Mdr, xdr by dr tasleem arifPresentation Transcript
MDR/XDR TB BY DR.TASLEEM ARIF DEPT. OF CHEST MEDICINE SKIMS MC/H BEMINA Srinagar, kashmir
Types of resistance
Some basic concepts
Previously RX & MDR TB
Causes/risk factors for MDR/XDR TB
Role of lab.
Groups of drugs
Programmatic approach to MDR/XDR
Standard RX regimen
Monitoring during MDR/XDR TB RX
Guidelines during pregnancy
MDR TB RX and renal insufficiency
STOP TB strategy
GREENLIGHT committee initiative
MDR TB : M.tub. Isolates resistant to at least isoniazid and rifampicin.
MDR => R (H+R)
XDR TB :MDR plus resistance to a FQ
and one second line injectable drugs (amikacin,capreomycin,kanamycin)
XDR = MDR+R(1FQ+1INJ )
TDR TB : resistance to all available drugs.No treatment options presently available
Types of resistance
MONORESISTANCE :Resistance to one type of drugs (e.g.,H)
POLY-RESISTANCE :Resistance to more than one type of drugs,other than both H and R
PRIMARY DRUG RESISTANCE :who have been infected with resistant bacilli by another Pt.
SECONDARY DRUG RESISTANCE :Resistance to one or more anti-TB drugs which arises during course of RX
PROGRESSION OF RESISTANCE
MDR TB 1990 XDR TB 2006 TOTAL DR TB
MANAGED WITH DOTS-4 DRUG REGIMENS
RESISTANCE TO H AND R
TREATED WITH 2 ND LINE DRUGS
RESISTANCE TO 2 ND LINE DRUGS
TREATMENT OPTIONS SERIOUSLY RESTRICTED
RESISTANCE TO ALL AVAILABLE DRUGS
NO TREATMENT OPTIONS
RESISTANCE BASED ON HISTORY
RESISTANCE AMONG NEW Pt.s i.e.,PTS who were never treated before or were treated for max one month.
RESISTANCE AMONG RETREATMENT PATIENTS
Drug resistance mechanism
NATURAL DRUG RESISTANCE is due to
- unusual multilayer cell envelope active multidrug efflux pumps
- neutralise the toxicity of antibiotic in the cytoplasm
ACQUIRED RESISTANCE is due to
- sequential accumulation of mutations in different genes involved in resistance to individual drugs ,due to inappropriate treatment or poor adherence to treatment
Spontaneous mutations develop as bacilli proliferate to > 10⁸
Every 10 6 pyrazinamide Every 10 6 isoniazid Every 10⁸ rifampicin Mutation rate Drug
Basic concepts to be understood
Tuberculosis suspect . Any person who presents with symptoms or signs suggestive of TB. The most common symptom of pulmonary TB is a productive cough for more than 2 weeks, which may be accompanied by other respiratory symptoms (shortness of breath, chest pains, haemoptysis) and/or constitutional symptoms .
• Definite case of tuberculosis . A patient with Mycobacterium tuberculosis complex identified from a clinical specimen, either by culture or by a newer method such as molecular line probe assay. In countries that lack the laboratory capacity to routinely identify M. tuberculosis , a pulmonary case with one or more initial sputum smear examinations positive for acid-fast bacilli (AFB) is also considered to be a “definite” case, provided that there is a functional external quality assurance (EQA) system with blind rechecking.
Cure A patient whose sputum smear or culture was positive at the beginning of the treatment but who was smear- or culture-negative in the last month of treatment and on at least one previous occasion.
Treatment completed A patient who completed treatment but who does not have a negative sputum smear or culture result in the last month of treatment and on at least one previous occasion
Treatment failure patient whose sputum smear or culture is positive at 5 months or later during treatment. Also included in this definition are patients found to harbour a multidrug-resistant (MDR) strain at any point of time during the treatment, whether they are smear-negative or -positive.
Died : A patient who dies for any reason during the course of treatment.
Transfer out A patient who has been transferred to another recording and reporting unit and whose treatment outcome is unknown
. Default: A patient whose treatment was interrupted for 2 consecutive months or more.
Treatment success A sum of cured and completed treatmentc
Epidemiology of MDR/XDR
4 th global report(1994-2007,WHO 2008 data from 105 countries)prev in new pts found to be = 920,85 ( 2.9 %)
Estimates(2004)=424,203( 4.3 %)
Estimates(2000)=272,906( 1.1 %)
43% of global MDR TB cases had previous treatment
China,India,Russian federation account for 62% of burden
Prevalence of XDR not known.
