Copyright, Purdue Research Foundation, 1996

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The Therapeutic Problem

Therapeutic Goals

The Disease

Mycobacterium tuberculosis an acid-fast, nonmotile, nonsporulating, weakly gram positive rod. An important characteristic is the high lipid (60% dry weight) content of the cell wall.

Mycoloic acid is a major component that is characteristic of Mycobacteria. Some drugs act by interfering with mycolic acid synthesis.

Slow growth, ability to survive within phagocytes, and resistance to chemical disinfectants are important factors to consider.

Body defenses are crucial for resistance. TB incidence is increasing as diseases and life styles harmful to body defense systems increase. Cellular immunity is crucial for control of TB.

Short-course regimen, example

Primary drugs used in combination --




Six month intensive course is less toxic, less expensive, as good as traditional 1-2 year treatment.


· Capreomycin Sulfate [Capastat Sulfate]

· Cycloserine [Seromycin]

· Ethambutol Hydrochloride [Myambutol]

· Ethionamide [Trecator-SC]

· Isoniazid (INH) [Dow-Isoniazid, Nydrazid]

· Pyrazinamide (PZA)

· Rifampin [Rifadin, Rimactane]

· Streptomycin Sulfate

· Rafabutin [Mycobutin] AMADE93, 1:33


General comments

· Used for prophylaxis as single agent

· Used for cure as part of combination therapy -- never used alone during curative therapy because of the development of resistant organisms.

Chemistry / structure

Resembles the B-vitamin, nicotinic acid.

Antibacterial activity

· Penetrates cells (e.g., human cells) easily, therefore MICs determined in vitro are generally applicable in vivo.

· Tuberculostatic at 0.025 to 0.05 ug/ml. Organisms undergo another 1-2 divisions before growth is arrested.

· Tuberculocidal at higher concentrations, but organisms must be growing.

· Among atypical mycobacteria, only M. kansasii is susceptible.


· Fairly stable in U.S. at 2-5% of fresh isolates (for M. tuberculosis)

· Is easy to create resistant population by serially increasing drug concentration. Conversion to a resistant population occurs by selection of the 1 in 10^6 organisms in many populations that is resistant. Because a tuberculous cavity may contain 10^7 organisms one can see that each cavity probably contains resistant organisms at the start of therapy. Use of isoniazid as a sole agent is, therefore, not advised.

· No cross resistance with other tuberculostatic drugs

· Mechanism of resistance is decreased penetration or uptake by the organism. The drug appears to be taken up by an active process and only sensitive organisms contain significant quantities of drug.

Mechanism of action

Not definitely known, but hypotheses include effects on: (GG8th90, p1147)

· lipids

· glycolysis

· nucleic acid synthesis

· Inhibition of mycolic acid biosynthesis may be a primary action. Isoniazid may prevent elongation of the "very-long-chain fatty acid precursors" of mycolic acid. Isoniazid also inhibits the first Step that is specific for mycolic acid synthesis, a desaturase enzyme.


· Drug is given parenterally (IM) or PO as tablets or syrup

· Rapidly absorbed , resulting in peak plasma concentrations of 3 to 5 ug/ml within 1 to 2 h after PO adm.

· Drug penetrates well into sites of infection, including CSF and center of areas of caseous necrosis.

· Elimination is primarily biotransformation and to lesser extent, renal elimination. Biotransformatin is by acetylation to acetylisoniazid (major) and hydrolysis to isonicotinic acid (minor).

· Population distribution by rate of elimination is bimodal!!!

* There are both fast and slow acetylators, genetically determined. This results in blood levels that vary by a factor of 4 to 6 fold.

* Elimination half-life: Fast = 70 min; slow = 180 min

* Tendency for fast acetylation is a Mendellian (autosomal) dominant.

* Ratio: Fast/slow is 50/50 in temperate zones of Western countries (Including African-Americans)

* Fast acetylation is found in Eskimos and Japanese (Orientals - fast/slow = 90/10)

* Slow acetylation predominant phenotype in most Scandinavians, Jews, and North African Caucasians.

* Dose all for fast acetylation because toxicity is low, but --

increases chance of toxicity if patient is a slow acetylator and has decreased renal function.

* Drug interaction is more likely with slow acetylators given 'normal' doses. Isoniazid inhibits hepatic mixed function oxidases.

Adverse Effects

ca. 5% of patients in one study. (2% rash; 1.2% fever; 0.6% jaundice; and 0.2% peripheral neuritis.)

<hdr4>Peripheral neuritis

Must supplement with PYRIDOXINE, a B vitamin, to prevent this. Isoniazid increases the elimination of pyridoxine. Doses of isoniazid of 6 mg/kg/d will cause neuritis in 20% of cases (usual dose 5 mg/kg). Signs related to this are: convulsions, if the patient has seizure tendencies; optic neuritis and atrophy; muscle twitching; dizziness; ataxia; paresthesias; stupor; toxic encephalopathy; and death. At a microscopic level, synaptic vesicles disappear, there is mitrochondrial alteration; axon terminal fragmentation; and occasionally, alterations in the spinal cord and various ganglia.

