Dr.T.V.Rao MD.

X-MDR TUBERCULOSIS

DR.T.V.RAO MD 1

TUBERCULOSIS CONTINUES TO BE A IMPORTANT

COMMUNICABLE PUBLIC HEALTH PROBLEM

DR.T.V.RAO MD 2

Table of drugs used for the treatment of tuberculosis.

First line drugs Second line drugs

Essential Other Old New

Isoniazid

Rifampicin

Pyrazinamide

Ethambutol

Streptomycin

Capreomycin

Amikacin

Kanamycin

Cycloserine

Ethionamide

PAS

Thioacetazone

Quinolones

ofloxacin

ciprofloxacin

moxifloxacin

Macrolides

clarithromycin

Clofazimine

Amoxycillin &

Clavulanic acid

Lanizolid

New rifamycins

Hifalutin

Rifapentine DR.T.V.RAO MD 3

DEVELOPMENT OF DRUG RESISTANCE

FROM THE PERSPECTIVE OF THE PATIENT:

• The presence of drug resistant strains results from simple Darwinian pressures, brought out by the presence of antibiotics

• Multiple drug resistant strains result from the step-wise accumulation of individual resistance elements therefore MDR-TB is MAN-MADE

DR.T.V.RAO MD 4

History Elements that place a patient at-risk for MDR-TB

or drug resistance

1. Previous TB treatment with multiple drugs

2. Failed TB Treatment that is documented

3. A known chronic TB case

4. Default from previous TB treatment or erratic use of TB drugs

5. Exposure to a known MDR case

6. Use of TB drugs of poor or unknown quality

7. Prior use of an inadequate regimen

8. Conditions associated with drug malabsorption or severe diarrhea DR.T.V.RAO MD 5

WHY INH AND RIFAMPIN ARE

IMPORTANT IN TUBERCULOSIS

• Most potent and bactericidal

• Tb can be treated effectively with INH+Rif alone

• Mono-resistance to one of them can be treated effectively with a regimen containing the other agent with very low failure rate (2.5-5%)

• Failure rate when INH+Rif resistant is 44% in non-HIV and 70% in HIV patients

• Duration required for cure doubles to triples.

DR.T.V.RAO MD 6

DR.T.V.RAO MD 7

DEFINITIONS • Multidrug-resistant tuberculosis

(MDRTB) Resistance to Isoniazid and

Rifampicin

• Extensively (extremely) drug-resistant

(XDR-TB) MDR-TB plus resistance to a

second line injectable drugs such as

Amikacin plus a quinolone.

DR.T.V.RAO MD 8

Magnitude of the MDR-TB Problem WHO/IUATLD Global Projection Drug Resistance

Surveillance, which surveyed fifty-eight different countries between 1996 and 1999, revealed the presence of new “hot spots” for MDR-TB in addition to those reported in the first phase of the WHO/IUATLD Global Project on Drug Resistance Surveillance.

MDR-TB was shown to range from 0% to 14.1% among new TB cases. Another review (1999) compiled by Harvard Medical School has shown that drug-resistant TB exists in 104 countries in recent years.

MULTIDRUG-RESISTANT TUBERCULOSIS

WHO and IUATLD

• The median prevalence of MDR-TB 1.1% in newly diagnosed patients.

• The median prevalence of MDR-TB 7.0% in patients who have previously received anti-TB treatment

• MDR-TB : Threatening to destabilize global tuberculosis control (Chest2006;130:261-272)

DR.T.V.RAO MD 10

TUBERCULOSIS CONTINUES TO BE A

PROBLEM….

• The problem is compounded by the emergence of drug

resistant strains, due to patients not completing antibiotic

courses.

• In 1980 50 per cent of TB bacilli were resistant to 1 drug.

• Multi-drug resistant TB (MDR-TB) began to emerge. There are

now an estimated 1.5m MDR cases worldwide.

