X-MDR Tuberculosis
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Transcript of X-MDR Tuberculosis
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
DR.T.V.RAO MD 37