ADAMA GENERAL HOSPITAL &

MEDICAL COLLEGE
PATHOLOGY 1ST ASSIGNMENT
GROUP MEMBERS ID No.
1. Afkar hussien MD/2526/21
2. Emnet gobena MD/2518/21
3. Maria mesfin MD/2042/20
4. Meha Khalid MD/2702/21
5. Nanati hussien MD/2698/21

SUBMITTED TO:Dr. haji

Submission date:March 5/2023

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TUBERCLOSIS(TB)

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 Table of content
1. TB diagnostic methods ……………………………………………………………………..…page 4
2. Drugs used in treatment of TB…………………………………………………………….…page 14
3. Principles of TB treatment……………………………………………………………………..page 21
4. TB classification based on sensitivity to drugs ……………………………………….page 23
5. Extra pulmonary TB………………………………………………………………………………..page 27

References …………………………………………………………………………………………….page 33

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TB DIAGNOSTIC METHODS

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 Early diagnosis of tuberculosis and drug resistance improves survival and by identifying
infectious cases promotes contact tracing, implementation of institutional cross-infection
procedures, and other public-health actions.
1. Screening method for TB
A. Mantoux tuberculin skin test
 It’s delayed hypersensitivity skin test used to detect cell mediated immunity to
tuberculosis. The test is done by intradermal injection of 0.1ml of PPD of tubercle bacilli
containing 5TU. In positive tests, a local area of induration 10mm in diameter or more
develops 48-72 hrs after injection. In negative individuals the test may be repeated using
250 TU.
 A positive tuberculin test tells us :
I. Individual has been previously exposed to tubercle bacilli or continues to carry viable
bacilli.
II. Can be of value in diagnosis of the disease in children below 5 years with no history of
previous vaccination.
III. It doesn't differentiate between active infection and immunity.
 A negative tuberculin test is of value as it excludes infection in a suspected cases or are not
immunized.

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B. Interferon gamma release assays (IGRAs)

 Are blood-based tests intended for diagnosis of latent tuberculosis infection (LTBI). IGRAs
offer logistical advantages and are supposed to offer improved specificity over the
tuberculin skin test (TST). However, recent serial testing studies of low-risk individuals have
revealed higher false conversion rates with IGRAs than with TST.
 IGRAs are ex vivo assays that measure T-cell response after overnight stimulation with
antigens that are relatively specific for Mycobacterium tuberculosis.
 This test can distinguish latent TB infection from BCG immunization and NTM infections. In
addition, the IGRA conversion rate is now being used as a measure of vaccine efficacy in TB
vaccine trials.
 The two most widely used IGRAs include the QuantiFERON-TB Gold In-Tube (QFT-GIT) assay
and the T-SPOT.TB (T-SPOT) assay.

QFT-GIT assay

 The QFT-GIT assay, the FDA-approved version, is an enzyme-linked immunosorbent assay

(ELISA)-based, whole-blood test that uses peptides from the two RD1 antigens (ESAT-6 and
CFP-10) as well as peptides from one additional antigen (TB7.7 [Rv2654c]) in an in-tube
format.
 The QFT-GIT assay consists of three tubes:
1) The negative-control (nil) tube that measures background IFN-γ response
2) The antigen tube that measures antigen-specific response, and
3) The positive-control (mitogen) tube that measures nonspecific T-cell response.
 The qualitative result (negative, positive, or indeterminate) is interpreted from
quantification of IFN-γ in international units (IU) per milliliter. An individual is considered
positive for M. tuberculosisinfection if the TB response (IFN-γ response to TB antigens
minus the background IFN-γ response) is above the test cutoff value.

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TB (T-SPOT) assay

 The T-SPOT is an enzyme-linked immunospot (ELISPOT) assay performed on separated and

counted peripheral blood mononuclear cells (PBMC) after incubation with ESAT-6 and CFP-
10 peptides in separate wells.
 The T-SPOT assay consists of four wells:
1) The negative-control (nil) well that measures background IFN-γ-producing T cells (spot-
forming cells [SFC])
2) The two antigen wells that measure M. tuberculosis-specific SFC to ESAT-6 and CFP-10 and
3) The positive-control (mitogen) well that measures nonspecific SFC.

 The qualitative result (negative, positive, or indeterminate) is interpreted from the number
of SFC. An individual is considered positive for M. tuberculosis infection if the spot counts in
the TB antigen wells exceed a specific threshold after subtracting the number of spots in
the negative-control well.
2. Conventional TB Diagnostic Methods
A. Smear Microscopy : was developed 100 years ago by Franz Ziehl and Frederick Neelsen, is
inexpensive, simple, rapid and specific but is only positive in around half of patients with
active TB. Two staining methods can be used to identify acid-fast bacilli: Ziel-Neelsen
staining (ZN) or fluorescent auramine staining (LED FM).

