X DRT TB

EXTENSIVELY DRUG RESISTENT TUBERCULOSIS : 

EXTENSIVELY DRUG RESISTENT TUBERCULOSIS AND WHITE

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Drug resistant Tb, particularly MDRTb pose a serious threat to universal goal of Tb cure Lack of new & effective alternative drug T/t Lack of rapid sensitive & specific diagnostic , culture, & sensitivity technology. Poor control programs & HIV Of recent the emergence XDR Tb

Drugs available : 

Drugs available FIRST Line Rx (4) Isoniazide Rifampin Pyrizinamide Ethambutol Second line Rx(6) Injectable Aminoglycoside- Streptomy, Kanamycin, amikacin Injectable polpeptide- Capreomycin Oral Agents- PAS, Ethionamide, Cycloserine Fluoroquinolones

Definition : 

Definition MULTIPLE DRUG RESISTENT Tb- Isoniazide + Rifampicin EXTENSIVELY DRUG RESISTANT Tb- Isoniazide + Rifampicin 3 of the 6 classes of second line agents WHO – Amikacin, Kanamycin, Capreomycin & Fluroquinolones (drug susceptibility reliable)

Epidemiology Of XDR Tb : 

Epidemiology Of XDR Tb 2006- KwaZulu Natal, SA, - several death in patients coinfected with HIV & Tb noted. 1539 Patients – suspicion of Tb 544 (35%) sputum +ve Tb 221 (41%) MDR Tb Of these 221 – 53 (23%) were XDR Tb Of these 53 – 44 were HIV +ve (CD4 – 64c/mm3) Only 15 (34%) of HIV received ART 52/53 died on average of 16 days from the time of sputum collection

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Survey (CDC & WHO) 17,690 isolates collected from 2000-2004 – overall prevalence of XDR Tb - 2%. Patients with XDR Tb when compared with MDR Tb – mortality risk 54% in Latvia 64% in US Feb 2008 – WHO reported XDR Tb in 45 countries Of the countries conducting routine surveillance XDR Tb represented 7 to 34% of MDR Tb

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Unfortunately – many countries don’t ve ability to test for 2nd drug suseptibility. Potential spread across the national boundaries- Air travel. 49 cases of XDR Tb reported in US (’93-06) Most important Risk Factor for XDR Tb Inadequate/poorly administrated Tb T/t HIV epidemic

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Although inadequate T/t of sensitive Tb may be the origin of resistant strain, majority of XDR Tb cases are by cluster transmission of primary resistance (fingerprint analysis). Once XDR Tb has appeared, it may be transmitted to patients who ve never been exposed to Tb before.

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Interaction between HIV & Tb – Bidirectional HIV increases Reactivation of Tb by 20 folds Risk of reinfection with potential resistant strain Tb Cellular activation Excessive cytokine & chemokine production that stimulates replication of HIV & contributes to AIDS Shorter overall survival Clinical manifestation of XDR Tb is not different from susceptible strains, h/e dis. course is fulminant.

Diagnostic test for XDR Tb : 

Diagnostic test for XDR Tb When do u suspect- Contact with other drug resistant cases. Previous self administered T/t for active Tb, T/t failure or relapse on emperic therapy especially with documented adherence. Presence of coinfection with HIV.

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Tools for Diagnosis – Clinical Radiological assessment Light microscopy of sputum smears Tuberculin test Interferon Gamma (bld/serum) Ag specific for M. Tb.- proposed as a complement or replacement for TST has higher specificity for M Tb Free of interpersonal interpretation of results Overcomes the lead for reevaluation at the second visit.

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Disadvantage Poor performance in HIV is poor & Test cannt differentiate b/e latent or active disease- making it less useful in dealing with XDR Tb. Confirmation of active XDR Tb – Acid fast stain Sputum c/s

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H/e when solid medium is used for culture- delay in diagnosis > 1 month. Automated liquid culture (detecting bacterial oxygen consumption/ CO2) ½ time but high rate of contamination and expensive. Other diagnostic methods for rapid identification are -

Management of XDR Tb : 

Management of XDR Tb Recommendation that follow – mainly based on guidelines for m/m MDR Tb All information about XDR Tb is based on expert opinion, rather than clinical trial data/ evidence. While no guidelines currently exist, occasion exist when empirically T/t for XDR Tb is started- Patient who develop active symptoms following contact with a known case or when a patient being treated with for MDR Tb has persistent +ve smear despite appropriate t/t

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The regimen selected must ve at least 4 drugs, till the time sensitivity is available. Self administration of medications as compared to direct observed therapy- Decreased compliance Poorer out come Optimal duration of T/t – unknown, inability to use rifampin, suggests at least 18 months of the therapy following sputum conversion.

