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Infectious Diseases in Clinical Practice:
doi: 10.1097/01.idc.0000240861.97435.d1
Editorial Comment

Treatment of Serious Infections Caused by Methicillin-resistant Staphylococcus aureus: The Perpetual Challenge

Rehm, Susan J. MD

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Department of Infectious Disease, Cleveland Clinic, Cleveland, OH.

Address correspondence and reprint requests to Susan J. Rehm, MD, Department of Infectious Disease, Cleveland Clinic, Desk S32, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: rehms@ccf.org.

In this issue, 3 articles1-3 describe clinical experience with daptomycin, a cyclic lipopeptide antibiotic approved for clinical use 3 years ago. An additional review of the results of daptomycin use in patients with orthopedic infections appeared in the May 2006 issue of Infectious Diseases in Clinical Practice.4 The impetus for the use of daptomycin in most of the cases in these reports was methicillin-resistant Staphylococcus aureus (MRSA).

With increasing frequency, newspaper and magazine headlines, radio reviews, and television images reinforce the daily experience of clinicians: infections caused by MRSA present enormous challenges. Rising rates of health care-associated MRSA infections were well documented in the past decade,5 before infections caused by community-associated MRSA (CA-MRSA) strains made their terrible impact.6 Now, CA-MRSA has made its way into health care settings, compounding the pain.7

The recognition of higher morbidity and mortality rates among patients with MRSA (compared with methicillin-susceptible S. aureus [MSSA]) bacteremia8,9 has the potential to be the first step in discovering the reason for the difference. Are the outcomes of MRSA infections worse because of patients' underlying conditions, unique features of the MRSA strains, or vulnerabilities of available therapies?

It is clear that patients with long-term, indwelling venous-access devices and a variety of implanted devices are susceptible to MRSA infection, and their underlying conditions (ie, diabetes, renal failure, and/or compromised immune systems) may impact their ability to clear infection before complications develop. Meta-analyses9 attempt to control for comorbidities. The relationship between certain virulence characteristics and aggressive infection has become increasing clear in the era of CA-MRSA infections10 when many patients have no underlying health problems.

Except for infection-control activities designed to reduce exposure to MRSA, there seems to be little that clinicians can do to impact the spread of these aggressive infections. Neither patients' conditions nor strain factors are amenable to intervention. In terms of treatments, the importance of therapeutic maneuvers such as incision and drainage of abscesses cannot be overlooked.11 However, all eyes are on antibiotics as the singular factor for innovation in treatment.

Despite years of experience with vancomycin and antibiotic combinations including vancomycin, doubts persist as to its effectiveness in treating serious infections caused by S. aureus. Time to clearance of bacteremia is slower with MRSA compared with MSSA infections,12 and cure rates in endocarditis are lower when patients infected with MSSA are treated with vancomycin.13 Some have implicated vancomycin in the poor clinical responses of patients with MRSA bacteremia and endocarditis.14 The emergence of vancomycin-intermediate and vancomycin-resistant strains of S. aureus and the demonstration of poorer clinical response rates among patients infected with S. aureus strains with higher vancomycin minimal inhibitory concentrations that are still in the susceptible range (vancomycin-heteroresistant strains)15-17 have added to the concern about vancomycin's long-term viability.

Quinupristin/dalfopristin and linezolid, the early contenders in the competition to surpass vancomycin, have experienced some victories and some defeats. Both have been associated with the emergence of resistant isolates,18-20 and both have been associated with treatment-limiting adverse reactions.21-23 The Food and Drug Administration-approved indications for both are limited, particularly with regard to treatment of serious infections caused by MRSA.

Daptomycin, previously approved for the treatment of complicated skin and skin structure infections caused by MSSA, MRSA, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and vancomycin-susceptible Enterococcus faecalis, recently received approval for important additional indications: treatment of bacteremia and right-sided endocarditis caused by MSSA and MRSA. Record-breaking sales of daptomycin attest to the clinicians' desire for alternatives to vancomycin therapy.

The review by Antony et al4 describes the successful outcomes of 17 of 31 orthopedic patients treated with daptomycin, 77% of whom were infected with MRSA. Nineteen patients were infected with MRSA alone, and 5 with MRSA and at least one other organism. All but 3 of 24 patients with MRSA infections received daptomycin as second- or third-line therapy after failing a prior therapy. Eighteen of 21 patients failing initial therapy had received vancomycin, with concomitant or sequential additional therapies in half of the patients in this category. All 4 of the patients who failed daptomycin salvage therapy were infected with MRSA but 2 of the 4 were successfully retreated with daptomycin in combination with rifampin and vancomycin.

Treatment of orthopedic infections is inherently difficult because of issues of bone penetration, adequacy of debridement, or the presence of prosthetic devices. The case report of Carlyn et al1 brings into focus other factors, including characteristics of the host and S. aureus, which influence response to antimicrobial therapy. Their patient with rheumatoid arthritis, diabetes mellitus, and several other comorbidities developed vertebral osteomyelitis, epidural abscess, and possible native aortic valve endocarditis caused by a small-colony variant of MRSA during vancomycin therapy for a prosthetic joint infection caused by MSSA. Treatment with daptomycin, in combination with minocycline, rifampin, and a short course of gentamicin, resulted in defervescence and clearance of the bacteremia that had persisted despite below-knee amputation. Unfortunately, the patient later had a relapse of MSSA sepsis.

The bone marrow transplant patient with relapsed chronic myelogenous leukemia and MRSA-native valve endocarditis of the mitral valve described by Paez et al2 had received 2 prior courses of vancomycin and was persistently bacteremic on vancomycin, leading to initiation of daptomycin therapy. As in other cases with reported development of resistance, host factors and strain characteristics likely contributed to the clinical course.

