The Changing Face of Staphylococcus aureus: A Continuing Surgical Challenge

Abstract

Background:

Staphylococcus aureus continues to be an important pathogen for surgeons. Surgical infections of interest caused by this pathogen include community-acquired infections, especially of skin and soft tissue; surgical site infections; and nosocomial infections during the post-operative period.

Methods:

A literature review was conducted to detail the history of S. aureus in surgical care; to identify the structural elements of the pathogen, the secreted exotoxins and enzymes, and the changing resistance patterns that make S. aureus an ever-formidable clinical foe; to consider whether screening for the pathogen and directed antimicrobial prophylaxis are useful; and to identify antimicrobial agents employed currently in treatment of established infections.

Results:

Staphylococcus aureus has shown a pattern of increasing prevalence of infections among hospitalized patients and a pattern of increasing resistance. A broad array of virulence factors account for its continued pathogenicity, and new virulence characteristics continue to be acquired. Staphylococcus aureus has an uncanny ability to adapt and develop resistance to each new antibiotic as it is introduced into clinical care. Although screening and directed surgical prophylaxis against methicillin- (now sometimes referred to as meticillin-) resistant S. aureus (MRSA) is controversial, effective efforts to decrease the incidence of nosocomial infections may be decreasing the numbers of MRSA infections encountered, and current agents remain effective for therapy.

Conclusions:

Staphylococcus aureus continues to be a major pathogen for surgical patients. The scope of infections has expanded recently to include toxic shock syndrome, severe community-acquired soft tissue infections with unique virulence characteristics, and highly resistant pathogens. The adaptability of the organism requires that new prevention and treatment strategies be developed continuously to meet the challenge of future infections.

S taphylococcus aureus has long been a pathogen of considerable interest to surgeons. “Laudable” pus exuding from infection of injured tissue has most commonly been attributable to S. aureus. Moreover, historically, S. aureus has been the most common pathogen of skin and soft tissue infections (SSTIs) and surgical site infections (SSIs), and it continues to be a major pathogen for hospital-acquired and ventilator-associated pneumonia (HAP, VAP), intra-vascular catheter infections, and hospital-acquired infections of the surgical patient at other anatomic sites.

The high prevalence of S. aureus infections in surgical patients has led to vigorous efforts to develop specific preventive and therapeutic measures directed against this pathogen. The threat of these infections has led to intensive efforts in the prevention of transmission by enhanced infection control practices, the liberal use of topical antiseptics, and specific systemic antibiotics. Despite these efforts, prevention has remained elusive, and therapeutic management of established infections continues to be difficult. An important key that has led to suboptimal prevention and treatment of S. aureus infections has been the rapid evolution of resistance to antimicrobial agents, and the development of new virulence factors.

In this paper, the changing epidemiology, risk profile, and antimicrobial susceptibility of S. aureus are reviewed, as are prophylaxis and therapy. This ever-changing phenotype of resistance and virulence is leading to new challenges and changes in the prevention and treatment of infection in the surgical patient.

Historical Evolution of Staphylococcus aureus

Studies of the microbiology of S. aureus led directly to the discovery of penicillin and the inauguration of the era of antibiotic treatment. An uncovered culture plate in a laboratory, an airborne fungal contaminant of the plate, and a recognized zone of inhibition about the perimeter of the unwelcome fungus resulted in the discovery of penicillin by Alexander Fleming [1,2]. Although available on a limited basis to the military during the war, penicillin and sulfonamide preparations were introduced into general clinical practice for the treatment of infection after World War II. Many believed at the time that the millennium of infection-free surgery was at hand, in that antibiotics for surgical patients held promise for both prevention and treatment of post-operative infections. This optimism was short-lived, as the first penicillin-resistant S. aureus was discovered in 1944 [3]. As the use of the first generation of antibiotics was expanded, so was the emergence of resistant strains of S. aureus, such that a pandemic was identified among hospitalized patients in the 1950s.

In 1959, methicillin (now sometimes referred to as meticillin) was introduced as a semi-synthetic penicillin with activity against penicillin-resistant S. aureus (PRSA), and it was deployed rapidly for hospital-acquired infections [4]. By 1961, the first methicillin-resistant S. aureus (MRSA) pathogens were identified. During the late 1960s and 1970s, additional semi-synthetic penicillins (e.g., oxacillin) and the first-generation cephalosporins were introduced into clinical practice to combat PRSA. By 1970, PRSA predominated in the hospital, but penicillin-sensitive pathogens persisted among community-acquired staphylococcal infections, and penicillin G still was recommended for community-acquired infections [5]. The liberal use in clinical practice of oral β-lactam antibiotics led to the extinction of penicillin-sensitive S. aureus by the mid-1970s [6]. The former PRSA pathogens then were re-named methicillin-sensitive S. aureus (MSSA), as expanded ambulatory and in-patient antibiotic use attended an increasing frequency of MRSA isolates in hospital-acquired infections. During the 1980s, this growth in the incidence of MRSA infections led to the re-emergence and widespread usage of vancomycin as the treatment of choice. Owing to cumbersome administration and the risk of ototoxicity and, to a lesser extent, nephrotoxicity, there arose considerable interest in the identification of alternative antibiotic therapies for MRSA.

As was observed with PRSA in the 1970s, in the 1990s, the paradigm was that community-acquired S. aureus infections were methicillin-sensitive whereas hospital-acquired infections became nearly uniformly MRSA. In 1993, the first community-associated MRSA (CA-MRSA) was identified [7], and in 1998, the first isolates were identified in the U.S. [8]. This MRSA variant expressed a unique genotype and phenotype, demonstrating new and unique virulence factors (e.g., Panton-Valentine leukocidin) not ordinarily seen in hospital-acquired MRSA (HA-MRSA), as well as a different pattern of antibiotic susceptibility, indicating that the organism arose de novo in the community and was not a feral, escaped hospital clone. Community-associated MRSA demonstrates susceptibility to selected non-β-lactam antibiotics (e.g., co-trimoxazole) and is now recognized worldwide as a virulent pathogen [9]. The rate of infections with both HA-MRSA and CA-MRSA increased rapidly in the U.S., the former until 2008, at least.

A recent report identified a reduction in 2008 rates of HA-MRSA infection [10] (Fig. 1). Whether this reduction signals a true decline or plateau in the frequency of HA-MRSA infections remains to be determined. Such a reduction is plausible owing to recent reductions in the rates of certain nosocomial infections often caused by S. aureus, including central line-associated blood stream infection (CLABSI) and VAP [11 –13], and possibly to recent controversial efforts to screen for and eradicate the staphylococcal carrier state as a tactic to reduce infections after surgery and in the intensive care unit (ICU) [14 –17]. How these efforts will mitigate MSSA infections, both in the community and in healthcare-associated settings, is an open question.

FIG. 1.

Increase in Infections with Methicillin-Resistant Staphylococcus aureus in Hospitalized Patients in the U.S. from 2001 to 2008 (Agency for Healthcare Research and Quality. HCUPnet. http://hcupnet.ahrq.gov/ Accessed December 10, 2010.)