• Extreme drug resistance (XDR-TB) was reported in 2006.

• The first completely drug resistant (CDR-TB) case was

reported in Italy in 2007.

DR.T.V.RAO MD 11

MULTI DRUG-RESISTANT TB (MDR TB)

OCCURS ..

• Occurs when resistance develops to first line drugs

• Currently approximately 5-25% of TB cases

• Non-adherence to DOTS / treatment programme

• Can have direct infection with MDR strain TB

• Drug use increases risk of conversion

• Co-infection, especially with HIV, increases risk

• Second level drugs 1000 times more expensive than

first line

• Patients remain infectious? DR.T.V.RAO MD Slide 12

GENESIS OF MDR TB

• Resistance is a man-made amplification of a natural

phenomenon.

• Inadequate drug delivery is main cause of secondary drug

resistance.

• Secondary drug resistance is the main cause of primary

drug resistance due to transmission of resistant strains.

• MDR due to spontaneous mutations is not possible as the

genes encoding resistance for anti TB are unlinked.

DR.T.V.RAO MD 13

DRUG–RESISTANT M. TUBERCULOSIS

Epidemiology

• Primary drug resistance

• initial drug resistance

• Secondary drug resistance

• acquire drug resistance

Treatment of tuberculosis: guidelines for national programmes , 3rd ed. Geneva, World Health Organization, 2003(WHO/CDS/TB/2003.313).

DR.T.V.RAO MD 14

DRUG–RESISTANT M. TUBERCULOSIS

• Drug resistance • Monodrug resistance

• Polydrug or Combined resistance (not INH and RIF)

• Multidrug resistance (MDR) (INH and RIF resistance)

• Extensively Multidrug resistance (XDR) • MDR-TB and

• Resist to at least 3 classes of second line drugs

Treatment of tuberculosis: guidelines for national programmes, 3rd ed. Geneva, World Health Organization, 2003(WHO/CDS/TB/2003.313).

DR.T.V.RAO MD 15

GENE LOCATION ASSOCIATED DRUG-RESISTANT TUBERCULOSIS

Drug Gene

Isoniazid Kat G, Inh A, Kas A

Rifampicin rpo B

Ethambutol emb B

Streptomycin rps L

Pyrazinamide pnc A

Fluoroquinolones gyr A

Dubaniewicz A, et al. Molecular sub-type of the HLA-DR antigens in

pulmonary tuberculosis. Int J Infect Dis2000;4:129-33.

DR.T.V.RAO MD 16

EPIDEMIOLOGY INFORMATION OF

MDR-TB

• Incidence varies according to reported sites.

• High incidence is located in some geographic area and not evenly distribution.

• Data of sensitivity can not be directly compared because of different methodology.

• No separation of previously treated and untreated cases.

• High incidence is associated with poor compliance previous treatment history, HIV infection, contact with drug resistant case, inborn country.

DR.T.V.RAO MD 17

MULTIDRUG RESISTANT TUBERCULOSIS TO

EXTENSIVELY DRUG RESISTANT TUBERCULOSIS

• Extensively drug-resistant tuberculosis (XDR-TB) is

a form of tuberculosis caused by bacteria that are

resistant to the most effective anti-TB drugs. Some

contend that XDR-TB strains have emerged from the

mismanagement of multidrug-resistant TB (MDR-TB)

and once created, can spread from one person to

another. The exact nature of this mismanagement is not

yet known, but origin of XDR-TB may coincide with the

institution of new policies to promote drug compliance,

such as DOTS

DR.T.V.RAO MD 18

DR.T.V.RAO MD 19

XDR – TB ON RAISE

• DR-TB raises concerns of a future TB epidemic with restricted

treatment options, and jeopardizes the major gains made in TB

control and progress on reducing TB deaths among people

living with HIV/AIDS. It is therefore vital that TB control be

managed properly and new tools developed to prevent, treat

and diagnose the disease.

