Ethionamide

Updated December, 2008

Rocsanna Namdar, Pharm.D.

Assistant Professor

University of Colorado Denver

School of Pharmacy

Denver, CO

Address:

University of Colorado Denver

Mail Stop C238-L15

12631 East 17th Avenue, Room 1407

P.O. Box 6511

Aurora, CO 80045

tel: (303) 724-6487

fax: (303) 724-2627

Email: rocsanna.namdar@ucdenver.edu

Charles A. Peloquin, Pharm.D.

Director, Infectious Disease Pharmacokinetics Laboratory

National Jewish Medical and Research Center

Denver, CO

and

Adjoint Associate Professor

Schools of Pharmacy and Medicine

University of Colorado

Denver CO

Address:

National Jewish Medical and Research Center

1400 Jackson St.

Denver, CO 80206

tel: (303) 398-1427

fax: (303) 398-2229

Email: peloquinc@njc.org

First Edition (1998): Shaun E. Berning, Pharm.D.

CLASS

Chemical Structure

               Ethionamide (ETA, 2-ethylisothionicotinamide, 2-ethyl-4-pyridinecarbothioamide) was first synthesized in 1956 (16,  22). Subsequently, prothionamide, the n-propyl derivative of ethionamide, was synthesized. Prothionamide is felt to be equivalent in activity to ethionamide; and is considered by some to be slightly better tolerated (16,5). However, prothionamide is not available in the United States.

               Ethionamide is a bright yellow powder with a slight sulfur-like odor. It is slightly soluble in water and less so in alcohol (19, 32). It is readily soluble in organic solvents. Ethionamide shares structural features with two other antimycobacterial agents, isonicotinic acid hydrazide (isoniazid) and, more distantly, thiacetazone (19, 27, 32).

Structure-Activity Relationships

               Experiments have shown that the free carbothionamide group, also found on thiacetazone, is essential for activity (35, 36). The pyridine ring of ethionamide also appears to have a special role in its mechanisms of action. The pyridine ring also is found in isoniazid.

ANTIMICROBIAL ACTIVITY

Spectrum

               Ethionamide is a very specific agent, active only against organisms of the genus Mycobacterium (12, 32, 35, 36, 32). Although it has activity against organisms such as M. bovis and M. kansasii, it is most often used to treat infections due to M. tuberculosis, M. avium-intracellulare and M. leprae. The MIC's of ethionamide versus M. tuberculosis vary depending upon the media in which they are tested. In 7H12 broth MIC's range from 0.3-1.2 µg/ml and in 7H11 agar MIC’s range from 2.5-10 µg/ml. The inhibitory effect of ethionamide versus M. avium strains is similar to its effect versus M. tuberculosis, with MIC's being 0.3 to >15 µg/ml in 7H12 broth and 2.5-15 µg/ml in 7H10 agar (12). Ethionamide also is very active against M. leprae with MIC's estimated to be 0.05 µg/ml (5, 16, 30).

               When considering in vitro activity, the potential for degradation of ethionamide should be considered. Within the test media, degradation can approach a 50% loss of drug over several days (32). Under certain conditions, heavy metal salts can have an inactivating effect. Increased alkalization and protein concentrations in the test media also may decrease ethionamide's apparent activity (32).

Pharmacodynamic Effects

Bactericidal Effects: The MBC's (minimal bactericidal concentration) of ethionamide in 7H12 broth are 2.5-5.0 µg/ml, producing MBC/MIC ratios of 2-4 (10, 12, 32). Ethionamide doses of 500 mg may produce serum concentrations in vivo above the MBC (23). The bactericidal activity versus M. avium is poor requiring MBC's of 80 µg/ml, to produce MBC/MIC ratios of 16-64. These MBC's are much higher than achievable serum or tissue ethionamide concentrations (12, 23, 32). Ethionamide has been shown to be bactericidal against M. leprae in mice at dietary doses of 0.01% but only bacteriostatic at dietary doses of 0.003% (5, 30).

Postantibiotic Effects (PAE): A 3-17 day delay in re-growth of mycobacteria was reported following pulse exposures of ethionamide at concentrations of 50 µg/ml. These concentrations were much higher than attainable maximum serum ethionamide concentrations, and the delay was partially due to the killing effect of the drug (9). Therefore, this cannot be considered to be indicative of a true PAE.

               Similar to many antimycobacterial drugs, ethionamide retains some activity when given to animals once or twice weekly (32). It is not clear if this represents an in vivo PAE, or simply reflects the relative slow growth of mycobacteria, with regrowth taking time to become apparent.

