Goodman and Gilman Manual of Pharmacology and Therapeutics

Section VII
Chemotherapy of Microbial Diseases

chapter 56
Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy

Mycobacteria cause tuberculosis (TB) and leprosy. Although the burden of leprosy has decreased, TB is still the most important infectious killer of humans. Mycobacterium avium-intracellulare (or Mycobacterium avium complex [MAC]) infection continues to be difficult to treat, mainly due to 3 natural barriers:

• Cell wall—More than 60% of the cell wall is lipid, mainly mycolic acids composed of 2-branched, 73-hydroxy fatty acids with chains made of 76-90 carbon atoms. This shield prevents many pharmacological compounds from getting to the bacterial cell membrane or inside the cytosol.

• Efflux pumps—These transport proteins export potentially harmful chemicals from the bacterial cytoplasm into the extracellular space, preventing accumulation of effective drug concentrations in the cell. These exporters are responsible for the native resistance of mycobacteria to many standard antibiotics. As an example, ATP-binding cassette (ABC) permeases comprise a full 2.5% of the genome of Mycobacterium tuberculosis.

• Location in host—Some of the bacilli hide inside the patient’s cells, adding an extra physicochemical barrier that antimicrobial agents must cross to be effective.

Mycobacteria are defined by their rate of growth on agar as rapid and slow growers (Table 56–1). Slow growers tend to be susceptible to antibiotics developed specifically for Mycobacteria; rapid growers tend to be also susceptible to antibiotics used against many other bacteria.

Table 56–1

Pathogenic Mycobacterial Rapid and Slow Growers (Runyon Classification)


The mechanisms of action of the anti-mycobacterial drugs are summarized in Figure 56–1Figure 56–2 depicts the mechanisms of resistance to these drugs. Tables 56–2 and 56–3summarize the pharmacokinetic parameters of the antimycobacterial agents.


Figure 56–1 Mechanisms of action of established and experimental drugs used for the chemotherapy of mycobacterial infections. Shown at the top are the sites of action of approved drugs for the chemotherapy of mycobacterial diseases. Rifamycin is a generic term for several drugs, of which rifampin is used most frequently. Also included are 2 experimental drugs now under investigation: TMC-207 and PA-824. Clofazimine, whose mode of action is not understood, is omitted.


Figure 56–2 Mechanisms of drug resistance in Mycobacteria.



Rifampin or rifampicin (RIFADIN; RIMACTANE, others), rifapentine (PRIFTIN), and rifabutin (MYCOBUTIN) are important in treatment of mycobacterial diseases.

MECHANISM OF ACTION. Rifampin’s action against M. tuberculosis typifies the mechanism by which rifamycins act. Rifampin enters bacilli in a concentration-dependent manner, achieving steady-state concentrations within 15 min. The drug binds to the β subunit of DNA-dependent RNA polymerase (rpoB) to form a stable drug–enzyme complex, suppressing chain formation in RNA synthesis.

ANTIBACTERIAL ACTIVITY. Rifampin inhibits the growth of most gram-positive bacteria as well as many gram-negative microorganisms. Rifampin inhibits the growth of many M. tuberculosis clinical isolates in vitro at concentrations of 0.06-0.25 mg/L. Rifampin is also bactericidal against Mycobacterium leprae. Mycobacterium kansasii is inhibited by 0.25-1 mg/L. Most strains of Mycobacterium scrofulaceum, Mycobacterium intracellulare, and M. avium are suppressed by concentrations of 4 mg/L. Mycobacterium fortuitum is highly resistant to the drug. Rifabutin inhibits the growth of most MAC isolates at concentrations ranging from 0.25-1 mg/L and of many strains of M. tuberculosis at concentrations of ≤0.125 mg/L.

BACTERIAL RESISTANCE. The prevalence of rifampin-resistant isolates (1 in every 107 to 108 bacilli) is due to altered rpoB. Mutations in genes involved in DNA repair mechanisms will impair the repair of multiple genes, which may lead to hyper-mutable strains (see Chapter 48). M. tuberculosis Beijing genotype clinical isolates have been associated with higher rates of simultaneous rifampin and isoniazid resistance associated with mutations in the repair genes mut and ogt. Inducible or environment-dependent mutators may be more common than these stable mutator phenotypes. Antibiotics, endogenous oxidative and metabolic stressors lead to DNA damage, which induces dnaE2. The induction is associated with error-prone DNA repair and leads to higher rates of rifampin resistance.

ADME. After oral administration, the rifamycins are absorbed to variable extents (Table 56–2). Food decreases the rifampin CPmax by one-third; a high-fat meal increases the area under the curve (AUC) of rifapentine by 50%. Food has no effect on rifabutin absorption. Rifapentine should be taken with food, if possible. Rifamycins are metabolized by microsomal B-esterases and cholinesterases. A major pathway for rifabutin elimination is CYP3A. Due to autoinduction, all 3 rifamycins reduce their own AUCs with repeated administration (Table 56–3). They have good penetration into many tissues, but levels in the CNS reach only ~5% of those in plasma, likely due to the activity of P-glycoprotein. The drugs and metabolites are excreted by bile and eliminated via feces, with urine elimination accounting for only one-third and less of metabolites. Tables 56–2 and 56–3 summarize the pharmacokinetic parameters of the rifamycins.

Table 56–2

Population Pharmacokinetic Parameter Estimates for Antimycobacterial Drugs in Adult Patients


Table 56–3

Pharmacokinetic Parameters of Rifampin, Rifabutin, and Rifapentine


PHARMACOKINETICS-PHARMACODYNAMICS. Rifampin’s bactericidal activity is best optimized by a high AUC/MIC ratio. However, resistance suppression and rifampin’s enduring post-antibiotic effect are best optimized by high Cmax/MIC. Therefore, the duration of time that the rifampin concentration persists above the MIC is of less importance. These results predict that the t1/2 of a rifamycin is less of an issue in optimizing therapy, and that if patients could tolerate it, higher doses would lead to higher bactericidal activities while suppressing resistance.

THERAPEUTIC USES. Rifampin for oral administration is available alone or as a fixed-dose combination with isoniazid (150 mg of isoniazid, 300 mg of rifampin; Rifamate, others) or with isoniazid and pyrazinamide (50 mg of isoniazid, 120 mg of rifampin, and 300 mg pyrazinamide; RIFATER). A parenteral form of rifampin is also available. The dose of rifampin for treatment of TB in adults is 600 mg, given once daily, either 1 h before or 2 h after a meal. Children should receive 10-20 mg/kg given in the same way. Rifabutin is administered at 5 mg/kg/day and rifapentine at 10 mg/kg once a week. Rifampin is also useful for the prophylaxis of meningococcal disease and Haemophilus influenzae meningitis. To prevent meningococcal disease, adults may be treated with 600 mg twice daily for 2 days or 600 mg once daily for 4 days; children >1 month of age should receive 10-15 mg/kg, to a maximum of 600 mg. Combined with a β-lactam antibiotic or vancomycin, rifampin may be useful for therapy in selected cases of staphylococcal endocarditis or osteomyelitis.

