Tuberculosis

ANTI-MYCOBACTERIALS

DIAGNOSIS OF TB

The recognition of an active TB case:

Symptomatic due to lesions caused by Mycobacterium tuberculosis.

Confirmed by microbiologic studies to harbor M.tuberculosis

The diagnosis of tuberculosis (TB) refers to the recognition of an active TB case: the identification of a patient who is symptomatic due to lesions caused by Mycobacterium tuberculosis. A TB case is a patient confirmed (by microbiologic studies) to harbor the organism Mycobacterium tuberculosis. Infrequently, a case of TB may also be one where microbiologic work-up is negative but other data support or suggest the presence of the organism.

The Gold Standard

TB Culture

with Drug Susceptibility Testing Because of the increased sensitivity of TB culture to detect TB cases compared to sputum microscopy alone, international standards recommend that all adults suspected to have pulmonary tuberculosis should have TB culture in addition to sputum microscopy where resources permit.

Classification of TB Cases

WHO Case Definitions: Latent TB Active TB

Pulmonary Smear (-) Smear (+)

Extra Pulmonary Smear (-) Smear (+)

Latent TB: TB infection but no evidence of the disease A Clinically Active TB is classified as either Pulmonary

or Extrapulmonary, smear (-) or smear (+)

TB Symptomatic

Cough > 2weeks

Unexplained fever and chills

Night sweats

Weight loss

Anorexia

Chest pain

Fatigue and Body malaise

When should one suspect that a patient may have PTB?

In the Philippines, cough of two weeks or more should make the physician and/or other healthcare workers suspect the possibility of pulmonary tuberculosis. Cough with or without the following: night sweats, weight loss, anorexia, unexplained fever and chills, chest pain, fatigue and body malaise, is suggestive of TB.

A patient exhibiting cough of two weeks or more with or without accompanying symptoms will be referred to as a TB Symptomatic.

TB Symptomatic : work up

Sputum microscopy for AFB Chest radiography (CXR) Tuberculin Skin Testing (PPD) Sputum TB culture and

Drug Susceptibility Testing Blood or serum tests Note: Other diagnostic modalities for TB

symptomatics with negative smears and cases of Extrapulmonary TB shall not be discussed in the interest of time and because these are beyond the scope of the subject matter and therefore for further discussion elsewhere.

Sputum microscopy for AFB

Preferably 3, at least 2

The most efficient way to ID TB cases

Easy to collect

Readily available, accessible, affordable, results rapidly available

Correlates well with infectiousness

The initial work-up of choice for a TB symptomatic is the sputum microscopy for Acid Fast Bacilli. All patients who present with cough of two weeks or more should preferably have three, but at the least two sputum specimens sent for sputum microscopy for Acid Fast Bacilli (AFB).

Sputum microscopy is still the most efficient way of identifying cases of tuberculosis.

Sputum collected first thing in the morning for three consecutive days is recommended.

How should results of sputum microscopy be interpreted? Results of sputum microscopy are interpreted and reported as follows: SMEAR POSITIVE if at least two sputum specimens are AFB (+). SMEAR NEGATIVE if none of the specimens are AFB (+). DOUBTFUL When only one of the 3 sputum specimens is (+). When results are doubtful, a second set of three must be collected

again. If at least one of the second three is (+), the diagnosis is SMEAR

POSITIVE. If all of the second three are (-), the diagnosis is SMEAR NEGATIVE.

Sputum smear for AFB is available, accessible, affordable, with results rapidly available, correlates well with infectiousness.

TB Symptomatic : work up

Chest radiography (CXR)

Tuberculin Skin Testing (PPD)

Sputum TB culture and Drug Susceptibility Testing

Blood or serum tests

Chest radiographs are not routinely necessary in the management of a TB symptomatic patient who is smear positive.A chest radiograph in smear positive TB symptomatics may be helpful if other concomitant diseases or life-threatening conditions are being considered.

