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Infectious Diseases in Clinical Practice:
doi: 10.1097/IPC.0b013e31821e260a
NFID Clinical Updates

Managing an Elusive Pathogen: Treatment of Methicillin-Resistant Staphylococcus aureus Infections in a Variety of Care Settings

Poretz, Donald M. MD*; Rehm, Susan J. MD†

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Author Information

From *Georgetown University School of Medicine and Virginia Commonwealth University, Annandale, VA; and †The National Foundation of Infectious Diseases (NFID) Washington, DC and the Cleveland Clinic, Cleveland, OH.

Correspondence to: Donald M. Poretz, MD, Infectious Diseases Physicians, Inc., 3289 Woodburn Road, Suite 200, Annandale, VA 22003. E-mail: donald2750@aol.com.

This manuscript is based on Dr Poretz's presentation during the 2008 satellite symposium at the Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Diseases Society of America Joint Annual Meeting. Portions of the manuscript have been updated to reflect subsequent developments.

This activity is supported by an unrestricted educational grant from Cubist Pharmaceuticals.

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Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) infections continue to be a major problem both within hospitals (hospital-acquired MRSA) and increasingly in community settings (community-acquired MRSA), leading to well-publicized media reports and, as a result, greater public awareness of this problem. Clinically, it is difficult to distinguish between a MRSA and a methicillin-sensitive S. aureus skin and soft tissue infection, and this should be taken into consideration when initiating empiric therapy. There are several oral and intravenous antibiotics available to treat MRSA infections, some of which are inexpensive, whereas others are extremely costly; all have potential adverse effects and possible drug-drug interactions with which the prescriber should be familiar. Careful monitoring of patients who receive outpatient intravenous antibiotics and an understanding of various intravenous devices and their associated possible complications in addition to knowledge of the economics involved are essential to make cost-effective decisions.

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TARGET AUDIENCE

Infectious disease physicians, nurses, hospital epidemiologists, clinical microbiologists, pharmacists, public health authorities, practicing physicians, and other health care professionals interested in the treatment of serious infections due to methicillin-resistant Staphylococcus aureus.

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EDUCATIONAL OBJECTIVE

Compare and contrast options for inpatient and outpatient treatment.

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PARTICIPATION IN THE LEARNING PROCESS

Credit is based on the approximate time it should take to read this publication and complete the assessment and evaluation. A minimum assessment score of 80% is required. Publication date is May 1, 2011. Requests for credit or contact hours must be postmarked no later than November 1, 2011, after which this material is no longer certified for credit.

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CONTINUING EDUCATION

Continuing Medical Education

The National Foundation for Infectious Diseases (NFID) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The NFID designates this educational activity for a maximum of 0.5 AMA PRA Category 1 credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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Continuing Nursing Education

The NFID is an approved provider of continuing nursing education by the Maryland Nurses Association, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation. This educational activity has been approved for a maximum of 0.5 contact hours.

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DISCLOSURE

The NFID must ensure balance, independence, objectivity, and scientific rigor in its educational activities. All individuals with control over content are required to disclose any relevant financial interest or other relationship with manufacturer(s) of any product or service discussed in an educational presentation and/or with the commercial supporters of this activity. Disclosure information is reviewed in advance to manage and resolve any conflict of interest, real or apparent, that may affect the balance and scientific integrity of an educational activity.

Marla Dalton, PE (managing editor), reported no relevant financial relationships.

Thomas M. File, Jr, MD (reviewer), served as an advisor or consultant for Astellas/Theravance, Cerexa/Forest, Ortho-McNeil, Protez, Merck, Nabriva, Pfizer Inc, and Tetraphase; and received grants for clinical research from Cerexa, Ortho-Mcniel, Protez, Pfizer Inc, Boehringer Ingelheim, Gilead, and Tibotec.

Marguerite Jackson, PhD, RN (reviewer), owns stock, stock options, or bonds from Cellestis, Inc.

Donald M. Poretz, MD (faculty), received grants for clinical research from Cubist Pharmaceuticals, Inc, and Merck; and served as an advisor or consultant for Merck.