The historical evolution of resistance of S. aureus continued with evidence of increasing minimum inhibitory concentrations (MICs) among vancomycin-susceptible isolates, vancomycin-intermediate resistance (VISA), and even a small number of vancomycin-resistant isolates (VRSA) (see below). It is likely that the continued use of antibiotics against MRSA will create environmental pressure for the continued decrease in the prevalence of infections caused by MSSA and evolution of the next generation of S. aureus that is highly resistant to current and future antibiotic agents [18].

Mechanisms of Virulence and Resistance

Understanding the complex issues of virulence and resistance in S. aureus requires at least a limited knowledge of bacterial genetics [19,20]. The genome of S. aureus is a single circular chromosome. This haploid genetic configuration means that changes in genotype have a direct influence on phenotypic expression (e.g., antibiotic resistance). The genome consists of 75 percent core genes that appear in all species and 25 percent accessory genes that are highly variable among strains. Within the accessory component of the genome are mobile genetic elements that are transferable among S. aureus strains. Accessory components may consist of pathogenicity islands, prophages (from bacteriophages), staphylococcal cassette chromosomes (SCC), genetic islands, and plasmids. Whereas specific definitions are used to distinguish mobile genetic elements one from another, a common feature is that specific clusters of transferrable genes move together, leading to expression of common phenotypes. Virulence factors of S. aureus may be common to all species (e.g., coagulase), or they may be highly specific for each strain. This ability to exchange mobile genetic units among strains of S. aureus, but also to acquire genetic material from other bacterial species (e.g., Enterococcus), results in patterns of virulence and resistance that are changing continually.

Microbial virulence factors of S. aureus generally have been grouped into bacterial structural factors, secreted bacterial products and enzymes, and resistance mechanisms to antimicrobial agents. Structural elements of the bacterial cell include a polysaccharide capsule that resists phagocytosis, and the peptidoglycan cell wall that anchors a number of surface adhesion proteins, permitting microbial binding to the extracellular matrix of targeted host tissues [21]. The surface adhesion proteins of the cell wall are referred to collectively as microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) [19 –21]. The MSCRAMMs are identified in many species of gram-positive organisms, of which several are unique to S. aureus. Table 1 identifies many (but not all) of the MSCRAMMs that have been identified [22 –29].

Table 1.

Microbial Surface Components Recognizing Adhesive Matrix Molecules (MSCRAMMs) Found Anchored to Cell Walls of Staphylococcus aureus that Facilitate Soft Tissue Infections by Promoting Bacterial Adherence to Extracellular Matrix

Specific MSCRAMM	Gene	Binding target
Fibronectin-binding proteins	FnbpA; FnbpB	Extracellular matrix [22]
Collagen-binding protein	Cna	Collagen and cartilage [23]
Clumping factors	ClfA; ClfB	Fibrinogen [23,24]
Protein A	Spa	von Willebrand factor [25]
Elastin-binding protein	EbpS	Elastin [26]
Bone sialoprotein-binding protein	Bbp	Bone sialoprotein [27]
Extracellular matrix-binding protein	EbhAB	Fibronectin [28]

A virulence factor that is a secreted product, but also part of the staphylococcal bacterial cell structure, is a polysaccharide and protein matrix, or biofilm [30 –32]. Biofilm is produced by several bacterial species, including selected strains of S. aureus, after adherence of the bacterial cell to a foreign surface. Biofilm encases a community of cells and changes the phenotype from planktonic (rapidly dividing) to dormancy, affording barrier protection from host defenses and imperviousness to antibiotics [33]. Not all strains of S. aureus are biofilm producers, but those that are have been identified in particular as pathogens associated with device-related infections.

Products secreted by S. aureus include those that enhance microbial adherence to host tissues, exotoxins that are directly toxic to host cells, and enzymes that degrade and digest the extracellular matrix. Secretable expanded repertoire adhesive molecules (SERAMs) are a group of secreted proteins that have duplicative functions of the MSCRAMMs identified above, except that they are secreted proteins, not part of the staphylococcal cell wall [34]. A SERAM of considerable interest for S. aureus is coagulase, which targets prothrombin and fibrinogen. The result of the action of coagulase is generation of a staphylococcal–fibrin matrix and creation of a local environment that facilitates microbial adherence to tissue and a protected environment against host defense mechanisms and antimicrobial therapy [34]. Coagulase has effects that are analogous to clumping factor of the MSCRAMMs, but it is a freely secreted and unique protein [35].

Exotoxins are those secreted products that are cytotoxic to host cells, whereas the superantigens are secreted products that provoke an over-exuberant inflammatory response by the host. Individual cytotoxins have different cell targets but generally function similarly by damaging the cell membrane, creating pores, and leading to extravasation of cellular contents. The cytotoxin of greatest recent interest has been the Panton-Valentine leukocidin (PVL) [36], which is but one of several leukocidins that are produced. The PVL consists of two proteins that insert into the plasma membrane of leukocytes and create pore-mediated damage to the target cell. The PVL has been particularly associated with CA-MRSA and has been implicated in the increased virulence of the community-acquired vs. the healthcare-acquired (HA-)MRSA [37].

A representative selection of exotoxins is identified in Table 2 [38 –50]. The superantigen toxins identified in Table 2 are powerful immuno-stimulatory proteins. They provoke an exaggerated response from T cells, with massive pro-inflammatory cytokine release being the result. The virulence expression from these superantigens is not necessarily from direct cytotoxicity, but rather from the consequences of severe local inflammation. For S. aureus, these superantigens play an important role in severe enterocolitis (food poisoning), scalded skin syndrome, and toxic shock syndrome.

Table 2.

Secreted Products from Staphylococcus aureus that Contribute to Its Virulence

	Gene(s)	Pathogenic role
Cytotoxins
α, β, δ, γ-hemolysins	hla, hlb, hld, hlb	Lyse erythrocytes and other cells [38]
Panton-Valentine leukocidin	lukS, lukF	Lysis of leukocytes [39]
Phenol-soluble modulins	PSMα1, PSMα2, PSMα3	Lysis of leukocytes and erythrocytes [40]
Superantigens
Enterotoxins A, B, C, D	sea, seb, sec, sed	Food poisoning, toxic shock syndrome [41]
Exfoliatin A, B	eta, etb	Scalded skin syndrome [42]
Toxic shock syndrome toxin-1	tst	Toxic shock syndrome [43,44]
Enzymes
Coagulase	coa	Clot initiation, clot digestion [45]
Staphylokinase	sak	Plasminogen activator [46]
Hyaluronidase	hys	Extracellular invasion [47]
Nuclease	nuc	Dissolution of extracellular matrix [48]
Lipase	lip	Dissolution of tissue [49]
V8 protease	ssp	Dissolution of tissue matrix [50]

