Prospective, randomized study comparing quinupristin–dalfopristin with linezolid in the treatment of vancomycin-resistant Enterococcus faecium infections

Issam Raad1,*, Ray Hachem1, Hend Hanna1, Claude Afif1,§, Carmen Escalante2, Hagop Kantarjian3 and Kenneth Rolston1

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


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives: Quinupristin–dalfopristin and linezolid have been shown to be efficacious in the treatment of vancomycin-resistant Enterococcus faecium (VREF) infections. However, the two antibiotics have not been compared in terms of safety and efficacy in a prospective randomized study. The objective of this study was to compare the safety and efficacy of the two drugs in the treatment of VREF infections in cancer patients.

Patients and methods: Forty cancer patients with VREF infection were randomized to receive linezolid 600 mg every 12 h or quinupristin–dalfopristin 7.5 mg/kg every 8 h. All patients were followed up for 30 days after discontinuation of study drugs.

Results: Linezolid and quinupristin–dalfopristin 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 quinupristin–dalfopristin, 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 quinupristin–dalfopristin group (P = 0.2).

Conclusion: In cancer patients, quinupristin–dalfopristin 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


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The most serious complications associated with vancomycin-resistant Enterococcus faecium (VREF) infections occur in severely immunocompromised patients, particularly cancer patients who are either neutropenic or have an underlying haematological malignancy.1,2 Edmond et al.1 studied the outcome of VREF bacteraemia in a population consisting mostly (70%) of patients with underlying haematological malignancy and demonstrated that such infections are associated with an attributable mortality of 37%. In addition, 81% of the patients developed hypoperfusion abnormalities and/or organ dysfunction. Montecalvo et al.2 determined that neutropenia is a risk factor for the persistence of VREF bacteraemia in immunocompromised patients.

Among conventional antimicrobial agents, no effective regimen was available for the treatment of VREF infections until two novel antibiotics were approved in the USA (quinupristin–dalfopristin in 1999 and linezolid in 2000).3 Quinupristin–dalfopristin 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 quinupristin–dalfopristin 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.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Between August 1998 and December 2001, adult cancer patients were evaluated for placement on the current study if they fulfilled all of the inclusion criteria: (1) male, or non-pregnant, non-lactating female age >18 years of age; (2) infection caused by VREF; (3) ability to obtain written informed consent prior to enrolment. Patients were excluded from the study if they: (1) were allergic to any of the study antibiotics; (2) were pregnant; (3) had used antibiotic therapy that is potentially effective against VREF for more than 24 h prior to enrolment; (4) had severe hepatic impairment (alanine aminotransferase or total bilirubin levels greater than five-fold of normal, or thrombin time greater than 1.5-fold of normal); (5) had renal insufficiency (creatinine clearance <50 mL/min, unless the patient was on dialysis). In conducting this study, we adhered to the ethical standards of medical research as outlined by our institutional guidelines. An informed consent approved by the Institutional Review Board was obtained on all patients prior to the initiation of the study drugs.

Eligible patients were randomized by the pharmacy—according to a computer-generated randomization list—to receive one of the following regimens: (1) quinupristin–dalfopristin 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 quinupristin–dalfopristin 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 quinupristin–dalfopristin 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 {chi}2 test or the Fisher’s exact test, as appropriate. Continuous variables with normal distribution were compared by using the Student’s t-test, whereas continuous variables that were not normally distributed were compared by using the Mann–Whitney test. We considered P < 0.05 to be significant.


    Results
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 Patients and methods
 Results
 Discussion
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As shown in Table 1, the characteristics of patients, including duration of treatment, in the two study groups were, for the most part, comparable. However, patients who received quinupristin–dalfopristin were more frequently critically ill (P < 0.05) or suffered from concurrent pneumonia (P < 0.05).


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Table 1. Quinupristin–dalfopristin versus linezolid as therapy for VREF infection: characteristics of patients receiving linezolid or quinupristin–dalfopristin
 
As shown in Table 2, the two study groups had comparable clinical and microbiological responses. No patients were withdrawn or declined to participate after knowing which of the two agents they were randomized to receive. Although the relapse rate was almost twice as high in patients who received linezolid compared with quinupristin–dalfopristin, this was not statistically significant. The rate of myalgias/arthralgias was 33% (7/21) in the quinupristin–dalfopristin study group (Table 3), whereas no myalgias/arthralgias were reported in patients who received linezolid (P < 0.01).


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Table 2. Outcome associated with linezolid and quinupristin–dalfopristin
 

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Table 3. Adverse events associated with linezolid and quinupristin–dalfopristin
 
Severe myalgias/arthralgias resulted in the discontinuation of quinupristin–dalfopristin in one patient. However, this adverse event improved in two patients when the dose of quinupristin–dalfopristin was reduced to every 12 h, and it resolved in all of the seven cases when this drug was discontinued. Other possibly related gastrointestinal adverse events occurred more frequently in patients receiving linezolid, but this difference was not significant.

