PRINCIPLE OF MDR TB MANAGEMENT

Dr Kaliprasanna ChatterjeeMD PGT 3rd year,

Department of Pulmonary Medicine,Burdwan Medical College and Hospital

GROUPING OF ANTI-TB DRUGSGROUPING DRUGS

Group 1: First-line oral anti-TB agents Isoniazid (H); Rifampicin (R); Ethambutol (E); Pyrazinamide (Z)

Group 2: Injectable anti-TB agents Streptomycin (S); Kanamycin (Km); Amikacin (Am);Capreomycin (Cm); Viomycin (Vm).

Group 3: Fluoroquinolones Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofloxacin (Lvx);Moxifloxacin (Mfx); Gatifloxacin (Gfx)

Group 4: Oral second-line anti-TB agents Ethionamide (Eto); Prothionamide (Pto); Cycloserine (Cs);Terizadone (Trd); para-aminosalicylic acid (PAS)

Group 5: Agents with unclear efficacy (notrecommended by WHO for routine use inMDR-TB patients)

Clofazimine (Cfz); Linezolid (Lzd); Amoxicillin/Clavulanate(Amx/Clv); thioacetazone (Thz); imipenem/cilastatin (Ipm/Cln);high-dose isoniazid (high-dose H); Clarithromycin (Clr)

MAGNITITUDE OF PROBLEM• Drug-resistant TB poses a major threat to control of TB worldwide.

• Among notified pulmonary TB patients in 2014, an estimated 300 000 (range: 220 000–370 000) had MDR-TB.

• Globally in 2014, 123 000 patients with MDR -TB or rifampicin resistant tuberculosis (RR-TB) were notified.

• Globally, 3.3% of new cases (95% CI: 2.2–4.4%) and 20% of previously treated cases (95%CI: 14–27%) have MDR-TB.

• In India (2014), an estimated 2.2% of new cases (95% CI: 1.9–2.6%) and 15% of previously treated cases (95%CI: 11–19%) have MDR-TB.

MAGNITITUDE OF PROBLEM

• Extensively drug-resistant TB (XDR-TB) has been reported by 105 countries.

• On average, an estimated 9.7% of people with MDR-TB have XDR-TB (95% CI: 7.4–12%).

• Sub-national drug resistance surveys (2005-09) showed 4-7% XDR & 21-24% Ofx resistance in MDR isolates.

TYPES OF DRUG RESISTANT Antibiotic Resistant - “ Resistance is defined as a decrease in sensitivity of

sufficient degree to be reasonably certain that the strain concerned is different from a sample of wild strains of human type that have never come into contact with the drug. ”

Primary (initial) resistance - When drug resistance is demonstrated in a patient who has never received anti-TB treatment previously, it is termed primary (Initial) resistance, i.e. TB patient’s initial M.TB population resistant to drugs

Secondary (Acquired) resistance is that which occurs as a result of specific previous treatment, i.e. Drug-resistant M. TB in initial population, selected by inappropriate drug use (inadequate treatment or non-adherence).

TYPES OF DRUG RESISTANT Mono resistance TB - Resistant in vitro to one first line anti-TB drug.

Poly drug resistance TB - Resistance to INH or RIF (not both) with resistance to one or more other 1st line drugs

Multi-drug resistant tuberculosis (MDR TB) is defined as resistance to isoniazid and Rifampicin (a laboratory diagnosis).

Extensively drug resistant TB (XDR-TB) is MDR + resistance to any fluoroquinolone + resistance to at least one 2nd-line injectable drug (amikacin, kanamycin, or capreomycin)

Total Drug Resistance TB ( TDR) Resitance to all first-line anti-TB drugs (FLD) and second-line anti-TB drugs (SLD) that were testedstance to all first-line anti-TB drugs (FLD) and second-line anti-TB drugs (SLD) that were tested.

MECHANISM FOR DEVELOPMENT OF DRUG -RESISTANT TB

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

BASIC CONCEPT IN TB RESISTANCE 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

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.

The mutation rate, rather than the mutation frequency, is the most reliable measure, as it records the risk of mutation per cell division rather than the proportion of mutant cells.

The rate at which resistance emerges, being highest for ethambutol and lowest for rifampicin & quinolones.

INTRINSIC DRUG RESISTANCE IN TB Unusual structure of its mycolic acid-containing cell wall.

low permeability for many antibiotics.

Intrinsic resistance is important .

Limits the number of drugs available for treatment & favors the emergence of strains with a high level of drug resistance

Recently, the role of efflux mechanisms has also been recognized as an important factor in the natural resistance against antibiotics such as Tetracycline, fluoroquinolones and aminoglycosides, among others.

