B) MDR-TB statistics for Malaysia and Sabah Picture 10.1: MDR-TB cases Malaysia 101
Table 10.1: Prevalence of individual drug resistance in Sabah *H: Ioniazid; R: Rifampicin; E: Ethambutol; Z: Pyrazinamide; S: Streptomycin. C) Pathways to DR-TB There are two pathways leading to drug resistance. 1. Primary drug resistance is becoming a more common cause of DR-TB due to transmission by infected individuals who have not been treated. This is a more worrying concern. 2. Acquired drug resistance (Due to non-compliance of treatment). Highest Risk Factors for DR-TB 1. Failure of retreatment regime (SHREZ). This regime should not be used anymore due to easier access to rapid molecular testing. 2. Failure of new TB regime. 3. Exposure to DR-TB patients. 4. Delayed sputum conversion ( especially still positive at Month 3 of treatment). 5. HIV positive patients. 102 Year H + R H + R + S H + R + Z H + R + S + E H + R + S + E + Z R R + S R + E H H + S H + E H + E + S S E S + E HrTB And RRTB Total 2016 6 1 1 13 18 6 1 38 1 85 2017 7 2 1 18 1 1 39 11 2 82 2018 5 3 3 58 12 3 84 2019 2 13 1 32 10 105 19 4 186 2020 8 1 20 1 20 6 38 1 1 96 Total 28 5 2 1 1 67 3 1 167 45 1 2 181 21 5 3 533 * MDR TB Monoresistant or polyresistant TB *
Laboratory Aspect Definitive diagnosis of DR-TB requires that MTB bacteria is detected and determined its resistance to ATT. A) Organization of the TB laboratory network Sabah labs capabilities • 105 acid fast bacilli (AFB) microscopy centres have been set up, with 95 microscopy centres actively performing AFB microscopy throughout the state of Sabah. • About 70% of the microscopy centres currently employ LEDbased fluorescence microscopy while the rest utilize bright-field microscopy with Ziehl-Neelsen staining. Quality assurance programs are regularly conducted throughout the state to monitor AFB microscopy performance in Sabah. • Kota Kinabalu Public Health Laboratory (Makmal Kesihatan Awam Kota Kinabalu, MKAKK) is the main AFB culture centre in Sabah processing about 12000 samples annually. • To date, hospitals appointed as AFB culture centres in the districts of Keningau, Lahad Datu, Tuaran, Kudat and Tenom perform AFB cultures on sputum specimens for hospital inpatients; or both in-patients and out-patients/registered TB patients from the district TB treatment centres. • Positive cultures are then sent to MKAKK for further testing. A few other hospitals including Hospital Kuala Penyu are also in line to become AFB culture centres in the near future. • In view of cost, >80% of AFB cultures are done using solid media (Modified Ogawa). At present, only select samples (extrapulmonary and complex cases) are cultured using the Mycobacteria Growth Indicator Tube (MGIT) culture system in MKAKK. MGIT culture system is able to render positive culture results in about half the time needed for solid cultures. • Identification tests are done on positive AFB cultures using Capilia-TB Neo, an immuno-chromatographic assay (ID-ICA) detecting the MPB64 proteins found in Mycobacterium tuberculosis Complex (MTBC). • In Sabah, identification tests are only done in MKAKK as isolate manipulation activities require a BSL 2 plus (High Containment TB Laboratory) laboratory. 103
• AFB isolates that tested negative with the ID-ICA are sent to the National TB Reference Laboratory in Sungai Buloh (MKAK Sg Buloh) for further laboratory investigation. (Note: Speciation of MTBC is not routinely done e.g. Mycobacterium bovis. However, the test could be done in MKAK Sg Buloh upon special request). • At present, there are 3 molecular tests for the detection of MTBC in MKAKK: i. Quantitative Polymerase Chain Reaction (qPCR) for simultaneous detection of MTBC/Non-tuberculous Mycobacteria (NTM) – reserved for CSF samples. ii. Line Probe Assay (LPA) for MTBC/MDRTB (DNA-RNA Hybridization method) – for the detection of MTBC, Rifampicin resistance (rpoB gene mutation) and Isoniazid resistance (katG/ nhA gene mutation). Smear positive samples will give reliable results. iii. Quantitative Polymerase Chain Reaction (qPCR) for MTB/ MDRTB - for the detection of MTBC, Rifampicin resistance (rpoB gene mutation) and Isoniazid resistance (katG/inhA gene mutation). Smear positive samples will give reliable results. • GeneXpert MTB/RIF, a multiplex qPCR point of care test that is able to simultaneously detect MTBC and Rifampicin resistance (rpoB gene mutation) is available in Sandakan Health Clinic, Queen Elizabeth Hospital, Tawau Hospital and Keningau Health Clinic. As a proxy indicator for MDR-TB, it is indeed a game changer in TB diagnostics as test results could be released in less than 24 hours (total hands-on and run time for a single sample ~90 minutes to 2 hours). • In 2020, WHO recommended that this test be used as the first line TB screening test, however this is not feasible as yet in Sabah due to steep testing costs. At present, this test is reserved for mainly suspected DR-TB cases only. 104
B) Mycobacteriology laboratory services for DR-TB programmes Microscopy (Conventional and LED) Smear microscopy cannot differentiate TB from DRTB (2-24 hour). Molecular methods The most commonly used to detect suspected DRTB rapidly. 1. Xpert MTB/RIF is most commonly used which shows RIF resistance (LTAT: 2-24 hours) 2. Line Probe Assay is used to detect both Isoniazid and Rifampicin resistance but can only be done in smear positive patients. (LTAT: 1-2days. Up to 7 days if batch testing done). It is important in designing an effective regimen by knowing the KatG and inhA mutations. Culture of MTB Liquid medium is the medium used as the “Gold Standard” (LTAT: 8-10days smear positive; 2-6 weeks smear negative). 105
Picture 10.2: Algorithm for interpretation of genotypic DST result 106
Treatment Strategies for DR-TB Ambulatory care (The preferred option) Indications for hospitalization: 1. If proper NPR rooms available, it would be ideal to admit patient for 2 weeks to educate and familiarize the patients with SLDs (can be done as an outpatient too). 2. Respiratory insufficiency. 3. Central nervous system (CNS) RR-TB disease. 4. Clinically unstable. 5. Unstable social situations that require intensive multidisciplinary management. 6. Administration of intravenous therapy. 7. Unable to attend primary care facility for treatment (e.g. too weak to ambulate). 8. Infection control challenges in the patient’s home environment. 9. Recurrent treatment interruption where previous outpatient treatment has been unsuccessful (risk of loss to follow-up). 107
