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MDR TB Guidelines

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					National Guidelines For The Management of Drug Resistant Tuberculosis

Submitted for final approval on March 18, 2009

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Table of Contents

S.No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Abbreviations Foreword

Contents

Message by the Manager of the National TB Control Program Message by the President Pakistan Chest Society Chapter: I Chapter: II Chapter: III Chapter: IV Chapter: V Chapter: VI Chapter: VII Chapter: VIII Chapter: IX Chapter: X Chapter: XI Background Definitions of drug resistance and diagnostic Category IV Case Finding Strategies Treatment Strategies MDR- TB Management of Side Effects of MDR- TB drugs Treatment of MDR-TB In Special Conditions Management of Treatment Failure Cases (XDR) of MDR TB Management of Contacts of MDR-TB Cases Category IV Recording and Reporting System Forms Annexes

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Abbreviations
ACSM AFB AIDS AK ART ATT BMU BSL CBC CDC CHW CPT CTBC CXR DoH DOTS DR DRS DR-TB DRTBMU DST EP EQA ESR FANA FATA FDC FIDELIS FLD GDF GLC GPs HBCs HIV HRD ICT IDs IDL IEC IHC IPT ISTC JICA KAP KFT LFT Advocacy, Communication & Social Mobilization Acid Fast Bacilli Acquired Immuno Deficiency Syndrome Azad Kashmir Anti- Retroviral Therapy Anti TB Treatment Basic Management Unit Bio Safety Level Complete Blood Picture Centers for Disease Control and Prevention Community Health Worker Co-trimoxazole Preventive Therapy Community-based TB Care Chest X-Ray Department of Health Directly Observed Treatment Short course Drug Resistance Drug Resistance Surveillance or Survey Drug Resistant Tuberculosis Drug Resistant Tuberculosis Management Unit Drug Susceptibility Testing Extra-pulmonary Tuberculosis External Quality Assurance Erythrocyte Sedimentation Rate Federally Administered Northern Areas Federally Administered Tribal Areas Fixed Dose Combination (or FDC anti-TB drug) Fund for Innovative DOTS Expansion, managed by IUATLD First Line Drugs Global TB Drug Facility Green Light Committee General Practitioners High Burden Countries Human Immuno-Deficiency Virus Human Resource Development Islamabad Capital Territory Infectious Diseases Intermediate District Laboratory Information, Education & Communication Integrated HIV Care (a programme of the Union) Isoniazid Preventive Therapy International Standards for Tuberculosis Care Japan International Cooperation Agency Knowledge, Attitudes & Practice Kidney Function Test Liver Function Test 3

LHWs LQAS MCH MDGs MDR MoH MTB NA NAP NGOs NRL NTM NTP PAL PAS PCS PHC PLWHA PPM PRL PT PZA QA R&R SLD SNRL SOPs The Union TSH TWG UNAIDS UNITAID USAID VCT WHO

Lady Health Workers Laboratory Quality Assurance Services Mother and Child Health Millennium Development Goals Multi Drug Resistant Ministry of Health Military Tuberculosis Northern Areas National AIDS Control Programme Non Governmental Organizations National Reference Laboratory Non Tuberculosis Mycobacteria National Tuberculosis Program Practical Approach to Lung Health Para-amino Salicylic Acid Pakistan Chest Society Primary Health Care Patients Living with HIV/AIDS Public–Private or Public–Public Mix Provincial Reference Laboratory Pulmonary Tuberculosis Pyrazinamide Quality Assurance Recording and Reporting Second Line Drugs Supra National Reference Laboratory Standard Operating Procedures International Union Against Tuberculosis and Lung Disease Thyroid Stimulating Hormone Technical Working Group Joint United Nations Programme on HIV/AIDS International Facility to Treat HIV/AIDS, Malaria and TB United States Agency for International Development Voluntary Counseling and Testing for HIV infection World Health Organization

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Foreword In pursuance of the mandate given to the guidelines committee by the Governing Council of Pakistan Chest Society (PCS), a working group of experts was organized to prepare guidelines for treatment of Multi-drug resistant Tuberculosis (MDR) and Extensively resistant tuberculosis(XDR).It was decided by way of an understanding between the President PCS and National Tuberculosis Programme (NPT) Manager that as in the case of Tuberculosis guidelines this document shall be adopted by the NTP. PCS guidelines committee agreed to prepare this these guideline in lines of the WHO programmatic management guidelines for practical application in the National Tuberculosis programme. Therefore, the working group of PCS in collaboration with NTP committee for Drug resistence in Tuberculosis has prepared the guidelines for the use by Physician who are faced with treatment of this very dreadful and deadly disease with a very expensive treatment protocol. This document is continuation of guidelines for the treatment of Tuberculosis already issued and recently updated by the PCS under endorsement by the National Tuberculosis Programme (STOPTb Pak) and published for use by all Physicians. This document is recommended to be read and understood by all Physicians but is to be used practically by only those Physicians who have the facilities to diagnose and treat MDR and XDR Tuberculosis. This is also a guideline for the policy makers and health logistics and management experts to plan, provide and create management facilities at all levels of health care delivery system. This is also an advocacy to create uniformity in thought and actions of all those dealing with this disease so that the present and future epidemiology of this disease can be understood and recorded. It is also essential to have a uniform guideline directed DOTS Plus programme to be able to qualify for Global Drug Facility under Green Light Committee (GLC). The National Tuberculosis Programme (NTP) endorses these guidelines and have adopted these as National MDR / XDR Tb management guidelines. Acknowledgement is due to all members and co-opted members of the working group and the partners from the National Tuberculosis Programme for their remarkable, dedicated and in depth review of the literature and their efforts to prepare this document which is tailored to meet our national tuberculosis control goals. Our very profound thanks are due to all the reviewers for their very valuable recommendations and suggestions. Pakistan Chest Society and National Tuberculosis programme shall make every effort to ensure widespread availability of these guidelines at all levels and undertake and advocacy project for dissemination of this knowledge. PCS and NTP stand committed to updating these
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guidelines periodically to remain in step with the ever expanding sea of knowledge based on evidence in this particular field.

Prof Dr WAJID ALI Chairman Working Group PCS Guidelines committee for MDR/XDR TB

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Message by the Manager of the National TB Control Program

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Message by the President Pakistan chest Society
It is with a measure of pleasure, satisfaction and pride that the guidelines on the management of MDR TB are being presented by the Pakistan Chest Society(PCS) along with National Tuberculosis Programme . The PCS having undertaken this very essential task has endeavored to bring locally relevant guidelines for use by the medicos because despite having one of the best medical education system for doctors, Pakistan performs poorly in several healthcare indicators even amongst the developing countries. Although this can be attributed to some extent to the lack of resources, this is only partially true. Even in the high priority areas such as communicable diseases and Mother and Child Health which attract relatively large proportion of resources the desirable results are rarely achieved. One of the major reasons for lack of improvement is the lack of uniform and valid guidelines to manage common disorders. The standard of care provided varies a lot even between different centres of excellence, depending much on the individual preferences rather than on any accepted guidelines. This is abundantly clear in the management of Tuberculosis. Failure to adhere to uniform and standard regimes of treatment is a major cause of MDR TB. In fact, it can be argued that lack of adherence to the standard guidelines is the cause of MDR TB. Therefore, the need of guidelines for the treatment of MDR TB can not be overemphasized and providing evidence based solutions for the treatment of MDR TB is vital. Only an evidence based approach which follows standard protocols and procedures can ensure that we can overcome the huge burden of disease posed by Tuberculosis and MDR TB. It is therefore encouraging to note that Pakistan Chest Society and NTP have taken up the challenge and developed these guidelines. These guidelines provide a highly valuable resource for the practicing physicians. Most evidence based national guidelines are extrapolated from the literature published in developed countries, and thus, may not be applicable for the large populations due to difference in resources, available interventions and lack of relevant investigations. These guidelines are local in context, guided by the resources and problems we have in our clinical practice. The real test of any guidelines is when these are applied in practice. Many of the problems in application of these guidelines will become evident when the practicing practitioners apply these in the clinical practice. We will, therefore, welcome any suggestions and criticism which will help us to improve these guidelines. I hope that Pakistan Chest Society and NTP will continue to improve these guidelines and make further improvements when new evidence becomes available. I hope that our society will be able to evolve a mechanism and forum by which new guidelines are continuously developed and updated for all the major disorders in Chest Medicine. Finally I would like to thank my colleagues who have put untiring efforts and time in preparing this document. Pakistan Chest Society remains committed to always endeavor for the achievement of best possible clinical practices and methodologies. Prof Arshad Javed President Pakistan Chest Society

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Chapter: I Background
Mycobacterium Tuberculosis has infected human beings all over the world for a very long time. The emergence of Mycobactericidal drugs like Streptomycin, Rifampacin and Isoniazid in 20th century with adequate drug combination treatment protocols, created a hope that the disease has been controlled. This resulted in the sense of security to allow these patients to live and be treated in the community rather than isolation. The result of this strategy was largely negative. After a few decades, especially in under developed and developing countries where case surveillance was inadequate to poor drug resistant strains started to emerge. The aspects of poor drug quality, non availability of drugs with interrupted supplies, poor health education and inadequate patient follow up, poverty and malnutrition and lack of political commitment and resource mobilization contributed to emergence of drug resistant strains of Mycobacteria. Initially the drug resistance was to single drugs and in local pockets of population, which gradually increased to multiple drug resistance in large populations. Keeping in view this resistance pattern newer drugs were introduced as second line Antituberclosis drugs as add on therapy to sensitive first line drugs. This although showed some promise, failed to actually control the pattern. However, it was established that if supervised First line therapy was adequately administered for sufficient length of time as in Directly Observed therapy (DOTS) it would show overall benefit and even some clinically resistant cases could be cured. This strategy is still working well although there are cases which require specialized diagnostics to establish resistance pattern and therapy thereof. Therapy for multi drug resistance is expensive, prolonged and associated with multiple drug adverse effects. These factors have contributed to poor patient compliance and further increase in prevalence of Multiple drug resistance in various communities. Stop Tb programme of WHO has addressed the issue by implementing DOTS programme in most communities and since year 2000 it has supplemented this programme with DOTS – plus strategy for drug resistance. DOTS Plus programme has shown definite scientific benefit in the communities where it has been implemented properly. On the other hand, resistance to second line Anti Tuberculosis drugs has been reported, again due to logistic inadequacies, poor training and lack of diagnostic and treatment facilities. Since 2006 WHO recognizes extreme or extensively resistant Mycobacterium Tuberculosis now classified as XDR. MDR / XDR TB has high association with immune incompetent states especially HIV infected individuals. Fortunately, HIV prevalence in Pakistan remains low. On the other hand increasing number of Transplant recipients, chronic liver disease patients, increasing populations of Diabetics and post Cancer chemotherapy individuals are at a greater risk of contracting MDR & XDR strains. Drug abuse especially Heroin addiction increases the risk many fold. Pakistan falls in the category of high burden countries of Tuberculosis infection as the country stands 8th in the High burden countries (out of 22 countries) and 4th among the 27 high burden MDR-TB countries. MDR/ XDR TB is emerging as serious threats to Pakistani nation and factors like poverty and malnutrition, poor housing and sanitation, inadequate health care facilities, population migration and urbanization, political instability and refugee influx have continued to aggravate the problem. MDR & XDR TB is resistant to the most powerful first
line drugs as well as some of the second-line drugs. Patients are left with treatment options that are often less effective, require prolonged period of treatment with very expensive drugs and higher risk of 9

side effects and treatment failure. Factors like proper diagnosis, isolation, implementing DOTS properly, prescribing correct treatment regimen by properly trained staff, and comprehensive social support for the duration of the treatment are some of the important steps to bring the high burden of MDR TB in Pakistan in line with WHO standard of MDR-TB strategy.

The National TB control program is actively working to submit an application to the Green Light Committee to ensure the procurement of quality assured 2nd line drugs for the treatment of DR-TB patients. We are very grateful for the leadership team and colleagues at the Pakistan Chest Society for their valuable contribution to this guidelines. We also want to express our gratitude to our expert team of Technical working group for their input and recommendations.

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Chapter: II
Definitions of Drug Resistance and Diagnostic Category IV
DR-TB is confirmed through laboratory tests that show that the infecting isolates of Mycobacterium tuberculosis grow in vitro in the presence of one or more anti-tuberculosis drugs. Four different categories of drug resistance have been established: • Mono-resistance: resistance to one antituberculosis drug. • Poly-resistance: resistance to more than one first line antituberculosis drug other than both isoniazid and rifampicin. • Multidrug-resistance: resistance to at least isoniazid and rifampicin. • Extensive drug-resistance: resistance to any fluoroquinolone, and at least one of three injectable second-line drugs (capreomycin, kanamycin and amikacin), in addition to multidrug-resistance.

Diagnostic Category IV includes patients with:
• Confirmed MDR-TB. * Poly-resistant TB. Some cases of poly-resistant TB will require Category IV treatments. These patients require prolonged treatment (18 months or more) with first-line drugs combined with two or more second-line drugs and should be entered into the Category IV register.

Site of drug-resistant TB disease
(pulmonary and extrapulmonary) In general, recommended treatment regimens for drug-resistant forms of TB are similar, irrespective of site. The importance of defining site is primarily for recording and reporting purposes. • Pulmonary TB. Tuberculosis involving only the lung parenchyma. • Extrapulmonary TB. Tuberculosis of organs other than the lungs, e.g. pleura, lymph nodes, abdomen, genitourinary tract, skin, joints and bones, meninges. Tuberculous intrathoracic lymphadenopathy (mediastinal and/ or hilar) or tuberculous pleural effusion, without radiographic abnormalities in the lungs, therefore constitutes a case of extrapulmonary TB. The definition of an extrapulmonary case with several sites affected depends on the site representing the most severe form of disease. Patients with both pulmonary and extra pulmonary TB should be classified as a case of pulmonary TB.

Bacteriology and sputum conversion
Bacteriological examinations used in patients with DR-TB include sputum smear microscopy and culture. Sputum smear microscopy and culture should be performed and results reported according to international standards of WHO guidelines.. These examinations should be done at the start of treatment to confirm TB disease and to group the patients according to infectiousness, sputum smear positive being most infectious. At least one sputum sample for smear and culture should always be taken at the time of starting Category IV treatment. In order for a patient to be considered culture- or sputum smear-positive at the start of Category IV treatment, the following criteria must be met: at least one pre-treatment culture or smear was positive; the collection date of the sample on which the culture or smear was performed was less than 30 days before, or 7 days after, initiation of Category IV treatment. Sputum conversion is defined as two sets of consecutive negative smears ( each set includes 3 consecutive samples collected on 3 separate days) and cultures, from samples collected at least 30 days apart. Both bacteriological techniques (smear and culture) should be used to monitor patients throughout therapy. The date of the first set of negative cultures and smears is used as the date of conversion (and the date to determine the length of the initial phase and treatment). 11

The recording and reporting system assesses the smear- and culture-status 6 months after the start of treatment as an interim outcome.