Susan J. Rehm, MD (senior editor), served as an advisor or consultant for Cubist Pharmaceuticals, Inc, Merck Vaccines, and Pfizer Vaccines; served as a speaker for Genentech; and received grants for clinical research from Cubist Pharmaceuticals, Inc.

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CME INSTRUCTIONS

To receive credits after reading the publication, complete the self-assessment examination, the evaluation, and your contact information. Return the completed form via fax to 301-907-0878 or by mail to NFID Office of CME, 4733 Bethesda Ave, Suite 750, Bethesda, MD 20814.

No fee is required. Please allow 4 to 6 weeks for processing. Inquiries may be directed by phone to 301-656-0003 or by e-mail to info@nfid.org.

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INTRODUCTION

Reports of community associated methicillin-resistant Staphylococcus aureus (community-acquired [CA-MRSA]) infections in the United States have become commonplace and are well publicized by the media. Many researchers have described this major health problem as one of epidemic proportion because of the scope and magnitude of CA-MRSA infections in the United States. By 2005, infections caused by MRSA resulted in approximately 19,000 deaths, a mortality rate greater than that associated with human immunodeficiency virus/acquired immunodeficiency syndrome in the same year.1,2

Greater public awareness of this communicable disease has caused increased anxiety across many segments of society including patients, parents of schoolchildren, government agencies, hospitals, and community settings (ie, gymnasiums, health clubs, and athletic organizations). Prevention of MRSA-related infections is critical to reducing healthcare costs related to treatment and hospitalizations and in reducing morbidity and mortality caused by the disease.

Treatment of MRSA-related infections can be challenging. Some particularly difficult questions that arise when making treatment decisions include the following: When should antibiotics be initiated? What is the appropriate treatment? In what setting should patients be treated (i.e., hospital, home, nursing home)?

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WHEN TO TREAT: DISTINGUISHING BETWEEN MRSA AND METHICILLIN-SUSCEPTIBLE S. AUREUS

Because of the difficulty in distinguishing between MRSA and methicillin-susceptible S. aureus (MSSA) skin and soft tissue infections, physicians would be wise to assume that patients with an abscess or a severe skin and soft tissue infection (SSTI) who present to their office or emergency room have CA-MRSA. The clinical and epidemiological risk factors for CA-MRSA cannot be reliably distinguished between MRSA and MSSA infections. In a prospective study of 280 patients hospitalized with S. aureus infections, the sensitivity, specificity, and predictive values for CA-MRSA risk factors were poor.3 Based on these data, the decision to prescribe empiric antibiotic therapy for a CA-MRSA infection is a difficult one. Many patients with localized mild to moderate SSTIs recover well with incision and drainage of abscesses alone and may not require antimicrobial therapy. On the other hand, concomitant antibiotic therapy should be considered for patients with severe or extensive disease or rapid progression in the presence of systemic symptoms or in certain circumstances (e.g., associated cellulitis, immunosuppression, comorbid disease, extremes of age, associated septic phlebitis, abscess in an area difficult to drain, progression after incision and drainage alone).4

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WHAT IS APPROPRIATE TREATMENT: ORAL AND PARENTERAL ANTIBIOTICS

The oral antibiotics commonly used to treat MRSA and their potential side effects are listed in Table 1. Note that rifampin use, either as a single agent or in combination with another agent, is not recommended for skin and soft tissue infections.4

Table 1
Table 1
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Patients with complex infections due to MRSA may require intravenous antibiotic therapy in addition to adjunctive treatments such as abscess drainage.4 Selection of a parenteral agent, whether for inpatient or outpatient use, requires knowledge of the comparative spectrum and mechanisms of action, pharmacokinetics, pharmacodynamics, indications for use, potential adverse events, and costs of the parenteral antibiotics active against MRSA. A detailed discussion of these factors is beyond the scope of this manuscript.