The tuberculin skin testing (TST), more popularly known as PPD (for purified protein derivative), will not add additional information if the patient is smear (+). But: TB symptomatic, smear (-) patients will benefit from Chest radiography, & Sputum TB culture and Drug susceptibility testing.To further strengthen the diagnosis. In the Philippines where resources are limited and laboratory capability for

sputum culture is still being strengthened, sputum TB culture with DST is primarily recommended for patients who are at risk for drug resistance and should be done in the following smear positive patients:

o All cases of retreatment/ o All cases of treatment failure/o All other cases of smear (+) patients suspected to have one or multi- drug resistant TB (MDR-TB)

Certain blood or serum tests may be taken when specific risks for possible adverse events during treatment are present

Classification of TB based on

Location & Sputum Smear

Location Smear Definition of Terms

Pulmonary TB

(+) 1. A patient w/ at least 2 sputum specimens (+) for AFB, w/ or w/o CXR abnormalities consistent with active TB or

2. A patient w/ 1 sputum specimen (+) for AFB & w/ CXR abnormalities consistent with active TB as determined by a clinician, or

3. A patient w/ sputum specimen (+) for AFB with sputum culture (+) for M. tb.

(-) A patient with at least 3 sputum specimens (-) for AFB with CXR abnormalities consistent with active TB, and there has been no response to a course of antibiotics and/or symptomatic medications, and the Medical Officer decides treatment with anti-TB drugs.

Location Definition of Terms

Extra- Pulmonary TB

1. A patient w/ at least 1 mycobacterial smear / culture (+) from an extra-pulmonary site (organs other than the lungs: pleura, lymph nodes, genito-urinary tract, skin, joints and bones, meninges, intestines, peritoneum and pericardium, among others), or

1. A patient with histiological and / or

clinical evidence consistent with active TB and there is a decision by a Medical Officer to treat the patient with anti-TB drugs.

Categories of TB Cases according to Previous Treatment Received by the

Patient

Once the diagnosis of active TB is made, a case is also categorized according to

previous treatment received. Thus, cases are either New, Relapse, Return to treatment after default, Failures,

Transferred-in, and Others

Category Definition

New Patient who has never had tx for TB or Patient who has taken anti-TB meds for < four weeks.

Relapse Patient declared cured of any form of TB in the past by a physician after one full course of anti-TB meds and now has become sputum smear (+)

Return to treatment after default

Patient stops taking his medications for two months or more and comes back to the clinic smear (+).

Category Definition

Failure Patient while on tx, remained or became smear (+) again at the 5th month of anti-TB tx or later; or Patient smear (-) at the start of treatment and becomes smear (+) at the 2nd month.

Transfer-in Patient whose mx was started from another area and now transferred to a new clinic

Chronic Case Patient who became or remained smear (+) after completing fully a supervised re-treatment regimen

Once the diagnosis of active TB is made, a case is also categorized according to previous treatment received. Thus, cases are either New, Relapse, Return to treatment after default, Failures, Transferred-in, and Others. This table provides definitions of TB cases according to previous treatment received. This categorization helps guide the health provider on the recommended treatment regimens for that particular patient.

Treatment

Drug Therapy aims to: Cure

Prevent death

Prevent relapse

Prevent drug resistance

Decrease transmission

Drug therapy of TB aims to achieve the following objectives:

Cure by rapidly eliminating most of the bacilli. Prevent death from active TB or its late effects.

Prevent relapse of TB by eliminating the dormant bacilli. Prevent the development of drug resistance by using a combination of drugs. Decrease the transmission to others.

The need for multiple drugs and prolonged duration of therapy = because naturally occurring drug resistant mutants are present within large bacterial populations even before chemotherapy is started. In addition, mycobacteria replicate slowly, can remain dormant for prolonged periods and can be eradicated only during replication.Finally, bacilli live in several sites within the host, and each site contains organisms with a different population size, metabolic activity and replication rate.

