JAC Advance Access originally published online on January 3, 2008
Journal of Antimicrobial Chemotherapy 2008 61(2):421-424; doi:10.1093/jac/dkm506
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Original research |
The role of vitamin B6 in the prevention of haematological toxic effects of linezolid in patients with cancer
Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
* Corresponding author. Tel: +1-713-792-6830; Fax: +1-713-745-6839; E-mail: rhachem{at}mdanderson.org
Received 14 August 2007; returned 15 November 2007; revised 26 September 2007; accepted 3 December 2007
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Abstract |
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Background: Linezolid is the first approved synthetic oxazolidinone with activity against multidrug-resistant Gram-positive pathogens. However, haematological toxic effects of linezolid frequently limit its prolonged use, especially in patients with poor marrow reserves such as those with cancer receiving chemotherapy. Previous authors have reported that administration of vitamin B6 with linezolid reversed pancytopenia in two patients.
Methods: This is an open-label study of 31 patients with cancer who received linezolid at 600 mg twice daily and vitamin B6 at 50 mg/day for at least 2 weeks mean therapy duration and they were matched to 62 control patients who received linezolid without vitamin B6 to determine whether the concomitant use of vitamin B6 attenuates the haematological toxicity of linezolid in patients with cancer.
Results: Patients were matched according to age, underlying disease, duration of therapy, creatinine level and use of chemotherapy. We found no significant differences in the rate of haematological toxic effects between the two patient groups. The rate of thrombocytopenia was 13% in the vitamin B6 group and 15% in the control group (P = 0.82). Also, the rate of leucopenia was 7% versus 5%, respectively (P = 0.75). None of the patients in the vitamin B6 group had anaemia compared with 5% in the control group.
Conclusions: Vitamin B6 given at 50 mg/day may have an impact on anaemia but did not prevent linezolid-induced thrombocytopenia or leucopenia in cancer patients.
Keywords: haematological toxicity , thrombocytopenia , leucopenia , oxazolidinones
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Introduction |
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Gram-positive bacteria have become the leading cause of bloodstream infections in hospitalized patients.1 This has correlated with increasing rates of methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci infections. The increased incidence of methicillin-resistant S. aureus infection has led to excessive use of vancomycin, resulting in the emergence of vancomycin-resistant enterococci. This has necessitated the development of alternative agents to vancomycin, such as linezolid.
Linezolid is the first approved synthetic oxazolidinone that is active against multidrug-resistant Gram-positive pathogens,2 several anaerobes, Nocardia species and some mycobacteria. However, haematological toxic effects of linezolid limit its prolonged use, especially in patients with cancer who have poor marrow reserves.3 These effects seem to occur more frequently in patients who receive linezolid for 2 weeks or more, and most commonly lead to anaemia and thrombocytopenia.4 The mechanism of linezolid-induced thrombocytopenia is most probably immune-mediated.5 Spellberg et al.6 associated the reversal of anaemia in two patients with Mycobacterium abscessus infections treated with linezolid for 9 months with the subsequent administration of vitamin B6. However, Plachouras et al.7 retrospectively assessed the effects of administration of vitamin B6 in 24 patients who received linezolid for bone infections and did not find a significant benefit of vitamin B6 in reducing linezolid-related haematological toxicities.
Given the inconclusive results concerning the benefits of vitamin B6, we sought to study its usefulness in patients treated with linezolid. Therefore, we conducted this open-label study in 31 patients at high risk of haematological complication who had infections treated with linezolid and vitamin B6 for at least 2 weeks and compared them with 62 historical patients who received linezolid alone.
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Methods |
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Our open-label study included patients admitted to The University of Texas (MDACC) from November 2005 to April 2006. The study was approved by the MDACC Institutional Review Board, and written informed consent to participate in the study was obtained from the enrolled patients. Patients were eligible for the study if they developed an infection due to Gram-positive bacteria and were expected to be treated with 600 mg of linezolid intravenously or orally every 12 h for at least 2 weeks and were not receiving concurrent myelosuppressive chemotherapy. Exclusion criteria included: hypersensitivity to linezolid; concomitant administration of adrenergic drugs, serotoninergic agents or selective serotonin reuptake inhibitors; use of an oral suspension containing phenylalanine; and active bone marrow suppression.
