Current Pharmaceutical Design - Volume 17, Issue 27, 2011

Treatment options for Tuberculosis (TB) have increased and knowledge has greatly increased in the past decades. To reduce the burden of TB, it's the intention to expand and enhance DOTS, to tackle TB/HIV and MDR -TB, empower health care systems, create political commitment and inspire health care providers and investigators. Yet new efforts are required to fight the new challenges and threats of multidrug-resistant and extensively drug-resistant TB. Two different approaches are necessary. First, the development and further testing of novel compounds and shorter treatment regimens; and second the optimization of treatment with currently available drugs. Early diagnosis, drug susceptibility testing and choosing the appropriate drugs are likely to contribute to the reduction and spread of TB. In this issue of the Journal we have selected several important aspects of the treatment of TB with an emphasis on optimization of currently available antimicrobial treatment. Van Altena and co-authors provide an update on the current concepts of local and systemic immune response to Mycobacterium tuberculosis, and focus on potentially modifiable factors - i.e., the micro-nutrients iron, and vitamin D. Along with drug treatment optimizing these may have a beneficial effect on the outcome of TB treatment. As emphasized by the WHO drug susceptibility testing is important to select the appropriate drug and appropriate dosage. New rapid testing can distinguish between drug susceptible and drug resistant TB and therefore guide the initial treatment. Simons and van Soolingen discuss the advantages of the recently developed methods - notably, molecular techniques, but also address important points like bio-safety, reproducibility and quality control. Finally they place drug sensitivity testing in a broader perspective of pharmacokinetics and pharmacodynamics of TB drugs and its potential use to tailor TB treatment and have an impact on global TB treatment strategies. Although the potential role of FDG PET in the routine diagnosis of tuberculosis is limited, Kosterink showed that especially FDG PET, as diagnostic tool, could be a noninvasive method that gives additional information about the disease status. These data can be of use to improve TB treatment. Besides, PET imaging could be useful in the evaluation of antimicrobial drugs for the treatment of TB as its enables to study bio-distribution and, tissue or TB lesions penetration or targeting. In vitro and in vivo modeling of TB drugs has increased our knowledge on how to optimize the use of TB drugs considerably. Integrating both pharmacokinetics and pharmacodynamics in in vitro and in vivo models made it possible to detect the correlation between drug exposure and killing of the TB bacteria. Srivastava and Gumbo discuss studies using static and dynamic models and their use to design and optimize dosage regimens. More importantly, they also discuss the translation of these optimized regimens into clinical practice. Population pharmacokinetics has been used to identify and explain variability among patients. As TB patients fail on current treatment regimens important parameters may be identified that can be related to the safety and efficacy of TB drugs. Egelund and colleagues give a clear introduction on population pharmacokinetics and compartmental modelling. They discuss the different studies that support the hypothesis that the current dosage of several TB drugs may be too low. While these studies investigated only mono therapy, the authors emphasize that combination regimens are used in daily practice and new studies are urgently needed to investigate the effect of combined antimicrobial treatment. Finally, the new dosage regimens based on population pharmacokinetics and simulations have to be evaluated in prospective clinical studies to assess their added value and superiority over the current treatment.....

Humans have always lived with tubercle bacilli. Host susceptibility - both inherited and acquired - determines whether an individual infected with Mycobacterium tuberculosis will eventually fall ill and develop tuberculosis (TB). After infection with M. tuberculosis, a latent TB infection may ensue reflected by immune recognition of specific antigenic epitopes expressed by M. tuberculosis - the Region of Difference 1 proteins ESAT-6 and CFP-10 leading to interferon gamma release in vitro. Multi-Drug-Resistant TB has emerged as an enormous infectious threat in certain regions in the world, and the Acquired immunodeficiency by co-infection with HIV has accelerated the TB epidemic even further. A paradoxical response - or Immune Response Inflammatory Syndrome in the context of treatment of HIV co-infection - is an increased inflammatory reaction during effective reduction in the bacterial load. This should be differentiated from treatment failure. A huge challenge is to develop novel markers that can differentiate paradoxical responses from treatment failure. We discuss the role of protection of vaccines - especially BCG, iron metabolism and the role of vitamin D.

The principles of our current drug susceptibility testing (DST) for tuberculosis (TB) have already been laid out in 1963. Since then, DST has not gained much popularity owing to the long turn-around time and the introduction of potent antituberculosis drug regimens. These and other barriers have led to a critical gap in laboratory capacity in DST of Mycobacterium tuberculosis. However, owing to the emergence of multidrug resistant tuberculosis there is a pressing need for adequate and rapid DST. In recent years, methods for fastening the diagnosis of drug resistant tuberculosis have been developed. Semi-automated (non)- radiometric liquid culture systems reduced the turn-around-time significantly. With the introduction of molecular diagnostic methods, such as reverse line probes and the recently introduced semi-automated real-time PCR, the turn-around time of at least an indicative resistance testing has dropped from days to hours. However, much more can be gained in the development of fast phenotypic and molecular DST methodologies. Recently also pharmacodynamic studies have also added significantly to our understanding of resistance development in tuberculosis treatment. This article provides an overview of the most important DST techniques now available, with their characteristics, biosafety aspects, reproducibility and required quality control. Also the findings in pharmacodynamic studies and required future research are discussed. We will argue that drug susceptibility testing in TB treatment is an essential tool for adequate TB control and prevention of resistance and should be applied to all patients to guide TB treatment. Perhaps in the near future even individualized treatment doses could be an important help to prevent further emergence or further development of resistance.

