Other products of KatG activation of INH include superoxide, H2O2, alkyl hydroperoxides, and the NO radical, which may also contribute to the mycobactericidal effects of INH (Timmins and Deretic, 2006). M. tuberculosis could be especially sensitive to damage from these radicals because the bacilli have a defect in the central regulator of the oxidative stress response, oxyR. Backup defense against radicals is provided by alkyl hydroperoxide reductase (encoded by ahpC), which detoxifies organic peroxides. Increased expression of ahpC reduces isoniazid effectiveness.
Antibacterial Activity. The isoniazid MICs with clinical M. tuberculosis strains vary from country to country. In the U.S., e.g., the MICs are 0.025-0.05 mg/L (Heifets, 1991). Activity against M. bovis and M. kansasii is moderate. Isoniazid has poor activity against MAC. It has no activity against any other microbial genus.
Mechanisms of Resistance. The prevalence of drug-resistant mutants is ~1 in 106 bacilli. Because TB cavities may contain as many as 107 to 109 microorganisms, preexistent resistance can be expected in pulmonary TB cavities of untreated patients. These spontaneous mutants can be selected by monotherapy; indeed, strains resistant to isoniazid will be selected and amplified by isoniazid monotherapy. Thus two or more agents are usually used. Because the mutations resulting in drug resistance are independent events, the probability of resistance to two antimycobacterial agents is small, ~1 in 1012 (1 × 106 × 106), a low probability considering the number of bacilli involved.
Resistance to INH is associated with mutation or deletion of katG, overexpression of the genes for inhA (confers low-level resistance to INH and some cross-resistance to ethionamide), and ahpC and mutations in the kasA and katG genes. KatG mutants exhibit a high level of resistance to isoniazid (Zhang and Yew, 2009). The most common mechanism of isoniazid resistance in clinical isolates is due to single point mutations in the heme binding catalytic domain of KatG, especially a serine to asparagine change at position 315. Although isolates with this mutation completely lose the ability to form nicotinoyl-NAD+/NADP+ adducts, they retain good catalase activity and maintain good biofitness. Compensatory mutations in the ahpC promoter occur and increase survival of katG mutant strains under oxidative stress.
KatG 315 mutants have a high probability of co-occurrence with ethambutol resistance (Hazbón et al., 2006; Parsons et al., 2005). Mutations in katG, ahpC, and inhA have also been associated with rpoB mutations (Hazbón et al., 2006). This suggests that mutations at different loci associated with resistance to different drugs may somehow interact to make multiple drug resistance more likely. In the laboratory, efflux pump induction by isoniazid has been demonstrated, and it also confers resistance to ethambutol (Colangeli et al., 2005). In an in vitro pharmacodynamic model, efflux pump-induced resistance developed within 3 days and was followed by development of katG mutations (Gumbo et al., 2007b).
Absorption, Distribution, and Excretion. The bioavailability of orally administered isoniazid is ~100% for the 300 mg dose. The pharmacokinetics of isoniazid are best described by a one-compartment model, with the pharmacokinetic parameters in Table 56–2 (Kinzig-Schippers et al., 2005). The ratio of isoniazid in the epithelial lining fluid to that in plasma is 1-2 and for CSF is 0.9 (Conte et al., 2002). Approximately 10% of drug is bound to protein. From 75-95% of a dose of isoniazid is excreted in the urine within 24 hours, mostly as acetylisoniazid and isonicotinic acid.
Isoniazid is metabolized by hepatic arylamine N-acetyltransferase type 2 (NAT2), encoded by a variety of NAT2* alleles (Figure 56–3). The drug is N-acetylated to N-acetylisoniazid in a reaction that uses acetyl-coA. Isoniazid clearance in patients has been traditionally classified as one of two phenotypic groups: "slow" and "fast" acetylators, as seen in Figure 56–4. Recently, the phenotypic groups have been expanded to fast, intermediate, and slow acetylators, and population pharmacokinetic parameters of isoniazid have been estimated and related to NAT2 genotype; the number of NAT2*4 alleles account for 88% of the variability of INH clearance (Kinzig-Schippers et al., 2005).
The frequency of each acetylation phenotype depends on race but is not influenced by sex or age. Fast acetylation is found in Inuit and Japanese. Slow acetylation is the predominant phenotype in most Scandinavians, Jews, and North African whites. The incidence of "slow acetylators" among various racial types in the U.S. is ~50%. Because high acetyltransferase activity (fast acetylation) is inherited as an autosomal dominant trait, "fast acetylators" of isoniazid are either heterozygous or homozygous. Although it has been useful to categorize different "racial" groups dominated by one or the other of these phenotypes, the more precise approach will be to determine the NAT2*4 alleles for each patient to guide therapy for that patient in the future.
Microbial Pharmacokinetics-Pharmacodynamics. Isoniazid's microbial kill is best explained by the AUC0-24-to-MIC ratio (Gumbo et al., 2007c). Resistance emergence is closely related to both AUC/MIC and Cmax/MIC (Gumbo et al., 2007c). Because AUC is proportional to dose/CL, this means that efficacy is most dependent on drug dose and CL, and thus on the activity of NAT-2 polymorphic forms. This also suggests that dividing the isoniazid dose into more frequent doses may be detrimental in terms of resistance emergence, and more intermittent dosing would be better (Chapter 48).
