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Definitions:
• Drug Resistant Tuberculosis

Cases of T.B. caused by an isolate of TB resistant to one of the first line anti TB drugs

PRIMARY DRUG RESISTANCE (P.D.R)
PDR is defined as resistance to [link widoczny dla zalogowanych] one of the frontline drugs in person with TB who is not known to have previous treatment with ATT

NATURAL DRUG RESISTANCE IN WILD STRAINS (Spontaneous Mutation)
SECONDARY (ACQUIRED) DRUG RESISTANCE (A.D.R)
ADR is defined as acquiring increasing level of resistance to one or more drugs in a strain recovered from a patient undergoing ineffective therapy.

TRANSMITTED DRUG RESISTANCE (T.D.R)
TDR is said to have occurred when a single or multi drug resistant strain is recovered from patient who is high risk contact of other individual known to be shedding strain with comparable patterns of drug resistance

MULTI DRUG RESISTANCE (M.D.R)
MDR defined as resistance to two or more first line drugs. Now usually used when resistance to Rifampicin & INH is seen with or without resistance to other drugs.

[link widoczny dla zalogowanych] Cross Resistance:
Capreomycin & Viomycin
Thiacetazone & Ethionamide

Epidemiology US:
Prevalence decreasing in US b/c of effective measures.
1991 National survey of all TB cases revealed
PDR to 1 or more drugs in 13.4%
PDR to RH in 3.2 % [link widoczny dla zalogowanych] of Isolates
New York highest incidence 33 % of isolates 1 drug
26% to INH
19 % to RH

Epidemiology US:
In 1997 decreased to 10%
INH most common 8%
R 1.7%
S 5.9%
E 1.6%
RH 2.5%

Epidemiology UK:
GRANGES & YATES 1993 In South East ENGLAND
8.5% of Immigrant Indian subcontinent population with tuberculosis had drug resistance

Epidemiology World Wide:

Epidemiology Local:
• Rifampicin 10/125 8%
• INH 32/184 17.3%
• Ethambutol 11/124 8.8%
• Strep 8/59 13.5%
• Sensitive to all drugs 137/184 74.4%
• Resistant to 1 drug 35/184 19.8%
• Resistant to 2 drugs 9/184 4.8%
• Resistant [link widoczny dla zalogowanych] to 3 drugs 3/184 1.6%

Institue Of Chest Disease Kotri:
16.4 % Pts did not convert to 5 drugs suggesting high prevalence of resistance

At Ash 100 Isolates Of Patients In Relapse / Retreatment Group:
No of resistance cases 60 60%
Resistance to single drug 38 38% 63%
Resistance to two drugs 18 18% 30%
Resistance to three drugs 2 2% 3.3%
Resistance to four drugs 2 2% 3.3 %
INH Resistance 14 28% 46.6%
Rates of Primary MDR are [link widoczny dla zalogowanych] generally low; median 1.4%
Secondary MDR TB much more common median 13.0%
Highest proportion
Latvia 54%
South Korea 28%
[link widoczny dla zalogowanych] Russia 27.7%

Predisposing Factors:
• Type of bacterial Population
• Insufficient Concentration of Drug
• Patients Drug inactivation status

Patient Factors:
• Contact with resistant case
• Irregular drug intake
• Premature drug stoppage
• Poor absorption (Intestinal TB Excessive vomiting).
• Economic reasons.

Disease Factors:
• In Cavitatory TB
• Drug concentration fluctuates
• Higher no. of bacteria.
• PH Factor
• Thickened Pleura
• Barrier to effective drug penetration

Iatrogenic Factors:
• Treatment with one effective drug
• Inadequate dosage
• Inadequate duration
• Use of cross resistant drugs

Inadequate Prescribing Practice:
• In 1995 25% of new cases of TB were initially treated with 2-3 drugs regimen
• 2 Surveys by AKUH among GP & Interns
• Once resistance develops, prescribing errors, usually by inexperienced physicians can exacerbate situation.
• Review of patients referred to National Jewish Hospital (Denver) for management of complex MDR-TB documented an average of 3.93 prescribing errors per patient.

Erratic Compliance:
• New York study by Brudrey showed that out of 178 patient only 11 % compliant
• Drug often taken erratically and often singly

Nosocomial Transmission:
• In Prisons
• In Hospitals
• In Nursing Homes

HIV [link widoczny dla zalogowanych] Infection is often associated with a high prevalence of drug resistance
• Patient fails to improve
• Patient improves initially but has recurrence of symptoms
• Patient fails to become smear negative
• Patients who have taken treatment previously
• Previously treated patients who have been non compliant.

Implication Of MDR:
• Prolonged hospital stay & Isolation
• Loss of benefit of short course chemotherapy
• High cost of treatment
• Low success rate
• High relapse rate

Diagnosis:
• Once suspected it is easy to diagnose
• Diagnosis follows same lines as standard TB
• AFB culture and sensitivity should be sent

Treatment:
General Principles
• Isolation to prevent spread of disease prolonged [link widoczny dla zalogowanych] hospital admission.
• D.O.T with effective drugs.
[link widoczny dla zalogowanych] • If already taking treatment add at least two new drugs.
• Adjust treatment according to sensitivities when available.

Treatment:
General Principles
• Never add one drug at a time.
• Treatment to be continued for longer period (12-24 months)
• INH is often useful even if the sensitivities don’t favour it.

Isoniazid Monoresistance:
• Rifamycin, Pyrazinamide and Ethambutol for 6 to 9 months or 4 months after culture conversion.

Rifampicin Monorisestancae:
• Most often seen in HIV positive patients.
• Uncommon but increasingly frequent.
• Because Rifampicin is corner stone of all six months regime, resistance requires prolongation of [link widoczny dla zalogowanych] treatment.

Streptomycin, Isoniazid, Pyrazinamide for 9 months. (12 months for HIV +ve)
• SHE for 3 months followed by HE for 18 months.

Pyrazinamide Monoresistance“
• Requires 9 months of Isoniazid and Rifampicin.

Monoresistance To Other Agents:
• Single drug resistance to Ethambutol, Streptomycin, or second line agents is of little clinical significance.
• Patient can still be treated with 2 RHZ followed by 4 to 6 months of RH.
Suggested Treatment regimens for multidrug resistant tuberculosis
Suggested Treatment regimens for multidrug resistant tuberculosis

Prevention [link widoczny dla zalogowanych] Of MDR:
• Educate the prescriber.
• Educate the patient.
• DOTS
• Availability of drugs.
• Using 4 drugs in initial phase, 3 [link widoczny dla zalogowanych] in continuation & giving treatment for 9 months.
• More frequent use of Microbiology services.
• Drug levels.
• Reference Lab.

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