This document provides information on pulmonary tuberculosis (TB), including its etiology, diagnosis, treatment and management. Some key points: - TB is caused by the bacterium Mycobacterium tuberculosis and is a global health problem, infecting millions of people annually and causing over a million deaths in 2013. - Diagnosis involves considering symptoms, physical exam, radiology and sputum microscopy. Treatment involves a standard multi-drug regimen administered over 6-9 months and aims to cure the patient and prevent transmission. - India has a high burden of TB cases, with over 2 million estimated in 2012. The Revised National TB Control Programme (RNTCP) implements the WHO-recommended DOTS strategy to improve

1. PULMONARY
TUBERCULOSIS
Dr. Bushra Hasan Khan
Department of Pharmacology
JNMC, AMU, Aligarh.

2. • Tuberculosis is a global pandemic
• TB is second leading cause of death from
a single infectious agent, after HIV.
• INCIDENCE : 9 million new cases in 2013
• MORTALITY : A total of 1.5 million people died
from TB in 2013 (including 360 000 people with HIV)
• TB is a leading killer of HIV-positive people
causing one fourth of all HIV-related deaths.

3. • 480 000 people developed MDR-TB in 2013.
• In 2012, out of the estimated global annual incidence
of 8.6 million TB cases, 2.3 million were estimated
to have occurred in India.
• The TB mortality rate has decreased 45% since 1990.
• About 37 million lives were saved worldwide between 2000
and 2013 through TB diagnosis and treatment

4. • The world is on track to achieve the global TB target
set for 2015 in the Millennium Development Goals
• The target for TB in the MDGs is to halt and
reverse global incidence.
• 86% of people who developed TB and were
put on treatment in 2012 were successfully treated.
(http://www.tbcindia.nic.in/rntcp.html)

5. ETIOLOGY
• TB is caused by Mycobacterium tuberculosis, a slow-growing
obligate aerobe and a facultative intracellular parasite.
• Non-spore-forming, rod-shaped, 0.5μm × 3μm
• Neutral on Gram's staining
• The organism grows in parallel groups called cords 
in which acid-fast bacilli are arranged in parallel chains .
• Cord formation is correlated with virulence.

6. • Mycobacteria are rich in lipids
– Mycolic acid  prevent attack of cationic proteins,
lysozyme, and oxygen radicals in the phagocytic granule
– Waxes
– Phosphatides
• Lipids are bound to proteins and polysaccharides.
• Muramyl dipeptide + mycolic acids  granuloma formation;
phospholipids  caseous necrosis.

7. • Once stained, the bacilli cannot be decolorized by
acid alcohol  acid-fast bacilli (AFB)
• Acid fastness is due mainly to the organisms'
– High content of mycolic acids,
– Long-chain cross-linked fatty acids，
– Other cell-wall lipids.

8. • Mycolic acids + Arabinogalactan and Peptidoglycan 
results in very low permeability of the cell wall 
effectiveness of most antibiotics is reduced.
• Lipoarabinomannan 
involved in the pathogen-host interaction 
facilitates the survival of M. tuberculosis within macrophages.

9. PHARMACOLOGICAL BARRIER:
 Cell wall Mainly contains Lipids (Mycolic acid)
 Efflux pumps pump out harmful chemicals
 Propensity to hide inside the host cells

10. CLINICAL FEATURES
• Fever
• Weight loss / anorexia
• Cough
• Hemoptysis
• Chest pain
• Night sweats
• Fatigue

11. DIAGNOSIS
• History
• Physical examination
• Radiology
• Sputum microscopy

12. NATURAL HISTORY & SPECTRUM OF DISEASE

13. AIMS OF TREATMENT
• To cure the patient ; restore quality of life & productivity
• To prevent death from active TB or its late effects
• To prevent relapse of TB
• To reduce transmission of TB to others
• To prevent the development & transmission of drug resistance

14. RNTCP
• RNTCP ( Revised National Tuberculosis Control Programme)
is an application of WHO recommended strategy of DOTS in
India.
• Objectives:
1- Detecting at least 70% of sputum positive TB patients in
the community.
2- Curing at least 85% of the newly detected sputum positive
cases.

15. Five components of DOTS:
1. Political commitment with increased & sustained financing
2. Case detection through quality-assured bacteriology
3. Standardized treatment with supervision & patient support
4. Regular, uninterrupted supply of Anti-TB drugs
5. Monitoring & evaluation system & impact measurement

16. Stop TB Strategy (WHO, 2006)
1. Pursue high-quality DOTS expansion & enhancement
2. Address TB-HIV, MDR-TB, & the needs of poor &
vulnerable populations
3. Contribute to health system strengthening based on
primary health care
4. Engage all health care providers
5. Empower people with TB, & communities through partnership
6. Enable & promote research

17. • Based on the nature/severity of the disease & the
patient's exposure to previous ATTs, RNTCP classifies
TB patients into 2 t/t categories 
– NEW
– PREVIOUSLY TREATED

