TUBERCULOSIS
Introduction:
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Etiology:
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Order: Actinomycetales.
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Family: Mycobcteriaceae.
1. Mycobacterium tuberculosis.
2. Mycobacterium bovis.
3. Mycobacterium africanum.
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Characteristics:
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Hallmark: acid-fastness.
Epidemiology:
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Infection: occurs after inhalation of infective droplet nuclei. Positive tuberculin test
is the hallmark of this stage in the absence of clinical or radiological findings.
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Disease: “Tuberculosis” signs and symptoms or radiographic changes when
apparent.
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Risk factors:
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environmental.
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genetics.
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Adults: 2/3 are males.
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Childhood: females more than males.
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Favored age: 5-14 years.
Where children get the infection?
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Drug resistant T.B.
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Transmission:
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By airborne mucus droplet nuclei.
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Rarely by direct contact with infected discharge or contaminated fomites.
What factors that will increase the chance of transmission?
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Young children with T.B. rarely infect other children or adults.
Pathogenesis:
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Primary complex: infection at the portal of entry and regional L.N.
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Tissue reaction intensifies over the next 2-12 weeks as tissue hypersensitivity
develops.
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The parenchymal portion will undergo caseous necrosis and encapsulation and it
heals by fibrosis or calcification.
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L.N. infection heals by fibrosis and encapsulation .
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Partial obstruction:
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Endobronchial T.B. or fistula tract.
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Complete obstruction:
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Segmental lesion.
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Disseminated T.B:
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Remote foci become encapsulated and maybe the origin of extra pulmonary or
reactivation T.B.
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Congenital T.B:
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It is rare and it occurs through a placental lesion transmitted by umbilical vein or
by aspiration or ingestion of infected amniotic fluid.
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More common with maternal primary infection.
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Neonatal infection occurs through airborne transmission.
Immunity:
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Antibodies have little role in the defense.
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Role of Sulfatides .
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Cell-mediated immunity develops 4-8 weeks after infection at the same time of
development of tissue hypersensitivity.
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It depends on:
1. Mycobacterial antigen load.
2. Cell-mediated immunity.
3. Tissue hypersensitivity.
Tuberculin skin test:
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It is due to delayed type hypersensitivity.
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Mantoux test vs. multi-puncture test.
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Induration is measured after 48-72 hours.
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The sensitivity & specificity are less than 100% but no better diagnostic test is
available.
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Performing an initial test before the initiation of immunosuppressive therapy in any
patient.
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It is interpreted on the basis of rule of 5,10,15 mm
Immediate skin testing:
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Those who have been in contact with persons with active or suspected T.B.
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Immigrants from countries in which T.B. is endemic or children with travel histories
to these countries.
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Those who have radiographic or clinical findings suggestive of T.B.
Annual testing for:
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children who are infected with HIV or those living in a household with persons
infected with HIV.
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Incarcerated adolescents.
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Testing at 2-3 year intervals is indicated if the child has been exposed to high-risk
individuals including those who are homeless, institutionalized adults who are
infected with HIV, users of illicit drugs, residents of nursing homes and incarcerated
adolescents or adults.
Testing when children aged 4-6 years and 11-16 years:
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Children without risk factors residing in high-prevalence areas.
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Children whose parents emigrated from regions of the world with a high prevalence
of T.B. or who have continued potential exposure by travel to the endemic areas &/
or household contacts.
Induration of 5mm or more is considered positive in:
1. Children having close contact with known or suspected contagious cases of the
disease, including those with household contacts with active T.B. whose
treatment cannot be verified before exposure.
2. Children with immunosuppressive conditions or medications.
3. Children with abnormal CXR finding consistent with active T.B., previously active
T.B., or clinical evidence of the disease.
Induration of 10mm or more is positive in:
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Children who are at higher risk of dissemination of tuberculosis disease including
those younger than 5 years or those who are immuno-suppressed because of
conditions such as lymphoma, D.M., and malnutrition.
