Drugs for Tuberculosis and Mycobacterium avium complex disease

Drugs for Tuberculosis and Mycobacterium avium complex disease NUR 3703 Pharmacology By Linda Self

History • Dates back to ancient Egypt and Babylonia • “consumption” • Sanitoriums • Robert Koch in 1905 • Development of BCG in 1924 • Streptomycin 1943

Mycobacterium tuberculosis • Gram positive mycobacterium • Divides slowly, only q15-20h • Can withstand weak disinfectants • Can survive in dry state for weeks • Must grow within a host organism

TB • Infectious disease caused by tubercle bacillus • 80% affect lungs • Multiplies slowly • Can lie dormant

TB • Identified microscopically by staining characteristics • Retains certain stains thus “acid-fast” • Can now obtain results of blood test within 24h—Quantiferon TB gold test (must follow specific guidelines for obtaining test sample)

TB • Occurrence had waned • Now resurgence due to international travel, persons with depressed immune systems (medications and conditions), emergence of AIDS • Incidence has been increasing since 1986

TB • Untreated, two of every three individuals with active disease will die • With treatment, mortality less than 5%

Epidemiology • Transmission—inhalation • Contributors: number of bacteria, closeness and duration of contact • Primary infection-30% exposed will become infected. Dormant until optimal conditions. Will test positive to PPD. • Latency-no symptoms but bacteria are there

Epidemiology • Active tuberculosis—reactivation of latent infection although new infection can also occur • Occurs more often in those with depressed immunity • Among people with both latent TB and HIV infection, latent TB will progress more rapidly, is more severe and is often extrapulmonary

Drug Resistant TB • Multiple drug therapy • Clinical monitoring monthly • Lab testing—obtain baseline. In populations with liver disease, will check liver function studies monthly. May have to stop INH if transaminase levels greater than 3 times upper limit of normal if s/s, to 5 times normal if no s/s

Drug Resistance • One of biggest contributors to this development is those who are not adherent

High Risk Groups • Should test certain groups which are at higher risk for developing active tuberculosis • Immigration from areas of world w/high incidence • Homeless • Injection drug user • Chronic renal failure • Diabetes mellitus • High dose steroids

High Risk Groups • HIV infection or AIDS • Chest xray with fibrotic lesions • Cachexic • Silicosis • Older groups who reside in congregate settings • Young children who test positive

Clinical Manifestations • Weight loss • Anorexia • Malaise • Fever • Productive cough • Night sweats • Older adults s/s less prominent; in children, resembles pneumonia

Testing • Health centers • Medical clinics • Homeless shelters • Jails • Methadone clinics • Businesses • institutions

How? • PPD • Aplisol, Aplitest, Tine test • Sterile isotonic solution of tuberculin • Intradermally injected • Spurs immune response • Should be interpreted in 48-72h • Anergy is an issue

Test Interpretation Induration of 5 mm or more deemed positive in those with HIV, w/risk factors for HIV, those with chest xrays consistent with previous TB, in those who have had close contact with someone with active TB • Organ transplants • Those on high dose steroids or on TNF antagonists

Test Interpretation Induration of 10mm or more—positive in those at high risk such as immigrants, residents and employees of prisons, children exposed to adults in high risk groups • Chronic renal failure • Gastrectomy patients • IV drug users • Possibly cancer

Test Interpretation • Induration of 15mm or more-essentially all others

Test Interpretation • False positives-may occur in those who have had BCG (from Mycobacterium bovis) • False negatives in those with anergy

BCG • Bacillus Calmette-Guerin • Vaccine developed from Mycobacterium bovis—lost virulence in humans secondary to engineering of the bacillus • Variable effectiveness, up to 15 years • May cloud reliability of PPD • Also useful in bladder cancer, leprosy

Preliminaries Before Treatment • Thorough history • Complete physical • Chest xray • Sputum studies • Baseline labs (liver enzymes, bili, CBC, lytes)

Primary Antitubular Drugs Isoniazid (INH) • Prototype of antituberculars • Bactericidal • Inhibits cell wall synthesis • Acetylators a consideration—slow, more prone to toxicity; rapid, may need larger dose

Isoniazid (INH) • Penetrates body cells and mycobacteria • Inhibits growth of dormant organisms in macrophages

INH Side Effects • Hepatotoxicity • Peripheral neuropathies • Pyridoxine is usually given with INH to minimize peripheral neuropathy

Rifampin Rifamycin • Bactericidal for intracellular and extracellular organisms • Inhibits synthesis of RNA so causes defective proteins to be produced • Synergistic with INH • Produces clinical improvement faster than any other drug regimen unless resistance is present

Rifampin • Diffuses well into tissues • Rapid oral absorption • Metabolized in liver, excreted in bile • Causes harmless red-orange discoloration of body fluids

