Akkerman, Onno W

Alffenaar, Jan-Willem C

Bolhuis, Mathieu S

de Lange, Wiel C M

Kerstjens, Huib A M

van der Werf, Tjip S

English

University of Groningen

   University of GroningenTreatment of multidrug-resistant tuberculosis using therapeutic drug monitoringBolhuis, Mathieu S; van der Werf, Tjip S; Kerstjens, Huib A M; de Lange, Wiel C M; Alffenaar,Jan-Willem C; Akkerman, Onno WPublished in:European Respiratory JournalDOI:10.1183/13993003.00580-2019IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionFinal author's version (accepted by publisher, after peer review)Publication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Bolhuis, M. S., van der Werf, T. S., Kerstjens, H. A. M., de Lange, W. C. M., Alffenaar, J-W. C., &Akkerman, O. W. (2019). Treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring:first experiences with sub-300 mg linezolid dosages using in-house made capsules. European RespiratoryJournal, 54(6), [1900580]. https://doi.org/10.1183/13993003.00580-2019CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 26-12-2020      Early View    Research letter    Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules   Mathieu S. Bolhuis, Tjip S. van der Werf, Huib A.M. Kerstjens, Wiel C.M. de Lange, Jan-Willem C. Alffenaar, Onno W. Akkerman    Please cite this article as: Bolhuis MS, van der Werf TS, Kerstjens HAM, et al. Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules. Eur Respir J 2019; in press (https://doi.org/10.1183/13993003.00580-2019).       This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online.    Copyright ©ERS 2019 Research letter ERJ Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules Mathieu S. Bolhuis1, Tjip S. van der Werf2,3, Huib A.M. Kerstjens2,4, Wiel C.M. de Lange2,4, Jan-Willem C. Alffenaar1,5, Onno W. Akkerman2,4 1University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands 2University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands. 3University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands. 4University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands. 5Sydney School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, Australia   Corresponding author: Mathieu S. Bolhuis, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Phone: +31 50 3614071, Fax: +31 50 3614087, e-mail :m.s.bolhuis@umcg.nl.    Funding: no funding was obtained for this research. Take home message: Therapeutic drug monitoring allows for sub-300 mg linezolid dosages once daily to successfully achieve PK/PD targets. Let’s confirm these retrospective data in a prospective study using dried blood spots.    Despite all our efforts, the disease burden of tuberculosis (TB) is not falling fast enough to reach the 2030 milestone of the End TB strategy [1]. Multidrug-resistant tuberculosis (MDR-TB) remains a public health crisis, with low treatment success rates [1]. The repurposed drug linezolid has  emerged as a core drug in MDR-TB treatment regimens [2,3], despite its toxicity, e.g. anemia, peripheral neuropathy and gastrointestinal disorders, optic neuritis, and thrombocytopenia [4,5].  Currently, linezolid is used off-label, as part of Group A “Medicines to be prioritised” of the World Health Organization MDR-TB treatment guideline [2] and in several large trials [6], such as the NIX- TB and END-TB trials. We use a holistic approach to treat MDR-TB, focusing multidisciplinarily on optimizing treatment using pharmacokinetics (PK) and pharmacodynamics, assessing and optimizing nutritional status, providing physical therapy and social care [7]. Treatment regimens are based on the WHO guidelines, but are individualized based on drug susceptibility testing (DST) combined with TDM if the regimen consists of second-line drugs or if patients are at risk for PK variability [8]. DST is performed at Dutch National Mycobacterial Reference Laboratory (RIVM, Bilthoven, The Netherlands).  Most patients start on a dose of 600 mg linezolid once daily. After two weeks, a full pharmacokinetic curve is obtained for all patients that receive linezolid, after which the dosage is lowered to 300 mg once daily. At steady state, the lowered dosage is again checked with TDM. Based on limited available literature, we strive for an area under the time – total fraction concentration curve (AUC0-24h) / minimum inhibitory concentration (MIC) ratio >100 [9]. If TDM allows, the dose of linezolid is reduced further to an optimal, lowest dose, with the aim to reduce toxicity of linezolid [4,5,10]. If the totalAUC0-24h/MIC ratio of linezolid is high enough, a dose reduction to 200 or even 150 mg of linezolid once daily is considered. In this study, we describe the first experiences of the treatment of MDR-TB using sub-300 mg dosages. We retrospectively searched for inpatients for whom linezolid PK data was collected between 2015-2018. As routine treatment data were collected retrospectively and anonymously, the Institutional Ethical Review Board waived the requirement to obtain informed consent (METc 2013/492). Patients that received a sub-300 mg dose of linezolid were included. Baseline characteristics co-morbidities (HIV/HBV/HCV/diabetes), MIC for linezolid, treatment regimen, and treatment outcome, were obtained from the electronic hospital record and the discharge letter from the treating lung physician.  Twenty-seven patients with linezolid pharmacokinetic data were identified. Of these patients, 18 (66%) had a final dose ≥300 mg linezolid once daily. Nine (34%) patients received a sub-300 mg dose of linezolid and were included in our study (see Table 1). These patients had a median (range) weight of 55 (43-77) kg. At admission, patients had a median (range) leucocyte count 6.6 (4.6-10.8) *109/L, thrombocytes 324 (238-461) *109/L, and hemoglobin 13.2 (11.8-16.3) g/dL. At admission, one of the patients was 32 weeks pregnant. Based on local policy, the individual patient and her preferences, it was decided – in contrast with standard practice – that the start of treatment of MDR-TB could be postponed until the patient gave birth to a healthy child. Four patients had pulmonary TB, two had extra-pulmonary TB, one had miliary TB, one had pleural TB, and one had a combination of pulmonary and extra-pulmonary TB. DST revealed that eight patients had MDR-TB and one had rifampin resistant TB. The MIC for linezolid of the Mycobacterium tuberculosis isolate was 0.25 mg/L for seven patients and 0.5 mg/L for two patients. Based on the available totalAUC0-24h/MIC ratios, dosages were lowered to 200 mg once daily in four (15%) patients and 150 mg in five (19%) patients.  The sub-300 mg dosages of linezolid are prepared as capsules at the compounding department of our pharmacy. Commercially available linezolid tablets are pulverized and sieved. Lactose-1-water is used to create the correct volume of the homogenized powder mixture, after which transparent empty capsules are filled. All capsules are checked visually and ten capsules are checked for the correct weight and percentage of deviation (≤3%) from the correct weight. The capsules are kept at room temperature for a maximum of one year.  With the sub-300 mg dosages of linezolid, the patients had a median (range) totalAUC0-24h of 50 (49-57) mg*h/L. In three cases, there was no AUC0-24h available for the lowest dose due to logistical issues. In these cases, the totalAUC0-24h of the lowest dose was calculated using our linezolid pharmacokinetic model [11] in MWPharm++ (Mediware, Groningen, the Netherlands). The median (range) totalAUC/MIC ratio was 196 (98-276), with all except one patient attaining the target of 100 that is used in our clinic, based on a systematic review of literature [12]. Since the AUC/MIC ratio of that patient was 98, we did not increase the dose.  As soon as the patients  received and tolerated their tailor-made regimen, treatment was continued at home. The included patients finished their treatment as outpatients under supervision of the staff of our center. At discharge, patients had a median (range) leucocyte count 4.7 (3.7-7.3) *109/L, thrombocytes 270 (159-327) *109/L, and hemoglobin 13.7 (11.1-16.4) g/dL. None of the patients had significant adverse events or toxicity from the linezolid dosages they received. Despite the fact that we cannot draw any conclusions about the safety or efficacy of our approach, after discharge, all except one patient (lost to follow-up) finished their treatment regimens successfully. This study describes the treatment of TB with linezolid dosages lower than 300 mg. Linezolid is known for its side effects, with a meta-analysis showing adverse events in 58.9% of patients with linezolid containing regimens to treat MDR-TB [4]. Higher dosages of linezolid (i.e. >600mg) show more side effects than lower dosages (i.e. between 300-600mg) [4,5]. In our study, in nine out of 27 patients, TDM combined with DST allowed for lowering the linezolid dosage to 200 mg or 150 mg once daily, thereby possibly limiting the number of side effects even further.  Obviously, there are limitations to this study, such as the small number of patients, missing data, and the retrospective character of the study. We do not yet have long term follow-up data, although so far no relapses occurred. We only performed PK analysis of blood samples, not of the affected tissue [13,14]. Also, the applicability of this study to low-income countries, where MDR-TB is most prevalent, might be limited. For instance, a compounding unit in a pharmacy that is able to produce linezolid capsules might not be readily available. In these cases, one could perhaps consider using quarter tablets of 600 mg linezolid (or 300 mg every two days) to administer 150 mg once daily, however one must then make sure splitting is done in a correct and safe manner. We have not studied the bioequivalence of our capsules. However, since the absorption of linezolid is usually fast and complete, PK of linezolid is non-linear, and we performed TDM, we do not expect this to impact the treatment outcome. Furthermore, TDM is not available everywhere, but dried blood spots (DBS) [15] combined with limited sampling methods [11] might allow for this strategy to be implemented in other settings. There is still an ongoing discussion on the most appropriate PK/PD target for linezolid. In our clinic, we use an AUC/MIC target of > 100 using the total fraction concentration of linezolid, based on a recent manuscript as a part of a WHO initiative to systematically review the current recommended dose for second-line TB drugs [12]. In future research, besides applicability and implementation of TDM in low-income countries, cost-benefit should also be studied. By administering lower dosages of linezolid in patients if the AUC0-24h and MIC allows, drug costs per patient of this rather expensive drug is reduced. Finally, lower dosing might reduce dose-related toxicity allowing treatment for a prolonged period of time [16].  In conclusion, sub-300 mg doses of linezolid can achieve putative PK/PD targets in certain patients. A large prospective study with DBS might provide us with valuable information on the possibilities to implement this strategy in other settings.   Table 1 baseline characteristics and pharmacokinetic/pharmacodynamic results patients receiving sub-300mg dosages of linezolid as a part of their tuberculosis treatment regimens Parameter Value Subjects 9 Age (years) 27 (17-55) Male 4 (44%) Weight (kg) 55 (43-77) Height (m) 1.65 (1.55-1.88) Body mass index (kg/m2) 20.5 (16.2-24.1) Continent of origin   Asia 4 (44%)  Europe 4 (44%)  Africa 1 (12%) HIV, Hepatitis B or C positive 0/7   Drug susceptibility   Multidrug-resistant 8  Rifampicin-resistant 1 Treatment regimen   Linezolid 9/9  Moxifloxacin 9/9  Amikacin 8/9  Ethambutol 8/9  Clofazimine 6/9  Pyrazinamide 5/9  Protionamide 2/9  (High dose) isoniazid 2/9  Cycloserin 1/9   Linezolid  Lowest dose (once daily)   200 mg  4 (44%)  150 mg 5 (56%) Dose per kg body weight (mg/kg) 3.1 (2.0-4.7) totalAUC0-24h (mg*h/L) Cmin (mg/L) 50 (35-73) 0.5 (0.3-1.2) MIClinezolid   0.25 mg/L 7 (78%)  0.5 mg/L 2 (22%) totalAUC0-24h/MIC 196 (98-276) All data are presented as median (range) or number (percentage); linezolid cocentrations are presented as total fraction concentrations (e.g. totalAUC); HIV: human immunodeficiency virus; weight, height, and body mass index were collected at admission; MIC: minimum inhibitory concentration; totalAUC: area under the time concentration curve.    References 1. World Health Organization (WHO). Global Tuberculosis Report 2018. 2018; WHO/CDS/TB/2018.20. 2. World Health Organization (WHO). Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) . WHO/CDS/TB/2018 18 August 2018. 3. Caminero JA, Piubello A, Scardigli A, Migliori GB. Proposal for a standardised treatment regimen to manage pre- and extensively drug-resistant tuberculosis cases. Eur Respir J 2017; 50: 10.1183/13993003.00648-2017. Print 2017 Jul. 4. Sotgiu G, Centis R, D'Ambrosio L, Alffenaar J, Anger H, Caminero J, Castiglia P, De Lorenzo S, Ferrara G, Koh W, Schecter G, Shim T, Singla R, Skrahina A, Spanevello A, Udwadia Z, Villar M, Zampogna E, Zellweger J, Zumla A, Migliori GB. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J 2012. 5. De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D'Ambrosio L, Tiberi S, Bolhuis MS, van Altena R, Viggiani P, Piana A, Spanevello A, Migliori GB. Efficacy and safety of meropenem/clavunate added to linezolid containing regimens in the treatment of M/XDR-TB. Eur Respir J 2012. 6. Borisov SE, Dheda K, Enwerem M, Romero Leyet R, D'Ambrosio L, Centis R, Sotgiu G, Tiberi S, Alffenaar JW, Maryandyshev A, Belilovski E, Ganatra S, Skrahina A, Akkerman O, Aleksa A, Amale R, Artsukevich J, Bruchfeld J, Caminero JA, Carpena Martinez I, Codecasa L, Dalcolmo M, Denholm J, Douglas P, Duarte R, Esmail A, Fadul M, Filippov A, Davies Forsman L, Gaga M, Garcia-Fuertes JA, Garcia-Garcia JM, Gualano G, Jonsson J, Kunst H, Lau JS, Lazaro Mastrapa B, Teran Troya JL, Manga S, Manika K, Gonzalez Montaner P, Mullerpattan J, Oelofse S, Ortelli M, Palmero DJ, Palmieri F, Papalia A, Papavasileiou A, Payen MC, Pontali E, Robalo Cordeiro C, Saderi L, Sadutshang TD, Sanukevich T, Solodovnikova V, Spanevello A, Topgyal S, Toscanini F, Tramontana AR, Udwadia ZF, Viggiani P, White V, Zumla A, Migliori GB. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J 2017; 49: 10.1183/13993003.00387-2017. Print 2017 May. 7. Akkerman OW, Grasmeijer F, de Lange WCM, Kerstjens HAM, de Vries G, Bolhuis MS, Alffenaar JW, Frijlink HW, Smith G, Gajraj R, de Zwaan R, Hagedoorn P, Dedicoat M, van Soolingen D, van der Werf TS. Cross border, highly individualised treatment of a patient with challenging extensively drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02490-2017. Print 2018 Mar. 8. Van Kampenhout E, Bolhuis MS, Alffenaar JC, Oswald LM, Kerstjens HA, de Lange WC, van der Werf TS, Akkerman OW. Pharmacokinetics of moxifloxacin and linezolid during and after pregnancy in a patient with multidrug-resistant tuberculosis. Eur Respir J 2017; 49: 10.1183/13993003.01724-2016. Print 2017 Mar. 9. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 10. Yew WW, Chan DP, Leung CC, Zhang Y, Wang R, Ng P, Lee SM. Can toxicities induced by antituberculosis drugs be better managed in diabetic patients? Eur Respir J 2017; 50: 10.1183/13993003.00409-2017. Print 2017 Jul. 11. Kamp J, Bolhuis MS, Tiberi S, Akkerman OW, Centis R, de Lange WC, Kosterink JG, van der Werf TS, Migliori GB, Alffenaar JC. Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis. Int J Antimicrob Agents 2017; 49: 688-694. 12. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 13. Akkerman OW, van Altena R, Klinkenberg T, Brouwers AH, Bongaerts AH, van der Werf TS, Alffenaar JW. Drug concentration in lung tissue in multidrug-resistant tuberculosis. Eur Respir J 2013; 42: 1750-1752. 14. Kempker RR, Heinrichs MT, Nikolaishvili K, Sabulua I, Bablishvili N, Gogishvili S, Avaliani Z, Little BP, Bernheim A, Derendorf H, Blumberg HM, Vashakidze S, Peloquin CA. A comparison of linezolid lung tissue concentrations among patients with drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02166-2017. Print 2018 Feb. 15. Vu DH, Bolhuis MS, Koster RA, Greijdanus B, de Lange WC, van Altena R, Brouwers JR, Uges DR, Alffenaar JW. Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis. Antimicrob Agents Chemother 2012; 56: 5758-5763. 16. van Altena R, Akkerman OW, Alffenaar JC, Kerstjens HA, Magis-Escurra C, Boeree MJ, van Soolingen D, de Lange WC, Bolhuis MS, Hoefsloot W, de Vries G, van der Werf TS. Shorter treatment for multidrug-resistant tuberculosis: the good, the bad and the ugly. Eur Respir J 2016; 48: 1800-1802.   

Treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring:first experiences with sub-300 mg linezolid dosages using in-house made capsules

Dissertations of the University of Groningen

   University of GroningenTreatment of multidrug-resistant tuberculosis using therapeutic drug monitoringBolhuis, Mathieu S; van der Werf, Tjip S; Kerstjens, Huib A M; de Lange, Wiel C M; Alffenaar,Jan-Willem C; Akkerman, Onno WPublished in:European Respiratory JournalDOI:10.1183/13993003.00580-2019IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionFinal author's version (accepted by publisher, after peer review)Publication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Bolhuis, M. S., van der Werf, T. S., Kerstjens, H. A. M., de Lange, W. C. M., Alffenaar, J-W. C., &Akkerman, O. W. (2019). Treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring:first experiences with sub-300 mg linezolid dosages using in-house made capsules. European RespiratoryJournal, 54(6), Article 1900580. https://doi.org/10.1183/13993003.00580-2019CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 05-12-2023      Early View    Research letter    Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules   Mathieu S. Bolhuis, Tjip S. van der Werf, Huib A.M. Kerstjens, Wiel C.M. de Lange, Jan-Willem C. Alffenaar, Onno W. Akkerman    Please cite this article as: Bolhuis MS, van der Werf TS, Kerstjens HAM, et al. Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules. Eur Respir J 2019; in press (https://doi.org/10.1183/13993003.00580-2019).       This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online.    Copyright ©ERS 2019 Research letter ERJ Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules Mathieu S. Bolhuis1, Tjip S. van der Werf2,3, Huib A.M. Kerstjens2,4, Wiel C.M. de Lange2,4, Jan-Willem C. Alffenaar1,5, Onno W. Akkerman2,4 1University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands 2University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands. 3University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands. 4University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands. 5Sydney School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, Australia   Corresponding author: Mathieu S. Bolhuis, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Phone: +31 50 3614071, Fax: +31 50 3614087, e-mail :m.s.bolhuis@umcg.nl.    Funding: no funding was obtained for this research. Take home message: Therapeutic drug monitoring allows for sub-300 mg linezolid dosages once daily to successfully achieve PK/PD targets. Let’s confirm these retrospective data in a prospective study using dried blood spots.    Despite all our efforts, the disease burden of tuberculosis (TB) is not falling fast enough to reach the 2030 milestone of the End TB strategy [1]. Multidrug-resistant tuberculosis (MDR-TB) remains a public health crisis, with low treatment success rates [1]. The repurposed drug linezolid has  emerged as a core drug in MDR-TB treatment regimens [2,3], despite its toxicity, e.g. anemia, peripheral neuropathy and gastrointestinal disorders, optic neuritis, and thrombocytopenia [4,5].  Currently, linezolid is used off-label, as part of Group A “Medicines to be prioritised” of the World Health Organization MDR-TB treatment guideline [2] and in several large trials [6], such as the NIX- TB and END-TB trials. We use a holistic approach to treat MDR-TB, focusing multidisciplinarily on optimizing treatment using pharmacokinetics (PK) and pharmacodynamics, assessing and optimizing nutritional status, providing physical therapy and social care [7]. Treatment regimens are based on the WHO guidelines, but are individualized based on drug susceptibility testing (DST) combined with TDM if the regimen consists of second-line drugs or if patients are at risk for PK variability [8]. DST is performed at Dutch National Mycobacterial Reference Laboratory (RIVM, Bilthoven, The Netherlands).  Most patients start on a dose of 600 mg linezolid once daily. After two weeks, a full pharmacokinetic curve is obtained for all patients that receive linezolid, after which the dosage is lowered to 300 mg once daily. At steady state, the lowered dosage is again checked with TDM. Based on limited available literature, we strive for an area under the time – total fraction concentration curve (AUC0-24h) / minimum inhibitory concentration (MIC) ratio >100 [9]. If TDM allows, the dose of linezolid is reduced further to an optimal, lowest dose, with the aim to reduce toxicity of linezolid [4,5,10]. If the totalAUC0-24h/MIC ratio of linezolid is high enough, a dose reduction to 200 or even 150 mg of linezolid once daily is considered. In this study, we describe the first experiences of the treatment of MDR-TB using sub-300 mg dosages. We retrospectively searched for inpatients for whom linezolid PK data was collected between 2015-2018. As routine treatment data were collected retrospectively and anonymously, the Institutional Ethical Review Board waived the requirement to obtain informed consent (METc 2013/492). Patients that received a sub-300 mg dose of linezolid were included. Baseline characteristics co-morbidities (HIV/HBV/HCV/diabetes), MIC for linezolid, treatment regimen, and treatment outcome, were obtained from the electronic hospital record and the discharge letter from the treating lung physician.  Twenty-seven patients with linezolid pharmacokinetic data were identified. Of these patients, 18 (66%) had a final dose ≥300 mg linezolid once daily. Nine (34%) patients received a sub-300 mg dose of linezolid and were included in our study (see Table 1). These patients had a median (range) weight of 55 (43-77) kg. At admission, patients had a median (range) leucocyte count 6.6 (4.6-10.8) *109/L, thrombocytes 324 (238-461) *109/L, and hemoglobin 13.2 (11.8-16.3) g/dL. At admission, one of the patients was 32 weeks pregnant. Based on local policy, the individual patient and her preferences, it was decided – in contrast with standard practice – that the start of treatment of MDR-TB could be postponed until the patient gave birth to a healthy child. Four patients had pulmonary TB, two had extra-pulmonary TB, one had miliary TB, one had pleural TB, and one had a combination of pulmonary and extra-pulmonary TB. DST revealed that eight patients had MDR-TB and one had rifampin resistant TB. The MIC for linezolid of the Mycobacterium tuberculosis isolate was 0.25 mg/L for seven patients and 0.5 mg/L for two patients. Based on the available totalAUC0-24h/MIC ratios, dosages were lowered to 200 mg once daily in four (15%) patients and 150 mg in five (19%) patients.  The sub-300 mg dosages of linezolid are prepared as capsules at the compounding department of our pharmacy. Commercially available linezolid tablets are pulverized and sieved. Lactose-1-water is used to create the correct volume of the homogenized powder mixture, after which transparent empty capsules are filled. All capsules are checked visually and ten capsules are checked for the correct weight and percentage of deviation (≤3%) from the correct weight. The capsules are kept at room temperature for a maximum of one year.  With the sub-300 mg dosages of linezolid, the patients had a median (range) totalAUC0-24h of 50 (49-57) mg*h/L. In three cases, there was no AUC0-24h available for the lowest dose due to logistical issues. In these cases, the totalAUC0-24h of the lowest dose was calculated using our linezolid pharmacokinetic model [11] in MWPharm++ (Mediware, Groningen, the Netherlands). The median (range) totalAUC/MIC ratio was 196 (98-276), with all except one patient attaining the target of 100 that is used in our clinic, based on a systematic review of literature [12]. Since the AUC/MIC ratio of that patient was 98, we did not increase the dose.  As soon as the patients  received and tolerated their tailor-made regimen, treatment was continued at home. The included patients finished their treatment as outpatients under supervision of the staff of our center. At discharge, patients had a median (range) leucocyte count 4.7 (3.7-7.3) *109/L, thrombocytes 270 (159-327) *109/L, and hemoglobin 13.7 (11.1-16.4) g/dL. None of the patients had significant adverse events or toxicity from the linezolid dosages they received. Despite the fact that we cannot draw any conclusions about the safety or efficacy of our approach, after discharge, all except one patient (lost to follow-up) finished their treatment regimens successfully. This study describes the treatment of TB with linezolid dosages lower than 300 mg. Linezolid is known for its side effects, with a meta-analysis showing adverse events in 58.9% of patients with linezolid containing regimens to treat MDR-TB [4]. Higher dosages of linezolid (i.e. >600mg) show more side effects than lower dosages (i.e. between 300-600mg) [4,5]. In our study, in nine out of 27 patients, TDM combined with DST allowed for lowering the linezolid dosage to 200 mg or 150 mg once daily, thereby possibly limiting the number of side effects even further.  Obviously, there are limitations to this study, such as the small number of patients, missing data, and the retrospective character of the study. We do not yet have long term follow-up data, although so far no relapses occurred. We only performed PK analysis of blood samples, not of the affected tissue [13,14]. Also, the applicability of this study to low-income countries, where MDR-TB is most prevalent, might be limited. For instance, a compounding unit in a pharmacy that is able to produce linezolid capsules might not be readily available. In these cases, one could perhaps consider using quarter tablets of 600 mg linezolid (or 300 mg every two days) to administer 150 mg once daily, however one must then make sure splitting is done in a correct and safe manner. We have not studied the bioequivalence of our capsules. However, since the absorption of linezolid is usually fast and complete, PK of linezolid is non-linear, and we performed TDM, we do not expect this to impact the treatment outcome. Furthermore, TDM is not available everywhere, but dried blood spots (DBS) [15] combined with limited sampling methods [11] might allow for this strategy to be implemented in other settings. There is still an ongoing discussion on the most appropriate PK/PD target for linezolid. In our clinic, we use an AUC/MIC target of > 100 using the total fraction concentration of linezolid, based on a recent manuscript as a part of a WHO initiative to systematically review the current recommended dose for second-line TB drugs [12]. In future research, besides applicability and implementation of TDM in low-income countries, cost-benefit should also be studied. By administering lower dosages of linezolid in patients if the AUC0-24h and MIC allows, drug costs per patient of this rather expensive drug is reduced. Finally, lower dosing might reduce dose-related toxicity allowing treatment for a prolonged period of time [16].  In conclusion, sub-300 mg doses of linezolid can achieve putative PK/PD targets in certain patients. A large prospective study with DBS might provide us with valuable information on the possibilities to implement this strategy in other settings.   Table 1 baseline characteristics and pharmacokinetic/pharmacodynamic results patients receiving sub-300mg dosages of linezolid as a part of their tuberculosis treatment regimens Parameter Value Subjects 9 Age (years) 27 (17-55) Male 4 (44%) Weight (kg) 55 (43-77) Height (m) 1.65 (1.55-1.88) Body mass index (kg/m2) 20.5 (16.2-24.1) Continent of origin   Asia 4 (44%)  Europe 4 (44%)  Africa 1 (12%) HIV, Hepatitis B or C positive 0/7   Drug susceptibility   Multidrug-resistant 8  Rifampicin-resistant 1 Treatment regimen   Linezolid 9/9  Moxifloxacin 9/9  Amikacin 8/9  Ethambutol 8/9  Clofazimine 6/9  Pyrazinamide 5/9  Protionamide 2/9  (High dose) isoniazid 2/9  Cycloserin 1/9   Linezolid  Lowest dose (once daily)   200 mg  4 (44%)  150 mg 5 (56%) Dose per kg body weight (mg/kg) 3.1 (2.0-4.7) totalAUC0-24h (mg*h/L) Cmin (mg/L) 50 (35-73) 0.5 (0.3-1.2) MIClinezolid   0.25 mg/L 7 (78%)  0.5 mg/L 2 (22%) totalAUC0-24h/MIC 196 (98-276) All data are presented as median (range) or number (percentage); linezolid cocentrations are presented as total fraction concentrations (e.g. totalAUC); HIV: human immunodeficiency virus; weight, height, and body mass index were collected at admission; MIC: minimum inhibitory concentration; totalAUC: area under the time concentration curve.    References 1. World Health Organization (WHO). Global Tuberculosis Report 2018. 2018; WHO/CDS/TB/2018.20. 2. World Health Organization (WHO). Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) . WHO/CDS/TB/2018 18 August 2018. 3. Caminero JA, Piubello A, Scardigli A, Migliori GB. Proposal for a standardised treatment regimen to manage pre- and extensively drug-resistant tuberculosis cases. Eur Respir J 2017; 50: 10.1183/13993003.00648-2017. Print 2017 Jul. 4. Sotgiu G, Centis R, D'Ambrosio L, Alffenaar J, Anger H, Caminero J, Castiglia P, De Lorenzo S, Ferrara G, Koh W, Schecter G, Shim T, Singla R, Skrahina A, Spanevello A, Udwadia Z, Villar M, Zampogna E, Zellweger J, Zumla A, Migliori GB. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J 2012. 5. De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D'Ambrosio L, Tiberi S, Bolhuis MS, van Altena R, Viggiani P, Piana A, Spanevello A, Migliori GB. Efficacy and safety of meropenem/clavunate added to linezolid containing regimens in the treatment of M/XDR-TB. Eur Respir J 2012. 6. Borisov SE, Dheda K, Enwerem M, Romero Leyet R, D'Ambrosio L, Centis R, Sotgiu G, Tiberi S, Alffenaar JW, Maryandyshev A, Belilovski E, Ganatra S, Skrahina A, Akkerman O, Aleksa A, Amale R, Artsukevich J, Bruchfeld J, Caminero JA, Carpena Martinez I, Codecasa L, Dalcolmo M, Denholm J, Douglas P, Duarte R, Esmail A, Fadul M, Filippov A, Davies Forsman L, Gaga M, Garcia-Fuertes JA, Garcia-Garcia JM, Gualano G, Jonsson J, Kunst H, Lau JS, Lazaro Mastrapa B, Teran Troya JL, Manga S, Manika K, Gonzalez Montaner P, Mullerpattan J, Oelofse S, Ortelli M, Palmero DJ, Palmieri F, Papalia A, Papavasileiou A, Payen MC, Pontali E, Robalo Cordeiro C, Saderi L, Sadutshang TD, Sanukevich T, Solodovnikova V, Spanevello A, Topgyal S, Toscanini F, Tramontana AR, Udwadia ZF, Viggiani P, White V, Zumla A, Migliori GB. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J 2017; 49: 10.1183/13993003.00387-2017. Print 2017 May. 7. Akkerman OW, Grasmeijer F, de Lange WCM, Kerstjens HAM, de Vries G, Bolhuis MS, Alffenaar JW, Frijlink HW, Smith G, Gajraj R, de Zwaan R, Hagedoorn P, Dedicoat M, van Soolingen D, van der Werf TS. Cross border, highly individualised treatment of a patient with challenging extensively drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02490-2017. Print 2018 Mar. 8. Van Kampenhout E, Bolhuis MS, Alffenaar JC, Oswald LM, Kerstjens HA, de Lange WC, van der Werf TS, Akkerman OW. Pharmacokinetics of moxifloxacin and linezolid during and after pregnancy in a patient with multidrug-resistant tuberculosis. Eur Respir J 2017; 49: 10.1183/13993003.01724-2016. Print 2017 Mar. 9. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 10. Yew WW, Chan DP, Leung CC, Zhang Y, Wang R, Ng P, Lee SM. Can toxicities induced by antituberculosis drugs be better managed in diabetic patients? Eur Respir J 2017; 50: 10.1183/13993003.00409-2017. Print 2017 Jul. 11. Kamp J, Bolhuis MS, Tiberi S, Akkerman OW, Centis R, de Lange WC, Kosterink JG, van der Werf TS, Migliori GB, Alffenaar JC. Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis. Int J Antimicrob Agents 2017; 49: 688-694. 12. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 13. Akkerman OW, van Altena R, Klinkenberg T, Brouwers AH, Bongaerts AH, van der Werf TS, Alffenaar JW. Drug concentration in lung tissue in multidrug-resistant tuberculosis. Eur Respir J 2013; 42: 1750-1752. 14. Kempker RR, Heinrichs MT, Nikolaishvili K, Sabulua I, Bablishvili N, Gogishvili S, Avaliani Z, Little BP, Bernheim A, Derendorf H, Blumberg HM, Vashakidze S, Peloquin CA. A comparison of linezolid lung tissue concentrations among patients with drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02166-2017. Print 2018 Feb. 15. Vu DH, Bolhuis MS, Koster RA, Greijdanus B, de Lange WC, van Altena R, Brouwers JR, Uges DR, Alffenaar JW. Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis. Antimicrob Agents Chemother 2012; 56: 5758-5763. 16. van Altena R, Akkerman OW, Alffenaar JC, Kerstjens HA, Magis-Escurra C, Boeree MJ, van Soolingen D, de Lange WC, Bolhuis MS, Hoefsloot W, de Vries G, van der Werf TS. Shorter treatment for multidrug-resistant tuberculosis: the good, the bad and the ugly. Eur Respir J 2016; 48: 1800-1802.   

