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ABSTRACT: This case emphasizes the value of meticulous observation and regular follow-up of patients receiving rifampicin therapy. The prognosis for complete improvement in renal function in such cases was excellent, with prompt recognition and discontinuation of rifampicin. Teaching patients about these possible adverse effects and encouraging immediate reporting of signs and symptoms are likely to be beneficial because acute kidney injury can manifest itself very quickly after rifampicin is started. Even if renal failure can happen with any dose of rifampicin, primary physicians must have awareness about patients on intermittent or irregular therapy and those who have previously used this medication. It is challenging to determine the prevalence of adverse reactions to common antibiotics where a state- or country-wide reporting system is absent. Along with withdrawal of the causative agent patients were treated with corticosteroids (0.5-1 mg/kg/day) for an average period of 4-12 weeks showing significant recovery of renal function.
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Antituberculosos , Nefritis Intersticial , Rifampin , Humanos , Nefritis Intersticial/inducido químicamente , Rifampin/efectos adversos , Rifampin/uso terapéutico , Antituberculosos/efectos adversos , Antituberculosos/uso terapéutico , Masculino , Granuloma/inducido químicamente , Granuloma/tratamiento farmacológico , Adulto , Femenino , Enfermedad AgudaRESUMEN
Antituberculosis drugs induce pharmacologic cholestatic liver injury with long-term administration. Liver injury resulting from rifampicin is potentially related to the bile acid nuclear receptor Farnesoid X Receptor (FXR). To investigate this, cholestasis was induced in both wild-type (C57BL/6N) mice and FXR knockout (FXR-null) mice through administration of rifampicin (200 mg/kg) via gavage for 7 consecutive days. Compared with C57BL/6N mice, FXR-null mice exhibited more severe liver injury after rifampicin administration, characterized by enlarged liver size, elevated transaminases, and increased inflammation. Moreover, under rifampicin treatment, FXR knockout impairs lipid secretion and exacerbates hepatic steatosis. Significantly, the expression of metabolism molecules BSEP increased, while NTCP and CYP7A1 decreased following rifampicin administration in C57BL/6N mice, whereas these changes were absent in FXR knockout mice. Furthermore, rifampicin treatment in both C57BL/6N and FXR-null mice was associated with elevated c-Jun N-terminal kinase phosphorylation (p-JNK) levels, with a more pronounced elevation in FXR-null mice. Our study suggests that rifampicin-induced liver injury, steatosis, and cholestasis are associated with FXR dysfunction and altered bile acid metabolism, and that the JNK signaling pathway is partially implicated in this injury. Based on these results, we propose that FXR might be a novel therapeutic target for addressing drug-induced liver injury.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Hígado , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Citoplasmáticos y Nucleares , Rifampin , Animales , Rifampin/efectos adversos , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hígado/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP/genética , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP/metabolismo , Colesterol 7-alfa-Hidroxilasa/genética , Colesterol 7-alfa-Hidroxilasa/metabolismo , Simportadores/genética , Simportadores/metabolismo , Ácidos y Sales Biliares/metabolismo , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Colestasis/inducido químicamente , Colestasis/tratamiento farmacológico , Colestasis/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/inducido químicamente , Hígado Graso/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismoRESUMEN
Objective: To explore the characteristics of adverse drug reactions during the 24-week therapy with delamanid-containing regimen for patients with multidrug-resistant and rifampicin-resistant pulmonary tuberculosis (MDR/RR-PTB). Methods: The prospective multicenter study was conducted from June 2020 to June 2023. A total of 608 eligible patients with MDR/RR-PTB were enrolled in 26 tuberculosis medical institutions in China including 364 males and 79 females, aged 39.6(19.0-68.0) years. Patients were treated with chemotherapy regimens containing delamanid. Patients were closely supervised during treatment of medication, and all adverse reactions occurring during treatment were monitored and recorded. The clinical characteristics of adverse reactions were evaluated by descriptive analysis. Chi-square test and multivariate logistic regression were used to analyze the related factors of QTcF interval prolongation (QT corrected with Fridericia's formula). Results: Of the 608 patients enrolled in this study, 325 patients (53.5%) reported 710 adverse events within 24 weeks of treatment. The top 6 most common complications were hematological abnormalities (143 patients, 23.5%), QT prolongation (114 patients, 18.8%), liver toxicity (85 patients, 14.0%), gastrointestinal reaction (41 patients, 6.7%), peripheral neuropathy (25 patients, 4.1%) and mental disorders (21 patients, 3.5%). The prolongation of QT interval mostly occurred in the 12th week after the first dose of medication. Serious adverse reactions occurred in 21 patients (3.5%). There were 7 patients (1.2%) with mental disorders, including 2 patients (0.3%) with severe mental disorders. Conclusions: The safety of dalamanid-based regimen in the staged treatment of MDR/RR-PTB patients was generally good, and the incidence of adverse reactions was similar to that reported in foreign studies. This study found that the incidence of QT interval prolongation in Chinese patients was higher than that reported overseas, suggesting that the monitoring of electrocardiogram should be strengthened when using drugs containing delamanid that may cause QT interval prolongation.
