Drug concentration in lung tissue in multidrug-resistant tuberculosis
Authors: Onno W. Akkerman, Richard van Altena, Theo Klinkenberg, Adrienne H. Brouwers, Alphons H.H. Bongaerts, Tjip S. van der Werf, Jan-Willem Alffenaar
Journal: European Respiratory Journal (2013)

Drug concentration in lung tissue in multidrug-resistant tuberculosisTo the Editor:Multidrug-resistant tuberculosis (MDR-TB) is emerging worldwide, with 3.7% of new cases and 20% of previously treated tuberculosis (TB) cases having MDR-TB.Unfortunately, second-line TB drugs, used for MDR-TB treatment, are less effective than first-line drugs [1].Sputum culture rather than sputum smear microscopy is recommended to monitor treatment response [1].Therapeutic drug monitoring (TDM), which may help optimise efficacy and minimise side-effects with the potential to safeguard intestinal absorption of drugs [2], is currently not recommended in World Health Organization (WHO) treatment guidelines [1].Although TDM yields information on serum drug concentrations, penetration of second-line TB drugs into diseased tissues such as destroyed lung tissue has, to our knowledge, not been addressed in studies [3].Herein, we report simultaneous blood and tissue concentrations of second-line TB drugs in lung tissue destroyed by MDR-TB.A 13-year-old Somalian, HIV sero-negative female, residing in the Netherlands since 2010, was admitted to our TB Unit (TB Center Beatrixoord, University Medical Center Groningen, Groningen, the Netherlands) in September 2011 with a 3-month history of cough, fever, chest pain and unintentional 14 kg weight loss.TB contacts were denied and she had not received a bacilli Calmette-Gue ´rin vaccination.Apart from almost absent breathe sounds and dullness to percussion over the left lung field her physical examination was normal.Chest radiography showed infiltrates in the left lung, particularly in the left upper lobe.Sputum microscopy revealed acid-fast bacilli, and she was started on TB treatment with isoniazid, rifampicin, pyrazinamide and ethambutol. 2 weeks later, molecular diagnostic tests revealed mutations in both the katG and rpoB genes.MDR-TB was now considered and she was transferred to our hospital (University Medical Center Groningen).We changed her treatment to pyrazinamide, ethambutol, kanamycin and moxifloxacin [4].Drug susceptibility testing (DST) by the National Tuberculosis Reference Laboratory showed resistance to all first-line drugs, as well as protionamide.The isolate appeared susceptible to co-amoxiclav, amikacin, capreomycin, moxifloxacin and linezolid, as well as ertapenem and co-trimoxazole [5].We started her on linezolid and ertapenem to replace ethambutol and pyrazinamide.Trough drug concentrations, part of TDM, as routinely performed in our centre, were 0.5 mg?L -1 and 0.5 mg?L -1 for linezolid and moxifloxacin, respectively.The minimal inhibitory concentrations for linezolid and moxifloxacin were 0.25 mg?L -1 and 0.125 mg?L -1 , respectively (D. van Soolingen, National Tuberculosis Reference Laboratory, National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands; personal communication).The area under the concentration-time curve (AUC) 0-24 for linezolid and moxifloxacin were 74.90 mg?h -1 ?L -1 and 30.04 mg?h -1 ?L -1 , respectively.As these AUCs were adequate, no dose adjustment of either drug was performed.