Anti-TB AgentsAnti-TB Agents

Dr. Jeff HobdenDr. Jeff Hobden

MIPMIP

Mycobacterium Mycobacterium tuberculosistuberculosis

• TB is hard to kill TB is hard to kill with antibiotics with antibiotics • Slow growthSlow growth• Fortified cell Fortified cell

wallwall• Intracellular Intracellular

growthgrowth• Very good at Very good at

developing developing resistance to resistance to single agents single agents

Treatment of TB – Old Treatment of TB – Old SchoolSchool

• Surgical collapse Surgical collapse of infected lungof infected lung

• Vitamin D & Vitamin D & heliotherapy heliotherapy (can you say (can you say “melanoma”“melanoma”

• Bed rest and Bed rest and fresh airfresh air

Modern Treatment of TB – A Modern Treatment of TB – A Rigorous Course of Multiple Rigorous Course of Multiple

AntibioticsAntibiotics • First line drugsFirst line drugs

• IsoniazidIsoniazid• RifampinRifampin• EthambutolEthambutol• StreptomycinStreptomycin• PyrazinomidePyrazinomide

• Second line drugsSecond line drugs• Moxi-or gatifloxacinMoxi-or gatifloxacin• EthionamideEthionamide• Aminosalicylic acidAminosalicylic acid• CycloserineCycloserine• Amikacin and Amikacin and

kanamycinkanamycin• CapreomycinCapreomycin• linezolidlinezolid

6 months of taking a handful 6 months of taking a handful of pills! of pills!

Multi-Drug Resistant TBMulti-Drug Resistant TB

Isoniazid (INH)Isoniazid (INH)• Synthetic hydrazide Synthetic hydrazide

of isonicotinic acid of isonicotinic acid • Requires catalase-Requires catalase-

peroxidase for peroxidase for activationactivation

• Bacteriocidal for Bacteriocidal for growing cells, static growing cells, static for resting cellsfor resting cells

• Prevents synthesis Prevents synthesis of mycolic acidsof mycolic acids

Isoniazid (INH)Isoniazid (INH)• Oral or parentalOral or parental• Water soluble, Water soluble,

penetrates into penetrates into caseous material of caseous material of granulomagranuloma

• Acetylated and Acetylated and secreted into urinesecreted into urine

• Rate of secretion has Rate of secretion has racial componentracial component

• ToxicityToxicity• Rash and fever (UC)Rash and fever (UC)• Jaundice (rare)Jaundice (rare)• Peripheral neuritis Peripheral neuritis

(rare)(rare)

RifamycinsRifamycins• Natural and semi-Natural and semi-

derived from derived from filamentous soil filamentous soil bacteriabacteria

• Complex Complex macrocyclic macrocyclic antibioticsantibiotics

• Members of the Members of the classclass• Rifabutin (for HIV+)Rifabutin (for HIV+)• RifapentineRifapentine• Rifampin = rifampicin Rifampin = rifampicin

(for everyone else)(for everyone else)

RifamycinsRifamycins• Broad Broad

spectrum, spectrum, bactericidalbactericidal

• Inhibit DNA-Inhibit DNA-dependent RNA dependent RNA polymerasepolymerase

• Resistance Resistance generated by generated by altering targetaltering target

RifamycinsRifamycins• Administered orallyAdministered orally• Absorbed in GI tractAbsorbed in GI tract• Asprin will interfere Asprin will interfere

with its absorbancewith its absorbance• Wide distributionWide distribution• Can discolor body Can discolor body

waste, saliva, tears waste, saliva, tears orange-redorange-red

• Acetylated and then Acetylated and then excreted into bile excreted into bile and ultimately and ultimately pooped outpooped out

Uses of Select Uses of Select RifamycinsRifamycins

• RifampicinRifampicin• Treatment of TBTreatment of TB• Prophylaxis Prophylaxis

against against meningocccusmeningocccus

• Staph infectionsStaph infections

• Rifabutin and Rifabutin and rifapentinerifapentine• TB therapy for TB therapy for

HIV+ patientsHIV+ patients• MAC infectionsMAC infections

Toxicity/Contraindications Toxicity/Contraindications

of Rifamycinsof Rifamycins• RifampicinRifampicin

• Flu-like illness (Flu-like illness (commoncommon))• Decreases half life of many drugs by Decreases half life of many drugs by

inducing CYPsinducing CYPs• HIV protease inhibitors and non-nucleoside HIV protease inhibitors and non-nucleoside

RT inhibitorsRT inhibitors• CorticosteroidsCorticosteroids• Oral contraceptivesOral contraceptives

• RifambutinRifambutin• Induces CYPs but not to the same Induces CYPs but not to the same

degree as rifampicindegree as rifampicin• Rash, red pee, neutropenia, leukopenia Rash, red pee, neutropenia, leukopenia

((commoncommon))

EthambutolEthambutol• Inhibits arabinosyl Inhibits arabinosyl

transferases transferases involved in cell involved in cell wall synthesiswall synthesis

• Given orally and Given orally and excreted mostly excreted mostly unchanged in the unchanged in the urineurine

• Dose dependent Dose dependent diminished visual diminished visual acuityacuity

PyrazinamidePyrazinamide• Synthetic Synthetic

pyrazine analog pyrazine analog of nicotinamideof nicotinamide

• Bactericidal at Bactericidal at weak pH, where weak pH, where TB can be found TB can be found in Min M

• Inhibits fatty Inhibits fatty acid synthase I acid synthase I genegene

PyrazinamidePyrazinamide• Oral administrationOral administration• Excellent Excellent

penetrationpenetration• Hydrolyzed and Hydrolyzed and

hydroxylated hydroxylated before being before being excreted by kidneysexcreted by kidneys

• Hepatotoxicity Hepatotoxicity (uncommon)(uncommon)

• Hyperuricermia – Hyperuricermia – gout (rare)gout (rare)

Mechanisms of Mechanisms of ActionAction

Mechanisms of Mechanisms of ResistanceResistance

The The End!End!

FinallyFinally……