Cellulitis is a common infection that can pose considerable diagnostic and therapeutic challenges.1 Most of these infections are caused by Staphylococcus aureus and β-hemolytic streptococci, although they are often difficult to isolate on culture. Blood culture results are positive in 5% or less of cases.2 Furthermore, many patients with extensive infections have concomitant conditions such as obesity, diabetes, lymphedema, and chronic venous insufficiency that can slow response to treatment.3 Antimicrobial resistance is also a major concern, and community-acquired methicillin-resistant S. aureus (cMRSA) has become a significant problem in treating cellulitis and soft tissue infections. In a recent study of adult patients with skin and soft tissue infections presenting to emergency departments (EDs) in 11 US cities, S. aureus was most commonly cultured, and 78% of these isolates were methicillin resistant.4
In patients with skin and soft tissue infections that do not require hospitalization, the choice between oral therapy and outpatient parenteral antimicrobial therapy (OPAT) is governed by factors such as antibiotic spectrum and resistance issues, absorption concerns, side effects and drug interaction potential, and allocation of costs.5 The utilization of OPAT also requires adequate home support or the ability of the patient to return to the hospital or the infusion center. Success rates for patients receiving OPAT compare favorably to hospital-based treatment with less expense than inpatient therapy.6 A suitable oral antibiotic may also be an effective option and is often less costly.7
Nowadays, fewer oral antibiotics are suitable alternatives to intravenous regimens for the treatment of cellulitis due to increasing antimicrobial resistance. Macrolide and tetracycline resistance among group A streptococci and β-lactam resistance among staphylococci is increasing in the United States.3 The potential for inducible resistance to clindamycin in cMRSA is also a concern. The oxazolidinone antibiotic, linezolid, has excellent activity against gram-positive bacteria including methicillin-resistant S. aureus (MRSA) and has been highly successful in the treatment of serious infections.8 Linezolid has also been shown to be as effective as vancomycin in hospitalized patients with skin and soft tissue infections and can decrease the duration of parenteral antibiotic therapy.9 Moreover, oral linezolid can be a suitable alternative to OPAT in patients with moderately severe cellulitis.10
To further analyze the potential cost-effectiveness of linezolid, we conducted a pilot study that compares the outcomes and costs of OPAT to oral linezolid in adult patients with skin and soft tissue infections referred to a hospital-based infusion center.
PATIENTS AND METHODS
Adult patients with moderately severe skin and soft tissue infections and stable comorbidities (class 2) who were referred to a hospital-based infusion center with an antibiotic prescription were eligible for enrollment into this prospective, randomized, pilot study.11 Clinically unstable patients or those with necrotizing infections were excluded from this study. Pregnant women, immunocompromised patients, and those with a foreign body infection were also excluded from participation. After the investigators received permission for enrollment from the patient's referring physician, they informed the patient about this investigation and obtained written informed consent from him or her before entry into the study. All guidelines for human research were followed in the conduct of this clinical trial.
Enrolled patients received either their prescribed parenteral antibiotic (normal care group) or the oral linezolid (600 mg every 12 hours) as predetermined by a random number code. None of these initial prescriptions were from an infectious diseases specialist. The duration of treatment and time to switch from intravenous to an oral antibiotic (OPAT group) as well as other patient care issues were determined by either the patient's primary physician or the ED for patients without a primary provider. Subjects were followed up daily by the investigators while on therapy and contacted at 2 and 4 weeks after completing antibiotic treatment of monitoring of clinical relapse and adverse drug events.
Outcome measures recorded for the economic analysis included all clinic, ED, wound care, and infusion center visits as well as any hospitalizations. Patients who were hospitalized or needing additional parenteral antibiotics after oral therapy were considered treatment failures. Other medical interventions (eg, laboratory tests, radiographs, etc) related to the patient's management were also recorded. The number of doses of all intravenous and oral antibiotics was documented for each subject. In addition, each patient was given a home worksheet to record antibiotic doses, side effects, medical care, and level of functioning.
The costs of medical care were standardized by using Medicare reimbursement payments as a model (Table 1). Outpatient antibiotic costs were formulated from a standard Medicare (part D) prescription drug benefit plan that requires an annual deductible of $265 and 25% cost sharing of total prescription charges from $265 to $2400.12
A total of 20 patients (10 men and 10 women) with extensive cellulitis were enrolled into this study (Figure 1). Ten subjects (mean age, 54 years; range, 38-84 years) received oral linezolid, and 10 subjects (mean age, 53 years; range, 34-68 years) received OPAT in a hospital-based infusion center. Two patients in each group had been initially hospitalized for treatment of their infection. Comorbid conditions were documented in all but 3 patients (Table 2). Before their initial visit to the infusion center, all but 2 patients (both in the linezolid group) had received antibiotics for their infection. Most infections in each treatment group involved the abdomen or the lower extremities. A pathogen was identified by culture in only 3 patients (15%); MRSA was the organism isolated in each case. None of the patient demographics or locations of infection in these 2 treatment groups were statistically different (P > 0.05, Fisher exact test and χ2 test).
