1 Roswell Park Cancer Institute, Buffalo, NY; 2 Clinical Pharmacokinetics Laboratory, State University of New York at Buffalo, NY; 3 Northwestern University Medical School, Chicago, IL, USA; 4 Department of Pharmacy Practice, Monash University, Parkville, Australia
Received 24 May 2002; revised 21 November 2002; accepted 21 November 2002
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Abstract |
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Linezolid is a recently approved oxazalidinone with extended activity against Gram-positive bacteria. We evaluated the results of linezolid therapy in neutropenic cancer patients with Gram-positive bacterial infections from a compassionate-use program.
Patients and methods:
This was a prospective, multicenter, open-label, non-comparative, non-randomized compassionate-use treatment program in patients with serious Gram-positive infections. To qualify for enrollment patients were required to have an infection resistant to available antimicrobial agents, or in whom available agents had failed or to which they were intolerant. Patients with absolute neutrophil counts (ANC) <500 cells/mm3 or <1000 cells/mm3 and expected to decrease to <500 cells/mm3, and who received linezolid 600 mg twice daily were included. Plasma samples for population pharmacokinetic analysis were collected. Clinical and microbiological assessments of outcomes were made at the end of therapy and at short-term follow-up.
Results:
Of the patients in the compassionate-use trial, 103 were neutropenic. The mean [standard deviation (SD)] age was 50.1 (17.5) years, 47% were female, and 47.6% had a baseline ANC 100 cells/mm3. The mean (SD) duration of linezolid therapy was 14.6 (11.4) days. The most common site of infection was the bloodstream (90.3%), and the most commonly identified pathogen was vancomycin-resistant Enterococcus faecium (83%). A total of 83 (80.5%) and 52 (50.4%) patients were evaluable for clinical and microbiological outcomes at the end of therapy, respectively. Clinical and microbiological cure rates in the evaluable patients were 79% and 86%, respectively. Linezolid was well-tolerated in this patient population, with an overall adverse event rate of 17.5%; 5% of patients required discontinuation of the drug due to side-effects. The pharmacokinetics of linezolid in patients with neutropenia did not differ from the overall compassionate-use population.
Conclusions:
Linezolid was safe and effective in treating resistant Gram-positive infections in neutropenic cancer patients. Comparative clinical trials to evaluate further the effectiveness and safety of linezolid in this patient population are warranted.
Key words: cancer, linezolid, neutropenia, resistance
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Introduction |
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This increasing prevalence of multidrug-resistant Gram-positive bacterial infections has prompted the development of new antimicrobials with expanded activity against organisms resistant to agents such as penicillin, methicillin (oxacillin) and vancomycin. A new class of synthetic antimicrobials with extended Gram-positive activity, the oxazolidinones, has recently been developed. Oxazolidinones provide activity against penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci [817]. This class of compounds possesses a unique mechanism of action, binding to the bacterial 50S ribosomal subunit to inhibit the initiation of protein synthesis [18]. Because of this unique mechanism, oxazolidinones do not demonstrate cross-resistance with currently available antibiotics.
Linezolid is the first member of the oxazolidinone class to be approved for use in the United States. Published reports have demonstrated its effectiveness for a variety of infections in immunocompetent individuals [1922]. Linezolid is administered either intravenously or orally, with a bioavailability of 100% and a half-life of 57 h, providing for twice-daily dosing [23, 24]. Before US Food and Drug Administration approval, linezolid was made available through a compassionate-use program for patients with serious Gram-positive bacterial infections without adequate alternative treatment options. Results from patients treated under this program have been previously described, and demonstrated the efficacy and safety of linezolid in treating Gram-positive infections [25]. The purpose of this report was to analyze the safety, effectiveness and pharmacokinetics of linezolid in the subset of patients with neutropenia treated under this compassionate-use program.
