1 Infectious Diseases Department, Dron Hospital, 135 rue du Président Coty, 59200 Tourcoing; 2 Department of Orthopaedic Surgery, Faculty of Lille, Lille; 3 Department of Orthopaedic Surgery, Dron Hospital, Tourcoing; 4 Clinical Microbiology Laboratory, Dron Hospital, Tourcoing, France
Received 23 February 2004; returned 14 April 2004; revised 24 June 2004; accepted 29 June 2004
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Abstract |
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Methods: The medical charts of patients given linezolid for >4 weeks were retrospectively analysed, especially their haematology. In a casecontrol study, we compared the respective characteristics of patients who developed anaemia during linezolid therapy and those who did not.
Results: Forty-five adults with chronic osteomyelitis received 600 mg linezolid intravenously twice daily for 7 days, and then orally, for a mean total duration of 15.9 weeks (range, 636). Anaemia episodes requiring blood transfusion occurred in 13/45 patients (28.9%). Median time from treatment initiation to anaemia onset was 7.4 weeks (range, 416). Anaemia was significantly associated with premature linezolid therapy cessation (P=0.0012). No linezolid-related thrombocytopenia was observed. By univariate analysis, four variables were associated with the occurrence of anaemia: age >58 years, alcohol abuse, diabetes mellitus and low haemoglobin before linezolid treatment. Logistic regression analysis revealed two independent risk factors for anaemia: age >58 years (OR = 20.5, 95% CI 0.69599; P=0.0001) and pre-treatment haemoglobin <10.5 g/dL (OR = 16.49, 95% CI 1.06255; P=0.04).
Conclusions: Profound anaemia may occur in adult patients with chronic osteomyelitis on prolonged linezolid therapy, and often necessitates linezolid cessation. These patients are likely to be aged >58 years and to have low pre-treatment haemoglobin. The results for the present series might help physicians to identify patients who should not be given long-term linezolid treatment for chronic osteomyelitis.
Keywords: oxazolidinones , toxicity , myelosuppression
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Introduction |
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Linezolid is a synthetic antibiotic which belongs to the new class of oxazolidinones. Certain recent results support the notion that linezolid might be useful for the management of multidrug-resistant Gram-positive chronic osteomyelitis.912 At present, however, available clinical data are not sufficient to determine whether prolonged linezolid therapy is safe for patients with chronic osteomyelitis.
Since most clinical studies of linezolid have only covered periods of <2 weeks, very little is known about its long-term toxicity, especially as regards myelosuppression. A few cases of reversible myelosuppression, especially thrombocytopenia and occasionally anaemia, have recently been reported.1316 Most patients who experienced anaemia were receiving concomitant medications known to cause bone marrow suppression, and many had complex illnesses.17
For the last 3 years, we have been using linezolid combined with other antibacterial agents, especially rifampicin, as long-term therapy for patients with Gram-positive chronic osteomyelitis. None of our patients experienced linezolid-related thrombocytopenia, but several of them developed profound linezolid-related anaemia and required blood transfusions. The present casecontrol study was undertaken to explore the possible existence of factors associated with the development of anaemia in osteomyelitis patients on long-term linezolid therapy.
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Patients and methods |
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The medical records of patients treated with linezolid for 4 weeks or more for chronic osteomyelitis were reviewed. The diagnosis of chronic osteomyelitis was assessed on the basis of the following data: fever >38°C, inflammation or purulent discharge in the area of the osteosynthesis devices or prostheses, or biological inflammatory syndrome (erythrocyte sedimentation rate >50 mm/h and C-reactive protein >10 mg/L), radiological evidence of loose osteosynthesis devices or prostheses (luxation or pseudarthrosis), evidence of chronic osteomyelitis on plain radiography, presence of leucocytes on direct examination of intraoperative samples and Gram-positive pathogens (methicillin-resistant S. aureus or coagulase-negative staphylococci, and Enterococcus spp.). Infection was considered chronic when it had started >4 weeks before the diagnosis of osteomyelitis. All microbiological cultures were obtained from intraoperative bone biopsies or joint aspirations. Bacteria were assessed on species identification using API (bioMérieux, Marcy l'Étoile, France), and the antibiotic susceptibility pattern was interpreted according to the recommendations of the Comité de l'Antibiogramme de la Société Française de Microbiologie.
