RESUMO
Ongoing Cryptococcus gattii outbreaks in the Western United States and Canada illustrate the impact of environmental reservoirs and both clonal and recombining propagation in driving emergence and expansion of microbial pathogens. C. gattii comprises four distinct molecular types: VGI, VGII, VGIII, and VGIV, with no evidence of nuclear genetic exchange, indicating these represent distinct species. C. gattii VGII isolates are causing the Pacific Northwest outbreak, whereas VGIII isolates frequently infect HIV/AIDS patients in Southern California. VGI, VGII, and VGIII have been isolated from patients and animals in the Western US, suggesting these molecular types occur in the environment. However, only two environmental isolates of C. gattii have ever been reported from California: CBS7750 (VGII) and WM161 (VGIII). The incongruence of frequent clinical presence and uncommon environmental isolation suggests an unknown C. gattii reservoir in California. Here we report frequent isolation of C. gattii VGIII MATα and MATa isolates and infrequent isolation of VGI MATα from environmental sources in Southern California. VGIII isolates were obtained from soil debris associated with tree species not previously reported as hosts from sites near residences of infected patients. These isolates are fertile under laboratory conditions, produce abundant spores, and are part of both locally and more distantly recombining populations. MLST and whole genome sequence analysis provide compelling evidence that these environmental isolates are the source of human infections. Isolates displayed wide-ranging virulence in macrophage and animal models. When clinical and environmental isolates with indistinguishable MLST profiles were compared, environmental isolates were less virulent. Taken together, our studies reveal an environmental source and risk of C. gattii to HIV/AIDS patients with implications for the >1,000,000 cryptococcal infections occurring annually for which the causative isolate is rarely assigned species status. Thus, the C. gattii global health burden could be more substantial than currently appreciated.
Assuntos
Criptococose/microbiologia , Infecções por HIV/microbiologia , Microbiologia do Solo , Árvores/microbiologia , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/microbiologia , Animais , California , Separação Celular , Criptococose/genética , Cryptococcus gattii/genética , Modelos Animais de Doenças , Feminino , Infecções por HIV/complicações , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Filogenia , Reação em Cadeia da PolimeraseRESUMO
Quantitative cerebrospinal fluid (CSF) cultures provide a measure of disease severity in cryptococcal meningitis. The fungal clearance rate by quantitative cultures has become a primary endpoint for phase II clinical trials. This study determined the inter-assay accuracy of three different quantitative culture methodologies. Among 91 participants with meningitis symptoms in Kampala, Uganda, during August-November 2013, 305 CSF samples were prospectively collected from patients at multiple time points during treatment. Samples were simultaneously cultured by three methods: (1) St. George's 100 mcl input volume of CSF with five 1:10 serial dilutions, (2) AIDS Clinical Trials Group (ACTG) method using 1000, 100, 10 mcl input volumes, and two 1:100 dilutions with 100 and 10 mcl input volume per dilution on seven agar plates; and (3) 10 mcl calibrated loop of undiluted and 1:100 diluted CSF (loop). Quantitative culture values did not statistically differ between St. George-ACTG methods (P= .09) but did for St. George-10 mcl loop (P< .001). Repeated measures pairwise correlation between any of the methods was high (r≥0.88). For detecting sterility, the ACTG-method had the highest negative predictive value of 97% (91% St. George, 60% loop), but the ACTG-method had occasional (â¼10%) difficulties in quantification due to colony clumping. For CSF clearance rate, St. George-ACTG methods did not differ overall (mean -0.05 ± 0.07 log10CFU/ml/day;P= .14) on a group level; however, individual-level clearance varied. The St. George and ACTG quantitative CSF culture methods produced comparable but not identical results. Quantitative cultures can inform treatment management strategies.
Assuntos
Líquido Cefalorraquidiano/microbiologia , Meningite Criptocócica/líquido cefalorraquidiano , Meningite Criptocócica/microbiologia , Micologia/métodos , Micologia/normas , Infecções Oportunistas Relacionadas com a AIDS/líquido cefalorraquidiano , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Adulto , Antifúngicos/uso terapêutico , Feminino , Humanos , Limite de Detecção , Masculino , Meningite Criptocócica/tratamento farmacológico , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
Carriers of the pork tapeworm, Taenia solium, are the sole source of cysticercosis, a parasitic tissue infection. When tapeworm eggs excreted by the carrier are ingested, tapeworm larvae can form cysts. When cysts form in the brain, the condition is called neurocysticercosis and can be especially severe. In Los Angeles County an average of 136 county residents are hospitalized with neurocysticercosis each year. The prevalence of Taenia solium carriage is largely unknown because carriage is asymptomatic, making detection difficult. The identification and treatment of tapeworm carriers is an important public health measure that can prevent additional neurocysticercosis cases.