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Patients and methods |
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From October 1997 to May 2000, 796 patients (828 treatment courses) were enrolled in the overall compassionate-use program. Of the 805 treatment courses in adults, the median (range) age was 55.8 (1893) years. Five hundred and fifty-six treatment courses (67.1%) were 28 days (mean 14.0) and the remaining 272 treatment courses (32.9%) were >28 days (mean 53.8). Oral therapy was used at some point in the treatment course for 46.1% of patients, and 21.7% were treated solely with oral linezolid. Clinical and microbiological response rates for the overall compassionate-use population in the evaluable patient population was 91.5% and 85.8%, respectively. For the intention-to-treat analysis of the overall compassionate-use population, clinical and microbiological cure rates were reported as 73.3% and 82.4%, respectively [25].
Study procedures
Written informed consent was obtained for each patient before enrollment, and the study protocol was approved by each local institutional review board. Patients received linezolid 600 mg intravenously or orally twice daily, and dosage adjustment was not required for either renal or hepatic dysfunction. Treatment duration ranged from 5 to 28 days, depending on site of infection, and up to 3 months of therapy was allowed with prior approval. Because of potential monoamine oxidase inhibition by linezolid [9], patients were screened and monitored for potential interacting medications, but the medications were not routinely discontinued if they were either medically necessary (i.e. vasopressors), or would have required a long duration to be completely eliminated before the initiation of linezolid therapy (i.e. serotonin-specific reuptake inhibitors).
Baseline peripheral blood cultures, cultures of the suspected infection site, laboratory tests and physical examination were obtained within 24 h before starting linezolid. The antimicrobial activity of the baseline isolates to linezolid was tested at the institutions local laboratory, and the majority of the isolates were sent to a central microbiology laboratory (Covance, Indianapolis, IN, USA) for additional evaluation. Routine laboratory tests included hematology, serum chemistry, liver function tests, urinalysis and pregnancy tests for females of child-bearing potential. Follow-up cultures were obtained every 48 h for 6 days, or until cultures became negative. Laboratory tests for safety were performed every 3 days for the first 21 days of treatment, and weekly thereafter until the end of therapy. Patients received daily clinical evaluations while receiving intravenous therapy, and every 3 days while on oral therapy. After 21 days of therapy, clinical assessments were performed weekly until linezolid treatment was completed.
Evaluation of outcomes
The clinical outcome for each patient was determined by the site investigator. Clinical response was categorized as cure (resolution of signs and symptoms of disease), failure (persistence of presenting signs or symptoms and/or new unfavorable findings relating to clinical efficacy measures by infection site), or indeterminate (extenuating circumstances preclude classification). Clinical response rates were computed as the number of patients in the cured category divided by the total number of patients. An intention-to-treat analysis was similarly performed in which all patients receiving at least one dose of study drug were included. Patients with indeterminate outcomes were excluded from the evaluable population, and treated as failures in the intention-to-treat population. The test of cure for this analysis was defined as the treatment outcome at the end of therapy.
Microbiological outcomes were classified as eradication, presumed eradication, persistence, eradication with reinfection, or indeterminate response. Presumed eradication was utilized in cases where clinical cure was achieved and the infection site precluded follow-up cultures at the end of therapy. Microbiological response rate was defined as the number of patients with eradication or presumed eradication divided by the total number of patients in the analysis. An intention-to-treat analysis was also performed for microbiological outcomes.
Adverse events
Both laboratory and clinical adverse events were evaluated prospectively by each investigator throughout the treatment and post-treatment periods. The causality of the adverse events (both serious and non-serious) to linezolid was determined by the site investigator as being either probably, possibly, or unlikely to be related to study drug. Adverse events that were classified as either probably or possibly related to linezolid were combined for this analysis. Adverse events requiring discontinuation of study drug were also recorded.
