Meeting the Challenges of Methicillin-Resistant Staphylococcus aureus with Outpatient Parenteral Antimicrobial Therapy

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1 INTRODUCTION SUPPLEMENT ARTICLE Meeting the Challenges of Methicillin-Resistant Staphylococcus aureus with Outpatient Parenteral Antimicrobial Therapy Alan D. Tice 1 and Susan J. Rehm 2,3 1 John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii; and 2 Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and 3 Department of Infectious Diseases, Cleveland Clinic Foundation, Cleveland, Ohio A brief review of medicine s war with Staphylococcus aureus during the past 4 decades reveals a remarkable sequence of survival through adaptation [1]. Although S. aureus was apparently defeated in the 1940s by penicillin (despite Sir Alexander Fleming s initial warning about eventual drug resistance from overuse and misuse [2]), a strain of S. aureus was rearmed within a decade with the resistance gene meca, determinant of a unique penicillinbinding protein, PBP2A [3]. Carried in a unique molecular vector called the staphylococcal chromosomal cassette (SCC mec ), the gene seems to have evolved from a domestic gene of the fully b-lactam susceptible Staphylococcus sciuri, a colonizer of both wild and domestic animals [3]. Although the mortality associated with S. aureus infection decreased after the introduction of penicillinase-resistant methicillin, this resistant S. aureus clone spread extensively in hospitals for over 17 years as a single clonal type [4]. Then new clones with different genetic backgrounds that carry a variety of different SCC mec types (mainly I, II, and III) began to appear and Reprints or correspondence: Dr Alan D. Tice, Infections Limited Hawaii, 1286 Queen Emma St, Honolulu, HI (alantice@idlinks.com). Clinical Infectious Diseases 2010; 51(S2):S171 S by the Infectious Diseases Society of America. All rights reserved /2010/5107S2-0001$15.00 DOI: / to spread globally, resulting in the worldwide epidemic of nosocomial or health care associated (HA) methicillin-resistant S. aureus (MRSA). Effective hygienic and antibiotic use policies had begun to reduce the frequency of MRSA infection in several countries by the late 1990s. Although many HA-MRSA isolates were resistant to many antibiotics, most have been susceptible to the glycopeptides, such as vancomycin [5]. However, reports of S. aureus strains with reduced vancomycin susceptibility (vancomycin-intermediate S. aureus [6]) were followed by other isolates with full resistance, such as vancomycin-resistant S. aureus, which had acquired the vana resistance gene, apparently transferred conjugatively from enterococci [7 9]. During the 1990s, MRSA isolates phenotypically and genotypically different from HA-MRSA strains were recognized in the community setting with increasing frequency [3, 10]. Similar to HA-MRSA, community-associated (CA) MRSA carries the meca gene; however, CA-MRSA isolates are predominantly characterized by SCC meca type IV or type V, whereas HA- MRSA is more likely to carry types I to III [3]. CA-MRSA has now become the most frequent cause of skin and soft-tissue infection among patients presenting to emergency departments in the United States [11]. At present, the emergence of CA-MRSA colonization and infection among hospitalized patients presents new challenges [12, 13]. Table 1 shows the proportion of patients presenting with invasive MRSA infection, by epidemiologic classification, according to the Active Bacterial Core surveillance system of the Emerging Infections Program of the US Centers for Disease Control and Prevention [14]. Table 1 shows complete information on 8792 cases contributed by clinical microbiology laboratories in acute care hospitals and all reference laboratories processing sterile site specimens for residents of 9 Emerging Infections Program sites from July 2004 through December Exacerbated by this evolution of multidrug-resistant organisms, the frequency of coagulase-negative staphylococcal bacteremia and prosthetic device infection has further challenged clinical medicine [15]. From their ecological niche on the human skin, coagulase-negative staphylococci have adapted to survive on inert material designed to persist indefinitely in the human body. Moreover, intermediate resistance to vancomycin was reported in these ubiquitous organisms several years before it occurred in S. aureus [16]. Different phenotypes and genotypes aside, CA-MRSA and HA-MRSA seem to be dynamically interdependent. For example, in a study of rural health care in the western United States, the rate of HA- MRSA infection was greater in commu- Meeting the Challenges of MRSA with OPAT CID 2010:51 (Suppl 2) S171

