XDR-TB Presented by: :Mona Ahmed Sherif Supervised by: DR. SEHAM HAFEZ Supervised by: DR. SEHAM HAFEZ

What is XDR-TB? OR XDR-TB (Extensive /Extreme Drug Resistant TB) is MDR-TB that is also resistant to three or more of second-line drugs. MDR-TB that is resistant as well to any one of the fluoroquinolones and to at least one of three injectable second-line drugs (Amikacin, Capreomycin or Kanamycin).

Causes for drug resistance to tuberculosis Although its causes are microbial, clinical and programmatic, DR-TB is essentially a man-made phenomenon. From a microbiological perspective, resistance is caused by a genetic mutation that makes a drug ineffective against the mutant bacilli. From a clinical and programmatic perspective, it is an inadequate or poorly administered treatment regimen that allows a drug-resistant strain to become the dominant strain in a patient infected with TB.

Causes for drug resistance to tuberculosis Health-care providers  Inadequate regimens  Inappropriate guidelines  Noncompliance / Absence of guidelines  Poor training  No treatment monitoring  Poorly organized or funded TB control programmes. Patients:  Inadequate drug intake  Poor adherence  Lack of information, money, transportation  Adverse effects  Social barriers  Malabsorption  Coinfection with HIV Drugs:  Inadequate supply or quality  Poor quality  Poor storage conditions  Wrong dose or combination

Risk factors for XDR-TB The two strongest risk factors for XDR-TB are: (i)Failure of an anti-TB regimen that contains second-line drugs including an injectable agent and a fluoroquinolone. (ii) Close contact with an individual with documented MDR-TB or with an individual for whom treatment with a regimen including second-line drugs has failed.

Assessment of patients at risk for treatment failure Patients who do not show signs of improvement after 4 months of treatment are at risk for treatment failure. All patients who show clinical, radiographical or bacteriological evidence of progressive active disease, or reappearance of disease after month 4 of treatment, should be considered as being at high risk for treatment failure.

Recommendation for patients at risk for treatment failure : XDR-TB poses a severe public health threat, especially in populations with high rates of HIV. Recommendations (acc to the WHO Guidelines ) for Prevention of XDR-TB include: The treatment card should be reviewed to confirm that the patient has adhered to treatment.  Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission.  The treatment regimen should be reviewed in relation to medical history contacts and all DST reports. If the regimen is inadequate, a new regimen should be designed.  The bacteriological data should be reviewed (the smear and culture data are the strongest evidence that a patient is not responding to therapy).  The health-care worker should confirm that the patient has taken all the prescribed medicines.  Other illnesses that may decrease absorption of medicines (e.g. chronic diarrhoea) or may result in immune suppression (e.g. HIV infection) should be excluded.  Apply infection-control measures to avoid MDR-TB and XDRTB transmission to protect patients, health workers, others working in broader community, especially in high HIV prevalence settings.  If surgical resection is feasible, it should be considered.

Diagnosis DR-TB must be diagnosed correctly before it can be treated effectively. Case-finding strategies may vary depending on the epidemiological situation and local capacity.

Practically All suspects of DR-TB should have DST of isoniazid and rifampicin, the second-line injectable agents and a fluoroquinolone. For people living with HIV who are at risk of XDR-TB, given the high and rapid risk of death, DST of first- and second-line drugs is recommended.

XDR-TB While drug-susceptible TB can be cured within 6 months, forms of DR-TB require extensive chemotherapy for up to 2 years. It has proven that treatment of XDR-TB is much more difficult to than treating MDR-TB and is extremely difficult to treat in HIV-positive patients. Treatment outcomes are significantly worse in XDR-TB patients than in MDR-TB patients. While for HIV positive patients being promptly diagnosed with XDR-TB and placed on an adequate regimen have been shown to have cure rates that exceed 50%.