Proceedings - University of Groningen

   University of GroningenTreatment of multidrug-resistant tuberculosis using therapeutic drug monitoringBolhuis, Mathieu S; van der Werf, Tjip S; Kerstjens, Huib A M; de Lange, Wiel C M; Alffenaar,Jan-Willem C; Akkerman, Onno WPublished in:European Respiratory JournalDOI:10.1183/13993003.00580-2019IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionFinal author's version (accepted by publisher, after peer review)Publication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Bolhuis, M. S., van der Werf, T. S., Kerstjens, H. A. M., de Lange, W. C. M., Alffenaar, J-W. C., &Akkerman, O. W. (2019). Treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring:first experiences with sub-300 mg linezolid dosages using in-house made capsules. 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For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 29-10-2022      Early View    Research letter    Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules   Mathieu S. Bolhuis, Tjip S. van der Werf, Huib A.M. Kerstjens, Wiel C.M. de Lange, Jan-Willem C. Alffenaar, Onno W. Akkerman    Please cite this article as: Bolhuis MS, van der Werf TS, Kerstjens HAM, et al. Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules. Eur Respir J 2019; in press (https://doi.org/10.1183/13993003.00580-2019).       This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online.    Copyright ©ERS 2019 Research letter ERJ Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules Mathieu S. Bolhuis1, Tjip S. van der Werf2,3, Huib A.M. Kerstjens2,4, Wiel C.M. de Lange2,4, Jan-Willem C. Alffenaar1,5, Onno W. Akkerman2,4 1University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands 2University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands. 3University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands. 4University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands. 5Sydney School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, Australia   Corresponding author: Mathieu S. Bolhuis, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Phone: +31 50 3614071, Fax: +31 50 3614087, e-mail :m.s.bolhuis@umcg.nl.    Funding: no funding was obtained for this research. Take home message: Therapeutic drug monitoring allows for sub-300 mg linezolid dosages once daily to successfully achieve PK/PD targets. Let’s confirm these retrospective data in a prospective study using dried blood spots.    Despite all our efforts, the disease burden of tuberculosis (TB) is not falling fast enough to reach the 2030 milestone of the End TB strategy [1]. Multidrug-resistant tuberculosis (MDR-TB) remains a public health crisis, with low treatment success rates [1]. The repurposed drug linezolid has  emerged as a core drug in MDR-TB treatment regimens [2,3], despite its toxicity, e.g. anemia, peripheral neuropathy and gastrointestinal disorders, optic neuritis, and thrombocytopenia [4,5].  Currently, linezolid is used off-label, as part of Group A “Medicines to be prioritised” of the World Health Organization MDR-TB treatment guideline [2] and in several large trials [6], such as the NIX- TB and END-TB trials. We use a holistic approach to treat MDR-TB, focusing multidisciplinarily on optimizing treatment using pharmacokinetics (PK) and pharmacodynamics, assessing and optimizing nutritional status, providing physical therapy and social care [7]. Treatment regimens are based on the WHO guidelines, but are individualized based on drug susceptibility testing (DST) combined with TDM if the regimen consists of second-line drugs or if patients are at risk for PK variability [8]. DST is performed at Dutch National Mycobacterial Reference Laboratory (RIVM, Bilthoven, The Netherlands).  Most patients start on a dose of 600 mg linezolid once daily. After two weeks, a full pharmacokinetic curve is obtained for all patients that receive linezolid, after which the dosage is lowered to 300 mg once daily. At steady state, the lowered dosage is again checked with TDM. Based on limited available literature, we strive for an area under the time – total fraction concentration curve (AUC0-24h) / minimum inhibitory concentration (MIC) ratio >100 [9]. If TDM allows, the dose of linezolid is reduced further to an optimal, lowest dose, with the aim to reduce toxicity of linezolid [4,5,10]. If the totalAUC0-24h/MIC ratio of linezolid is high enough, a dose reduction to 200 or even 150 mg of linezolid once daily is considered. In this study, we describe the first experiences of the treatment of MDR-TB using sub-300 mg dosages. We retrospectively searched for inpatients for whom linezolid PK data was collected between 2015-2018. As routine treatment data were collected retrospectively and anonymously, the Institutional Ethical Review Board waived the requirement to obtain informed consent (METc 2013/492). Patients that received a sub-300 mg dose of linezolid were included. Baseline characteristics co-morbidities (HIV/HBV/HCV/diabetes), MIC for linezolid, treatment regimen, and treatment outcome, were obtained from the electronic hospital record and the discharge letter from the treating lung physician.  Twenty-seven patients with linezolid pharmacokinetic data were identified. Of these patients, 18 (66%) had a final dose ≥300 mg linezolid once daily. Nine (34%) patients received a sub-300 mg dose of linezolid and were included in our study (see Table 1). These patients had a median (range) weight of 55 (43-77) kg. At admission, patients had a median (range) leucocyte count 6.6 (4.6-10.8) *109/L, thrombocytes 324 (238-461) *109/L, and hemoglobin 13.2 (11.8-16.3) g/dL. At admission, one of the patients was 32 weeks pregnant. Based on local policy, the individual patient and her preferences, it was decided – in contrast with standard practice – that the start of treatment of MDR-TB could be postponed until the patient gave birth to a healthy child. Four patients had pulmonary TB, two had extra-pulmonary TB, one had miliary TB, one had pleural TB, and one had a combination of pulmonary and extra-pulmonary TB. DST revealed that eight patients had MDR-TB and one had rifampin resistant TB. The MIC for linezolid of the Mycobacterium tuberculosis isolate was 0.25 mg/L for seven patients and 0.5 mg/L for two patients. Based on the available totalAUC0-24h/MIC ratios, dosages were lowered to 200 mg once daily in four (15%) patients and 150 mg in five (19%) patients.  The sub-300 mg dosages of linezolid are prepared as capsules at the compounding department of our pharmacy. Commercially available linezolid tablets are pulverized and sieved. Lactose-1-water is used to create the correct volume of the homogenized powder mixture, after which transparent empty capsules are filled. All capsules are checked visually and ten capsules are checked for the correct weight and percentage of deviation (≤3%) from the correct weight. The capsules are kept at room temperature for a maximum of one year.  With the sub-300 mg dosages of linezolid, the patients had a median (range) totalAUC0-24h of 50 (49-57) mg*h/L. In three cases, there was no AUC0-24h available for the lowest dose due to logistical issues. In these cases, the totalAUC0-24h of the lowest dose was calculated using our linezolid pharmacokinetic model [11] in MWPharm++ (Mediware, Groningen, the Netherlands). The median (range) totalAUC/MIC ratio was 196 (98-276), with all except one patient attaining the target of 100 that is used in our clinic, based on a systematic review of literature [12]. Since the AUC/MIC ratio of that patient was 98, we did not increase the dose.  As soon as the patients  received and tolerated their tailor-made regimen, treatment was continued at home. The included patients finished their treatment as outpatients under supervision of the staff of our center. At discharge, patients had a median (range) leucocyte count 4.7 (3.7-7.3) *109/L, thrombocytes 270 (159-327) *109/L, and hemoglobin 13.7 (11.1-16.4) g/dL. None of the patients had significant adverse events or toxicity from the linezolid dosages they received. Despite the fact that we cannot draw any conclusions about the safety or efficacy of our approach, after discharge, all except one patient (lost to follow-up) finished their treatment regimens successfully. This study describes the treatment of TB with linezolid dosages lower than 300 mg. Linezolid is known for its side effects, with a meta-analysis showing adverse events in 58.9% of patients with linezolid containing regimens to treat MDR-TB [4]. Higher dosages of linezolid (i.e. >600mg) show more side effects than lower dosages (i.e. between 300-600mg) [4,5]. In our study, in nine out of 27 patients, TDM combined with DST allowed for lowering the linezolid dosage to 200 mg or 150 mg once daily, thereby possibly limiting the number of side effects even further.  Obviously, there are limitations to this study, such as the small number of patients, missing data, and the retrospective character of the study. We do not yet have long term follow-up data, although so far no relapses occurred. We only performed PK analysis of blood samples, not of the affected tissue [13,14]. Also, the applicability of this study to low-income countries, where MDR-TB is most prevalent, might be limited. For instance, a compounding unit in a pharmacy that is able to produce linezolid capsules might not be readily available. In these cases, one could perhaps consider using quarter tablets of 600 mg linezolid (or 300 mg every two days) to administer 150 mg once daily, however one must then make sure splitting is done in a correct and safe manner. We have not studied the bioequivalence of our capsules. However, since the absorption of linezolid is usually fast and complete, PK of linezolid is non-linear, and we performed TDM, we do not expect this to impact the treatment outcome. Furthermore, TDM is not available everywhere, but dried blood spots (DBS) [15] combined with limited sampling methods [11] might allow for this strategy to be implemented in other settings. There is still an ongoing discussion on the most appropriate PK/PD target for linezolid. In our clinic, we use an AUC/MIC target of > 100 using the total fraction concentration of linezolid, based on a recent manuscript as a part of a WHO initiative to systematically review the current recommended dose for second-line TB drugs [12]. In future research, besides applicability and implementation of TDM in low-income countries, cost-benefit should also be studied. By administering lower dosages of linezolid in patients if the AUC0-24h and MIC allows, drug costs per patient of this rather expensive drug is reduced. Finally, lower dosing might reduce dose-related toxicity allowing treatment for a prolonged period of time [16].  In conclusion, sub-300 mg doses of linezolid can achieve putative PK/PD targets in certain patients. A large prospective study with DBS might provide us with valuable information on the possibilities to implement this strategy in other settings.   Table 1 baseline characteristics and pharmacokinetic/pharmacodynamic results patients receiving sub-300mg dosages of linezolid as a part of their tuberculosis treatment regimens Parameter Value Subjects 9 Age (years) 27 (17-55) Male 4 (44%) Weight (kg) 55 (43-77) Height (m) 1.65 (1.55-1.88) Body mass index (kg/m2) 20.5 (16.2-24.1) Continent of origin   Asia 4 (44%)  Europe 4 (44%)  Africa 1 (12%) HIV, Hepatitis B or C positive 0/7   Drug susceptibility   Multidrug-resistant 8  Rifampicin-resistant 1 Treatment regimen   Linezolid 9/9  Moxifloxacin 9/9  Amikacin 8/9  Ethambutol 8/9  Clofazimine 6/9  Pyrazinamide 5/9  Protionamide 2/9  (High dose) isoniazid 2/9  Cycloserin 1/9   Linezolid  Lowest dose (once daily)   200 mg  4 (44%)  150 mg 5 (56%) Dose per kg body weight (mg/kg) 3.1 (2.0-4.7) totalAUC0-24h (mg*h/L) Cmin (mg/L) 50 (35-73) 0.5 (0.3-1.2) MIClinezolid   0.25 mg/L 7 (78%)  0.5 mg/L 2 (22%) totalAUC0-24h/MIC 196 (98-276) All data are presented as median (range) or number (percentage); linezolid cocentrations are presented as total fraction concentrations (e.g. totalAUC); HIV: human immunodeficiency virus; weight, height, and body mass index were collected at admission; MIC: minimum inhibitory concentration; totalAUC: area under the time concentration curve.    References 1. World Health Organization (WHO). Global Tuberculosis Report 2018. 2018; WHO/CDS/TB/2018.20. 2. World Health Organization (WHO). Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) . WHO/CDS/TB/2018 18 August 2018. 3. Caminero JA, Piubello A, Scardigli A, Migliori GB. Proposal for a standardised treatment regimen to manage pre- and extensively drug-resistant tuberculosis cases. Eur Respir J 2017; 50: 10.1183/13993003.00648-2017. Print 2017 Jul. 4. Sotgiu G, Centis R, D'Ambrosio L, Alffenaar J, Anger H, Caminero J, Castiglia P, De Lorenzo S, Ferrara G, Koh W, Schecter G, Shim T, Singla R, Skrahina A, Spanevello A, Udwadia Z, Villar M, Zampogna E, Zellweger J, Zumla A, Migliori GB. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J 2012. 5. De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D'Ambrosio L, Tiberi S, Bolhuis MS, van Altena R, Viggiani P, Piana A, Spanevello A, Migliori GB. Efficacy and safety of meropenem/clavunate added to linezolid containing regimens in the treatment of M/XDR-TB. Eur Respir J 2012. 6. Borisov SE, Dheda K, Enwerem M, Romero Leyet R, D'Ambrosio L, Centis R, Sotgiu G, Tiberi S, Alffenaar JW, Maryandyshev A, Belilovski E, Ganatra S, Skrahina A, Akkerman O, Aleksa A, Amale R, Artsukevich J, Bruchfeld J, Caminero JA, Carpena Martinez I, Codecasa L, Dalcolmo M, Denholm J, Douglas P, Duarte R, Esmail A, Fadul M, Filippov A, Davies Forsman L, Gaga M, Garcia-Fuertes JA, Garcia-Garcia JM, Gualano G, Jonsson J, Kunst H, Lau JS, Lazaro Mastrapa B, Teran Troya JL, Manga S, Manika K, Gonzalez Montaner P, Mullerpattan J, Oelofse S, Ortelli M, Palmero DJ, Palmieri F, Papalia A, Papavasileiou A, Payen MC, Pontali E, Robalo Cordeiro C, Saderi L, Sadutshang TD, Sanukevich T, Solodovnikova V, Spanevello A, Topgyal S, Toscanini F, Tramontana AR, Udwadia ZF, Viggiani P, White V, Zumla A, Migliori GB. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J 2017; 49: 10.1183/13993003.00387-2017. Print 2017 May. 7. Akkerman OW, Grasmeijer F, de Lange WCM, Kerstjens HAM, de Vries G, Bolhuis MS, Alffenaar JW, Frijlink HW, Smith G, Gajraj R, de Zwaan R, Hagedoorn P, Dedicoat M, van Soolingen D, van der Werf TS. Cross border, highly individualised treatment of a patient with challenging extensively drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02490-2017. Print 2018 Mar. 8. Van Kampenhout E, Bolhuis MS, Alffenaar JC, Oswald LM, Kerstjens HA, de Lange WC, van der Werf TS, Akkerman OW. Pharmacokinetics of moxifloxacin and linezolid during and after pregnancy in a patient with multidrug-resistant tuberculosis. Eur Respir J 2017; 49: 10.1183/13993003.01724-2016. Print 2017 Mar. 9. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 10. Yew WW, Chan DP, Leung CC, Zhang Y, Wang R, Ng P, Lee SM. Can toxicities induced by antituberculosis drugs be better managed in diabetic patients? Eur Respir J 2017; 50: 10.1183/13993003.00409-2017. Print 2017 Jul. 11. Kamp J, Bolhuis MS, Tiberi S, Akkerman OW, Centis R, de Lange WC, Kosterink JG, van der Werf TS, Migliori GB, Alffenaar JC. Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis. Int J Antimicrob Agents 2017; 49: 688-694. 12. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 13. Akkerman OW, van Altena R, Klinkenberg T, Brouwers AH, Bongaerts AH, van der Werf TS, Alffenaar JW. Drug concentration in lung tissue in multidrug-resistant tuberculosis. Eur Respir J 2013; 42: 1750-1752. 14. Kempker RR, Heinrichs MT, Nikolaishvili K, Sabulua I, Bablishvili N, Gogishvili S, Avaliani Z, Little BP, Bernheim A, Derendorf H, Blumberg HM, Vashakidze S, Peloquin CA. A comparison of linezolid lung tissue concentrations among patients with drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02166-2017. Print 2018 Feb. 15. Vu DH, Bolhuis MS, Koster RA, Greijdanus B, de Lange WC, van Altena R, Brouwers JR, Uges DR, Alffenaar JW. Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis. Antimicrob Agents Chemother 2012; 56: 5758-5763. 16. van Altena R, Akkerman OW, Alffenaar JC, Kerstjens HA, Magis-Escurra C, Boeree MJ, van Soolingen D, de Lange WC, Bolhuis MS, Hoefsloot W, de Vries G, van der Werf TS. Shorter treatment for multidrug-resistant tuberculosis: the good, the bad and the ugly. Eur Respir J 2016; 48: 1800-1802.   

