Departments of 1 Infectious Diseases, Infection Control and Employee Health, 2 General Internal Medicine, and 3 Leukemia, The University of Texas M. D. Anderson Cancer Center, Texas, USA
Received 31 July 2003; returned 21 October 2003; revised 5 January 2004; accepted 15 January 2004
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Abstract |
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Patients and methods: Forty cancer patients with VREF infection were randomized to receive linezolid 600 mg every 12 h or quinupristindalfopristin 7.5 mg/kg every 8 h. All patients were followed up for 30 days after discontinuation of study drugs.
Results: Linezolid and quinupristindalfopristin had comparable clinical responses (58% and 43%, respectively, P = 0.6). Myalgias and/or arthralgias occurred at a frequency of 33% in patients who received quinupristindalfopristin, but were not observed in the linezolid group (P = 0.03). In contrast, drug-related thrombocytopenia occurred in 11% of patients who received linezolid, but was not observed in the quinupristindalfopristin group (P = 0.2).
Conclusion: In cancer patients, quinupristindalfopristin treatment is associated with a relatively high frequency of myalgias/arthralgias; however, profound thrombocytopenia might limit the choice of linezolid in a subpopulation of cancer patients.
Keywords: enterococcal infections, enterococcal bacteraemia, resistant Gram-positive infections, Synercid, Zyvox
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Introduction |
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Among conventional antimicrobial agents, no effective regimen was available for the treatment of VREF infections until two novel antibiotics were approved in the USA (quinupristindalfopristin in 1999 and linezolid in 2000).3 Quinupristindalfopristin has been shown to be efficacious in the treatment of VREF infections; however, its use has been limited by myalgias/arthralgias and phlebitis if given through a peripheral vein.4 Linezolid, which is not associated with these adverse events, is available in an oral form and has a broader spectrum of activity that includes Enterococcus faecalis.5 Although several studies have independently investigated the efficacy and safety of quinupristindalfopristin and linezolid in the treatment of VREF infections, these two antibiotics have not been compared in a prospective, randomized study. In this pilot, prospective, randomized study, we compared the safety and efficacy of these two drugs in the cancer patient population.
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Patients and methods |
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Eligible patients were randomized by the pharmacyaccording to a computer-generated randomization listto receive one of the following regimens: (1) quinupristindalfopristin 7.5 mg/kg intravenously (iv) every 8 h; or (2) linezolid 600 mg iv or orally every 12 h. All patients were to receive treatment up to 30 days if necessary. Follow-up was continued for 30 days after discontinuation of the study drug. Patients were evaluated during treatment, at the end of treatment and during the follow-up period.
Type of infection (e.g. bacteraemia, surgical wound infection or upper urinary tract infection) and clinical or microbiological efficacy (cure, failure or indeterminate), were defined as previously described.4,5 The microbiological identification of all VREF isolates and their susceptibility to quinupristindalfopristin and linezolid were determined as previously described.6 In brief, clinical cure was defined as the resolution of all signs and symptoms relating to the original infections with no new signs or symptoms associated with the original infection. Microbiological cure was defined as complete eradication of the organism from the original site of the infection with no relapse of the microbiological organism during the 30 day follow-up period. An adverse event was defined as any undesirable event associated with the use of the study drug and was characterized as definite, possible or not related as described elsewhere.5 Thrombocytopenia or leukopenia was defined as 50% reduction in platelet or white cell counts compared with baseline while on study drug.
The primary analysis was a comparison of the safety of the two drugs with the efficacy being a secondary objective. Since myalgias/arthralgias was previously the most reported treatment-limiting adverse event,3,4 and given the fact that 36% of our patients who previously received quinupristindalfopristin developed myalgias/arthralgias,6 we estimated that the frequency of such an adverse event in patients who received linezolid would be 4%. It was, therefore, assumed that a sample size of 20 patients in each arm (total of 40 patients) would be needed in order to show a significant difference in myalgias/arthralgias with a power of 80% and 95% confidence. Differences between frequencies of categorical variables were determined by using the 2 test or the Fishers exact test, as appropriate. Continuous variables with normal distribution were compared by using the Students t-test, whereas continuous variables that were not normally distributed were compared by using the MannWhitney test. We considered P < 0.05 to be significant.
