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BACKGROUND: TBAJ-876 is a next-generation diarylquinoline. In vivo, diarylquinoline metabolites are formed with activity against Mycobacterium tuberculosis. Species-specific differences in parent drug-to-metabolite ratios might impact the translational value of animal model-based predictions. This study investigates the contribution of TBAJ-876 and its major active metabolite, TBAJ-876-M3 (M3), to the total bactericidal activity in a mouse tuberculosis model. METHODS: In vitro activity of TBAJ-876 and M3 was investigated and compared to bedaquiline. Subsequently, a dose-response study was conducted in M. tuberculosis-infected BALB/c mice treated with TBAJ-876 (1.6/6.3/25 mg/kg) or M3 (3.1/12.5/50 mg/kg). Colony-forming units in the lungs and TBAJ-876 and M3 plasma concentrations were determined. M3's contribution to TBAJ-876's bactericidal activity was estimated based on M3-exposure following TBAJ-876 treatment and corresponding M3-activity observed in M3-treated animals. RESULTS: TBAJ-876 and M3 demonstrated profound bactericidal activity. Lungs of mice treated for 4 weeks with 50 mg/kg M3 were culture-negative. Following TBAJ-876 treatment, M3-exposures were 2.2-3.6x higher than for TBAJ-876. TBAJ-876 activity was substantially attributable to M3, given its high exposure and potent activity. CONCLUSION: These findings emphasize the need to consider metabolites and their potentially distinct exposure and activity profiles compared to parent drugs to enhance the translational value of mouse model-driven predictions.
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BACKGROUND: Immunocompromised patients (ICPs) have an increased risk for a severe and prolonged COVID-19. SARS-CoV-2 monoclonal antibodies (mAbs) were extensively used in these patients, but data from randomized trials that focus on ICPs are lacking. We evaluated the clinical and virological outcome of COVID-19 in ICPs treated with mAbs across SARS-CoV-2 variants. METHODS: In this multicenter prospective cohort study, we enrolled B-cell- and/or T-cell-deficient patients treated with casirivimab/imdevimab, sotrovimab, or tixagevimab/cilgavimab. SARS-CoV-2 RNA was quantified and sequenced weekly, and time to viral clearance, viral genome mutations, hospitalization, and death rates were registered. RESULTS: Two hundred and forty five patients infected with the Delta (50%) or Omicron BA.1, 2, or 5 (50%) variant were enrolled. Sixty-seven percent were vaccinated; 78 treated as outpatients, of whom 2 required hospital admission, but both survived. Of the 159 patients hospitalized at time of treatment, 43 (27%) required mechanical ventilation or died. The median time to viral clearance was 14 days (interquartile range, 7-22); however, it took >30 days in 15%. Resistance-associated spike mutations emerged in 9 patients in whom the median time to viral clearance was 63 days (95% confidence interval, 57-69; P < .001). Spike mutations were observed in 1 of 42 (2.4%) patients after treatment with 2 active mAbs, in 5 of 34 (14.7%) treated with actual monotherapy (sotrovimab), and 3 of 20 (12%) treated with functional monotherapy (ie, tixagevimab/cilgavimab against tixagevimab-resistant variant). CONCLUSIONS: Despite treatment with mAbs, morbidity and mortality of COVID-19 in ICPs remained substantial. Combination antiviral therapy should be further explored and may be preferred in severely ICPs.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Huésped Inmunocomprometido , SARS-CoV-2 , Humanos , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Femenino , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Anticuerpos Monoclonales/uso terapéutico , COVID-19/inmunología , COVID-19/virología , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Adulto , Resultado del Tratamiento , MutaciónRESUMEN
BACKGROUND: Illness after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is less severe compared with previous variants. Data on the disease burden in immunocompromised patients are lacking. We investigated the clinical characteristics and outcomes of immunocompromised patients with coronavirus disease 2019 (COVID-19) caused by Omicron. METHODS: Organ transplant recipients, patients on anti-CD20 therapy, and allogenic hematopoietic stem cell transplantation recipients infected with the Omicron variant were included. Characteristics of consenting patients were collected and patients were contacted regularly until symptom resolution. To identify possible risk factors for hospitalization, a univariate logistic analysis was performed. RESULTS: 114 consecutive immunocompromised patients were enrolled. Eighty-nine percent had previously received 3 mRNA vaccinations. While only 1 patient died, 23 (20%) were hospitalized for a median of 11 days. A low SARS-CoV-2 immunoglobulin G (IgG) antibody response (<300 BAU [binding antibody units]/mL) at diagnosis, being older, being a lung transplant recipient, having more comorbidities, and having a higher frailty score were associated with hospital admission (all P < .01). At the end of follow-up, 25% had still not fully recovered. Of the 23 hospitalized patients, 70% had a negative and 92% had a low IgG (<300 BAU/mL) antibody response at admission. Sotrovimab was administered to 17 of these patients, and 1 died. CONCLUSIONS: While the mortality in immunocompromised patients infected with Omicron was low, hospital admission was frequent and the duration of symptoms often prolonged. In addition to vaccination, other interventions are needed to limit the morbidity from COVID-19 in immunocompromised patients.
