TUBERCULOSIS

Tuberculosis (TB) is caused by organisms of the Mycobacterium tuberculosis complex.

This complex includes M. tuberculosis (MTB), the most frequent and important agent of
human mycobacterial disease, and M. bovis, which is acquired via ingestion of unpasteurized
milk.

MTB is a thin aerobic bacterium that is neutral on Gram’s staining but that, once stained, is
acid-fast—i.e., it cannot be decolorized by acid alcohol because of the cell wall’s high content
of mycolic acids and other lipids.

Epidemiology

• It is estimated that >8.8 million new cases of TB occurred worldwide in 2005, mostly in
developing countries. In 2005, 1.6 million deaths due to TB are estimated to have occurred.

• Disease from a pt with pulmonary TB is spread by droplet nuclei that are aerosolized by
coughing, sneezing, or speaking. Droplets may be suspended in air for several hours.
Transmission is determined by the intimacy and duration of contact with a pt with TB, the
degree of infectiousness of the pt, and the shared environment. Pts with cavitary or laryngeal
disease are most infectious, with as many as 105–107 acid-fast bacilli (AFB)/mL of sputum.

• Risk factors for development of active disease after MTB infection include recent
acquisition (within the preceding year), co-morbidity (e.g., HIV disease, diabetes, silicosis,
immunosuppression, gastrectomy), malnutrition, and presence of fibrotic lesions.

Pathogenesis

AFB that reach alveoli are ingested by macrophages. If the bacilli are not contained, they
multiply, lyse the macrophages, and spread to regional lymph nodes, from which
dissemination throughout the body may occur.

About 2–4 weeks after infection, delayed-type hypersensitivity (DTH) destroys nonactivated
macrophages that contain multiplying bacilli, and a macrophageactivating response activates
cells capable of killing AFB.( DTH is the basis for tuberculin skin testing) (TST).

A granuloma forms at the site of the primary lesion and at sites of dissemination. The lesions
can then either heal by fibrosis or undergo further evolution. Despite “healing,” viable bacilli
can remain dormant within macrophages or in necrotic material for years.
Cell-mediated immunity confers partial protection against TB. Cytokines secreted by alveolar
macrophages contribute to disease manifestations, granuloma formation, and mycobacterial
killing.

Clinical Features

Pulmonary TB TB is limited to the lungs in >80% of cases in HIV-negative pts.

1. Primary disease: The initial infection is frequently located in the middle and lower lobes.
The primary lesion usually heals spontaneously, and a calcified nodule (Ghon lesion)
remains. Hilar and paratracheal lymphadenopathy are common.

In immunosuppressed pts and children, primary disease may progress rapidly to clinical
disease, with cavitation, pleural effusions, and hematogenous dissemination.

2. Postprimary (adult-type, reactivation, or secondary) disease: usually localized to the apical

and posterior segments of the upper lobes and the superior segments of the lower lobes.

a. Early symptoms of fever, night sweats, weight loss, anorexia, malaise, and weakness are
nonspecific and insidious.

b. Cough and purulent sputum production, often with blood streaking, occur. Occasionally,
massive hemoptysis follows erosion of a vessel located in the wall of a cavity.

c. Disease can be limited, or extensive cavitation may develop. Extensive disease may cause
dyspnea and respiratory distress.

Extrapulmonary TB (Any site in the body can be involved).

1. Lymphadenitis occurs in >40% of extrapulmonary TB cases, especially among HIV-infected

pts. Painless swelling of cervical and supraclavicular nodes (scrofula) is typical.

2. Pleural involvement is common in primary TB, resulting from penetration of bacilli into
the pleural space or contiguous spread of parenchymal inflammation

A. DTH in response to these bacilli can result in effusion.

B. Empyema is uncommon and results from rupture of a cavity with many bacilli into the
pleural space.

3. In genitourinary disease, local symptoms predominate (e.g., frequency and dysuria).

4. Skeletal disease: The spine, hips, and knees are the most common sites. Spinal TB (Pott’s
disease) often involves two or more adjacent vertebral bodies; in adults, lower
thoracic/upper lumbar vertebrae are usually affected.
5. Meningitis occurs most often in young children and HIV-seropositive pts. Disease typically
evolves over 1–2 weeks.

