Invasive fungal infections have emerged as im- portant causes of morbidity and mortality in im- m... more Invasive fungal infections have emerged as im- portant causes of morbidity and mortality in im- munocompromised patients. In response to this challenge, the field of antifungal chemotherapy has considerably expanded. Fluconazole and itra- conazole, introduced in the late 1980s, were the first durably useful alternatives to amphotericin B deoxycholate. The clinical development of the lipid formulations of amphotericin B, and,
Invasive fungal infections have emerged as important causes of morbidity and mortality in profoun... more Invasive fungal infections have emerged as important causes of morbidity and mortality in profoundly immuno- compromised patients with cancer. Current treatment strategies for these infections are limited by antifungal resistance, toxicity, drug interactions, and expense. In order to overcome these limitations, new antifungal compounds are being developed, which may improve our therapeutic armamentarium for prevention and treatment of invasive mycoses
Abstract Opportunistic invasive fungal infections are important infectious complications in sever... more Abstract Opportunistic invasive fungal infections are important infectious complications in severely immunocompromised children with hematological malignancies and/or hematopoietic stem cell transplantation, and are causes of considerable morbidity and mortality. Voriconazole is a broad-spectrum, second generation antifungal triazole with activity against yeast and filamentous fungi and first line indications against invasive aspergillosis and invasive candidiasis. While the compound has been approved in ...
Abstract Zygomycosis is an emerging fungal disease that is associated with considerable excess mo... more Abstract Zygomycosis is an emerging fungal disease that is associated with considerable excess morbidity and mortality. Standard approaches to treatment include reversal of the underlying immunodeficiency or metabol-ic disorder, surgical interventions, and antifungal therapy ...
Abstract Invasive fungal infections still play a major role in morbidity and mortality in pediatr... more Abstract Invasive fungal infections still play a major role in morbidity and mortality in pediatric patients, especially in children undergoing therapy for an underlying malig-nancy and in preterm infants. Relative to the adult population, pediatric age groups display important differ- ...
The activity of liposomal nystatin (L-Nys) against subacute disseminated candidiasis was investig... more 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 stu...
Voriconazole is approved for management of invasive fungal diseases (IFDs) in paediatric patients... more Voriconazole is approved for management of invasive fungal diseases (IFDs) in paediatric patients. We analysed plasma trough concentrations and explored their association with endpoints of antifungal therapy. The cohort included 74 immunocompromised patients (0.2-18 years of age) who received 101 courses of voriconazole for possible (7) and probable/proven (13) IFDs, as prophylaxis (79) or empirical therapy (2). Voriconazole was given intravenously (4), intravenously and orally (15) and orally (82) at recommended dosages until intolerance or maximum efficacy. IFDs and outcomes were assessed by EORTC/MSG consensus criteria. Voriconazole was administered at a median maintenance dosage of 4.8 mg/kg twice daily (range 2.2-17.4) for a median of 40 days (range 6-1002). Trough plasma concentrations at steady state (251 samples; 3.4 ± 4.3/patient) ranged from <0.2 to 14.9 mg/L with high intra- and inter-individual variability and no apparent relationship to dose (P = 0.074, ANOVA). Of th...
Children and adolescents with acute myeloid leukaemia (AML) and recurrent acute leukaemias (RALs)... more Children and adolescents with acute myeloid leukaemia (AML) and recurrent acute leukaemias (RALs) are at high risk of life-threatening invasive fungal infections (IFIs). We analysed implementation, safety and efficacy of a standard operating procedure for oral, azole-based, mould-active antifungal prophylaxis. Patients with AML and RALs aged ≥13 years received 200 mg of posaconazole three times daily and patients aged 2-12 years received 200 mg of voriconazole two times daily from the completion of chemotherapy until haematopoietic recovery. Algorithms for fever or focal findings in all patients with haematological malignancies included blood cultures, high-resolution CT and other appropriate imaging, serial serum galactomannan, invasive diagnostics and pre-emptive therapy with change in class if on antifungal medication. From 2006 to 2010, 40 patients (0.8-17 years; 21 males) with newly diagnosed AML (n = 31) or RAL (n = 9) were admitted, of whom 36 received a total of 149 courses ...