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Antígenos de Grupos Sanguíneos , COVID-19 , Humanos , SARS-CoV-2 , Estudios Prospectivos , Anticuerpos Antivirales , Huésped Inmunocomprometido , Inmunoglobulina GRESUMEN
BACKGROUND: Given the persistently high global burden of tuberculosis, effective and shorter treatment options are needed. We explored the relationship between relapse and treatment length as well as interregimen differences for 2 novel antituberculosis drug regimens using a mouse model of tuberculosis infection and mathematical modeling. METHODS: Mycobacterium tuberculosis-infected mice were treated for up to 13 weeks with bedaquiline and pretomanid combined with moxifloxacin and pyrazinamide (BPaMZ) or linezolid (BPaL). Cure rates were evaluated 12 weeks after treatment completion. The standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was evaluated as a comparator. RESULTS: Six weeks of BPaMZ was sufficient to achieve cure in all mice. In contrast, 13 weeks of BPaL and 24 weeks of HRZE did not achieve 100% cure rates. Based on mathematical model predictions, 95% probability of cure was predicted to occur at 1.6, 4.3, and 7.9 months for BPaMZ, BPaL, and HRZE, respectively. CONCLUSION: This study provides additional evidence for the treatment-shortening capacity of BPaMZ over BPaL and HRZE. To optimally use preclinical data for predicting clinical outcomes, and to overcome the limitations that hamper such extrapolation, we advocate bundling of available published preclinical data into mathematical models.
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Mycobacterium tuberculosis , Tuberculosis , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Quimioterapia Combinada , Humanos , Pirazinamida/uso terapéutico , Rifampin/farmacología , Rifampin/uso terapéutico , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiologíaRESUMEN
Given the low treatment success rates of drug-resistant tuberculosis (TB), novel TB drugs are urgently needed. The landscape of TB treatment has changed considerably over the last decade with the approval of three new compounds: bedaquiline, delamanid and pretomanid. Of these, delamanid and pretomanid belong to the same class of drugs, the nitroimidazoles. In order to close the knowledge gap on how delamanid and pretomanid compare with each other, we summarize the main findings from preclinical research on these two compounds. We discuss the compound identification, mechanism of action, drug resistance, in vitro activity, in vivo pharmacokinetic profiles, and preclinical in vivo activity and efficacy. Although delamanid and pretomanid share many similarities, several differences could be identified. One finding of particular interest is that certain Mycobacterium tuberculosis isolates have been described that are resistant to either delamanid or pretomanid, but with preserved susceptibility to the other compound. This might imply that delamanid and pretomanid could replace one another in certain regimens. Regarding bactericidal activity, based on in vitro and preclinical in vivo activity, delamanid has lower MICs and higher mycobacterial load reductions at lower drug concentrations and doses compared with pretomanid. However, when comparing in vivo preclinical bactericidal activity at dose levels equivalent to currently approved clinical doses based on drug exposure, this difference in activity between the two compounds fades. However, it is important to interpret these comparative results with caution knowing the variability inherent in preclinical in vitro and in vivo models.