18. NEW PATIENT CATEGORY
• New sputum smear-positive,
• New sputum smear-negative,
• New extrapulmonary tuberculosis,

19. PREVIOUSLY TREATED
• Sputum smear-positive relapse,
• Sputum smear-positive failure,
• Sputum smear-positive treatment after default,
• Others (patients who are Sputum Smear-Negative
or who have Extra-pulmonary disease who can have
recurrence)

20. RECOMMENDED DOSES OF FIRST-LINE
ANTITUBERCULOSIS DRUGS FOR ADULTS

21. DRUGS AND THEIR TARGET SITES

22. STANDARD REGIMENS FOR NEW TB PATIENTS
DOSING FREQUENCY

23. SETTINGS WITH HIGH LEVELS OF ISONIAZID
RESISTANCE IN NEW PATIENTS

24. SPUTUM MONITORING BY SMEAR MICROSCOPY
IN NEW PULMONARY TB PATIENTS

25. STANDARD REGIMENS FOR PREVIOUSLY
TREATED PATIENTS

26. SPUTUM MONITORING OF PULMONARY TB PATIENTS
RECEIVING THE 8-MONTH RETREATMENT REGIMEN
WITH FIRST-LINE DRUGS

27. A POSITIVE SPUTUM SMEAR AT THE END
OF THE INTENSIVE PHASE 
• Poorly supervised initial phase of t/t & poor patient adherence
• Poor quality of anti-TB drugs
• Doses of anti-TB drugs  below the recommended range
• Slow resolution  extensive cavitation & a heavy initial
bacillary load
• Co-morbid conditions
• MDR-TB that is not responding to first-line treatment
• Non-viable bacteria remain visible by microscopy

28. COHORT ANALYSIS OF TREATMENT OUTCOMES
• COHORT  a group of patients diagnosed & registered
for t/t during one-quarter of a year
• Evaluation of t/t outcome in new pulmonary smear-positive
patients  major indicator of programme quality.
• Outcomes in other patients
(retreatment, pulmonary smear-negative, extrapulmonary)
are analysed in separate cohorts.

29. • Outcomes are routinely evaluated at the beginning
of the quarter following the completion of treatment
by the last patient in that cohort.

30. TREATMENT OUTCOMES
• CURED
• TREATMENT COMPLETED
• TREATMENT FAILURE
• DIED
• DEFAULT
• TRANSFER OUT
• TREATMENT SUCCESS

32. MANAGEMENT OF TREATMENT INTERRUPTION
• If a patient misses an arranged appointment to receive
treatment  the NTP should ensure that the patient is
contacted within a day after missing treatment during the
initial phase, & within a week during the continuation phase.
• Culture and DST should be performed upon return of patients
who meet the definition for default

33. MAJOR ADVERSE EFFECTS OF ATT
• The most common ADR is Hepatitis.
• Cutaneous reactions
• Shock, purpura
• Visual impairment
• Deafness, dizziness
• Acute renal failure

34. SYMPTOM-BASED APPROACH TO MANAGING
SIDE-EFFECTS OF ANTI-TB DRUGS
(continued…….)

35. (continued…….)

37. IMPORTANT DRUG INTERACTIONS
• Rifampicin reduces the conc. & effect of the following drugs 
o Anti-infectives (antiretroviral drugs, mefloquine, azole
antifungal agents, erythromycin, doxycycline);
o Hormone therapy, including ethinylestradiol,
norethindrone, tamoxifen, levothyroxine;
o CVS drugs including digoxin, digitoxin, verapamil,
nifedipine, diltiazem, propranolol, metoprorol, enalapril,
losartan;
(continued…….)

38. o Anticonvulsants (including phenytoin);
o Haloperidol, quetiapine, benzodiazepines (including
diazepam, triazolam), zolpidem, buspirone;
o Warfarin;
o Cyclosporin;
o Corticosteroids;
o Theophylline;
o Sulfonylurea hypoglycaemics;
o Hypolipidaemics including simvastatin and fluvastatin;

39. T/T REGIMENS IN SPECIAL SITUATIONS
• Pregnancy & Lactation
• Liver disorders
• Renal failure

40. PREGNANCY AND BREASTFEEDING
• Streptomycin  ototoxic to the fetus ; must not be used
• Lactation is not a C/I to ATT
• After active TB in the baby is ruled out, the baby should be
given 6 months of Isoniazid preventive therapy, followed by
BCG vaccination
• Pyridoxine supplementation is recommended for all pregnant
or breastfeeding women taking Isoniazid

41. LIVER DISORDERS
• Patients with the following conditions can receive the usual
TB regimens provided that there is no clinical evidence of
chronic liver disease:
Hepatitis virus carriage,
A past history of acute hepatitis,
Current excessive alcohol consumption
• Hepatotoxic reactions to anti-TB drugs  more common
among these patients & should therefore be anticipated

42. • In patients with unstable or advanced liver disease, LFTs
should be done at the start of treatment, if possible.
• The more unstable or severe the liver disease is,
the fewer hepatotoxic drugs should be used.
• If the serum ALT level is more than 3 times normal before the
initiation of treatment, the following regimens should be
considered.
(continued…….)

