Linezolid: low pre-treatment platelet values could increase the risk of thrombocytopenia

Santiago Grau*, José A. Morales-Molina, Javier Mateu-de Antonio, Mónica Marín-Casino and Francisco Alvarez-Lerma

Hospital del Mar, Passeig Marítim, 25–29, 08003 Barcelona, Spain


* Corresponding author. Tel: +34-93-248-30-00; Fax: +34-93-248-32-56; E-mail: sgrau{at}imas.imim.es

Keywords: oxazolidinones , toxicity , platelet count , critical illness

Sir,

Recently, Senneville et al.1 published a study including 45 patients with prolonged linezolid therapy (4 weeks or longer) for chronic osteomyelitis in whom risk factors for anaemia were assessed. The authors found that two independent risk factors were associated with anaemia: age >58 years and low pre-treatment haemoglobin. Patients who developed anaemia presented nearly 17 times more frequently with pre-treatment haemoglobin less than 10.5 g/dL (P = 0.04).

In similar work, we have studied prospectively 49 critical non-thrombocytopenic patients with short course linezolid therapy for risk factors related to moderate to severe thrombocytopenia (platelet count 100 x 103 cells/µL or less) at the end of linezolid treatment.2 Statistical tests used were Mann–Whitney U-test for quantitative independent variables, and {chi}2 and Fischer exact tests for dichotomous variables. Patients were mainly male 27 (55.1%) and admitted to the intensive care unit (ICU) due to medical (21/49, 42.9%), surgical (27/49, 55.1%) and trauma (1/49, 2.0%) causes. The rest of patient characteristics are shown in Table 1. The mean duration of linezolid treatment lasted 14.4 days (95%CI 11.9–17.0, range 3–41). Thrombocytopenia was detected in 12 patients (24.5%). Through a univariate analysis, three factors were related to thrombocytopenia: Simplified Acute Physiologic Score II, pre-treatment albumin and pre-treatment platelet count. Through a multivariate analysis, only the pre-treatment platelet count remained as an independent factor related to thrombocytopenia (P = 0.034) and to platelet decrease (P < 0.001). There were significant differences between the thrombocytopenic group and the non-thrombocytopenic group in mean initial pre-treatment platelet count [240.7 x 103 cells/µL (95%CI 160.3 x 103 to 321 x 103) versus 354.2 x 103 cells/µL (95%CI 295.3 x 103 to 413.0 x 103), P = 0.021] and in the mean platelet drop [–161.2 x 103 cells/µL (95%CI –240.1 x 103 to –82.3 x 103) versus –52.6 x 103 cells/µL (95%CI –111.5 x 103 to 6.4 x 103), P = 0.023]. Patients with a pre-treatment platelet count of 240.7 x 103 cells/µL or less had more incidence of thrombocytopenia (8/18, 44.4%) than those with higher pre-treatment values (4/31, 12.9%, P = 0.018), odds ratio: 5.4 (95%CI 1.33–21.95). When all patients were considered, crude mortality rate, ICU and hospital length of stay did not differ between patients who developed thrombocytopenia and those who did not (P = 0.504, P = 0.321 and P = 0.732, respectively). When only survivors were considered (18/49, 36.7%), patients who developed thrombocytopenia had a longer ICU length of stay [87.3 days (95%CI 4.45–170.0) versus 33.3 days (95%CI 16.7–50.0), P = 0.025]. Economic outcomes were not assessed.


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Table 1. Patient characteristics at admission to the intensive care unit and at the beginning of linezolid treatment

 
Thrombocytopenia occurred in 3% of the patients who received linezolid in clinical trials. Gerson et al.,3 extracting data from previous clinical trials, analysed anaemia, thrombocytopenia (<75% of baseline value) and neutropenia from 2046 linezolid-treated patients versus 2001 comparator (vancomycin, ceftriaxone, cefpodoxime, clarithromycin, or oxacillin-dicloxacillin)-treated patients. The overall rate was 2.9% in the linezolid group and 1.5% in the comparator group. Nasraway et al.,4 extracting data from two prospective studies, compared the risk of thrombocytopenia (platelet count < 150 x 103 cells/µL) between linezolid and vancomycin in 862 patients with nosocomial pneumonia. Thrombocytopenia occurred in 2.8% in the linezolid group and in 3.6% in the vancomycin group. However, these percentages have been considered underrated by other authors. In two post-marketing studies, the linezolid-associated thrombocytopenia rate was about 47% in both cases and a platelet count lower than 100 x 103 cells/µL occurred in 32% and 19% of the patients, respectively.5,6 Our incidence of thrombocytopenia, considering the same definition, was in this range. Two factors have to be taken into account for this high rate. Our patients were not selected as those enrolled in clinical trials and, in addition, were critical patients with high severity scores, and had increased risk of developing thrombocytopenia.4

Gerson et al.3 stated that thrombocytopenia and/or anaemia occurred most often in patients with underlying haematological abnormalities or lower haematological baseline values. That statement seems to be supported by the results of the Senneville et al.1 study for red blood cells in patients with osteomyelitis and by our study for platelets in critical patients.

Outcomes in patients with linezolid-associated haematological disturbances have not been generally assessed in the published studies and, therefore, it is unknown whether these disturbances caused prolonged hospital stay or higher mortality rate. In our study, thrombocytopenia did not increase mortality rate or hospital stay when considering all patients. However, survivors who developed linezolid-associated thrombocytopenia more that doubled their ICU length of stay compared with patients who did not.

Patients on linezolid therapy with lower pre-treatment haematological values are at risk not only to develop anaemia, as Senneville et al. concluded, but also they are at risk to develop thrombocytopenia. Patients with short treatments, especially in severe conditions, are also at risk to develop thrombocytopenia.

References

1. Senneville E, Legout L, Valette M et al. Risk factors for anaemia in patients on prolonged linezolid therapy for chronic osteomyelitis: a case–control study. J Antimicrob Chemother 2004; 54: 798–802.[Abstract/Free Full Text]

2. Morales JA, Mateu-de Antonio J, Grau S et al. Linezolid in critical patients: risk factors related to thrombocytopenia. In: Abstracts of the Forty-fourth Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, 2004. Abstract 696, K-1570, p. 368. American Society for Microbiology, Washington, DC, USA.

3. Gerson SL, Kaplan SL, Bruss JB et al. Haematological effects of linezolid: summary of clinical experience. Antimicrob Agents Chemother 2002; 46: 2723–6.[Abstract/Free Full Text]

4. Nasraway SA, Shorr AF, Kuter DJ et al. Linezolid does not increase the risk of thrombocytopenia in patients with nosocomial pneumonia: comparative analysis of linezolid and vancomycin use. Clin Infect Dis 2003; 37: 1609–16.[CrossRef][ISI][Medline]

5. Attassi K, Hershberger E, Alam R et al. Thrombocytopenia associated with linezolid therapy. Clin Infect Dis 2002; 34: 695–8.[CrossRef][ISI][Medline]

6. Orrick JJ, Johns T, Janelle J et al. Thrombocytopenia secondary to linezolid administration: what is the risk? Clin Infect Dis 2002; 35: 348–9.[CrossRef][ISI][Medline]





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