Pharmacokinetics
Plasma samples were collected for quantification of linezolid concentrations. After harvesting plasma by centrifugation, samples were frozen and shipped on dry ice to a central laboratory and assayed by a validated high performance liquid chromatography assay with ultraviolet detection. The assay has a lower limit of quantification of 0.01 mg/l, and an interday coefficient of variation (CV) <7% [27].
Population pharmacokinetic procedures as previously reported were used to analyze the plasma concentration data [28]. In summary, the pharmacokinetic parameters of linezolid were characterized using iterative two-stage analysis, a population analysis technique that also provides parameter estimates for each individual in the study sample [29], and developed using the maximum a posteriori Bayesian parameter value estimator in Adapt II, Release 4 [30]. The pharmacokinetic results from normal volunteers were utilized as initial Bayesian priors [31].
The following pharmacokinetic parameters were fitted or derived using data from each subject: volume of distribution of the central and peripheral compartments, volume of distribution at steady state, distributional clearance, ratio of drug cleared by the linear pathway divided by the estimated creatinine clearance, the MichaelisMenten constant (Km), intrinsic clearance (CLi), and the maximum velocity of capacity limited clearance (= Km x CLi). Area under the concentrationtime curve (AUC) was determined by numeric integration of the fitted model. Because none of the neutropenic patients received oral linezolid, bioavailability could not be assessed in this patient population. The pharmacokinetics of linezolid in patients with neutropenia was compared with the overall compassionate-use population.
Statistical analysis
Differences in clinical outcomes and pharmacokinetic parameters were evaluated using non-parametric methods, 2 or the KruskalWallis one-way analysis of variance or the MannWhitney test in cases involving two independent groups. All statistical tests were computed in SYSTAT (Version 10; SPSS, Inc., Chicago, IL, USA). A P value <0.05 was required for a declaration of statistical significance.
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Results |
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Clinical and microbiological outcomes
Of the 103 patients enrolled, 77 were evaluable for clinical outcome, and 52 for microbiological outcome. The majority of patients who were not evaluable received <5 days of therapy, the majority died before the fifth day. The overall mortality rate, at the completion of all study follow-up visits, for all neutropenic patients enrolled in the compassionate-use program was 33% (34 of 103).
Clinical and microbiological response rates for the evaluable population were 79% and 86%, respectively (Figure 1). For the intention-to-treat analysis, the response rates were 57% for clinical outcomes, and 45% for microbiological outcomes. Evalable patients with ANCs <100 cells/mm3 tended to have a lower clinical response rate, 69% compared with 86% for patients with a baseline ANC >100 cells/mm3. However, this difference did not meet statistical significance (P = 0.07). For the intention-to-treat population, the overall clinical response rate was 55% in patients with a baseline ANC <100 cells/mm3, and 59% for those >100 cells/mm3 (P = 0.70).
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Safety
The overall adverse event rate in this population was 17.5%, and two patients had multiple events (Table 3). The most common side-effects were increased liver function tests (n = 5), rash (n = 5) and gastrointestinal disturbances (n = 4). Three patients required discontinuation of therapy for rash, one for elevated liver function tests and one for thrombocytopenia. Overall, linezolid treatment was well-tolerated in 85% of all patients, with 7% having some tolerability problems not requiring discontinuation, and 5% requiring discontinuation of therapy due to side-effects. No clinical evidence of monoamine oxidase inhibition was observed, even in patients treated with potentially interacting medications.
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Discussion |
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As expected, the neutropenic population was more difficult to treat than the overall compassionate-use population, with lower clinical cure rates (79% versus 92% in the evaluable patients). The clinical cure rates with quinipristin/dalfopristin in patients with neutropenia have also been reported. Raad et al. [32] reported a clinical response rate of 68% in 56 immunocompromised cancer patients, while the cure rate in 14 evaluable patients from the quinipristin/dalfopristin emergency-use protocol was 64.3% [33]. These patients were limited to those with vancomycin-resistant Enterococcus faecium infections.
