ANTI TUBERCULAR DRUGS

REGIMEN (RNTCP)

Categories of tuberculosis and their treatment regimens have been recommended by WHO.

bone tuberculosis is classified to be a severe form of extrapulmonary tuberculosis and hence should be given Category I treatment (2HRZE & 4HR i.e. 2 months of H,R,Z and E followed by 4 months of H and R).

two phases: an initial ‘Intensive phase’, consisting of four to five drugs to rapidly destroy the majority of the organisms

a ‘continuation phase’ which consists of two to three drugs.

Historically, the recommended duration was - 18 to 24-no scientific basis

Even today there is lack of consensus regarding the ideal duration of treatment for bone TB.

Uncertainty about the penetration of osteoarticular lesions by the available drugs and the fear of early or late recurrence forced the surgeons to continue chemotherapy for prolonged periods.

Modern anti-tuberculous drugs have been shown to penetrate osseous tissue in amounts much higher than the minimal inhibitory concentrations.

Wallace Fox for the first time proved that addition of R or Z to regimens containing H made it possible to shorten the duration of treatment

FIRST LINE AGENTS

ISONIAZID (INH)

Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains

structural similarity to pyridoxine. MOA: Isoniazid inhibits synthesis of

mycolic acids, which are essential components of mycobacterial cell walls.

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orally administered, well absorbed, widely distributed in body, including cerebrospinal fluid.

INH can also penetrate into macrophages.

Most INH is metabolized in the liver.

PHARMACOLOGIC ACTIVITY

bactericidal - actively growing tubercle bacilli. bacteriostatic -resting tubercle bacilli.

Isoniazid is able to penetrate into phagocytic cells and thus is active again both extracellular and intracellular organisms.

DOSE: ADULTS: PO/IM 5 mg/kg/day as single daily dose (max 300 mg/day). INFANTS & CHILDREN: PO/IM 10 to 20 mg/kg/day in single daily dose (max 300 mg/day).

ADVERSE EFFECTS

Allergic Reaction: fever,skin rash Hepatotoxicity : Up to 20% of patients taking

INH develop elevated serum amino transferase levels.

Severe hepatic injury occurs more frequently in patients over the age of 35, especially in those who are alcoholic.

Isoniazid is discontinued if symptoms of hepatitis develop or if the aminotransferase activity increases to more than three times normal.

Peripheral and CNS toxicity - toxicity results from an increased excretion of pyridoxine induced by isoniazid, which produces a pyridoxine deficiency.

Peripheral neuritis, urinary retention, insomnia, and psychotic episodes can occur.

Concurrent pyridoxine 25–50 mg/d administration with INH prevents most of these complications.

Isoniazid as a single agent is also indicated for treatment of latent tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or 900 mg twice weekly for 9 months.

RIFAMPIN

Synthetic derivates of rifamycin B produced by Sterptomyces mediterranei

oral administration, well absorbed, widely distributed in body.

most of the drug is excreted as a deacylated metabolite in feces and in the urine.

half-life is about 4 hours.

PHARMACOLOGY

It is bactericidal for mycobacteria. It can kill organisms that are poorly accessible to

many other drugs, such as intracellular organisms and those sequestered in abscesses.

MOA: It binds strongly to the β-subunit of DNA-dependent RNA polymerase and thereby inhibits RNA synthesis.

Drug-resistance is due to target mutations in RNA polymerase, occurs readily.

No cross-resistance to other classes of antimicrobial drugs.

ADVERSE EFFECTS

Urine, sweat, tears, and contact lenses may take on an orange color because of rifampin administration, this effect is harmless.

Light-chain proteinuria and impaired antibody response may occur.

Rifampin induces hepatic microsomal enzymes and therefore, affects the half-life of a number of drugs.

When taken erratically in large doses, a febrile “flu-like” syndrome can occur.

DOSE

Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be administered with isoniazid or other antituberculous drugs to patients with active tuberculosis to prevent emergence of drug-resistant mycobacteria.

ETHAMBUTOL

bacteriostatic Well absorbed from the gut and widely

distributed in all body tissues and fluids. resistance to ethambutol emerges rapidly

when the drug is used alone. The most common serious adverse effect

is dose-related optic neuritis, causing loss of visual acuity and red-green color-blindness, but are reversible.

