1. • Drug resistance mechanisms in Mycobacterium TB
started if there is Inhalation of Mtb. The next
mechanism Are
• Phagocytosis of bacilli
• Inflammatory cell recruitment
AM secreted IL-12 and IL-18
IFN-γ induce bacterial killing
TNF-α is essential in the control of Mtb growth and
granuloma formation
• Control of mycobacteria growth
• Stops Mtb proliferation
• Chronic cytokine stimulation
• Granuloma is formed by several cells recruited to
• the lung. Inside, infected macrophages contain the Mtb
preventing their spread.
• Postprimary tuberculosis
Mycobacteria persistence
is associated to a failurein
the immune-surveillance
• Disease may reactivate
• Damage of nearby
bronchi
• Spreading of the Mtb to
other areas ofthe lung
2. • The primary step to treat drug resistance in Mycobacterium is to
understand the mechanisms involved in antibiotic resistance
Primary resistance results from infection with a drug-resistant strain,
whereas resistance that develops during therapy is referred to as
secondary or acquired resistance.
• Failure in TB treatment due to Drug resistance mechanisms in
Mycobacterium both Intrinsic drug resistance (newly acquired
mutations) antibiotic resistance and Acquired drug resistance
1. Acquired drug resistance
drug resistance in Mtb primarily emerges due to mutations in chromosome,
genes encoding drug targets or drug-activating enzymes, in response to
selection pressure of antibiotics
3. 2. Intrinsic drug resistance
The following are the mechanisms contributing to the overall intrinsic drug resistance in Mtb
1 Impermeability of cell envelope
• Mycobacterial cell envelope subdivides it into three distinct entities namely outermost layer
called capsule, cell wall and cell membrane. The periplasmic space separating the cell wall
from the membrane lipid bilayer protects the cells from environmental stresses and acts as
permeability barrier for antibiotics Furthermore, presence of wide array of lipids makes
the Mtb cell envelope extremely thick, highly hydrophobic and hinders the diffusion of
even hydrophobic molecules, which include antibiotics such as rifamycins,
macrolides, fluoroquinolones
2 Drug efflux
Drug efflflux pump proteins constitute an active efflux mechanism which expels the
drug molecules entering the bacterial cell. Upon exposure to isoniazid and rifampicin,
overexpression of Rv1258c was found in clinical MDR-TB isolates. Furthermore, point
mutations (V219A and S292L) were identifified in efflflux pump Rv1258c and in
conferring drug resistance in clinical isolates to multiple drugs including isoniazid,
pyrazinamide and streptomycin
4. 3 Drug degradation and modification
• Several enzymes produced by Mtb have evolved to
modify or degrade antibiotics.Bacterial transpeptidases
are enzymes involved in Peptidoglikan cross-linking and
thus, essential for cell wall synthesis.
4. drug target modification
• drug target modification which can prevent binding of
antibiotic to target site. These drugs bind to a specifific
site within 50S subunit of bacterial ribosomal RNA. and
prevent translocation of peptidyl-tRNA, thus inhibiting
protein synthesis and mycobacterial growth
5. • There are 6 categori of drTb Monoresistance: is caused by M. tb strains that are
resistant to one of antiTB drugs ex:isoniazid
• Polyresistance: is caused by M. tb strains that are resistant to more one of other
antiTB drugs (neither Rifampicinn nor Isoniazid)
• Rifampicin-resistant TB (RR-TB) is caused by M.Tb strains that are resistant to
rifampicin. RR-TB strains may be susceptible to isoniazid or resistant to it (i.e. MDR-TB),
or resistant to other first line or second-line TB medicines.
• Multidrug-resistant TB (MDR-TB) is caused by M. Tb strains that are resistant to at least
both isoniazid and rifampicin.
• Pre-XDR-TB defined as ‘MDR-TB with additional resistance to either a
fluoroquinolone or a second-line injectable drug’
• Extensively drug-resistant TB (XDR-TB) is TB that is resistant to any
fluoroquinolone and to at least one of three second-line injectable drugs (capreomycin,
kanamycin and amikacin), in addition to multidrug resistance.
• Totally DRTB has been used in the literature to refer to strains of M tuberculosis that
show in-vitro resistance to all medications that are available for Testing
6. • In high burden country the rate of DRTB is higher than low burden country
• Most people that were diagnosed with DR-TB had a history of having
received treatment for TB.
