INFECTIOUS DISEASES April 2009
Challenging Clinical Cases in Adult Immunization: Focus On MRSA

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Introduction Community-Associated MRSA Stanley C. Deresinski, MD, Catherine Liu, MD, and David A. Talan, MD Case 1: Bacteremia Stanley C. Deresinski, MD Case 2: Pneumonia Catherine Liu, MD Case 3: Cellulitis without Drainage David A. Talan, MD

In the last decade, the exclusive association of methicillin-resistant Staphylococcus aureus (MRSA) to healthcare settings has been challenged by the emergence of community-associated MRSA (CA-MRSA), and infections in both settings are on the increase. This highly adaptable organism is capable of becoming resistant to other antibiotics in addition to methicillin, and its increasing contribution to conditions that have traditionally been associated with other organisms is forcing emergency department physicians and infectious disease specialists to carefully consider empirical treatment for their patients with infections. Accordingly, the obligation to be knowledgeable about the epidemiology, latest diagnostic techniques, and treatment strategies for CA-MRSA infections is clear.

Vindico Medical Education assembled an expert panel in February 2009 to discuss three cases to provide the basis for an up-to-date assessment of conditions that are experiencing an increase in MRSA as the causative agent: bacteremia, pneumonia, and cellulitis. Their shared experience and insight inform readers of the current best practices in these cases. In addition to summaries of these cases, this monograph includes relevant epidemiologic and management updates. The status of MRSA vaccine development is also reviewed.

I thank the participants for their contributions to the development of this monograph. Readers should expect to acquire an increased awareness of the evolving face of CA-MRSA, which will assist them in their approach to patients with infections.

Stanley C. Deresinski, MD
Course Chair

Stanley C. Deresinski, MD Course Chair Clinical Professor of Medicine Stanford University Medical Center Redwood City, CA   Catherine Liu, MD Assistant Clinical Professor University of California, San Francisco Division of Infectious Diseases San Francisco, CA   David A. Talan, MD Professor of Medicine UCLA School of Medicine Chairman, Department of Emergency Medicine Faculty, Division of Infectious Diseases Olive View UCLA Medical Center Sylmar, CA

Community-Associated MRSA
Stanley C. Deresinski, MD, Catherine Liu, MD, and David A. Talan, MD

Methicillin-resistant Staphylococcus aureus (MRSA) was first reported in 1961 shortly after the introduction of methicillin (Figure 1). Over the subsequent 3 decades, the prevalence of MRSA has steadily increased, although infections were largely confined to patients with exposure to healthcare environments. In the late 1990s, MRSA infections were reported among previously healthy individuals in the community who lacked the usual healthcare-associated risk factors. Since then, outbreaks of community-associated MRSA (CA-MRSA) have been reported in multiple diverse populations including prison inmates, athletic teams, military personnel, and households.¹ In 2006, CA-MRSA was identified as the predominant cause of skin and soft tissue infections in patients presenting to the emergency department.² CA-MRSA is genetically distinct from healthcare-associated MRSA. It carries a novel staphylococcal chromosomal cassette (SCC) mec element (type IV) that does not contain multiple antibiotic resistance genes, and it also has several potential virulence factors such as Panton-Valentine leukocidin (PVL), the arginine catabolic mobile element (ACME), and phenol soluble modulins not found in healthcare-associated MRSA strains. Compared with healthcare-associated MRSA, patients with CA-MRSA are younger, nonwhite, and have a lower median household income.^3,4

Figure 1. History of methicillin-resistant Staphylococcus aureus (MRSA)

The prevalence of MRSA has steadily increased over the past 3 decades, with community-associated MRSA emerging in the late 1990s in multiple diverse populations.

Source: Catherine Liu, MD

Although CA-MRSA can present with severe manifestations such as necrotizing pneumonia or fasciitis, the majority of infections due to CA-MRSA are skin and soft tissue infections, which comprised 77% of CA-MRSA cases in a multi-state surveillance study.⁵ CA-MRSA was also observed to cause a variety of other infections including urinary tract infections, sinusitis, bacteremia, pneumonia, osteomyelitis, arthritis, and meningitis.

Staphylococcus aureus Vaccine

Development of a vaccine for MRSA will not be easy, as its pathophysiology is poorly understood. In addition, Staphylococcus aureus has numerous virulence factors, many of which interact in a complex fashion. As a consequence, a successful vaccine will most likely be multicomponent. A capsular polysaccharide-based vaccine showed initial promise, but, after it was found to be ineffective after extensive testing in a confirmatory trial, development was stopped. Other potential vaccine antigens are being tested, including cell wall–anchored adhesion proteins and exotoxins.⁶ In December 2008, Nabi Pharmaceuticals (Rockville, MD), the developer of the unsuccessful polysaccharide vaccine, entered into a cooperative agreement with the US Department of Defense to develop a new generation vaccine, which includes 3 polysaccharides plus a nonvirulent form of PVL. Planned studies include safety and immunogenicity studies of PVL and α-toxin; a trivalent vaccine containing the capsular polysaccharide types 5 and 8 and cell wall polysaccharide type 336; and a pentavalent vaccine given as 2 separate, simultaneous doses.⁷

In collaboration with Merck (Whitehouse Station, NJ), Intercell (Vienna, Austria) is evaluating a single-antigen vaccine against iron surface determinant B (IsdB), part of the S aureus heme acquisition system that is involved with iron regulation and is highly conserved throughout all S aureus strains.⁸ High antibody levels to this protein develop in patients recovering from S aureus infections, and it has been shown to be protective in several preclinical animal models of sepsis, disseminated infection, and IV catheter-related infection. A completed phase 1 trial of the vaccine, currently called V710, showed it to be highly immunogenic and well tolerated.⁹ Two phase 2 randomized, double-blind, placebo-controlled studies are currently underway. One is testing vaccine immunogenicity, efficacy, and safety in adults scheduled for cardiothoracic surgery. The other trial is investigating the immunogenicity and safety of the vaccine in adult patients with end-stage renal disease who are on chronic hemodialysis, with a planned enrollment of 198 patients.¹⁰

CA-MRSA will continue to provide challenges to clinicians, with implications for treatment and vaccine management strategies that may require frequent revision. Knowledge of its epidemiology, clinical manifestations, available effective antimicrobials, and antimicrobial resistance patterns is critical to the clinician in the management of the healthcare issues presented by this pathogen. The ultimate control of MRSA is likely to require the development of an effective vaccine.

