Speaker's Highlight

• Don Sin University of British Columbia, St. Paul Hospital (Canada)
  Kenneth R. Chapman Toronto General Hospital Research Institute (Canada)
• Parameswaran Nair McMaster University (Canada)
  Carolyn Calfee UCSF (U.S.A.)
• Gregory P. Downey University of Colorado School of Medicine (U.S.A.)
  David A. Schwartz University of Colorado School of Medicine (U.S.A.)
• Neil Schluger Tuberculosis Control Branch, California Department of Public Health (U.S.A.)
  Nick Kim Critical Care & Sleep Medicine, University of California San Diego (U.S.A.)
• Nicola Hananiah Baylor College of Medicine (U.S.A.)
  Jae-Joon Yim Seoul National University College of Medicine (Republic of Korea)
• Koichiro Asano Tokai University School of Medicine (Japan)
  Diahn-Warng Perng Taipei Veterans General Hospital (Taiwan)
• Konstantinos Kostikas University of Ioannina (Greece)
  Karin Klooster University Medical Center Groningen (Kingdom of the Netherlands)

• Therapeutic drug monitoring for anti-tuberculosis agents

  Therapeutic drug monitoring (TDM) involves measuring the concentration of medicines in patient serum or plasma to tailor dosing to the individual. In tuberculosis management, where treatment regimens rely on prolonged courses of multiple agents, TDM provides an evidence-based pathway to ensure adequate drug exposure. The concept aligns with broader moves in respiratory medicine toward personalised therapy, where fixed doses are increasingly seen as inadequate for many patients.

  Anti-tuberculosis drugs such as isoniazid, rifampicin, pyrazinamide and ethambutol show wide interpatient pharmacokinetic variability, influenced by genetics, body composition, comorbidities and adherence. Australian clinicians managing complex cases, from Aboriginal and Torres Strait Islander communities in remote Northern Territory settings to recently arrived migrants in Sydney and Melbourne, frequently encounter situations where standard World Health Organization dosing falls short. TDM offers a practical bridge between population-based protocols and individual patient needs.

  Clinical rationale for monitoring anti-TB drug levels

  The core justification for TDM in tuberculosis is the poor correlation between administered dose and the resulting drug exposure at the site of infection. Rifampicin exhibits up to five-fold variability in plasma concentrations among adults receiving identical weight-based doses. Subtherapeutic exposure is linked to slower sputum conversion, treatment failure and the emergence of drug resistance, including multi-drug resistant TB (MDR-TB). Conversely, supratherapeutic levels of pyrazinamide and ethambutol can produce hepatotoxicity and ocular toxicity respectively, complicating otherwise effective regimens.

  TDM is particularly relevant when treatment failure occurs despite documented adherence, when drug interactions are suspected, or when malabsorption is plausible. Patients living with HIV, those with diabetes mellitus, and individuals with gastrointestinal disease often absorb anti-tuberculosis medications unpredictably. In Australia, where TB incidence is low overall but concentrated in specific populations, careful use of TDM helps preserve the effectiveness of first-line agents in settings where treatment failure carries outsized public health consequences.

  Pharmacokinetic variability across populations

  Several physiological and genetic factors influence anti-TB drug pharmacokinetics. Isoniazid metabolism is governed by N-acetyltransferase 2 (NAT2) polymorphism, producing slow, intermediate and rapid acetylator phenotypes. Australians of European, Asian and Indigenous descent show different distributions of these phenotypes, meaning a "standard" 5 mg/kg dose produces markedly different serum concentrations across patients. Similar variability affects rifampicin exposure through hepatic enzyme induction and gastrointestinal absorption.

  Body weight composition, nutritional status and pregnancy each alter drug distribution. In Australia's multicultural population, clinicians frequently manage patients from high-burden regions including Papua New Guinea, the Philippines, India and Vietnam, where background rates of malnutrition and latent infection differ from the host country average. Pharmacokinetic studies in these groups consistently show that weight-based dosing alone is insufficient, supporting routine consideration of TDM in complex presentations.

  Sampling strategies and laboratory methods

  The most widely used sampling approach for anti-tuberculosis agents is the two-hour post-dose serum concentration, which approximates the peak level (Cmax) and reflects drug absorption. Some protocols also collect a three-hour sample or a trough level to better characterise the concentration-time curve. For rifampicin, a Cmax target of 8–24 mg/L is commonly cited, while isoniazid efficacy correlates with levels above 3 mg/L in rapid acetylators.