Staphylococcal Resistance Mechanisms and their Clinical Consequences

Since the introduction of antibiotics into clinical practice, the rapid evolution of resistance by S. aureus has been of great interest to, and problematic for, clinicians. Changes in the penicillin-binding protein on the staphylococcal cell membrane was the mechanism for the emergence of resistance to penicillin, but more recently also has been important in the emergence of methicillin resistance. Using pulsed-field gel electrophoresis (PGFE), eight strains of MRSA have been characterized and labeled as PGFE USA100 through USA800 [51]. The resistance determinant lies in the staphylococcal cassette chromosome within the accessory portion of the genome (SCCmec) [52]. However, the genetics of resistance differs among these strains. Seven SCCmec gene cassettes have been identified in MRSA. Types I, V, VI, and VII of SCCmec are lower molecular weight cassettes of genes and typically carry only resistance for β-lactam antibiotics. By contrast, SCCmec type IV has been most commonly associated with the prevalent CA-MRSA in the U.S. (USA300) [53]. Accordingly, the CA-MRSA has retained susceptibility to non-β-lactam antibiotics such as clindamycin, trimethoprim/sulfamethoxazole, and others. By contrast, HA-MRSA has the higher molecular weight SCCmec types II and III gene cassettes, which results in resistance to most non-β-lactam antibiotics as well. The continuing genetic changes within the accessory genes, the acquisition of plasmids with additional resistance genes, and the increasing presence of CA-MRSA within the hospital environment suggest that the phenotypic difference in susceptibility among all strains of MRSA is likely to become less distinct [54 –56].

A looming threat that may enhance dramatically the adverse consequences of S. aureus infection is vancomycin-intermediate (susceptibility) resistant S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA). First reported in 1997 [57], VISA (historically, with minimum inhibitory concentrations [MICs] 4–16 mcg/mL) appears to be increasing steadily in frequency. Moreover, although controversial, “MIC creep” has been observed among S. aureus isolates within the susceptible range [58], meaning that even among isolates that are “susceptible” (i.e., vancomycin-susceptible S. aureus; VSSA) by definition [MIC <2 mcg/mL], susceptibility is reduced. This correlates clinically with an increased risk of failure of therapy of isolates at the higher end of the range [59,60] (Table 3) and has led to revision of the susceptibility breakpoints for S. aureus to vancomycin by the Clinical and Laboratory Standards Institute (Table 4) [61] to decrease the possibility of treatment failure by labeling the formerly “borderline” VSSA isolates as being either VISA or VRSA, thereby influencing antibiotic choice. Higher reported prevalences of VISA and VRSA will be the inevitable result.

Table 3.

Causes of Vancomycin Failure in a Single-Center Cohort of 320 Patients with Documented MRSA Bacteremia, Determined by Logistic Regression Analysis

Predictor of failure	Adjusted odds ratio	95% CI
Infective endocarditis	4.55	2.26–9.15
Nosocomial acquisition of infection	2.19	1.21–3.97
Initial vancomycin trough concentration <15 mcg/mL	2.00	1.25–3.22
Vancomycin MIC >1 mcg/mL	1.52	1.09–2.49

CI=confidence interval; MIC=Minimum inhibitory concentration.

From reference 60.

Table 4.

Interpretive Criteria for Vancomycin Minimum Inhibitory Concentration (mcg/mL) for Staphylococcus aureus

Old breakpoints	New breakpoints
Susceptible: ≤4	Susceptible: ≤2
Intermediate: 8–16	Intermediate: 4–8
Resistant: ≥32	Resistant: ≥16

From reference 61.

The definition of VISA (i.e., MIC of 4–8 mcg/mL by the 2006 revised breakpoints) and the laboratory methods for testing isolates (disc diffusion can be inaccurate) also have become issues [62]. The VISA phenotype is not the consequence of vancomycin-resistance genes transmitted from enterococci. The natural history of VISA expression is believed to begin with adaptive thickening of the cell wall of the occasional heteroresistant organism, which leads to its emergence as the dominant phenotype when exposed to environmental pressures, including vancomycin use. The thickened cell wall impedes penetration of the vancomycin molecule, and up-regulates expression of peptidoglycan binding sites to create the relative resistance problem [63]. Unremitting vancomycin utilization pressure is likely to make the evolution of VISA a continuing problem.

Heteroresistant VISA (hVISA) strains are those for which MICs conventionally indicate susceptibility (≤2 mcg/mL) by routine testing, except when high-density inocula are used. Within such inocula, minority sub-populations emerge for which MICs are in the intermediate range (4–8 mcg/mL) [64]. The detection of hVISA requires inocula containing >10⁶ bacteria, because resistant clones occur infrequently spontaneously (∼1/1,000,000) [65]. The MICs for most heteroresistant clones are in the 4–8 mcg/mL range [66], but unstable heteroresistance can be detected [66,67]. Clones of S. aureus demonstrating unstable heteroresistance grow in the presence of high concentrations of vancomycin (>4 mcg/mL), although conventional MICs for such clones are not elevated; i.e., non-susceptible clones revert rapidly to normal phenotypes and therefore cannot be detected by the usual laboratory tests. Clinical failure with vancomycin or MICs to vancomycin of ≥2 mcg/mL should alert the laboratory to proceed with the more specific methods of population analysis profiling along with hVISA screening performed by the macro-Etest (MET) to identify hVISA or VISA isolates [68]. Both VISA and hVISA appear to emerge in SCCmec II isolates among vancomycin-exposed patients and are detected better by MET [69].

A total of 11 VRSA infections have now been identified in the U.S. (Table 5) [70 –79]. It appears that the vanA gene was acquired by plasmid-mediated gene transfer from vancomycin-resistant enterococci encodes for highly resistant VRSA. All VRSA are methicillin resistant. Most are classified as USA100. These clinical infections have been associated with preceding MRSA or enterococcal infections, and the patients have had prior vancomycin therapy. Chronic co-morbid conditions are present, notably chronic kidney disease/end-stage renal disease. All infections followed surgical care or have occurred in patients with soft tissue infections (e.g., chronic ulcers), where surgeons are involved in patient management.

Table 5.

Clinical Summary of 11 Cases of Vancomycin-Resistant Staphylococcus aureus Infections in the United States as of December 2010

Case	Year [reference]	Age	Site of infection	Co-morbidities
1	2002 [71]	40	Plantar soft tissue, temporary dialysis catheter	Diabetes mellitus, chronic kidney disease/renal replacement therapy, peripheral vascular disease
2	2002 [72]	70	Chronic heel ulcer/osteomyelitis	Obesity
3	2004 [73]	63	Urinary tract/nephrostomy tube	Diabetes mellitus, multiple sclerosis, nephrolithiasis
4	2005 [74]	78	Gangrene of toe	Diabetes mellitus, peripheral vascular disease
5	2005 [75]	58	Abdominal wall surgical site	Obesity
6	2005 [75]	48	Plantar ulcer/osteomyelitis	Motor vehicle crash, chronic ulcers
7	2006 [75]	43	Necrotizing fasciitis/triceps wound	Diabetes mellitus, chronic kidney disease/renal replacement therapy, chronic ulcers
8	2007 [76]	48	Toe wound/osteomyelitis	Diabetes mellitus, chronic ulcers, obesity
9	2007 [77]	54	Osteomyelitis/surgical site post-foot amputation	Diabetes mellitus, hepatic encephalopathy
10	2009 [78]	53	Plantar soft tissue	Diabetes mellitus, lupus erythematosus, rheumatoid arthritis, obesity
11	2010 [79]	64	Prosthetic joint surgical site	Diabetes mellitus, chronic kidney disease/renal replacement therapy

Modified from U.S. Centers for Disease Control and Prevention: CDC reminds clinical laboratories and healthcare infection preventionists of their role in the search and containment of vancomycin-resistant Staphylococcus aureus, May 2010. www.bt.cdc.gov/coca/reminders/2010/2010may06.asp) [70].

