Linezolid Pharmacokinetics and Its Association with Adverse Drug Reactions in Patients with Drug-Resistant Pulmonary Tuberculosis

Abstract

We evaluated the relationship between the pharmacokinetic parameters of linezolid (LZD) and development of adverse drug reactions (ADRs) in patients with pulmonary drug-resistant tuberculosis. A prospective cohort of adults with pulmonary multidrug-resistant tuberculosis with additional resistance to fluoroquinolone (MDR-TBFQ+) received treatment with bedaquiline, delamanid, clofazimine, and LZD. Blood samples were collected during weeks 8 and 16 at eight time points over 24 h. The pharmacokinetic parameters of LZD were measured using high-performance liquid chromatography and associated with ADRs. Of the 165 MDR-TBFQ+ patients on treatment, 78 patients developed LZD-associated anemia and 69 developed peripheral neuropathy. Twenty-three patients underwent intense pharmacokinetic testing. Plasma median trough concentration was 2.08 µg/mL and 3.41 µg/mL, (normal <2 µg/mL) and AUC0-24 was 184.5 µg/h/mL and 240.5 µg/h/mL at weeks 8 and 16, respectively, showing a linear relationship between duration of intake and plasma levels. Nineteen patients showed LZD-associated ADRs-nine at week 8, twelve at week 16, and two at both weeks 8 and 16. Thirteen of the nineteen had high plasma trough and peak concentrations of LZD. A strong association between LZD-associated ADRs and plasma LZD levels was noted. Trough concentration alone or combinations of trough with peak levels are potential targets for therapeutic drug monitoring.

Prolonged use of linezolid in bone and joint infections: a retrospective analysis of adverse effects

“…The risk for neuropathy is increased after prolonged use and has been reported primarily in patients treated for TB with a linezolid-based regimen for 6 to 12 months or longer. 9 Toxic optic neuritis is reversible in most cases, but recovery may take weeks to months, while peripheral neuropathy is sometimes irreversible. 10 , 11 Previous studies have provided little detailed information on the tolerability of linezolid when used for the limited duration of 4 to 12 weeks.…”

Molecular mechanisms of resistance and treatment efficacy of clofazimine and bedaquiline against Mycobacterium tuberculosis

“…Indeed, numerous clinical studies confirm that the strong bactericidal and sterilizing activity of BDQ-containing regimen originally found in mouse models of TB (123,124). BDQ has demonstrated potent clinical activity against MDR-and XDR-TB complex strains (27,118,121,122). Importantly, BDQ-containing treatment regimens have showed improved outcomes rate over SLIDcontaining regimens for the treatment of patients with RR-/MDR-TB (120).…”

“…CFZ, a riminophenazine antibiotic, was initially discovered in Dublin in the 1950s' and used in the treatment of leprosy caused by M. leprae (24,25). CFZ possesses both anti-inflammatory, pro-oxidative, and anti-mycobacterial properties (26,27). Recently, this drug has gained attention once more as a substitute for treating Mtb infections (24,28).…”

“…The BDQ, an anti-TB drug, has been approved for the treatment of MDR-TB, and recommended for 24 weeks duration (11). Most of the BDQ-containing treatment studies conducted in different countries, i.e., France, Armenia, Georgia, Congo, South Africa, China, Nigeria, India etc., have demonstrated great therapeutic success (the total of cure and treatment completed) rates between 58.5 and 93.5% (Table 3) (11,12,14,15,27,(113)(114)(115)(116)(117)(118)(119)(120)(121)(122).…”

Therapie bei MDR-, prä-XDR-, XDR-Tuberkulose und Rifampicin-Resistenz oder bei Medikamentenunverträglichkeit gegenüber mindestens Rifampicin

“…▪ Leukopeniebei Abnahme der absoluten Neutrophilenzahl (ANC) auf weniger als 0,75 × 10 Wochen nach Beginn der Linezolid-Einnahme und Dosisreduktion bei 10 %igem Abfall der Hämoglobinwerte sowie engmaschige Überwachung von Neuropathiesymptomen [23]. Die Messung der Linezolid-Talspiegel wird ebenfalls zur Therapieüberwachung evaluiert [24].…”