Fortunately, of the 4 mechanisms through which antimicrobial resistance appears (mutation, transduction, transformation and conjugation), M. TB only uses mutations

DRUG RESISTANCE : MOLECULAR BASIS

• ISONIAZID- Point mutations in katG are more commonly observed.

Results in a significant reduction in catalase & peroxidase activity & causes high-level INH resistance.

Interestingly, the mutation in katG occurs more frequently in MDR than in isoniazid mono resistant strains.

Mutations in inhA result in reduced affinity of the enzyme for NADH without affecting its enoyl reductase activity and Usually confer low-level resistance.

Mutations in inhA also cause resistance to the structurally related second-line drug ethionamide.

DRUG RESISTANCE : MOLECULAR BASIS ndh mutations reduce the activity of NADH dehydrogenase and produce resistance

to isoniazid and ethionamide.

ahpC codes for an alkyl hydroperoxidase reductase that is implicated in resistance to reactive oxygen and reactive nitrogen intermediates.

Studies have found that an increase in the expression of ahpc seems to be more a compensatory mutation for the loss of catalase/peroxidase activity rather than the basis for isoniazid resistance.

Studies have found that mutations in katG, inhA and ahpC were most strongly associated with INH resistance

DRUG RESISTANCE : MOLECULAR BASIS• RIFAMPICIN- The great majority of clinical isolates shows mutations in the gene rpoB that

encodes the b-subunit of RNA polymerase.

Mutations in a ‘hot-spot’ region of 81 bp of rpoB have been found in about 96% of rifampicin-resistant M. tuberculosis isolates.

This region, spanning codons 507–533, is also known as the rifampicin resistance-determining region (RRDR).

Cross-resistance between rifampicin and other rifamycins do exist

An important finding is that almost all rifampicin-resistant strains also show resistance to other drugs, particularly to isoniazid.

For this reason, rifampicin resistance detection has been proposed as a surrogate molecular marker for MDR.

DRUG RESISTANCE : MOLECULAR BASIS

• PYRAZINAMIDE-

Mutations in pncA is the main mechanism

Some PZA-resistant strains do not show mutations in pncA or its promoter region.

In this case, it has been postulated that resistance could be due to mutations in an unknown pncA regulatory gene

DRUG RESISTANCE : MOLECULAR BASIS• STREPTOMYCIN-

As it was used as mono-therapy, resistance to emerged quite rapidly.

Due to mutations in rrs or rpsL, which produce alterations in the STM binding site.

The majority of point mutations resulting in STM resistance occur in rpsL, with the most common mutation being K43R.

Recently it has been shown that mutations in gidB, which encodes a conserved 7-methylguanosine methyltransferase specific for the 16S rRNA, can confer a low level of streptomycin resistance.

DRUG RESISTANCE : MOLECULAR BASIS• ETHAMBUTOL-

Close to 50% strains had mutations in codon 306 of embB.

It has been postulated that mutations in embB306 may be related to variable degrees of ethambutol resistance but not sufficient for high-level ethambutol resistance.

There is an important percentage that don’t have mutations in embB, suggesting undiscovered mechanism for ethambutol resistance.

DRUG RESISTANCE : MOLECULAR BASIS• FLUOROQUINOLONES-

Initial studies showed amino acid substitutions in the putative fluoroquinolone binding region in gyrA or gyrB.

Quinolone resistance-determining region (QRDR) of gyrA and gyrB and resistance to fluoroquinolones has been confirmed now in multiple studies.

Several studies have already shown the presumptive participation of efflux mechanisms in resistance to fluoroquinolones.

DRUG RESISTANCE : MOLECULAR BASIS• AMINOGYCOSIDES AND CYCLIC PEPTIDE –

The most common molecular mechanism of drug resistance has been associated with an A1401G mutation in the rrs gene coding for 16S rRNA.

This mutation occurs more frequently in strains with high-level resistance to kanamycin and amikacin.

Mutations in the gene tlyA have been implicated in resistance to capreomycin and viomycin.

This gene codes an rRNA methyltransferase specific for 2 -O-methylation of ribose ′in rRNA.

Cross-resistance between kanamycin and amikacin or kanamycin, capreomycin and viomycin to variable degrees have been reported.

