Drug treatment is usually in 2 phases: Initial intensive phase (designed to kill actively g rowing bacteria), followed by a continuation phase (designed to eliminate residual bacteria ). \200 The intensive phase (8 weeks) shortens the duration of infectiousness At least three drugs are needed, e.g. isoniazid (bactericidal), rifampicin (bacteriostatic), and pyrazinamide (b acteriostatic/partially bacteriocidal). Three drugs reduces the treatment time from 9 to 6 months Ethambutol added if there is a likelihood of drug resistance (in practice this is st andard therapy for non-Caucasian patients, who are more likely to have come from an area wi th a high prevalence of resistance) The continuation phase is usually with two drugs. Fewer bacteria are present at the start of this phase, and there is therefore a lower chance tha t drug-resistant mutants will emerge, making drug resistance less of a problem. Compliance is of major importance and all patients should have a risk assess- ment for trea tment adherence. If the clinical response is not satisfactory, check sputum 2 months before the end of the planned treatment period. TB: MANAGEMENT 1 495 Compliance can be monitored with urine color testing (turns red with rifampicin) and tablet counts. If concerns about compliance, consider directly observed treatment (DOT). Every TB patient should have a key worker, who should be easily contactable. From September 2007 there are no prescription costs for TB drugs in the UK. Table 42.1 Annual risk of TB/100 000 in England and Wales based on age and place of birth Age Place of birth Years after All patient rate Indian subcontinent rate \201 rst entry 0 \200\22314 UK 3 21 Abroad 31 88 >15 UK 4 59 15 \200\22334 Abroad 0 \200\2234 180 540 >5 53 87 >35 Abroad 0 \200\2234 146 593 >5 39 108 496 CHAPTER 42 Respiratory infection: mycobacterial TB: management 2 Directly observed therapy (DOT) aims to increase compliance, by nurse-supe rvised and observed daily or weekly tablet swallowing. This has been shown to increase trea tment completion, reduce relapses, and reduce development of drug resistance, as the ingest ion of each dose is witnessed. This is recommended for patients unlikely to comply, includi ng alcoholics, drug abusers, the homeless, those with serious mental illness, and those wit h MDR-TB. Consider other incentives to improve adherence such as providing food and transpo rtation costs. Compulsory detention under Sections 37 and 38 of the Public Health Act (England) is allowed for infectious pulmonary TB, but compulsory treatment is not allowed. This is only used in extreme circumstances to protect public health. Standard treatment regimes (see p 498) \200 The standard regime is for 6 months \200\224four drugs in the initial 2-month phase (rifamp icin (R), isoniazid (H), pyrazinamide (Z), and ethambutol (E) (or streptomycin) and 2 drugs in the last 4 months (rifampicin and iso- niazid) in patients with fully sensitive organis ms If drug sensitivity is unavailable at 2 months, continue the 4-drug regime until it is a vailable (even if this is for more than 2 months) The fourth drug (usually ethambutol) can be omitted in those at low risk of isoniazid resistance (non-previously treated, HIV-negati ve, UK-born Caucasians, with no drug-resistant contacts). There is a higher risk of isoniaz id resistance in ethnic minority groups, immigrants, refugees, those who have had previous treatment, and those who are HIV positive. This depends on local policy and the ethnic make -up of the local area. If in doubt, start treatment with 4 drugs Other treatment regimes ar e also effective (e.g. daily for 2 months, then 2 or 3 times weekly for 4 months, or 3 time s weekly for the whole 6 months), though are used less commonly Check baseline renal and li ver function in all patients. If normal, and not at high risk of adverse drug reaction, the y do not need to be re-checked Dosages are weight dependent, and may need to be changed for weight loss or gain during the treatment course A 6-month treatment course is effective fo r all other forms of non-CNS extrapulmonary TB (including lymph node and spinal disease), w ith the same drugs as for respiratory disease. Surgery may be needed in addition, for spina l disease CNS disease needs a 12-month treatment course Steroids may be useful for large pl eural effusions, pericardial effusions (60 mg/day for constrictive pericarditis), and CNS d isease, especially if associated with neurological impairment. Steroids may also be indicat ed in ureteric disease, and to suppress hypersensitivity reactions to the TB drugs. \200 TB: MANAGEMENT 2 497 Peripheral lymph nodes may enlarge and abscesses may form during treatment; this does not i mply failure of treatment, but should prompt a compliance check Pyridoxine is not required, unless subjects are at higher risk of pyrazinamide-related