UNTOWARD EFFECTS. Rifampin is generally well tolerated in patients. Fewer than 4% of patients with TB develop significant adverse reactions; the most common are rash, fever, and nausea and vomiting. Chronic liver disease, alcoholism, and old age appear to increase the incidence of severe hepatic problems. GI disturbances have occasionally required discontinuation of the drug. Various nonspecific symptoms related to the nervous system also have been noted.

Hypersensitivity reactions may be encountered. Adverse events associated with high rifampin dose are more commonly encountered when the time between doses is long; thus, high-dose rifampin should not be administered on a dosing schedule of less than twice weekly; less frequent administration is associated with a flu-like syndrome of fever, chills, and myalgias in 20% of patients; adverse effects may also include eosinophilia, interstitial nephritis, acute tubular necrosis, thrombocytopenia, hemolytic anemia, and shock. Light chain proteinuria, thrombocytopenia, transient leukopenia, and anemia have occurred during rifampin therapy. Rifampin crosses the placenta and its teratogenic potential; thus, its use is best avoided during pregnancy.

Rifabutin is generally well tolerated; primary reasons for discontinuation of therapy include rash (4%), GI intolerance (3%), and neutropenia (2%; 25% in patients with severe HIV infection). Uveitis and arthralgias have occurred in patients receiving rifabutin doses >450 mg daily in combination with clarithromycin or fluconazole. Patients should be cautioned to discontinue the drug if visual symptoms (pain or blurred vision) occur. Rifabutin causes an orange-tan discoloration of skin, urine, feces, saliva, tears, and contact lenses, like rifampin. Rarely, thrombocytopenia, a flu-like syndrome, chest pain, and hepatitis develop in patients treated with rifabutin. Unique side effects include polymyalgia, pseudojaundice, and anterior uveitis.

RIFAMYCIN OVERDOSE. Rifampin overdose is uncommon. The most prominent symptoms are the orange discoloration of skin, fluids, and mucosal surfaces, leading to the term red-man syndrome. Overdose can be life-threatening; treatment consists of supportive measures; there is no antidote.

DRUG INTERACTIONS. Because rifampin potently induces CYPs, its administration results in a decreased t1/2 for a number of compounds that are metabolized by these CYPs. Rifabutin is a less potent inducer of CYPs than rifampin; however, rifabutin does induce hepatic microsomal enzymes and decreases the t1/2 of zidovudine, prednisone, digitoxin, quinidine, ketoconazole, propranolol, phenytoin, sulfonylureas, and warfarin. It has less effect than rifampin on serum levels of indinavir and nelfinavir. Compared to rifabutin and rifampin, the CYP-inducing effects of rifapentine are intermediate.


Pyrazinamide is the synthetic pyrazine analog of nicotinamide.

MECHANISM OF ACTION. Pyrazinamide is activated to pyrazinoic acid under acidic conditions that likely prevail at the edges of necrotic TB cavities where inflammatory cells produce lactic acid. Some of the parent drug diffuses into M. tuberculosis where a nicotinamidase (pyrazinaminidase) deaminates pyrazinamide to pyrazinoic acid (POA?), which is exported by an efflux pump. In an acidic extracellular milieu, a fraction of POA? is protonated to POAH and enters the bacillus. As the pH of the extracellular medium declines toward the pKa of pyrazinoic acid, 2.9, the Henderson-Hasselbalch equilibrium (see Figure 2–3) progressively favors the formation of POAH, its equilibration across bacillar membrane, and its accumulation within the bacillus; acidic conditions also enhance microbial killing. Although the actual mechanism of microbial kill is still unclear, 4 mechanisms have been proposed:

• Inhibition of fatty acid synthase type I leading to interference with mycolic acid synthesis

• Binding to ribosomal protein S1 (RpsA) and inhibition of trans-translation

• Reduction of intracellular pH disruption of membrane transport by HPOA

ANTIBACTERIAL ACTIVITY. Pyrazinamide exhibits antimicrobial activity in vitro only at acidic pH. At pH of 5.8-5.95, 80-90% of clinical isolates have an MIC of ≤100 mg/L.

MECHANISMS OF RESISTANCE. Pyrazinamide-resistant M. tuberculosis express nicotinamidase with reduced affinity for pyrazinamide. This reduced affinity decreases the conversion of pyrazinamide to POA. Single point mutations in the pncA gene are encountered in up to 70% of resistant clinical isolates.

ADME. Oral bioavailability of pyrazinamide is >90%. GI absorption segregates patients into 2 groups: fast absorbers (56%) with an absorption rate constant of 3.56/h and slow absorbers (44%) with an absorption rate of 1.25/h. The drug is concentrated 20-fold in lung epithelial lining fluid. Pyrazinamide is metabolized by microsomal deamidase to POA and subsequently hydroxylated to 5-hydroxy-POA, which is excreted by the kidneys. CL (clearance) and Vd (volume of distribution) increase with patient mass (0.5 L/h and 4.3 L for every 10 kg above 50 kg), and Vd is larger in males (by 4.5 L) (see Table 56–2). This has several implications: the t1/2 of pyrazinamide will vary considerably based on weight and gender, and the AUC0-24 will decrease with increase in weight for the same dose (same mg drug/kg body weight). Pyrazinamide clearance is reduced in renal failure; therefore, the dosing frequency must be reduced to 3 times a week at low glomerular filtration rates. Hemodialysis removes pyrazinamide; therefore, the drug needs to be re-dosed after each session of hemodialysis.

MICROBIAL PHARMACOKINETICS-PHARMACODYNAMICS. Pyrazinamide’s sterilizing effect is closely linked to AUC0-24/MIC. However, resistance suppression is linked to the fraction of time that CP persists above MIC (T > MIC). Because patient weight impacts both SCL and volume, both AUC and t1/2 will be impacted by high weight. Simulations indicate that optimal AUC0-24/MIC and T > MIC are likely to be achieved only by doses much higher than the currently recommended 15-30 mg/kg/day; the safety of such higher doses in patients is unclear.

