| isoniazid mechanism | Isoniazid (INH) is a structural congener of pyridoxine.
Its mechanism of action involves inhibition of the synthesis of mycolic acids, essential parts of mycobacterial cell walls.
It is a prodrug that is activated by a mycobacterial catalase-peroxidase (KatG).
It inhibits enoyl acyl carrier protein reductase (InhA) and a β-ketoacyl-ACP synthase (KasA) within the unique Type II fatty acid synthase system for mycolic acids.
INH is bactericidal for actively growing tubercle bacilli, but is less effective against dormant organisms. |
| isoniazid resistance | Resistance can emerge rapidly if the drug is used alone. High-level resistance is associated with deletion in the katG gene that codes for a catalase-peroxidase involved in the bioactivation of INH. Low-level resistance occurs via deletions in the inhA gene that encodes the target enzyme, an acyl carrier protein reductase.
Cross-resistance does not occur between isoniazid and other antitubercular drugs. |
| Inh pharmacokinetics | INH is taken orally and penetrates cells to act on intracellular mycobacteria.
The liver metabolism of INH is by acetylation and is under genetic control.
Patients may be fast or slow inactivators of the drug.
It enters CSF.
Absorption is impaired if isoniazid is taken with food, particularly carbohydrates, or with aluminum-containing antacids.
Infected tissue tends to retain the drug longer. Isoniazid undergoes N acetylation and hydrolysis, resulting in inactive products.
INH halflife in fast acetylators is 60–90 min; in slow acetylators it may be 3–4 h. Fast acetylators may require higher dosage than slow acetylators for equivalent therapeutic effects. |
| clinical use inh | INH is the single most important drug used in tuberculosis
It is a component of most drug combination regimens.
In the treatment of latent infection (formerly known as prophylaxis), skin test converters and for close contacts of patients with active disease, INH is given as the sole drug. |
| Inh toxicity | Neurotoxic effects i.e peripheral neuritis, restlessness, muscle twitching, and
insomnia.These effects are due to pyridoxine defeciency and can be fixed by giving pyridoxine (25–50 mg/d orally).
INH is hepatotoxic and may cause abnormal liver function tests, jaundice, and hepatitis. Hepatotoxicity is rare in children.It has been suggested that this is caused by a toxic metabolite of monoacetylhydrazine , formed during the metabolism of isoniazid. The incidence increases among patients with increasing age, among patients who also take rifampin, or among those who drink alcohol daily.
INH may inhibit the hepatic metabolism of drugs (eg, carbamazepine, phenytoin, warfarin). Slow acetylators are particularly at risk.
Hemolysis has occurred in patients with glucose-6-phosphate dehydrogenase (G6PDH) deficiency.
A lupus-like syndrome has also been reported, rashes and fever, optic neuritis |
| rifampin mechanism | Rifampin, a derivative of rifamycin, is bactericidal against M tuberculosis. The drug inhibits DNA-dependent RNA polymerase (encoded by the rpo gene) in M tuberculosis and many other microorganisms.
It has broader spectrum than isoniazid
Rifampin blocks transcription by interacting with the β subunit of bacterial, but not human, DNAdependent RNA polymerase and inhibiting mRNA synthesis
Resistance via changes in drug sensitivity of the polymerase often emerges rapidly if the drug is used alone. |
| rifampin pharmacokinetics | rifampin is given orally
it is distributed to most body tissues, including the central nervous system even without inflammation it is present in csf
The drug undergoes enterohepatic cycling and is partially metabolized in the liver.
Both free drug and metabolites, which are orange-colored, are eliminated mainly in the feces. |
| Uses of rifampin | rifampin is almost always used in combination with other drugs for tuberculosis
rifampin can be used as the sole drug in treatment of latent tuberculosis in INH-intolerant patients or in close contacts of patients with INH-resistant strains of the organism.
In leprosy, rifampin given monthly delays the emergence of resistance to dapsone. |
| rifampin toxicity | Rifampin commonly causes light-chain proteinuria and may impair antibody responses.
skin rashes, thrombocytopenia,nephritis, and liver dysfunction nausea vomiting
hepatitis and liver failure rare but shouldnt be used for elderly and alcoholics increased incidence with isoniazid
If given less than twice weekly, rifampin may cause a flu-like syndrome and anemia, fever, chills, and myalgias, acute renal failure, hemolytic anemia, and shock.
