2. INTRODUCTION
β’ TUBERCULOSIS ( TB)
- infectious disease βcaused by tubercle bacilli
-genus : Mycobacterium
- 3 obligate parasites that cause TB β M. tuberculosis, M.bovis,
M. africanum (mycobacterium tuberculosis complex)
- transmitted by inhalation droplet nuclei
-respiratory TB is the contagiuos form
β’ DRUG RESISTANT TB
-infectious TB caused by the mycobacteria that has become resistant
to the anti- TB drugs.
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3. INTRODUCTION
β’ CAUSES OF DRUG RESISTANCE
οΌ microbiological perspective β dominance of mutant bacteria
οΌ clinical perspective β inadequate drug levels of first line
therapy
οΌ programmatic perspective β delay in detection and initiation
of therapy
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5. CLASSIFICATION
o Based on Drug Resistance:
- Mono Resistance (MR) βresistant to one first- line anti TB drug only
- Poly Drug Resistance (PDR) β resistant to more than one first line anti
TB drug, other than both H and R.
- Multi-Drug Resistance (MDR)- resistant to both H and R , with or
without resistance to other first line drugs based on results from a QAL
- Rifampicin Resistance (RR)- managed as an MDR TB case
- Extensive Drug Resistance (XDR)- case where patient is additionally
resistant to a FQ (ofloxacin,levofloxacin, moxifloxacin) and a second
line inj anti-TB drug (kanamycin, amikacin or capreomycin ) from a
QAL.
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9. FLUOROQUINOLONES
β’ MOA : inbition of DNA gyrase and topoisomerase 4 enzyme
β’ SPECTRUM : inhibit strains of M tuberculosis at concentrations less
than 2 mcg/mL. Also active against atypical mycobacteria.
β’ ADR: Headache, Elevation of LFT enzymes, QTc prolongation,
Tendonitis
β’ Monitoring Parameters: ECG, LFT, Blood Glucose
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Levofloxacin (Lfx) Moxifloxacin (Mfx)
FDA approval Dec 1996 Oct 1999
Dose Adult 10-15 mg/kg 400mg once a day
Dose PD < 5yrs : 15-20 mg/kg
> 5yrs : 10- 15 mg/kg/day
7.5 β 10mg/kg
Half life 5-7 hours 9-10 hours
Bio availability 95% > 85%
Elimination Renal Non-renal
10. AMINOGLYCOSIDES
β’ MOA : inhibition of protein synthesis at 3Os ribosomal unit
β’ SPECTRUM : streptomycin-resistant or multidrug-resistant strains.
Also active against atypical mycobacteria.
β’ ADR: Ototoxicity, Nephrotoxicity
β’ Monitoring Parameters: RFT, auditory and vestibular monitoring
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Amikacin (Am) Kanamycin (Km)
FDA approval Jan 1981 Feb 1973
Dose Adult β€59 yrs 15mg/kg/day
>59 yrs 10mg/kg/day
15-20 mg/kg/day
Dose PD 15-22.5 mg/kg 15-30 mg/kg
Half life 2-3 hours 2-3 hours
Elimination Renal (GF) Renal (GF)
11. POLYPEPTIDES
β’ MOA : inhibit protein synthesis by binding to 70s ribosomal unit
β’ SPECTRUM : Strains of M tuberculosis that are resistant to
streptomycin or amikacin.
β’ ADR: Ototoxicity, Nephrotoxicity, Eosinophilia, Painful injection
β’ Monitoring Parameters: RFT, auditory and vestibular monitoring
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Capreomycin(Cm)
FDA approval June 1971
Dose Adult β€59 yrs 15mg/kg/day
>59 yrs 10mg/kg/day
Dose PD 15-30 mg/kg
Half life 4-6 hours
Elimination Renal
12. CARBOTHIONAMIDES
β’ MOA : inhibition of mycolic acid bio synthesis
β’ SPECTRUM : M. tuberculosis, M. bovis , M. segmatis
β’ ADR: GI manifestations, neurologic symptoms
β’ Monitoring Parameters: LFTs, TFTs, blood glucose(diabetic patients)
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Ethionamide (Eto) Prothionamide (Pto)
FDA approval April 1965 (Germany ) June 2005
Dose Adult 15-20mg/kg/day 15-20mg/kg
Dose PD 10-20mg/kg /day N/A
Half life 2 hours -
Bio availability 100% (oral) -
Elimination Renal -
14. OXAZOLIDONES
β’ MOA : inhibit protein synthesis initiation by binding to 23s rRNA
β’ SPECTRUM : Strains of MRSA, gram positive rods like corynebacteria,
Nocardia sp., L. monocytogenes and M.tuberculosis
β’ ADR: hematologic β thrombocytopenia,neutropenia, anemia,optic
and peripheral neuropathy
β’ Monitoring Parameters: CBC ,LFT
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Linezolid (Lzd)
FDA approval April 2000
Dose Adult 600mg once a day
Dose PD 10mg/kg (max. 600mg) with pyridoxine
Half life 4-6 hours
Bioavailability 100% (oral)
15. Phenazine Derivative
β’ MOA : ( unknown) antibacterial and anti- inflammatory action
β’ SPECTRUM : M.avium, M. ulcereans, S. aureus, coagulase-negative
staphylococci, streptococcus pyogenes, L.monocytogenes
β’ ADR: photosensitivity , skin discolouration ,GI problems
β’ Monitoring Parameters: ECG
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Clofazimine (Cfz)
FDA approval Dec 1986
Dose Adult 100-200mg once daily
Dose PD 1mg/kg/day
Half life 10 days
Bioavailability 40-60%
16. Diarylquinolone
β’ MOA : inhibition of mycobacterium ATP synthase
β’ SPECTRUM : MAC, M.leprae,M.tuberculosis, M.ulcereans, M.
kansassi, M.fortuitum
β’ ADR: arthralgia , chest pain
β’ Monitoring Parameters: ECG, LFT, calcium and magnesium
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Bedaquiline (Bdq)
FDA approval Dec 2012
Dose Adult 400 mg daily
Dose PD Not recommended <18 yrs
Half life 5.5 months
Elimination Fecal
17. Nitroimidazole
β’ MOA : inhibition of mycolic acid synthesis
β’ SPECTRUM : main action against M.tuberculosis
β’ ADR: (limited data) urticaria, GI disturbances, dizziness, hemoptysis
β’ Monitoring Parameters: ECG, calcium ,magnesium, albumin
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Delamanid (Dlm)
FDA approval (EMA) April 2014
Dose Adult 18-64yrs : 100mg twice daily
Dose PD Not recommended
Half life 30-38 hours
Elimination Fecal
19. Principlesof DesigningWHO recommened
Regimen
ο regimen with at least 5 effective TB medicines during the IP
is recommended- Z and four core second-line TB medicines
- 1 chosen from group A, 1 from group B and at least 2 from
group C.
- If effective TB medicines cannot be composed as above, an
agent from group D2 and other agents from D3 may be added
to bring the total to five.
- In patients with MDR/RR-TB, it is recommended that the
regimen be further strengthened with Hh and/or E.
οNewer drugs containing regimen would contain the new drug
as one of at-least four core second-line drugs considered to be
effective (selection based on DST pattern)
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