Anti tuberculous therapy update

1. Anti-tuberculous therapy :
Update
By
Mahmoud El-Hussieny Abou El-Magd
Assistant lecturer of pulmonary and critical care medicine

2. Objectives
 Become familiar with the first and second line anti-
tuberculosis antibiotics and the standard treatment
regimes.
 Identify the common adverse effects and drug
interactions associated with these antibiotics.
 Describe problem-solving techniques that are
used to help identify and manage common
adverse effects.

3. Outline
 Review the first line agents
 Discuss duration of therapy
 Review common side effects and
management
 Review treatment of TB in special populations
 Short talk about drug resistance and second
line agents

4. The scope of the problem
 A 2 cm cavity contains 108 organisms.
 There are naturally occurring mutations to all our TB
drugs.
 Use of monotherapy allows the selective growth of
the resistant organisms and gives rise to drug
resistance.
 A prolonged course of antibiotics is required to kill the
semi-dormant and dormant organisms.

5. In order to treat TB you must
 Take into consideration:
 Known or suspected drug resistance
• Hx of prior TB treatment
 Location of disease
• Standard tx is 6 months
• TB meningitis: 9-12 months
 Likelihood of adherence and/or adverse
reactions
 Co morbidities and host immune status

6. Category I
•New (untreated)smear positive pulmonary TB
•New smear negative pulmonary TB
•New cases of severe forms of extrapulmonary TB
( meningitis,spinal,intestinal,genitourinary TB).
Category II
These are smear positive failure, relapse and
Interrupted treatment cases
Patient catogories

7. Category III
These are new cases of smear negative pulmonary TB
With less severe form of extrapulmonary TB, (skin
Bone,peripheral joint TB).
Category IV
These are chronic cases who have become smear
Positive after completing fully supervised retreatment.
These are mostly MDR cases.(multi drug resistant)

8. TB Category Initial phase Continuation
phase
Total duration
I 2 HRZE (S) 4 HR/ 4 H3R3
Or 6 HE
6
8
II 2 HRZES + 1 HRZE 5 HRE or 5H3R3E3 8
8
III 2 HRZ 4 HR/ 4 H3R3 0r 6
HE
6
8
IV Chronic case

9. Standard treatment regime
 Intensive phase
 Goal is to quickly kill the rapidly dividing
organism to control disease
 render patient non-infectious
 prevent emergence of drug resistance
 Continuation phase
 Sterilize the lungs by killing dormant and
semi-dormant organisms to prevent
relapse

10. Give all meds together as a
single dose unless:
Profound nausea, vomiting
Swallowing issues

11. Antituberculosis drugs (by group)
Group Description Drug Abbreviation
1. First-line oral antituberculosis drugs isoniazid
rifampicin
ethambutol
pyrazinamide
rifabutin
H
R
E
Z
Rfb
2. Injectable antituberculosis drugs kanamycin
amikacin
capreomycin
streptomycin
Km
Amk
Cm
S
3. Fluoroquinolones levofloxacin
moxifloxacin
ofloxacin
Lfx
Mfx
Ofx
4. Oral bacteriostatic second-line
antituberculosis drugs
ethionamide
protionamide
cycloserine
terizidone
p-aminosalicylic acid
Eto
Pto
Cs
Trd
PAS
5. Antituberculosis drugs with unclear efficacy
or unclear role in MDR-TB treatment (not
recommended by WHO for routine use in MDR-
TB patients)
clofazimine
linezolid
amoxicillin/clavulanate
thioacetazone
clarithromycin
imipenem
Cfz
Lzd
Amx/Clv
Thz
Clr
Ipm

12. ADRs commonly associated with anti-TB drugs
First-line drugs* Second-line drugs**
Hepatitis Nausea/vomiting
Nausea/vomiting/GI upset Diarrhoea
Rash Arthralgia
Weakness/fatigue Dizziness/vertigo
Arthralgia Hearing disturbances
Fever Headache
Pruritus Sleep disturbances
Headache Electrolyte disturbances
Vertigo/tinnitus Abdominal pain
Anorexia/weight loss Peripheral neuropathy
Abdominal pain Depression
Swelling Tinnitus
Palpitations Allergic reaction
Dyspnoea Rash
Seizures Visual disturbances
Neutrophilia Seizures
Hypothyroidism
Psychosis
Hepatitis
Renal failure/nephrotoxicity