Management guidelines for patients with XDR-TB 1.Use any oral First line agents that may be effective. 2.Use an injectable agent (kanamycin, amikacin,capreomycin,streptomycin ) to which the strain is susceptible and consider an extended duration of use (12 months). If resistant to all injectable agents, it is recommended to use one that patient has never used before. 3.Use a later-generation fluoroquinolone such as moxifloxacin. 4.Use all Group 4 agents (Oral bacteriostatic second-line antituberculosis drugs) ethionamide,protionamide,cycloserine,terizidone,p-aminosalicylic acid that have not been used extensively in a previous regimen. 5.Use 2 or more agents from Group 5 (Antituberculosis drugs with unclear efficacy or unclear role in MDR-TB treatment (not recommended by WHO for routine use in MDR-TB patients) clofazimine,linezolid,amoxicillin/clavulanate,thioacetazone, clarithromycin, imipenem 6.Consider high-dose isoniazid treatment if low-level resistance is documented. 7.Consider adjuvant surgery if there is localized disease. 8.Ensure strong infection control measures. 9.Treat HIV. 10.Provide comprehensive monitoring and full adherence support.

Conclusion Programmatic management of DR-TB is a complex health intervention, and no one strategy will fit all situations. Programe managers need to consider the epidemiological, financial and operational factors when deciding which strategy to use.

DR-TB and HIV co-infection HIV infection is a significant challenge for the prevention, diagnosis and treatment of DR-TB, especially in the case of MDR-TB and XDR-TB. The diagnosis of TB (including MDR-TB and XDR-TB) in HIV-infected people is more difficult and may be confused with other pulmonary or systemic infections. The presentation is more likely to be extrapulmonary or sputum smear-negative than in HIV-uninfected TB patients, especially as immunosuppression advances. This can result in misdiagnosis or delays in diagnosis, and in turn, higher morbidity and mortality. Reports have shown high mortality rates among HIV- infected patients with DR-TB.

Mangment of DR-TB and HIV Coinfection Use mycobacterial cultures and newer more rapid methods of diagnosis. Perform DST at the start of antituberculosis therapy. Determine the extent (or prevalence) of TB drug resistance in patients with HIV. Introduce ART (AntiRetrovial Therapy )rapidly in DR-TB/HIV patients. Consider empirical therapy with second-line antituberculosis drugs. Provide CPT (co-trimoxazole preventive therapy) for patients with active TB and HIV. Arrange treatment follow-up by a specialized team. Implement additional nutritional and socioeconomic support. Ensure effective infection control.

Concomitant treatment of DR-TB and HIV The treatment of DR-TB in patients with HIV is very similar to that in patients without HIV, with the following exceptions: ART plays a vital role, as mortality in MDR-TB/HIV patients without the use of ART is extremely high (91–100% ). The use of ART in HIV-infected patients with TB improves survival for both drug-resistant and susceptible disease. Adverse effects are more common in patients with HIV, due to multiple medicines involved in DR-TB with recognized high toxicity risks, often combined with ART, results in a high incidence of adverse effects. Some toxicities are common to both antituberculosis treatment and ART, which may result in added rates of adverse events. Monitoring needs to be more intense for both response to therapy and adverse effects. IRIS (immune reconstitution inflammatory syndrome) may complicate therapy.

Supportive care for patients in whom all the possibilities of XDR-TB treatment have failed A number of supportive measures can be used once the therapy has been suspended. It is very important that medical visits continue and that the patient is not abandoned.

These supportive measures are :  Pain control and symptom relief. Paracetamol, or codeine with paracetamol,gives relief from moderate pain. Codeine also helps control cough.Other cough suppressants can be added. If possible, stronger analgesics,including morphine, could be used when appropriate to keep the patient adequately comfortable.  Relief of respiratory insufficiency. Oxygen can be used to alleviate shortness of breath. Morphine also provides significant relief from respiratory insufficiency and should be offered if available.  Nutritional support. Small and frequent meals are often best for a person at the end of life. It should be accepted that the intake will reduce as the patient’s condition deteriorates and during end-of-life care. Nausea and vomiting or any other conditions that interfere with nutritional support should be treated.  Regular medical visits. When therapy stops, regular visits by the treating physician and support team should not be discontinued.  Continuation of supplementary medicines. All necessary additional medications should be continued as needed. Depression and anxiety, if present, should be addressed.  Hospitalization or nursing home care.  Preventive measures. Oral care, prevention of bedsores, bathing and prevention of muscle contractions are indicated in all patients. Regular scheduled movement of the bedridden patient is very important.  Infection control measures. The patient who is taken off antituberculosis treatment because of failure often remains infectious for long periods of time. Infection control measures should be continued.