RESUMO
Antifungal infections are becoming a major concern to human health due to antimicrobial resistance. Echinocandins have been promising agents against resistant fungal infections, primarily caspofungin, which has a more effective mechanism of action than azoles and polyenes. However, fungi such as Cryptococcus neoformans appear to be inheritably resistant to these drugs, which is concerning due to the high clinical importance of C. neoformans. In this review, we review the history of C. neoformans and the treatments used to treat antifungals over the years, focusing on caspofungin, while highlighting the C. neoformans problem and possible explanations for its inherent resistance.
Caspofungin is a drug used to treat several types of fungal infections. Resistance to caspofungin is a huge problem, especially in those that are immunocompromised. It is important to understand the history of caspofungin discovery, its clinical applications and its mechanism of action, as well as if a new drug target could be used overcome resistance. This review may perform guide new studies combining caspofungin with other drugs and indicate new potential targets for caspofungin.
Assuntos
Antifúngicos , Caspofungina , Criptococose , Cryptococcus neoformans , Farmacorresistência Fúngica , Caspofungina/uso terapêutico , Caspofungina/farmacologia , Cryptococcus neoformans/efeitos dos fármacos , Antifúngicos/uso terapêutico , Antifúngicos/farmacologia , Humanos , Criptococose/tratamento farmacológico , Criptococose/microbiologia , Equinocandinas/uso terapêutico , Equinocandinas/farmacologia , Animais , Testes de Sensibilidade Microbiana , Lipopeptídeos/uso terapêutico , Lipopeptídeos/farmacologiaRESUMO
Las nuevas opciones de tratamiento prolongan la hospitalización y aumentan las infecciones intrahospitalarias bacterianas y fúngicas, pero también mejoran la sobrevida de los recién nacidos hospitalizados en la unidad de cuidados intensivos neonatales. Las infecciones fúngicas invasivas en neonatos están asociadas con una morbimortalidad significativa. También pueden diseminarse a órganos específicos y causar endocarditis, endoftalmitis, artritis séptica, nefropatía obstructiva y meningitis. En el caso de la endocarditis, se recomiendan tratamientos antimicóticos sistémicos agresivos y, en algunos casos, la intervención quirúrgica del neonato. Informamos el caso de un lactante prematuro, de bajo peso al nacer, con vegetación intracardíaca. Esta es una complicación rara y potencialmente mortal de infecciones fúngicas invasivas. El paciente recibió tratamiento con caspofungina y un activador tisular del plasminógeno recombinante, en vez de una intervención quirúrgica.
Developing treatment options have resulted in prolonged admission and increased bacterial and fungal nosocomial infections as well as improved survival in neonatal intensive care unit. Invasive fungal infections in newborns are associated with significant morbidity and mortality and can cause endorgan dissemination such as endocarditis, endophthalmitis, septic arthritis, obstructive nephropathy and meningitis. Endocarditis requires aggressive systemic antifungal therapy and sometimes surgical intervention in neonates. We report a low birth weight premature infant with intracardiac vegetation that is rare and a life-threatening complication of invasive fungal infections. He was treated with caspofungin and recombinant tissue plasminogen activator in stead of surgical intervention.
Assuntos
Humanos , Masculino , Recém-Nascido , Candidíase/tratamento farmacológico , Ativador de Plasminogênio Tecidual , Endocardite/microbiologia , Endocardite/tratamento farmacológico , Equinocandinas/uso terapêutico , Lipopeptídeos/uso terapêutico , Candida parapsilosis , Antifúngicos/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Recém-Nascido de muito Baixo PesoRESUMO
Developing treatment options have resulted in prolonged admission and increased bacterial and fungal nosocomial infections as well as improved survival in neonatal intensive care unit. Invasive fungal infections in newborns are associated with significant morbidity and mortality and can cause endorgan dissemination such as endocarditis, endophthalmitis, septic arthritis, obstructive nephropathy and meningitis. Endocarditis requires aggressive systemic antifungal therapy and sometimes surgical intervention in neonates. We report a low birth weight premature infant with intracardiac vegetation that is rare and a life-threatening complication of invasive fungal infections. He was treated with caspofungin and recombinant tissue plasminogen activator in stead of surgical intervention.
