The rifamycins are bactericidal antibiotics; they inhibit bacterial DNA-dependent RNA polymerase, suppressing RNA synthesis. The following drugs are rifamycins:
Rifabutin, rifampin, and rifapentine have similar pharmacokinetics, antimicrobial spectra, and adverse effects.
Oral absorption is good, producing wide distribution in body tissues and fluids, including cerebrospinal fluid.
Rifampin is concentrated in polymorphonuclear granulocytes and macrophages, facilitating clearance of bacteria from abscesses. It is metabolized in the liver and eliminated in bile and, to a much lesser extent, in urine.
Rifampin is active against
Most gram-positive and some gram-negative bacteria
Resistance develops rapidly, so rifampin is rarely used alone. Rifampin is used with other antibiotics for
Atypical mycobacterial infection (rifampin is active against many nontuberculous mycobacteria, but rapidly growing mycobacteria, such as Mycobacterium fortuitum, M. chelonae, or M. abscessus, are naturally resistant)
Leprosy (with dapsone with or without clofazimine)
Staphylococcal infections, including osteomyelitis, prosthetic valve endocarditis, and infections involving foreign bodies such as a prosthetic joint (with other antistaphylococcal antibiotics)
Pneumococcal meningitis when organisms are susceptible to rifampin (with vancomycin with or without ceftriaxone or cefotaxime for ceftriaxone- or cefotaxime-resistant organisms [minimum inhibitory concentration > 4 mcg/mL]) or when expected clinical or microbiologic response is delayed
Rifabutin and rifampin are equally efficacious in regimens for tuberculosis in HIV-positive and HIV-negative patients. However, if patients are receiving antiretroviral therapy (ART), rifabutin is preferred because it is less likely to induce cytochrome P-450 metabolic enzymes that lower serum levels of protease inhibitors and non-nucleoside reverse transcriptase inhibitors.
Rifampin is preferred over rifabutin for Mycobacterium avium complex (MAC) lung disease, unless patients are receiving ART; in such cases, rifabutin may be substituted. However, rifabutin is preferred over rifampin for disseminated MAC infections because of its superior activity in vitro and reduced drug interaction potential.
Rifapentine is used to treat pulmonary and latent tuberculosis.
Some animal reproduction studies with rifabutin showed adverse effects when drug levels were higher than those typically achieved in humans. No adequate and well-controlled studies have been done in pregnant or breastfeeding women. Safety during breastfeeding is unknown.
Animal reproduction studies with rifampin or rifapentine show some risk (ie, teratogenicity) at drug levels less than or equal to those typically achieved in humans. No adequate and well-controlled studies with either drug have been done in pregnant women.
Because of potential tumorigenicity shown in animal studies, the manufacturer does not recommend use of rifampin during breastfeeding. However, the Centers for Disease Control and Prevention (CDC) does not consider rifampin a contraindication to breastfeeding; a decision to stop breastfeeding or to stop the drug should be made depending on the importance of the drug to the mother.
Adverse effects of rifamycins include
Hepatitis occurs much more often when isoniazid or pyrazinamide is used concurrently with rifampin. During the first week of therapy, rifampin may cause a transient rise in unconjugated serum bilirubin, which results from competition between rifampin and bilirubin for excretion and which is not in itself an indication for interrupting treatment.
Central nervous system effects may include headache, drowsiness, ataxia, and confusion. Rash, fever, leukopenia, hemolytic anemia, thrombocytopenia, interstitial nephritis, acute tubular necrosis, renal insufficiency, and interstitial nephritis are generally considered to be hypersensitivity reactions and occur when therapy is intermittent or when treatment is resumed after interruption of a daily dosage regimen; they are reversed when rifampin is stopped.
Less serious adverse effects are common; they include heartburn, nausea, vomiting, and diarrhea. Rifampin, rifabutin, and rifapentine can cause reddish orange discoloration of urine, saliva, sweat, sputum, and tears.
If patients have a liver disorder, liver tests should be done before rifampin therapy is started and every 2 to 4 weeks during therapy, or an alternate drug should be used. Dose adjustments are unnecessary for renal insufficiency.
Rifampin interacts with many drugs because it is a potent inducer of hepatic cytochrome P-450 (CYP450) microsomal enzymes. Rifampin accelerates elimination and thereby may decrease the effectiveness of the following drugs: angiotensin-converting enzyme inhibitors, atovaquone, barbiturates, beta-blockers, calcium channel blockers, chloramphenicol, clarithromycin, oral and systemic hormone contraceptives, corticosteroids, cyclosporine, dapsone, digoxin, doxycycline, fluconazole, haloperidol, itraconazole, ketoconazole, the non-nucleoside reverse transcriptase inhibitors delavirdine and nevirapine, opioid analgesics, phenytoin, protease inhibitors, quinidine, sulfonylureas, tacrolimus, theophylline, thyroxine, tocainide, tricyclic antidepressants, voriconazole, warfarin, and zidovudine. To maintain optimum therapeutic effect of these drugs, clinicians may have to adjust the dosage when rifampin is started or stopped.
Conversely, protease inhibitors, as well as other drugs (eg, azoles, the macrolide clarithromycin, non-nucleoside reverse transcriptase inhibitors) inhibit CYP450 enzymes and increase levels of rifamycins and thus potentially increase the frequency of toxic reactions. For example, uveitis occurs more commonly when rifabutin is used with clarithromycin or azoles.
Rifaximin is a derivative of rifamycin that is poorly absorbed after oral administration; 97% is recovered primarily unchanged in feces.
Rifaximin can be used for empiric treatment of
Traveler’s diarrhea, which is caused primarily by enterotoxigenic and enteroaggregative Escherichia coli
Rifaximin is not known to be effective for diarrhea due to enteric pathogens other than E. coli. Because rifaximin is not systemically absorbed, it should not be used to treat infectious diarrhea caused by invasive enteric bacterial pathogens (eg, Shigella species, Salmonella species, Campylobacter species). The dose for traveler's diarrhea is 200 mg orally every 8 hours for 3 days in adults and children > 12 years.
Rifaximin may also be used for the treatment of
Adverse effects of rifaximin include nausea, vomiting, abdominal pain, and flatulence.