THERAPEUTIC USES. The coadministration of pyrazinamide with isoniazid or rifampin has led to a one-third reduction in the duration of anti-TB therapy, and a two-thirds reduction in TB relapse. The combination has reduced the length of therapy to 6 months, producing the current “short course” regimen. Pyrazinamide is administered at an oral dose of 15-30 mg/kg/day.

UNTOWARD EFFECTS. Injury to the liver is the most serious side effect of pyrazinamide. With an oral dose of 40-50 mg/kg, signs and symptoms of hepatic disease appear in ~15% of patients, with jaundice in 2-3% and death due to hepatic necrosis in rare instances. Current regimens (15-30 mg/kg/day) are much safer. Prior to pyrazinamide administration, all patients should undergo studies of hepatic function, and these studies should be repeated at frequent intervals during the entire period of treatment. If there is evidence of significant hepatic damage, therapy must be stopped. Pyrazinamide should not be given to patients with hepatic dysfunction unless its use is unavoidable.

In nearly all patients, pyrazinamide inhibits excretion of urate, and causes a hyperuricemia that may result in acute episodes of gout. Other untoward effects observed with pyrazinamide include arthralgias, anorexia, nausea and vomiting, dysuria, malaise, and fever. Pyrazinamide is not approved in the U.S. during pregnancy because of inadequate data on teratogenicity.


Isoniazid (isonicotinic acid hydrazide, INH; NYDRAZID, others) is a primary agent for TB. All patients infected with isoniazid-sensitive strains should receive the drug if they can tolerate it. The combination of isoniazid + pyrazinamide + rifampin provides a “short-course” therapy with improved remission rates.

MECHANISM OF ACTION. Isoniazid enters bacilli by passive diffusion. The drug is not directly toxic to the bacillus but must be activated to its toxic form within the bacillus by KatG, a multifunctional catalase-peroxidase. The activated drug forms adducts with bacillar NAD+ and NADP+ that inhibit essential steps in mycolic acid synthesis (cell wall) and nucleic acid synthesis (Figure 56–3). 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.


Figure 56–3 Metabolism and activation of isoniazid. metabolized in humans by NAT2 isoforms to its principal metabolite, N-acetyl isoniazid, which is excreted by the kidney. Isoniazid diffuses into mycoplasma where it is “activated” by KatG (oxidase/peroxidase) to the nicotinoyl radical. The nicotinoyl radical reacts spontaneously with NAD+ to produce adducts that inhibit essential enzymes in synthesis of the cell-wall component mycolic acid, and with NADP+ to produce an inhibitor of nucleic acid synthesis. InhA, enoyl acyl carrier protein; KasA, enoyl acyl carrier protein synthase; DHFR, dihydrofolate reductase.

MECHANISMS OF RESISTANCE. 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 gene. The prevalence of drug-resistant mutants is ~1 in 106 bacilli. Because TB cavities may contain as many as 107-109 microorganisms, preexistent resistance can be expected in pulmonary TB cavities of untreated patients. These spontaneous mutants will be selected and amplified by monotherapy. Thus, 2 or more agents are usually used. Because the mutations resulting in drug resistance are independent events, the probability of resistance to 2 antimycobacterial agents is small, ~1 in 1012 (1 × 106 × 106), a low probability considering the number of bacilli involved.

ADME. 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. Isoniazid is metabolized by hepatic arylamine N-acetyltransferase type 2 (NAT2), encoded by a variety of NAT2* alleles (see Figure 56–3). Isoniazid clearance in patients has been traditionally classified as 1 of 2 phenotypic groups: “slow” and “fast” acetylators (Figure 56–4), and more recently as 3 groups, including “intermediate” metabolizers; this variability largely reflects expression of various NAT2 alleles. Most (75-95%) of a dose of isoniazid is excreted in the urine within 24 h, predominantly as acetylisoniazid and isonicotinic acid.


Figure 56–4 Multi-modal distribution of INH clearance due to NAT2 polymorphisms. A group of matched male volunteers received INH (250 mg orally) and the time courses of plasma drug levels (Cp) were assessed. One-third of the subjects had INH elimination t1/2 values >1.5 h; these are the fast acetylators. Two-thirds had t1/2 values ranging from 2.1 to 4.0 h, with a suggestion of multiple groups; these are the slow acetylators. Plots of the mean data (Cp vs. time after administration) demonstrate the pharmacokinetic effects of acetylation rate. Both groups reached CPmax at 1 h. The slow acetylators (red line) achieved a higher Cp (4 μg/mL) with a mean elimination t1/2 = 3.0 h; the fast acetylators (green line) reached a lower maximal Cp (2 μg/mL) with a mean elimination t1/2 = 1.0 h. The acetylation rate reflects variable expression of active and defective polymorphic forms of NAT2. Slow acetylators may be a greater risk for adverse effects from INH, sulfonamides, and procainamide; fast acetylators may have diminished responses to standard doses of these agents but greater risk from bioactivation by NAT2 of arylamine/hydrazine carcinogens. Recently, researchers have identified 3 elimination subgroups for INH metabolism: fast, slow, and intermediate (codominant fast and slow alleles).

MICROBIAL PHARMACOKINETICS-PHARMACODYNAMICS. Isoniazid’s microbial kill is best explained by the AUC0-24-to-MIC ratio. Resistance emergence is closely related to both AUC/MIC and Cmax/MIC. Because AUC is proportional to dose/CL, 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 total isoniazid dose into more frequent doses may be detrimental in terms of resistance emergence (see Figure 48–4).

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. Children should receive 10-15 mg/kg/day (300 mg maximum). Pyridoxine, vitamin B6, (10-50 mg/day) should be administered with isoniazid to minimize the risks of neurological toxicity in patients predisposed to neuropathy (e.g., the malnourished, elderly, pregnant women, HIV-infected individuals, diabetic patients, alcoholic patients, and uremic patients).

UNTOWARD EFFECTS. The initial metabolite acetylisoniazid may be further acetylated by NAT-2 to diacetylhydrazine, which is nontoxic. Alternatively, acetylisoniazid can be converted to acetylhydrazine and then to hepatotoxic metabolites by CYP2E1. Thus, 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 the mechanism by which it potentiates isoniazid hepatotoxicity. Elevated serum aspartate and alanine transaminases are encountered commonly in patients on isoniazid. 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. Overall risk is increased by coadministration with rifampin to ~3%. Most cases of hepatitis occur 4-8 weeks after the start of therapy.

If pyridoxine is not given concurrently, peripheral neuritis 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.