• risk factors include close contact to a patient with MDR-TB, and young age
• Socioeconomic or behavioural risk factors for MDR
• Poor access to high-quality health care
• the development of DR-TB in Abusers of alcohol might be associated
with its substantial role in failure rate among new TB cases.
• , WHO concluded that people living with HIV are facing the emerging threats of
drug resistant TB.
Risk factors for DRTB
7. Tb infection occur whenThe inhalation of at least one viable and
virulent M.Tb droplet nucleus must reach the alveolar macrophages
within the lung. And its depend on Cough strength and frequency, -
Presence of lung cavities, - Sputum viscosity -Ventilation, frequency and
duration of contact. hypertramission happened in prolonged
hospitalization, delayed diagnosis of drug resistance and poor
ventilation
From animal studi A cut-off time of 8 h for exposure, and need 12 to 18
month of contacts with The number of infectious doses was 340 m3 of
air are leading to effective TB transmission
8. • Patients , Health staff and visitors are factors favour disease transmission.
• The sources of transmission in hospitals can involve to Hypertransmitions if
Undetected, - Untreated TB - Patients with known TB, but unknown drug
resistance (receiving ineffective therapy)
• The important questions is Who is infectious?
Patient TB is still infectious When not treated with effective treatment, acid
fast bacilli Smear and culture did not convert and there are no clinical and
radiological improvement.
Smear sputum M.Tb positive more infectious than smear sputum M.Tb
negative whether culture M.Tb positive or negative
Contacts of patients with multidrug resistant tuberculosis were at higher risk
of tb infection than contacts exposed to drug sensitive tuberculosis
9. • DRTB Therapy consist of 2 regimen Standar regimen and
individualized
• the decision to use the newer recommended short course
versus individualized regimen in selected patients will be
dependent on several factors, including previous treatment,
local resistance profiles, patient acceptance, and the
requirement for proven or highly likely fluoroquinolone and
aminoglycoside isolate susceptibility, and absence of probable
or proven resistance to any of the components of the regimen
(except isoniazid)68 •
• What ever the duration of the regimen used, psychosocial and
financial support are crucial elements to maintain adherence •
Patients should be monitored for adverse drug reactions
10. Treatment outcome definitions for DRTB
• Died A TB patient who dies for any reason before starting or during the
course of treatment.
Lost to follow-upA TB patient who did not start treatment or whose treatment
was interrupted for 2 consecutive months or more.
Treatment failureLack of conversion by the end of the intensive phasea , or
bacteriological reversion in the continuation phase after conversion to
negative, or evidence of additional acquired resistance to fluoroquinolones or
second-line injectable drugs, or adverse drug reactions (ADRs)
11. • Cured Treatment completed as recommended by the national policy
without evidence of failure and three or more consecutive cultures
taken at least 30 days apart are culture negative after the intensive
phase. However, recurrences after treatment completion
would need to differentiate between relapse (disease caused
by the same strain) and re-infection caused by a different
strain.
• The definition of relapse and reinfection was based on comparison of
M. tuberculosis DNA fingerprint patterns using RFLP restriction
fragment length polymorphism analysis . More advanced methods
such as Whole Genome Sequencing (WGS) may be more powerful to
discriminate different strains.
12. the management of DR-TB patients remains highly challenging
due to the psyhosocial issues
• The long duration of DRTB treatment increase poor adherence
• Side effect : prolong QT from bedaquline an fluoroquinolone,
(depression, convulsions, consciousness, psychosis, suicide; ),
especially due to the cycloserine. Major adverse events related to
linezolid include anaemia, peripheral neuropathy, optic neuritis and
thrombocytopenia.
• Stigma in the context of MDR-TB negatively impacts the
patient in accessing healthcare facilities.The impact of stigma
reported has led to divorce, breakdown of family relationships
13. • Inability to work due to the side effects of the drugs and
therefore loss of income has been a major leading to
treatment default.
• Because of these barrier most of patient experiented
Treatment faulire and psychological distress and the status
remain infectious so the patient cannot return to work
14. • Monitoring therapy for DRTB patients
• - Clinical,
• - Laboratory
• - Microbiology and
• - Radiology.
• WHO guidelines suggest monthly sputum smear microscopy and
• culture as an adjunct to clinical monitoring of patients to assess
treatment outcome.
• in DRTB patient Modest specificity and the best maximum combined
sensitivity and specificity occurred between month 6 and month 10 of
treatment
15. .