FACTORS FAVOURING DEVELOPMENT OF MDR TB

MDR SUSPECT CRITERIA

Criteria A – Criteria B- Criteria C –

All failures of new TB cases

Smear +ve previously treated cases who remain smear +ve at 4th month onwards

All pulmonary TB cases who are contacts of known MDR TB case

In addition to Criteria A:

All smear +ve previously treated pulmonary TB cases at diagnosis

Any smear +ve follow up result in new or previously treated cases

In addition to Criteria B

All smear -ve previously treated pulmonary TB cases at diagnosis.

HIV TB co-infected cases at diagnosis.

LABORATORY DIAGNOSIS Phenotypic DST (conventional DST):. Phenotypic testing determines if an isolate is

resistant to an anti-TB drug by evaluating growth (or metabolic activity) in the presence of the drug.

Genotypic DST (molecular DST): Genotypic testing detects mutations in the TB genome associated with specific drug resistance. (Note: genotypic testing is also used to identify M.tuberculosis by detecting the presence of TB-specific mycobacterial DNA).

Direct testing: Direct testing refers to testing directly from a clinical sample (most commonly a sputum specimen). In direct DST, processed clinical samples are directly inoculated onto media with and without drugs, or processed for molecular testing.

Indirect testing: Indirect testing refers to testing performed on cultured isolates of M.tuberculosis .

LABORATORY DIAGNOSIS Presently, 3 technologies are available for

diagnosis of MDR TB (1)the conventional solid egg-based Lowenstein-

Jensen (LJ) media,(2) the liquid culture (MGIT), and(3) the rapid molecular assays such as Line Probe

Assay (LPA) and similar Nucleic Acid Amplification Tests likeXpert MTB/Rif.

Phenotypic DST is available for more drugs, and is considered very reliable for isoniazid (H), rifampicin (R), and streptomycin (S), and somewhat less reliable for other drugs such as ethambutol (E).

Molecular/genotypic DST is highly reliable for rifampicin, but has limited sensitivity fordetection of isoniazid resistance.

The turnaround time for C-DST results by Solid LJ media is around 84 days, by Liquid Culture(MGIT) is around 42 days, by LPA is around 72 hours and by CB-NAAT is around 2 hours

SUMMARY OF TB DIAGNOSTIC AND DST METHODS

SUMMARY OF TB DIAGNOSTIC AND DST METHODS

Algorithm for interpretation of results from molecular methods

SYSTEMATIC APPROACH TO IMPLEMENTATION OF DST UNDER ROUTINE PROGRAMMATIC CONDITIONS

PRETREATMENT EVALUATION 1. Detailed history (including screening for mental illness, drug/alcohol abuse etc.) 2. Weight 3. Height 4. Complete Blood Count with platelets count 5. Blood sugar to screen for Diabetes Mellitus 6. Liver Function Tests 7. Blood Urea and S. Creatinine to assess the Kidney function 8. TSH levels to assess the thyroid function 9. Urine examination – Routine and Microscopic 10. Pregnancy test (for all women in the child bearing age group) 11. Chest X-Ray

All MDR-TB cases will be offered referral for HIV counseling and testing at the nearest centre if the HIV status is not known or the HIV test is found negative with results more than 6 months old.

TSH levels alone are usually sufficient to assess the thyroid function of the patient.

Patients should receive counselling on 1) the nature and duration of treatment, 2) need for regular treatment, 3) possible side effects of these drugs and 4) the consequences of irregular treatment or pre-mature cessation of treatment.

Female patients should receive special counselling on family planning.

GENERAL PRINCIPLES OF TREATMENT The intensive phase of MDR-TB treatment should consist of at least four second-line anti-TB

drugs that are likely to be effective (including an injectable anti-TB drug), as well as pyrazinamide.

MDR regimens should include at least pyrazinamide, a fluoroquinolone, an injectable anti-TB drug, ethionamide (or prothionamide) and either cycloserine or PAS (paraaminosalycylic acid) if cycloserine cannot be used.

A fluoroquinolone should be used .A later-generation fluoroquinolone rather than an earlier-generation fluoroquinolone should be used.

In the treatment of patients with MDR-TB, ethionamide (or prothionamide) should be used.

In the treatment of patients with MDR-TB, an intensive phase of eight months is suggested for most patients, and the duration may be modified according to the patient’s response to therapy.

The total length of treatment is expected to be at least 20 months in most patients notpreviously treated for MDR-TB.