Previously treated pts and MDR: Strong relation
At the global level, 15% of previously treated patients have MDR which is five times higher than the global average of 3% in new patients
WHO surveillance data from 10 countries found the level of MDR to be 32% in patients returning after defaulting or relapsing and significantly higher (49%) in patients whose prior treatment has failed
Other studies show MDR levels of up to 80–90% in patients whose prior treatment courses have failed
when a first course of treatment containing 6 months of rifampicin fails, 50–94% of patients have MDR-TB (compared with 4–56% of patients upon failure of a regimen containing 2 months of rifampicin).
Lung predominantly substantial reports reveal occurrence at extra pulmonary sites viz., skin and soft tissue ,lymph nodes,CNS and other organs
Extra-pulmonary MDR TB more in HIV + PTS.
POOR QUALITY TREATMENT
poor quality drugs
inappropriate rx regimens
non-compliant drug taking
WEAK TB PROGRAMME lowcompletion/cure rates
unreliable drug supply
lack of proper follow up
lack of pt support
UNCONTROLLED USE OF 2 ND LINE DRUGS
High MDR prevalence areas
Co-morbid conditions like malabsorption,HIV+,rapid transit diarrhoe,etc.
Treatment without drug susceptibility and culture
Fact in 2005 ;only 2% of estimated culture proven MDR are treated with 2 nd line drugs
OUTCOME OF XDR TB counted cases in US ,defined on initial DST ,1993-2007 2 1 Lost 2 1 Other 4 2 Removed from meds 9 4 Currently on RX 15 7 Moved 33 15 Died while on therapy 35 16 Completed therapy 46 Alive at DX % N
ROLE OF LAB
Helps to design effective regimen
Initial M.tub isolate should be tested against primary drugs
-H –R –Z –E - S
for rif-R isolates ,test secondary drugs as needed
-FQ –AMI –KAN –CAP .
DRUG SUSCEPTIBILITY TESTS :
CULTURE –BASED METHODS
- solid (6-8 weeks)
- liquid (8-10 days )
Absolute conc. Methods
Relative ratio method
line probe assays (1-2 days )
luciferase reporter assay(48 hrs)
Agar proportion method
Plate bacteria on media containing no drugs and critical conc. Of a drug
Incubate for 3 weeks
Isolate is resistant if the no. of colonies on drug-containing media is >1% of colonies on drug free media
CRITICAL CONC . The lowest conc. of a drug that : 1) inhibits growth of all susceptible strains ,and 2) allows growth of all resistant strains
MANAGEMENT OF MDR/XDR
GENERAL GUIDELINES FOR MANAGEMENT OF MDR/XDR :
In most cases,Treatment has to be individualised
Treatment regimen needs to be build up depending upon culture sensitivity tests.
Intermittent therapy should not be used in treating MDR TB
The use of drugs to which there is demonstrated in vitro resistance is not encouraged because there is little or no efficacy of these drugs
A good response does not justify continuation of an inadequate regimen
Resistance to RIF is associated in most cases with cross resistance to rifabutin and in all cases to rifapentine
Patients should receive either hospital-based or domiciliary DOT
A single drug should never be added to a failing regimen
Sufficient numbers of oral drugs should be started at onset of therapy to make sure there is an adequate regimen once the injectable agent is discontinued
The treatment of MDR-TB must be undertaken by a physician experienced in the treatment of MDR-TB
Bactericidal drugs with proven efficacy should be used
Cultures should be done monthly to monitor response of MDR TB to therapy
Two years of total treatment after conversion of cultures to negative is usually recommended
Occasional patients with limited disease are cured after 18 months
It is not possible to use more than one injectable (STM, capreomycin or amikacin), because the toxic effect of these drugs is additive: If possible, the aminoglycoside should be given daily for a minimum of three months (and perhaps thrice weekly thereafter).
There is no intermittent regimen validated for use in MDR-TB, but clinical experience is that giving injectable drugs for five days a week (because there is no-one available to give the drug at weekends) does not seem to result in inferior results.
Directly observed therapy helps to improve outcomes in MDR-TB and should be considered an integral part of the treatment of MDR-TB
Treatment cannot be stopped until the patient has been culture-negative for a minimum of nine months.
Patients with MDR-TB should be isolated in negative-pressure rooms, if possible.
Repeat DST should be performed when culture remains positive for 3 months
A good response does not justify continuation of an inadequate regimen
Groups of drugs to treat MDR /XDR T B .
For MDR treatment, anti-TB drugs are grouped according to efficacy, experience of use and drug class
Group 1. Group 1 drugs are the most potent and best tolerated. If there is good laboratory evidence and clinical history that suggests that a drug from this group is effective, it should be used.