Patients may develop hypersensitivity to isoniazid. Hematological reactions also may occur. Arthritic symptoms also have been attributed to this agent. Miscellaneous reactions associated with isoniazid therapy include dryness of the mouth, epigastric distress, methemoglobinemia, tinnitus, and urinary retention. A drug-induced syndrome resembling systemic lupus erythematosus has also been reported.

ISONIAZID OVERDOSE. Isoniazid overdose has been associated with the clinical triad of:

• Seizures refractory to treatment with phenytoin and barbiturates

• Metabolic acidosis with an anion gap that is resistant to treatment with sodium bicarbonate

• Coma

Treatment involves cessation of isoniazid dosing and administration of intravenous pyridoxine over 5-15 min 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 used.

DRUG INTERACTIONS. Isoniazid is a potent inhibitor of CYP2C19, CYP3A, and a weak inhibitor of CYP2D6. However, isoniazid induces CYP2E1. Drugs that are metabolized by these enzymes will potentially be affected (Table 56–4).

Table 56–4

Isoniazid-Drug Interactions via Inhibition and Induction of CYPs



Ethambutol hydrochloride (MYAMBUTOL) is a water-soluble and heat-stable compound.

MECHANISM OF ACTION. Ethambutol inhibits arabinosyl transferase III (catalyzes the transfer of arabinose in arabinogalactan biosynthesis), thereby disrupting the assembly of mycobacterial cell wall.

ANTIBACTERIAL ACTIVITY. Ethambutol has activity against a wide range of mycobacteria. Ethambutol MICs are 0.5-2 mg/L in clinical isolates of M. tuberculosis, ~0.8 mg/L for M. kansasii, and 2-7.5 mg/L for M. avium. The following species are also susceptible: Mycobacterium gordonae, M. marinum, M. scrofulaceum, M. szulgai. However, the majority of M. xenopi, M. fortuitum, and M. chelonae are resistant.

MECHANISMS OF RESISTANCE. In vitro, mycobacterial resistance to the drug develops via mutations in the embB gene, which encodes arabinosyl transferases. Enhanced efflux pump activity induces resistance to both isoniazid and ethambutol in vitro.

ADME. The oral bioavailability of ethambutol is ~80%. The decline in ethambutol is biexponential, with a t1/2 of 3 h in the first 12 h, and a t1/2 of 9 h between 12 and 24 h, due to redistribution of drug. Clearance and Vd are greater in children than in adults on a per kilogram basis. Slow and incomplete absorption is common in children, so that good peak concentrations of drug are often not achieved with standard dosing. See Table 56–2 for PK data on this drug. About 80% of the drug is not metabolized and is renally excreted. Therefore, in renal failure ethambutol should be dosed at 15-25 mg/kg, 3 times a week instead of daily. The remainder of ethambutol (~20%) is excreted as aldehyde and dicarboxylic acid derivatives (produced by alcohol and aldehyde dehydrogenases).

MICROBIAL PHARMACOKINETICS-PHARMACODYNAMICS. Ethambutol’s microbial kill of M. tuberculosis is optimized by AUC/MIC, while that against disseminated MAC is optimized by Cmax/MIC. Thus, to optimize microbial kill, high intermittent doses such as 25 mg/kg every other day to 50 mg/kg twice a week may be superior to daily doses of 15 mg/kg.

THERAPEUTIC USES. Ethambutol is available for oral administration in tablets containing the D-isomer. It is used for the treatment of TB, disseminated MAC, and in M. kansasii infection.

UNTOWARD EFFECTS. Ethambutol produces very few serious untoward reactions: ~1% experience diminished visual acuity resulting from a reversible optic neuritis, 0.5% a rash, and 0.3% drug fever. Other side effects that have been observed are pruritus, joint pain, GI upset, abdominal pain, malaise, headache, dizziness, mental confusion, disorientation, and possible hallucinations. Therapy with ethambutol results in an increased concentration of urate in the blood in ~50% of patients, owing to decreased renal excretion of uric acid.


Streptomycin, amikacin, and kanamycin are used for the treatment of mycobacterial diseases. These aminoglycosides inhibit protein synthesis by binding to the 30S ribosomal subunit (see Figure 54–2). The pharmacological properties and therapeutic uses of aminoglycosides are discussed in full in Chapter 54.

The MICs for M. tuberculosis in Middlebrook broth are 0.25-3.0 mg/L for all 3 aminoglycosides. For M. avium streptomycin and amikacin, MICs are 1-8 mg/L; those of kanamycin are 3-12 mg/L. M. kansasii is frequently susceptible to these agents but other nontuberculous mycobacteria are only occasionally susceptible.

BACTERIAL RESISTANCE. Primary resistance to streptomycin is found in 2-3% of M. tuberculosis clinical isolates. Resistance results from mutations in 2 components of the 30S ribosomal subunit, rpsLand rrs; in the rRNA methyltransferase gene gidB, and in efflux pumps.


Clofazimine (LAMPRENE), a fat-soluble riminophenazine dye, was discontinued in 2005 but remains licensed as an orphan drug.

MECHANISM OF ACTION. Clofazimine has both antibacterial activity as well as anti-inflammatory effects via inhibition of macrophages, T cells, neutrophils, and complement. Clofazimine is recommended as a component of multiple drug therapy for leprosy. The compound also is useful for treatment of chronic skin ulcers (Buruli ulcer) produced byMycobacterium ulcerans. Possible mechanisms of action include:

• Membrane disruption

• Inhibition of mycobacterial phospholipase A2

• Inhibition of microbial K+ transport

• Generation of hydrogen peroxide

• Interference with the bacterial electron transport chain

ANTIBACTERIAL ACTIVITY. The MICs for M. avium are 1-5 mg/L. The MICs for M. tuberculosis are ~1.0 mg/L. It also has activity against many gram-positive bacteria.

ADME. Clofazimine is administered orally at doses up to 300 mg/day. Bioavailability is variable (45-60%) and is increased 2-fold by high-fat meals and decreased 30% by antacids. After a single dose of 200 mg of clofazimine, the tmax is 5.3-7.8 h. After prolonged repeated dosing, the t1/2 is ~70 days. For PK data, see Table 56–2. Clofazimine is metabolized by the liver.

UNTOWARD EFFECTS. GI problems are encountered in 40-50% of patients. In patients who have died following the abdominal pain, crystal deposition in intestinal mucosa, liver, spleen, and abdominal lymph nodes has been demonstrated. Body secretion discoloration, eye discoloration, and skin discoloration occur in most patients.

DRUG INTERACTIONS. Anti-inflammatory effects may be inhibited by dapsone.