Patients who received OPAT were treated with an average of 8 doses (range, 1-30 doses). These patients received 4 commonly prescribed antibiotics for skin or soft tissue infections: 4 received clindamycin and 2 each received cefazolin, ertapenem, and vancomycin.5 No significant side effects occurred in these subjects, but 4 were hospitalized due to lack of improvement of their infection. One of these patients had been initially hospitalized for their infection, and 2 patients had previous soft tissue infections. One patient received cefazolin, who was subsequently found to be infected with MRSA, 2 received clindamycin, and 1 received ertapenem. These patients did well after an average of 5 days (range, 2-11 days) of hospitalization. Four patients received oral antibiotics for an additional 7 to 10 days after improvement with OPAT, which included clindamycin (2 patients), amoxicillin and clavulanate (1 patient), and cephalexin (1 patient). These generic antibiotics were prescribed at no cost to the patient.
Patients treated with oral linezolid received an average of 19 doses (range, 9-40 doses) (9.5 days). One patient did not finish her course of therapy due to the development of skin and tongue pruritus. This subject received trimethoprim-sulfamethoxazole for 7 days at no cost to complete therapy. One other patient developed loose stools while receiving linezolid but completed the therapy. None of these patients were hospitalized during this study, but 3 received wound care while receiving linezolid. The success (cure and improvement) rates for patients receiving oral linezolid (100%) were higher than those in the OPAT group (60%) but not quite statistically significant (P = 0.09, Fisher exact test).
Medicare reimbursement costs for patients receiving OPAT would include infusion center visits (mean, $360), physician visits (mean, $114), and antibiotics (mean, $120). The overall average reimbursement cost for patients in this study would be $594 per patient (Table 3). In the 4 patients who were hospitalized, the average cost to Medicare per patient would be $3153 (mean, $1261 per 10 patients enrolled). In patients who received oral linezolid, physician visits would cost Medicare an average of $171 per patient (Table 4). In those 3 patients needing wound care, there would be an additional average cost of $185 per patient (mean, $55 per 10 patients enrolled). The overall average reimbursement cost would be $356 in patients receiving wound care (mean, $226 per 10 patients enrolled). The mean cost of oral linezolid ($57/dose) would be $1083 (19 doses). Medicare patients enrolled in a standard Medicare (part D) prescription drug benefit plan would pay $271 (Medicare cost, $812) to $536 (including the deductible) for this antibiotic until they reached $2400 for their prescriptions. No additional laboratory tests were performed in either treatment group.
A comparison of the mean costs to Medicare for each treatment arm is shown in Table 5. Based on total treatment costs, including hospitalizations, OPAT therapy in this study would average $1855 per patient compared with $1038 for oral linezolid, a difference of $817.
Outpatient parenteral antimicrobial therapy has become an accepted standard of treatment of many infections in patients who do not require hospitalization.6 In an OPAT outcomes registry of 24 sites in the United States, cellulitis was found to be the most common infection treated with OPAT.13 This method of administering antibiotics has increased steadily over the past decade due to the shortened durations of hospitalization and the increased antimicrobial resistance to oral agents. Moreover, economic incentives for hospitals as well as physicians who supervise this service have led to the emergence of OPAT as a multibillion-dollar-a-year industry.14
In patients with moderately severe cellulitis and stable comorbidities, OPAT or oral antimicrobials are suitable treatment modalities.3 The recent growth of OPAT in many communities is due to limited efficacy data with oral therapy against MRSA, which has become increasingly recognized in skin and soft tissue infections.3,4 Older oral antibiotics such as trimethoprim-sulfamethoxazole, clindamycin, and doxycycline have activity against community-acquired strains of MRSA, but each has limitations as empiric therapy for cellulitis.15 These include variable susceptibility of Streptococcus pyogenes and cutaneous reactions to trimethoprim-sulfamethoxazole, increasing resistance of MRSA to clindamycin, and limited clinical experience along with intolerance to doxycycline.3 Linezolid has proven effectiveness in the treatment of skin and soft tissue infections and is well tolerated.16 Oral linezolid has also been associated with lower resource utilization and total medical costs compared with intravenous vancomycin in outpatients with complicated skin or soft tissue infections.17 Its major disadvantage compared with other oral agents is its high cost.
In this preliminary investigation, oral linezolid was found to be a suitable alternative to OPAT in patients referred to a hospital-based infusion center for treatment of cellulitis. All but 1 patient completed their course of therapy, and none had to be hospitalized. The average costs to Medicare in this group of study patients would be $1038 for physician visits, wound care, and oral linezolid. This overall mean cost would be considerably less than the average cost of OPAT and hospitalizations ($1855) to Medicare in this investigation. Oral linezolid therapy would still have been less costly even if only 2 patients who received OPAT had been hospitalized ($1038 vs $1225). Although oral linezolid has the potential to lessen the costs of care of skin and soft tissue infections for Medicare, there would be a significant cost shift to patients for this therapy. Out-of-pocket costs would average $271 (25% of total) for Medicare part D patients in this study excluding any deductible if they have not exceeded $2400 in total prescription costs. This expense could prevent some patients from receiving this drug, so additional drug coverage would be necessary.
