OBAT ANTI TBERKULOSIS

OBAT ANTI TBERKULOSISDAN LEPRAE

PROF. M ARIS WIDODO

PPD UNISMA

Diseases can be sorted into five categories: genetic, infectious, environmental,due to “storage handling”, and apoptosis, time (aging). They often combine severalfactors from more than one category.

For example, patients with a genetic predisposition and living in a low socioeconomic environment may be predisposed to chronic tuberculosis and to developamyloidosis due to 2-microglobulin deposition over

time

MIROORGANSM

PRODUCTENDOTOKSINEXOTOKSN

HOSTRESPON

CYTOKAINENZIM HIDROLISA

MANIFESTASI KLINIK

PENYAKIT INFEKSI

INTRASEL

MICROORGANISM

EKTRASEL

OBAT ANTI MICROBA

macrophage

OBAT ANTI TUBERKULOSIS

TUBERKULO CIDAL MEMBUNUH BACTERI BERKEBAMNG CEPAT DILUAR SEL

BERKEMBANG LAMBAT DIDALAM SEL RIFAMPIN

ISONIAZID STREPTOYCINE TUBERCULOCIDAL EXTRCEL

PYRAZINAMIDE TUBERKULOCIDAL INTRACEL

TUBEKULO STATIK ETHAMBUTOL

ETHIONAMIDE P-AMINO SALYCILIC ACID

Drugs used in the treatment of tuberculosis can be divided into two major categories

"First-line" agents combine the greatest level of efficacy with an acceptable degree of toxicity these include

isoniazid, rifampin, ethambutol, streptomycin, and pyrazinamide

The large majority of patients with tuberculosis can be treated successfully with these drugs. Excellent results for patients with non-drug-resistant tuberculosis can be obtained with a 6-month course of treatment; for the first 2 months, isoniazid, rifampin, ethambutol, and pyrazinamide are given, followed by isoniazid and rifampin

for the remaining 4 months .

Administration of rifampin in combination with isoniazid for 9 months also is effective therapy for all forms of disease caused by strains of Mycobacterium tuberculosis susceptible to both agents

because of microbial resistance, it may be necessary to resort to "second-line" drugs in addition; thus, treatment may be initiated with 5 to 6 drugs. This category of agents includes moxifloxacin or gatifloxacin, ethionamide, aminosalicylic acid, cycloserine, amikacin, kanamycin, capreomycin, and linezolid

Obat anti tuberkulosis

Isoniazid is a prodrug; mycobacterial catalase-peroxidase converts isoniazid into an active metabolite. A primary action of isoniazid is to inhibit the biosynthesis of mycolic acids¾long, branched lipids that are attached to a unique polysaccharide, arabino galactan, to form part of the mycobacterial cell

wall .

Isoniazid also inhibits mycobacterial catalase-peroxidase (the isoniazid-activating enzyme), which may increase the likelihood of damage to the mycobacteria from reactive oxygen spesies and H2o2

Exposure to isoniazid leads to a loss of acid-fastness and a decrease in the quantity of methanol-extractable lipids in the microorganisms .

Isoniazid diffuses readily into all body fluids and cells. The drug is detectable in significant quantities in pleural and ascitic fluids; concentrations in the cerebrospinal fluid (CSF) with inflamed meninges are similar to those in the

Isoniazid penetrates well into caseous material .

Isoniazid

Isoniazid is bacteriostatic for "resting" bacilli, but is bactericidal for rapidly dividing Microorganisms

The minimal tuberculostatic concentration is 0.025 to 0.05 mg/ml.The bacteria undergo one or two divisions before multiplication is arrested

The drug is remarkably selective for mycobacteria, and concentrations in excess mg/ml are required to inhibit the growth of other microorganisms.of 500 Bacterial Resistance

When tubercle bacilli are grown in vitro in increasing concentrations of isoniazid, mutants are readily selected that are resistant to the drug, even when the drug is

present in enormous concentrations .

mechanism of isoniazid resistance is mutations in catalase-peroxidase (katg) that decrease its activity, preventing conversion of the prodrug isoniazid to its active metabolite

Another mechanism of resistance is related to a mutation in the mycobacterial inhA and KasA genes involved in mycolic acid biosynthesis