43. POSSIBLE REGIMENS INCLUDE:
• Two hepatotoxic drugs
 9 months of Isoniazid and Rifampicin, plus Ethambutol (until
or unless Isoniazid susceptibility is documented);
 2 months of Isoniazid, Rifampicin, Streptomycin &
Ethambutol, followed by 6 months of Isoniazid & Rifampicin;
 6–9 months of Rifampicin, Pyrazinamide and Ethambutol.

44. • One hepatotoxic drug:
 2 months of Isoniazid, Ethambutol & Streptomycin,
followed by 10 months of Isoniazid & Ethambutol.
• No hepatotoxic drugs:
 18–24 months of Streptomycin, Ethambutol &
a Fluoroquinolone.

45. RENAL FAILURE
• The recommended initial TB t/t regimen :
– 2 months of Isoniazid, Rifampicin, Pyrazinamide &
Ethambutol, followed by 4 months of Isoniazid & Rifampicin.
• There is significant renal excretion of Ethambutol and
metabolites of Pyrazinamide, & doses should therefore be
adjusted.

46. • Three times/week administration of Pyrazinamide (25 mg/kg),
& Ethambutol (15 mg/kg) is recommended
• While receiving Isoniazid, patients with severe renal
insufficiency or failure should also be given Pyridoxine in
order to prevent peripheral neuropathy.

47. • Because of an increased risk of nephrotoxicity & ototoxicity,
Streptomycin should be avoided in patients with renal failure.
• If Streptomycin must be used, the dosage is 15 mg/kg,
two or three times/week, to a maximum of 1 gram per dose,
& serum levels of the drug should be monitored.

49. • MAIN FIRST LINE ANTITUBERCULAR DRUGS
– ISONIAZID
– RIFAMPICIN
– ETHAMBUTOL
– PYRAZINAMIDE
• OTHER FIRST LINE ANTITUBERCULAR DRUGS
– RIFABUTIN
– RIFAPENTINE
– STREPTOMYCIN

50. SECOND-LlNE ANTI-TB DRUGS
• Fluoroquinolones
– Levofloxacin
– Moxifloxacin
– Gatifloxacin
• Injectable Agents
– Capreomycin
– Amikacin
– Kanamycin
• Others
– Cyclosrine
– PAS
– Ethionamide
– clofazimine

51. NEWER ANTl-TB DRUGS
• Oxazolidinones  Linezolid
• Amoxicillin-Clavulanate
• Carbapenems
• Diarylquinolines  Bedaquiline
• Nitroimidazoles  Delamanid
• Diamines  SQ109 (an Ethambutol analogue)
• Pyrroles  LL3858

52. DRUGS AND THEIR TARGET SITES

53. ISONIAZID
• MOA  Mycolic acid synthesis inhibitor

54.  Nicotinoyl-NAD adduct→
inhibits the activities of enoyl-ACP reductase (inhA) &
β-ketoacyl acyl carrier protein synthase (KasA)→
interfere with mycolic acid synthesis.
 Nicotinoyl-NADP adduct→ inhibit mycobacterial
dihydrofolate reductase (DHFRase)→
interfere with nucleic acid synthesis.

55. MECHANISM OF RESISTANCE:
• Mutation or deletion of katG gene (MC).
• Mutation in kasA gene.
• Over-expression of the inhA & aphC gene (detoxify organic
peroxide)
PHARMACOKINETICS:
• Oral BA ~ 100%.
• Only ~10% is protein bound.
• Metabolised in liver by Arylamine N-acetyltransferase2 (NAT2).
• Excreted in urine as Acetylisoniazid & Isonicotinic acid.

56. DOSE:
• 5mg/kg (4-6 mg/kg) daily, maximum 300 mg
• 10 mg/kg (8-12 mg/kg) three times/week; maximum 900 mg
• Oral / im / iv
ADRs:
• Peripheral neuritis : INH binds with Pyridoxal 5-phosphate →
decreased neuronal Pyridoxal 5-phosphate
• Liver damage : Acetylisoniazid→ Acetylhydralazine  Liver
damage
• Others : Optic neuritis, Convulsions, Hypersensitivity reactions

57. DRUG INTERACTIONS:
• Al(OH)3 inhibit INH absorption.
• With Acetaminophen → Hepatotoxicity
• With Carbamazepine, Diazepam, Ethosuximide 
Neurological & Psychiatric toxicities by inhibiting CYP3A
• With Isoflurane, Enflurane  decrease their effectiveness
by inducing CYPE1

