**7. Management approaches for the contacts of MDR TB patients**

MDR-TB and XDR-TB cases are currently on the increase and it is expected that the number of their contacts will also increase, especially in densely populated area. Therefore, identifica‐ tion and proper management of these contacts are major components of drug resistant TB containment. In this regard, WHO recommend the identification of all close contacts of MDR-TB cases through contact tracing and their evaluation for TB infection.

A contact is defined as an individual who has a risk of acquiring TB because it has been exposed to Mtb by sharing air space with a person with infectious TB (the source case). The index case (a person with suspected or confirmed TB disease) is defined as the initial case of TB for a contact investigation [76]. He is not necessarily identical with the source case [76]. Many guidance documents focus on the source case and not the index case, as it is the source case who will have exposed the contacts, not necessarily the index case. Close contacts are those people sharing common habitation rooms with the source case. This can also include individ‐ uals with evidence of prolonged and frequent exposure to a source case in the workplace, school, prison, hospital ward, or social settings [77]. Contact tracing is defined as the systematic finding of contacts of patients with infectious TB disease [77]. The tracing helps identifying individuals who are particularly at high risk, such as individuals with HIV infection, young children and elderly.

agonist of the neuronal NMDA (*N*-methyl-D-aspartate) receptor for glutamate [71], which is a major excitatory neurotransmitter in the mammalian CNS [72]. The most dramatic effect of cycloserine reported so far is the suicide of 2 patients during the postoperative antibiotic treatment course following pulmonary resection [73]. Because of its neurological toxicities, cycloserine was prevented very early from being part of first line TB drugs but was recently reintroduced as one of the cornerstones of treatment for MDR- and XDR-TB [46]. Although coadministration of pyridoxine (vitamin B6) with cycloserine can reduce partially the neurolog‐ ical side effects, the later should be prescribed after psychiatric evaluation for patients with apparent convulsions and agitation [55]. Some clinicians favor terizidone (two cycloserine molecules combined) as they found the side effects associated with it are less severe and more manageable [55]. However, given the little evidence demonstrating safety and efficacy of

**Table 3.** Frequency of adverse events and suspected agents among 818 patients receiving MDR-TB treatment.PAS: para-aminosalicyclic acid; TM: thioamides; FQ: fluoroquinolones; CS: cycloserine; AG: aminoglycosides; CM: capreomycin.. Reprinted from Ref. 62 with permission of the International Union Against Tuberculosis and Lung

Disease. Copyright © The Union.

212 Tuberculosis - Current Issues in Diagnosis and Management

terizidone, it should be used with caution in TB patients intolerant to cycloserine.

Although adverse events associated with second-line drugs are a major obstacle in the management of MDR-TB, compared with first line treatment, DOTS-Plus programmes have achieved cure rates of greater than 70% even in resource-poor settings [74,75]. In general, the

Themanagement of contacts ofdrug-resistantTBpatients, in termofpreventive chemoprophy‐ laxis, remains a complex issue with a significant ethical dimension. In case of drug-susceptible TB, the provision of preventive INH therapy to suspect LTBI individuals is effective at reduc‐ ing the risk of developing disease among infected contacts [10]. In theory, such a preventive approach should also work for LTBI individuals exposed to MDR and XDR Mtb strains. Unfortunately, health care providers cannot predict with certainty the susceptibility pattern of a contact's isolate fromthe source case's isolate.Indeed,manydivergentdrug susceptibility test profiles in source-contact pairs have been reported [78,79], due either to infection of the contact by another source case or to infection before the source case acquires resistance. Such a scenar‐ io likely occurs in high-burden TB areas where different drug resistant strains may circulate in homes, schools, and workplaces.Therefore,the lack of effectivedrugs with acceptable adverseevent profile in an otherwise healthy individual is a prominent barrier to the treatment of drug resistant TB contacts. Indeed, if, to some extent, the occurrence of toxicity is accepted by MDR-TB patients (since the alternative is high risk of death), convincing healthy contacts to cope with adverse-events during preventive therapy in is fundamentally different.

Given the lack of clear evidence in support of preventive therapy, the WHO does not recom‐ mend universal use of second-line drugs for chemoprophylaxis in MDR-TB contacts. Current guidance for the management of drug resistant TB contacts are largely based on expert opinions, which do not reject nor support provision of preventive therapy with the currently available drugs. In this context a guidance document presenting the most up-to-date evidence and expert opinion regarding the management of contacts of MDR- and XDR-TB patients has been recently proposed (March 2012) by the European Centre for Disease Prevention and Control (ECDC) [76]. Box 1 summarizes key recommendations provided by ECDC document.

assessments. No specific time period for follow-up or periodicity of clinical assessments is recommended, but regular

Management of Drug-Resistant TB http://dx.doi.org/10.5772/55531 215

Studies conducted so far on the benefits and adverse events of preventive therapy are not conclusive in term of optimal treatment and duration for preventive treatment of MDR-TB contacts [80]. Therefore, well-designed randomized clinical trials for preventive therapy are urgently needed in settings where MDR-TB therapy and a strong national programme infrastructure are already in place. Further research is also needed to define the most effective contact-tracing procedures for contacts and the most effective follow-up procedures in healthcare workers constantly exposed to drug resistant TB. In addition, specific management approaches need to be established for children below the age of five years, children with HIV infection, immunocompromised individuals, pregnant women, and the elderly. Finally, whether MDR Mtb strains are more or less infectious and/or transmissible than drug-suscep‐

Individuals repeatedly in contact with infectious MDR TB or XDR TB cases (e.g. healthcare workers) should be re-

systematic, clinical observation is essential for the early detection of TB disease.