Clinical Consequences of Staphylococcal Infection

Staphylococcus aureus can cause a host of infections, of skin and soft tissue, the blood stream, the lungs, and prosthetic devices, among others (Table 6). The 15 heat-stable (and thus not destroyed by cooking) enterotoxins elaborated by S. aureus may cause food-borne disease characterized by malaise, nausea, vomiting, abdominal pain, and diarrhea. The epidemiology of infection depends on the organism (MSSA vs. HA-MRSA vs. CA-MRSA) and the clinical setting (outpatient vs. inpatient vs. ICU). In a retrospective analysis of the Agency for Healthcare Research and Quality Nationwide Inpatient Sample database (2000 and 2001 editions), S. aureus infection was reported as a discharge diagnosis for 0.8% of hospitalized patients, and was estimated to include 292,045 inpatients/year in the U.S. [80]. Mean hospital length of stay was increased three-fold, from 4.5 days to 14.3 days, and hospital charges also were increased three-fold, from $14,141 to $48,824. The risk of in-hospital death increased nearly five-fold, from 2.3% to 11.2%. In 2005, more than 85% of the deaths of hospitalized patients with staphylococcal infections were attributed to HA-MRSA [81]. Although attribution of death is complex and error-prone for patients with multi-system disease, and estimates do not always account properly for differences in severity of illness and delays or errors in treatment (or serious morbidity therefrom), the risk of death from invasive MRSA infection (i.e., bacteremia) is approximately double that of MSSA infection [82,83]. Excess mortality and hospital cost has been associated as well for SSIs caused by MRSA [84], but other data are conflicting [85].

Table 6.

Clinical Manifestations of Infections Caused by Staphylococcus aureus

Skin and soft tissue

Animal and human bites

Carbunculosis

Cellulitis

Folliculitis

Furunculosis

Impetigo

Hidradenitis suppurativa

“Ludwig angina”: Deep-space infection of the floor of the mouth/neck; usually odontogenic)

Mastitis

Maxillofacial trauma

Mediastinitis

Necrotizing soft tissue infection

Surgical site infection

Cardiovascular

Cavernous sinus thrombosis (usually odontogenic)

Community-onset bacteremia

Infective endocarditis: native- and prosthetic-valve

Metastatic infections (almost anywhere)

Mycotic aneurysm

Nosocomial bacteremia: Catheter-related

Suppurative thrombophlebitis

Toxic shock syndrome

Device-related

Any implanted device or prosthesis in any location

Gastrointestinal

Enterocolitis

Food-borne gastroenteritis

Peritonitis/intra-abdominal abscess

Musculoskeletal

Osteomyelitis (including odontogenic; also extension of vertebral involvement into paraspinal soft tissues)

Prosthetic joint infection

Pyomyositis

“Septic” arthritis and bursitis

Neurological

Brain abscess: metastatic or by direct extension

Epidural abscess

Meningitis: Community-onset and post-operative

Otitis media

Parotitis

Pericarditis

Pulmonary

Community-onset pneumonia (CA-MRSA)

Empyema thoracis

Lung abscess

Nosocomial pneumonia: Hospital- and ventilator-associated

Prevention of MRSA Infection

Population-based studies have consistently identified male gender and both extremes of age as important risk factors for the acquisition of staphylococci. Dialysis dependence, diabetes mellitus, cancer, human immunodeficiency virus infection, intravenous drug use, alcohol abuse, recent surgery, critical illness, and staphylococcal nasal carriage have been identified as independent risk factors [86,87]. Therefore, identification of the patient at risk is a crucial first step. Much recent work in prevention of invasive staphylococcal infections focused on prevention of colonization of the patient at risk and decolonization of staphylococcal carriers. Although work is being pursued with novel antimicrobial molecules, other tactics being investigated include phage therapy, molecules aimed at blocking regulation of virulence determinants and surface adhesins, and vaccination. Although anti-staphylococcal vaccines have been raised against a variety of targets, multiple efforts have failed to demonstrate efficacy, including in Phase III trials.

Individuals who are nasal carriers (the primary locus, although other sites are possible) of S. aureus may represent as much as 50% of the population, although the persistent (rather than intermittent) carriers make up 20%–30% of healthy people. Most persistent carriers (as many as 90%) harbor a single strain of MSSA, although MRSA nasal carriage is recognized to be increasing (now up to 10% of carriers). Patients who are persistent carriers are at higher risk of acquiring S. aureus infection. Eradication of the carrier state decreases the risk of nosocomial infection, but routine screening for the carrier state is controversial in that the evidence extant is mixed regarding effectiveness [15,88]. Eradication of the carrier state with topical nasal 2% mupirocin ointment twice or thrice daily for five to seven days may be effective about 60% of the time if undertaken according to established protocol [89], but treatment failures are common [90]. Alternatively, topical application of 2% chlorhexidine gluconate-impregnated cloths to critically ill trauma patients as a “sponge bath” decreased the rates of colonization with MRSA, and MRSA VAP [91].

It has long been speculated that alteration of antimicrobial prophylaxis regimens can be used as an anti-MRSA infection control tactic. Fukatsu et al. demonstrated that using first- rather than third-generation cephalosporins for surgical prophylaxis and reducing the duration of prophylaxis to emphasize pre- and intra-operative rather than postoperative dosing was associated with control of an outbreak of post-operative MRSA SSIs [92]. However, providing an anti-MRSA agent (e.g., intravenous vancomycin) as surgical prophylaxis generally is discouraged [93 –95] unless the patient has an allergy to beta-lactams, and even then, clindamycin is preferred [95]. However, countervailing arguments in favor of vancomycin prophylaxis for cardiac [95] and orthopedic surgery have been put forth. Vancomycin is the recommended antibiotic for prophylaxis of major surgical procedures when MRSA is a source of concern [95 –97]; although the threshold level of prevalence of MRSA SSI is vague in the literature, it may be as low as 10% [96]. In a randomized clinical trial in patients undergoing cardiac surgery, vancomycin was compared with cefazolin for prevention of SSI in a MRSA SSI high-prevalence medical center with high MRSA infection rates [98]. Overall, SSI rates in the two groups were the same, but cefazolin patients had a higher rate of MRSA infection, whereas vancomycin patients had a higher MSSA infection rate. Moreover, vancomycin prophylaxis of SSI has not been subject to rigorous evaluation in clean elective surgery, despite the recommendation to use it when MRSA is the target pathogen. In the case of orthopedic surgery, a bewildering array of delivery vehicles have been described (e.g., topical vancomycin powder [99], antibiotic-loaded cement or allograft bone [100]) without much scientific rigor, leaving this question largely unanswered.