Assuntos
Portador Sadio/diagnóstico , Fezes/microbiologia , Neurocisticercose/diagnóstico , Taenia solium/isolamento & purificação , Adulto , Animais , El Salvador/etnologia , Feminino , Guatemala/etnologia , Humanos , Los Angeles , ÓvuloRESUMO
BACKGROUND: The WHO recommended 1200mg/day of fluconazole (FCZ) in the induction phase of cryptococcal meningitis (CM) in HIV prior to 2018 in regions where amphotericin-B (AMB) was unavailable. A 2-stage AMB-controlled, dose-escalation study to determine the maximum tolerated dose and the safety/efficacy of an induction-consolidation strategy of higher doses FCZ (1200mg-2000mg/day), adjusted for weight and renal function (eGFR)in adults with CM was undertaken. METHODS: In Stage-1, three induction doses of FCZ (1200mg/day, 1600mg/day and 2000mg/day) were tested in sequential cohortsand compared with AMB in a 3:1 ratio. A particular dose was not tested in Stage 2 if there were significant predetermined safety or efficacy concerns. In Stage-2, the 1200mg dose was excluded per protocol because of increased mortality, and participants were randomised to 1600mg, 2000mg FCZ or AMB in a 1:1:1 ratio. FINDINGS: One hundred and sixty eight participants were enrolled with 48, 50, and 48 in the AMB, 1600mg and 2000mg cohorts. The Kaplan Meier proportion for mortality (90% CI) at 10 and 24 weeks for AMB was 17% (10, 29) and 24% (15, 37), compared to 20% (12, 32) and 30% (20, 43) for 1600mg, and 33% (23, 46) and 38% (27, 51) for 2000mg/day FCZ. With the exception of a higher incidence of gastrointestinal side effects in the 2000mg cohort, both induction doses of FCZ were safe and well tolerated. There were no life-threatening changes in electrocardiogram QTc which were similar across all doses of FCZ and AMB. The median (IQR) change in log10 cryptoccal colony forming units (CFU) from week 0 to week 2 was -8(-4.1,-1.9) for AMB; -2.5(-4.0, -1.4) for 1600mg FCZ and -8 (-3.2, -1.0) for 2000mg FCZ. The proportion (90% CI) CSF CM negative at 10 weeks was 81%(71,90) for AMB; 56%(45,69) for 1600mg FCZ and 60%(49,73) for 2000mg FCZ. INTERPRETATION: Induction phase weight and renal-adjusted doses of 1600mg and 2000mg/day FCZ for CM were safe and well tolerated except for increased GI side effects in the 2000mg/day dose, and had similar times to achieve CSF sterilization, but took significantly longer than AMB. The WHO recommended 1200mg FCZ was associated with a high mortality. While not statistically significant, mortality was numerically lower in the AMB compared to 1600mg and 2000mg FCZ These data make a case for a phase 3 study of higher doses of FZC.
Assuntos
Síndrome da Imunodeficiência Adquirida , Infecções por HIV , Meningite Criptocócica , Adulto , Humanos , Anfotericina B/efeitos adversos , Fluconazol/efeitos adversos , Meningite Criptocócica/complicações , Antifúngicos/efeitos adversos , Síndrome da Imunodeficiência Adquirida/complicações , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Flucitosina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Resultado do Tratamento , Quimioterapia CombinadaRESUMO
We describe an approach to antifungal susceptibility testing of the yeast Cryptococcus neoformans that shows promise for predicting the mycological response in patients to treatment. Quantitative cultures of the cerebrospinal fluid provide a direct measure of the patient's mycological response to treatment and have been used in multiple studies to identify the most promising antifungal drugs for subsequent testing in larger clinical studies. Using these quantitative measures of response, a modified macrobroth dilution assay system shows the potential for predicting the response of an individual patient to treatment with amphotericin B, fluconazole, or the combination of amphotericin B plus flucytosine. We describe this modified macrobroth dilution assay method, the statistical approach for assessing susceptibility, and the clinical decisions that can be guided by this in vitro antifungal drug susceptibility testing.
Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Cryptococcus neoformans/efeitos dos fármacos , Combinação de Medicamentos , Fluconazol/farmacologia , Flucitosina/farmacologia , Meios de Cultura/química , Humanos , Testes de Sensibilidade Microbiana/métodosRESUMO
Coccidioidal meningitis is a potentially lethal infection. Disease progression while taking fluconazole is a common complication and safe, effective, alternative treatments are limited. Posaconazole therapy resulted in symptomatic and laboratory improvement in 2 patients and clinical improvement in a third patient with chronic, previously unresponsive coccidioidal meningitis.
Assuntos
Antifúngicos/administração & dosagem , Coccidioides/isolamento & purificação , Coccidioidomicose/diagnóstico , Coccidioidomicose/tratamento farmacológico , Meningite Fúngica/diagnóstico , Meningite Fúngica/tratamento farmacológico , Triazóis/administração & dosagem , Adolescente , Adulto , Doença Crônica/terapia , Coccidioidomicose/microbiologia , Coccidioidomicose/patologia , Humanos , Masculino , Meningite Fúngica/microbiologia , Meningite Fúngica/patologia , Resultado do Tratamento , Adulto JovemRESUMO
Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)-infected individuals, (2) organ transplant recipients, and (3) non-HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.
Assuntos
Administração de Caso/normas , Criptococose/diagnóstico , Criptococose/terapia , Antifúngicos/uso terapêutico , Criança , Pré-Escolar , Criptococose/complicações , Feminino , Humanos , Hipertensão Intracraniana/cirurgia , Gravidez , Estados UnidosRESUMO
A prospective multicenter study of cryptococcal immune reconstitution inflammatory syndrome (IRIS) was conducted as a substudy of the Bacteriology and Mycology Study Group 3-01. Of 101 AIDS patients with cryptococcal meningitis who received highly active antiretroviral therapy (HAART), 13 experienced cryptococcal IRIS. No association between the timing of HAART initiation and the diagnosis of IRIS was identified. Increased baseline serum cryptococcal antigen (CrAg) titer was a risk factor for cryptococcal IRIS.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/complicações , Síndrome da Imunodeficiência Adquirida/complicações , Fármacos Anti-HIV/efeitos adversos , Síndrome Inflamatória da Reconstituição Imune/complicações , Meningite Criptocócica/complicações , Infecções Oportunistas Relacionadas com a AIDS/sangue , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Síndrome da Imunodeficiência Adquirida/sangue , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/microbiologia , Anfotericina B/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Antifúngicos/uso terapêutico , Antígenos de Fungos/sangue , Terapia Antirretroviral de Alta Atividade , Ensaios Clínicos Fase II como Assunto , Fluconazol/uso terapêutico , Humanos , Síndrome Inflamatória da Reconstituição Imune/sangue , Síndrome Inflamatória da Reconstituição Imune/tratamento farmacológico , Síndrome Inflamatória da Reconstituição Imune/epidemiologia , Hospedeiro Imunocomprometido , Incidência , Estimativa de Kaplan-Meier , Modelos Logísticos , Meningite Criptocócica/sangue , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/epidemiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Fatores de TempoRESUMO
BACKGROUND: Cryptococcosis is a life-threatening infection among patients with human immunodeficientcy virus (HIV) infection. Therapeutic options for the treatment of central nervous system cryptococcosis are limited, especially in resource-limited settings. METHODS: We conducted a randomized, open-label, phase II trial in Thailand and the United States that compared the safety and efficacy of intravenous amphotericin B deoxycholate (AmB) 0.7 mg/kg (the standard therapy) with that of AmB 0.7 mg/kg plus fluconazole 400 mg (the low-dosage combination) or AmB 0.7 mg/kg plus fluconazole 800 mg (the high-dosage combination) administered daily for 14 days, followed by fluconazole alone at the randomized dosage (400 or 800 mg per day) for 56 days. The primary safety end point was the number of severe or life-threatening treatment-related toxicities; the primary efficacy end point was a composite of survival, neurologic stability, and negative cerebrospinal fluid culture results after 14 days of therapy. RESULTS: A total of 143 patients were enrolled. There were no differences in treatment-related toxicities among the 3 arms. Toxicity was predictable and was most often related to AmB, and it included electrolyte abnormalities, anemia, nephrotoxicity, and infusion-related events. At day 14, 41%, 27%, and 54% of patients in the standard therapy, low-dosage combination, and high-dosage combination therapy arms, respectively, demonstrated successful outcomes. A trend towards better outcomes in the combination therapy arms was seen at days 42 and 70. CONCLUSIONS: AmB plus fluconazole administered at a dosage of 800 mg for 14 days, followed by fluconazole administered at a dosage of 800 mg daily for 56 days, is well-tolerated and efficacious among HIV-positive patients with central nervous system cryptococcosis. These results have significant treatment implications and should be validated in a randomized phase III trial.
Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Fluconazol/uso terapêutico , Infecções por HIV/complicações , Meningite Criptocócica/tratamento farmacológico , Adulto , Anfotericina B/administração & dosagem , Anfotericina B/efeitos adversos , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Líquido Cefalorraquidiano/microbiologia , Feminino , Fluconazol/administração & dosagem , Fluconazol/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Tailândia , Resultado do Tratamento , Estados UnidosRESUMO
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.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antifúngicos/administração & dosagem , Meningite Criptocócica/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/líquido cefalorraquidiano , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Adulto , Anfotericina B/administração & dosagem , Antígenos de Fungos/líquido cefalorraquidiano , Líquido Cefalorraquidiano/citologia , Líquido Cefalorraquidiano/microbiologia , Pressão do Líquido Cefalorraquidiano , Contagem de Colônia Microbiana , Cryptococcus neoformans/isolamento & purificação , Quimioterapia Combinada , Feminino , Fluconazol/administração & dosagem , Flucitosina/administração & dosagem , Humanos , Masculino , Meningite Criptocócica/líquido cefalorraquidiano , Meningite Criptocócica/diagnóstico , Meningite Criptocócica/microbiologiaRESUMO
OBJECTIVES: To examine HIV-positive patients' reports of whether HIV care providers ever talked with them about practicing safer sex and disclosing seropositive status to sex partners. DESIGN: Cross-sectional survey (1998-1999) of HIV-positive men and women sampled randomly at six public HIV clinics in California. METHODS: Participants were interviewed and asked whether applicable clinic providers (physician, physician assistant, nurse practitioner, nurse, social worker, health educator, psychologist, psychiatrist) ever talked with them about safer sex or disclosure. Responses were analyzed by clinic site, HIV medical status (viral load), demographic, and behavioral variables (unprotected intercourse, non-disclosure). RESULTS: The sample (n = 839) included heterosexual men (n = 127), men who have sex with men (MSM; n = 607), and women (n = 105). Thirty-nine percent were white, 36% Hispanic, 17% black, and 8% other/mixed ethnicity. Overall, 71% reported that an applicable provider had talked with them at least once about safer sex (range across clinics, 52-94%); 50% reported discussion of disclosure (range across clinics, 31-78%). Discussion of safer sex was more prevalent with physicians than with other clinic staff. In multivariate analyses, in addition to significant clinic differences, MSM (versus heterosexual men) and whites (versus blacks or Hispanics) were less likely to receive prevention messages on these topics. Patients' behaviors (unsafe sex, non-disclosure) and HIV medical status were not independently associated with provider communication. CONCLUSIONS: HIV clinics differed substantially in the percentage of patients who reported that they received prevention messages from clinic staff. Care providers should assess and overcome barriers to providing prevention messages to patients.