ARTS repository - University of Groningen

   University of GroningenTreatment of multidrug-resistant tuberculosis using therapeutic drug monitoringBolhuis, Mathieu S; van der Werf, Tjip S; Kerstjens, Huib A M; de Lange, Wiel C M; Alffenaar,Jan-Willem C; Akkerman, Onno WPublished in:European Respiratory JournalDOI:10.1183/13993003.00580-2019IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionFinal author's version (accepted by publisher, after peer review)Publication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Bolhuis, M. S., van der Werf, T. S., Kerstjens, H. A. M., de Lange, W. C. M., Alffenaar, J-W. C., &Akkerman, O. W. (2019). Treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring:first experiences with sub-300 mg linezolid dosages using in-house made capsules. European RespiratoryJournal, 54(6), Article 1900580. Advance online publication. https://doi.org/10.1183/13993003.00580-2019CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 11-09-2023      Early View    Research letter    Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules   Mathieu S. Bolhuis, Tjip S. van der Werf, Huib A.M. Kerstjens, Wiel C.M. de Lange, Jan-Willem C. Alffenaar, Onno W. Akkerman    Please cite this article as: Bolhuis MS, van der Werf TS, Kerstjens HAM, et al. Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules. Eur Respir J 2019; in press (https://doi.org/10.1183/13993003.00580-2019).       This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online.    Copyright ©ERS 2019 Research letter ERJ Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules Mathieu S. Bolhuis1, Tjip S. van der Werf2,3, Huib A.M. Kerstjens2,4, Wiel C.M. de Lange2,4, Jan-Willem C. Alffenaar1,5, Onno W. Akkerman2,4 1University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands 2University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands. 3University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands. 4University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands. 5Sydney School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, Australia   Corresponding author: Mathieu S. Bolhuis, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Phone: +31 50 3614071, Fax: +31 50 3614087, e-mail :m.s.bolhuis@umcg.nl.    Funding: no funding was obtained for this research. Take home message: Therapeutic drug monitoring allows for sub-300 mg linezolid dosages once daily to successfully achieve PK/PD targets. Let’s confirm these retrospective data in a prospective study using dried blood spots.    Despite all our efforts, the disease burden of tuberculosis (TB) is not falling fast enough to reach the 2030 milestone of the End TB strategy [1]. Multidrug-resistant tuberculosis (MDR-TB) remains a public health crisis, with low treatment success rates [1]. The repurposed drug linezolid has  emerged as a core drug in MDR-TB treatment regimens [2,3], despite its toxicity, e.g. anemia, peripheral neuropathy and gastrointestinal disorders, optic neuritis, and thrombocytopenia [4,5].  Currently, linezolid is used off-label, as part of Group A “Medicines to be prioritised” of the World Health Organization MDR-TB treatment guideline [2] and in several large trials [6], such as the NIX- TB and END-TB trials. We use a holistic approach to treat MDR-TB, focusing multidisciplinarily on optimizing treatment using pharmacokinetics (PK) and pharmacodynamics, assessing and optimizing nutritional status, providing physical therapy and social care [7]. Treatment regimens are based on the WHO guidelines, but are individualized based on drug susceptibility testing (DST) combined with TDM if the regimen consists of second-line drugs or if patients are at risk for PK variability [8]. DST is performed at Dutch National Mycobacterial Reference Laboratory (RIVM, Bilthoven, The Netherlands).  Most patients start on a dose of 600 mg linezolid once daily. After two weeks, a full pharmacokinetic curve is obtained for all patients that receive linezolid, after which the dosage is lowered to 300 mg once daily. At steady state, the lowered dosage is again checked with TDM. Based on limited available literature, we strive for an area under the time – total fraction concentration curve (AUC0-24h) / minimum inhibitory concentration (MIC) ratio >100 [9]. If TDM allows, the dose of linezolid is reduced further to an optimal, lowest dose, with the aim to reduce toxicity of linezolid [4,5,10]. If the totalAUC0-24h/MIC ratio of linezolid is high enough, a dose reduction to 200 or even 150 mg of linezolid once daily is considered. In this study, we describe the first experiences of the treatment of MDR-TB using sub-300 mg dosages. We retrospectively searched for inpatients for whom linezolid PK data was collected between 2015-2018. As routine treatment data were collected retrospectively and anonymously, the Institutional Ethical Review Board waived the requirement to obtain informed consent (METc 2013/492). Patients that received a sub-300 mg dose of linezolid were included. Baseline characteristics co-morbidities (HIV/HBV/HCV/diabetes), MIC for linezolid, treatment regimen, and treatment outcome, were obtained from the electronic hospital record and the discharge letter from the treating lung physician.  Twenty-seven patients with linezolid pharmacokinetic data were identified. Of these patients, 18 (66%) had a final dose ≥300 mg linezolid once daily. Nine (34%) patients received a sub-300 mg dose of linezolid and were included in our study (see Table 1). These patients had a median (range) weight of 55 (43-77) kg. At admission, patients had a median (range) leucocyte count 6.6 (4.6-10.8) *109/L, thrombocytes 324 (238-461) *109/L, and hemoglobin 13.2 (11.8-16.3) g/dL. At admission, one of the patients was 32 weeks pregnant. Based on local policy, the individual patient and her preferences, it was decided – in contrast with standard practice – that the start of treatment of MDR-TB could be postponed until the patient gave birth to a healthy child. Four patients had pulmonary TB, two had extra-pulmonary TB, one had miliary TB, one had pleural TB, and one had a combination of pulmonary and extra-pulmonary TB. DST revealed that eight patients had MDR-TB and one had rifampin resistant TB. The MIC for linezolid of the Mycobacterium tuberculosis isolate was 0.25 mg/L for seven patients and 0.5 mg/L for two patients. Based on the available totalAUC0-24h/MIC ratios, dosages were lowered to 200 mg once daily in four (15%) patients and 150 mg in five (19%) patients.  The sub-300 mg dosages of linezolid are prepared as capsules at the compounding department of our pharmacy. Commercially available linezolid tablets are pulverized and sieved. Lactose-1-water is used to create the correct volume of the homogenized powder mixture, after which transparent empty capsules are filled. All capsules are checked visually and ten capsules are checked for the correct weight and percentage of deviation (≤3%) from the correct weight. The capsules are kept at room temperature for a maximum of one year.  With the sub-300 mg dosages of linezolid, the patients had a median (range) totalAUC0-24h of 50 (49-57) mg*h/L. In three cases, there was no AUC0-24h available for the lowest dose due to logistical issues. In these cases, the totalAUC0-24h of the lowest dose was calculated using our linezolid pharmacokinetic model [11] in MWPharm++ (Mediware, Groningen, the Netherlands). The median (range) totalAUC/MIC ratio was 196 (98-276), with all except one patient attaining the target of 100 that is used in our clinic, based on a systematic review of literature [12]. Since the AUC/MIC ratio of that patient was 98, we did not increase the dose.  As soon as the patients  received and tolerated their tailor-made regimen, treatment was continued at home. The included patients finished their treatment as outpatients under supervision of the staff of our center. At discharge, patients had a median (range) leucocyte count 4.7 (3.7-7.3) *109/L, thrombocytes 270 (159-327) *109/L, and hemoglobin 13.7 (11.1-16.4) g/dL. None of the patients had significant adverse events or toxicity from the linezolid dosages they received. Despite the fact that we cannot draw any conclusions about the safety or efficacy of our approach, after discharge, all except one patient (lost to follow-up) finished their treatment regimens successfully. This study describes the treatment of TB with linezolid dosages lower than 300 mg. Linezolid is known for its side effects, with a meta-analysis showing adverse events in 58.9% of patients with linezolid containing regimens to treat MDR-TB [4]. Higher dosages of linezolid (i.e. >600mg) show more side effects than lower dosages (i.e. between 300-600mg) [4,5]. In our study, in nine out of 27 patients, TDM combined with DST allowed for lowering the linezolid dosage to 200 mg or 150 mg once daily, thereby possibly limiting the number of side effects even further.  Obviously, there are limitations to this study, such as the small number of patients, missing data, and the retrospective character of the study. We do not yet have long term follow-up data, although so far no relapses occurred. We only performed PK analysis of blood samples, not of the affected tissue [13,14]. Also, the applicability of this study to low-income countries, where MDR-TB is most prevalent, might be limited. For instance, a compounding unit in a pharmacy that is able to produce linezolid capsules might not be readily available. In these cases, one could perhaps consider using quarter tablets of 600 mg linezolid (or 300 mg every two days) to administer 150 mg once daily, however one must then make sure splitting is done in a correct and safe manner. We have not studied the bioequivalence of our capsules. However, since the absorption of linezolid is usually fast and complete, PK of linezolid is non-linear, and we performed TDM, we do not expect this to impact the treatment outcome. Furthermore, TDM is not available everywhere, but dried blood spots (DBS) [15] combined with limited sampling methods [11] might allow for this strategy to be implemented in other settings. There is still an ongoing discussion on the most appropriate PK/PD target for linezolid. In our clinic, we use an AUC/MIC target of > 100 using the total fraction concentration of linezolid, based on a recent manuscript as a part of a WHO initiative to systematically review the current recommended dose for second-line TB drugs [12]. In future research, besides applicability and implementation of TDM in low-income countries, cost-benefit should also be studied. By administering lower dosages of linezolid in patients if the AUC0-24h and MIC allows, drug costs per patient of this rather expensive drug is reduced. Finally, lower dosing might reduce dose-related toxicity allowing treatment for a prolonged period of time [16].  In conclusion, sub-300 mg doses of linezolid can achieve putative PK/PD targets in certain patients. A large prospective study with DBS might provide us with valuable information on the possibilities to implement this strategy in other settings.   Table 1 baseline characteristics and pharmacokinetic/pharmacodynamic results patients receiving sub-300mg dosages of linezolid as a part of their tuberculosis treatment regimens Parameter Value Subjects 9 Age (years) 27 (17-55) Male 4 (44%) Weight (kg) 55 (43-77) Height (m) 1.65 (1.55-1.88) Body mass index (kg/m2) 20.5 (16.2-24.1) Continent of origin   Asia 4 (44%)  Europe 4 (44%)  Africa 1 (12%) HIV, Hepatitis B or C positive 0/7   Drug susceptibility   Multidrug-resistant 8  Rifampicin-resistant 1 Treatment regimen   Linezolid 9/9  Moxifloxacin 9/9  Amikacin 8/9  Ethambutol 8/9  Clofazimine 6/9  Pyrazinamide 5/9  Protionamide 2/9  (High dose) isoniazid 2/9  Cycloserin 1/9   Linezolid  Lowest dose (once daily)   200 mg  4 (44%)  150 mg 5 (56%) Dose per kg body weight (mg/kg) 3.1 (2.0-4.7) totalAUC0-24h (mg*h/L) Cmin (mg/L) 50 (35-73) 0.5 (0.3-1.2) MIClinezolid   0.25 mg/L 7 (78%)  0.5 mg/L 2 (22%) totalAUC0-24h/MIC 196 (98-276) All data are presented as median (range) or number (percentage); linezolid cocentrations are presented as total fraction concentrations (e.g. totalAUC); HIV: human immunodeficiency virus; weight, height, and body mass index were collected at admission; MIC: minimum inhibitory concentration; totalAUC: area under the time concentration curve.    References 1. World Health Organization (WHO). Global Tuberculosis Report 2018. 2018; WHO/CDS/TB/2018.20. 2. World Health Organization (WHO). Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) . WHO/CDS/TB/2018 18 August 2018. 3. Caminero JA, Piubello A, Scardigli A, Migliori GB. Proposal for a standardised treatment regimen to manage pre- and extensively drug-resistant tuberculosis cases. Eur Respir J 2017; 50: 10.1183/13993003.00648-2017. Print 2017 Jul. 4. Sotgiu G, Centis R, D'Ambrosio L, Alffenaar J, Anger H, Caminero J, Castiglia P, De Lorenzo S, Ferrara G, Koh W, Schecter G, Shim T, Singla R, Skrahina A, Spanevello A, Udwadia Z, Villar M, Zampogna E, Zellweger J, Zumla A, Migliori GB. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J 2012. 5. De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D'Ambrosio L, Tiberi S, Bolhuis MS, van Altena R, Viggiani P, Piana A, Spanevello A, Migliori GB. Efficacy and safety of meropenem/clavunate added to linezolid containing regimens in the treatment of M/XDR-TB. Eur Respir J 2012. 6. Borisov SE, Dheda K, Enwerem M, Romero Leyet R, D'Ambrosio L, Centis R, Sotgiu G, Tiberi S, Alffenaar JW, Maryandyshev A, Belilovski E, Ganatra S, Skrahina A, Akkerman O, Aleksa A, Amale R, Artsukevich J, Bruchfeld J, Caminero JA, Carpena Martinez I, Codecasa L, Dalcolmo M, Denholm J, Douglas P, Duarte R, Esmail A, Fadul M, Filippov A, Davies Forsman L, Gaga M, Garcia-Fuertes JA, Garcia-Garcia JM, Gualano G, Jonsson J, Kunst H, Lau JS, Lazaro Mastrapa B, Teran Troya JL, Manga S, Manika K, Gonzalez Montaner P, Mullerpattan J, Oelofse S, Ortelli M, Palmero DJ, Palmieri F, Papalia A, Papavasileiou A, Payen MC, Pontali E, Robalo Cordeiro C, Saderi L, Sadutshang TD, Sanukevich T, Solodovnikova V, Spanevello A, Topgyal S, Toscanini F, Tramontana AR, Udwadia ZF, Viggiani P, White V, Zumla A, Migliori GB. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J 2017; 49: 10.1183/13993003.00387-2017. Print 2017 May. 7. Akkerman OW, Grasmeijer F, de Lange WCM, Kerstjens HAM, de Vries G, Bolhuis MS, Alffenaar JW, Frijlink HW, Smith G, Gajraj R, de Zwaan R, Hagedoorn P, Dedicoat M, van Soolingen D, van der Werf TS. Cross border, highly individualised treatment of a patient with challenging extensively drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02490-2017. Print 2018 Mar. 8. Van Kampenhout E, Bolhuis MS, Alffenaar JC, Oswald LM, Kerstjens HA, de Lange WC, van der Werf TS, Akkerman OW. Pharmacokinetics of moxifloxacin and linezolid during and after pregnancy in a patient with multidrug-resistant tuberculosis. Eur Respir J 2017; 49: 10.1183/13993003.01724-2016. Print 2017 Mar. 9. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 10. Yew WW, Chan DP, Leung CC, Zhang Y, Wang R, Ng P, Lee SM. Can toxicities induced by antituberculosis drugs be better managed in diabetic patients? Eur Respir J 2017; 50: 10.1183/13993003.00409-2017. Print 2017 Jul. 11. Kamp J, Bolhuis MS, Tiberi S, Akkerman OW, Centis R, de Lange WC, Kosterink JG, van der Werf TS, Migliori GB, Alffenaar JC. Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis. Int J Antimicrob Agents 2017; 49: 688-694. 12. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 13. Akkerman OW, van Altena R, Klinkenberg T, Brouwers AH, Bongaerts AH, van der Werf TS, Alffenaar JW. Drug concentration in lung tissue in multidrug-resistant tuberculosis. Eur Respir J 2013; 42: 1750-1752. 14. Kempker RR, Heinrichs MT, Nikolaishvili K, Sabulua I, Bablishvili N, Gogishvili S, Avaliani Z, Little BP, Bernheim A, Derendorf H, Blumberg HM, Vashakidze S, Peloquin CA. A comparison of linezolid lung tissue concentrations among patients with drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02166-2017. Print 2018 Feb. 15. Vu DH, Bolhuis MS, Koster RA, Greijdanus B, de Lange WC, van Altena R, Brouwers JR, Uges DR, Alffenaar JW. Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis. Antimicrob Agents Chemother 2012; 56: 5758-5763. 16. van Altena R, Akkerman OW, Alffenaar JC, Kerstjens HA, Magis-Escurra C, Boeree MJ, van Soolingen D, de Lange WC, Bolhuis MS, Hoefsloot W, de Vries G, van der Werf TS. Shorter treatment for multidrug-resistant tuberculosis: the good, the bad and the ugly. Eur Respir J 2016; 48: 1800-1802.   

