TB treatment 2024 slides Alffenaar.pdf

Tuberculosis treatment Professor Jan-Willem Alffenaar Sydney Infectious Diseases Institute Sydney Vietnam Academic Center School of Pharmacy Westmead Hospital TEQSA PRV12057 CRICOS 00026A Learning objectives - TB treatment - Drug sus...

Tuberculosis treatment Professor Jan-Willem Alffenaar Sydney Infectious Diseases Institute Sydney Vietnam Academic Center School of Pharmacy Westmead Hospital TEQSA PRV12057 CRICOS 00026A Learning objectives - TB treatment - Drug susceptible TB - Various treatments for drug resistant TB - TB drugs - Treatment management - Management of side effects - Therapeutic drug monitoring - Supervised treatment The University of Sydney  Why is Mycobacterium tuberculosis so successful? Cell thick, waxy cell Wall highly resistant to desiccation, disinfectants, and the host immune system Intracellular Survival survival in macrophages normally responsible for engulfing and destroying pathogens Latent Infection can enter a dormant state within the host, allowing it to persist for years without causing symptoms. Latent infection can be reactivated later, often when the host's immune system is weakened, leading to active tuberculosis Immune Evasion can manipulate the host's immune response, promoting a granuloma formation that walls off the bacteria but doesn't eliminate them Slow Growth Rate less susceptible to antibiotics that target rapidly dividing bacteria Genetic Diversity and Adaptation adapt to different environmental conditions and host immune responses through genetic mutations, which may contribute to drug resistance Drug resistance can develop resistance to antibiotics Transmission Efficiency The University of Sydney highly efficient at spreading from person to person via respiratory droplets Mechanisms of action of anti-TB drugs The University of Sydney https://www.niaid.nih.gov/diseases-conditions/tbdrugs Anti TB drugs Type of activity - Bactericidal => kill - Bacteriostatic => inhibit growth/replication Effects: - Early bactericidal activity - Sterilising activity - Prevention of resistance development - In combination therapy - Monotherapy The University of Sydney Early bactericidal activity - Rapid decline of number of bacteria after start of treatment - Important for reducing risk of transmission of infection - Early bactericidal activity is a characteristic of an antibiotic Start of antibiotic Start of antibiotic with EBA effect without EBA effect Bacteria in sputum Bacteria in sputum Positive Positive Negative Negative The University of Sydney day 7 day 14 Time day 7 day 14 Time Sterilising activity - Ability of antibiotic to kill non-replicating / dormant bacteria - Important for cure and preventing relapse Start of antibiotic with sterilising effect Bacteria in sputum Bacteria in sputum End of antibiotic with End of antibiotic without sterilising effect sterilising effect Positive Positive Negative Negative M1 The University of Sydney M2 M4 M6 M12 Time M1 M2 M4 M6 M12 Time Supervised treatment - TB treatment is long and complex making it difficult for patients to complete treatment - DOT = Direct Observed Treatment - Via nurses, family members - VOT = Video Observed Treatment - completion of treatment, increase cure, prevent relapse The University of Sydney WHO treatment guidelines - World Health Organisation develops global guidelines - TB experts from across the world help the WHO with creating the guidelines - Countries implement these guidelines in their health system The University of Sydney First-line treatment – drug susceptible TB - Isoniazid (1952) - Rifampicin (1966) - Pyrazinamide (1952) - Ethambutol (1961) 58- to 72-year-old drugs - Intensive phase: 2 months all 4 drugs - Continuation phase: 4 months 2 drugs (isoniazid/rifampicin) The University of Sydney  Shorter First-line treatment – drug susceptible TB - Minimal disease - Chest X-ray consistent with minimal disease - No need for hospitalisation - Sputum smear negative / traces via PCR based test - Two shorter regimens: 1. isoniazid/rifampicin/pyrazinamide/ethambutol for 2 months followed by 2 months isoniazid/rifampicin 2. isoniazid/rifapentine/pyrazinamide/moxifloxacin for 2 months followed by 2 months of isoniazid/rifapentine/moxifloxacin The University of Sydney Isoniazid - Mode of action: inhibiting synthesis of mycolic acids, constituents of the mycobacterial cell wall. It is bactericidal against actively dividing M. tuberculosis and bacteriostatic against resting bacteria; it is active against intra- and extracellular organisms - Dose: once daily 5mg/kg – max 300mg (adults) - Precaution: Severe malnutrition, diabetes, HIV infection, alcoholism greater risk of peripheral neuropathy (use pyridoxine 25 mg daily as prophylaxis). - Side effects (>1%): hepatitis - increases in serum