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Cryptococcal meningitis (CM) remains a significant global health burden, especially for persons living with HIV. Despite effective antiretroviral and antifungal therapy, mortality rates are still approximately 70% in low- and middle-income countries and 20-30% in high-income countries. Central nervous system symptoms range from mild to severe, depending on burden of disease, and prompt and appropriate therapy is critical to reducing mortality. Treatment consists of three phases: induction, consolidation, and maintenance. Although treatment regimens have largely remained unchanged for decades, recent clinical trials have led the World Health Organization to update guidelines to reflect best practices in resource-limited settings. We review the clinical presentation, diagnosis, and standard therapy for CM, present a case with a challenging diagnostic and treatment course complicated by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, and discuss the benefits of a new treatment dosing strategy highlighting potential advantages of adopting this novel dosing option in high-income countries.
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West Nile Virus (WNV) can result in clinically severe neurologic disease. There is no treatment for WNV infection, but administration of anti-WNV polyclonal human antibody has demonstrated efficacy in animal models. We compared Omr-IgG-am, an immunoglobulin product with high titers of anti-WNV antibody, with intravenous immunoglobulin (IVIG) and normal saline to assess safety and efficacy in patients with WNV neuroinvasive disease as part of a phase I/II, randomized, double-blind, multicenter study in North America. During 2003-2006, a total of 62 hospitalized patients were randomized to receive Omr-IgG-am, standard IVIG, or normal saline (3:1:1). The primary endpoint was medication safety. Secondary endpoints were morbidity and mortality, measured using 4 standardized assessments of cognitive and functional status. The death rate in the study population was 12.9%. No significant differences were found between groups receiving Omr-IgG-am compared with IVIG or saline for either the safety or efficacy endpoints.
Asunto(s)
Enfermedades Virales del Sistema Nervioso Central/tratamiento farmacológico , Enfermedades Virales del Sistema Nervioso Central/virología , Inmunoglobulina G/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Fiebre del Nilo Occidental/tratamiento farmacológico , Fiebre del Nilo Occidental/virología , Virus del Nilo Occidental , Adulto , Anciano , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/administración & dosificación , Anticuerpos Antivirales/inmunología , Enfermedades Virales del Sistema Nervioso Central/inmunología , Femenino , Humanos , Inmunoglobulina G/administración & dosificación , Inmunoglobulinas Intravenosas/administración & dosificación , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Fiebre del Nilo Occidental/inmunología , Virus del Nilo Occidental/inmunologíaRESUMEN
Mold deterioration of historical documents in archives and libraries is a frequent and complex phenomenon that may have important economic and cultural consequences. In addition, exposure to toxic fungal metabolites might produce health problems. In this work, samples of broths of fungal species isolated from the documentary material and from indoor environmental samples of the Archive of Bogotá have been analyzed to investigate the presence of mycotoxins. High resolution mass spectrometry made possible to search for a large number of mycotoxins, even without reference standards available at the laboratory. For this purpose, a screening strategy based on ultra-high pressure liquid chromatography coupled to quadrupole-time of flight mass spectrometry (UHPLC-QTOF MS) under MS(E) mode was applied. A customized home-made database containing elemental composition for around 600 mycotoxins was compiled. The presence of the (de)protonated molecule measured at its accurate mass was evaluated in the samples. When a peak was detected, collision induced dissociation fragments and characteristic isotopic ions were also evaluated and used for tentative identification, based on structure compatibility and comparison with literature data (if existing). Up to 44 mycotoxins were tentatively identified by UHPLC-QTOF MS. 34 of these tentative compounds were confirmed by subsequent analysis using a targeted LC-MS/MS method, supporting the strong potential of QTOF MS for identification/elucidation purposes. The presence of mycotoxins in these samples might help to reinforce safety measures for researchers and staff who work on reception, restoration and conservation of archival material, not only at the Archive of Bogotá but worldwide.