Picture 10.3: Overall flow diagram on treatment of MDR/RR-TB DR-TB Guideline Treatment Regimes A) Shorter MDR-TB treatment regimen Preferred option for patients with confirmed MDR/RR-TB (with at least confirmed resistance to rifampicin), for whom resistance to fluoroquinolones has been ruled out, in the following situations: • without resistance or suspected ineffectiveness of a medicine in the shorter regimen (except isoniazid), • without exposure to previous treatment with second-line medicines in the regimen for more than 1 month (unless susceptibility to these medicines is confirmed), • with no extensive TB disease and with no severe extrapulmonary TB (presence of bilateral cavitary disease or extensive parenchymal damage on chest radiography. In children aged under 15 years, advanced disease is usually 108
defined by the presence of cavities or bilateral disease on chest radiography), • not pregnant, • if a child, aged 6 years or more, or • NO mutations in BOTH inhA and katG regions (LPA). The intensive phase of 4 months (extended to 6 months in case of lack of sputum smear conversion) including the following drugs: • High dose Moxifloxacin (Levofloxacin may be considered if difficulty in obtaining Mfx) • Amikacin • Ethionamide • Clofazimine • High-dose isoniazid • Pyrazinamide • Ethambutol This is followed by a maintenance phase of 5 months with the following medicines: • High dose Moxifloxacin (Levofloxacin may be considered) • Clofazimine • Ethambutol • Pyrazinamide Doses can be obtained from Table 10.6 & 10.7 If all oral regime are preferred (WHO short regime) A shorter all-oral bedaquiline-containing regimen of 9–12 months duration is recommended in eligible patients with confirmed multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) who have not been exposed to treatment with secondline TB medicines used in this regimen for more than 1 month, and in whom resistance to fluoroquinolones has been excluded. Injectable agent is replaced by bedaquiline (used for 6 months), in combination with levofloxacin/moxifloxacin, ethionamide, clofazamine, isoniazid (high-dose), ethambutol and pyrazinamide for 4 months (with the possibility of extending to 6 months if the patient remains sputum smear positive at the end of 4 months). This is followed by 5 months of treatment with levofloxacin/ moxifloxacin, clofazimine, ethambutol and pyrazinamide. 109
Patients on shorter MDR-TB regimen are advice to convert to conventional TB treatment when: 1. Lack of response to treatment (e.g. no sputum smear conversion by 6 months or deterioration of clinical condition despite treatment), 2. Patient is treated for more than one month, interrupts treatment and returns after an interval >2 months (i.e. fulfils another exclusion criterion), 3. Emergence of another exclusion criterion (e.g. EP-TB disease, pregnancy, intolerance to a medicine in the regimen) etc, 4. There is genotypic or phenotypic resistance to fluoroquinolone that was detected at the beginning of treatment, 5. There is positive culture result at month 4 (delayed culture conversion or reconversion back to positive), or 6. Bedaquiline, linezolid, levofloxacin or clofazimine is prematurely and permanently discontinued because of toxicity (all oral regimen). If the patient switches to a longer regimen due to shorter regimen treatment failure, the treatment episode should be register as “treatment failure” and the patient should be assigned a new treatment episode. If the patient switches from a shorter to a longer regimen due to detection of second-line drug resistance, then the treatment episode should be continued and the patient switches categories to the longer regimen. B) Longer MDR-TB Treatment Regimen • The aim is to have 4 core second line drugs (1 from group A, 1 from group B and 2 from group C) and strengthened with D1 drugs for a total of at least 5 drugs. • If a minimum number of 5 cannot be achieved, drugs from D2 and D3 may be added. 110
Table 10.2: Medicines recommended for longer MDR-TB treatment regime *If culture shows no resistance to Streptomycin If all oral regime are preferred (WHO long regime) For patients in whom two agents from Group A are more likely to be stopped before the end of treatment (e.g. pre-existing comorbidities require that both bedaquiline and linezolid be stopped early because of health risks), then starting with five effective agents rather than four may be advisable. While high dose isoniazid is not included in Groups A–C given the rarity of its use in contemporary longer regimens for adults with MDR/RR-TB, it may still be used in patients with confirmed susceptibility or in the presence of mutations that do not usually confer complete resistance to isoniazid. 111 Group name Name of the drugs A. Flouroquinolones Levofloxacin Moxifloxacin B. Second-line injectable agents Amikacin Capreomycin Streptomycin* C. Other core second-line agents Ethionamide Cycloserine Linezolid Clofazimine D. Add-on agents (not part of the core MDR-TB regimen) D1 Pyrazinamide Ethambutol High-dose isoniazid D2 Bedaquiline Delamanid D3 p-aminosalicylic acid Imipenem-cilastatin Meropenem Amoxicillin-clavulanate
Table 10.3: WHO drug groupings and steps to designing a longer treatment regime Duration of second-line anti-TB regimen • In the conventional longer treatment of patients with MDR-TB, an INTENSIVE PHASE of 6-8 months is suggested for most patients, and the duration may be modified according to the patient’s response to therapy. • In the treatment of the patients newly diagnosed with MDR-TB, TOTAL TREATMENT duration of 18-20 months(15-17months after culture conversion) is suggested for most patients, and the duration may be modified according to the patient’s response to therapy. • Shorter MDR-TB regimen duration is 9-11 months. • The duration of treatment may need to be longer than 20 months overall in MDR/RR-TB cases with additional resistance, subject to the clinical response to treatment. 112 GROUPS MEDICINE GROUP A: Include all three medications, where possible Levofloxacin or moxifloxacin Bedaquiline Linezolid GROUP B: Add one or both medications, if possible Clofazimine Cycloserine Group C: Add to complete the regime and when medication from Group A and B cannot be used Ethambutol Delaminid Pyrazinamide Imipenem-cilastatin, or meropenem, or ertapenem Amikacin Ethionamide Para-aminosalicylic acid