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Antituberculosos , Nitroimidazoles , Oxazoles , Rifampin , Tuberculosis Resistente a Múltiples Medicamentos , Tuberculosis Pulmonar , Humanos , Masculino , Femenino , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adulto , Estudios Prospectivos , Rifampin/efectos adversos , Persona de Mediana Edad , Oxazoles/efectos adversos , Oxazoles/uso terapéutico , Oxazoles/administración & dosificación , Antituberculosos/efectos adversos , Tuberculosis Pulmonar/tratamiento farmacológico , Nitroimidazoles/efectos adversos , Nitroimidazoles/uso terapéutico , Nitroimidazoles/administración & dosificación , Anciano , China , Adulto Joven , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiologíaRESUMEN
RATIONALE: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening systemic inflammatory syndrome characterized by an overactive immune response. This hyperactivation can arise from genetic mutations, infections, malignancies, or autoimmune disorders. Medication-induced HLH is extremely rare and requires special attention. PATIENT CONCERNS: A 53-year-old female diagnosed with pulmonary and urinary tract tuberculosis. She underwent quadruple therapy, including isoniazid, rifampin, ethambutol, and pyrazinamide. Subsequently, she developed fever, hepatosplenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia, increased soluble CD25 levels, decreased natural killer cell activity, and hemophagocytosis, notably without eosinophilia. Her clinical symptoms were exacerbated by rifampin intake. DIAGNOSES: Pulmonary and left kidney tuberculosis, multiple organ failure, and rifampin-induced HLH. INTERVENTIONS: Anti-tuberculosis regimen (isoniazid, pyrazinamide, ethambutol, and levofloxacin, excluding rifampin) combined with glucocorticoid therapy. OUTCOMES: Satisfactory recovery with improved clinical symptoms, laboratory tests, and chest imaging studies. LESSONS: Early correct diagnosis and appropriate management of HLH are essential to save the lives of affected patients. The potential severe side effects of rifampin should not be ignored.
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Linfohistiocitosis Hemofagocítica , Rifampin , Humanos , Linfohistiocitosis Hemofagocítica/inducido químicamente , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/diagnóstico , Femenino , Persona de Mediana Edad , Rifampin/efectos adversos , Rifampin/uso terapéutico , Tuberculosis Pulmonar/tratamiento farmacológico , Antituberculosos/efectos adversos , Antituberculosos/uso terapéuticoRESUMEN
BACKGROUND: Pharmacovigilance entails monitoring of patients for timely detection of ADR and reporting them so that more information about drug safety can be obtained. This may help in the future for dose modification or alteration of regimen. In NTEP, ADSm (Active Drug Safety monitoring) is part of pharmacovigilance. In this study we shall be studying ADRs to Anti TB drugs in DRTB. METHODOLOGY: This study is observational, retrospective and record based, of patients admitted from 2021 to 2023 in the DOTS ward of Respiratory Medicine Department of a tertiary care hospital in Goa. Data such as age, sex, regimen, date of AKT initiation and adverse effects documented has been noted and compiled. RESULTS: ADRs have been tabulated in the form of tables. Statistical analysis is done to find out the commonest ADR, time when they are likely to occur, which age and gender are most likely affected and if there are any other associated risk factors for ADRs. CONCLUSION: This study will enable in future to better monitor patients with regard to particular adverse drug reaction, patient safety and if needed to alter the regimen as early as possible.