References

1. Weber JT. Community-associated methicillin-resistant Staphylococcus aureus. Clinical Infectious Diseases : an official publication of the Infectious Diseases Society of America. 2005 Aug 15;41 Suppl 4:S269-72.
2. Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, McDougal LK, Carey RB, Talan DA; EMERGEncy ID Net Study Group. Methicillin-resistant S. aureus infections among patients in the emergency department. The New England Journal of Medicine. 2006 Aug 17;355(7):666-74.
3. Naimi TS, LeDell KH, Como-Sabetti K, Borchardt SM, Boxrud DJ, Etienne J, Johnson SK, Vandenesch F, Fridkin S, O'Boyle C, Danila RN, Lynfield R. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA: the journal of the American Medical Association. 2003; 290:2976-2984.
4. Liu C, Graber CJ, Karr M, Diep BA, Basuino L, Schwartz BS, Enright MC, O'Hanlon SJ, Thomas JC, Perdreau-Remington F, Gordon S, Gunthorpe H, Jacobs R, Jensen P, Leoung G, Rumack JS, Chambers HF. A population-based study of the incidence and molecular epidemiology of methicillin-resistant Staphylococcus aureus disease in San Francisco, 2004-2005. Clinical Infectious Diseases : an official publication of the Infectious Diseases Society of America. 2008 Jun 1;46(11):1637-46.
5. Fridkin SK, Hageman JC, Morrison M, Sanza LT, Como-Sabetti K, Jernigan JA, Harriman K, Harrison LH, Lynfield R, Farley MM; Active Bacterial Core Surveillance Program of the Emerging Infections Program Network. Methicillin-resistant Staphylococcus aureus disease in three communities. The New England Journal of Medicine. 2005 Apr 7;352(14):1436-44.
6. Schaffer AC, Lee JC. Staphylococcal vaccines and immunotherapies. Infectious disease clinics of North America. 2009 Mar;23(1):153-71.
7. Nabi Pharmaceuticals. Nabi Biopharmaceuticals Enters Clinical Initiative With US Military to Advance Penta-Staph™. 2008. Available at: www.nabi.com.
8. Kuklin NA, Clark DJ, Secore S, Cook J, Cope LD, McNeely T, Noble L, Brown MJ, Zorman JK, Wang XM, Pancari G, Fan H, Isett K, Burgess B, Bryan J, Brownlow M, George H, Meinz M, Liddell ME, Kelly R, Schultz L, Montgomery D, Onishi J, Losada M, Martin M, Ebert T, Tan CY, Schofield TL, Nagy E, Meineke A, Joyce JG, Kurtz MB, Caulfield MJ, Jansen KU, McClements W, Anderson AS. A novel Staphylococcus aureus vaccine: iron surface determinant B induces rapid antibody responses in rhesus macaques and specific increased survival in a murine S. aureus sepsis model. Infection and Immunity. 2006 Apr;74(4):2215-23.
9. Harro C, et al. International Symposium on Staphylococci and Staphylococcal Infections. Sep 2008. Available at: http://www.intercell.com.
10. V710 Clinical Trials. A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Immunogenicity of Merck Staphylococcus aureus Vaccine (V710) in Adult Patients With End-Stage Renal Disease on Chronic Hemodialysis. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00572910?term=v710&rank=4.

Case #1: Bacteremia
Stanley C. Deresinski, MD

Chief Complaint

The patient, a man aged 64 years, was admitted to the hospital through the emergency department (ED) with a 2-day history of fever, chills, and occasional rigor. Infectious disease consultation was requested on hospital day 9 because of persisting methicillin-resistant Staphylococcus aureus (MRSA) bacteremia despite therapy with vancomycin.

History and Examination

The patient was previously healthy, except for hypertension and hyperlipidemia, which were well controlled with medication. He had never been hospitalized and had an outpatient right knee arthroscopic meniscectomy 4 years previously. He had no known medication allergies. There was no personal or family history of diabetes mellitus and no history of valvular heart disease. The patient denied HIV risk factors. He had no recent history of skin infection or chronic dermatitis. He did not use illicit drugs. A review of systems was noncontributory.

Treatment

In the ED, empiric antibiotic therapy with vancomycin (1 g every 12 hours) and ceftriaxone (2 g every 24 hours) was initiated. Culture samples were obtained that subsequently yielded MRSA with a vancomycin minimum inhibitory concentration (MIC) of <2 µg/mL. Accordingly, ceftriaxone was discontinued and vancomycin was continued. On day 4, the vancomycin trough concentration was 7.8 µg/mL, and the dose was increased to 2 g every 12 hours. Blood cultures were drawn daily and were positive on day 5. No valvular vegetations or significant abnormalities were detected by transthoracic and transesophageal echocardiography (TEE). Despite antibiotic therapy, the patient continued to have a daily temperature to a maximum of 38.2° C, and the white blood cell (WBC) count, which was 23,000/mL on admission, subsequently remained mildly elevated in the range of 12,000/mL to 14,000/mL. The chest radiograph was normal on admission and remained so. Blood cultures drawn on day 8 were again positive. Vancomycin trough concentration had risen to 17 µg/mL. An E test was performed, and the vancomycin MIC of a recent MRSA isolate from the patient was 1.5 µg/mL. On day 9, an infectious disease consultation was requested.