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Children with increased risk of exposure to the disease including exposure to
adults in high-risk categories, those who were born in or whose parents were born
in high-prevalence areas of the world, and those with travel histories to high-
prevalence areas of the world.
Induration of 15mm or more is considered positive in:
•
Children aged 5 years or older without any risk factor for the disease.
False positive:
1. Cross sensitization to antigens of non tuberculous Mycobacteria.
2. BCG vaccine.
False negative:
1. Vaccination with live attenuated viruses or infection by them.
2. Anergy .
3. Immuno-suppression & immune-deficiency.
4. Malnutrition.
5. Improper administration
6. Improper storage & contamination.
7. Overwhelming T.B..
8. Very young age.
Clinical picture and diagnosis:
A. Primary pulmonary disease: usually sub-pleural associated with pleurisy.
1. All lobar segments are at equal risk of initial infection.
2. Symptoms and physical findings are variable.
3. Diagnosis: early morning gastric aspirate but negative cultures do not rule out
the disease.
4. Adequate proof: +ve P.P.D. + abnormal CXR consistent with T.B. + history of
exposure to adult with infectious T.B.
5. Complication:
a) Pneumothorax.
b) Broncho-esophageal fistula.
c) Segmental lesion.
d) Bacterial super infection.
e) Bronchiectasis.
B. Progressive primary pulmonary disease:
1. Primary pulmonary focus enlarges & develops large caseous center.
2. Liquefaction causes formation of primary cavity.
3. Intrapulmonary dissemination.
4. Symptoms and signs: high fever, productive sputum, weight loss, night
sweats.
5. Prognosis: excellent for full and slow recovery with appropriate therapy.
C. Reactivation Tuberculosis:
1. Rare in children and occurs in those who acquire the initial infection after 7
years of age.
2. Most common sites:
a) Remains localized to the lungs….why?
3. They are more likely to experience fever, anorexia, malaise, weight loss, night
sweats, productive cough, hemoptysis and chest pain.
4. Physical examination: minor or absent findings even when cavities or large
infiltrates are present.
5. CXR:
a) Most symptoms & signs improve within several weeks of starting effective
treatment.
b) It is highly contagious if there is significant sputum production.
6. Prognosis: excellent.
D. Pleural Effusion:
1. Localized or generalized originate in discharge of bacilli into pleural space
from subpleural pulmonary focus or caseated L.N.
2. Usually unilateral, infrequent if the age is less than 6 years.
3. Symptoms and signs: fever, S.O.B, chest pain.
4. Radiology: more extensive than symptoms.
5. Pleural fluid analysis:
a) Culture is positive in less than 30%, P.P.D is positive only in 70-80%.
b) Biopsy of pleural membrane.
c) Excellent prognosis but radiological resolution often takes several months.
E. Pericardial disease:
1. Pericarditis is due to direct invasion or lymphatic drainage from subcarinal
lymph node.
2. Clinical picture: nonspecific.
3. Pericardial fluid is serofibrinous or hemorrhagic.
4. Cultures are positive in 30-70% and more from pericardial biopsy.
F. Lymphohematogenous disease:
1. Clinical picture depends on the quantity of organisms released from the
primary focus and adequacy of host immune response.
2. The onset is indolent and prolonged with spiking fever but usually it is
asymptomatic.
3. Multi-organ involvement.
4. Early pulmonary involvement is mild but diffuse one becomes apparent with
prolonged infection.
G. Miliary disease:
1. Massive number of tubercle bacilli released into the bloodstream causing
disease in 2 or more organs.
2. Clinical picture: variable.
3. Mostly insidious onset with early systemic signs.
4. Anorexia, weight loss, low-grade fever with absent physical signs.
Generalized lymphadenopathy and hepatosplenomegaly develop within
several weeks after which the severity of fever will be increased.
5. C.X.R usually normal initially.
6. Alveolar-air block syndrome.
7. Meningitis, peritonitis, papulonecrotic tuberculids.
8. P.P.D. is negative in 40%.
9. Diagnosis: high index of suspicion.
10. Biopsy of liver or bone marrow with appropriate bacteriologic and histological
examination can lead to early diagnosis.