2 Table 1. Number and Percentage of Invasive Methicillin-Resistant Staphylococcus aureus (MRSA) Infections, by Clinical Condition and Epidemiologic Classification Condition a No. (%) of CA-MRSA infections (n p 1226) No. (%) of HA-MRSA infections Community onset (n p 5191) Hospital onset (n p 2375) Total no. of MRSA infections (n p 8792) b Bacteremia 798 (65.1) 4019 (77.4) c 1794 (75.5) c 6611 Pneumonia 172 (14.0) 616 (11.9) d 383 (16.1) 1171 Cellulitis 278 (22.7) 456 (8.8) c 114 (4.8) c 848 Osteomyelitis 99 (8.1) 415 (8.0) 142 (6.0) d 656 Endocarditis 155 (12.6) 341 (6.6) c 60 (2.5) d 556 Septic shock 46 (3.8) 233 (4.5) 99 (4.2) 378 NOTE. Data are from Active Bacterial Core Surveillance, United States, July 2004 December Epidemiologic classification: community-associated (CA) infections are defined by a positive culture result within 48 h of admission. Health care associated (HA) infections are defined by a positive culture result only after 48 h of admission. Adapted with permission from JAMA 2007;298: [14] American Medical Association. All rights reserved. a Conditions can involve 1 syndrome. b Of 8987 patients with MRSA infection, 114 could not be classified, and conditions were not reported for 81. c P!.01. d P!.05 (all comparisons use CA as referent category). nities with a high incidence of CA-MRSA infection [17]. A university hospital reported that the USA300 genotype accounted for 34% of bacteremia isolates in 2004, including 20% of nosocomial MRSA bacteremia isolates [13]. Thus, CA-MRSA infection may contribute to nosocomial dissemination of MRSA in hospitals because of increased prevalence of MRSA carriage at the time of admission, followed by transmission to other hospitalized patients [10, 18, 19]. Increased incidence of HA-MRSA infection may, in turn, foster dissemination of MRSA in community populations. In other words, there is a blurring of the distinction between the USA300 strain as community associated and USA100 and USA200 strains as health care associated. CA-MRSA strains differ from HA- MRSA strains, because CA-MRSA strains seem to be resistant to fewer antibiotics. Table 2 shows a comparison of the clinical features of CA-MRSA infection with those of HA-MRSA infection, as well as the most effective antibiotic agents for empirical therapy [20]. The latest Infectious Diseases Society of America guidelines for the management of skin and soft-tissue infections, including those caused by multidrug-resistant organisms, recommend consideration for hospitalization of patients with hypotension, elevated creatinine level, low serum bicarbonate level, elevated creatine phosphokinase level, marked left white blood cell shift, and C-reactive protein level 113 mg/l [22, 23]. Most abscesses can be incised and drained in the emergency department or outpatient clinic and treated (with or without antibiotics) on an outpatient basis, whereas some deep or extensive lesions may require hospitalization and surgical intervention [23]. Patients with infections associated with osteomyelitis, septic arthritis, and endocarditis are usually hospitalized initially [23]. Oral antibiotics with activity against CA-MRSA isolates include trimethoprimsulfamethoxazole (TMP-SMX), rifampin, linezolid [24], tetracycline, and clindamycin. Because of rifampin s ability to select resistant strains, it should not be used as monotherapy but may be of added value when used with antibiotics [23]. Long-acting tetracyclines (such as doxycycline and minocycline) may be used as alternate agents for specific types of MRSA infection, particularly those of the skin and skin structure [25]. Some strains of MRSA exhibit inducible clindamycin resistance, which can be detected by the erythromycin-clindamycin D-zone test [26]. These strains demonstrate in vitro clindamycin susceptibility before therapy; however, after exposure to clindamycin during therapy, they develop in vitro resistance. Outpatient treatment of mild cellulitis could include a first-generation cephalosporin or penicillinase-resistant penicillin for methicillin-susceptible strains [27]. For moderate-to-severe infections or in areas with high MRSA prevalence, empirical coverage should include TMP-SMX plus a first-generation cephalosporin or penicillinase-resistant penicillin, or alternatively, clindamycin alone [23] (linezolid and tigecycline are also available if the staphylococci are resistant to methicillin). Intravenous antibiotics are appropriate for patients with abscesses