Group 2. All patients should receive a Group 2 injectable agent if susceptibility is documented or suspected. Among aminoglycosides, kanamycin or amikacin is the first choice of an injectable agent, given the high rates of streptomycin resistance in drug-resistant TB Group If an isolate is resistant to both streptomycin and kanamycin ,capreomycin (a polypeptide) should be used.
Group -3 One of the higher generation fluoroquinolones, such as levofloxacin or moxifloxacin, is the fluoroquinolone of choice. Ciprofloxacin is no longer recommended to treat drug-susceptible or drug-resistant TB.
Group 4 . Ethionamide (or protionamide) is often added to the treatment regimen because of its low cost. If cost is not a constraint, p -aminosalicylic acid (PAS) may be added first, given that the enteric-coated formulas are relatively well tolerated and that there is no cross-resistance to other agents.
Group 5. Group 5 drugs are not recommended by WHO for routine use in drug-resistant TB treatment because their contribution to the efficacy of multidrug regimens is unclear. They can be used in cases where it is impossible to design adequate regimens with the medicines from Groups 1–4, such as in patients with XDR-TB.
Group-3 Flouroquinolones Kanamysin(Km) Amikacin(Am) Capreomycin(Cm) Streptomycin(S) Group-2 Injectable agents Pyrazinamide(Z) Ethambutol(E) Rifabutin(Rfb) Group -1 First line oral drugs
GROUP 5 :DRUGS WITH UNCLEAR ROLE
clofazimine (Cfz), linezolid(Lzd) ,AMOX/CLV
High-dose isoniazid is defined as 16–20 mg/kg/day
Some experts recommend using high-dose isoniazid in the presence of resistance to low concentrations of isoniazid (>1% of bacilli resistant to 0.2 μg/ml but susceptible to 1 μg/ml of isoniazid), whereas isoniazid is not recommended for high-dose resistance (>1% of bacilli resistant to 1 μg/ml of isoniazid)
Programmatic approach to Rx of MDR/XDR :
depend on the type of laboratory method used to confirm MDR /XDR
For NTPs using conventional DST methods , there is often a delay of months before results are available to confirm or exclude MDR. While awaiting results, patients who are highly likely to have MDR-TB (such as those whose prior treatment has failed) need an empirical MDR regimen. If MDR is confirmed, this regimen may be continued, or it may be tailored on the basis of susceptibility to drugs other
NTPs using rapid molecular-based DST will be able to confirm MDR-TB within 1–2 days,2 and then can initiate treatment with a standard MDR regimen immediately,or may tailor the regimen later when DST results for second-line drugs become available
Include drugs from Groups 1–5 in a hierarchical order based on potency
Use any of the first-line oral agents ( Group 1) that are likely to be effective.
Use an effective aminoglycoside or polypeptide by injection (Group 2).
Use a fluoroquinolone (Group 3).
Use the remaining Group 4 drugs to complete a regimen of at least four ,preferably five effective drugs.
For regimens with fewer than four effective drugs, consider adding two Group 5 drugs. The total number of drugs will depend on the degree of uncertainty, and regimens often contain five to seven.
Avoid streptomycin even if DST suggests susceptibility because of high rates of resistance with resistant TB strains and higher incidence of ototoxicity.
Standard treatment regimen :
Standardized Category 4 regimen :
Z - Km - Lfx - Eto - Cs – PAS
All patients receiving cycloserine or terizidone should receive pyridoxine.
The recommended daily dose is 50 mg for every 250 mg of cycloserine.
Criteria for standard category 4 Rx
Should not be pregnant
no jaundice or a known liver problem
no chronic illness such as diabetes
mellitus, heart or kidney disease, etc
household contact of a patient with
patient ever has taken second-line anti-TB drugs
If any of 5 present,don’t give standard cat-4;pt. will need individualised cat-4 ;refer to an MDR/XDR TB specialist
D uration of RX for MDR -T B:
In MDR-TB treatment, the intensive phase is defined by the duration of treatment with the injectable agent .
The injectable agent should be continued for a minimum of 6 months , and for at least 4 months after the patient first becomes and remains smear- or culture-negative. ( WHO)
Conversion is defined as two consecutive negative smears and cultures taken 30 days apart.
DURATION OF INJECTABLE : The decision to stop the injectable should depend on the clinical status of the pt.,
the bacteriological data (smears and cultures), the chest X-ray, and the DST results.
In patients infected with highly resistant strains, the clinician may opt to continue the injectable during the entire course of treatment. In these cases, the clinician may decrease the frequency to three times per week
guidelines recommend continuing therapy for a minimum of 18 months after culture conversion. Extension of therapy to 24 months may be indicated in chronic cases with extensive pulmonary damage .