• The true scale of XDR-TB is unknown as many countries lack

the necessary equipment and capacity to accurately diagnose it.

It is estimated however that there are around 40,000 cases per

year. As of June 2008, 49 countries have confirmed cases of

XDR-TB. By 2010, that number had risen to 58.

DR.T.V.RAO MD 20

• Moldova has one of the highest

rates of multi-drug resistant

tuberculosis (MDR-TB) anywhere

in the world. This deadly strain of

the disease can emerge as a

result of low quality health

systems, poor quality drugs, lack

of accessibility to treatment, and

when a patient intermittently

takes his medicine or fails to

complete his treatment. After the

fall of the Soviet Union,

HIGH INCIDENCE OF MDR-TB

DR.T.V.RAO MD 21

DEFINITION OF XDR-TB • XDR-TB is defined as TB that has developed resistance to at

least rifampicin and isoniazid (resistance to these first line anti-

TB drugs defines Multi-drug-resistant tuberculosis, or MDR-TB),

as well as to any member of the quinolone family and at least

one of the following second-line anti-TB injectable drugs:

kanamycin, Capreomycin, or Amikacin This definition of XDR-

TB was agreed by the WHO Global Task Force on XDR-TB in

October 2006. The earlier definition of XDR-TB as MDR-TB that

is also resistant to three or more of the six classes of second-

line drugs, is no longer used, but may be referred to in older

publication

DR.T.V.RAO MD 22

XDR-TB A GLOBAL THREAT

• Between 2000-2004, of 17,690 TB

isolates in the world were MDR-TB

20% and XDR-TB 2% (Lancet2006;368:964)

• Between 2003-2005, of 1,284 TB

isolates in Iran were MDR-TB 9.3%

and XDR-TB 1% (CID2006;316:216)

DR.T.V.RAO MD 23

RISK FACTORS FOR INFECTION WITH DRUG-RESISTANT TUBERCULOSIS

• Expose to person who has known drug-resistant tuberculosis

• Exposure to a person with active tuberculosis who has prior treatment for tuberculosis (treatment failure or relapse) and whose susceptibility test results are not known

• Expose to persons with active tuberculosis from areas in which there is a high prevalence of drug resistance. .

DR.T.V.RAO MD 24

WHO NEEDS SPUTUM CULTURING

AND DRUG RESISTANCE TESTING

DR.T.V.RAO MD 25

SPUTUM CULTURE FOR TB AND SUSCEPTIBILITY TESTING

High-risk patient who has drug resistance TB

Relapse case History of irregular treatment Treatment failure case Expose to person who has known Drug-Resistant Tuberculosis HIV co-infection Addictions Born in high prevalence country

(Current Practice in Common Infectious Diseases2001. สมาคมโรคติดเชื้ อแห่งประเทศไทย;20:339-353.)

DR.T.V.RAO MD 26

• Quality of laboratory sensitivity testing

• Maintenance of standards over time

• Selection of specimens

• Only 1% of patients surveyed

PROBLEMS WITH DRUG RESISTANCE

SURVEILLANCE

DR.T.V.RAO MD 27

DIAGNOSIS : MDR-TB

• Isoniazid and Rifampicin resistance case

• Short course treatment failure : sputum for AFB + after 5

months of treatment

• “fall and rise” sputum for AFB +

• Long course treatment failure : sputum for AFB + after

complete 12 months

• Long duration of treatment : 18 – 24 months

• Susceptibility testing : MDR-TB

DR.T.V.RAO MD 28

STANDARD SHORT COURSE REGIMEN OF ANTI-TB DRUGS (WHO)

• Category I : 2HRZE/4HR

New case of pulmonary TB with sputum AFB +

• Category II : 2HRZES/HRZE/5HRE

New case of pulmonary TB with sputum AFB + Suspected Drug-Resistant TB

• Category III : 2HRZ/4HR

New case of pulmonary TB without sputum AFB +, no extensive lesion

• Category IV Chronic case with MDR-TB

( Management of tuberculosis modified WHO modules of managing tuberculosis at district level 1991)