peripheral neuropathy \200\224i n diabetes, renal failure, HIV, and alcoholics. Meningitis A 12-month course of rifampicin and isoniazid, with pyrazina- mide and a fourth drug (e.g. ethambutol) for at least the \201 rst 2 months, is effective. If pyrazinamide not used, extend treatment period to 18 months. Steroids may be needed for severe disease, equivalent to prednisolone 20 \200\223 40 mg OD if on rifampicin, otherwise 10 \200\22320 m g OD. Steroids can usually be tapered after the initial 2 \200\2233 weeks of treatment. Eth ambutol should be used with caution in unconscious patients, as visual acuity cannot be tes ted and there is a small risk of ocular toxicity. Cerebral tuberculoma without meningitis 12-month regime. Disseminated TB/miliary TB 6-month regime unless CNS involvement. Exclude CNS disease in miliary TB with CSF examination, whe ther or not symptoms are present. Start treatment even if LFTs are abnormal (this may be du e to intrahepatic granulomas). Seek advice if LTFs deterio- rate signi \201 cantly on trea tment. See p 505. Bone and spinal TB 6-month standard regime. A CT or MRI should be perform ed in patients with active spinal disease who have neurological symptoms and signs. If ther e is direct spinal cord involvement (e.g. a spinal cord tuberculoma), treatment should be a s for meningeal TB. There is no place for routine spinal surgery (e.g. anterior spinal fusi on) in the absence of spinal instability. Pericardial TB standard 6-month regime. Steroids, e.g. prednisolone 60 mg OD, tapered after 2 \200\2233 weeks of treatment may be required. Peripheral lymph node TB standard 6-month regime, which should be used even if the infected node has been surgically removed. Stop treat- ment at the end of the 6-month course, regar dless of the appearance of new nodes, residual nodes, or draining sinuses. Patient advice to document on starting standard anti-TB chemotherapy \200 \200 Possibility of nausea and abdominal pain Persistent vomiting and/or jaundice \200\224stop d rugs immediately and contact doctor Red urine with rifampicin Red contact lenses with rifam picin Contraception advice, if on the oral contraceptive pill as ef \201 cacy reduced Visu al acuity (Snellen chart) (ethambutol) Visual disturbance (ethambutol) \200\224stop drugs i mmediately and contact doctor Potential drug interactions. \200 \200 \200 498 CHAPTER 42 Respiratory infection: mycobacterial First-line antituberculosis drugs Isoniazid (H) Bactericidal. Single daily dose, well toler ated. Major side-effect is age-dependent hepatitis. Increased toxicity with alcohol. Periph eral neu- ropathy is uncommon; although increased risk with diabetes and preg- nancy; reduc e incidence with 10 mg pyridoxine daily Rifampicin (R) Bactericidal. Single daily dose, wel l tolerated. Increases hepatic microsomal enzymes; therefore increases clearance of hepatic metabolized drugs, including prednisolone and the oral contraceptive pill, thus the risks of pregnancy must be highlighted. Red discoloration of urine and contact lenses also occurs , and GI upset. Pyrazinamide (Z) Bactericidal. Single daily dose. GI upset common. Major si de-effect is hepatic toxicity. Renal excretion leads to hyperuricaemia. Ethambutol (E) has some bactericidal effect, mostly bacteriostatic at usual doses. Single daily dose, well tol erated. Side-effect \200\224optic neuritis, uncommon. Document visual acuity (Snellen chart ) before starting. Streptomycin Bactericidal. Given parenterally. Increased risk of ototox- icity in the fetus and the elderly. Combined preparations Ri \201 nah 150 (contains rifampicin 150 mg and isoniazid 100 mg), Ri \201 nah 300 (contains rifampicin 300 mg and isoniazid 150 mg). Rifater (contains 120 mg rifampicin, 50 mg isoniazid, and 300 mg pyrazi- namide). Table 42.2 Recommended doses of standard antituberculosis drugs Drug Daily dose Intermittent dose Isoniazid (H) 300 mg 15 mg/kg 3 times weekly <50 kg \211 50 kg <50 kg \211 50 kg 450 mg 600 \200\223900 mg 3 times weekly Rifampicin (R) 600 mg <50 kg 2.0 g \211 50 kg 2.5 g 3 times weekly or 3.5 g twice weekly Pyrazinamide (Z) 1.5 g 2.0 g Ethambutol (E) 15 mg/kg 30 mg/kg 3 times weekly or 45 mg/kg twice weekly For example, a 75-kg adult commencing quadruple therapy would be given: \200 \200 \200 \200 Isoniazid 300 mg od Rifampicin 600 mg od Pyrazinamide 2.0 g od Ethambutol 1.2 g. od pyri doxine 10 mg od If using a combined preparation e.g. Rifater with ethambutol, \200 45 kg adult: Rifater 4 tablets and ethambutol 700 mg od \200 60 kg adult: Rifater 5 tablets and ethambuto l 900 mg od \200 80 kg adult: Rifater 6 tablets and ethambutol 1.2 g od FIRST-LINE ANTITUBERCULOSIS DRUGS 499 Drug regimes are often abbreviated to the number of months each phase of treatment lasts, f ollowed by the letters for the drugs being administered during that treatment phase, e.g. 