58. RIFAMYCINS
MECHANISM OF ACTION:
Binds with β-subunit of DNA-dependent RNA Polymerase (rpoB)
↓
Inhibit RNA synthesis
MECHANISM OF RESISTANCE:
Mutation at codons 526 & 531 site of rpoB gene.
PHARMACOKINETICS:
• Absorption is variable
[Oral bioavailability Rifampicin (68%) & Rifabutin (20%)]
• Food- ↓Rifampicin absorbtion but no effect on Rifabutin
• High fat diet- ↑Rifapentin absorption

59. • Half life of Rifampicin→2-5hrs
Rifabutin →32-67hrs
Rifapentine →14-18hrs
• Metabolized by microsomal β-esterases & cholinesterases mainly
(deacetylation).
• Excretion is mainly through bile.
DOSE:
• Rifampicin- 10 mg/kg (8-12 mg/kg) daily or 3 times weekly ;
1hr before or 2hrs after meal ; oral or iv
• Rifabutin- 5mg/kg/day
• Rifapentine- 10mg/kg/week

60. ADRs:
• Rashes, G.I intolerance, Liver damage, Hemolysis,
Neutropenia .
• Rifampicin  flu-like syndrome → higher dose,
schedule ; twice weekly
• Rifabutin  Uveitis; arthralgia; polymylgia; orange
discoloration of skin, urine, feces, saliva & tears.
INTERACTIONS:
• Enzyme inducers  Rifampicin> Rifapentin>Rifabutin

61. PYRAZINAMIDE
• Is synthetic pyrazine analog of Nicotinamide.
MOA:
Pyrazinamide
↓ Passive diffusion
Enter M.tuberculosis
Deamination ↓ Nicotinamidase/Pyrazinamidase
Pyrazinoic acid (POAˉ)
Transported to extracellular environment ↓ Protonation
HPOA

62. • HPOA → Inhibit fatty acid synthase-1→ interfere with
mycolic acid synthesis.
→ disruption of membrane transport
MECHANISM OF RESISTANCE:
• Point mutation in pncA gene (encodes Pyrazinamidase).
PHARMACOKINETICS:
• Oral bioavailability >90%.
• Highly concentrated in lung lining fluid.
• T1/2 variable depends upon weight.
• Metabolised by microsomal deaminidase.
• Excreted in urine.

63. DOSE:
• Orally
• 25 mg/kg (20-30 mg/kg) daily
• 35 mg/kg (30-40 mg/kg) three times weekly
ADRs:
• Hepatic damage
• Hyperuricemia- inhibit excretion of urate
• Others- arthralgia, rashes, g.i upset, dysuria

64. ETHAMBUTOL
• Tuberculostatic drug.
MOA:
Inhibit Arabinosyl transferase-Ш enzyme
↓
Disrupt the transport of Arabinose sugar
↓
Arbinogalactan biosynthesis impaired
↓
Disruption in mycobacterial cell wall formation

65. MECHANISM OF RESISTANCE:
• Mainly by mutation in codon 306 of embB gene.
• KatG 315 mutation Co-occurance of Ethambutol & Isoniazid
resistance.
PHARMACOKINETICS:
• Oral bioavailability ~80%.
• ~10-40% bound to plasma proteins.
• Half life: 3hrs (1st 12hrs) & 9hrs (next 12hrs) → redistribution.
• Rest of drug excreted unchanged in urine.

66. DOSE:
• 15 mg/kg (15-20 mg/kg) daily
• 30 mg/kg (25-35 mg/kg) three times weekly
ADRs:
• Optic neuritis (dose related & daily schedule for >9mnths)
• Colour blindness
• Hyperuriceamia
• Rashes, drug fever, joint pain
C/I:
• Children <5 years

67. STREPTOMYCIN
MOA:
Binds with 30s ribosomal subunit
↓
Misreading of genetic code
↓
Inhibit protein synthesis

68. MECHANISM OF RESISTANCE:
• Mutation in rpsL gene
• Mutation in GidB gene
PHRAMACOKINETICS:
• Very poor oral bioavailability hence given in injectable form.
• Distributed extracellularly mainly
• Excreted unchanged in urine

69. DOSE:
• 15mg/kg (12-18 mg/kg) daily, or 2 or 3 times weekly; im.
ADRs:
• Nephrotoxicity
• Ototoxicity
• Neuromuscular blockade- ↓release of Ach by inhibiting fusion
of vesicles with terminal membrane

70. THANKYOU

73. ISONIAZID
•
For treatment of TB disease， isoniazid is used in combination with
other agents to ensure killing of both actively dividing M.
tuberculosis
and slowlygrowing "persister" organisms. Unless the organism is
resis
tant， the standard regimen includes isoniazid， rifampin，
ethambutol，
and pyrazinamide (Table 20元-2). 1soniazid is often given together
with 25-50 mg of pyridoxine daily to prevent drug-related peripheral
neuropathy.