13. 2HREZ/4HR
 In intensive phase
 H,R: kill rapidly dividing TB
 Z: works to kill semi dormant TB in the acidic
environment of the cavity or in macrophages
 E: used to prevent the emergence of RIF
resistance when primary resistance to INH may be
present
 In continuation phase
 H,R: kill any remaining rapidly dividing cells as
well as sterilizing fibrotic areas

14. 14
Rifampin
 Binds to DNA-dependent RNA polymerase
 The most important drug we use
 Bactericidal against rapidly dividing agents, and
penetrates into fibrotic areas to kill semidormant
organisms
 Without rifampin treatment course is 12-18 months
 Usual dose 10 mg/kg max 600mg

15. Rifampin side effects
 Change in colour of urine, sweat
 Pruritis with or without rash: 6%
 Hepatotoxicity
 Significant transaminase elevation: rare
 Can be seen as part of hypersensitivity rx
 Dose dependent interference with bilirubin
uptake causing unconjugated hyperbilirubinemia
or jaundice without LFT abnormalities
 Thrombocytopenia
 Hypersensitivity rx in 0.07-0.3%

16. 16
Rifampin Drug Interactions
Potent inducer of cytochrome P450 enzyme
system
Rifampin decreases drug concentration of:
 amiodarone, anticoagulants (oral), barbiturates, beta-blockers,
buspirone, calcium channel blockers, clarithromycin, oral
contraceptives, corticosteroids, cyclosporine, dapsone, digoxin,
azole antifungals,, losarten, macrolides, morphine, phenytoin,
quinidine, sulfonylureas, theophylline, tricyclic antidepressants
 Rifampin concentration decreased by:
 protease inhibitors

17. 17
Isoniazid
Inhibits mycolic acid synthesis
Profound early bactericidal activity
against rapidly dividing cells
Usual dose 300 mg daily (5 mg/kg)

18. 18
Isoniazid side effects
Peripheral neuropathy
Dose related side effect
Vit B6 supplements to prevent
Rare: seizures
+ANA antibodies in 20%, less than 1%
develop lupus
*

19. INH Hepatotoxicity
 Hepatitis
 Incidence increases with age
 Generally occurs within weeks to months rather
than days
 Takes weeks to regress, recovery is complete in
most following drug cessation

20. 20
INH Drug Interactions
INH inhibits cytochrome P450 system
Increase concentrations of:
carbamazepine, phenytoin, cycloserine,
theophylline, warfarin
These effects are offset with rifampin
Check levels

21. 21
Pyrazinamide
Active against dormant and semi-
dormant TB within macrophages or in
acidic environments
No PZA → minimum of 9 months of tx
Dose is 25 mg/kg, requires renal dosing

22. 22
Pyrazinamide side effects
Hepatotoxicity
Actual incidence hard to predict as PZA always
used with other TB meds, in one study
hepatotoxicity attributed to PZA in 1%
Rash
Non gouty arthralgia
Seen in up to 40% of patients on daily Z

23. 23
Ethambutol
Inhibits arabinosyl transferase (synthesis of
TB cell wall component), (This may
increase penetration of other drugs into
the organisms).
Suppresses growth (static)
Less bactericidal compared to INH or RIF
Dose: 15 mg/kg
Requires renal dosing

24. 24
Ethambutol side effects
retrobulbar neuritis
• Manifests as decreased visual acuity or decreased
red-green colour discrimination in one or both eyes
• Risk higher in pts with renal failure
Rarely used in children due to an inability to
monitor for symptoms

