Pharmacokinetics and pharmacodynamics of high-dose isoniazid for the treatment of rifampicin- or multidrug-resistant tuberculosis in Indonesia.

BACKGROUND: Pharmacokinetic data on high-dose isoniazid for the treatment of rifampicin-/multidrug-resistant tuberculosis (RR/MDR-TB) are limited. We aimed to describe the pharmacokinetics of high-dose isoniazid, estimate exposure target attainment, identify predictors of exposures, and explore exposure-response relationships in RR/MDR-TB patients. METHODS: We performed an observational pharmacokinetic study, with exploratory pharmacokinetic/pharmacodynamic analyses, in Indonesian adults aged 18-65 years treated for pulmonary RR/MDR-TB with standardized regimens containing high-dose isoniazid (10-15 mg/kg/day) for 9-11 months. Intensive pharmacokinetic sampling was performed after ≥2 weeks of treatment. Total plasma drug exposure (AUC0-24) and peak concentration (Cmax) were assessed using non-compartmental analyses. AUC0-24/MIC ratio of 85 and Cmax/MIC ratio of 17.5 were used as exposure targets. Multivariable linear and logistic regression analyses were used to identify predictors of drug exposures and responses, respectively. RESULTS: We consecutively enrolled 40 patients (median age 37.5 years). The geometric mean isoniazid AUC0-24 and Cmax were 35.4 h·mg/L and 8.5 mg/L, respectively. Lower AUC0-24 and Cmax values were associated (P < 0.05) with non-slow acetylator phenotype, and lower Cmax values were associated with male sex. Of the 26 patients with MIC data, less than 25% achieved the proposed targets for isoniazid AUC0-24/MIC (n = 6/26) and Cmax/MIC (n = 5/26). Lower isoniazid AUC0-24 values were associated with delayed sputum culture conversion (>2 months of treatment) [adjusted OR 0.18 (95% CI 0.04-0.89)]. CONCLUSIONS: Isoniazid exposures below targets were observed in most patients, and certain risk groups for low isoniazid exposures may require dose adjustment. The effect of low isoniazid exposures on delayed culture conversion deserves attention.

Cutaneous Vasculitis and Generalized Lymphadenopathy Associated with Extended-Spectrum Beta-Lactamase (ESBL)-Producing Escherichia coli Endocarditis: A Rare Case Report.

INTRODUCTION: Infective endocarditis (IE) has been known as the great imitator due to variable clinical manifestation, making its diagnosis challenging. A missed diagnosis could lead to inappropriate therapy. We presented a rare case of blood culture-negative infective endocarditis (BCNIE) due to extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli manifest with cutaneous vasculitis and generalized lymphadenopathy. We highlighted its diagnostic challenge and management. CASE ILLUSTRATION AND DISCUSSION: A 36-year-old male with known asymptomatic ruptured sinus of Valsalva (SOV) presented with fever of unknown origin for six months, fatigue, weight loss with a history of multiple hospitalizations. The physical examination revealed a continuous murmur at Erb's point, cutaneous vasculitis, and bilateral inguinal lymphadenopathy. The laboratory result was leukocytosis and elevated C-Reactive Protein (CRP). Generalized lymphadenopathy was detected from the thorax and abdominal Computed Tomography (CT) Scans. Positive Anti Nuclear Antibody (ANA) Indirect Immunofluorescence (IF) speckled pattern led us to consider an autoimmune as the etiology, but we still considered IE as a differential diagnosis due to history of structural heart disease. Detection of multiple tiny oscillating masses at the tricuspid valve from the echocardiogram and cardiac CT led to possible IE diagnosis. Negative three consecutive blood cultures led the diagnosis to BCNIE. Surgery was performed to evacuate the vegetations, repair the SOV, and tricuspid valve replacement with a bioprosthetic valve. These results in improvement of the patient's condition. ESBL-producing Escherichia coli yielded in tissue culture made the diagnosis of IE became definite. CONCLUSION: ESBL-producing Escherichia coli should be considered as the etiology of BCNIE. Cutaneous vasculitis and generalized lymphadenopathy as a manifestation of IE could lead to diagnostic confusion. A thorough investigation will help clinician to avoid delay or inappropriate treatment that could be detrimental for the patient.

Improving Diagnostic of Pulmonary Tuberculosis in HIV Patients by Bronchoscopy: A Cross Sectional Study.

BACKGROUND: diagnostic of pulmonary TB in HIV patients is a problem due to non specific clinical features, or radiological appearance. HIV patients with CD4≤200 cells/mL infected with M. tuberculosis have less capacity in containing M. tuberculosis, developing granulomas, casseous necrosis, or cavities. This condition is caused by weakend inflammatory which later reduced sputum production and may cause false negative result. This study aimed to assess differences in the positivity level of acid fast bacilli (AFB) and cultures of M. tuberculosis from non-bronchoscopic sputum (spontaneous and induced sputum) compared to bronchoscopic sputum (bronchoalveolar lavage) in HIV positive patients suspected pulmonary tuberculosis with CD4<200 cells/µL. METHODS: this cross sectional study was conducted in adult HIV patients treated in Hasan Sadikin Hospital with CD4≤200 cells/µL suspected with pulmonary tuberculosis by using paired comparative analytic test. All patients expelled sputum spontaneously or with sputum induction on the first day. On the next day, bronchoalveolar lavage (BAL) was performed. The two samples obtained from two methods were examined by AFB examination with staining Ziehl Neelsen (ZN) and cultured of M. tuberculosis on solid media Ogawa on all patients. Positivity, sensitivity and increased sensitivity of AFB and culture of M. tuberculosis in the non bronchoscopic and bronchoscopic groups were compared. RESULTS: there were differences in the positivity level of AFB with ZN staining between non-bronchoscopic and bronchoscopic groups which were 7/40 (17.5%) vs 20/40 (50.0%) (p<0.001). The differences between the cultures of non-bronchoscopic and bronchoscopic groups were 16/40 (40.0%) vs 23/40 (57.5%) (p=0.039). Bronchoscopic sputum increased the positivity level of the ZN AFB examination by 32.5% (from 17.5% to 50.0%) as well as on culture examination by 17.5% (from 40.0% to 57.5%). CONCLUSION: Bronchoalveolar lavage can improve the positivity level of smears and cultures in patients suspected of pulmonary TB in HIV patients with CD4<200 cells/µL.