Category IV patient registration group based on history of previous antituberculosis treatment:
Category IV patients should be assigned a registration group based on their treatment history, which is useful in assessing the risk for MDR-TB. The treatment history should be assessed at the time of collecting the sputum sample, which is ultimately used to confirm MDR-TB. Patients registered as Category IV without laboratory confirmation of MDR-TB should be grouped by their status when registered as diagnostic Category IV. Each Category IV patient should be classified in two different ways: I. Classification according to history of previous drug use and treatment, mainly to assign the appropriate treatment regimen. • New. A patient who has received no or less than one month of antituberculosis treatment. Patients are placed in this group if they had sputum collected for DST at the start of a Category I regimen and were then switched to a Category IV regimen because MDR-TB was later confirmed. They should be considered “new” if DST was performed within one month of the start of treatment (even if they had received more than one month of Category I treatment by the time the results of DST returned and they were registered as Category IV). • Previously treated with first-line drugs only. A patient who has been treated for one month or more for TB with only first-line drugs. • Previously treated with second-line drugs. A patient who has been treated for one month or more for TB with one or more second-line drugs, with or without first-line drugs. • Relapse. A patient whose most recent treatment outcome was “cured” or “treatment completed”, and who is subsequently diagnosed with bacteriologically positive TB by sputum smear microscopy or culture. • Treatment after default. A patient who returns to treatment, bacteriologically positive by sputum smear microscopy or culture, following interruption of treatment for two or more consecutive months. • Treatment after failure of Category I. A patient who has received Category I treatment for TB and in whom treatment has failed. Failure is defined as sputum smear positive at five months or later during treatment. • Treatment after failure of Category II. A patient who has received Category II treatment for TB and in whom treatment has failed. Failure is defined as sputum smear positive at five months or later during treatment. • Transfer in. A patient who has transferred in from another register for treatment of DR-TB to continue Category IV treatment. • Other. There are several types of patients who may not fit into any of the above categories. Programs are encouraged to classify these patients into groups that are meaningful according to the local epidemiology of disease. Examples include the following: sputum smear positive patients with unknown previous treatment outcome; sputum smear positive patients who received treatment other than Category I or II (possibly in the private sector); previously treated patients with extrapulmonary TB; patients who have received several unsuccessful treatments, were considered incurable by health staff and who have lived with active TB disease with no or inadequate treatment for a period of time (duration depends on country situation) until Category IV treatment became available 12

Definitions for Treatment Outcomes of Category IV patients
The following are mutually exclusive Category IV outcome definitions that rely on the use of laboratory smear and culture as a monitoring tool. • Cured. A Category IV patient who has completed treatment according to program protocol and has at least five consecutive negative cultures from samples collected at least 30 days apart in the final 12 months of treatment. If only one positive culture is reported during that time, and there is no concomitant clinical evidence of deterioration, a patient may still be considered cured, provided that this positive culture is followed by a minimum of three consecutive negative cultures taken at least 30 days apart. • Treatment completed. A Category IV patient who has completed treatment according to program protocol but does not meet the definition for cure because of lack of bacteriological results (i.e. fewer than five cultures were performed in the final 12 months of treatment). • Died. A Category IV patient who dies for any reason during the course of MDR-TB treatment. • Failed. Treatment will be considered to have failed if two or more of the five cultures recorded in the final 12 months of therapy are positive, or if any one of the final three cultures is positive. (Treatment will also be considered to have failed if a clinical decision has been made to terminate treatment early because of poor clinical or radiological response or adverse events. These latter failures can be indicated separately in order to do subanalysis). • Defaulted. A Category IV patient whose treatment was interrupted for two or more consecutive months for any reason without medical approval. • Transferred out. A Category IV patient who has been transferred to another reporting and recording unit and for whom the treatment outcome is unknown. Patients who have transferred in should have their outcome reported back to the treatment centre from which they originally were registered. The responsibility of reporting their final outcomes belongs to the original treatment center.

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Chapter: III
CASE FINDING STRATEGIES
General Consideration It is very important to identify DR-TB cases as early as possible and initiate the treatment to prevent the patient from spreading the disease to other healthy members of the community.

Strategy for case finding of DR- TB
Access to DST is required. Under exceptional and extremely rare circumstances , and while building the NRL capacity, patients with a very high risk of DR-TB may be enrolled in CAT IV regimen without individual DST. The two groups that are most likely to be considered for direct enrolment in Category IV regimens are discussed below. • Category II failures (chronic TB cases) . Patients in whom Category II treatment has failed in sound NTPs often have DR-TB. If the quality of DOT is poor or unknown (i.e. if regular ingestion of the medicines during Category II treatment is uncertain), patients may fail Category II treatment for reasons other than DR-TB. • Close contacts of DR-TB cases who develop active TB disease. Close contacts of DR-TB patients who develop active TB disease can be enrolled for treatment with Category IV regimens.

Table: Target Groups of drug susceptibility testing
Failure of re-treatment Chronic TB cases are defined as patients who are regimens and chronic TB still sputum smear-positive at the end of a recases treatment regimen. These patients have perhaps the highest MDR-TB rates of any group, often exceeding 80% Exposure to a known Most studies have shown close contacts of MDRMDR-TB case TB patients to have very high rates of MDR-TB. Failure of Category I Failures of Category I are patients who while on treatment are sputum smear-positive at month 5 or later during the course of treatment. Not all patients who fail a regimen have MDR-TB, and the percentage may depend on a number of factors, including whether rifampicin was used in the continuation phase and whether DOT was used throughout treatment. Failure of anti-tuberculosis Anti-tuberculosis regimens from the private sector treatment in the private can vary greatly. A detailed history of drugs used is sector essential. If both Isoniazid and Rifampicin were used, the chances of MDR-TB may be high. Sometimes second-line anti-tuberculosis drugs may have been used, and this is important information for designing the re-treatment regimen. Relapse and return after Evidence suggests that most relapse and return after
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default without treatment failure

recent default cases do not have MDR-TB. However, certain histories may point more strongly to possible MDR-TB; for example, erratic drug use or early relapses. Exposure in institutions that Patients who frequently stay in homeless shelters, have MDR-TB out breaks prisoners in many countries and health-care workers or a high MDR-TB in clinics, laboratories and hospitals can have high prevalence rates of MDR-TB. Residence in areas with MDR-TB rates in new cases in many areas of the high MDR-TB prevalence world can be high enough to justify routine MDRTB testing in all new cases. History of using anti- The percentage of MDR-TB caused by use of poortuberculosis drugs of poor quality drugs is unknown but considered significant. or unknown quality It is known that poor-quality drugs are prevalent in all countries. All drugs should comply with qualityassured WHO standards. Co-morbid conditions associated with malabsorption or rapid transit diarrhea HIV in some settings Malabsorption may result in selective low serum drug levels and may occur in either HIV-negative or -positive patients. The 1999–2002 Global Surveillance did not find HIV to be a risk factor. However, numerous MDRTB outbreaks have been documented in HIV patients, and in some areas of the world HIV is a risk factor for MDR-TB.

Laboratory aspects
A definitive diagnosis of DR-TB requires that M. tuberculosis be isolated on culture, identified and DST completed. Rationalized use of culture and DST for DOTS plus programmes is however recommended and need to be based on guidelines for case finding and treatment monitoring strategy for DR TB cases . Key recommendations  All patients suspected of DR-TB shall have an free access to laboratory services for adequate and timely diagnosis of DR-TB;  TB Laboratories should develop proficiency to isoniazid and rifampicin as a minimum and then consider DST of other drugs *  Only TB Laboratories having adequate capacity and expertise for First line drugs should develop DST of the fluoroquinolones and second-line injectable agents e exist;*  Standard procedures and guidelines should be followed for safe transportation of infective material (clinical and culture isolates));  Tb Laboratories should follow all standardized protocols for infection control and biosafety;  Quality control and quality assurance should be in place for microscopy, culture and DST. Links with National TB reference laboratories are strongly encouraged.

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1. General definitions for the laboratory and DST The following are common definitions of the laboratory aspects : • Critical drug concentration. The lowest concentration of drug that will inhibit 95% (90% for pyrazinamide) of wild strains of M. tuberculosis that have never been exposed to drugs, while at the same time not inhibiting clinical strains of M. tuberculosis that are considered to be resistant (e.g. from patients who are not responding to therapy). • Minimum inhibitory drug concentration. The lowest concentration of drug that will inhibit growth of the M. tuberculosis isolate in vitro. • Reproducibility. The ability of a test or experiment to be accurately reproduced, or replicated, under independent conditions. Reproducibility relates to the agreement of test results across different laboratories and laboratory technicians or technologists. • Reliability. The extent to which a test result remains consistent when repeated under identical conditions. Reliability does not imply validity. A reliable test generates a consistent result that may not necessarily be accurate, e.g. clinical efficacy may not be accurately predicted, even if a test is highly reliable. • Cross-resistance. Resistance mutations to one anti-tuberculosis drug may confer resistance to some or all of the members of the drug family and, less commonly, to members of different drug families. 2. Organization of the laboratory network: Quality assured Microscopy Network which is considered cornerstone for TB diagnosis is appropriately established providing access to all TB suspects and patients. This section concentrates on the activities of Level III TB laboratories performing culture and DST To enhance laboratory diagnostic capacity for early and appropriate case detection and treatment of MDRTB, Plans for scale up of culture and DST network is being implemented in phased manner starting from National, provincial and regional level . All culture and DST laboratories would be supported initially to build capacity using conventional methods ( solid egg base media) against First line drug susceptibility testing of isoniazid and rifampicin as a minimum; and then DST of other first-line anti tuberculosis drugs will be added . Once DST of first-line drugs operates at a consistently high level of proficiency, laboratories serving at National and Provincial level would be supported for extending their services to DST of secondline drugs. Routine DST of second-line drugs is not recommended unless  The required laboratory infrastructure and capacity have been established,  Rigorous quality assurance is in place and  Sustainable proficiency has been demonstrated to isoniazid and rifampicin. Only after demonstrated experience in culture and DST using conventional methods, liquid base systems would be be introduced in the NRL as a first priority After this subsequent expansion of liquid culture and DST capacity to provincial and regional TB culture and DST laboratories will be determined by need and availability of funding.

3.General considerations
Given the urgent need for expansion of laboratory services in support of DR-TB control programmes, NTP recommend adoption of existing laboratory standards outlined in guidelines published by WHO and the IUATLD on laboratory services for TB control, incorporating key points from new WHO policies on the use of liquid culture, second-line DST and use of molecular methods . National manual giving details of all relevant SOP to ensure standardization in TB laboratories providing culture identification and DST services will soon be made available .

3.1:Essential laboratory services and infrastructure
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All diagnostic services for DOTS Plus programme shall be provided free of cost to the patients. All DRTBMU need to be formally linked with laboratories for diagnostic services (mycobacterial /clinical ).These laboratories may either be housed within MDR management units/treatment centres or outside DR TBMU in same city or other city . Diagnostic services for Optimal management of DR-TB requires both mycobacterial and clinical laboratory services. At a minimum,  Mycobacteriology laboratory service  For DR TB case finding :should provide culture, confirmation of M. tuberculosis and DST of isoniazid and rifampicin.  For DR TB case treatment monitoring :should provide culture . All laboratories providing culture and DST services for DOTS plus programme shall be enrolled in EQA scheme with National or supra National reference laboratory. NTP  Clinical laboratory services should provide basic haematology, biochemistry, serology and urine analysis, required for the adequate evaluation and monitoring of patient Surveillance of prevailing drug resistance pattern: In addition to diagnostic services, laboratories supporting DR-TB control programmes shall also play critical role in surveillance of prevailing drug resistance pattern and trends, . 3.2:Transport of infectious specimen: Specimens from patients suspected of having DR-TB as well as cultures of M. tuberculosis pose a significant public health risk. Sputum Specimen from MDR patients shall be collected in safe place by trained laboratory staff in MDR management unit/treatment centre. In case of non availability of appropriate laboratory facility within MTBDR unit , collected specimen shall be transported to TB culture and DST laboratory linked with this centre. It is recommended that Laboratory of the treatment centre (DRTBMU) shall be responsible for safe transportation of specimen recording and reporting of culture and DST result and liaison with referral laboratory for specimen transport and collection of reports of the MDR suspect/patients . Laboratory staff of DRTBMU shall also be responsible to ensure rapid, reliable and safe means of collection and transfer of specimens/ cultures along with request /clinical information to preidentified TB laboratory and for receiving results.(annex: instruction for transportation of specimen) 3.3:Time for testing and reporting: turnaround time: To ensure rapid diagnosis of M. tuberculosis and DR-TB, laboratories need to monitor turnaround time :Growth detection and identification of M. tuberculosis may take 3–8 weeks on solid media and 1–2 weeks in broth media. DST of an M. tuberculosis isolate takes an additional 2–4 weeks in solid media and 1 week in broth media. 3.4:Transmission of TB – M. tuberculosis is classified as a Risk Group 3 laboratory pathogen by WHO Transmission of TB including MDR-TB and XDR-TB – is a well recognized risk for laboratory workers. requires specific laboratory containment measures. 3.5:Infection control and biosafety in the laboratory:. Mycobacteriological culture and DST generate high-concentration aerosols requiring bio-safety level- III containment precautions. 3.6:Health and medical surveillance of laboratory personnel involved in mycobacteriological culture and DST are strongly recommended. Surveillance need to include a detailed medical history, targeted baseline health assessment, monitoring of respiratory signs and symptoms, and a proactive plan for appropriate medical investigations when indicated. 3.7:Quality control and quality assurance: A diagnosis of DR-TB has profound implications for the individual patient therefore, accuracy of the laboratory diagnosis is crucial, and a comprehensive laboratory quality assurance programme must be in place to ensure the accuracy, reliability and 17

reproducibility of DST results. Quality control or quality assurance procedures needs to be performed regularly as an integral part of laboratory operations. In this regard National reference laboratory soon after establishing formal links with supranational reference laboratory make necessary arrangement for EQA of TB culture and DST services in other laboratories (public and private). 3.8:Exchange of M. tuberculosis cultures between countries (e.g. for diagnostic DST, retesting or proficiency testing) shall be subject to international regulations, including specific national import and export regulations. 4.MYCOBACTERIOLOGICAL SERVICES IN DOTs Plus Programme . 4.1: Microscopy: Microscopy for acid-fast bacilli (AFB) cannot distinguish viable from nonviable organisms, nor differentiate between drug-susceptible and drug-resistant M. tuberculosis or between different species of mycobacteria. Its utility for monitoring patient infectiousness and response to treatment in DOTS plus programme is limited. Therefore all patients need to be monitored by both smear and culture examination . AFB smear culture Frequency How many where Frequency How Where many Intensive phase Hospitalization Every *Three DRTBMU Every One ** DRTBMU month samples month samples Ambulatory Every Three DRTBMU* Every One ** DRTBMU Care treatment month samples month samples Continuation Phase Ambulatory Every Three sample Every Two One ** DRTBMU Care months DRTBMU* months sample
* Three morning specimen *in-case patients is receiving DOTS in TBMU located in city other than DRTBMU he may be submit 2/3 sputum for smear examination in district TBMU ** inoculated on minimum 2 LJ slopes or 1LJ and one liquid media.