The patient’s physical examination by the consultant was unremarkable, except for fever, mild tachycardia, and an I/VI systolic ejection murmur maximal at the cardiac apex. There were no peripheral stigmata suggestive of endocarditis.

Clinical and Microbiological Considerations

Daily blood cultures, at least from day 3 until negative, are desirable in these types of patients. There is disagreement regarding what duration constitutes persistence of bacteremia; some studies suggest that bacteremia beyond day 3 is significant. Accordingly, positive blood cultures at day 8 are cause for concern. Therefore, the decision that antibiotic therapy is failing is difficult. Patients on antibiotic therapy may appear to be healthy, despite continuing bacteremia. It may be preferable, therefore, to review bacteriological data and clinical response in making this decision.

In these patients, possible complications such as a metastatic focus of infection and infective endocarditis must be considered. Bone scans, tagged WBC scans, or gallium scans can be used to evaluate metastatic foci. False-positive results are common with these tests, however, which can result in patients undergoing painful and unnecessary biopsies. This patient underwent echocardiography, consistent with current guidelines that recommend TEE in patients with S aureus bacteremia because of the high frequency of endocarditis. The sensitivity of TEE for the diagnosis of infective endocarditis is approximately 96% and is somewhat less for patients with prosthetic valves; thus, while it is an excellent test, it will miss some cases.¹ If the suspicion for endocarditis is low and the bacteremia clears rapidly, TEE may not be necessary.

Although the E test provides a more precise MIC value, it has been reported to overestimate the vancomycin MIC relative to the microbroth dilution method. Despite this, the E test vancomycin MIC of 1.5 µg/mL in this patient is a concern. A recent study showed that patients treated with vancomycin who had MIC values 1.5 µg/mL or higher, which is less than the Clinical and Laboratory Standards Institute (CLSI) and FDA breakpoint of 2.0 µg/mL, had a greater possibility of treatment failure. Heteroresistance, where clones of cells have resistance in the intermediately susceptible range, is not detected by standard susceptibility tests. Tolerance is also not routinely determined in clinical microbiology laboratories. Both of these may be associated with failure of vancomycin therapy.^2,3

The initial dose of vancomycin (1 g/12 h) used for this patient was inadequate, achieving a trough concentration of only 7.8 µg/mL. Evidence supports that failure to reach adequate trough concentrations (currently suggested to be 15 µg/mL to 20 µg/mL) with the initial doses is associated with increased potential for therapeutic failure. In fact, a recent joint consensus statement from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists recommends that seriously ill patients should receive a loading dose of 25 mg/kg to 30 mg/kg (a 2.5-g to 3.0-g dose in this case), followed by 15 mg/kg every 12 hours.⁴

Treatment Options for MRSA Bacteremia

There are several options for antibiotic therapy in this case, none of which has demonstrated superiority. The dose of vancomycin could be increased even further, targeting maintenance of trough concentrations higher than 20µg/mL; however, this would increase the risk for toxicity. Vancomycin could also be used in combination with one or more antibiotics. Gentamicin and rifampin are used most frequently; however, evidence of clinical benefit is absent and each may contribute toxicity.^5,6 In an early randomized trial of vancomycin compared with vancomycin plus rifampin, the median duration of bacteremia was 2 days longer in patients who received rifampin compared with those on vancomycin monotherapy (9 vs. 7 days, respectively).⁷ Other agents including quinupristin-dalfopristin also have been added to vancomycin in a setting such as this. Alternatively, vancomycin could be discontinued and another agent substituted. When bactericidal activity is required, daptomycin and perhaps trimethoprim-sulfamethoxazole may be considered, although the latter was inferior to vancomycin in a randomized trial of therapy of a variety of S aureus infections in IV drug users.⁸

In a randomized trial comparing daptomycin with vancomycin plus gentamicin for the first 4 days in patients with MRSA bacteremia with or without endocarditis, prespecified criteria for the noninferiority of daptomycin were met.⁹ Many clinicians use doses of daptomycin higher than the approved bacteremia dose of 6 mg/kg once daily in attempts to improve outcome and reduce the selection of resistant isolates. A phase 2 randomized trial of daptomycin 10 mg/kg/d in patients with MRSA bacteremia is underway.¹⁰ In vitro data suggest synergy against MRSA using a combination of daptomycin with gentamicin or rifampin; however, no clinical data support this approach.¹¹

Two other agents with reliable activity against MRSA include linezolid, the first commercially available member of the oxazolidinone class, and tigecycline, a semi synthetic glycylcycline.^12,13 These compounds are bacteriostatic, as opposed to bactericidal, against MRSA. Use of the latter is associated with low serum drug concentrations that routinely do not exceed the MIC of the organism, peaking at approximately 0.06 µg/mL, and raising concern among some clinicians regarding its use in bacteremic patients.

