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Published on 1 November 2007

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Use of linezolid for treatment of complex skin infections

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Safety, efficacy and economic data show that linezolid is a useful treatment option for suspected or confirmed skin and skin structure infections caused by Gram-positive pathogens

William J Peppard
PharmD

Clinical Pharmacist

Surgical Critical Care
Froedtert Hospital
Milwaukee
Wisconsin
USA

E: wpeppard@fmlh.edu

The rise in incidence of methicillin-resistant Staphylococus aureus (MRSA) in healthcare contexts is of growing concern, both clinically and economically. In particular, it poses challenges for the medical management of patients with complicated skin and skin structure infections (cSSSIs) due to a depleted number of drugs from which to select therapy. As the incidence of nosocomial and community-acquired MRSA continues to increase, so must practitioner awareness. While there is some disparity based on geographical location, the most recent surveillance estimates that MRSA accounts for nearly 25% of all skin and soft tissue infections (see Figure 1).[1] When other sites of infection are factored in the rate is closer to 50%, and even higher in intensive care units.[2] Additionally, the minimum inhibitory concentration (MIC) for vancomycin against MRSA continues to increase.[3] With this increase, practitioners have witnessed an increasing frequency of treatment failure with vancomycin,[4] prompting the Clinical and Laboratory Standards Institute to adjust vancomycin breakpoints for MRSA.[5,6] Despite national guidelines, the selection of appropriate therapy can still be difficult when dealing with these resistant organisms.[7]

Linezolid assessment
Linezolid, the first of the oxazolidinone drug class, manifests its antimicrobial activity by the unique inhibition of protein synthesis at the ribosomal 50S subunit, preventing the formation of the 70S initiation complex which is a necessary component for bacterial cell life.8 Linezolid has potent activity against most clinically significant Gram-positive pathogens, including methicillin-sensitive Staphylococcus aureus (MSSA), MRSA, Streptococcus spp, vancomycin-sensitive and vancomycin-resistant enterococci (VRE), and Gram-positive anaerobes.[8] It has demonstrated an oral bioavailability of nearly 100%.9 Mean blister fluid penetration is estimated to be roughly 104%, with mean plasma and inflammatory fluid levels exceeding the MIC90 for staphylococci, streptococci and enterococci throughout the dosing interval.[10] Linezolid is approved for multiple indications, but here our concern is only to the treatment of cSSSIs as defined by the FDA.[11,12] These include those involving deep soft tissue or that may require significant surgical intervention. Examples include, but are not limited to, infected ulcers and burns, major abscesses or infections in patients with significant underlying disease states which may complicate treatment response.
Stevens and colleagues first evaluated the role of linezolid for the treatment of cSSSIs in 2000 in a randomised, double-blinded, double-dummy, multicentre, multinational study (n = 819).[13] Patients with MRSA infections were not included. The study compared 10 to 21 days of linezolid (600 mg IV or PO q12 h) to either oxacillin (2 g IV q6 h) or ­dicloxacillin (500 mg PO q6 h). Cure rates for the clinically evaluable (CE) and microbiologically evaluable (ME) groups were assessed at the test-of-cure (TOC) visit 15 to 21 days after the first dose of study medication. Linezolid clinical cure rates were 89% and 88% respectively, while the oxacillin/dicloxacillin group yielded rates of 86% and 86% respectively. Linezolid was found to be statistically non-inferior to oxacillin/dicloxacillin.
With established efficacy against Gram-positive organisms such as Streptococcus spp and MSSA, the focus shifted to more resistant Gram-positive pathogens. Two years later, in a randomised, open-label, multicentre, multinational trial, Stevens and colleagues again reported linezolid data. This time they compared linezolid (600 mg IV q12 h with the option to switch to PO at the investigators’ discretion) to vancomycin (1 g IV q12 h) for the treatment of known or suspected MRSA infections in hospitalised patients.[14] Of the 460 patients evaluated, the most common infections were skin infections (50%) and pneumonia (22%). Comparable clinical cure rates were observed in all study populations at the TOC visit. In patients with MRSA cSSSIs (n = 186), clinical cure rates were 65% and 62% for linezolid and vancomycin, respectively. Linezolid was found to be statistically non-inferior to vancomycin.