Treatment

Therapeutic Principles

Treatment of disease must contain multiple drugs to which organisms are susceptible.

Drugs must be taken regularly.

Therapy must continue for a sufficient length of time.

Multiple drugs are given simultaneously: Since mutant organisms naturally resistant to multiple drugs are extremely rare, this strategy decreases the likelihood of selecting out drug-resistant organisms and prevents the emergence of resistance.

Treatment

2 Phases of Treatment Intensive Phase

kills actively replicating bacilli

Continuation Phase kills slowly dividing bacilli

Intensive phase: initial, consisting of more than 2 drugs promotes efficient killing of actively dividing organisms and leads to the rapid reduction of large bacillary populations; provides relief of symptoms, terminates transmission and prevents the emergence of drug resistance.

Continuation phase: uses fewer drugs, kills slowly or irregularly dividing bacilli, sterilizes lesions, prevents relapse

Treatment Regimens

TB Patient To Be Given Tx Drugs /TxDuration

I New PTB smear (+) cases New seriously ill PTB smear (-) cases w/ extensive parenchymal involvement New severely ill Extra-Pulmonary TB

cases

2HRZE / 4HR

II Failure cases Relapse cases Return after default smear(+) Others smear (+)

2HRZES/1HREZ/ 5HRE

III New smear (-) but minimal PTB on CXR as confirmed by Medical officer New Extra-Pulmonary TB (not

serious)

2HRZ / 4HR

Take s of drugs used for Intensive and Continuation phases For Regimens I & II For Patients >50kg BW: add 1 tab each INH 100mg, PZA 500mg, Ethambutol 400mg before initiation of treatment. For Regimen III For Patients >50kg BW: add 1 tab each INH 100 mg, PZA 500mg before initiation of treatment. Category IV (not present in the 2001 NTP manual: Chronic and multidrug-resistant TB (smear positive after supervised retreatment). Multidrug-resistant or individualized regimen per country protocol. Given if there is resistance and/or decreased tolerance to 1st line drugs, Amikacin and Quinolone are the only 2nd line drugs in Philippines

Outcomes of Treatment

Cure

Treatment Completed

Died

Treatment Failure

Defaulter Failure

Transfer Out

Cure: sputum smear (+) patient who has completed tx and is sputum smear (-) in the last month of tx and on at least one previous occasion.

Treatment completed: a patient who has completed tx but does not meet the criteria to be classified as cure or failure. This group includes:

(1)a sputum smear-positive patient initially who has completed treatment without follow-up sputum examinations during the treatment, or with only one negative smear during the treatment, or without sputum in the last month of treatment; and

(2)a sputum smear (-) patient who has completed treatment Died - A patient who dies for any reason during the course of treatment Failure: A patient who is smear(+)at five months or later during treatment

or a sputum smear (-) patient initially before starting tx and becomes smear (+) during the treatment.

A defaulter is one whose treatment was interrupted for 2 consecutive months or more

Transfer out: A patient who has been transferred to another facility with proper referral/transfer slips for continuation of treatment.

Issues Unique to the Infant and Child

with Tuberculosis

How and from whom do infants and children acquire Tuberculosis? A. playmates & classmates B. yaya/driver/parents/grandparent C. house pet D. ingestion of cows milk

How?: airborne route/transmission Childhood TB arises most often as a result of the inhalation of droplet nuclei approximately 1-5 microns containing M.tuberculosis bacilli expectorated by a sputum smear positive adult with pulmonary TB. TB infected infants and postpubertal adolescents are at increased risk for progression to TB disease and children aged less than 4 yrs are at increased risk for disseminated disease. From whom?: yaya/driver or parents/grandparent - by close contact with adults who are TB(+) TB is not a zoonotic disease so children cant get TB from their pets Filipinos are not fond of drinking fresh milk(mycobacterium bovis), besides, most fresh milk is pasteurized.