Rifampin strongly induces liver drug-metabolizing enzymes and enhances the elimination rate of many drugs, including anticonvulsants, contraceptive steroids, cyclosporine, ketoconazole, methadone, terbinafine, and warfarin. |
| ethambutol mechanism | It inhibits arabinosyltransferases (encoded by the embCAB operon) involved in the synthesis of arabinogalactan, a component of mycobacterial cell walls.
Resistance occurs rapidly via mutations in the emb gene if the drug is used alone.
it is bacteriostatic
Resistance is not a serious problem if the drug is employed with other antitubercular agents. |
| ethambutol pharmacokinetics | The drug is well absorbed orally and distributed to most tissues, including the CNS.
A large fraction is eliminated unchanged in the urine.
Dose reduction is necessary in renal impairment. |
| uses of ethambutol | The main use of ethambutol is in tuberculosis,and it is always given in combination with other drugs. |
| ethambutol adverse effects | The most common adverse effects are dose-dependent visual disturbances, including decreased visual acuity, red-green color blindness, optic neuritis, and possible retinal damage (from prolonged use at high doses).
Most of these effects regress when the drug is stopped.
Other adverse effects include headache, confusion,hyperuricemia and peripheral neuritis.
increased urate levels |
| pyrazinamide mechanism | The mechanism of action of pyrazinamide is not known; however, it has bacteriostatic action that appears to require metabolic conversion via pyrazinamidases (encoded by the pncA gene) present in M tuberculosis.
Resistance occurs via mutations in the gene that encodes enzymes involved in the bioactivation of pyrazinamide and by increased expression of drug efflux systems. This develops rapidly when the drug is used alone, but there is minimal cross-resistance with other antimycobacterial drugs.
Some resistant strains lack the pyrazinamidase. Pyrazinamide is active against tubercle bacilli in the acidic environment of lysosomes, and macrophages. |
| pharmacokinetics pyrazinamide | Pyrazinamide is absorbed orally and penetrates most body tissues, including the CNS.
The drug is partly metabolized to pyrazinoic acid which is its active form, and both parent molecule and metabolite are excreted in the urine.
The plasma half-life of pyrazinamide is increased in hepatic or renal failure |
| clinical use pyrazinamide | combined use of pyrazinamide with other antituberculous drugs is an important factor in the success of shortcourse treatment regimens. |
| toxicity pyrazinamide | Approximately 40% of patients develop nongouty polyarthralgia
urate accumulation leads to gout hyperurecemia
one in 5 people experience liver dysfunction
Other adverse effects are myalgia, gastrointestinal irritation, maculopapular rash, hepatic dysfunction, porphyria, and photosensitivity reactions. Pyrazinamide should be avoided in pregnancy. |
| streptomycin | Streptomycin is used principally in drug combinations for the treatment of life-threatening tuberculous disease, including meningitis, miliary dissemination, and severe organ tuberculosis. |
| anikacin | Amikacin is a second line drug indicated for the treatment of tuberculosis suspected to be caused by streptomycin-resistant or multidrugresistant mycobacterial strains.
To avoid emergence of resistance, amikacin should always be used in combination drug regimens. |
| ciprafloxacin and ofloxacin | Ciprofloxacin and ofloxacin are often active against strains of
M tuberculosis resistant to first-line agents.
They are second line drugs.
The fluoroquinolones should always be used in combination regimens with two or more other active agents. |
| ethionamide | Ethionamide is a congener of INH, but cross-resistance does not occur.
Ethionamide can inhibit acetylation of isoniazid
It is effective after oral administration and is widely distributed including the CSF Adverse effects that limit its use include gastric irritation, hepatotoxicity, peripheral neuropathies, and optic neuritis.
Supplementation with vitamin B6 (pyridoxine) may lessen the severity of the neurologic side effects. |
| p aminosalicylic acid | p-Aminosalicylic acid (PAS) is rarely used because primary resistance is common.
In addition, its toxicity includes gastrointestinal irritation, peptic ulceration, hypersensitivity reactions, and effects on kidney, liver, and thyroid function. |
| drugs not in use | Other drugs of limited use because of their toxicity include capreomycin (ototoxicity, renal dysfunction) and cycloserine which inhibits synthesis of d-alanine(peripheral neuropathy, CNS dysfunction). |
| Standard regimen | For empiric treatment of pulmonary TB (in most areas of <4% INH resistance), an initial 3-drug regimen of INH, rifampin, and pyrazinamide is recommended.