75. PHARMACOLOGY
• 1soniazid is 出e hydrazide of isonicotinic ac此 a small，
water-soluble molecule. The usual adult oral daily dose of 300 mg
results in peak serum levels of 3-5 吨/mL within 30 min to 2 h after
ingestion-well in excess ofthe M1Cs for most susceptible strains ofM.
tubercu/osis. Both oral and 1M preparations of isoniazid reach effective
levels in the body， although antacids and high-carbohydrate meals may
interfere with oral absorption. 1soniazid diffuses well throughout the
body， reaching therapeutic concentrations in body cavities and fluids，
with concentrations in cerebrospinal fluid (CSF) comparable to those
m serum.
1soniazid is metabolized in the liver via acetylation by
N-acetyltransferase 2 (NAT2) and hydrolysis. Both fast- and slow
acetylation phenotypes occur; patients who are "fast acetylators" may
have lower serum levels of ison阳id， whereas "slow acetylators" may
have higher levels and experience more toxicity. Satisfactory isoniazid
levels are attained in the majority of homozygous fast NAT2 acetylators
given a dose of 6 mg/kg and in the majority of homozygous slow
acetylators given only 3 mg/kg. Genotyping is increasingly being used
to charaιterize isoniazid-related pharmacogenomic responses.

76. 1soniazid's interactions with other
drugs
• are due primarily to its
inhibition of the cytochrome P450 system.
Among the drugs with
significant isoniazid interactions are warfarin
， carbamazepine， ben
zodiazepines， acetaminophen， clopidogrel
， maraviroc， dronedarone，
salmeterol， tamoxifen， eplerenone， and
phenytoin.

77. DOSING
• The recommended daily dose for the treatment of
TB in the
United States is 5 mg/kg for adults and 10-20
mg/kg for children， with
a maximal daily dose of 300 mg for both. For
intermittent therapy in
adults (usually twice per week)， the dose is 15
mg/kg， with a maximal
daily dose of 900 mg. 1soniazid does not require
dosage adjustment in
patients with renal disease.

78. RESISTANCE
• Five separate pa出ways for isoniazid
resistance have been elucidated.
• Most strains have amino acid changes
in either the catalase-peroxidase gene (katG) or the
mycobacterial ketoenoylreductase gene (inhA).
• Less frequently， alterations in kasA，
the gene for an enzyme involved in mycolic acid
elongation， and loss of NADH dehydrogenase 2 activity
confer isoniazid resistance.
• 1n 20-30% of isoniazid-resistant M. tuberculosis isolates,
increased expression of efflux pump genes， such as
efpA， mmpL7， mmr， p55，and the Tap-like gene
Rv1258c， has been implicated as the underlying
mechanism of resistance.

79. ADVERSE EFFECTS
• Although isoniazid is generally well tolerated， druginduced liver injury
and peripheral neuropathy are signi且cant adverse
effects associated with this agent. 1soniazid may cause as严nptomatic
transient elevation of aminotransferase levels (often termed hepatic
adaptation) in up to 20% of recipients. Other adverse reactions include
rash (2%)， fever (1.2%)， anemia， acne， arthritic s严nptoms， a
systemic
lupus erythematosus-like syndrome， optic atrophy， seizures， and
psy
chiatric symptoms. Symptomatic hepatitis occurs in fewer than 0.1% of
persons treated with isoniazid alone for LTB1， and fulminant hepatitis
with hepatic failure occurs in fewer than 0.01%. 1soniazid-associated
hepatitis is idiosyncratic， but its incidence increases with age， with
daily alcohol consumption， and in women who are within 3 months
postpartum.

80. • Guidelines recommend that isoniazid be
discontinued in the presence of hepatitis
S严nptoms or jaundice and an ALT level
three times the upper limit of
normal or in the absence of symptoms
with an ALT level five times the
upper limit ofnormal

81. • Peripheral neuropathy associated with isoniazid occurs
in up to
2% of patients given 5 mg/kg. 1soniazid appears to
interfere with
P严idoxine (vitamin B
6) metabolism. The risk of isoniazid-related
neurotoxicity is greatest for patients with preexisting
disorders that
also pose a risk of neuropathy， such as H1V infection;
for those with
diabetes mellitus， alcohol abuse， or malnutrition; and
for those simultaneously receiving other potentially
neuropathiι medications， such
as sta叽ldine. These patients should be given

82. RIFAMPIN
• Rifampin is a semisynthetic derivative of Amycolatopsis
rifamycinica (formerly known as Streptomyces mediterranei).
The most
active antimycobacterial agent available， rifampin is the
keystone of
first-line treatment for TB. 1ntroduced in 1968， this drug
eventually
permitted dramatic shortening of the TB treatment course.
Rifampin
has both sterilizing and bactericidal activity against dividing
and
nondividing M. tuberculosis.

83. MOA
• Rifampin exerts both intracellular and
extracellular bactericidal activity. Like other
rifamycins， rifampin specifically
binds to and inhibits mycobacterial DNA-
dependent RNA polymerase， blocking
RNA synthesis.