2 HRZE/4HR is the standard 6-month recommended regime, 2HRE/7HR is 2 months of isoniazid, rif ampicin, and ethambutol, followed by 7 months of isoniazid and rifampicin. Table 42.3 Interactions of TB drugs Drug Increases level of Decreases level of Rifampicin (Level decreased by Warfarin ketoconazole & PAS) OCP Phenytoin Glucocorticoids Theophyllines, Digoxin Methadone Sulphonylureas ciclosporin Isoniazid Phenytoin Azoles, e.g. ketoconazole carbamazepine Warfarin Diazepam Pyrazinamide Probenecid 500 CHAPTER 42 Respiratory infection: mycobacterial TB: in-patient admission \200 This is rarely needed but, if necessary, patients with suspected pulmonary TB should initia lly be admitted to a side room vented to the outside air (until proven non-infectious) Pati ents with smear-positive non-MDR-TB should be managed as infectious (in a side room, with f ace mask). This especially applies if they are on a ward with immunosuppressed patients (wh o may be at higher risk) A risk assessment (including an assessment of the immune status of other ward patients) can be made once the infectiousness and likelihood of drug resistance of the patient are known Patients with non-pulmonary TB can be nursed on a general ward (b ut aerosol-generating procedures, e.g. abscess irrigation, may need patient isolation) Staf f should wear face masks if the patient is potentially infectious In-patients with smear-po sitive pulmonary TB should be asked to wear a face mask whenever they leave their room, unl ess they have received 2 weeks \200\231 drug treatment Barrier nursing is unnecessary for s mear-negative non-MDR-TB Liaise closely with infection control/microbiology/public health s pecialists If a patient on an open ward is found to have infectious TB, the risk to the oth er patients is small. Patients whose exposure is considered comparable to that of a househo ld contact should be screened. Only those in the same bay as a coughing infectious case, fo r at least 8 h, are considered at risk. Exposure should be documented and the patient and t he GP contacted Non-MDR-TB HIV-negative patients usually become non-infectious after 2 week s chemotherapy. Any bacilli seen in smears after that time are likely to be dead Patients w ith HIV and those with TB should not be nursed in close proximity All patients with known o r suspected MDR-TB should be admitted to negative pressure ventilated side room. Staff shou ld wear protective face masks (FFP3) At discharge, a clear plan must be in place for the ad ministration and supervision of all chemotherapy; this is particularly important for patien ts with MDR-TB, where close liaison with the infection control team and consultant in commu nicable disease control is paramount. \200 \200 Treatment failure/disease relapse \200 This is usually due to poor compliance \200 Drug resistance may have developed \200 Never add a single drug to a failing regime. Add only 2 or 3, ideally those to which the patient has not been previously exposed Assume drug res istance to all or some of the drugs in the failed regime Repeat cultures and sensitivity te sting in this situation. Consider speci \201 c molecular tests for rifampicin resistance. If found, then treat as for MDR-TB (see p 508). \200 TB: IN-PATIENT ADMISSION 501 TB: treatment follow-up \200 \200 CXR is advised at the end of therapy for pulmonary disease Relapse is uncommon in those com pliant with standard treatment regimes in the UK (0 \200\2233%); therefore long-term follow -up is not recommended Follow-up at 12 months after treatment completion is recommended for patients treated for drug-resistant TB Relapse after good compliance is usually due to ful ly sensitive organism; therefore treatment can be with the same regime again Relapse due to poor compliance needs a fully supervised regime. MDR-TB follow-up Prolonged follow-up is recommended; lifelong for HIV-positive patients. 502 CHAPTER 42 Respiratory infection: mycobacterial TB in pregnancy There is no increased risk of developing clinical disease in pregnancy. Pre sentation is the same as in non-pregnant individuals, but the diagnosis may be delayed by t he non-speci \201 c nature of the symptoms in the early stages of disease, with malaise an d fatigue being common in the early stages of pregnancy. A CXR is more likely to be delayed . The tuberculin skin test result is not affected by pregnancy; this applies to HIV positive and negative subjects. A negative skin test should not lead to BCG vaccination, as live vac cines are contraindicated in pregnancy. In this situation, the skin test should be repeated after delivery, and BCG given then, after a second negative test. TB outcome in pregnancy \200 If diagnosed in the \201 rst trimester, the disease has the same outcome as for non-pregn ant women If diagnosed in the second or third trimester, studies give more vari- able