Mutations in NADH dehydrogenase (ndh) also confer isoniazid resistance

. The incidence of adverse reactions to isoniazid was estimated to be 5.4% among more than 2000 patients treated with the drug; the most prominent of these reactions were rash (2%), fever (1.2%), jaundice (0.6%), and peripheral neuritis (0.2%)

Pyridoxine, vitamin B6 dose 10-50 mg per day should be administered with isoniazid to minimize the risks of peripheral neuropathy and central nervous system

In malnourished patients and those predisposed to neuropathy (eg:pregnant .women, diabetics, alcoholics, uremics and eldery , HIV-infected

Rifampin and Other Rifamycins

Rifampin inhibits DNA-dependent RNA polymerase of mycobacteria and other microorganisms by forming a stable drug-enzyme complex, leading to suppression of initiation of chain formation (but not chain elongation) in RNA synthesis

More specifically, the subunit of this complex enzyme is the site of action of the drug, although rifampin binds only to the holoenzyme .

Nuclear RNA polymerases from a variety of eukaryotic cells do not bind rifampin, and RNA synthesis is correspondingly unaffected in eukaryotic cells

High concentrations of rifamycin antibiotics can inhibit RNA synthesis in mammalian mitochondria, viral DNA-dependent RNA polymerases, and reverse transcriptases. Rifampin is bactericidal for both intracellular and extracellular microorganisms

When given in usual doses, fewer than 4% of patients with tuberculosis have significant adverse reactions; the most common are rash (0.8%), fever (0.5%), and

nausea and vomiting (1.5%) .

Because rifampin potently induces CYP1A2, 2C9, 2C19, and 3A4, its administration results in a decreased half-life for a number of compounds, including HIV protease and non-nucleoside reverse transcriptase inhibitors, digitoxin, digoxin, quinidine, disopyramide, mexiletine, tocainide, ketoconazole, propranolol, metoprolol, clofibrate, verapamil, methadone, cyclosporine, corticosteroids, oral anticoagulants, theophylline, barbiturates, oral contraceptives, halothane, fluconazole, and the sulfonylureas

Ethambutol

Mycobacteria take up ethambutol rapidly when the drug is added to cultures that are in the exponential growth phase. However, growth is not significantly inhibited before about 24 hours. Ethambutol inhibits arabinosyl transferases involved in cell wall biosynthesis. Bacterial resistance to the drug develops in vivo via single amino acid mutations in the embA gene when ethambutol is given in the absence of other effective agents

The most important side effect is optic neuritis, resulting in decreased visual acuity and loss of ability to differentiate red from green. The incidence of this reaction is proportional to the dose of ethambutol and is observed in 15% of patients receiving 50 mg/kg per day, in 5% of patients receiving 25 mg/kg per day, and in fewer than 1% of patients receiving daily doses of 15 mg

Ethambutol produces very few untoward reactions. Fewer than 2% of nearly 2000 patients who received daily doses of 15 mg/kg of ethambutol had adverse reactions: 0.8% experienced diminished visual acuity, 0.5% had a rash, and 0.3% developed drug fever. Other side effects that have been observed are pruritus, joint pain, gastrointestinal upset, abdominal pain, malaise, headache, dizziness, mental confusion, disorientation, and possible hallucinations. Numbness and tingling of the

fingers owing to peripheral neuritis are infrequent. .

Streptomycin

Streptomycin is bactericidal for the tubercle.bacillus invtroConcentrations as low as 0.4 mg/ml may inhibit growth

The vast majority of strains of M. tuberculosis are sensitive to 10 mg/ml .

Large populations of all strains of tubercle bacilli include a number of cells that are markedly resistant to streptomycin because of mutation. However, primary resistance to the antibiotic is found in only 2% to 3% of isolates of M.

Untoward effects of streptomycin . In one series of 515 patients with tuberculosis who were treated with this aminoglycoside, 8.2% had adverse reactions; half of these involved the auditory and vestibular functions of the eighth cranial nerve. Other relatively frequent problems included

rash (in 2%) and fever (in 1.4%) .

Since other effective agents have become available, the use of streptomycin for the treatment of pulmonary tuberculosis has been sharply reduced. Many clinicians prefer to give 4 drugs, of which streptomycin may be one, for the most serious forms of tuberculosis, such as

disseminated disease or meningitis.tuberculosis.