If the organisms are fully susceptible (and the patient is HIV-negative), pyrazinamide can be discontinued after 2 month and treatment continued for a further 4 month with a 2-drug regimen.
ethambutol can be given with 3 drugs too |
| alternative regimen | Alternative regimens in cases of fully susceptible organisms include INH + rifampin for 9 month, or INH + ethambutol for 18 month.
Intermittent (2 or 3 × weekly) high-dose 4-drug regimens are also effective. |
| resistance in regimen | If resistance to INH is higher than 4%, the initial drug regimen should include ethambutol or streptomycin.
Tuberculosis resistant only to INH (the most common form of resistance) can be treated for 6 month with a regimen of rifampin + pyrazinamide + ethambutol or streptomycin.
Multidrug-resistant organisms (resistant to both INH and rifampin) should be treated with 3 or more drugs to which the organism is susceptible for a period of more than 18 month, including 12 mo after sputum cultures become negative. |
| tuberculosis test | Diagnostic testing for tuberculosis can be accomplished via the standard tuberculin skin test with purified protein derivative (PPD) or by an interferon-gamma release assay (IGRA) blood test, Quantiferon-TB Gold, approved by the FDA in 2005. The advantages that the blood test offers is that it requires only a single test visit, and it is less susceptible to false positive results due to BCG vaccination or to infection with mycobacteria other than Mycobacterium tuberculosis. |
| first line drugs | Ethambutol MYAMBUTOL Isoniazid (INH) NYDRAZID, OTHERS
Pyrazinamide
Rifamycins RIFADIN |
| 2nd line drugs | Aminoglycosides
Aminosalicylic acid PASER
Capreomycin CAPASTAT SULFATE
Cycloserine SEROMYCIN
Ethionamide TRECATOR
Fluoroquinolones
Macrolides |
| Antibacterial spectrum isoniazid | For bacilli in the stationary phase, isoniazid is bacteriostatic, but for rapidly dividing organisms, it is bactericidal.
It is effective against intracellular bacteria.
Isoniazid is specific for treatment of M. tuberculosis, although Mycobacterium kansasii(an organism that causes three percent of the clinical illness known
as tuberculosis) may be susceptible at higher drug levels. |
| rifamycins include | Rifampin, rifabutin and rifapentine |
| antimicrobial spectrum rifampin | Rifampin is bactericidal for both intracellular and extracellular mycobacteria, including M. tuberculosis, and atypical mycobacteria, such as M. kansasii.
It is used against many gram-positive and gram-negative organisms
it may be used with vancomycin for infections due to resistant staphylococci (methicillin-resistant Staphylococcus aureus [MRSA] strains) or pneumococci (penicillin-resistant Streptococcus pneumoniae [PRSP] strains).
Other uses of rifampin include the meningococcal and staphylococcal carrier states.
it is used prophylactically for individuals exposed to meningitis caused by meningococci or Haemophilus influenzae. |
| resistance rifampin | Resistance to rifampin can be caused by a mutation in the affinity of the bacterial DNA-dependent RNA polymerase for the drug, or by decreased permeability. |
| rifabutin | It is a derivative of rifampin, is the preferred drug for use in tuberculosis-infected patients with (HIV), who are concomitantly treated with protease inhibitors or nonnucleoside reverse transcriptase inhibitors, because it is a less potent inducer of cytochrome P450 enzymes.
Rifabutin has adverse effects similar to those of rifampin, but can also cause uveitis, skin hyperpigmentation, and neutropenia. |
| rifapentine | It has activity comparable to that of rifampin but has a longer half-life than rifampin and rifabutin, which permits weekly dosing.
However, for the intensive phase(initial 2 months) of the short-course therapy for tuberculosis, rifapentine is given twice weekly. In the subsequent phase, rifapentine is dosed once per week for 4 months.
To avoid resistance issues, rifapentine should not be used alone but, rather, be included in a three to four-drug regimen. |
| rifamixin | it is not properly absorbed from git and used for travelers diarrhea |
| fluoroquinolones | The fluoroquinolones, specifically, ciprofloxacin, moxifloxacin and levofloxacin have an important place in the treatment of multidrug-resistant tuberculosis.
Some atypical strains of mycobacteria are also susceptible |
| macrolides | The macrolides, such as azithromycin and clarithromycin, are part of the regimen that includes ethambutol and rifabutin used for the treatment of infections by M. avium-intracellulare complex.
Azithromycin is preferred for HIV-infected patients because it is least likely to interfere with the metabolism of antiretroviral drugs. |