Therapeutic Uses. Isoniazid is available as a pill, as an elixir, and for parenteral administration. The commonly used total daily dose of isoniazid is 5 mg/kg, with a maximum of 300 mg; oral and intramuscular doses are identical. Children should receive 10-15 mg/kg/day (300 mg maximum). Dosing information in the treatment of M. tuberculosis and M. kansasii infections is given in section II and VI.
Untoward Effects. After NAT2 converts isoniazid to acetylisoniazid, which is excreted by the kidney; acetylisoniazid can also be converted to acetylhydrazine (Roy et al., 2008), and then to hepatotoxic metabolites by CYP2E1. Alternatively, acetylhydrazine may be further acetylated by NAT-2 to diacetylhydrazine, which is nontoxic. In this scenario, rapid acetylators will rapidly remove acetylhydrazine while slower acetylators or induction of CYP2E1 will lead to more toxic metabolites. Rifampin is a potent inducer of CYP2E1, which is why it potentiates isoniazid hepatotoxicity.
Elevated serum aspartate and alanine transaminases are encountered commonly in patients on isoniazid. However, the enzyme levels often normalize even when isoniazid therapy is continued (Blumberg et al., 2003). Severe hepatic injury occurs in ~0.1% of all patients taking the drug. Hepatic damage is rare in patients <20 years old but the incidence increases with age to 1.2% between 35 and 49 years and to 2.3% over 50 years of age. Overall risk is increased by co-administration with rifampin to ~3%. Fatal hepatitis is even rarer (0.02%). Most cases of hepatitis occur 4-8 weeks after the start of therapy.
If pyridoxine is not given concurrently, peripheral neuritis (most commonly paresthesias of feet and hands) is encountered in ~2% of patients receiving isoniazid 5 mg/kg of the drug daily. Neuropathy is more frequent in "slow" acetylators and in individuals with diabetes mellitus, poor nutrition, or anemia. Other neurological toxicities include convulsions in patients with seizure disorders, optic neuritis and atrophy, muscle twitching, dizziness, ataxia, paresthesias, stupor, and toxic encephalopathy. Mental abnormalities may appear during the use of this drug, including euphoria, transient impairment of memory, separation of ideas and reality, loss of self-control, and florid psychoses. The prophylactic administration of pyridoxine prevents the development not only of peripheral neuritis, as well as most other nervous system disorders in practically all instances, even when therapy lasts as long as 2 years.
Patients may develop hypersensitivity to isoniazid. Hemato-logical reactions also may occur. Vasculitis associated with antinuclear antibodies may appear during treatment but disappears when the drug is stopped. Arthritic symptoms (back pain; bilateral proximal interphalangeal joint involvement; arthralgia of the knees, elbows, and wrists; and the "shoulder-hand" syndrome) have been attributed to this agent.
Miscellaneous reactions associated with isoniazid therapy include dryness of the mouth, epigastric distress, methemoglobinemia, tinnitus, and urinary retention. In persons predisposed to pyridoxine-deficiency anemia, the administration of isoniazid may result in dramatic anemia. Treatment of the anemia with large doses of vitamin B6 gradually returns the blood count to normal. A drug-induced syndrome resembling systemic lupus erythematosus has also been reported.
Isoniazid Overdose. Intentional isoniazid overdose occurs most often in young women with concomitant psychiatric problems prescribed isoniazid for latent TB (Sullivan et al., 1998). As little as 1.5 g can be toxic. Isoniazid overdose has been associated with the clinical triad of:
The common early symptoms appear within 0.5-3 hours of ingestion and include ataxia, peripheral neuropathy, dizziness, and slurred speech. The most dangerous are grand mal seizures and coma, encountered when patients ingests ≥30 mg/kg of the drug. Mortality in these circumstances is as high as 20%. Intravenous pyridoxine is administered over 5-15 minutes on a gram-to-gram basis with the ingested isoniazid. If the dose of ingested isoniazid is unknown, then a pyridoxine dose of 70 mg/kg should be used. In patients with seizures, benzodiazepines are utilized.
Isoniazid's toxicity may be interpreted in terms of effects on pyridoxine metabolism. Isoniazid binds to pyridoxal 5′-phosphate to form isoniazid-pyridoxal hydrazones, thereby depleting neuronal pyridoxal 5′-phosphate and interfering with pyridoxal phosphate-requiring reactions, including the synthesis of the inhibitory neurotransmitter, GABA. Decreased levels of GABA lead to cerebral overexcitability and lowered seizure threshold. The antidote is replenishment of pyridoxal 5′-phosphate.
Drug Interactions. Isoniazid is a potent inhibitor of CYP2C19, CYP3A, and a weak inhibitor of CYP2D6 (Desta et al., 2001). However, isoniazid induces CYP2E1. Drugs that are metabolized by these enzymes will potentially be affected. Table 56–4, based on work by Desta et al. (2001), is a summary of drugs that interact with isoniazid via these mechanisms.