11. Slow resolution even with proper therapy.
12. Steroids will fasten the symptomatic relief.
13. Excellent prognosis with early diagnosis and adequate treatment.
H. Upper Respiratory Tract Disease:
1. Larynx: cough, sore throat, hoarseness, dysphagia.
2. Middle ear: painless unilateral otorrhea, tinnitus, decreased hearing, facial
paralysis, perforated tympanic membrane.
3. Difficult diagnosis.
I. Lymph Node Diseases:
1. Scrofula: the most common form of extra pulmonary disease and it occurs
within 6-9 months of initial infection and sometimes years later.
2. Tonsillar, anterior cervical, submandibular, supraclavicular nodes become
involved secondary to extension of the primary lesion of upper lung fields or
the abdomen.
3. Infected nodes in the inguinal, epitrochlear or axillary regions results from
regional lymphadenitis associated with skin or skeletal disease.
4. The nodes will enlarge gradually become firm, discrete, nontender.
5. Usually low grade fever only.
6. P.P.D. is positive.
7. CXR is normal in 70% of cases.
8. If left untreated, it may resolve but more often it progresses to caseation and
necrosis.
9. Complications: node or capsule rupture.
10. Good response to antituberculous treatment.
11. Diagnosis: excisional biopsy of the involved node.
J. Central Nervous System:
1. Most serious complication.
2. It is due to presence of metastatic caseous lesions which increase in size and
exudate into corticomeningeal blood vessels causing inflammation,
obstruction and subsequent infarction of cerebral cortex.
3. Brainstem is the most common site.
4. Communicating hydrocephalus.
5. SIADH.
6. Age: 6 months-4years.
7. The onset is usually gradual in 3 stages:
a) 1-2 weeks: nonspecific symptoms: fever, headache, irritability,
drowsiness, malaise but without focal deficits.
b) Abrupt onset of lethargy, nuchal rigidity, seizures, +ve Kernig or Brudzinski
signs, hypertonia, vomiting, cranial nerve palsies. Some patients have
signs of encephalitis.
c) Coma, hemiplegia, paraplegia,nhypertension, decerebrate posturing and
death.
8. Prognosis:
9. Diagnosis: P.P.D is negative in 50% of cases,CXR is normal in 20-50% of
cases.
10. Lumber puncture: increased protein.
11. Ventricular C.S.F may be normal.
12. Success for obtaining +ve culture and stain depends on the amount of C.S.F
sample.
13. C.T., MRI: basilar enhancement, communicating hydrocephalus, cerebral
edema, Tuberculoma.
K. Tuberculoma:
1. It constitutes 40% of brain tumors.
2. Site:
a) May be multiple.
3. The patient presents with headache, fever, convulsion.
4. C.X.R :normal.
5. P.P.D usually positive.
6. C.T, MRI: discrete lesion with significant edema.
7. Treatment is medical (steroids) but surgery is needed to differentiate from
other brain tumors.
L. Bone and joint disease:
1. Potts disease.
2. Complications:
3. Gibbus deformity.
4. Scoliosis.
M. Abdominal and G.I. disease:
1. Oral cavity and pharynx: painless ulcer on mucosa,palate,tonsils with regional
L.A.P.
2. Esophagus: associated with T.E. fistula.
3. It is associated with extensive pulmonary disease and swallowing of
infectious respiratory secretions or from mediastinal or peritoneal lymph node
without pulmonary disease.
4. Tuberculous peritonitis:
a) Generalized: from subclinical or miliary hematogenous spread.
b) Localized: from direct extension from abdominal lymph node ,
inflammatory focus or genitourinary T.B.
c) The patient presents with pain, low grade fever, ascites and mass.
d) P.P.D is usually positive.
e) Paracentesis.