Las nuevas opciones de tratamiento prolongan la hospitalización y aumentan las infecciones intrahospitalarias bacterianas y fúngicas, pero también mejoran la sobrevida de los recién nacidos hospitalizados en la unidad de cuidados intensivos neonatales. Las infecciones fúngicas invasivas en neonatos están asociadas con una morbimortalidad significativa. También pueden diseminarse a órganos específicos y causar endocarditis, endoftalmitis, artritis séptica, nefropatía obstructiva y meningitis. En el caso de la endocarditis, se recomiendan tratamientos antimicóticos sistémicos agresivos y, en algunos casos, la intervención quirúrgica del neonato. Informamos el caso de un lactante prematuro, de bajo peso al nacer, con vegetación intracardíaca. Esta es una complicación rara y potencialmente mortal de infecciones fúngicas invasivas. El paciente recibió tratamiento con caspofungina y un activador tisular del plasminógeno recombinante, en vez de una intervención quirúrgica.
Assuntos
Antifúngicos/uso terapêutico , Candida parapsilosis , Candidíase/tratamento farmacológico , Equinocandinas/uso terapêutico , Endocardite/tratamento farmacológico , Endocardite/microbiologia , Lipopeptídeos/uso terapêutico , Ativador de Plasminogênio Tecidual/uso terapêutico , Caspofungina , Humanos , Recém-Nascido , Recém-Nascido de muito Baixo Peso , Masculino , Proteínas Recombinantes/uso terapêuticoRESUMO
BACKGROUND: Infective endocarditis is a disease characterised by heart valve lesions, which exhibit extracellular matrix proteins that act as a physical barrier to prevent the passage of antimicrobial agents. The genus Candida has acquired clinical importance given that it is increasingly being isolated from cases of nosocomial infections. OBJECTIVE: To evaluate the activity of caspofungin compared to that of liposomal amphotericin B against Candida albicans in experimental infective endocarditis. METHODS: Wistar rats underwent surgical intervention and infection with strains of C. albicans to develop infective endocarditis. Three groups were formed: the first group was treated with caspofungin, the second with liposomal amphotericin B, and the third received a placebo. In vitro sensitivity was first determined to further evaluate the effect of these treatments on a rat experimental model of endocarditis by semiquantitative culture of fibrinous vegetations and histological analysis. FINDINGS: Our semiquantitative culture of growing vegetation showed massive C. albicans colonisation in rats without treatment, whereas rats treated with caspofungin showed significantly reduced colonisation, which was similar to the results obtained with liposomal amphotericin B. CONCLUSIONS: The antifungal activity of caspofungin is similar to that of liposomal amphotericin B in an experimental model of infective endocarditis caused by C. albicans.
Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Candida albicans , Candidíase/tratamento farmacológico , Equinocandinas/uso terapêutico , Endocardite/tratamento farmacológico , Lipopeptídeos/uso terapêutico , Animais , Candidíase/complicações , Caspofungina , Modelos Animais de Doenças , Endocardite/microbiologia , Feminino , Ratos , Ratos WistarRESUMO
Mutations in the dihydropteroate synthase (DHPS) gene of Pneumocystis jirovecii are associated with the failure of sulfa prophylaxis. They can develop by selection in patients receiving sulfa drugs or be acquired via person-to-person transmission. DHPS mutations raise concern about the decreasing efficacy of sulfa drugs, the main available therapeutic tool for Pneumocystis pneumonia (PCP). The prevalence of Pneumocystis DHPS mutations was examined in Pneumocystis isolates from 56 sulfa-prophylaxis-naive adults with a first episode of PCP from 2002 to 2010 in Santiago, Chile. Their clinical history was reviewed to analyze the effect of these mutations on response to trimethoprim-sulfamethoxazole (TMP-SMX) therapy and outcome. Mutant genotypes occurred in 22 (48%) of 46 HIV-infected patients and in 5 (50%) of 10 HIV-uninfected patients. Compared to patients with a wild-type genotype, those with mutant genotypes were more likely to experience sulfa treatment-limiting adverse reactions and to have a twice-longer duration of mechanical ventilation if mechanically ventilated. Specific genotypes did not associate with death, which occurred in none of the HIV-infected patients and in 50% of the non-HIV-infected patients. Chile has a high prevalence of DHPS mutations, which were presumably acquired through interhuman transmission because patients were not on sulfa prophylaxis. These results contrast with the low prevalence observed in other Latin American countries with similar usage of sulfa drugs, suggesting that additional sources of resistant genotypes may be possible. The twice-longer duration of mechanical ventilation in patients with mutant DHPS genotypes suggests a decreased efficacy of TMP-SMX and warrants collaborative studies to assess the relevance of DHPS mutations and further research to increase therapeutic options for PCP.