Extrapulmonary and Central Nervous System DR-TB Based on table 10.2, the regime chosen will have to a Longer treatment regimen. Intensive phase: Amikacin, Linezolid, Moxifloxacin, Ethionamide, Cycloserine, High dose INH and Pyrazinamide. (Meropenem can be added if Linezolid can’t be used either due to cost or side effects. Best to have a PIC line). Maintenance phase: Linezolid (for as long as possible), Moxifloxacin, Ethionamide, Cycloserine, High dose INH and Pyrazinamide. Treatment duration should be for a minimum of 20 months. Table 10.4: ATT penetration through blood brain barrier *High rate of seizure reported in children with meningitis treated with imipenem Penetration to CSF Medications Good Isoniazid Pyrazinamide Ethionamide Cycloserine Linezolid Imipenem Meropenem Good penetration only in the presence of meningeal inflammation Amikacin Streptomycin Poor or no penetration PAS Ethambutol Variable cerebrospinal fluid penetration Levofloxacin Moxifloxacin Better penetration of based on animal studies Moxifloxacin No data available Clofazimine Clarithromycin 113
Role of Surgery in the Treatment of DR-TB In patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB), elective partial lung resection (lobectomy or wedge resection) may be used alongside a recommended MDR-TB regimen. Treatment Strategies of XDR-TB Success in XDR-TB patients was highest if at least six drugs were used in the intensive phase and four in the continuation phase. The use of later-generation fluoroquinolone significantly improved treatment outcome in patients with XDR-TB, even though DST demonstrated resistance to a representative fluoroquinolone. Treatment Management for Patients with Documented or Almost Certain XDR-TB Currently, Bedaquiline is the main drug to be used in pre-XDR and XDR-TB treatment. However, access to it is still not immediate and need to liaise with IPR to get it. (Requires around 3 months). Generally, XDR-TB patients generally receive at least 24 months of therapy in most. 114
Table 10.5: Treatment strategies for XDR-TB 115 Step 1 Use a higher-generation fluoroquinolone Group A such as moxifloxacin. Step 2 Use Bedaquiline for up to one year if possible. If Bdq is not available, use an injectable agent Group B to which the strain in susceptible and consider an extended duration of use (12 months or possibly the whole treatment). If resistant to all injectable agents it is recommended to use one the patient has never used before. Step 3 Use all Group C agents that have not been used extensively in a previous regimen or any that are likely to be effective. Step 4 Use pyrazinamide and any other Group D1 agent that may be effective. Step 5 Use Group D2 and D3 agents that have not been used extensively in a previous regimen or any that are likely to be effective.
Anti-TB dosage Table 10.6: Weight-based oral anti-TB drug daily dosing in adults >30 kg DRUGS DAILY DOSE 30-35 KG 36-45 KG 46-55 KG 56-70 KG >70 KG High-dose isoniazid 10-15 mg/kg once daily 500 mg 600 mg 700 mg 900 mg 900 mg High dose Rifampicin 20-30 mg/kg once daily 600 mg 900 mg 1200 mg 1350 mg 1500 mg Pyrazinamide 20-30 mg/kg once daily 800 mg 1000 mg 1200 mg 1600 mg 2000 mg Ethambutol 15-25 mg/kg once daily 600 mg 800 mg 1000 mg 1200 mg 1600 mg Levofloxacin 750-1000 mg once daily 750 mg 750 mg 1000 mg 1000 mg 1000 mg Moxifloxacin 400 mg once daily 400 mg 400 mg 400 mg 400 mg 400 mg Ethionamide 500-750 mg/ day in 2 divided doses 500 mg 500 mg 750 mg 750 mg 1000 mg Cycloserine 500-750 mg/ day in 2 divided doses 500 mg 500 mg 500 mg 750 mg 750 mg paminosalicylic acid 8 g/day in 2 divided doses 8 g 8 g 8 g 8 g 8-12 g Bedaquiline 400 mg once daily for 2 weeks then 200 mg 3 times per week Clofazimine 200-300 mg (2 first month) then 100 mg OD Linezolid 600 mg once daily 600 mg 600 mg 600 mg 600 mg 600 mg Amoxicillin/ clavulanic acid 80 mg/kg/ day in 2 divided doses 2600 mg 2600 mg 2600 mg 2600 mg 2600 mg Imipenem/ cilastatin 1000 imipenem/1000 mg cilastatin twice daily Meropenem 1000 mg three times daily (alternative dosing is 2000 mg twice daily) 116
Table 10.7: Weight-based injectable anti-TB daily dosing in adult >30 kg TDM Guided Injectables • All injectables to be given maximum 5 times a week. 2 rest days on weekends. • TDM guided injectables are started with 15mg/kg and doses adjusted based on TDM. • For those with high risk of renal disease, dose started with 10mg/kg and doses adjusted based on TDM. • For those with underlying renal disease, dose can be started with 10mg/kg three times weekly and adjusted according to TDM. Isoniazid Resistant TB Confirmed Hr-TB, Rifampicin susceptible: • Where possible, isoniazid resistance testing should also include information on the specific mutations associated with resistance to isoniazid (katG or inhA).( From either LPA or MTB C/S) • Use of high dose InH: In vitro evidence suggests that when specific inhA mutations are detected (and when katG mutations are absent), increasing the dose of isoniazid is likely to be effective; thus, additional isoniazid up to a maximum dose of 15 mg/kg per day could be considered. In the case of katG mutations, which usually confer a higher level resistance, the use of isoniazid even at a higher dose is less likely to be effective. • Rifampicin resistance must be ruled out. • Preferably to rule out Fluroquinolone* and Pyrazinamide resistance too. 117 DRUGS DAILY DOSE For all weight range > 30KG Streptomycin 15 mg/kg once daily For injectables to be calculated to the exact dose based on weight with a maximum of 1g OD Amikacin 15 mg/kg once daily Capreomycin 15 mg/kg once daily