outco mes (some studies show a good fetal outcome; some show higher rates of small-for-dates babi es, pre-eclampsia, and spontaneous abortion), but these effects tend to be related to late diagnosis and incomplete drug treatment. Some studies also show a poorer fetal outcome in e xtrapulmonary disease Late diagnosis of pulmonary TB can lead to a 4-fold increased obstetr ic mortality and 9-fold increased pre-term labor in some developing countries. Treatment in pregnancy \200 Isoniazid, rifampicin, and ethambutol are not teratogenic, and can be used safely in pregna ncy. The \200\230standard \200\231 short course therapy is recommended (i.e. 6-month treat ment) Limited pyrazinamide data on the risk of teratogenicity Streptomycin may be ototoxic to the fetus Active TB must be treated in pregnancy, because of the risk of untreated disea se to the mother and fetus Reserve drugs may be toxic, and the risk/bene \201 t ratio of e ach case must be assessed individually if second-line drugs are needed Babies of sputum-pos itive mothers, who have had less than 2 weeks treatment by delivery, should be treated with isoniazid and have a skin test at 6 weeks. If the skin test is negative, the chemoprophyla xis should be stopped and BCG given 1 week later (as BCG is sensitive to isoniazid) Congeni tal infection is very rare (less than 300 reported cases). The child can be infected at del ivery (this is rare). \200 \200 TB IN PREGNANCY 503 Breast feeding \200 Most antituberculosis drugs are safe. Isoniazid \200\224monitor infant for possible toxicit y, as there is a theoretical risk of convulsions and neuropathy. Give prophylactic pyridoxi ne to the mother and infant Concentrations of drugs reaching breast milk are too low to pre vent or treat infection in the infant 504 CHAPTER 42 Respiratory infection: mycobacterial TB chemotherapy with comorbid disease Liver disease \200 Drug-induced hepatitis can be fatal. A raised ALT is more common in those who regularly con sume alcohol, have viral hepatitis or other chronic liver disease, take concomitant hepatot oxic drugs, are pregnant, or are within 3 months post partum About 20% of those treated wit h isoniazid alone will have an asymp- tomatic transient rise in ALT. In the majority, this represents hepatic adaptation. Acetylator status (fast or slow) may in \202 uence this Iso niazid-induced hepatitis can be symptomatic or asymptomatic usually occurs within weeks or months of treatment, and is age related Isoniazid inhibits several cytochrome P450 enzymes, potentially increasing the plasma concentrations of other hepatotoxic drugs Rifampicin can cause subclinical hyperbilirubinaemia without hepatocellular damage. It can also cause dir ect hepatocellular damage and potentiate the hepatotoxicity of other TB drugs Pyrazinamide should not be used in patients with known chronic liver disease Decompensated liver disease \200\224use a drug regime without rifampicin Baseline and regular monitoring of liver func tion is necessary (weekly LFTs for the \201 rst 2 weeks, then at 2-weekly intervals). \200 Renal failure \200 Isoniazid and rifampicin have biliary excretion, so can be given in normal doses in renal d isease Pyrazinamide metabolites are renally cleared; the dose may need to be less frequent in those with renal insuf \201 ciency Give pyridoxine in addition to isoniazid in those wi th severe renal disease to prevent isoniazid-induced peripheral neuropathy Ethambutol can a ccumulate causing optic neuropathy; therefore use a lower dose Dialysis patients should rec eive drugs after dialysis. HIV infection \200 Regimes are similar for HIV-positive and HIV-negative patients; give a standard 4-drug regi me. Liaise closely with HIV specialists Better outcome with regimes including rifampicin De ath during tuberculosis chemotherapy is more common in HIV-infected patients, who also have higher relapse rates than non- HIV-infected subjects Higher incidence of miliary disease i n those with low CD4 counts Protease inhibitors and non-nucleoside reverse transcription in hibitors should not be used with rifampicin (they interfere with each other \200\231s metab olism) Paradoxical worsening of disease (worsening fever, CXR in \201 ltrates, or new mani festations of the disease) at the initiation of HIV treatment are more common in HIV-positi ve patients. This is probably due to \200 \200 TB CHEMOTHERAPY WITH COMORBID DISEASE 505 immune reconstitution, and the increased recognition of mycobacterial antigens with improve ment of the subject \200\231s immune response Patients co-infected with TB and HIV should b e considered potentially infectious at each admission, until proved otherwise, and should b e segregated from others. Review the immune status of other patients and their likely drug resistances, and their potential infectiousness In HIV-infected individuals (in whom