[[HPE_75]]

Lipsky and colleagues evaluated 371 patients with diabetic foot infections (DFIs)15 in a randomised, open-label, 2:1 comparator-controlled, multinational trial. Patients received either linezolid (600 mg IV or PO) ±aztreonam, or they received ampicillin/sulbactam (1.5–3 g IV q6 h) or amoxicillin/clavulanate (500–875 mg PO q8-12 h) ±vancomycin and ­±aztreonam. Clinical cure rates were similar between the two groups for both the ITT population and the MRSA subset (p = nonsignificant); linezolid was found to be non-inferior to the comparator.
Weigelt and colleagues then evaluated 1,200 patients with cSSSIs in the largest trial to date,16 an open-label, randomised, 1:1 comparator-controlled, multicentre, multinational clinical study. Patients received either linezolid (600 mg IV or PO q12 h) or vancomycin (1 g IV q12 h initially, then adjusted per standard of care thereafter) for seven to 21 days. There was an option to change therapy to oxacillin/nafcillin/flucloxacillin (1-2 g IV q6 h) or dicloxacillin (500 mg PO q6 h) if the infection was determined to be MSSA. At baseline, most infections were cellulitis (46.4%), major skin abscesses (25.8%), and surgical site infections (SSIs) (10.8%). In total, 1,180 patients met the ITT criteria; 592 were randomised to the linezolid group and 588 to the comparator group. At the TOC, clinical cure rates were similar between the two groups for the ITT (92 vs 89%, p = 0.057), CE (94 vs 90%, p = 0.023), and ME (95 vs 90%, p = 0.022) populations. Microbiological success favoured the linezolid arm in the ME group (88 vs 75%, p < 0.0001) and the MRSA subset (89 vs 67%, p < 0.0001).
Of the 1,200 original patients, a subset analysis was performed to evaluate the 135 with suspected or proven MRSA SSIs.[17] Clinical success was similar between the two groups for both ITT and CE populations. Microbiological success, however, was found to be superior in the linezolid arm for MRSA infections (87 vs 48%, p = 0.0022), but not MSSA infections (89 vs 56%, p = nonsignificant).
Most recently, Sharpe and colleagues performed a single-centre, open-label evaluation of linezolid (600 mg PO q12 h) in lower-limb MRSA-related cSSSI requiring surgical intervention compared to vancomycin (1g IV q12 h) for seven to 21 days.[18] Clinical cure rates were 50 vs 20% and clinical improvement rates were 47 vs 23% for linezolid and vancomycin, respectively (p = 0.015 for both groups combined). A summary of the above trial data is provided in Table 1.

Safety
Linezolid has been well tolerated throughout clinical trials and adverse events are reported in the package insert.[11,13–18] The most common are diarrhoea, headache, nausea and insomnia. All other adverse events are reported to have an incidence of less than 3%. So far, clinical experience has matched previous findings. In common with other antibiotics, linezolid use may be associated with the development of Clostridium difficile-associated diarrhoea. Other severe, but rare, adverse effects include reversible myelosuppression with prolonged use, lactic acidosis, peripheral and optic neuropathy, and serotonin syndrome when used concurrently with serotonergic agent(s).

Healthcare costs
In the face of a rapid rise in healthcare costs,[19] practitioners are encouraged to make cost-effective decisions in treatment provision. Although direct drug costs have not increased as dramatically as a percentage of total healthcare costs, it is still a variable which can have a significant impact on cost control.
MRSA infections are not always associated with higher mortality, but they are associated with longer LOS and higher costs.[20–21] This has been specifically documented with SSIs.[22–23] Several pharmacoeconomic evaluations have been performed to provide cost justification of the use of linezolid over cheaper comparator agents. The development of a viable oral formulation has been shown to shorten hospital length of stay and, consequently, a reduction in healthcare costs.
Weigelt’s trial demonstrated shorter duration of IV therapy in the linezolid arm for the ITT, MITT, CE, ME and MRSA populations (range 1.8–4 and 9–12.6 days, respectively, p < 0.001.24 Additionally, all-cause LOS was shorter for the same groups (range 7.4–8.1 and 9.8–10.7 respectively, p < 0.0026). It is suggested that the transition to oral therapy resulted in reduced patient hospital stays for MRSA patients. Using the same patient population, it was estimated that the treatment costs associated with the ITT and MRSA populations were reduced by using linezolid ($4,864 vs $,5738, p = 0.017 and $4,881 vs $6,006, p = 0.041, respectively).[25]
A similar evaluation was carried out retrospectively on Stevens’ data, comparing linezolid to vancomycin for the treatment of known or suspected MRSA infections in hospitalised patients.[26] Again, an earlier discharge rate was observed for both the ITT and CE populations, consistent with previous ­evaluations.
Evaluation of Sharpe’s data produced similar results. The median LOS was three days shorter with linezolid in the 60 patients evaluated, resulting in a total hospital charge saving of $6,438 ($277 vs $160 per day, p < 0.069).18 Interestingly, the total cost of outpatient therapy was also lower with the linezolid group ($103 vs $200 per day, p < 0.001). The use of oral linezolid rather than IV vancomycin for outpatients is also associated with a significant reduction in use of laboratory and diagnostic tests and fewer physician office visits.[27]
An additional decision-model analysis of cost and efficacy cost-effectiveness which focused on linezolid for treatment of ventilator-associated pneumonia,[28] produced positive results when measured by cost per added quality-adjusted life year. But because this data represent an entirely different disease state, with higher mortality, the principles cannot necessarily be applied to cSSSIs.