The parenteral antibiotics used for treatment of MRSA infections are listed in Table 2. Vancomycin, daptomycin, linezolid, and, to a lesser extent, clindamycin have been the workhorses of this group, but a number of newer agents have become available in the last few years. Clindamycin use may be limited in regions where clindamycin resistance has been detected. Although it is active against MRSA, quinupristin/dalfopristin is used less frequently because of adverse effects and potential difficulties in administration, particularly in an outpatient setting.6 Telavancin, a semisynthetic derivative of vancomycin, was approved for use in complicated skin and skin structure infections due to MRSA and other susceptible gram-positive bacteria in 2009.7,8 It should not be administered to pregnant women, and it must be used with caution among patients with renal dysfunction. In the setting of complex polymicrobial skin or skin structure infection (SSSI), tigecycline,9,10 or the newly approved cephalosporin, ceftaroline,11,12 may be useful.

Table 2
Table 2
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Because several of these agents are new and all require close monitoring, the cost of treating MRSA with parenteral drugs may be extraordinary. According to some researchers, vancomycin is a much less expensive 10-day course of therapy compared with daptomycin, linezolid, and tigecycline. However, other studies have shown that when monitoring, length of hospital stay, and other measures are taken into account, daptomycin and linezolid may be more cost-effective than vancomycin.13-16

Vancomycin has been the gold standard for the treatment of MRSA for many years, but difficulties of vancomycin use on an outpatient basis may limit its use in this setting. The trend in hospitals is to discharge patients with MRSA infections quickly. Monitoring vancomycin plasma concentrations in the outpatient setting to ensure proper dosage, particularly in patients with poor renal function, is a challenge. There is a risk of underdosing patients with serious infections with 1 g every 12 hours. According to published treatment guidelines, the recommended vancomycin troughs for MRSA pneumonia and central nervous system infection are 15-20 mg/L and 10-15 mg/L for MRSA bacteremia/endocarditis.4,17-20 Newer analyses support the recommendations for targeting higher vancomycin trough levels.21 As trough levels are pushed higher, increased rates of nephrotoxicity may be a concern.22

Several reports have compared the overall costs of treatment of MRSA SSTIs with daptomycin, linezolid, and vancomycin. In a retrospective study of 150 hospitalized patients with MRSA SSTIs, the overall costs of treatment (including drug expenditures and hospital charges) with daptomycin, linezolid, and vancomycin were compared.13 Total treatment costs for daptomycin were lower ($8170) compared with linezolid ($12,920) and vancomycin ($13,860).

Similarly, total treatment costs with daptomycin were lower than with vancomycin in a prospective study of patients with complicated skin and soft tissue MRSA infections.14 Furthermore, patients treated with daptomycin achieved a faster clinical cure and had decreased duration of hospital stay compared with those receiving vancomycin, which suggests that daptomycin may be a cost-effective alternative to vancomycin in treating MRSA skin and soft tissue infections. Finally, the mean total hospital treatment cost of daptomycin in 65 patients with MRSA bacteremia and/or endocarditis in a small follow-up study was lower ($13,468) than with vancomycin ($14,838).16

The cost-effectiveness of linezolid and vancomycin in the treatment of nosocomial pneumonia caused by MRSA was compared in a retrospective study based on 2 randomized controlled, double-blind studies and claims submitted to a large health care plan in the mid-Atlantic region of the United States.15 Although linezolid had higher acquisition costs, linezolid was the more cost-effective treatment than vancomycin based on improved survival and a reduction in health care costs associated with improved survival.

Third-party payors are aware of the high costs of parenteral treatment associated with MRSA infections in the hospital and subsequent to discharge. Physicians should know about the guidelines used by third-party payors regarding duration of hospitalization and outpatient care. Insurance companies commonly adhere to products such as the Milliman Care Guidelines® to determine appropriate length of stay in hospitals and other aspects of treatment in a variety of care delivery sites.23 These evidence-based guidelines include care pathway information and quality measures.

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TREATMENT WITH PARENTERAL ANTIBIOTICS IN THE OUTPATIENT SETTING

When appropriate, outpatient treatment of MRSA-related infections with oral instead of intravenous medications can reduce complications and costs. In a longitudinal study of claims data from 80 health care plans, oral linezolid therapy in the outpatient setting was associated with significantly lower resource utilization (office visits, laboratory/diagnostic claims, pharmacy claims, emergency room visits, and hospitalizations) and total medical costs compared with parenteral administration of vancomycin ($8401 vs $13,108).24

