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Rifampin is readily absorbed from the gastrointestinal tract. Peak serum levels in healthy adults and pediatric populations vary widely from individual to individual. Following a single 600 mg oral dose of rifampin in healthy adults, the peak serum level averages 7 mcg/mL but may vary from 4 to 32 mcg/mL.
Absorption of rifampin is reduced by about 30% when the drug is ingested with food. In a study of 14 normal human adult males, peak blood levels of rifampin occurred 1 ½ to 3 hours following oral administration of two RIFAMATE capsules. The peaks ranged from 6.9 to 14 mcg/mL with an average of 10 mcg/mL.
In healthy adults, the biological half-life of rifampin in serum averages 3.35 ± 0.66 hours after a 600 mg oral dose, with increases up to 5.08 ± 2.45 hours reported after a 900 mg dose. With repeated administration, the half-life decreases and reaches average values of approximately 2 to 3 hours. The half-life does not differ in patients with renal failure at doses not exceeding 600 mg daily and, consequently, no dosage adjustment is required. The half-life of rifampin at a dose of 720 mg daily has not been established in patients with renal failure. Following a single 900 mg oral dose of rifampin in patients with varying degrees of renal insufficiency, the mean half-life increased from 3.6 hours in healthy adults to 5.0, 7.3, and 11.0 hours in patients with glomerular filtration rates of 30 to 50 mL/min, less than 30 mL/min, and in anuric patients, respectively. Refer to the WARNINGS section for information regarding patients with hepatic insufficiency.
After absorption, rifampin is rapidly eliminated in the bile, and an enterohepatic circulation ensues. During this process, rifampin undergoes progressive deacetylation so that nearly all the drug in the bile is in this form in about 6 hours. This metabolite has antibacterial activity. Intestinal reabsorption is reduced by deacetylation, and elimination is facilitated. Up to 30% of a dose is excreted in the urine, with about half as unchanged drug.
Rifampin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampin is about 80% protein bound. Most of the unbound fraction is not ionized and therefore is diffused freely in tissues.
In one study, pediatric patients 6 to 58 months old were given rifampin suspended in simple syrup or as dry powder mixed with applesauce at a dose of 10 mg/kg body weight. Peak serum concentrations of 10.7 ± 3.7 and 11.5 ± 5.1 mcg/mL were obtained 1 hour after preprandial ingestion of the drug suspension and the applesauce mixture, respectively. After the administration of either preparation, the t½ of rifampin averaged 2.9 hours. It should be noted that in other studies in pediatric populations, at doses of 10 mg/kg body weight, mean peak serum concentrations of 3.5 mcg/mL to 15 mcg/mL have been reported.
After oral administration, isoniazid is readily absorbed from the GI tract and produces peak blood levels within 1 to 2 hours which decline to 50% or less within 6 hours. It diffuses readily into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues, organs, and excreta (saliva, sputum, and feces). Isoniazid is not substantially bound to plasma proteins. The drug also passes through the placental barrier and into milk in concentrations comparable to those in the plasma. The plasma half-life of isoniazid in patients with normal renal and hepatic function ranges from 1 to 4 hours, depending on the rate of metabolism. From 50% to 70% of a dose of isoniazid is excreted in the urine in 24 hours, mostly as metabolites.
Isoniazid is metabolized in the liver mainly by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50% of African Americans and Caucasians are “slow inactivators” and the rest are “rapid inactivators”; the majority of Eskimos and Asians are “rapid inactivators.”
The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of the drug, and thus an increase in toxic reactions. Pyridoxine (B6) deficiency is sometimes observed in adults with high doses of isoniazid and is probably due to its competition with pyridoxal phosphate for the enzyme apotryptophanase.
Rifampin and isoniazid at therapeutic levels have demonstrated bactericidal activity against both intracellular and extracellular Mycobacterium tuberculosis organisms.
Mechanism Of Action
Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible Mycobacterium tuberculosis organisms. Specifically, it interacts with bacterial RNA polymerase, but does not inhibit the mammalian enzyme.
Isoniazid inhibits the biosynthesis of mycolic acids which are major components of the cell wall of Mycobacterium tuberculosis.
Organisms resistant to rifampin are likely to be resistant to other rifamycins. β-lactamase production should have no effect on rifampin activity.
In the treatment of tuberculosis (See INDICATIONS AND USAGE), the small number of resistant cells present within large populations of susceptible cells can rapidly become predominant. In addition, resistance to rifampin has been determined to occur as single-step mutations of the DNA-dependent RNA polymerase. Since resistance can emerge rapidly, appropriate susceptibility tests should be performed in the event of persistent positive cultures.
Activity In Vitro And In Vivo
Rifampin has bactericidal activity against slow and intermittently growing Mycobacterium tuberculosis organisms.
Prior to initiation of therapy, appropriate specimens should be collected for identification of the infecting organism and in vitro tests.
In Vitro Testing For Mycobacterium Tuberculosis Isolates
Two standardized in vitro susceptibility methods are available for testing isoniazid and rifampin against Mycobacterium tuberculosis organisms. The agar proportion method (CDC or CLSI M24-P) utilizes Middlebrook 7H10 medium impregnated with isoniazid at 0.2 and 1.0 mcg/mL and rifampin at 1.0 mcg/mL for the final concentrations of drug. After 3 weeks of incubation MIC99 values are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures.
Mycobacterial growth in the presence of drug ³1% of the control indicates resistance. The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 0.2 and 1.0 mcg/mL of isoniazid and 2.0 mcg/mL of rifampin. Strict adherence to the manufacturer's instructions for sample processing and data interpretation is required for this assay.
Susceptibility test results obtained by the two different methods can only be compared if the appropriate rifampin or isoniazid concentrations are used for each test method as indicated above. Both test procedures require the use of Mycobacterium tuberculosis H37Rv, ATCC 27294, as a control organism. The clinical relevance of in vitro susceptibility test results for mycobacterial species other than Mycobacterium tuberculosis using either the radiometric broth method or the proportion method has not been determined.
Last reviewed on RxList: 4/15/2016
This monograph has been modified to include the generic and brand name in many instances.
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