BUILDING AN MDR-TB REGIMEN

BUILDING AN MDR-TB REGIMEN

RNTCP Regimen for MDR TB• This regimen comprises of 6 drugs - Kanamycin, Levofloxacin, Ethionamide,

Pyrazinamide,Ethambutol and Cycloserine during 6-9 months of the Intensive Phase and 4 drugs- Levofloxacin, Ethionamide, Ethambutol and Cycloserine during the 18 months of the Continuation

Phase.• 6 (9) Km Lvx Eto Cs Z E / 18 Lvx Eto Cs E .• SPECIAL SITUATION:1) In case of intolerance to Kanamycin, then Capreomycin (or PAS if injectable agent not feasible) is

the available substitute drug.

2) In case of intolerance leading to discontinuation of other oral second-line drug, paminosalicylic acid (PAS) is the available substitute drug.

3) Baseline Kanamycin mono - resistance should lead to substitution of Kanamycin with Capreomycin.

4) Baseline Ofloxacin mono - resistance should lead to substitution of Levofloxacin with the combination of Moxifloxacin and PAS.

5) Baseline Ofloxacin and Kanamycin resistance (i.e. XDR TB) should lead to declaration of outcome, referral to DR-TB Centre for pre-treatment evaluation for Regimen for XDR TB.

REGIMEN FOR MDR TB DOSAGE AND WEIGHT BAND RECOMMENDATIONS

INTEGRATED ALGORITHM FOR MDR-TB TREATMENT

ALGORITHM FOR MANAGEMENT OF MDR PATIENTS WHO DEFAULT AND RETURN FOR TREATMENT WITHIN 6 MONTHS OF DISCONTINUING REGIMEN FOR MDR TB

ALGORITHM FOR MANAGEMENT OF MDR PATIENTS WHO DEFAULT AND RETURN FOR TREATMENT AFTER 6 MONTHS OF DISCONTINUING REGIMEN FOR MDR TB

FOLLOW UP SMEAR AND CULTURE EXAMINATION DURING TREATMENT

The most important objective evidence of response to M/XDR treatment is the conversion of sputum culture to negative.

Patients will be considered smear converted after having two consecutive negative smears taken at least one month apart.

Patients will be considered culture converted after having two consecutive negative cultures taken at least one month apart.

Smear conversion is less reliable than culture conversion, which reflects viability of tubercle bacilli and is a more accurate reflection of response to treatment.

For follow up examination the required number of sputum specimens will be collected and examined by smear and culture at least 30 days apart from the 3rd to 7th month of treatment(i.e. at the end of the months 3, 4, 5, 6 and 7) and at 3-monthly intervals from the 9th month onwards till the completion of treatment (i.e. at the end of the months 9, 12, 15, 18, 21 and 24).

M/XDR TB TREATMENT OUTCOME Cure: A patient who has completed treatment and has been consistently culture negative

(with at least 5 consecutive negative results in the last 12 to 15 months). If one follow-up positive culture is reported during the last three quarters, patient will still be considered cured provided this positive culture is followed by at least 3 consecutive negative cultures, taken at least 30 days apart, provided that there is clinical evidence of improvement.

Treatment completed: A patient who has completed treatment according to guidelines but does not meet the definition for cure or treatment failure due to lack of bacteriological results.

Treatment failure: Treatment will be considered to have failed if two or more of the five cultures recorded in the final 12-15 months are positive, or if any of the final three cultures are positive.

Treatment default: A patient whose treatment was interrupted for two or more consecutive months for any reasons.

ADVERSE EFFECTS OF MDR-TB DRUGS

MANAGEMENT OF ADR

MANAGEMENT OF ADR

NEWER DRUGS FOR MDR-TB PREVENTION STRATEGIES : BEDAQUILINE

• Oral diarylquinoline• Target: ATP synthase

– Activity specific to mycobacteria• Bactericidal activity

comparable to RIF-INH-PZA in mice

• Sterilizing activity comparable to rifampin in mice

• Synergy with PZA• No cross-resistance with other

antimycobacterial drugs (INH, RIF, EMB, PZA, streptomycin, amikacin, or moxifloxacin)

NEWER DRUGS FOR MDR-TB PREVENTION STRATEGIES : BEDAQUILINE Approved by FDA in 2012 as part of combination therapy in adults with pulmonary MDR-TB

Should be used only when an effective treatment regimen cannot otherwise be provided.

Recommended dose: 400 mg PO OD for 2 wks, then 200 mg PO TIW, for a total duration of 24 wks

First drug with novel mechanism approved by FDA for TB since 1971.

BDQ may be added to a WHO-recommended regimen in adult MDR-TB patients under following conditions:

1) When an effective treatment regimen containing 4 second-line drugs in addition to PZA, according to WHO recommendations, cannot be designed

2) When there is documented resistance to any fluoroquinolone in addition to MDR3) Recommended for adults older than 18 yrs of age under carefully monitored conditions

NEWER DRUGS FOR MDR-TB PREVENTION STRATEGIES : BEDAQUILINE All patients should be monitored wkly for adverse effects.

