Stacene R. Maroushek
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.
Isoniazid (INH ) is a hydrazide form of isonicotinic acid and is bactericidal for rapidly growing M. tuberculosis. The primary target of INH involves the INHA 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 INHA gene or in other genes encoding enzymes that activate INH, such as katG .
INH is indicated for the treatment of M. tuberculosis, M. kansasii, and M. bovis. The pediatric dosage is 10-15 mg/kg/day orally (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 (DOT) , 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 241.1 ). INH needs to be taken 1 hr before or 2 hr after meals because food decreases absorption. It is available in liquid, tablet, intravenous (IV; not approved by the FDA), and intramuscular (IM) preparations.
Table 241.1
Recommended Usual Treatment Regimens for Drug-Susceptible Tuberculosis in Infants, Children, and Adolescents
| INFECTION/DISEASE CATEGORY | REGIMEN | COMMENTS |
|---|---|---|
| LATENT MYCOBACTERIUM TUBERCULOSIS INFECTION a | ||
| Isoniazid susceptible |
12 weeks of isoniazid plus rifapentine, once a week or |
|
|
4 mo of rifampin, once a day or |
Continuous daily therapy is required. Intermittent therapy even by DOT is not recommended. | |
| 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 | 4 mo of rifampin, once a day | Continuous daily therapy is required. Intermittent therapy even by DOT is not recommended. |
| Isoniazid-rifampin resistant | Consult a tuberculosis specialist. | Moxifloxacin or levofloxacin with or without ethambutol or pyrazinamide. |
| PULMONARY AND EXTRAPULMONARY INFECTION | ||
| Except meningitis b | 2 mo of isoniazid, rifampin, pyrazinamide, and ethambutol daily or twice weekly, followed by 4 mo of isoniazid and rifampin c by DOT d for drug-susceptible M. tuberculosis |
Some experts recommend a 3-drug initial regimen (isoniazid, rifampin, and pyrazinamide) if the risk of drug resistance is low. DOT is highly desirable. If hilar adenopathy only and the risk of drug resistance is low, 6 mo course of isoniazid and rifampin is sufficient. Drugs can be given 2 or 3 times/wk under DOT. |
| 9-12 mo of isoniazid and rifampin for drug-susceptible Mycobacterium bovis | ||
| Meningitis |
2 mo of isoniazid, rifampin, pyrazinamide, and an aminoglycoside e or ethionamide, once daily, followed by 7-10 mo of isoniazid and rifampin, once daily or twice weekly (9-12 mo total) for drug-susceptible M. tuberculosis At least 12 mo of therapy without pyrazinamide for drug-susceptible M. bovis |
For patients who may have acquired tuberculosis in geographic areas where resistance to streptomycin is common, kanamycin, amikacin, or capreomycin can be used instead of streptomycin. |
a Positive TST or IGRA result, no disease. See text for comments and additional acceptable/alternative regimens.
b Duration of therapy may be longer for human immunodeficiency virus (HIV)-infected people, and additional drugs and dosing intervals may be indicated
c Medications should be administered daily for the 1st 2 wk to 2 mo of treatment and then can be administered 2-3 times/wk by DOT. (Twice-weekly therapy is not recommended for HIV-infected people.)
d If initial chest radiograph shows pulmonary cavities, and sputum culture after 2 mo of therapy remains positive, the continuation phase is extended to 7 mo, for a total treatment duration of 9 mo.
e Streptomycin, kanamycin, amikacin, or capreomycin.
DOT, Directly observed therapy; IGRA, interferon-γ release assay; TST, tuberculin skin test.
Adapted from American Academy of Pediatrics: Red book: 2018–2021 report of the Committee on Infectious Diseases, ed 31, Elk Grove Village, IL, 2018, AAP (Table 3.85).
Major adverse effects include hepatotoxicity in 1% of children and approximately 3% of adults (increasing with age) and dose-related peripheral neuropathy. Pyridoxine can prevent the peripheral neuropathy and is indicated for breastfeeding 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 241.2 ). The metabolism of INH is by acetylation. Acetylation rates have minimal 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 receiving concomitant hepatotoxic drugs, including other antimycobacterial agents, acetaminophen, or alcohol. Monthly clinic visits while taking INH alone are encouraged to monitor adherence, adverse effects, and worsening of infection.