4.2:Culture: Quality of laboratory processing is of crucial importance. False-negative or false-positive culture may result due to delays in specimen transport, excessively harsh or insufficient decontamination, Poor-quality culture media, Incorrect incubation temperature ,laboratory errors, such as mislabeling ,cross-contamination between specimens during aerosol-producing procedures. In this context, laboratory findings need to be correlated with the patient’s clinical condition and any diagnostic test may be repeated if necessary. Smear result Positive Positive Culture result Positive Negative Clinical condition Irrespective improving No change Remarks Infectious Non viable bacilli False Negative culture ,due to Lab .quality issues Still infectious but excreting lesser number of bacilli Non infectious

1 2a 2b 3 4

Negative Negative

Positive Negative Irrespective

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4.3:Identification of M. tuberculosis: It is imperative that all mycobacterial isolates be speciated at least to the level of M. tuberculosis complex vs. non-tuberculosis mycobacteria (NTM). Identification of MTB may either be carried out by conventional biochemical identification tests or by other methods that follow international guidelines 4.4:Drug susceptibility testing;A number of different techniques are available for DST. Classic phenotypic methods for DR detection: confirmation of MDR-TB by conventional DST is still regarded as the gold standard, and adequate laboratory capacity to ensure a quality-assured diagnosis of MDR-TB therefore remains a fundamental requirement.. This involve culturing of M. tuberculosis in the presence of anti-tuberculosis drugs to detect inhibition of growth. Methods commonly used for Drug susceptibility testing  Conventional method using egg or agar based media  Rapid method using liquid media with (MGIT, Bactec) or without automation Laboratories in private sector in Pakistan have already introduced liquid culture media however culture and DST laboratories in public sector under umbrella of National TB control programme are required will be provided support to initially build capacity /develop proficiency against FLD on conventional methods (solid egg base media) before introducing liquid media. Systematic approach to implementation of DST under routine Programmatic conditions Step 1: rifampicin isoniazid and High proficiency in DST of isoniazid should first be established as DST of these drugs rifampicin is the most reliable and reproducible. Minimum performance indicator:, proficiency testing showing sensitivity >90% to correctly identify resistance to isoniazid and rifampicin in two out of three recent rounds of proficiency testing.

Step 2: ethambutol Steps 1 and 2 may be merged if technical capacity and streptomycin pyrazinamide resources allow extended DST capacity. Step 3: amikacin, kanamycin Steps 1 and 3 may be merged in settings if , XDR is a concern capreomycin Ofloxacin (or in order to rapidly allow the identification of XDR-TB fluoroquinolone of Given patients. choice

Use of second line DST in case finding
Routine DST of second-line drugs is not recommended unless the required laboratory infrastructure and capacity have been established, rigorous quality assurance is in place and sustainable proficiency has been demonstrated for isoniazid and rifampicin. In order to retain proficiency and expertise, it is recommended that second-line DST only be performed if at least 200 specimens from high-risk patients are expected per year.

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Chapter: IV
Treatment Strategies for MDR-TB

General Principles
For case finding and selection please refer to chapter III of this guidelines. Any patient who is diagnosed as an MDR-TB falls under the diagnostic category IV and will require specialized regimens termed category IV regimen. The patient will be referred to the closest available treatment site that is convenient to the patient. For more info on the list please see Annex II.

Classes of antituberculous drugs:
Group 1 – First-line oral antituberculosis agents Isoniazid (H); Rifampicin (R); Ethambutol (E); Pyrazinamide (Z) Group 2 – Injectable antituberculosis agents Streptomycin (S); Kanamycin (Km); Amikacin (Am); Capreomycin (Cm); Viomycin (Vi) Group - 3 Fluoroquinolones Ofloxacin (Ofx); Levofloxacin (Lfx); Moxifloxacin (Mfx); Group 4 – Oral bacteriostatic second-line antituberculous agents Ethionamide (Eto); Protionamide (Pto); Cycloserine (Cs); Terizidone (Trd); P-aminosalicylic acid (PAS) Group 5 – Antituberculosis agents with unclear efficacy (not recommended by WHO for routine use in MDR-TB patients) Clofazimine (Cfz); Amoxicillin/Clavulanate (Amx/Clv); Clarithromycin (Clr); Linezolid (Lzd) Thioacetazone(Thz); Imipenem/Cilastin(Imp/Cln);High dose Isoniazid. The National TB Control Program acknowledges and supports Individualized treatment regimen when DST to first and second line drugs are available from a BSL3 laboratory with proven and documented EQA certificates. Otherwise, Standardized regimen will be used for treatment in Pakistan keeping in mind the necessity for individual adjustment to treatment as indicated in the following general principles and treatment strategy. This will enable more patients to access care. Other advantages for standardized regimen include:  Simpler operational aspects of implementation  Simpler drug ordering.  Easier training.  Less likelihood of mismanagement.
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 Less dependence on highly technical laboratories.

Designing a treatment regimen
General principles

The following are the basic principles involved in any regimen design: • Regimens should be based on the history of drugs taken by the patient. • Drugs commonly used in the country and prevalence of resistance to first line and second-line drugs should be taken into consideration when designing a regimen. • Regimens should consist of at least four drugs with either certain, or almost certain, effectiveness. If the evidence about the effectiveness of a certain drug is unclear, the drug can be part of the regimen but it should not be depended upon for success. Often, more than four drugs may be started if the susceptibility pattern is unknown, effectiveness is questionable for an agent(s) or if extensive, bilateral pulmonary disease is present. • When possible, pyrazinamide, ethambutol and fluoroquinolones should be given once per day as the high peaks attained in once-a-day dosing may be more efficacious. Once-a-day dosing is permitted for other second-line drugs depending on patient tolerance, however ethionamide/ protionamide, cycloserine and PAS have traditionally been given in split doses during the day to reduce adverse effects. • The drug dosage should be determined by body weight. A suggested weight based dosing scheme is shown in Annex # 1. • Treatment of adverse drug effects should be immediate and adequate in order to minimize the risk of treatment interruptions and prevent increased morbidity and mortality due to serious adverse effects (for more information on side effects and treatment please refer to Chapter 5. • An injectable agent (an aminoglycoside or capreomycin) is used for a minimum of six months and at least four months past culture conversion. • The minimum length of treatment is 18 months after culture conversion • Each dose is given as directly observed therapy (DOT) throughout the treatment. A treatment card is marked for each observed dose.

Designing a programme treatment strategy
The following table is a treatment strategy guide based on different situations and it attempts to cover most situations; How to build a treatment regimen for MDR-TBa STEP 1 Use any available Group 1: First-line oral agents: pyrazinamide ethambutol

STEP 2 Plus one of these Group 2: Injectable agents kanamycin (or amikacin), capreomycin

Begin with any first-line agents that have certain, or almost certain, efficacy. If a first-line agent has a high likelihood of resistance, do not use it. (For example, most Category IV regimens used in treatment failures of Category II do not include ethambutol because it is likely to be resistant based on treatment history.) Add an injectable agent based on DST and treatment history. Avoid streptomycin, even if DST suggests susceptibility, because of high rates of resistance with DR-TB strains and higher incidence of ototoxicity. 21

STEP 3 Plus one of these Group 3: Fluoroquinolones Levofloxacin, moxifloxacin, ofloxacin

STEP 4 Pick one or more of Group 4: Second-line oral bacteriostatic agents: p-aminosalicylic acid, cycloserine (or terizadone) ethionamide (or protionamide) STEP 5 Consider use of these Group 5: Drugs of unclear role in DR-TB treatment: Clofazimine, linezolid, amoxacillin/clavulanate, thioacetazoneb imipenem/cilastatin, high-dose isoniazid, clarithromycin

Add a fluoroquinolone based on DST and treatment history. In cases where resistance to ofloxacin or XDR-TB is suspected, use a highergeneration fluoroquinolone, but do not rely upon it as one of the four core drugs. Add Group 4 drugs until you have at least four drugs likely to be effective. Base choice on treatment history, adverse effect profile and cost. DST is not standardized for the drugs in this group. Consider adding Group 5 drugs in consultation with an MDR-TB expert if there are not four drugs that are likely to be effective from Groups 1–4. If drugs are needed from this group, it is recommended to add at least two. DST is not standardized for the drugs in this group.

Duration of treatment
The recommended duration of treatment is guided by culture conversion 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. Completion of the injectable agent (intensive phase) The recommended duration of administration of the injectable agent, or the intensive phase, is guided by culture conversion. The injectable agent should be continued for at least six months and at least four months after the patient first becomes and remains smear- or culture-negative. Intermittent therapy with the injectable agent (three times a week) can also be considered in patients in whom the injectable has been used for a prolonged period of time and when toxicity becomes a greater risk.

Extrapulmonary MDR-TB and MDR-TB treatment
The treatment strategy is the same for patients with pulmonary and extrapulmonary MDR-TB.

Surgery in Category IV treatment
The most common operative procedure in patients with pulmonary DR-TB is resection surgery (taking out part or all of a lung). It is considered an adjunct to chemotherapy and appears to be beneficial for patients ONLY when a review panel decision is made, skilled thoracic surgeons and excellent postoperative care are available. It is NOT indicated in patients with extensive bilateral disease. Resection surgery should be timed to offer the patient the best possible chances of cure with the least morbidity. Thus, the timing of surgery may be earlier in the course of the disease when the patient’s risk of morbidity and mortality is lower, for example, when the disease is still localized to one lung or one lung lobe. In other words, surgery should not be considered as a last resort. Generally, at least two months of therapy should be given before resection surgery in order to decrease the bacterial infection in the surrounding lung tissue. Even with successful resection, an additional 12–24 months of chemotherapy should be given. In some selected extra-pulmonary DR-TB cases a group decision should be made to include specialists in various medical and surgical disciplines. 22

Guidelines for patient’s enrollment at the treatment site:
The NTP acknowledges and supports the following 2 strategies for patients enrollment into treatment:
1- Ambulatory based strategy: The treatment center would enroll the patient under CAT-IV

treatment on an ambulatory basis provided that a strong DOT policy is in place, an infection control policy is well implemented to prevent household transmission of MDR-TB bacteria to another contact and a proper mechanism for early recognition / management of treatment adverse reaction is established including admission into a designated treatment site where inpatient facility for DR-TB is available, 2- Hospitalization based strategy: The treatment center would admit the patient into the hospital to begin CAT- IV treatment until such a time when the patient shows evidence of treatment tolerance and no signs or symptoms of adverse reaction. At this time, the patient could be discharged to an ambulatory basis provided that a strong DOT policy is in place, continuous monitoring for an early recognition and management of treatment adverse reaction and, and an infection control policy is in place to prevent household transmission of MDR-TB bacteria to another contact.

Upon arrival to the treatment site the patient should bring the following items: 1- A referral letter. For further information please see chapter IX form 10. 2- Old CXRs and any other medical documents from previous centers, hospitals etc. indicating previous or any current treatment 3- An ID card, 2 phone numbers and a complete address information 4- An official report of the result of Sputum Culture and DST from the laboratory.

The following work up will be done upon admission:
1- Complete history and physical exam ( include past medical history, family history, previous treatment in details, previous or current family TB history, detailed history of previous contact with a TB case, previous history of incarceration/travel/work place, HIV status). 2- A baseline chemistry and hematological tests include: CBC,Diff, ESR, KFT, LFT, Lytes, TSH, Blood Sugar, HIV screening, Urinlysis 3- CXR 4- Sputum for Direct AFB smear. 5- Sputum for Culture and DST ( if a recent test not done within the last 30d) 6- Audiometry and visual tests