  Australian laboratories capable of performing anti-TB drug assays include specialised units at major tertiary hospitals in Sydney, Melbourne and Brisbane, often using liquid chromatography-mass spectrometry (LC-MS/MS). Sample handling is critical, as rifampicin degrades rapidly in heat; timely processing and cold-chain transport are essential. Where local access is limited, clinicians can arrange referral through state tuberculosis control programmes, ensuring results inform dose adjustments within a clinically relevant timeframe.

  Interpretation requires clinical context. A "low" peak level should prompt assessment of adherence, timing of blood draw relative to dose, and concurrent medications such as antacids or proton pump inhibitors that impair absorption. Dose increases should generally not exceed 50 percent increments, and repeat measurement after each change is recommended.

  Practical application in Australian clinical settings

  In metropolitan referral centres such as Royal Prince Alfred Hospital in Sydney and the Royal Melbourne Hospital, TDM is integrated into complex TB management pathways. Cases referred for monitoring typically include patients with smear-positive disease after two months of therapy, those with MDR-TB requiring second-line agents like linezolid or levofloxacin, and individuals on concomitant antiretroviral or antifungal therapy where drug interactions are predictable.

  Rural and remote services, including clinics serving Aboriginal communities in the Kimberley and Central Australia, face logistical challenges in sample collection and transport. Programs supported by the National Tuberculosis Advisory Committee and state health departments have developed referral pathways linking remote services to metropolitan laboratories. Therapeutic Guidelines: Antibiotic provides Australian clinicians with locally endorsed thresholds, although individualised targets often supersede general recommendations.

  Cost considerations are relevant in the Australian private and public sectors. TDM assays are not universally reimbursed under the Medicare Benefits Schedule for anti-tuberculosis indications, so institutional funding and public health programme support often determine access. Early involvement of infectious diseases pharmacists helps justify testing and integrate results into multidisciplinary case discussions.

  Comparing pharmacokinetic targets for first-line agents

  The table below summarises commonly referenced serum concentration targets and timing for first-line oral anti-tuberculosis drugs in adult patients. Values are derived from international literature and Therapeutic Guidelines Australia, with adjustments often made for clinical context.

  Drug	Standard adult dose	Target Cmax (mg/L)	Sampling time	Toxicity threshold consideration
  Isoniazid	5 mg/kg (max 300 mg)	3–6	2 hours post-dose	Peripheral neuropathy risk above 10 mg/L
  Rifampicin	10 mg/kg (max 600 mg)	8–24	2 hours post-dose	Hepatotoxicity rises with higher levels
  Pyrazinamide	25 mg/kg (max 2000 mg)	20–60	2 hours post-dose	Arthralgia, hyperuricaemia
  Ethambutol	15–20 mg/kg	2–6	2–3 hours post-dose	Ocular toxicity above 10 mg/L

  Recommendations for clinicians considering TDM

  Routine TDM is not necessary for every patient undergoing standard TB treatment, but selected scenarios benefit from targeted measurement. Practical recommendations for Australian clinicians include:

  • Consider TDM in patients with persistently positive sputum cultures after two months of directly observed therapy, particularly when adherence is confirmed.
  • Request two-hour post-dose serum levels for isoniazid, rifampicin and pyrazinamide when drug interactions, malabsorption or treatment failure is suspected.
  • Engage infectious diseases pharmacists early to coordinate sample handling, especially for remote patients requiring interstate transport to reference laboratories.
  • Use Therapeutic Guidelines Australia and local expert consensus to interpret results, adjusting doses by 25–50 percent rather than discontinuing agents unnecessarily.
  • Document the rationale for TDM, results and subsequent dose changes clearly to support continuity of care across primary, secondary and tertiary providers.

  Routine use of standard doses will continue to underpin tuberculosis control programmes, but the limitations of weight-based protocols are increasingly recognised in settings of complex pharmacokinetics. Embedding therapeutic drug monitoring within Australian TB services, supported by accessible reference laboratories, clear referral pathways and multidisciplinary review, offers a pragmatic path toward more effective individualised care without compromising the efficiency gains of population-based treatment strategies.

  Richard Russell Nuffield Department of Clinical Medicine, University of Oxford (United Kingdom)
• Mona Bafadhel King’s College London (United Kingdom)
  David Jackson Guy’s and St Thomas’ Hospital, King’s College London (United Kingdom)
• James Chalmers University of Dundee (United Kingdom)
  David Price University of Aberdeen (United Kingdom)