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Antituberculosos , Farmacovigilancia , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Femenino , Antituberculosos/efectos adversos , Antituberculosos/uso terapéutico , Masculino , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Estudios Retrospectivos , Adulto , Persona de Mediana Edad , Adulto Joven , India/epidemiología , Adolescente , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Anciano , Isoniazida/efectos adversos , Isoniazida/uso terapéutico , Rifampin/efectos adversos , Rifampin/uso terapéutico , Factores de RiesgoRESUMEN
BACKGROUND: Tuberculosis (TB) lymphadenitis is the most common form of extra-pulmonary TB, and the treatment duration is six months. This non-inferiority based randomized clinical trial in South India evaluated the efficacy and safety of a four-month ofloxacin containing regimen in tuberculosis lymphadenitis (TBL) patients. METHODS: New, adult, HIV-negative, microbiologically and or histopathologically confirmed superficial lymph node TB patients were randomized to either four-month oflaxacin containing test regimen [ofloxacin (O), isoniazid (H), rifampicin (R), pyrazinamide (Z) -2RHZO daily/ 2RHO thrice-weekly] or a six-month thrice-weekly control regimen (2HRZ, ethambutol/4RH). The treatment was directly observed. Clinical progress was monitored monthly during and up to 12 months post-treatment, and thereafter every three months up to 24 months. The primary outcome was determined by response at the end of treatment and TB recurrence during the 24 months post-treatment. RESULTS: Of the 302 patients randomized, 298 (98.7%) were eligible for modified intention-to-treat (ITT) analysis and 294 (97%) for per-protocol (PP) analysis. The TB recurrence-free favourable response in the PP analysis was 94.0% (95% CI: 90.1-97.8) and 94.5% (95% CI: 90.8-98.2) in the test and control regimen respectively, while in the ITT analysis, it was 92.7% and 93.2%. The TB recurrence-free favourable response in the test regimen was non-inferior to the control regimen 0.5% (95% CI: -4.8-5.9) in the PP analysis based on the 6% non-inferiority margin. Treatment was modified for drug toxicity in two patients in the test regimen, while one patient had a paradoxical reaction. CONCLUSION: The 4-month ofloxacin containing regimen was found to be non-inferior and as safe as the 6-month thrice-weekly control regimen.
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Antituberculosos , Ofloxacino , Tuberculosis Ganglionar , Humanos , Ofloxacino/administración & dosificación , Ofloxacino/efectos adversos , Ofloxacino/uso terapéutico , Adulto , Masculino , Femenino , Tuberculosis Ganglionar/tratamiento farmacológico , Antituberculosos/uso terapéutico , Antituberculosos/efectos adversos , Antituberculosos/administración & dosificación , Resultado del Tratamiento , Persona de Mediana Edad , India , Rifampin/uso terapéutico , Rifampin/administración & dosificación , Rifampin/efectos adversos , Adulto Joven , Isoniazida/uso terapéutico , Isoniazida/administración & dosificación , Isoniazida/efectos adversos , Quimioterapia Combinada , Pirazinamida/uso terapéutico , Pirazinamida/administración & dosificación , Pirazinamida/efectos adversos , Etambutol/uso terapéutico , Etambutol/administración & dosificación , Etambutol/efectos adversos , Esquema de Medicación , AdolescenteRESUMEN
Some anti-mycobacterial drugs are known to cause QT interval prolongation, potentially leading to life-threatening ventricular arrhythmia. However, the highest leprosy and tuberculosis burden occurs in settings where electrocardiographic monitoring is challenging. The feasibility and accuracy of alternative strategies, such as the use of automated measurements or a mobile electrocardiogram (mECG) device, have not been evaluated in this context. As part of the phase II randomized controlled BE-PEOPLE trial evaluating the safety of bedaquiline-enhanced post-exposure prophylaxis (bedaquiline and rifampicin, BE-PEP, versus rifampicin, SDR-PEP) for leprosy, all participants had corrected QT intervals (QTc) measured at baseline and on the day after receiving post-exposure prophylaxis. The accuracy of mECG measurements as well as automated 12L-ECG measurements was evaluated. In total, 635 mECGs from 323 participants were recorded, of which 616 (97%) were of sufficient quality for QTc measurement. Mean manually read QTc on 12L-ECG and mECG were 394 ± 19 and 385 ± 18 ms, respectively (p < 0.001), with a strong correlation (r = 0.793). The mean absolute QTc difference between both modalities was 11 ± 10 ms. Mean manual and automated 12L-ECG QTc were 394 ± 19 and 409 ± 19 ms, respectively (n = 636; p < 0.001), corresponding to moderate agreement (r = 0.655). The use of a mECG device for QT interval monitoring was feasible and yielded a median absolute QTc error of 8 ms. Automated QTc measurements were less accurate, yielding longer QTc intervals.