84. PHARMACOLOGY
• Rifampin is a fat-soluble， complex macrocyclic molecule readily absorbed
after oral administration. Serum levels of
10-20 Ilg/mL are achieved 2.5 h after the usual adult oral dose of 10
mg/kg (given without food). Rifampin has a half-life of 1.5-5 h. The
drug distributes well throughout most body tissues， includi吨 CSF.
Rifampin turns body tluids such as urine， saliva， sputum， and tears a
reddish-orange color-an effect that offers a simple means of assessing
patients' adherence to this medication. Rifampin is excreted primarily
through the bile and enters the enterohepatic circulation; <30% of a
dose is renally excreted.
As a potent inducer of the hepatic cytochrome P450 system，
rifampin can decrease the half-life of some drugs， such as digoxin，
warfarin， phenytoin， prednisone， cyclosporine， methadone， oral con
traceptives， clarithromycin， azole antifungal agents， quinidine， antiret
roviral protease inhibitors， and non-nucleoside reverse transcriptase
inhibitors.

85. DOSING
• The daily dosage ofrifampin is 10 mg/kg
for adults and 10-20
mg/kg for children， with a maximum
of600 mg/d forboth. The drug is
given once daily， twice weekly， or three
times weekly. No adjustments
of dose or frequency are necessary in
patients with renal insufficiency

86. RESISTANCE
• Resistance to rifampin in M. tuberculosis，
Mycobacterium
leprae， and other organisms is the
consequence ofspontaneous， mostly
missense point mutations in a core region of
the bacterial gene coding
for the BETA subunit of RNA polymerase
(rpoB). RNA polymerase altered
in this manner is no longer subject to
inhibition by rifampin

87. ADVERSE EFFECTS
• Adverse events associated with rifampin are infrequent and
generally mild.
• Hepatotoxicity due to rifampin alone is
uncommon in the absence of preexisting liver disease and
often consists of isolated hyperbilirubinemia rather than
aminotransferase elevation.
• Other adverse reactions include rash， pruritus，
gastrointestinal symptoms， and pancytopenia.
• Rarely， a hypersensitivity reaction may
occur with intermittent therapy， manifesting as fever， chills
， malaise，rash， and-in some instances-renal and hepatic
failure.

88. ETHAMBUTOL
• ME(HANISM OF AaJON Ethambutol is
bacteriostatiι against M. tuberculosis. Its
prima巧 mechanism ofaction is the
inhibition of tlle arabinosyltransferases
involved in cell wall s严lthesis， which
probably inhibits
the formation of arabinogalactan and
lipoarabinomannan.

89. PHARMACOLOGYAND DOSING
• From a single dose of etllambutol， 75-80% is
absorbedwitllin 2-4 h ofadministration. Serum levels peak at 2-4
Ilg/mL
after tlle standard adult da让y dose of 15 mg/kg. Ethambutol is well
dis-
tributed tllroughout the body except in tlle CSF; a dosage of 25
mg/kg
is necessary for attainment of a CSF level half of that in serum. For
intermittent tllerapy， tlle dosage is 50 mg/kg twice weekly. To
prevent toxicity， tlle dosage must be lowered and the frequency
ofadministration
reduced for patients with renal insufficiency.

90. ADVERSE EFFECTS
• Ethambutol is usually well tolerated and has no
significant interactions with other drugs. Optic neuritis， the most
serious adverse effect reported， typically presents as reduced visual
acuity， central scotoma， and loss of the ability to see green (or， less
commonly， red). The cause of this neuritis is unknown， but it may be
due to an effect of ethambutol on the amacrine and bipolar cells of
the retina. Symptoms typically develop several months after initiation
of therapy， but ocular toxicity soon after initiation of ethambutol has
been described. The risk of ocular toxicity is dose dependent， occur
ring in 1-5% of patients， and can be increased by renal insufficiency.
The routine use of ethambutol in younger children is not recom
mended because monitoring for visual complications can be difficult.
Ifdrug-resistant TB is suspected， ethambutol can be used for treatment
of children

91. • All patients starting therapywith ethambutol should have a baseline
test for visual acuity， visual fields， and color vision and should
undergo
an examination of the optic fundus. Visual acuity and color vision
should be monitored monthly or less often as needed. Cessation of
ethambutol in response to early symptoms of ocular toxicity usually
results in reversal of the deficit within several months. Recovery of
all
叽sual function may take up to 1 year. In the elderly and in patients
whose symptoms are not recognized 巳a由， defic山 may be
permanent
Some experts think that supplementation with hydroxocobalamin
(vitamin B
12) is beneficial for patients with etllambutol-related ocular
toxicity. Other adverse effects of ethambutol are rare. Peripheral
sensory neuropathy occurs in rare instances

92. RESISTANCE
• Ethambutol resistance in M. tuberculosis and NTM
is
associated primarily with missense mutations in
the embB gene that
encodes for arabinosyltransferase. Mutations have
been found in resistant strains at codon 306 in 50-
70% of cases. Mutations at embB306
can cause slgm且cantly increased MICs of
ethambutol， resulting in
clinical resistance.