• If both katG and inhA mutation is present, rapid LPA testing for quinolone resistance is strongly recommended. Treatment regime • Rifampicin, Ethambutol, Pyrazinamide and Levofloxacin for 6 months (6REZL) can be given as fixed dose combination tablet PLUS Levofloxacin. • Empirical treatment not advised. But treatment can be given in highly suspected cases pending laboratory confirmation provided Rifampicin resistance ruled out. • For patients in whom Hr-TB is detected after the start of treatment with the 2HREZ/4HR regimen, the (H)REZcomponent drugs are continued (or pyrazinamide and ethambutol are reintroduced) and levofloxacin added, once rifampicin resistance has been excluded. • The duration of an (H)REZ–levofloxacin regimen is usually determined by the need to complete 6 months of a levofloxacincontaining regimen. • Thus, in cases where the diagnosis of Hr-TB is made after firstline TB treatment has already been initiated, the patient may receive more than 6 months of (H)REZ by the end of treatment. • If the confirmation of isoniazid resistance arrives late (e.g. 5 months into a 2HREZ/4HR regimen). In such cases, a decision to start 6 months of (H)REZ–levofloxacin depends on the patient’s clinical condition and microbiological status. • The addition of levofloxacin to (H)REZ is recommended in all patients with Hr-TB, with the exception of the following situations: • resistance to rifampicin cannot be excluded, • known or suspected resistance to levofloxacin, • known intolerance to fluoroquinolones, • known or suspected risk for prolonged QT interval, or • pregnancy or during breastfeeding (not an absolute contraindication). • In Hr-TB cases in whom a fluoroquinolone cannot be used, the patient may still be treated with 6(H)REZ. Injectables (Streptomycin) NOT advised. • When additional resistance (especially to pyrazinamide) is suspected or confirmed, appropriate treatment regimens will have to be designed individually. 118
Subgroup Considerations Patients with extensive disease: May be extended more than 6 months with extra vigilance for AE. HIV positive patients: Similar duration and regime Monitoring All patients should be tested regularly (preferably monthly) especially those with risk for liver toxicity for levels of AST and ALT. Monthly eye monitoring to be done (Visual acuity and Red green colour discrimination). If suspicion of MDR-TB is high but Xpert MTB/RIF is negative: • If the Xpert MTB/RIF Ultra test negative for M. tuberculosis, or if there is a possibility or suspicion that rifampicin resistance was missed by Xpert testing, the phenotypic testing for rifampicin should be requested. While awaiting phenotypic DST results, regimen options should be discussed with an experienced clinician. This may include continuing first-line TB therapy with increased doses of isoniazid (10mg/kg/day) and rifampicin (up to 20mg/kg/day), or initiating an empiric RR-TB treatment regimen, depending on the clinical status and risk factors of the individual patient. Recommendations for management of hetero-resistant TB: • If hetero-resistance is suspected or confirmed, treatment should be based on the strain with the highest level of resistance. 119
Treatment of DR-TB: Special Conditions and Situations Pregnancy • DRTB and its treatment during pregnancy pose great risk to the mother and fetus however pregnancy is not a contraindication for treatment of active drug-resistant TB. A decision to start treatment especially in the first trimester or to postpone should be agreed upon by the patient and the doctor. • All female patients of child bearing age who are diagnosed DRTB should be tested for pregnancy. • Pregnant patients should be started on treatment as soon as the diagnosed is made. However, treatment may be delayed until the second trimester if the patient is stable with minimum disease. • Regimen: Levofloxacin, Cycloserine, Clofazamine, Amoxicillin/ Clavulanate, High dose INH, Ethambutol and Pyraziname should be considered as the drug of choice when selecting drugs for MDR-TB treatment. Linezolid may be added if the disease is severe instead of Augmentin • Injectable agents (Amikacin and Streptomycin) should be avoided. However, capreomycin may be considered in life threatening situation due to MDR-TB/XDR-TB. • Capreomycin thrice weekly from the start may be considered to decrease drug exposure to the foetus if an injectable agent need to be given. • Injectable agent may be given for three to six months postpastum even in the middle of treatment but it is not necessary if the patient remain well and past eight months period for injectable agent. • Ethionamide should be avoided due to risk of nausea and vomiting associated with pregnancy, and potential teratogenic effects. • Termination of pregnancy should be considered if the mother’s life is compromised. • Treatment should be given for duration the same as for standard MDR-TB treatment. • All oral short course regimen for pregnancy if Bedaquiline available. 120
Breastfeeding Breastfeeding woman who has active drug-resistant TB should receive a full course of anti-TB treatment. The infant formula is preferred to reduce transmission and avoid side effects of the drugs in smear positive mother: i. the care of infant should be left to family members until smear become negative, or ii. the mother should wear surgical mask whenever the mother and infant are together and they should be in wellventilated areas or outdoors until sputum negative. 121
Renal Impairment Table 10.8: Adjustment of anti-TB drugs in renal insufficiency 122 Drug Recommended dose and frequency for patients with creatinine clearance <30 ml/min or for patients receiving haemodialysis (unless indicated dose after dialysis) Isoniazid No adjustment necessary Rifampicin No adjustment necessary Pyrazinamide 25-35 mg/kg per dose three times per week (not daily) Ethambutol 15-25 mg/kg per dose three times per week (not daily) Rifabutin Normal dose can be used, if possible monitor drug concentrations to avoid toxicity Rifapentine No adjustment necessary Streptomycin Injectables to strictly use TDM as a guide and starting with 10mg/ kg 3/week and adjust accordingly . Capreomycin Amikacin Levofloxacin 750-1000 mg per dose three times per week (not daily) Moxifloxacin No adjustment necessary Cycloserine 250 mg once daily, or 500 mg/dose three times per week Ethionamide No adjustment necessary Para-aminosaliclic acid 4 g/dose, twice daily maximum dosed Bedaquiline No dosage adjustment is required in patients with mild to moderate renal impairment (dosing not established in severe renal impairment, use with caution) Linezolid No adjustment necessary Clofazimine No adjustment necessary Amoxicillin/ clavulanate For creatinine clearance 10-30 ml/min dose 1000 mg as amoxicillin component twice daily; for creatinine clearance <10 ml/min dose 1000 mg as amoxicillin component once daily. Imipenem/cilastin For creatinine clearance 20-40 ml/min dose 500 mg every 8 hours; for creatinine clearance <20 ml/min dose 500 mg every 12 hours
