Principles of Antimycobacterial Therapy

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Chapter 206 Principles of Antimycobacterial Therapy

The treatment of mycobacterial infection and disease can be challenging. Patients require therapy with multiple agents, the offending pathogens commonly exhibit complex drug resistance patterns, and patients often have underlying conditions that affect drug choice and monitoring. Several of the drugs have not been well studied in children, and current recommendations are extrapolated from the experience in adults.

Single-drug therapy of Mycobacterium tuberculosis and nontuberculous mycobacteria is not recommended because of the high likelihood of developing antimicrobial resistance. Susceptibility testing of mycobacterial isolates often can aid in therapeutic decision making.

Agents Used Against Mycobacterium Tuberculosis

Commonly Used Agents

Isoniazid

Isoniazid (INH) is a hydrazide form of isonicotinic acid and is bactericidal for rapidly growing M. tuberculosis. The primary target of INH involves the INH A gene, which encodes the enoyl ACP (acyl carrier protein) reductase needed for the last step of the mycolic acid biosynthesis pathway of cell wall production. Resistance to INH occurs following mutations in the INH A gene or in other genes encoding enzymes that activate INH, such as kat G.

INH is indicated for the treatment of M. tuberculosis, M. kansasii, and M. bovis. The pediatric dosage is 10-15 mg/kg/day PO in a single dose not to exceed 300 mg/day. The adult dosage is 5 mg/kg/day PO in a single dose not to exceed 300 mg/day. Alternative pediatric dosing is 20-30 mg/kg PO in a single dose not to exceed 900 mg/dose given twice weekly under directly observed therapy, in which patients are observed to ingest each dose of antituberculosis medication to maximize the likelihood of completing therapy. The duration of treatment depends on the disease being treated (Table 206-1). INH needs to be taken 1 hr before or 2 hr after meals because food decreases absorption. It is available in liquid, tablet, IV (not approved by the Food and Drug Administration [FDA]), and IM preparations.

Table 206-1 RECOMMENDED TREATMENT REGIMENS FOR DRUG-SUSCEPTIBLE TUBERCULOSIS IN INFANTS, CHILDREN, AND ADOLESCENTS

INFECTION OR DISEASE CATEGORY	REGIMEN	REMARKS
LATENT TUBERCULOSIS INFECTION*
Isoniazid susceptible	9 mo of isoniazid, once a day	If daily therapy is not possible, DOT twice a week can be used for 9 mo
Isoniazid resistant	6 mo of rifampin, once a day	If daily therapy is not possible, DOT twice a week can be used for 6 mo
Isoniazid-rifampin resistant^‡	Consult a tuberculosis specialist
PULMONARY AND EXTRAPULMONARY INFECTION
Except meningitis	2 mo of isoniazid, rifampin, pyrazinamide, and ethambutol daily, followed by 4 mo of isoniazid and rifampin^† by DOT^§ for drug-susceptible Mycobacterium tuberculosis 9-12 mo of isoniazid and rifampin for drug-susceptible Mycobacterium bovis	If possible drug resistance is a concern (see text), another drug (ethambutol or an aminoglycoside) is added to the initial 3-drug therapy until drug susceptibilities are determined; DOT is highly desirable If hilar adenopathy only, a 6-mo course of isoniazid and rifampin is sufficient Drugs can be given 2 or 3 ×/wk under DOT in the initial phase if nonadherence is likely
Meningitis	2 mo of isoniazid, rifampin, pyrazinamide, and an aminoglycoside or ethambutol or ethionamide, once a day, followed by 7-10 mo of isoniazid and rifampin, once a day or twice a week (9-12 mo total) for drug-susceptible M. tuberculosis ≥12 mo of therapy without pyrazinamide for drug-susceptible M. bovis	A fourth drug, such as an aminoglycoside, is given with initial therapy until drug susceptibility is known For patients who might have acquired tuberculosis in geographic areas where resistance to streptomycin is common, kanamycin, amikacin, or capreomycin can be used instead of streptomycin

DOT, directly observed therapy; IGRA, interferon-γ release assay; TST, tuberculin skin test.

* Positive TST or IGRA result, no disease.

^† Duration of therapy is longer for human immunodeficiency virus (HIV)-infected people, and additional drugs may be indicated.

