Background: The first-line TB antibiotic isoniazid (INH) serves as a central component of combined
first-line anti-tuberculosis drug therapy. However, resistance to INH has hindered the functioning of this drug. Resistance
is caused by several known and unknown mutations in genes/regions in Mycobacterium tuberculosis (M.
tuberculosis), followed by selection of these mutants in the presence of the drug. INH resistance can be categorised
as either “high-level” (minimum inhibitory concentration (MIC) of > 1µg/mL to INH) or “low-level” (MIC between
0.1-1.0 µg/L) resistance and is dependent on the specific mutation acquired. The level of resistance is relevant, as
INH resistance is often considered to be the first step in development of Multi-Drug Resistant (MDR) and extremely
resistant (XDR) TB. Isoniazid is a pro-drug in which first pass metabolism happens via N-acetyltransferase and is
fast, intermediate or slow, depending on the genetics of the host. Thus, low-level INH resistance, particularly in the
presence of fast metabolism, could allow additional mutations, development of high-level resistance and progression
to multi-drug resistance.
Methods: A structured search of bibliographic databases for peer-reviewed research literature was performed. Set
parameters and specific inclusion criteria were used to filter the literature, based on our specified review questions.
The quality and relevance of included papers was deduced using standard tools. The relevant content of cited papers
was described, and an inferential qualitative content analysis methodology was utilised to analyse the inferences and
findings of included studies using a conceptual framework.
Results: Seventy-eight papers were included in the review, of which a sub-set (36) of the papers describe how different
genetic mutations result in low or high-level resistance to INH. These papers were also used to set up a diagram
detailing how each mutation affects INH functionality in order to visualise the interactome of INH and
M.tuberculosis A further twenty-eight out of the seventy-eight papers detail the methods for testing for INH resistance,
current treatment regimens and factors that influence treatment outcome in order to better understand the role
of INH within the current anti-tuberculosis treatment therapy and how its use can be optimised.
Conclusion: The findings of this review suggest that low-level INH resistance, in the presence of fast-acetylation, is
an underrated component of the global TB epidemic worldwide, and may be a significant problem in terms of treatment
outcome and progression to antibiotic resistance. Thus, more research must be done to test whether personalised
diagnostics and targeted high dose treatment with INH will reduce the incidence of isoniazid mono-resistant and
multi-drug resistant (MDR) tuberculosis.