Our study consisted of 31 patients in the study group; 5 patients had haematological malignancy and 26 patients had solid tumour as underlying diseases. These patients received 600 mg of linezolid twice daily and 50 mg of vitamin B6 daily for at least 2 weeks. All of the patients began receiving vitamin B6 at 50 mg/day within 3 days of initiation of linezolid-based therapy. These 31 study patients were matched with 62 historical control patients who received only linezolid. Ten of the control group patients had haematological malignancy and the remaining 52 had solid tumour as their underlying diseases. Each study patient was matched to two control patients according to age, underlying malignancy (haematological versus solid tumour) duration of treatment, creatinine level and use of anticancer chemotherapy. The patients who completed haematology and chemistry panels were checked at baseline, during therapy, at the end of therapy and within 1 month after therapy to examine any haematological toxic effects.
Linezolid-related haematological toxic effects were defined for patients with normal baseline haemoglobin levels and platelet counts as <75% of the lower limit of normal and those with normal neutrophil baseline as absolute neutrophil counts <50% of the lower limit of normal. For patients with abnormal baseline haemoglobin, platelets and neutrophil count, toxic effects were defined as haemoglobin levels and platelet counts <75% of the baseline values and absolute neutrophil counts <50% of the baseline values. Normal platelet count was defined as 140–440 x 109 cells/L, normal white blood cell count was defined as 4–11 x 109 cells/L and normal haemoglobin level was defined as 14–18 g/DL. By using linezolid in combination with vitamin B6, a 20% improvement in the haematological toxicity was considered clinically meaningful.
The Cochran–Mantel–Haenszel tests were used for categorical analyses, and t-tests were applied to compare continuous variables. All tests were two-sided, and statistical significance was set at P 
0.05. SAS version 9.1 (SAS Institute, Cary, NC, USA) was used for all statistical analyses.
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Results |
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The patients' demographic and clinical characteristics are presented in Table 1. The mean duration of treatment with linezolid and vitamin B6 was 19 days (median, 17 days; range, 4–45 days), whereas the mean duration of treatment with linezolid in the control group was 18 days (median, 17 days; range, 2–40 days). This difference was not statistically significant (P = 0.58).
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Four patients (13%) in the vitamin B6 group received platelet transfusions during treatment with linezolid and vitamin B6. In comparison, in the control group, 10 patients (16%) received platelet transfusions, a difference that was not statistically significant (P = 0.62). Additionally, in the vitamin B6 group, 12 patients (39%) received packed red blood cell transfusions compared with 30 patients (48%) in the control group (P = 0.30, Table 1).
The rates of thrombocytopenia, leucopenia and anaemia in the vitamin B6 and control groups were 13% versus 15% (P = 0.82), 7% versus 5% (P = 0.75) and 0% versus 5% (P = 0.16), respectively (Table 2). In addition, neutropenia occurred in 8% of patients using vitamin B6 compared with 4% of patients using linezolid alone (P = 0.41).
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Two patients in the vitamin B6 group had a high creatinine level, which was defined as >1.5 g/dL. One of these patients had thrombocytopenia. We were unable to draw any conclusions regarding the significance of creatinine on the rates of haematological complications.
Most of the haematological toxic effects occurred after 2 weeks of therapy. We found no peripheral neuropathies in our patients. Four patients had thrombocytopenia in the vitamin B6 group, in three of them their platelet count returned to normal after completion of linezolid therapy. The fourth patient's platelet count recovered after a platelet transfusion.
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Discussion |
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Administration of vitamin B6 at 50 mg/day did not prevent haematological toxic effects of linezolid in patients with cancer. However, based on our data, use of vitamin B6 may reduce the risk of anaemia. None of the patients in the vitamin B6 group had anaemia, whereas 5% of the patients in the control group did.
There was no significant difference in the anaemia rates between the two groups, but there was a possible trend in favour of the vitamin B6 group. Moreover, the vitamin B6 group required fewer packed red blood cell transfusions than the control group; this may be due to the impact of vitamin B6 in reducing anaemia among this group. Another explanation for the insignificant difference in the incidence of anaemia between the two groups could be the low incidence of anaemia associated with linezolid in our population and the small sample size.
Administration of vitamin B6 is required for the synthesis of 
-aminolevulinic acid, which is a precursor of haem. Mutation of haem can lead to sideroblastic anaemia, which is responsive to vitamin B6.8 Vitamin B6-responsive anaemia has been classically described as sideroblastic in the context of gene mutations affecting the haem synthetic pathway.8 Also, sideroblastic anaemia has occurred in patients receiving linezolid. Furthermore, treatment with linezolid inhibits mitochondrial protein synthesis, which was postulated to be an important factor leading to sideroblastic anaemia9 similar to chloramphenicol toxicity. The only report demonstrating the reversal of linezolid-associated cytopenia with the administration of vitamin B6 involved mainly the resolution of linezolid-related anaemia,6 which was consistent with our finding. Hence, vitamin B6 may prevent linezolid-associated anaemia without demonstrating any impact on leucopenia or thrombocytopenia.