Ziel-Neelsen staining (ZN)

 The Ziehl-Neelsen smear exploits the acid-fast property of mycobacteria by staining bacilli
with carbol-fuschin, using gentle heat to facilitate penetration of the dye, and then using a
decolorising acid solution, which fails to penetrate the mycobacteria, leaving them stained
red while other bacilli are decolorised. The slide is usually then counterstained with
methylene blue to improve visualization of the mycobacteria . The Kinyoun stain is an
alternative cold-stain method.

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 Fig. Zeil- Neelsen stain of tubercle bacilli

Fluorescent auramine staining (LED FM)

 Recent efforts to improve the sensitivity of basic smear microscopy have developed
improved fluorescent microscopes to decrease the reading time and increase the sensitivity
of smear microscopy without significantly affecting specificity if training and quality control
are maintained.

fig . Auramine staining of tubercle bacilli

 In a further policy change, WHO recommended in 2010 that two sputum samples are
sufficient, rather than the standard three samples (spot-morning-spot) .This is due to the
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 low diagnostic yield of a third sputum sample and the resource limitations of TB
programmes.
 A single positive smear is now also considered sufficient for a TB diagnosis .Although
Sputum-smear microscopy has a relatively low sensitivity (25-75% compared to culture)
and unable to distinguish drug-susceptible strains from drug-resistant strains, it has been
used as front line test.
B. TB Culture:The current gold standard method for the bacteriological confirmation of TB is
culture using commercially available liquid media. However, culture is not used as a
primary diagnostic test because of the cost, infrastructure requirements or TB
containment laboratoryand long time required to generate results (1–3 weeks for a positive
result and up to 6 weeks for a negative result). Nonetheless, conventional culture remain
necessary to monitor a patient’s response to treatment. It permits detection of a minimum
of 10 to 100 viable bacilli per ml of sputum. It allows to perform drug susceptibility testing
(DST) for TB from the isolates.
 There are two types of TB culture techniques:
1) Solid culture: Lowenstien-Jensen (LJ) media is culture media which with ease of
preparation, low cost, and low contamination rate. Solid culture may take several weeks,
21-42 days, to detect growth and produce results. It is the gold standard for diagnosis of
MTB.
2) Liquid culture: Mycobacterial Growth Indicator Tube (MGIT) is highly enriched media for
growing mycobacteria with added 10 % more sensitivity than LJ media, and can produce
positive results rapidly. However, the method is prone to higher contamination rate and
expensive.
 The rapid identification of Mycobacterium tuberculosis complex is done using an immune-
chromatographic assay to differentiate MTB from Non-Tuberculosis mycobacterium (NTM)
isolates grown on MGIT or LJ AFB medium. Positive cultures should followed by drug
susceptibility testing.
C. Drug-Susceptibility Testing:Is a technique that is used to screen for susceptibility of the TB
bacilli for various Anti-TB drugs using either phenotypic or genotypic means:

1) Phenotypic methods
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 The conventional method for detecting resistance to anti-TB drugs relies on culture-based
phenotypic DST using liquid or solid media. However, phenotypic testing is time-consuming
(taking from weeks to months to generate results), primarily because of the slow growth
rate of M.tuberculosis.Significant effort has been invested into further development of
simple, alternative phenotypic methods such as the nitrate reductase assay (NRA), thin-
layer agar (TLA), colour test (Color Test), the microscopic observation drug susceptibility
assay (MODS), the colorimetric redox indicator (CRI) method and phage-based assays, most
of which can be set up directly on specimens. These methods can detect MTB and
resistance to INH and RMP. While MODS, NRA and CRI have been endorsed by the WHO,
current evidence was considered to be insufficient for recommending the use of TLA or
phage-based assays .
 MODS is an extensively validated method that has almost perfect agreement with conven‐
tional DST for INH, RMP and MDR-TB (100%, 97% and 99%).The results are available with‐
in a median of 7 days; the method is cheap, non-commercial and works well on all types of
primary specimens as well as on isolates. However, it requires relatively long, detailed staff
training.
 TLA recently demonstrated a good performance of the MDR-/XDR-TB colour test for the
identification of MTB complex and detection of resistance to INH, RMP and ciprofloxacin in
cultures.

2) Genotypic/ Molecular DST techniques

Employs DNA PCR technologies that are specifically designed to detect/confirm genetic
mutations associated with drug resistance. These techniques produce rapid results if DST is
performed directly from sputum samples but may take weeks if done from culture isolates.
Their role is mainly limited to diagnostic purpose and cannot help to monitor patient’s
treatment response as they don’t distinguish between live and dead bacilli. The techniques
may not detect uncommon mutations for which the technique is not designed; hence, are not
definitive test to exclude resistance in some patients.