Assuntos
Di-Hidropteroato Sintase/genética , Mutação , Pneumocystis carinii/genética , Pneumonia por Pneumocystis/tratamento farmacológico , Combinação Trimetoprima e Sulfametoxazol/farmacologia , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Caspofungina , Chile/epidemiologia , Dapsona/uso terapêutico , Equinocandinas/uso terapêutico , Feminino , Humanos , Lipopeptídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pneumocystis carinii/efeitos dos fármacos , Pneumonia por Pneumocystis/epidemiologia , Pneumonia por Pneumocystis/microbiologia , Resultado do Tratamento , Combinação Trimetoprima e Sulfametoxazol/uso terapêuticoRESUMO
Las infecciones fúngicas invasivas son una importante causa de morbimortalidad en pediatría. La caspofungina es una equinocandina utilizada como alternativa en la prevención y/o tratamiento de ciertas infecciones fúngicas invasivas en niños, aunque con poca evidencia sobre su eficacia y seguridad en comparación con el tratamiento habitual. Objetivos. Evaluar la eficacia y seguridad de la caspofungina comparada con otros antifúngicos en la prevención y/o tratamiento de infecciones fúngicas invasivas en pediatría. Material y métodos. La estrategia de búsqueda inicial tuvo como objetivo identificar estudios controlados aleatorizados de aceptable calidad metodológica (escala de Jadad > 3) mediante la palabra clave "caspofungin" realizados en pacientes de entre los 0 y los 18 años. Resultados. Solo 3 publicaciones cumplieron los criterios de inclusión. De ellas, 2 fueron en población pediátrica y una en neonatal. No se documentó una mayor incidencia de efectos adversos para la caspofungina y su eficacia no se diferenció de otros antifúngicos (RR típico 1,47; IC 95%: 0,78-2,79). Conclusiones. Esta revisión sistemática sugiere que la caspofungina podría considerarse como una alternativa para su indicación en pediatría en la prevención y tratamiento de las infecciones fúngicas invasivas. Sin embargo, dado el pequeño número de publicaciones existentes, se requieren más estudios para alcanzar conclusiones definitivas.
Invasive fungal infections are a significant cause of morbidity and mortality in children. Caspofungin is an echinocandin used as an alternative treatment in the prevention and/or treatment of certain invasive fungal infections in children, although compared to the standard treatment there is little evidence on its efficacy and safety. Objectives. To evaluate the efficacy and safety of caspofungin compared with other antifungal drugs for the prevention and/or treatment of invasive fungal infections in children. Material and methods. The objective of the initial search strategy was to identify randomized controlled studies of acceptable methodological quality (Jadad scale >3), through the key word "caspofungin", conducted in patients with an age range from 0 to 18 years old. Results. Only 3 publications met the inclusion criteria. Two of them were studies conducted in children and one in newborn infants. A higher incidence of adverse events was not documented for caspofungin and its efficacy was not different from that of other antifungal drugs (typical RR 1.47; CI 95%: 0.78-2.79). Conclusions. This systematic review suggests that caspofungin could be considered as an alternative drug in children for the prevention and treatment of invasive fungal infections. However, given the small number of existing publications, more studies are required to reach definite conclusions.
Assuntos
Humanos , Criança , Equinocandinas/uso terapêutico , Lipopeptídeos/uso terapêutico , Micoses/tratamento farmacológico , Antifúngicos/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: Invasive fungal infections are a significant cause of morbidity and mortality in children. Caspofungin is an echinocandin used as an alternative treatment in the prevention and/or treatment of certain invasive fungal infections in children, although compared to the standard treatment there is little evidence on its efficacy and safety. OBJECTIVE: To evaluate the efficacy and safety of caspofungin compared with other antifungal drugs for the prevention and/or treatment of invasive fungal infections in children. MATERIALS AND METHODS: The objective of the initial search strategy was to identify randomized controlled studies of acceptable methodological quality (Jadad scale >3), through the key word "caspofungin", conducted in patients with an age range from 0 to 18 years old. RESULTS: The objective of the initial search strategy was to identify randomized controlled studies of acceptable methodological quality (Jadad scale >3), through the key word "caspofungin", conducted in patients with an age range from 0 to 18 years old. CONCLUSIONS: This systematic review suggests that caspofungin could be considered as an alternative drug in children for the prevention and treatment of invasive fungal infections. However, given the small number of existing publications, more studies are required to reach definite conclusions.