References

1. Feuchtner GM, Stolzmann P, Dichtl W, Schertler T, Bonatti J, Scheffel H, Mueller S, Plass A, Mueller L, Bartel T, Wolf F, Alkadhi H. Multislice computed tomography in infective endocarditis: comparison with transesophageal echocardiography and intraoperative findings. Journal of the American College of Cardiology. 2009 Feb 3;53(5):436-44.
2. Lodise TP, Graves J, Evans A, Graffunder E, Helmecke M, Lomaestro BM, Stellrecht K. Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin. Antimicrobial Agents and Chemotherapy. 2008 Sep;52(9):3315-20. Epub 2008 Jun 30.
3. Diederen BM, van Duijn I, Willemse P, Kluytmans JA. In vitro activity of daptomycin against methicillin-resistant Staphylococcus aureus, including heterogeneously glycopeptide-resistant strains. Antimicrobial Agents and Chemotherapy. 2006 Sep;50(9):3189-91.
4. Rybak M, Lomaestro B, Rotschafer JC, Moellering R Jr, Craig W, Billeter M, Dalovisio JR, Levine DP. 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.American journal of health-system pharmacy. 2009; 66:82-98.
5. Riedel DJ, Weekes E, Forrest GN. Addition of rifampin to standard therapy for treatment of native valve infective endocarditis caused by Staphylococcus aureus. Antimicrobial Agents and Chemotherapy. 2008 Jul;52(7):2463-7. Epub 2008 May 12.
6. Mulazimoglu L, Drenning SD, Muder RR. Vancomycin-gentamicin synergism revisited: effect of gentamicin susceptibility of methicillin-resistant Staphylococcus aureus. Antimicrobial Agents and Chemotherapy. 1996 Jun;40(6):1534-5.
7. Levine DP, Fromm BS, Reddy BR. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis. Annals of internal medicine. 1991 Nov 1;115(9):739-41.
8. Markowitz N, Quinn EL, Saravolatz LD. Trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of Staphylococcus aureus infection. Annals of internal medicine. 1992 Sep 1;117(5):390-8.
9. Fowler VG Jr, Boucher HW, Corey GR, Abrutyn E, Karchmer AW, Rupp ME, Levine DP, Chambers HF, Tally FP, Vigliani GA, Cabell CH, Link AS, DeMeyer I, Filler SG, Zervos M, Cook P, Parsonnet J, Bernstein JM, Price CS, Forrest GN, Fätkenheuer G, Gareca M, Rehm SJ, Brodt HR, Tice A, Cosgrove SE; S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. The New England Journal of Medicine. 2006 Aug 17;355(7):653-65.
10. Phase 2 Study of Safety, Efficacy, and PK of Higher Doses of Daptomycin and Vancomycin in MRSA Bacteremia (HDSAB). Available at: http://clinicaltrials.gov/ct2/show/NCT00695903.
11. Credito K, Lin G, Appelbaum PC. Activity of daptomycin alone and in combination with rifampin and gentamicin against Staphylococcus aureus assessed by time-kill methodology. Antimicrobial Agents and Chemotherapy. 2007 Apr;51(4):1504-7. Epub 2007 Jan 12.
12. Stevens DL, Herr D, Lampiris H, Hunt JL, Batts DH, Hafkin B. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America. 2002 Jun 1;34(11):1481-90. Epub 2002 May 13.
13. Florescu I, Beuran M, Dimov R, Razbadauskas A, Bochan M, Fichev G, Dukart G, Babinchak T, Cooper CA, Ellis-Grosse EJ, Dartois N, Gandjini H; 307 Study Group. Efficacy and safety of tigecycline compared with vancomycin or linezolid for treatment of serious infections with methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci: a Phase 3, multicentre, double-blind, randomized study. The Journal of Antimicrobial Chemotherapy. 2008 Sep;62 Suppl 1:i17-28.
14. Julian K, Kosowska-Shick K, Whitener C, Roos M, Labischinski H, Rubio A, Parent L, Ednie L, Koeth L, Bogdanovich T, Appelbaum PC. Characterization of a daptomycin-nonsusceptible vancomycin-intermediate Staphylococcus aureus strain in a patient with endocarditis. Antimicrobial Agents and Chemotherapy. 2007 Sep;51(9):3445-8. Epub 2007 Jul 9.
15. Tsuji BT, Rybak MJ. Short-course gentamicin in combination with daptomycin or vancomycin against Staphylococcus aureus in an in vitro pharmacodynamic model with simulated endocardial vegetations. Antimicrobial Agents and Chemotherapy. 2005 Jul;49(7):2735-45.
16. Baltch AL, Ritz WJ, Bopp LH, Michelsen P, Smith RP. Activities of daptomycin and comparative antimicrobials, singly and in combination, against extracellular and intracellular Staphylococcus aureus and its stable small-colony variant in human monocyte-derived macrophages and in broth. Antimicrobial Agents and Chemotherapy. 2008 May;52(5):1829-33. Epub 2008 Mar 10.
17. Rose WE, Leonard SN, Rybak MJ. Evaluation of daptomycin pharmacodynamics and resistance at various dosage regimens against Staphylococcus aureus isolates with reduced susceptibilities to daptomycin in an in vitro pharmacodynamic model with simulated endocardial vegetations. Antimicrobial Agents and Chemotherapy. 2008 Sep;52(9):3061-7. Epub 2008 Jun 30.
18. Jacqueline C, Caillon J, Le Mabecque V, Miegeville AF, Donnio PY, Bugnon D, Potel G. In vitro activity of linezolid alone and in combination with gentamicin, vancomycin or rifampicin against methicillin-resistant Staphylococcus aureus by time-kill curve methods. The Journal of Antimicrobial Chemotherapy. 2003 Apr;51(4):857-64. Epub 2003 Mar 13.
19. Booker BM, Stahl L, Smith PF. In Vitro Antagonism with the Combination of Vancomycin and Clindamycin Against Staphylococcus aureus. The Journal of Applied Research. 2004; 4:385-395.
20. Lodise TP Jr, McKinnon PS, Levine DP, Rybak MJ. Impact of empirical-therapy selection on outcomes of intravenous drug users with infective endocarditis caused by methicillin-susceptible Staphylococcus aureus. Antimicrobial Agents and Chemotherapy. 2007 Oct;51(10):3731-3. Epub 2007 Jul 30.
21. Ohlsen K, Ziebuhr W, Koller KP, Hell W, Wichelhaus TA, Hacker J. Effects of subinhibitory concentrations of antibiotics on alpha-toxin (hla) gene expression of methicillin-sensitive and methicillin-resistant Staphylococcus aureus isolates. Antimicrobial Agents and Chemotherapy. 1998 Nov;42(11):2817-23.