Ultimately, the tenets of infection control—hand hygiene, barrier precautions, and responsible antibiotic prophylaxis—-are the most effective prevention. Concerted effort has reduced the incidence of both CLABSI and VAP recently [101,102]. In 2001, an estimated 43,000 CLABSIs occurred among patients hospitalized in ICUs in the U.S. [103]. In 2009, the estimated number of ICU CLABSIs had decreased to 18,000. Reductions in CLABSIs caused by S. aureus were more marked than reductions in infections caused by gram-negative bacilli, Candida spp., and Enterococcus spp. In 2009, an estimated 23,000 CLABSIs occurred among patients in in-patient wards and, in 2008, an estimated 37,000 CLABSIs occurred among patients receiving out-patient hemodialysis. In 2009 alone, an estimated 25,000 fewer CLABSIs occurred in U.S. ICUs than in 2001, a 58% reduction. As many as 6,000 lives and $414 million in excess health-care costs were saved in 2009, and approximately $1.8 billion in cumulative excess health-care costs have been saved since 2001.

These efforts may be decreasing the number of invasive MRSA infections overall. According to data submitted to the National Healthcare Safety Network (HNSN) of the U.S. Centers for Disease Control and Prevention (CDC), the incidence of MRSA CLABSI decreased significantly in all U.S. ICU types from 2001 through 2007 except in pediatric units, for which incidence rates remained static [13,104]. Decreases in MRSA CLABSI incidence ranged from −51.5% (95% confidence interval [CI] −33.7%, −64.6%; p<0.001) in non-teaching-affiliated medical-surgical ICUs (0.31 vs. 0.15/1,000 central line days) to −69.2% (95% CI −57.9%, −77.7%; p<0.001) in surgical ICUs (0.58 vs. 0.18/1,000 central line days). In all ICU types, the MSSA CLABSI incidence decreased from 1997 through 2007, with changes in incidence ranging from −60.1% (95% CI −41.2%, −73.1%; p<0.001) in surgical ICUs (0.24 vs. 0.10/1,000 central line days) to −77.7% (95% CI −68.2%, −84.4%; p<0.001) in medical ICUs (0.40 vs. 0.09/1,000 central line days). Although the overall proportion of S. aureus CLABSIs attributable to MRSA increased 25.8% (p=0.02) in the 1997–2007 period, the overall MRSA CLABSI incidence decreased 49.6% (p<0.001) over the period.

Corroborative data were obtained from a population-based study of nine diverse U.S. metropolitan areas [10]. Rates of invasive health care-associated MRSA infections over the 2005–2008 period decreased among patients for infections that began in the community and those with hospital-onset invasive disease. From 2005 through 2008, there were 21,503 episodes of invasive MRSA infection; 17,508 were health care-associated. Of these, 15,458 were MRSA BSIs. The incidence rate of hospital-onset invasive MRSA infections was 1.02 per 10,000 population in 2005 and decreased 9.4% per year (95% CI 14.7%, 3.8%; p=0.005), whereas the incidence of health care-associated community-onset infections was 2.20 per 10,000 population in 2005 and decreased 5.7% per year (95% CI 9.7%, 1.6%; p=0.01). The decrease was most prominent for the subset of infections with BSIs (hospital-onset: −11.2%; 95% CI −15.9%, −6.3%; community-onset: −6.6%; 95% CI −9.5%, −3.7%).

Treatment of MRSA Infection

The challenge of treating S. aureus infections lies particularly with MRSA infection, although MSSA infections remain common among community-onset SSTIs, and MSSA is still the most common staphylococcal pathogen of SSI. Treatment of MSSA SSTI is local drainage and debridement with appropriate β-lactam antibiotic therapy [105,106]. Pneumonia and bacteremic infections attributable to MSSA similarly require appropriate systemic β-lactam treatment; little controversy surrounds these antibiotic choices.

For surgeons, treatment of a staphylococcal infection begins with the determination of a need for debridement (in cases of SSTI and SSI), and then of the specific antibiotic to be used. By contrast, staphylococcal pneumonia and CLABSI are treated primarily with an antimicrobial agent. Staphylococcal soft tissue abscesses, even when caused by CA-MRSA, may respond to incision and drainage alone [107]; if the characteristic central, superficial area of necrosis has not suppurated, they may be managed with antibiotics alone. Surgical site infections with either CA-MRSA or HA-MRSA require drainage of the site and systemic antibiotics for erythema that extends more than 2 cm beyond the margin of the incision or for sepsis. Infections of prosthetic devices and indwelling catheters usually require removal of the infected foreign body, although mesh implanted for hernioplasty sometimes may be salvaged with antibiotic therapy and local wound care [108]. Except for soft tissue abscesses, MRSA infections require antibiotic therapy. When culture and susceptibility testing have documented MRSA infection, the selection of antibiotics is governed by those data and the severity of the infection.

Vancomycin

This glycopeptide antibiotic has been available clinically for more than 50 years, with resurgent use coincident with the emergence of MRSA infection as a major clinical problem in the 1980s. Vancomycin has a unique spectrum of coverage for gram-positive cocci and bacilli, including both CA-MRSA and HA-MRSA, but lacks any activity against gram-negative bacilli or enteric anaerobes (e.g., Bacteroides spp.). The antibacterial effect is mediated by inhibition of cell wall synthesis by mechanisms that are independent of penicillin-binding proteins. It is the MRSA antibiotic with the longest track record of use, and it is used commonly for infections of all anatomic sites. It also is prescribed commonly as an empiric choice when MRSA is suspected in patients with severe clinical infection before microbiology data become available.

Vancomycin has historically been dosed at 1 g intravenously (IV) q 12 h for patients with normal renal function, but higher doses are now recommended owing to higher MICs for MRSA for vancomycin [109,110] (Table 7) and concern about vancomycin failures [61] (see Table 3). Parenteral vancomycin is a generic preparation and remains relatively inexpensive compared with the alternatives, but the cost of mandatory monitoring of serum trough concentrations must also be accounted for.

Table 7.

Therapeutic Vancomycin Dose Adjustment and Drug Monitoring Guidelines

Initial dosages should be calculated on the basis of actual body weight, including for obese patients. Intravenous vancomycin 15–20 mg/kg/dose (actual body weight) every 8–12 h, not to exceed 2 g per dose, is recommended for most patients with normal renal function.

For seriously ill patients (e.g., those with sepsis, meningitis, pneumonia, or infective endocarditis) with suspected MRSA infection, a loading dose of 25–30 mg/kg (actual body weight) may be considered.

Subsequent dosage adjustments should be based on serum trough concentrations, measured just before the fourth dose, to achieve targeted therapeutic concentrations. Trough vancomycin monitoring is recommended for serious infections and patients who are morbidly obese, have renal dysfunction (including those receiving renal replacement therapy), or have fluctuating volumes of distribution.