the HI V diagnosis is new), usual practice is to start tuberculosis chemotherapy before HIV chemo- therapy. Antiretroviral therapy is usually started later (but there is no consensus as to when). Liaise closely with HIV specialists. Diabetes Increased risk of TB, and the disease may be more extensive. Rifampicin reduces th e ef \201 cacy of sulphonylureas. TB drugs and abnormal liver function tests \200 Chronic liver disease \200\224regular monitoring of LFTs, weekly for the \201 rst 2 weeks , then at 2-weekly intervals New drug-induced hepatitis \200 \200 Virological tests to exclude concomitant viral hepatitis AST/ALT rise 2 \227 normal \200 \224monitor LFTs weekly for 2 weeks, then 2-weekly until normal. AST/ALT rise under 2 \227 normal \200\224repeat LFT at 2 weeks. AST/ALT rise 5 \227 normal or bilirubin rise \200\224 cease rifampicin, iso- niazid, and pyrazinamide unless the patient is unwell. If the patien t is unwell, or sputum still positive, consider admission for parenteral therapy, e.g. stre ptomycin and ethambutol with appropriate monitoring \200 Drug re-challenge once LFTs are normal: Re-introduce sequentially, in order: \200 Isoniazid: at 50 mg/day, sequential increase to 300 mg/day after 2 \200\2233 days if no rea ction Rifampicin: at 75 mg/day, increase to 300 mg/day after 2 \200\2233 days if no reactio n, then to maximum dose/kg Pyrazinamide: start at 250 mg/day, increase to 1 g/day after 2 \200\2233 days, and to maximum dose/kg if no reaction Daily monitoring of LFTs and clinical condition If no further reaction, continue chemotherapy If there is a further reaction, ex clude the offending drug, and change to an alternative regime If intolerant of pyrazinamide , use rifampicin and isoniazid for 9 months, with ethambutol for 2 months. \200 \200 506 CHAPTER 42 Respiratory infection: mycobacterial TB: adverse drug reactions These occur in around 10% of patients, often requiring a change of therapy. Reactions are more common in those on non-standard therapy and in HIV-positive individuals. Isoniazid peripheral neuropathy can be prevented by pyridoxine 10 mg daily (re commended in those at highest risk \200\224diabetes, renal failure, alco- holics, HIV-posit ive). Rifampicin causes shock, acute renal failure, thrombocytopenia. Withdraw and do not r eintroduce the drug. Double maintenance steroid doses at the start of treatment (because of enzyme induction). Ethambutol causes rare optic toxicity; recommend baseline visual acuity assessment with a Snellen chart. Use only in those with adequate visual acuity, and those able to report changes in visual acuity or new visual symptoms. Document that the patient h as been told to cease the drug immediately at the onset of new visual symptoms. Check basel ine renal function before starting ethambutol, and avoid in renal failure. HIV-positive pat ients Rifampicin and isoniazid lead to reduced serum concentrations of antifungals. Ketocon azole can inhibit rifampicin absorp- tion. Rifampicin may reduce drug levels of protease in hibitors (as they are metabolized via the cytochrome P450 pathway, which is induced by rifa mpicin). Rifabutin can cause a severe iritis. Liaise closely with HIV specialist. Drug resi stance occurs in less than 2% of Caucasian cases in the UK, with higher levels in ethnic mi nority groups. \200 Isoniazid resistance is seen in up to 6% in patients of African and Indian subcontinent ori gin. Increased drug resistance is seen in HIV-positive patients (fourfold increased risk). Second-line drugs are generally more toxic and less effective than \201 rst- line drugs, and the treatment of drug resistance can therefore often be complex and dif \201 cult The regime must include at least three drugs to which the organism is known to be susceptible. An injectible drug is often added, as this has shown improved outcomes The initial regime w ill depend on the incidence of drug resistance in the community, and should be altered depe nding on local drug suscep- tibility patterns In general, always add at least two drugs to which the MTB is suscep- tible Parenteral treatment is usually recommended when there is re sistance to two or more drugs. TB: ADVERSE DRUG REACTIONS 507 Table 42.4 Recommended drug regimes for non-MDR drug resistant TB Drug resistance Initial phase Continuation phase S 2RHZE 4RH H known before treatment 2RZSE 7RE H known after treatment 2RZE 10RE Z 2RHE 7HR E 2RHZ 4RH R (only if con \201 rmed as isolated resistance) 2HZE 16HE S and H 2RZE 10RE Isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E) Rifampicin monoresistance is uncommon, but does require regime modi- \201 cation. In most cases, rifampicin resistance is a marker of MDR-TB, and should be treated as such until fu ll sensitivities are known. 