Results: The 64 patients received caspofungin for a median of 37 days (range 3-218) as single age... more Results: The 64 patients received caspofungin for a median of 37 days (range 3-218) as single agent (20) or in combination (44). The median daily maintenance dosage was 1.07 mg/kg (95% CI 1.09-1.35; range 0.40-2.92) or 34.3 mg/m2 (95% CI 32.3-37.3; range 16.3-57.5). In none of the patients was therapy discon- tinuedduetoadverseevents(AEs).ClinicalAEsweremildtomoderateandobservedin34patients(53.1%). While mean glutamate pyruvate transaminase and glutamate oxalate
ABSTRACT Mucormycosis is associated with significant morbidity and mortality in both children and... more ABSTRACT Mucormycosis is associated with significant morbidity and mortality in both children and adults. Studies have shown an increase in the incidence of mucormycosis, particularly among hematopoietic stem cell transplant (HSCT) recipients, patients with hematologic malignancies, and those with diabetic ketoacidosis. The infection typically presents as soft tissue, rhinoorbitocerebral, pulmonary, or disseminated disease and is characterized by rapid clinical progression and high mortality rates. Treatment with amphotericin B lipid formulations in combination with surgery offers the best option for treatment and survival; posaconazole, a relatively new antifungal triazole, is increasingly used for consolidation or salvage therapy. Because of the poor prognosis of zygomycosis, particularly in immunocompromised cancer patients, adjunctive treatments such as hyperbaric oxygen therapy, use of immunomodulatory cytokines, and in vivo iron chelation continue to be explored. Thus far, it is unclear how these adjunctive treatments can be harnessed to impact outcomes and which patients may benefit from them.
Invasive candidiasis (IC) and candidaemia are leading causes of infectious morbidity and mortalit... more Invasive candidiasis (IC) and candidaemia are leading causes of infectious morbidity and mortality among immunocompromised paediatric patients and those admitted to intensive care units. Despite improvements in diagnosis, prevention and treatment, both mortality rates and the economic burden of disease still remain high. To address this issue, several international societies and organisations have proposed guidelines for the management of IC/candidaemia in both neonates and children. In this article, we review current recommendations of the Infectious Diseases Society of America, the European Conference on Infection in Leukaemia, the European Society of Clinical Microbiology and Infectious Diseases and the German Speaking Mycological Society/Paul-Ehrlich Society for Chemotherapy for the management and prevention of IC/candidaemia in children and neonates.
Dyskeratosis congenita (DC) is a rare inherited disorder characterized by reticular skin pigmenta... more Dyskeratosis congenita (DC) is a rare inherited disorder characterized by reticular skin pigmentation, oral cavity leukoplakia, and nail dystrophy. Bone marrow failure in DC can only be cured by allogeneic hematopoietic stem cell transplantation (HSCT). After a nonmyeloablative, matched unrelated donor transplant, the 21-year-old patient experienced severe lower gastrointestinal tract hemorrhage caused by diffuse colitis. The etiology remained unclear. Diffuse colitis with life-threatening hemorrhage has now been reported in 3 DC patients after unrelated allogeneic HSCT. To identify the underlying causes and the disease-specific risks, and to allow for prevention and/or optimal management, data should be prospectively collected.