For serious infections, such as bacteremia, infective endocarditis, osteomyelitis, meningitis, pneumonia, and severe SSTI (e.g., necrotizing fasciitis) caused by MRSA, vancomycin trough concentrations of 15–20 mcg/mL are recommended.

Monitoring of peak vancomycin concentrations is not recommended.

Doses of 1 g should be infused over 1 h. Doses of more than 1 g should be infused over 1.5–2 h. Continuous infusion of vancomycin is not recommended.

Adapted from references 104 and 105.

Vancomycin has several shortcomings in clinical use. Infusion time requires at least 60 min (for a 1-g dose; 90–120 min for larger doses) to avoid complications from histamine release (e.g., “red man” syndrome, hypotension). The incidence of renal dysfunction is increasing with the use of higher doses despite the use of pharmacokinetic dosing. A major shortcoming is the apparent suboptimal effectiveness it has against MSSA. Higher mortality rates have been observed with vancomycin in bacteremic MSSA pneumonia compared with conventional β-lactam antibiotics [111] Poor lung penetration has been a suspected reason for poorer outcomes in the MSSA pneumonia patient [112]. Studies of bacteremic patients in other settings have suggested similarly that MSSA infections are best treated with β-lactam agents (preferably, nafcillin or oxacillin) rather than vancomycin [113,114].

Linezolid

Linezolid is a member of the oxazolidinone class of antibiotics, which bind to bacterial ribosomes and inhibit protein synthesis. It is bacteriostatic against all bacteria except Streptococcus pneumoniae. As does vancomycin, linezolid has antimicrobial activity only against gram-positive organisms. Unlike vancomycin, linezolid is efficiently absorbed after oral administration (tablets and an oral suspension are available), permitting effective out-patient treatment. It is generally dosed at 600 mg twice daily regardless of the route of administration or renal function. Whereas data have been presented in a subset analysis of a randomized trial suggesting superior outcomes with linezolid compared with vancomycin in complicated SSTI with MRSA [115], a prospective trial was non-confirmatory [116]. Better outcomes were identified with linezolid in a subgroup analysis of MRSA pneumonia patients in a randomized trial [117], but that conclusion has been contested [118]. Linezolid is non-inferior to vancomycin in the treatment of complicated SSTIs and in HAP/VAP. A positive feature of linezolid is activity against VISA, VRSA, and vancomycin-resistant enterococci (VRE). Linezolid does not have an indication for surgical prophylaxis and is not recommended.

The major shortcoming of linezolid has been its high cost. Both the oral and the intravenous preparation have a wholesale cost of approximately $200 per day [119]. This procurement cost exceeds by ten-fold the daily cost of intravenous vancomycin [78]. High cost has undoubtedly inhibited the use of this drug. Linezolid also is associated with myelosuppression, principally thrombocytopenia, when treatment is extended for more than two weeks [120]. Even in limited usage, S. aureus has demonstrated resistance to linezolid [121].

Daptomycin

Daptomycin is a cyclic lipopeptide antibiotic that exerts its antimicrobial action by insertion of the drug into, and depolarization of, the bacterial plasma membrane [122]. It is bactericidal rapidly. It is available only for IV use, but its long biological elimination half-life permits once-daily dosing (4 mg/kg for SSTI, and 6 mg/kg for bacteremia, although much higher doses have been reported for highly resistant pathogens or especially deep-seated infections) [123]. Daptomycin has excellent in vitro activity against MRSA and has been effective in the treatment of complicated SSTIs and in the management of MRSA bacteremia. However, daptomycin penetrates into lung tissue poorly and is inactivated by lung surfactant, and has failed in clinical trials for the treatment of gram-positive community-acquired pneumonia. It should not be used to treat HAP/VAP or empirically when HAP/VAP is in the differential diagnosis. Daptomycin does have activity against VISA, VRSA, and VRE. There is no role for daptomycin in surgical prophylaxis, for which it does not have an indication.

Daptomycin therapy has several issues. As is linezolid, daptomycin is expensive and costs more than $200/day to procure [119]. Daptomycin is associated with increases in the serum creatine phosphokinase concentration and skeletal muscle myopathy [124]. Recently, there has been a rare association with an eosinophilic pneumonia syndrome [125]. Finally, as with all antimicrobials, resistance of S. aureus to daptomycin has emerged [126].

Tigecycline

Tigecycline is a derivative of minocycline that binds to microbial ribosomes and inhibits protein synthesis [127]. It is a bacteriostatic agent with a large volume of distribution, indicating that tissue penetration is excellent but that serum concentrations decrease rapidly after administration. Tigecycline is only an IV preparation; the loading dose is 100 mg followed by 50 mg q 12 h, without regard for renal function. Tigecycline's broad spectrum of activity includes enteric gram-negative bacilli, enteric anaerobic bacteria, and gram-positive cocci, including MRSA and VRE, which may be unsuitable when targeted monotherapy is indicated. Approved indications for tigecycline include complicated SSTIs [128] and intra-abdominal infections [129].

Concern has been raised recently by a post-hoc analysis that the mortality rate of tigecycline-treated patients is higher in pooled Phase III–IV clinical trials, including unpublished registration trials [130]. The adjusted risk difference for all-cause mortality based on a random effects model stratified by trial weight was 0.6% (95% CI 0.1–1.2) between tigecycline and comparator agents. However, an independent meta-analysis found no such survival disadvantage in an analysis of eight published randomized controlled trials (4,651 patients) [131]. Overall, no difference was identified for the pooled clinically (odds ratio [OR] 0.92; 95% CI 0.76, 1.12) or microbiologically evaluable populations (OR 0.86; 95% CI 0.69–1.07) from the trials.

Synthetic lipoglycopeptides

This new group of semi-synthetic antibiotics is targeted specifically for gram-positive pathogens, particularly MRSA. They are rapidly bactericidal drugs, with the bacterial membrane as the site of action to depolarize and lyse the cell [132]. All have demonstrated in vitro activity against vancomycin-resistant bacteria. Telavancin has been approved for treatment of complicated SSTIs, having been shown to be non-inferior to vancomycin in the treatment of SSTIs at a single daily dose of 10 mg/kg [133]. As with all lipoglycopeptides, drug-associated adverse events are similar to those observed with vancomycin.

Dalbavancin has not been approved for any clinical indications at this time. The drug has a long elimination half-life that permits once-weekly dosing. One clinical trial of therapy of SSTIs with 1 g given on day one and 500 mg on day eight demonstrated non-inferiority compared with 14 days of linezolid treatment [134]. Oritavancin likewise is not approved currently for any clinical indication. As with dalbavancin, oritavancin has a long elimination half-life that may permit a single dose to be administered every 3–7 days. Unlike the other lipoglycopeptides, oritavancin is cleared primarily by the liver, which may obviate any reduction in dosing with renal insufficiency. Non-inferiority trials have been presented at clinical meetings, but the results have not been published.

