PHR 948 - Block 4: Tuberculosis

mycobacterium tuberculosis

causative agent of tuberculosis

- acid-fast, obligate intracellular aerobic bacteria

- very slow growing

- only grows in humans

- horizontal transmission via respiratory droplets

tuberculosis (TB)

- typically causes pneumonia

- can be extrapulmonary

- mortality rate: 5%

TB transmission

- spread by airborne droplet nuclei

- transmission affected by: infectiousness of patient, environmental conditions, and duration of exposure

- most people who are exposed do not become infected

latent TB (LTBI)

inactive TB infection without symptoms

- asymptomatic = non-infectious

- bacteria can survive and remain dormant, but viable, for years

progression to active TB

- soon after infection: small number

- during lifetime: 5-10% of untreated LTBI

- 10% of people with HIV + untreated LTBI per year

LTBI diagnosis

1. tuberculin skin test (TST)

- delayed hypersensitivity to purified protein derivative tuberculin

- intradermal injection, then read results in 48-72 hours

- false negatives seen in immunosuppressed pts, false positives seen in pts that received BCG or exposed to other mycobacteria

2. interferon-gamma release assay (IGRA)

- measured IFNγ released by T cells in response to TB antigens

- more specific, only one visit required

- fast negatives seen in kids <5, HIV infection + low CD4

- preferred test

active TB

Infected, symptomatic, and contagious

- symptoms: weight loss, fatigue, productive cough, fever, night sweats

- lab tests: some WBC elevation, lymphocyte predominance

- chest xray: patchy/ nodular infiltrates in upper lobes, cavitation

factors increasing risk for infectiousness

- coughing

- undergoing cough-inducing or aerosol-generating procedure

- chest cavitation on xray

- positive acid-fast bacilli )AFB) sputum smear

- inadequate TB treatment

suspected active TB

- if suspected, obtain: acid-fast bacilli smear/ stain, culture, and susceptibility testing

- put pt in respiratory isolation

- pt is considered noninfectious when they meet all 3 criteria:

> receiving effective therapy

> clinical improvement

> negative results for 3 consecutive sputum AFB smears (on different days)

TB treatment overview

- must use a combination of drugs

- 4 drug regiment is most common for active TB

- intensive phase for x2 months, susceptibility testing done, then additional 4-7 months in some patients

- many ADEs, drug interactions, and counseling points

antituberculosis drugs

first-line

- isoniazid (INH): cell wall synthesis

- rifampin (RIF): RNA transcription

- pyrazinamide (PZA): lowers pH

- ethambutol (EMB): cell wall synthesis

- rifapentine (RPT)

- rifabutin (RBT)

- moxifloxacin (FQ): DNA replication

second line

- streptomycin (SM)

- cycloserine

- kanamycin

- P-aminosalicylic acid

- ethionamide

- amikacin (AGL): protein translation

- capreomycin

- levofloxacin

last line

- bedaquiline

- pretomanid

- linezolid

isoniazid (INH)

- MOA: inhibits synthesis of mycolic acids in the cell wall

- advantages: relatively nontoxic, easy to give, inexpensive

- PK: good CSF and tissue penetration, prolonged t1/2 in renal and hepatic failure

- toxicity: hepatotoxicity (NO alcohol), peripheral neuropathy (interferes w pyridoxine metabolism)

> supplement B6 in high risk pts

- DDI: CYP450 inhibitor, warfarin, carbamazepine, phenytoin, cycloserine; aluminum salts

> caution acetaminophen (hepatotoxicity)

rifampin (RIF)

- MOA: binds to bacterial RNA polymerase, inhibiting transcription

- advantages: rapidly bactericidal for TB, relatively nontoxic, easily administered

- PK: oral bioavailability >90%, good penetration into cells/tissues, poor CNS penetration

- counseling: discoloration of urine, tears, and other bodily fluids

- toxicity: GI disturbances, hepatitis, skin rash, thrombocytopenia, cholestatic jaundice

- DDI: potent inducer of CYP450s, steroids, methadone, warfarin, -azoles, estrogens

- alternatives: rifapentine, rifabutin

rifapentine and rifabutin

alternatives to rifampin

rifapentene

- used to be once weekly, now used daily

- once weekly for LTBI

- similar toxicities and DDIs to rifampin

rifabutin

- less potent hepatic enzyme inducer

- good for HIV+ patients

pyrazinamide (PZA)