Case 2: Pneumonia
Catherine Liu, MD

Chief Complaint

The patient, a 35-year-old man, came to the emergency department (ED) with a 4-day history of fever, chills, myalgia, and productive cough, now with increasing dyspnea and hemoptysis over the past 24 hours.

History and Examination

The patient has no significant medical history and lives with his girlfriend, who was sick with a “cold” 1 week previously. He smokes approximately one-half pack of cigarettes per day, drinks alcohol occasionally, takes no medications, and has no known drug allergies. The patient denies illicit drug use, has no recent travel or animal exposure, reports no known exposure to tuberculosis, and has never been hospitalized.

His physical examination is unremarkable. He is well developed and well nourished, but is in moderate respiratory distress, with tachycardia and coarse rhonchi at the bases bilaterally.

Treatment

In this case, in addition to blood cultures, a sputum sample for gram stain and culture should be obtained prior to starting antibiotic therapy. Although empiric therapy for methicillin-resistant Staphylococcus aureus (MRSA) is not currently indicated for most cases of routine community- acquired pneumonia (CAP), it should be considered in patients with severe CAP with preceding or concurrent influenza-like illness, patients with necrotizing or cavitary infiltrates, or patients requiring intensive care unit admission. Accordingly, given the severity of his clinical presentation, particularly in the setting of influenza, empiric therapy for MRSA should be initiated in this patient pending further microbiologic data.

Clinical and Microbiological Considerations

This is a seriously ill patient who presents with influenza, most likely complicated by a secondary bacterial pneumonia. Proper management would include starting him on empiric antibiotic therapy. Although limited epidemiologic data are available, MRSA currently appears to be an infrequent cause of CAP,¹ and empiric therapy for MRSA is not routinely recommended by current guidelines. The most recent American Thoracic Society (ATS) and Infectious Diseases Society of America joint CAP guidelines, however, recommend that, if community-associated MRSA (CA-MRSA) is a consideration, vancomycin or linezolid therapy should be added.²

MRSA has emerged as a bacterial complication of influenza, although the relative contribution of MRSA compared to Streptococcus pneumoniae, Haemophilus influenzae, and other bacterial pneumonia etiologies is unknown. During the 2003-2004 and 2006-2007 influenza seasons, the majority of reported cases of staphylococcal CAP were due to MRSA and were associated with significant morbidity and mortality.^3,4

In the 2006-2007 season, only 43% of patients with MRSA pneumonia received empiric treatment for MRSA. The lack of clinical, laboratory, and radiographic findings that clearly distinguish patients with MRSA pneumonia from other causes of bacterial pneumonia poses a challenge for the clinician when choosing empiric therapy for a patient presenting with CAP.⁴

Although cavitary lesions have been described as a finding suggestive of infection with S aureus, they were observed in a minority of patients during the 2006-2007 influenza season; patients presented with a variety of radiographic abnormalities including interstitial, single lobar, and multilobar infiltrates. Recent history of documented or suspected MRSA skin infection in the patient or a close contact may be helpful in identifying individuals at risk, as this association has been described in several case reports of patients with MRSA pneumonia.^4,5

Vancomycin or linezolid are the currently recommended agents for the treatment of MRSA pneumonia. Vancomycin, however, penetrates poorly into pulmonary tissue and lung epithelial lining fluid.⁶ Linezolid levels in lung epithelial lining fluid are greater than plasma levels and exceed the MIC₉₀ for S aureus throughout the 12-hour dosing interval.⁷ Although no studies specifically examined patients with MRSA CAP, comparable cure rates between linezolid and vancomycin were observed in 2 prospective studies of patients with nosocomial pneumonia.^8,9 However, a retrospective pooled analysis of the MRSA subgroup found higher cure rates (59% vs. 35.5%, P = .01) and improved survival (80% vs. 63.5%, P = .02) in the linezolid arm.¹⁰ Vancomycin trough concentrations in the original studies were not reported, and it is unknown whether levels were sufficient to attain a target AUC/MIC of 400 or higher, which 1 study suggests is required for efficacy.¹¹ For this reason, as well as concerns about the validity of the post-hoc analysis, a large randomized clinical trial is ongoing to compare the efficacy of linezolid and vancomycin in nosocomial MRSA pneumonia.

Several exotoxins including Panton-Valentine leukocidin (PVL), α-toxin, and phenol-soluble modulins have been described in CA-MRSA.^12,13 Both clindamycin and linezolid have been shown to inhibit MRSA toxin production in vitro,^14-16 although the importance of toxin production, including PVL, in the pathogenesis of MRSA pneumonia remains controversial.^17,18 In 1 mouse model study of pneumonia, PVL was shown to be an important causative factor,¹⁷ while in a different murine model, it did not appear to have a significant causative role in lethal pneumonia.¹⁸

A single case series involving 4 patients presenting with necrotizing pneumonia, 3 of whom have failed vancomycin therapy, suggested potential clinical benefit of the use of antibiotics that inhibit toxin production.¹⁹ Although some experts may consider using these agents in selected scenarios such as necrotizing pneumonia and severe sepsis, data are insufficient to recommend the routine use of protein synthesis inhibitors for the management of invasive disease caused by MRSA, and further studies are needed.