^‡ Medications should be administered daily for the first 2 weeks to 2 months of treatment and then can be administered 2 to 3 × per week by DOT.

^§ If initial chest radiograph shows cavitary lesions and sputum after 2 months of therapy remains positive, duration of therapy is extended to 9 months.

From American Academy of Pediatrics: Tuberculosis. In Pickering LK, Baker CJ, Kimberlin DW, Long SS, editors: Red Book 2009 Report of the Committee on Infectious Diseases, ed 28, Elk Grove Village, IL, 2009, American Academy of Pediatrics.

Major adverse events include hepatotoxicity in 1% of children and ∼3% of adults (increasing with age) and dose-related peripheral neuropathy. Pyridoxine can prevent the peripheral neuropathy and is indicated for breast-feeding infants and their mothers, children and youth on milk- or meat-deficient diets, pregnant adolescents, and symptomatic HIV-infected children. Minor adverse events include rash, worsening of acne, epigastric pain with occasional nausea and vomiting, decreased vitamin D levels, and dizziness. The liquid formulation of INH contains sorbitol, which often causes diarrhea and stomach upset.

INH is accompanied by significant drug-drug interactions (Table 206-2). The metabolism of INH is by acetylation. Acetylation rates have little effect on efficacy, but slow acetylators have an increased risk for hepatotoxicity, especially when used in combination with rifampin. Routine baseline liver function testing or monthly monitoring is only indicated for persons with underlying hepatic disease or on concomitant hepatotoxic drugs, including other antimycobacterial agents, acetaminophen, and alcohol. Monthly clinic visits while on INH alone are encouraged to monitor adherence, adverse effects, and worsening of infection.

Table 206-2 ISONIAZID DRUG-DRUG INTERACTIONS

DRUG USED WITH ISONIAZID	EFFECTS
Acetaminophen, alcohol, rifampin	Increased hepatotoxicity of isoniazid or listed drugs
Aluminum salts (antacids)	Decreased absorption of isoniazid
Carbamazepine, phenytoin, theophylline, diazepam, warfarin	Increased level, effect, or toxicity of listed drugs due to decreased metabolism
Itraconazole, ketoconazole, oral hypoglycemic agents	Decreased level or effect of listed drugs due to increased metabolism
Cycloserine, ethionamide	Increased central nervous system adverse effects of cycloserine and ethionamide
Prednisolone	Increased isoniazid metabolism

Less Commonly Used Agents

Aminoglycosides

The aminoglycosides used for mycobacterial infections include streptomycin, amikacin, kanamycin, and capreomycin. Streptomycin is isolated from Streptomyces griseus and was the 1st drug used to treat M. tuberculosis. Capreomycin, a cyclic polypeptide from Streptomyces capreolus, and amikacin, a semisynthetic derivative of kanamycin, are newer agents that are recommended when streptomycin is unavailable. Aminoglycosides act by binding irreversibly to the 30S subunit of ribosomes and inhibiting subsequent protein synthesis. Streptomycin exhibits concentration-dependent bactericidal activity, and capreomycin is bacteriostatic. Resistance results from mutation in the binding site of the 30S ribosome, by decreased transport into cells, or by inactivation by bacterial enzymes. Cross-resistance between aminoglycosides has been demonstrated.

The aminoglycosides are indicated for the treatment of M. tuberculosis and M. avium complex. All are considered 2nd-line drugs in the treatment of M. tuberculosis and should be used only when resistance patterns are known. Aminoglycosides are poorly absorbed orally and are administered by IM injection. Pediatric dosing ranges for streptomycin are 20 mg/kg/day if given daily and 20-40 mg/kg/day if given twice weekly; dosing is IM in a single daily dose. Capreomycin, amikacin, and kanamycin dosages are 15-30 mg/kg/day IM in a single dose not to exceed 1 g/day. Dosage adjustment is necessary in renal insufficiency.

Aminoglycosides have adverse effects on proximal renal tubules, the cochlea, and the vestibular apparatus of the ear. Nephrotoxicity and ototoxicity account for most of the significant adverse events. Rarely, patients exhibit fever or rash with the administration of aminoglycosides. Concomitant use of other nephrotoxic or ototoxic agents should be avoided, because adverse effects may be additive. An infrequent but serious, synergistic, dosage-dependent, aminoglycoside effect with nondepolarizing neuromuscular blockade agents can result in respiratory depression or paralysis.

