Page 863 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 47 Antimycobacterial Drugs 849

be an important new agent for treatment of tuberculosis, at this with HIV infection because of an unacceptably high relapse rate
point it should be used only for multidrug-resistant strains that with rifampin-resistant organisms. Rifapentine in combination
also are resistant to several other first- and second-line agents. It is with isoniazid, typically both dosed at 900 mg once weekly for
generally avoided in patients on concomitant serotonergic agents 3 months (12 doses each in total), is an effective short course treat-
due to concern for serotonin syndrome. ment for latent tuberculosis infection.

Rifabutin Bedaquiline
Rifabutin is derived from rifamycin and is related to rifampin. Bedaquiline, a diarylquinoline, is the first drug with a novel mech-
It has significant activity against M tuberculosis, MAC, and anism of action against M tuberculosis to be approved since 1971.
Mycobacterium fortuitum (see below). Its activity is similar to Bedaquiline inhibits adenosine 5′-triphosphate (ATP) synthase
that of rifampin, and cross-resistance with rifampin is virtually in mycobacteria, has in vitro activity against both replicating and
complete. Some rifampin-resistant strains may appear susceptible nonreplicating bacilli, and has bactericidal and sterilizing activity
to rifabutin in vitro, but a clinical response is unlikely because in the murine model of tuberculosis. Cross-resistance has been
the molecular basis of resistance, rpoB mutation, is the same. reported between bedaquiline and clofazimine, likely via upregu-
Rifabutin is both substrate and inducer of cytochrome P450 lation of the multisubstrate efflux pump, MmpL5.
enzymes. Because it is a less potent inducer, rifabutin is often Peak plasma concentration and plasma exposure to bedaquiline
used in place of rifampin for treatment of tuberculosis in patients increase approximately twofold when administered with high-fat
with HIV infection who are receiving antiretroviral therapy with food. Bedaquiline is highly protein-bound (>99%), is metabolized
a protease inhibitor, a nonnucleoside reverse transcriptase inhibi- chiefly through the cytochrome P450 system, and is excreted
tor (eg, efavirenz), or an integrase strand transfer inhibitor (eg primarily via the feces. The mean terminal half-life of bedaquiline
dolutegravir), drugs that also are cytochrome P450 or UDP gluc- and its major metabolite (M2), which is four to six times less
uronosyltransferase (UGT) substrates. active in terms of antimycobacterial potency, is approximately
The typical dosage of rifabutin is 300 mg/d unless the patient 5.5 months. This long elimination phase probably reflects slow
is receiving a protease inhibitor, in which case the dosage should release of bedaquiline and M2 from peripheral tissues. CYP3A4 is
be reduced, typically by half. If efavirenz (also a cytochrome the major isoenzyme involved in the metabolism of bedaquiline,
P450 inducer) is used, the recommended dosage of rifabutin is and potent inhibitors or inducers of this enzyme cause clinically
600 mg/d. Rifabutin may accumulate in severe renal impairment, significant drug interactions.
and the dose should be reduced by half if creatinine clearance is Current recommendations state that bedaquiline, in combina-
less than 30 mL/min. Rifabutin is associated with similar rates tion with at least three other active medications, may be used for
of hepatotoxicity or rash compared to rifampin; it can also cause 24 weeks of treatment in adults with laboratory-confirmed pul-
leukopenia, thrombocytopenia, and optic neuritis. monary tuberculosis if the isolate is resistant to both isoniazid and
rifampin. The recommended dosage for bedaquiline is 400 mg
Rifapentine once daily orally for 2 weeks, followed by 200 mg three times a
week for 22 weeks taken orally with food in order to maximize
Rifapentine is another analog of rifampin. It is active against both absorption. The most common adverse effects, occurring at rates
M tuberculosis and MAC. As with all rifamycins, it is a bacterial of 25% or more, are nausea, arthralgia, and headache. Bedaquiline
RNA polymerase inhibitor, and cross-resistance between rifampin has been associated with both hepatotoxicity and cardiac toxicity.
and rifapentine is complete. Like rifampin, rifapentine is a potent The FDA has issued a black-box warning related to the risk of
inducer of cytochrome P450 enzymes, and it has the same drug QT prolongation and associated mortality. It should be reserved
c
interaction profile; however, when rifapentine is administered for patients who do not have other treatment options and used
intermittently, induction of metabolism of other medications is with caution in patients with other risk factors for cardiac conduc-
less pronounced compared to rifampin. Toxicity is similar to that tion abnormalities.
of rifampin. Rifapentine and its microbiologically active metabo-
lite, 25-desacetylrifapentine, have an elimination half-life of
13 hours. Rifapentine, 600 mg (10 mg/kg) once or twice weekly, ■ DRUGS ACTIVE AGAINST
has been used for treatment of tuberculosis caused by rifampin-
susceptible strains during the continuation phase (ie, after the NONTUBERCULOUS
first 2 months of therapy and ideally after conversion of sputum MYCOBACTERIA
cultures to negative); however, this regimen has decreased efficacy
compared with the standard rifampin-based regimen. Revised Many mycobacterial infections seen in clinical practice in the
guidelines for treatment of drug-susceptible tuberculosis pub- United States are caused by nontuberculous mycobacteria (NTM),
lished in 2016 recommend against it. In particular, its use should formerly known as “atypical mycobacteria.” These organisms have
be avoided in patients at higher risk of failure, including those distinctive laboratory characteristics, are present in the environ-
with positive cultures at the end of the intensive treatment phase ment, and are generally not communicable from person to person.
and those with evidence of cavitation on chest radiographs. Rifa- As a rule, these mycobacterial species are less susceptible than
pentine should not be used to treat active tuberculosis in patients M tuberculosis to antituberculous drugs. On the other hand, agents