Pyrazinamide

Pyrazinamide exhibits bactericidal activity in vitro only at a slightly acidic pH. Activity at acid pH is ideal, since M. tuberculosis resides in an acidic phagosome within the macrophage Tubercle bacilli within monocytes in vitro are inhibited or killed by the drug at a concentration of 12.5 mg/ml. Resistance develops rapidly if pyrazinamide is used alone. The target of pyrazinamide appears to be the mycobacterial fatty acid synthase I gene involved in mycolic

acid biosynthesis Pyrazinamide has become an important component of short-term (6-month) multiple-drug therapy of

tuberculosis

Injury to the liver is the most serious side effect of pyrazinamide. When a dose of 40 to 50 mg/kg is administered orally, signs and symptoms of hepatic disease appear in about 15% of patients, with jaundice in 2% to 3% and death due to hepatic necrosis in rare instances. Elevations of plasma alanine and aspartate aminotransferases are the earliest abnormalities produced by the drug. Regimens employed currently (15 to 30 mg/kg per day) are much safer. Prior to pyrazinamide administration all patients should undergo studies of hepatic function and these studies should be repeated at frequent intervals during the entire period of treatment. If evidence of significant hepatic damage becomes apparent, therapy must be stopped. Pyrazinamide should not be given to individuals with any degree of hepatic dysfunction unless this is

absolutely unavoidable .

The drug inhibits excretion of urate, resulting in hyperuricemia in nearly all patients; acute episodes of gout have occurred. Other untoward effects that have been observed with pyrazinamide are arthralgias, anorexia, nausea and vomiting, dysuria, malaise, and fever. While some international organizations recommend the use of pyrazinamide in pregnancy, this is not the case in the United States because of inadequate data on teratogenicity

Ethionamide

Antibacterial Activity, Resistance. The multiplication of M. tuberculosis is suppressed by concentrations of ethionamide ranging from 0.6 to 2.5 mg/ml. Resistance can develop rapidly in vitro and in vivo when ethionamide is used as a single-agent treatment, and can include low-level cross-resistance to isoniazid . A concentration of 10 mg/ml or less will inhibit approximately 75% of photochromogenic mycobacteria; the scotochromogens are more resistant.

Mechanism of Action. In the manner of isoniazid, ethionamide is also an inactive prodrug that is activated by a mycobacterial redux system. EtaA, an NADPH-specific, FAD-containing monooxygenase, converts ethionamide to a sulfoxide, and thence to 2-ethyl-4-aminopyridine Although these products are not toxic to mycobacteria, it is believed that a closely related and transient intermediate is the active antibiotic. Ethionamide inhibits mycobacterial growth by inhibiting the activity of the inhA gene product, the enoyl-ACP reductase of fatty acid synthase II . This is the same enzyme that activated isoniazid . . Although the exact mechanisms of inhibition may differ, the results are the same: inhibition of mycolic acid biosynthesis

and consequent impairment of cell-wall synthesis .

Untoward Effects. The most common reactions to ethionamide are anorexia, nausea and vomiting, gastric irritation, and a variety of neurologic symptoms .

Severe postural hypotension, mental depression, drowsiness, and asthenia are common. Convulsions and peripheral neuropathy are rare .

Other reactions referable to the nervous system include olfactory disturbances, blurred vision, diplopia, dizziness, paresthesias, headache, restlessness, and tremors .

Pyridoxine (vitamin B6) relieves the neurologic symptoms and its concomitant administration is recommended. Severe allergic skin rashes, purpura, stomatitis, gynecomastia, impotence, menorrhagia, acne, and alopecia also have been observed .

A metallic taste also may be noted. Hepatitis has been associated with the use of the drug in about 5% of cases. The signs and symptoms of hepatotoxicity clear when treatment is stopped. Hepatic function should be assessed at regular intervals in patients receiving ethionamide .

Aminosalicylic Acid

Aminosalicylic acid is bacteriostatic. In vitro, most strains of M. tuberculosis are sensitive to a concentration of 1 mg/ml. The antimicrobial activity of aminosalicylic acid is highly specific, and microorganisms other than M. tuberculosis are unaffected. Most nontuberculous mycobacteria are not inhibited by the drug. Aminosalicylic acid alone is of little value in the treatment of tuberculosis in

humans .

Bacterial Resistance. Strains of tubercle bacilli insensitive to several hundred times the usual bacteriostatic concentration of aminosalicylic acid can be produced in vitro. Resistant strains of tubercle bacilli also emerge in patients treated with aminosalicylic acid, but much more slowly than with streptomycin .