6. Gastrointestinal disease affects the terminal ileum and cecum, causing abdominal pain
and diarrhea, and can present with a clinical picture similar to that of Crohn’s disease.

7. Pericarditis is characterized by an acute or subacute onset of fever, dull retrosternal pain,

and sometimes a friction rub.

8. Miliary disease arises from hematogenous spread of MTB throughout the body.

Diagnosis

• Maintain a high index of suspicion, perform appropriate radiographic studies, and obtain
appropriate clinical specimens.

• Examine diagnostic specimens for AFB with auramine-rhodamine stain and fluorescence
microscopy.

• Isolate and identify MTB on culture.

• Nucleic acid amplification is useful for rapid confirmation of TB in AFBpositive specimens.

Treatment of Tuberculosis
DRUGS

First-Line Agents

• Rifampicin: the most important and potent anti-tuberculous agent. The standard dosage in
adults is 600 mg/d.

The drug distributes well throughout body tissues, including inflamed meninges. It turns
body fluids (e.g., urine, saliva, tears) red-orange and is excreted through bile and the
enterohepatic circulation. Rifampicin is usually well tolerated but may cause GI upset.

The drug can cause hepatitis when given in combination with isoniazid or pyrazinamide.
Rash, anemia, and thrombocytopenia are less common side effects.

Of note, rifampicin is a potent inducer of hepatic microsomal enzymes and decreases the
half-life of many other drugs.
• Isoniazid (INH): the best agent available after rifampicin. The usual adult dosage is 300
mg/d or 900 mg 2 or 3 times per week.

INH is distributed well throughout the body and infected tissues, including CSF and caseous
granulomas. The most important toxicities are hepatotoxicity and peripheral neuropathy.

INH-associated hepatitis is idiosyncratic and increases with age, alcohol use, pregnancy or
the postpartum period, active hepatitis B infection, and concomitant use of rifampicin.

Because peripheral neuropathy can result from interference with pyridoxine metabolism,
pyridoxine (25–50 mg/d) should be given to pts with other risk factors for neuropathy, such
as diabetes, alcohol abuse, or malnutrition.

• Ethambutol: the least potent first-line agent, ethambutol is usually given at a dosage of
15–20 mg/kg daily.

It is distributed throughout the body but reaches only low levels in CSF.

At higher doses, retrobulbar optic neuritis can occur, causing central scotoma and impairing
both visual acuity and the ability to see green.

• Pyrazinamide: the usual dosage is 15–30 mg/kg daily (maximum, 2 g/d).

The drug distributes well throughout the body, including the CSF.

Other Effective Agents

• Streptomycin: the usual adult dose is 0.5–1.0 g IM daily or 5 times per week. Streptomycin
causes ototoxicity, affecting both hearing and vestibular function, but is less nephrotoxic
than other aminoglycosides.

• Rifabutin: may be as effective as rifampicin, eliciting fewer drug interactions, and is active
against some rifampicin-resistant TB strains.

• Rifapentine: similar to rifampicin but can be given once or twice weekly.

Second-Line Agents

• Fluoroquinolones (e.g., levofloxacin, ciprofloxacin, and moxifloxacin) have solid, broad

antimycobacterial activity.

Other agents are used uncommonly but may be needed in disease caused by resistant
strains of MTB.

REGIMENS

• Nonadherence to the regimen is the most important impediment to cure.

• Bacteriologic evaluation is the preferred method of monitoring response to treatment.

Virtually all pts should have negative sputum cultures by the end of 2–3 months of
treatment. If the culture remains positive, treatment failure and drug resistance should be
suspected.