Assuntos
Aconselhamento/normas , Infecções por HIV/prevenção & controle , Educação de Pacientes como Assunto , Comportamento Sexual , Comunicação , Aconselhamento/estatística & dados numéricos , Estudos Transversais , Infecções por HIV/psicologia , Soropositividade para HIV/psicologia , Soropositividade para HIV/transmissão , Pesquisas sobre Atenção à Saúde , Pessoal de Saúde , Humanos , Masculino , Assunção de Riscos , Sexo Seguro , Parceiros Sexuais , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: To test the efficacy of brief, safer-sex counseling by medical providers of HIV-positive patients during medical visits. SETTING: Six HIV clinics in California. DESIGN: Clinics were randomized to intervention arms evaluated with cohorts of randomly selected patients measured before and after the intervention. PARTICIPANTS: Five-hundred and eighty-five HIV-positive persons, sexually active prior to enrollment. INTERVENTIONS: Prevention counseling from medical providers supplemented with written information. Two clinics used a gain-framed approach (positive consequences of safer-sex), two used a loss-frame approach (negative consequences of unsafe sex), and two were attention-control clinics (medication adherence). Interventions were given to all patients who attended the clinics. OUTCOME MEASURE: Self-reported unprotected anal or vaginal intercourse (UAV). RESULTS: Among participants who had two or more sex partners at baseline, UAV was reduced 38% (P < 0.001) among those who received the loss-frame intervention. UAV at follow-up was significantly lower in the loss-frame arm [odds ratio (OR), 0.42; 95% confidence interval (CI), 0.19-0.91; P = 0.03] compared with the control arm. Using generalized estimating equations (GEE) to adjust for clustering did not change the conclusions (OR, 0.34; 95% CI, 0.24-0.49; P = 0.0001). Similar results were obtained in participants with casual partners at baseline. No effects were seen in participants with only one partner or only a main partner at baseline. No significant changes were seen in the gain-frame arm. CONCLUSIONS: Brief provider counseling emphasizing the negative consequences of unsafe sex can reduce HIV transmission behaviors in HIV-positive patients presenting with risky behavioral profiles.
Assuntos
Aconselhamento , Infecções por HIV/prevenção & controle , Soropositividade para HIV/psicologia , Sexo Seguro , Adulto , California , Estudos de Coortes , Feminino , Humanos , Masculino , Educação de Pacientes como Assunto/métodos , Parceiros SexuaisRESUMO
We conducted a prospective, multicenter observational study of adults (n=1447) and children (n=144) with candidemia at tertiary care centers in the United States in parallel with a candidemia treatment trial that included nonneutropenic adults. Candida albicans was the most common bloodstream isolate recovered from adults and children (45% vs. 49%) and was associated with high mortality (47% among adults vs. 29% among children). Three-month survival was better among children than among adults (76% vs. 54%; P<.001). Most children received amphotericin B as initial therapy, whereas most adults received fluconazole. In adults, Candida parapsilosis fungemia was associated with lower mortality than was non-parapsilosis candidemia (24% vs. 46%; P<.001). Mortality was similar among subjects with Candida glabrata or non-glabrata candidemia; mortality was also similar among subjects with C. glabrata candidemia who received fluconazole rather than other antifungal therapy. Subjects in the observational cohort had higher Acute Physiology and Chronic Health Evaluation II scores than did participants in the clinical trial (18.6 vs. 16.1), which suggests that the former subjects are more often excluded from therapeutic trials.
Assuntos
Candidíase/epidemiologia , Fungemia/tratamento farmacológico , Fungemia/epidemiologia , Adolescente , Adulto , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Candidíase/tratamento farmacológico , Criança , Pré-Escolar , Estudos de Coortes , Esquema de Medicação , Feminino , Fluconazol/uso terapêutico , Fungemia/mortalidade , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Taxa de Sobrevida , Estados Unidos/epidemiologiaRESUMO
An all oral treatment for cryptococcal meningitis is attractive, particularly where amphotericin B use is impractical. Both fluconazole and flucytosine are available in oral formulations and have activity against Cryptococcus neoformans. We conducted a prospective phase II dose escalation study employing doses of fluconazole ranging from 800 to 2000 mg daily for 10 weeks used alone or combined with flucytosine at 100 mg/kg per day for the first 4 weeks. We found that increasing doses of fluconazole were associated with an increase in survival and a decrease in the time to conversion of the cerebrospinal fluid from culture positive to culture negative. Addition of flucytosine to fluconazole improved outcomes in each dosing cohort. High doses of fluconazole alone or combined with flucytosine were well tolerated.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Antifúngicos/uso terapêutico , Fluconazol/uso terapêutico , Flucitosina/uso terapêutico , Meningite Criptocócica/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/líquido cefalorraquidiano , Administração Oral , Adulto , Antifúngicos/efeitos adversos , Estudos de Coortes , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Fluconazol/efeitos adversos , Flucitosina/efeitos adversos , Humanos , Masculino , Meningite Criptocócica/líquido cefalorraquidiano , Náusea/induzido quimicamente , Estudos Prospectivos , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