<hdr4>Drug interaction -- at higher plasma concentrations, depression of hepatic mixed function oxidases. Phenytoin, e.g., is metabolized by these oxidases and could accumulate in the presence of excess isoniazid.Approximately 27% of patients given both drugs show signs of excessive sedation and incoordination.

<hdr4>Age dependent jaundice

May see severe hepatic injury (bridging & multilobular necrosis) often leading to death. Mostly occurs 4 to 8 weeks after start of therapy. Must monitor hepatic function (e.g.,serum aspartate aminotransferase) at least once per month, especially if signs of hepatitis (anorexia, malaise, fatigue, nausea, and jaundice). May result from metabolite, acetylhydrazine. There is some contribution from alcoholic hepatitis.

* Rare if less than 20 years old

* More than 2% if over 35 years old

* Incidence higher in slow acetylators


Including fever, skin eruptions, hepatitis, and various kinds of rashes. Hematological reactions, e.g., thrombocytopenia, agranulocytosis, eosinophilia, and anemia) may occur. Reversible vasculitis may occur and arthritic symptoms at various joints may be observed.


Effects include dry mouth and epigastric distress; methemoglobinemia, tinnitus, and urinary retention.

RIFAMPIN [Rifadin; Rimactane]


Rifampin is one of a family of macrocyclic antibiotics obtained from Streptomyces mediterranei.


Includes M. tuberculosis which is killed (cidal) at concentrations less than 1 ug/ml. Other mycobacteria have variable sensitivity. Rifampin is also used against other bacterial species and has a very broad spectrum, including many gram negative cocci and gram positive bacteria (MICs = 0.001 to 0.1 ug/ml). Gram negative bacilli require 0.1 to 10 ug/ml which is achievable in vivo. Many chlamydiae are sensitive.


Can develop quickly. Must not use the drug alone because of this. Resistance, which is due to an altered DNA-dependent RNA polymerase, may occur in one-step. Approximately 1 in 10^7 to 10^^8 M. tuberculosis are resistant. Resistance has developed in as little as 2 days in meningococcal carrier states. Less than 1% of tuberculosis patients have organisms that are resistant to rifampin at the start of treatment.

Mechanism of Action

Mechanism of action is via inhibition of DNA-dependent RNA polymerase at the initiation step. Elongation is not inhibited. Rifampin binds to the beta-subunit of the holoenzyme. Higher concentrations are required to inhibit mammalian mitochondrial RNA synthesis.


Rifampin is well absorbed after PO administration, usually q1d. Dose of 600 mg to human will produce average of 7 ug/ml, but high variation.

Rifampin is broadly distributed, even into the CSF. Its presence in many body fluids is shown by the orange-red color it gives to urine, feces, saliva, sputum, tears, and sweat (GG8th90,p1150).

The half-life of rifampin is 1.5 to 5 h and is increased by hepatic dysfunction.

Rifampin is deacetylated to a form that is still active as an antibacterial. Rifampin and its deacetylated form are eliminated in the bile, but the deacetylated form is less bioavailable so, despite the enterohepatic circulation, rifampin is eventually eliminated.

Elimination is slowed by hepatic dysfunction and slow acetylators taking isoniazid.

Elimination is increased by autoinduction which shortens half-life by about 40% over the first 14 days of therapy. Hepatic microsomes which deacetylate the drug are induced.

Adverse reactions

Drug is said to be 'relatively' safe, i.e., less than 4%. Most common are rash (0.8%), fever (0.5%), and nausea and vomiting (1.5%). (GG8th90).


Most notable problem and has resulted in death. Hepatitis is rare in patients with normal liver function, but chronic liver disease, alcoholism, and old age appear to increase the incidence.

Flu-like syndrome

Seen in 20% of patients treated with an unrecommended schedule of therapy: intermittent schedule (2 x/wk) and/or daily doses of 1200 mg or greater. Flu-like syndrom includes fever, chills, and arthralgias and, in some cases, eosinophilia, interstitial nephritis, acute tubular necrosis, thrombocytopenia, hemolytic anemia and shock.

Drug interaction due to hepatic microsomal induction

SHORTENS half-life of many drugs, e.g., prednisone, digitoxin, quinidine, ketoconazole, propranolol, metoprolol, clofibrate, and sulfonylureas, oral contraceptives, and oral anticoagulants. It has precipitated methadone withdrawal.

Redman syndrome -- caused by marked overdosage, and shown by severe liver damage, bright red urine, tears, saliva; skin resembles that of broiled lobster.


Other effects include gastrointestinal disturbances (e.g., epigastric pain ...), hypersensitivity reactions, and immunosuppression.

Recent applications

NEVER USED ALONE because of rapid development of resistance.

·Treatment of tuberculosis

· Leprosy

· Fungi /yeasts -- additive or synergistic with amphotericin B versus Histoplasma capsulatum, Blastomyces dermatitidis

· Various bacterial infections, e.g., with a beta-lactam or vancomycin for staphylococcal endocarditis.

RIFABUTIN [Mycobutin]

· Semisynthetic ansamycin antibiotic derived from rifamycin S. (related to rifampin)


· Pobably acts as bactericide by inhibiting DNA-dependent RNA polymerase.