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At present, the national TBL Control Program recommends the following molecular DST
techniques for use :

 Xpert MTB/RIF Assay

 Xpert MTB/RIF Ultra assays,
 Line Probe Assays (GenoTypeMTBDRplus and GenoType MTBDRsl) ,MTB Plus and MTBRIF
Dx tests
 Xpert MTB/XDR Assay as a follow on diagnostic test for detection of additional drug-
resistance
3. Phage Amplification Technique (PAT)

This is a bacteriophage based test to detect MTB in sputum. Non-pathogenic mycobacteria

(sensor cells) were used for control bacteria in the test. The phage replicate, infect and lyses
the sensor cells leaving zones of clearing (holes) in the agar. The areas of clearing indicates
that the patient sputum contain viable MTB. It is fast with a turnaround time of 2 days. It is
cheap, requires few equipments, sensitive (detection as low as 100 tubercles per ml of
sputum). It can be adapted for sensitivity testing.

Additional supportive methods

1) Histo-Pathological Examination

Pathology plays a complementary role in confirming the diagnosis of TB. Multiplication of

tubercle bacilli in any site of the human body causes a specific type of inflammation, with
formation of characteristic granuloma that can be found on histo-pathological examination.
Samples for pathologic examination can be collected using:

 Fine needle aspiration from accessible mass like peripheral enlarged lymph nodes
 Aspiration of effusions from serous membranes; serous fluid analysis however, is much
less useful for diagnosis than histology and culture of a serous membrane biopsy specimen.
 Tissue biopsy from any body tissues such as serous membranes, skin, endometrium as well
as bronchial, pleural, peritoneal, colonic, gastric or liver tissue.

2) Radiological Examination
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Chest radiography, or chest X-ray (CXR), is an important tool for triaging and screening for
pulmonary TB, and it is also useful to aid diagnosis when pulmonary TB cannot be confirmed
bacteriologically.

Fig. This radiograph shows a patient with typical radiographic findings of TB

On typical radiological examination the following can be seen:

 cavity formation; indicates advanced infection; associated with a high bacteria load
 Non calcified round infiltrates; may be confused with lung carcinoma
 Homogeneously calcified nodules (usually 5-20mm) tuberculomas, representing old
infection
 primary TB: Typically, pneumonia like picture of infiltrative process in middle or lower lung
regions
 Reactivation TB: Pulmonary lesions in posterior segment of right upper lobe, apicoposterior
segment of left upper lobe, and apical segments of lower lobes
 TB associated with HIV disease: Frequently atypical lesions or normal chest radiographic
findings
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 Healed and latent TB: Dense pulmonary nodules in hilar or upper lobes; smaller nodules in
upper lobes
 Miliary TB: Numerous small, nodular lesions that resemble millet seeds
 Pleural TB: Empyema may be present, with associated pleural effusions

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DRUGS USED IN TB
TREATMENT

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 Antituberculosis drugs are mainly divided into two parts.
1) First-line antituberculosis drugs- Isoniazid (INH), rifampicin (RIF), ethambutol (EMB),

pyrazinamide (PZA) and streptomycin (SM).

2) Second-line antituberculosis drugs- Sub divided into two

i. Fluoroquinolones- Ofloxacin (OFX), levofloxacin (LEV), moxifloxacin (MOX)

and ciprofloxacin (CIP).

ii. Injectable antituberculosis drugs- Kanamycin (KAN), amikacin (AMK) and

capreomycin (CAP).

iii. Less-effective second-line antituberculosis drugs- Ethionamide (ETH)/Prothio‐

namide (PTH), Cycloserine (CS)/Terizidone, P-aminosalicylic acid (PAS).

First-line antituberculosis drugs

1. Isoniazid

 Isoniazid (INH) is one of the most effective and specific antituberculosis drugs, which has
been a key to treatment since its introduction in 1952 .M. tuberculosis is highly susceptible
to INH.INH is only active against growing tubercle bacilli, and is not active against non-
replicating bacilli or under anaerobic conditions.
 INH enters the mycobacterial cell by passive diffusion .The most significant adverse
reactions associated with isoniazid administration are hepatotoxicity and neurotoxicity.
Activated INH inhibits the synthesis of essential mycolic acids by inactivating the NADH-
dependent enoyl-acyl carrier protein reductase encoded by inhA.