508 CHAPTER 42 Respiratory infection: mycobacterial Multiple drug resistant TB (MDR-TB) De \201 ned as MTB resistant to two or more \201 rst-line agents, usually isoni- azid an d rifampicin. \200 Treatment is complex and time-consuming MDR-TB is not more infectious than other forms of T B, but the conse- quences of acquiring it are more serious Seek specialist advice; patients should be managed by experts with experience of managing resistant cases, in a hospital wi th isolation facili- ties. The mdrtbcentre@ctc.nhs.uk email address, based in Liverpool, ca n be used to seek advice from experts in the management of MDR disease. An MDR-TB UK databa se is run from the Cardiothoracic Center in Liverpool Rapid molecular tests for rifampicin resistance should be carried out in all patients suspected of having MDR-TB. Liaise closely with the refer- ence laboratory Close monitoring (because of increased drug toxicity) is n eeded Compliance is paramount MDR-TB comprised 1.3% of all UK cases in 1998 Start treatment with 5 or more drugs to which the organism is likely to be susceptible. Continue until spu tum cultures are negative. Continue with at least 3 drugs to which TB is sensitive, for a m inimum of 9 months, sometimes for 24 months Surgery may be indicated. \200 \200 \200 Contacts of MDR-TB Chemoprophylaxis for contacts should include at least 2 drugs. Base the drug choice on the sensitivities of the index case for a minimum of 6 months (although ther e are no data to support this treatment period). If there is extensive resistance, no regim e may be suit- able, and regular follow-up needed instead. Risk factors for resistant disease \200 \200 \200 \200 \200 \200 Previous anti-TB treatment, prior treatment failure HIV infection Contact with drug-resista nt disease Residence in London Male gender, age 25 \200\22344 Treatment failure. XDR-TB \200\230extensively drug-resistant TB \200\231 is disease resistant to at least thr ee classes of second line drugs. 347 infected patients are described worldwide so far, and the disease appears to be emerging in regions with high HIV prevalence, where it has a mort ality of nearly 100%. 2004 data estimates that 0.4% of the global burden of TB is XDR-TB, a bout 30 000 cases. Genotyping data suggest the emergence of XDR-TB is due to the trans- mis sion of XDR strains between individuals, and is not a consequence of previous unsuccessful treatment. 85% of South African XDR isolates are from the KZN family of tuberculosis strain s, which were mostly fully susceptible when \201 rst described in 1996. MULTIPLE DRUG RESISTANT TB 509 Table 42.5 Second-line tuberculosis chemotherapy Drug Dose Potential side-effects Amikacin 15 mg/kg Tinnitus, ataxia, renal impairment, vertigo Azithromycin 500 mg od GI upset Capreomycin 15 mg/kg As for amikacin Cipro \202 oxacin 750 mg bd Abdominal upset, headache, drug interactions Clarithromycin 500 mg bd GI upset Ethionamide (or protionamide) <50 kg: 375 mg bd \211 50 kg: 500 mg bd GI upset, hepatitis. Avoid in pregnancy Kanamycin 15 mg/kg As for amikacin O \202 oxacin 400 mg bd Abdominal upset, headache PAS 10 g od or 5 g bd GI upset, fever, rash, hepatitis Rifabutin 300 \200\223450 mg od As for rifampicin. Uveitis (particulary with HIV infection) with drug interactions, e.g. wi th macrolides Streptomycin 15 mg/kg (max dose 1 g od) As for amikacin Thiacetazone 150 mg GI upset, rash, conjunctivitis,vertigo. Avoid if HIV-positive (risk of Stevens \200\223 Joh nson syndrome) If the drug choice is limited by drug resistance and intolerance, consider desensitization and reintroduction of the offending drug. Desensitization must be carried out with concurre nt treatment with 2 other drugs (to minimize emergence of resistant strains). Immunotherapy Additional treatments aimed at immunomodulation may facilitate bacillary clearance and inc rease cure rates, particularly in MDR disease. Small studies suggest that IL-2 and nebulize d interferon- gamma may have some bene \201 t in this setting, and in patients with HIV co -infection. A larger study in HIV-negative patients with pulmonary TB has not shown improve d bacillary clearance, suggesting that single cytokine therapy in individuals with drug-sus ceptible TB is unlikely to improve the outcome. In MDR-TB, however, there may be greater be ne \201 ts of treat- ment. Administration of M. vaccae has been postulated to enhance the Th1 response and suppress Th2 responses to MTB, but clinical trials of this agent have been disappointing, despite promising in vitro studies. 