• Drug resistance may be either

primary (i.e., infection caused by a strain resistant prior to therapy) or

acquired (i.e., resistance arising during treatment because of an inadequate regimen or the
pt’s noncompliance).

MDR: TB is defined as that caused by strains resistant to isoniazid and rifampicin.

• Close monitoring for drug toxicity should take place during treatment and should include
baseline liver function tests (LFTs) and monthly questioning about possible hepatitis
symptoms.

High-risk pts (e.g., older pts, pts who use alcohol daily) should have LFT values monitored
during treatment.

• HIV-associated TB: Three considerations are important for HIV-infected pts receiving TB
treatment.

1. Immune reconstitution inflammatory syndrome (IRIS) may occur when antiretroviral

therapy (ART) is initiated. Symptoms and signs of TB are exacerbated as immune function
improves.

2. ART agents and rifampicin may interact.

3. Rifampicin monoresistance may develop with widely spaced intermittent

treatment.
Tuberculosis and pregnancy
Untreated tuberculosis (TB) represents a greater hazard to a pregnant woman and her fetus
than does its treatment.

Treatment of pregnant women should be initiated whenever the probability of TB is

moderate to high.

Infants born to women with untreated TB may be of lower birth weight than those born to
women without TB and, rarely, the infant may be born with TB.

Treatment

Latent TB Infection (LTBI)

• Isoniazid (INH) administered either daily or twice weekly for 9 months is the
preferred regimen for the treatment of LTBI in pregnant women.
• Women taking INH should also take pyridoxine (vitamin B6) supplementation.

TB Disease

• Pregnant women should start treatment as soon as TB is suspected.

• The preferred initial treatment regimen is INH, rifampicin (RIF), and ethambutol
daily for 2 months, followed by INH & RIF daily, or twice weekly for 7 months, for
9 months of total treatment.
• Streptomycin should not be used because it has been shown to have harmful effects
on the fetus.

Contraindications

The following anti-tuberculosis drugs are contraindicated in pregnant women:

1. Streptomycin
2. Kanamycin
3. Amikacin
4. Capreomycin
5. Fluoroquinolones

Breastfeeding
Breastfeeding should not be discouraged for women being treated with the first-line anti-
tuberculosis drugs because the concentrations of these drugs in breast milk are too small to
produce toxicity in the nursing newborn.
 For the same reason, drugs in breast milk are not an effective treatment for TB disease or
LTBI in a nursing infant. Breastfeeding women taking INH should also take pyridoxine
(vitamin B6) supplementation.

Anti-tuberculosis medication and the liver: dangers and

recommendations in management

The current recommended treatment regimens for tuberculosis involve drugs which are
potentially hepatotoxic.

How common is liver dysfunction with antituberculosis chemotherapy?

The Joint Tuberculosis Committee of the British Thoracic Society recommends that initial
therapy should consist of at least three drugs for 2 months; isoniazid, rifampicin and
pyrazinamide are the drugs of choice, with ethambutol being added if resistance is
suspected.

After two months, a further 4 months of isoniazid and rifampicin are recommended, with
more prolonged therapy for bone, joint and meningeal disease, or for resistant organisms.

Several anti-tuberculosis agents have been implicated as being hepatotoxic. Isoniazid

(particularly in association with rifampicin) and pyrazinamide cause hepatic dysfunction
more frequently than ethambutol and streptomycin, which cause hepatitis problems rarely,
if at all.

Isoniazid (INH). Injury is mostly acute hepatocellular in type, though a mixed hepatocellular-
cholestatic has some structural resemblance to isoniazid.

Para-aminosalicyclic acid (PAS). Hypersensitivity to PAS. Hypersensitivity to PAS has been

recorded in up to 5% of recipients from the largest published series of 277 cases. Jaundice
occurred in 23% of these cases, with the onset usually between 2–6 weeks after
commencing treatment.