93. PYRAZINAMIDE
• A nicotinamide analog， pyrazinamide is an
important
bactericidal drug used in the initial phase of
TB treatment. Its administration for the first 2
months of therapy with rifampin and isoniazid
allows treatment duration to be shortened
from 9 months to 6 months
and decreases rates of relapse

94. MOA
• Pyrazinamide's antimycobaιterial activity is
essentially limited to M. tuberculosis. The drug is more active
against
slowly replicating organisms than against actively replicating
organisms. Pyrazinamide is a prodrug that is converted by the
mycobacterial pyrimidase to the active form， pyrazinoic acid
(POA). This agent
is active only in acidic environments (pH <6.0)， as are found within
phagocytes or granulomas. The exact mechanism of action of POA
is unclear， but fatty acid synthetase 1 may be the primary target in
M. tuberculosis. Susceptible strains of M. tuberculosis are inhibited
by
pyrazinamide concentrations of 16-50 Ilg/mL at pH 5.5.

95. PHARMACOLOGY AND DOSING
• Pyrazinamide is well absorbed after oral
administration， with peak serum concentrations of 20-60 Ilg/mL at
1-2 h after ingestion of the recommended adult daily dose of 15-30
mg/kg (maximum， 2 g/d). It distributes well to various body
compartments， including CSF， and is an important component
oftreatment for
tuberculous meningitis. The serum half-life of the drug is 9-1 1 h with
normal renal and hepatic function. Pyrazinamide is metabolized in
the
liver to POA， 5-hydroxypyrazinamide， and 5-hydroxy-POA. A high
proportion of pyrazinamide and its metabolites (-70%) is excreted in
the urine. The dosage must be adjusted according to the level of
renal
function in patients with reduced creatinine clearance

96. ADVERSE EFFECTS
• At the higher dosages used previously， hepatotoxic
ity was seen in as many as 15% of patients treated with pyrazinamide
However， at the currently recommended dosages， hepatotoxic盯 now
occurs less commonly when this drug is administered with isoniazid
and rifampin during the treatment of TB. Older age， active liver dis
ease， HIV infection， and low albumin levels may increase the risk of
hepatotoxicity. The use of pyrazinamide with rifampin for the treatment of
LTBI is no longer recommended because of unacceptable
rates of hepatotoxicity and death in this setting. Hyperuricemia is a
common adverse effect of pyrazinamide therapy that usually can be
managed conservatively. Clinical gout is rare
Although pyrazinamide is recommended by international TB
organizations for routine use in PI吨nancy， it is not recom
mended in the United States because of inadequate teratogenicity data.

97. RESISTANCE
• The basis of pyrazinamide resistance in M. tuberculosis is
a mutation in the pncA gene coding for pyrazinamidase， the
enzyme
that converts the prodrug to active POA. Resistance to pyrazinamide
is associated with loss of pyrazinamidase activity， which prevents
conversion of pyrazinamide to POA. Of pyrazinamide-resistant M.
tuberculosis isolates， 72-98% have mutations in pncA.
Conventional
methods of testing for susceptibility to p严azinamide may produce
both false-negative and false-positive results because the high-
acidity
environment required for the drug's activation also inhibits the
growth
ofM. tuberculosis. There is some controversy as to the clinical
significance of in vitro pyrazinamide resistance

98. Rifabutin
• Rifabutin， a semisynthetic derivative of rifamycin S， inhibits
mycobacterial DNA-dependent RNA polymerase. Rifabutin is
recommended in place of rifampin for the treatment of HIV-co-
infected
individuals who are taking protease inhibitors or non-
nucleoside
reverse transcriptase inhibitors， particularly nevirapine.
Rifabutin's
effect on hepatic enzyme induction is less pronounced than
that of
rifampin. Protease inhibitors may cause sign凶cant increases
in rifabutin levels through inhibition of hepatic metabolism

99. PHARMACOLOGY
• Like rifampin， rifabutin is lipophilic and is absorbed
rapidly after oral administration， reaching peak serum levels 2-4 h
after ingestion. Rifabutin distributes best to tissues， reaching levels
5一10 times higher than those in plasma. Unlike rifampin， rifabutin
and
its metabolites are partially cleared by the hepatic microsomal
system.
Rifabutin's slow clearance results in a mean serum half-life of 45 h
much longer than the 3- to 5-h half-life of rifampin. Clarithromycin
(but not azithromycin) and fluconazole appear to increase rifabutin
levels by inhibiting hepatic metabolism

100. ADVERSE EFFECTS
• Rifabutin is generallywell tolerated， with adverse effects
oιcurring at higher doses. The most common adverse events are
gastrointestinal; other reactions include rash， headache， asthenia
， chest pain，
myalgia， and insomnia. Less common adverse reactions include
fever，
chills， a flulike syndrome， anterior uveitis， 1叩atitis，
Clostridium d伊cileassociated diarrhea， a diffuse polymyalgia
syndrome， and yellow skin
discoloration ("pseudo-jaundice"). Laboratory abnormalities include
neutropenia， leukopenia， 出rombocytopenia， and increased
levels ofliver
enzymes. Approximately 80% of patients who develop rifampin-
related
adverse events are able to complete TB treatment with rifabutin