Table 241.2
The rifamycins (rifampin, rifabutin, rifapentine) are a class of macrolide antibiotics developed from Streptomyces mediterranei. Rifampin is a synthetic derivative of rifamycin B, and rifabutin is a derivative of rifamycin S. Rifapentine is a cyclopentyl derivative. The rifamycins inhibit the DNA-dependent RNA polymerase of mycobacteria, resulting in decreased RNA synthesis. These agents are generally bactericidal at treatment doses, but they may be bacteriostatic at lower doses. Resistance is from a mutation in the DNA-dependent RNA polymerase gene (rpoB ) that is often induced by previous incomplete therapy. Cross-resistance between rifampin and rifabutin has been demonstrated.
Rifampin is active against M. tuberculosis, M. leprae, M. kansasii, and M. avium complex. Rifampin is an integral drug in standard combination treatment of active M. tuberculosis disease and can be used as an alternative to INH in the treatment of latent tuberculosis infection in children who cannot tolerate INH. Rifabutin has a similar spectrum, with increased activity against M. avium complex. Rifapentine is undergoing pediatric clinical trials and appears to have activity similar to the activity of rifampin. The pediatric dosage of rifampin is 10-15 mg/ kg/day PO in a single dose, not to exceed 600 mg/day. The adult dosage of rifampin is 5-10 mg/kg/day PO in a single dose, not to exceed 600 mg/day. Commonly used rifampin preparations include 150 and 300 mg capsules and a suspension that is usually formulated at a concentration of 10 mg/mL. The shelf life of rifampin suspension is short (approximately 4 wk), so it should not be compounded with other antimycobacterial agents. An IV form of rifampin is also available for initial treatment of patients who cannot take oral preparations. Dosage adjustment is needed for patients with liver failure. Other rifamycins (rifabutin and rifapentine) have been poorly studied in children and are not recommended for pediatric use.
Rifampin can be associated with adverse effects such as transient elevations of liver enzymes; gastrointestinal (GI) upset with cramps, nausea, vomiting, and anorexia; headache; dizziness; and immunologically mediated fever and flulike symptoms. Thrombocytopenia and hemolytic anemias can also occur. Rifabutin has a similar spectrum of toxicities, except for an increased incidence of rash (4%) and neutropenia (2%). Rifapentine has fewer adverse effects but is associated with hyperuricemia and cytopenias, especially lymphopenia and neutropenia. All rifamycins can turn urine and other secretions (tears, saliva, stool, sputum) orange, which can stain contact lenses. Patients and families should be warned about this common but otherwise innocuous adverse effect.
Rifamycins induce the hepatic cytochrome P450 (CYP) isoenzyme system and are associated with the increased metabolism and decreased level of several drugs when administered concomitantly. These drugs include digoxin, corticosteroids such as prednisone and dexamethasone, dapsone, fluconazole, phenytoin, oral contraceptives, warfarin, and many antiretroviral agents, especially protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Rifabutin has less of an effect on lowering protease inhibitor levels.
The use of pyrazinamide in combination with rifampin for short-course latent tuberculosis therapy has been associated with serious liver dysfunction and death. This combination has never been well studied or recommended for pediatric patients and should not be used.
No routine laboratory monitoring for rifamycins is indicated unless the patient is symptomatic. In patients with signs of toxicity, complete blood count (CBC) and kidney and liver function tests are indicated.
Pyrazinamide (PZA ) is a synthetic pyrazide analog of nicotinamide that is bactericidal against intracellular M. tuberculosis organisms in acidic environments, such as within macrophages or inflammatory lesions. A bacteria-specific enzyme (pyrazinamidase) converts PZA to pyrazinoic acid, which leads to low pH levels not tolerated by M. tuberculosis. Resistance is poorly understood but can arise from bacterial pyrazinamidase alterations.
PZA is indicated for the initial treatment phase of active tuberculosis in combination with other antimycobacterial agents. The pediatric dosage is 15-30 mg/kg/day PO in a single dose, not to exceed 2,000 mg/day. Twice-weekly dosing with directly observed therapy only is with 50 mg/kg/day PO in a single dose, not to exceed 4,000 mg/day. It is available in a 500 mg tablet and can be made into a suspension of 100 mg/mL.
Adverse effects include GI upset (e.g., nausea, vomiting, poor appetite) in approximately 4% of children, dosage-dependent hepatotoxicity, and elevated serum uric acid levels that can precipitate gout in susceptible adults. Approximately 10% of pediatric patients have elevated uric acid levels but with no associated clinical sequelae. Minor reactions include arthralgias, fatigue, and, rarely, fever.
Use of PZA in combination with rifampin for short-course treatment of latent tuberculosis is associated with serious liver dysfunction and death, and this combination should be avoided.