2. Rifampicin
 Rifampicin (RIF) was introduced in 1972 as an antituberculosis drug and has excellent
steriliz‐ing activity. Rifampicin acts by binding to the β-subunit of RNA polymerase, the
enzyme responsible for transcription and expression of mycobacterial genes, resulting in
inhibition of the bacterial transcription activity and thereby killing the organism. An
important characteristic of rifampicin is that it is active against actively growing and slowly
metabolizing (non-growing) bacilli .RIF produces relatively few adverse reactions. It may
cause gastro‐intestinal upset. Hepatotoxicity occurs less frequently than with isoniazid
administration.
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3. Pyrazinamide
 Pyrazinamide (PZA) is an important first-line antituberculosis (anti-TB) drug that is used in
short-course chemotherapy and is one of the cornerstone drugs in the treatment of MDR-
TB. One key characteristic of pyrazinamide is its ability to inhibit semidormant bacilli
residing in acidic environments .
 Pyrazinamide is a structural analogue of nicotinamide and is pro-drug that needs to be
converted into its active form, pyrazinoic acid, by the enzyme pyrazinamidase (PZase). PZA
is only active against M. tuberculosis at acidic pH.Hypersensitivity reactions and
gastrointestinal upset may occur with PZA administration.
4. Ethambutol
 Ethambutol (EMB) [dextro-2,2’-(ethylenediimino)di-1-butanol], which is an essential first-
line drug in tuberculosis treatment, plays an important role in the chemotherapy of drug-
resistant TB . EMB is a bacteriostatic agent that is active for growing bacilli and has no
effect on non-replicating bacilli. EMB interferes with the biosynthesis of cell wall
arabinogalactan .It inhibits the polymerization of cell-wall arabinan of arabinogalactan and
of lipoarabinomannan, and induces the accumulation of D-arabinofuranosyl-P-decaprenol,
an intermediate in arabinan biosynthesis .
 The most common side effects observed with ethambutol are dizziness, blurred vision,
color blindness, nausea,vomiting, stomach pain, loss of appetite, headache, rash, itching,
breathlessness, swelling of the face, lips or eyes, numbness or tingling in the fingers or toes.
Patients taking ethambutol should have their visual acuity and color vision checked at least
monthly.
5. Streptomycin
 Streptomycin (SM), an aminocyclitol glycoside antibiotic, was the first drug to be used in
the treatment of TB, in 1948 .SM kills actively growing tubercle bacilli ,but it is inactive
against non-growing or intracellular bacilli . The drug binds to the 16S rRNA, interferes with
translation proofreading, and thereby inhibits protein synthesis.Ototoxicity and
nephotoxicity are associated with SM administration.

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 Recommended Adult dosage Recommended pediatric Dosage

FIRST LINE
TB DRUGS Daily Dose range Maximum (mg) Daily Dose range Maximum (mg)
(mg/kg body weight) (mg/kg body weight)

Isoniazid 5(4-6) 300 10 (7-15) 300

Rifampicin 10(8-12) 600 15 (10-20) 600

Pyrazinamide 25(20-30) - 35 (30-40) -

Ethambutol 15(15-20) - 20 (15–25) -

Children weighing 25kg and more can be treated using recommendation for adults.

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 Second-line antituberculosis drugs
1. Fluoroquinolones
 The fluoroquinolones (FQs) have broad-spectrum antimicrobial activity and so are widely
used for the treatment of bacterial infections of the respiratory, gastrointestinal and
urinarytracts, as well as sexually transmitted diseases and chronic osteomyelitis .In contrast
tomany other antibiotics used to treat bacterial infections, the FQs have excellent in vitro
and invivo activity against M. tuberculosis.
 FQs include ciprofloxacin, ofloxacin, levofloxacin,and moxifloxacin. So, FQs are currently in
use as second-line drugs in the treatment of TB. The cellular target of FQs in M. tuberculosis
is DNA gyrase, a type II topoisomerase consisting of two A and two B subunits encoded by
gyrA and gyrB genes, respectively.
 Adverse effects are relatively infrequent and include gastrointestinal intolerance, rashes,
dizziness, and headache. Most studies of fluoroquinolone side effects have been based on
relatively short-term administration for bacterial infections, but trials have now shown the
relative safety and tolerability of fluoroquinolones administered for months during
TB treatment in adults.
2. Aminoglycosides (kanamycin, amikacin and capreomycin)
 The aminoglycosides amikacin (AMK)/kanamycin (KAN) and the cyclic polypeptide cap‐
reomycin (CAP) are important injectable drugs in the treatment of multidrug-resistant
tuberculosis. AMK/KAN and CAP primarily affect protein synthesis in M. tuberculosis .
Although belonging to two different antibiotic families, all exert their activity at the level of
protein translation. Renal toxicity occurs from these drugs. Regular monitoring of hearing
and renal function is recommended.
3. Ethionamide/prothionamide
 Ethionamide (ETH, 2-ethylisonicotinamide) is a derivative of isonicotinic acid and has been
used as an antituberculosis agent since 1956. Ethionamide and the similar drug
prothionamide (PTH, 2-ethyl-4-pyridinecarbothioamide) act as prodrugs, like isoniazid and
inhibits the same target as INH, the InhA of the mycolic acid synthesis pathway .Once
delivered into the bacterial cell, ethionamide undergoes several changes. Its sulfo group is
oxidized by flavin monooxygenase, and the drug is then converted to 2-ethyl-4-
aminopyridine. The intermediate products formed before 2-ethyl-4-aminopyridine seem to
be toxic to mycobacteria, but their structures are unknown (may be highly unstable
compounds). ETH frequently causes gastrointestinal side effects, such as abdominal pain,

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 nausea, vomiting and anorexia. It can cause hypothyroidism, particularly if it is used with
para-aminosalicyclic acid.