Another factor that may interfere with the frequency of anaemia or thrombocytopenia is transfusion of packed red blood cells or platelets, respectively. However, we did not observe a significant difference in the transfusion rate or filgrastin used between the vitamin B6 and the control groups.
Previous studies noted an increased incidence of pancytopenia in patients with renal failure.10 In our population, only two patients had high creatinine levels, and none were receiving haemodialysis during the study. Hence, the number of patients with high creatinine was too small to draw any conclusions about the effect of renal dysfunction on the occurrence of pancytopenia in patients treated with linezolid.
The rate of thrombocytopenia in our study was 13% in the vitamin B6 group versus 15% in the control group (P = 0.82). These rates are in concordance with the previously published range of thrombocytopenia rates of 2.4% to 32.0%.4 Even though treatment with linezolid has been linked with both peripheral and optic neuropathy, we did not observe such an association in our study.
The present study has the advantage of being the first comparative trial evaluating the effect of vitamin B6 in patients taking linezolid. Furthermore, most of our patients were inpatients, so the compliance rate was high. However, our study had multiple limitations. First, the small sample size could have contributed to the lack of significant difference, particularly with respect to the linezolid-associated anaemia. Second, the population was restricted to patients with cancer. In addition, several patients received platelet or packed red blood cell transfusions, which could have resulted in the underestimation of the side effects of linezolid and benefit of vitamin B6 even though the transfusion rates were similar in both groups.
The critical conditions of our patients and the presence of malabsorption related to mucositis in some of them raise the question of the adequacy of the dose of vitamin B6 used. The daily required dose of vitamin B6 for prophylaxis and treatment of drug-induced neuritis is 25–100 and 100–200 mg/day, respectively. Therefore, the question about which dose of vitamin B6 is sufficient remained to be validated. Thus, further studies using higher doses of vitamin B6 may be warranted.
In conclusion, vitamin B6 given at 50 mg/day was not beneficial in preventing thrombocytopenia or leucopenia caused by treatment with linezolid in patients with cancer. However, we did observe a possible trend towards prevention of anaemia by the addition of vitamin B6. Hence, a higher dose of vitamin B6 and a larger sample size are needed to validate these observations.
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Funding |
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Pfizer Pharmaceutical provided funding.
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Transparency declarations |
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I. R.: Speakers Bureau (Pfizer). R. F. C.: Speakers Bureau (Pfizer).
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References |
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1 Wisplinghoff H, Bischoff T, Tallent SM, et al. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis (2004) 39:309–17.[CrossRef][Web of Science][Medline]
2
Yanagihara K, Kaneko Y, Hirakata Y, et al. Efficacy of linezolid against methicillin-resistant or vancomycin-insensitive Staphylococcus aureus in a model of hematogenous pulmonary infection. Antimicrob Agents Chemother (2002) 46:3288–91.
3 Birmingham MC, Rayner CR, Meagher AK, et al. Linezolid for the treatment of multidrug-resistant, Gram-positive infections: experience from a compassionate-use program. Clin Infect Dis (2003) 36:159–68.[CrossRef][Web of Science][Medline]
4
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.
5
Bernstein W, Barile A. Mechanisms for linezolid-induced anemia and thrombocytopenia. Ann Pharmacother (2003) 37:517–20.
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Spellberg B, Yoo T, Bayer A. Reversal of linezolid-associated cytopenias, but not peripheral neuropathy, by administration of vitamin B6. J Antimicrob Chemother (2004) 54:832–5.
7 Plachouras D, Giannitsioti E, Athanassia S, et al. No effect of pyridoxine on the incidence of myelosuppression during prolonged linezolid treatment. Clin Infect Dis (2006) 43:e89–91.[CrossRef][Web of Science][Medline]
8
Harris JW. X-linked, pyridoxine-responsive sideroblastic anemia. N Engl J Med (1994) 330:709–11.
9 Dawson MA, Davis A, Elliott P, et al. Linezolid-induced dyserythropoiesis: chloramphenicol toxicity revisited. Intern Med J (2005) 35:626–8.[CrossRef][Web of Science][Medline]
10 Wu VC, Wang YT, Wang CY, et al. High frequency of linezolid-associated thrombocytopenia and anemia among patients with end-stage renal disease. Clin Infect Dis (2006) 42:66–72.[CrossRef][Web of Science][Medline]
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