No routine laboratory monitoring for PZA is required, but monthly visits to reinforce the importance of therapy are desirable.
Ethambutol is a synthetic form of ethylenedi-imino-di-1-butanol dihydrochloride that inhibits RNA synthesis needed for cell wall formation. At standard dosages ethambutol is bacteriostatic, but at dosages >25 mg/kg it has bactericidal activity. The mechanism of resistance to ethambutol is unknown, but resistance develops rapidly when ethambutol is used as a single agent against M. tuberculosis.
Ethambutol is indicated for the treatment of infections caused by M. tuberculosis, M. kansasii, M. bovis, and M. avium complex. Ethambutol should only be used as part of a combination treatment regimen for M. tuberculosis. Daily dosing is 15-20 mg/kg PO in a single dose, not to exceed 2,500 mg/day. Twice-weekly dosing is with 50 mg/kg PO in a single dose, not to exceed 2,500 mg/day. Dosage adjustment is needed in renal insufficiency. Ethambutol is available in 100 and 400 mg tablets.
The major adverse effect with ethambutol is optic neuritis , and thus ethambutol should generally be reserved for children old enough to have visual acuity and color discrimination reliably monitored. Visual changes are usually dosage dependent and reversible. Other adverse events include headache, dizziness, confusion, hyperuricemia, GI upset, peripheral neuropathy, hepatotoxicity, and cytopenias, especially neutropenia and thrombocytopenia.
Routine laboratory monitoring includes baseline and periodic visual acuity and color discrimination testing, CBC, serum uric acid levels, and kidney and liver function tests.
The aminoglycosides used for mycobacterial infections include streptomycin, amikacin, kanamycin, and capreomycin. Streptomycin is isolated from Streptomyces griseus and was the first 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 second-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 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, derived from Streptomyces orchidaceus or Streptomyces garyphalus, is a synthetic analog of the amino acid D -alanine that interferes with bacterial cell wall synthesis through 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 1 g/day. It is available in a 250 mg capsule.
The major adverse effect is neurotoxicity with significant psychologic disturbance, including seizures, acute psychosis, headache, confusion, depression, and personality changes. The neurotoxic effects are additive with ethionamide and INH. Cycloserine has also been associated with megaloblastic anemia. It must be dosage-adjusted in patients with kidney impairment and 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 <30 µg/mL.
Ethionamide is structurally related to INH and is an ethyl derivative of thioisonicotinamide that inhibits peptide synthesis by an unclear mechanism thought to involve nicotinamide adenine dinucleotide and NAD phosphate 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, INH, and PZA. 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.
Gastrointestinal 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. Ethionamide 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 taking ethionamide, blood glucose levels should be monitored.
The fluoroquinolones are fluorinated derivatives of the quinolone class of antibiotics. Ciprofloxacin is a first-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 old, 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 by inhibition of DNA gyrase. The alterations in DNA gyrase result in relaxation of supercoiled 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 second-line drug in the treatment of multidrug-resistant (MDR) M. tuberculosis. Ciprofloxacin has activity against Mycobacterium fortuitum complex and against M. tuberculosis. The pediatric dosage of ciprofloxacin is 20-30 mg/kg/day PO or intravenously (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 in 2 divided 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, 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 CYP isoenzymes that can increase the concentrations of dually administered theophylline and warfarin. Nonsteroidal antiinflammatory drugs (NSAIDs) 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 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 mycobacterial 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 mycobacteria, but studies reveal in vitro activity against rapidly growing mycobacteria (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 old, 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 preexisting myelosuppression.
In addition to monitoring for GI upset and CNS perturbations, routine laboratory monitoring includes CBC at least weekly.
Paraaminosalicylic acid (PAS ) is a structural analog of paraaminobenzoic 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 effects 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.
This oral diarylquinoline has been recommended for the treatment of MDR tuberculosis. Bedaquiline fumarate should be used as part of combination therapy and administered by direct observation. Although approved for patients ≥18 yr old, bedaquiline may be considered for children on a case-by-case basis.
Serious adverse effects include hepatotoxicity and a prolonged QT interval.
Delamanid is a dihydro-nitroimidazooxazole derivative recently approved for use in the treatment of MDR tuberculosis. It acts by inhibiting the synthesis of mycobacterial cell wall compounds such as methoxymycolic acid and ketomycolic acid. Limited studies are available in the pediatric population, and delamanid should be used only in conjunction with a tuberculosis specialist.
Adverse effects include nausea, vomiting, dizziness, anxiety, shaking, and QT prolongation.