who require hospitalization, are immunocompromised, have evidence of systemic toxicity associated with significant cellulitis, or have large ( 5 cm), multiple, or recurring abscesses. As noted, although vancomycin is the most frequently used intravenous antibiotic for serious infections caused by MRSA in the United States, there is concern for increased emergence of vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus [6 8]. Newer intravenous antibiotics with enhanced activity against MRSA include, in order of commercial introduction, quinupristin-dalfopristin, linezolid, daptomycin, and tigecycline [16]. At present, nosocomial infections pose a significant threat to patients worldwide that is greatly increased by the increase in the prevalence of both HA-MRSA and CA-MRSA. At any one time, 10% of patients in hospitals have an HA infection [28], defined as an infection occurring 48 h after admission [23]. An equal number of hospitalized patients have infections acquired in the community. Infected or colonized patients are a potential source of cross infection to other persons in the hospital and at home. The increasing use of S172 CID 2010:51 (Suppl 2) Tice and Rehm

3 Table 2. Comparative Clinical and Laboratory Features of Community-Associated (CA) and Health Care Associated (HA) Methicillin-Resistant Staphylococcus aureus (MRSA) Infections Feature CA-MRSA HA-MRSA Epidemiology Young adults; community origin Older adults and elderly; hospital origin Cassette chromosome type SCC mec IV SCC mec I, II, III Toxins PVL positive or negative PVL negative Susceptibility testing In vitro susceptibility leads to in vivo effectiveness In vitro susceptibility does not lead to in vivo effectiveness Antibiotic susceptibility pattern Clinical features Pauci-resistant (susceptible to many antibiotics) Severe necrotizing CAP postviral influenza with PVL-positive strains, nonsevere CAP with PVL-negative strains, severe pyomyositis and/or fasciitis with PVL-positive strains, nonsevere csssi with PVL-negative strains (folliculitis, abscesses) Multidrug resistant (not susceptible to most antibiotics) Bacteremia, nosocomial ABE, SSSI, respiratory secretion colonization common in patients receiving mechanical ventilation, MRSA VAP uncommon Empirical antibiotic therapy TMP-SMX, doxycycline, clindamycin Daptomycin, a linezolid, tigecycline, minocycline, quinupristin-dalfopristin, vancomycin NOTE. ABE, acute bacterial endocarditis; CAP, community-associated pneumonia; cssi, complicated skin or soft-tissue infection; PVL, Panton- Valentine leukocydin; SCC, staphylococcal cassette chromosome; TMP-SMX, trimethoprim-sulfamethoxazole; VAP, ventilator-associated pneumonia. Adapted with permission from [20]. a All drugs are also effective against CA-MRSA; daptomycin is not effective for CAP [21]. antimicrobials for MRSA infection will undoubtedly lead to more drug resistance and new genes and mechanisms of survival for these wily organisms. Finally, antimicrobials are used in both hospitals and the community, and drug resistance emerging from their use or misuse in either setting inevitably has an effect in the hospital [27]. Excess mortality of 4% for infections due to medical care has been reported, and mortality of 22% is associated with postoperative septicemia [29]. The attributable mortality that is directly associated with the infection of nosocomial bloodstream infection, the most common HA infection, is frequently 35% 60% in US hospitals annually. In a 2-year study of patients with nosocomial bloodstream infection who were admitted to the surgical intensive care unit, mortality was 35%, with a median length of hospital stay of 40 days, resulting in excess hospital costs of $40,000 per survivor [30]. For nosocomial pneumonia, the second most common HA infection, attributable mortality is 20% 50%, with longer hospital stays and increased hospital costs [31, 32]. The terrible toll of HA infections led the Centers for Medicare and Medicaid to stop payments for certain HA infections [33]. A number of studies have described the potential dangers of hospitalization, particularly for patients who require longterm therapy. For example, a 5-year study of bacteremia as a marker of severe infection in a population of 550,000 served by 2 hospitals concluded that prior hospital admission is a major risk factor for bacteremia at a subsequent hospital admission [34]. In fact, the hospital-exposed population, defined as patients hospitalized in the previous year, accounted for 55% of all admissions and 42% of emergency admissions to medical, pediatric, or surgery