Anti-TB agents

Question 1

what to give individuals with LTBI?

Answer 1

isoniazid (INH) for 9 mos.

or can combine INH + rifapentine for 12 weeks by DOT

or daily rifampin for patients for 4 months, that are intolerant to INH

Question 2

empiric therapy for patients with active TB?

Answer 2

INH, rifampin, Isoniazid, pyrazinamide

Question 3

which two factors increase the risk of tx failure and relapse?

Answer 3

cavitary disease at presentation

positive sputum culture taken at 2 months

Question 4

combinatorial therapy?

Answer 4

two or more active agents should always be used to tx active TB in order to prevent emergence of resistance during therapy

INH and rifampin are the most active anti-TB drugs

• a rifamycin: rifampin, rifabutin, rifapentine - considered key component of TB tx - and are necessary for regimen to be succesful
• addition of pyrazinaminde to INH/rifampin tx allows the duration of therapy to be 6 months

Question 5

AE’s of first-line agents?

Answer 5

hepatitis, most common serious AE (espec. INH, rifampin, pyrazinamide**) - pyr. is probably most hepatotoxic (stop tx if serum AST levels are >3x)

• ocular toxicity (ethambutol), rash, fever

Question 6

what can you switch for rifampin?

Answer 6

rifabutin

Question 7

tx if resistant to INH?

Answer 7

(1) Treat with rifampin, pyrazinamide, and ethambutol for 6 months
(2) Rifampin and ethambutol for 12 months for patients who cannot take pyrazinamide
(3) A fluoroquinolone (levofloxacin or moxifloxacin) may be added as they are well tolerated in patients with drug-induced hepatic dysfunction

Question 8

tx if resistant to rifamycins?

Answer 8

(1) At least 12 months of treatment with INH, ethambutol, and a fluoroquinolone
(2) Pyrazinamide should also be used during the initial 2 months of therapy

Question 9

tx for multidrug resistance, MDR?

Answer 9

(4) MDR-TB and XDR-TB should be treated with daily (not intermittent) DOT therapy
(5) Empiric therapy for suspected MDR-TB often includes isoniazid, rifampin, ethambutol, pyrazinamide, an aminoglycoside (streptomycin, kanamycin or amikacin) or capreomycin, a fluoroquinolone and, if needed, cycloserine, ethionamide and/or p-aminosalicylic acid (PAS)
(6) Once susceptibility data are available, the MDR-TB regimen should include all active first-line agents, a fluoroquinolone, and one injectable drug (e.g., capreomycin or an aminoglycoside)

Question 10

MDR-TB vs XDR-TB?

Answer 10

(2) MDR-TB: Multidrug-resistant TB; isolates with resistance to at least INH and rifampin
(3) XDR-TB: Extensively drug-resistant TB; isolates with resistance to isoniazid, rifampin, any fluoroquinolone, and at least one of three other injectable second-line drugs (capreomycin, kanamycin, or amikacin)

Question 11

Tx of patients not on ART with TB?

Answer 11

(a) TB is an AIDS-defining illness, meaning that an HIV-positive patient who is relatively asymptomatic and not on ART progresses to an AIDS diagnosis when TB is confirmed, thus ART is recommended
(b) Initiation of ART during anti-TB therapy has been shown to improve survival and virologic outcome
(c) In patients with CD4 counts 50 cells/mm3) should probably wait until after the initial phase of TB treatment to begin ART in order to reduce the risk of adverse events and IRIS

Question 12

immunomodulators?

Answer 12

patients should stop using TNF-alpha inhibitors before beginning anti-TB tx

Question 13

pregnancy and tx of TB?

Answer 13

ii) Delayed treatment for LTBI is recommended 2-3 months after delivery (due to risk of hepatotoxicity and lack of data on teratogenicity risk) unless the woman is HIV-positive or has been recently infected with TB (do not delay treatment in these patients)
iv) Active TB in pregnancy requires treatment because the risk of TB to the fetus is much greater than the risk of adverse drug effects
v) The initial regimen should include INH, rifampin, and ethambutol (all cross placenta but none are known to be teratogenic) for two months followed by isoniazid and rifampin for seven months

Question 14

Isoniazid

Answer 14

i) The most active drug for the treatment of TB caused by susceptible strains (less effective against atypical mycobacterial species)

MOA: inhibits synthesis of mycolic acids (essential components of the mycobacterial cell wall)

Clinical uses

(1) Approved for the treatment of susceptible active tuberculosis infections and latent tuberculosis infections (LTBI)
(2) Typically dosed once daily, but may be dosed twice-weekly in combination with a second anti-TB agent
(3) Single agent treatment (for LTBI) duration is 9 months

AE’s:

• hepatoxicity and hepatitis (increases with increasing age) - see loss of appetite, nausea, vomiting, jaundice, RUQ pain
• increased risk of hep in alcoholics and pregnant pts.
• peripheral neuropathy due to pyridoxine (vit B6) defiency
• CNS toxicity: memory loss, psychosis, seizures
• fever, skin rashes, SLE