In contrast, the patient described by Edwards et al3 had no significant medical history, except for gastric bypass and recent repair of a torn rotator cuff. She received daptomycin empirically for suspected postoperative infection and had a good clinical response. However, she developed myalgia associated with elevated creatine phosphokinase levels within the first 48 hours of daptomycin administration. The symptoms and signs cleared within a week.

The 3 case reports and the case series represent a portion of the accumulating clinical experience with daptomycin. Most patients received treatment for documented infection caused by MRSA, and most had failed vancomycin (and sometimes other therapies) before receiving daptomycin. Intriguing studies suggest that exposure of S. aureus to vancomycin may affect susceptibility to daptomycin.24

In the case series of orthopedic infections treated with daptomycin, success rates were very good. The 2 case reports describing treatment of immunocompromised patients demonstrate the complexity of the interactions between the patient, the microorganism, and the antimicrobial agent(s). In the presence of a persistent or protected focus of infection and suboptimal host defenses, MRSA still has the advantage over antibiotics.

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1. Carlyn CJ, Baltch AL, George MJ, et al. Daptomycin in the treatment of persistent bacteremia with invasive complications caused by a small colony variant of methicillin-resistant Staphylococcus aureus in an orthopedic patient. Infect Dis Clin Pract. 2006;14: In press.

2. Paez AS, Brown RB, Wilk PA, et al. Rapid loss of daptomycin susceptibility in methicillin-resistant Staphylococcus aureus blood culture isolates from an infective endocarditis patient. Infect Dis Clin Pract. 2006;14:322-324.

3. Edwards CM, King K, Garcia RJ. Early-onset rhabdomyolosis associated with daptomycin. Infect Dis Clin Pract. 2006;14:327-328.

4. Antony SJ, Angelos E, Stratton CW. Clinical experience with daptomycin in patients with orthopedic-related infections. Infect Dis Clin Pract. 2006;14:144-149.

5. Noskin GA, Rubin RJ, Schentag JJ, et al. The burden of Staphylococcus aureus infections on hospital in the United States: an analysis of the 2000 and 2001 Nationwide Inpatient Sample Database. Arch Intern Med. 2005;165:1756-1761.

6. Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med. 2005;352:1436-1444.

7. Seybold U, Koubatova EV, Johnson JG, et al. Emergence of community-associated methicillin-resistant Staphylococcus aureus USA300 genotype as a major cause of health care-associated blood stream infections. Clin Infect Dis. 2006;42:647-656.

8. Whitby M, McLaws ML, Berry G. Risk of death from methicillin-resistant Staphylococcus aureus bacteremia. Med J Aust. 2001;175:264-267.

9. Cosgrove SE, Sakoulas G, Perencevich EN, et al. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis. 2003;36:53-59.

10. Chambers HF. Community-associated MRSA-resistance and virulence converge. N Engl J Med. 2005;352:1485-1487.

11. Young DM, Harris HW, Charlebois ED, et al. An epidemic of methicillin-resistant Staphylococcus aureus soft tissue infections among medically underserved patients. Arch Surg. 2004;139:947-951.

12. Siegman-Igra Y, Reich P, Omi-Wasserlauf R, et al. The role of vancomycin in the presence or recurrence of Staphylococcus aureus bacteremia. Scand J Infect Dis. 2005;37:572-578.

13. Gentry CA, Rodvold KA, Novak RM, et al. Retrospective evaluation of therapies for Staphylococcus aureus endocarditis. Pharmacotherapy. 1997;17:990-997.

14. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Ann Intern Med. 1991;115:674-680.

15. Moore MR, Perdreau-Remington F, Chambers HF. Vancomycin treatment failure associated with heterogeneous vancomycin-intermediate Staphylococcus aureus in a patient with endocarditis and in the rabbit model of endocarditis. Antimicrob Agents Chemother. 2003;47:1262-1266.

16. Charles PG, Ward PB, Johnson PB, et al. Clinical features associated with bacteremia due to heterogeneous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis. 2004;38:448-451.

17. Howden BP, Ward PB, Charles PG, et al. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis. 2004;38:521-528.

18. Malbruny B, Canu A, Bozdogan B, et al. Resistance to quinupristin-dalfopristin due to mutation of L22 ribosomal protein in Staphylococcus aureus. Antimicrob Agents Chemother. 2002;46:2200-2207.

19. Tsiodras S, Gold HS, Sakoulas G, et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet. 2001;358:207-208.

20. Peeters JM, Sarria JC. Clinical characteristics of linezolid-resistant Staphylocccus aureus infections. Am J Med Sci. 2005;330:102-104.

21. Olsen KM, Rebuck JA, Rupp ME. Arthralgias and myalgias related to quinupristin-dalfopristin administration. Clin Infect Dis. 2001;32:e83-e86.

22. Gerson SL, Kaplan SL, Bruss JB, et al. Hematologic effects of linezolid: summary of clinical experience. Antimicrob Agents Chemother. 2002;46:2723-2726.

23. Rucker JC, Hamilton SR, Bardenstein D, et al. Linezolid-associated toxic optic neuropathy. Neurology. 2006;66:595-598.

24. Sakoulas G, Alder J, Thauvin-Eliopoulos C, et al. Induction of daptomycin heterogeneous susceptibility in Staphylocccus aureus by exposure to vancomycin. Antimicrob Agents Chemother. 2006;50:1581-1585.

© 2006 Lippincott Williams & Wilkins, Inc.