Monitoring and follow up
sputum smears and cultures should be performed monthly until smear and culture conversion.
After conversion, the minimum frequency recommended for bacteriological monitoring is monthly for smears and quarterly for cultures.
Monitoring of MDR-TB patients by a clinician should be at least monthly until sputum conversion, then every 2–3 months
At every DOT and clinician encounter, the patient should be screened for side-effects of medication.
For all quinolones, the daily dose should be given in a single dose once a day.
For ethionamide, cycloserine, and PAS , the daily dose is divided into morning and evening doses for better tolerance.
All patients should receive pyridoxine . The recommended daily dose is 50 mg for every 250 mg of cycloserine/terizidone:
50 mg daily if they are receiving cycloserine 250 mg daily
100 mg daily if they are receiving cycloserine 500 mg daily
150 mg daily if they are receiving cycloserine 750 mg daily, etc.
Standardized Category 4 regimen instructions (for a 60 kg patient)
3 tablets (1750 mg)
Kanamycin: 1 injection (1000 mg)
Levofloxacin: 2 tablets (500 mg)
Ethionamide: 1 tablet (250 mg)
Cycloserine: 1 capsule (250 mg)
PAS: 1 sachet (4 g)†
Ethionamide: 2 tablets (500 mg)
Cycloserine: 2 capsules (500 mg)
PAS: 1 sachet (4 g)†
Pyridoxine: 6 tablets (150 mg)
PASER formulation of PAS must be taken with an acidic liquid. S
Special consideration during pregnancy
NOT A CI FOR MDR TB RX
DISCUSS RISKS AND BENEFIT
START RX IN 2 ND TRIMESTER OR SOONER IF CONDITION IS SEVERE
MAJORITY OF TERATOGENIC EFFECTS OCCUR IN IST TRIMESTER,THERAPY MAY BE DELAYED UNTIL 2 ND TRIMESTER
AVOID INJECTABLES ,IF UNAVOIDABLE CAPREOMYCIN IS THE AGENT OF CHOICE
AVOID ETHIONAMIDE ,INCREASES NAUSEA AND VOMITING ASSOCIATED WITH PREGNANCY AND TERATOGENIC EFFECTS HAVE BEEN SEEN IN ANIMALS
Special considerations for patients with renal insufficiency
250 mg once daily, or 500 mg/dose three times per week. Yes Cycloserine 400 mg per dose three times per week (not daily) Yes Gatifloxacin 400 mg once daily No change Moxifloxacin 750-1000 mg per dose three times per week (not daily) Yes Levofloxacin 600–800 mg per dose three times per week (not daily) Yes Ofloxacin 25–35 mg/kg per dose three times per week(not daily) Yes Pyrazinamide 15–25 mg/kg per dose three times per week (not daily) Yes Ethambutol Recommended dose &frequency for patients with creatinine clearance < 30 ml/min , or for patients receiving haemodialysis Frequency Drug
12–15 mg/kg per dose two or three times per week (not daily) caution Yes Capreomycin 12–15 mg/kg per dose two or three times per week(not daily) caution Yes Kanamycin 12–15 mg/kg per dose two or three times per week(not daily) caution Yes Streptomycin 4 g/dose, twice daily (PASER ｮ )† No change PAS 250–500 mg per dose daily No change Ethionamide NA - Terizidone Creatinine clearence <30 ml/min or pts receiving hemodialysis Frequency Drug
Applicble to areas of high MDR TB prevalence
Provides additional services in such areas to provide high cure rates and reduce transmission
DOTS-plus modifies all elements of DOTS strategy :
RX may need to be individualised
Lab to provide culture and DST
Reliable supplies of expensive 2 nd line drugs
Operational studies reqd to determine indications of modified RX
Financial and technical support from international orgs. In addition to local Gvt.
Green Light Committee Initiative
GLC is a sub group of MDR-TB working grp of STOP TB Partnership ,and an advisory body of WHO that promotes access to quality-assured ,life –saving MDR TB rx
Through GLC initiative ,NTPs have access to :
Expertise in programmatic Mt of DRTB
High quality drugs to RX DR-TB
Support via network of technical partners
Peer support & knowledge sharing
Independent external monitoring & evaluation
MDR/XDR-TB – Take Home Messages
MDR TB is a manmade problem…..It is costly, deadly, debilitating, and the biggest threat to our current TB control strategies
Present in all regions – but distribution and magnitude unknown
Prevention of MDR/XDR TB is crucial
Management of MDR and XDR TB must be integrated into TB control programs