Perspectives for personalized therapy for patients with multidrug‐resistant tuberculosis

Abstract

According to the World Health Organization (WHO), tuberculosis is the leading cause of death attributed to a single microbial pathogen worldwide. In addition to the large number of patients affected by tuberculosis, the emergence of Mycobacterium tuberculosis drug-resistance is complicating tuberculosis control in many high-burden countries. During the past 5 years, the global number of patients identified with multidrug-resistant tuberculosis (MDR-TB), defined as bacillary resistance at least against rifampicin and isoniazid, the two most active drugs in a treatment regimen, has increased by more than 20% annually. Today we experience a historical peak in the number of patients affected by MDR-TB. The management of MDR-TB is characterized by delayed diagnosis, uncertainty of the extent of bacillary drug-resistance, imprecise standardized drug regimens and dosages, very long duration of therapy and high frequency of adverse events which all translate into a poor prognosis for many of the affected patients. Major scientific and technological advances in recent years provide new perspectives through treatment regimens tailor-made to individual needs. Where available, such personalized treatment has major implications on the treatment outcomes of patients with MDR-TB. The challenge now is to bring these adances to those patients that need them most.

Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation

“…There are approximately 500,000 new MDR-TB cases per year and the treatment success rates for MDR-TB is currently 55% compared to 85% for drug-susceptible TB [1]. MDR-TB treatment is associated with costly therapy by second-line drugs for longer periods, sometimes up to two years, which is accompanied with more complex side-effects [10]. In addition, extensively drug-resistant-TB (XDR-TB) is the most severe form that has a global treatment success rate of 30%, leading to high mortality and morbidity, especially in TB/HIV co-infected patients [11].…”

Current research toward optimizing dosing of first-line antituberculosis treatment

“…For some antituberculosis drugs, dose adjustments are indicated in patients with renal or hepatic impairment. Therapeutic drug concentration monitoring may have a role in some settings and is reviewed elsewhere as part of the approach to personalized therapy for DR-TB [28,29]. These topics are not included in this review.…”

Towards individualised treatment of tuberculosis

“…As this is a major pitfall detection of resistance mutations by gDST can elucidate whether isolates with MIC below but close to the critical concentration are wild-type or not i.e. the gDST result may overrule pDST (59,92).…”

“…Furthermore, opinions vary regarding the utility and cost-benefit of TDM (139)(140)(141). Despite knowledge gaps, experts in the field promote the use of TDM for TB and guidelines and reviews have also acknowledged this, but not routinely for all patients (92,108,141,142). Presently, therapeutic drug monitoring is mainly used in high-resource settings in case of therapy failure, MDR/XDR-TB or severe adverse drug reactions.…”

“…Until a universal reference method for pDST has been established and breakpoints properly revised, it is advisable in difficult cases with complicated resistance to use pDST in combination with gDST because of the influence of the inherent technical variability of pDST. Further, a reliable standardised pDST is needed to draw the map of genotype-phenotype correlations by gathering data on the phenotypic profiles of the different drug resistance mutations, as well as for resistance screening of new drugs entering the market (92). Hopefully in the future, WGS will have the ability to relate all resistance mutations of TB drugs to phenotypic susceptibility, enabling early design of an adequate treatment regimen and correct dose prescriptions.…”