4. p-Amino salicylic acid

 p-Amino salicylic acid (PAS) was one of the first antibiotics to show anti-TB activity and was
used to treat TB in combination with isoniazid and streptomycin .Later, with the discovery
of other more potent drugs including rifampicin, its use in first line regimens was
discontinued.PAS is still useful as part of a treatment regimen for XDR TB although its
benefit is limited and it is extremely toxic. Thymidylate synthase A, encoded by thyA, an
enzyme involved in the biosynthesis of thymine, has been proposed recently as the target
of PAS in M. bovis BCG.
5. Cycloserine
 Cycloserine (CS) is an antibiotic that is used to treat TB. The exact mechanism of action of
cycloserine is unknown, but it is thought to prevent the tuberculosis bacteria from making
substances called peptidoglycans, which are needed to form the bacterial cell wall. This
results in the weakening of bacteria’s cell wall, which then kills the bacteria. But it causes
adverse psychiatric effects; which is its main drawback. So,psychiatric interrogation is
necessary before prescribing cycloserine drug.

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Treatment in Special Situations

A. Infection with Human Immunodeficiency Virus

 An important consideration in treating tuberculosis in patients with HIV infection
is the potential for interactions of antituberculosis agents, especially the rifamycins, with
other drugs, especially the protease inhibitor class of antiretroviral agents. The most
practical means of minimizing the effects of the interactions is to use an antiretroviral
regimen that excludes protease inhibitors and consists of two nucleoside reverse
transcriptase inhibitors plus efavirenz (because animal studies suggest a possibility of
congenital abnormalities with efavirenz, pregnant women should be treated with
nevirapine.), and rifabutin, although much more expensive, should be used in place of
rifampin.
B. Pregnancy and Breast-feeding
 In a pregnant woman or a mother of a young infant, it is important that the most effective
therapy for tuberculosis be given. Thus, treatment should be initiated with isoniazid,
rifampin, and ethambutol. Pyrazinamide is included in WHO’s recommendations for
treating tuberculosis in pregnant women.
C. Other Associated Conditions
 In patients with impaired renal function, streptomycin, kanamycin, amikacin, and
capreomycin should be avoided if at all possible or given two to three times a week in
the usual dose. If there is severe impairment of renal function, reduction in the frequency
of administration of ethambutol and pyrazinamide to two to three times a week may be
necessary . The drugs should be administered after hemodialysis.
 Liver disease, particularly alcoholic hepatitis and cirrhosis, is common among
patients with tuberculosis. For isoniazid, rifampin, and pyrazinamide, there is an increased
frequency of hepatotoxicity in the presence of preexisting liver disease

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 3) Principles of TB treatment
I. For initial empiric treatment of TB, start patients on a 4-drug regimen: isoniazid, rifampin, pyrazinamide,
and either ethambutol or streptomycin. Once the TB isolate is known to be fully susceptible, ethambutol
(or streptomycin, if it is used as a fourth drug) can be discontinued.
II. After 2 months of therapy (for a fully susceptible isolate), pyrazinamide can be stopped. Isoniazid plus
rifampin are continued as daily or intermittent therapy for 4 more months. If isolated isoniazid resistance is
documented, discontinue isoniazid and continue treatment with rifampin, pyrazinamide, and ethambutol for
the entire 6 months.
III. Therapy must be extended if the patient has cavitary disease and remains culture-positive after 2 months of
treatment.
IV. Directly observed therapy (DOT) is recommended for all patients. With DOT, patients on the above
regimens can be switched to 2- to 3-times per week dosing after an initial 2 weeks of daily dosing. Patients
on twice-weekly dosing must not miss any doses.
V. Dosages should be calculated based on weight.
VI. All TB medication should be ingested together at the same time daily.
VII. Children are treated like adults with dose adjustment.

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DRUG RESISTANT TB

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 TB classification based on sensitivity to drugs
 Drug resistance is defined as a decrease in the in-vitro susceptibility of M. tuberculosis of a
sufficient degree to be reasonably certain that the strain concerned is different from a wild
strain that has never come into contact with the drug.
 A drug resistant isolate can be categorized as single drug resistant or multi-drug
resistant(MDR). It can be further categorized as exhibiting primary or secondary (acquired)
resistance. In primary resistance,the patient from whom the isolate is obtained has never
received any of the anti-tuberculosis drugs. In secondary resistance, the patient has been
previously treated for tuberculosis with the specific drug(s) to which the isolate is resistant .
 Acquired resistance may thus be found in culture positive cases in the following categories:
patients with treatment failure,patients who relapse after successful completion of
treatment and those who return after treatment interruption .

