Linezolid pharmacokinetics affected by age and weight in patients with drug-resistant tuberculosis
11 Jan 2019 - 10:00
The oxazolidinone antibiotic linezolid significantly improves treatment outcomes in patients with multi- and extensively-drug-resistant tuberculosis (MDR- and XDR-TB), and is now prioritised in treatment of these infections. However, the optimal linezolid dosing strategy is unclear: its use is frequently limited by dose- and duration-related toxicity.
CIDRI-Africa team members Sean Wasserman, Siphokazi Hlungulu, Graeme Meintjes and Gary Maartens, along with colleagues from Albert Einstein College of Medicine, Stellenbosch University, Emory University, and other divisions at the University of Cape Town, set out to address this knowledge gap.
The team conducted a prospective observational pharmacokinetic/pharmacodynamic (PK/PD) study of linezolid in adult South African DR-TB patients. Drug resistant TB is a serious condition—in 2017 an estimated 14 000 South Africans developed DR-TB, which is frequently fatal. TB is also a very common HIV-associated infection in South Africa; the potential for drug-drug interactions in cases of co-infection must be considered.
Patients who were already taking linezolid volunteered to provide blood samples before and at intervals after a dose of the antibiotic. Linezolid concentrations in the blood samples were then measured. Mycobacterium tuberculosis samples were also provided by sixteen patients; these were tested to determine the minimum linezolid concentration that would inhibit growth of the bacteria.
Analysis of the results showed that HIV status and use of the antiretroviral drug combination lopinavir-ritonavir did not appear to influence the blood concentration of linezolid.
Notably, the team found that patients who were older or had a lower body weight did not clear linezolid from their blood as quickly as younger, heavier patients. This failure of clearance could have negative consequences such as toxicity, since these patients are effectively exposed to a higher dose for a longer period of time.
Standard linezolid dosing of 600mg daily attained the efficacy PK target in only 60% of patients at the critical concentration for M. tuberculosis, suggesting that higher doses may be needed for more resistant infections. Although targets were achieved for less resistant infections, the toxicity threshold was exceeded in over half of patients. These findings illustrate the narrow therapeutic window of linezolid and support the use of therapeutic drug monitoring.
This information contributes to a growing body of knowledge on linezolid pharmacokinetics, and suggests that alternative dosing strategies and therapeutic drug monitoring are important strategies for optimising the use of this antibiotic.
Wasserman S, Denti P, Brust JCM, Tareq M, Hlungulu S, Wiesner L, Norman J, Sirgel FA, Warren RM, Esmail A, Dheda K, Gandhi NR, Meintjes G, Maartens G. Linezolid pharmacokinetics in South African patients with drug resistant tuberculosis and a high prevalence of HIV co-infection. Antimicrobial Agents and Chemotherapy. (2019): AAC.02164-18.
 World Health Organisation. Global Tuberculosis Report 2018. Geneva; 2018.