25. 1) In case of resistance to first line agents;
2) In case of failure of clinical response to conventional
therapy.
3) In case of serious treatment limiting adverse drug
reactions.
4) When expert guidance is available to deal with the
toxic effects, because the dosage, emergence of
resistance & long-term toxicity have not been fully
established.
Second Line / Alternate Anti T.B Drugs:

26. 26
Third Line
Amoxicillin/clavulanate
Imipenem/cilastatin
Linezolid
Clarithromycin
Thiacetazone

27. Streptomycin
 Aminoglycoside antibiotic.
 First line Anti TB drug, given by injection.
 Given I/M or I/V as Streptomycin sulfate.
 Crosses BBB & achieves therapeutic conc. if meninges
are inflamed.

28. Clinical Uses
Mycobacterium TB Infections:
Used when an injectable drug is required in severe ,life
threatening form of infection:
• Disseminated Tuberculosis
• Tuberculous Meningitis
• Infections resistant to other drugs.
Dose: 1 g / (15mg/kg/day) I/M or I/V daily.
20-40mg/kg/day for children-not to exceed
1-1.5 G/d.
Given in combination with other drugs to delay /
prevent emergence of resistance.

29. Adverse Effects
Main toxic effects are:
 Ototoxicity—vertigo & hearing loss ,may be permanent.
 Nephrotoxicity—dose related ,more in elderly.
 Dosage adjustment according to Creatinine CL.
 Toxicity can be reduced by limiting the therapy for 6
months.

30.  Antibiotic derived from Rifamycin & is related to Rifampin.
 Less potent inducer of cytochrome P450 less D/I.
 Active against Myco. TB & Atypical mycobacteria.
Rifabutin

31. Uses: For treatment of mycobacterial TB infection in
place of Rifampin in HIV-infected patients receiving Anti-
viral treatment.
In AIDS patients.
 Prevention of T.B: alone for 6 months or with
pyrazinamide for 2 months
 Prevention and treatment of disseminated atypical
mycobacterial infection.
Dose: 300mg/day orally.--- 150mg/day with protease
inhibitor.
450mg/day with Efavirenz ( also an inducer of p450
enzymes)

32.  Analog of Rifampin.
 Cross resistance with Rifampin
 Potent inducer of cytochrome P450 like Rifampin
, so similar drug interactions.
 Active against Myco .TB & Atypical mycobacteria.
Rifapentine

33. Therapeutic uses:
 For ttt of Rifampin susceptible strains during
continuation phase. 600mg / week orally.
C/I: HIV infected patients --- high relapse rate with
Rifampin resistant Mycobacteria.

34.  Activates macrophages to kill Myco. T.B
 Given by Aerosol to the lungs of patients with
multidrug resistant TB.
 There is wide pulmonary distribution &
enhanced local immune stimulation.
Interferon-γ

35. Kanamycin (Km)
 Aminoglycoside
 Interferes with protein
synthesis through disruption of
ribosome
Dose: 1 g IM/IV (15-20 mg/kg)
Side effects:
 Nephrotoxicity
 Ototoxicity
 Electrolyte wasting
Adjust dose for renal failure

36. Amikacin (Amk)
Aminoglycoside
 Highly similar to kanamycin (can
be essentially considered the
same drug)
Dose: 1 g IM/IV (15-20 mg/kg)
daily
Side effects:
 Same as kanamycin; renal
failure and ototoxicity
High cross-resistance with
kanamycin
Adjust dose in renal failure
(same as kanamycin)

37. Capreomycin (Cm)
 Structurally and
functionally similar to
aminoglycosides
Dose: 1 g IM/IV (15-20
mg/kg) daily
Side effects
 same as Km/Amk
Some cross-resistance
with Km/Amk
Adjust dose for renal failure

38. Ofloxacin (Ofx)
 Inhibits DNA-gyrase
Dose: 800 mg daily
Side effects
 Generally well-tolerated
 GI upset, rash, CNS
disturbance
Avoid antacids around time of
ingestion (reduces
absorption)
Near complete cross-resistance
with other fluoroquinolones