Mechanism of Action. Aminosalicylic acid is a structural analog of para-aminobenzoic acid, and its mechanism of action appears to be very similar to that of the sulfonamides Nonetheless, the sulfonamides are ineffective against M. tuberculosis, and aminosalicylic acid is inactive against sulfonamide-susceptible bacteria. This differential sensitivity presumably reflects differences in the enzymes responsible for folate biosynthesis in the various

microorganisms .

Untoward Effects. The incidence of untoward effects associated with the use of aminosalicylic acid is approximately 10% to 30%. Gastrointestinal problems¾including anorexia, nausea, epigastric pain, abdominal distress, and diarrhea¾are predominant and often limit patient adherence. Patients with peptic ulcers tolerate the drug especially poorly. Hypersensitivity reactions to aminosalicylic acid are seen in 5% to 10% of patients. High fever may develop abruptly, with intermittent spiking, or it may appear gradually and be low-grade. Generalized malaise, joint pains, and sore throat may be present at the same time. Skin eruptions of various types appear as isolated reactions or accompany the fever. Among the hematological abnormalities that have been observed are leukopenia, agranulocytosis, eosinophilia, lymphocytosis, an atypical mononucleosis syndrome, and thrombocytopenia. Acute hemolytic anemia may

appear in some instances .

OBAT ANTI TUBERKULOSIS YANG LAIN

Quinolones The fluoroquinolones, are highly active against M. tuberculosis as well as nontuberculous mycobacteria and are important components of treatment regimens of multidrug-resistant tuberculosis The C-8-methoxy-fluoroquinolones, such as gatifloxacin (TEQUIN) and moxifloxacin (AVELOX), are the most active and therefore least likely to result in the development of quinolone resistance. Unfortunately, when resistance develops to one fluoroquinolone in mycobacteria, cross-resistance develops within this entire class of antibiotics. Thus the most active fluoroquinolones should be used, and only in combination with other antimycobacterial agents, to prevent resistance form developing

Linezolid Linezolid (ZYVOX),, is highly active in vitro against M. tuberculosis and some nontuberculous mycobacteria Clinical experience with its use to treat these

infections is limited at present .

Interferon-g Interferon-g (IFN-g) (ACTIMMUNE) activates macrophages to kill M. tuberculosis. Aerosol delivery of IFN-g to the lungs of patients with multidrug-resistant tuberculosis results in wide pulmonary distribution and enhanced local immune

stimulation

Chemotherapy of Tuberculosis

The availability of effective agents has so altered the treatment of tuberculosis that most patients are now treated in the ambulatory setting, often after diagnosis and initial therapy in a general hospital. Prolonged bed rest is not necessary or even helpful in speeding recovery. Patients must, however, be seen at frequent intervals to follow the course of their disease and treatment. The local health department must be notified of all cases. Contacts should be investigated for the possibility of disease and for the

appropriateness of prophylactic therapy with isoniazid .

To prevent the development of resistance to these agents that frequently occurs, treatment must include at least 2 drugs to which the bacteria are sensitive. The preferred standard 6-month treatment program for drug-sensitive tuberculosis in adults and children consists of isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by isoniazid and rifampin (for sensitive organisms) for 4 additional months. The combination of isoniazid and rifampin for 9 months is equally effective for drug-sensitive tuberculosis. Because of the increasing frequency of drug resistance, the Centers for Disease Control and Prevention (CDC) has recommended that initial therapy should be with a 4-drug regimen (isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin) pending sensitivity results. Directly observed therapy is the most effective approach to ensure treatment completion rates of about 90% Drug interactions are a special concern in patients receiving highly active

antiretroviral therapy ..

Problems in Chemotherapy. Bacterial Resistance to Drugs One of the more important problems in the chemotherapy of tuberculosis is bacterial resistance. The primary reason for development of drug resistance is poor patient adherence. To prevent noncompliance and the attendant development of drug-resistant tuberculosis, directly observed therapy is advisable for most patients, in which a health care provider observes the patient ingest the medications 2 to 5 times weekly

Where drug resistance is suspected but sensitivities are not yet known (as in patients who have undergone several courses of treatment), therapy should be instituted with 5 or 6 drugs, including 2 or 3 that the patient has not received in the past. Such a regimen might include isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin, and ethionamide. Some physicians include isoniazid in the therapeutic regimen, even if microorganisms are resistant, because of some evidence that disease with isoniazid-resistant mycobacteria does not "progress" during such therapy. Others prefer to discontinue isoniazid to lessen the

possibility of toxicity. Therapy should be continued for at least 24 months .

