Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes

Annals of Clinical Microbiology and Antimicrobials, Oct 2017

Tuberculosis (TB) is considered as one of the most serious threats to public health in many parts of the world. The threat is even more severe in the developing countries where there is a lack of advanced medical amenities and contemporary anti-TB drugs. In such situations, dosage optimization of existing medication regimens seems to be the only viable option. Therapeutic drug monitoring study results suggest that high-dose treatment regimens can compensate the low serum concentration of anti-TB drugs and shorten the therapy duration. The article presents a critical review on the possible changes that occur in the host and the pathogen upon the administration of standard and high-dose regimens. Some of the most common factors that are responsible for low anti-TB drug concentrations in the serum are differences in hosts’ body weight, metabolic processing of the drug, malabsorption and/or drug–drug interaction. Furthermore, failure to reach the cavitary pulmonary and extrapulmonary tissues also contributes to the therapeutic inefficiency of the drugs. In such conditions, administration of higher doses can help in compensating the pathogenic outcomes of enhancement of the pathogen’s physical barriers, efflux pumps and genetic mutations. The present article also presents a summary of the recorded treatment outcomes of clinical trials that were conducted to test the efficacy of administration of high dose of anti-tuberculosis drugs. This review will help physicians across the globe to understand the underlying pathophysiological changes (including side effects) that dictate the clinical outcomes in patients administered with standard and/or high dose anti-TB drugs.

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Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes

Xu et al. Ann Clin Microbiol Antimicrob Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes Yuhui Xu 2 Jianan Wu 0 1 Sha Liao 0 1 Zhaogang Sun 0 1 0 National Tuberculosis Clinical Laboratory, Beijing Chest Hospital, Capital Medical University , 9 Beiguan Street, Tongzhou District, Beijing 101149 , China 1 Beijing Key Laboratory in Drug Resistant Tuberculosis Research, Beijing Tuberculosis & Thoracic Tumor Research Institute , Beijing 101149 , China 2 Institute of Chinese Materia Medica, China Academy of Chinese Medical Science , Beijing 100700 , China Tuberculosis (TB) is considered as one of the most serious threats to public health in many parts of the world. The threat is even more severe in the developing countries where there is a lack of advanced medical amenities and contemporary anti-TB drugs. In such situations, dosage optimization of existing medication regimens seems to be the only viable option. Therapeutic drug monitoring study results suggest that high-dose treatment regimens can compensate the low serum concentration of anti-TB drugs and shorten the therapy duration. The article presents a critical review on the possible changes that occur in the host and the pathogen upon the administration of standard and high-dose regimens. Some of the most common factors that are responsible for low anti-TB drug concentrations in the serum are differences in hosts' body weight, metabolic processing of the drug, malabsorption and/or drug-drug interaction. Furthermore, failure to reach the cavitary pulmonary and extrapulmonary tissues also contributes to the therapeutic inefficiency of the drugs. In such conditions, administration of higher doses can help in compensating the pathogenic outcomes of enhancement of the pathogen's physical barriers, efflux pumps and genetic mutations. The present article also presents a summary of the recorded treatment outcomes of clinical trials that were conducted to test the efficacy of administration of high dose of anti-tuberculosis drugs. This review will help physicians across the globe to understand the underlying pathophysiological changes (including side effects) that dictate the clinical outcomes in patients administered with standard and/or high dose anti-TB drugs. Tuberculosis; Treatment; Anti-TB drugs; High dosage Background Tuberculosis is a highly contagious disease caused due to Mycobacterium tuberculosis infection. Though the methods of treatment of the disease have been standardized since long, many people, especially in the developing countries, still succumb to it. According to recent statistical figures published by the World Health Organization (WHO) [ 1 ], 10.4 million new cases of TB were reported worldwide in the year 2015 alone. It was also observed that while 1.4 million died of the disease in the same year, an estimated 480,000 were diagnosed with multidrugresistant TB [MDR-TB, defined as resistant to at least isoniazid (INH) and rifampin (RFP)] and an additional 100,000 with rifampicin-resistant TB (RR-TB). Since the standard treatment regimens are ineffective in the treatment of such patients, they were compelled to undertake the MDR-TB specific treatment. Hence, it is proposed that the advent and worldwide distribution of new antiTB drugs (MDR-TB drugs) is indispensable for winning the war against TB on a global level. Interestingly, it was observed that over 95% of the total number of TB associated fatality cases recorded in 2015 occurred in low- and middle-income countries. This points towards the need of improving the standards of medical care and accessibility to traditional as well as contemporary (MDR) antiTB drugs, which can be achieved by lowering the prices and maintaining consistent supplies. However, the process of development of new (MDR) anti-TB drugs that has improved efficacy and safety is still under experimentation. The only option to control the situation presently is to devise new methods that can help in deriving maximum benefits from traditionally available therapeutic agents. Dosage optimization of existing medication regimens is one such method that can improve the efficacy of the anti-TB drugs. The required drug concentrations of a highly effective TB therapy have already been reviewed and written into the guidelines by the WHO [ 2–4 ]. The most currently accepted norms for determining the dosage of anti-TB drugs are based on the recommendations made by WHOM [ 4 ]. Table  1 presents the summary of the recommended drug concentrations for TB treatment as given in the WHO guidelines. Though the regimens recommended based on these values are sometimes considered lengthy and complex, yet they are found to be highly effective in most of the cases [ 2 ]. However, the percentage of success of such anti-TB drug based therapies vary from country to country and is most often determined by the severity of the disease at the time of diagnosis. Furthermore, it has also been observed that the r (...truncated)


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Yuhui Xu, Jianan Wu, Sha Liao, Zhaogang Sun. Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes, Annals of Clinical Microbiology and Antimicrobials, 2017, pp. 67, DOI: 10.1186/s12941-017-0239-4