DR.T.V.RAO MD 29

SECOND LINE DRUGS (6 CLASSES) • Aminoglycosides :

Streptomycin (15 MKD)

Kanamycin, Amikacin (15 MKD)

-first 2-3 mo, at least 5 days/wk

-after sputum for AFB – negative 2-3 days/wk to 6 mo or patient has adverse effects (ototoxic and nephrotoxic)

• Fluoroquinolones : cross resistance

ofloxacin (10MKD)

levofloxacin (10MKD) nausea vomiting, dizziness

ciprofloxacin (30MKD)

no cross resistance

DR.T.V.RAO MD 30

• Polypeptides : Capreomycin

• Serine analog : Cycloserine

• Ethionamide(10-20MKD)

• Para-amino salicylic acid (PAS)

SECOND LINE DRUGS

DR.T.V.RAO MD 31

GUIDELINES FOR TREATMENT OF DRUG-RESISTANT ORGANISM

• Never add one drug into the failing regimen

• Use > 3 drug with in vitro susceptibility (1 drug should be injectable)

• Should not use intermittent therapy

• Need DOTS

• Amikacin cross-R with Kana, SM not cross-R with other

• Two-inject-drug is not recommended

Frequency of resistance mutation

RIF: 10‾18 INH, SM: 10‾6 ETB: 10‾5

DR.T.V.RAO MD 32

WHAT DO WE NEED IN MDR AND X-MDR-TB

• Specialized and experienced institute. • Correct identification of drug resistance case. • Good laboratory support. • Availability and adequate drugs. • DOTS (directly observed therapy strategy). • Strictly monitoring of treatment. • Follow up patient to prevent relapse case.

DR.T.V.RAO MD 33

NEW DRUGS FOR TUBERCULOSIS TREATMENT

• Fixed dose combination (FDC)-WHO formulation

• Fluoroquinolones: ofloxacin, levofloxacin, gatimoxacin, moxifloxacin

• MPC below Cmax

• Sterilizing activity

• Oxazolidinones : linezolid

• Imidazole derivatives : PA824

• Diaryquinolone : TMC207

• Ketolides : telithromycin (no activities)

• Drug on latency stage : Glyoxylate shunt

(Mendell, et al.Principle and Practice of INFECTIOUS DISEASES;2005:2852-2886.) DR.T.V.RAO MD 34

BIOSAFETY A MUST IN LABORATORY PRACTICE

• I advise all the medical microbiologists, laboratory workers not to take

up project works, research work and diagnostic work on

Mycobacterium ( decontamination, culturing and drug susceptibility

testing with out standard Bio hazard protection which includes use

grade 3 bio safety cabinet. As many strains are becoming MDR-TB

and X-MDR tuberculosis. Our students and lab workers are the real

victims. In spite of severe bio hazards of Mycobacterium many Doctors

directors and managers do not have idea about the dangers of

Tuberculosis, putting some ones life at risk. I request all the younger

generation of Microbiologists to work with Biosafety precautions Even

the Medical council of India should implement strict regulations on this

matter Dr.T.V.Rao MD

DR.T.V.RAO MD 35

WHO - REPORT-BE CAUTIOUS

• TB drug resistance needs a frontal assault. If countries and the international community fail to address it aggressively now we will lose this battle," said Dr Mario Raviglione, Director of the WHO Stop TB Department.

• "In addition to specifically confronting drug-resistant TB and saving lives, programmes worldwide must immediately improve their performance in diagnosing all TB cases rapidly and treating them until cured, which is the best way to prevent the development of drug resistance."

DR.T.V.RAO MD 36

• Programme created by Dr.T.V.Rao MD for

Medical and Health care Workers in the

Developing World

• Email

• doctortvrao@gmail.com

DR.T.V.RAO MD 37