Standardized Treatment Regimen will be divided into 2 phases:
 The Intensive Phase: As stated earlier, this phase will take place for at least 6 months. During this phase the following drugs may be used: o Kanamycin inj 1gm/d for 6 days a week. o Cycloserine 250 mg Tab: begin with 2 tabs a day and increase gradually according to patient’s weight until maximum 1 gm daily in 2 divided doses as tolerated o Ethionamide 250 mg : follow the same recommendation as for Cyclocerine above. o Levoflaxacin 500 mg: Give 500-1000mg daily in single dose or 2 divided doses if single dose is not tolerated well. 23

o Para-Amino-Saliycylic Acid(PAS): This drug may be used in order to provide 4 new drugs if needed. Give 5-7 gms granules twice/day. o Vit B6 200 mg daily should be given to every MDR TB patient. o Add to the above drugs PZA o Add Ethambutol ( if DST shows that the patient is sensitive to Ethambutol). o All drugs are given daily except the injectable which is given 6 days/weekly o All drugs are given according to the body wt dosage listed in chart annex I . During the intensive phase treatment the following tests will be done: o Monthly Sputum for direct AFB microscopy on 3 consecutive days. o Monthly Sputum for AFB Culture. o Monthly Hgb, ESR o Kidney Function Tests, Electrolytes every 2 months. . o Monthly CXR for the 1st 3 months then every 3-6 months. o Monthly Audiometry and visual tests. o Thyroid Function Test every 3-6 months. If the patient is being followed on an ambulatory basis, he/she must report to the treatment site or the district / peripheral TB center on a weekly basis. Every treatment dose must be given under DAILY DOT. However if the patient is being hospitalized, he/she will remain in the hospital until is stable enough to be discharged. The patient could be discharged to receive ambulatory care provided that:  A patient supporter ( social worker, family member, volunteer etc.) has been properly trained to administer daily DOT and watch for early signs and symptoms of side effects.  The patient and his DOT’s care provider will visit the nearest TB center weekly for review and medicine refilling. A copy of the patient’s category IV treatment card ( see chapter IX /form 01) will be forwarded to the local TB center.  The patient will visit the treatment site monthly for work up, monitoring and thorough evaluation by the clinician. A copy of the patient’s category IV treatment card ( see chapter IX /form 01) will be transferred to the treatment site for review and update. When the patient completes at least 6 months of intensive phase, has 2 negative Cultures with at least 30 days apart, he/ she could be moved to the Continuation Phase. Otherwise the intensive phase will remain until 2 consecutive negative cultures are available with 30 days apart.  The Continuation Phase: During this phase the injectable drug only is discontinued otherwise the patient continues to receive the same oral drugs which have been used during the intensive phase. During this phase the local TB center and/or health provider is responsible for: o Arranging for DAILY DOT. The patient could report daily to the center or have a trained volunteer who would administer DOTS under the supervision of the center. A special treatment card will be provided. o Requesting the drugs from the Central Supply dept, making sure that drugs are available at anytime, and stored properly. A refrigerator should be available at the center to store the drugs that need to be refrigerated. Please see chapter IX form 11 for requesting drugs from the NTP storage dept. For further information on 2nd line drug management please refer to Annex # 4. o Monitoring the patient on a weekly basis for early SXS of side effects. 24

o Performing direct smear microscopy on a monthly basis at least on 3 consecutive specimens ( collected on 3 separate days). o Referring the patient to the treatment site every 2 months for:  CBC, ESR, TSH etc  CXR ( every 3- 6 months)  Sputum for Culture A copy of the patient’s category IV treatment card ( see chapter IX /form 01) will be used for referring the patient to the treatment site. The continuation phase will remain for 18 months from the time the patient became and remained culture negative. For determining when the patient is considered cured on treatment complete please refer to chapter II on: Definitions for diagnostic Category IV treatment outcomes

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Chapter: V
Management of Side Effects MDR- TB Drugs
ADVERSE REACTION SUSPECTED AGENT (S) SUGGESTED MANAGEMENT STRATEGIES 1) Intitiate anticonvulsant therapy (e.g. phenytion, valproic acid) 2) Increase pyridoxine to 300mg daily 3) Lower dose of suspected agent, if this can be done without compromising regimen 4) Discontinue suspected agent if this can be done without compromising regimen 1) Increase pyridoxine to 300mg daily 2) Change parenteral to Cm if patient has documented susceptibility to Cm 3) Begin exercise regimen, focusing on affected regions 4) Initiate therapy with tricyclic anti-depressant drugs 5) Lower dose of suspected agent, if this can be done without compromising regimen 6) Discontinue suspected agent if this can be done without compromising regimen 7) Initiate therapy with neurontin 1)change parenteral to Cm if patient has documented susceptibility to Cm 2)Lower dose of suspected agent, if this can be done without compromising regimen. 3)Discontinue suspected agent if this can be done without compromising regimen. 1)Initiate anti-psychotic drugs. 2)Hold suspected agent for short period of time (one to four weeks) while COMMENTS

Seizures

Cs, H, O, L, Cx

Peripheral neuropathy

Sm, Km, Amk, Cm, M, Tha, Cs, E, O, L, Cx

1) Anti-convulsant is generally continued until MDR, TB treatment completed or suspected agent discontinued. 2) History of prior seizure disorder is not a contraindication to the use of agents listed here if patients, seizures are well-controlled and/ or patient is receiving anticonvulsanttherapy. 3) Patients with history of prior seizures may be at increased risk for development of seizures during MDR –TB therapy 4) Seizures not a permanent squealae of MDR –TB treatment 1) patients with co-morbid disease (e.g. diabetes, HIV, alcoholism) may be more likely to develop peripheral neuropathy, but these conditions are not contrainditions to the use of the agents listed here. 2) Neuropathy is generally not reversible, although only a minority (approximately 10%) of patients require continued intervention to keep symptomas controlled once MDR –TB treatment completed.

Hearing loss

Sm, Km, Amk, Cm, Clr

1)If patients have received prior treatment with amino-glycosides, they may start therapy with hearing loss. 2)Hearing loss is generally not reversible.

Psychotic symptoms

Cs,O,L,Cx,H,Tha

1)Some patients will need to continue antipsychotic treatment throughout MDR –TB therapy. 2)Prior history of psychiatric disease is not a contraindication to the use of agents listed

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Depression

Socioeconomic circumstances, Cs, O, L, Cx,H,Tha

psychotic symptoms brought under control). 3)Lower dose of suspected agent, if this can be done without compromising regimen. 4)Discontinue suspected agent if this can be done without compromising regimen. 1) Improve socioeconomic conditions 2) Group or individual supportive counseling 3) Initiate anti-depressant drugs 4) Lower dose of suspected agent, if this can be done without compromising regimen. 5) Discontinue suspected agent if this can be done without compromising regimen 1Initiate thyroxine therapy 2)Substitute equally efficacious agent for Tha or PAS. 1)Rehydration 2)Initiate anti-emetic therapy 3)Lower dose of suspected agent, if this can be done without compromising regimen. 4)Discontinue suspected agent if this can be done without compromising regimen. 1)Antacids (e.g. calcium carbonate, H2-blockers, proton-pump isoniazidibitors). 2)Hold suspected agent(s) for short periods of time (e.g. one to seven days) 3)Lower dose of suspected agent, if this can be done without compromising regimen. 4)Discontinue suspected agent if this can be done without compromising regimen. 1)Stop therapy 2)Rule out other potential causes of hepatitis 3)Re-introduce drugs grouped serially while monitoring liver function, with most likely agent introduced last. 1)Discontinue suspected agent

here but may increase the likelihood of development of psychotic symptoms. 3)Psychotic symptoms generally reversible upon MDR-TB treatment completion or discontinuation of offending agent.

1) Importance of socioeconomic conditions should not be underestimated as contributing factor to depression. 2) Depression and depressive symptoms may fluctuate during therapy. 3)History of prior depression is not a contraindication to the use of the agents listed here however, these patients may be at increased risk for developing depression during MDR –TB treatment.

Hypothyroidism

PAS, Tha, Especially when given in combination

Completely reversible upon discontinuation of PAS or Tha

Nausea and vomiting

PAS, Tha, H,E,Cfz, Pz

1)Nausea and vomiting ubiquitous in early weeks of therapy and usually abate with supportive therapy. 2)Electrolytes should be monitored and repleted if vomiting severe. 3)Reversible upon discontinuation of suspected agent

Gastritis

PAS, Tha,H,E,Cfz, Pz

1)Severe gastritis as manifest by hematemesis, melena or hematechezia not observed in this cohort. 2)Dosing of antacids should be carefully timed so as to not interfere with the absorption of anti-TB drugs. 3)Reversible upon discontinuation of suspected agents(s)

Hepatitis

PZ,H,R,Tha,O,L,Cx,E,PAS

1)history of prior hepatitis should be carefully analyzed to determine most likely causative agent(s): these should be avoided in future regimens. 2)Generally reversible upon discontinuation of suspected agent.

Renal failure

Sm,Km,Amk, Cm

1)History of diabetes or renal disease is not a contraindication to the use of the agents

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Optic neuritis Arthralgias

E PZ,O,L,Cx

2) Consider using Cm if an amino-glycoside had been prior parenteral in regimen Stop E 1)Initiate therapy with non-steroidal antiinflammatory drugs. 2)Initial exercise regimen 3)Lower dose of suspected agent, if this can be done without compromising regimen. 4)Discontinue suspected agent if this can be done without compromising regimen.

listed here, although patients with these comorbidities may be at increased risk for developing renal failure. 2)Renal impairment may be permanent. 1)Not observed in this cohort of patients. 1)Symptoms of arthralgia generally diminish over time, even without intervention. 2)Uric acid levels may be elevated in some patients but are of little therapeutic relevance and anti-gout therapy (e.g. allopurinol, colchicines) is of no proven benefit in these patients.

For the management of severe complications such as Nephrotoxicity, Severe Depression and or Psychological Disorders, Severe Liver Failure ,or severe hemoptysis the patient should be referred to a specialist or treatment center for further consultation and management of the side effects. The patient will return back to the TB center as soon as he/she is cleared by the Specialist. The TB center should maintain a close monitoring and keep a close contact with the Specialist concerned.

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Chapter VI
Treatment of MDR TB in Special conditions Objectives
This Chapter outlines the management of drug-resistant TB in the following special conditions and situations:           Pregnancy Breastfeeding Contraception Children Diabetes mellitus Renal insufficiency Liver disorders Seizure disorders Psychiatric disorders Substance dependence

Pregnancy
All female patients of childbearing age should be tested for pregnancy upon initial evaluation. Pregnancy is not a contraindication for treatment of MDR-TB, which poses great hazards to both the mother and foetus. However, birth control is strongly recommended for all non-pregnant women receiving therapy for MDR-TB. Pregnant patients should be carefully evaluated, taking into consideration the gestational age and severity of the MDR TB. The risks and benefits of treatment should be carefully considered. Because the major teratogenic effects occur in the first trimester, therapy may be delayed until the second trimester if clinically feasible. For the most part, aminoglycosides should be avoided in treatment regimens for MDRTB, as it can be particularly ototoxic to the foetus. Capreomycin may carry the same risk although perhaps to a lesser extent. Ethionamide can aggravate nausea and vomiting in some pregnant women, and teratogenic effects have been observed in animal studies. It appears to be safer to add this drug after delivery.

Breastfeeding
A woman who is breastfeeding and has active drug-resistant TB should receive a full course of antituberculosis treatment. Timely and properly applied chemotherapy is the best way to prevent transmission of tubercle bacilli to her baby. In lactating mothers on treatment, most antituberculosis drugs will be found in the breast milk in concentrations that would equal only a small fraction of the therapeutic dose used in an infant. However, any effects on infants of such exposure during the full course of MDR-TB treatment have not been established. Therefore, when resources and training are available, it is recommended to provide infant formula options as an alternative to breastfeeding. The mother and her baby should not be completely separated. However, if the
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mother is sputum smear-positive, the care of the infant should be left to family members until she becomes sputum smear-negative. When the mother and infant are together, this common time should be spent in wellventilated areas or outdoors. In some settings, the mother may be offered the option of using a surgical mask or an N-95 respirator until she becomes sputum smear-negative.

Contraception
There is no contraindication to the use of oral contraceptives with the non rifamycin containing regimens. Patients who vomit directly after taking an oral contraceptive can be at risk of decreased absorption of the drug and therefore of decreased efficacy. These patients should be advised to take their contraceptives apart from times when they may experience vomiting caused by the antituberculos treatment. Patients who vomit at any time directly after, or within the first two hours after, taking the contraceptive tablet, should use a barrier method of contraception until a full month of the contraceptive tablets can be tolerated. For patients with mono- and poly-resistant TB that is susceptible to rifampicin, the use of rifampicin interacts with the contraceptive drugs resulting in decreased efficacy of protection against pregnancy. A woman on oral contraception while receiving rifampicin treatment may choose between two options: following consultation with a physician, use of an oral contraceptive pill containing a higher dose of estrogen (50 μg); or use of another form of contraception.

Children
Children with drug-resistant TB generally have primary resistance transmitted from an index case with drug-resistant TB. When DST is available it should be used to guide therapy, although children with paucibacillary TB are often culture-negative. Nevertheless, every effort should be made to confirm drug-resistant TB bacteriologically by the use of DST and to avoid exposing children unnecessarily to toxic drugs. The treatment of culture-negative children with clinical evidence of active TB disease and contact with a documented case of drug-resistant TB should be guided by the results of DST and the history of the contact's exposure to antituberculosis drugs. There is only limited reported experience with the use of second-line drugs for extended periods in children. The risks and benefits of each drug should be carefully considered in designing a regimen. Frank discussion with family members is critical, especially at the outset of therapy. MDR-TB is life threatening, and no antituberculosis drugs are absolutely contraindicated in children. Children who have received treatment for drug-resistant TB have generally tolerated the second-line drugs well. Although fluoroquinolones have been shown to retard cartilage development in beagle puppies, experience with the use of fluoroquinolones has not demonstrated similar effects in humans. It is considered that the benefit of fluoroquinolones in treating MDR-TB in children outweighs any risk. Additionally, ethionamide, PAS and cycloserine have been used effectively in children and are well tolerated.
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In general, antituberculosis drugs should be dosed according to body weight (see Table below; Pediatric dosage of second-line antituberculosis drugs). Monthly monitoring of body weight is therefore especially important in pediatric cases, with adjustment of doses as children gain weight. All drugs, including the fluoroquinolones, should be dosed at the higher end of the recommended dose whenever possible, except Ethambutol which should be used at 15 mg/kg, and not at 25 mg/kg as sometimes used in adults with MDR-TB, since it is more difficult to monitor for optic neuritis in children. In children who are not culture-positive initially, treatment failure is difficult to assess. Persistent abnormalities on chest radiograph do not necessarily signify a lack of improvement. In children, weight loss or, more commonly, failure to gain weight adequately, is of particular concern and often one of the first (or only) signs of treatment failure. This is another key reason to monitor weight carefully in children. TABLE Pediatric dosage of second-line antituberculosis drugs
DRUG DAILY DOSE( mg/kg) FREQUENCY MAXIMUM DAILY DOSE

Streptomycin Kanamycin Amikacin Capreomycin Ofloxacin Levofloxacin Moxifloxacin Gatifloxacin Ethionamide Protionamide Cycloserine

20–40 15–30 15–22.5 15–30 15–20 7.5–10 7.5–10 7.5–10 15–20 15–20 10–20

Once daily Once daily Once daily Once daily Twice daily Once daily Once daily Once daily Twice daily Twice daily Once or twice daily
Twice or thrice daily

1g 1g 1g 1g 800 mg 750 mg 400 mg 400 mg 1g 1g 1g
12 g

P-aminosalicylic acid 150

Diabetes Mellitus
Diabetic patients with MDR-TB are at risk for poor outcomes. In addition, the presence of diabetes mellitus may potentate the adverse effects of antituberculous drugs, especially renal dysfunction and peripheral neuropathy. Diabetes must be managed closely throughout the treatment of drug-resistant TB. The health-care provider should be in close communication with the physician who manages the patient’s diabetes. Oral hypoglycemic agents are not contraindicated during the treatment of drug-resistant TB but the daily dosage may have to be adjusted to provide a better blood sugar control. The use of ethionamide or protionamide may increase the difficulty in controlling the daily Insulin levels. KFT and lytes have to be monitered regularly throughout treatment.