· Active in vitro against wide variety of gram-positive and gram-negative bact.

· Active in vitro against Mycobacterium tuberculosis and "atypical species" which includes MAC complex (M. avium and M. intracellulare)

· Estimate of MAC infection in AIDS patients ranges from 15-24% (early estimates) to 43% by 2 years after diagnosis of AIDS [AMADE93,1:33]

· Indication: prevention of disseminated MAC disease in advanced AIDS. Currently being investigated for M. tuberculosis infections.


· ORAL -- absorbed, but F in HIV-positive patients is 20%!

· Highly lipophilic, therefore, fact that high fat meal decreases rate (not extent) of absorption is surprising and contrasts with griseofulvin.

· Widely distributed and concentrated intracellularly

· Elimination, primarily hepatic metabolism; major metabolites are 25-O-deacetyl (equal activity to parent) and 31-hydroxy derivative.

· Half-life (mean terminal) is 45 h. During long term therapy, may decrease by 38% (induction of intestinal and/or hepatic metabolism)

· Dose -- variable, example - 300 mg q1d.

Adverse Effects

· Well tolerated up to 300 mg/day.

Reasons for discontinuing Rx with rifabutin

rash (1%); GI intolerance (3%); neutropenia (2%)

Other reactions

1% greater incidence than with placebo: impairment of taste, abdominal pain, eructation, nausea and vomiting, myalgia, and fever.

· Probable cause of following (<1% of cases): flu-like syndrome, hepatitis, hemolysis, arthralgia, myositis, and chest pressure or pain with dyspnea.

· Neutropenia in 4.4% of treated patients versus 3.4% receiving placebo. May need to do periodic hematologic screening.

· May color skin and bodily secretions or excretions orange brown. Permanently stains contact lenses.

Drug interactions

Induces hepatic isoforms of cytochrome P450, but half to a third as potent as rifampin.

Alters (decreases) zidovudine plasma concentrations by 48%!

Kinetics of didanosine and fluconazole appear unaffected.

Because is similar to rifampin, should suspect of altering pharmacokinetics of many compounds.


· A synthetic pyrazine analog of nicotinamide

· Cidal to tubercle bacilli within monocytes at 12.5 ug/ml.

· Resistance develops rapidly when used alone.

· Mechanism unknown.

· Orally administered at 1 gram gives 45 ug/ml at 2 h and 10 ug/ml at 15 h (Normal dose is 20-30 mg/kg po)

· Broadly distrubuted

· Eliminated primarily by glomerular filtration; also biotransformed

· Liver injury --most common and serious side effect

* Dose of 40 to 50 mg/kg per day po produces hepatic disease in 15% of patients and jaundice in 2 to 3 %. Death due to hepatic necrosis can occur.

* Must monitor hepatic function

Gout can be precipitated by inhibition of excretion of urate resulting in hyperuricemia

· Other -- arthralgias, anorexia, nausea, vomiting, dysuria, malaise, fever


· No effect on bacteria other than mycobacteria

· Suppresses growth (static) of organisms resistant to streptomycin and isoniazid, i.e., no cross resistance. Resistance to ethambutol develops slowly.

· One of four main drugs for treatment of tuberculosis

· Always used in combination

· Must adjust dose if impaired renal function

· Optic neuritis (reversible) -- most important adverse effect

* Occurs in 15% of patients receiving 50 mg/kg per day and less than 1% of those receiving 25 mg/kg per day.

* Decreased visual acuity and red/green color blindness

· Minimally toxic (<2%) at 15 mg/kg per day (usual dose)

* decreased visual acuity -- 0.8 %

* rash -- 0.5%

* drug fever --0.3%

· Gout -- Increased urate in blood in about 50% of patients caused by decreased renal excretion of uric acid. May appear as early as 24 h or 90 days after start therapy. May be worsened by isoniazid and pyridoxine.

· Other effects that have been observed -- pruritus, joint pain, gastrointestinal upset, abdominal pain, malaise, headache, dizziness, mental confusion, disorientation, and possible hallucination.


· From Streptomyces orchidaceus

· Destroyed by neutral and acid pH

· Inhibits M. tuberculosis at 5 to 20 ug/ml in vitro

· Also inhibits other organisms, e.g., Enterococci, E. coli, Staphylococcus aureus, Nocardia spp., Chlamydia

· Administered P.O.

Dose: 20 mg/kg children, peak 20-35 ug/ml. gone by 12 h

· Eliminated in urine, 60% as active

· Toxicity - especially a problem if >30ug/ml

* CNS reaction, w/in first two weeks. (reversible)

* Somnolence, headache, tremor, dysarthia, vertigo, confusion, nervousness, irritability, psychotic states w/ suicidal tendencies.


See Antileprosy drugs handout

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Gordon L. Coppoc, DVM, PhD
Professor of Veterinary Pharmacology
Head, Department of Basic Medical Sciences
School of Veterinary Medicine
Purdue University
West Lafayette, IN 47907-1246
Tel: 317-494-8633Fax: 317-494-0781

Last modified 9:42 PM on 4/16/96 GLC