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Whenever possible- Add Ethambutol and Pyrizinamide (improve survival). In susceptible cases- Pzd is used for initial 2 months only; h/e in XDR Tb it is used during the entire course under the assumption that chronically inflamed lung tissue will keep the required acidic environment for Pzd to be effective. An injectable agent should be a part of the regimen for XDR Tb

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Kanamycin: used in case of streptomycin resistant cases. Amikacin: used in kanamycin & streptomycin resistant cases. Capreomycin and Vyomycin: used when all above resistance is noted. Fluoroquinolones should be part of the t/t when possible. Potency however differ – levo, oflox & cipro are less potent in vitro than moxiflox or gatiflox.

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Other 2nd line drugs include thioamides- Ethionamide, prothionamide, PAS, Cycloserine. These ‘ve potential adverse effects, none of them comparable efficacy to other ATT. Thiacetazone – not used in HIV +ve – severe & potentially lethal cutaneous hypersensitivity rxns. Unproven agents with potential utility- Linezolid, amox/clavulanate, clarithromycin, clofazimine, imipenem, High dose of INH Special precautions -pregnancy & Children

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After several decades of draught in the pipeline of new ATT, sever al promising candidates are undergoing pharmacological evaluation & some are in clinical trails. Surgical resection in conjunction with pharmacological t/t ,might be useful in select patients with XDR Tb. Small series of patients with MDR Tb ve shown improved outcome with surgery as compared with antibiotics alone.

Pipeline of drugs in development with potential utility for XDR Tb : 

Pipeline of drugs in development with potential utility for XDR Tb

HIV Co Infection : 

HIV Co Infection All Patients with XDR Tb – to be tested for HIV. HIV +ve Patients on ART should continue therapy with specific ATT. For those not on ART, diagnosis of XDR Tb is an indication to start ART. Choice and timing of ART are important- Drug interaction – Rifampin & Protease Inhibitor well know – not to be given together

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Non nucleoside reverse transcriptor inhibitor based regimens are used. Nucleoside reverse transcriptor inhibitor considered only when 4 drugs are used. Rifabutin may be substituted for rifampin and co administrated with Protease inhibitor. WHO suggests deffering initiation of ART for 2 weeks/2 months following initiation of ATT- based on concerns: complexity of t/t regimens, risk of adverse events, Rx – Rx interaction, development of IRIS

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IRIS – Immune reconstitution inflammatory syndrome is paradoxical worsening of Tb manifestations or clinical appearance of previously asymptomatic ds associated with an increase of CD 4+ cell counts following initiation of ART. Concerns of developing IRIS – overrated Though common- 32%, usaully self limiting, fatal 1% Because of poor prognosis when associated with XDR Tb – best course- Initiate ART

Prevention & control Of XDR Tb : 

Prevention & control Of XDR Tb Conventional Chemoprophylaxis with 1st line Rx after exposure to XDR Tb- ineffective As with MDR Tb – use 1 0r 2 drugs to which primary isolate is susceptible for 6 – 12 months (consider in selected cases at risk of progressing from latent to active XDR Tb) BCG- Its protective effect against XDR Tb- unknown.

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Attempts to modify BCG- vaccine with urease BCG deleted & copy of Listeria monocytogenes gene encoding lysin inserted. Use of recombinant modified vaccinia virus General infection control for Tb Rapid recognition of cases & Prompt contact investigation. Cough hygiene & Etiquette Use of well ventilated rooms or High efficiency particulate air filtration

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Patients with XDR Tb – forbidden to travel by air until sputum smear negative In the event of an inadvertent exposure, all airplane crew & passenger exposed – contacted and investigated of its transmission. Involuntary detention who refuse to be treated/don’t adhere to the infection control procedure.

Global Strategies : 

Global Strategies In ’93 WHO identified Tb as a global health emergency & launched the “Global Plan to stop Tb”. Important component- DOTS DOTS Plus –includes the use to 2nd line drug. This expanded program- satisfactory results in management of MDR Tb, including OPD T/t. WHO– established Green Light Committee- coordinates with Pharma companies preferential prices for 2nd line drugs, & new guidelines for m/m & control of XDR Tb

CONCLUSION : 

CONCLUSION XDR Tb is emerging as highly threatening pathogen – in pervasive association with AIDS epidemic. Rapid test needed- resistance to 1st and 2nd line Rx T/t options for XDR Tb limited Infection control measures- reinforcements. Combined interventions of national, supragovernmental, transnational, public and private efforts required.

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