unrelated donor (MMUD, recipient and donor CMV-positive). CMV-reactivation two months post transplantation (Tx) could only be controlled by the use of cidofovir. Because of secondary graft failure, the boy received a second HSCT with peripheral blood stem cells (PBSC) of the same donor after overall 6 months. CMV-infection was noticed three weeks later, associated with a considerable rise of both CMV-copy number and pp65-antigen. Since reinduction with cidofovir was ineffective and ganciclovir not warranted due to the history of graft failure, the child then received a combination of foscarnet/leflunomide, leading to a rapid decline of his CMV-copy number and to an afebrile state. Hematological, hepatic or renal toxicities were not observed. CONCLUSION: This case report suggests that leflunomide may be of use in the management of transplant recipients with CMV-infection refractory or intolerant to conventional antiviral therapy.

Antiviral Agents↗
PubMedDate not supplied

[Progress in prevention and therapy of infectious complications in children and adolescents with neoplastic diseases].

Due to the high dose-intensity of most current treatment protocols, the growing number of marrow transplantations, the routine use of aggressive supportive care and certain pathogen-related problems, infections remain an important cause for morbidity and mortality in children and adolescents with cancer. Over the last decade, however, considerable progress has been made in diagnosis, prevention and treatment of infectious complications in the immunocompromised host. This article first delineates both clinical approach and current treatment strategies in the pediatric cancer patient presenting with neutropenia and fever of unknown origin. It then reviews diagnosis and treatment of the most common specific infections and concludes with a discussion of preventive measures in the setting of anticancer treatment.

Adolescent↗
PubMedDate not supplied

Lipid formulations of amphotericin B: clinical perspectives for the management of invasive fungal infections in children with cancer.

During the past four decades, amphotericin B deoxycholate has been the cornerstone of systemic chemotherapy for life-threatening fungal infections. Despite a broad spectrum of antifungal activity, its utility is greatly hampered by renal toxicity and limited clinical efficacy, in particular in patients with profound and persistent neutropenia. The novel lipid formulations of amphotericin B have distinct physicochemical properties resulting in different distribution patterns. Nevertheless, they all share a considerable reduction of nephrotoxicity, which allows for the delivery of higher daily dosages of amphotericin B. Preliminary efficacy data indicate that these compounds are overall at least as effective as amphotericin B deoxycholate. However, information for children is limited, and comparative studies for their use as first line agents are only in their beginnings. In this article, we review the clinical pharmacokinetics, safety, and efficacy of the lipid formulations of amphotericin B with special emphasis on pediatric data, and we seek to provide a rational framework for the determination of their current role in patients with cancer and proven or suspected invasive fungal infections.

Amphotericin B↗
PubMedDate not supplied

Trimethoprim-sulfamethoxazole salvage for refractory listeriosis during maintenance chemotherapy for acute lymphoblastic leukemia.

A 5-year-old boy with acute lymphoblastic leukemia (ALL) and intolerance to oral trimethoprim-sulfamethoxazole (TMP/SMX) had Listeria monocytogenes bacteremia and meningitis develop during maintenance chemotherapy. Despite prompt administration of IV amoxicillin/gentamicin and microbiologic clearance of the bloodstream, the patient had no response to therapy after a course of 7 days. Intravenous TMP/SMX (10 mg/kg per day of TMP) was added to the antibiotic regimen after desensitization. Fever and meningeal signs rapidly resolved, and the patient was ultimately cured. Amoxicillin and gentamicin, although highly active and synergistic in vitro against L. monocytogenes, have limited intracellular penetration and activity. In contrast, TMP/SMX has bactericidal extracellular and intracellular activity against Listeria and excellent central nervous system penetration, and thus may be effective for the treatment of refractory listeriosis.

Aminoglycosides↗