- MOA: converted to pyrazinoic acid by TB = lowers pH of environment

- advantages: highly effective in first few months when inflammation is present

- PK: large Vd, good CSF penetration, adjust dose in renal impairment

- warnings: CI in severe hepatic impairment, caution in elevated LFTs/ history of alcoholism, caution in combo with other hepatotoxic drugs

- toxicity: hepatic injury, hyperuricemia, skin rash, GI upset

- DDI: small increase in isoniazid levels, combo with rifampin = severe liver toxicity

ethambutol (EMB)

- MOA: inhibits arabinosyl transferase, impairing mycobacterial cell wall synthesis

- PK: adjust dose in renal impairment

- toxicity: retrobulbar neuritis (frequent and serious)

> signs: blurred vision, central scotomata, R-G color blindness; report any visual changes

> dose and duration dependent

- DDI: aluminum salts decrease absorption

bedaquiline

last line TB therapy

- MOA: diarylquinoline antimycobacterial = inhibits mycobacterial ATP synthase

- PK: CYP3A4 metabolism

- toxicity: increase of mortality (unrelated to TB), QT prolongation, hepatotoxicity, anorexia, nausea, arthralgia

- limited data in HIV+ people

pretomanid

last line TB therapy

- MOA: nitroimidazooaxazine antimycobacterial prodrug

> activated by TB to inhibit mycolic acid biosynthesis (respiratory poison)

- toxicity: hepatotoxicity, QT prolongation, testicular atrophy

- DDI: CYP3A4 inducers, linezolid (myelosuppression, neuropathies, lactic acidosis)

active TB treatment

intensive phase: 2 months

- RIPE: RIF + INH + PZA + EMB

- frequency options: daily, 5x week, or 3x week

- can drop EMB if susceptible to other 3

continuation phase: 4-7 months

- INH + RIF

- frequency options: daily, 5x week, 3x week, or 2x week

extend to 7 months if:

> initial chest xray shows a cavitary lesion AND (+) culture at 2 months

> only RIF + INH + EMB was used in initial phase

use clinical judgement to extend to 7 months if:

> initial chest xray shows a cavitary lesion OR (+) culture at 2 months

treatment monitoring

1. sputum for AFB smear and culture

- smear daily until out of isolation

- AFB and culture initially, then every month until 2 are negative

2. drug susceptibility test

- initially, then once if culture (+) after 3 months of treatment

3. lab testing

- renal function, AST, ALY, bilirubin, platelet count

- baseline, then only if abnormal or symptoms develop

4. if on EMB for >2 months

- visual acuity and color vision monthly

5. chest xray

- initially, then again in 2 months if culture (+)

6. monthly evaluation to assess adherence and identify ADEs

LTBI treatment

treat ALL patients diagnosed with LTBI

preferred regimens

1. INH weekly + RPT weekly x12 weeks

- directly observed or self administered

- 3+ years old

- okay for HIV+ as long as DDIs are addressed

- high pill burden

2. RIF/RBT daily x16 weeks

- no evidence in HIV+

- many DDIs

3. INH daily + RIF daily x12 weeks

- conditional recommendation

alternative regiments

1. INH daily or twice weekly (DOT) x26 weeks

- strong recommendation for HIV-

- conditional recommendation for HIV+

2. INH daily or twice weekly (DOT) x38 weeks

- conditional recommendation

drug resistance risk factors

risk factors

- prior TB therapy

- failed treatment/ relapsed

- high resistance areas

- homeless, institutionalized, IVDU, HIV (+)

- known exposure to patient infected with drug resistant TB

drug resistant TB regimen

INH resistance

- RIF + PZA + EMB x6-9 months

- could sub SM for EMB

INH + RIF resistance

- consult specialist

- give 4+ susceptible drugs

RIF resistance

- 6 month regimen (BPaL pr BPaLM)

- bedaquiline, pretomanid, linezolid, moxifloxacin

- lots of monitoring

INH + RIF + FQ + AGL resistance

- cure rates low, treatment outcomes bad, no guidelines

treatment failure

positive cultures after 4 months of treatment in patients for whom medication ingestion was ensured

mitigate:

- add at least 3 new drugs to exisiting regimen

> FQ, ethionamide, and injectable

- retest for drug resistance

- one single new drug should never be added