The use of human IV polyclonal immunoglobulin (IVIG) is another potential, but unproven, therapeutic approach in patients with severe invasive disease due to necrotizing pneumonia or necrotizing fasciitis. In vitro studies suggest that IVIG has neutralizing activity against staphylococcal exotoxins,²⁰ including PVL,²¹ although with lesser inhibition than achieved against streptococcal superantigens.²²

In a recent study, children with invasive disease had a higher concentration of antibody to PVL compared with children with skin and soft tissue infections (SSTIs), suggesting that additional antibody to PVL provided by IVIG may not necessarily be beneficial in these patients.²³ In addition, there are no published clinical trial data regarding the use of IVIG in MRSA disease; accordingly, IVIG is not routinely recommended in its management, although it may be considered in cases of severe sepsis and necrotizing pneumonia known or suspected to be due to S aureus.²⁴

In this patient, either vancomycin or linezolid would be acceptable choices to use as empiric therapy for CA-MRSA pneumonia. For vancomycin, a recently published consensus statement from the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists (SIDP) recommends adjusting doses to achieve target vancomycin trough concentrations of 15 µg/mL to 20 µg/mL.²⁵ Daptomycin should not be used in the treatment of patients with MRSA pneumonia because of its inactivation by pulmonary surfactant.

Vaccine Potential

Developing a MRSA vaccine is a valiant pursuit, fraught with numerous constraints. The primary challenge is completely understanding the molecular basis of the pathogenesis of the disease and the role of the huge panoply of the organism’s virulence factors. An important example is the conflicting data regarding the role of PVL in pneumonia pathogenesis.²⁶ A recent study indicates an important role of α-toxin (hemolysin) in S aureus pneumonia and that vaccination with a nontoxic mutant α-toxin is highly protective against subsequent infection. This study showed that passive immunization with anti-α-toxin but not anti-PVL antibodies was protective against lethal pneumonia.²⁷ In another study of active immunization, mice were immunized intradermally and intranasally with PVL subunits, with protection against intradermal and pulmonary infections correlating with the route of vaccination.²⁸ Mice immunized intranasally were protected against pneumonia but not intradermal infection; in contrast, mice immunized intradermally were protected against skin infections but not pneumonia, suggesting that route of administration may play an important role in targeting specific disease manifestations of MRSA.

References

1. Centers for Disease Control and Prevention (CDC). Severe methicillin-resistant Staphylococcus aureus community-acquired pneumonia associated with influenza--Louisiana and Georgia, December 2006-January 2007. MMWR. Morbidity and Mortality Weekly Report. 2007 Apr 13;56(14):325-9.
2. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher DM, Niederman MS, Torres A, Whitney CG; Infectious Diseases Society of America; American Thoracic Society. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America. 2007 Mar 1;44 Suppl 2:S27-72.
3. Hageman JC, Uyeki TM, Francis JS, Jernigan DB, Wheeler JG, Bridges CB, Barenkamp SJ, Sievert DM, Srinivasan A, Doherty MC, McDougal LK, Killgore GE, Lopatin UA, Coffman R, MacDonald JK, McAllister SK, Fosheim GE, Patel JB, McDonald LC. Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season. Emerging Infectious Diseases. 2006 Jun;12(6):894-9.
4. Kallen AJ, Brunkard J, Moore Z, Budge P, Arnold KE, Fosheim G, Finelli L, Beekmann SE, Polgreen PM, Gorwitz R, Hageman J. Staphylococcus aureus community-acquired pneumonia during the 2006 to 2007 influenza season. Annals of Emergency Medicine. 2009 Mar;53(3):358-65. Epub 2008 Jun 4.
5. Gupta RK, George R, Nguyen-Van-Tam JS. Bacterial pneumonia and pandemic influenza planning. Emerging Infectious Diseases. 2008 Aug;14(8):1187-92.
6. Cruciani M, Gatti G, Lazzarini L, Furlan G, Broccali G, Malena M, Franchini C, Concia E. Penetration of vancomycin into human lung tissue. The Journal of Antimicrobial Chemotherapy. 1996 Nov;38(5):865-9.
7. Conte JE Jr, Golden JA, Kipps J, Zurlinden E. Intrapulmonary pharmacokinetics of linezolid. Antimicrobial Agents and Chemotherapy. 2002 May;46(5):1475-80.
8. Rubinstein E, Cammarata S, Oliphant T, Wunderink R; Linezolid Nosocomial Pneumonia Study Group. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double-blind, multicenter study. Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America. 2001 Feb 1;32(3):402-12. Epub 2001 Jan 26.
9. Skrupky LP, Micek ST, Kollef MH. Optimizing therapy for MRSA pneumonia. Seminars in Respiratory and Critical Care Medicine. 2007 Dec;28(6):615-23.
10. Wunderink RG, Rello J, Cammarata SK, Croos-Dabrera RV, Kollef MH. Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest. 2003 Nov;124(5):1789-97.
11. Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clinical Pharmacokinetics. 2004;43(13):925-42.
12. Dinges MM, Orwin PM, Schlievert PM. Exotoxins of Staphylococcus aureus. Clinical Microbiology Reviews. 2000 Jan;13(1):16-34, table of contents.
13. DeLeo FR, Diep BA, Otto M. Host defense and pathogenesis in Staphylococcus aureus infections. Infectious Disease Clinics of North America. 2009 Mar;23(1):17-34.
14. Stevens DL, Ma Y, Salmi DB, McIndoo E, Wallace RJ, Bryant AE. Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus. The Journal of Infectious Diseases. 2007 Jan 15;195(2):202-11. Epub 2006 Dec 18.
15. Stevens DL, Wallace RJ, Hamilton SM, Bryant AE. Successful treatment of staphylococcal toxic shock syndrome with linezolid: a case report and in vitro evaluation of the production of toxic shock syndrome toxin type 1 in the presence of antibiotics. Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America. 2006 Mar 1;42(5):729-30.
16. Bernardo K, Pakulat N, Fleer S, Schnaith A, Utermöhlen O, Krut O, Müller S, Krönke M. Subinhibitory concentrations of linezolid reduce Staphylococcus aureus virulence factor expression. Antimicrobial Agents and Chemotherapy. 2004 Feb;48(2):546-55.
17. Labandeira-Rey M, Couzon F, Boisset S, Brown EL, Bes M, Benito Y, Barbu EM, Vazquez V, Höök M, Etienne J, Vandenesch F, Bowden MG. Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science. 2007 Feb 23;315(5815):1130-3. Epub 2007 Jan 18.
18. Bubeck Wardenburg J, Palazzolo-Ballance AM, Otto M, Schneewind O, DeLeo FR. Panton-Valentine leukocidin is not a virulence determinant in murine models of community-associated methicillin-resistant Staphylococcus aureus disease. The Journal of Infectious Diseases. 2008 Oct 15;198(8):1166-70.
19. Micek ST, Dunne M, Kollef MH. Pleuropulmonary complications of Panton-Valentine leukocidin-positive community-acquired methicillin-resistant Staphylococcus aureus: importance of treatment with antimicrobials inhibiting exotoxin production. Chest. 2005 Oct;128(4):2732-8.
20. Yanagisawa C, Hanaki H, Natae T, Sunakawa K. Neutralization of staphylococcal exotoxins in vitro by human-origin intravenous immunoglobulin. The Journal of Infection and Chemotherapy. 2007 Dec;13(6):368-72. Epub 2007 Dec 25.
21. Gauduchon V, Cozon G, Vandenesch F, Genestier AL, Eyssade N, Peyrol S, Etienne J, Lina G. Neutralization of Staphylococcus aureus Panton Valentine leukocidin by intravenous immunoglobulin in vitro. The Journal of Infectious Diseases. 2004 Jan 15;189(2):346-53. Epub 2004 Jan 9.
22. Darenberg J, Söderquist B, Normark BH, Norrby-Teglund A. Differences in potency of intravenous polyspecific immunoglobulin G against streptococcal and staphylococcal superantigens: implications for therapy of toxic shock syndrome. Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America. 2004 Mar 15;38(6):836-42. Epub 2004 Mar 1.
23. Brown EL, Bowden MG, Bryson RS, Hulten KG, Bordt AS, Forbes A, Kaplan SL. Pediatric antibody response to community-acquired Staphylococcus aureus infection is directed to Panton-Valentine leukocidin. Clinical and Vaccine Immunology. 2009 Jan;16(1):139-41. Epub 2008 Nov 12.
24. Nathwani D, Morgan M, Masterton RG, Dryden M, Cookson BD, French G, Lewis D; British Society for Antimicrobial Chemotherapy Working Party on Community-onset MRSA Infections. Guidelines for UK practice for the diagnosis and management of methicillin-resistant Staphylococcus aureus (MRSA) infections presenting in the community. The Journal of Antimicrobial Chemotherapy. 2008 May;61(5):976-94. Epub 2008 Mar 13.
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Case #3: Cellulitis Without Drainage
David A. Talan, MD