5. Tuberculous enteritis:
a) It occurs either from hematogenous spread or from swallowing of tubercle
bacilli discharged from the patient own lungs.
b) Most common sites: jejunum, ileum, near Peyer patches and appendix.
c) Shallow ulcers will cause pain, diarrhea or constipation and weight loss
with low grade fever.
6. Mesenteric adenitis can cause obstruction or peritonitis.
a) Diagnosis:acid fast stain,culture of the lesion.
N. Genitourinary disease:
1. Renal involvement is rare.
2. True renal tuberculosis:
a) Small caseous foci which release the bacilli into tubules.
b) Large mass which discharges bacteria by fistula into renal pelvis.
c) Hydronephrosis and strictures.
d) Clinical picture: initially silent sterile pyria, and microscopic hematuria.
e) Dysuria, flank pain, gross Hematuria, super infection with other bacteria.
f) Diagnosis: urine culture is positive in 80-90%, acid fast stain of large
volume of urine sediment is positive in 50-70%, P.P.D is negative in 20%
of patients.
g) I.V.P: mass lesion, dilatation of proximal ureters, multiple small filling
defects, hydronephrosis mostly unilateral.
O. Genital T.B. Is uncommon before puberty:
1. Due to lymphohematogenous spread or due to direct spread from intestinal
tract or bone.
2. P.P.D is usually positive.
P. Perinatal disease:
1. Symptoms present at birth but more common to begin by the second or third
week of life.
2. Most common: respiratory distress, fever, HSM, poor feeding, lethargy,
irritability, L.A.P, abdominal distension, F.T.T., ear drainage, skin lesions and
it depends on the site and size of caseous lesion.
3. C.X.R:
a) Generalized lymphadenopathy and meningitis in 30-50%.
4. Diagnosis: maternal or family history of T.B.
5. P.P.D:, acid fast stain of early morning gastric aspirate, middle ear discharge,
tracheal aspirate, biopsy tissues.
6. C.S.F:
Treatment:
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The ultimate goal of treatment is to achieve sterilization of the T.B. lesion in the
shortest possible time.
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Drug susceptibility studies may not be required if the risk of drug resistance is not
significant.
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The risk factors include:
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Residence in a community with greater than 4% primary resistance to I.N.H.
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History of previous treatment with anti-T.B drugs.
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History of exposure to a drug –resistant case.
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Origin in a country with a high prevalence of drug resistance.
Treatment of pulmonary T.B.:
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6-month course of INH and rifampin, supplemented during the first 2 months with
pyrazinamide.
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Ethambutol or Streptomycin may need to be included in the initial regimen until
results of drug susceptibility are available.
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Another treatment option is a 2-month regimen of INH, rifampin and pyrazinamide
daily followed by 4 months of INH and rifampin twice a week.
Treatment of hilar adenopathy is:
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9 month regimen of INH and rifampin daily or a 1 month regimen of INH and
rifampin once a day followed by 8 months of INH and rifampin twice a week.
Most cases of extra pulmonary T.B.: Can be treated with the same regimens used to
treat pulmonary T.B. exceptions include bone and joint disease, miliary disease and
meningitis
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Recommendation is a regimen of 2-months of INH, rifampin, pyrazinamide and
streptomycin once a day followed by 7-10 months of INH and rifampin once a day.
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Or 2 months on INH, rifampin twice a week.Streptomycin may be administered as
an initial therapy.
Therapy for drug-resistant T.B.:
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Primary and secondary resistance.
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At least 2 drugs are used.
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If multi-drug resistant, initial treatment should include 4 drugs.
Isoniazid:
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Cheap,can diffuse into all tissues and body fluids with low rate of side effects.
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Can be given orally or I.M.
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At the usual daily dose, the concentration is > MIC.
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Peak concentration in blood, sputum, & C.S.F reaches within few hours and persist
for at least 6-8 hours.
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Metabolised by acetylation in the liver
Rifampicin:
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It is well absorbed for the gastrointestinal tract during fasting & peak levels are
achieved within 2 hours and widely distributed in tissues and body fluids.
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Orally or I.V.