Conclusion
Linezolid has demonstrated safety and efficacy for the treatment of cSSTIs, including SSIs and DFIs, caused by MRSA and other Gram-positive pathogens. Most of the available data were designed to detect non-inferiority and did so successfully. However, in the case of suspected or proven MRSA SSIs, linezolid has retrospectively demonstrated superiority over vancomycin.
Despite its cost, economic analyses have demonstrated overall healthcare cost savings with use of linezolid for the treatment of cSSSIs. Current safety, efficacy, and economic data show that linezolid is a reasonable treatment option for suspected or confirmed cSSSIs caused by Gram-positive pathogens, especially MRSA.
oral formulation has been shown to shorten hospital length of stay and, consequently, a reduction in healthcare costs.
Weigelt’s trial demonstrated shorter duration of IV therapy in the linezolid arm for the ITT, MITT, CE, ME and MRSA populations (range 1.8–4 and 9–12.6 days, respectively, p < 0.001.24 Additionally, all-cause LOS was shorter for the same groups (range 7.4–8.1 and 9.8–10.7 respectively, p < 0.0026). It is suggested that the transition to oral therapy resulted in reduced patient hospital stays for MRSA patients. Using the same patient population, it was estimated that the treatment costs associated with the ITT and MRSA populations were reduced by using linezolid ($4,864 vs $,5738, p = 0.017 and $4,881 vs $6,006, p = 0.041, respectively).[25]
A similar evaluation was carried out retrospectively on Stevens’ data, comparing linezolid to vancomycin for the treatment of known or suspected MRSA infections in hospitalised patients.26 Again, an earlier discharge rate was observed for both the ITT and CE populations, consistent with previous ­evaluations.
Evaluation of Sharpe’s data produced similar results. The median LOS was three days shorter with linezolid in the 60 patients evaluated, resulting in a total hospital charge saving of $6,438 ($277 vs $160 per day, p < 0.069).18 Interestingly, the total cost of outpatient therapy was also lower with the linezolid group ($103 vs $200 per day, p < 0.001). The use of oral linezolid rather than IV vancomycin for outpatients is also associated with a significant reduction in use of laboratory and diagnostic tests and fewer physician office visits.27
An additional decision-model analysis of cost and efficacy cost-effectiveness which focused on linezolid for treatment of ventilator-associated pneumonia,28 produced positive results when measured by cost per added quality-adjusted life year. But because this data represent an entirely different disease state, with higher mortality, the principles cannot necessarily be applied to cSSSIs.