Spectrum of TB

TB exposure: child in close contact with a source case

(-) Signs & symptoms presumptive of TB

(-) Tuberculin Skin Test (TST)

TB infection: child is found to have

(-) Signs & symptoms presumptive of TB

(+)Tuberculin Skin Test

(-) radiologic/laboratory evidence suggestive of TB

Spectrum of TB

TB disease:

(+) signs & symptoms presumptive of TB

(+) Tuberculin Skin Test and/or

(+) radiologic/laboratory evidence suggestive of TB

Diagnosis of TB in Children

GOLD STANDARD

a positive culture with or without a positive AFB smear for Mycobacterium tuberculosis

Why is the diagnosis of Tuberculosis in a child so difficult?

the diagnosis of childhood

tuberculosis (TB) is especially difficult compared to that of an adult in the absence of a gold

standard in many cases because of the following reasons:

Diagnosis of TB in Children

The occurrence of asymptomatic infection (latent TB infection) and early disease in childhood.

The poor bacteriologic yield.

The difficulty of collecting specimen in the young.

The occurrence of asymptomatic infection (latent TB infection) and early disease in childhood,

The poor bacteriologic yield brought about by the paucibacillary character of TB in the young.

The difficulty of collecting specimen in the young: i.e. children

Diagnosis of TB in Children

Demonstration of acidfast bacilli on microscopy and histologic changes on biopsy can only provide presumptive diagnosis in the absence of a positive culture.

Radiologic evidence is often equivocal: it requires consensus among radiologists.

The Tuberculin Skin Test has logistic limitations on top of high false negative findings even under ideal settings.

Demonstration of acid-fast bacilli on microscopy and histologic changes on biopsy can only provide presumptive diagnosis in the absence of a positive culture.

Radiologic evidence is often equivocal: it requires consensus among radiologists for a clear-cut set of criteria.

The Tuberculin skin test has logistic limitations on top of high false negative findings even under ideal settings.

Diagnosis of TB in Children

In the absence of bacteriologic evidence, a child is presumed to have active TB if 3 or more of the following criteria are present:

Epidemiologic

Clinical

Immunologic

Radiologic

Laboratory

Epidemiologic

Exposure to an adult/adolescent with active TB disease

Clinical: TB symptomatic

cough or wheezing of >2wks

unexplained fever of >2wks

loss of appetite, wt. loss, failure to gain wt.

failure to respond to 2wks of AB tx for LRTI

failure to regain previous state of health after 2

wks of viral infection or exanthema (measles)

fatigue, reduced playfulness, lethargy, loss of normal energy

TB symptomatic: 3 or more of the following signs and symptoms suggestive of TB

Immunologic

(+) Tuberculin Skin Test

>5mm induration

Hx: close contact with known or suspected case of TB

Clinical findings suggestive of TB

Chest X-ray suggestive of TB

Immunocompromised condition

>10mm induration

2008 PPS Evidence Based Clinical Practice Guidelines for Childhood TB recommendation statement: After intradermal administration of 0.1ml of 5 TU PPD purified protein derivative, the mantoux test is read at 48-72hours, regardless of BCG status, an induration of >5 mm is considered positive in the presence of any of the following:history of close contact with a known or suspected infectious case of TB, clinical findings suggestive of TB, chest x-ray suggestive of TB, immunocompromised condition. Otherwise, an induration >10mm is considered positive.

Radiologic

No pathognomonic radiologic findings

Most suggestive of PTB:

hilar/paratracheal adenopathy

parenchymal changes

Laboratory

Laboratory findings suggestive of TB

Histologic

Cytologic

Biochemical

Immunologic

Molecular

Classification: TB Disease in Children

Pulmonary TB

Latent Infection

Primary TB

Progressive Primary TB

Extra-Pulmonary TB

Latent Infection : infection associated with tuberculin hypersensitivity and a positive tuberculin skin test but with no striking clinical or roentgenographic manifestations. Occasionally, low grade fever is found , usually by chance. Primary TB: Infection among infants more frequently results in disease with local progression and dissemination: the younger the patient, the greater the risk of progressive disease until the age of 5 yrs. When disease occurs it is usually the childhood type of pulmonary TB referred to as Primary TB. A radiographic correlate is the demonstration of the Ghon complex: the primary focus, lymphangitis, regional lymphadenitis. Progressive Primary disease: latent primary infection and primary disease can progress into an area of advancing pneumonia. The pulmonary focus enlarges and develops a large caseous center, instead of resolving or calcifying. Persistent fever or cough, with malaise and weight loss with lung findings suggestive of cavitation occur. Crepitant rales and/or diminution of breath sounds over the affected area may be appreciated. Extrapulmonary Tuberculosis: TB of organs other than the lungs. Signs and symptoms are referable to the site of lesion.

The First-Line Anti-TB Drugs

INH

Rifampicin

Pyrazinamide

Ethambutol

Streptomycin

First line drugs have superior efficacy and acceptable toxicity

Second-line drugs haave less efficacy, greater toxicity or both. These are used as alternatives when there is either resistance, toxicity or hypersensitivity to first-line drugs, in cases of failure of clincal response to first line drugs and when expert guidance is available.

Unfortunately, none of the secon-line drugs are widely available locally.a

Except for ethambutol, all first-line drugs are bactericidal agents.

The ATS, IDSA, and CDC no longer consider streptomycin as a first-line drug

INH MOA

Bactericidal for actively growing bacilli

Acts on extra/intracellular populations

Inhibit biosynthesis of mycolic acid (cell wall component)

The INH prodrug is activated by KatG, mycobacterial catalase peroxidase. Once activated, forms a covalent complex that blocks mycolic acid synthesis.

INH

Pharmacokinetics

Absorption Readily absorbed fr GIT

Distribution Diffuses to all body fluids and tissues

CSF concn 20-100% of serum

Metabolism genetically determined

Rapid acetylators T/2 1hr; achieves subtherapeutic levels if given once/wk

Slow acetylators T/2 3hrs

Absroption is decreased by aluminum hydroxide

Excreted in urine

Drug interactions may reduce the metabolism of pheynytoin, carbamazepine and ethosuximide

Routine monitoring of transaminases not believed necessary for children

Protect drug from light.

INH

Adverse Reactions

Hepatotoxicity INH induced hepatitis

most frequent major toxic effect

d/c INH if (+) sx or if transaminases increase >3.5 x upper limits of normal

Fever and rash hypersensitivity rxns

Peripheral neuropathy

due to increased pyridoxine excretion

Supplement 10mg B6 daily if with sz/malnut

Seizures in high doses

Optic neuritis, toxic psychosis

Rifampicin

Bactericidal / acts on extra and intracellular bacillary populations

MOA: binds strongly to subunit of bacterial DNA-dependent RNA polymerase inhibits RNA synthesis.

Pharmacokinetics

Well absorbed orally, enterohepatic circulation

Well distributed in tissues, body fluids with therapeutic levels in CSF

Rifampicin

Pharmacokinetics

Metabolism even deacetylated form (metabolized form) has antibacterial activity

Excreted mainly through liver into bile and urine (deacylated form)

Drug interactions:

Potentiate microsomal Cytochrome P450 mediated enzymatic activities causing increased metabolism of digoxin, phenytoin, chloramphenicol,coumadin, ketoconazole, prednisone, theophyline

Rifampicin

Adverse Effects

GI intolerance may be severe

Produce reddish coloration of body fluids - urine, tears, saliva

Cholestatic jaundice/hepatitis

Hypersensitivity: flushing, fever, pruritus, flu-like sx

Increases risk of hepatotoxicity if used with INH (adjust doses)

Rifampicin

Other clinical uses

Leprosy in combination with other drugs

For chemoprophylaxis- household contacts of meningococcal and H.flu dis.