From a trial comparing interventions to improve adherence to antiretroviral therapy-directly administered antiretroviral therapy (DAART) or an intensive adherence case management (IACM)-to standard of care (SOC), for HIV-infected participants at public HIV clinics in Los Angeles County, California, we examined the cost of adherence programs and associated health care utilization. We assessed differences between DAART, IACM, and SOC in the rate of hospitalizations, hospital days, and outpatient and emergency department visits during an average of 1.7 years from study enrollment, beginning November 2001. We assigned costs to health care utilization and program delivery. We calculated incremental costs of DAART or IACM v SOC, and compared those costs with savings in health care utilization among participants in the adherence programs. IACM participants experienced fewer hospital days compared with SOC (2.3 versus 6.7 days/1000 person-days, incidence rate ratio [IRR]: 0.34, 97.5% confidence interval [CI]: 0.13-0.87). DAART participants had more outpatient visits than SOC (44.2 versus 31.5/1000 person-days, IRR: 1.4; 97.5% CI: 1.01-1.95). Average per-participant health care utilization costs were $13,127, $8,988, and $14,416 for DAART, IACM, and SOC, respectively. Incremental 6-month program costs were $2,120 and $1,653 for DAART and IACM participants, respectively. Subtracting savings in health care utilization from program costs resulted in an average net program cost of $831 per DAART participant; and savings of $3,775 per IACM participant. IACM was associated with a significant decrease in hospital days compared to SOC and was cost saving when program costs were compared to savings in health care utilization.
Assuntos
Terapia Antirretroviral de Alta Atividade/economia , Terapia Diretamente Observada/economia , Infecções por HIV/tratamento farmacológico , Custos de Cuidados de Saúde , Serviços de Saúde/estatística & dados numéricos , Cooperação do Paciente/estatística & dados numéricos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Síndrome da Imunodeficiência Adquirida/economia , Terapia Antirretroviral de Alta Atividade/métodos , California , Administração de Caso/economia , Intervalos de Confiança , Redução de Custos , Efeitos Psicossociais da Doença , Análise Custo-Benefício , Estudos Transversais , Feminino , Infecções por HIV/economia , Serviços de Saúde/economia , Humanos , Masculino , Medição de Risco , Estados Unidos , United States Public Health Service/economia , United States Public Health Service/estatística & dados numéricos , População UrbanaRESUMO
A pilot candidate gene association study was conducted to investigate the role of three common functional genetic polymorphisms of the low-affinity Fc gamma receptors, FCGR2A (131H/R), FCGR3A (158F/V) and FCGR3B (NA1/NA2) in Cryptococcus neoformans infections in individuals not infected with HIV. The FCGR2A 131RR and FCGR3A 158VV genotypes were over-represented [OR: 1.67 (1.05-2.63) and 2.04 (1.06-4.00), respectively] whereas the FCGR3B NA2NA2 was under-represented in patients with cryptococcosis (28% vs. 40% in controls). An analysis of haplotypes showed a significant difference in distribution between cases and controls overall and in Caucasians.
Assuntos
Antígenos CD/genética , Criptococose/genética , Soronegatividade para HIV , Polimorfismo Genético , Receptores de IgG/genética , Estudos de Casos e Controles , Criptococose/epidemiologia , Cryptococcus neoformans , Feminino , Proteínas Ligadas por GPI , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Fatores de Risco , População BrancaRESUMO
Cryptococcus isolates from AIDS patients in southern California were characterized by molecular analyses. Pheromone MFalpha1 and MFa1 gene fragments were polymerase chain reaction-amplified with fluorescently labeled primers and analyzed by capillary electrophoresis (CE) on DNA analyzer. CE-fragment-length analyses (CE-FLAs) and CE-single-strand conformation polymorphisms (CE-SSCPs) were used to determine Cryptococcus gattii (Cg), C. neoformans (Cn) varieties neoformans (CnVN) and grubii (CnVG), mating types, and hybrids. Corroborative tests carried out in parallel included growth on specialized media and serotyping with a commercial kit. All 276 clinical strains tested as haploid MATalpha by CE-FLA. CE-SSCP analyses of MFalpha1 showed 219 (79.3%) CnVG, 23 (8.3%) CnVN, and 34 (12.3%) Cg isolates. CE-FLA and CE-SSCP are promising tools for high-throughput screening of Cryptococcus isolates. The high prevalence of Cg was noteworthy, in view of its sporadic reports from AIDS patients in North America and its recent emergence as a primary pathogen on Vancouver Island, Canada.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Criptococose/complicações , Cryptococcus/classificação , Proteínas Fúngicas/genética , Feromônios/genética , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , California , Criptococose/epidemiologia , Criptococose/microbiologia , Cryptococcus/genética , Cryptococcus/isolamento & purificação , Meios de Cultura , Primers do DNA , Eletroforese Capilar , Infecções por HIV/complicações , Humanos , Técnicas de Tipagem Micológica , Reação em Cadeia da Polimerase/métodos , Polimorfismo Conformacional de Fita Simples , Kit de Reagentes para Diagnóstico , SorotipagemRESUMO
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.
