MDR TB

DR KHALED HASSANIMO(RESPITARORY MEDICINE)

DMCH

• Multidrug-resistant TB (MDR-TB) is defined as TB resistant to at least the two most potent drugs against TB, isoniazid and rifampicin

• Although its causes are microbial, clinical and programmatic, MDR-TB is essentially a man-made phenomenon

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Definition and causes of MDR-TB

• Multidrug-resistant TB (MDR-TB) is defined as TB resistant to at least the two most potent drugs against TB, isoniazid and rifampicin

• Although its causes are microbial, clinical and programmatic, MDR-TB is essentially a man-made phenomenon

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Definition and causes of MDR-TB

M. tuberculosis ResistanceBasic Concepts

• Natural resistance• Resistance in previously treated patients• Resistance in previously untreated patients• Transient resistance• Poly-resistance

Basic Concepts Resistance of M. Tuberculosis

NATURAL Resistance

M. tuberculosis Resistance Natural Resistance (1)

- When all live species reach a certain number of divisions (in order to perpetuate the specie), they undergo genomic mutations at random, which gives rise to organisms with certain altered functions.

- This always occurs in the successive divisions of each species. It is therefore a dynamic function.

15 million

12 hours

M. tuberculosis Resistance Natural Resistance (2)

• Ever since M. tuberculosis has attacked humans, way back in time, it has always presented multiple genomic mutations in its continuous divisions

• Some of these mutations affect the genes in which anti-tuberculous drugs work

• This means that these antibiotics cannot work against M. tuberculosis, and therefore phenotypically, they show resistance to them

M. tuberculosis Resistance Naturally resistant mutants according to bacillary

population

• INH 1 x 105-106 Bacilli• RIF 1 x 107-108 Bacilli• SM 1 x 105-106 Bacilli• EMB 1 x 105-106 Bacilli• PZ 1 x 102-104

Bacilli ?• Quinolones 1 x 105-106

Bacilli ?• Others 1 x 105-106

Bacilli ?

M. tuberculosis Resistance Bacillary population in different TB lesions

• TB Sm+ 107-109 Bacilli• Cavitary 107-109 Bacilli• Infiltrated 104-107 Bacilli• Nodules 104-106 Bacilli• Adenopathies 104-106 Bacilli• Renal TB 107-109 Bacilli• Extrapul. TB 104-106 Bacilli

M. tuberculosis Resistance Selection of resistant mutants

• If Smear positive TB is treated with just ONE drug (H), for each million bacilli, it will kill 999,999, but it will select the resistant mutant (1 individual) that exists.

• If this TB has a minimum of 1,000 million (109) organisms, in 2-8 weeks it will have selected the 1,000 mutant bacilli (1 per million) that are resistant in this population

• These 1,000 bacilli are insufficient to cause clinical symptoms or to be smear +. Good clinical progression!

• The problem is that these 1,000 soon will be 109

Appearance of resistance to INH administered as Monotherapy

Resistant Mutants

Sensitive Bacilli

Months after Start of Treatment No. of viable bacilli

Mitchison DA. En: Heaf F, et al. Churchill, London, 1968

The fall and Rise Mechanism

Organisms in Pansusceptible

new case

Development (cre-ation)

Transmission (spread)

Development and Spread of Drug Resistance

INH,SM:10-5-6 RIF:10-6-7 EMB:10-4-5

New caseswith Primary drug resistance

Drug resistant mutants

Treatment failurewith Acquireddrug resistance

Programmatic Errors

Mismanagement Delay in diagnosis and treat-ment

Modified SJ Kim

M. tuberculosis Resistance PRIMARY or INITIAL Resistance

• If a person is infected by a patient with selected resistant mutants (Acquired R.), he/she may suffer TB with the same resistance pattern PRIMARY RESISTANCE

• Primary resistance is the one presenting in TB patients who have never received treatment (< 1 month)

• Initial R. is the same concept as primary R., but it is a practical term, and includes all patients who state they have never been treated (some do not remember, others lie)

Resistance in “previously untreated patients”

In TB, resistance is always the result of poor

individual or programmatic management of patients

The most Basic Concept in TB Resistance

M. tuberculosis Resistance

Fortunately, of the 4 mechanisms through which antimicrobial

resistance appears (mutation, transduction, transformation

and conjugation), M. TB only uses mutations

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Definitions: Drug Resistance

Resistance Cases

Definition

Mono resistance Resistant to only one Anti TB DrugExm: E or H or S resistance etc.