In a situation of failure (e.g. when
- Smear and culture do not convert, Initial response with subsequent
culture reversion,
- The need for a regimen change because of adverse events or
acquired drug resistance (the treatment is not effective).
- Clinical and radiological indicators deteriorate
the patient is likely to be still infectious.
Colony numbers (in smear cultures) and time or cycles to positivity in molecular
detection can also be used to assess the treatment response in clinical trials, but not
for assessing infectiousness unless providing evidence of treatment failure
16. • A TB patient should be discharged from hospital if:
• There is no continuing clinical need for inpatient treatment
• Clinical improvement is observed after administration of
effective therapy
• Effective treatment has been ensured
• and continuity of care and DOT have been ensured in
outpatient, home or community settings.
• Effective treatment of TB can rapidly render patients
noninfectious, long before conversion of sputum acid-fast
smear or culture to negative occurs The median time to
convert sputum culture to a negative result was 38.5 days
• positive smear is not a contraindication for hospital
discharge.
17. HOSPITAL DISCHARGE CRITERIA
• Confirmed MDR-TB Prior to discharge from the hospital,
continuation of care and monitoring during the outpatient
phase of treatment must be ensured.
If patient
• Unable to produce sputum
• Overall symptoms have improved
Discharge decisions should be taken by a multidisciplinary
team
18. Criteria for hospital admission
• A proportion of cases still need to be admitted for medical
reasons, including
• Severe cases,
• Life threatening conditions,
• Comorbidities,
• Psychiatric problems,
• Adverse drug reactions and,
• For social reasons
20. • The rate of diagnosis of active TB in HCWs has consistently been
reported to be higher than that for the general population in a
number of studies conducted in countries with low and high TB
prevalence
• in low and middle-income countries , In these settings, drug-
resistant TB (DR-TB) also affects HCWs at a greater frequency
than the communities they serve.
• Clinical staff (nurses and doctors) appear to be at highest risk
21. TB among HCWs leads to :
- Worker absenteism,
- Disruption of health services,
- Loss of productivity.
22. Return to work Criteria for DR TB patients
• 1. Have had three negative AFB sputum smear results collected 8–24
hours apart (at least one of which should be an early morning
specimen)
• 2. Have responded to anti-TB treatment that should be effective
based on drug susceptibility testing results
• The assessment of whether TB patient is no longer infectious and can
return to work should be made by a physician who has expertise in
the management of TB.
• Return to work will be linked to medical certification that the
employee is no longer infectious and is not otherwise ill or
incapacitated for his or her usual work.
23. Patients with pulmonary DR TB can be considered non-infectious when:
1. They have received adequate chemotherapy for two to three weeks;
2. They show clinical improvement; and
3. There is a negligible chance of MDR-TB
• Dharmadhikari et al. and Finenelly et al concluded that the standard MDR-TB
treatment used in South Africa rapidly and effectively suppresses MDR-TB
disease transmission, regardless of the sputum smear and culture status
• rapid fall in infectiousness of patients after starting treatment, Loudon
theorized that evaporation of the droplet nuclei could increase the drug
concentration around bacilli
• This mechanism might inactivate the bacilli or hamper their capacity to
successfully infect human hosts
24. Mycobacterium tuberculosis as Biohazards
Precautions against airborne infection transmission are necessary because
biohazards, such as the Mycobacterium tuberculosis that causes TB, are
transmitted by airborne droplets.
WHO suggests that people deemed to be at a low risk of RR-TB and /MDR-
TB should be placed in single rooms and that those at a high risk should
ideally be accommodated in a negative-pressure room while rapid
diagnostic tests are urgently performed until effective treatment starts
Precautions against airborne infection transmission
are necessary because biohazards, such as the
Mycobacterium tuberculosis that causes TB, are
transmitted by airborne droplets.
WHO suggests that people deemed to be at a low
risk of RR-TB and /MDR-TB should be placed in
single rooms and that those at a high risk should
ideally be accommodated in a negative-pressure
room while rapid diagnostic tests are urgently
performed until effective treatment starts
25. Administrative controls more important to control DRTB infection
International Labour Office Health WISE Action Manual. 2014;1
• Control the spread of pathogens by using cough etiquette
• Reduce the time a person stays in a health facility and treat
promptly those infected
• Identify promptly and early people with TB symptoms, quarantinee
infectious patients.
• Train health workers TB signs, symptoms, prevention, treatment,
and infection control.