Community-acquired MRSA antibiotics

As identified above, CA-MRSA commonly expresses the SCCmec type IV gene cassette in the USA300 strain, which does not have the genotype for resistance to selected non-β-lactam antibiotics. Thus, commonly used “old” and relatively inexpensive antibiotics still have a place in the treatment of these infections and should not be forgotten. Clindamycin, trimethoprim/sulfamethoxazole, doxycycline, and minocycline have in vitro and clinical experience, which indicates that these oral agents still have a role in the treatment of CA-MRSA soft tissue infections. Caution must be exercised with the apparent clindamycin-sensitive isolate that is erythromycin-resistant because of the risk of inducible resistance developing during therapy. The D-test is one method to identify and avoid this risk [135], and the other would be simply to choose another antibiotic (e.g., trimethoprim/sulfamethoxazole).

Iclaprim

Iclaprim is an advanced-generation dihydrofolate reductase inhibitor that has activity against a broad array of gram-positive organisms including MSSA, MRSA, VISA, VRSA, and VRE. It also has activity against Enterobacteriaceae and Haemophilus influenzae. Oral and intravenous preparations have been formulated. Iclaprim has been studied for the treatment of resistant gram-positive SSTIs [136], but has not been approved for use.

Cephalosporins

Despite the identity of MRSA as resistant to cephalosporins, ceftobiprole [137] and ceftaroline [138] are cephalosporin agents with binding affinity for the mutant penicillin-binding protein of MRSA. Ceftobiprole has activity against MRSA and most gram-negative and anaerobic species but no reliable activity against Pseudomonas aeruginosa. Published data demonstrate non-inferiority to vancomycin in complicated skin and skin-structure infections [139]. Ceftobiprole is approved in Canada for the treatment of complex SSTIs at a dose of 500 mg IV q 12 h, but it has not been approved for any indication in the U.S.

Ceftaroline has microbiological activity similar to that of ceftobiprole. Two randomized trials comparing ceftaroline with vancomycin in “complicated acute bacterial skin and skin structure infections” demonstrated a non-inferiority outcome [140,141]. Ceftaroline has been approved in the U.S. to treat “acute bacterial skin and skin structure infections” at a dose of 600 mg q 12 h.

Summary

Staphylococcus aureus is currently, and will remain in the future, a major pathogen among surgical patients. It offers a large catalogue of virulence factors that make infections a likely outcome following bacterial contamination of soft tissues, implanted and indwelling devices, and the respiratory tract. It demonstrates new patterns of infections (e.g., toxic shock syndrome and CA-MRSA SSTI). It was identified briefly 50 years ago as a cause of nosocomial enterocolitis [142], which may be re-emerging [143]. However, the most dramatic “changing face” of Staphylococcus aureus is the continued evolution of resistance to antibiotics. Resistant strains are identified soon after a drug is introduced into clinical practice, and evolution of resistance among the entire population of bacteria results in obsolescence of the drug over a period of years. Whereas the capacity of S. aureus to develop resistance is uncanny, the patterns of antibiotic utilization in clinical practice only fan the flames of evolution to resistant forms. Innovation in new drug development and other forms of treatment is needed urgently.

Author Disclosure Statement

Dr. Fry has received honoraria for being on the speakers bureau for Merck, and is a consultant for both Johnson & Johnson/Ethicon and Forrest Laboratories.

References

Fleming

. On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenza. Br J Exp Pathol, 1929; 10:226–236.

Nespoli

, Geroulanos

, Nardone

et al. The history of surgical infections. Surg Infect, 2011; 12:3–13.

Kirby

. Extraction of a highly potent penicillin inactivator from penicillin resistant staphylococci. Science, 1944; 99:452–453.

Enright

, Robinson

, Randle

et al.

The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA)

Proc Nat Acad Sci USA, 2002; 99:7687–7692.

Shinefield

, Ruff

. Staphylococcal infections: A historical perspective. Infect Dis Clin North Am, 2009; 23:1–15.

Ross

, Rodriguez

, Controni

et al. Staphylococcal susceptibility to penicillin G: The changing pattern among community strains. JAMA, 1974; 229:1075–1077.

Udo

, Pearman

, Grubb

. Genetic analysis of community isolates of methicillin-resistant Staphylococcus aureus in Western Australia. J Hosp Infect, 1993; 25:97–108.

Herald

, Immergluck

, Maranan

et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA, 1998; 279:593–598.

Vandenesch

, Naimi

, Enright

et al. Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: Worldwide emergence. Emerg Infect Dis, 2003; 9:987–994.

10.

Kallen

, Mu

, Bulens

et al. Active Bacterial Core surveillance (ABCs) MRSA Investigators of the Emerging Infections Program. Health care-associated invasive MRSA infections, 2005–2008. JAMA, 2010; 304:641–648.

11.

U.S. Centers for Disease Control and Prevention (CDC). Vital signs: Central line-associated blood stream infections—United States, 2001, 2008, and 2009. MMWR Morb Mortal Wkly Rep, 2011; 60:243–248.

12.

Edwards

, Peterson

, Mu

et al. National Healthcare Safety Network (NHSN) report: Data summary for 2006 through 2008, issued December 2009. Am J Infect Control, 2009; 37:783–805.

13.

Burton

, Edwards

, Horan

et al. Methicillin-resistant Staphylococcus aureus central line-associated bloodstream infections in US intensive care units, 1997–2007. JAMA, 2009; 301:727–736.

14.

Byrnes

, Adegboyega

, Riggle

et al. Nasal swabs collected routinely to screen for colonization by methicillin-resistant Staphylococcus aureus in intensive care units are a sensitive screening test for the organism in clinical cultures. Surg Infect, 2010; 11:511–515.

15.

Kollef

, Barie

. Methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization predicts intensive care unit-acquired MRSA infections: True or false? Surg Infect, 2010; 11:497–499.

16.

Henteleff

, Barie

, Hamilton

. Members of the Evidence-Based Reviews in Surgery Group. Universal screening for methicillin-resistant Staphylococcus aureus in surgical patients. J Am Coll Surg, 2010; 211:833–835.

17.

Harbarth

, Fankhauser

, Schrenzel

et al. Universal screening for methicillin-resistant Staphylococcus aureus at hospital admission and nosocomial infection in surgical patients. JAMA, 2008; 299:1149–1157.

18.

Sánchez García

, De la Torre

, Morales

et al. Clinical outbreak of linezolid-resistant Staphylococcus aureus in an intensive care unit. JAMA, 2010; 303:2260–2264.

19.

Lindsay

, Holden

MTG

. Staphylococcus aureus: Superbug, super genome? Trends Microbiol, 2004; 12:378–385.

20.

Plata

, Rosat

, Wegrzyn

. Staphylococcus aureus as an infectious agent: Overview of biochemistry and molecular genetics of its pathogenicity. Acta Biochim Polon, 2009; 56:597–612.

21.

Patti

, Allen

, McGavin

et al. MSCRAMM-mediated adherence of microorganisms to host tissues. Annu Rev Microbiol, 1994; 48:585–617.

22.