aminotransferases occur in 10–20% of people in the first few months of treatment, rash, fever, peripheral neuritis (if pyridoxine is not given concurrently), tiredness The University of Sydney  N-Acetyltransferase 2 - Activate and deactivate arylamine and hydrazine drugs and carcinogens. - Polymorphisms in this gene are responsible for the N-acetylation polymorphism in which human populations segregate into rapid, intermediate, and slow acetylator phenotypes. Important for isoniazid: - Fast acetylators; high risk of failure due to low isoniazid levels - Slow acetylators: high risk of side effects due to high isoniazid levels - Normal dose 5mg/kg once daily - Increased dose 7.5mg/kg once daily for fast acetylators - Decreased dose 2.5 mg/kg once daily for slow acetylators The University of Sydney Rifampicin - Mode of action: Inhibit bacterial RNA polymerase; bactericidal against rapidly dividing M. tuberculosis and active against those which are semi- dormant (intracellular organisms). - Dose: once daily 10mg/kg - max 600mg (adults) - Precaution: may worsen hepatic impairment, treatment with hepatotoxic drugs may increase the risk of hepatotoxicity - Side effects (>1%): arthralgia and myalgia (in the first weeks), headache, dizziness, drowsiness, ataxia, confusion, fatigue and weakness, orange-red colouration of body fluids - Drug-Drug interactions: induces CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, UDP-glucuronyl transferase (UGT), P-glycoprotein (Pgp) - Drug-food interaction: food reduces bioavailability, take on empty stomage The University of Sydney  High dose rifampicin - Rifampicin dose historically decided based on costs and not pharmacology - Current studies explore higher dosages of rifampicin aiming to shorten treatment - Normal dose 10mg/kg - High dose up to 35-40mg/kg The University of Sydney Lancet 1972 PK/PD principles behind dose increase Safety/tolerability PK/PD The University of Sydney AUC - % sputum culture conversion at week 8 Jayaram et al AAC 2003, Diacon et al AAC 2007, Boeree et al AJRCCM 2015, Svensson et al CID 2018 Pyrazinamide - Mode of action: Bactericidal against M. tuberculosis in acid pH; active against bacteria within macrophage; activity declines with time (pH increases as inflammation decreases). - Dose: once daily 20–25 mg/kg – max 2 g (adults) - Precaution: contraindicated in acute gout (pyrazinamide inhibits the renal excretion of urate and raises uric acid concentrations) and significant liver disease. - Side effects (>1%): hyperuricaemia, polyarthralgia, nausea The University of Sydney Ethambutol - Mode of action: May inhibit incorporation of mycolic acid into the mycobacterial cell wall. It is bacteriostatic against M. tuberculosis. - Dose: once daily 15-20 mg/kg (adults) - Precaution: Contraindicated in optic neuritis. Further deterioration in vision may occur where there are visual defects, eg diabetic retinopathy, cataract. - Side effects (>1%): Dose-related, usually reversible, and characterised by decreased visual acuity, scotoma or colour blindness The University of Sydney Ethambutol - Obese - Total body weight vs ideal body weight? - What should we use for the dose? - For this patient 18.3 mg/kg TBW 31.3 mg/kg IBW The University of Sydney Tuberculosis meningitis Higher dose + Longer duration Pulmonary TB TB meningitis Isoniazid 10 mg/kg 15-20 mg/kg Rifampicin 15 mg/kg 22.5-30 mg/kg Pyrazinamide 35 mg/kg 35-45 mg/kg Ethambutol 20 mg/kg - Ethionamide - 17.5-22.5 mg/kg Duration 4-6 months 6-9 months The University of Sydney Second line treatment – resistant TB (1) Regimen for rifampicin-susceptible, isoniazid-resistant tuberculosis - rifampicin, ethambutol, pyrazinamide and levofloxacin for 6 months Shorter regimen for multidrug- or rifampicin-resistant tuberculosis - Bedaquiline, levofloxacin (or moxifloxacin), clofazimine, pyrazinamide, ethambutol, high dose isoniazid, ethonamide for 4-6 months followed by levofloxacin (or moxifloxacin), clofazimine, pyrazinamide, ethambutol for 5 months. - Criteria: < 1 month of second line TB medicines, no resistance to fluoroquinolones, no severe TB, not pregnant The University of Sydney Second line treatment – resistant TB (2) Longer regimen for multidrug- or rifampicin-resistant tuberculosis - Bedaquiline, levofloxacin (or moxifloxacin), linezolid, clofazimine (or cycloserine) for 6 months followed by 12 months of levofloxacin (or moxifloxacin), linezolid, clofazimine (or cycloserine) - for patients with multidrug- or rifampicin-resistant tuberculosis (MDR/RR-TB) patients not eligible for the shorter regimen The University of Sydney Second line treatment – resistant TB (3) BPAL regimen for multidrug- or rifampicin-resistant tuberculosis with fluoroquinolone resistance - Bedaquiline, pretomanid, linezolid for 6-9 months. Criteria: laboratory-confirmed resistance to rifampicin and fluoroquinolones with or without resistance to injectable agents, aged > 14yrs, weighs >35 kg, willing and able to provide informed consent, not pregnant or breastfeeding and is willing to use effective contraception, no known allergy to any of the BPaL component drugs, no evidence in DST results of resistance to any of the component drugs, or has not been previously exposed to any of the component drugs for 2 weeks or longer; no extrapulmonary TB (including meningitis, other CNS TB, or TB osteomyelitis). The University of Sydney Bedaquiline - Mode of action: inhibits the c subunit of ATP synthase responsible for synthesizing ATP (generation of energy in M. tuberculosis) - Dose: once daily 400mg for 2 weeks, followed by 200mg 3 times per week - Precaution: QT prolongation by blocking hERG channel - Side effects (>1%): Nausea, headache, joint pain, chest pain, abnormal liver function tests - Drug-drug interaction: bedaquiline is a CYP3A4 substrate - Drug-food interaction: needs to be taken with food for good bioavailability The University of Sydney Bedaquiline’s delayed mode of action Bedaquiline was tested in an Early Bactericidal Activity study and showed effect from day 4 onward while isoniazid showed effect from the first day onward. Mode of action: inhibits the c subunit of ATP synthase responsible for synthesizing ATP apparently, the TB bacteria has a “storage of ATP for 4 days” which resulted in a noticeable effect after 4 days The University of Sydney Pretomanid - Mode of action: pretomanid is a prodrug which is metabolically activated by a nitroreductase enzyme, producing various active metabolites that are responsible increased levels of nitric oxide, leading to bactericidal activities under anaerobic conditions. - Dose: 200mg once daily for 26 weeks - Precaution: can only be used as part of BPAL regimen as there is no evidence from clinical trials for other drug combinations. - Side effects (>1%): nausea, loss of appetite, headache, muscle pain, chest pain, abnormal liver function tests - Drug-drug interaction: pretomanid is a CYP3A4 substrate - Drug-food interaction: needs to be taken with food for good bioavailability. The University of Sydney Linezolid - Mode of action: binds to bacterial 23S ribosomal RNA of the 50S subunit, preventing the formation of a functional 70S initiation complex, which is essential for bacterial reproduction. - Dose: 300-1200mg once daily - Precaution: myelosuppression : risk of anaemia and thrombocytopenia - Linezolid inhibits mitochondrial protein synthesis, which is thought to result in adverse effects such as optic and peripheral neuropathy, anaemia and lactic acidosis. These usually resolve after stopping linezolid, but there may be permanent damage, eg blindness. - Side effects (>1%): diarrhoea, nausea, vomiting, abdominal pain, taste disturbance, raised hepatic enzymes, candidiasis, myelosuppression - Drug-drug interactions: Rifampicin reduces linezolid concentrations and clarithromycin increases linezolid concentrations The University of Sydney Linezolid drug-drug interaction - Increase in AUC from 29 mg·h/liter to 108 mg·h/liter. - >3 fold increase The University of Sydney Bolhuis et al AAC 2010 Moxifloxacin - Mode of action: inhibit bacterial DNA synthesis by blocking DNA gyrase and topoisomerase IV. - Dose: once daily 400-800mg - Precaution: Contraindicated if the QT interval is prolonged, tendon damage, - Side effects (>1%): dizziness, gastrointestinal complaints, QT prolongation - Drug-drug interaction: aluminium-, calcium- or -30% magnesium containing antacids (take 4h before or after), rifampicin The University of Sydney Ruslami et al CID 2007 Moxifloxacin acquired resistance (1) - Moxifloxacin was developed for ‘normal respiratory infections’ - It was repurposed in the same dose for TB. Problems: 1) Pharmacokinetics are different in TB patients (lower drug concentrations) 2) Treatment duration is months instead of days 3) TB bacteria are ‘real survivors’ The University of Sydney  Moxifloxacin acquired resistance (2) AUC/MIC 24 - Bacterial kill is a result of the balance between antimicrobial concentration and bacteria susceptibility. - Bacterial kill is a result of the balance between antimicrobial concentration and bacteria susceptibility. - Bacterial susceptibility is AUC/MIC 40 expressed as MIC Minimal Inhibitory Concentration At moxifloxacin dose of 400mg 10% of the patients acquire drug resistance despite combination therapy. A higher dose of 800mg is needed for resistant TB (higher MICs) while AUC/MIC 101 for drug susceptible (lower MICs) TB 400mg is sufficient. The University of Sydney Gumbo et al JID 2004, Pranger et al ERJ 2011 Levofloxacin - Mode of action: inhibit bacterial DNA synthesis by blocking DNA gyrase and topoisomerase