References
1. Moet GH, Jones RN, Biedenbach DJ, Stilwell MG, Fritsche TR. Contemporary causes of skin and soft tissue infections in North America, Latin America, and Europe. Diagn Microbiol Infect Dis 2007;57:7-13.
2. US Centers for Disease Control. Methicillin
(oxacillin)-resistant Staphylococcus aureus (MRSA) among ICU patients, 1995–2004. Bethesda MD: US Department of Health and Human Services. Available online at: http://www.cdc.gov/ncidod/dhqp/pdf/ar/ICU_RESTrend1995-2004.pdf
3. Wang G, Hindler JF, Ward KW, Bruckner DA. Increased vancomycin MICs for Staphylococcus aureus clinical isolates from a university hospital during a 5-year period.
J Clin Microbiol 2006;44:3883-6.
4. Moise-Broder PA, Sakoulas G, Eliopoulos GM, Schentag JJ, Forrest A, Moellering RC. Accessory gene regulator group II polymorphism in
methicillin-resistant Staphylococcus aureus is predictive of failure of vancomycin therapy. Clin Infect Dis 2004;38:1700-5.
5. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing: CLSI approved standard M-100-S16. Wayne PA: CLSI; 2006.
6. Tenover FC, Moellering RC. The rationale for revising the Clinical and Laboratory Standards Institute vancomycin minimal inhibitory concentration interpretive criteria for Staphylococcus aureus. Clin Infect Dis 2007;44:1208-15.
7. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 2005;41:1373-1406.
8. Ford CW, Zurenko GE, Barbachyn MR. The discovery of linezolid, the first oxazolidinone antibacterial agent.
Curr Drug Targets Infect Disord 2001;1:181-99.
9. French G. Linezolid. Int J Clin Pract 2001;55:59-63.
10. Gee T, Ellis R, Marshall G, Andrews J, Ashby J, Wise R. Pharmacokinetics and tissue penetration of linezolid following multiple oral doses.
Antimicrob Agents Chemother 2001;45:1843-86.
11. Pfizer. Zyvox® (linezolid) (package insert). New York: Pfizer; 2007.
12. US Food and Drug Administration. Guidance for industry: uncomplicated skin and skin structure infections. Developing antimicrobial drugs for treatment. Bethesda MD: FDA; 2007. Available online at: http://www.fda.gov/cder/guidance/2566dft.pdf
13. Stevens DL, Smith LG, Bruss JB, et al. Randomized comparison of linezolid (PNU-100766) versus
oxacillin-dicloxacillin for treatment of complicated skin and soft tissue infections.
Antimicrob Agents Chemother 2000;44(12):3408-13.
14. Stevens DL, Herr D, Lampiris H, Hunt JL, Batts DH, Hafkin B. Linezolid MRSA Study Group. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections.
Clin Infect Dis 2002;34:1481-90.
15. Lipsky BA, Itani K, Norden C. Linezolid Diabetic Foot Infections Study Group. Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus
ampicillin-sulbactam/amoxicillin-clavulanate.
Clin Infect Dis 2004;38:17-24.
16. Weigelt J, Itani K, Stevens D, Lau W, Dryden M, Knirsch C. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections.
Antimicrob Agents Chemother 2005;49:2260-66.
17. Weigelt J, Kaafarani H, Itani K, Swanson R. Linezolid eradicates MRSA better than vancomycin from
surgical-site infections. Am J Surg 2004;188:760-66.
18. Sharpe JN, Shively EH, Polk HC. Clinical and economic outcomes of oral linezolid versus intravenous vancomycin in the treatment of MRSA-complicated, lower-extremity skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus.
Am J Surg 2005;189:425-8.
19. US Department of Health and Human Services. Centers for Medicare and Medicaid Services. Baltimore MD: CMMS; 2007. Available online at: http://www.cms.gov
20. Kopp BJ, Nix DE, Armstrong EP. Clinical and economic analysis of methicillin-susceptible and
-resistant Staphylococcus aureus infections.
Ann Pharmacother 2004;38:1377-82.
21. Cosgrove SE, Qi Y, Kaye KS, Harbarth S, Karchmer AW, Carmeli Y. The impact of methicillin resistance in Staphylococcus aureus bacteremia on patient outcomes: mortality, length of stay, and hospital charges.
Infect Control Hosp Epidemiol 2005;26:166-74.
22. Engemann JJ, Carmeli Y, Cosgrove SE, et al. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infection. Clin Infect Dis 2003;36:592-8.
23. Kaye KS, Engemann J, Mozaffari E, Carmeli Y. Reference group choice and antibiotic resistance outcomes. Emerg Infect Dis 2004;10:1125-8.
24. Itani KM, Weigelt J, Li JZ, Duttagupta S. Linezolid reduces length of stay and duration of intravenous treatment compared with vancomycin for complicated skin and soft tissue infections due to suspected or proven methicillin-resistant Staphylococcus aureus (MRSA). Int J Antimicrob Agents 2005;26:442-8.
25. McKinnon PS, Sorensen SV, Liu LZ, Itani KM. Impact of linezolid on economic outcomes and determinants of cost in a clinical trial evaluating patients with MRSA complicated skin and soft-tissue infections.
Ann Pharmacother 2006;40:1017-23.
26. 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. Pharmacother 2001;21:263-74.
27. McKinnon PS, Carter CT, Girase PG, Liu LZ, Carmeli Y. The economic effect of oral linezolid versus intravenous vancomycin in the outpatient setting: the payer perspective. Manag Care Interface 2007;20(1):23-34.
28. Shorr AF, Susla GM, Kolleff MH. Linezolid for treatment of ventilator-associated pneumonia: a
cost-effective alternative to vancomycin.
Crit Care Med 2004;32:137-43.
29. Wunderink RG, Cammarata SK, Oliphant TH, Kollef MH. Continuation of a randomized double blind multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia.
Clin Ther 2003;32:402-12.

Forthcoming events
European Congress of Clinical Microbiology and Infectious Diseases, Barcelona, Spain, 19–22 April 2008
108th General Meeting of the American Society for Microbiology, Boston, USA, 1–5 June 2008
13th International Congress on Infectious Diseases, Kuala Lumpur, Malaysia, 19–22 June 2008
Annual Conference on Antimicrobial Resistance, Bethesda, USA, 23–25 June 2008
48th ICAAC/46th IDSA, Washington DC, USA, 25–28 October 2008
International Meeting on Emerging Diseases and Surveillance, Vienna, Austria, 13–16 February 2009



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