Hearing and kidney function should be monitored at baseline and periodically. Early signs of ototoxicity include tinnitus, vertigo, and hearing loss. Ototoxicity appears to be irreversible, but early kidney damage may be reversible. As with other aminoglycosides, peak and trough drug levels are helpful in dosing and managing early toxicities.

Cycloserine

Cycloserine, derived from Streptomyces orchidaceus or Streptomyces garyphalus, is a synthetic analog of the amino acid D-alanine that interferes with bacterial cell wall synthesis via competitive inhibition of D-alanine components to be incorporated into the cell wall. It is bacteriostatic, and the mechanism of resistance is unknown.

Cycloserine is used to treat M. tuberculosis and M. bovis. The dosage is 10-20 mg/kg/day PO divided into 2 doses not to exceed 1g/day. It is available in a 250 mg capsule.

The major adverse event is neurotoxicity with significant psychologic disturbance, including seizures, acute psychosis, headache, confusion, depression, and personality changes. The neurotoxic effects are additive with ethionamide and isoniazid. It has also been associated with megaloblastic anemia. Cycloserine must be dosage adjusted with kidney impairment. It should be used with caution in patients with underlying psychiatric illness.

Routine laboratory monitoring includes kidney and hepatic function, CBC, and cycloserine levels. Psychiatric symptoms are less common at blood levels of <30 µg/mL.

Ethionamide

Ethionamide is structurally related to isoniazid and is an ethyl derivative of thioisonicotinamide that inhibits peptide synthesis by an unclear mechanism thought to involve NAD and NADP dehydrogenase disruptions. Ethionamide is bacteriostatic at most therapeutic levels. Resistance develops quickly if ethionamide used as a single-agent therapy, although the mechanism is unknown.

Ethionamide is used as an alternative to streptomycin or ethambutol in the treatment of M. tuberculosis and has some activity against M. kansasii and M. avium complex. A metabolite, ethionamide sulfoxide, is bactericidal against M. leprae. Ethionamide has been shown to have good central nervous system (CNS) penetration and has been used as a 4th drug in combination with rifampin, isoniazid, and pyrazinamide. The pediatric dosing is 15-20 mg/kg/day PO in 2 divided doses not to exceed 1 g/day. It is available as a 250 mg tablet.

GI upset is common, and other adverse effects include neurologic disturbances (anxiety, dizziness, peripheral neuropathy, seizures, acute psychosis), hepatic enzyme elevations, hypothyroidism, hypoglycemia, and hypersensitivity reaction with rash and fever. It should be used with caution in patients with underlying psychiatric or thyroid disease. The psychiatric adverse effects can be potentiated with concomitant use of cycloserine.

In addition to close assessment of mood, routine monitoring includes thyroid and liver function tests. In diabetic patients, blood glucose levels should be monitored.

Fluoroquinolones

The fluoroquinolones are fluorinated derivatives of the quinolone class of antibiotics. Ciprofloxacin is a 1st-generation fluoroquinolone, and levofloxacin is the more active L-isomer of ofloxacin. Moxifloxacin and gatifloxacin are agents with emerging use in pediatric mycobacterial disease. Fluoroquinolones are not indicated for use in children <18 yr of age, but studies of their use in pediatric patients continue to indicate that they may be used in special circumstances. Fluoroquinolones are bactericidal and exert their effect via inhibition of DNA gyrase. The alterations in DNA gyrase result in relaxation of super-coiled DNA and breaks in double-stranded DNA. The mechanism of resistance is not well defined but likely involves mutations in the DNA gyrase.

Levofloxacin is an important 2nd-line drug in the treatment of multidrug-resistant M. tuberculosis. Ciprofloxacin has activity against M. fortuitum complex and against M. tuberculosis. The pediatric dosage of ciprofloxacin is 20-30 mg/kg/day PO or IV not to exceed 1.5 mg/day PO or 800 mg/day IV. The adult dosage of ciprofloxacin is 500-750 mg/dose PO divided into 2 doses or 200-400 mg/dose IV every 12 hr. Ciprofloxacin is available in 100, 250, 500, and 750 mg tablets and can be made in 5% (50 mg/mL) or 10% (100 mg/mL) suspensions. The dosage of levofloxacin for children is 5-10 mg/kg/day given once daily either PO or IV not to exceed 1,000 mg/day, and for adults it is 500-1,000 mg/day PO or IV not to exceed 1,000 mg/day. Levofloxacin is available in 250, 500, and 750 mg tablets, and a 50 mg/mL suspension can be extemporaneously compounded. The suspension has a shelf life of only 8 wk.