Question 15

rifampin

Answer 15

(1) MOA: binds to the β-subunit of bacterial DNA-dependent RNA polymerase and inhibits RNA synthesis
(2) Bactericidal for mycobacteria (doesn’t bind to human RNA polymerase)
(3) Active in vitro against gram-positive and gram negative cocci, some enteric bacteria, mycobacteria, and chlamydia

iv) Clinical uses
Mycobacterial infections-
(a) Co-administered with INH or other anti-TB agents to patients with active TB
(b) Typically dosed PO once/day; twice-weekly dosing is effective in combination against atypical mycobacterial infections and in leprosy
(c) May be given as a single drug in patients with latent TB only (alternative to INH) who are unable to take INH, or who have had exposure to active TB caused by an INH-resistant, rifampin-susceptible strain
Other indications: meningococcal carriage, staph infections

AE’s: Strong P450 inducer - used in caution w/ patients taking HIV medications

• harmless red/orange color to urine, feces, saliva, sweat, tears, CSF
• rashes, GI disturbances, thrombocytopenia, nephritis
• hepatoxicity occurs but is less common
• flu like syndrome

Question 16

pyrazinamide?

Answer 16

use: used in conjunction with INH and rifampin in short course (6 mos) regimines

AE’s:

(1) Hepatotoxicity (1-5% of patients, probably the most hepatotoxic of first-line agents)
(2) GI upset (nausea, vomiting) is fairly common
(3) Hyperuricemia (may provoke gouty arthritis)
(4) Most common cause of drug rash among the first-line agents

Question 17

Ethambutol?

Answer 17

(1) MOA: inhibits mycobacterial arabinosyl transferases, which are encoded by the embCAB operon

Clinical uses

(1) Given in four-drug initial combination therapy for TB until drug sensitivities are known
(2) Higher dose is recommended for treatment of TB meningitis

v) Adverse reactions
(1) Retrobulbar neuritis, resulting in loss of visual acuity and red-green color blindness, is the most common serious adverse event and is dose-dependent
(2) Relatively contraindicated in children too young to permit assessment of visual acuity and red-green color discrimination

Question 18

Streptomycin

Answer 18

typically administered IV!
(4) Crosses the blood-brain barrier and achieves therapeutic concentrations with inflamed meninges

(1) MOA: irreversible inhibitor of protein synthesis, but exact mechanism for bactericidal activity is not known

Clinical use:

(1) Used when an injectable drug is needed or desirable – patients with severe or life-threatening forms of TB (e.g., meningitis and disseminated disease) and in the treatment of infections resistant to other drugs
(2) IM or IV dosing daily for adults for several weeks followed by 2-3x/week dosing for several months

AE’s:

(1) Ototoxicity—vertigo and hearing loss are the most common adverse effects and may be permanent—and nephrotoxicity
(2) Toxicity is dose-related and may be reduced by limiting therapy to no more than 6 months
(3) Relative contraindication in pregnancy

Question 19

Ethionamide

Answer 19

iv) Poorly tolerated due to hepatotoxicity, intense gastric irritation, thyroid, and neurologic adverse effects (may be alleviated by pyridoxine)
v) Single-agent therapy results in rapid resistance; low-level cross-resistance can occur with INH

Question 20

Capreomycin

Answer 20

ii) IM injections at appropriate levels inhibit many mycobacteria, including multidrug-resistant strains of TB (MDR-TB)
iii) Resistance may occur due to rrs mutations
iv) Nephrotoxic and ototoxic (tinnitus, deafness, vestibular disturbances)
v) Other adverse effects include significant pain and formation of sterile abscesses at the injection site

Question 21

Cycloserine

Answer 21

i) Inhibitor of cell wall synthesis
ii) Twice daily oral dosing, reduce dosage by half in patients with renal impairment
iii) Most serious toxic effects—occurring in 25% or more of patients—are peripheral neuropathy and CNS dysfunction (depression, psychotic reactions, or seizures)
iv) Concomitant treatment with pyridoxine reduces neurologic toxicity

Question 22

Aminosalicylic Acid (PAS)

Answer 22

i) Folate synthesis antagonist that is not typically used due to adverse effects
ii) Active almost exclusively against M. tuberculosis

iv) Well absorbed from the GI tract and widely distributed except for the cerebrospinal fluid

vi) Adverse effects include GI effects (e.g., peptic ulceration and hemorrhage)
vii) Hypersensitivity reactions can be so severe (e.g., fever, joint pain, hepatosplenomegaly, hepatitis, adenopathy, granulocytopenia) that PAS administration should be stopped temporarily or permanently

Question 23

Kanamycin and Amikacin

Answer 23

ii) Kanamycin has previously been used to treat streptomycin-resistant TB but due to the availability of less toxic alternatives (capreomycin, amikacin) its use is less common
iii) Amikacin is a semisynthetic derivative of kanamycin; it is less toxic than the parent compound
iv) Most multi-drug resistant and streptomycin-resistant TB strains (indications for use) are susceptible to amikacin; most atypical mycobacteria are also susceptible to amikacin

vi) Adverse effects include nephrotoxicity, ototoxicity, tinnitus, high-frequency hearing loss