IV. - Dose: 15mg/kg 750-1500mg - Precaution: may worsen hepatic impairment, treatment with hepatotoxic drugs may increase the risk of hepatotoxicity - Side effects (>1%): dizziness, gastro-intestinal complaints, - Drug-Drug interaction: aluminium-, calcium- or magnesium containing antacids (take 4h before or after) The University of Sydney  The Union “The Clinical Standards for Lung Health complement existing WHO guidelines and integrate their recommendations to focus on person centred care” The University of Sydney Dosing and management of TB drugs 1. Every patient should receive the most appropriate drug dose when starting TB treatment to avoid too low or too high drug exposure, which could result in treatment failure or adverse drug effects 2. Patients should be re-evaluated when demonstrating slower response to TB treatment than expected 3. The risk of TB drug toxicity should be minimised by initial screening and ongoing clinical monitoring. Toxicity specific to TB drugs should be prevented and appropriately managed to prevent harm and limit its contribution to poor treatment-adherence 4. Patients can benefit from TDM in specific situations for specific drugs using resource-and setting-appropriate assays 5. Each patient should undergo counselling/health education regarding their TB treatment and potential adverse effects to improve treatment results, organised according to feasibility and cost-effectiveness criteria, based on the local organisation of health services and tailored to the individual patient’s needs 6. Education for healthcare professionals is important when applying tailored dosing to better understand the link between clinical condition and drug exposure. Additional technical education is required when TDM is used to ensure the quality of the procedure; this includes sampling requirements, drug exposure targets and how to adjust the dose based on drug concentrations The University of Sydney DOI: 10.5588/ijtld.22.0188 Management of adverse effects during treatment for TB 1. Be counselled regarding AE before and during treatment for TB. 2. Be evaluated for factors that might increase AE risk with regular review to actively identify and manage these. 3. When AE occur, be carefully assessed and possible allergic or hypersensitivity reactions considered. 4. Receive appropriate care to minimise the morbidity and mortality associated with AE. 5. Be restarted on TB drugs after a serious AE according to a standardised protocol that includes active drug safety monitoring 6. Healthcare workers should be trained on AE including how to counsel people undertaking TB treatment, as well as active AE monitoring and management. 7. There should be active AE monitoring and reporting for all new TB drugs and regimens. 8. Knowledge gaps identified from active AE monitoring should be systematically addressed through clinical research The University of Sydney DOI: 10.5588/ijtld.23.0078 Risk factors for side effect Better understanding of “who is at risk” helps clinicians and pharmacists to provide better care for patients The University of Sydney  aDSM details Pharmacovigilance: Active tuberculosis drug-safety monitoring and management (aDSM) - System for - Detection - Management - Reporting of presumed or confirmed AE - Not only new TB drugs, but also novel regimens. - By prospectively using agreed monitoring strategies, findings from different countries can be easily interpreted and data aggregated, allowing for a timely international/global response to observed and reported AE. - Findings from the analysis could result in immediate safety warnings or prompt alertness for specific AE. The University of Sydney Therapeutic drug monitoring Blood saliva urine TDM provides the opportunity to make informed decisions on the drug dose to improve either the efficacy or reduce the toxicity of the treatment using an appropriately collected and measured sample (blood, saliva, urine) in an individual patient. The University of Sydney  When thinking of TDM for.. Potential altered drug exposure in patients with: - inadequate response despite adherence despite proven drug susceptibility - potential malabsorption - co-morbidities - drug-interactions - toxicity Which type of sample? The University of Sydney Nahid et al CID 2016, Nahid et al AJRCCM 2019, vd Burgt et al ERJ 2016 TDM strategies Type of sample samples Quality C2 1  C2 + C6 2  Limited sampling 1-3   Short AUC 4-6   Full AUC 8-12   The University of Sydney Why C2 is not appropriate for most drugs.. 12/55 patients had rifampicin Cmax at 2h after intake - C2 does not correlate with response in most studies while Cmax does. - Cmax can only be measured when collection a larger number of samples The University of Sydney Sturkenboom et al AAC 2015 Why C2-C6 can be appropriate… C2>C6 C2=C6 C2