Fluoroquinolones are DNA gyrase inhibitors (see Chapter 52). Drugs such as ofloxacin and ciprofloxacin have been second-line anti-TB agents for many years, but they are limited by the rapid development of resistance.

Adding C8 halogen and C8 methoxy groups markedly reduces the propensity for drug resistance. Of the C8 methoxy quinolones, moxifloxacin (FDA-approved for nontubercular infections) is furthest along in clinical testing as an anti-TB agent. Moxifloxacin is being studied to replace either isoniazid or ethambutol.

THERAPEUTIC USES IN TREATMENT OF TB. In TB patients, moxifloxacin (400 mg/day) has bactericidal effects similar to that of standard doses of isoniazid. When replacing ethambutol in the standard multidrug regimen, 400 mg/day of moxifloxacin produces faster sputum conversion at 4 weeks than ethambutol. Moxifloxacin is currently being studied in a phase 3 trial that may eventually lead to 4-month duration of anti-TB therapy compared to the current 6 months.

TMC-207 (R207910)

MECHANISM OF ACTION. TMC-207 is a experimental diarylquinone for treatment of multidrug-resistant TB. The compound targets bacillar energy metabolism, acting on subunit c of the ATP synthase of M. tuberculosis and leading to inhibition of the proton pump activity of the ATP synthase. The TMC-207 MIC for M. tuberculosis is 0.03-0.12 mg/L. It has good activity against MAC, M. leprae, M. bovis, M. marinum, M. kansasii, M. ulcerans, M. fortuitum, M. szulgai, and M. abscessus.

PHARMACOKINETICS, EFFICACY, AND THERAPEUTIC USE. A regimen of TMC207 400 mg daily for 2 weeks followed by 200 mg 3 times day thereafter was added to a background second-line regimen of either kanamycin or amikacin, ofloxacin with or without ethambutol in patients with TB resistant to both isoniazid and rifampin (MDRTB), and led to an 8-week sputum conversion of ~50% with TMC207 compared to 9% without.

UNTOWARD EFFECTS. The adverse events encountered in the limited number of patients exposed to this experimental agent are mild and include nausea in 26% of patients and diarrhea in 13% of patients, with others (e.g., arthralgia, pain in extremities, and hyperuricemia) in a small proportion of patients.


PA-824, an experimental agent, is a nitroimidazopyran prodrug that requires activation by the bacteria via a nitro-reduction step, similar to the structurally related agent, metronidazole. Activation requires a specific glucose-6-phosphate dehydrogenase, FGD1.

MECHANISM OF ACTION. PA-824 inhibits M. tuberculosis mycolic acid and protein synthesis. Another mechanism involves generation of reactive nitrogen species such as NO by PA-824’s des-nitro metabolite, which then augment the kill of intracellular nonreplicating persistent bacilli by the innate immune system.

ANTIBACTERIAL ACTIVITY. In vitro, the drug kills both nonreplicating M. tuberculosis that are under anaerobic conditions as well as replicating bacteria in ambient air. The MICs of PA-824 against M. tuberculosis range from 0.015–0.25 mg/L, but the drug lacks activity against other mycobacteria.

BACTERIAL RESISTANCE. The proportion of mutants resistant to 5 mg/L of PA-824 is 10–6. Resistance can arise due to changes in structure of FGD, resulting from point mutations in fgd gene. However, resistant isolates have also been identified that lack fgd mutations, so that resistance may also be due to other mechanisms.


Ethionamide (TRECATOR) is a congener of thioisonicotinamide.

MECHANISM OF ACTION. Ethionamide is a prodrug that is activated to a sulfoxide by a mycobacterial NADPH-specific monooxygenase (EthaA), and then to 2-ethyl-4-aminopyridine. Although these products are not toxic to mycobacteria, it is believed that a closely related and transient intermediate is the active antibiotic. Like isoniazid, ethionamide inhibits mycobacterial growth by inhibiting the activity of the inhA gene product, the enoyl-ACP reductase of fatty acid synthase II. Both drugs inhibit mycolic acid biosynthesis with consequent impairment of cell-wall synthesis.

ANTIBACTERIAL ACTIVITY. The multiplication of M. tuberculosis is suppressed by concentrations of ethionamide ranging from 0.6-2.5 mg/L. A concentration of ≤10 mg/L will inhibit ~75% of photochromogenic mycobacteria; the scotochromogens are more resistant.

BACTERIAL RESISTANCE. Resistance occurs mainly via changes in the enzyme that activates ethionamide. Mutations in inhA gene lead to resistance to both ethionamide and isoniazid.

ADME. The oral bioavailability of ethionamide approaches 100%. The pharmacokinetics are adequately explained by a one-compartment model with first-order absorption and elimination; see PK values inTable 56–2. The t1/2 is ~2 h. Ethionamide is cleared by hepatic metabolism. Metabolites are eliminated in the urine. Ethionamide is administered only orally. The initial dosage for adults is 250 mg twice daily; it is increased by 125 mg/day every 5 days until a dose of 15-20 mg/kg/day is achieved. The maximal dose is 1 g daily. The drug is best taken with meals in divided doses to minimize gastric irritation. Children should receive 10-20 mg/kg/day in 2 divided doses, not to exceed 1 g/day.

UNTOWARD EFFECTS. Approximately 50% of patients are unable to tolerate a single dose larger than 500 mg because of GI upset. The most common reactions are anorexia, nausea and vomiting, gastric irritation, and a variety of neurologic symptoms. Severe postural hypotension, mental depression, drowsiness, and asthenia are common. Convulsions and peripheral neuropathy are rare. Other reactions referable to the nervous system include olfactory disturbances, blurred vision, diplopia, dizziness, paresthesias, headache, restlessness, and tremors. Pyridoxine (vitamin B6) relieves the neurologic symptoms, and its concomitant administration is recommended. Severe allergic skin rashes, purpura, stomatitis, gynecomastia, impotence, menorrhagia, acne, and alopecia have also been observed. A metallic taste also may be noted. Hepatitis has been associated with the use of the ethionamide in ~5% of cases. Hepatic function should be assessed at regular intervals in patients receiving the drug.


Para-aminosalicylic acid (PAS) was the first effective treatment for TB.

MECHANISM OF ACTION. PAS is a congener of para-aminobenzoic acid, the substrate of dihydropteroate synthase (fol P1/P2); this structural similarity accounted for PAS’s postulated action as a competitive inhibitor of the enzyme (Figure 56–5). PAS is a poor inhibitor of dihydropteroate synthase in vitro; moreover, only 37% of the PAS-resistant clinical isolates or spontaneous mutants encode a mutation in any genes for enzymes in the folate pathway or biosynthesis of thymine nucleotides. Furthermore, mutations in thyA (the gene for thymidylate synthase) lead to drug resistance in only a minority of drug-resistant isolates. Unidentified actions of PAS likely play important roles in its anti-TB effects.


