Antituberculosis Chemotherapy

Tuberculosis (TB) remains one of the major infectious diseases of mankind although drugs for its treatment have been available for nearly 60 years. The standard short-course 6-month regimen used since about 1980 has helped to save millions of lives, but co-infection with HIV has had a devastating effect on the epidemic, and multidrug-resistant TB is a growing problem, particularly in communities with a high incidence of HIV. Following the declaration by the WHO in the early 1990s that TB was a ‘global health emergency’, interest in TB research and the development of new drugs has increased significantly.This volume reviews anti-TB chemotherapy with the emphasis on the actions and pharmacology of existing drugs and the development and evaluation of new agents. A close look is taken at new research regarding our existing drugs by some of the best-known specialists in the field, and historical aspects of these agents are reviewed from a modern perspective. The prospects for the introduction of new drugs and different approaches of how to assess them in adults and in children are discussed in detail. Several papers address the problems associated with drug resistance, its spread and diagnosis.Compiled by two editors from Cape Town, which has a particularly high incidence of TB and is a centre of tuberculosis research, this publication is an indispensable reference for anyone involved in the management of TB either as a researcher, clinician or administrator, and those working in drug development.

This volume deals specifically with those antituberculosis drugs which passed the preclinical phase and have been or are used in the treatment of tuberculosis and other mycobacterial diseases (except leprosy) in at least some parts of the world. Despite this restriction, there are 14 such drugs, and as a result this volume has reached rather large proportions. To prevent it from becoming even larger and more unwidely, most derivatives of antituberculotics have been omitted, especially where it is claimed that they provide only better bioavailibility or tolerability. Only in the chapter on the chemotherapy of diseases due to so-called atypical mycobacteria is the clinical use of the drugs described to a certain extent. In addition to antituberculotics, also discussed are antimicrobials which have been found to be effective against these mycobacteria. The sequence in which the drugs are described is historical, reflecting not the time of discovery but rather the first clinical application. This order was selected for reasons which are now no longer relevant. In this volume less emphasis is placed on detection, biological or synthetic production of antituberculotics, and structure-activity relationships. In contrast, emphasis is put on the degree, type, and mechanism of antimyco bacterial activity, pharmacokinetics, and biotransformation in animals and man, on experimental pharmacodynamics, and on the toxicity of antituberculotics used therapeutically.

In the global war to control tuberculosis (TB), there are several critical battles which must be waged and won if we are to make significant progress. Broadly speaking, these battlefields may be regarded as diagnosis, treatment and prevention. Within the arena of treatment are various critical elements. Current drug regimens require 6 months to achieve predictable cures; it is essential that shorter regimens be developed to lessen non-adherence and to improve affordability. To facilitate directly-observed therapy, intermittent (less than daily) regimens have been employed. To ensure favourable outcomes, including patients with AIDS, thrice-weekly regimens are the current standard; reducing the frequency of dosing to twice- or once-weekly may offer significant advantages. Drug resistance to the current major medications, the rifamycins and isoniazid, threatens to make tuberculosis untreatable for rising numbers of patients in many regions of the world. Finding new, effective agents is essential to ensure cures for these cases and to halt transmission of multidrug-resistant tuberculosis to others. Additional issues include reducing the side effects and toxicity of anti-tuberculosis regimens and developing regimens that can be given simultaneously with anti-retroviral therapy without deleterious drug-drug interactions or unacceptable toxicity. Finally, attention must be directed to the potential utility of treating latent infection to prevent the evolution of active disease. The current vaccine Bacille Calmette-Guerin (BCG), while protecting infants and children against potentially lethal forms of TB, has done little to control the incidence of communicable adult pulmonary disease. Research is underway to develop improved vaccines, but due to the prolonged period to determine the efficacy of a TB vaccine (a minimum of 10 to 20 years) -- alternative strategies must be pursued. Furthermore, the utility of a traditional vaccine would be sorely limited by the fact that roughly two billion persons today harbour latent tuberculosis infection. This huge reservoir of future disease would not be eligible for a traditional pre-infection vaccine. "Preventive therapy" with isoniazid has been shown to reduce the subsequent risk of tuberculosis by about 70% in large, randomised placebo-controlled clinical trials. However, this strategy is limited by the requirement for extended duration of treatment (6 to 9 months), the risks of drug-induced hepatitis and rising rates of resistance to isoniazid in many regions of the world where the TB epidemic is most intense. Alternative means for the treatment of latent tuberculosis infection should be given high priority. The authors have assembled an outstanding panel of contributors to address these issues. The topics herein have great relevance both in the industrialised nations where contemporary medications and strategies appear to have exacted their maximum benefits and for the developing nations where this ancient scourge remains rampant. This book will provide an impetus for authorities and organisations devoted to the development of new drugs to address the aforementioned growing problems of TB world-wide.

This volume represents the first comprehensive review of the preclinical evaluation of all 14 antituberculosis drugs which have come into clinical use from the beginnings of antituberculosis chemotherapy to the present. The following topics are dealt with exhaustively for each drug: chemical properties; experimental activity in vitro in cells, and in animals; type and mechanism of action; experimental pharmacology and toxicology; and pharmacokinetics in animals and man. The experimental aspects of the combined use of antituberculotics, which is essential for the success of treatment in human tuberculosis, are described in full. A special chapter is devoted to the use of antituberculotics and other antimicrobial agents in the experimental and clinical chemotherapy of mycobacterioses due to socalled atypical mycobacteria.

Mycobacteria is divided into two volumes. The first volume deals with the basic biology of mycobacteria. With its emphasis on the state of the art outlook, this volume includes taxonomy and molecular biology of mycobacteria, modern approaches for detection of mycobacteria, and immunology and immunization against tuberculosis. The second volume covers drug trestments for mycobacteria anad tuberculosis. It outlines trends of discovery and development of chemotherapy, starting from the mid-50's to present day uses of chemotherapy in treating AIDS, drug-resistant tuberculosis, and other non-tuberculosis mycobacterial diseases.

Infectious diseases are the leading cause of death globally, particularly among children and young adults. The spread of new pathogens and the threat of antimicrobial resistance pose particular challenges in combating these diseases. Major Infectious Diseases identifies feasible, cost-effective packages of interventions and strategies across delivery platforms to prevent and treat HIV/AIDS, other sexually transmitted infections, tuberculosis, malaria, adult febrile illness, viral hepatitis, and neglected tropical diseases. The volume emphasizes the need to effectively address emerging antimicrobial resistance, strengthen health systems, and increase access to care. The attainable goals are to reduce incidence, develop innovative approaches, and optimize existing tools in resource-constrained settings.