Question 24

Fluoroquinolones

Answer 24

i) Block bacterial DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV
ii) Ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of M. tuberculosis and are also active against atypical mycobacteria

iv) Utilized in patients with TB resistant to first-line agents
v) Usually well tolerated, but GI and CNS disturbances can occur; impaired glucose control can occur, especially in the elderly and in patients with diabetes
mycobacteria

Question 25

Linezolid

Answer 25

ii) Significant (and potentially treatment-limiting) adverse effects include bone marrow suppression and irreversible peripheral and optic neuropathy
iii) Considered a last resort for MDR-TB (uses include treatment of vancomycin-resistant Enterococcus faecium (VRE) infections, nosocomial pneumonia caused by Staphylococcus aureus including MRSA or Streptococcus pneumoniae (including multidrug-resistant strains (MDR-SP)), and community- acquired pneumonia caused by susceptible gram-positive organisms)

Question 26

Rifabutin

Answer 26

i) Derived from rifamycin and related to rifampin
ii) Active against M. tuberculosis, M. avium-intracellulare, and M. fortuitum
iii) Efficacy similar to that of rifampin; complete cross-resistance with rifampin due to the same basis of resistance (rpoB mutation)

v) Indicated in preference of rifampin in patients with HIV who are receiving concurrent antiretroviral therapy with a protease inhibitor or nonnucleoside reverse transcriptase inhibitor (e.g., efavirenz), which are also substrates of CYP450s
vi) Has limited distribution in resource-limited settings, where TB is endemic, due to its expense
vii) Effective in prevention and treatment of disseminated atypical mycobacterial infection in patients with AIDS (also for prevention of TB)

Question 27

Rifapentine

Answer 27

i) Long-acting analog of rifampin; complete cross-resistance with rifampin; same drug interaction profile as rifampin (also induces CYP450s); toxicity is similar to that of rifampin
ii) Active against M. tuberculosis and M. avium
iii) Indicated for treatment of rifampin-susceptible TB during the continuation phase only (after 2 months of therapy, and preferably after conversion of sputum cultures to negative)

Question 28

multidrug tx for m. leprae?

Answer 28

dapsone, rifampin, clofazimine

Question 29

dapsone

Answer 29

ii) Well absorbed from the GI tract and widely distributed; excreted in the bile; typically acetylated
iii) Hemolysis and methemoglobinemia are common
iv) May also be used to prevent and treat Pneumocystis jiroveci pneumonia in AIDS patients

Question 30

Clofazimine

Answer 30

iii) Indicated for sulfone-resistant leprosy or when patients are intolerant to sulfones
iv) Adverse effects include skin discoloration ranging from red-brown to black; gastrointestinal intolerance occasionally occurs

Question 31

which first-line anti-TB agent most likely causes hepatotoxicity?

Answer 31

pyrazinamide

Question 32

which second line agents with INH?

Answer 32

ethionamide

Question 33

how does INH work?

Answer 33

inhibits mycolic acid synthesis

** this is the most active drug for tx of TB**

Question 34

how does INH most likely develop resistance?

Answer 34

mutations in katG (enzyme in mycobacteria that activates the drug)

Question 35

which combination of agents is most recommended for a patient that has just recently developed TB in the US that is active?

Answer 35

INH, rifampin, pyrazinamide, ethambutol

why is it important to use Multi-drug regimen? b/c it quickly becomes resistant to single drug - should always do all 4 before have the test results back regarding resistance

why isn’t streptomycin used? only administered IV/IM

Question 36

embB gene mutation?

Answer 36

ethambutol - visual CE

Question 37

mutations in inhA, katG, ahpC, kasA?

Answer 37

INH - hepatotoxocitiy/neuro problems/rashes, SLE

Question 38

mutations in rpoB?

Answer 38

rifampin - red/orange color, rashes, GI problems

Question 39

mutations in pncA gene?

Answer 39

pyrazinamide - most hepatotoxic

Question 40

what are three most active anti-TB meds?

Answer 40

INH and rifampin and pyrazinamide

Question 41

what lab value is most likely elevated with use of anti-TB meds?

Answer 41

serum aminotransferase activity (AST) - seen in INH, rifampin, pyraminizide

alcohol consumption, other drugs –> increased risk of liver damage

see clinical hepatitis: (with loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain)

Question 42

frequent tingling as well as general mm. aches and weakness?

Answer 42

Vit. B6 deficiency - INH promotes excretion of this vitamin resulting in this AE

Question 43

Which drug is worried about with HIV?

Answer 43

rifampin, rifabutin, rifapentine - these all induce the CYP450’s, (antiretroviral therapy are metabolized by CYP450’s, resulting in increased metabolism of these drugs, thus if you have HIV + patient on ART you will need to measure the drug levels and make sure that all of the therapies are staying at the same levels)

• ** rifampin is most potent inducer
• ** rifabutin is the LEAST potent inducer! would want to use this on an HIV+ patient that is taking ART, if they have the means to pay for it