All patients had given written consent to receive linezolid for >4 weeks and had accepted weekly haematological monitoring and monthly clinical assessment.
Treatment protocol
Linezolid was administered intravenously at a dosage of 600 mg twice daily for 7 days, and then orally at the same dosage until the completion of therapy. In agreement with previous reports, the expected durations of linezolid treatment in the present patients were at least 3, 4 and 6 months for chronic osteomyelitis or osteosynthesis devices, total hip prosthesis and total knee prosthesis, respectively. Antibiotic treatment was combined with surgical debridement or removal of the orthopaedic material in some situations (unstable device and severe sepsis) and in delayed re-implantation. In other cases, patients retained the infected material during treatment. When there was mixed infection that included Gram-negative bacteria, appropriate antibiotics were added to linezolid.
Follow-up
Haematology was assessed weekly and included haemoglobin, haematocrit, counts of red and white blood cells (WBC), absolute neutrophil counts and platelet counts (PLTC). For patients with normal or abnormal baseline values, anaemia, thrombocytopenia and leucopenia were defined, respectively, as haemoglobin and PLTC <75% and WBC <50% of the lower limit of normal (i.e. 12 g/dL in men and 11 g/dL in women for haemoglobin, 150 x 103 PTL/mm3 for PTLC and 4 x 103 cells/mm3 for WBC) or baseline values. In cases of anaemia, levels of vitamin B12, folates, iron and haptoglobin were measured, reticulocytes counted and bone marrow analysis was performed if the patient accepted the procedure.
Statistical analysis
Variables were compared using the Wilcoxon rank sum test for quantitative variables and Fisher's exact test for qualitative variables adapted to small numbers if necessary. Logistic regression analysis was used for the multivariate study.
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Results |
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Anaemia occurred in 13/45 patients (28.9%) and was significantly associated with the premature cessation of linezolid therapy (P=0.0012, Figure 1). Three patients without anaemia had to stop linezolid therapy because they developed peripheral sensitive neuropathy. Among the patients with anaemia and those without, 10 (76.9%) and 14 (43.7%), respectively, had an abnormal pre-treatment haemoglobin as defined above. Mean pre-treatment haemoglobin was 10.1 g/dL in patients who developed anaemia and 11.8 in those who did not (P=0.01). The mean ratios of the expected/observed duration of linezolid treatment were 17.2/11.6 and 14.7/18.6 weeks in patients with and without anaemia, respectively. All patients with anaemia required blood transfusions because their haemoglobin levels were <8.0 g/dL. A low absolute reticulocyte count was associated with anaemia. The median time from linezolid therapy initiation to onset of anaemia was 7.4 weeks (range, 416). All patients with anaemia had normal baseline serum iron, vitamin B12 and folic acid levels, and none had either underlying haematological disease or severe renal impairment. No events involving leucopenia were reported, and only one case of thrombocytopenia occurred under linezolid treatment but that was due to alcohol abuse. Bone marrow analysis in seven of the 13 patients with anaemia showed moderate eosinophilia, decreased cellular marrow with red blood cell aplasia but no myelopoietic dysplasia and normal platelet development.
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Discussion |
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The oxazolidinones, initially developed as monoamine oxidase inhibitors for the treatment of depression, were not used in humans for some time despite their antimicrobial activity, because they were found to be lethal in animals. The development of their use for clinical purposes started with the discovery of linezolid, which was markedly less toxic than the original agents. The precise mechanism of action of linezolid is not known, but it is thought to interfere with protein synthesis at a very early stage.17 The main advantage of this totally synthetic antimicrobial agent is the absence of cross-resistance with the other current classes of antibacterial drugs.17 Linezolid exhibits a spectrum of activity at least as wide as that of the glycopeptides, and has the advantage of an available oral formulation with a bioavailability of 100%. Clinical studies have already shown that linezolid was as efficient as vancomycin for the treatment of severe systemic methicillin-resistant Gram-positive infections, including bacteraemia due to vancomycin-resistant enterococci.18 It has been suggested that linezolid is more effective than vancomycin in shortening the hospital stay for patients with methicillin-resistant staphylococcal infections.19 This is important, given the very high cost of linezolid in France (>60 for both one 600 mg tablet and one intravenous vial). Although local concentrations of linezolid and vancomycin are comparable, linezolid appears to be more effective than vancomycin against staphylococcal biofilms, possibly because its biofilm protein binding is lower than of that of vancomycin.20 Linezolid activity against methicillin-resistant S. aureus and vancomycin-resistant Enterococcus faecium is maintained under anaerobic conditions.21 In addition, in vitro studies have shown that combining linezolid with rifampicin prevented the occurrence of rifampicin- or linezolid-resistant isolates.22 These data support the notion that linezolid could be used together with rifampicin to treat chronic bone and joint infections due to resistant Gram-positive cocci as a replacement for glycopeptides, which are not easy to administer in a long course of parenteral therapy.