**Box 1.** ECDC expert opinions regarding preventive therapy of MDR- and XDR-TB contacts.

**8. Compliance issues from patients and health care providers**

1. Strengthen quality of basic TB and HIV/AIDS control 2. Scale up programmatic management of MDR-TB and XDR-TB

5. Develop and implement infection control measures

6. Strengthen advocacy, communication and social mobilization

3. Strengthen laboratory services

**Box 2.** WHO 8-point plan

4. Expand MDR-TB and XDR-TB surveillance

7. Pursue resource mobilization at all levels 8. Promote research and development of new tools

The treatment for MDR-TB is long and complex and relies on a handful of antibiotics with uncertain efficacy. The WHO has launched an 8-point plan to ensure optimal management of XDR-TB patients with currently available drugs (Box 2). However, guidelines do not always translateeasilyintorealworldpractice.Inadditiontodirectlyobservedtreatment,what support can be offered to convince a patient to continue painful treatment? And how should patients who have exhausted all treatment options with existing second-line drugs be cared for?

In many cases, MDR-TB treatment results in poor compliance with subsequent development of further drug resistance (i.e. XDR-TB), which leaves infected patients, namely HIV positive individuals, virtually untreatable using currently available drugs. The WHO defines a

examined periodically.

tible strains need to be clarified.

#### **Which factors should be evaluated to decide whether to provide preventive therapy to MDR TB contacts considered to have LTBI?**

When evaluating an MDR TB contact and deciding between the two options (to provide preventive therapy and/or careful clinical observation and information), an overall individual risk assessment should be conducted, taking into consideration the following: the MDR TB contact's risk for progression to TB disease; the drug susceptibility pattern of the source case of infection; and the contact's risk for adverse drug events if initiating preventive therapy.

#### **Are there any specific risk groups to whom special attention should be paid?**

Children below the age of five years and immunocompromised persons in close contact with MDR TB patients and considered to have LTBI are at particular risk of progressing to TB disease. These risk groups might benefit from preventive therapy. The preventive therapy may be interrupted if, based on further examination, infection is found to be unlikely.

Persons over five years of age in close contact with MDR TB patients and considered to have LTBI could also be considered for preventive therapy if the individual risk assessment indicates this course of action.

If the decision is made to put an individual on preventive therapy, the selection of the drugs should be based on:

the drug susceptibility pattern of the source case's likely infecting strain;

local patterns of drug resistance;

the potential adverse events in individual patients, taking into account age and other risk factors;

the selection of single or multiple drugs and the duration of treatment will depend on the availability of drugs with bactericidal activity for the particular infecting strain; alternatively, the decision can follow national guidelines.

#### **Which arrangements should be in place if preventive therapy is considered?**

If preventive therapy is considered by the expert physician or other healthcare provider, national legislation should ensure that the treatment costs for the patient are covered.

If preventive therapy is considered to be relevant for a particular individual, careful clinical monitoring and follow-up is essential for the detection of drug-adverse events and signs of TB disease if the preventive therapy is not effective.

#### **Specific opinions for XDR TB contacts**

As the currently available treatment options are very limited for XDR TB, it is likely that the risks of preventive therapy outweigh the benefits for contacts of XDR TB patients. Thus, the option to inform and observe the contacts will be preferable, given the currently available drugs and evidence.

**How should health authorities conduct follow-ups for MDR TB and XDR TB contacts suspected to have LTBI?** All MDR TB and XDR TB contacts considered to have LTBI who, after a comprehensive individual risk assessment, are not given preventive therapy should be followed-up by careful clinical observation.

Follow-ups should be performed according to existing national guidelines.

All persons in contact with MDR TB or XDR TB (after exclusion of TB disease) should be informed about the risks and symptoms, carefully observed, and provided with easy access to a specialized TB clinic in case of symptoms between assessments. No specific time period for follow-up or periodicity of clinical assessments is recommended, but regular systematic, clinical observation is essential for the early detection of TB disease. Individuals repeatedly in contact with infectious MDR TB or XDR TB cases (e.g. healthcare workers) should be reexamined periodically.

**Box 1.** ECDC expert opinions regarding preventive therapy of MDR- and XDR-TB contacts.

Studies conducted so far on the benefits and adverse events of preventive therapy are not conclusive in term of optimal treatment and duration for preventive treatment of MDR-TB contacts [80]. Therefore, well-designed randomized clinical trials for preventive therapy are urgently needed in settings where MDR-TB therapy and a strong national programme infrastructure are already in place. Further research is also needed to define the most effective contact-tracing procedures for contacts and the most effective follow-up procedures in healthcare workers constantly exposed to drug resistant TB. In addition, specific management approaches need to be established for children below the age of five years, children with HIV infection, immunocompromised individuals, pregnant women, and the elderly. Finally, whether MDR Mtb strains are more or less infectious and/or transmissible than drug-suscep‐ tible strains need to be clarified.