Antimicrobial agents are among the most common therapeutics prescribed to children and adolescent... more Antimicrobial agents are among the most common therapeutics prescribed to children and adolescents with hematologic/oncologic disorders. Because of the polymorbid state of most patients, they are frequently administered concomitantly with other drugs, resulting in a considerable potential for drug interactions. While many of these interactions are of marginal clinical significance, others are associated with substantial risks of decreased therapeutic efficacy or increased drug toxicity. Prevention and recognition of drug interactions are therefore of vital importance to optimizing effective use of antimicrobials and enhancing patient outcome. Key to minimize drug interactions are a thorough understanding of the pharmacology of frequently used antimicrobial agents and a careful evaluation of risks and benefits of potentially interacting drugs. This article reviews mechanisms and clinical relevance of drug interactions of antimicrobial agents in the supportive care of children and ado...
Advances in pharmacology (San Diego, Calif.), 1998
... and other molds require high doses of AmB (Denning and Stevens, 1990; Anaissie, 1992; Walsh e... more ... and other molds require high doses of AmB (Denning and Stevens, 1990; Anaissie, 1992; Walsh et al., 1996a). In contrast, resistance to polyenes is common in emerging pathogens, such as Malassezia furfur (Marcon et al., 1987), T. beigelii (Walsh et al., 1990c), Fusarium spp. ...
Zusammenfassung Pneumonien sind die häufigsten Organinfektionen bei Kindern und Jugendlichen mit... more Zusammenfassung Pneumonien sind die häufigsten Organinfektionen bei Kindern und Jugendlichen mit neoplastischen Erkrankungen bzw. hämatopoetischer Stammzelltransplantation und können nach wie vor einen unbeeinflussbar tödlichen Verlauf nehmen. Bei überwiegend günstiger Prognose der meisten onkologischen Grunderkrankungen, der Verfügbarkeit zuverlässiger mikrobiologischer Nachweisverfahren und effektiven antiinfektiven und supportiven Behandlungsmöglichkeiten kommt einem zügigen und rationalen diagnostischen und therapeutischen Vorgehen eine wichtige Bedeutung zu. Der vorliegende Beitrag
The safety and antifungal activity of LY303366 (LY), a new broad-spectrum semisynthetic echinocan... more 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
Invasive fungal infections have emerged as im- portant causes of morbidity and mortality in im- m... more Invasive fungal infections have emerged as im- portant causes of morbidity and mortality in im- munocompromised patients. In response to this challenge, the field of antifungal chemotherapy has considerably expanded. Fluconazole and itra- conazole, introduced in the late 1980s, were the first durably useful alternatives to amphotericin B deoxycholate. The clinical development of the lipid formulations of amphotericin B, and,
Invasive fungal infections have emerged as important causes of morbidity and mortality in profoun... more Invasive fungal infections have emerged as important causes of morbidity and mortality in profoundly immuno- compromised patients with cancer. Current treatment strategies for these infections are limited by antifungal resistance, toxicity, drug interactions, and expense. In order to overcome these limitations, new antifungal compounds are being developed, which may improve our therapeutic armamentarium for prevention and treatment of invasive mycoses
Abstract Opportunistic invasive fungal infections are important infectious complications in sever... more Abstract Opportunistic invasive fungal infections are important infectious complications in severely immunocompromised children with hematological malignancies and/or hematopoietic stem cell transplantation, and are causes of considerable morbidity and mortality. Voriconazole is a broad-spectrum, second generation antifungal triazole with activity against yeast and filamentous fungi and first line indications against invasive aspergillosis and invasive candidiasis. While the compound has been approved in ...
Abstract Zygomycosis is an emerging fungal disease that is associated with considerable excess mo... more Abstract Zygomycosis is an emerging fungal disease that is associated with considerable excess morbidity and mortality. Standard approaches to treatment include reversal of the underlying immunodeficiency or metabol-ic disorder, surgical interventions, and antifungal therapy ...
Abstract Invasive fungal infections still play a major role in morbidity and mortality in pediatr... more Abstract Invasive fungal infections still play a major role in morbidity and mortality in pediatric patients, especially in children undergoing therapy for an underlying malig-nancy and in preterm infants. Relative to the adult population, pediatric age groups display important differ- ...