However, the prolonged use of linezolid can lead to myelosuppression, including neutropenia, thrombocytopenia and anaemia.23 As a result, weekly monitoring of haematological values is recommended for patients on linezolid therapy.17 Reversible myelosuppression with red-cell hypoplasia after therapy with linezolid has already been reported in Phase 3 clinical trials of linezolid and in other recent studies: thus, Monson and co-workers13 reported a case of reversible pure red blood cell aplasia that developed in a patient who had been on linezolid therapy for 8 weeks, and Green and co-workers14 reported reversible linezolid-associated hypoproliferative anaemia in three patients who were receiving 600 mg linezolid twice daily for 612 weeks. Decreased haemoglobin/haematocrit levels were reported in 4.1% of patients treated for miscellaneous multidrug-resistant Gram-positive infections, and subsequently in 5% of diabetic patients with foot infections.12,24
The present results for the overall haematological tolerance of linezolid therapy differ slightly from those of previous authors, who reported thrombocytopenia episodes in up to 10% of the patients, but rarely anaemia.16 The inclusion in previous studies of patients with more severely compromised immune status, haematological disorders and septic conditions than those of our patients may explain these differences. In particular, most of our patients had no sepsis or concomitant medications potentially toxic for the bone marrow.
Our data confirm previous reports that myelosuppression rarely occurs before day 14 of linezolid therapy and appears to be due to the prolonged duration of therapy.12,14 In our patients and those included in previous studies, rapid recovery of normal erythropoiesis occurred after the cessation of linezolid therapy. Bone marrow examinations performed in our patients showed abnormalities not entirely different from those seen in patients with chloramphenicol toxicity. This might be due to certain similarities between the mechanisms of action of linezolid and phenicols.17 In animal studies, hypersegmentation of megakaryocytes and ringed sideroblasts were reported to be present in bone marrow samples.25 Here, the respective roles of deficient B-vitamins, abnormal folates and renal impairment could not be evaluated, because they were not present in any of our patients. Nevertheless, these abnormalities should probably be taken into account before considering long-term linezolid therapy, because they may impair haematopoiesis. After discontinuation of linezolid therapy, we observed no cases of anaemia in patients given glycopeptides instead of linezolid. The high frequency of anaemia episodes in our patients was probably due to the very long duration of their therapy, because most of them had chronic infection of an orthopaedic device. In univariate analysis, age, haemoglobin baseline values, diabetes mellitus and alcohol abuse were significantly associated with anaemia. By multivariate analysis, we found that age >58 years and a pre-treatment haemoglobin <10.5 g/dL were independent risk factors for the occurrence of anaemia in patients treated for chronic osteomyelitis. Note that the haemoglobin level of some of the present patients who had a value of <10.5 g/dL at the start of linezolid therapy rose during treatment. These patients had normal haemoglobin before surgery and no other risk factor for anaemia (data not shown). Therefore, patients with low pre-treatment haemoglobin but no other risk factors could probably be given long-term linezolid therapy, provided their haemoglobin level before surgery is normal. We did not find any correlation between anaemia and the antimicrobial agent associated with linezolid. In particular, patients treated with the rifampicinlinezolid combination did not differ from those treated with other combinations as regards myelosuppression. All the patients with an infected orthopaedic device received linezolid combined with another antistaphylococcal agent, because the emergence of resistance during therapy has been reported in patients with indwelling prosthetic devices who were given linezolid.26
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Conclusions |
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Acknowledgements |
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Footnotes |
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References |
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