Isoniazid: An overview

INTRODUCTION — Isoniazid (INH) is used for treatment of tuberculosis (as part of combination therapy) or for latent tuberculosis infection (as monotherapy or part of combination therapy). Less frequently, INH may be used as part of a combination regimen for nontuberculous mycobacterial infections.

Basic issues related to clinical use of INH will be reviewed here. The clinical settings in which INH may be used are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy" and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection" and "Treatment of Mycobacterium avium complex pulmonary infection in adults".)

PHARMACOLOGY

Mechanism of action — The antimicrobial activity of INH is selective for mycobacteria, likely due to its ability to inhibit mycolic acid synthesis, which interferes with cell wall synthesis, thereby producing a bactericidal effect [1]. INH also disrupts DNA, lipid, carbohydrate, and nicotinamide adenine dinucleotide (NAD) synthesis and/or metabolism.

Spectrum of activity — INH is active against intracellular and extracellular Mycobacterium tuberculosis. The organism is considered most susceptible to INH during its logarithmic phase of growth [1]. The minimum inhibitory concentration (MIC) of M. tuberculosis for INH-susceptible isolates generally ranges from 0.03 to 0.125 mcg/mL [2]. The MICs and minimum bactericidal concentrations (MBCs) for the organism are equivalent for most isolates [1].

Of the nontuberculous mycobacteria spp, M. kansasii and M. xenopi are considered the most susceptible, while M. avium complex is generally resistant to INH.

Resistance mechanisms — Resistance to INH occurs through alteration in one of at least four pathways [3,4]:

●Loss of the katG-encoded catalase peroxidase

●Overexpression or alterations in the INH target InhA

●Loss of NADH dehydrogenase II activity (ndh)

●Alterations and overexpression of KasA

Some isolates with low-level INH resistance do not have mutations in these genes, suggesting that additional genes may be involved in INH resistance [5]. (See "Epidemiology and molecular mechanisms of drug-resistant tuberculosis".)

Newer genotypic methods to detect resistance testing have been developed to detect INH resistance more rapidly; these correlate well with slower, phenotypic methods of resistance detection [6]. However, less frequent mutations conferring resistance may evade such detection [5].

In general, drug susceptibility depends on the resistance mechanism. In one report, strains exhibiting only an InhA promoter change or a mutation at codon 315 of katG had MIC distributions of 0.25 to 2 and 4 to 16 mcg/mL, respectively, while those strains with both mutations exhibited higher MICs (8 to 64 mcg/mL) [4].

It may be possible to overcome low-level resistance to INH by increasing the INH dose [7,8]. This approach may be used for treatment of tuberculosis caused by isolates with low-level INH resistance in vitro and evidence of an inhA mutation (which is associated with low-level INH resistance) but is unlikely to be beneficial in the presence of a katG mutation (which is associated with high-level INH resistance). (See 'Dosing and administration' below.)

In the United States, drug resistance has been observed more frequently among certain patient populations. These include African-Americans, Mexican-Americans, and Indochinese refugees. In 2017, the rate of INH monoresistance among culture-positive cases was 9.2 percent and was higher among foreign-born than United States-born patients (10.7 versus 5.6 percent) [9]. In addition, the rate of INH resistance is higher among patients with a previous history of tuberculosis than among patients with no previous history of tuberculosis (19.9 versus 8.8 percent).

Primary INH resistance is more prevalent in resource-limited countries of Southeast Asia, Africa, and Latin America.

Pharmacokinetics — INH is well absorbed after oral administration (approximately 90 percent). Peak serum concentrations occurring 0.5 to 2 hours after an oral dose range from 3 to 6 mcg/mL after a 300 mg dose and from 9 to 18 mcg/mL after a 900 mg dose [10,11].

Absorption following oral therapy may be delayed or reduced by food and antacids. Limited evidence is available to suggest that patients with HIV infection may exhibit malabsorption of antituberculous agents, including INH [12].

INH is widely distributed in the body (including cerebrospinal fluid and breast milk), with a volume of distribution ranging from 0.6 to 1.2 L/kg. Protein binding is low (<10 percent).

Acetylation is the main route of INH metabolism, which is genetically determined and differs among ethnic groups. Acetylation rates can vary four- to fivefold [13]. Approximately 50 percent of White and Black individuals are rapid acetylators; in addition, 80 to 90 percent of Asian individuals and native peoples of Alaska and other Arctic regions are rapid acetylators. The elimination half-life ranges from 1 to 1.8 hours in fast acetylators to 3 to 4 hours in slow acetylators [10].

In rapid acetylators, use of once-weekly regimens has been associated with higher rates of treatment failure when standard dosing is utilized. For other treatment regimens, acetylator status does not appear to influence the clinical outcome, and testing for acetylator status at initiation of therapy is not routinely performed [14].