departments. According to a 4- month prospective observation cohort study designed to determine the rates of colonization with multidrug-resistant bacteria after prolonged hospitalization, 19.8% of patients were colonized or infected with at least 1 type of multidrugresistant bacteria on hospital day 30 [35]. As these studies suggest, long-term hospitalization may actually fuel the MRSA epidemic [35]. After stabilization in the hospital, however, patients with invasive infections, including those caused by MRSA, can be treated as outpatients even if the infection requires intravenous antibiotic therapy [36, 37]. More than 250,000 Americans receive intravenous antibacterial agents in an outpatient setting each year, and this number continues to increase [38]. In many settings, outpatient parenteral antimicrobial therapy (OPAT) is standard for patients with stable infections requiring long-term treatment. Table 3 lists the infectious conditions that have been treated successfully with OPAT [38]. Osteomyelitis and serious skin and soft-tissue infections are 2 of the most common infections treated with parenteral antibiotics outside the hospital [39, 40]. The Infectious Diseases Society of America published comprehensive guidelines for OPAT [38]. As the number of infections due to S. aureus has increased, OPAT has become a common modality for treatment of serious infections due to this organism. Most published series describing the results of OPAT in patients with S. aureus infection have not distinguished between methicillin-susceptible S. aureus and MRSA infections, but results have been favorable. A single retrospective re- Meeting the Challenges of MRSA with OPAT CID 2010:51 (Suppl 2) S173

4 Table 3. Infections Treated with Outpatient Parenteral Antimicrobial Therapy (OPAT) Infections treated with OPAT Soft-tissue infection, including cellulitis and wound infection Osteomyelitis Septic arthritis or bursitis Prosthetic joint infection Pneumonia and/or severe lower respiratory tract infection Cystic fibrosis (infectious exacerbation) Sinusitis (complicated) Chronic otitis and/or mastoiditis Endocarditis Bacteremia Intravenous catheter associated infection Vascular graft infection Hepatic or splenic abscess Intra-abdominal infection or peritonitis Complicated urinary tract infection Pelvic inflammatory disease and/or tubo-ovarian abscess Meningitis or encephalitis Brain or epidural abscess Neutropenic fever Lyme disease Fungemia and/or systemic mycosis Cytomegalovirus infection NOTE. Adapted with permission from [38]. view demonstrated that infections due to methicillin-susceptible strains can be effectively and safely treated with OPAT [37]. In the articles comprising this supplement, leading authorities consider the challenges of treatment of serious infection due to MRSA and the potential role of OPAT. The experts review the remarkably rapid evolution of MRSA from ancestral, antibiotic-susceptible clones to their current, seemingly unstoppable epidemic proportions. In a discussion of infections due to MRSA, 3 infectious diseases specialists emphasize the more aggressive and invasive nature of MRSA, compared with the already predominant human pathogen S. aureus. A brief history of OPAT describes this continually growing health care modality from its beginning in 1974 as a quality-of-life issue for children and a solution to the high cost of hospitalization to the current multibillion-dollar industry. The business of OPAT is discussed by the physician director of an active practice, and the current status of Medicare and managed care regulations concerning OPAT are explained by an experienced OPAT administrator. The unique issues, problems, and advantages of OPAT for children and adolescents are reviewed, with emphasis on serious childhood infections and MRSA. Finally, a clinician describes the possible role of telemedicine in outpatient management in the future [41]. Acknowledgments Potential conflicts of interest. S.J.R is a member of the speakers bureau and the scientific advisory board and has served as a principle investigator for Cubist Pharmaceuticals, is a member of an advisory committee for Pfizer, and is a member of the speakers bureaus for Wyeth and Roche. A.T. has been a consultant and advisory board member for Astellas, Cubist, Novartis, Pfizer, and Roche; has been on the speakers bureaus for Cubist, Merck, and Schering-Plough; and has received research funding from Cubist, GlaxoSmithKline, and Merck. Financial support. Cubist Pharmaceuticals Supplement sponsorship. 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