39. Levofloxacin (Lfx)
Dose: 750 mg daily for
<50 kg (1000 mg daily
for > 75kg)
 A higher dose for
tuberculosis is used than
for other infections
Side effects
 Generally well-tolerated
 GI upset, rash, CNS
disturbance
Adjust dose in renal failure

40. Moxifloxacin (Mfx)
 May be more active than earlier
generation quinolones
Dose: 400 mg daily
Near complete cross-resistance
with other fluoroquinolones
No dose adjustment in renal
failure
 Hepatically cleared

41. Ethionamide (Eto)
 Derivative of isonicotinic acid
(same family as isoniazid)
Dose: 500-1000 mg daily in
divided doses
Side effects
 GI upset, hypothyroidism,
peripheral neuropathy
Partial cross-resistance with
isoniazid, complete with
prothionamide
Hepatically excreted
Co-administer vitamin B6

42. Prothionamide (Pto)
 Structurally similar to
ethionamide
Dose: 500-1000 mg daily
in divided doses
Overall side effect profile
similar to ethionamide
 Slightly less GI side
effects
Complete cross-resistance
with ethionamide

43. Cycloserine (Cs)
 Interferes with cell-wall
proteoglycan synthesis
Dose: 500-1000 mg daily
in divided doses
Side effects:
 Seizures, psychosis,
depression, irritability,
headache
Renally excreted
Effective CNS penetration
Co-administer B6

44. Terizidone (Trd)
 Structure is composed of two connected molecules
of cycloserine
 Commonly used in South Africa in place of
cycloserine
Dose: 500-1000 mg daily in divided doses
Possibly less side effects than cycloserine
Not yet recommended by the WHO

45. Para-aminosalicylic acid (PAS)
 Various formulations; delayed-
release microcapsules best
tolerated
Dose of PASER is 4 g (1 sachet)
twice daily
Side effects
 GI upset, hypothyroidism
 Hepatitis, electrolyte abnormalities
Hepatic metabolism, renal
excretion
Administer with acidic food or
drink

46. Group 5: Possible reinforcing agents
Minimal clinical data to support use in MDR-TB
therapy.
Should only be used in cases of extreme drug
resistance (XDR-TB):
 Amoxicillin/clavulanic acid
 Clofazamine
 Linezolid
 High dose isoniazid
 Imipenem

47. Amoxicillin-clavulanic acid (AMX-CLV)
GROUP 5
 Beta-lactam antibiotic with
beta-lactamase inhibitor
Dose
 1000/250 mg twice daily or
 875/125mg twice daily
Side effects
 GI upset, rash
Contraindicated: Penicillin
allergy

48. Clofazimine (CFZ)
GROUP 5
 Substituted
iminophenazine
Usual adult dose is 100
mg daily
Side effects
 Bronzing of skin
 Malabsorption
 Abdominal pain (can
be severe)

49. Linezolid (LZD)
GROUP 5
 Oxazolidinone: inhibits protein synthesis,
interacting with ribosomal RNA
Dosing
 Coated tablets: 400 and 600 mg
 Intravenous solution: 2 mg/ml; 100, 200, or
300 mg bags
 Usual dose: 600 mg twice daily.
 Some case series have successfully used daily
half dosing (600 mg once daily) to decrease
toxicity and maintain efficacy

50. Linezolid (LZD) (Continued)
Side effects
 Generally well tolerated for treatment courses ≤28
days.
 Common: diarrhea, nausea, headache, insomnia, and
rash.
 More serious:
• myelosuppression (generally reversible with discontinuation of
the drug)
• optic neuropathy (usually resolved over time with drug
discontinuation)
• peripheral neuropathy (possibly irreversible).
 Rare: hypertension, lactic acidosis, pancreatitis