Poly resistance Resistant to more than one Anti TB Drug other than both H and R

Exm: HE or ES or SRE- resistance etc.

MDR-TB Resistant to at least both most potent Anti TB Drug, H and R

XDR-TB(Extensive

Drug –resistance)

Resistance to any fluoroquinolone, and at least one of three injectable second line drugs (Capreomycin, Kanamycin and

Amikacin), in addition to MDR-TB

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Definitions: Diagnostic Cat IV

Cases DefinitionConfirmed MDR-

TBTB resistant to at least both most potent Anti TB Drug, H and R

Suspected MDR-TB

Patient may be entered in Cat-IV register and can be started on Cat-IV treatment before MDR-TB is confirmed only the relevant health authority recommends

RR-TB Rifampicin Resistant detected by Gene Xpert

Definitions: As per Site

Cases DefinitionPulmonary TB Involving only the lung parenchyma

Extra Pulmonary TB

TB of organs other than the lungs

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Definitions: According to previous Anti TB Drug historyCases Definition

DR-TB New patients Patients who have never received anti-TB treatment, or who have

received anti-TB treatment for < 1 month.

DR-TB patients previously treated with only first-line drugs.

Patients who have been treated for 1 or > 1 month with only first-line

drugs. DR-TB patients previously treated with second-line drugs.

Patients who have been treated for 1 or > 1 month with one or more

second-line drugs, with or without first-line drugs.

Suspects of DR-TB1. Failures of Category I (remain positive Month 5 or starts Category I

as smear negative and becomes smear positive at month 2);2. Failures of Category II (remain positive Month 5 or 8); 3. Non-converters of Category I (remain positive at month 3);4. Non-converters of Category II (remain positive at month 4);5. All relapses (Category I and Category II); 6. All return after default (Category I and Category II); 7. Close contacts of MDR-TB patients with symptoms;8. All TB/HIV infected patients at the start of TB therapy;9. Others (Specify):………………………..

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Factors of inadequate anti-TB treatmentHealth care providers:inadequate regimens

Drugs:inadequate supply/quality

Patients:inadequate drug intake

Noncompliance with guidelinesPoor trainingNo monitoring of treatmentPoorly organized or funded TB control programme

Poor quality Unavailability of certain drugs (stock-outs or delivery disruptions)Poor storage conditionsWrong dose or combination

Poor adherenceLack of information Lack of money Lack of transportationAdverse effectsSocial barriersMalabsorptionSubstance dependency disorders

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Summary table of bacteriological examination

Test Sensitivity Time Additional time for DST

location

microscopy >5000 2h N/A NTRL,RTRL,DOTS centre

LJ (Solid culture) 100 cfu/ml 4 wk 6 wk NTRL,RTRL

MGIT(Lequid culture)

10 cfu/ml 10-12 days 12 days NTRL

Xpert 10 cfu/ml 2h N/A NTRL,RTRL,DOTS centre

LPA Only on smear positive

3 days N/A NTRL

Regimen• 8(km,Z,Ofx/Lfx,Eto,Cs)-Intensive Phase

• 12(Z,Ofx/Lfx,Eto,Cs)-Continuation Phase

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Hospitalization

• All patient should be hospitalized- where facility is designed for MDR TB

Reasons-

• To have an intensive time for patient education

• To document that patient is tolerating the drugs

• To make patient smear negative and less infectious

Re-admission

• Very sick,clinicaly and physically unfit to receive treatment at home

• Adherence problem• Severe adverse effect• Immobility

Discharge criteria

• Smear negative ( 2 sample one week apart)• Clinically improving• patient is tolerating the drugs• At least 4 wks of hospitalization• OPD is trained and ready to give

community/home based DOT

Laboratory monitoring scheduleBaseline Follow up

Sputum Smear microscopy Weekly until Smear negative ( 2 sample one week apart)Then monthly

culture Monthly-intensive phaseQuarterly- continuation phase

DST Any culture positive at or beyond 4 months

RFT Monthly-intensive phase

LFT 3 Monthly Who are at risk (alcoholics,HBV,HCV)

TSH 6 Monthly if getting PAS,ETO,PTO

Laboratory monitoring scheduleBaseline Follow up

CD4 6 Monthly

CBC As required

Audiometry Monthly-intensive phase

Weight Monthly

CXR 6 Monthly

Specific infectious control measures

• Implement NTP• Educate all health care provider• Restrict attendants presence a minimum• Separate Smear positive in ward• Separate HIV pt from MDR TB pt• Isolate treatment failure cases, XDR cases

Treatment of MDR TB in special situation