What is the treatment for latent TB?
Diagnosis
- Mantoux
- IGRA
Tx
- Isoniazid + rifapentin weekly for 3 weeks OR
- Rifampin daily for 4 moths OR
- Isoniazid + rifampin daily for 3 months
OR
Isoniazid daily for 6 or 9 months
4 months of rifampicin = 9 months of isoniazid = 3 months of isoniazid + rifampicin
Treatment for active TB
Intensive Phase:
Rifampicin + Isoniazid + Pyrazinamide + Ethambutol for 2 months
Continuation Phase
Rifampicin + Isoniazid for 4 months
How does mycobacterium tuberculosis survive?
M. tuberculosis survives within macrophages because of the inhibition of both phagosome maturation and phagolysosome fusion
The cellular immune response in TB
Th1 cell activation
Macrophage activation and bacterial killing
Granulomatous inflammation and tissue destruction - IFNy activated macrophages secrete TNF a
Granuloma limits the spread of infection
Typically affect upper lobes of the lungs
What is the mantoux test
Tests cell-mediated immunity against M. tuberculosis through delayed hypersensitivity reaction (type IV HSR) mounted by T cells
Specificity compromised by previous BCG and exposure to non-TB mycobacterium
False Negatives
- Sarcoidosis
- Immunosuppressed state
- Recent TB infection within 6-8 weeks
- Recent live virus vaccine
- Disseminated TB
What is the IGRA
- Tests cell-mediated immunity against M. tuberculosis- specific antigens by measuring the amount of IFN-γ released by T cells
- Advantage over mantoux is that antigens used are specific to TB and not present in BCG or the majority of non-tuberculosis myocbateria.
- Positive test indicates active TB or latent TB;
- Negative; Indeterminate, and commonly seen in: Immunosuppressed states, children < 5yo
Can IGRA or Mantoux differentiate between acute or latent TB?
○ Both the tests are unable to differentiate between active and latent TB
○ Neither TST or IGRA differentiate latent or active disease, new infection/reinfection and have a poor predictive value for who will develop active disease
○ Both perform less well in immunocompromised patient
○ Test at least 8 weeks since last exposure
Target testing to those at high risk of developing TB (i.e. test those you will treat)
What does drug resistant TB mean?
The term “drug-resistant TB” refers to cases of TB caused by an isolate of M. tuberculosis that is resistant to one of the first-line anti-TB drugs: isoniazid, rifampicin, pyrazinamide, ethambutol, or streptomycin.
What does mutli-drug resistant TB mean?
The term “multidrug-resistant TB” (MDR-TB) refers to an isolate of M. tuberculosis that is resistant to at least isoniazid AND rifampicin and possibly additional chemotherapeutic agents.
What does pre-extensively drug resistant TB mean?
The term “pre-extensively drug-resistant TB” (pre-XDR-TB) refers to an isolate of M. tuberculosis that is resistant to isoniazid and rifampcin as well as fluoroquinolones (levofloxacin or moxifloxacin)
What does extensively drug resistant TB mean?
The term “extensively drug-resistant TB” (XDR-TB) refers to an isolate of M. tuberculosis that is resistant to at least isoniazid, rifampicin, and any fluoroquinolone and at least 1/3 injectable drugs (Kanamycin, capreomycin, amikacin)
Risk factors for drug resistant TB
- Previous treatments
- Contact with MDR-TB or residence in a high burden centre
- 60-70% have no history of prior treatment
- Patients with history of TB (current or past)
- Persistent or progressive clinical and/or radiographic findings while on anti-TB therapy
- Lack of conversion of cultures to negative during first 3 months of anti TB therapy
- Incomplete adherence to prescribed anti TB therapy
- Lack of directly observed therapy or poorly supervised anti TB therapy
- Documented treatment failure or relapse
- Hx of inappropriate treatment regimen
Patient without prior history of TB
- Exposure to an individual with known or suspected drug resistant TB
- Residence in or travel to region with high prevalence of drug resistnat TB
Risk factors for progression to active TB
Highest Risk - HIV - Transplant Silicosis - Chronic renal failure
In terms of TB drugs, what is the extent of activity for
- prevention of resistance
- Early bactericidal activity
Prevention of resistance From HIGH to LOW - Isoniazid - Rifampicin - Ethambutol - Streptomycin - Pyrazinamide
Early bactericidal activity - high to low
- Isoniazid
- Ethambutol
- Rifampicin
What are the 1st and 2nd line TB medications?
1st Line
- Rifampicin
- Isoniazid
- Pyrazinamide
- Ethambutol
2nd Line
(a) Aminoglycosides
- Streptomycin
- Amikacin
(b) Fluoroquinolones
- Levofloxacin
- Moxifloxacin
(c) Ethionamide
(d) Linezolid
MOA of rifampicin and SE
- MOA: inhibits bacterial DNA-dependent RNA polymerase → prevention of transcription (mRNA synthesis) → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
- SE: drug interactions (cytochrome P450 induction), hepatitis, hypersensitivity, orange discolouration of body fluids (urine, tears)
The 6 Rs of Rifampin: Red or organge urine, RNA polymerase Repression, Ramping up cytochrome P450 activity and Rapid Resistance if used alone
Rifampin really amplifies (induces) cytochrome P450 but rifabutin does not
Isoniazid MOA and SE
- MOA: prodrug and needs to be converted into its active metabolite by bacterial catalase peroxidase (encoded by KatG). Prevents cell wall synthesis by inhibiting the synthesis of mycolic acid
- SE: hepatitis, rash, peripheral neuropathy (due to vitamin B6 deficiency, prevented with pyidoxine)
- The only drug that can be used as monoprophylaxis against TB
INH is Not Healthy In Neurons and Hepatocytes
Neurotoxicity may be prevented by supplementing with pyridoxine
MOA and SE of pyrazinamide
- MOA:
Not completely understood
Prodrug: converted into active form pyrazinoic acid, most effective at acidic pH
Bactericidal effect
SE: hepatitis, skin, polyarthralgia, gout
MOA and SE of ethambutol?
- MOA: inhibits arabinosyltransferase → ↓ carbohydrate polymerization → prevention of myobacterial cell wall synthesis (bacteriostatic effect)
- SE: optic neuropathy
EYEthambutol: Ethambutol causes optic neuropathy
Which TB medications causes hepatitis?
Pyrazinamide > Isoniazid»_space; Rifampicin
ALT:
- 2-5 x ULN and asymptomatic – monitor closely
- > 5 x ULN or >3x ULN with symptoms – stop
- If can’t safely stop then use: Amikacin, E, Moxi
- Once ALT near baseline restart with drug challenge
- Up to 75% of patients will tolerate re-introduction of isoniazid and rifampicin
How does rifampin and isoniazid affect cytochrome P450?
Rifampin and isoniazid alter the efficacy of drugs metabolised by cytochrome P450 especially protease inhibitors, NNRTis, OCP, warfarin, sulfonylureas
Primary vs secondary drug resistance
- Primary drug resistance is said to occur in a patient who has never received anti-TB therapy.
- Secondary drug resistance refers to the development of resistance during or following chemotherapy in patients who had previously had drug-susceptible TB - selection of drug resistant mutants by inadequate treatment
Treatment for TB meningitis
isoniazid, rifampicin, pyrazinamide, moxifloxacin– moxifloxacin better CSF penetration than ethambutol
What is the treatment for Mycobacterium avium infection?
Azithromycin/Clarithromycin +
Ethambutol +
Rifampicin/Rifabutin