   University of GroningenTreatment of multidrug-resistant tuberculosis using therapeutic drug monitoringBolhuis, Mathieu S; van der Werf, Tjip S; Kerstjens, Huib A M; de Lange, Wiel C M; Alffenaar,Jan-Willem C; Akkerman, Onno WPublished in:European Respiratory JournalDOI:10.1183/13993003.00580-2019IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionFinal author's version (accepted by publisher, after peer review)Publication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Bolhuis, M. S., van der Werf, T. S., Kerstjens, H. A. M., de Lange, W. C. M., Alffenaar, J-W. C., &Akkerman, O. W. (2019). Treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring:first experiences with sub-300 mg linezolid dosages using in-house made capsules. European RespiratoryJournal, 54(6), [1900580]. https://doi.org/10.1183/13993003.00580-2019CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 29-04-2023      Early View    Research letter    Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules   Mathieu S. Bolhuis, Tjip S. van der Werf, Huib A.M. Kerstjens, Wiel C.M. de Lange, Jan-Willem C. Alffenaar, Onno W. Akkerman    Please cite this article as: Bolhuis MS, van der Werf TS, Kerstjens HAM, et al. Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules. Eur Respir J 2019; in press (https://doi.org/10.1183/13993003.00580-2019).       This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online.    Copyright ©ERS 2019 Research letter ERJ Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules Mathieu S. Bolhuis1, Tjip S. van der Werf2,3, Huib A.M. Kerstjens2,4, Wiel C.M. de Lange2,4, Jan-Willem C. Alffenaar1,5, Onno W. Akkerman2,4 1University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands 2University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands. 3University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands. 4University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands. 5Sydney School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, Australia   Corresponding author: Mathieu S. Bolhuis, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Phone: +31 50 3614071, Fax: +31 50 3614087, e-mail :m.s.bolhuis@umcg.nl.    Funding: no funding was obtained for this research. Take home message: Therapeutic drug monitoring allows for sub-300 mg linezolid dosages once daily to successfully achieve PK/PD targets. Let’s confirm these retrospective data in a prospective study using dried blood spots.    Despite all our efforts, the disease burden of tuberculosis (TB) is not falling fast enough to reach the 2030 milestone of the End TB strategy [1]. Multidrug-resistant tuberculosis (MDR-TB) remains a public health crisis, with low treatment success rates [1]. The repurposed drug linezolid has  emerged as a core drug in MDR-TB treatment regimens [2,3], despite its toxicity, e.g. anemia, peripheral neuropathy and gastrointestinal disorders, optic neuritis, and thrombocytopenia [4,5].  Currently, linezolid is used off-label, as part of Group A “Medicines to be prioritised” of the World Health Organization MDR-TB treatment guideline [2] and in several large trials [6], such as the NIX- TB and END-TB trials. We use a holistic approach to treat MDR-TB, focusing multidisciplinarily on optimizing treatment using pharmacokinetics (PK) and pharmacodynamics, assessing and optimizing nutritional status, providing physical therapy and social care [7]. Treatment regimens are based on the WHO guidelines, but are individualized based on drug susceptibility testing (DST) combined with TDM if the regimen consists of second-line drugs or if patients are at risk for PK variability [8]. DST is performed at Dutch National Mycobacterial Reference Laboratory (RIVM, Bilthoven, The Netherlands).  Most patients start on a dose of 600 mg linezolid once daily. After two weeks, a full pharmacokinetic curve is obtained for all patients that receive linezolid, after which the dosage is lowered to 300 mg once daily. At steady state, the lowered dosage is again checked with TDM. Based on limited available literature, we strive for an area under the time – total fraction concentration curve (AUC0-24h) / minimum inhibitory concentration (MIC) ratio >100 [9]. If TDM allows, the dose of linezolid is reduced further to an optimal, lowest dose, with the aim to reduce toxicity of linezolid [4,5,10]. If the totalAUC0-24h/MIC ratio of linezolid is high enough, a dose reduction to 200 or even 150 mg of linezolid once daily is considered. In this study, we describe the first experiences of the treatment of MDR-TB using sub-300 mg dosages. We retrospectively searched for inpatients for whom linezolid PK data was collected between 2015-2018. As routine treatment data were collected retrospectively and anonymously, the Institutional Ethical Review Board waived the requirement to obtain informed consent (METc 2013/492). Patients that received a sub-300 mg dose of linezolid were included. Baseline characteristics co-morbidities (HIV/HBV/HCV/diabetes), MIC for linezolid, treatment regimen, and treatment outcome, were obtained from the electronic hospital record and the discharge letter from the treating lung physician.  Twenty-seven patients with linezolid pharmacokinetic data were identified. Of these patients, 18 (66%) had a final dose ≥300 mg linezolid once daily. Nine (34%) patients received a sub-300 mg dose of linezolid and were included in our study (see Table 1). These patients had a median (range) weight of 55 (43-77) kg. At admission, patients had a median (range) leucocyte count 6.6 (4.6-10.8) *109/L, thrombocytes 324 (238-461) *109/L, and hemoglobin 13.2 (11.8-16.3) g/dL. At admission, one of the patients was 32 weeks pregnant. Based on local policy, the individual patient and her preferences, it was decided – in contrast with standard practice – that the start of treatment of MDR-TB could be postponed until the patient gave birth to a healthy child. Four patients had pulmonary TB, two had extra-pulmonary TB, one had miliary TB, one had pleural TB, and one had a combination of pulmonary and extra-pulmonary TB. DST revealed that eight patients had MDR-TB and one had rifampin resistant TB. The MIC for linezolid of the Mycobacterium tuberculosis isolate was 0.25 mg/L for seven patients and 0.5 mg/L for two patients. Based on the available totalAUC0-24h/MIC ratios, dosages were lowered to 200 mg once daily in four (15%) patients and 150 mg in five (19%) patients.  The sub-300 mg dosages of linezolid are prepared as capsules at the compounding department of our pharmacy. Commercially available linezolid tablets are pulverized and sieved. Lactose-1-water is used to create the correct volume of the homogenized powder mixture, after which transparent empty capsules are filled. All capsules are checked visually and ten capsules are checked for the correct weight and percentage of deviation (≤3%) from the correct weight. The capsules are kept at room temperature for a maximum of one year.  With the sub-300 mg dosages of linezolid, the patients had a median (range) totalAUC0-24h of 50 (49-57) mg*h/L. In three cases, there was no AUC0-24h available for the lowest dose due to logistical issues. In these cases, the totalAUC0-24h of the lowest dose was calculated using our linezolid pharmacokinetic model [11] in MWPharm++ (Mediware, Groningen, the Netherlands). The median (range) totalAUC/MIC ratio was 196 (98-276), with all except one patient attaining the target of 100 that is used in our clinic, based on a systematic review of literature [12]. Since the AUC/MIC ratio of that patient was 98, we did not increase the dose.  As soon as the patients  received and tolerated their tailor-made regimen, treatment was continued at home. The included patients finished their treatment as outpatients under supervision of the staff of our center. At discharge, patients had a median (range) leucocyte count 4.7 (3.7-7.3) *109/L, thrombocytes 270 (159-327) *109/L, and hemoglobin 13.7 (11.1-16.4) g/dL. None of the patients had significant adverse events or toxicity from the linezolid dosages they received. Despite the fact that we cannot draw any conclusions about the safety or efficacy of our approach, after discharge, all except one patient (lost to follow-up) finished their treatment regimens successfully. This study describes the treatment of TB with linezolid dosages lower than 300 mg. Linezolid is known for its side effects, with a meta-analysis showing adverse events in 58.9% of patients with linezolid containing regimens to treat MDR-TB [4]. Higher dosages of linezolid (i.e. >600mg) show more side effects than lower dosages (i.e. between 300-600mg) [4,5]. In our study, in nine out of 27 patients, TDM combined with DST allowed for lowering the linezolid dosage to 200 mg or 150 mg once daily, thereby possibly limiting the number of side effects even further.  Obviously, there are limitations to this study, such as the small number of patients, missing data, and the retrospective character of the study. We do not yet have long term follow-up data, although so far no relapses occurred. We only performed PK analysis of blood samples, not of the affected tissue [13,14]. Also, the applicability of this study to low-income countries, where MDR-TB is most prevalent, might be limited. For instance, a compounding unit in a pharmacy that is able to produce linezolid capsules might not be readily available. In these cases, one could perhaps consider using quarter tablets of 600 mg linezolid (or 300 mg every two days) to administer 150 mg once daily, however one must then make sure splitting is done in a correct and safe manner. We have not studied the bioequivalence of our capsules. However, since the absorption of linezolid is usually fast and complete, PK of linezolid is non-linear, and we performed TDM, we do not expect this to impact the treatment outcome. Furthermore, TDM is not available everywhere, but dried blood spots (DBS) [15] combined with limited sampling methods [11] might allow for this strategy to be implemented in other settings. There is still an ongoing discussion on the most appropriate PK/PD target for linezolid. In our clinic, we use an AUC/MIC target of > 100 using the total fraction concentration of linezolid, based on a recent manuscript as a part of a WHO initiative to systematically review the current recommended dose for second-line TB drugs [12]. In future research, besides applicability and implementation of TDM in low-income countries, cost-benefit should also be studied. By administering lower dosages of linezolid in patients if the AUC0-24h and MIC allows, drug costs per patient of this rather expensive drug is reduced. Finally, lower dosing might reduce dose-related toxicity allowing treatment for a prolonged period of time [16].  In conclusion, sub-300 mg doses of linezolid can achieve putative PK/PD targets in certain patients. A large prospective study with DBS might provide us with valuable information on the possibilities to implement this strategy in other settings.   Table 1 baseline characteristics and pharmacokinetic/pharmacodynamic results patients receiving sub-300mg dosages of linezolid as a part of their tuberculosis treatment regimens Parameter Value Subjects 9 Age (years) 27 (17-55) Male 4 (44%) Weight (kg) 55 (43-77) Height (m) 1.65 (1.55-1.88) Body mass index (kg/m2) 20.5 (16.2-24.1) Continent of origin   Asia 4 (44%)  Europe 4 (44%)  Africa 1 (12%) HIV, Hepatitis B or C positive 0/7   Drug susceptibility   Multidrug-resistant 8  Rifampicin-resistant 1 Treatment regimen   Linezolid 9/9  Moxifloxacin 9/9  Amikacin 8/9  Ethambutol 8/9  Clofazimine 6/9  Pyrazinamide 5/9  Protionamide 2/9  (High dose) isoniazid 2/9  Cycloserin 1/9   Linezolid  Lowest dose (once daily)   200 mg  4 (44%)  150 mg 5 (56%) Dose per kg body weight (mg/kg) 3.1 (2.0-4.7) totalAUC0-24h (mg*h/L) Cmin (mg/L) 50 (35-73) 0.5 (0.3-1.2) MIClinezolid   0.25 mg/L 7 (78%)  0.5 mg/L 2 (22%) totalAUC0-24h/MIC 196 (98-276) All data are presented as median (range) or number (percentage); linezolid cocentrations are presented as total fraction concentrations (e.g. totalAUC); HIV: human immunodeficiency virus; weight, height, and body mass index were collected at admission; MIC: minimum inhibitory concentration; totalAUC: area under the time concentration curve.    References 1. World Health Organization (WHO). Global Tuberculosis Report 2018. 2018; WHO/CDS/TB/2018.20. 2. World Health Organization (WHO). Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) . WHO/CDS/TB/2018 18 August 2018. 3. Caminero JA, Piubello A, Scardigli A, Migliori GB. Proposal for a standardised treatment regimen to manage pre- and extensively drug-resistant tuberculosis cases. Eur Respir J 2017; 50: 10.1183/13993003.00648-2017. Print 2017 Jul. 4. Sotgiu G, Centis R, D'Ambrosio L, Alffenaar J, Anger H, Caminero J, Castiglia P, De Lorenzo S, Ferrara G, Koh W, Schecter G, Shim T, Singla R, Skrahina A, Spanevello A, Udwadia Z, Villar M, Zampogna E, Zellweger J, Zumla A, Migliori GB. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J 2012. 5. De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D'Ambrosio L, Tiberi S, Bolhuis MS, van Altena R, Viggiani P, Piana A, Spanevello A, Migliori GB. Efficacy and safety of meropenem/clavunate added to linezolid containing regimens in the treatment of M/XDR-TB. Eur Respir J 2012. 6. Borisov SE, Dheda K, Enwerem M, Romero Leyet R, D'Ambrosio L, Centis R, Sotgiu G, Tiberi S, Alffenaar JW, Maryandyshev A, Belilovski E, Ganatra S, Skrahina A, Akkerman O, Aleksa A, Amale R, Artsukevich J, Bruchfeld J, Caminero JA, Carpena Martinez I, Codecasa L, Dalcolmo M, Denholm J, Douglas P, Duarte R, Esmail A, Fadul M, Filippov A, Davies Forsman L, Gaga M, Garcia-Fuertes JA, Garcia-Garcia JM, Gualano G, Jonsson J, Kunst H, Lau JS, Lazaro Mastrapa B, Teran Troya JL, Manga S, Manika K, Gonzalez Montaner P, Mullerpattan J, Oelofse S, Ortelli M, Palmero DJ, Palmieri F, Papalia A, Papavasileiou A, Payen MC, Pontali E, Robalo Cordeiro C, Saderi L, Sadutshang TD, Sanukevich T, Solodovnikova V, Spanevello A, Topgyal S, Toscanini F, Tramontana AR, Udwadia ZF, Viggiani P, White V, Zumla A, Migliori GB. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J 2017; 49: 10.1183/13993003.00387-2017. Print 2017 May. 7. Akkerman OW, Grasmeijer F, de Lange WCM, Kerstjens HAM, de Vries G, Bolhuis MS, Alffenaar JW, Frijlink HW, Smith G, Gajraj R, de Zwaan R, Hagedoorn P, Dedicoat M, van Soolingen D, van der Werf TS. Cross border, highly individualised treatment of a patient with challenging extensively drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02490-2017. Print 2018 Mar. 8. Van Kampenhout E, Bolhuis MS, Alffenaar JC, Oswald LM, Kerstjens HA, de Lange WC, van der Werf TS, Akkerman OW. Pharmacokinetics of moxifloxacin and linezolid during and after pregnancy in a patient with multidrug-resistant tuberculosis. Eur Respir J 2017; 49: 10.1183/13993003.01724-2016. Print 2017 Mar. 9. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 10. Yew WW, Chan DP, Leung CC, Zhang Y, Wang R, Ng P, Lee SM. Can toxicities induced by antituberculosis drugs be better managed in diabetic patients? Eur Respir J 2017; 50: 10.1183/13993003.00409-2017. Print 2017 Jul. 11. Kamp J, Bolhuis MS, Tiberi S, Akkerman OW, Centis R, de Lange WC, Kosterink JG, van der Werf TS, Migliori GB, Alffenaar JC. Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis. Int J Antimicrob Agents 2017; 49: 688-694. 12. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 13. Akkerman OW, van Altena R, Klinkenberg T, Brouwers AH, Bongaerts AH, van der Werf TS, Alffenaar JW. Drug concentration in lung tissue in multidrug-resistant tuberculosis. Eur Respir J 2013; 42: 1750-1752. 14. Kempker RR, Heinrichs MT, Nikolaishvili K, Sabulua I, Bablishvili N, Gogishvili S, Avaliani Z, Little BP, Bernheim A, Derendorf H, Blumberg HM, Vashakidze S, Peloquin CA. A comparison of linezolid lung tissue concentrations among patients with drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02166-2017. Print 2018 Feb. 15. Vu DH, Bolhuis MS, Koster RA, Greijdanus B, de Lange WC, van Altena R, Brouwers JR, Uges DR, Alffenaar JW. Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis. Antimicrob Agents Chemother 2012; 56: 5758-5763. 16. van Altena R, Akkerman OW, Alffenaar JC, Kerstjens HA, Magis-Escurra C, Boeree MJ, van Soolingen D, de Lange WC, Bolhuis MS, Hoefsloot W, de Vries G, van der Werf TS. Shorter treatment for multidrug-resistant tuberculosis: the good, the bad and the ugly. Eur Respir J 2016; 48: 1800-1802.   