Liver Impairment Patients with history of liver disease can receive the usual anti TB drug regimen provided there is no clinical evidence of severe chronic liver disease, Active Hep B/C carrier/disease and recent history of acute Hepatitis or excessive alcohol consumption. In patients where a more Hepato friendly regimen is needed: • Regimen: Amikacin, Levofloxacin, Cycloserine, Clofazamine, and Ethambutol. Seizure disorders • Cycloserine should be avoided if possible in patients with active disorder that are not well controlled. • High dose isoniazid should be avoided in patients with active seizure disorders because it carries higher risk of seizure. • Pyridoxine 100mg OD to used prophylactically in patients with seizure disorders to protect against the neurological adverse effects of isoniazid or cycloserine. Psychiatric disorders Cycloserine can be used in patients with psychiatric disorders because its benefits may outweigh the risk, however close monitoring of psychiatric symptom is recommended. But it is better to avoid if other options are available such as Ethionamide or Clofazamine. DR-TB and HIV infection ART should thus be initiated regardless of CD4 cell count and as soon as antituberculosis treatment is tolerated, ideally as early as 2 weeks and no later than 8 weeks after initiation of antituberculosis treatment. However, for HIV-positive TB patients with profound immunosuppression (e.g. CD4 counts less than 50 cells/mm3), they should receive ART within the first 2 weeks of initiating TB treatment. 123
The treatment of DR-TB in patients with HIV is very similar to that in patients without HIV, with the following exceptions: • the need of ART and possibility of IRIS, • the potential drug-drug interaction between ART and anti-TB drugs, and • more frequent adverse effects requiring more intense monitoring. Initiating Treatment and Monitoring of Treatment Table 10.9: Conditions to be screened for at initial medical evaluation 124 HIV Infection Acute or chronic liver disease Seizures Diabetes mellitus Mental illness Malnutrition Hypertension Drug or alcohol dependency Renal insufficiency Pregnancy Thyroid disease Breastfeeding
Table 10.10: Follow-up schedule for uncomplicated MDR-TB patients 125 Monitoring parameters at baseline and beyond Longer regimen: Intensive phase Longer regimen: Continuation phase Shorter regimen: Intensive phase Shorter regimen : Continuation phase Month 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 - 20 Clinical consultation & family planning counselling √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ Weight & BMI √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ Smear √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ Culture √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ FBC, RP & LFT √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ RBS √ Repeat if necessary TSH only if on PAS or ETO √ √ √ √ √ HIV √ Repeat at 3 months if initially negative. Repeat again at one year in high risk behaviour patients. Visual Acuity √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ ECG √ √ √ √ √ √ √ √ √ √ UPT √ Repeat if necessary Audiometry √ √ √ Repeat 3 monthly if on injectable CXR √ √ √ √ Adverse drug reaction checklist √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √
Adverse Event Screening Questionnaire This checklist should be completed at each follow up visit for anyone receiving RR-TB treatment, regardless of any regimen. Any ‘YES’ answer should be followed up for more details. Ask the patient: “since your last visit, have you experience any of the following symptoms?” Table 10.11: Adverse event screening questionnaire for MDRTB treatment 126 Symptom Yes No Headache Vision changes Depression/sadness Anxiety/worries Rashes or sores Chest pain Coughing blood Difficulty breathing New cough Nausea/vomiting Diarrhoea Abdominal pain Fainting episode Joint pain/swelling Burning/tingling sensation at the hands or feet Fatigue/tiredness Easy bruising/bleeding Changes in hearing Others(specify)_______________________
Table 10.12: Summary table of identification and management of key adverse event 127 TYPE OF ADVERSE EVENT LIKELY CULPRIT TB DRUGS Anaemia Linezolid Arthritis/arthralgia Pyrazinamide, fluoroquinolones Depression or anxiety Terizidone, high-dose isoniazid Diarrhoea Para-aminosalicylic acid Electrolyte disturbances (hypokalaemia and hypomagnesaemia) Amikacin, kanamycin, capreomycin Hearing problem Amikacin, kanamycin, capreomycin Hepatotoxicity Pyrazinamide, ethionamide, bedaquiline,clofazimine, delamanid, paraaminosalicylic acid, fluoroquinolones, rifabutin Ichthyosis / dry skin Clofazimine Leucopaenia / neutropaenia Linezolid Nausea and vomiting Ethionamide, para-aminosalicylic acid Peripheral neuropathy Isoniazid, linezolid, moxifloxacin, terizidone Psychosis Terizidone, high-dose isoniazid, fluoroquinolones QT interval prolongation Bedaquiline, clofazimine, delamanid, moxifloxacin Rash (severe), Stevens Johnson Syndrome (SJS) Any drug, but some drugs are more likely to cause rash, such as pyrazinamide Renal impairment Amikacin, kanamycin, capreomycin Seizures Terizidone, high-dose isoniazid, fluoroquinolones Skin hyperpigmentation Clofazimine Thrombocytopaenia Linezolid Thyroid dysfunction Ethionamide, para-aminosalicylic acid Visual problems Ethambutol, linezolid
Key points • All patients diagnosed with drug resistant TB need to be discussed with Respiratory team/Infectious Disease team for optimal regime. • RR/MDR TB patient need to be reviewed every month & update to Respiratory team/Infectious Disease team. •All oral regime are preferred option whenever available. 128
Chapter 11 : Long Term Complications of PTB Dr Hema Yamini Ramarmuty Pulmonary TB is associated with various long-term sequelae. Data on the full spectrum of these complications in patients with TB are limited and the published literature are mostly based on case reports and case series. Commonly reported complications are as below. 129