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Diarilquinolinas , Electrocardiografía , Estudios de Factibilidad , Lepra , Rifampin , Humanos , Diarilquinolinas/administración & dosificación , Diarilquinolinas/efectos adversos , Masculino , Adulto , Femenino , Lepra/tratamiento farmacológico , Lepra/diagnóstico , Rifampin/administración & dosificación , Rifampin/efectos adversos , Persona de Mediana Edad , Leprostáticos/efectos adversos , Leprostáticos/administración & dosificación , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/diagnóstico , Adulto Joven , Quimioterapia Combinada/métodosRESUMEN
Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation. The trial included participants from South Africa, Uzbekistan, and Belarus. A post hoc analysis of electrocardiogram data was undertaken. Random effects regression was used to model QTcF longitudinally over 24 weeks and causal frameworks guided the analysis of non-randomized independent variables. 328 participants were included in BPaL-based arms. The longitudinal analysis of investigational arms showed an initial QTcF steep increase in the first week. QTcF trajectories between weeks 2 and 24 differed slightly by regimen, with highest mean peak for BPaLC (QTcF 446.5 ms). Overall, there were 397 QTcF >450 ms (of 3,744) and only one QTcF >500 ms. The odds of QTcF >450 ms among participants in any investigational arm, was 8.33 times higher in Uzbekistan compared to Belarus (95% confidence interval: 3.25-21.33). No effect on QTcF prolongation was found for baseline age or body mass index (BMI). Clinically significant QTc prolongation was rare in this cohort of closely monitored participants. Across BPaL-based regimens, BPaLC showed a slightly longer and sustained effect on QTcF prolongation, but the differences (both in magnitude of change and trajectory over time) were clinically unimportant. The disparity in the risk of QTc prolongation across countries would be an important factor to further investigate when evaluating monitoring strategies. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT02589782.
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Antituberculosos , Electrocardiografía , Síndrome de QT Prolongado , Moxifloxacino , Rifampin , Humanos , Rifampin/uso terapéutico , Rifampin/efectos adversos , Masculino , Adulto , Femenino , Moxifloxacino/uso terapéutico , Moxifloxacino/efectos adversos , Antituberculosos/efectos adversos , Antituberculosos/uso terapéutico , Síndrome de QT Prolongado/inducido químicamente , Persona de Mediana Edad , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Sudáfrica , Clofazimina/uso terapéutico , Clofazimina/efectos adversos , Diarilquinolinas/uso terapéutico , Diarilquinolinas/efectos adversos , República de BelarúsRESUMEN
BACKGROUND: Chronic kidney disease (CKD) patients are at a high risk of tuberculosis (TB), with a relative risk of developing active TB of 10%-25%. Similarly, glomerular disease increases the risk of TB due to diminished glomerular filtration rate, proteinuria, and immunosuppression use. Further, the first-line anti-TB drugs are associated with acute kidney injury (AKI) even in patients with normal kidney functions. METHODS: We retrospectively identified 10 patients hospitalized with unusual adverse effects of antituberculosis therapy (ATT) from 2013 to 2022. RESULTS: We found three cases of AKI caused by rifampicin: acute interstitial nephritis, crescentic glomerulonephritis, and heme pigment-induced acute tubular necrosis. We observed rifampicin-induced accelerated hypertension and thrombocytopenia in two patients on maintenance hemodialysis. Isoniazid caused pancreatitis and cerebellitis in two CKD patients, respectively. In a CKD patient, we detected acute gout secondary to pyrazinamide-induced reduced uric acid excretion. We also observed cases of drug rash with eosinophilia and systemic symptoms and hypercalcemia due to immune reconstitution inflammatory syndrome in patients with glomerular disease on ATT. Immediate discontinuation of the offending drug, along with specific and supportive management, led to a recovery in all cases. CONCLUSION: The adverse effects of ATT may be unusually severe and varied in kidney patients due to decreased renal elimination. Early recognition of these adverse effects and timely discontinuation of the offending drug is essential to limit morbidity and mortality.