The most common adverse effect of fluoroquinolones is GI upset, with nausea, vomiting, abdominal pain, and diarrhea, including pseudomembranous colitis. Other less common adverse effects include bone marrow depression, CNS effects (e.g., lowered seizure threshold, confusion, tremor, dizziness, headache), elevated liver transaminases, photosensitivity, and arthropathies. The potential for arthropathies (e.g., tendon ruptures, arthralgias, tendinitis) is the predominant reason that fluoroquinolones are not recommended for pediatric use. The mechanism of injury appears to involve the disruption of extracellular matrix of cartilage and depletion of collagen, a particular concern related to the bone and joint development of children.

Fluoroquinolones induce the cytochrome P450 isoenzymes that can increase the concentrations of dually administered theophylline and warfarin. Nonsteroidal anti-inflammatories can potentiate the CNS effects of fluoroquinolones and should be avoided while taking a fluoroquinolone. Both ciprofloxacin and levofloxacin should be dosage adjusted in patients with significant renal dysfunction.

While taking fluoroquinolones, patients should be monitored for hepatic and renal dysfunction, arthropathies, and hematologic abnormalities.

Linezolid

Linezolid is a synthetic oxazolidinone derivative. This drug is not currently approved for use against mycobacterial infection in pediatric or adult patients but has activity against some myobacterial species. Studies on efficacy of treatment of mycobacterial infections are under way. Linezolid inhibits translation by binding to the 23S ribosomal component of the 50S ribosome subunit, preventing coupling with the 70S subunit. Resistance is thought to be from a point mutation at the binding site but is poorly studied, because only a few cases of resistance have been reported.

The approved indications for linezolid are for bacterial infections other than myobacteria, but studies reveal in vitro activity against rapidly growing mycobacterium (M. fortuitum complex, M. chelonae, M. abscessus), M. tuberculosis, and M. avium complex. The dosage for 0-11 yr old children is 10 mg/kg/day PO or IV in divided doses every 8-12 hr. For persons >12 yr of age, the dosage is 600 mg PO or IV every 12 hr. Linezolid is available in 400 and 600 mg tablets and as a 20 mg/mL suspension.

Adverse effects of linezolid include GI upset (e.g., nausea, vomiting, diarrhea), CNS disturbances (e.g., dizziness, headache, insomnia, peripheral neuropathy), lactic acidosis, fever, myelosuppression, and pseudomembranous colitis. Linezolid is a weak inhibitor of monoamine oxidase A, and patients are advised to avoid foods with high tyramine content. Linezolid should be used cautiously in patients with pre-existing myelosuppression.

In addition to monitoring for GI upset and CNS perturbations, routine laboratory monitoring includes CBC at least weekly.

Para-Amino Salicylic Acid

para-Aminosalicylic acid (PAS) is a structural analog of para-aminobenzoic acid (PABA). It is bacteriostatic and acts by competitively inhibiting the synthesis of folic acid similar to the action of sulfonamides. Resistance mechanisms are poorly understood.

PAS acts against M. tuberculosis. The dosage is 150 mg/kg/day PO in 2 or 3 divided doses. PAS is dispensed in 4 g packets, and the granules should be mixed with liquid and swallowed whole.

Common adverse events include GI upset, and less common events include hypokalemia, hematuria, albuminuria, crystalluria, and elevations of hepatic transaminases. PAS can decrease the absorption of rifampin, and co-administration with ethionamide potentiates the adverse effects of PAS.

In addition to monitoring for weight loss, routine laboratory monitoring includes liver and kidney function tests.

Agents Used Against Mycobacterium Leprae

Dapsone

Dapsone is a sulfone antibiotic with characteristics similar to sulfonamides. Similar to other sulfonamides, dapsone acts as a competitive antagonist of PABA, which is needed for the bacterial synthesis of folic acid. Dapsone is bacteriostatic against M. leprae. Resistance is not well understood but is thought to occur after alterations at the PABA-binding site.