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Contaminantes Ambientales/análisis , Micotoxinas/análisis , Contaminación del Aire Interior , Archivos , Cromatografía Líquida de Alta Presión , Colombia , ADN de Hongos/análisis , ADN Ribosómico/análisis , Monitoreo del Ambiente , Hongos/genética , Hongos/aislamiento & purificación , Papel , Análisis de Secuencia de ADN , Espectrometría de Masas en TándemRESUMEN
Clostridium difficile infection causes serious diarrheal disease. Although several drugs are available for treatment, including vancomycin, recurrences remain a problem. LFF571 is a semisynthetic thiopeptide with potency against C. difficile in vitro. In this phase 2 exploratory study, we compared the safety and efficacy (based on a noninferiority analysis) of LFF571 to those of vancomycin used in adults with primary episodes or first recurrences of moderate C. difficile infection. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The primary endpoint was the proportion of clinical cures at the end of therapy in the per-protocol population. Secondary endpoints included clinical cures at the end of therapy in the modified intent-to-treat (mITT) population, the time to diarrhea resolution, and the recurrence rate. Seventy-two patients were randomized, with 46 assigned to receive LFF571. Based on the protocol-specified definition, the rate of clinical cure for LFF571 (90.6%) was noninferior to that of vancomycin (78.3%). The 30-day sustained cure rates for LFF571 and vancomycin were 56.7% and 65.0%, respectively, in the per-protocol population and 58.7% and 60.0%, respectively, in the modified intent-to-treat population. Using toxin-confirmed cases only, the recurrence rates were lower for LFF571 (19% versus 25% for vancomycin in the per-protocol population). LFF571 was generally safe and well tolerated. The incidence of adverse events (AEs) was higher for LFF571 (76.1% versus 69.2% for vancomycin), although more AEs in the vancomycin group were suspected to be related to the study drug (38.5% versus 32.6% for LFF571). One patient receiving LFF571 discontinued the study due to an AE. (This study has been registered at ClinicalTrials.gov under registration no. NCT01232595.).
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Antibacterianos/uso terapéutico , Clostridioides difficile/efectos de los fármacos , Infecciones por Clostridium/tratamiento farmacológico , Tiazoles/uso terapéutico , Vancomicina/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tiazoles/efectos adversos , Vancomicina/efectos adversosRESUMEN
Cadazolid, a novel fluoroquinolone-oxazolidinone antibiotic, exhibits potent in vitro activity against Clostridium difficile, including the epidemic BI/NAP1/027 strain. This multicenter, randomized, double-blind, active reference group, phase 2 study evaluated the efficacy and safety of oral cadazolid in treatment of adult patients with C. difficile infection (CDI). Eligible patients with first occurrence/first recurrence of CDI were randomized 1:1:1:1 to 250, 500, or 1,000 mg cadazolid twice daily (BID) or oral 125 mg vancomycin four times daily (QID) for 10 days. The primary endpoint was clinical cure at test of cure (48 ± 24 h after the end of treatment; modified intent-to-treat population), defined as resolution of diarrhea with no further CDI treatment required. Secondary endpoints included recurrence rate, sustained clinical response (clinical cure without recurrence), and time to diarrhea resolution. Of 84 patients enrolled, 20, 22, 20, and 22 received 250, 500, or 1,000 mg cadazolid BID or 125 mg vancomycin QID, respectively. The primary endpoint was achieved in 76.5% (80% confidence interval [CI], 58.4, 89.3), 80.0% (63.9, 91.0), 68.4% (51.1, 82.5), and 68.2% (52.3, 81.3) of patients, respectively. There was no evidence of a cadazolid dosage-dependent response. Each dosage of cadazolid resulted in a lower recurrence rate than with vancomycin (18.2 to 25.0% versus 50%). Consequently, higher sustained clinical response rates were observed with cadazolid (46.7 to 60.0%) than with vancomycin (33.3%). The times to diarrhea resolution were similar for cadazolid and vancomycin. Cadazolid was well tolerated, with no safety signal observed. The results of this phase 2 study support further clinical development of cadazolid. (This study has been registered in the United States at ClinicalTrials.gov under registration no. NCT01222702 and in Europe with the European Medicines Agency under registration no. EUDRA-CT 2010-020941-29.).
