1. Risk Factors for Linezolid-Associated Thrombocytopenia in Adult Patients Cristina Gervasoni Ospedale Luigi Sacco, Milano

2.  Linezolid is an oxazolidinone antibiotic active against Gram- positive pathogens resistant to β-lactams and glycopeptides and XDR-M.tuberculosis  Clinical trials have shown that linezolid is safe and generally well tolerated  The major adverse event associated with linezolid treatment is reversible myelosuppression, mostly thrombocytopenia (and, to a lesser extent, leukopenia and anemia), eventually requiring drug discontinuation Background

3.  To determine the risk factors for linezolid-associated thrombocytopenia Aim of the study

4.  Retrospective study conducted among consecutive patients who received linezolid therapy (600 mg bid/day) between January 2011 and December 2014 at Luigi Sacco University Hospital, in Milan  Any relevant information on the clinical status and safety outcome of the patient was collected in a standardized database  Linezolid trough concentrations were determined in patients receiving the drug for at least 3 days  The patients with other causes for myelosuppression or treated with rifampicin were excluded  Thrombocytopenia was defined as ≥ 50% decrease in platelet count from baseline Patients and methods

5. All patients (n=70) Patients with toxicity (n=14) Patients without toxicity (n=56) Age, years54.7 ± 20.569.8 ± 11.7*50.8 ± 11.7 Males, % 64%78%61% Weight, Kg64.9 ± 12.768.9 ± 5.764.1 ± 13.9 Height, cm169 ± 9169 ± 10170 ± 9 S. Creatinine, mg/dL1.1 ± 0.71.8 ± 1.2*0.9 ± 0.4 GFR, mL/min82.9 ± 41.948.5 ± 37.9*93.8 ± 38.6 AST (IU/L)37 ± 4034 ± 3037 ± 42 ALT (IU/L)40 ± 6230 ± 3342 ± 68 Bone infections (30%), skin infections (25%) and drug-resistant tuberculosis (38%) Data were given as mean ± standard deviation *p<0.01 vs patients without toxicity Baseline characteristics of patients who subsequently did (n=14) or did not (n=56) develop drug-related thrombocytopenia during linezolid treatment

6. Box-plot of linezolid plasma trough concentrations measured in patients that did or did not develop thrombocytopenia (first TDM assessment) Thrombocytopenia [Linezolid], mg/L 0 2 4 6 8 10 12 14 16 18 20 No thrombocytopenia p = 0.01

7. Linezolid trough levels, mg/L Patients with toxicity (n=14) 1 st evaluation9.0 ± 6.4 2 nd evaluation10.7 ± 5.3 3 th evaluation (n=8)*4.0 ± 1.4 Patients without toxicity (n=56) 1 st evaluation4.9 ± 3.7 2 nd evaluation4.8 ± 3.3 3 th evaluation4.9 ± 4.6 °Data were given as mean ± standard deviation *Six patients withdrew linezolid after the adverse events, while the remaining reduced drug dose.

8. Time from initiation of linezolid therapy to development of thrombocytopenia Days after initiation of treatment Probability of developing thrombocytopenia

9.  A significant proportion of patients treated with the conventional LZD dose are at higher risk to experience thrombocytopenia  Age, renal function, length of treatment and LZD plasma concentrations were associated with the development of haematological toxicity  Patients treated with LZD may benefit from TDM-driven adjustments of linezolid doses  TDM-guided dose adjustment may provide potential advantages in terms of costs and tolerability compare with fixed dose LZD regimen treatment Conclusions

10.  Concomitant rifampicin administration significantly reduces linezolid concentrations  It is currently unknown for how long such effect may persist and when linezolid could be safely administered to guarantee optimal drug exposure in patients previously treated with rifampicin  A significant effect of rifampicin on linezolid concentrations up to 2–3 weeks after its discontinuation was observed  It is mandatory to monitor linezolid concentrations not just before and during concomitant rifampicin administration but also extensively later (i.e., up to 3 weeks) after rifampicin withdrawal in order to guarantee appropriate linezolid exposure

11. The PD patients had concentrations that were 3- to 4-fold higher than the upper therapeutic threshold of 8 mg/L 3 out of the 4 patients experienced severe toxicity, whereas in the remaining case, the development of toxicity was probably avoided due to an early reduction of the dosage of linezolid These findings call for a careful revision of the most appropriate linezolid dose in PD patients, especially when they are elderly and/or require prolonged treatment Our case series also confirmed that linezolid-related toxicity can be easily handled in clinical practice by TDM-guided early dose adjustments or, if TDM is not available, by stringent haemato- chemical examinations

12.  No indications on linezolid dose adjustments are given for patients with renal insufficiency or with renal replacement therapy  Emerging evidence shows that these patients treated with the conventional linezolid dose have higher drug exposure and higher frequency of haematological toxicity  This case report shows that in patients on peritoneal dialysis safety outcomes may be improved by applying TDM as soon as possible after starting treatment with linezolid