The activity of liposomal nystatin (L-Nys) against subacute disseminated candidiasis was investig... more 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 stu...
Voriconazole is approved for management of invasive fungal diseases (IFDs) in paediatric patients... more Voriconazole is approved for management of invasive fungal diseases (IFDs) in paediatric patients. We analysed plasma trough concentrations and explored their association with endpoints of antifungal therapy. The cohort included 74 immunocompromised patients (0.2-18 years of age) who received 101 courses of voriconazole for possible (7) and probable/proven (13) IFDs, as prophylaxis (79) or empirical therapy (2). Voriconazole was given intravenously (4), intravenously and orally (15) and orally (82) at recommended dosages until intolerance or maximum efficacy. IFDs and outcomes were assessed by EORTC/MSG consensus criteria. Voriconazole was administered at a median maintenance dosage of 4.8 mg/kg twice daily (range 2.2-17.4) for a median of 40 days (range 6-1002). Trough plasma concentrations at steady state (251 samples; 3.4 ± 4.3/patient) ranged from <0.2 to 14.9 mg/L with high intra- and inter-individual variability and no apparent relationship to dose (P = 0.074, ANOVA). Of th...
Children and adolescents with acute myeloid leukaemia (AML) and recurrent acute leukaemias (RALs)... more Children and adolescents with acute myeloid leukaemia (AML) and recurrent acute leukaemias (RALs) are at high risk of life-threatening invasive fungal infections (IFIs). We analysed implementation, safety and efficacy of a standard operating procedure for oral, azole-based, mould-active antifungal prophylaxis. Patients with AML and RALs aged ≥13 years received 200 mg of posaconazole three times daily and patients aged 2-12 years received 200 mg of voriconazole two times daily from the completion of chemotherapy until haematopoietic recovery. Algorithms for fever or focal findings in all patients with haematological malignancies included blood cultures, high-resolution CT and other appropriate imaging, serial serum galactomannan, invasive diagnostics and pre-emptive therapy with change in class if on antifungal medication. From 2006 to 2010, 40 patients (0.8-17 years; 21 males) with newly diagnosed AML (n = 31) or RAL (n = 9) were admitted, of whom 36 received a total of 149 courses ...
Results: The 64 patients received caspofungin for a median of 37 days (range 3-218) as single age... more Results: The 64 patients received caspofungin for a median of 37 days (range 3-218) as single agent (20) or in combination (44). The median daily maintenance dosage was 1.07 mg/kg (95% CI 1.09-1.35; range 0.40-2.92) or 34.3 mg/m2 (95% CI 32.3-37.3; range 16.3-57.5). In none of the patients was therapy discon- tinuedduetoadverseevents(AEs).ClinicalAEsweremildtomoderateandobservedin34patients(53.1%). While mean glutamate pyruvate transaminase and glutamate oxalate
ABSTRACT Mucormycosis is associated with significant morbidity and mortality in both children and... more ABSTRACT Mucormycosis is associated with significant morbidity and mortality in both children and adults. Studies have shown an increase in the incidence of mucormycosis, particularly among hematopoietic stem cell transplant (HSCT) recipients, patients with hematologic malignancies, and those with diabetic ketoacidosis. The infection typically presents as soft tissue, rhinoorbitocerebral, pulmonary, or disseminated disease and is characterized by rapid clinical progression and high mortality rates. Treatment with amphotericin B lipid formulations in combination with surgery offers the best option for treatment and survival; posaconazole, a relatively new antifungal triazole, is increasingly used for consolidation or salvage therapy. Because of the poor prognosis of zygomycosis, particularly in immunocompromised cancer patients, adjunctive treatments such as hyperbaric oxygen therapy, use of immunomodulatory cytokines, and in vivo iron chelation continue to be explored. Thus far, it is unclear how these adjunctive treatments can be harnessed to impact outcomes and which patients may benefit from them.