51. Linezolid (LZD) (Continued)
Monitoring
 CBC weekly during the initial period, then monthly, and then as
needed based on symptoms.
 Visual function should be monitored in all patients taking linezolid
for extended periods (≥3 months) and in all patients reporting new
visual symptoms regardless of length of therapy.
Alerting symptoms:
 Black, tarry stools or severe diarrhea
 Unusual bleeding or bruising
 Extreme tiredness or weakness
 Numbness, tingling, or burning pain in your hands, arms, legs, or
feet
 Change in visual acuity, vision blurring, or visual field defect
 Headache, nausea, or vomiting

52. High-dose isoniazid (H)
GROUP 5 (AT HIGH
DOSES)
Dosing
 16 to 18 mg/kg per day,
typically 600 mg to 1200
mg per week
 Some clinicians give it
three times a week
instead of daily at the 16
to 18 mg/kg dosing

53. Imipenem/Cilastin
GROUP 5—BETA-LACTAM/CARBAPENEM
In vitro activity—very limited clinical experience
Dosing
 Adults: 1000 mg IV every 12 hours
 In children, meropenem preferred: 20-40 mg/kg/dose
IV every 8 hours up to 2 grams per day (high rates of
seizures were seen in children treated with imipenem
for TB meningitis
Side effects
 Diarrhea, nausea, vomiting
 Seizure noted in CNS infections

54. Management of patients with adverse drug
reactions to Anti-tubercular drugs:
 Minor A/E ---- managed symptomatically without altering
medication.
 Severe A/E ---- stop the offending drug if possible isoniazid ,
rifampin should be continued or re-introduced after the
reaction has subsided.
 Never re-introduce in case haemolysis, thrombocytopenia or
renal failure.

55. Monitoring for side effects during
therapy
 Clinical
 Screen for common side effects
 Microbiological response
 Sputum at 2 months
 Sputum at completion of therapy
 Laboratory response
 First 2 weeks: twice weekly
 At 1 month then monthly
 Check: AST, ALT, Bilirubin, CBC

56. Common problems during therapy
 Nausea and vomiting
 Abnormal LFTs
 Drowsiness
 Rash/puritis
 Missed doses

57. SYMPTOM MANAGEMENT
 Drowsiness:
 HS dosing
 Nausea:
 Have light food 30 – 60 minutes prior to DOT
 Antiemetic 30 minutes prior to DOT
 Stronger antiemetic/ranitidine/PPI
 Rash/Itch:
 Minor itch continue meds with antihistamine (usually
RMP)
 Major rash drug challenge after rest
– RMP/INH/EMB/PZA (usually PZA)

58. Hepatotoxicity
 Asymptomatic increases in LFTs occur in
20% of pts on tx for TB
 Most common serious side effect
 Defined as AST >5xULN or >3xULN with
symptoms
 Incidence depends on
 Age
 Pre-existing liver disease
 ETOH: appears to more than double risk of INH
hepatotoxiticity
 INH more hepatotoxic than rifampin

59. What to do if a patient develops
abnormal LFTs on therapy?
 AST/ALT 5X ULN asymptomatic or
 AST/ALT 3X ULN symptomatic or
 Jaundice
 → HOLD TB Meds
 Once ALT returns to <2x ULN then
• Restart rifampin alone or with ethambutol, repeat ALT on
day 3
• IF ALT <2x ULN then add in INH and repeat ALT in 3
days
• Rechallenge with PZA may be hazardous and consider
D/C and extending tx to 9 months

60. Drug-induced hepatitis
Diagnosis
 AST/ALT > 3-5x upper limit of normal
 Rise in bilirubin above normal
Action
 Stop RHZ
 If treatment required  SEFq

61. Re-introduction of TB drugs (1)
 LFTs normal or AST/ALT <2x upper limit
 If LFTs due to EtOH (or not due to TB drugs)
 restart RHZ together
 If bilirubin and ALP
 rifampicin most likely
 start HE
 add Z 1 week later if OK
 If OK, use S (+Fq)

62. Re-introduction of TB drugs (2)
 ATS : R  RH  RHE (2RHE/7RH)
 Common: H  RH  RHE (2RHE/7RH)
 NYBTC: E  ER  REZ (2REZ/7RE)
• If R the problem, 2SHEZ/10HE
• If H the problem, 2REZ/7RE
• If Z the problem, 2SHE(Fq)/10HE

