DRUG RESISTANCE

TUBERCULOSIS

group F/cmc/microbiology/drug resistance in tuberculosis

 Clinical
case
A 12-year-old boy complained of low-grade fever and mi ld
headache for the previous two weeks, which worsened over the last
two days. He also had vomiting, confusion and stiffness in the neck,
for which his parents sought medical attention. History revealed that
his father was a known case of pulmonary TB but had defaulted on
treatment CSF examination showed a mild increase in cell counts
with predominant lymphocytes. Proteins were raised and glucose
was low. ZN or Gram stain of CSF did not reveal any organisms. PCR
assay of the CSF targeting the unique sequence of M. tuberculosis
was positive. Two weeks later, the culture by automated system was
also positive for this organism. A drug sensitivity test showed that
the strain was resistant to rifampicin and INH. He was treated with
second-line drugs, Ofloxacin, PAS Cycloserine and Ethionamide

group F/cmc/microbiology/drug resistance in tuberculosis

Mycobacteria are slender rod bacteria that
stained with special differential stains
(Ziehl-Neelsen). the most important
mycobacteria are the tuberculosis bacteria
(TB)M. tuberculosis and M. bovis and
leprosy pathogen (LB) M.leprae PRESENTER NAME
Morphology and culturing TB are slender,
acid-fast rods, nonsporing and nonmotile.
They can be stained with special agents
(Ziehl-Neelsen
Ziehl-Neelsen staining of a urine
preparation Culture of M. tuberculosis
 Tuberculosis
• Tuberculosis is a potentially fatal infection, caused mainly by M.tuberculosis complex
(MTC), that affect any part of the body, with lungs being the most common organ
involved.
• the tubercle bacilli establish infection in the lungs after they are carried in droplets
small enough (5 to 10 microns) to reach the alveolar spaces. If the defense
system of the host fails to eliminate the infection, the bacilli proliferate inside
alveolar macrophages and eventually kill the cells. The infected macrophages
produce cytokines and chemokines that attract other phagocytic cells, including
monocytes, other alveolar macrophages and neutrophils, which eventually form a
nodular granulomatous structure called the tubercle.
• Unchecked bacterial growth may lead to haematogenous spread of bacilli to
produce disseminated TB. Disseminated disease with lesions resembling millet
seeds is termed miliary TB. Bacilli can also spread by erosion of the caseating
lesions into the lung airways -and the host becomes infectious to others. In the
absence of treatment, death ensues in 80 per cent of cases 
group F/cmc/microbiology/drug resistance in tuberculosis
Antigenic properties

The mycobacterial
Lipids: These induce Group specificity is

Proteins:

Polysaccharides:
cell wall is rich in delayed type due to
l9ngchain fatty acids hypersensitivity and polysaccharides.
called mycolic acid. elicit tuberculin Their role in
Mycolic acids play a reaction. pathogenesis is not
role in pathogenesis clear but they can
and, when induce immediate
complexed with type of
peptidoglycan, are hypersensitivity
responsible for
granuloma
formation.

group F/cmc/microbiology/drug resistance in tuberculosis

The goals of antitubercular chemotherapy are:

Kill dividing bacilli Drugs
with early bacteric idal
action
Prevent emergence of
Kill persisting bacilli To
resistance So that the
effect cure, sterilize the
bacilli remain
patient
susceptible to the drugs.

group F/cmc/microbiology/drug resistance in tuberculosis

Drug used for treatment of Tuberculosis
First line drugs Second line drugs
Isoniazid
Rifampin Fluoroquinolones
Pyrazinamide Ethambutol Ethionamide Prothionamide Cycloserine(oral drugs )
Streptomycin Kanamycin Amikacin Capreomycin (Injectable drugs)

group F/cmc/microbiology/drug resistance in tuberculosis

TYPE OF DRUG RESISTANCE
TYPE OF DRUG RESISTANCE

1.Drug-sensitive TB: The patient's bacilli are susceptible to all 5 first line anti-TB drugs (ATDs). All new TB patients who
have never taken any ATD or have taken them for less than one month are presumed to have drug-sensitive TB.

2. Mullidrug resistant TB (MDR-TB): The patient's bacilli are resistant to both R and H with or without resistance to any
number of other I st line drugs.

3. Rifampin resistant TB (RR-TB): The patient's bacilli are resistant to R but not to H, with or without resistance to
other ATDs. These patients are to be treated as if they have MDR-TB.

4. Mono-resistant TB: The bacilli are resistant to one ) st line ATD, but not R-resistant.

5. Poly-drug resistant TB (PDR-TB): The patient's bacilli are resistant to more than one 1st line ATD, except both R and
H resistance.