Figure 56–5 Effects of antimicrobials on folate metabolism and deoxynucleotide synthesis. Two forms of thymidylate synthase are relevant here: the human form, thyA (EC and the bacterial form, thyX (EC; molecular differences may permit development of form-specific inhibitors.

ANTIBACTERIAL ACTIVITY. PAS is bacteriostatic. In vitro, most strains of M. tuberculosis are sensitive to a concentration of 1 mg/L. It has no activity against other bacteria.

ADME. PAS is administered orally in a daily dose of 12 g, with the daily dose divided into 3 equal portions. Children should receive 150-300 mg/kg/day in 3-4 divided doses. PAS oral bioavailability is >90%. PK data are shown in Table 56–2. The CPmax increases 1.5-fold and AUC 1.7-fold with food; indeed, PAS should be administered with food, which also reduces gastric irritation. PAS is N-acetylated in the liver to N-acetyl PAS, a potential hepatotoxin. Over 80% of the drug is excreted in the urine; >50% is in the form of the acetylated compound. Excretion of PAS is reduced by renal dysfunction, requiring a reduction in dosage.

UNTOWARD EFFECTS. The incidence of untoward effects associated with the use of PAS is ~10-30%. GI problems predominate and often limit patient adherence. Hypersensitivity reactions to PAS are seen in 5-10% of patients and manifest as skin eruptions, fever, eosinophilia, and other hematological abnormalities.


Cycloserine (SEROMYCIN) is a broad-spectrum antibiotic produced by Streptococcus orchidaceous that is used in the multi-agent treatment of TB when primary agents have failed.

MECHANISM OF ACTION. Cycloserine is a congener of D-alanine. D-alanyl-D-alanine is an essential component of the peptidoglycan of the bacterial cell wall (see Figure 55–4). Cycloserine inhibits 2 enzymes that are necessary for incorporation of alanine into the cell wall: a racemase that converts L-alanine to D-alanine, and a ligase that joins 2 D-alanines to make D-alanyl-D-alanine.

ANTIBACTERIAL ACTIVITY; RESISTANCE. Cycloserine inhibits M. tuberculosis at concentrations of 5-20 mg/L. It has good activity against MAC, enterococci, Escherichia coli, Staphylococcus aureus, Nocardia species, and Chlamydia. Resistance of M. tuberculosis occurs in 10-82% of clinical isolates. Mutations involved in cycloserine resistance of pathogenic Mycobacteria are currently unknown.

ADME. The usual dose for adults is 250-500 mg orally, twice daily. Oral cycloserine is almost completely absorbed. Cmax in plasma is reached in 45 min in fasting subjects, but is delayed for up to 3.5 h with a high-fat meal. See Table 56–2 for PK values. Cycloserine is well distributed throughout body. About 50% of cycloserine is excreted unchanged in the urine in the first 12 h; a total of 70% is recoverable in the active form over a period of 24 h. The drug may accumulate to toxic concentrations in patients with renal failure. About 60% of it is removed by hemodialysis.

UNTOWARD EFFECTS. Neuropsychiatric symptoms are common and occur in 50% of patients on 1 g/day, so much so that the drug has earned the nickname “psych-serine.” Symptoms range from headache and somnolence to severe psychosis, seizures, and suicidal ideas. Large doses of cycloserine or the concomitant ingestion of alcohol increases the risk of seizures. Cycloserine is contraindicated in individuals with a history of epilepsy and should be used with caution in individuals with a history of depression.


Capreomycin (CAPASTAT) is an antimycobacterial cyclic peptide. Antimycobacterial activity is similar to that of aminoglycosides as are adverse effects, and capreomycin should not be administered with other drugs that damage cranial nerve VIII. Bacterial resistance to capreomycin develops when it is given alone; such microorganisms show cross-resistance with kanamycin and neomycin. The adverse reactions associated with the use of capreomycin are hearing loss, tinnitus, transient proteinuria, cylindruria, and nitrogen retention. Eosinophilia is common. Leukocytosis, leukopenia, rashes, and fever have also been observed. Capreomycin is a second-line antituberculosis agent. The recommended daily dose is 1 g (no more than 20 mg/kg) per day for 60-120 days, followed by 1 g 2 to 3 times a week.


The pharmacology, bacterial activity, resistance mechanisms of macrolides are discussed in Chapter 55. Azithromycin and clarithromycin are used for the treatment of MAC.


Dapsone is a broad-spectrum agent with antibacterial, anti-protozoal, and antifungal effects.


MECHANISM OF ACTION. Dapsone (DDS, diamino-diphenylsulfone) is a structural analog of para-aminobenzoic acid (PABA) and a competitive inhibitor of dihydropteroate synthase (fol P1/P2) in the folate pathway, shown in Figure 56–5 (see also Figures 52–1 and 52–1). The anti-inflammatory effects of dapsone occur via inhibition of tissue damage by neutrophils. Dapsone is extensively used for acne, but this therapy is not recommended.


Antibacterial. Dapsone is bacteriostatic against M. leprae at concentrations of 1-10 mg/L. More than 90% of clinical isolates of MAC and M. kansasii have an MIC of <8 mg/L, but the MICs for M. tuberculosis isolates are high. It has little activity against other bacteria.

Anti-parasitic. Dapsone is highly effective against Plasmodium falciparum with IC50 of 0.006-0.013 mg/mL (0.6-1.3 mg/L) even in sulfadoxine-pyrimethamine–resistant strains. Dapsone has an IC50 of 0.55 mg/L against Toxoplasma gondii tachyzoites.

Antifungal. Dapsone is effective at concentrations of 0.1/mg/L against the fungus Pneumocystic jiroveci.

DRUG RESISTANCE. Resistance to dapsone results primarily from mutations in genes encoding dihydropteroate synthase (see Figure 56–5).

ADME. After oral administration, absorption is complete; the elimination t1/2 is 20-30 h. The population pharmacokinetics of dapsone are shown in Table 56–2. Dapsone undergoes N-acetylation by NAT2 and N-oxidation to dapsone hydroxylamine via CYP2E1 and CYP2C. Dapsone hydroxylamine enters red blood cells, leading to methemoglobin formation. Sulfones (e.g., dapsone) tend to be retained for up to 3 weeks in skin and muscle and especially in liver and kidney. Intestinal reabsorption of sulfones excreted in the bile contributes to long-term retention in the bloodstream; periodic interruption of treatment is advisable for this reason. Approximately 70-80% of a dose of dapsone is excreted in the urine as an acid-labile mono-N-glucuronide and mono-N-sulfamate.