Ethambutol hydrochloride, 15–25 mg/kg, is usually given as a single daily dose

50 mg/kg when a twice-weekly dosing schedule

PYRAZINAMIDE

Pyrazinamide is a pyrazine analogue of nicotinamide.

pH 5.5 it inhibits tubercle bacilli and some other mycobacteria.

Quickly absorbed after oral administration

Widely distributed in body tissues,including inflamed meninges.

Excreted mainly by glomerular filtration

ADVERSE EFFECTS

Major adverse effects of pyrazinamide include hepatotoxicity (in 1–5% of patients)

nausea, vomiting, drug fever, and hyperuricemia.

Hyperuricemia may provoke acute gouty arthritis.

DOSE: 40–50 mg/kg is used for thrice-weekly or twice-weekly treatment regimens

STREPTOMYCIN

Streptomycin - first antimicrobial drug used to treat tuberculosis.

It is effective against most tubercle bacilli, but its activity is weaker than that of INH and RFP.

Streptomycin penetrates cells poorly-produce drug resistance.

It is always given together with other drugs to prevent emergence of resistance.

The typical adult dose is 1 g/d (15 mg/kg/d). If the creatinine clearance is less than 30 mL/min or the patient is on hemodialysis, the dose is 15 mg/kg two or three times a week

MDR TB

Multi-drug-resistant tuberculosis (MDR-TB) is defined as tuberculosis that is resistant to at least isoniazid (INH) and rifampicin.

multidrug-resistant tuberculosis can be cured with long treatments of second-line drugs, but these are more expensive than first-line drugs and have more adverse effects.

SECOND LINE AGENTS

WHEN CAN IT BE USED

(1) in case of resistance to first-line agents;

(2) in case of failure of clinical response to conventional therapy;

(3) in case of serious treatment-limiting adverse drug reactions;

(4) when expert guidance is available to deal with the toxic effects

ETHIONAMIDE

Ethionamide is chemically related to isoniazid blocks the synthesis of mycolic acids. It is poorly water-soluble and available only in

oral form. It is metabolized by the liver Ethionamide is administered at an initial dose of

250 mg once daily, which is increased in 250-mg increments to the recommended dosage of 1 g/d (or 15 mg/kg/d), if possible.

ADVERSE EFFECTS

intense gastric irritation , neurologic symptoms

Ethionamide is also hepatotoxic. Neurologic symptoms may be alleviated

by pyridoxine. Resistance to ethionamide as a single

agent develops rapidly in vitro and in vivo. low-level cross-resistance between

isoniazid and ethionamide.

CAPREOMYCIN

peptide protein synthesis inhibitor, antibiotic obtained from Streptomyces capreolus.

Daily injection of 1 g intramuscularly Capreomycin (15 mg/kg/d) is an important

injectable agent for treatment of drug-resistant tuberculosis.

Strains of M tuberculosis resistant to streptomycin or amikacin (eg, the multidrug-resistant W strain) are susceptible to capreomycin.

Resistance to capreomycin, may be due to an rrs mutation.

nephrotoxic and ototoxic. Tinnitus, deafness, and vestibular

disturbances occur. The injection causes significant local

pain, and sterile abscesses may occur. Toxicity is reduced if 1 g is given two or

three times weekly after an initial response has been achieved with a daily dosing schedule

CYCLOSERINE

Cycloserine is an inhibitor of cell wall synthesis.

Cycloserine is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min.

ADVERSE:peripheral neuropathy and central nervous system dysfunction, depression and psychotic reactions

Pyridoxine 150 mg/d should be given with cycloserine to ameliorates neurologic toxicity. Adverse effects - most common during the first 2 weeks of therapy, occur at higher doses.

Side effects can be minimized by monitoring peak serum concentrations.

The peak concentration is reached 2–4 hours after dosing. The recommended range of peak concentrations is 20–40 mcg/mL

Contraindications- Epilepsy; depression; severe anxiety or psychosis; severe renal insufficiency; excessive concurrent use of alcohol.

Route/DosageADULTS: PO 250–500 mg q 12 hr; start with

250 mg q 12 hr for first 2 wk (maximum 1 g/day). CHILDREN: PO 10–20 mg/kg/day administered in 2 equally divided doses (maximum 1 g/day).