Effects of Subinhibitory Concentrations: No specific activity has been attributed to subinhibitory concentrations of ethionamide. In vitro, subinhibitory concentrations may enhance the ability to isolate resistant subpopulations (32). It is not known if subinhibitory concentrations of ethionamide contribute to resistance in vivo.

Effects on Host Immunity: Ethionamide does not have known direct effects on host immunity.

Pharmacodynamic Correlates With Outcome: In animals and in man, 10 mg/Kg generally is recognized as the threshold dose for activity (32). In vitro, sustained concentrations above the MIC appear to be more effective than widely fluctuating concentrations (32). Increasing the concentration from 4 to 16 µg/ml does not potentiate the short-term bactericidal activity of ethionamide (4 days of incubation); although the higher concentrations are more effective during longer incubation periods (32).

               It is tempting to compare ethionamide with the ß-lactams, due to its potentially bactericidal activity and its effect on cell wall synthesis. As a result, time above MIC would be the most important parameter. However, unlike the ß-lactams, ethionamide's cell-wall activity may be indirect, involving the disruption of synthesis of mycolic acids that are subsequently incorporated into the mycobacterial cell wall. As such, ethionamide's action may resemble that of other intracellular poisons, like the aminoglycosides, where the Cmax:MIC ratio appears to be the more important pharmacodynamic parameter. At tolerable doses, ethionamide only can achieve a Cmax ≤5 µg/ml yielding a maximum Cmax:MIC ratio of 1. The low Cmax:MIC ratio, combined with ethionamide's short serum half-life does not allow for adequate inhibitory concentrations to be sustained. For these reasons, it is common to dose ethionamide twice-daily.

               Further complicating the analysis is the slow growth of mycobacteria relative to the serum concentration-versus-time curve of most antimycobacterial drugs. Mycobacteria appear to exist in different subpopulations in vivo, and these subpopulations may vary in their responses to antimycobacterial drugs (10). Mycobacterium tuberculosis are capable of remaining dormant for long periods of time in vivo; and these dormant bacteria appear relatively impervious to the short-term effects of antimycobacterial drugs. Therefore, it remains difficult to draw inclusive and conclusive pharmacodynamic correlates for ethionamide.

MECHANISMS OF ACTION

               The mechanism of action of ethionamide is not fully understood. It appears to share some aspects of activity with isoniazid and with thiacetazone (12, 32, 35, 36, 42). In fact, ethionamide has been shown to share a common molecular target with isoniazid. Despite evidence of a common site of action, isoniazid and ethionamide are activated by different mechanisms, as resistance to isoniazid does not necessarily confer resistance to ethionamide. Ethionamide is a prodrug that must be converted to its active form by the bacterial cell. It is activated in Mycobacterium tuberculosis by the protein, EtaA, encoded by the gene Rv3854c (3, 7). EtaA is a flavoprotein monooxygenase that catalyzes two steps in the activation of ethionamide. First, ethionamide undergoes NADPH and oxygen dependent mono-oxygenation to the S-oxide yielding ETH-NAD, necessary for antimycobacterial activity of the drug. Then, it is further oxidized to ETA-SO, the cytotoxic metabolite. Thiobenzamide, isothionicotinamide and thiacetazone also are substrates for EtaA. This may explain the observed cross-resistance ethionamide has with thiacetazone (34).

               Ethionamide once was thought to work through inhibition of protein synthesis or disruption of ATP-controlled metabolism (32, 33, 42). However, more recent work suggests that, like isoniazid, activated ethionamide disrupts mycolic acid synthesis through a common cellular target, the enoyl-acyl carrier protein reductase, InhA (2, 11, 35, 36, 42). When added to cultures of actively multiplying mycobacteria, ethionamide can induce a rapid loss of acid-fastness. Ethionamide has been shown to be active against both extra- and intracellular mycobacteria in monocytes (12, 32, 35, 36, 42).

               Still, there are differences between isoniazid and ethionamide that remain unresolved (28). Quémard and colleagues postulated that ethionamide selectively alters the formation of oxygenated mycolic acids early in the synthetic pathway. This stands in contrast to isoniazid, which acts at a very early step of mycolic acid synthesis, resulting in complete inhibition of all types of mycolic acid synthesis (28). Consistent with these differences in mechanisms of action is the frequently observed lack of cross-resistance between isoniazid and ethionamide when mycobacterial isolates are tested in vitro.