First line drug resistance

I. Isoniazid (INH)
INH is a prodrug that requires activation to an unstable electrophilic species by the
catalaseperoxidase katG of MTB, encoded by katG gene. . KatG is the only MTB enzyme
capable of activating this drug. As a result, katG-mutant MTB strains are INH resistant.
II. Streptomycin (SM)
The mode of action of SM against mycobacterial species is through its binding to the 30S
ribosomal subunit, which affects polypeptide synthesis and which ultimately leads to
inhibition of translation. M. tuberculosis becomes resistant by mutating the target of SM
in the ribosomes.The principal site of mutation is the rpsL gene, encoding the ribosomal
protein S12. The loops of 16S rRNA that interact with the S12 protein constitute a
secondary mutation site.
III. Ethambutol (EMB)
Ethambutol is a specific anti tubercular bactericidal agent used in most modern
combination therapy. Resistance to ethambutol is associated with changes in a defined
genomic region, the embCAB, which encodes arabinosyltransferases involved in the
synthesis of unique mycobacterial cell wall components, arabinogalactan and
lipoarabinomannan.
IV. Pyrazinamide
Susceptible strains of MTB produce the enzyme pyrazinamidase, which converts pyrazina‐
23
 mide (PZA) to pyrazinoic acid, the putatively active moiety. Resistance to PZA is usually
accompanied by loss of pyrazinamidase activity in MTB.

Second line drug resistance

I. Fluoroquinolones
 Ciprofloxacin (CIP) and ofloxacin (OFX) are synthetic derivatives of nalidixic acid that are
currently used as second –line or alternative TB drugs. These FQ drugs are bactericidal
against M. tuberculosis. Their target is DNA gyrase an ATP-dependent type II DNA topoiso‐
merase that catalyzes negative supercoiling of DNA. FQ resistance develops rapidly when
used alone against M. tuberculosis or when as a single drug to a failing therapy. Clinical
isolates of M. tuberculosis with acquired resistance to FQs are usually resistant to RIF and
one or more other first line drugs. Mutations associated with high level FQ resistance are
clustered in a short region of 40 aminoacids in gyrA referred to as the quinolone resistance
determining region (QRDR).
II. Kanamycin (KAN), Amikacin (AMI), Viomycin (VIO) and Capreomycin (CAP)
 KAN and AMI are aminoglycoside antibiotics that inhibit protein synthesis by inhibiting the
normal function of ribosomes. VIO and CAP are basic peptide antimicrobial agents that also
inhibit protein synthesis. These drugs are used as second-line anti-TB agents. Resistance to
KAN, AMI, VIO, and CAP is relatively uncommon in clinical isolates, presumably because
these drugs are used relatively rarely to treat TB. As is the case for FQs, most organisms
resistant to these drugs are also resistant to several first-line agents [9]. human
M.tuberculosis strains resistant to KAN and AMI and judged to be distinct by IS6110
subtyping.
III. Cycloserine
 D- cycloserine (DCS) is a second-line antiTB drug. This agent is a cyclic structural analog of
D-alanine that inhibits cell wall synthesis . Although an effective antimycobacterial agent,
its use is limited by adverse side effects, including neurologic reactions . The molecular
genetic bases of resistance in M. tuberculosis is unknown, but a study provided potentially
important insights as they founded that D-alanine recemase gene
was necessary and sufficient to confer cycloserine resistance to this
organism.

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 Multidrug-Resistant Tuberculosis (MDR-TB)
 MDR-TB strains generally considered to be those resistant to at least INH and RIF.
These strains have been described worldwide, and their existence poses a serous threat
to TB control programs in many countries . The frequency of resistance to multiple
drugs varies geographically, and acquired (secondary) resistance is more common than
primary resistance.
 In principle, MDR-TB strains could arise as a consequence of sequential accumulation of
mutations conferring resistance to single therapeutic agents or by a single step process
such as acquisition of an MDR element, or mutation that alters (for example) cell wall
structure.
 Currently, there is no evidence that processes commonly mediating multidrug resistance in
other bacteria, such as conjugal transfer of plasmids encoding combinations of resistance
genes or transfer of transposable elements with resistance genes occur in M. tuberculosis.

Extensively drug-resistant tuberculosis (XDR-TB)

 XDR-TB is TB caused by Mycobacterium tuberculosis (M. tuberculosis) strains that fulfil the
definition of MDR-TB and which are also resistant to any fluoroquinolone and at least one
additional Group A drug (Group A drugs are the most potent group of drugs in the ranking
of second-line medicines for the treatment of drug-resistant forms of TB using longer
treatment regimens and comprise levofloxacin, moxifloxacin, bedaquiline and linezolid).

