http://repub.eur.nl/res/aut/39610/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/39717/ 2013-03-01T00:00:00Z Relapse of tuberculosis (TB) is defined as re-emergence of clinical symptoms after stopping anti-TB treatment, while this treatment appeared effective initially. Relapse of TB can occur in patients that are therapy-compliant, but the risk of relapse is dramatically increased when patients are non-compliant. Additionally, the probability of antibiotic resistance is higher in those patients who have a relapse of TB and thus longer treatment is recommended. Further insight in the pathogenesis of relapsing TB could provide a basis for future treatment improvement. In the present study, using a murine TB model, we assessed the differences between primary TB and relapse of TB in terms of mycobacterial load in infected organs, (immuno-) histopathology, and plasma cytokine concentrations. Compared to primary TB, in relapse of TB we observed a lower mycobacterial load in lung, spleen and liver at the phase of established infection. Also the levels of TNF-α, IFN-γ, IL-6, MIG/CXCL9, IP-10/CXCL10 and IL-17 were significantly lower. It was observed that in relapse of TB memory Th-1 cells were locally and systemically expanded and congregated in the lung, permitting an efficient control of Mtb growth. Treatment response in relapse of TB is as good as the treatment response in primary TB; thereby no supportive evidence could be given for the recommended longer treatment duration in case of relapse of TB. http://repub.eur.nl/res/pub/40017/ 2013-03-01T00:00:00Z http://repub.eur.nl/res/pub/37932/ 2012-11-16T00:00:00Z Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is still a global health problem of immense proportion. Indeed, TB is considered the second most frequent cause of infectious disease-related death worldwide (after HIV-AIDS). The World Health Organization (WHO) is increasing its efforts to reduce the global threat of TB. Nevertheless, the morbidity and mortality statistics for TB remain shocking. For example, the WHO estimates that the global burden of disease caused by TB in 2010 comprised 8.8 million incident cases, including 1.1 million deaths from TB among HIV-negative individuals, and an additional 0.35 million deaths from HIV-associated TB.1 Additional to these impressive figures is the underlying problem of latent TB infections, with as many as one-third of the world’s population being thought to be latently infected with this bacterium, an immense pool of potential patients around. Further, all current treatment programs tend to be specifically aimed towards the treatment of active TB infection, leaving the huge underlying problem of latent TB infections untouched, essentially meaning that the worldwide elimination of TB is still a distant dream. http://repub.eur.nl/res/pub/30710/ 2011-10-07T00:00:00Z There are limitations on diagnostic methods to differentiate between active and latent tuberculosis (TB), and the prediction of latent progression to TB disease is yet complex. Traditionally, tuberculosis-specific host immune response was visualized using the tuberculin skin test. Nowadays, IFN-γ release assays (IGRA) provide a more specific and sensitive tool, by which exposure to Mtb could be determined. However, the merit of IGRA aids in diagnosing active TB is yet unclear. We adapted IGRA for use in mice, and quantifying bead-based flow cytometry techniques were used to assess cytokine profiles during the course of untreated infection and to investigate the value of IGRA and cytokines as biomarkers for therapy response. High variability of IGRA results during progression of active TB infection related to various phases of infection was obtained. However, a significant decrease in IGRA results and in levels of IFN-γ, IL-17, IP-10 or MIG was observed and appeared to be associated with successful therapy. This outcome does not support the value of IGRA to accurately diagnose active TB or to monitor infection progression. However, IGRA proved to be a useful biomarker to monitor therapy success. In addition, different cytokines might serve as biomarkers. http://repub.eur.nl/res/pub/27914/ 2010-12-01T00:00:00Z Objectives: The pharmacodynamics of tuberculosis (TB) treatment should be further explored, to prevent emergence of resistance, treatment failure and relapse of infection. The diagnostic drug susceptibility tests guiding TB therapy investigate metabolically active Mycobacterium tuberculosis (Mtb) isolates under static