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Lesión Renal Aguda , Antituberculosos , Insuficiencia Renal Crónica , Humanos , Antituberculosos/efectos adversos , Antituberculosos/uso terapéutico , Masculino , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , Lesión Renal Aguda/inducido químicamente , Anciano , Adulto , Insuficiencia Renal Crónica/complicaciones , Rifampin/efectos adversos , Rifampin/uso terapéutico , Isoniazida/efectos adversos , Isoniazida/uso terapéutico , Nefritis Intersticial/inducido químicamente , Tuberculosis/tratamiento farmacológico , Tuberculosis/complicaciones , Pirazinamida/efectos adversos , Pirazinamida/uso terapéutico , Glomerulonefritis/inducido químicamente , Síndrome Inflamatorio de Reconstitución InmuneRESUMEN
BACKGROUND: The implementation of modified, all-oral shorter regimens for treatment of rifampicin-resistant tuberculosis has started in Armenia since August 2020 under the conditions of operational research. OBJECTIVE: This study aims to evaluate the safety and effectiveness of shorter regimens. METHODS: We evaluated cumulative incidence rates of serious adverse events, adverse events of grade 3 and greater and events resulting in treatment modifications or suspension for 52 study participants. RESULTS: A new, different pattern of adverse events emerged compared with the previous evaluations of drug safety of treatment for rifampicin-resistant tuberculosis. Arthralgia (23.1%) and peripheral neuropathy (21.2%) took leading positions among the adverse events resulting in modifications of treatment. Some adverse events of interest (prolonged QT interval, elevated liver enzymes and anemia) remained relevant for the patients receiving new combinations of anti-TB drugs. The other adverse events (impaired hearing, acute kidney injury and hypokalemia) lost their significance for safety surveillance of rifampicin-resistant tuberculosis treatment. One unexpected serious adverse event (lymphoproliferative skin lesion) brought to a "failed treatment" outcome. The other serious adverse event was anemia. CONCLUSION: The shorter regimens proved to be safe and effective for treatment of rifampicin-resistant tuberculosis, but proper follow-up of adverse events is necessary.
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Antituberculosos , Rifampin , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Masculino , Femenino , Armenia , Adulto , Persona de Mediana Edad , Rifampin/efectos adversos , Rifampin/administración & dosificación , Rifampin/uso terapéutico , Antituberculosos/efectos adversos , Antituberculosos/administración & dosificación , Antituberculosos/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Administración Oral , Esquema de Medicación , AncianoRESUMEN
BACKGROUND: To compare the effectiveness, cost, and safety of four regimens recommended by the World Health Organization (WHO) for rifampicin resistance/multidrug-resistance tuberculosis (RR/MDR-TB) Treatment in Eastern China. METHODS: We performed a cohort study among patients with RR/MDR between 2020 and 2022 in Jiangsu Province. The treatment success rate, cost, and drug adverse reaction rate were compared. RESULTS: Between 2020 and 2022, 253 RR/MDR-TB patients were enrolled in the study. 37 (14.62%), 76 (30.04%), 74 (29.25%), and 66 (26.09%) patients had the short-term regimens, the new long-term oral regimens, the new long-term injectable regimens, and the traditional long-term regimens, respectively. The treatment success rate was the highest among patients treated with the short-term regimen (75.68%) and was the lowest among patients treated with the traditional long-term regimens (60.61%). The estimated mean cost per favorable outcome was 142.61 thousand Chinese Yuan (CNY), and the short-term regimens showed the lowest cost in the four regimes (88.51 thousand CNY vs. 174.24 thousand CNY, 144.00 thousand CNY, and 134.98 thousand CNY). Incremental cost-effectiveness ratios of the short-term regimens, the new long-term oral regimen, and the new long-term injectable regimens were -3083.04, 6040.09, and 819.68 CNY compared to the traditional long-term regimens. CONCLUSIONS: For RR/MDR-TB patients in China who meet the criteria for short-term regimens, the short-term regimens were proven to be the most cost-effective of the four regimens recommended by WHO. For RR/MDR-TB patients in China who don't meet the criteria for short-term regimens, the new long-term injectable regimens are more cost-effective than the remaining two regimens.