63. Rash
 If minor, consisting of mainly puritis or
affecting limited area
 → trial antihistamines
 Petechial rash
 Check platelet count
 Generalized rash especially with fever or
involving mucocutaneous areas
 → hold all TB meds
 Once rash subsides: restart drugs one by one
 Rif → INH→ethambutol or PZA. If no rash with 3rd
drug then assume it is the 4th drug that is the
cause

64. Manitoba Communicable Disease Control – Tuberculosis Protocol 2009
Missed doses

65. Paradoxical Reactions
 Worsening of TB adenitis with
development of new lymph nodes,
increasing lymph node size or sinus
drainage
 Seen in up to 20% of patients
 Median time to onset: 1.5 months
 Can present with new pleural effusions
during trt for Pulm TB

66. Mgmt of Paradoxical Reactions
 Rule out drug resistant TB
 Aspiration of lymph nodes, effusions
 Corticosteroids
 Unproven benefit
 NSAIDS

67. Treatment of patients in special
populations
 Hepatic Disease
 Epilepsy
 Renal insufficiency/ESRD
 HIV infection
 Pregnancy/breastfeeding

68. Treatment in patients with pre-existing
liver disease
 Remember ↑ AST/ALT may be secondary to
TB
 If ALT more than 3xULN not related to TB
 Avoid PZA
 IF patient has cirrhosis
 Rifampin + ethambutol + fluoroquinolone

69.  Severe liver disease with encephalopathy
 Ethambutol, fluoroquinolone, aminoglycoside (or
capreomycin), cycloserine
 recommended regimens are;
2SHRE/6HR OR 2SHE/10HE

70.  INH may be associated with an increased
risk of seizures.
 Pyridoxine 10 mg daily should be given to
all epileptics taking INH.
 There is no evidence that INH causes
seizures in patients who are not epileptic.
Epilepsy

71.  TB treatment involves numerous drug
interactions with anti-epileptic drugs
and serum drug levels should be
closely monitored.
 There are serious interactions between
rifampicin and carbamazepine,
rifampicin and phenytoin, and
rifampicin and sodium valproate.

72. Renal insufficiency/ESRD:
 Dose adjust Z and E if CrCl<30ml/min or on
PD or HD
 Intensive:
 INH/RMP OD post HD
 PZA/EMB 3X per week post HD
 Continuation
 INH/RMP 3X per week post HD
 No data on peritoneal dialysis
 2HRZ/4HR

73. Antituberculosis drugs in
hemodialysis patients
 Confusion exists regarding regimen,
duration etc however,
 Treatment duration should follow NICE
guidelines (UK) namely,
 6 months for most cases of fully sensitive
disease, with the exception of
 TB involving the CNS when treatment
should be for 1 year

74. Recommended doses of first-line
drugs in CKD

75.  For patients on haemodialysis, dosing
intervals should be increased to three times
weekly to reduce the risk of drug
accumulation and toxicity
 pryazinamide Variable doses of 25-30 mg/kg
three times weekly or 40 mg/kg three times
weekly have been recommended

76.  Treatment can be given immediately after
haemodialysis to avoid premature drug removal
 With this strategy there is a possible risk of raised drug
levels of ethambutol and pyrazinamide between dialysis
sessions. Alternatively, Treatment can be given 4-6 h before
dialysis, increasing the possibility of premature drug removal
but reducing possible ethambutol or pyrazinamide toxicity
 Both rifampicin and isoniazid may be given in their usual
daily doses.