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EXTRAPULMONARY
TB

26
 5. EXTRA PULMONARY TB

Extra pulmonary involvement occurs in one fifth of all TB cases; 60% of patients with
extrapulmonary manifestations of TB have no evidence of pulmonary infection on chest
radiographs or in sputum cultures. The most common types of extra-pulmonary tuberculosis
are:

I. MILIARY TB
 Miliary tuberculosis (TB) is the widespread dissemination of Mycobacterium tuberculosis
via hematogenous spread. Classic miliary TB is defined as milletlike (mean, 2 mm; range, 1-
5 mm) seeding of TB bacilli in the lung, as evidenced on chest radiography. This pattern is
seen in 1-3% of all TB cases.
 Miliary TB may occur, in several organs, or throughout the entire body (>90%), including
the brain. If the brain is involved, neurological symptoms may include headache, reduced
consciousness and cranial nerve palsies. The infection is characterized by a large amount of
TB bacilli, although it may easily be missed and is fatal if left untreated.
 Miliary TB may mimic many diseases. In some case series, up to 50% of cases are
undiagnosed antemortem. Therefore, a high index of clinical suspicion is important to
obtain an early diagnosis and to ensure improved clinical outcomes.

II. Pleural Tuberculosis

 Between 3 and 25 % of TB patients will have tuberculous pleuritis or pleural TB. As with all
forms of extrapulmonary TB, incidence is higher in HIV-infected patients. Typical
presentation is acute with fever, cough and localized pleuritic chest pain. It may follow
recent primary infection or result from reactivation. If part of primary infection, the
effusion may be self-limiting. However, if it occurs in pregnancy it signals a potential risk to
foetus, since recent primary infection is frequently associated with the occult
dissemination.
 TB pleural effusions are usually unilateral and of variable size. Approximately 20 % of
patients have concurrent parenchymal involvement on chest X-ray, however CT-scans have
higher sensitivity and may detect parenchymal lesions in up to 80 % of patients . HIV
infected patients may present with atypical symptoms, often with less pain and longer
duration of illness and more generalized signs.

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  Pleural fluid is mostly lymphocytic with high protein content. Bacillary load is generally low
and smear is typically negative, although this may be higher in HIV positive patients, in
whom diagnostic yield from smear may be as high as 50 %. Elevated levels of adenosine
deaminase (ADA) may be indicative; sensitivity and specificity estimates from a meta-
analysis of published studies were 92 and 90 % respectively, with a cut-off value of 40U/l.
Finding on clinical examination may include; tracheal and mediastinal shift from the side of
the effusion, decreased chest movement with stony dullness on percussin on the side of
the effusion.

III. Central Nervous System Tuberculosis

 The most common clinical manifestation of central nervous system (CNS) TB is tuberculous
meningitis (TBM). Other entities are CNS tuberculoma, which may be present without
symptoms or rarely with seizures, tuberculous encephalopathy (rare, only described in
children) and tuberculous radiculomyelitis. Pathogenesis is thought to be through a two-
step process, in which heamotogenous spread leads to a tuberculous focus (Rich focus) in
the brain, which then invades and release bacilli in the subarachnoid space. is the most
lethal form of TB.Early recognition and appropriate treatment are key to improved
outcome. Early symptoms are non-specific. In the more advanced stages patients become
more confused, present with reduced consciousness, hemiplegia, paraplegia and urinary
retention (seen with spinal involvement) and cerebral nerve palsies, most frequently
involved is nerve VI (up to 40 % of cases), but also III and VII.
 Seizures often reported in children (50 % of TBM cases).
 Diagnosis is often based on a clinical algorithm rather than mycobacterial isolation.
 In contrast to pulmonary TB where sputum smear is less often positive in HIV-infected
individuals, CSF is more often positive in HIV-infected individuals with TBM.
IV. Tuberculous Pericarditis
 Cardiac TB most frequently involves the pericardium. TB endocarditis or involvement of the
myocardium is extremely rare. Clinical progression is characterized by insidious onset,
classically with a presentation with fever of unknown origin. Upon examination a
pericardial friction rub may be auscultated. ECG changes consist of diffuse ST elevations,
without reciprocal changes, T wave inversion, PR segment deviations. Typical changes as
found in acute pericarditis (The PR-segment deviation and ST-segment elevation) are only
found in roughly 10 % of cases .