EKGs should be monitored at baseline and at least 2, 12, and 24 wks after starting treatment.

Serum potassium, calcium, and magnesium should be measured at baseline and whenever clinically indicated, especially if QT interval prolongation is detected.

All patients started should be included in a registry for ongoing monitoring.

Additional notes: 1) Bedaquiline should never be used as a single drug.2) Bedaquiline has a long terminal half-life of 4-5 mos; should be discontinued before

other drugs in regimen.3) Rifamycins and other CYP3A4 inducers reduce bedaquiline concentrations.4) Bioavailability is significantly affected by food.

NEWER DRUGS FOR MDR-TB PREVENTION STRATEGIES : DELAMANID Nitro-dihydro-

imidazooxazole derivative of metronidazole

Inhibits mycolic acid synthesis

Potent preclinical in vitro and in vivo activity against both drug-susceptible and drug-resistant strains of TB

NEWER DRUGS FOR MDR-TB PREVENTION STRATEGIES : DELAMANID

• In November 2013, the European Committee for Medicinal Products for Human Use recommended granting a conditional marketing authorization for delamanid for the treatment of MDR-TB

• Recommended indication: – Use as part of an appropriate combination regimen for

pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability

NEWER DRUGS FOR MDR-TB PREVENTION STRATEGIES :LINEZOLID

Oxazolidinone, approved to treat drug-resistant, Gram-positive bacteria.

Good activity against MDR-TB in vitro and in animal studies.

Use in TB often limited due to long-term toxicities (bone marrow suppression, neuropathy)

However, retrospective chart review (2003-2007) of 30 pts (29 with pulmonary TB) who received linezolid 600 mg QD (plus vitamin B6) as part of a regimen for MDR-TB concluded -

1) Culture conversion occurred in all pulmonary cases at median of 7 wks

2) AEs occurred in only 9 patients, including peripheral and optic neuropathy, anemia/thrombocytopenia, rash, and diarrhea

3) Only 3 patients stopped linezolid treatment because of AEs

NEWER DRUGS FOR MDR-TB PREVENTION STRATEGIES :SUTEZOLID

Oxazolidinone, related to linezolid.

MOA: protein synthesis inhibition.

Like LZD, has a high barrier to resistance.

More potent than LZD in mice, whole blood culture.

Efficacy in mice similar to isoniazid and/or rifampin and may be synergistic with other first-line drugs.

May be safer than LZD.

NEWER DRUGS FOR MDR-TB PREVENTION STRATEGIES :PA-824

• PA-824: nitroimidazole-oxazine– Active in vitro and in mouse

models• Cross-resistant with delamanid• High protein binding may render PA-824 less accessible in cavities of

pulmonary TB• May be useful in combination regimens; synergistic with other drugs

MDR-TB WITH HIV CO-INFECTION

The treatment of HIV positive individual with MDR-TB is the same as for HIV negative patients.

Irrespective of CD4 cell counts, patients co-infected with HIV and TB should be started on ART as soon as possible after starting TB treatment. ART should be initiated as soon as possible in all HIV/TB-co-infected patients with active TB (within 8 weeks after the start of TB treatment).

For patients who are already on ART at the time of MDR-TB diagnosis be continued on ART when MDR-TB therapy is initiated.

MDR-TB IN PATIENTS WITH RENAL IMPAIRMENT Renal insufficiency due to

longstanding TB disease itself, previous use of aminoglycosides or concurrent renal disease is not uncommon.

Consideration needs to be taken that MDR-TB patients require aminoglycosides for 6 months or more.

Other drugs, which also might require dose or interval adjustment in presence of mild to moderate renal impairment,are: Ethambutol, Quinolones, Cycloserine and PAS.

MDR-TB IN PATIENTS WITH PRE-EXISTING LIVER DISEASE

In the RNTCP Regimen for MDR TB, Pyrazinamide, PAS and Ethionamide are potentially hepatotoxic drugs.

The potential for hepatotoxicity is increased in elderly, alcoholics and in patients with pre-existing liver disease.

In general, most of second line drugs can be safely used in presence of mild hepatic impairment, as they are relatively less hepatotoxic than the first-line drugs.

Pyrazinamide should be avoided in such patients.

MDR patients having deranged liver function test (LFT) during pre-treatment evaluation should be strictly monitored through monthly LFTs while on treatment.However routine LFT is not recommended in all cases.

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