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Formulations: capsules, suspension
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major excretion through biliary tract.
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Side effects:
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orange discoloration of urine and tears with permanent staining of contact
lenses.
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G.I.T disturbances.
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Hepatotoxicity.
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Thrombocytopenia.
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Interaction with other drugs.
Pyrazinamide:
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Children dosage is unknown but the adult dose cause high levels in C.S.F ,well-
tolerated and correlates with the clinical success.
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Side effects:
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Hyperuricemia.
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Hypersensitivity.
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I.N.H & RIF are highly bactericidal.
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STM is highly bactericidal for extracellular bacilli.
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PZA is killing in the patient but not in vitro.
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EMB at low dose and ETH and cycloserine are bacteriostatic for M.T.B and used to
inhibit the development of drug resistance.
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I.N.H , RIF & EMB are effective in preventing emergence of resistance to other
drugs but PZA has not similar activity.
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Only tablet form 500mg.
Streptomycin:
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It is less frequently used .
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Useful for drug resistant cases.
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Given I.M. or I.V.
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Penetrate the meninges if they are only inflammed.
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Used if there is initial INH resistance or life-threatening form of T.B.
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Side effects: nephrotoxicity and toxicity to vestibular and auditory portion of C.N 8
Ethambutol:
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Used to prevent emergence of resistance to other drugs.
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Well tolerated by adults and children when given orally.
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Side effects:optic neuritis and red-green color blindness.
Ethinoamide:
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It is a bacteriostatic drug used for treatment of drug-resistant cases.
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Penetrates C.S.F well and so it is useful for meningitis.
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Well tolerated by children and given in 2 or 3 divided doss because of G.I
disturbances.
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Can cause significant hepatitis.
Aminoglycosides:
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Kanamycin, amikacin.
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They are used in STM resistant cases
Capreomycin:
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is used in adults.
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They are bactericidal without cross-resistance with STM.
Cycloserine:
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It is infrequently used in children
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Given in 1 or 2 divided doses.
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Side effects: impairment with thought processes , depression, with other psychiatric
abnormalities.
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Pyridoxine supplementation.
Ciprofloxacin:
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Used in adults with drug-resistant cases.
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Contraindicated in children
Corticosteroids:
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It is useful when the host inflammatory reaction contributes significantly to tissue
damage or impairment of organ function.
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It is used in:
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T.B meningitis.
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Endobronchial T.B.
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Acute tuberculous pericardial effusion .
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Tuberculous pleural effusion.
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Severe miliary T.B.
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Prednisone is the most used drug.
Treatment of T.B infection:
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INH started for children <6 years with -ve PPD but with recent exposure to adult
with infectious T.B. including infants born to mothers who have T.B.
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Repeat P.P.D in 3 months.
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If resistant to INH, use RIF.
Prevention:
A. BCG vaccination:
1. it was a strain of M.bovis attenuated by subculture Q3 hours for 13 years and
was distributed to dozens of lab.
2. Route: intradermal multipunture technique.
3. Schedule: single dose during infancy but some countries repeat the vaccine.
4. It is 50% effective in inhibition of pulmonary disease and 50-80% effective in
preventing disseminated and meningeal disease.
5. Side effects:
a) local ulceration and regional suppurative adenitis in 0.1-1% of recipients.
b) Osteitis.
c) Systemic: fever, convulsion, loss of appetite, irritability.
d) Dissemination in Immunocompromised patients.
6. Variable responses is due to:
a) Methodological and statistical variation within the trials.
b) Interaction with non-tuberculous Mycobacteria which stimulate or
decrease protection afforded by BCG.
c) Different potencies among various BCG response within the study
population.
d) Genetic factors.
Vaccination:
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It is recommended in children with -ve PPD and those with high risk of intimate and
prolonged exposure to persistently untreated or ineffectively treated adults with
infectious pulmonary T.B. and cannot be removed from the source of infection or
placed on long term preventive therapy.
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Those children with continuous exposure to persons with T.B. who have bacilli that
are resistant to INH and RIF.