MRSA

In combination with Vancomycin or Ceftriaxone for meningitis

Pyrazinamide Weakly bactericidal but with potent sterilizing activity

within macrophages and areas of acute inflammation, vs residual intracellular organisms that may cause relapse.

MOA

Converted to active pyrazinoic acid (unknown drug target and MOA)

Pharmacokinetics Well absorbed from GIT

Widely distributed to body tissues and inflammed meninges

T/2 8-11hrs

Pyrazinamide

Adverse Effects Most hepatotoxic of all TB agents

GI sx

Photosensitivity and rash

Hyperuricemia due to decreased urate excretion

Arthralgia, esp of shoulders

If patient is diabetic: monitor glucose levels

Protect from light.

Ethambutol

Bacteriostatic in macrophages, but with some cidal action at higher doses.

Acts on extra and intracellular bacillary populations, active vs bacilli in cavities.

MOA

Inhibitor of mycobacterial arabinosyl transferases leading to inhibition of polymerization of arabinoglycan, an essential component of the mycobacterial cell wall.

Ethambutol

Pharmacokinetics

Well absorbed from the gut

CSF concn increases with inflammed meninges = 4-64% of serum levels

50% of dose is excreted in the urine unchanged

20% excreted in feces

Reduce dose by half if Cr clearance is

Ethambutol

Adverse Effects

Retrobulbar neuritis

Reduced visual acuity

contraction of visual fields

green-red color blindness

Not usually seen at recommended doses

Hypersensitivity reactions rare

Should not be given to children

Streptomycin

Bactericidal aminoglycoside vs M.tb in vitro but inactive vs intracellular bacilli limited activity to suppression, activity limited to extracellular bacteria.

MOA

Binds to 30S ribosomal subunit and interferes with initiation of protein synthesis by fixing the 30S-50S ribosomal complex at the start codon (AUG) of mRNA.

Streptomycin

Pharmacokinetics

Poorly absorbed orally

Must be given parenterally

Poor CSF penetration, unless meninges inflammed

Elimination renal reduce dose if with decreased UO or if (+) casts/albumin in urine

Streptomycin

Adverse Effects

Ototoxicity

Nephrotoxicity

Vertigo and hearing loss most common side effects

Sterile abscess

Lupoid reactions rare

Do not give with other nephrotoxic and ototoxic drugs

Adverse Reactions

What are the recommendations in case the patient develops these adverse drug reactions?

GI intolerance

Mild skin reactions

Orange-red colored urine

Pain at the injection site

Burning sensation in the feet (periph neuropathy)

Arthralgia due to hyperuricemia

Flu-like sx

Side Effects Drug Responsible

What to Do

GI intolerance Rifampicin Give medication at bedtime

Mild skin reactions

Any kind Give anti-histamines

Orange-red colored urine

Rifampicin Reassure the patient

Side Effects Drug Responsible

What to Do

Burning sensation feet

INH Give vit B6

Arthralgia hyper-uricemia

PZA Give NSAID

Flu-like sx Rifampicin Give anti-pyretics

Side Effects Drug Responsible

What to Do

severe rash hyper- sensitivity

Any kind esp streptomycin

d/c anti TB drugs, refer to MD

Jaundice -hepatitis

Any kind esp INH,Rifampicin PZA

d/c anti TB refer, resume tx if sx gone

Impaired visual acuity/color

vision-optic neuritis

Ethambutol d/c etham, refer to ophtha

Side Effects Drug Responsible

What to Do

Hearing impairmnt, tinnitus CN8

Streptomycin d/c anti-TB drugs and refer to MD

Oliguria/albuminuria Renal dis.