Dapsone is used in the treatment of M. leprae in combination with other antileprosy agents (rifampin, clofazimine, ethionamide). The pediatric dosage is 1-2 mg/kg/day PO as a single dose not to exceed 100 mg/day for a duration of 3-10 yr. The adult dosage is 100 mg/day PO as a single dose. Dapsone is available in 25 and 100 mg scored tablets and as an oral suspension of 2 mg/mL. The dosage should be adjusted in renal insufficiency.

Dapsone has many reported adverse events, including dosage-related hemolytic anemia, especially in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, pancreatitis, renal complications (acute tubular necrosis, acute renal failure, albuminuria), increased liver enzymes, psychosis, tinnitus, peripheral neuropathy, photosensitivity, and a hypersensitivity syndrome with fever, rash, hepatic damage, and malaise. A lepra reaction may occur with treatment, which is a nontoxic, paradoxical worsening of lepromatous leprosy with the initiation of therapy. This hypersensitivity reaction is not an indication to discontinue therapy. Dapsone should be used with caution in patients with G6PD deficiency or taking other folic acid antagonists. Dapsone levels can decrease with concomitant rifampin and can increase with concomitant clotrimazole.

Routine laboratory monitoring includes CBC weekly during the 1st mo of therapy, weekly through 6 mo of therapy, and then every 6 mo thereafter. Other periodic assessments include kidney function with creatine levels and urinalysis and liver function tests.

Clofazimine

Clofazimine is a synthetic phendimetrazine tartrate derivative that acts by binding to the mycobacterial DNA at guanine sites. It has a slow bactericidal activity against M. leprae. Mechanisms of resistance are not well studied. No cross-resistance between clofazimine and dapsone or rifampin has been shown.

Clofazimine is indicated as part of a combination therapy for the treatment of M. leprae. It appears there may be some activity against other mycobacteria such as M. avium complex, although treatment failures are common. Safety and efficacy of clofazimine are poorly studied in children. The pediatric dosage is 1 mg/kg/day PO as a single dose not to exceed 100 mg/day in combination with dapsone and rifampin for 2 yr and then additionally as a single agent for >1 yr. The adult dosage is 100 mg/day PO. It should be taken with food to increase absorption.

The most common adverse effect is a dosage-related, reversible pink to tan-brown discoloration of the skin and conjunctiva. Other adverse effects include a dry, itchy skin rash, headache, dizziness, abdominal pain, diarrhea, vomiting, peripheral neuropathy, and elevated hepatic transaminases.

Routine laboratory monitoring includes periodic liver function tests.

Agents Used Against Nontuberculous Mycobacteria

Cefoxitin

Cefoxitin, a cephamycin derivative, is a 2nd-generation cephalosporin that, like other cephalosporins, inhibits cell wall synthesis by linking with penicillin binding proteins to create an unstable bacterial cell wall. Resistance develops by alterations in penicillin binding proteins.

Cefoxitin is often used in combination therapy for mycobacterial disease (Table 206-3). Pediatric dosing is based on disease severity, with a range of 80-160 mg/kg/day divided every 4-8 hr not to exceed 12 g/day. Adult dosages are 1-2 g/day not to exceed 12 g/day. Cefoxitin is available in IV or IM formulations. Increased dosing intervals are needed with renal insufficiency.