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Antibacterianos/uso terapéutico , Clostridioides difficile/efectos de los fármacos , Infecciones por Clostridium/tratamiento farmacológico , Diarrea/tratamiento farmacológico , Oxazolidinonas/uso terapéutico , Administración Oral , Adulto , Anciano , Antibacterianos/farmacocinética , Clostridioides difficile/crecimiento & desarrollo , Clostridioides difficile/patogenicidad , Infecciones por Clostridium/microbiología , Infecciones por Clostridium/fisiopatología , Diarrea/microbiología , Diarrea/fisiopatología , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxazolidinonas/farmacocinética , Seguridad del Paciente , Recurrencia , Vancomicina/farmacocinética , Vancomicina/uso terapéuticoRESUMEN
The mitochondrial (mt) genomes of two soybean rust pathogens, Phakopsora pachyrhizi and P. meibomiae, have been sequenced. The mt genome of P. pachyrhizi is a circular 31 825-bp molecule with a mean GC content of 34.6%, while P. meibomiae possesses a 32 520-bp circular molecule with a mean GC content of 34.9%. Both mt genomes contain the genes encoding ATP synthase subunits 6, 8 and 9 (atp6, atp8 and atp9), cytochrome oxidase subunits I, II and III (cox1, cox2 and cox3), apocytochrome b (cob), reduced nicotinamide adenine dinucleotide ubiquinone oxidoreductase subunits (nad1, nad2, nad3, nad4, nad4L, nad5 and nad6), the large and small mt ribosomal RNA genes, one ORF coding for a ribosomal protein (rps3), and a set of 24 tRNA genes that recognize codons for all amino acids. The order of the protein-coding genes and tRNA is identical in the two Phakopsora species, and all genes are transcribed from the same DNA strand clockwise. Introns were identified in the cox1, cob and mnl genes of both species, with three of the introns having ORFs with motifs similar to the LAGLIDADG endonucleases of other fungi. Phylogenetic analysis of the 14 shared protein-coding genes agrees with commonly accepted fungal taxonomy.
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Basidiomycota/genética , ADN Mitocondrial/química , Glycine max/microbiología , Secuencia de Bases , Basidiomycota/clasificación , Codón , Datos de Secuencia Molecular , Filogenia , ARN de Transferencia/genéticaRESUMEN
Antibiotic treatment for pelvic inflammatory disease (PID) is often broad spectrum and targets a diverse range of vaginal flora. Treatment of PID in nursing mothers presents a particular clinical challenge because use of antimicrobials during breastfeeding poses several potential risks to infants. Excretion of drugs into breast milk can occur through different mechanisms and depends on the characteristics of both the drug and the mother. Whether daptomycin is excreted into breast milk is unknown, as is its subsequent exposure to breastfeeding infants and the associated risks. We describe a case of PID caused by methicillin-resistant Staphylococcus aureus, an uncommon pathogen in PID, in a breastfeeding mother who was successfully treated with daptomycin. Daptomycin concentrations in her breast milk were measured to determine potential exposure to her infant. These concentrations were extremely low, with an estimated milk:plasma ratio of 0.0012. Although additional confirmatory studies are needed, daptomycin may be a reasonable option in the treatment of PID caused by gram-positive organisms that are resistant to other antibiotics.