Chief Complaint

A 28-year-old man presented to the emergency department (ED) with an enlarging area of redness, swelling, warmth, and pain on his right anterior thigh for 3 days. It started as a painful red bump that he thought was due to a spider bite, although he did not see a spider. He does not recall any trauma. He has subjective fevers and chills, and denies nausea and vomiting. His pain is somewhat controlled with ibuprofen, which is his only medication.

History and Examination

The patient denies significant past medical illness. He is heterosexual and denies illicit drug use, alcoholism, exposure to others with skin infections, and exposure to animals or insects. He has not been in prison and denies participating in contact sports.The patient is well developed, nourished, alert, and fully oriented. He appears moderately uncomfortable.

Treatment

This patient’s description and assessments suggest hospital admission is not necessary. Some clinicians, however, believe all febrile patients with an SSTI should be admitted. In this patient, there is no drainage to culture or on which to perform a rapid polymerase chain reaction (PCR) test; accordingly, empirical treatment should be started, which should include coverage for CA-MRSA. The presence of streptococcal infection should also be considered, against which trimethoprim-sulfamethoxazole does not demonstrate in vitro or clinical effectiveness. A logical empirical choice would be trimethoprim-sulfamethoxazole, which is active against CA-MRSA, combined with a drug such as cephalexin that is active against streptococcal infection. Both of these drugs can be administered orally. Another possibility would be clindamycin, which is also administered orally and should be active against both, except in certain areas in patients who may be at risk of clindamycin-resistant CA-MRSA.

Epidemiology

In 2006, the EMERGEncy ID Net Study Group published a series from 11 university-affiliated EDs, comprising every patient presenting with a chief complaint related to skin and soft tissue infection (SSTI).¹ Staphylococcus aureus was isolated from 320 of 422 patients (76%) with SSTI; of these, 249 (78% of S aureus infections; 59% of SSTI) were attributed to methicillin-resistant S aureus (MRSA). This reflects the dramatic increase in community-associated MRSA (CA-MRSA) SSTI since 2000. For example, MRSA prevalence in patients with SSTI in a participating institution increased from 29% to 64% between 2001 and 2004.² This was a significant change compared to even just a few years before.