Because the incidence of vancomycin- and methicillin-resistant Gram-positive infections in immunocompromised hosts continues to increase, alternative options for treatment are necessary. Currently available antimicrobial agents such as linezolid and quinupristin/dalfopristin provide new options to treat such patients. Unfortunately, experience with these drugs in patients with neutropenia is limited. This is the first report summarizing the experience of linezolid in this patient population from the compassionate-use program. Based on the results, linezolid appears to be an effective antimicrobial agent for previously difficult-to-treat pathogens.
It should be noted that the majority of these patients were infected with vancomycin-resistant enterococci, most frequently of the bloodstream. While enterococci are not particularly pathogenic organisms, they have been clearly shown to result in significant morbidity and mortality [3436]. Further study and clinical experience is needed to evaluate more thoroughly linezolid use in such infections involving immunocompromised hosts.
Linezolid has demonstrated excellent activity against a broad range of Gram-positive bacterial pathogens. This extended activity should make it less likely for patients treated with linezolid to experience superinfection with other Gram-positive organisms during therapy, and superinfection was not observed in this patient population. This is in contrast to alternatives such as quinupristin/dalfopristin, which lacks activity against organisms such as Enterococcus faecalis. Superinfection with Gram-positive bacteria has been reported in patients undergoing quinupristin/dalfopristin therapy [33].
The pharmacokinetics of linezolid in patients with neutropenia was also evaluated in this report. This is of particular importance for immunocompromised hosts, to ensure that adequate drug concentrations are achieved. The pharmacokinetics of linezolid in these patients did not differ from the overall compassionate-use population. Therefore, dose adjustments for neutropenia are not necessary for pharmacokinetic reasons, with equivalent dosages resulting in equivalent drug concentrations, regardless of neutrophil counts.
It has been shown that the time to neutrophil recovery is an important aspect of caring for patients with neutropenia [37]. When a new drug is used in this population, it should be evaluated for a potential impact on the neutrophil recovery process. This is also relevant to linezolid, as long-term treatment has been associated with the potential to cause reversible myelosuppression [3841]. This effect has not been well characterized in this patient population; however, the incidence appears to be low, and the onset delayed [42, 43]. The average duration of treatment in this study was 14 days, and may not be of sufficient duration to appreciate fully such an effect. The heterogeneous population and lack of information available regarding prior myelosuppressive chemotherapy and use of colony-stimulating factors precluded a formal evaluation. However, the majority of patients in this population did recover from neutropenia, and there was no obvious trend that would suggest time to recovery was blunted. Similarly, the effect of linezolid on platelet counts could not be readily assessed, and should be considered carefully in this patient population, as linezolid has been associated with thrombocytopenia when administered for >2 weeks [42, 43]. In the current study, two patients were diagnosed with thrombocytopenia, one requiring discontinuation. Continued vigilant post-marketing surveillance or a randomized comparative trial in a homogeneous population would be needed to evaluate fully the potential effect of linezolid on hematological indices.
An important limitation of this study is its non-comparative, unblinded design. However, based on these results from the compassionate-use program, it appears that linezolid is an effective agent in the treatment of infections in neutropenic patients that are caused by resistant Gram-positive organisms, primarily vancomycin-resistant enterococci. The microbiological results, a more objective measure of an antimicrobial agents effectiveness, illustrated that linezolid was effective in eradicating the causative organisms in these immunocompromised patients. Future clinical trials to evaluate the effectiveness and safety of linezolid in this patient population are warranted.