Because of the number of both old and newer parenteral antibiotics active against MRSA (Table 2), there are many treatment options available for patients who require outpatient intravenous therapy. Choice of the most appropriate agent must be individualized, based not only on drug acquisition cost but also the site and type of infection, antibiotic dose frequency, need for monitoring, and potential adverse events. When patients are carefully selected and monitored, even those with severe but stabilized infections may safely complete therapy outside the hospital.25

Treatment of MRSA infections with parenteral antibiotics can be accomplished in a variety of settings including the office, the patient's home, and an infusion center. If a patient receives treatment at home, the services are contracted to a commercial company or a physician's office that provides personnel, supplies, drugs, and equipment. If the treatment is administered in the physician's office, staffing may be a challenge and may cause scheduling conflicts with regular practice activities. An infusion center generally encompasses the physician's office, laboratory, and treatment facilities along with nursing, pharmacy, and financial services. Regardless of treatment location, the attending physician is ultimately responsible for the patient's clinical status.

Various intravenous access devices are used in the outpatient setting including heparin (hep)-locks and midline and peripherally inserted central catheter (PICC) devices. Hep-locks are easy to insert and have a low risk of infection; however, the device can be used only for a few days. The midline device has the same advantages and can be used for several weeks, but requires heparin flushes. Although the PICC line can be used for longer periods than the hep-lock or the midline devices, the PICC line requires professional insertion and maintenance and is expensive. The PICC line also requires heparin flushes and can cause infection, thrombophlebitis, and clotting. Total costs of inserting a PICC line may be as much as $3000, depending on the institution. Physicians must therefore carefully weigh the cost versus the benefits of inserting a PICC line for administration of antibiotics. For these reasons, many physicians prefer the midline device, which is less expensive to insert. The Infectious Diseases Society of America practice guidelines are an excellent resource for outpatient parenteral antimicrobial therapy, particularly with regard to adverse effects of outpatient treatment including catheter- and infusion-related effects, drug toxicities, and drug interactions.26

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SUMMARY

Preventing and treating MRSA infections are an incredible and ongoing challenge for the health care community. The decision regarding when to initiate treatment with antibiotics is a clinical decision based on individual patient risk factors and history of recurrence of MRSA infections. The choice of appropriate treatment will be determined by published clinical and pharmacoeconomic data and will be influenced by the changing clinical situation. The treatment setting may be largely determined by factors outside physician control, but it is more frequently occurring in the outpatient setting including the physician's office, the patient's home, or an infusion center.

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REFERENCES

1. Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA. 2007;298(15):1763-1771.

2. Centers for Disease Control and Prevention. S. aureus and MRSA surveillance summary. Available at: http://www.cdc.gov/mrsa/library/MRSA-Surveillance-Summary.html. Accessed February 27, 2011.

3. Miller LG, Perdreau-Remington F, Bayer AS, et al. Clinical and epidemiologic characteristics cannot distinguish community-associated methicillin-resistant Staphylococcus aureus infection from methicillin-susceptible S. aureus infection: a prospective investigation. Clin Infect Dis. 2007;44(4):471-482.

4. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus in adults and children: executive summary. Clin Infect Dis. 2011;52(3):285-292.

5. Moellering RC Jr. A 39-year old man with a skin infection. JAMA. 2008;299(1):79-87.

6. Rehm SJ, Graham DR, Srinath L, et al. Successful administration of quinupristin/dalfopristin in the outpatient setting. J Antimicrob Chemother. 2001;47(5):639-645.

7. Saravolatz LD, Stein GE, Johnson LB. Telavancin: a novel lipoglycopeptide. Clin Infect Dis. 2009;49(12):1908-1914.

8. Chang MH, Kish TB, Fung HB. Telavancin: a lipoglycopeptide antimicrobial for the treatment of complicated skin and skin structure infections caused by gram-positive bacteria in adults. Clin Ther. 2010;32(13):2160-2185.

9. Doan TL, Fung HB, Mehta D, et al. Tigecycline: a glycylcycline antimicrobial agent. Clin Ther. 2006;28(8):1079-1106.

10. Breedt J, Teras J, Gardovskis J, et al. Safety and efficacy of tigecycline in treatment of skin and skin structure infections: results of a double-blind phase 3 comparison study with vancomycin-aztreonam. Antimicrob Agents Chemother. 2005;49(11):4658-4566.