Renal insufficiency

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Renal insufficiency caused by longstanding TB infection itself or previous use of aminoglycosides is not uncommon. A great care should be taken in the administration of second-line drugs in patients with renal insufficiency, and the dose and/or the interval between dosing should be adjusted according to the following table. TABLE Adjustment of antituberculosis medication in renal insufficiency
DRUG CHANGE IN FREQUENCY? RECOMMENDED DOSE AND FREQUENCY FOR PATIENTS WITH CREATININE CLEARANCE <30 ml/min OR FOR PATIENTS RECEIVING HAEMODIALYSIS

Isoniazid Rifampicin

No change No change

300 mg once daily, or 900 mg three times per week 600 mg once daily, or 600 mg three times per week 25–35 mg/kg per dose three times per week (not daily) 15–25 mg/kg per dose three times per week (not daily) 1000–1500 mg per dose three times per week (not daily) 600–800 mg per dose three times per week (not daily) 750–1000 mg per dose three times per week (not daily) 400 mg once daily 400 mg per dose three times per week (not daily) 250 mg once daily, or 500 mg/dose three times per week Recommendations not available 250–500 mg per dose daily 250–500 mg per dose daily 4 g/dose, twice daily

Pyrazinamide Yes Ethambutol Yes

Ciprofloxacin Yes Ofloxacin Yes

Levofloxacin Yes Moxifloxacin No change Gatifloxacin Cycloserine Terizidone Yes Yes –

Protionamide No change Ethionamide No change P-aminosalicylic No change acid Streptomycin Yes

12–15 mg/kg per dose two or three times per week (not daily) 12–15 mg/kg per dose two or three times per week (not daily) 12–15 mg/kg per dose two or three times per week (not daily) 12–15 mg/kg per dose two or three times per week (not daily) 32

Capreomycin Yes

Kanamycin Amikacin

Yes Yes

Liver disorders
The first-line drugs isoniazid, rifampicin and pyrazinamide are all associated with hepatotoxicity. Among them, rifampicin is least likely to cause hepatocellular damage, although it is associated with cholestatic jaundice. Pyrazinamide is the most hepatotoxic of the three first-line drugs. Among the second-line drugs, ethionamide, protionamide and PAS can also be hepatotoxic, although to a lesser level than first-line drugs. Hepatitis occurs rarely with the flouroquinolones. Patients with a history of liver disease can receive the usual drug-resistant TB chemotherapy regimens provided there is no clinical evidence of chronic liver disease, hepatitis virus carriage, past history of acute hepatitis or excessive alcohol consumption. However, hepatotoxic reactions to antituberculosis drugs may be more common in these patients and should be anticipated. In general, patients with chronic liver disease should not receive pyrazinamide. All other drugs can be used, but close monitoring of liver enzymes is advised. If significant aggravation of liver inflammation occurs ( more than 5 times the normal liver enzymes level) the drug(s) responsible may have to be stopped. Uncommonly, a patient with TB may have concurrent acute hepatitis that is unrelated to TB or antituberculosis treatment. In this case, clinical judgment is necessary. In some cases, it is possible to defer antituberculosis treatment until the acute hepatitis has been resolved. In other cases, when it is necessary to treat drugresistant TB during acute hepatitis, the combination of four non-hepatotoxic drugs is the safest option.

Seizure disorders
Some patients requiring treatment for drug-resistant TB will have a previous or current medical history of a seizure disorder. The first step in evaluating such patients is to determine whether the seizure disorder is under control and whether the patient is taking anti-seizure medication. If the seizures are not under control, initiation or adjustment of anti-seizure medication will be needed before the start of drug-resistant TB therapy. In addition, any other underlying conditions or causes of seizures should be corrected. Cycloserine should be avoided in patients with active seizure disorders that are not well controlled with medication. However, in cases where cycloserine is a crucial component of the treatment regimen, it can be given and the anti-seizure medication adjusted as needed to control the seizure disorder. The risks and benefits of using cycloserine should be discussed with the patient and the decision on whether to use cycloserine made together with the patient. In mono- and poly-resistant cases, the use of isoniazid and rifampicin may interfere with many of the anti-seizure medications. Drug interactions should be checked before their use Seizures that present for the first time during antituberculosis therapy are likely to be the result of an adverse effect of one of the antituberculosis drugs.
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Psychiatric disorders
It is advisable for psychiatric patients to be evaluated by a health-care worker with psychiatric training before the start of treatment for drug-resistant TB. The initial evaluation documents any existing psychiatric condition and establishes a baseline for comparison if new psychiatric symptoms develop while the patient is on treatment. Any psychiatric illness identified at the start of or during treatment should be fully addressed. There is a high baseline incidence of depression and anxiety in patients with MDR-TB, often connected with the chronicity and socioeconomic stress factors related to the disease. Treatment with psychiatric medication, individual counseling and/or group therapy may be necessary to manage the patient suffering from a psychiatric condition or an adverse psychiatric effect caused by medication. Group therapy has been very successful in providing a supportive environment for MDR-TB patients and may be helpful for patients with or without psychiatric conditions. (Adequate measures to prevent infection risk should be in place for the group therapy.) The use of cycloserine is not absolutely contraindicated for the psychiatric patient. Adverse effects from cycloserine may be more prevalent in the psychiatric patient, but the benefits of using this drug may outweigh the potentially higher risk of adverse effects. Close monitoring is recommended if cycloserine is used in patients with psychiatric disorders. All health-care workers treating drug-resistant TB should work closely with a mental health specialist and have an organized system for psychiatric emergencies. Psychiatric emergencies include psychosis, suicidal ideation and any situation involving the patient’s being a danger to him or herself or others.

Substance dependence
Patients with substance dependence disorders should be offered treatment for their addiction. Complete abstinence from alcohol or other substances should be strongly encouraged, although active consumption is not a contraindication for antituberculosis treatment. If the treatment is repeatedly interrupted because of the patient’s dependence, therapy should be suspended until successful treatment or measures to ensure adherence have been established. Good DOT gives the patient contact with and support from health-care providers, which often allows complete treatment even in patients with substance dependence. Cycloserine will have a higher incidence of adverse effects (as in the psychiatric patient) in patients dependent on alcohol or other substances, including a higher incidence of seizures. However, if cycloserine is considered important to the regimen, it should be used and the patient closely observed for adverse effects, which are then adequately treated.

HIV infection and MDR-TB

34

Perform routine HIV testing in all TB patients. WHO and the Joint United Nations Programme on HIV/AIDS (UNAIDS) recommend that all patients with TB should be routinely offered an HIV test, and these data can be used as the basis for surveillance of HIV among TB patients. Introduce antiretroviral therapy (ART) promptly in MDR-TB/HIV patients. TB is an indicator disease for ART, irrespective of CD4 cell count. If CD4 cell counts are available, they can guide the decision on when to start ART. ART is similarly recommended for MDR-TB/HIV-infected cases, given the elevated mortality in these coinfected patients. In general, ART should not be delayed for fear of giving the patient too many medicines. The usual protocols to prevent immune-reconstitution syndrome should be followed. • Arrange close treatment follow-up by a specialized team. The teams Should be familiar with the treatment of both MDR-TB and HIV, with close monitoring of potential additive adverse effects, prophylaxis and treatment of opportunistic infections, general primary care, vaccinations and nutritional support. Clinical features and diagnosis of MDR-TB in HIV-infected patients The presentation of MDR-TB in the HIVinfected patient does not differ from that of drug-susceptible TB in the HIV-infected patient. The diagnosis of TB in HIV-positive 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. This can result in misdiagnosis or delays in diagnosis and, in turn, higher morbidity and mortality. The use of X-ray and/or culture improves the ability to diagnose TB in HIV patients and is recommended where available. In areas where MDR-TB is known to be a problem in HIV-positive patients, and where resources permit, all HIV patients with TB should be screened for MDR-TB with DST. Rapid diagnostic techniques for MDR-TB should be employed when possible since HIVinfected patients with TB on inadequate antituberculosis treatment, or no treatment, for even short periods of time are at a high risk of death. 1. Concomitant treatment of drug-resistant TB and HIV The recommended treatment of TB, whether drug-susceptible or -resistant, is the same for HIV-infected and non-HIV-infected patients, except for the use of thioacetazone, which should not be used in HIV-infected patients. However, treatment is much more difficult and adverse events more common. Deaths during treatment, caused by TB itself or by other HIV-related diseases, are more frequent in HIV-infected patients, particularly in the advanced stages of immunodeficiency. The use of ART in HIV-infected patients with TB improves survival and slows progression to AIDS. However, initiation of ART in HIV-infected patients with drug-susceptible or drug-resistant TB is often associated with adverse events that may lead to the interruption of both TB and/or HIV therapy. Information on when and how to design regimens for HIV treatment is available in other WHO publications. However, given the large amount of pills that need to be ingested and the potential of overlying toxicities, the following issues should be considered. 1. Potential drug interactions in the treatment of drug-resistant TB and HIV
35

There are several known interactions between drugs used to treat TB and HIV. Rifamycins (rifampicin, rifabutin), while not used in MDR-TB treatment, are needed in the treatment of many poly- and mono-resistant cases. Rifamycins may lower the levels of protease inhibitors and non-nucleoside reverse transcriptase inhibitors, contributing to the development of resistance to these drugs. In this regard, rifabutin has the least effect of all the rifamycins. Antiretroviral drugs increase the level of rifampicin and the risk of toxicity. Other interactions include those between fluoroquinolones and didanosine. Nonenteric-coated didanosine contains an aluminium/magnesium-based antacid that, if given jointly with fluoroquinolones, may result in decreased fluoroquinolone absorption; it should therefore be given six hours before or two hours after fluoroquinolone administration. Clarithromycin, a drug not routinely recommended for MDR-TB by WHO but used by some programmes, has several interactions with HIV medications. 2. Potential drug toxicity in the treatment of drug-resistant TB and HIV In general, HIV patients have a higher rate of adverse drug reactions to both TB and non-TB medications. Known adverse effects of increased severity in coinfected patients include peripheral neuropathy (stavudine, aminoglycosides, cycloserine, pyrazinamide), cutaneous and hypersensitivity reactions (thioacetazone), gastrointestinal adverse effects, renal toxicity (injectables) and neuropsychiatric effects (cycloserine, efavirenz). 3. Monitoring of drug-resistant TB and HIV therapy in coinfected patients HIV medicines must be given every day. While the treatment of MDR-TB is being administered, DOT of ART should be included. The complexity of antiretroviral regimens and treatment of drug-resistant TB, each with its specific toxicity profiles – some of which may be potentiated by concomitant therapy – demands rigorous monitoring in this particular group of patients. Ideally, ART should be initiated and monitored in collaboration with a health-care provider knowledgeable in both drug-resistant TB and HIV. Chapter 11 describes the monitoring requirements for treatment of drug-resistant TB and also indicates where monitoring in HIV-infected individuals is required with increased frequency. Standard monitoring procedures for those on ART should be followed. Monitoring of chest X-rays, smears and cultures in the co-infected patient is the same as for HIV-negative MDR-TB patients. If the patient shows signs of treatment failure, the same evaluation as described in Chapter 13 is warranted. In addition, the ART regimen should be re-evaluated as described above. Patients with HIV-associated MDR-TB will usually require special socioeconomic support. The regimens together are particularly difficult to tolerate, the stigma of both diseases can result in serious discrimination and the risk of mortality is very high. Antiretroviral drugs increase the level of rifampicin and the risk of toxicity. Other interactions include those between fluoroquinolones and didanosine. Nonentericcoated didanosine contains an aluminium/magnesium-based antacid that, if given jointly with fluoroquinolones, may result in decreased fluoroquinolone absorption; it should therefore be given six hours before or two hours after fluoroquinolone administration. Clarithromycin, a drug not routinely recommended for MDR-TB by WHO but used by some programmes, has several interactions with HIV medications.
36

Monitoring of chest X-rays, smears and cultures in the coinfected patient is the same as for HIV-negative MDR-TB patients. If the patient shows signs of treatment failure, the same evaluation as described in Chapter 13 is warranted. In addition, the ART regimen should be reevaluated as described above. Patients with HIV-associated MDR-TB will usually require special socioeconomic support. The regimens together are particularly difficult to tolerate, the stigma of both diseases can result in serious discrimination and the risk of mortality is very high.

HIV-infected subjects
The WHO recommends that certain collaborative activities should be carried out to decrease the dual burden of TB and HIV. These activities broadly include: (i) establishment of mechanisms for collaboration; (ii) decreasing the burden of TB in people living with HIV/AIDS (through intensified TB casefinding, introduction of isoniazid preventive therapy, and ensuring TB infection control in health-care and congregate settings); and (iii) decreasing the burden of HIV in TB patients (through HIV testing and counselling, HIV prevention methods, co-trimoxazole prophylaxis and antiretroviral therapy). Such activities constitute the backbone of the WHOTB/HIV collaborative strategy. Just as the DOTS programme should be in place before undertaking MDR-TB treatment strategies, these TB/HIV collaborative strategies should be in place before embarking on MDR-TB/HIV management activities. Failure to do so might result in failure of MDR-TB programmes among HIVinfected subjects with disastrous results. MDR-TB in a HIV-infected patient carries a high risk of mortality, especially when diagnosed late. Furthermore, extrapulmonary localization has also been identified as an independent poor prognostic factor. Thus, judicious drug susceptibility testing should be carried out in cases of active TB in HIV-infected individuals with risk factors for MDR-TB, or in areas where high rates of MDR-TB have been identified.136 Antiretroviral therapy is recommended for MDR-TB/HIV-infected patients, given the excessive mortality in these subjects.136 In general, antiretroviral therapy should not be delayed for fear of giving the patient too many medications. The usual protocols to ameliorate immune reconstitution inflammatory syndrome should be followed. Known drug interaction in MDR-TB/HIV is relatively uncommon. One example is the fluoroquinolone–didanosine interaction, resulting in decreased absorption of the fluoroquinolone when suitable spacing is not allowed between the administration of the two drugs. HIV-infected patients usually have a higher rate of adverse drug reactions to both antituberculosis drugs and other concomitant medications. Known adverse effects with increased severity in MDR-TB/HIV patients include peripheral neuropathy (stavudine, aminoglycosides, cycloserine, pyrazinamide), cutaneous hypersensitivity reactions (thiacetazone), gastrointestinal adverse effects, renal toxicity (injectables), and neuropsychiatric effects (cycloserine, efavirenz). Patients with HIVassociated MDR-TB usually require special psychosocial support, as the stigmata of both diseases can result in potential discrimination in some communities. Coordinated training activities should focus on developing a group of health-care providers in a specialized multidisciplinary team with adequate expertise in both HIV infection and TB.