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Mycobacterium tuberculosis , Nitroimidazoles , Tuberculosis Resistente a Múltiples Medicamentos , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Diarilquinolinas/uso terapéutico , Humanos , Nitroimidazoles/farmacología , Nitroimidazoles/uso terapéutico , Oxazoles/farmacología , Oxazoles/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
BACKGROUND: The Dutch Working Party on Antibiotic Policy (SWAB) in collaboration with relevant professional societies, has updated their evidence-based guidelines on empiric antibacterial therapy of sepsis in adults. METHODS: Our multidisciplinary guideline committee generated ten population, intervention, comparison, and outcome (PICO) questions relevant for adult patients with sepsis. For each question, a literature search was performed to obtain the best available evidence and assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The quality of evidence for clinically relevant outcomes was graded from high to very low. In structured consensus meetings, the committee formulated recommendations as strong or weak. When evidence could not be obtained, recommendations were provided based on expert opinion and experience (good practice statements). RESULTS: Fifty-five recommendations on the antibacterial therapy of sepsis were generated. Recommendations on empiric antibacterial therapy choices were differentiated for sepsis according to the source of infection, the potential causative pathogen and its resistance pattern. One important revision was the distinction between low, increased and high risk of infection with Enterobacterales resistant to third generation cephalosporins (3GRC-E) to guide the choice of empirical therapy. Other new topics included empirical antibacterial therapy in patients with a reported penicillin allergy and the role of pharmacokinetics and pharmacodynamics to guide dosing in sepsis. We also established recommendations on timing and duration of antibacterial treatment. CONCLUSIONS: Our multidisciplinary committee formulated evidence-based recommendations for the empiric antibacterial therapy of adults with sepsis in The Netherlands.
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Antibacterianos , Sepsis , Adulto , Antibacterianos/uso terapéutico , Humanos , Países Bajos , Políticas , Sepsis/tratamiento farmacológicoRESUMEN
BACKGROUND: The treatment success rate of drug-resistant (DR) tuberculosis is alarmingly low. Therefore, more effective and less complex regimens are urgently required. METHODS: We compared the efficacy of an all oral DR tuberculosis drug regimen consisting of bedaquiline (25 mg/kg), delamanid (2.5 mg/kg), and linezolid (100 mg/kg) (BDL) on the mycobacterial load in the lungs and spleen of tuberculosis-infected mice during a treatment period of 24 weeks. This treatment was compared with the standard regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). Relapse was assessed 12 weeks after treatment. Two logistic regression models were developed to compare the efficacy of both regimens. RESULTS: Culture negativity in the lungs was achieved at 8 and 20 weeks of treatment with BDL and HRZE, respectively. After 14 weeks of treatment only 1 mouse had relapse in the BDL group, while in the HRZE group relapse was still observed at 24 weeks of treatment. Predictions from the final mathematical models showed that a 95% cure rate was reached after 20.5 and 28.5 weeks of treatment with BDL and HRZE, respectively. CONCLUSION: The BDL regimen was observed to be more effective than HRZE and could be a valuable option for the treatment of DR tuberculosis.
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Antituberculosos/uso terapéutico , Diarilquinolinas/uso terapéutico , Linezolid/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Nitroimidazoles/uso terapéutico , Oxazoles/uso terapéutico , Tuberculosis/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada , Ratones , Mycobacterium tuberculosis/aislamiento & purificación , Pirazinamida/uso terapéutico , RecurrenciaRESUMEN
BACKGROUND: Despite intensive treatment regimens, the outcome of Mycobacterium abscessus infections is extremely poor and thus novel treatment regimens are needed. Although tigecycline seems to be one of the best options currently available, its long-term use is hampered by severe toxic side effects as well as the need for intravenous administration and the relatively high concentrations required for efficacy. OBJECTIVES: To assess the in vitro activity of omadacycline against M. abscessus and compare it with the activity of tigecycline. METHODS: The concentration- and time-dependent killing capacities of omadacycline and tigecycline against M. abscessus subspecies abscessus were determined using a time-kill kinetics assay. Time-kill curves as well as concentration-effect curves were generated. RESULTS: Time-kill curves showed strong concentration-dependent antimicrobial activity for both omadacycline and tigecycline. Omadacycline showed inhibition of mycobacterial growth at 4 mg/L and mycobacterial killing at concentrations ≥16 mg/L. Tigecycline showed mycobacterial killing at concentrations ≥4 mg/L, achieving elimination at concentrations ≥16 mg/L. The concentration-effect curves after 7 days of exposure showed stasis, 1 log mycobacterial killing and 2 log mycobacterial killing at 3.3, 4.0 and 4.8 mg/L for omadacycline and 2.2, 2.7 and 3.4 mg/L for tigecycline, respectively. CONCLUSIONS: The results of this in vitro study on omadacycline activity, together with its favourable (pharmacokinetic) properties, suggest that omadacycline is a potential new agent for the treatment of M. abscessus infections.