Picture 11.1: Common post PTB complications • Pleural thickening • Fibrothorax 130
Post TB Complications Affecting Airways Bronchiectasis • Is characterized by persistent airway dilation and a chronic productive cough leading to repeated respiratory infections, deterioration in lung function and reduced quality of life. • Bronchiectasis may appear in the course of active TB or develop as a sequela of TB. • Co-existence of bronchiectasis and TB was first noted by Laennec in 1819. • While bronchiectasis may be localized or diffuse, it most frequently affects the apical and posterior segments of the upper lobes (the most common sites of post primary TB). • Investigations: • CXR- ‘tram-track opacities’ and ‘ring shadows’, HRCT still required to confirm the diagnosis and quantify the extent. • HRCT a. Bronchial dilatation: ‘Signet ring sign’ where the bronchial diameter is larger than the adjacent pulmonary artery ( Broncho-arterial ratio>1) b. Lack of airway tapering c. Airway visibility within 1 cm of pleural surface. • Sputum C&S: to guide antibiotic therapy during exacerbations. • Lung function test: May be obstructive, mixed obstructive and restrictive pattern. • Treatment: • Chest physiotherapy: Airway clearance techniques and postural drainage. • Mucolytics. • Bronchodilators in patients who have dyspnoea/co-existing COPD. • Pulmonary rehabilitation: for patients who have reduced effort tolerance. • Vaccination: Influenza (yearly) and Pneumococcal vaccinations should be offered. • Antibiotics: Indicated for infective exacerbations, guided by sputum C&S. Empirical antibiotics should be started while waiting for results of sputum C&S. Refer to previous cultures to guide treatment while waiting for results of sputum C&S. 131
• Referral to chest physician for patients with recurrent infective exacerbations (more than 2 per year) and progressive dyspnoea: Assessment for suitability of long term antibiotics e.g. macrolide/inhaled gentamicin. • Haemoptysis: IV/oral Tranexamic acid, bronchial artery embolization depending on assessment with CT angiogram and availability of resources. • Surgical resection may be considered in patients with focal disease complicated with recurrent hemoptysis and patients with persistent symptoms despite maximum medical therapy. Picture 11.2 : CXR shows bilateral upper zone bronchiectasis and fibrosis with reduced lung volume on the right side. The trachea is slightly shifted to the right due to right apical fibrosis. 132
Tracheobronchial Stenosis • Endobronchial TB is defined as tuberculous infection affecting the endobronchial tree caused by direct inoculation of the TB bacilli from the lung parenchyma, erosion through infected lymph nodes and peri-bronchial seeding by hematogenous spread. • Granulomatous changes in the tracheobronchial wall or extrinsic pressure from enlarged peri-bronchial lymph nodes may start as simple edema and subsequently progress to fibrosis with narrowing of tracheobronchial diameter. • Endobronchial TB is diagnosed on histopathological examination of bronchoscopically obtained specimens showing granulomatous inflammation with caseation necrosis and/or positive acid-fast bacilli culture on the microbiological exam. • Endobronchial TB usually responds to anti TB however in some cases airway stenosis may occur during treatment or many years later. • In TB endemic countries, endobronchial TB with airway stenosis remains a common cause for benign airway stenosis. • The diagnosis of tracheobronchial stenosis is usually delayed as chest radiography is not very sensitive. • If the diagnosis is suspected the most useful modality for diagnosis and assessment is flexible bronchoscopy. • Many studies show that this condition is more commonly reported in females. In our own local setting in Serdang Hospital, 5 out of 7 patients with tracheobronchial stenosis were females. A study in Singapore which looked at 21 patients revealed that 16 (76%) were female. This predominance in the female sex has also been reported in Japan, Hong Kong and Korea. It is postulated that this could be due to a narrower bronchus in females and the fact that females expectorate less, leading to stasis of sputum containing tuberculous bacilli on the bronchial wall. • Left main bronchus has been reported to be the most common site of tracheobronchial stenosis. This could be because the left mainstem bronchus is easily compressed by the aortic arch. Lymph node tuberculosis is also more often noted on the left, making the left mainstem bronchus more vulnerable to pathological strictures. 133
• High degree of suspicion, early assessment and diagnosis is important to prevent and control obstructive symptoms. • Symptoms: • Unilateral wheeze (if obstruction is distal to carina) • Stridor (tracheal obstruction) • Dyspnea • Productive cough • Recurrent pneumonia • Investigations: • CXR: may show narrowing of the trachea or main bronchus however is insensitive and may be easily missed. Lung collapse may also be seen on CXR. • Lung function test (flow-volume curve): may reveal fixed airway obstruction. • CT thorax (with 3-dimensional reconstruction): to identify the stenotic segment, to assess if the airway distal to the lesion is patent and to assess the relationship with surrounding structures such as vessels. • Flexible bronchoscopy: to diagnose and to plan the subsequent interventional procedure required. • Treatment options: • Multidisciplinary team meeting involving pulmonologists, radiologists, cardiothoracic surgeons and ENT surgeons to discuss the best modality of treatment is crucial for a better patient outcome. • Surgical option • Surgical resection and reconstruction (surgical tracheobronchoplasty) is the preferred therapy for tracheobronchial stenosis. • Surgery may not be feasible if patient has inadequate lung reserve or if there is an anatomical limitation (multiple or long segment stenosis). • Possible complications: recurrence of stenosis, anastomotic leakage, etc. • Non- surgical options • Bronchoscopy can be performed in patients with tracheobronchial airway stenosis with progressive deterioration in symptoms (dyspnea), recurrent post obstructive pneumonia or if there is total lung collapse. 134