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Acknowledgements |
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Footnotes |
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References |
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2. van den Berg AP, Klompmaker IJ, Haagsma EB et al. Evidence for an increased rate of bacterial infections in liver transplant patients with cytomegalovirus infection. Clin Transplant 1996; 10: 224231.[ISI][Medline]
3. Gold HS, Moellering RC. Antimicrobial-drug resistance. N Engl J Med 1996; 335: 14451453.
4. Linden PK, Pasculle AW, Manez R et al. Differences in outcomes for patients with bacteremia due to vancomycin-resistant Enterococcus faecium or vancomycin-susceptible E. faecium. Clin Infect Dis 1996; 22: 663670.[ISI][Medline]
5. Montecalvo MA, Shay DK, Patel P et al. Bloodstream infections with vancomycin-resistant enterococci. Arch Intern Med 1996; 156: 14581462.[Abstract]
6. Newell KA, Millis JM, Arnow PM et al. Incidence and outcome of infection by vancomycin-resistant Enterococcus following orthotopic liver transplantation. Transplantation 1998; 65: 439442.[ISI][Medline]
7. Voss A, Milatovic D, Wallrauch-Schwarz C et al. Methicillin-resistant Staphylococcus aureus in Europe. Eur J Clin Microbiol Infect Dis 1994; 13: 5055.[ISI][Medline]
8. Bhavnani SM, Ballow CH. New agents for Gram-positive bacteria. Curr Opin Microbiol 2000; 3: 528534.[CrossRef][ISI][Medline]
9. Clemett D, Markham A. Linezolid. Drugs 2000; 59: 815828.
10. Cercenado E, Garcia-Garrote F, Bouza E. In vitro activity of linezolid against multiply resistant Gram-positive clinical isolates. J Antimicrob Chemother 2001; 47: 7781.
11. Cuny C, Witte W. In vitro activity of linezolid against staphylococci. Clin Microbiol Infect 2000; 6: 331333.[CrossRef][ISI][Medline]
12. Eliopoulos GM, Wennersten CB, Gold HS, Moellering RC Jr. In vitro activities in new oxazolidinone antimicrobial agents against enterococci. Antimicrob Agents Chemother 1996; 40: 17451747.[Abstract]
13. Fines M, Leclercq R. Activity of linezolid against Gram-positive cocci possessing genes conferring resistance to protein synthesis inhibitors. J Antimicrob Chemother 2000; 45: 797802.
14. Henwood CJ, Livermore DM, Johnson AP et al. Susceptibility of Gram-positive cocci from 25 UK hospitals to antimicrobial agents including linezolid. J Antimicrob Chemother 2000; 46: 931940.
15. Johnson AP, Warner M, Livermore DM. Activity of linezolid against multi-resistant Gram-positive bacteria from diverse hospitals in the United Kingdom. J Antimicrob Chemother 2000; 45: 225230.
16. Noskin GA, Siddiqui F, Stosor V et al. In vitro activities of linezolid against important Gram-positive bacterial pathogens including vancomycin-resistant enterococci. Antimicrob Agents Chemother 1999; 43: 20592062.
17. Patel R, Rouse MS, Piper KE, Steckelberg JM. In vitro activity of linezolid against vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae. Diagn Microbiol Infect Dis 1999; 34: 119122.[CrossRef][ISI][Medline]
18. Shinabarger DL, Marotti KR, Murray RW et al. Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions. Antimicrob Agents Chemother 1997; 41: 21322136.[Abstract]
19. Stevens DL, Smith LG, Bruss JB et al. Randomized comparison of linezolid (PNU-100766) versus oxacillindicloxacillin for treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2000; 44: 34083413.