Not only has the etiology of the infection changed, with MRSA instead of methicillin-sensitive S aureus (MSSA) as the more common causative agent, but also a review of the National Hospital Ambulatory Medical Care Survey data for 1993-2005 revealed that the number of healthcare visits for SSTIs is significantly increased (1993: 1.2 million visits, 2005: 3.4 million visits; P for trend <.001).³

Reports of MRSA outbreaks in special groups were published, prompting an expectation that risk factors that could predict who is likely to be infected with MRSA may be possible. Although EMERGEncy ID Net Study Group data identified common factors associated with MRSA infections by multivariate analysis, almost one half (31/64; 48%) of patients without any of these factors were infected with MRSA.¹ Accordingly, it is reasonable for a clinician to assume that SSTI has MRSA as a causative etiology, regardless of the presence of putative risk factors.

Clinical and Microbiological Considerations

Bedside ultrasonography has proven to be useful in the ED for the evaluation of SSTIs.⁴ In many cases with a large area of indurated erythema, the infection appears to be cellulitis. When an ultrasound probe is passed over the area, occult, deep, subcutaneous abscesses are occasionally revealed. This procedure can, therefore, guide management and assure drainage procedures and additional diagnostics and treatment are appropriately performed.

A controversy with SSTI is the etiology of uncomplicated cellulitis, which does not involve drainage. In these cases, there is nothing to culture. Although blood cultures occasionally provide an idea of the etiology, the yield not only is minimal but also may represent contaminants rather than the causative agent,⁵ particularly because blood cultures tend to be overrepresented by group A and group B streptococcus. There is a persistent belief that erysipelas, a pure cellulitis without purulent exudates, drainage, or abscess formation, is usually due to Streptococcus pyogenes. In the EMERGEncy ID Net Study Group data, however, MRSA was isolated from 16 of 34 (47%) patients with purulent cellulitis, and group A streptococcus was only rarely isolated.¹ Although the small numbers preclude a conclusion regarding the contribution of MRSA, its association has implications in terms of empirical therapy.

Tests to identify MRSA are improving. In September 2008, the FDA approved a rapid, automated PCR test that detects, in less than 1 hour, S aureus and MRSA from SSTI swabs.⁶ Concomitant cultures for susceptibility testing or epidemiological typing should still be performed.

Clinically, the circumference of the area of cellulitis is monitored for change, and laboratory tests that can identify organ dysfunction or metabolic acidosis may be ordered.

Necrotizing infection also must be considered in patients such as in this case who have a moderate degree of pain and elevated pulse. Delayed diagnosis can adversely affect survival, as early debridement is a determinant of outcome. A scoring system, the laboratory risk indicator for necrotizing fasciitis (LRINEC) score, was shown in a retrospective trial to have a positive predictive value (PPV) of 92% and a negative predictive value (NPV) of 96%.⁷

Treatment

Current treatment recommendations for more serious cases of cellulitis and necrotizing fasciitis include adding clindamycin or linezolid to a broad-spectrum antibiotic. Both experimental and clinical data suggest this is effective in cases of group A streptococcal infection with necrotizing fasciitis. Necrotizing fasciitis caused by MRSA may be different from that caused by streptococcus and clostridia. A report from Harbor-UCLA described 14 patients with necrotizing infections due to CA-MRSA.⁸ None of the patients died, compared with a typical mortality rate of 33% in patient with necrotizing fasciitis. In addition, there were no amputations. Disease onset was often subacute. Because of these differences, toxin inhibitors may not be as important in cases of CA-MRSA necrotizing fasciitis as they are in streptococcal or clostridial infections.

References

1. Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, McDougal LK, Carey RB, Talan DA; EMERGEncy ID Net Study Group. Methicillin-resistant S. aureus infections among patients in the emergency department. The New England Journal of Medicine. 2006 Aug 17;355(7):666-74.
2. Moran GJ, Amii RN, Abrahamian FM, Talan DA. Methicillin-resistant Staphylococcus aureus in community-acquired skin infections. Emerging Infectious Diseases. 2005 Jun;11(6):928-30.
3. Pallin DJ, Egan DJ, Pelletier AJ, Espinola JA, Hooper DC, Camargo CA Jr. Increased US emergency department visits for skin and soft tissue infections, and changes in antibiotic choices, during the emergence of community-associated methicillin-resistant Staphylococcus aureus. Annals of Emergency Medicine. 2008 Mar;51(3):291-8. Epub 2008 Jan 28.
4. Tayal VS, Hasan N, Norton HJ, Tomaszewski CA. The effect of soft-tissue ultrasound on the management of cellulitis in the emergency department. Academic emergency medicine: official journal of the Society for Academic Emergency Medicine. 2006 Apr;13(4):384-8. Epub 2006 Mar 10.
5. Perl B, Gottehrer NP, Raveh D, Schlesinger Y, Rudensky B, Yinnon AM. Cost-effectiveness of blood cultures for adult patients with cellulitis. Clinical Infectious Diseases: an official publication of the Infectious Diseases Society of America. 1999 Dec;29(6):1483-8.
6. FDA. 501k summary. Xpert MRSA/SA SSTI Assay. Available at: http://www.fda.gov/cdrh/pdf8/K080837.pdf.
7. Wong CH, Khin LW, Heng KS, Tan KC, Low CO. The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections. Critical Care Medicine. 2004 Jul;32(7):1535-41.
8. Miller LG, Perdreau-Remington F, Rieg G, Mehdi S, Perlroth J, Bayer AS, Tang AW, Phung TO, Spellberg B. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. The New England Journal of Medicine. 2005 Apr 7;352(14):1445-53.
9. Van Rijen M, Bonten M, Wenzel R, Kluytmans J. Mupirocin ointment for preventing Staphylococcus aureus infections in nasal carriers. Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No.: CD006216. DOI: 10.1002/14651858.CD006216.pub2.
10. Siegel RM, et al. Management of Multidrug-Resistant Organisms in Healthcare Settings, 2006. CDC. Available at: http://www.cdc.gov/ncidod/dhqp/pdf/ar/mdroguideline2006.pdf.