NARCIS 

Treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules

   University of GroningenTreatment of multidrug-resistant tuberculosis using therapeutic drug monitoringBolhuis, Mathieu S; van der Werf, Tjip S; Kerstjens, Huib A M; de Lange, Wiel C M; Alffenaar,Jan-Willem C; Akkerman, Onno WPublished in:European Respiratory JournalDOI:10.1183/13993003.00580-2019IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionFinal author's version (accepted by publisher, after peer review)Publication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Bolhuis, M. S., van der Werf, T. S., Kerstjens, H. A. M., de Lange, W. C. M., Alffenaar, J-W. C., &Akkerman, O. W. (2019). Treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring:first experiences with sub-300 mg linezolid dosages using in-house made capsules. European RespiratoryJournal, 54(6), [1900580]. https://doi.org/10.1183/13993003.00580-2019CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-10-2022      Early View    Research letter    Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules   Mathieu S. Bolhuis, Tjip S. van der Werf, Huib A.M. Kerstjens, Wiel C.M. de Lange, Jan-Willem C. Alffenaar, Onno W. Akkerman    Please cite this article as: Bolhuis MS, van der Werf TS, Kerstjens HAM, et al. Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules. Eur Respir J 2019; in press (https://doi.org/10.1183/13993003.00580-2019).       This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online.    Copyright ©ERS 2019 Research letter ERJ Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules Mathieu S. Bolhuis1, Tjip S. van der Werf2,3, Huib A.M. Kerstjens2,4, Wiel C.M. de Lange2,4, Jan-Willem C. Alffenaar1,5, Onno W. Akkerman2,4 1University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands 2University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands. 3University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands. 4University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands. 5Sydney School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, Australia   Corresponding author: Mathieu S. Bolhuis, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Phone: +31 50 3614071, Fax: +31 50 3614087, e-mail :m.s.bolhuis@umcg.nl.    Funding: no funding was obtained for this research. Take home message: Therapeutic drug monitoring allows for sub-300 mg linezolid dosages once daily to successfully achieve PK/PD targets. Let’s confirm these retrospective data in a prospective study using dried blood spots.    Despite all our efforts, the disease burden of tuberculosis (TB) is not falling fast enough to reach the 2030 milestone of the End TB strategy [1]. Multidrug-resistant tuberculosis (MDR-TB) remains a public health crisis, with low treatment success rates [1]. The repurposed drug linezolid has  emerged as a core drug in MDR-TB treatment regimens [2,3], despite its toxicity, e.g. anemia, peripheral neuropathy and gastrointestinal disorders, optic neuritis, and thrombocytopenia [4,5].  Currently, linezolid is used off-label, as part of Group A “Medicines to be prioritised” of the World Health Organization MDR-TB treatment guideline [2] and in several large trials [6], such as the NIX- TB and END-TB trials. We use a holistic approach to treat MDR-TB, focusing multidisciplinarily on optimizing treatment using pharmacokinetics (PK) and pharmacodynamics, assessing and optimizing nutritional status, providing physical therapy and social care [7]. Treatment regimens are based on the WHO guidelines, but are individualized based on drug susceptibility testing (DST) combined with TDM if the regimen consists of second-line drugs or if patients are at risk for PK variability [8]. DST is performed at Dutch National Mycobacterial Reference Laboratory (RIVM, Bilthoven, The Netherlands).  Most patients start on a dose of 600 mg linezolid once daily. After two weeks, a full pharmacokinetic curve is obtained for all patients that receive linezolid, after which the dosage is lowered to 300 mg once daily. At steady state, the lowered dosage is again checked with TDM. Based on limited available literature, we strive for an area under the time – total fraction concentration curve (AUC0-24h) / minimum inhibitory concentration (MIC) ratio >100 [9]. If TDM allows, the dose of linezolid is reduced further to an optimal, lowest dose, with the aim to reduce toxicity of linezolid [4,5,10]. If the totalAUC0-24h/MIC ratio of linezolid is high enough, a dose reduction to 200 or even 150 mg of linezolid once daily is considered. In this study, we describe the first experiences of the treatment of MDR-TB using sub-300 mg dosages. We retrospectively searched for inpatients for whom linezolid PK data was collected between 2015-2018. As routine treatment data were collected retrospectively and anonymously, the Institutional Ethical Review Board waived the requirement to obtain informed consent (METc 2013/492). Patients that received a sub-300 mg dose of linezolid were included. Baseline characteristics co-morbidities (HIV/HBV/HCV/diabetes), MIC for linezolid, treatment regimen, and treatment outcome, were obtained from the electronic hospital record and the discharge letter from the treating lung physician.  Twenty-seven patients with linezolid pharmacokinetic data were identified. Of these patients, 18 (66%) had a final dose ≥300 mg linezolid once daily. Nine (34%) patients received a sub-300 mg dose of linezolid and were included in our study (see Table 1). These patients had a median (range) weight of 55 (43-77) kg. At admission, patients had a median (range) leucocyte count 6.6 (4.6-10.8) *109/L, thrombocytes 324 (238-461) *109/L, and hemoglobin 13.2 (11.8-16.3) g/dL. At admission, one of the patients was 32 weeks pregnant. Based on local policy, the individual patient and her preferences, it was decided – in contrast with standard practice – that the start of treatment of MDR-TB could be postponed until the patient gave birth to a healthy child. Four patients had pulmonary TB, two had extra-pulmonary TB, one had miliary TB, one had pleural TB, and one had a combination of pulmonary and extra-pulmonary TB. DST revealed that eight patients had MDR-TB and one had rifampin resistant TB. The MIC for linezolid of the Mycobacterium tuberculosis isolate was 0.25 mg/L for seven patients and 0.5 mg/L for two patients. Based on the available totalAUC0-24h/MIC ratios, dosages were lowered to 200 mg once daily in four (15%) patients and 150 mg in five (19%) patients.  The sub-300 mg dosages of linezolid are prepared as capsules at the compounding department of our pharmacy. Commercially available linezolid tablets are pulverized and sieved. Lactose-1-water is used to create the correct volume of the homogenized powder mixture, after which transparent empty capsules are filled. All capsules are checked visually and ten capsules are checked for the correct weight and percentage of deviation (≤3%) from the correct weight. The capsules are kept at room temperature for a maximum of one year.  With the sub-300 mg dosages of linezolid, the patients had a median (range) totalAUC0-24h of 50 (49-57) mg*h/L. In three cases, there was no AUC0-24h available for the lowest dose due to logistical issues. In these cases, the totalAUC0-24h of the lowest dose was calculated using our linezolid pharmacokinetic model [11] in MWPharm++ (Mediware, Groningen, the Netherlands). The median (range) totalAUC/MIC ratio was 196 (98-276), with all except one patient attaining the target of 100 that is used in our clinic, based on a systematic review of literature [12]. Since the AUC/MIC ratio of that patient was 98, we did not increase the dose.  As soon as the patients  received and tolerated their tailor-made regimen, treatment was continued at home. The included patients finished their treatment as outpatients under supervision of the staff of our center. At discharge, patients had a median (range) leucocyte count 4.7 (3.7-7.3) *109/L, thrombocytes 270 (159-327) *109/L, and hemoglobin 13.7 (11.1-16.4) g/dL. None of the patients had significant adverse events or toxicity from the linezolid dosages they received. Despite the fact that we cannot draw any conclusions about the safety or efficacy of our approach, after discharge, all except one patient (lost to follow-up) finished their treatment regimens successfully. This study describes the treatment of TB with linezolid dosages lower than 300 mg. Linezolid is known for its side effects, with a meta-analysis showing adverse events in 58.9% of patients with linezolid containing regimens to treat MDR-TB [4]. Higher dosages of linezolid (i.e. >600mg) show more side effects than lower dosages (i.e. between 300-600mg) [4,5]. In our study, in nine out of 27 patients, TDM combined with DST allowed for lowering the linezolid dosage to 200 mg or 150 mg once daily, thereby possibly limiting the number of side effects even further.  Obviously, there are limitations to this study, such as the small number of patients, missing data, and the retrospective character of the study. We do not yet have long term follow-up data, although so far no relapses occurred. We only performed PK analysis of blood samples, not of the affected tissue [13,14]. Also, the applicability of this study to low-income countries, where MDR-TB is most prevalent, might be limited. For instance, a compounding unit in a pharmacy that is able to produce linezolid capsules might not be readily available. In these cases, one could perhaps consider using quarter tablets of 600 mg linezolid (or 300 mg every two days) to administer 150 mg once daily, however one must then make sure splitting is done in a correct and safe manner. We have not studied the bioequivalence of our capsules. However, since the absorption of linezolid is usually fast and complete, PK of linezolid is non-linear, and we performed TDM, we do not expect this to impact the treatment outcome. Furthermore, TDM is not available everywhere, but dried blood spots (DBS) [15] combined with limited sampling methods [11] might allow for this strategy to be implemented in other settings. There is still an ongoing discussion on the most appropriate PK/PD target for linezolid. In our clinic, we use an AUC/MIC target of > 100 using the total fraction concentration of linezolid, based on a recent manuscript as a part of a WHO initiative to systematically review the current recommended dose for second-line TB drugs [12]. In future research, besides applicability and implementation of TDM in low-income countries, cost-benefit should also be studied. By administering lower dosages of linezolid in patients if the AUC0-24h and MIC allows, drug costs per patient of this rather expensive drug is reduced. Finally, lower dosing might reduce dose-related toxicity allowing treatment for a prolonged period of time [16].  In conclusion, sub-300 mg doses of linezolid can achieve putative PK/PD targets in certain patients. A large prospective study with DBS might provide us with valuable information on the possibilities to implement this strategy in other settings.   Table 1 baseline characteristics and pharmacokinetic/pharmacodynamic results patients receiving sub-300mg dosages of linezolid as a part of their tuberculosis treatment regimens Parameter Value Subjects 9 Age (years) 27 (17-55) Male 4 (44%) Weight (kg) 55 (43-77) Height (m) 1.65 (1.55-1.88) Body mass index (kg/m2) 20.5 (16.2-24.1) Continent of origin   Asia 4 (44%)  Europe 4 (44%)  Africa 1 (12%) HIV, Hepatitis B or C positive 0/7   Drug susceptibility   Multidrug-resistant 8  Rifampicin-resistant 1 Treatment regimen   Linezolid 9/9  Moxifloxacin 9/9  Amikacin 8/9  Ethambutol 8/9  Clofazimine 6/9  Pyrazinamide 5/9  Protionamide 2/9  (High dose) isoniazid 2/9  Cycloserin 1/9   Linezolid  Lowest dose (once daily)   200 mg  4 (44%)  150 mg 5 (56%) Dose per kg body weight (mg/kg) 3.1 (2.0-4.7) totalAUC0-24h (mg*h/L) Cmin (mg/L) 50 (35-73) 0.5 (0.3-1.2) MIClinezolid   0.25 mg/L 7 (78%)  0.5 mg/L 2 (22%) totalAUC0-24h/MIC 196 (98-276) All data are presented as median (range) or number (percentage); linezolid cocentrations are presented as total fraction concentrations (e.g. totalAUC); HIV: human immunodeficiency virus; weight, height, and body mass index were collected at admission; MIC: minimum inhibitory concentration; totalAUC: area under the time concentration curve.    References 1. World Health Organization (WHO). Global Tuberculosis Report 2018. 2018; WHO/CDS/TB/2018.20. 2. World Health Organization (WHO). Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) . WHO/CDS/TB/2018 18 August 2018. 3. Caminero JA, Piubello A, Scardigli A, Migliori GB. Proposal for a standardised treatment regimen to manage pre- and extensively drug-resistant tuberculosis cases. Eur Respir J 2017; 50: 10.1183/13993003.00648-2017. Print 2017 Jul. 4. Sotgiu G, Centis R, D'Ambrosio L, Alffenaar J, Anger H, Caminero J, Castiglia P, De Lorenzo S, Ferrara G, Koh W, Schecter G, Shim T, Singla R, Skrahina A, Spanevello A, Udwadia Z, Villar M, Zampogna E, Zellweger J, Zumla A, Migliori GB. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J 2012. 5. De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D'Ambrosio L, Tiberi S, Bolhuis MS, van Altena R, Viggiani P, Piana A, Spanevello A, Migliori GB. Efficacy and safety of meropenem/clavunate added to linezolid containing regimens in the treatment of M/XDR-TB. Eur Respir J 2012. 6. Borisov SE, Dheda K, Enwerem M, Romero Leyet R, D'Ambrosio L, Centis R, Sotgiu G, Tiberi S, Alffenaar JW, Maryandyshev A, Belilovski E, Ganatra S, Skrahina A, Akkerman O, Aleksa A, Amale R, Artsukevich J, Bruchfeld J, Caminero JA, Carpena Martinez I, Codecasa L, Dalcolmo M, Denholm J, Douglas P, Duarte R, Esmail A, Fadul M, Filippov A, Davies Forsman L, Gaga M, Garcia-Fuertes JA, Garcia-Garcia JM, Gualano G, Jonsson J, Kunst H, Lau JS, Lazaro Mastrapa B, Teran Troya JL, Manga S, Manika K, Gonzalez Montaner P, Mullerpattan J, Oelofse S, Ortelli M, Palmero DJ, Palmieri F, Papalia A, Papavasileiou A, Payen MC, Pontali E, Robalo Cordeiro C, Saderi L, Sadutshang TD, Sanukevich T, Solodovnikova V, Spanevello A, Topgyal S, Toscanini F, Tramontana AR, Udwadia ZF, Viggiani P, White V, Zumla A, Migliori GB. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J 2017; 49: 10.1183/13993003.00387-2017. Print 2017 May. 7. Akkerman OW, Grasmeijer F, de Lange WCM, Kerstjens HAM, de Vries G, Bolhuis MS, Alffenaar JW, Frijlink HW, Smith G, Gajraj R, de Zwaan R, Hagedoorn P, Dedicoat M, van Soolingen D, van der Werf TS. Cross border, highly individualised treatment of a patient with challenging extensively drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02490-2017. Print 2018 Mar. 8. Van Kampenhout E, Bolhuis MS, Alffenaar JC, Oswald LM, Kerstjens HA, de Lange WC, van der Werf TS, Akkerman OW. Pharmacokinetics of moxifloxacin and linezolid during and after pregnancy in a patient with multidrug-resistant tuberculosis. Eur Respir J 2017; 49: 10.1183/13993003.01724-2016. Print 2017 Mar. 9. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 10. Yew WW, Chan DP, Leung CC, Zhang Y, Wang R, Ng P, Lee SM. Can toxicities induced by antituberculosis drugs be better managed in diabetic patients? Eur Respir J 2017; 50: 10.1183/13993003.00409-2017. Print 2017 Jul. 11. Kamp J, Bolhuis MS, Tiberi S, Akkerman OW, Centis R, de Lange WC, Kosterink JG, van der Werf TS, Migliori GB, Alffenaar JC. Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis. Int J Antimicrob Agents 2017; 49: 688-694. 12. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 13. Akkerman OW, van Altena R, Klinkenberg T, Brouwers AH, Bongaerts AH, van der Werf TS, Alffenaar JW. Drug concentration in lung tissue in multidrug-resistant tuberculosis. Eur Respir J 2013; 42: 1750-1752. 14. Kempker RR, Heinrichs MT, Nikolaishvili K, Sabulua I, Bablishvili N, Gogishvili S, Avaliani Z, Little BP, Bernheim A, Derendorf H, Blumberg HM, Vashakidze S, Peloquin CA. A comparison of linezolid lung tissue concentrations among patients with drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02166-2017. Print 2018 Feb. 15. Vu DH, Bolhuis MS, Koster RA, Greijdanus B, de Lange WC, van Altena R, Brouwers JR, Uges DR, Alffenaar JW. Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis. Antimicrob Agents Chemother 2012; 56: 5758-5763. 16. van Altena R, Akkerman OW, Alffenaar JC, Kerstjens HA, Magis-Escurra C, Boeree MJ, van Soolingen D, de Lange WC, Bolhuis MS, Hoefsloot W, de Vries G, van der Werf TS. Shorter treatment for multidrug-resistant tuberculosis: the good, the bad and the ugly. Eur Respir J 2016; 48: 1800-1802.   