AMINOSALICYLIC ACID (PAS)

Competitively antagonizes metabolism of para-aminobenzoic acid, resulting in bacteriostatic activity against Mycobacterium tuberculosis.

Adverse:Peptic ulceration and hemorrhage may occur. Hypersensitivity reactions may occur after 3–8 weeks of aminosalicylic acid therapy.

Infrequently used now since better tolerated drugs are available

ADULTS: PO 12 to 16 g/day in 2 to 3 divided doses. CHILDREN: PO 275 to 420 mg/kg/day in 3 to 4 divided doses.

Contraindications; Severe hypersensitivity to aminosalicylate sodium and its congeners

KANAMYCIN & AMIKACIN

Aminoglycoside antibiotics Kanamycin has been used for treatment

of TB caused by streptomycin-resistant strains, but the availability of less toxic alternatives (eg, capreomycin and amikacin) has rendered it obsolete

Most MDR strains are amikacin sensitive Amikacin is also active against atypical

mycobacteria

no cross-resistance between streptomycin and amikacin, but kanamycin resistance often indicates resistance to amikacin as well.

Serum concentrations of 30–50 mcg/mL are achieved 30–60 minutes after a 15 mg/kg intravenous infusion.

indication- treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multidrug-resistant strains.

Amikacin must be used in combination . The recommended dosages are the same as that for

streptomycin.

FLUOROQUINOLONES

ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of M tuberculosis

Moxifloxacin is the most active against M tuberculosis by weight

the drug must be used in combination with two or more other active agents-to prevent resistance

standard dosage of ciprofloxacin is 750 mg orally twice a day, levofloxacin is 500–750 mg once a day, moxifloxacin is 400 mg once a day.

LINEZOLID

Prevents the formation of a functional 70S initiation complex, which is essential to the bacterial translation process.

It achieves good intracellular concentrations.

Linezolid has been used in combination with other second- and third-line drugs to treat patients with tuberculosis caused by multidrug-resistant strains

adverse effects; bone marrow suppression and irreversible peripheral and optic neuropathy, have been reported with the prolonged courses

600-mg (adult) dose administered once a day

it should be considered a drug of last resort for infection caused by multidrug-resistant strains.

RIFABUTIN

Inhibits DNA-dependent RNA polymerase in susceptible strains of bacteria.

Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete.

Rifabutin is both substrate and inducer of cytochrome P450 enzymes.

it is a less potent inducer, rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected patients who are receiving concurrent antiretroviral therapy with a protease inhibitor or NNRTI (eg, efavirenz)

DOSE; ADULTS: PO 300 mg once daily. INFANTS

AND CHILDREN: PO Up to 5 mg/kg/day.

RIFAPENTINE

Rifapentine is an analog of rifampin it is a bacterial RNA polymerase inhibitor. potent inducer of CYT P450 600 mg (10 mg/kg) once weekly is indicated for

treatment of tuberculosis caused by rifampin-susceptible strains during the continuation phase only .

Rifapentine should not be used to treat HIV-infected patients because of an unacceptably high relapse rate with rifampin-resistant organism.

XDR TB

XDR-TB is defined as TB that has developed resistance to at least rifampicin and isoniazid , as well as to any member of the quinolone family and at least one of the following second-line anti-TB injectable drugs: kanamycin, capreomycin, or amikacin

TB AND HIV CO-INFECTION

3–5 % of patients with pulmonary TB develops musculoskeletal lesions but the incidence of musculoskeletal lesions increases to 60 % in patients who are HIV positive.

Direct observational therapy is even more important for HIV-positive tuberculosis patients and is known to significantly decrease mortality in these patients

addition of rifampicin to the drug regimens in HIV patients significantly reduces mortality ,

protease inhibitors and NNRTI interact with rifampicin and therefore should not be prescribed along with rifampicin.

PARADOXICAL WORSENING- when antiretroviral therapy is started in a patient being treated with tb, there is rapid worsening of symptoms-improvement in inflamatory response

anti-retroviral is known to activate latent tuberculosis in HIV-positive patients which is supposed to be due to the immune reconstitution syndrome