11. Steed ME, Rybak MJ. Ceftaroline: a new cephalosporin with activity against resistant gram-positive pathogens. Pharmacotherapy. 2010;30(4):375-389.

12. Corey GR, Wilcox M, Talbot GH, et al. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis. 2010;51(6):641-650.

13. Fossaceca C. Retrospective review of clinical and pharmacoeconomic outcomes associated with daptomycin, vancomycin, and linezolid usage in the treatment of complicated skin and skin structure infections. Presented at the American Society of Health-Systems Pharmacists Mid-summer Meeting; June 24-27, 2007; San Francisco CA. Poster P53E.

14. Davis SL, McKinnon PS, Hall LM, et al. Daptomycin versus vancomycin for complicated skin and skin structure infections: clinical and economic outcomes. Pharmacotherapy. 2007;27(12):1611-1618.

15. Mullins CD, Kuznik A, Shaya FT, et al. Cost-effectiveness analysis of linezolid compared with vancomycin for the treatment of nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus. Clin Ther. 2006;28(8):1184-1198.

16. Bhavnani SM, Prakhya A, Hammel JP, et al. Cost-effectiveness of daptomycin versus vancomycin and gentamicin for patients with methicillin-resistant Staphylococcus aureus bacteremia and/or endocarditis. Clin Infect Dis. 2009;49(5):691-698.

17. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009;66(1):82-98.

18. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171(4):388-416.

19. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267-1284.

20. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Disease Society of America. Circulation. 2005;111(23):e394-e434.

21. Kullar R, Davis SL, Levine DP, et al. Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets. Clin Infect Dis. 2011;52(8):975-981.

22. Hidayat LK, Hsu DI, Quist R, et al. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med. 2006;166(19):2138-2144.

23. Milliman Care Guidelines®. Available at: http://www.milliman.com/expertise/healthcare/products-tools/milliman-care-guidelines/. Accessed April 1, 2011.

24. McKinnon PS, Carter CT, Girase PG, et al. The economic effect of oral linezolid versus vancomycin in the outpatient setting: the payer perspective. Manag Care Interface. 2007;20(1):23-34.

25. Rehm S, Campion M, Katz DE, et al. Community-based outpatient parenteral antimicrobial therapy (CoPAT) for Staphylococcus aureus bacteraemia with or without infective endocarditis: analysis of the randomized trial comparing daptomycin with standard therapy. J Antimicrob Chemother. 2009;63(5):1034-1042.

26. Tice AD, Rehm SJ, Dalovisio JR, et al. Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines. Clin Infect Dis. 2004;38(12):1651-1672.

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Self-Assessment Examination
A minimum assessment score of 80% is required.

Options for treatment of complicated skin and soft tissue infection due to MRSA include all of the following except:

daptomycin

vancomycin

a cephalosporin

a macrolide

azithromycin

Which of the following statements about vancomycin in the treatment of MRSA infections is/are true?

High vancomycin troughs always lead to better outcomes in MRSA infections.

There is an inverse relationship between the vancomycin minimum inhibiting concentration (MIC) and patient outcomes.

Monitoring peak rather than trough levels is preferred.

All of the above

A and C only

Which of the following statements regarding intravenous access devices used in the administration of parenteral antibiotics in the outpatient setting is/are false?

Hep-lock and midline and PICC devices can be used for intravenous access in the outpatient or home setting.

A PICC line is less expensive to insert and maintain compared with a hep-lock or midline device.

A PICC line can be left in place for a longer period than a midline catheter.

All of the above

B and C only

Oral antibiotics used for the treatment of selected CA-MRSA infections include:

tetracycline antibiotics (doxycycline, minocycline).

trimethoprim-sulfamethoxazole

clindamycin

linezolid

all of the above

Potential limitations in use of oral linezolid for the treatment of MRSA infections include all of the following except:

cytopenias

cost

discoloration of body fluids

neuropathies

serotonin syndrome with skin and skin-structure infections

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Keywords:

MRSA; HA-MRSA; CA-MRSA

© 2011 Lippincott Williams & Wilkins, Inc.

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