This is the first study to evaluate the effectiveness, cost, and safety of four regimens recommended by the WHO for RR/MDR-TB treatment in China.For RR/MDR-TB patients in China who meet the criteria for the short-term regimens, the short-term regimens were proven to be the most cost-effective of the four regimens recommended by WHO.
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Antituberculosos , Rifampin , Tuberculosis Resistente a Múltiples Medicamentos , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Antituberculosos/efectos adversos , Antituberculosos/administración & dosificación , Antituberculosos/economía , China , Estudios de Cohortes , Análisis de Costo-Efectividad , Quimioterapia Combinada , Rifampin/efectos adversos , Rifampin/administración & dosificación , Rifampin/economía , Rifampin/uso terapéutico , Resultado del Tratamiento , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/economía , Organización Mundial de la SaludRESUMEN
This open-label, phase 1 study was conducted with healthy adult participants to evaluate the potential drug-drug interaction between rilzabrutinib and quinidine (an inhibitor of P-glycoprotein [P-gp] and CYP2D6) or rifampin (an inducer of CYP3A and P-gp). Plasma concentrations of rilzabrutinib were measured after a single oral dose of rilzabrutinib 400 mg administered on day 1 and again, following a wash-out period, after co-administration of rilzabrutinib and quinidine or rifampin. Specifically, quinidine was given at a dose of 300 mg every 8 hours for 5 days from day 7 to day 11 (N = 16) while rifampin was given as 600 mg once daily for 11 days from day 7 to day 17 (N = 16) with rilzabrutinib given in the morning of day 10 (during quinidine dosing) or day 16 (during rifampin dosing). Quinidine had no significant effect on rilzabrutinib pharmacokinetics. Rifampin decreased rilzabrutinib exposure (the geometric mean of Cmax and AUC0-∞ decreased by 80.5% and 79.5%, respectively). Single oral doses of rilzabrutinib, with or without quinidine or rifampin, appeared to be well tolerated. These findings indicate that rilzabrutinib is a substrate for CYP3A but not a substrate for P-gp.
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Área Bajo la Curva , Interacciones Farmacológicas , Voluntarios Sanos , Quinidina , Rifampin , Humanos , Rifampin/administración & dosificación , Rifampin/efectos adversos , Quinidina/administración & dosificación , Quinidina/efectos adversos , Quinidina/farmacología , Quinidina/farmacocinética , Adulto , Masculino , Femenino , Adulto Joven , Persona de Mediana Edad , Inductores del Citocromo P-450 CYP3A/farmacología , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Inductores del Citocromo P-450 CYP3A/efectos adversos , Citocromo P-450 CYP3A/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Administración Oral , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Pirimidinas/efectos adversosRESUMEN
Rifampicin (RFP) has demonstrated potent antibacterial effects in the treatment of pulmonary tuberculosis. However, the serious adverse effects on the liver intensively limit the clinical usage of the drug. Deacetylation greatly reduces the toxicity of RFP but also retains its curative activity. Here, we found that Krüppel-like factor 15 (KLF15) repressed the expression of the major RFP detoxification enzyme Cyp3a11 in mice via both direct and indirect mechanisms. Knockout of hepatocyte KLF15 induced the expression of Cyp3a11 and robustly attenuated the hepatotoxicity of RFP in mice. In contrast, overexpression of hepatic KLF15 exacerbated RFP-induced liver injury as well as mortality. More importantly, the suppression of hepatic KLF15 expression strikingly restored liver functions in mice even after being pretreated with overdosed RFP. Therefore, this study identified the KLF15-Cyp3a11 axis as a novel regulatory pathway that may play an essential role in the detoxification of RFP and associated liver injury. SIGNIFICANCE STATEMENT: Rifampicin has demonstrated antibacterial effects in the treatment of pulmonary tuberculosis. However, the serious adverse effects on the liver limit the clinical usage of the drug. Permanent depletion and transient inhibition of hepatic KLF15 expression significantly induced the expression of Cyp3a11 and robustly attenuated mouse hepatotoxicity induced by RFP. Overall, our studies show the KLF15-Cyp3a11 axis was identified as a novel regulatory pathway that may play an essential role in the detoxification of RFP and associated liver injury.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Citocromo P-450 CYP3A , Factores de Transcripción de Tipo Kruppel , Hígado , Ratones Endogámicos C57BL , Ratones Noqueados , Rifampin , Animales , Rifampin/efectos adversos , Rifampin/toxicidad , Rifampin/farmacología , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP3A/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Ratones , Masculino , Hígado/efectos de los fármacos , Hígado/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Antibióticos Antituberculosos/efectos adversos , Antibióticos Antituberculosos/farmacología , Antibióticos Antituberculosos/toxicidad , Proteínas de la MembranaRESUMEN
