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Drugs for Tuberculosis

DRUG-RESISTANT TB DISEASE

Resistance to Isoniazid – TB that is resistant to isoniazid can be treated with rifampin, pyrazinamide and ethambu- tol for 6-9 months. If the organism is susceptible, strepto- mycin is an alternative to ethambutol. Patients who can- not tolerate pyrazinamide can take rifampin and ethamb- utol for 12 months. A fluoroquinolone or an injectable drug (capreomycin, amikacin, kanamycin or strepto- mycin) is sometimes added, especially if the patient can- not tolerate pyrazinamide or if there is extensive disease.

Multidrug Resistance – Recommendations for treat- ment of MDRTB and XDRTB are based on limited data and should be undertaken in collaboration with someone familiar with the management of these con- ditions. MDRTB and XDRTB should be treated with >4 drugs to which the organism is susceptible. When MDRTB is likely, or in patients with a history of treat- ment for TB, some experienced clinicians start with combinations of 5-7 drugs before laboratory suscepti- bility data become available. Typically, empiric thera- py for suspected MDRTB includes isoniazid, rifampin, ethambutol, pyrazinamide, an aminoglycoside (strep- tomycin, kanamycin or amikacin) or capreomycin, a fluoroquinolone and either cycloserine, ethionamide or aminosalicylic acid (PAS).30-32 Drug selection is based on a hierarchy of drugs to which the isolate is suscep- tible. This involves inclusion of all active first-line drugs (pyrazinamide, ethambutol), a fluoroquinolone and one injectable drug.

To minimize the emergence of drug-resistant TB, co- infected patients in the continuation phase of TB treat- ment should take medication once daily or three times weekly.34 Twice-weekly regimens have been associat- ed with acquisition of rifamycin resistance in patients with CD4 cell counts <100 cells/mm3.35 Once-weekly rifapentine is not recommended for TB treatment in HIV-infected patients because it has been associated with development of rifamycin resistance. 28

Patients Not on HAART – For HIV-infected patients requiring TB treatment who are not currently being treated with highly active antiretroviral therapy (HAART), it may be prudent to delay HAART for 2-3 months in order to avoid a paradoxical worsening of TB due to immune reconstitution, decrease the risk of over- lapping drug adverse effects and interactions, reduce pill burden, and enhance adherence to both drug regi- mens,36-38 but the optimal timing for initiating HAART in patients with newly diagnosed TB is not known.

Patients on HAART – Rifamycins induce hepatic CYP enzymes, especially CYP3A4, and can accelerate metabolism of protease inhibitors and some non-nucle- oside reverse transcriptase inhibitors (NNRTIs), decreasing their serum concentrations, possibly to ineffective levels. The degree to which each drug induces CYP3A4 differs: rifampin is the most potent and rifabutin the least. In addition, rifabutin is a sub- strate for CYP3A4; protease inhibitors decrease its metabolism, increasing serum concentrations and pos- sibly toxicity.

Monthly bacteriologic results (AFB smear and culture) should be monitored and treatment continued for 18- 24 months, or 12-18 months after the culture becomes negative. The parenteral drug should be continued for 6 months after culture conversion. Surgical resection has improved outcome in some patients and should be considered if cultures fail to convert to negative after 3-4 months of appropriate treatment. 33

Standard 4-drug treatment regimens including rifampin can be given to HIV-infected patients with active TB who are simultaneously receiving HAART if the HAART regimen consists of efavirenz (Sustiva) and two nucleoside reverse transcriptase inhibitors (NRTIs). Standard doses of rifampin can also be used in patients taking ritonavir (Norvir) as the only pro- tease inhibitor, combined with 2 NRTIs. 39

HIV-INFECTED PATIENTS

Testing for HIV infection is recommended for all patients with active TB. Persons with HIV, once infect- ed, are at markedly increased risk of developing active TB disease. HIV-infected patients with a history of prior untreated or inadequately treated TB disease should be re-evaluated for active disease regardless of age or results of tests for latent TB infection. If active TB disease is ruled out, patients should receive treat- ment for latent TB infection. HIV-infected persons who have had recent close contact with a patient with active TB disease should receive empiric treatment for latent infection regardless of age, results of tests for TB infection, or history of previous treatment.

Two alternative TB/HAART regimens are based on rifabutin, which appears to be as effective as rifampin against TB and has less effect on protease inhibitor concentrations. The first substitutes low-dose rifabutin (150 mg once/day or 300 mg 3x/week) for rifampin in the standard TB regimen (i.e., isoniazid, rifabutin, pyrazinamide and ethambutol) and uses higher-than- usual doses of indinavir (Crixivan) or nelfinavir ( iracept), or standard doses of amprenavir (Agenerase) or fosamprenavir (Lexiva) as the HIV pro- tease inhibitor. The second decreases the rifabutin dose further to 150 mg every other day or 3 times weekly and the HAART regimen includes standard doses of atazanavir (Reyataz), ritonavir/lopinavir (Kaletra) or

Treatment Guidelines from The Medical

Letter 19

Vol. 5

(Issue 55)

March 2007

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