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 effects , 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. Treatment may produce a lepra reaction, 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, urinalysis, and liver function tests.
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. Clofazimine 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.
Cefoxitin, a cephamycin derivative, is a second-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 241.3 ). 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 and IM formulations. Increased dosing intervals are needed with renal insufficiency.
Table 241.3
Treatment of Nontuberculous Mycobacteria Infections in Children
| ORGANISM | DISEASE | INITIAL TREATMENT |
|---|---|---|
| SLOWLY GROWING SPECIES | ||
| Mycobacterium avium complex (MAC); Mycobacterium haemophilum ; Mycobacterium lentiflavum | Lymphadenitis | Complete excision of lymph nodes; if excision incomplete or disease recurs, clarithromycin or azithromycin plus ethambutol and/or rifampin (or rifabutin). |
| Pulmonary infection | 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 with mild to moderate disease support that 3-times-weekly therapy is as effective as daily therapy, with less toxicity. For patients with advanced or cavitary disease, drugs should be given daily. | |
| Mycobacterium chimaera | Prosthetic valve endocarditis | Valve removal, prolonged antimicrobial therapy based on susceptibility testing. |
| Disseminated | See text. | |
| Mycobacterium kansasii | Pulmonary infection | Rifampin plus ethambutol with isoniazid daily. If rifampin resistance is detected, a 3-drug regimen based on drug susceptibility testing should be used. |
| Osteomyelitis | Surgical debridement and prolonged antimicrobial therapy using rifampin plus ethambutol with isoniazid. | |
| Mycobacterium marinum | Cutaneous infection | None, if minor; rifampin, TMP-SMX, clarithromycin, or doxycycline* for moderate disease; extensive lesions may require surgical debridement. Susceptibility testing not routinely required. |
| Mycobacterium ulcerans | Cutaneous and bone infections | Daily intramuscular streptomycin and oral rifampin for 8 wk; excision to remove necrotic tissue, if present; potential response to thermotherapy. |
| RAPIDLY GROWING SPECIES | ||
| Mycobacterium fortuitum group | Cutaneous infection | Initial therapy for serious disease is amikacin plus meropenem IV, followed by clarithromycin, doxycycline,* TMP-SMX, or ciprofloxacin PO, on the basis of in vitro susceptibility testing; may require surgical excision. Up to 50% of isolates are resistant to cefoxitin. |
| Catheter infection | Catheter removal and amikacin plus meropenem IV; clarithromycin, TMP-SMX, or ciprofloxacin, orally, on the basis of in vitro susceptibility testing. | |
| Mycobacterium abscessus | Otitis media; cutaneous infection | There is no reliable antimicrobial regimen because of variability in drug susceptibility. Clarithromycin plus initial course of amikacin plus cefoxitin or imipenem/meropenem; may require surgical debridement on the basis of in vitro susceptibility testing (50% are amikacin resistant). |
| Pulmonary infection (in cystic fibrosis) | Serious disease, clarithromycin, amikacin, and cefoxitin or imipenem/meropenem on the basis of susceptibility testing; most isolates have very low MIC to tigecycline; may require surgical resection. | |
| Mycobacterium chelonae | Catheter infection, prosthetic valve endocarditis | Catheter removal; debridement, removal of foreign material; valve replacement; and tobramycin (initially) plus clarithromycin, meropenem, and linezolid. |
| Disseminated cutaneous infection | Tobramycin and meropenem or linezolid (initially) plus clarithromycin. | |
* Doxycycline can be used for short durations (i.e., ≤21 days) without regard to patient age, but for longer treatment durations is not recommended for children <8 yr old. Only 50% of isolates of M. marinum are susceptible to doxycycline.
IV, Intravenously; MIC, minimum inhibitory concentration; PO, orally (by mouth); TMP-SMX, trimethoprim-sulfamethoxazole.
From American Academy of Pediatrics: Red book: 2018–2021 report of the Committee on Infectious Diseases, ed 31, Elk Grove Village, IL, 2018, AAP (Table 3.90).
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 is in the tetracycline family of antibiotics and has limited use in pediatrics. As with 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 241.3 ). Although it can be used to treat Mycobacterium marinum, adult treatment failures have occurred. Pediatric dosing is based on age and weight. For children >8 yr old who weigh <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 becomes 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.
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 Mycobacterium abscessus, 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 (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 241.3 ). Oral or IV pediatric dosage for serious infections is TMP 15-20 mg/kg/day divided every 6-8 hr, and for mild infections, TMP 6-12 mg/kg/day divided every 12 hr. 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.