INTRODUCCIÓN: Las infecciones fúngicas invasivas son una importante causa de morbimortalidad en pediatría. La caspofungina es una equinocandina utilizada como alternativa en la prevención y/o tratamiento de ciertas infecciones fúngicas invasivas en niños, aunque con poca evidencia sobre su eficacia y seguridad en comparación con el tratamiento habitual. OBJETIVO: Evaluar la eficacia y seguridad de la caspofungina comparada con otros antifúngicos en la prevención y/o tratamiento de infecciones fúngicas invasivas en pediatría. MATERIAL Y MÉTODOS: La estrategia de búsqueda inicial tuvo como objetivo identificar estudios controlados aleatorizados de aceptable calidad metodológica (escala de Jadad ã 3) mediante la palabra clave "caspofungin" realizados en pacientes de entre los 0 y los 18 años. RESULTADOS: Solo 3 publicaciones cumplieron los criterios de inclusión. De ellas, 2 fueron en población pediátrica y una en neonatal. No se documentó una mayor incidencia de efectos adversos para la caspofungina y su eficacia no se diferenció de otros antifúngicos (RR típico 1,47; IC 95%: 0,78-2,79). CONCLUSIONES: Esta revisión sistemática sugiere que la caspofungina podría considerarse como una alternativa para su indicación en pediatría en la prevención y tratamiento de las infecciones fúngicas invasivas. Sin embargo, dado el pequeño número de publicaciones existentes, se requieren más estudios para alcanzar conclusiones definitivas.
Assuntos
Antifúngicos/uso terapêutico , Equinocandinas/uso terapêutico , Lipopeptídeos/uso terapêutico , Micoses/tratamento farmacológico , Caspofungina , Criança , Humanos , Resultado do TratamentoRESUMO
INTRODUCTION: The treatment of fungal infections in severely ill patients is a clinical and economic challenge worldwide. Liposomal amphotericin B and caspofungin are highly effective antifungal drugs; however, they are very expensive and health systems must select the drug that results in the best clinical outcomes and is economically feasible. AREAS COVERED: A systematic search was conducted in PubMed, Scopus, Web of Science, Cochrane Library, Health Economic Evaluation Database, and Centre for Review and Dissemination to find complete economic evaluations that directly compared the two treatment strategies. Expert commentary: Because of the high cost, patients in developing countries experience difficulty accessing highly effective treatments. These data can subsidize a decision for an effective antifungal treatment with reduced costs from all perspectives.
Assuntos
Anfotericina B/uso terapêutico , Equinocandinas/uso terapêutico , Lipopeptídeos/uso terapêutico , Micoses/tratamento farmacológico , Anfotericina B/economia , Antifúngicos/economia , Antifúngicos/uso terapêutico , Caspofungina , Análise Custo-Benefício , Custos de Medicamentos , Equinocandinas/economia , Humanos , Lipopeptídeos/economia , Micoses/economia , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
INTRODUCTION: Invasive candidiasis is responsible for â¼ 10% of nosocomial sepsis in very-low-birth-weight infants and is associated with substantial morbidity and mortality. Over the last two decades, the antifungal armamentarium against Candida spp. has increased; however, efficacy and safety studies in this population are lacking. AREAS COVERED: We reviewed the medical literature and extracted information on clinical and observational studies evaluating the use of antifungal agents in neonates with invasive candidiasis. EXPERT OPINION: Efficacy and safety data for antifungals in neonates are lacking, and the majority of studies conducted to date have concentrated on pharmacokinetic/pharmacodynamic evaluations. Unlike other anti-infective agents, efficacy data in the setting of neonatal candidiasis cannot be extrapolated from adult studies due to differences in the pathophysiology of the disease in this population relative to older children and adults. Data for amphotericin B deoxycholate, fluconazole, and micafungin suggest that these are the current agents of choice for this disease in neonates until data for newer antifungal agents become available. For prophylaxis, data from fluconazole randomized controlled trials will be submitted to the regulatory agencies for labeling. Ultimately, the field of therapeutics for neonatal candidiasis will require multidisciplinary collaboration given the numerous challenges associated with conducting clinical trials in neonates.
Assuntos
Antifúngicos/uso terapêutico , Candidíase Invasiva/tratamento farmacológico , Anfotericina B/uso terapêutico , Ácido Desoxicólico/uso terapêutico , Combinação de Medicamentos , Equinocandinas/uso terapêutico , Humanos , Recém-Nascido , Lipopeptídeos/uso terapêutico , Micafungina , Triazóis/uso terapêuticoRESUMO
We identified a case of breakthrough candidemia in a 25-year-old patient receiving micafungin prophylaxis (50 mg/day). Five Candida glabrata isolates were obtained from blood cultures and were classified as multidrug-resistant isolates, since all of them exhibited high MICs for echinocandin and azole drugs. A mutation (S663F) in hot spot 1 of the FKS2 gene was found in all five isolates. This mutation yielded a 1,3-ß-D-glucan synthase enzyme with highly reduced sensitivities to echinocandin drugs.