Summary
37

Understanding the regional prevalence of HIV, MDR-TB and MDR/HIV co-infection is the first step in guiding the strategies for MDR-TB/HIV activities. In some areas, MDR-TB is an important potential problem for HIV-infected patients. The patient with drug-resistant TB disease and HIV will require intensive medical care to decrease the high level of mortality. Rigorous infection control measures should be part of the planning. Coordination between the team treating drug-resistant TB and the HIV control program for training, care and treatment is an essential component. MDR-TB/HIV co-infection has the potential to increase rapidly. All drug-resistant TB and HIV control programs should coordinate the collaborative activities described in this chapter, which are an integral element of both HIV/AIDS and TB control, aimed at avoiding epidemics of HIV-associated MDR-TB.

Adverse reactions to second-line drugs
Second-line drugs for treating MDR-TB are generally more toxic and difficult to tolerate. The adverse effects of second-line drugs are shown in some detail in the Table below. A Close monitoring of patients is necessary to ensure that the adverse effects of these drugs are quickly recognized. Aside from clinical monitoring, basic audiometric screens and simple vestibular function assessment, as well as biochemical monitoring of liver function, renal function, electrolytes and thyroid function, are useful. In addition to visual acuity assessment, tests to detect peripheral neuropathy are sometimes needed. Regarding the management of adverse reactions, if the adverse effect is mild and not dangerous, only continuation with supportive therapy (psychological and/or pharmacological) or minor reduction of dosage of the drug in question is required. If the adverse event is severe or potentially dangerous, then a special consultation with a Specialist is required for further management strategy. The effective management of peripheral neuropathy has been shown to be possible without sacrificing the clinical efficacy of MDR-TB treatment. It is also of importance to note that while depression, anxiety and psychosis during MDR-TB treatment have been found to be quite common in one study, cycloserine could still be continued (with dosage modification) in the majority of patients when concurrent psychiatric pharmacotherapy was given. Psychosocial support is also an important component in the management of adverse effects. The DOT workers, professional or otherwise, would have an important role to play through education, counseling and encouragement of patients with MDR-TB. Adverse reactions to antituberculosis drugs used for treatment of MDR-TB Reactions Drug
Pyrazinamide Common Anorexia Nausea Flushing Photosensitisation Uncommon Hepatitis Vomiting Arthralgia Cutaneous reactions Retrobulbar neuritis Arthralgia Rare Sideroblastic anaemia Gout

Ethambutol

Hepatitis Cutaneous reactions Peripheral neuropathy Renal damage Aplastic anaemia

Streptomycin

Cutaneous hypersensitivity Giddiness Numbness Tinnitus

Vertigo Ataxia Deafness

38

Thiacetazone

Gastrointestinal reactions Cutaneous hypersensitivity Vertigo Conjunctivitis

Hepatitis Erythema multiforme Exfoliative dermatitis Haemolytic anaemia

Agranulocytosis

Amikacin Kanamycin Capreomycin

Ototoxicity: hearing damage Vestibular disturbance Nephrotoxicity: deranged renal function tests

Clinical renal failure

Hypokalaemia Hypocalcaemia Hypomagnesaemia

Ofloxacin Ciprofloxacin

Gastrointestinal reactions Insomnia Thrush

Anxiety Dizziness Headache Tremor

Convulsions Haemolysis Tendonitis/tendon rupture Arthropathy Colitis

Levofloxacin Moxifloxacin

Similar to those of ofloxacin or ciprofloxacin, except less central nervous system dysfunction

Ethionamide Prothionamide

Metallic taste Salivation Gastrointestinal reactions

Hepatitis Peripheral neuropathy Headache

Convulsions Mental disturbances Impotence Menstrual disturbances Gynaecomastia Hypothyroidism Hypoglycaemia Alopecia Sideroblastic anaemia Stevens–Johnson syndrome

Cycloserine

Dizziness Headache Depression Memory loss Gastrointestinal reactions

Agitation Psychosis Convulsions

Para-aminosalicylic

Hepatitis Drug fever Cutaneous reactions

Hypothyroidism Haematological reactions Hypokalaemia Metabolic acidosis Sodium overload

Clofazimine

Photosensitisation Hyperpigmentation Cutaneous reactions Gastrointestinal reactions Cutaneous hypersensitivity

Gastrointestinal reactions Intestinal obstruction Retinopathy

AmoxicillinClavulanate

Headache Hepatitis Haematological reactions Colitis Hypersensitivity vasculitis Stevens–Johnson syndrome Convulsions Colitis Peripheral and optic neuropathies†

Linezolid

Diarrhoea Dyspepsia

Thrombocytopenia Aplastic anaemia†

Headache

39

Chapter: VII Management of Treatment Failure Cases (XDR) of MDR TB XDR TUBERCULOSIS
Definition: XDR-TB (Extensively Drug Resistant Tuberculosis) is resistance to at least Isoniazid and Rifampicin (i.e. multidrug-resistant TB or MDR-TB), plus resistance to any fluroquinolones, and any one of the second-line anti-TB injectable drugs (Amikacin, Kanamycin or Capreomycin). Epidemiology : There is an increasing incidence of this subset of resistant tuberculosis with incidence ranging from 2% to 8% in different countries. The incidence is higher in high Tb burden countries where control programs are not well established.. The description of XDR-TB was first used earlier in 2006, following a joint survey by WHO and the US Centers for Disease Control and Prevention (CDC). Resistance to anti-TB drugs in populations is a phenomenon that occurs primarily due to poorly managed TB care. Problems include incorrect drug prescribing practices by providers, poor quality drugs or erratic supply of drugs, and also patient non-adherence. DRUGS AVAILABLE TO TREAT XDR TUBERCULOSIS  Aminoglycosides: kanamycin & amikacin (15 mg/Kg. Maximum dose 1 Gram/day) are bactericidal. Amikacin is better tolerated and can be given IM & IV.  Capreomycin(15 mg/Kg. Maximum dose 1 Gram/day): It is bactericidal and very expensive. At present it is not available in Pakistan. It is very useful in cases with tubercle bacilli resistant to streptomycin, kanamycin and amikacin.  Thioamides: Ethionamide(10-20 mg/kg. Maximum 750 mg/day) is bactericidal but causes more GI upset.  Cycloserine (10-20 mg/kg. Maximum 750 mg/day): It is bacteriostatic with no crossresistance with other antituberculosis agents.  Para-aminosalicylic acid (PAS) (120mg/Kg. Maximum dose 12 Gm/day in divided doses): It is bacteriostatic and need large number of tablets to swallow.  Thioacetazone (4mg/Kg/150mg/day): It is a weak bacteriostatic drug with risk of cross-resistance with ethionamide and additional toxicity when thioacetazone is used along with thioamide.  Clofazimine: It inhibits mycobacterial growth.  Oxazolidinones: Linizolid is bacteriostatic and have shown activity against M. tuberculosis in a murine model. Linezolid has been used sporadically in MDR-TB patients. Although all reports are anecdotal, linezolid does seem to have biologic activity as evidenced by sputum culture conversion. Linizolid (600 mg twice daily in adults) is safe for courses of therapy of <28 days, but on long-term use causes reversible haematopoietic suppression, primarily thrombocytopenia and peripheral and optic neuropathy on prolonge use.
40

 Macrolides: Second generation macrolides i.e. Clarithromycin, roxithromycin, and azithromycin are the most active clinical agents against the MAC (Mycobacterium Avium Complex) but unfortunately it is not effective against M. tuberculosis.  Co-amoxyclav: It is active against M. tuberculosis in vitro but it penetrates poorly in mammalian tissue that limits its effectiveness in tuberculosis treatment.  Pyrazinamide: Some authorities recommend use of pyrazinamide because resistance is neither easy to acquire nor to prove by susceptibility testing. Pyrazinamide is bactericidal in an acid medium (bacilli inside macrophages).

Others: Streptomycin and Ethambutol can be used if they are sensitive.
When resistance to streptomycin is proved or highly suspected, one of the other aminoglycosides can be used as a bactericidal agent against actively multiplying organisms.

Principles of treatment:
It must be made clear to the patient the prescribed regimen is the last chance to cure. The patient must try to tolerate any unpleasant side effects in order to achieve survival.  All patients with XDR TB should be admitted at least for intensive phase.  The regimen should be tailor-made according to susceptibility pattern of the strain.  The treatment regimen should include minimum of three drugs but preferably 4-6 drugs if possible.  The treatment should be undertaken in specialized centers under supervision of a specialist trained in management of XDR Tb. The centre should have access to adequate laboratory facilities, isolation arrangements and sufficient drug supplies with facility to manage adverse drug reactions.  While devising regimen, cross resistance should be kept in mind: 1. Ethionamide and thioacetazone: There is cross resistance between ethionamide and thioacetazone: strains naturally resistant to thioacetazone are usually still susceptible to ethionamide; strains resistant to ethionamide are usually resistant also to thioacetazone, in more than 70% of cases. 2. Aminoglycosides: Strains resistant to streptomycin are susceptible to kanamycin & amikacin. Resistance to kanamycin induces a complete cross-resistance with amikacin: they should be considered as the same drug. Resistance to kanamycin & amikacin induces also resistance to streptomycin. Strains resistant to streptomycin, kanamycin, amikacin are still susceptible to capreomycin. 3. Fluoroquinolones: There is no cross-resistance with other classes of drugs. 4. Cycloserine: There is no cross-resistance with other classes of drugs.  It is of no use to combine two drugs of the same group.  An intensive phase of at least 6 months followed by a continuation phase of app. 18 months.  All medication should be given under direct observation, at least until the sputum is negative.  The patient must receive personal attention and psychological support.

41

THERAPEUTIC REGIMEN
Resistance to Intensive phase Minimum duration (Months) Capreomycin*, 6 Ethambutol, 6 Pyrazinamide, 6 Ethionamide, 6 Cycloserine 6 Capreomycin*, 6 Ethambutol, 6 Pyrazinamide, 6 Ethionamide, 6 Cycloserine 6 Streptomycin, 6 Ethambutol, 6 Pyrazinamide, 6 Ethionamide, 6 Cycloserine 6 Capreomycin*, 6 Ethambutol, 6 Pyrazinamide, 6 PAS, 6 Cycloserine 6 Capreomycin*, 6 Ethambutol, 6 Pyrazinamide, 6 PAS, 6 Ethionamide 6 Capreomycin*, 6 Ethambutol, 6 Pyrazinamide, 6 PAS, 6 Clofazimine 6 Drugs Capreomycin*, Pyrazinamide, PAS, Clofazimine 6 6 6 6 6 Drugs Continuation phase Duration (Months) 18 18 18

INH, Rifampicin, Quinolone, kanamycin INH, Rifampicin, Quinolone, Amikacin INH, Rifampicin, Quinolone, Capreomycin INH, Rifampicin, Quinolone, kanamycin, Ethionamide INH, Rifampicin, Quinolone, kanamycin, Cycloserine INH, Rifampicin, Quinolone, kanamycin, Ethionamide, Cycloserine INH, Rifampicin, Ethambutol, Streptomycin, Quinolone, kanamycin, Ethionamide, Cycloserine INH, Rifampicin, Ethambutol, Pyrazinamide, Streptomycin,

Ethambutol, Ethionamide, Cycloserine

Ethambutol, Ethionamide, Cycloserine

18 18 18

Ethambutol, Ethionamide, Cycloserine

18 18 18

Ethambutol, PAS, Cycloserine

18 18 18

Ethambutol, PAS, Ethionamide

18 18 18

Ethambutol, PAS, Clofazimine

18 18 18

PAS, Clofazimine

18 18

Capreomycin*, Linizolid, PAS, Clofazimine, Clarithromycin

6 6 6 6 6

PAS, Clofazimine, Linizolid,

18 18 18

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Quinolone, kanamycin, Ethionamide, Cycloserine INH, Rifampicin, Ethambutol, Pyrazinamide, Streptomycin, Quinolone, kanamycin, Ethionamide, Cycloserine, PAS * If available

Capreomycin*, Linizolid, Clofazimine, Clarithromycin, Co-Amoxyclav

6 6 6 6 6

Clarithromycin, Clofazimine, Linizolid,

18 18 18

Role of surgery
In all these patients, surgery along with ATT should be considered at the outset as studies15, 16, 17 have shown greater response rate in comparison to ATT alone. But unfortunately most of these patients have extensive lung involvement. If the disease is unilateral and/or localized with good lung function surgery should definitely be considered.

Notification and Registry
It is imperative for a good TB control program to develop registry of all TB cases. In our setup keeping in view a large population being treated in setups other than Tb control centres it is difficult to develop a comprehensive notification and registration plan. However, for MDR and XDR TB a mandatory proforma of notification should be initiated by the treating Physician. A central registration number should be allotted and follow up reports of the patients should be filed periodically.

43

Chapter VIII
Management of Contacts of MDR TB Cases General considerations
Opportunities to halt the transmission of resistant mycobacteria in communities and to treat MDR-TB in a timely fashion are often squandered. The main reasons are lack of investigation of contacts of MDR-TB patients, failure to ask patients presenting with active TB disease about any history of exposure to MDR-TB, and lack of access by national treatment programs to second line regimens and/or DST. Close contacts of MDR-TB patients are defined as people living in the same household, or spending many hours a day together with the patient in the same indoor living space. The available data indicate that close contacts of MDR-TB patients who develop active TB most commonly have drug-resistant disease. While all contacts of TB require investigation, DR-TB requires the most vigilance. Because of the severe risk of morbidity and mortality of XDR-TB, contact tracing of cases of XDR-TB should be given the highest level of alertness and priority. Contact investigation of XDR-TB is an emergency situation.

Management of symptomatic adult contacts of patients with MDR-TB
All close contacts of MDR-TB cases should be identified through contact tracing and evaluated for active TB by a health-care provider. If the contact appears to have active TB disease, culture and DST should be performed. If DST is not available, or while DST results are awaited, an empirical regimen based either on the resistance pattern of the index case or on the most common resistance pattern in the community may be started. Delay in the diagnosis of MDR-TB and start of appropriate treatment can lead to increased morbidity and mortality as well as unchecked amplification and transmission of drugresistant strains of TB. When investigation of a symptomatic adult contact yields no evidence of TB, a trial of a broadspectrum antibiotic, particularly one that is not active against TB, such as trimethoprim / sulfamethoxazole, can be used. If the patient continues to have symptoms, chest computed tomography and/or directed bronchoscopy for smear and culture should be considered if available. Where these diagnostic tools are not available or the results are not conclusive, a diagnosis should be based on the clinical information at hand. If the initial investigation is not suggestive of active TB but the contact remains symptomatic, repeat physical examinations, smears and cultures should be performed monthly with repeat chest X-ray as needed.