Streptomycin Rifampicin

Psychosis and convulsion

INH

Clinical Form Intensive Phase

Continuation Phase

TB Exposure < 5 yrs 5 yrs

3H to be modified based on follow up TST result

Latent TB PPD conversion within past 1-2 yrs (-)Cxray

9H

Latent TB PPD(+) with stable healed lesion (-) previous Tx

9H

Clinical Form Intensive Phase

Continuation Phase

Latent TB PPD(+),stable/healed lesion, previous tx(+) At risk for reactivation due to measles/pertussis

1-2 H

Latent TB PPD(+),stable/healed lesion, previous tx(+) At risk for reactivation due to immunosuppression

H for the duration immuno-suppression

Clinical Form Intensive Phase

Continuation Phase

Active TB disease New, smear(-) pulmonary TB

2HRZ 4HR or 6HE

Active TB disease Less severe form extrapulmonary TB

2HRZ 4HR or 6HE

Active TB disease New, smear(+) pulmonary TB

2HRZE(S) 4HR or 6HE

Clinical Form Intensive Phase

Continuation Phase

Active TB Disease New smear (-) pulmonary TB with extensive parenchymal involvement

2HRZE(S)

4HR or 6HE

Active TB Disease Severe forms of extrapulmonary TB (other than TB meningitis)

2HRZE(S)

4HR or 6HE

Clinical Form Intensive Phase

Continuation Phase

Active TB Disease TB Meningitis

2HRZS 4HR

Active TB Disease Miliary TB Bone & Joint TB

2HRZS 7-10HR

Active TB Disease previously treated smear(+)Pulmo TB, Relapse tx after interruption tx failure

2HRZES/ 1HRZE

5HRE

TB & Pregnancy

TB in pregnancy should be treated without delay.

H,R,Z,E have no known teratogenic effects

2HRZE then 4HR

Pyridoxine 25mg/day

Streptomycin - contraindicated

Tuberculosis in pregnancy should be treated without delay. Untreated TB will cause more harm than adverse events associated with treatment of pregnant women and babies. Infants born to women with untreated TB have higher risks of having fetal growth retardation, small for gestational age,

low APGAR scores, low birth weight and rarely congenital TB. Isoniazid, rifampicin, pyrazinamide, and ethambutol have no known teratogenic effects and are considered safe for pregnant patients with TB. Although the safety of PZA is not yet well established, the WHO recommends the use of PZA for 2 months. The standard short- course chemotherapy consisting of an initial

phase using HRZE for two months followed by HR for four months is recommended if the probability of TB is moderate to high.

Pregnant women taking isoniazid should be given pyridoxine (Vitamin B6) at 25 mg/day because isoniazid may cause demyelination in the patient and in the fetus.

Streptomycin may cause ototoxicity in fetuses and should not be used in the treatment of pregnant patients with TB. [Grade B]

TB and Breastfeeding

Lactating women being treated for TB with the first-line anti-TB drugs may continue to breastfeed.

The small concentrations of anti-TB drugs in breast milk do not produce toxicity in nursing newborns.

Drugs in breast milk should not be considered as an effective treatment for active TB or latent TB infection in a nursing infant. Drug levels in breast milk are not sufficient for Treatment of TB in the infant.

Review

Mechanisms of Action of first line & second line anti-TB drugs

Pharmacokinetics

Adverse Drug Reactions

INH inhibits mycolic acid synthesis (cell wall synthesis)-Cidal Rifampicin inhibits RNA synthesis by binding to RNA polymerase and

penetrates phagocytic cells Cidal PZA Intracellular drug (macrophage) and works within the lysosome

MOA unknown Cidal/ not for longterm tx bec. Dormant bacilli resistant to PZA

Ethambutol inhibits mycolic acid synthesis by inhibiting transferases involved polymerization of cell wall components Static

Streptomycin inhibits protein synthesis So INH/Ethambutol inhibit mycobacterial cell wall synthesis/ While

Rifampicin inhibits RNA synthesis/Streptomycin inhibitsProtein synthesis PZA MOA unknown. Adverse Drug Reactions: INH hepatitis, peripheral neuropathy, seizures Rifampicin- orange color of body fluids, cholestatic jaundice PZA most hepatotoxic, gout hyperuricemia Ethambutol retrobulbar neuritis, difficult to administer to