Page 859 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 47 Antimycobacterial Drugs 845

Isoniazid promotes excretion of pyridoxine, and this toxicity is (see Chapters 4 and 66). Co-administration of rifampin results in
readily reversed by administration of pyridoxine in a dosage as low significantly lower serum levels of these drugs.
as 10 mg/d. Central nervous system toxicity, which is less com-
mon, includes memory loss, psychosis, ataxia, and seizures. These Clinical Uses
effects may also respond to pyridoxine.
Miscellaneous other reactions include hematologic abnormali- A. Mycobacterial Infections
ties, provocation of pyridoxine deficiency anemia, tinnitus, and Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be
gastrointestinal discomfort. administered with isoniazid or other antituberculous drugs to
patients with active tuberculosis to prevent emergence of drug-
resistant mycobacteria. In some short-course therapies, 600 mg
RIFAMPIN of rifampin is given twice weekly. Rifampin, 600 mg daily or
twice weekly for 6 months, also is effective in combination with
Rifampin is a semisynthetic derivative of rifamycin, an antibi- other agents in some atypical mycobacterial infections and in
otic produced by Amycolatopsis rifamycinica, formerly named leprosy. Rifampin, 600 mg daily for 4 months as a single drug,
Streptomyces mediterranei. It is active in vitro against Gram-positive is an alternative to isoniazid for patients with latent tuberculosis
organisms, some Gram-negative organisms, such as Neisseria and who are unable to take isoniazid or who have had exposure to
Haemophilus species, mycobacteria, and chlamydiae. Susceptible a case of active tuberculosis caused by an isoniazid-resistant,
organisms are inhibited by less than 1 mcg/mL. Resistant mutants rifampin-susceptible strain.
are present in all microbial populations at approximately 1 in
6
10 organisms and are rapidly selected out if rifampin is used as B. Other Indications
a single drug, especially in a patient with active infection. There Rifampin has other uses in bacterial infections. An oral dosage
is no cross-resistance to other classes of antimicrobial drugs, but of 600 mg twice daily for 2 days can eliminate meningococcal
there is cross-resistance to other rifamycin derivatives, eg, rifabutin carriage. Rifampin, 20 mg/kg (maximum 600 mg) once daily
and rifapentine. for 4 days, is used as prophylaxis in contacts of children with
Haemophilus influenzae type b disease. Rifampin combined
Mechanism of Action, Resistance, & with a second agent is sometimes used to eradicate staphy-
Pharmacokinetics lococcal carriage. Rifampin combination therapy is also used
for treatment of serious staphylococcal infections such as
Rifampin binds to the β subunit of bacterial DNA-dependent osteomyelitis, prosthetic joint infections, and prosthetic valve
RNA polymerase and thereby inhibits RNA synthesis. Resistance endocarditis.
results from any one of several possible point mutations in rpoB,
the gene for the β subunit of RNA polymerase. These muta-
tions result in reduced binding of rifampin to RNA polymerase. Adverse Reactions
Human RNA polymerase does not bind rifampin and is not Rifampin imparts a harmless orange color to urine, sweat, and
inhibited by it. Rifampin is bactericidal for mycobacteria. It read- tears (soft contact lenses may be permanently stained). Occasional
ily penetrates most tissues and penetrates into phagocytic cells. It adverse effects include rashes, thrombocytopenia, and nephritis.
can kill organisms that are poorly accessible to many other drugs, Rifampin may cause cholestatic jaundice and occasionally hepa-
such as intracellular organisms and those sequestered in abscesses titis, and it commonly causes light-chain proteinuria. If adminis-
and lung cavities. tered less often than twice weekly, rifampin may cause a flu-like
Rifampin is well absorbed after oral administration and syndrome characterized by fever, chills, myalgias, anemia, and
excreted mainly through the liver into bile. It then undergoes thrombocytopenia. Its use has been associated with acute tubular
enterohepatic recirculation, with the bulk excreted as a deacylated necrosis.
metabolite in feces and a small amount excreted in the urine.
Dosage adjustment for renal or hepatic insufficiency is not neces-
sary. Usual doses result in serum levels of 5–7 mcg/mL. Rifampin ETHAMBUTOL
is distributed widely in body fluids and tissues. The drug is
relatively highly protein-bound, and adequate cerebrospinal fluid Ethambutol is a synthetic, water-soluble, heat-stable compound,
concentrations are achieved only in the presence of meningeal the dextro-isomer of the structure shown below, dispensed as the
inflammation. dihydrochloride salt.
Rifampin strongly induces most cytochrome P450 isoforms
(CYP1A2, 2C9, 2C19, 2D6, and 3A4), which increases the elimi- CH OH C H
2
2 5
nation of numerous other drugs including methadone, antico- H C NH NH C H
agulants, cyclosporine, some anticonvulsants, protease inhibitors, (CH 2 ) 2
some nonnucleoside reverse transcriptase inhibitors or integrase C H CH 2 OH
2 5
strand transfer inhibitors, contraceptives, and a host of others Ethambutol