R. van Crevel

Common variants at 11p13 are associated with susceptibility to tuberculosis

After imputation of data from the 1000 Genomes Project into a genome-wide dataset of Ghanaian individuals with tuberculosis and controls, we identified a resistance locus on chromosome 11p13 downstream of the WT1 gene (encoding Wilms tumor 1). The strongest signal was obtained at the rs2057178 SNP (P = 2.63 × 10−9). Replication in Gambian, Indonesian and Russian tuberculosis case-control study cohorts increased the significance level for the association with this SNP to P = 2.57 × 10−11.

Rifampicin Reduces Plasma Concentrations of Moxifloxacin in Patients with Tuberculosis

BACKGROUND The long duration of the current tuberculosis (TB) treatment is demanding and warrants the development of new drugs. Moxifloxacin shows promising results and may be combined with rifampicin to shorten the duration of TB treatment. Rifampicin induces the phase II metabolic enzymes that are involved in the biotransformation of moxifloxacin. Therefore, the interaction between rifampicin and moxifloxacin should be investigated. PATIENTS AND METHODS Nineteen Indonesian patients with pulmonary TB who were in the last month of their TB treatment completed a 1-arm, 2-period, fixed-order pharmacokinetic study. In phase 1 of the study, they received 400 mg of moxifloxacin every day for 5 days in addition to 450 mg of rifampicin and 600 mg of isoniazid 3 times per week. In phase 2 of the study, after a 1-month washout period, patients received moxifloxacin for another 5 days (without rifampicin and isoniazid). A 24-h pharmacokinetic curve for moxifloxacin was recorded on the last day of both study periods, and its pharmacokinetic parameters were evaluated for an interaction with rifampicin, using a bioequivalence approach. RESULTS Coadministration of moxifloxacin with rifampicin and isoniazid resulted in an almost uniform decrease in moxifloxacin exposure (in 18 of 19 patients). The geometric means for the ratio of phase 1 area under the curve to phase 2 area under the curve and for the ratio of phase 1 peak plasma concentration to phase 2 peak plasma concentration were 0.69 (90% confidence interval, 0.65-0.74) and 0.68 (90% confidence interval, 0.64-0.73), respectively. The median time to reach peak plasma concentration for moxifloxacin was prolonged from 1 h to 2.5 h when combined with rifampicin and isoniazid (P=.003). CONCLUSIONS Coadministration of moxifloxacin with intermittently administered rifampicin and isoniazid results in reduced moxifloxacin plasma concentrations, which is most likely the result of induced glucuronidation or sulphation by rifampicin. Further studies are warranted to evaluate the impact of the interaction on the outcome of TB treatment.

The role of interferon-gamma in the increased tuberculosis risk in type 2 diabetes mellitus

As patients with diabetes mellitus are at increased risk of developing tuberculosis, we hypothesized that this susceptibility to mycobacterial infection is due to a defective Th1-cytokine response. To explore this hypothesis, we examined four groups of subjects in Indonesia: 23 patients with tuberculosis, 34 patients with tuberculosis and diabetes, 32 patients with diabetes only and 36 healthy controls. Ex-vivo production of interferon (IFN)γ, tumour necrosis factor-α and interleukin (IL)-1β, 6, 10, -12 and -4 was measured following stimulation with Mycobacterium tuberculosis, Escherichia coli lipopolysaccharide and phytohaemagglutinin. Patients with active tuberculosis were found to have lower IFNγ levels and a higher production of other pro-inflammatory cytokines and IL-4, both in the presence and absence of diabetes. Diabetes patients without tuberculosis, however, showed strongly reduced non-specific IFNγ production, which is essential for inhibition of the initial growth of M. tuberculosis. Our data suggest that a defective non-specific immune response in diabetes may contribute to an increased susceptibility to develop tuberculosis.

Pharmacokinetics of Antituberculosis Drugs in Pulmonary Tuberculosis Patients with Type 2 Diabetes

ABSTRACT Altered pharmacokinetics of antituberculosis drugs may contribute to an increased risk of tuberculosis treatment failure for diabetic patients. We previously found that rifampin exposure was 2-fold lower in diabetic than in nondiabetic tuberculosis patients during the continuation phase of treatment. We now examined the influence of diabetes on the pharmacokinetics of antituberculosis drugs in the intensive phase of tuberculosis treatment, and we evaluated the effect of glycemic control. For this purpose, 18 diabetic and 18 gender- and body weight-matched nondiabetic tuberculosis patients were included in an Indonesian setting. Intensive pharmacokinetic sampling was performed for rifampin, pyrazinamide, and ethambutol at steady state. The bioavailability of rifampin was determined by comparing rifampin exposure after oral versus intravenous administration. Pharmacokinetic assessments were repeated for 10 diabetic tuberculosis patients after glycemic control. No differences in the areas under the concentration-time curves of the drugs in plasma from 0 to 24 h postdose (AUC0-24), the maximum concentrations of the drugs in plasma (Cmax), the times to Cmax (Tmax), and the half-lives of rifampin, pyrazinamide, and ethambutol were found between diabetic and nondiabetic tuberculosis patients in the intensive phase of tuberculosis treatment. For rifampin, oral bioavailability and metabolism were similar in diabetic and nondiabetic patients. The pharmacokinetic parameters of antituberculosis drugs were not correlated with blood glucose levels or glucose control. We conclude that diabetes does not alter the pharmacokinetics of antituberculosis drugs during the intensive phase of tuberculosis treatment. The reduced exposure to rifampin of diabetic patients in the continuation phase may be due to increased body weight and possible differences in hepatic induction. Further research is needed to determine the cause of increased tuberculosis treatment failure among diabetic patients.