THERAPEUTIC USES. Dapsone is administered as an oral agent. Therapeutic uses of dapsone in the treatment of leprosy are described later. Dapsone is combined with chlorproguanil for the treatment of malaria. The anti-inflammatory effects are the basis for therapy for pemphigoid, dermatitis herpetiformis, linear IgA bullous disease, relapsing chondritis, and ulcers caused by the brown recluse spider.

DAPSONE AND G6PD DEFICIENCY. Glucose-6-phosphate dehydrogenase (G6PD) protects red cells against oxidative damage. However, G6PD deficiency is encountered in nearly half a billion people worldwide. Dapsone, an oxidant, causes severe hemolysis in patients with G6PD deficiency. Thus, G6PD deficiency testing should be performed prior to use of dapsone wherever possible.

OTHER UNTOWARD EFFECTS. Doses of ≤100 mg in healthy persons and ≤50 mg in healthy individuals with a G6PD deficiency do not cause hemolysis. Hemolysis develops in almost every individual treated with 200-300 mg of dapsone per day; methemoglobinemia also is common. A genetic deficiency in the NADH-dependent methemoglobin reductase can result in severe methemoglobinemia after administration of dapsone. Isolated instances of headache, nervousness, insomnia, blurred vision, paresthesias, reversible peripheral neuropathy, drug fever, hematuria, pruritus, psychosis, and a variety of skin rashes have been reported. An infectious mononucleosis-like syndrome, which may be fatal, occurs occasionally.


Tuberculosis is not caused by a single species, but by a mixture of species with 99.9% similarity at the nucleotide level. The complex includes M. tuberculosis (typus humanus), M. canettii, M. africanum, M. bovis, and M. microti. They all cause TB, with M. microti responsible for only a handful of human cases.

ANTITUBERCULOSIS THERAPY. With anti-TB drug monotherapy, emergence of resistance renders the drugs ineffective. The mutation rates to first-line anti-TB drugs are between 10–7 and 10–10, so that the likelihood of resistance is high to any single anti-TB drugs in patients with cavitary TB who have ~109 CFU of bacilli in a 3-cm pulmonary lesion. However, the likelihood that bacilli would develop mutations to 2 or more different drugs is the product of 2 mutation rates (between 1 in 1014 and 1 in 1020), a probability of resistance emergence that is acceptably small. Thus, only combination therapy anti-TB therapy is currently recommended for treatment of TB. Multidrug therapy has led to a reduction in length of therapy.

Isoniazid, pyrazinamide, rifampin, ethambutol, and streptomycin are currently considered first-line anti-TB agents. Moxifloxacin is being studied as a first-line agent. First-line agents are more efficacious and better tolerated, relative to second-line agents. Second-line drugs include ethionamide, PAS, cycloserine, amikacin, kanamycin, and capreomycin.


PROPHYLAXIS. After infection with M. tuberculosis, ~10% of people will develop active disease over a lifetime. The highest risk of reactivation TB is in patients with Mantoux tuberculin skin test reaction ≥5 mm who also fall into 1 of the following categories: recently exposed to TB, have HIV co-infection, or are immunosuppressed. If the tuberculin skin test is ≥10 mm, high risk of TB is encountered in recent (≤5 years) immigrants from areas of high TB prevalence, children <4 years of age, intravenous drug users, as well as residents and employees of high-risk congregate settings. Any person with a skin test >15 mm is also at high risk. In these patients at high risk of active TB, prophylaxis is recommended to prevent active disease. Prophylaxis consists of oral isoniazid, 300 mg daily or twice weekly, for 6 months in adults. Those who cannot take isoniazid should be given rifampin, 10 mg/kg daily, for 4 months. In children, isoniazid 10-15 mg/kg daily (maximum 300 mg) is administered, or 20-30 mg/kg 2 times a week directly observed, for 9 months. In children who cannot tolerate isoniazid, rifampin 10-20 mg/kg daily for 6 months is recommended.

DEFINITIVE THERAPY. The current standard regimen for drug-susceptible TB consists of isoniazid (5 mg/kg, maximum 300 mg/day), rifampin (10 mg/kg, maximum 600 mg/day), and pyrazinamide (15-30 mg/kg, maximum of 2 g/day) for 2 months, followed by intermittent 10 mg/kg rifampin and 15 mg/kg isoniazid 2 or 3 times a week for 4 months. Children should receive 10-20 mg/kg isoniazid per day (300 mg maximum). Rifabutin 5 mg/kg/day can be used for the entire 6 months of therapy in adult HIV-infected patients because rifampin can adversely interact with some antiretroviral agents to reduce their effectiveness. In case there is resistance to isoniazid, initial therapy also may include ethambutol (15-20 mg/kg/day) or streptomycin (1 g/day) until isoniazid susceptibility is documented. Ethambutol doses in children are 15-20 mg/kg/day (maximum 1 g) or 50 mg/kg twice weekly (2.5 g). Because monitoring of visual acuity is difficult in children <5 years old, caution should be exercised in using ethambutol in these children.

The first 2 months of the 4-drug regimen is termed the initial phase of therapy, and the last 4 months the continuation phase of therapy. Rifapentine (10 mg/kg once a week) may be substituted for rifampin in the continuation phase in patients with no evidence of HIV infection or cavitary TB. Pyridoxine, vitamin B6, (10-50 mg/day) should be administered with isoniazid to minimize the risks of neurological toxicity in patients predisposed to neuropathy. The duration of therapy for drug-susceptible pulmonary TB is 6 months. A 9-month duration should be used for patients with cavitary disease who are still sputum culture positive at 2 months. Most cases of extrapulmonary TB are treated for 6 months. TB meningitis is an exception that requires a 9- to 12-month duration. In addition, corticosteroids are recommended for TB pericarditis, and results of a meta-analysis suggest they should also be used in TB meningitis.

DRUG-RESISTANT TB. In documented drug resistance, therapy should be based on evidence of susceptibility and should include:

• At least 3 drugs to which the pathogen is susceptible, with at least 1 injectable anti-TB agent

• In the case of multidrug resistant-TB, use of 4 to 6 medications for better outcomes

• At least 18 months of therapy

The addition to the regimen of a fluoroquinolone and surgical resection of the main lesions have been associated with improved outcome. There are currently no data to support intermittent therapy.