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Antibacterianos/metabolismo , Daptomicina/metabolismo , Staphylococcus aureus Resistente a Meticilina , Leche Humana/metabolismo , Enfermedad Inflamatoria Pélvica/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Adulto , Antibacterianos/uso terapéutico , Lactancia Materna , Daptomicina/uso terapéutico , Femenino , Humanos , Lactante , Enfermedad Inflamatoria Pélvica/microbiologíaRESUMEN
BACKGROUND: Cadazolid is a novel quinoxolidinone antibiotic developed for treating Clostridium difficile infection. We aimed to investigate the safety and efficacy of cadazolid compared with vancomycin in patients with C difficile infection. METHODS: IMPACT 1 and IMPACT 2 were identically designed, multicentre, double-blind, placebo-controlled, non-inferiority, randomised phase 3 trials. IMPACT 1 was done in Australia, Brazil, Canada, France, Germany, Italy, the Netherlands, Peru, Poland, Romania, Spain, and the USA, and IMPACT 2 was done in Argentina, Belgium, Brazil, Canada, Chile, Croatia, Czech Republic, Greece, Hungary, Israel, Romania, Slovakia, South Korea, the UK, and the USA. Patients (aged 18 years or older) with mild-to-moderate or severe C difficile infection (diarrhoea with positive glutamate dehydrogenase and toxin A or B enzyme immunoassays) were randomly assigned (1:1) with a randomisation list stratified by centre and C difficile infection episode type (block size of four), and allocation was masked to investigators and participants. Patients received either oral cadazolid 250 mg twice daily with vancomycin-matching placebo capsule four times daily or oral vancomycin 125 mg four times a day with cadazolid-matching placebo suspension twice daily for 10 days, with 30 days of follow-up. The primary efficacy outcome was non-inferiority (margin -10%) of cadazolid versus vancomycin for clinical cure in the modified intention-to-treat and per-protocol populations. Clinical cure was defined as resolution of diarrhoea with no additional treatment for C difficile infection. These trials are registered with ClinicalTrials.gov, numbers NCT01987895 (IMPACT 1) and NCT01983683 (IMPACT 2). FINDINGS: Between March 28, 2014, and March 24, 2017, for IMPACT 1, and Dec 13, 2013, and May 2, 2017, for IMPACT 2, 1263 participants were randomly assigned to receive cadazolid (306 in IMPACT 1 and 298 in IMPACT 2) or vancomycin (326 in IMPACT 1 and 311 in IMPACT 2). In the modified intention-to-treat population in IMPACT 1, 253 (84%) of 302 had clinical cure in the cadazolid group versus 271 (85%) of 318 in the vancomycin group. In IMPACT 2, 235 (81%) of 290 versus 258 (86%) of 301 had clinical cure. In the per-protocol population, 247 (88%) of 282 versus 264 (92%) of 288 had clinical cure in IMPACT 1 and 214 (87%) of 247 versus 237 (92%) of 259 in IMPACT 2. Non-inferiority for clinical cure to vancomycin was shown in IMPACT 1 but not in IMPACT 2 (IMPACT 1 treatment difference: -1·4 [95% CI -7·2 to 4·3] for modified intention to treat and -4·1 [-9·2 to 1·0] for per protocol; IMPACT 2: -4·7 [-10·7 to 1·3] for modified intention to treat and -4·9 [-10·4 to 0·6] for per protocol). The safety and tolerability profiles of the two antibiotics were similar. INTERPRETATION: Cadazolid was safe and well tolerated but did not achieve its primary endpoint of non-inferiority to vancomycin for clinical cure in one of two phase 3 C difficile infection trials. Therefore, further commercial development of cadazolid for C difficile infection is unlikely. FUNDING: Actelion Pharmaceuticals.
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Antiinfecciosos/administración & dosificación , Clostridioides difficile/efectos de los fármacos , Infecciones por Clostridium/tratamiento farmacológico , Oxazolidinonas/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antiinfecciosos/efectos adversos , Ensayos Clínicos Fase III como Asunto , Infecciones por Clostridium/patología , Diarrea/etiología , Diarrea/patología , Método Doble Ciego , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Oxazolidinonas/efectos adversos , Placebos/administración & dosificación , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Adulto JovenRESUMEN
In persons with advanced immunosuppression, Mycobacterium avium complex (MAC) typically causes disseminated disease with systemic symptoms. We report 2 cases in which MAC caused localized osteomyelitis in human immunodeficiency virus (HIV)-infected individuals on antiretroviral therapy with rising CD4 counts. We summarize 17 additional cases of HIV-associated MAC osteomyelitis from the literature and compare CD4 count at presentation for vertebral cases versus nonvertebral cases, which reveals a significantly higher CD4 at presentation for vertebral cases (median 251 cells/µL vs 50 cells/µL; P = .043; Mann-Whitney U test). The literature review demonstrates that the majority of cases of MAC osteomyelitis, especially vertebral, occurs in individuals with CD4 counts that have increased to above 100 cells/µL on antiretroviral therapy. Among HIV-infected individuals with osteomyelitis, MAC should be considered a possible etiology, particularly in the setting of immune reconstitution.