Analysis of association of the TIRAP (MAL) S180L variant and tuberculosis in three populations

Reply to ”Analysis of association of the TIRAP (MAL) S180L variant and tuberculosis in three populations”

Low plasma concentrations of rifampicin in tuberculosis patients in Indonesia

SETTING Although rifampicin is a key drug in tuberculosis treatment, little is known about its quality and bioavailability in countries endemic for tuberculosis. High drug levels may lead to increased toxicity, while low drug levels may predispose to treatment failure and relapse. OBJECTIVE To investigate possible variations in the bioavailability of plasma rifampicin in tuberculosis patients in Indonesia. DESIGN Plasma concentrations of rifampicin and the rifampicin content of drug formulations in use were measured among 62 non-selected tuberculosis patients in Jakarta, Indonesia. RESULTS Plasma concentrations of rifampin were generally low: 70% of patients had 2-hour plasma concentrations (Cmax) below 4 mg/L. No toxic plasma concentrations of rifampicin (>20 mg/L) were found. The strongest predictive factor for the magnitude of rifampicin concentrations was the drug manufacturer. The rifampicin content of the different drug preparations used was normal (90.5-103.6% of the reference standard). No association was found between low plasma rifampicin concentrations and delayed sputum conversion or treatment failure. CONCLUSION The unexpectedly low plasma concentrations of rifampicin in this setting are most likely due to reduced bioavailability of local drug preparations, as the rifampicin content of the drug preparations was found to be normal. The clinical significance of these findings remains to be determined.

Toxoplasmosis after Renal Transplantation: Implications of a Missed Diagnosis

ABSTRACT We describe a renal transplant patient with a primary Toxoplasma gondii infection presenting as pneumonitis, with subsequent chorioretinitis and encephalitis. The diagnostic challenges of T. gondii infection in immunocompromised patients are discussed.

Disease-specific ex vivo stimulation of whole blood for cytokine production : applications in the study of tuberculosis

As a simple method for field studies to assess the cytokine-status of patients with tuberculosis (TB), the use of whole blood instead of isolated cells has advantages, especially since the risk of contamination is minimal. Therefore, cytokine production in whole blood cultures was determined using non-specific and disease-specific stimuli. Heparinized blood from healthy volunteers was either incubated in closed vacutainer tubes or in tissue culture wells after dilution in culture medium. Dose-response and kinetics were investigated for the production of TNFalpha, IL-1beta, IL-1ra, IL-10 and IFNgamma. Patients with TB and healthy individuals were examined for IFN-gamma production in whole blood. In the absence of a stimulus, the production of cytokines is negligible in whole blood cultures. LPS induces the production of TNFalpha, IL-1beta, IL-1ra and IL-10; PHA induces the production of IFNgamma and IL-10. Live BCG induces the production of proinflammatory cytokines, irrespective of tuberculin skin status. In contrast, PPD and MTB-culture filtrate induce production of IFNgamma in skin-test positive and not in skin-test negative healthy subjects. Five out of 13 patients with TB had a low antigen-specific IFNgamma production, suggestive of a minimal or absent specific T-cell response. For most purposes, cultures in closed vacutainer tubes are optimal. If one wishes to focus on T-cell cytokines or if only small volumes of blood are available, dilution of whole blood in culture medium before incubation in tissue culture wells may be preferable.

Functional and morphological monocyte abnormalities in a patient with malakoplakia

netic resonance images of bone marrow in vertebral bones and femora were entirely normal. Ultrasonography of the abdomen did not show any organ involvement or detectable lymphadenopathy. Endoscopic examination of the upper gastrointestinal tract did not reveal any alterations. With these results, the patient was diagnosed with primary pulmonary plasmacytoma, and the intermittent administration of melphalan and prednisolone (MP) was introduced. After six cycles of therapy, the patient became free of complaints, and there was a remarkable improvement of reticulonodular infiltrate on chest roentgenograms and a reduction of serum IgA concentrations. At the submission of this report, the patient has received 16 cycles of the MP therapy and is alive and well. Differential diagnosis in the present case should include pulmonary small lymphocytic lymphoma with plasmacytoid differentiation (6,7). However, in diffuse small lymphocytic lymphoma, tumor cells express surface immunoglobulins, mostly IgM (8), and the isotype of paraprotein detected in such patients has been reported to be exclusively IgM (7). The present case has shown a good clinical response to melphalan-based chemotherapy, which may also support the diagnosis of plasmacytoma. Our experience implies that pulmonary plasmacytoma has to be considered for differential diagnosis in patients with diffuse pulmonary infiltrates accompanied by monoclonal gammopathy.

The impact of nontuberculous mycobacteria on management of presumed pulmonary tuberculosis.

AbstractBackground: The presence of nontuberculous mycobacteria (NTM) in sputum or bronchial washings may cause diagnostic problems which affect clinical management. Patients and Methods: In a retrospective analysis of 135 patients in a Dutch tuberculosis center, patients with NTM isolates were thoroughly investigated. Colonization or contamination by NTM was differentiated from true lung disease. Results: 25 HIV-seronegative and two HIV-seropositive patients with NTM were identified. NTM were a likely cause of disease in only 14 (52%) patients. In 15 (55%), their presence led to preliminary diagnosis and treatment of tuberculosis. Unnecessary or inappropriate treatment was instituted in 17 (63%) patients with NTM. In two patients, detection of NTM in sputum also led to delay in diagnosing malignant disease. Conclusion: In this series, NTM in sputum or bronchial washings poorly reflected disease and often led to diagnostic and therapeutic errors. Although it is common knowledge that the presence of NTM should be considered in smear-positive patients, this apparently is a diagnostic pitfall in clinical practice. Reliable DNA-based techniques and better communication between physicians and microbiologists may improve management of suspected mycobacterial infections.