Rifampin Adverse Effects • GI upset • Skin rashes • Hepatitis • Drug interactions • Accelerates metabolism of some drugs • See p. 554

Rifabutin Another rifamycin • Works like rifampin • Main uses are in those with HIV infection, in MAC and to substitute for rifampin in those who need both antitubercular and certain antiviral medications • Advantages are its longer serum half-life and reduced hepatic induction of metabolyzing enzymes

Rifabutin Causes: • Discoloration of body fluids • GI upset • Hepatitis • Muscular aches • Neutropenia • Skin rash • Uveitis • Rare hepatotoxicity

Ethambutol Tuberculostatic drug that inhibits synthesis of RNA and thus, protein synthesis • Not recommended in young children (under 5) • Well absorbed in GI tract • Total daily dosage is given at one time • Can affect renal function • Can cause optic neuritis

Pyrazinamide • Used with INH and rifampin for first two months of treating active TB and possibly as single agent for four months in those with LTBI • Pyrazinamide is contraindicated in pregnancy

Pyrazinamide • Bactericidal but mechanism is unclear • Good GI absorption • Rapid onset, peaks in two hours • Metabolized by liver, excreted by kidneys

Pyrazinamide Can cause: • Hepatotoxicity • Inhibits urate excretion • Not to be used in liver compromise • Monitor liver enzymes every 2 weeks during course of Tx (usually 8 weeks)

Streptomycin Aminoglycoside • Does not penetrate macrophages and tuberculous lesions • May be used in multi-drug therapy

Drugs in Multidrug Resistant Tuberculosis MDR means the TB is resistant to at least two of the first line medications (INH, RIF, PZA, Ethambutol) so add: • Amikacin • Kanamycin • fluoroquinolones

For exceptionally drug resistant TB • Resistance present to INH, RIF, PZA, ethambutol will use quinolones and at least one of three injectable drugs (amikacin, Kanamycin and capreomycin)

RIF-PZA • Caution in those taking other hepatotoxic drugs or who use alcohol • Recommended in those who are unlikely to complete longer courses of Tx and who can be monitored closely • Perform LFTs at baseline and at 2,4, 6 weeks. Stop if levels are higher than five times the upper limit, if s/s hepatitis are present or if bilirubin is elevated

Second Line Drugs • Para-aminosalicyclic acid • Capreomycin • Cycloserine • ehtionamide

Active TB • Different regimens • Dosing most important element • Combination therapy • INH, Rifampin, and pyrazinamide daily for 2 months followed by INH and Rifampin for 4 additional months • If resistance in community, should add fourth drug such as ethambutol or streptomycin until susceptibility reports are available

INH Resistant TB • Rifampin, pyrazinamide, and ethambutol for 6 months

Treatment of Latent Tuberculosis Infection • INH daily or twice weekly for 9 months incl. those with HIV infection or xray evidence of prior TB • INH daily or twice weekly for 6 mos. Less costly. Okay in HIV negative adults with normal chest xrays. Not in HIV, <18 yo or those with fibrotic lesions on chest films.

Treatment of LTBI • RIF and PZA daily or twice weekly for 2 months. Indicated in those in contact with INH resistant TB and for those unlikely to complete a longer course of Tx.

Special Populations • Pregnancy—INH daily or twice weekly for 6-9 months. Take B6. INH, rifampin, and ethambutol relative safety. Pyrazinamide and streptomycin are contraindicated.

Special Populations • Children and adolescents. INH daily or twice weekly for 9 months is optimum. Infants and children under 5 are at high risk for progression of disease. • INH more effective in children than adults • Risk for INH hepatitis in children is small • Felt not necessary for B6 supplementation

Special Populations • Can’t use rifampin in people being treated with PIs or NNRTIs. May substitute Rifabutin, in one half the dose, unless patient is taking delavirdine or saquinavir.

Treatment • When INH and rifampin cannot be given because of resistance, drug therapy should continue for 24 months after sputum smears or cultures become negative • Cannot use fluoroquinolones in children

Treatment Older adults: • Treatment may be based on both PPD and other factors • INH hepatotoxic in elderly • Active disease-- INH, rifampin and pyrazinamide are given cautiously • Closely monitor liver function

Treatment • Tailor to the circumstances, allow patient participation in selecting treatment • Directly Observed Therapy (DOT) should be used consistently with intermittent regimens, in those who are high risk for non-adherence and in institutional settings • Ensure completion of therapy by determining both total time and number of doses of medication taken

Monitoring Antitubercular Therapy • Clinical monitoring is indicated for all patients. • Monitor for s/s of liver disease such as: dark urine, jaundice, numbness or tingling of hands or feet, jaundice, vomiting, loss of appetite, abdominal tenderness, bruising or bleeding. • Lab monitoring. Stop INH if LFTs 3x normal with s/s or 5x normal if no s/s.

Drugs for Tuberculosis and Mycobacterium avium complex disease