Table 206-3 TREATMENT OF NONTUBERCULOUS MYCOBACTERIA INFECTIONS IN CHILDREN

ORGANISM	DISEASE	TREATMENT
SLOWLY GROWING SPECIES
Mycobacterium avium complex (MAC); Mycobacterium haemophilus; Mycobacterium lentiflavum	Lymphadenitis Pulmonary infection	Complete excision of lymph nodes; if excision is incomplete or disease recurs, clarithromycin or azithromycin plus ethambutol or rifampin (or rifabutin) Clarithromycin or azithromycin plus ethambutol with rifampin or rifabutin (pulmonary resection in some patients who fail to respond to drug therapy). For severe disease, an initial course of amikacin or streptomycin often is included. Clinical data in adults support that 3 ×/week therapy is as effective as daily therapy, with less toxicity.
	Disseminated	See text
Mycobacterium kansasii	Pulmonary infection	Rifampin plus ethambutol with isoniazid
Mycobacterium kansasii	Osteomyelitis	Surgical débridement and prolonged antimicrobial therapy using rifampin plus ethambutol with isoniazid
Mycobacterium marinum	Cutaneous infection	None, if minor; rifampin, trimethoprim-sulfamethoxazole, clarithromycin, or doxycyclinea for moderate disease; extensive lesions might require surgical débridement. Susceptibility testing not required.
Mycobacterium ulcerans	Cutaneous and bone infections	Excision of tissue; rifampicin plus streptomycin under investigation
RAPIDLY GROWING SPECIES
Mycobacterium fortuitum group	Cutaneous infection	Initial therapy for serious disease is amikacin plus meropenem IV, followed by clarithromycin, doxycycline,* or trimethoprim-sulfamethoxazole or ciprofloxacin, orally, on the basis of in vitro susceptibility testing; might require surgical excision
Mycobacterium fortuitum group	Catheter infection	Catheter removal and amikacin plus meropenem, IV; clarithromycin, trimethoprim-sulfamethoxazole, or ciprofloxacin, orally, on the basis of in vitro susceptibility testing
Mycobacterium abscessus	Otitis media	Clarithromycin plus initial course of amikacin plus cefoxitin; might require surgical débridement on the basis of in vitro susceptibility testing (50% are amikacin resistant)
Mycobacterium abscessus	Pulmonary infection (in cystic fibrosis)	Serious disease, clarithromycin, amikacin, and cefoxitin on the basis of susceptibility testing; might require surgical resection
Mycobacterium chelonae	Catheter infection	Catheter removal and tobramycin (initially) plus clarithromycin
Mycobacterium chelonae	Disseminated cutaneous infection	Tobramycin and meropenem or linezolid (initially) plus clarithromycin

* Doxycycline should not be given to children <8 yr of age unless the benefits of therapy are greater than the risks of dental staining. Only 50% of isolates of M. marinum are susceptible to doxycycline.

Adverse effects are primarily hematologic (eosinophilia, granulocytopenia, thrombocytopenia, hemolytic anemia), GI (nausea, vomiting, diarrhea with possible pseudomembranous colitis), and CNS-related (dizziness, vertigo). Potential additive adverse effects can occur when cefoxitin is used with aminoglycosides.

Routine laboratory monitoring with long-term use includes CBC and liver and renal function tests.

Doxycycline

Doxycycline is in the tetracycline family of antibiotics and has limited use in pediatrics. Like other tetracyclines, doxycycline acts to decrease protein synthesis by binding to the 30S ribosome and to transfer RNA. It can also cause alterations to the cytoplasmic membrane of susceptible bacteria.

Doxycycline is used to treat M. fortuitum (see Table 206-3). Although it can be used to treat M. marinum, adult treatment failures have occurred. Pediatric dosing is based on age and weight. For children >8 yr of age and <45 kg, the dosage is 4.4 mg/kg/day divided twice daily. Dosing for larger children and adults is 100 mg twice daily. Doxycycline is available as 50 and 100 mg capsules or tablets and in 25 mg/5 mL and 50 mg/5 mL suspensions.

Doxycycline use in children is limited by a permanent tooth discoloration, which is worse with long-term use. Other adverse effects include photosensitivity, liver and kidney dysfunction, and esophagitis, which can be minimized by dosing with large volumes of liquid. Doxycycline can decrease the effectiveness of oral contraceptives. Rifampin, carbamazepine, and phenytoin can decrease the concentration of doxycycline.

Routine laboratory monitoring with long-term use includes kidney and liver function tests as well as CBC.

Macrolides

Clarithromycin and azithromycin belong to the macrolide family of antibiotics. Clarithromycin is a methoxy derivative of erythromycin. Macrolides act by binding the 50S subunit of ribosomes, subsequently inhibiting protein synthesis. Resistance mechanisms for mycobacteria are not well understood but might involve binding site alterations. Clarithromycin appears to have synergistic antimycobacterial activity when combined with rifamycins, ethambutol, or clofazimine.