Management of symptomatic pediatric contacts of patients with MDR-TB
MDR-TB should be suspected in children with active TB in the following situations: • A child who is a close contact of an MDR-TB patient. • A child who is a contact of a TB patient who died while on treatment when there are reasons to suspect that the disease was MDR-TB (i.e. the deceased patient had been a contact of another MDRTB case, had poor adherence to treatment or had received more than two courses of antituberculosis treatment). • Children with bacteriologically proven TB who are not responding to first line drugs given with direct observation. The diagnosis of TB is more difficult in children than in adults. Symptoms of TB in young children can be nonspecific, e.g. chronic cough or wheeze, failure to thrive and recurrent fevers. Bacteriological confirmation may be difficult to obtain because of the inability of children to generate a sputum sample, as well as the paucibacillary nature of paediatric TB and the increased likelihood of extrapulmonary TB in children. While every effort should be made to establish a bacteriological 44

diagnosis (and obtain DST) in a child with suspected MDR-TB, in practice pediatric cases are often not confirmed bacteriologically. Use of scoring systems that have been produced to aid screening and diagnosis of active TB is strongly recommended (see Guidance for nationaltuberculosis programmes on the management of tuberculosis in children ). Symptomatic pediatric household contacts should receive: • An evaluation by a physician, including history and physical examination. • Tuberculin skin testing with purified protein derivative (PPD). • A chest X-ray examination (computerized tomography is helpful especially in documenting hilar adenopathy but this is often not available in lowresource areas). • Sputum smear, culture and DST: every effort should be made to establish a bacteriological diagnosis (and obtain DST) in a child with suspected DRTB. Bacteriological confirmation may include more aggressive measures such as induced sputum, gastric aspirate, lymph node aspirate or other relevant sample, plus culture and DST. (Note: gastric aspiration should only be undertaken where culture facilities are available due to the low yield from microscopy and the distress involved for the child. Culture specimens need to be processed within the hour because the acidic juices will kill the bacteria relatively quickly) • HIV counselling and testing (in areas of high HIV prevalence or if parent(s) known, or suspected to be, HIV-infected).When the tuberculin (PPD) skin test result is >5 mm but the chest radiograph and gastric aspirate or sputum smear are negative, the symptomatic child can be treated with a broadspectrum antibiotic that is not active against TB, such as trimethoprim/sulfamethoxazole. The child be followed closely, with evaluations including smear test and culture on samples from induced sputum or gastric aspirates, or sputum samples whenever possible, as well as chest X-rays. The optimal frequency of these evaluations has not yet been determined. It is not clear whether the frequency of evaluation recommended for adults can be applied to children. If a child’s clinical condition is highly suggestive of TB, or progressively deteriorates, empirical therapy designed according to the DST pattern of the strain from the index case can be started. Children with MDR-TB who are incorrectly entered in SCC may suffer significant and protracted morbidity as a result of ongoing active disease, with the possibility of lifelong disability or even death. Because children with TB may never become sputum smear-positive, it is reasonable to initiate empirical MDR-TB therapy based on the DST pattern of the contact. If DST of the contact is not available, therapy can be based on the common DST patterns of resistance in the community.

Chemoprophylaxis of contacts of MDR-TB index cases
The only chemoprophylaxis regimens to have been studied are based on isoniazid and, to a lesser extent, rifampicin. Since by definition MDR-TB is resistant to both of these drugs, it is unlikely that use of these drugs to treat latent infection caused by an MDR-TB strain will prevent the development of active TB disease. Contacts of MDR-TB patients in whom latent infection is diagnosed may not be infected with the same strain; some may be infected with isoniazid susceptible strains, particularly in high-burden areas where many different strains of TB may circulate in homes, schools, workplaces, etc. Studies from highburden TB areas have shown that approximately one-half to two-thirds of household members had the same strain of TB, as determined by genetic testing . (The degree of strain concordance could be higher in contacts who are children aged under 5 years because they have less exposure to strains circulating outside the household.) Close contacts of DR-TB patients should receive careful clinical follow-up for a period of at least two years. If active disease develops, prompt initiation of treatment with a regimen designed to treat MDR-TB is recommended. On the basis of the currently available evidence, WHO does not recommend the universal use of second-line drugs for chemoprophylaxis in MDR-TB contacts.

45

Chapter IX Category IV Recording and Reporting System
This chapter describes the information system for category IV patients, with the objective of recording information needed to monitor program performance and treatment outcomes.

Main Forms/Registers and Flow of information:
The forms and registers include the following: • Category IV Treatment Card (Form 01); • Category IV Register (Form 03); • Laboratory Register for culture and DST (Form 04). • Request for sputum examination, culture and DST (Form 05); Reports include: • Quarterly report on MDR-TB detection and Category IV treatment start (Form 07); • Six-month interim outcome assessment of confirmed MDR-TB cases (Form 06); • Annual report of treatment result of confirmed MDR-TB patients starting Category IV treatment (Form 09). Category IV Treatment Card (Form 01) When the relevant health authority (such as a review panel) decides that a patient should start Category IV treatment, the health staff in the treatment unit should enter the patient in the Category IV Register. The staff should complete the Category IV Treatment Card when the patient is actually starting treatment. This card is a key instrument for DOT workers who administer drugs to patients on a daily basis. The card should be updated daily by ticking off the supervised administration of drugs. The card represents the primary source of information to complete and periodically update the Category IV Register. The card, or a copy of the card, must always follow the patient (e.g. from a specialized hospital to an ambulatory facility). A copy of the card may be used as a notification form and later also to report the final outcome of treatment. The Category IV Treatment Card contains the following sections:
Page 1

• Basic demographic and clinical information. Records name, address, sex, age, weight and site of disease. • Category IV registration number. This is a new unique identification number assigned when the patient is entered in the Category IV Register. • Date of Category IV registration. Provides registration date in the Category IV Register. • Previous district TB registration number and date of registration. • Registration group according to result of previous antituberculosis treatment. See Chapter II for definitions. • Previous TB treatment episodes. Lists and describes any previous antituberculosis treatment and outcomes. Start with the earliest treatment and label it number 1. Use the drug abbreviations given on the front of the treatment card. Also note here the outcome of any previous treatment. • HIV testing information. This section is filled in for all patients. If tested for HIV, include date of testing and results. If HIV-infected, indicate whether patient is on ART and/or CPT. • Previous use of second-line antituberculosis drugs. Documents use of any of the second-line drugs listed at the front of the chart for antituberculosis treatment for more than one month. • Medical diagnoses other than TB. All other important medical diagnoses are recorded here, including diabetes, hypertension, cardiomyopathy, HIV, opportunistic infections, etc. 46

• Meetings of review panel (medical commission, selection committee, concilium). These guidelines promote periodic meetings with the group of caregivers involved with Category IV patients. This section provides a space to record major decisions by the panel.
Page 2

• HIV flow sheet. This section is only filled in for HIV-infected patients. • Monitoring of laboratory data including creatinine, potassium, liver function tests, and thyroid tests. • Monitoring of smear and culture. Record date of sputum collection, sample number in the laboratory register and result of smear and culture. “Prior” refers to the sample used to indicate Category IV registration; include the date and result of that sample. Month “0” is the time of specimen collection at the start of the Category IV regimen. • DST results. Record the date of sputum collection and results of all DST performed.

Page 3 (Both sides of the page) • Regimen. Record the initial Category IV regimen and later changes. Use one line for each date on which a drug(s) is changed. If drug dosage is progressively increased (e.g. starting 250 mg of ethionamide daily and increasing by 250 mg over 2–3 days until the full dose is reached), record this in the patient’s medical record (not on the treatment card). • Record of daily observed administration of drugs. This is constructed with one line per month to facilitate assessment of adherence. Mark one box for each day the entire treatment is administered. Additionally, if dosing is twice daily, one slash mark could be made for the A.M. dose and a second, intersecting mark could be made for the P.M. dose; if both are received, the box would contain an “x”. An alternative is a more detailed system containing one box for each drug prescribed daily, since there may be some inconsistency in administration among drugs. • Monitoring and recording adverse effects. Record date, adverse effects and suspected drug(s). • Monitoring of weight. Weight should be recorded at least monthly. Page 4 • Monitoring of chest X-ray. • Outcome of treatment. Chapter II provides definitions. Record the outcome of treatment when the final bacteriology results become available.

Category IV Register (Form 02)
The NTP should have two TB registers: a District Tuberculosis Register and a Category IV Register. The Category IV Register is the record of all patients who start Category IV treatment. This register allows quick assessment of the implementation of Category IV, facilitating quarterly reporting and analysis of treatment start and outcomes. The District Tuberculosis Register is the traditional register used by DOTS programmes in which all TB patients are first registered. In order to integrate the treatment of Categories I, II, III and IV, this register should be modified in three ways: 1. If culture is being done in addition to smear examination in a substantial number of cases, dates of collection and results should be added to both the initial testing and the follow-up areas. 2. Capability to record DST should be added, including the date of collection of the sample and the drugs that are being tested. 47

3. Any patient who is switched to a Category IV regimen because of resistance (without meeting the formal criteria of failure) should have the outcome category “Change to Category IV” entered in the District Tuberculosis Register. When a patient is starting Category IV treatment, the health staff in the treatment unit should enter the patient in the Category IV Register and indicate in the District Tuberculosis Register that the patient has entered Category IV. The date of registration should be the day when the health staff enters the patient in the Category IV Register. The Category IV Register should be updated regularly from the Category IV Treatment Card and from the laboratory registers. Patients should be recorded consecutively by their date of registration. There should be a clear separation (extra line) when a new quarter is started. These guidelines recommend that patients infected with strains with relatively simple resistance patterns (H, HS, HE and HZ) stay in the District Tuberculosis Register, where adjustment of their regimen should be recorded, including any second-line agents used. Patients infected with more complicated mono- and poly-resistance strains (involving R or HEZ resistance) or any mono- and poly-resistant strains that may have developed into MDR-TB should be entered into the Category IV Register. Some patients started on Category IV regimens may be found to have drug susceptible disease. Patient in this situation can be removed from Category IV treatment and placed on appropriate first-line therapy. The patient should be crossed out of the Category IV Register (but the name still left legible) and a comment noted in the last column that s/he has drug-susceptible disease. All patients who are switched should be registered in the District Tuberculosis Register. (if they are already registered in the district register, the final outcome should be documented in the original line of registration (do not create a new registration). These patients do not need to appear in Forms 06 and 0, and 09 of the DR-TB reporting forms as they do not have MDR-TB. Any patient with mono- or poly resistance whom it has been determined should stay in the DR-TB program should not be crossed out of the Category IV Register. Whether the patient continues on the same Category IV regimen (often done in programs using standardized regimens) or gets an individualized regimen based on DST can be documented on the treatment card and the final outcome reported in the Category IV Register. These patients do not need to appear in Forms 06 and 07 and 09 of the DR-TB reporting forms as they do not have MDR-TB. The following information is recorded in the Category IV Register • Category IV registration number. • Date of Category IV registration. • Name, sex, date of birth, address (from treatment card, p. 1). • District TB registration number. All patients should have been entered in a District Tuberculosis Register. A patient who for any reason has never been registered in the District Tuberculosis Register should be registered there and the number transferred to the Category IV Register. • Site of disease (from treatment card). Pulmonary, extrapulmonary or both. Patients with both pulmonary and extrapulmonary TB should be classified as a case of pulmonary TB. • Registration group (from treatment card). • Second-line drugs received for more than one month prior to registration (from treatment card). • DST (from treatment card). Date sample taken, date of DST result and the results. Enter the DST that resulted in the patient being registered as a Category IV patient. Follow-up DSTs are not recorded in the register.

48

If the patient has more than one DST, results are recorded on the treatment card. If DST is performed in a staged fashion (e.g. of rifampicin and isoniazid first, followed by other first-line drugs, and then of second-line drugs). All results from the same sample should be recorded in the register. • Category IV regimen (from treatment card). Record the initial Category IV regimen using the drug abbreviations. Include milligram doses and number of tablets. • Date of start of Category IV treatment (from treatment card). • Smear and culture monitoring results (from treatment card). Record all smear and culture results, even if done more often than the recommended frequency. • Final outcome (from treatment card). • HIV status (from treatment card). Testing results, CPT and ART treatment information. • Comments.

Request for sputum examination (Form 05)
Form 05 is the same as that recommended for DOTS programs in the Revised TB recording and reporting forms and registers – version 2006; the upper portion is for requesting smear microscopy, the middle portion for culture and the lower portion for DST; the last section is used for reporting the results. When DST is requested, the registration group should be added. Results should be sent stepwise as they become available.

Laboratory Register for culture and DST (Form 04)
Laboratories will have separate registers for sputum smear microscopy and culture, while reference laboratories carrying out DST should have additional space in the culture register for DST results (see Form 05). The Laboratory Register for culture and DST should contain samples from all MDR-TB suspects, indicating the registration group (including if positive smear at 3 or 4 months), and be filled in from the request form. The Laboratory Register should be compared regularly with the Category IV Register to ensure that all confirmed MDR-TB cases are entered in the Category IV Register.

Quarterly report on MDR-TB detection and Category IV treatment start (Form 07)
This report is used to assess the number of MDR-TB cases detected (distribution and trends) and the number of MDR-TB cases who start treatment. The report should be made quarterly in line with the routines of the NTP. The report should be made by the unit managing MDR-TB. The quarterly report includes: • The number of patients, with date of result showing MDR-TB during the relevant quarter taken from the Laboratory Register (Form 04). Optionally, the patients could be split by registration group • The number of MDR-TB patients started on Category IV treatment during the quarter, taken from the Category IV Register (Form 03). If relevant, the number of XDR-TB cases registered (after cross-checking DST results with type of resistance) and the number of XDR-TB cases started on XDR-TB treatment should be added. Since there may be a considerable delay between Category IV registration and the start of Category IV treatment, patients who start treatment during the quarter may not be the same as those detected with DR-TB. The information provides an approximation of treatment coverage. These guidelines encourage program to calculate the average delay between detection of DR-TB and treatment start.