77. HIV infection:
 CD4 count <200
 OD 7/7 X 2 months for intensive phase
 3X per week for continuation phase
 Protease inhibitor interaction with Rifampin
Rifabutin in consultation with HIV pharmacist
 Starting of ART (on new HIV DX)
 Dependent on CD4 count

78. 78
TB and HIV Drug Interactions
 Rifampin and Protease inhibitors (PI)
 Effect: Decreased PI serum levels
 Substitute Rifampin with Rifabutin 150 mg po thrice
weekly (may need to increase to 300 mg thrice
weekly or 150 mg po daily)
 Rifampin and Efavirenz
 Effect: Decreased efavirenz levels
 Increase efavirenz dose to 800 mg po daily (usual
600 mg daily)
 Rifampin and Raltegravir
 Effect: Decreased raltegravir levels
 Increase raltegravir to 800 mg po BID (usual dose
400 mg po BID and continue higher dose for at least
2 weeks post completion of Rifampin)

79.  Initial phase for 2 months
 Continuation phase for 7- 10months (total 9-12 M)
 In resistant cases up to 18 months
T.B in AIDs patients

80. Pregnancy
 TB not an indication for pregnancy
termination
 First line drugs safe in pregnancy (H,E,R)
 PZA: limited data with respect to teratogenic
effects. Recommended by WHO and IUATLD
 Fluoroquinolones and aminoglycosides
contraindicated while pregnant

81. Breastfeeding Moms
 1st line drugs
 Very small concentrations in breast milk
 Encourage breast feeding
 Have not shown to produce toxic effects in newborn
 Mum should be on pyridoxine supplements
 Drugs level in breast milk not sufficiently high to be
considered effective tx for infant
 Certain 2nd line drugs not recommended - data
unknown

82. Concerns re poor absorption
 Consider if significant malnutrition, diabetic
gastroparesis, HIV, underlying GI disease, treatment
failure
 INH/RMP serum levels:
 Usually 2 hours (+/- 6 hours) post oral drug adminstration
 Available IV drugs include INH, RIF,
fluoroquinolones, aminoglycocides
 Recommendations-Parental route (delays discharge)
 Only select drugs via Home Care/Mount Carmel Clinic/Lions
Place in WRHA

83. Drug resistance
 Primary versus acquired
 PZA resistance: treat for 9 months
 INH monoresistance
 6 month R,Z,E
 12 months of 2RZE/10RE
 MDR= resistance to INH and RIF

85. Management of MDR-TB

86. Management of MDR-TB
 Injectable: used daily for first 2-6 months then
can be stepped down to 3x/week, ideally for
>6 months
 Must have daily directly observed therapy for
the duration of therapy
 Duration: 18-24 months after sputum
conversion

87. Treatment Monitoring
 Sputum smear microscopy for AFB at 2 months
and 6 months
 If positive at two months, repeat at 3
 If still smear positive at 3 months, continuation
phase (4HR) is still started while awaiting DST
results
 Continue drug-susceptibility tests if smear-
positive after 3 months of treatment

88. Monitoring during treatment of DR-TB
Monitoring evaluation Recommended frequency
Evaluation by clinician At baseline, and at least monthly until conversion, then
every 2–3 months
Screening by DOT worker At every DOT encounter
Sputum smears and
cultures
Monitor smears and cultures monthly throughout treatment. (Note:
programmes with limited resources may choose to do smears monthly
but cultures only every other month)
Weight At baseline and then monthly
Drug susceptibility At baseline in programmes doing individualized treatment
Chest radiograph At baseline, and then every 6 months
Serum creatinine At baseline, then monthly if possible while receiving an
injectable drug. Every 1–3 weeks in HIV-infected patients,
diabetics and other high-risk patients
Serum potassium Monthly while receiving an injectable agent. Every 1–3
weeks in HIV-infected patients, diabetics and other high-risk
patients