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Antibacterianos/farmacología , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Mycobacterium abscessus/efectos de los fármacos , Tetraciclinas/farmacología , Humanos , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Tigeciclina/farmacologíaRESUMEN
The favorable treatment outcome rate for multidrug-resistant tuberculosis (MDR-TB) is only 54%, and therefore new drug regimens are urgently needed. In this study, we evaluated the activity of the combination of moxifloxacin and linezolid as a possible new MDR-TB regimen in a murine TB model and the value of the addition of the efflux pump inhibitor verapamil to this backbone. BALB/c mice were infected with drug-sensitive Mycobacterium tuberculosis and were treated with human-equivalent doses of moxifloxacin (200 mg/kg of body weight) and linezolid (100 mg/kg) with or without verapamil (12.5 mg/kg) for 12 weeks. Pharmacokinetic parameters were collected during treatment at the steady state. After 12 weeks of treatment, a statistically significant decline in mycobacterial load in the lungs was observed with the moxifloxacin-linezolid regimen with and without verapamil (5.9 and 5.0 log CFU, respectively), but sterilization was not achieved yet. The spleens of all mice were culture negative after 12 weeks of treatment with both treatment modalities, and the addition of verapamil caused a significant reduction in relapse (14/14 positive spleens without versus 9/15 with verapamil, P = 0.017). In conclusion, treatment with a combination regimen of moxifloxacin and linezolid showed a strong decline in mycobacterial load in the mice. The addition of verapamil to this backbone had a modest additional effect in terms of reducing mycobacterial load in the lung as well as reducing the spleen relapse rate. These results warrant further studies on the role of efflux pump inhibition in improving the efficacy of MDR-TB backbone regimens.
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Antituberculosos/farmacología , Linezolid/farmacología , Moxifloxacino/farmacología , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Verapamilo/farmacología , Animales , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos BALB C , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Resistente a Múltiples Medicamentos/microbiologíaRESUMEN
Mycobacterium tuberculosis Beijing strains are associated with lower treatment success rates in tuberculosis (TB) patients. In contrast, laboratory strains such as H37Rv are often used in preclinical tuberculosis models. Therefore, we explored the impact of using a clinical Beijing strain on treatment outcome in our mouse tuberculosis model. Additionally, the predictive value of bactericidal activity on treatment outcome was assessed. BALB/c mice were infected with a Beijing strain and treated with one of 10 different combinations of conventional anti-TB drugs. Bactericidal activity was assessed by determining reductions in mycobacterial load after 7, 14, and 28 days and after 2, 3, and 6 months of treatment. Treatment outcome was evaluated after a 6-month treatment course and was based on lung culture status 3 months posttreatment. None of the anti-TB drug regimens tested could achieve 100% treatment success. Treatment outcome depended critically on rifampin. Four non-rifampin-containing regimens showed 0% treatment success compared to success rates between 81 and 95% for six rifampin-containing regimens. Bactericidal activity was predictive only for treatment outcome after 3 months of treatment. Our data advocate the use of multiple mycobacterial strains, including a Beijing strain, to increase the translational value of mouse TB models evaluating treatment outcome. Additionally, our findings support the notion that bactericidal activity in the first 2 months of treatment, as measured in clinical phase IIa/b trials, has limited predictive value for tuberculosis treatment outcome, thus emphasizing the need for better parameters to guide future phase IIII trials.
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Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Rifampin/uso terapéutico , Tuberculosis Pulmonar/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada , Etambutol/uso terapéutico , Femenino , Isoniazida/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/clasificación , Pirazinamida/uso terapéutico , Estreptomicina/uso terapéutico , Resultado del TratamientoRESUMEN
Thein vitroactivities of clarithromycin and tigecycline alone and in combination againstMycobacterium aviumwere assessed. The activity of clarithromycin was time dependent, highly variable, and often resulted in clarithromycin resistance. Tigecycline showed concentration-dependent activity, and mycobacterial killing could only be achieved at high concentrations. Tigecycline enhanced clarithromycin activity againstM. aviumand prevented clarithromycin resistance. Whether there is clinical usefulness of tigecycline in the treatment ofM. aviuminfections needs further study.