The major route of elimination is the kidney, with 75 to 96 percent of the dose excreted in urine as unchanged drug or metabolites. Slow acetylators excrete a higher percentage as unchanged drug compared with rapid acetylators (30 to 35 versus 10 percent) [15].

Drug interactions — Drug interactions result from the ability of INH to inhibit cytochrome (CYP) CYP2E1 (moderate) and CYP3A4 (weak). Such interactions include (but are not limited to) phenytoin, theophylline, carbamazepine, primidone, and warfarin. Details about specific interactions may be obtained by using the drug interactions program included within UpToDate.

Rare reports have been published of monoamine oxidase inhibitor-like activity resulting from the coadministration of INH with foods containing a high content of tyramine. However, the significance of such interactions and the relevance among fast versus slow acetylators remains to be determined.

Early studies suggest that absorption of INH may be reduced by concomitant administration of aluminum-containing antacids. However, this has not been supported by more recent trials [16-18].

CLINICAL USE

Dosing and administration — INH dosing is dependent upon the patient weight, age, indication, and frequency of administration. The usual adult dose of INH is 5 mg/kg orally once daily. Higher single doses (up to 15mg/kg maximum 900mg) are used for intermittent regimens, latent infections and for treatment of multidrug-resistant tuberculosis with low-level INH resistance [14,19]. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection" and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy" and "Treatment of drug-resistant pulmonary tuberculosis in adults" and "Treatment of Mycobacterium avium complex pulmonary infection in adults".)

Dosing recommendations for children vary with indication (latent infection versus active disease), frequency of administration, and patient age. (See "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis" and "Tuberculosis infection (latent tuberculosis) in children".)

Oral INH should be administered one hour before or two hours after meals. INH is available in tablet (100 and 300 mg), liquid (50 mg/5 mL), and injectable forms. The liquid formulation in the United States is available in a sorbitol base and often in combination with pyridoxine (vitamin B6). The sorbitol in this preparation may induce diarrhea, especially at higher doses. The intramuscular preparation should be administered at the same dose as oral therapy. It has been given intravenously, although it has not been approved by the US Food and Drug Administration for this route. INH is also available in combination preparations, which in the United States may include rifampin and pyrazinamide. These fixed-dose combinations may facilitate compliance but make dose individualization difficult.

The risk of peripheral neuropathy can be reduced by concomitant administration of pyridoxine (vitamin B6). (See 'Adverse reactions' below and 'Neurologic reactions' below.)

Patients with renal insufficiency do not require a reduction in INH dose; however, they may be more susceptible to development of neuropathy (see 'Neurologic reactions' below). INH is removed by both hemodialysis and continuous peritoneal dialysis. Among patients on hemodialysis, INH should be administered after the dialysis.

Patients with any risk factors for INH toxicity should be considered to have a relative or absolute contraindication to INH therapy. (See 'Hepatotoxicity' below.)

Clinical monitoring — Issues related to clinical and laboratory monitoring for patients on INH for treatment of latent tuberculosis infection are discussed separately. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection", section on 'Monitoring and adherence' and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection", section on 'Monitoring and adherence'.)

Issues related to clinical and laboratory monitoring for patients on INH and other antituberculous drugs for treatment of active tuberculosis infection are discussed separately. (See "Antituberculous drugs: An overview", section on 'Clinical and laboratory monitoring'.)

Serum concentration monitoring — The role of serum INH concentration monitoring is controversial, since serum concentrations in both adults and children receiving standard doses are variable and dependent on acetylator status (high versus low) [11]. In addition, data supporting target ranges for either efficacy or safety are sparse [20,21].

Such testing may be most useful in the setting of suspected INH malabsorption or in patients with slow culture conversion despite adherence to the treatment regimen [22]. Patients undergoing treatment for multidrug-resistant tuberculosis should be considered for serum concentration monitoring to minimize the potential for suboptimal drug exposure [14]. While select patient populations (such as those with renal dysfunction, persons living with HIV, and/or diabetes mellitus) are often included in populations prioritized for such monitoring, these conditions are less impactful on variability in INH concentrations.

Rather than a defined target concentration range, results of serum concentrations obtained two hours after a stable (1 to 2 week) dose of isoniazid can be compared to expected concentrations of 3 to 6 mcg/mL after once daily (300mg) dosing and 9 to 15 mcg/mL after higher (900mg) biweekly doses [10]. Such timing, however, may not capture the true peak concentration in those patients with delayed absorption.

Special populations

Patients with hepatic dysfunction — INH should be used with caution in patients with hepatic dysfunction since they are at increased risk of INH-induced hepatotoxicity. In patients with severe hepatic dysfunction, use of an alternative regimen is warranted.

Pregnant or breastfeeding patients — Considerations for use of INH in pregnancy are discussed separately. (See "Tuberculosis disease (active tuberculosis) in pregnancy".)