Six-month interim outcome assessment of confirmed MDR-TB cases (Form 06)
Since treatment takes on average two years before final results are known, the TB control program needs more updated information on treatment outcome. Form 06 can be used to report bacteriological status (negative, positive or no information) of those still on treatment at 6 months, and for those who have already defaulted, died or transferred out, this can be 49

recorded as the final outcome. Bacteriological results are based on the smear and culture data during months 5 and 6 of treatment. Consider the 6-month outcome assessment unknown for a particular patient if a culture or smear result is unknown for either month 5 or 6. All cases from the Category IV Register should be included in this report. The form should be completed 9 months after the closing day of the cohort. This allows culture information at month 6 of treatment to be included for all patients in the cohort. For instance, TB patients who started treatment during the first quarter of a year (1 January to 31 March), should have the form filled in from 1 January of the following year.

Annual report of treatment result of confirmed MDR-TB patients starting Category IV treatment (Form 09)
This report is made by the central unit and shows the final result of treatment by year of treatment start. All the patients are classified by previous use of antituberculosis drugs (none, only first-line drugs, also second-line drugs). If relevant, results for patients with XDR-TB could be added. All data can be extracted from treatment cards and Category IV Register. Form 07 is first completed at 24 months after the last patient in the cohort started treatment. Most of the patients will have finished treatment by 24 months, allowing preliminary assessment of cure rates. Since a few patients may be on treatment for longer than 24 months, the form may be completed again at 36 months, which will then be considered the final result.

Addressing the backlog of patients who failed Category II treatment in the past
When Category IV treatment is being introduced, there may be a large group of patients who are still sputum smear-positive after supervised Category II treatment from previous years. There may also be patients who have received several unsuccessful treatments, are considered incurable by health staff and who have lived with active TB disease with no or inadequate treatment for a period of time. While preparing for Category IV treatment, TB control program should keep a list of these patients. When Category IV treatment becomes available, such cases with evidence of active disease should follow the national protocol for Category IV treatment start, ideally having a DST done at the start to confirm MDR-TB. The number of patients waiting for Category IV treatment should be estimated as this will facilitate planning of drug and other resource needs. As the Category IV treatment program progresses, the list of chronic cases will become smaller and eventually include only patients who have failed Category IV treatment.

Assuring the quality of the recording and reporting system
In order for the information system for DR-TB to function well, adequate training and supervision are needed. The staff require basic knowledge of the DOTS information system, with additional training on the specifics of the Category IV forms. Regular supervisory visits by a central unit to the units using the information system as well as meetings with staff from different levels will be conducted. The person responsible for Category IV management should regularly (at least weekly) compare the Category IV Register with the DST register in all the laboratories performing DST to ensure that all patients in whom MDR-TB is diagnosed are started on Category IV treatment. The inclusion of MDR-TB patients from the Laboratory Register should take into consideration the quality of the DST performed in the laboratory. Patients diagnosed with MDR-TB in laboratories without proper quality assurance (i.e. in many private laboratories, the quality of DST is completely unknown) should not be included in the Laboratory Register for Culture and DST (Form 04) until their DST has been confirmed in a qualified laboratory. 50

Computerized systems
The recording and reporting system can be managed by hand. However, an electronic system is highly desirable since it facilitates better quality of information as well as data analysis; it will also obviate the need for transcription and repeated entry into different forms. Patient data may be entered in a format similar to the Category IV Treatment Card, and lists similar to the Category IV Register can then be generated. Print-outs of the list may be compared with the handwritten Category IV Register to ensure completeness of the system. The corrected database may then be used to generate quarterly and annual reports. Even if a computerized system is in place, a handwritten Category IV Register should be maintained, since otherwise corrections cannot be seen.

51

Chapter X Forms
Table of Forms
FORMS & REGISTERS to be used for DR-TB Control Program DR-TB 01 DR-TB 02 DR-TB 03 DR-TB 04 DR-TB 05 DR-TB 06 DR-TB 06 A DR-TB 07 DR-TB 07 A DR-TB 08 DR-TB 09 DR-TB 10 DR-TB 11 CATEGORY IV PATIENT TREATMENT CARD PATIENT IDENTITY / APPOINTMENT CARD CATEGORY IV PATIENT REGISTER LABORATORY REGISTER for SPUTUM SMEAR DIRECT MICRSOCOPY REQUEST FOR SPUTUM EXAMINATION /CULTRE AND SENSITIVITY
Six Month Interim Outcome Assessment of confirmed MDR-TB cases (to be filled out 9 months after treatment start)

LABORTAORY REGISTER for CULTURE QUARTERLY REPORT on CATEGORY IV CASE REGISTRATION Proportion of confirmed MDR-TB cases started on treatment by quarter registered as MDR-TB case and reason for not yet starting on treatment INTERIM RESULT OF MDR-TB TREATMENT BY QUARTER OF TREATMENT START IN CONFIRMED MDR-TB CASES ANNUAL REPORT ON TREATMENT OUTCOME OF CATEGORY IV Regimens TRANSFER / REFERRAL FORM QUARTERLY ORDER for TUBERCULOSIS SUPPLIED (DRUGS)

Hard Copies of forms 1-9 will be provided with the guidelines. Otherwise an electronic file is available upon request.

52

Form 10 A Referral Letter Format To the Treatment Site
Patient’s Name: Patient’s full address: Referring Physician’s Name/ Address/ Phone Number:

Referring TB Center ( if available) Patient’s TB Number ( if available) Brief Medical History and Reason for referral

Sputum C/S Result: Date: Positive DST Result : Resistant to ( please circle the correct answer)

H

Negative (please circle the correct answer) R E S

Names of previous anti TB drugs and any other drugs used: Name of the Drug Date of starting treatment Date of stopping the Drug -

Note: Please send all old CXRs with the patient and any other medical records.

Date:

Signature

53

Form 11 Request for second line drugs From the Central NTP Unit
Date: From: Name of the Officer requesting the drugs: Patient’s Name: Patient’s CAT IV TB Registry Number Drug’s name Cyloserine Ethionamide/Prothionamide Ofloxacin Ofloxacin PAS Kanamycin Others Dosage 250 mg/ cap 250 mg/tab or caps 200mg/tab 400mg/tab 2gm/sachet 1 gm/ inj Quantity requested

Signature of the Registrar requesting the drugs

54

Chapter XI Annexes Table Of Annexes Annex # 1 Annex # 2 Annex # 3

Weight-based dosing of antituberculosis drugs in the treatment of DR-TB
Hospitals list of Dr-TB ctrs involved

2nd line drug management

Please refer to attached documents for above annexes

55

Social and Medical Support to DR-TB patients during the course of treatment:
Following constitutes a package of services under Community and Hospital Based Care center (CHBCC) for MDR-TB. Setting up the CHBCC Sites: With private sector/NGO support and any other related agencies, a CHBCC will be established in each treatment site. These centers will provide coordination, operational management and implementation of MDR-CHBC package. There would be organization of regular coordination meeting among partners in the same area to ensure high quality. The key elements include: 1. Psychosocial Support A new cadre of health care providers, community mobilizers and volunteers will be trained on counseling for psychosocial support on MDR. 2. Nutritional Support Food support that includes fruits, wheat, milk, cereals, sugar and cooking oil. Set up referral mechanisms and referral support. Each treatment site will develop a Criteria and procedures for referral of DR-TB patients to the CHBCC. Referral services comprises referral for investigations, consultations and treatment including specialized medical care. NGOs would facilitate access to health care facilities by providing support for transport when needed and accompanying the patients. Referral Support:-Regular Medical Referral and Follow up for possible adverse effects/complications including logistic and meals. Special travel / logistics from and to distant cities needs to be supported through GBF R9. Supportive medical investigations/services, not covered through PC-1 or by the local treatment site, would be supported through RD9 Global Fund. 3. Establish Social support network for MDR-TB The formation of people living with MDR-TB peer support groups and networks would be facilitated, they would facilitate linkages and access to social support networks/organizations and others, including those implementing income generating activities, or vocational training, legal services, etc. They would also be mentored on how to refer to and access Provincial and District Social Welfare Services. They would also address Human Right issues. 4. Strengthening of civil society and institutional capacity building for CHBC for MDR-TB and special support for the chronically ill. National Strategic Framework will be developed that would guide how to conduct various operations for CHBCC. Who will do it?

56

57

REQUEST FOR SPUTUM EXAMINATION FOR SMEAR, CULTURE AND DST (to be completed by treatment center) Category IV registration #______________________ District TB registration #_______________________
Treatment Unit Patient Name: ____________________ Date ____________________

Age:________ Address (precise)

Date of Birth: ____________________

Sex : M { } F

{ }

______________________________________ ______________________________________ Diagnosis{ } Follow-up examination{ } Months of follow-up:___

Reason for examination (check one ):

Test(s) requested: Smear{ } Culture{ } Drug susceptibility Testing{ } If DST, specify registration group: ______________________ Signature of person requesting examination: ________________________________

RESULTS (to be completed in laboratory)

SMEAR RESULTS:
Date Collected Specimen Laboratory Specimen No. Appearance* neg Result (check one) 1-9 + ++ +++

1 2 *visual appearance of sputum (blood-stained, muco-purulent, saliva) Date _____________________ Examined by (Signature) _______________________
No AFB 1 – 9 AFB per 100 HPF 10 – 99 AFB per 100 HPF 1 – 10 AFB per HPF > 10 AFB per HPF 0 Scanty (and report number of AFB) + ++ +++

CULTURE RESULTS:
Result (check one)
Date Collected Specimen 1 2 Date _____________________ _________________________
No growth reported Fewer than 10 colonies 10 -100 colonies More than 100 colonies Innumerable or confluent grwoth 0 Report number of colonies + ++ +++

Laboratory Specimen No.

neg

1–9 colonies

+

++

+++

contaminated

Examined by (Signature)

DST RESULTS:
Date collected Laboratory Specimen No. S H R E Z Km Am Cm Ofx Pto /Eto Other

Date

_____________________

Resistant Susceptible

R S

Examined by (Signature) ______________________________

58

The form (with each set of new results) should be copied and sent promptly to the treatment unit

59

DR-TB Control Program

DR-TB 06

Laboratory Register for Culture and DST (page 1)
Date specimen received Lab serial number Type of specimen received Referring health facility Cat IV Register number District TB Register number Patient Name Patient address if new patient Registration group Gender Age Date specimen collected Date specimen inoculated

Page 1 of 3 60

DR-TB Control Program

DR-TB 06

Laboratory Register for Culture and DST (page 2)
Reason for examination Result of smear examination Result of culture*** Result of confirmatory-test for M. Tuberculosis (pos or neg) Culture sent for DST (yes or no) Date DST started/ino culated DST method Date of DST result

Diagnosis*

Follow-up**

* New patients or patients starting a retreatment regimen ** Patient on TB treatment, indicate months of treatment at which follow-up examination is performed *** Outcome of culture reported as follows:

Page 2 of 3 61

DR-TB 06

Laboratory Register for Culture and DST (page 3)
Result: S=susceptible R=resistant C= contaminated R H E S Km Cm Fq Comments Pto/Eto Other Other Other

Page 3 of 3 62

DR-TB 07A Proportion of confirmed MDR-TB cases started on treatment by quarter registered as MDR-TB case and reason for not yet starting on treatment

63

DR-TB Control Program

DR-TB 07

Form 07: Quarterly report on MDR-TB detection and Category IV treatment start

Name of area ____________________________________ Patients identified during _______ quarter of year ______

Name of area coordinator _________________________ Date _____________

1 - Number of patients detected with MDR-TB/XDR-TB in the lab (by date of result of MDR-TB/XDR-TB in lab register) during the quarter: MDR-TB XDR-TB

Optional: separate patients by registration group

2 - Number of MDR-TB patients who started Category IV treatment during the quarter New case Confirmed cases Suspected cases Previously treated with 1st-line drugs Previously treated with 2nd-line drugs

1 quarter: nd 2 quarter: rd 3 quarter: th 4 quarter:

st

1 January - 31 March er 1 April - 30 June er 1 July - 30 September er 1 October - 31 December

st

Signature

64

DR-TB Control Program

DR-TB 08

Six Month Interim Outcome Assessment of confirmed MDR-TB cases (to be filled out 9 months after treatment start)
Name of Unit:___________________________________ Date filled in: ___________________________________ Quarter treatment was started: ______________________ Date of the report: ________________________________
Number started on treatment Bacteriological results at 6 months of treatment
Negative (Smear and culture negative) Positive (Smear and/or culture positive) Unknown

No longer on treatment Died Defaulted Transferred Out

65

DR-TB Control Program

DR-TB 08 A

Interim result of MDRTB treatment by quarter of treatment start in confirmed MDR-TB cases
1 2 At how many months after treatment start assessment is made 3 Number started on MDR-TB treatment 4 5 6 Bacteriological results at time of assessment Negative (Smear and culture negative) Positive (Smear and/or culture positive) Unknown 7 8 9 No longer on treatment Defaulted Transferred out

Died

Quarter of MDRTB treatment start

66

DR-TB Control Program

DR-TB 09

Annual report of treatment result of confirmed MDR-TB patients starting Category IV treatment
(to be filled in 24 and 36 months past the closing date of year of treatment)

Year of Treatment start:_____

Patient group New Previously treated with 1.line drugs only Previously treated with both 1.and 2.line drugs Total

Cured

Treatment Completed

Failed

Defaulted

Died

Transferred Out

Still on Treatment

Total

67

Form 10 A Referral Letter Format To the Treatment Site
Patient’s Name: Patient’s full address: Referring Physician’s Name/ Address/ Phone Number:

Referring TB Center ( if available) Patient’s TB Number ( if available) Brief Medical History and Reason for referral

Sputum C/S Result: Date:
correct answer)

Positive H

Negative (please circle the R E S

DST Result : Resistant to ( please circle the correct answer)

Names of previous anti TB drugs and any other drugs used: Name of the Drug Date of starting treatment Date of stopping the Drug -

Note: Please send all old CXRs with the patient and any other medical records. Date: Signature

68

Form 11 Request for second line drugs From the Central NTP Unit
Date: From: Name of the Officer requesting the drugs: Patient’s Name: Patient’s CAT IV TB Registry Number Drug’s name Cyloserine Ethionamide/Prothionamide Ofloxacin Ofloxacin PAS Kanamycin Others Dosage 250 mg/ cap 250 mg/tab or caps 200mg/tab 400mg/tab 2gm/sachet 1 gm/ inj Quantity requested

Signature of the Registrar requesting the drugs

69


				
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