RATIONALE: Rifampicin, as a main chemotherapy drug treating brucellosis, is widely used in clinical practice. Rifampicin-associated ARF is not rare, especially in those rifampicin re-exposure patients. However, this was rare complication of severe renal involvement due to multiple factors including rifampicin, nephrotoxic gentamicin, and contrast medium, and few studies have reported it. PATIENT CONCERNS: A 59-year-old male presented to our hospital with acute renal failure (ARF) caused by anti-brucellosis treatment with rifampicin (675 mg/day), gentamicin (320 mg/day), and doxycycline (200 mg/day). He had a contrast-enhanced CT of the upper abdomen before the onset of. After stopping rifampicin and undergoing integrated therapy, the patient's renal function gradually recovered. DIAGNOSES: Considering that the patient had a history of using rifampicin for pulmonary tuberculosis in the past, based on the examination results, the patient was diagnosed with rifampicin-associated ARF. INTERVENTIONS: Symptomatic treatment such as hemodialysis, and anti-brucella treatment with doxycycline and moxifloxacin were given. OUTCOMES: The patient had significant anuric and polyuric periods and acute tubular necrosis is considered. After treatment, his renal function and urine volume returned to normal, and Brucella melitensis was not isolated from blood cultures. LESSONS: The case reveals that severe renal involvement due to multiple factors including rifampicin, nephrotoxic gentamicin, and contrast medium. Misdiagnosis and mistreatment can deteriorate the patient's condition. Renal function should be closely monitored in the susceptible patients. Early recognition can provide appropriate therapy to patients. If unexplained renal failure during the use of rifampicin, especially in those rifampicin re-exposure patients, rifampicin-associated ARF should be considered.
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Lesión Renal Aguda , Brucelosis , Masculino , Humanos , Persona de Mediana Edad , Rifampin/efectos adversos , Doxiciclina/efectos adversos , Brucelosis/complicaciones , Brucelosis/diagnóstico , Brucelosis/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/terapia , Lesión Renal Aguda/diagnóstico , Gentamicinas/efectos adversos , Antibacterianos/efectos adversosRESUMEN
BACKGROUND: Managing health care acquired and device-associated intracranial infections in young children can be challenging given adverse antibiotic side effects and difficulties in achieving adequate central nervous system (CNS) antibiotic concentrations. Ceftaroline is a cephalosporin with a favorable safety profile and activity against methicillin-resistant Staphylococci and several Gram-negative organisms. Published data on the use of ceftaroline for CNS infections in children and adults are limited. METHODS: We describe a 2-month-old infant with ventriculo-subgaleal shunt-associated methicillin-resistant Staphylococcus epidermidis ventriculitis, which was successfully treated with ceftaroline, in addition to vancomycin and rifampin. We conducted a scoping review of English-language literature retrieved from PubMed, EMBASE and Web of Science that assessed the use of ceftaroline for CNS infections. RESULTS: We identified 22 articles for inclusion in our review, which described 92 unique patients, of whom 2 were <21 years old. Ceftaroline was commonly used in conjunction with other antibiotics to treat infections caused by Staphylococcus aureus , coagulase-negative Staphylococci and Streptococcus pneumoniae . Most case reports described clinical success with ceftaroline, though small case series and cohort studies yielded mixed efficacy assessments. Adverse effects attributed to ceftaroline were rare and included reversible myelosuppression, eosinophilia, hepatotoxicity and nephrotoxicity. Pharmacokinetic/pharmacodynamic studies suggested similar CNS penetration through inflamed meninges as other beta lactam antibiotics. CONCLUSIONS: We identified a growing body of published evidence supporting the use of ceftaroline in combination with other agents for the treatment of CNS infections. In absence of clinical trials, additional real-world data are needed to define the efficacy and safety of ceftaroline for children and adults with CNS infections.