6. Extensive drug resistant TB (XDR-TB): A MDR-TB case whose bacilli are additionally resistant to a FQ and one 2nd
line injectable ATD.
group F/cmc/microbiology/drug resistance in tuberculosis
 Isoniazid Rifampin Pyrazina Ethambutol Streptomycin REMARK
mide

Drug-sensitive TB nr nr nr nr nr

Mullidrug resistant TB (MDR- R R nr nr nr

TB

(RR-TB): R nr nr nr nr
Mono-resistant TB May be R nr May be R May be R May be R Only one

Poly-drug resistant TB (PDR- nr nr May be R May be R May be R

TB)

Extensive drug resistant TB R R R R R R to other as

well

group F/cmc/microbiology/drug resistance in tuberculosis

Drug resistance can be:

• Primary (pre-treatment, initial), when the patient is infected

with a strain of the tubercle bacilli which is already resistant,

• Acquired (secondary, post-treatment), when the infecting

strain initially sensitive becomes resistant, usually as a result of
improper or inadequate treatment. This is the more common
type of resistance
group F/cmc/microbiology/drug resistance in tuberculosis
When to suspect drug resistance?
• Persistent sputum positivity
• Fall and rise phenomenon of sputum of AFB
• Clinical and or radiological deterioration in positive sputum
• When patient misses the doze
• When there is relapse of TB.
• Low completion/cure rates
• Lack of treatment follow up and patient support
• Unreliable drug supply
• Diagnostic delay
• Absent or inadequate infection control measures
• Uncontrolled use of 2nd line drugs
group F/cmc/microbiology/drug resistance in tuberculosis
Drug susceptibility test:

CONVENTIONAL CULTURE-BASED METHODS Using standardized DST procedures with conventional methods, eight to 12
weeks are required to identify drug-resistant microorganisms on solid media (ie, Lowenstein-Jensen medium

Proportion method The proportion method allows precise determination of the proportion of resistant mutants to a certain drug; the
resistance ratio method compares the resistance of an unknown strain with that of a standard laboratory strain.

Conventional Methods are Outdated In addition, delayed identification of drug resistance results in inadequate treatment, which may
generate additional drug resistance and continued transmission in the community.

LIQUID CULTURE-BASED METHODS The BACTEC 460 TB radiometric system (Becton Dickinson, USA) was considered to
be a major advancement when it was introduced, but has been replaced by the Mycobacteria Growth Indicator Tube system (detection
of resistance to first- and second-line anti-TB drugs) . Detection of drug resistance can be accomplished in days rather than weeks,
although still constrained by high cost (equipment and consumables).

group F/cmc/microbiology/drug resistance in tuberculosis

group F/cmc/microbiology/drug resistance in tuberculosis
TREATMENT OF DRUG
RESISTANT TB

group F/cmc/microbiology/drug resistance in tuberculosis

group F/cmc/microbiology/drug resistance in tuberculosis
 Multi Drug Resistance
Intensive phase (6- 9 months) Continuation phase (18 months)
1. Kanamycin (Km) ) 1. Levofloxacin
2. 2. Levofloxacin (Lfx) \\ 2. Ethionamide
3. 3. Ethionamide (Eto) 3. Cycloserine
4. 4. Cycloserine (Cs) 4. Ethambutol + Pyridoxine 100 mg/day
5. 5. Pyrazinamide (Z)
6. 6. Ethambutol (E

group F/cmc/microbiology/drug resistance in tuberculosis

(RR-TB):
Mono-resistant TB
Poly-drug resistant TB (PDR-TB)
Extensive drug resistant TB
the intensive phase of 6 months has 7 drugs (Km, Lfx, the continuation phase ( 18
Eto, Cs, Z, E and I-1), months) has 5 drugs (Lfx, Eto, Cs, E
and H).
R + two of the I 51 line drugs to which bacilli are nr
sensitive + one injectable second line drug + one FQ to
make a total of 5 drugs given daily in the intensive
phase of 3- 6 months.
R + one injec table 2 nd line drug + o ne FQ + any I st In the continuation phase for both
line drug to which the bacilli are sensitive - one of the mono and poly drug resistant TB,
oral 2nd line drugs (Eto/Cs/ PAS). The duration of the inj ectable drug is stopped while
intensive phase is 3- 6 months. the remaining 4 oral drugs are
continued for a fixed duration o f 6
months. Thus, the total duration of
regimens for mono and po ly drug
resistant TB is 9- 12 months.
The RNTCP (201 6) has recommended a treatment 6 drugs in the continuation phase
regimen for XDR-TB consisting of 7 drugs in the ( 18 months).
intensive phase (6-12 months)
group F/cmc/microbiology/drug resistance in tuberculosis
 Drug single drug
sensetivity resistance

Pre-
Poly drug
antibiotic
resistance
era

Extensive
Multi drug
drug
resistance
resistant

group F/cmc/microbiology/drug resistance in tuberculosis

 Clinical
case
A 12-year-old boy complained of low-grade fever and mi ld
headache for the previous two weeks, which worsened over the last
two days. He also had vomiting, confusion and stiffness in the neck,
for which his parents sought medical attention. History revealed that
his father was a known case of pulmonary TB but had defaulted on
treatment CSF examination showed a mild increase in cell counts
with predominant lymphocytes. Proteins were raised and glucose
was low. ZN or Gram stain of CSF did not reveal any organisms. PCR
assay of the CSF targeting the unique sequence of M. tuberculosis
was positive. Two weeks later, the culture by automated system was
also positive for this organism. A drug sensitivity test showed that
the strain was resistant to rifampicin and INH. He was treated with
second-line drugs, Ofloxacin, PAS Cycloserine and Ethionamide

group F/cmc/microbiology/drug resistance in tuberculosis

Group members:

• Obada Ansari
• Aslam Ali
• Manju Tamang
• Manish Gupta
• Mandil Adhikari
• Mala khatri
• Kriti kc
• Krishna Chandra das

group F/cmc/microbiology/drug resistab=nce in tuberculosis

 THANK YOU

group F/cmc/microbiology/drug resistance in tuberculosis