MECHANISMS OF RESISTANCE

Organisms Commonly Resistant

               As mentioned previously, ethionamide is effective only against organisms of the genus Mycobacteria. Among the mycobacteria, M. africanum is often resistant (16, 28). Although ethionamide does not show cross-resistance with any agents commercially available in the US, it does show cross-resistance with thiosemicarbazones, such as thiacetazone, and diphenylthioureas, namely thiocarlide (DATC) (12, 16, 32, 35, 36, 42).

               While drug resistant tuberculosis is increasing worldwide, primary drug resistance of tuberculosis in the United States has decreased since the early 1990s (3.5% in 1991 vs 1.1% in 2006) (31). Overall resistance to ethionamide has been reported at 1.1 % and was reported higher in certain ethnic groups such as Hispanics and Asians. It also was higher in certain regions such as the US-Mexico border region and in Chicago (16, 40).

Mechanisms of Resistance

               As with other antimycobacterial agents, resistance in previously susceptible organisms may develop rapidly both in vivo and in vitro when ethionamide is used as a single agent in the treatment of tuberculosis (12, 16, 32, 35, 36, 43). This appears to be due to naturally occurring resistant mutants present in a population of mycobacteria. Under the selective pressure of a single drug, all organisms are eliminated except the resistant subpopulation, which continues to multiply, eventually becoming the dominant population. Co-resistance to isoniazid and ethionamide has been demonstrated by several different mechanisms: target modifications of inhA to prevent adduct binding; (Banerjee 1994, vilcheze 2006) inhA target overexpession; (17, 38) modification of EtaA resulting in prevention of prodrug activation and adduct formation; and mutations in ndh, the gene that regulates the intracellular NADH/NAD+ ratios, resulting in inhibited binding of the ETH-NAD adduct to InhA (7, 20, 39)

               A novel mechanism of ethionamide resistance has been discovered in M. tuberculosis which demonstrates that mycothiol plays a role in the prodrug activation by EtaA encoded monooxygenase (37).  The mshA gene is a gene that mediates the first step in the biosynthesis of mycothiol. This resistance is a loss of function and is consistent with mycothiol playing a role in the ethionamide activation process. Mycobacterium with mutants in mshA have been found to confer co-resisitance to isoniazid and ethionamide (21, 29).

Methods to Overcome and Prevent Resistance

               Because most of the clinical strains resistant to ethionamide contain mutations in the EthaA gene, it would be advantageous to find agents that inhibit inhA, without the need for EthaA activation as effective chemotherapy for resistant bacteria.(40). Using ethionamide in combination with at least one or two other antimycobacterial drugs may prevent acquired resistance to ethionamide (16, 19). Higher doses of ethionamide as monotherapy do not prevent the emergence of resistance (32). In vitro, subinhibitory concentrations enhance the selection of resistant organisms (32). It is not known if this also occurs in vivo, although the possibility exists. Therefore, it is desirable to achieve serum concentrations above the MIC of the isolate.

PHARMACOKINETICS

Review Article:  Nuermberger E, Grossett J.  Pharmacokinetic and Pharmacodynamic Issues in the Treatment of Mycobacterial Infections. 2004.

Absorption

               The absolute bioavailability of ethionamide has not been determined. The available data suggests that its absorption is nearly complete (13, 14, 15, 23, 24). The time to maximum concentration (Tmax) following 500 mg oral doses is 1.75 ± 0.75 hours, with maximum serum concentrations (Cmax) of 2.24 ± 0.82 µg/ml. The AUC0-∞ following 500 mg doses in 12 healthy volunteers is reported at 10.34 µg*hr/ml (24).

               The effects of food, orange juice and antacids were evaluated in twelve healthy volunteers. Each patient was administered 500 mg of ethionamide orally to determine the effect on the absorption of ethionamide. Compared with the fasting state, the Cmax, Tmax and the AUC0-∞ were not significantly affected by food, orange juice or antacids (1). Therefore, co-administration can be tried in selected patients in an effort to improve ethionamide’s tolerability. Before doing this, one should check the effect that food will have concurrently administered drugs.

               When administered as a 500 mg rectal dose in 12 normal volunteers, the bioavailability of ethionamide was 57.3% of that after oral administration, based on the area under the serum-concentration-versus-time curve (AUC) (24). Maximum serum concentrations following the rectal doses were 33% of those from oral doses, and Tmax occurred 3-5 hours after the rectal doses.

               The pharmacokinetics of ethionamide was evaluated in fifty-five patients with tuberculosis (TB). Compared with healthy volunteers, delayed absorption and flat concentration versus time curves were seen in the TB patients. In addition, higher clearance values were observed in patients with TB, resulting in smaller AUC estimates. As linear AUC changes were observed with increasing oral doses from 250-1000 mg, ethionamide doses of at least 500 mg are recommended to obtain adequate inhibitory serum concentration in patients with TB (43).