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Antibacterianos , Ceftarolina , Cefalosporinas , Infecciones Estafilocócicas , Humanos , Cefalosporinas/uso terapéutico , Cefalosporinas/efectos adversos , Antibacterianos/uso terapéutico , Antibacterianos/efectos adversos , Antibacterianos/farmacología , Lactante , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus epidermidis/efectos de los fármacos , Vancomicina/uso terapéutico , Vancomicina/efectos adversos , Masculino , Ventriculitis Cerebral/tratamiento farmacológico , Ventriculitis Cerebral/microbiología , Infecciones del Sistema Nervioso Central/tratamiento farmacológico , Infecciones del Sistema Nervioso Central/microbiología , Rifampin/uso terapéutico , Rifampin/efectos adversosRESUMEN
BACKGROUND: Human brucellosis is a neglected, re-emerging, and endemic zoonosis in many countries. The debilitating and disabling potential of the disease is a warning about its morbidity, generating socioeconomic impact. This review aims to update the current evidence on the efficacy and safety of therapeutic options for human brucellosis using the network meta-analysis (NMA). METHODOLOGY: A systematic search was conducted in four different databases by independent reviewers to assess overall therapy failure, adverse events, and time to defervescence associated with different therapies. Randomized clinical trials (RCTs) evaluating any therapeutic drug intervention were selected, excluding non-original studies or studies related to localized forms of the disease or with less than 10 participants. Data were analyzed by frequentist statistics through NMA by random effects model. The risk of bias and certainty of evidence was assessed, this review was registered at PROSPERO. RESULTS: Thirty-one (31) RCTs involving 4167 patients were included. Three networks of evidence were identified to evaluate the outcomes of interest. Triple therapy with doxycycline + streptomycin + hydroxychloroquine for 42 days (RR: 0.08; CI 95% 0.01-0.76) had a lower failure risk than the doxycycline + streptomycin regimen. Doxycycline + rifampicin had a higher risk of failure than doxycycline + streptomycin (RR: 1.96; CI 95% 1.27-3.01). No significant difference was observed between the regimens when analyzing the incidence of adverse events and time to defervescence. In general, most studies had a high risk of bias, and the results had a very low certainty of evidence. CONCLUSIONS: This review confirmed the superiority of drugs already indicated for treating human brucellosis, such as the combination of doxycycline and aminoglycosides. The association of hydroxychloroquine to the dual regimen was identified as a potential strategy to prevent overall therapy failure, which is subject to confirmation in future studies.
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Antibacterianos , Brucelosis , Doxiciclina , Quimioterapia Combinada , Metaanálisis en Red , Estreptomicina , Humanos , Brucelosis/tratamiento farmacológico , Antibacterianos/uso terapéutico , Antibacterianos/efectos adversos , Doxiciclina/uso terapéutico , Doxiciclina/efectos adversos , Estreptomicina/uso terapéutico , Hidroxicloroquina/uso terapéutico , Hidroxicloroquina/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Rifampin/uso terapéutico , Rifampin/efectos adversos , Resultado del TratamientoRESUMEN
Ritonavir (RTV), which is used in combination with nilmatrelvir (NMV) to treat coronavirus disease 2019 (COVID-19), inhibits cytochrome P450 (CYP) 3A, thereby increasing blood tacrolimus (TAC) levels through a drug-drug interaction (DDI). We experienced a case in which a DDI between the two drugs led to markedly increased blood TAC levels, resulting in vasospastic angina (VSA) and acute kidney injury (AKI). Rifampicin (RFP) was administered to induce CYP3A and promote TAC metabolism. A 60-year-old man with dermatomyositis who was taking 3 mg/day TAC contracted COVID-19. The patient started oral NMV/RTV therapy, and he was admitted to the hospital after 4 days because of chest pain and AKI. On day 5, his blood TAC level increased markedly to 119.8 ng/mL. RFP 600 mg was administered once daily for 3 days, and his blood TAC level decreased to the therapeutic range of 9.6 ng/mL on day 9, leading to AKI improvement. Transient complete atrioventricular block and nonsustained ventricular tachycardia were present during chest pain. In the coronary spasm provocation test, complete occlusion was observed in the right coronary artery, leading to a diagnosis of VSA. VSA and AKI are possible side effects of high blood TAC levels caused by DDI, and attention should be paid to cardiovascular side effects such as VSA and AKI associated with increased blood levels of TAC when it is used together with NMV/RTV. When blood levels of TAC increase, oral RFP can rapidly decrease TAC blood levels and potentially reduce its toxicity.