Thrombocytopenia occurred at a frequency of 11% with linezolid (Table 3), but was not observed in patients who received quinupristin–dalfopristin (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 quinupristin–dalfopristin group. All VREF organisms isolated from patients in the two study groups were susceptible to quinupristin–dalfopristin or linezolid at an MIC < 1 mg/L or < 2 mg/L, respectively.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In this study, quinupristin–dalfopristin and linezolid had comparable efficacy in the treatment of VREF infections in cancer patients. The fact that patients who received quinupristin–dalfopristin were more frequently critically ill with an underlying pneumonia could have contributed to the slightly higher rate of indeterminate clinical response in the quinupristin–dalfopristin group, since clinical response is more difficult to evaluate in critically ill patients.

The response rate of 43% to quinupristin–dalfopristin 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 quinupristin–dalfopristin. 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 quinupristin–dalfopristin 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 quinupristin–dalfopristin (21% versus 10%, respectively—not 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 quinupristin–dalfopristin 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 quinupristin–dalfopristin, 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 quinupristin–dalfopristin, 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 quinupristin–dalfopristin 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 quinupristin–dalfopristin, 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 quinupristin–dalfopristin (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, quinupristin–dalfopristin 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 quinupristin–dalfopristin 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 quinupristin–dalfopristin 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.


    Footnotes
 
* Correspondence address. Department of Infectious Diseases, Infection Control and Employee Health (Unit 402), The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA. Tel: +1-713-792-7943; Fax: +1-713-792-8233; E-mail: iraad{at}mdanderson.org Back

§ Present address. University of Balamand Faculty of Medicine & Medical Sciences, Beirut, Lebanon Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 . Edmond, M. B., Ober, J. F., Dawson, J. D. et al. (1996) Vancomycin-resistant enterococcal bacteraemia: natural history and attributable mortality. Clinical Infectious Diseases 23, 1234–9.[ISI][Medline]

2 . Montecalvo, M. A., Shay, D. K., Patel, P. et al. (1996). Bloodstream infections with vancomycin-resistant enterococci. Archives of Internal Medicine 156, 1458–62.[Abstract]

3 . Eliopoulos, G. M. (2003). Quinupristin/dalfopristin and linezolid: evidence and opinion. Clinical Infectious Diseases 36, 473–81.[CrossRef][ISI][Medline]

4 . Linden, P. K., Moellering, R. C., Wood, C. A. et al. for the Synercid Emergency-Use Study Group. (2001). Treatment of vancomycin-resistant Enterococcus faecium infections with quinupristin/dalfopristin. Clinical Infectious Diseases 33, 1816–23.[CrossRef][ISI][Medline]

5 . Birmingham, M. C., Rayner, C. R., Meagher A. K. et al. (2003). Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-use program. Clinical Infectious Diseases 36, 159–68.[CrossRef][ISI][Medline]

6 . Raad, I., Hachem, R., Hanna, H. et al. (2001). Treatment of vancomycin-resistant enterococcal infections in the immunocompromised host: quinupristin-dalfopristin in combination with minocycline. Antimicrobial Agents and Chemotherapy 45, 3202–4.[Abstract/Free Full Text]

7 . Linden, P. K. (2002). Treatment options for vancomycin-resistant enterococcal infections. Drugs 62, 437–41.

8 . Winston, D. J., Emmanouilides, C., Kroeber, A. et al. (2000). Quinupristin/dalfopristin therapy for infections due to vancomycin-resistant Enterococcus faecium. Clinical Infectious Diseases 30, 790–7.[CrossRef][ISI][Medline]

9 . Olsen, K. M., Rebuck, J. A. & Rupp, M. E. (2001). Arthralgias and myalgias related to quinupristin-dalfopristin administration. Clinical Infectious Diseases 32, e83–6.[CrossRef][ISI][Medline]

10 . Carver, P. L., Whang, E., VandenBussche, H. L. et al. (2003). Risk factors for arthralgias or myalgias associated with quinupristin-dalfopristin therapy. Pharmacotherapy 23, 159–64.[ISI][Medline]

11 . Gerson, S. L., Kaplan, S. L., Bruss, J. B. et al. (2002). Haematological effects of linezolid: summary of clinical experience. Antimicrobial Agents and Chemotherapy 46, 2723–6.[Abstract/Free Full Text]

12 . Hachem, R. Y., Hicks, K., Huen, A. et al. (2003). Myelosuppression and serotonin syndrome associated with concurrent use of linezolid and selective serotonin reuptake inhibitors in bone marrow transplant recipients. Clinical Infectious Diseases 37, e8–11.[CrossRef][ISI][Medline]