20. Stevens DL, Herr D, Lampiris H et al. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2002; 34: 14811490.[CrossRef][ISI][Medline]
21. Rubinstein E, Cammarata S, Oliphant T, Wunderink R. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clin Infect Dis 2001; 3: 402412.[CrossRef]
22. Li Z, Willke RJ, Pinto LA et al. Comparison of length of hospital stay for patients with known or suspected methicillin-resistant Staphylococcus species infections treated with linezolid or vancomycin: a randomized, multicenter trial. Pharmacotherapy 2001; 21: 263274.[ISI][Medline]
23. Welshman IR, Sisson TA, Jungbluth GL et al. Linezolid absolute bioavailability and the effect of food on oral bioavailability. Biopharm Drug Dispos 2001; 22: 9197.[CrossRef][ISI][Medline]
24. Anon. Linezolid (Zyvox). Med Lett Drugs Ther 2000; 42: 4546.[ISI][Medline]
25. 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: 159168. [CrossRef][ISI][Medline]
26. Hughes WT, Pizzo PA, Wade JC et al. Evaluation of new anti-infective drugs for the treatment of febrile episodes in neutropenic patients. Infectious Diseases Society of America and the Food and Drug Administration. Clin Infect Dis 1992; 15 (Suppl 1): S206S215.[ISI][Medline]
27. Upjohn PA. Determination of linezolid, PNU-100766, in human plasma and urine using high-performance liquid chromatography with UV detection. J Pharm Res 1997; 14: 374 (Abstr).
28. Meagher A, Forrest A, Rayner C et al. Population pharmacokinetic model for linezolid in adult patients treated in the compassionate use protocol for significant, resistant Gram (+) infections 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, ON, 2000 (Abstr 501).
29. Steimer JL, Mallet A, Golmard JL, Boisvieux JF. Alternative approaches to estimation of population pharmacokinetic parameters: comparison with the nonlinear mixed-effect model. Drug Metab Rev 1984; 15: 265292.[ISI][Medline]
30. DArgenio DZ, Schumitzky A. A program package for simulation and parameter estimation in pharmacokinetic systems. Comp Prog Biomed 1979; 9: 115134.[CrossRef][ISI]
31. Turnak MR, Forrest A. Linezolid (PNU-100766): in vivo eradication rates of nasal Staphylococcus aureus following oral administration. 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998 (Abstr A51).
32. Raad I, Hachem R, Hanna H et al. Treatment of vancomycin-resistant enterococcal infections in the immunocompromised host: quinupristin-dalfopristin in combination with minocycline. Antimicrob Agents Chemother 2001; 45: 32023204.
33. Linden PK, Moellering RC Jr, Wood CA et al. Treatment of vancomycin-resistant Enterococcus faecium infections with quinupristin/dalfopristin. Clin Infect Dis 2001; 33: 18161823.[CrossRef][ISI][Medline]
34. Shay DK, Maloney SA, Montecalvo M et al. Epidemiology and mortality risk of vancomycin-resistant enterococcal bloodstream infections. J Infect Dis 1995; 172: 9931000.[ISI][Medline]
35. Noskin GA, Peterson LR, Warren JR. Enterococcus faecium and Enterococcus faecalis bacteremia: acquisition and outcome. Clin Infect Dis 1995; 20: 296301.[ISI][Medline]
36. Bryan CS, Reynolds KL, Brown JJ. Mortality associated with enterococcal bacteremia. Surg Gynecol Obstet 1985; 160: 557561.[ISI][Medline]
37. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966; 64: 328340.[ISI][Medline]
38. Abena PA, Mathieux VG, Scheiff JM et al. Linezolid and reversible myelosuppression. J Am Med Assoc 2001; 286: 1973.
39. Arellano FM. Linezolid and reversible myelosuppression. J Am Med Assoc 2001; 286: 19731974.
40. Green SL, Maddox JC, Huttenbach ED. Linezolid and reversible myelosuppression. J Am Med Assoc 2001; 285: 1291.
41. Lawyer MC, Lawyer EZ. Linezolid and reversible myelosuppression. J Am Med Assoc 2001; 286: 1974.
42. Gerson SL, Kaplan SL, Bruss JB et al. Hematologic effects of linezolid: summary of clinical experience. Antimicrob Agents Chemother 2002; 46: 27232726.
43. Kuter DJ, Tillotson GS. Hematologic effects of antimicrobials: focus on the oxazolidinone linezolid. Pharmacotherapy 2001; 21: 10101013.[ISI][Medline]