Streptomycin, ethambutol and cycloserine. Hepatic injury due to these agents occurs rarely,
if at all.

Prothionamide and ethionamide. These similar agents may produce elevated serum
transaminases in about 10% of recipients, usually after 8–12 weeks.
TB Drugs & Hepatotoxicity
Hepatotoxic

Pyrazinamide and isoniazid are the most common causes

Pyrazinamide causes the most severe

Rifampicin hepatotoxicity is less common and less severe

Ethionamide

NOT Hepatotoxic

Ethambutol

Streptomycin

Isoniazid Hepatotoxicity

Isoniazid hepatotoxicity is a common complication of antituberculosis therapy that ranges in

severity from asymptomatic elevation of serum transaminases to hepatic failure requiring
liver transplantation.

It presents a difficult management problem for several reasons.

Causes

•Genetic predisposition is an important factor, but the specific genes responsible have not
been adequately defined.

•Age is an important risk factor, presumably reflecting aged-related changes in hepatic

metabolism.

•Female gender increases both the risk of developing isoniazid hepatitis and the risk of
death once hepatitis develops.

•Previous or concurrent exposure to drugs that induce cytochrome P-450 enzymes increases
the risk. These drugs include the following:

◦Phenobarbital

◦Rifampin6

◦Alcohol
Adverse Effects of Anti-tuberculosis Chemotherapy

Table 1: Adverse Effects of First-line Anti-TB Drugs

Table 2: Adverse Effects of Second-line Anti-TB Drugs

GLOSARY
H: Isoniazid Z: Pyrazinamide R: Rifampicin E: Ethambutol S: Streptomycin Km: KanamycinAm:
Amikacin Cm: Capreomicin Vi: Viomycin F: Fluoroquinolones: Cfx: Ciprofloxacin Ofx: Ofloxacin
Lfx: Levofloxacin Mfx: Moxifloxacin Gfx: Gatifloxacin Eto: Ethionamide Pto: Prothionamide
Cs: Cycloserine Trd: Terizidone Pas: Para-aminosalicylic acid Th: Thioacetazone

Reintroduction of Drugs After Hepatoxicity

Continue EMB, streptomycin, +/- ciprofloxacin INH 300 mg daily x 4 days

If no symptoms, add

Rifampicin 600 mg daily x 4 days If no symptoms, 2 options:

Do not try PZA ,Try PZA

D/C streptomycin and ciprofloxacin when back on E, H, R.

Kidney disease
Patients with renal failure have a 10 to 30-fold increase in risk of getting TB. Patients with
kidney disease who are being given immunosuppressive drugs or are being considered for
transplant should be considered for treatment of latent tuberculosis if appropriate.

Aminoglycosides (STM, capreomycin and amikacin) should be avoided in patients with mild
to severe kidney problems because of the increased risk of damage to the kidneys.

In mild renal impairment, no change needs to be made in dosing any of the other drugs
routinely used in the treatment of TB. In severe renal insufficiency (GFR<30), the EMB dose
should be halved (or avoided altogether).

The PZA dose is 20 mg/kg/day (UK recommendation) or three-quarters the normal dose (US
recommendation), but not much published evidence is available to support this.

Epilepsy
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.

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. The advice
of a pharmacist should always be sought.

Drug-resistant tuberculosis (MDR- and XDR-TB)

Multi-drug resistant tuberculosis (MDR-TB) is defined as TB that is resistant at least to INH
and RMP. Isolates that are multiply-resistant to any other combination of anti-TB drugs but
not to INH and RMP are not classed as MDR-TB.

"Extensively drug-resistant tuberculosis" (XDR-TB) is defined as MDR-TB that is resistant to

quinolones and also to any one of kanamycin, capreomycin, or amikacin.[

The principles of treatment for MDR-TB and for XDR-TB are the same. The main difference is
that XDR-TB is associated with a much higher mortality rate than MDR-TB, because of a
reduced number of effective treatment options.