101. • RESISTANCE Similar to rifampin
resistance， resistance to rifabutin is
mediated by some mutations in rpoB

102. Rifapentine
• Rifapentine is a semisynthetic cyclopentyl rifamycin，
sharing a mechanism of action with rifampin. Rifapentine is lipophilic
and has a prolonged half-life that permits weekly or twice-weekly dosing.
Therefore， this drug is the subjeιt ofintensive clinical investigation
aimed at determining optimal dosing and frequency ofadministration
Currently， rifapentine is an alternative to rifampin in the continuation
phase of treatment for noncavitary drug-susceptible pulmonary TB in
HIV-seronegative patients who have negative sputum smears at completion
of the initial phase of treatment. When administered in these
specific circumstances， rifapentine (10 mg/峙， up to 600 mg) is given
once weekly with isoniazid. Because of higher rates of relapse， this
regimen is not recommended for patients with TB disease and HIV co
infection. The regimen is not recommended for preg
nant women， for persons with hypersensitivity reactions to isoniazid
or rifampin， or for HIV-infected individuals taking ART.

103. • PHARMACOLOGY Rifapentine's absorption is improved when the
drug is taken with food. After oral administration， rifapentine
reaches peak serum concentrations in 5-6 h and achieves a steady
state in 10 days.
The half-life of rifapentine and its active metabolite， 25-desacetyl
rifapentine， is -13 h. The administered dose is excreted via the
liver (70%).
• ADVERSE EFFECTS The adverse-effects profile of rifapentine is
similar to that of other rifamycins. Rifapentine is teratogenic in
animal models and is relatively contraindicated in pregnancy.
• RESISTANCE Rifapentine resistance is mediated by mutations in
rpoB Mutations that cause resistance to rifampin also cause
resistance to rifapentine

104. Streptomycin
• Streptomycin was the first antimycobacterial
agent used for the treatment ofTB. Derived from Streptomyces
griseus， streptomycin is bactericidal against dividing M. tuber
culosis organisms but has onlylow-level early bactericidal activity.
This
drug is administered only by the 1M and IV routes. In developed
nations， streptomycin is used infrequently because of its toxicity，
the
inconvenience of injections， and drug resistance. In developing
countries， however， streptomycin is used because of its low cost.
•
MECHANISM OF ACTlON Streptomycin inhibits protein synthesis
by binding at a site on the 30S mycobacterial ribosome

105. Pharmacology and dosing
• Serum levels of Streptomycin peak at 25-45
microgram/mL a丘er a l-g dose. This agent penetrates poorly into
the CSF，
reaching levels that are only 20% ofserum levels. The usual daily
dose
of streptomycin (given 1M either daily or 5 days per week) is 15
mg/kg
for adults and 20-40 mg/kg for children， with a maximum of 1 g/d
for both. For patients �60 years of age， 10 mg/kg is the
recommended
daily dose， with a maximum of 750 mg/d. Because streptomycin is
eliminated almost exclu盯ely by the kidneys， 出 use in patients
with
renal impairment should be avoided or implemented with caution，
with lower doses and less frequent administration

106. ADVERSE EFFECTS
• Adverse reactions occur frequently with streptomycin (10-20%
of patients). Ototoxicity (primarily vestibulotoxicity)，
neuropathy， and renal toxicity are the most common and the
most
serious. Renal toxicity， usually manifested as nonoliguric
renal failure，
is less common with streptomycin than with other frequently
used
aminoglycosides， such as gentamicin. Manifestations of
vestibular
toxicity include loss of balance， vertigo， and tinnitus.
Patients receiving streptomycin must be monitored carefully
for these adverse effects，
undergoing audiometry at baseline and monthly thereafter.

107. RESISTANCE
• Spontaneous mutations conferring resistance to streptomycin are
relatively common， occurring in 1 in 106 organisms. In the
two-thirds of streptomycin-resistant M. tuberculosís strains exhibiting
high -level resistanιe， mutations have been identified in one of two
genes: a 16S rRNA gene (rrs) or the gene encoding ribosomal protein
S12 (rpsL). Both targets are believed to be involved in streptomycin
ribosomal binding. However， low-level resistance， which is seen in
about one-third of resistant isolates， has no associated resistance
mutation. A gene (gídB) that confers low-level resistance to
streptomycin has recently been identified. Strains ofM. tuberculosis
resistant
to streptomycin generally are not cross-resistant to capreomycin or
amikacin. Streptomycin is not used for the treatment of MDR-TB or
XDR-TB because of (1) the high prevalence of streptomycin resistance
among strains resistant to isoniazid and (2) the unreliability of drug
susceptibility testing