The results from this pilot study are limited due to the size of the study population and the different agents used for OPAT and should be recognized as preliminary findings to stimulate additional economic analysis in outpatients receiving antibiotics for skin or soft tissue infections. Furthermore, the severity of each infection was not quantified in these subjects; however, the patient's physician felt that there was a need for parenteral therapy. It is important to note that 4 patients were hospitalized while receiving OPAT. They had abdominal or lower limb infections and were receiving a β-lactam antibiotic or clindamycin as therapy. Despite the increase in cMRSA infections, there is still high rate of β-lactam use as empirical therapy for skin and soft tissue infections.18 Whether linezolid would have been more effective in these patients is unknown, although MRSA was cultured from a leg abscess in 1 subject who was receiving treatment with cefazolin, an antibiotic not active against this organism. In another case, ertapenem was being used in a very obese patient for abdominal cellulitis. A recent pharmacodynamic analysis found that standard doses (1 g daily) of ertapenem would not provide adequate drug exposure against skin pathogens in obese adults.19
In conclusion, oral linezolid can be a cost-effective alternative to OPAT in patients with cellulitis and soft tissue infections. Concerns with absorption and tolerability are not usually an issue with standard treatment durations (<2 weeks) of this drug.8,20 Moreover, oral therapy is less intrusive and time consuming compared with OPAT. The use of oral linezolid shifts a significant amount of cost for care to the patient, which may prevent its utilization. A lower deductible or percentage of cost sharing from Medicare or other managed care organizations could lessen this cost burden for patients while still lowering the overall cost of care.
The authors thank the staff at the Sparrow Hospital Infusion Center for their invaluable help in conducting this study.
1. Swartz MN. Cellulitis. N Engl J Med
2. Perl B, Gottehrer NP, Raveh D, et al. Cost-effectiveness of blood cultures for adult patients with cellulitis. Clin Infect Dis
3. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissues infections. Clin Infect Dis
4. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant S. aureus
infections among patients in the emergency department. N Engl J Med
5. Tice AD, Rehm SJ, Dalovisio JR, et al. Practice guidelines for outpatient parenteral antimicrobial therapy. Clin Infect Dis
6. DeMaio J. Outpatient parenteral antibiotic therapy. Infect Med
7. MacGregor RR, Graziani AL. Oral administration of antibiotics: a rational alternative to the parenteral route. Clin Infect Dis
8. Cupo-Abbott J, Louie SG, Rho JP. Linezolid: a synthetic oxazolidinone antimicrobial for treatment of serious gram-positive infections. Formulary
9. Itani KMF, Weigelt J, Li JZ, et al. 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
10. Stein GE, Schooley S, Kak V, et al. Oral linezolid as alternative therapy in patients with cellulitis who have been referred to an infusion center. Pharmacol Ther
11. Eron LJ. Infections of skin and soft tissue: outcomes of a classification scheme. Clin Infect Dis
12. Medicare Prescription Drug, Improvement, and Modernization Act of 2003. H.R.I. Available at: http://thomas.loc.gov/
. Accessed August 2007.
13. Nathwani D, Tice A. Ambulatory antimicrobial use: the value of an outcomes registry. J Antimicrob Chemother
14. Chary A, Tice AD, Martinelli LP, et al. Experience of infectious diseases consults with outpatient parenteral antimicrobial therapy: results of an emerging infections network survey. Clin Infect Dis
15. Sabol KE, Echevarria KL, Lewis JS. Community-associated methicillin-resistant Staphylococcus aureus
: new bug, old drugs. Ann Pharmacother
16. Weigelt J, Itani K, Stevens D, et al. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother
17. McKinnon PS, Carter CT, Girase PG, et al. The economic effect of oral linezolid versus intravenous vancomycin in the outpatient setting: the payer perspective. Manag Care Interface
18. Gupta K, MacIntyre A, Vanasse G, et al. Trends in prescribing beta-lactam antibiotics for treatment of community-associated methicillin-resistant Staphylococcus aureus
infections. J Clin Microbiol
19. Chen M, Nafziger AN, Drusano GL, et al. Comparative pharmacokinetics and pharmacodynamic target attainment of ertapenem in normal-weight, obese, and extremely obese adults. Antimicrob Agents Chemother
© 2008 Lippincott Williams & Wilkins, Inc.
20. Gee T, Ellis R, Marshall G, et al. Pharmacokinetics and tissue penetration of linezolid following multiple oral doses. Antimicrob Agents Chemother