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Infective endocarditis is an uncommon manifestation of infection with Histoplasma capsulatum. The diagnosis is frequently missed, and outcomes historically have been poor. We present 14 cases of Histoplasma endocarditis seen in the last decade at medical centers throughout the United States. All patients were men, and 10 of the 14 had an infected prosthetic aortic valve. One patient had an infected left atrial myxoma. Symptoms were present a median of 7 weeks before the diagnosis was established. Blood cultures yielded H. capsulatum in only 6 (43%) patients. Histoplasma antigen was present in urine and/or serum in all but 3 of the patients and provided the first clue to the diagnosis of histoplasmosis for several patients. Antibody testing was positive for H. capsulatum in 6 of 8 patients in whom the test was performed. Eleven patients underwent surgery for valve replacement or myxoma removal. Large, friable vegetations were noted at surgery in most patients, confirming the preoperative transesophageal echocardiography findings. Histopathologic examination of valve tissue and the myxoma revealed granulomatous inflammation and large numbers of organisms in most specimens. Four of the excised valves and the atrial myxoma showed a mixture of both yeast and hyphal forms on histopathology. A lipid formulation of amphotericin B, administered for a median of 29 days, was the initial therapy in 11 of the 14 patients. This was followed by oral itraconazole therapy, in all but 2 patients. The length of itraconazole suppressive therapy ranged from 11 months to lifelong administration. Three patients (21%) died within 3 months of the date of diagnosis. All 3 deaths were in patients who had received either no or minimal (1 day and 1 week) amphotericin B.
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Anfotericina B/administración & dosificación , Antígenos Fúngicos , Endocarditis , Histoplasma , Histoplasmosis , Itraconazol/administración & dosificación , Mixoma , Infecciones Relacionadas con Prótesis , Anciano , Anciano de 80 o más Años , Antifúngicos/administración & dosificación , Antígenos Fúngicos/sangre , Antígenos Fúngicos/orina , Válvula Aórtica/patología , Válvula Aórtica/cirugía , Ecocardiografía Transesofágica/métodos , Endocarditis/diagnóstico , Endocarditis/etiología , Endocarditis/inmunología , Endocarditis/terapia , Atrios Cardíacos/patología , Atrios Cardíacos/cirugía , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas/métodos , Histoplasma/efectos de los fármacos , Histoplasma/inmunología , Histoplasmosis/complicaciones , Histoplasmosis/diagnóstico , Histoplasmosis/inmunología , Histoplasmosis/terapia , Humanos , Masculino , Registros Médicos Orientados a Problemas , Persona de Mediana Edad , Mixoma/complicaciones , Mixoma/patología , Mixoma/cirugía , Infecciones Relacionadas con Prótesis/complicaciones , Infecciones Relacionadas con Prótesis/diagnóstico , Infecciones Relacionadas con Prótesis/microbiología , Infecciones Relacionadas con Prótesis/terapia , Resultado del Tratamiento , Estados UnidosRESUMEN
Twenty-four simple sequence repeat markers were developed for Phakopsora pachyrhizi, a fungal pathogen of soybean (Glycine max) and other legumes. All 24 of the loci were evaluated on 28 isolates of P. pachyrhizi. Twenty-one loci were polymorphic, with allelic diversity ranging from two to eight alleles, and null alleles were observed for eight of the 24 loci. A preliminary screen with the closely related species, P. meibomiae, indicated that these primer pairs are specific to P. pachyrhizi.
RESUMEN
Soybean rust is caused by the obligate fungal pathogen Phakopsora pachyrhizi Sydow. A unidirectional cDNA library was constructed using mRNA isolated from germinating P. pachyrhizi urediniospores to identify genes expressed at this physiological stage. Single pass sequence analysis of 908 clones revealed 488 unique expressed sequence tags (ESTs, unigenes) of which 107 appeared as multiple copies. BLASTX analysis identified 189 unigenes with significant similarities (Evalue<10(-5)) to sequences deposited in the NCBI non-redundant protein database. A search against the NCBI dbEST using the BLASTN algorithm revealed 32 ESTs with high or moderate similarities to plant and fungal sequences. Using the Expressed Gene Anatomy Classification, 31.7% of these ESTs were involved in primary metabolism, 14.3% in gene/protein expression, 7.4% in cell structure and growth, 6.9% in cell division, 4.8% in cell signaling/cell communication, and 4.8% in cell/organism defense. Approximately 29.6% of the identities were to hypothetical proteins and proteins with unknown function.