89. Monitoring evaluation Recommended frequency
Thyroid stimulating hormone
(TSH)
Every 6 months if receiving ethionamide/protionamide
hormone and/or PAS; and monitor monthly for
signs/symptoms of hypothyroidism. TSH is sufficient for screening for
hypothyroidism; it is not necessary to measure hormone thyroid levels
Liver serum enzymes Periodic monitoring (every 1–3 months) in patients
receiving pyrazinamide for extended periods or for patients
at risk for or with symptoms of hepatitis. For HIV-infected
patients, do monthly monitoring
HIV screening At baseline, and repeat if clinically indicated
Pregnancy tests At baseline for women of childbearing age, and repeat if
indicated
Haemoglobin and
white blood count
If on linezolid, monitor weekly at first, then monthly or as
needed based on symptoms; there is little clinical experience
with prolonged use
For HIV-positive patients on an ART regimen that includes AZT,
monitor monthly initially and then as needed based on symptoms
Lipase Indicated for work up of abdominal pain to rule out
pancreatitis in patients on linezolid, D4T, ddI, ddc.
Lactic acidosis Indicated for work up of lactic acidosis in patients on linezolid or ART
Serum glucose If receiving gatifloxacin, monitor glucose frequently (weekly) and educate patient on
signs and symptoms of hypoglycaemia and hyperglcycaemia

90. Mode of action & Recommended dose mg/kg
Twice/wk3times/wkDaily dose
mg/kg
Mode of
action
Essential anti-
tuberculosis drug
15105bactericidalINH
101010bactericidalRifampicin
503525bactericidalpyrazinamide
151515bactericidalstreptomyicin
453015bacteriostaticEthambutol

91. Pharmacokinetic
ExcretionMetabolismlife-HalfDrugs name
renal 15to 030%
Faecal 60%
andHepatic
intestinal wall
6 to 7 hoursrifampicin
urine (primarily),
feces
liver0.5-1.6h (fast
acetylators), 2-5h
(slow acetylators)
INH
renalliver3-4 hr (increased in
impaired renal
function)
Ethambutol
renalliver9-10hrpyrazinamide
renalWithout hepatic
metabolism
5-6hrstreptomycin

92. Cross-resistance
Aminoglycosides
 Minimal cross resistance between SM and
other aminoglycosides
 KM and AM have almost complete cross
resistance
 Cross resistance between CM and KM
and/or AM has been documented
Fluoroquinolones
 Mutations that confer resistance to one
fluoroquinolone will confer some degree of

93.  It is the practice of treating latent infection to prevent
progression to active disease
Indications:
1. In close contacts of active pulmonary TB patients
2. Immunosuppressed / HIV infection & AIDS pts , Diabetes
Mellitus
3. Recent converters.
4. Neonate of tubercular mother.
Chemoprophylaxis/Prevention of TB

94.  Isoniazid: DOC
300 mg (10mg/kg in children daily for 6-12 months) with
pyridoxine.
 Rifampin: (10 mg/kg) alone for 4 months.
 Pyrazinamide: With rifampin for 2 months.
For multidrug resistant mycobacteria with fluroquinolones /
Rifabutin
 In pregnancy prophylaxis should be delayed untill delivery.
Drugs Used for chemoprophylaxis:

95.  Initial intensive phase is longer (3 months)
 5 drugs for 2 months & 4 drugs for 1 months
 Continuation phase is longer i.e. 5 months
 Use alternate drugs if mycobacteria are resistant to first line
drugs.
Treatment of Previously
treated / failure / default / relapse cases:

96. a) In seriously ill patients (miliary or severe pulmonary TB) to
buy time for drugs to act.
b) When hypersensitivity reactions occur to antitubercular
drugs.
c) In meningeal or renal TB or pleural effusion – to reduce
exudation and prevent its organisation, strictures etc.
d) In AIDS patients with severe manifestations of T.B
Role of corticosteroids in tubercular patients:

97.  Contraindication: Intestinal T.B --- silent perforation can
occur.
 Precaution: Corticosteroids, if given, should be
gradually withdrawn when the general condition of the
patient improves.

98. Take home points
 Duration of tx depends on results of 2 month
cultures and the inclusion of PZA
 Treatment completion depends on the
number of doses taken not duration of tx
 Many side effects do not require
discontinuation of tx

99. Take home points-cont
 Beware of drug-drug interactions
 Hepatotoxicity is the most common serious
side effect requiring discontinuation of drug
 Introduce Rif then INH once LFTs return to normal

100. Questions or Comments?