Early diagnosis of TB is essential for community health and infection control, as well as for starting appropriate therapy for patients. Early detection of MDR is essential for the same reasons, plus the fact that currently a very high percentage of MDR patients die, especially in developing countries. Both genotypic and phenotypic methods allowing assessment of MDR tuberculosis on the bacilli isolated from fluids of infected patients are available, but these tests are lengthy (6-16 weeks) and require infected body fluids, which are not always easily assessable. Patients presenting pulmonary TB can also be culture-negative. Diagnosis of active disease in a pulmonary tuberculoma has long been problematic because the non-specific character of the disease, its changing manifestations and the slow growth of the organisms make its isolation a long and time-consuming process. Determination of pulmonary tuberculoma activity may be mandatory for optimal treatment strategy, therefore imaging techniques may be helpful in early detection. The aim of this review is to assess the role of Positron Emission Tomography (PET) imaging in the diagnosis and therapy management of TB. Although studies and data on the potential role of FDG PET in the diagnosis of tuberculosis are limited, a literature search revealed some interesting studies on this subject. Most of the studies described indicate that PET imaging, especially FDG PET as diagnostic tool, could be a noninvasive method that gives additional information about the disease status, enabling improved therapeutic management of pulmonary mycobacterial infection. Furthermore, several studies provide evidence that PET imaging could be useful in tuberculostatic therapy evaluation.

It has become increasingly clear that anti-tuberculosis regimens need optimization. Information gained using pharmacokinetics/ pharmacodynamics (PK/PD) methods in hollow fiber and animal model studies, in conjunction with Monte Carlo simulations, can be used to achieve this goal. PK/PD models of anti-tuberculosis drugs in hollow fibers, mice and guinea pigs have been remarkably concordant. Using exposures derived in these models it has been shown that the standard doses of pyrazinamide, rifampin, and ethambutol should be increased for a better efficacy, while doses of isoniazid need to be individualized. In addition, PK/PD driven doses have been proposed for new anti-tuberculosis agents such as moxifloxacin and PA-824.

Tuberculosis (TB) has survived for millennia due to its unique physiochemical properties and its ability to persist in a “dormant” state. Because of these unique properties, the treatment of TB involves multiple drugs for half of a year or longer. Although the incidence of TB has declined in most developing countries, it remains poorly controlled in much of the developing world. This is partly driven by co-infection with HIV in these settings. Concern about this dual epidemic has renewed interest in anti-tuberculosis drugs, and this in turn has led to increasing amounts of pharmacokinetic data regarding TB drugs. Population pharmacokinetics has proven useful for many disease states, providing a valuable tool with which to explore data and predict future events. It not only generates pharmacokinetic parameter estimates, but it includes patient characteristics (covariates) that may alter those parameters. We review the population pharmacokinetic studies undertaken with anti-TB medications. In addition to the primary medications used in TB treatment (rifampin, isoniazid, pyrazinamide, and ethambutol) we discuss the fluoroquinolones, various software packages, and the covariates that were found to be significant in each study.

Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-administered agents on these characteristics, for the currently used FQs (ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and moxifloxacin) in TB treatment. Future FQs that are being developed may overcome the problems with FQs that are used in daily practice. Therefore PK and pharmacodynamic (PD) properties of novel FQs (clinafloxacin, garenoxacin, lomefloxacin, sitafloxacin, sparfloxacin, trovafloxacin, gemifloxacin, grepafloxacin and DC-159a) were evaluated in TB treatment as well. Integrating both excellent PK and PD properties, moxifloxacin, possibly at a higher dosage, may fulfil a far more important role in the treatment of multi-drug and early-generation FQ resistant TB than proposed in the current WHO guideline. Sparfloxacin, trovafloxacin and sitafloxacin are upcoming novel FQs that may be useful for drug-resistant TB based on their favourable PK properties or microbiological susceptibility against M. tuberculosis. Finally, the 8-methoxy moiety, as present in the chemical structure of MFX, will possibly provide DC- 159a with promising PK/PD characteristics and consequently this FQ may develop into a key FQ in future drug resistant TB treatment.

Tuberculosis (TB) is a high-burden infectious disease, especially in low and middle-income countries. The efforts to eliminate this disease are challenged by the emergence of multidrug resistance and TB-HIV coinfection. The cumulative knowledge on pharmacokinetics/ pharmacodynamics of antituberculosis agents has recently encouraged therapeutic drug monitoring (TDM) in patient care. However, logistical problems related to conventional sampling limit the application of TDM in research-oriented institutions. Dried blood spot (DBS) compared with conventional venous blood sampling has the advantages of easier sampling, storage and transportation, thus enabling the application of TDM even in remote areas. In addition, DBS with its lower biohazardous risk can be safely performed in a high HIV prevalence area, which also tends to have a high TB burden. Another benefit of DBS sampling is that it requires a smaller blood volume than conventional sampling and is highly recommended for application in pediatric TB. A limitation of DBS is that additional considerations are required for analysis method development and validation. The accuracy of the DBS method is influenced by a number of factors that need to be thoroughly examined in method development and validation. Further, the agreement between DBS and plasma/serum concentrations is not always understood and further investigations are required.

Tuberculosis (TB) with central nervous system (CNS) manifestation is a form of TB with a high mortality and morbidity. Tuberculous meningitis (TM) is the most common form of CNS-TB. Although diagnosis of CNS-TB can be challenging, early treatment of CNS-TB is related to a better outcome. If CNS-TB is suspected, even though the clinical picture is not specific, it should be immediately treated. For the treatment of CNS-TB, knowledge of the penetration across the blood-brain barrier of the various antituberculosis agents used in TB treatment is important. These will be described here in order to serve as a guide in choosing a treatment for CNS-TB. Corticosteroids have an evidence-based value in the treatment of TM and so are recommended. As for thalidomide use in CNS-TB, sound evidence is still lacking. We will also include a description of the adverse neurotoxic effects of the various other agents including their psychiatric, ototoxic and ophthalmic adverse effects.