Clarithromycin is widely used for the prophylaxis and treatment of M. avium complex disease and also has activity against M. abscesses, M. fortuitum, and M. marinum. Azithromycin has significantly different pharmacokinetics compared with other macrolide agents and has not been studied and is not indicated for mycobacterial infections. The pediatric dosage of clarithromycin for primary prophylaxis of M. avium complex infections is 7.5 mg/kg/dose PO given twice daily not to exceed 500 mg/day. This dosage is used for recurrent M. avium complex disease in combination with ethambutol and rifampin. The adult dosage is 500 mg PO twice daily to be used as a single agent for primary prophylaxis or as part of combination therapy with ethambutol and rifampin. Dosage adjustment is needed for renal insufficiency but not liver failure. Clarithromycin is available in 250 and 500 mg tablets and suspensions of 125 mg/5 mL and 250 mg/5 mL.

The primary adverse effect of clarithromycin is GI upset, including vomiting (6%), diarrhea (6%), and abdominal pain (3%). Other adverse effects include taste disturbances, headache, and QT prolongation if used with inhaled anesthetics, clotrimazole, antiarrhythmic agents, or azoles. Clarithromycin should be used cautiously in patients with renal insufficiency or liver failure.

Routine laboratory monitoring with prolonged use of clarithromycin includes periodic liver enzyme tests. Diarrhea is an early sign of pseudomembranous colitis.

Trimethoprim-Sulfamethoxazole

Trimethoprim-sulfamethoxazole (TMP-SMX) is formulated in a fixed ratio of 1 part TMP to 5 parts SMX. SMX is a sulfonamide that inhibits synthesis of dihydrofolic acid by competitively inhibiting PABA, similar to dapsone. TMP blocks production of tetrahydrofolic acid and downstream biosynthesis of nucleic acids and protein by reversibly binding to dihydrofolate reductase. The combination of the 2 agents is synergistic and often bactericidal.

TMP-SMX is often used in combination therapy for mycobacterial disease (see Table 206-3). Oral or IV dosing for pediatric patients is TMP 15-20 mg/kg/day divided every 6-8 hr for serious infections and TMP 6-12 mg/kg/day divided every 12 hr for mild infections. The adult dosage is 160 mg TMP and 800 mg SMX every 12 hr. Dosage reduction may be needed in renal insufficiency. TMP-SMX is available in single-strength tablets (80/400 mg TMP/SMX) and double-strength tablets (160/800 mg TMP/SMX) and in a suspension of 40 mg TMP and 200 mg SMX per 5 mL.

The most common adverse effect with TMP-SMX is myelosuppression. It must be used with caution in patients with G6PD deficiency. Other adverse effects include renal abnormalities, rash, aseptic meningitis, GI disturbances (e.g., pancreatitis, diarrhea), and prolonged QT interval if co-administered with inhaled anesthetics, azoles, or macrolides.

Routine laboratory monitoring includes monthly CBC and periodic electrolytes and creatinine to monitor renal function.

Bibliography

Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167:603-662.

Dooley KE, Sterling TR. Treatment of latent tuberculosis infection: challenges and prospects. Clin Chest Med. 2005;26:313-326. vii

Duncan K, Barry CE. Prospects for new antitubercular drugs. Curr Opin Microbiol. 2004;7:460-465.

Fortun J, Martin-Davila P, Navas E, et al. Linezolid for the treatment of multidrug-resistant tuberculosis. J Antimicrob Chemother. 2005;56:180-185.

Hampel B, Hullmann R, Schmidt H. Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use—safety report. Pediatr Infect Dis J. 1997;16:127-129. 160–162

Marshall JD, Abdel-Rahman S, Johnson K, et al. Rifapentine pharmacokinetics in adolescents. Pediatr Infect Dis J. 1999;18:882-888.

McNeill L, Allen M, Estrada C, Cook P. Pyrazinamide and rifampin vs isoniazid for the treatment of latent tuberculosis: improved completion rates but more hepatotoxicity. Chest. 2003;123:102-106.

Rieder HL. Fourth-generation fluoroquinolones in tuberculosis. Lancet. 2009;373:1148-1149.

Samigun M, Santoso B. Lowering of theophylline clearance by isoniazid in slow and rapid acetylators. Br J Clin Pharmacol. 1990;29:570-573.