Excretion of INH in breast milk is thought to be minimal, and the risk of adverse events to the infant of a nursing mother receiving INH is generally considered to be low [23]. Pregnant women receiving INH and breastfeeding infants of mothers receiving INH should receive pyridoxine supplementation.

Adverse reactions

Neurologic reactions — INH competes with vitamin B6 (pyridoxine) in its action as a cofactor in the synthesis of synaptic neurotransmitters. Resulting dose-related neurologic side effects include peripheral neuropathy, ataxia, and paresthesia. Such side effects are uncommon in the absence of risk factors. (See "Overview of acquired peripheral neuropathies in children", section on 'Vitamin deficiency or excess'.)

Patients at increased risk for INH-induced neurotoxicity include:

●Older adults

●Pregnant or breastfeeding women

●Children

●Individuals who are malnourished

●Individuals with alcohol use disorder

●Individuals with chronic liver disease

●Individuals with renal failure

●Individuals with diabetes

●Individuals with HIV infection (most notably when receiving concomitant administration of INH with antiretrovirals that may exacerbate such effects, such as stavudine, didanosine, and zalcitabine) [24].

When prescribing or switching isoniazid or antiretroviral drugs, clinicians should consider the potential for drug interactions and consult an expert in pharmacology. They should also monitor the patients for therapeutic efficacy and/or concentration-related toxicities.

The risk of neurologic side effects can be reduced by concomitant administration of pyridoxine (vitamin B6). The usual dose is 25 to 50 mg/day (in those with one or more risk factors) [25]. Treatment of INH-induced neuropathies with pyridoxine and those with pre-existing neuropathy should be considered for higher pyridoxine doses (100 to 200 mg/day).

Hepatotoxicity — INH-induced hepatotoxicity is probably related to metabolites of INH and is not correlated with serum concentrations of the parent compound. This is most likely due to genetic polymorphisms that affect the metabolic rates of drug enzymes responsible for the production of toxic metabolites [26,27]. The onset of INH-induced hepatotoxicity is observed within the first two months of therapy in approximately 50 percent of patients.

The patient risk factors, frequency, clinical manifestations, diagnosis, and management of INH hepatotoxicity are discussed separately. (See "Isoniazid hepatotoxicity".)

Other reactions — Acute INH overdose presents with altered or depressed mental status or seizures, including status epilepticus. This is discussed further separately. (See "Isoniazid (INH) poisoning".)

INH has been associated with a variety of relatively uncommon complications; these include rheumatologic (including drug-induced lupus syndrome), dermatologic (urticarial rash), gastrointestinal (abdominal pain, nausea, vomiting), and hematologic abnormalities.

Diarrhea associated with the liquid preparation is thought to be secondary to sorbitol contained in the formulation.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Tuberculosis (Beyond the Basics)")

SUMMARY

●Isoniazid (INH) is used for treatment of tuberculosis (as part of combination therapy) or for latent tuberculosis infection (as monotherapy or part of combination therapy). Less frequently, INH may be used as part of a combination regimen for nontuberculous mycobacterial infections. (See 'Introduction' above.)

●The antimicrobial activity of INH is selective for mycobacteria, likely due to its ability to inhibit mycolic acid synthesis, which interferes with cell wall synthesis, thereby producing a bactericidal effect. (See 'Mechanism of action' above.)

●INH is well absorbed after oral administration (approximately 90 percent) and widely distributed in the body, including cerebrospinal fluid and breast milk. (See 'Pharmacokinetics' above.)

●Drug interactions result from the ability of INH to inhibit the cytochrome hepatic enzyme system. Such interactions include (but are not limited to) phenytoin, theophylline, carbamazepine, primidone, and warfarin. (See 'Drug interactions' above.)

●Dosing of INH varies with indication, patient age, and frequency of administration. (See 'Dosing and administration' above.)

●INH should be used with caution in patients with hepatic dysfunction, since they are at increased risk of INH-induced hepatotoxicity. (See 'Patients with hepatic dysfunction' above.)

●INH is generally considered safe for use in pregnant patients. Excretion in breast milk is thought to be minimal, and the risk of adverse events to the infant of a nursing mother receiving INH is generally considered to be low. Pyridoxine supplementation is recommended for pregnant women and breastfeeding infants of mothers receiving INH. (See 'Pregnant or breastfeeding patients' above.)

●INH competes with vitamin B6 (pyridoxine) in its action as a cofactor in the synthesis of synaptic neurotransmitters. Resulting dose-related neurologic side effects include peripheral neuropathy, ataxia, and paresthesia. Neurotoxicity can be prevented by pyridoxine supplementation in most patients. (See 'Neurologic reactions' above.)

●Issues related to clinical and laboratory monitoring for patients on INH are discussed separately. (See 'Clinical monitoring' above.)