   University of GroningenTreatment of multidrug-resistant tuberculosis using therapeutic drug monitoringBolhuis, Mathieu S; van der Werf, Tjip S; Kerstjens, Huib A M; de Lange, Wiel C M; Alffenaar,Jan-Willem C; Akkerman, Onno WPublished in:European Respiratory JournalDOI:10.1183/13993003.00580-2019IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionFinal author's version (accepted by publisher, after peer review)Publication date:2019Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Bolhuis, M. S., van der Werf, T. S., Kerstjens, H. A. M., de Lange, W. C. M., Alffenaar, J-W. C., &Akkerman, O. W. (2019). Treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring:first experiences with sub-300 mg linezolid dosages using in-house made capsules. 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For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 13-02-2023      Early View    Research letter    Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules   Mathieu S. Bolhuis, Tjip S. van der Werf, Huib A.M. Kerstjens, Wiel C.M. de Lange, Jan-Willem C. Alffenaar, Onno W. Akkerman    Please cite this article as: Bolhuis MS, van der Werf TS, Kerstjens HAM, et al. Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules. Eur Respir J 2019; in press (https://doi.org/10.1183/13993003.00580-2019).       This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online.    Copyright ©ERS 2019 Research letter ERJ Treatment of MDR-TB using therapeutic drug monitoring: first experiences with sub-300 mg linezolid dosages using in-house made capsules Mathieu S. Bolhuis1, Tjip S. van der Werf2,3, Huib A.M. Kerstjens2,4, Wiel C.M. de Lange2,4, Jan-Willem C. Alffenaar1,5, Onno W. Akkerman2,4 1University of Groningen, University Medical Center Groningen, Department of Clinical Pharmacy and Pharmacology, Groningen, The Netherlands 2University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases and Tuberculosis, Groningen, The Netherlands. 3University of Groningen, University Medical Center Groningen, Department of Internal Medicine, Groningen, The Netherlands. 4University of Groningen, University Medical Center Groningen, Tuberculosis Center Beatrixoord, Haren, The Netherlands. 5Sydney School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, Australia   Corresponding author: Mathieu S. Bolhuis, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands, Phone: +31 50 3614071, Fax: +31 50 3614087, e-mail :m.s.bolhuis@umcg.nl.    Funding: no funding was obtained for this research. Take home message: Therapeutic drug monitoring allows for sub-300 mg linezolid dosages once daily to successfully achieve PK/PD targets. Let’s confirm these retrospective data in a prospective study using dried blood spots.    Despite all our efforts, the disease burden of tuberculosis (TB) is not falling fast enough to reach the 2030 milestone of the End TB strategy [1]. Multidrug-resistant tuberculosis (MDR-TB) remains a public health crisis, with low treatment success rates [1]. The repurposed drug linezolid has  emerged as a core drug in MDR-TB treatment regimens [2,3], despite its toxicity, e.g. anemia, peripheral neuropathy and gastrointestinal disorders, optic neuritis, and thrombocytopenia [4,5].  Currently, linezolid is used off-label, as part of Group A “Medicines to be prioritised” of the World Health Organization MDR-TB treatment guideline [2] and in several large trials [6], such as the NIX- TB and END-TB trials. We use a holistic approach to treat MDR-TB, focusing multidisciplinarily on optimizing treatment using pharmacokinetics (PK) and pharmacodynamics, assessing and optimizing nutritional status, providing physical therapy and social care [7]. Treatment regimens are based on the WHO guidelines, but are individualized based on drug susceptibility testing (DST) combined with TDM if the regimen consists of second-line drugs or if patients are at risk for PK variability [8]. DST is performed at Dutch National Mycobacterial Reference Laboratory (RIVM, Bilthoven, The Netherlands).  Most patients start on a dose of 600 mg linezolid once daily. After two weeks, a full pharmacokinetic curve is obtained for all patients that receive linezolid, after which the dosage is lowered to 300 mg once daily. At steady state, the lowered dosage is again checked with TDM. Based on limited available literature, we strive for an area under the time – total fraction concentration curve (AUC0-24h) / minimum inhibitory concentration (MIC) ratio >100 [9]. If TDM allows, the dose of linezolid is reduced further to an optimal, lowest dose, with the aim to reduce toxicity of linezolid [4,5,10]. If the totalAUC0-24h/MIC ratio of linezolid is high enough, a dose reduction to 200 or even 150 mg of linezolid once daily is considered. In this study, we describe the first experiences of the treatment of MDR-TB using sub-300 mg dosages. We retrospectively searched for inpatients for whom linezolid PK data was collected between 2015-2018. As routine treatment data were collected retrospectively and anonymously, the Institutional Ethical Review Board waived the requirement to obtain informed consent (METc 2013/492). Patients that received a sub-300 mg dose of linezolid were included. Baseline characteristics co-morbidities (HIV/HBV/HCV/diabetes), MIC for linezolid, treatment regimen, and treatment outcome, were obtained from the electronic hospital record and the discharge letter from the treating lung physician.  Twenty-seven patients with linezolid pharmacokinetic data were identified. Of these patients, 18 (66%) had a final dose ≥300 mg linezolid once daily. Nine (34%) patients received a sub-300 mg dose of linezolid and were included in our study (see Table 1). These patients had a median (range) weight of 55 (43-77) kg. At admission, patients had a median (range) leucocyte count 6.6 (4.6-10.8) *109/L, thrombocytes 324 (238-461) *109/L, and hemoglobin 13.2 (11.8-16.3) g/dL. At admission, one of the patients was 32 weeks pregnant. Based on local policy, the individual patient and her preferences, it was decided – in contrast with standard practice – that the start of treatment of MDR-TB could be postponed until the patient gave birth to a healthy child. Four patients had pulmonary TB, two had extra-pulmonary TB, one had miliary TB, one had pleural TB, and one had a combination of pulmonary and extra-pulmonary TB. DST revealed that eight patients had MDR-TB and one had rifampin resistant TB. The MIC for linezolid of the Mycobacterium tuberculosis isolate was 0.25 mg/L for seven patients and 0.5 mg/L for two patients. Based on the available totalAUC0-24h/MIC ratios, dosages were lowered to 200 mg once daily in four (15%) patients and 150 mg in five (19%) patients.  The sub-300 mg dosages of linezolid are prepared as capsules at the compounding department of our pharmacy. Commercially available linezolid tablets are pulverized and sieved. Lactose-1-water is used to create the correct volume of the homogenized powder mixture, after which transparent empty capsules are filled. All capsules are checked visually and ten capsules are checked for the correct weight and percentage of deviation (≤3%) from the correct weight. The capsules are kept at room temperature for a maximum of one year.  With the sub-300 mg dosages of linezolid, the patients had a median (range) totalAUC0-24h of 50 (49-57) mg*h/L. In three cases, there was no AUC0-24h available for the lowest dose due to logistical issues. In these cases, the totalAUC0-24h of the lowest dose was calculated using our linezolid pharmacokinetic model [11] in MWPharm++ (Mediware, Groningen, the Netherlands). The median (range) totalAUC/MIC ratio was 196 (98-276), with all except one patient attaining the target of 100 that is used in our clinic, based on a systematic review of literature [12]. Since the AUC/MIC ratio of that patient was 98, we did not increase the dose.  As soon as the patients  received and tolerated their tailor-made regimen, treatment was continued at home. The included patients finished their treatment as outpatients under supervision of the staff of our center. At discharge, patients had a median (range) leucocyte count 4.7 (3.7-7.3) *109/L, thrombocytes 270 (159-327) *109/L, and hemoglobin 13.7 (11.1-16.4) g/dL. None of the patients had significant adverse events or toxicity from the linezolid dosages they received. Despite the fact that we cannot draw any conclusions about the safety or efficacy of our approach, after discharge, all except one patient (lost to follow-up) finished their treatment regimens successfully. This study describes the treatment of TB with linezolid dosages lower than 300 mg. Linezolid is known for its side effects, with a meta-analysis showing adverse events in 58.9% of patients with linezolid containing regimens to treat MDR-TB [4]. Higher dosages of linezolid (i.e. >600mg) show more side effects than lower dosages (i.e. between 300-600mg) [4,5]. In our study, in nine out of 27 patients, TDM combined with DST allowed for lowering the linezolid dosage to 200 mg or 150 mg once daily, thereby possibly limiting the number of side effects even further.  