Invasive candidiasis (IC) and candidaemia are leading causes of infectious morbidity and mortalit... more Invasive candidiasis (IC) and candidaemia are leading causes of infectious morbidity and mortality among immunocompromised paediatric patients and those admitted to intensive care units. Despite improvements in diagnosis, prevention and treatment, both mortality rates and the economic burden of disease still remain high. To address this issue, several international societies and organisations have proposed guidelines for the management of IC/candidaemia in both neonates and children. In this article, we review current recommendations of the Infectious Diseases Society of America, the European Conference on Infection in Leukaemia, the European Society of Clinical Microbiology and Infectious Diseases and the German Speaking Mycological Society/Paul-Ehrlich Society for Chemotherapy for the management and prevention of IC/candidaemia in children and neonates.
Dyskeratosis congenita (DC) is a rare inherited disorder characterized by reticular skin pigmenta... more Dyskeratosis congenita (DC) is a rare inherited disorder characterized by reticular skin pigmentation, oral cavity leukoplakia, and nail dystrophy. Bone marrow failure in DC can only be cured by allogeneic hematopoietic stem cell transplantation (HSCT). After a nonmyeloablative, matched unrelated donor transplant, the 21-year-old patient experienced severe lower gastrointestinal tract hemorrhage caused by diffuse colitis. The etiology remained unclear. Diffuse colitis with life-threatening hemorrhage has now been reported in 3 DC patients after unrelated allogeneic HSCT. To identify the underlying causes and the disease-specific risks, and to allow for prevention and/or optimal management, data should be prospectively collected.
Antimicrobial agents are among the most common therapeutics prescribed to children and adolescent... more Antimicrobial agents are among the most common therapeutics prescribed to children and adolescents with hematologic/oncologic disorders. Because of the polymorbid state of most patients, they are frequently administered concomitantly with other drugs, resulting in a considerable potential for drug interactions. While many of these interactions are of marginal clinical significance, others are associated with substantial risks of decreased therapeutic efficacy or increased drug toxicity. Prevention and recognition of drug interactions are therefore of vital importance to optimizing effective use of antimicrobials and enhancing patient outcome. Key to minimize drug interactions are a thorough understanding of the pharmacology of frequently used antimicrobial agents and a careful evaluation of risks and benefits of potentially interacting drugs. This article reviews mechanisms and clinical relevance of drug interactions of antimicrobial agents in the supportive care of children and ado...
Advances in pharmacology (San Diego, Calif.), 1998
... and other molds require high doses of AmB (Denning and Stevens, 1990; Anaissie, 1992; Walsh e... more ... and other molds require high doses of AmB (Denning and Stevens, 1990; Anaissie, 1992; Walsh et al., 1996a). In contrast, resistance to polyenes is common in emerging pathogens, such as Malassezia furfur (Marcon et al., 1987), T. beigelii (Walsh et al., 1990c), Fusarium spp. ...
Zusammenfassung Pneumonien sind die häufigsten Organinfektionen bei Kindern und Jugendlichen mit... more Zusammenfassung Pneumonien sind die häufigsten Organinfektionen bei Kindern und Jugendlichen mit neoplastischen Erkrankungen bzw. hämatopoetischer Stammzelltransplantation und können nach wie vor einen unbeeinflussbar tödlichen Verlauf nehmen. Bei überwiegend günstiger Prognose der meisten onkologischen Grunderkrankungen, der Verfügbarkeit zuverlässiger mikrobiologischer Nachweisverfahren und effektiven antiinfektiven und supportiven Behandlungsmöglichkeiten kommt einem zügigen und rationalen diagnostischen und therapeutischen Vorgehen eine wichtige Bedeutung zu. Der vorliegende Beitrag
The safety and antifungal activity of LY303366 (LY), a new broad-spectrum semisynthetic echinocan... more 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
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Papers by Andreas Groll