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  Usually the rise in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are
less marked compared to the same parameters measured in viral or bacterial
pericarditis.Echocardiogram is central in diagnosis, revealing effusion and if present,
tamponade. Confirmation of diagnosis is by demonstration of AFB in the pericardial
aspirate by smear.
 In pericardial TB the sensitivity of smear is 15–20 % and of mycobacterial culture 30–75 % .
The presence of cardiac tamponade is the most predictive sign of later development of
constrictive pericarditis.

V. SKELETAL TB
 The most common site of skeletal TB involvement is the spine (Pott disease); symptoms
include back pain or stiffness. Lower-extremity paralysis occurs in up to half of patients
with undiagnosed Pott disease.
 Tuberculous arthritis usually involves only 1 joint. Although any joint may be involved, the
hips and knees are affected most commonly, followed by the ankle, elbow, wrist, and
shoulder. Pain may precede radiographic changes by weeks to months. It is seen both in
children and adults and can be severe, with neurological sequelae.
 Inmany cases more than one intervertebral disc is involved. It is characterized by loss of
bone density and slow bone erosion, with the disc space being maintained for a long time
(differentiating it from pyogenic infections). Involvement of the thoracic vertebrae causes
localized back pain, deformity of the spine, and in extreme cases an angulated kyphosis
(gibbus). Spread may occur into the soft paravertebral tissue to form a so-called “cold
abscess”.
VI. Extra-Thoracic Lymph node Disease
 Cervical lymphadenitis (scrofula) is the most common form of extra-pulmonary TB. In the
middle-ages it was known as ‘the King’s evil’ because it was believed the touch of royalty
could cure the disease. Before the pasteurization of milk, the more likely causative agent
was Mycobacterium bovis, which is non-distinguishable from M. tuberculosis on ZN stain.
Some non-tuberculous mycobacteria (NTM) are known to cause lymphadenitis.
 Mycobacterium avium-intracellular complex is the most common causative agent . The
route of entry is thought to be through ingestion, via the oropharyngeal mucosa or tonsils,
or through skin abrasions.
 The most common site is the cervical region, followed by mediastinal, axillary, mesenteric,
hepatic portal, peripancreatic, and inguinal lymphnodes. Lymph node involvement may
follow first-time infection as part of the primary (Ghon) focus, with subsequent
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 haematogenous or lymphatic spread, with reactivation of a dormant focus or with direct
extension of a contiguous focus.
 The patient usually presents with a palpable (lymph node) mass greater than 2 × 2 cm and
mostly in the cervical area (60 %), either in the jugular, posterior triangle or supraclavicular
region, with or without fistula or sinus formation . Other complications are overlying
violaceous skin inflammation and cold abscess formation. Tenderness or pain is not
typically described, unless there is secondary bacterial infection. Generalised constitutional
symptoms and pulmonary symptoms or signs may be absent, but are more often reported
in HIV-infected patients.

Other Forms of Extra-Pulmonary Tuberculosis

 Tuberculous arthritis, almost always affects only a single joint, usually the hip and knee. It
can be diagnosed by examination of synovial fluid or synovial tissue biopsies.
 Gastrointestinal TB may mimic Crohn’s disease, both clinically and radiographically.
Preferred sites are the ileocecum, ileum and jejunum and is usually associated with
peritonitis. Barium contrast studies can reveal ulceration, strictures, bowel wall thickening,
skip lesions and fistulae. In endemic countries, diagnosis is usually made on clinical
suspicion. Biopsies may be useful in establishing the diagnosis.
 Urogenital TB is notoriously asymptomatic. TB of the urinary tract, occasionally causes flank
pain or present with a renal or pelvic mass. Persistent “sterile” pyuria on urine analysis,
especially early morning samples, require further investigation with urine AFB smear, PCR
and culture. Further investigations include intravenous urography.
 Laryngeal TB is one of the most infectious forms of TB. Sputum smear is reported positive
in up to 70 % of cases. It can result from primary infection with infected droplet nuclei or
secondary to pulmonary disease. Hoarseness and dysphagia can be among the presenting
signs. Laryngeal TB can be primary, when bacilli directly invade the larynx or secondary
from bronchial spread of advanced pulmonary TB. It presents with hoarseness and
dysphagia, or chronic cough if associated with pulmonary TB . It should be differentiated
from laryngeal malignancy.

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 fig .Tuberclosis arthritis in a 2yrs old toddler

Fig .Spinal tuberculosis

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Fig. CNS tuberculosis

Fig . miliary tuberclosis

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REFERENCE

1. Guidelines for clinical and programmatic management of TB, TB HIV DR-TB and Leprosy in
Ethiopia 7th edition
2. Tuberculosis in Adults and children by Dorothee Heemskerk and Maxine Caws
3. Tuberclosis ,The essentials by Mario C.Raviglione
4. Tuberclosis,current issues in diagnosis and management by Bassam H. Mahboub and
Mayank G. Vats
5. WHO consolidated guidelines on tuberculosis
6. www.medscape.com

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