510 CHAPTER 42 Respiratory infection: mycobacterial Latent TB infection De \201 ned as a positive skin test, with a normal CXR and no symptoms . This represents the presence of a small total number of bacteria. Tuberculin skin test A positive skin test results from the development of cell-mediated immunity against TB. The m ultiple puncture method (Heaf) is being phased out. Mantoux testing is used more commonly i n the UK. Potential problems with skin testing: \200 Low sensitivity in the immunocompromised, and cross-reactivity with BCG The patient has to return to have the test read after 48 \200\22372 h Criteria for a positive test depend on t he population in which it is being used. \200 Interferon gamma tests Two blood tests (T-SPOT.TB, Oxford Immunotec Ltd. and QuantiFERON-TB Gold, Cellestis Ltd.) are now commercially available, and are based on the detection of IF N released by T cells in response to M. tuberculosis speci \201 c antigens. The T-SPOT.T B test is an ELISpot test, counting individual T cells producing IFN ; the QuantiFERON tes t is based on a whole-blood ELISA, and measures the IFN level in the supernatant of the s timulated whole blood sample. Both assays use two proteins (ESAT-6 and CFP10) encoded by a unique genomic sequence of MTB, which is absent from M. bovis BCG and the majority of oppor tun- istic mycobacteria. These proteins are the main targets for IFN -secreting T lymphocy tes in individuals infected with MTB. These tests have several advantages over the tubercul in skin test: no return visit for test reading is required, the result is available the nex t day, and repeated testing does not cause boosting. With both tests, blood must be collect ed in a heparinized tube, and processed within 6 \200\2238 h of venepuncture. The blood sho uld be transferred to the laboratory at room temperature. Validation of these new tests has been dif \201 cult in the absence of a gold standard, although data suggest that the T-SP OT.TB test is more sensitive for the diagnosis of latent TB than the tuberculin skin test, particularly in children and HIV- positive individuals, and is probably more sensitive than the QuantiFERON test in the diagnosis of active TB. Latent infection versus active disease It is important to differentiate between active and latent disease. Active disease is a positive skin test (usually), abnormal CXR, and symptom s. Latent infection (small numbers of bacilli present) is usually treated with chemoprophyl axis (see below). Treatment of latent TB reduces the risk of subsequent development of acti ve disease by about 90%. HIV infection The tuberculin skin test may be falsely negative, an d radio- logical changes may be atypical. Current guidelines recommend close monitoring and no chemoprophylaxis, because of the dif \201 culties in iden- tifying active from latent disease, and because of the risk of emergence of resistant strains. Exposure to smear-posit ive disease should lead to che- moprophylaxis in the absence of clinical disease. Recommend ed follow-up is at 3 and 12 months for those not receiving chemophrophylaxis (but who were eligible for it). LATENT TB INFECTION 511 HIV-positive patients should receive long-term follow-up as part of their ongoing HIV management. Chemoprophylaxis is given to contacts with strongly positive Heaf r eactions, who have no radiological or clinical evidence of active disease. The risk of deve loping disease after exposure depends on a number of factors, including BCG and HIV/immune status, and whether infection was recent. Younger patients must have had relatively recent infection, and have a longer life expectancy from which to gain the bene \201 ts of chemo- prophylaxis. Chemoprophylaxis is recommended for: \200 \200 \200 Those with recent documented tuberculin conversion HIV-infected contacts of smear-positive cases Children aged <16 with a strongly positive Heaf (grade 2 \200\2234 if no prior BCG, g rade 3 \200\2234 if prior BCG) Individuals with HIV, injecting drugs, with hematological ma lignancy, chronic renal failure or on dialysis, with silicosis, gastrectomy, solid organ tr ansplant or receiving anti-TNFA therapy have a higher risk of developing active TB Drug regimes \200 Rifampicin and isoniazid daily for 3 months (3RH). Best compliance, but slightly higher sid e-effect pro \201 le Isoniazid daily for 6 months (6H). Lowest toxicity regime. Has a 60 \200\22390% effectiveness in reducing progression of latent infection to clinical disease 6 H is recommended for people with HIV 6R is recommended for contacts of patients with isonia zid resistant disease Individuals who decline chemoprophylaxis should be given the \200 \230Inform and advise \200\231 information lea \202 et, and have a CXR at 3 and 12 months. \200 512 CHAPTER 42 Respiratory infection: mycobacterial TB and anti-TNFA treatment Humanized monoclonal anti-TNFA antibody has recently been approv ed for the treatment of rheumatoid arthritis (RA), Crohn \200\231s disease, psori- atic art hropathy, and juvenile idiopathic arthritis. Etanercept (Enbrel) is a fusion protein that b inds free TNFA using a soluble portion of the TNFA receptor, and is licensed for use in rhe umatoid arthritis. Adalimumab (Humira) is a recombinant humanized monoclonal antibody again st TNFA, also licensed for use in RA. In \202 iximab (Remicade) is a human chimera monoclo nal antibody, licensed for the treatment of RA, Crohn \200\231s disease, and ankylosing spo ndylitis. These drugs cause profound immunosuppression, and patients treated with them have an increa sed risk of developing TB. Most TB cases have been seen with in \202 iximab (242 at time o f publication), with most occurring within three treatment cycles (within a mean of 12 week s of starting treat- ment). TB is the most frequently described opportunistic infection in this context. 