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)