ANTIBIOTICS -RESISTANCE MECHANISMS

Bacteria can become resistant by

•Alterations in the antibiotic binding site by mutations

•Preventing the antibiotic from reaching high intracellular levels

•Chemically modifying the antibiotic thus destroying its function

ANTIBIOTICS -RESISTANCE MECHANISMS

•Spontaneous mutations

Typically occur on the ribosomal components, both at the 16SrRNA

and the ribosomal proteins

-

ANTIBIOTICS -RESISTANCE MECHANISMS

•Prevention of antibiotic accumulation via an efficient

transporter proteins pumping the antibiotic out of the cell, provides

Tetracycline resistance

ANTIBIOTICS -DRUG RESISTANCE

•Enzymatic inactivation of antibiotic

-hydrolysis of beta-lactam ring- phosphorylation of

aminocyclitos

-acetylation of chloramphenicol

DISSEMINATION OF ANTIBIOTIC

RESISTANCE GENESAntibiotic resistance genes can

easily spread among related and even unrelated bacterial species

via several routes.•By conjugation•By transposition•By transduction, transformation

Chemoprophylaxis of Tuberculosis. The chemoprophylaxis of tuberculosis is the practice of treating latent infection to prevent progression to active disease. Latent infection may be diagnosed by a positive delayed-type hypersensitivity reaction to a purified protein derivative (PPD) of tuberculosis injected intradermally (the "tuberculin test") .

There are several approaches to the chemoprophylaxis of tuberculosis. The classical prophylaxis with 12 months of isoniazid resulted in a 75% reduction in the risk of active tuberculosis (from an incidence of 14.3% to 3.6% over 5 years). A 6-month course of isoniazid therapy was nearly as effective, with a 65% risk reduction and a lower incidence of isoniazid-induced hepatitis (International Union Against Tuberculosis, 1982) .

Currently the CDC recommends isoniazid for 6 to 9 months or rifampin for 4 months if isoniazid cannot be used (Centers for Disease Control, 2001) .A 2-month regimen of daily rifampin and pyrazinamide was shown to be as effective as 12 months of isoniazid in one study of HIV-infected individuals (Halsey et al., 1998). 2001

Patients with old "inactive" tuberculosis who have not received adequate chemotherapy in the past should be considered for 1 year of treatment with isoniazid (Comstock, 1983). HIV-infected intravenous drug abusers with a positive skin test have an approximately 8% chance per year of developing active tuberculosis (Selwyn et al., 1989). Isoniazid prophylaxis in HIV-infected persons appears to be as effective as in nonimmunocompromised persons (Wilkinson et al., 1998) .

The CDC recommends that isoniazid prophylaxis be continued for 12 months. Persons infected with HIV who are exposed to multidrug-resistant tuberculosis should receive prophylaxis with rifampin and pyrazinamide (with close monitoring for hepatic toxicity; Centers for Disease Control, 2001) or high-dose ethambutol and pyrazinamide, with or without a fluoroquinolone

KETIDAK BER HASILAN TERAPI TUBERKULOSISOBAT RESISTENKETIDAK PATUHANMONOTERAPI

TERAPI TUBERKULOSIS ADEQUATPANAS, BATUK REDA DALAM BEBERPA MINGGUNAMUN MANFESTASI KLINIK MENGHILANG DALAM WAKTU LAMA

PROTOKOL TERAPI 6 ULANISONIAZID + RIFAMPIN STIAP HARI SELAMA 6 BULANDITAMBAH PYRAZINAIDE SETIAP HARI SELAMA 2 BULAN

DITAMBAH ETHAMBUTOL SELAMA 6 BULAN

PROTOKOLTERAPI 9 BULANISONIAZID +RIFAMPIN SELAMA 9 BULANDITAMBAH ETHAMBUTOL SELAMA 9 BULAN

TUBERKULOSIS EKTRA PULMONAL TERAPI DENGAN 4 MACAM OBATSELAMA 18-24 BULAN