• It is usually performed in patients who are no longer smear positive. • However, in patients who have life-threatening symptoms (acute respiratory failure requiring mechanical ventilation), it can be performed despite patient being smear positive, provided adequate infection control measures are taken. • Endoscopic approaches include: 1. Bronchoscopic balloon dilatation/balloon bronchoplasty: can be performed using both rigid or flexible bronchoscopy. 2. Mechanical dilatation using rigid bronchoscope: dilatation is performed using progressively larger diameter rigid bronchoscopes. 3. Stenting post dilatation in patients with recurrence or malacic airways; silicone stent preferred. 4. Laser photo-resection- to resect fibrotic bands causing stenosis. 5. Mitomycin application post intervention to prevent recurrence. • Most of the time, a combination of few techniques is needed to achieve a favorable outcome. • A major disadvantage of bronchoscopy management is that repeat sessions may be required due to recurrence. • A high degree of suspicion is required to identify patients with endobronchial TB who are at high risk of tracheobronchial stenosis (during and post treatment). These group of patients may need early assessment with CT scan and flexible bronchoscopy. Further studies are needed to establish the need of longer duration of follow up for this cohort of patients. 135
Picture 11.3: Mechanical dilatation using rigid bronchoscopy Picture 11.4 : Balloon bronchoplasty 136
Picture 11.5 : Silicon stenting at Right Main Bronchus 137
Post TB Complications Affecting Lung Parenchyma Lung fibrosis • Excessive collagen deposition and fibrotic scarring can occur throughout the course of TB disease and treatment. • Permanent destruction of lung architecture after TB occurs due to aberrant wound healing process. • Normal lung parenchyma is replaced by collagenous tissue resulting in thickening and stiffening of the lung parenchyma. • This may lead to symptoms such as chest pain, cough, dry cough and reduced effort tolerance. • CXR and HRCT will reveal areas of fibrosis (mainly affecting the upper lobes) and reduced lung volume. • Lung function test will show a restrictive ventilatory defect, with a normal or increased FEV1/FVC ratio and decreased FVC. • The six-minute walking test (6MWT) is a simple tool used to evaluate functional exercise capacity in these patients. • Treatment: • Chest physiotherapy and referral for pulmonary rehabilitation. • Nutritional assessment and support: Referral to dietician. • Psychological support. • Vaccination (Pneumococcal and influenza) should be given to reduce the risk of respiratory infections. • Smoking cessation. • For patients with low oxygen saturation confirmed by arterial blood gas analysis, referral to respiratory physician for consideration of long term oxygen therapy. 138
Chronic Pulmonary Aspergillosis (CPA) • Commonly found in those with underlying lung disease leading to air cavity or bulla. • The major subtypes of CPA include chronic cavitary aspergillosis (CCA), chronic fibrosing aspergillosis (CFA), aspergilloma, and Aspergillus nodules. • Most common causative species are A. fumigatus however Aspergillus niger and Aspergillus flavus infections have also been reported. • Patients with residual pulmonary cavities of ≥2 cm after TB treatment have a higher chance of developing aspergillomas. • Indolent presentation with fever, weight loss, chronic productive cough, fatigue, dyspnoea, and haemoptysis. • A simple aspergilloma without concurrent CCA/CFA often causes few or no symptoms. • Investigations: • Sputum samples may allow isolation of hyphae. • Imaging: CXR or computed tomography (CT) scan can reveal one or more cavities, typically within the upper lobes, of variable size, with or without the presence of pleural thickening and fibrosis. Cavities can be thin- or thick-walled, and may or may not contain fungal balls. • Aspergillus-specific IgG in serum. • PCR-based detection of Aspergillus species. • Bronchoalveolar lavage sent for galactomannan. • Management: • Referral to ID physician and respiratory physician. • Management depends on the extent and type of disease and whether the patient is a candidate for surgical resection. • Data on the optimal duration and choice of antifungal agents are limited. • Voriconazole or itraconazole are first-line treatment options for individuals with CCA or CFA. • Amphotericin B, micafungin, or caspofungin are intravenous alternatives if there is failure, intolerance, or resistance to the above treatment options. • For individuals with a simple aspergilloma, surgical resection can prevent or treat severe haemoptysis. 139
• Embolization can be done prior to surgery, or in patients for whom surgery is not possible. NTM (Non-Tuberculous Mycobacterium) Infection • Patients with pre-existing structural lung disease including bronchiectasis and prior TB are at risk of developing NTM lung disease. • NTM co-isolation occurs in 7–11% of patients with pulmonary TB • The most frequently isolated NTM from pulmonary samples i s M y c o b a c t e r i u m a v i u m – i n t r a c e l l u l a r e c o m p l e x (MAC). Mycobacterium kansasii is another important cause of progressive pulmonary disease. • Clinical features of MAC lung disease are variable and nonspecific- cough, fatigue, dyspnoea, chest discomfort, haemoptysis, weight loss, and fever. M. kansasii presents more acutely. • Investigations: • Radiological findings for both include parenchymal infiltration, nodules, and cavitation. • Diagnostic criteria include compatible clinical and radiological features with either one or two positive microbiological results from bronchial lavage or sputum samples, respectively, or with suggestive histopathological features on biopsy. • Treatment: • The decision to start treatment for patients who meet diagnostic criteria is influenced by the severity of disease, the risk of progression, the presence of comorbidities, the tolerability of treatment, and the goals of treatment. • The presence of fibro-cavitary disease is associated with more rapid progression and requires rapid start of treatment. • Once the diagnosis is made, patient should be referred to the ID physician or respiratory physician to decide on treatment regimen. 140