Obviously, there are limitations to this study, such as the small number of patients, missing data, and the retrospective character of the study. We do not yet have long term follow-up data, although so far no relapses occurred. We only performed PK analysis of blood samples, not of the affected tissue [13,14]. Also, the applicability of this study to low-income countries, where MDR-TB is most prevalent, might be limited. For instance, a compounding unit in a pharmacy that is able to produce linezolid capsules might not be readily available. In these cases, one could perhaps consider using quarter tablets of 600 mg linezolid (or 300 mg every two days) to administer 150 mg once daily, however one must then make sure splitting is done in a correct and safe manner. We have not studied the bioequivalence of our capsules. However, since the absorption of linezolid is usually fast and complete, PK of linezolid is non-linear, and we performed TDM, we do not expect this to impact the treatment outcome. Furthermore, TDM is not available everywhere, but dried blood spots (DBS) [15] combined with limited sampling methods [11] might allow for this strategy to be implemented in other settings. There is still an ongoing discussion on the most appropriate PK/PD target for linezolid. In our clinic, we use an AUC/MIC target of > 100 using the total fraction concentration of linezolid, based on a recent manuscript as a part of a WHO initiative to systematically review the current recommended dose for second-line TB drugs [12]. In future research, besides applicability and implementation of TDM in low-income countries, cost-benefit should also be studied. By administering lower dosages of linezolid in patients if the AUC0-24h and MIC allows, drug costs per patient of this rather expensive drug is reduced. Finally, lower dosing might reduce dose-related toxicity allowing treatment for a prolonged period of time [16].  In conclusion, sub-300 mg doses of linezolid can achieve putative PK/PD targets in certain patients. A large prospective study with DBS might provide us with valuable information on the possibilities to implement this strategy in other settings.   Table 1 baseline characteristics and pharmacokinetic/pharmacodynamic results patients receiving sub-300mg dosages of linezolid as a part of their tuberculosis treatment regimens Parameter Value Subjects 9 Age (years) 27 (17-55) Male 4 (44%) Weight (kg) 55 (43-77) Height (m) 1.65 (1.55-1.88) Body mass index (kg/m2) 20.5 (16.2-24.1) Continent of origin   Asia 4 (44%)  Europe 4 (44%)  Africa 1 (12%) HIV, Hepatitis B or C positive 0/7   Drug susceptibility   Multidrug-resistant 8  Rifampicin-resistant 1 Treatment regimen   Linezolid 9/9  Moxifloxacin 9/9  Amikacin 8/9  Ethambutol 8/9  Clofazimine 6/9  Pyrazinamide 5/9  Protionamide 2/9  (High dose) isoniazid 2/9  Cycloserin 1/9   Linezolid  Lowest dose (once daily)   200 mg  4 (44%)  150 mg 5 (56%) Dose per kg body weight (mg/kg) 3.1 (2.0-4.7) totalAUC0-24h (mg*h/L) Cmin (mg/L) 50 (35-73) 0.5 (0.3-1.2) MIClinezolid   0.25 mg/L 7 (78%)  0.5 mg/L 2 (22%) totalAUC0-24h/MIC 196 (98-276) All data are presented as median (range) or number (percentage); linezolid cocentrations are presented as total fraction concentrations (e.g. totalAUC); HIV: human immunodeficiency virus; weight, height, and body mass index were collected at admission; MIC: minimum inhibitory concentration; totalAUC: area under the time concentration curve.    References 1. World Health Organization (WHO). Global Tuberculosis Report 2018. 2018; WHO/CDS/TB/2018.20. 2. World Health Organization (WHO). Rapid Communication: Key changes to treatment of multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) . WHO/CDS/TB/2018 18 August 2018. 3. Caminero JA, Piubello A, Scardigli A, Migliori GB. Proposal for a standardised treatment regimen to manage pre- and extensively drug-resistant tuberculosis cases. Eur Respir J 2017; 50: 10.1183/13993003.00648-2017. Print 2017 Jul. 4. Sotgiu G, Centis R, D'Ambrosio L, Alffenaar J, Anger H, Caminero J, Castiglia P, De Lorenzo S, Ferrara G, Koh W, Schecter G, Shim T, Singla R, Skrahina A, Spanevello A, Udwadia Z, Villar M, Zampogna E, Zellweger J, Zumla A, Migliori GB. Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J 2012. 5. De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D'Ambrosio L, Tiberi S, Bolhuis MS, van Altena R, Viggiani P, Piana A, Spanevello A, Migliori GB. Efficacy and safety of meropenem/clavunate added to linezolid containing regimens in the treatment of M/XDR-TB. Eur Respir J 2012. 6. Borisov SE, Dheda K, Enwerem M, Romero Leyet R, D'Ambrosio L, Centis R, Sotgiu G, Tiberi S, Alffenaar JW, Maryandyshev A, Belilovski E, Ganatra S, Skrahina A, Akkerman O, Aleksa A, Amale R, Artsukevich J, Bruchfeld J, Caminero JA, Carpena Martinez I, Codecasa L, Dalcolmo M, Denholm J, Douglas P, Duarte R, Esmail A, Fadul M, Filippov A, Davies Forsman L, Gaga M, Garcia-Fuertes JA, Garcia-Garcia JM, Gualano G, Jonsson J, Kunst H, Lau JS, Lazaro Mastrapa B, Teran Troya JL, Manga S, Manika K, Gonzalez Montaner P, Mullerpattan J, Oelofse S, Ortelli M, Palmero DJ, Palmieri F, Papalia A, Papavasileiou A, Payen MC, Pontali E, Robalo Cordeiro C, Saderi L, Sadutshang TD, Sanukevich T, Solodovnikova V, Spanevello A, Topgyal S, Toscanini F, Tramontana AR, Udwadia ZF, Viggiani P, White V, Zumla A, Migliori GB. Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: a multicentre study. Eur Respir J 2017; 49: 10.1183/13993003.00387-2017. Print 2017 May. 7. Akkerman OW, Grasmeijer F, de Lange WCM, Kerstjens HAM, de Vries G, Bolhuis MS, Alffenaar JW, Frijlink HW, Smith G, Gajraj R, de Zwaan R, Hagedoorn P, Dedicoat M, van Soolingen D, van der Werf TS. Cross border, highly individualised treatment of a patient with challenging extensively drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02490-2017. Print 2018 Mar. 8. Van Kampenhout E, Bolhuis MS, Alffenaar JC, Oswald LM, Kerstjens HA, de Lange WC, van der Werf TS, Akkerman OW. Pharmacokinetics of moxifloxacin and linezolid during and after pregnancy in a patient with multidrug-resistant tuberculosis. Eur Respir J 2017; 49: 10.1183/13993003.01724-2016. Print 2017 Mar. 9. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 10. Yew WW, Chan DP, Leung CC, Zhang Y, Wang R, Ng P, Lee SM. Can toxicities induced by antituberculosis drugs be better managed in diabetic patients? Eur Respir J 2017; 50: 10.1183/13993003.00409-2017. Print 2017 Jul. 11. Kamp J, Bolhuis MS, Tiberi S, Akkerman OW, Centis R, de Lange WC, Kosterink JG, van der Werf TS, Migliori GB, Alffenaar JC. Simple strategy to assess linezolid exposure in patients with multi-drug-resistant and extensively-drug-resistant tuberculosis. Int J Antimicrob Agents 2017; 49: 688-694. 12. Bolhuis MS, Akkerman OW, Sturkenboom MGG, Ghimire S, Srivastava S, Gumbo T, Alffenaar JC. Linezolid-based Regimens for Multidrug-resistant Tuberculosis (TB): A Systematic Review to Establish or Revise the Current Recommended Dose for TB Treatment. Clin Infect Dis 2018; 67: S327-S335. 13. Akkerman OW, van Altena R, Klinkenberg T, Brouwers AH, Bongaerts AH, van der Werf TS, Alffenaar JW. Drug concentration in lung tissue in multidrug-resistant tuberculosis. Eur Respir J 2013; 42: 1750-1752. 14. Kempker RR, Heinrichs MT, Nikolaishvili K, Sabulua I, Bablishvili N, Gogishvili S, Avaliani Z, Little BP, Bernheim A, Derendorf H, Blumberg HM, Vashakidze S, Peloquin CA. A comparison of linezolid lung tissue concentrations among patients with drug-resistant tuberculosis. Eur Respir J 2018; 51: 10.1183/13993003.02166-2017. Print 2018 Feb. 15. Vu DH, Bolhuis MS, Koster RA, Greijdanus B, de Lange WC, van Altena R, Brouwers JR, Uges DR, Alffenaar JW. Dried blood spot analysis for therapeutic drug monitoring of linezolid in patients with multidrug-resistant tuberculosis. Antimicrob Agents Chemother 2012; 56: 5758-5763. 16. van Altena R, Akkerman OW, Alffenaar JC, Kerstjens HA, Magis-Escurra C, Boeree MJ, van Soolingen D, de Lange WC, Bolhuis MS, Hoefsloot W, de Vries G, van der Werf TS. Shorter treatment for multidrug-resistant tuberculosis: the good, the bad and the ugly. Eur Respir J 2016; 48: 1800-1802.   

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Treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring:first experiences with sub-300 mg linezolid dosages using in-house made capsules

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