conditions and as such are not informative with respect to the time-kill kinetics of anti-TB drugs and the emergence of resistance in metabolically lowly active or even dormant mycobacterial cells. Methods: In vitro, the killing capacity of rifampicin, isoniazid, ethambutol and amikacin regarding the degree of killing, killing rate and selection of resistant mutants was investigated in metabolically highly active versus metabolically lowly active Mtb cells. Results: Isoniazid showed rapid and high killing capacity towards highly active mycobacteria, but due to the emergence of resistance could not eliminate the Mtb. Efflux pump-mediated isoniazid resistance was predominant. Rifampicin revealed a relatively slow and time-dependent killing capacity, but achieved elimination of all mycobacteria. Ethambutol was not bactericidal. Amikacin showed a high and extremely rapid killing activity that was not time dependent and could eliminate all mycobacteria. Exposure of lowly active Mtb populations to isoniazid, rifampicin or amikacin led to the emergence of resistant mutants. Compared with the highly active mycobacteria, elimination of the susceptible lowly active mycobacteria required a 64-fold increased isoniazid concentration and a 4-fold increased rifampicin concentration, whereas amikacin was equally effective irrespective of the metabolic state of the mycobacteria. Conclusions: The anti-TB drugs differ significantly regarding their time-kill kinetics. In addition, the metabolic state of Mtb significantly affects its susceptibility to antimicrobials, with the exception of amikacin. Optimization of dosage of anti-TB drugs is required to achieve maximum drug concentrations at the site of infection in order to maximize reduction in Mtb load and to minimize the emergence and selection of resistance. http://repub.eur.nl/res/pub/28985/ 2008-05-01T00:00:00Z A 5-month-old girl was diagnosed with tuberculosis, mimicking ileocecal intussusception. The mother of the patient was later diagnosed with renal tuberculosis attributable to the same (unique) Mycobacterium tuberculosis strain. Possibly, that transmission occurred by aspiration or ingestion of infected amniotic fluid or urine, which could occur before or during birth. This case illustrates that tuberculosis can mimic other common diseases and, therefore, can be a difficult diagnosis to make. Because respiratory infection was very unlikely in this case, congenital tuberculosis or postnatal infection via infected urine or breast milk should be in the differential diagnosis. In this article, we focus on different (nonrespiratory) transmission routes of Mycobacterium tuberculosis and give a short review of the recent literature on congenital tuberculosis. Copyright http://repub.eur.nl/res/pub/36005/ 2007-11-01T00:00:00Z Objectives: Improvement of the efficacy of drug treatment in mycobacterial infection by the development and application of targeted drug delivery. Methods: In disseminated Mycobacterium avium infection in mice, the relative efficacy of the antimycobacterial agents that are currently used in combination therapy was investigated. Next, the effect of the addition of targeted delivery of amikacin to the infected tissues in the initial phase of treatment was studied. Amikacin was chosen because of its unique rapid and high mycobacterial killing capacity. As drug delivery tool, long-circulating sterically stabilized liposomes were used. Results: Treatment with clarithromycin alone daily (6 days aweek) slowly killed most of the mycobacteria in the lung, liver, spleen, inguinal and mesenterial lymph nodes. However, after 24 weeks of treatment, persistence of substantial numbers of mycobacteria in the infected organs was observed. The addition of ethambutol to the clarithromycin regimen did not significantly enhance the efficacy of treatment, neither did rifampicin as a third agent. In contrast, the addition of liposomal amikacin in the initial phase of therapy resulted in rapid and complete elimination of the mycobacteria in all infected organs within 12 weeks of treatment without relapse of infection. As a result, total treatment duration could be significantly reduced to 12 weeks. Conclusions: In M. avium infection in mice, the approach of targeted drug delivery was successful. The rapid decrease in the mycobacterial load followed by complete killing, including the persistent mycobacteria considered responsible for relapse of infection, allows a significant reduction of the total treatment duration.