Post TB Complications Affecting Pleura Pleural thickening and fibrothorax • Although TB pleura usually resolves completely even in the absence of treatment, in some patients’ chronic complications may occur during the healing process. • Pleural thickening and pleural calcification may occur as late complications. • Patients are usually asymptomatic. Some may present with pleuritic chest pain and dyspnea. • Fibrothorax, a severe form of pleural fibrosis is characterized by extensive and dense fibrosis of the visceral pleura leading to fusion of the visceral and parietal pleura. • Fibrothorax leads to contracture of the involved hemithorax and reduced mobility of the lung (i.e. Lung entrapment). • On CT scan it will appear as diffuse pleural thickening (≥10 mm) without effusion suggesting inactivity. • Patients with diffuse pleural thickening should be closely monitored for the development of restrictive lung disease with serial pulmonary function tests. 141
Chapter 12 : Preventions Dr Suzalinna Binti Sulaiman & Dr Amabel Seow Min Hui Prevention of Tuberculosis aims to educated the community on Tuberculosis and provide early detection of the disease, hence reducing morbidity and mortality cause by the disease. Screening programmes are as the following: 11.1 Screening for TB disease among household and other close contacts of individuals with TB disease 11.2 Screening of TB high risk groups 11.3 Screening of TB in the community 11.4 Prevention of TB among Health Care Worker 142
11.1 Screening for TB disease among household and other close contacts of individuals with TB disease Forms: Table 12.1: List of form required in the management of TB contacts No. Referrence No./ No Rujukan Title / Tajuk 1 TBIS 10A-1 Maklumat permulaan rawatan pesakit TB 2 TBIS 10A-3 Maklumat penyiasatan kes TB 3 TBIS 10C-1 Notis menjalani pemeriksaan pengesahan penyakit TB 4 TBIS 10C-2 Senarai kontak untuk pemeriksaan saringan TB 5 TBIS 10C-3 Kad pemeriksaan kontak 6 TBIS 10D Notis pesakit TB cicir rawatan 7 TBIS 101B Daftar kes TB dalam rawatan 8 TBIS 201B Laporan bulanan kedudukan pesakit dalam rawatan dan pemeriksaan kontak 143
Picture 12.1: Conceptual framework for the 2021 WHO update to guidelines for systematic screening for TB. *Numbers in parentheses refer to the PICO (population, intervention, comparator & outcome) questions that guided the evidence gathering 144
Picture 12.2: Flowchart of management of TB contacts *Adapted from MANUAL SISTEM MAKLUMAT TIBI KEBANGSAAN Cetakan 2015 145
11.2 Screening of TB high risk groups High risk groups: i. Contacts to confirmed TB cases ii. HIV patients iii. End Stage Renal Disease (ESRD) patients who requires dialysis iv. Prison Inmates v. Inmates and clients of Cure and Care Rehabilitation Centre (CCRC) vi. Residents of old folks home vii. Rheumatoid arthirtis patients on anti-TNF treatment viii. Diabetic Mellitus patients ix. 60 years old and above x. Patients with Chronic Obsctuctive Diseases (COPD) xi. Clients of Quit Smoking Clinic (Klinik Berhenti Merokok) xii. Registered clients of methadone and related substance abuse services. Form to use: TB Screening form / Borang Saringan TB 146
Flowchart for TB high risk groups Picture 12.3: Flowchart for TB high risk groups *Surat Pekeliling for PENGUKUHAN SARINGAN GOLONGAN BERISIKO TINGGI TUBERKULOSIS (TIBI) DI BAWAH PROGRAM KAWALAN TIBI KEBANGSAAN, KEMENTERIAN KESIHATAN MALAYSIA with kkm.600-29/4/34(01) dated 11th January 2016 147
11.3 Screening of TB in the community Programme Intensified Case Finding (ICF) for Tuberculosis among the general population is important and requires co-operation with different units in the health sector and community. With reference to Manual Pencarian Kes TB Secara Intensif Dalam Komuniti 2009, Unit Kawalan TB/Kusta, Jabatan Kesihatan Negeri Sabah, the 4 components to execute a project is to Identify, Train, Trace and Treat. The aim of the programme is to educate the population on Tuberculosis and detect TB early through d ifferent screening tools. TB Hotspots are identified based on these criteria: i. TB Notification rate >100/100,000 population at a district and ii. TB Notification rate >100/100,000 population at a locality or iii. TB endemic with prevalance >1% at a locality with a compact housing area/ population. Tools available on site are: • Symptomatic screening for TB • Sputum taking for suspected TB person • CXR (collaboration with Mobile X-ray Service Team, JKN Sabah) Form to be used: TB Screening form/Borang Saringan TB 148
Flowchart for ICF Picture 12.4 : Flowchart for ICF 149
11.4 Prevention of TB among Health Care Worker (HCW) Programme The framework of Prevention of TB among HCW programme can be seen in the Guidelines of Prevention and Management of Tuberculosis for Health Care Worker in Ministry of Health, Malaysia by Occupational Health Unit, Disease Control Division, Ministry of Health Malaysia, 2012. In the guideline, the control measures are based on a three – level hierarchy of controls which are: i. Environmental controls - adequate ventilation, HEPA filtration or UVGI. ii. Administrative controls (managerial) - Screening, TB Infection Control Committee, TB Infection Control Plan, Workplace risk assessment, Triaging, Training and education and Patient education. iii. Personal protective equipment In the programme, screening for TB among HCW are done during pre-placement medical examination and periodically. Modalities used for screening are symptomatic screening, mantoux, CXR or IGRA. Forms for confirmed TB case for HCW a) Form to be submitted to TB/Leprosy sector JKN Sabah: Laporan Siasatan Kes TB di Kalangan Anggota Kesihatan Negeri Sabah b) Forms to be submitted to Occupational Health Unit (KPAS), JKN Sabah: i. Format penyiasatan Kes Tuberkulosis Anggota Kementerian Kesihatan Malaysia and ii. Notification of Occupational Lung Disease and iii. WEHU L1 & L2 (JKKP7) : All diseases related to the lungs including Pulmonary TB or iv. WEHU D1D2 (JKKP7) : All diseases apart from the lungs, skin and hearing loss (e.g extra-pulmonary TB) or v. WEHU S1S2 (JKKP7): All diseases related to the skin including Skin TB 150