               The effect of acquired immune deficiency syndrome (AIDS) and gender on ethionamide plasma concentrations was studied in forty patients. The CD4 counts of the men and women with AIDS were 256 + 135 and 371 + 283, respectively. Ethionamide serum, alveolar, and pulmonary epithelial lining concentrations were measured after nine oral doses of ethionamide, 250 mg, were given every twelve hours. A majority of the patients had subinhibitory alveolar and plasma concentrations. However, there was no significant effect of gender or AIDS on the concentrations of ethionamide in plasma, alveoli or epithelial lining (6).

Distribution

               Ethionamide is widely distributed into most body tissues and fluids (12, 23). An estimated 10-30% of the drug is protein-bound. The oral volume of distribution relative to bioavailability (V/F) estimates for patients with TB are significantly higher than those for healthy volunteers. This may reflect poorer absorption (lower F), wider distribution in the body, or both (43).

               The drug readily crosses both normal and inflamed meninges, with CSF concentrations reported to be equal to those in the plasma. Ethionamide readily crosses the placenta. It is unknown if it is distributed into human breast milk (16, 23). Ethionamide is of similar size and chemical structure as isoniazid. Therefore, it is likely that some ethionamide passes into breast milk.

Routes of Elimination

Metabolism and Excretion: Ethionamide is extensively metabolized by sulfoxidation, desulfuration and deamination, followed by methylation. Metabolism most likely occurs in the liver, producing both active and inactive metabolites (13, 15, 16, 27, 23). The sulfoxide metabolite appears to have comparable activity to the parent compound, and interconversion between the two compounds has been described in animals and in humans (13, 15, 27). The serum concentration profile of the sulfoxide metabolite parallels that of ethionamide, at slightly lower concentrations (13). Limited amounts (≤ 5% of the dose) are excreted in the urine as unchanged drug and as ethionamide sulfoxide, its principal metabolite (12, 16, 23, 24). The serum elimination half-life of ethionamide ranges from 1.5 to 3.0 hours. Renal elimination of ethionamide generally is complete at 13 hours (13). Faster oral clearances (Cl/F) have been observed in patients with TB. Again, a lower F may increase these values or these patients may in fact clear ethionamide faster (43).

DOSAGE

Normal

               The usual dose of ethionamide ranges from 250-1000 mg per day. Most patients tolerate doses of 250-500 mg every 12 hours (16, 19). Ethionamide also may be dosed as 15-20 mg/kg/day, with a maximum dose of 30 mg/kg or 1000 mg (19). Doses greater than 500 mg at one time usually are not tolerated (8).

Therapeutic Drug Monitoring

               At National Jewish Medical and Research Center, therapeutic drug monitoring (TDM) of the anti-mycobacterial drugs is the standard of practice. Serum ethionamide concentrations are drawn at 2 and 6 hours post dose (26). The two-hour concentration provides information on the maximum concentration; while the 6 hour concentration lends information on the rate and completeness of absorption and on the clearance of the drug (26). Previously reported wide variations of serum concentrations were probably due to problems with enteric coated tablets, which are no longer used (9, 16). At National Jewish, serum concentrations of 1-5 µg/ml are considered "normal range" for doses of 250-500 mg (8). When used to treat leprosy, lower doses of 250-375 mg (5-10 mg/kg) daily may be employed (16).

               Although the manufacturer states that the optimum pediatric dose has not been established, doses have been reported at 15-20 mg/kg/day, with a 1000 mg/day maximum (16, 25).

Renal Failure

               Ethionamide is not significantly cleared by hemodialysis. Malone studied eight long-term hemodialysis patients and measured only 2.1% of a 500 mg oral ethionamide dose in the dialysate fluid. It appears hemodialysis does not effectively compete with metabolism for elimination of ethionamide from the body. No dosage adjustment is necessary in renal impairment or in patients undergoing hemodialysis (18, 23).

Hepatic Failure

               Ethionamide is relatively contraindicated in those patients with severe hepatic impairment (19). The relative contraindication clearly depends on the availability of therapeutic alternatives. To date, there is insufficient data demonstrating enhanced ethionamide toxicity in the face of hepatic impairment. Elimination of ethionamide may be compromised in patients with severe hepatic impairment. Therefore, serum concentration monitoring of ethionamide would be indicated in such patients (23, 26).

Obesity, Ascites, and Edema

               Ethionamide is fairly lipophilic, and it appears to be distributed into most body tissues and fluids (12, 19, 23). It has not been studied in obese patients or those with ascites or edema; so it is not known if larger doses should be used in such patients. Serum concentration monitoring would be indicated in these settings.