The MAC is made up of at least 2 species: M. intracellulare and M. avium. M. intracellulare causes pulmonary disease often in immunocompetent individuals. M. avium is further divided into a number of subspecies: M. avium subsp. hominissuis causes disseminated disease in immunocompromised patients, M. avium subsp. paratuberculosis has been implicated in the etiology of Crohn disease, and M. avium subsp. avium causes TB of birds. These bacteria are ubiquitous in the environment and can be encountered in water, food, and soil.


M. intracellulare often infects immunocompetent patients. In newly diagnosed patients with MAC pneumonia, triple drug therapy is recommended: a rifamycin, ethambutol, and a macrolide. For the macrolides, either oral clarithromycin or azithromycin may be used. Rifampin is often the rifamycin of choice. Clarithromycin, 1000 mg, or azithromycin, 500 mg, are combined with ethambutol, 25 mg/kg, and rifampin, 600 mg, and administered 3 times a week for nodular and bronchiectatic disease. Therapy is continued for 12 months after the last negative culture. The same drugs are administered for patients with cavitary disease, but the dosing regimens are azithromycin 250 mg, ethambutol 15 mg/kg, and rifampin 600 mg. Parenteral streptomycin or amikacin at 15 mg/kg is recommended as a fourth drug. Duration of therapy is as for nodular disease. In advanced pulmonary disease or during re-treatment, rifabutin 300 mg daily may replace rifampin. Because clarithromycin susceptibility correlates with outcome, risk of failure is high when high clarithromycin MICs are documented. Patients at risk for failure also include those with cavitary disease, presumably due to higher bacillary load. Even with these therapies, long-term success is still fairly limited (~50%).


Disseminated MAC disease is caused by M. avium in 95% of patients. This is a disease of the immunocompromised patient. Patients at risk for infection are those who have had other opportunistic infections, are colonized with MAC, or have an HIV RNA burden >5 log10 copies/mm3.

The symptoms of disseminated disease are nonspecific and include fever, night sweats, weight loss, elevated serum alkaline phosphates, and anemia at the time of diagnosis. However, when disease occurs in patients already on anti-retroviral therapy, it may manifest as a focal disease of the lymph nodes, osteomyelitis, pneumonitis, pericarditis, skin or soft-tissue abscesses, genital ulcers, or CNS infection.

PROPHYLACTIC THERAPY. Monotherapy with either oral azithromycin 1200 mg once a week or clarithromycin 500 mg twice a day is started when patients present with a CD4 count <50/mm3. For patients intolerant of macrolides, rifabutin 300 mg/day is administered. Once the CD4 count is >100 per mm3 for ≥3 months, MAC prophylaxis should be discontinued.

DEFINITIVE AND SUPPRESSIVE THERAPY. In patients with disease due to MAC, the goals of therapy include suppression of symptoms and conversion to negative blood cultures. The infection itself is not completely eradicated until immune reconstitution. Recommended therapy consists of a combination of clarithromycin 500 mg twice a day with ethambutol 15 mg/kg daily, administered orally. Azithromycin 500-600 mg daily is an acceptable alternative to clarithromycin. The addition of rifabutin 300 mg/day may improve outcomes. Mortality in disseminated MAC is high in patients with either a CD4 cell count <50/mm3 or a MAC burden of >2 log10 CFU/mm3 of blood, or in the absence of effective antiretroviral therapy. In these patients, a fourth drug may be added, based on susceptibility testing. Potential fourth agents include amikacin, 10-15 mg/kg intravenously daily; streptomycin, 1 g intravenously or intramuscularly daily; ciprofloxacin, 500-750 mg orally twice daily; levofloxacin, 500 mg orally daily; or moxifloxacin, 400 g orally daily. Patients should be continued on suppressive therapy until all of these criteria are met:

• Therapy duration of at least 12 months

• CD4 count >100/mm3 for at least 6 months

• Asymptomatic for MAC infection


The global prevalence of leprosy has declined by 90% since 1985, largely due to the global initiative of the WHO to eliminate leprosy (Hansen disease) as a public health problem by providing multidrug therapy (rifampin, clofazimine, and dapsone) free of charge.


Therapy for leprosy is based on multidrug regimens using rifampin, clofazimine, and dapsone. The reasons for using combinations of agents include reduction in the development of resistance, the need for adequate therapy when primary resistance already exists, and reduction in the duration of therapy. The most bactericidal drug in current regimens is rifampin. Because of high kill rates and massive release of bacterial antigens, rifampin is not often given during a “reversal” reaction (see below) or in patients with erythema nodosum leprosum. Clofazimine is only bacteriostatic against M. leprae. However, it also has anti-inflammatory effects and can treat reversal reactions and erythema nodosum leprosum. The third major agent in the regimen is dapsone. The objective of administering these drugs is total cure.

PAUCI-BACILLARY LEPROSY. The WHO regimen consists of a single dose of oral rifampin, 600 mg, combined with dapsone, 100 mg, administered under direct supervision once every month for 6 months, and dapsone, 100 mg a day, in between for 6 months. In the U.S., the regimen consists of dapsone, 100 mg, and rifampin, 600 mg, daily for 6 months, followed by dapsone monotherapy for 3-5 years.

MULTIBACILLARY THERAPY. The WHO recommends the same regimen as for paucibacillary leprosy, with 2 major changes. First, clofazimine, 300 mg a day, is added for the entirety of therapy. Second, the regimen lasts 1 year instead of 6 months. In the U.S., the regimen is also the same as for paucibacillary, but dual therapy continues for 3 years, followed by dapsone monotherapy for 10 years. Clofazimine is added when there is dapsone resistance or chronically reactional patients. Viable bacilli are killed within 3 months of therapy, suggesting that the length of current therapy for multibacillary leprosy may be unnecessarily long. Recently, the WHO proposed that all forms of leprosy be treated with the same dose as for paucibacillary leprosy. This new shorter regimen promises to reduce duration of therapy radically.

TREATMENT OF REACTIONS IN LEPROSY. Patients with tuberculoid leprosy may develop “reversal reactions,” manifestations of delayed hypersensitivity to antigens of M. leprae. Early therapy with corticosteroids or clofazimine is effective. Reactions in the lepromatous form of the disease (erythema nodosum leprosum) are characterized by the appearance of raised, tender, intracutaneous nodules, severe constitutional symptoms, and high fever. Treatment with clofazimine or thalidomide is effective.


Mycobacteria other than those already discussed can be recovered from a variety of lesions in humans. Therapy for infections from these organisms is summarized in Table 56–5.

Table 56–5

Drugs Used in the Treatment of Mycobacteria Other Than for Tuberculosis, Leprosy, or MAC