50% of the reported cases are extrapulmonary disease. The initial high incide nce of cases has now plateaued, presumably due to improved assessment and awareness and the use of isoniazid chemoprophylaxis. The calculated TB prevalence in etanercept/in \202 ixi mab-treated RA patients in America is 41 per 100 000, 9 per 100 000 for Crohn \200\231s dis ease. Overall, there is an average 5-fold increased risk of developing TB with anti-TNFA. A ll patients due to start anti-TNFA antibody treatment should be screened for active and lat ent TB \200 All patients should have a clinical examination, with history of previous TB treatment and exposure carefully documented. All should have a CXR and tuberculin test Those with an abno rmal CXR consistent with previous TB or those who have a history of extrapulmonary TB, who have received adequate treatment (as assessed by an expert), can start anti-TNFA therapy, b ut need monitoring every 3 months with a CXR and symptom assessment. The onset of any new r espiratory symptoms, especially within 3 months of starting anti-TNFA therapy, should be in vestigated promptly Those with an abnormal CXR consistent with previous TB or those who hav e a prior history of extrapulmonary TB, who have NOT had adequate treatment, need to have a ctive tuberculosis excluded by appropriate investigations. They should receive chemoprophyl axis before anti-TNFA therapy commences (assuming active disease is not identi \201 ed). I f there is clinical concern because of the delay in starting anti-TNFA treatment, a shorter course of chemoprophylaxis can be given, but this may be more toxic Any TB diagnosed (pulm onary or extra-pulmonary) should be treated with standard chemotherapy If active TB is pres ent, patients should receive a minimum of 2 months anti-TB chemotherapy before starting ant i-TNFA therapy If the CXR is normal, the tuberculin test may be helpful if the patient is n ot on immunosuppressants, and must be interpreted knowing the BCG history. A tuberculin ski n test is unhelpful if the patient is on immunosuppressants. In this situation, an individu al assessment should be made: if the risk of drug-induced hepatitis is less than the annual risk of developing TB, chemoprophylaxis should be given. However, if the TB AND ANTI-TNFA TREATMENT 513 risk of hepatitis is greater, the patient should be monitored regularly and any suggestive symptoms investigated promptly. See Table 42.6 No chemoprophylaxis regime is 100% effective : the protective ef \201 cacy of 6H is reported at 60 and 50% for 3HR In those without pre vious BCG, Heaf grades 0 \200\2231 (Mantoux 1 in 10 000, 0 \200\2235 mm) are negative, and Heaf grades 2 \200\2234 (Mantoux 1 in 10 000, >6 mm) are positive and should lead to a risk assessment In those with prior BCG, Heaf grades 0 \200\2232 (Mantoux 1 in 10 000, 0 \200 \22314 mm) are negative, and Heaf grades 3 \200\2234 (Mantoux 1 in 10 000, >15 mm) may repr esent either latent infection or BCG effect, and therefore need further investigation In ge neral, all black African patients aged >15 and all South Asians born outside the UK should be considered for chemoprophylaxis with 6 months isoniazid If a patient develops TB, whilst on anti-TNFA therapy, treat with the full standard course of antituberculous chemotherapy. The anti-TNFA can be continued if indicated Close liaison between the prescriber of the TN FA antibody treatment and TB specialists is needed. Table 42.6 Sample calculations for aiding TB risk assessment for patients starting anti-TNF -A treatment. Risk/bene \201 t conclusion TB risk adjusted \2275 for anti- TNFA effect Case type Annual risk of TB disease/ 100 000 Risk of hepatitis following 6H chemoprophy- laxis/100 000 White, UK born, age 55 \200\22374 7 35 278 Observation ISC, in UK >3 years, age >35 593 2965 278 Prophylaxis Black African age 35 \200\22354 168 840 278 Prophylaxis Other ethnic group, in UK >5 years, age >35 39 195 278 Observation ISC = Indian subcontinent. The risk of hepatitis with 3RH chemoprophylaxis is 1766/100, 000 Further information BTS recommendations for assessing risk and for managing Mycobacterium t uberculosis infection and disease in patients due to start anti-TNF-A treatment. Thorax 200 5; 60: 800 \200\2235. 514 CHAPTER 42 Respiratory infection: mycobacterial