Assuntos
Antifúngicos/farmacologia , Cryptococcus neoformans/efeitos dos fármacos , Fluconazol/farmacologia , Animais , Antifúngicos/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fluconazol/uso terapêutico , Humanos , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/microbiologia , Camundongos , Testes de Sensibilidade Microbiana/métodos , Análise de RegressãoRESUMO
A promising approach to improving outcomes in patients with cryptococcal meningitis is to use adjunctive passive immunotherapy with a monoclonal antibody (MAb) directed against the capsular polysaccharide of Cryptococcus neoformans. This is the first application of MAb therapy for the treatment of a fungal disease in humans. We determined the safety and maximum tolerated dose of the murine anticryptococcal MAb 18B7 in a phase I dose-escalation study. The subjects were human immunodeficiency virus-infected patients who had been successfully treated for cryptococcal meningitis. Six dosing cohorts received MAb 18B7 at 0.01 to 2 mg/kg of body weight as a single infusion. Three patients each received 0.01, 0.05, 0.2, and 0.5 mg of MAb 18B7 per kg without significant adverse events. Four of the subjects who received the 1-mg/kg dose had mild study drug-associated toxicity, including transient nausea, vomiting, back pain, and urticarial rash. Two of the subjects who received 2 mg/kg developed drug-associated mild to moderate nausea, vomiting, chills, and myalgias. One of the subjects who received 2 mg/kg developed intracranial hypertension 10 weeks after MAb 18B7 administration. Serum cryptococcal antigen titers in the cohorts receiving doses of 1 and 2 mg/kg declined by a median of twofold at 1 week and a median of threefold at 2 weeks postinfusion, but the titers subsequently returned toward the baseline values by week 12. The half-life of MAb 18B7 in serum was approximately 53 h, while the MAb was undetectable in the cerebrospinal fluid of all patients. These data support the continued investigation of MAb 18B7 at a maximum single dose of 1.0 mg/kg.
Assuntos
Anticorpos Antifúngicos/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Cryptococcus neoformans/imunologia , Imunização Passiva , Meningite Criptocócica/terapia , Animais , Anticorpos Antifúngicos/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Antígenos de Fungos/sangue , Área Sob a Curva , Infecções por HIV/complicações , Humanos , CamundongosRESUMO
Antiretroviral therapy (ART) is effective in controlling viral load in many people infected with HIV, but high levels of adherence to ART are needed for prolonged viral suppression. This study evaluated a brief adherence intervention delivered to HIV-positive patients by primary care providers during routine medical examinations. Six clinics were randomly allocated to deliver an intervention focusing on ART adherence (2 clinics) or safer sex (4 clinics). Interventions included written information (posters, brochures, and flyers) and brief counseling from providers and were evaluated with cohorts of randomly selected patients (n = 437) measured before and after a 10-month intervention. Among those 95% or greater adherent at baseline, 91% of patients who received the adherence intervention remained 95% or greater adherent at follow-up compared with 75% of the patients who received the safer sex intervention (chi = 12.59, P < 0.01). This difference was significant in a logistic regression analysis (odds ratio = 2.26; 95% confidence interval = 1.27-4.04), adjusting for baseline adherence, demographics, and HIV medical status. The adherence intervention did not significantly increase the prevalence of 95% or greater adherence among patients less than 95% adherent at baseline. Similar but nonsignificant results were observed for viral load. A brief intervention delivered to HIV patients by their primary providers helped to maintain adequate adherence to ART regimens. More intensive intervention is needed to improve adherence among patients who are initially less than 95% adherent.