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Antibacterianos/farmacología , Claritromicina/farmacología , Farmacorresistencia Bacteriana , Minociclina/análogos & derivados , Mycobacterium avium/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Sinergismo Farmacológico , Pruebas de Sensibilidad Microbiana , Minociclina/farmacología , Mycobacterium avium/crecimiento & desarrollo , Tigeciclina , Factores de TiempoRESUMEN
OBJECTIVES: The mycobacterial cell wall is an effective permeability barrier that limits intracellular concentrations of anti-TB drugs and hampers the success of treatment. We hypothesized that colistin might enhance the efficacy of anti-TB drugs by increasing mycobacterial cell wall permeability. In this study, we investigated the additional effect of colistin on the activity of anti-TB drugs against Mycobacterium tuberculosis in vitro. METHODS: The concentration-dependent and time-dependent killing activity of isoniazid, rifampicin or amikacin alone or in combination with colistin against M. tuberculosis H37Rv was determined. Mycobacterial populations with both high and low metabolic activity were studied, and these were characterized by increasing or steady levels of ATP, respectively. RESULTS: With exposure to a single drug, striking differences in anti-TB drug activity were observed when the two mycobacterial populations were compared. The addition of colistin to isoniazid and amikacin resulted in sterilization of the mycobacterial load, but only in the M. tuberculosis population with high metabolic activity. The emergence of isoniazid and amikacin resistance was completely prevented by the addition of colistin. CONCLUSIONS: The results of this study emphasize the importance of investigating mycobacterial populations with both high and low metabolic activity when evaluating the efficacy of anti-TB drugs in vitro. This is the first study showing that colistin potentiates the activity of isoniazid and amikacin against M. tuberculosis and prevents the emergence of resistance to anti-TB drugs. These results form the basis for further studies on the applicability of colistin as a potentiator of anti-TB drugs.
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Antituberculosos/farmacología , Colistina/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Farmacorresistencia Bacteriana , Sinergismo Farmacológico , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/metabolismo , Factores de TiempoRESUMEN
BACKGROUND: Impaired signaling in the IFN-γ/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis. OBJECTIVE: We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections. METHODS: PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-γ/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated. RESULTS: We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-γ-induced gene expression, but we found impaired responses to IFN-γ restimulation. CONCLUSION: Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-γ-mediated inflammation.
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Coccidioidomicosis/genética , Histoplasmosis/genética , Mutación , Factor de Transcripción STAT1/genética , Adolescente , Adulto , Línea Celular Transformada , Niño , Coccidioidomicosis/diagnóstico , Coccidioidomicosis/inmunología , Citocinas/biosíntesis , Femenino , Regulación de la Expresión Génica , Histoplasmosis/diagnóstico , Histoplasmosis/inmunología , Humanos , Masculino , Fosforilación , Proteínas Inhibidoras de STAT Activados/metabolismo , Factor de Transcripción STAT1/metabolismo , Células Th17/inmunología , Activación Transcripcional , Adulto JovenRESUMEN
Mycobacterium abscessus is an emerging opportunistic pathogen causing severe pulmonary infections in patients with underlying lung disease and cystic fibrosis in particular. The rising prevalence of M. abscessus infections poses an alarming threat, as the success rates of available treatment options are limited. Central to this challenge is the absence of preclinical in vitro models that accurately mimic in vivo conditions and that can reliably predict treatment outcomes in patients. M. abscessus is notorious for its association with biofilm formation within the lung. Bacteria in biofilms are more recalcitrant to antibiotic treatment compared to planktonic bacteria, which likely contributes to the lack of correlation between preclinical drug activity testing (typically performed on planktonic bacteria) and treatment outcome. In recent years, there has been a growing interest in M. abscessus biofilm research. However, the absence of standardized methods for biofilm culture, biofilm characterization and drug activity testing has led to a wide spectrum of, sometimes inconsistent, findings across various studies. Factors such as strain selection, culture medium, and incubation time hugely impact biofilm development, phenotypical characteristics and antibiotic susceptibility. Additionally, a broad range of techniques are used to study M. abscessus biofilms, including quantification of colony-forming units, crystal violet staining and fluorescence microscopy. Yet, limitations of these techniques and the selected readouts for analysis affect study outcomes. Currently, research on the activity of conventional antibiotics, such as clarithromycin and amikacin, against M. abscessus biofilms yield ambiguous results, underscoring the substantial impact of experimental conditions on drug activity assessment. Beyond traditional drug activity testing, the exploration of novel anti-biofilm compounds and the improvement of in vitro biofilm models are ongoing. In this review, we outline the laboratory models, experimental variables and techniques that are used to study M. abscessus biofilms. We elaborate on the current insights of M. abscessus biofilm characteristics and describe the present understanding of the activity of traditional antibiotics, as well as potential novel compounds, against M. abscessus biofilms. Ultimately, this work contributes to the advancement of fundamental knowledge and practical applications of accurate preclinical M. abscessus models, thereby facilitating progress towards improved therapies for M. abscessus infections.