Pregnancy

               Although the drug has been used safely on occasion in pregnant women, the safe use of ethionamide in pregnancy has not been established. Its use during pregnancy has been associated with premature delivery, congenital deformities and Down's Syndrome. The drug also has caused teratogenic effects in animals at high doses. Ethionamide generally should be avoided in women who are pregnant, provided therapeutic alternatives are available (19, 23).

ADVERSE EFFECTS

               The most significant adverse effect of ethionamide is gastrointestinal intolerance, primarily nausea or vomiting (8, 9, 16, 19). Disturbances may occur at any dose of ethionamide, and are reported more frequently in females than males. Some patients struggle with gastrointestinal effects when individual doses are increased beyond 250 mg. Other adverse effects are not clearly dose related (8).

               Because gastrointestinal intolerance is common and at times severe, the potential benefit of enteric-coated tablets was studied. Unfortunately, the enteric coating did not offer any significant reduction in gastrointestinal symptoms, and caused erratic absorption of the drug (9). These findings led the authors to conclude that the gastrointestinal intolerance with ethionamide was more likely due to the toxicity of the drug than to irritation of the gastric mucosa. Gastrointestinal intolerance also has been reported with ethionamide when administered intravenously, suggesting the mechanism of reaction is centrally-mediated. However, ethionamide accumulates in gastric fluids even after intravenous doses, so local irritation remains a potential sole cause of this toxicity (12). Ethionamide suppositories, alone or combined with smaller oral doses, have been used successfully in some patients to circumvent gastrointestinal toxicity.

               The pharmacokinetic behavior of ethionamide is not significantly altered by food. Therefore, ethionamide can be administered with food, or prior to bedtime, to minimize gastrointestinal intolerance in selected patients (1, 16).

               Hepatocellular injury is possible with ethionamide (8, 16, 19). It usually is manifested as a rise in AST and ALT, with occasional increases in the total bilirubin as well. It is not known if this hepatotoxicity is due to a direct toxic effect or to a hypersensitivity reaction. In our experience, the duration of the biochemical abnormalities with ethionamide-hepatitis may be considerably greater (4-6 weeks) than that seen with isoniazid or rifampin (1-2 weeks). It has been reported that concomitant use of rifampin may increase the risk of hepatotoxicity, although data appear to be sparse  (16).

               Ethionamide may cause central nervous system (CNS) toxicity (8, 16, 19). Various CNS effects such as headache, drowsiness, giddiness, depression, psychosis, peripheral neuritis and visual disturbances have been reported during treatment with ethionamide (8, 16, 19). Since ethionamide generally is used with other drugs, isolating the toxicity to ethionamide may not have been possible. Although some reports indicate that the use of a B complex vitamin may reduce or prevent these effects, it also has been found that these vitamins offered no benefit in reducing these symptoms (8, 16, 19).

               Other adverse effects reported with ethionamide include goiter, with or without hypothyroidism, gynecomastia, alopecia, impotence, menorraghia, photodermatitis, acne, and arthritis (16, 19). The management of diabetes also may be more difficult in patients receiving ethionamide. It is not known how ethionamide interferes with hormonal regulation to produce some of these effects.

DRUG INTERACTIONS

               There are some reports that the incidence of CNS effects may be increased when ethionamide is used in combination with isoniazid or cycloserine. Therefore, caution should be taken when these drug combinations are used (19).

             It also has been our observation at National Jewish that the incidence of hypothyroidism is increased when ethionamide is used in combination with para-aminosalicylic acid (PAS). Therefore, we recommend checking the thyroid-stimulating hormone (TSH) concentrations every 1-2 months.

               The pharmacokinetic behavior of ethionamide is not significantly altered by antacids. Therefore, ethionamide can be administered with antacids, if necessary, to improve tolerability for the patient (1). Before doing this, one should check the effect that antacids will have concurrently administered drugs. Ethionamide appears to be primarily metabolized by CYP3A. Therefore, a clinically relevant interaction may occur with protease inhibitors. Protease inhibitors may result in an increase serum concentration of ethionamide and increased rates of toxicity (4).

CLINICAL INDICATIONS

               Ethionamide generally is reserved for patients with multidrug-resistant tuberculosis (MDR-TB), or those patients intolerant of the "first-line" agents such as isoniazid and rifampin. It frequently causes gastrointestinal intolerance, and therefore doses should be gradually increased over several days. Patients typically will require counseling and encouragement to complete regimens that contain ethionamide.

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