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Results |
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Thrombocytopenia occurred at a frequency of 11% with linezolid (Table 3), but was not observed in patients who received quinupristindalfopristin (P = 0.2). The two cases of thrombocytopenia that were possibly related to linezolid occurred within 1 week of the initiation of this antibiotic. These two cases occurred in patients with underlying acute myelocytic leukaemia whose platelet counts dropped (while on linezolid) at least three-fold to as low as 9 x 103 platelets/mm3 for each of the two cases.
Most of the VREF infections were bacteraemias, but there were two VREF surgical wound infections in the linezolid group and one upper urinary tract infection in the quinupristindalfopristin group. All VREF organisms isolated from patients in the two study groups were susceptible to quinupristindalfopristin or linezolid at an MIC < 1 mg/L or < 2 mg/L, respectively.
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Discussion |
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The response rate of 43% to quinupristindalfopristin in this population (consisting mostly of patients with haematological malignancy) is consistent with a previous study by Linden et al.4 whereby leukaemia patients with VREF infection had a 44% clinical response to quinupristindalfopristin. Recently, Birmingham et al. 5 reported a clinical response of 78% among patients with VREF bacteraemia treated with linezolid. However, only 16.7% of the patients had an underlying haematological malignancy and 14.1% had long-term immunosuppression. We have previously reported a response rate of 69% among VREF-infected cancer patients (90% with haematological malignancy) who were treated with quinupristindalfopristin and minocycline.6 It is possible that the addition of minocycline could have contributed to this improved outcome.
The relapse rate of VREF infection was almost two-fold greater in those patients who received linezolid compared with those who received quinupristindalfopristin (21% versus 10%, respectivelynot significant). In this particular patient population (with prolonged neutropenia), the source of the bacteraemia is most likely the gastrointestinal tract. The fact that 75% of the quinupristindalfopristin is eliminated through the hepatobiliary/faecal route could have contributed to the decrease in the inoculum of VREF in the gastrointestinal tract, and hence, a lower relapse rate associated with this antibiotic. In contrast, <10% of linezolid or its inactive metabolites are excreted through the gastrointestinal tract.7
In a multicentre, prospective, non-comparative trial involving 396 patients with VREF infection treated with quinupristindalfopristin, myalgias and arthralgias were the most frequently reported adverse event.4 Winston et al.8 recently reported myalgias/arthralgias as the only adverse event related to quinupristindalfopristin, occurring in 33% of patients. Myalgia/arthralgia in that study was dose-related, whereby it occurred only in patients who received 7.5 mg/kg every 8 h and did not occur in patients who received 5 mg/kg every 8 h. In a previous study at our centre, myalgia/arthralgia was noted in 36% of patients treated with quinupristindalfopristin and was associated with biliary dysfunction.6 More recently, two studies reported myalgia/arthralgia at a rate of 47%9 and 50%10 in patients receiving quinupristindalfopristin, and in one10 of those studies this adverse event occurred more frequently in patients with chronic liver disease, or who had received a liver transplant. In this current pilot study, myalgia/arthralgia was associated only with the use of quinupristindalfopristin (Table 3). In all cases, this adverse event resolved with discontinuation of the drug.
Thrombocytopenia was reported in 7.4% of 796 patients treated with linezolid as part of the compassionate use programme.11 Thrombocytopenia, as well as other haematological events (including leukopenia and decreased haemoglobin), seemed to occur more frequently after 2 weeks of initiating treatment with linezolid.11 In this current study, the two cases of thrombocytopenia occurred within a week of therapy with linezolid. However, most of the patients (90%) had received less than 2 weeks of treatment with this agent. Linezolid-induced thrombocytopenia could be fatal in patients with haematological malignancy.12
In conclusion, quinupristindalfopristin and linezolid have comparable efficacy in the treatment of VREF infections in cancer patients, most of whom had haematological malignancy. Myalgias/arthralgias are the most frequent treatment-limiting adverse events associated with the use of quinupristindalfopristin and should be enquired for, especially in patients with biliary dysfunction. In order to decrease the risk of myalgia/arthralgias, clinicians should consider adjusting the dose of quinupristindalfopristin in those patients with biliary dysfunction or those receiving medication that can cause hepatic cholestasis. Large, prospective, randomized comparative studies are required to assess the relevance of linezolid-associated myelosuppression in patients with underlying haematological malignancy, and the impact of dose adjustment in reducing the risk of myalgias/arthralgias in patients with biliary dysfunction.
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Footnotes |
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Present address. University of Balamand Faculty of Medicine & Medical Sciences, Beirut, Lebanon
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References |
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