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Immunosuppression-associated lymphoproliferative disorders can be related to primary as well as acquired immune disorders. Interferon gamma receptor (IFN-γR) deficiency is a rare primary immune disorder, characterized by increased susceptibility to mycobacterial infections. Here we report the first case of an Epstein Barr Virus (EBV) related B-cell lymphoma in a patient with complete IFN-γR1 deficiency. The patient was a 20-year-old man with homozygous 22Cdel in IFNGR1 resulting in complete absence of IFN-γR1 surface expression and complete lack of responsiveness to IFN-γ in vitro. He had disseminated refractory Mycobacterium avium complex and Mycobacterium abscessus infections. At age 18 he presented with new spiking fever and weight loss that was due to an EBV-positive B-cell non-Hodgkin lymphoma. Two years later he died of progressive lymphoma. IFN-γ plays an important role in tumor protection and rejection. Patients with IFN-γR deficiencies and other immune deficits predisposing to mycobacterial disease seem to have an increased risk of malignancies, especially those related to viral infections. As more of these patients survive their early infections, cancer awareness and tumor surveillance may need to become a more routine part of management.
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Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/fisiología , Síndromes de Inmunodeficiencia/inmunología , Interferón gamma/metabolismo , Linfoma de Células B/inmunología , Complejo Mycobacterium avium/fisiología , Infección por Mycobacterium avium-intracellulare/inmunología , Receptores de Interferón/genética , Adulto , Consanguinidad , Infecciones por Virus de Epstein-Barr/genética , Humanos , Tolerancia Inmunológica , Síndromes de Inmunodeficiencia/genética , Vigilancia Inmunológica , Lactante , Interferón gamma/inmunología , Linfoma de Células B/genética , Masculino , Infección por Mycobacterium avium-intracellulare/genética , Eliminación de Secuencia/genética , Adulto Joven , Receptor de Interferón gammaAsunto(s)
Clofazimina , Síndrome de QT Prolongado , Arritmias Cardíacas , Diarilquinolinas , Corazón , HumanosRESUMEN
Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.
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Infecciones por VIH , VIH-1 , Humanos , Linfocitos T CD4-Positivos , Infecciones por VIH/tratamiento farmacológico , VIH-1/fisiología , Pirimetamina/farmacología , Pirimetamina/uso terapéutico , ARN , Ácido Valproico/farmacología , Activación Viral , Latencia del VirusRESUMEN
STAT1 is a key component of Interferon (IFN)-γ and IFN-α signaling and mediates protection against mycobacteria, fungal, viral infections, and cancer. Dominant negative inhibitory as well as gain of function heterozygous STAT1 mutations demonstrate that IFN-γ driven cellular responses need to be tightly regulated to control infections. We describe an autosomal dominant mutation in the SH2 domain of STAT1 that disrupts protein phosphorylation, c.1961T>A (M654K). The mutant allele does not permit STAT1 phosphorylation, and impairs STAT1 phosphorylation of the wild type allele. Protein dimerization is preserved but DNA binding activity, IFN-γ driven GAS-luciferase activity, and expression of IFN-γ target genes are reduced. IFN-α driven ISRE response, but not IFN-α driven GAS response, are preserved when cells are co-transfected with wild type and the mutant STAT1 constructs. M654K exerts a dominant negative effect on IFN-γ related immunity and is recessive for IFN-α induced immune function.
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Infecciones por Mycobacterium no Tuberculosas/genética , Complejo Mycobacterium avium/patogenicidad , Factor de Transcripción STAT1/genética , Linfocitos B , Línea Celular , Preescolar , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Interferón-alfa/genética , Interferón-alfa/metabolismo , Interferón gamma/genética , Interferón gamma/metabolismo , Masculino , Mutación , Infecciones por Mycobacterium no Tuberculosas/microbiología , Fosforilación , Multimerización de Proteína , Factor de Transcripción STAT1/metabolismo , Transducción de Señal/genéticaRESUMEN
OBJECTIVES: Mycobacterium abscessus is an opportunistic respiratory pathogen in patients with underlying lung disease. It is infamously known for its low treatment success rates because of its resistance to multiple classes of antibiotics. Further insight into M. abscessus resistance mechanisms is needed to improve treatment options. In this in vitro study, the role of efflux pumps in reaction to antibiotic stress is explored, as well as the ability of the putative efflux inhibitors, thioridazine and verapamil, to potentiate the activity of guideline-recommended antibiotics. METHODS: To evaluate the effects of antibiotic stress on mycobacterial efflux pumps, M. abscessus subspecies abscessus was exposed to amikacin, cefoxitin, clarithromycin, clofazimine, and tigecycline for 24 hours. Transcriptomic responses were measured by RNA sequencing to gain insight into upregulation of efflux pump encoding genes. Subsequently, in time-kill kinetics assays, the above-mentioned antibiotics were combined with thioridazine and verapamil to evaluate their potentiating capacity. RESULTS: All five antibiotics led to a fold change of ≥2 Log2 in expression of one or more genes encoding transporter systems. This effect was most pronounced for the ribosome-targeting antibiotics amikacin, clarithromycin, and tigecycline. Time-kill kinetics assays demonstrated synergy between amikacin, tigecycline, clofazimine, cefoxitin, and both thioridazine and verapamil. CONCLUSION: Antibiotic stressors induce expression of efflux pump encoding genes in M. abscessus, especially antibiotics that target the ribosome. Putative efflux inhibitors thioridazine and verapamil show synergy with various guideline-recommended antibiotics, making them interesting candidates for the improvement of M. abscessus treatment.
Asunto(s)
Mycobacterium abscessus , Humanos , Mycobacterium abscessus/genética , Amicacina/farmacología , Claritromicina/farmacología , Tigeciclina/farmacología , Clofazimina/farmacología , Cefoxitina/farmacología , Pruebas de Sensibilidad Microbiana , Tioridazina/farmacología , Antibacterianos/farmacología , Farmacorresistencia Bacteriana Múltiple/genética , Verapamilo/farmacologíaRESUMEN
Purpose: Because of the current lack of evidence-based antimicrobial treatment guidelines, Left Ventricular Assist Device (LVAD) infections are often treated according to local insights. Here, we propose a flowchart for protocolized treatment, in order to improve outcome. Methods: The flowchart was composed based on literature, consensus and expert opinion statements. It includes choice, dosage and duration of antibiotics, and indications for suppressive therapy, with particular focus on Staphylococcus aureus (SA) (Figure 1). The preliminary treatment results of 28 patients (2 from start cephalexin suppressive therapy) after implementation in July 2018 are described. Results: Cumulative incidence for first episode of infection in a 3-year time period was 27% (26 of 96 patients with an LVAD). Twenty-one of 23 (91%) first episodes of driveline infection (10 superficial and 13 deep; nine of 13 caused by SA) were successfully treated with antibiotics according to flowchart with complete resolution of clinical signs and symptoms. For two patients with deep driveline infections, surgery was needed in addition. There were no relapses of deep driveline infections, and only 2 SA deep driveline re-infections after 6 months. Nine patients received cephalexin of whom four patients (44%) developed a breakthrough infection with cephalexin-resistant gram-negative bacteria. Conclusions: The first results of this protocolized treatment approach of LVAD infections are promising. Yet, initiation of cephalexin suppressive therapy should be carefully considered given the occurrence of infections with resistant micro-organisms. The long-term outcome of this approach needs to be established in a larger number of patients, preferably in a multi-center setting.