Roche

, Downer

, Keane

et al. The N-terminal A domain of fibronectin-binding proteins A and B promotes adhesion of Staphylococcus aureus to elastin. J Biol Chem, 2004; 279:38433–38440.

23.

Switalski

, Patti

, Butcher

et al. A collagen receptor on Staphylococcus aureus strains isolated from patients with septic arthritis mediates adhesion to cartilage. Mol Microbiol, 1993; 7:99–107.

24.

McDevitt

, Nanavaty

, House-Pompeo

et al. Characterization of the interaction between the Staphylococcus aureus clumping factor (ClfA) and fibrinogen. Eur J Biochem, 1997; 247:416–424.

25.

Ni Eidhin

, Perkins

, Francois

et al. Clumping factor B (ClfB), a new surface-located fibrinogen-binding adhesin of Staphylococcus aureus. Mol Microbiol, 1998; 30:245–257.

26.

Hartleib

, Kohler

, Dickinson

et al. Protein A is the von Willebrand factor binding protein on Staphylococcus aureus. Blood, 2000; 96:2149–2156.

27.

Park

, Broekelmann

, Mecham

, Medham

. Characterization of the elastin binding domain in the cell-surface 25-kDa elastin-binding protein of Staphylococcus aureus (EbpS) J Biol Chem, 1999; 274:2845–2850.

28.

Tung

, Buss

, Hellman

et al. A bone sialoprotein-binding protein from Staphylococcus aureus: A member of the staphylococcal Sdr family. Biochem J, 2000; 345:611–619.

29.

Clarke

, Harris

, Richards

, Foster

. Analysis of Ebh, a 1.1 megadalton cell wall-associated fibronectin-binding protein of Staphylococcus aureus. Infect Immun, 2002; 70:6680–6687.

30.

Hauck

, Ohlsen

. Sticky connections: Extracellular matrix protein recognition and integrin-mediated cellular invasion by Staphylococcus aureus. Curr Opin Microbiol, 2006; 9:5–11.

31.

Gordon

, Lowy

. Pathogenesis of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis, 2008; 46:S350–S359.

32.

Otto

. Staphylococcal biofilms. Curr Top Microbiol Immunol, 2008; 322:207–228.

33.

Weigel

, Donlan

, Shin

et al. High-level vancomycin-resistant Staphylococcus aureus isolates associated with a polymicrobial biofilm. Antimicrob Agents Chemother, 2007; 51:231–238.

34.

Chavakis

, Wiechmann

, Preissner

, Herrmann

. Staphylococcus aureus interactions with the endothelium: The role of bacterial “Secretable Expanded Repertoire Adhesive Molecules” (SERAM) in disturbing host defense systems. Thromb Haemost, 2005; 94:278–285.

35.

McDevitt

, Vaudaux

, Foster

. Genetic evidence that bound coagulase of Staphylococcus aureus is not clumping factor. Infect Immun, 1992; 60:1514–1523.

36.

Panton

, Valentine

FCO

. Staphylococcal toxin. Lancet, 1932; 1:506–508.

37.

Otto

. Basis of virulence in community-associated methicillin-resistant Staphylococcus aureus. Annu Rev Microbiol, 2010; 64:143–162.

38.

Burnside

, Lembo

, de los Reyes

et al. Regulation of hemolysin expression and virulence of Staphylococcus aureus by a serine/threonine kinase and phosphatase. PLoS One, 2010; 5:e11071.

39.

Gillet

, Issartel

, Vanhems

et al. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotizing pneumonia in young immunocompetent patients. Lancet, 2002; 359:753–759.

40.

Wang

, Braughton

, Kretschmer

et al. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nat Med, 2007; 13:1510–1514.

41.

Balaban

, Rasooly

. Staphylococcal enterotoxins. Int J Food Microbiol, 2000; 61:1–10.

42.

Nishifuji

, Sugai

, Amagai

. Staphylococcal exfoliative toxins: “Molecular scissors” of bacteria that attack the cutaneous defense barrier in mammals. J Dermatol Sci, 2008; 49:21–31.

43.

Lappin

, Ferguson

. Gram-positive toxic shock syndromes. Lancet Infect Dis, 2009; 9:281–290.

44.

Larkin

, Carman

, Krakauer

, Stiles

. Staphylococcus aureus: The toxic presence of a pathogen extraordinaire. Curr Med Chem, 2009; 16:4003–4019.

45.

Rivera

, Vannakambadi

, Höök

, Speziale

. Fibrinogen-binding proteins of gram-positive bacteria. Thromb Haemost, 2007; 98:503–511.

46.

Bokarewa

, Jin

, Tarkowski

. Staphylococcus aureus: Staphylokinase. Int J Biochem Cell Biol, 2006; 38:504–509.

47.

Hart

, Hart

, Roop

. Genotypic and phenotypic assessment of hyaluronidase among type strains of a select group of staphylococcal species. Int J Microbiol, 2009; 2009:614371.

48.

Cotton

, Hazen

Jr , Legg

. Staphylococcal nuclease: Proposed mechanism of action based on structure of enzyme—thymidine 3′,5′-bisphosphate-calcium ion complex at 1.5-Å resolution. Proc Nat Acad Sci USA, 1979; 76:2551–2555.

49.

Jacobsson

, Colque-Navarro

, Gustafsson

et al. Antibody responses in patients with invasive Staphylococcus aureus infections. Eur J Clin Microbiol Infect Dis, 2010; 29:715–725.

50.

Burlak

, Hammer

, Robinson

et al. Global analysis of community-associated methicillin-resistant Staphylococcus aureus exoproteins reveals molecules produced in vitro and during infection. Cell Microbiol, 2007; 9:1172–1190.

51.

McDougal

, Steward

, Killgore

et al. Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: Establishing a national database. J Clin Microbiol, 2003; 41:5113–5120.

52.

Ito

, Okuma

, Ma

et al. Insights on antibiotic resistance of Staphylococcus aureus from its whole genome: Genomic island SCC. Drug Resist Update, 2003; 6:41–52.

53.

Daum

, Ito

, Hiramatsu

et al. A novel methicillin resistance cassette in community-acquired methicillin-resistant Staphylococcus aureus isolates of diverse genetic backgrounds. J Infect Dis, 2002; 186:1344–1347.

54.

Rehm

. Staphylococcus aureus: The new adventures of a legendary pathogen. Cleve Clin J Med, 2008; 75:177–180.

55.

Diep

, Chambers

, Graber

et al. Emergence of multidrug-resistant, community-acquired, methicillin-resistant Staphylococcus aureus clone USA300 in men who have sex with men. Ann Intern Med, 2008; 148:249–257.

56.

Hawley

, Jones

. The changing epidemiology of resistance. J Antimicrob Chemother, 2009; 64,Suppl:i3–i10.

57.

U.S. Centers for Disease Control and Prevention. Reduced susceptibility of Staphylococcus aureus to vancomycin: Japan, 1996. Morb Mort Wkly Rep, 1997; 46:624–626.

58.

Sader

, Moet

, Farrell

, Jones

. Antimicrobial susceptibility of daptomycin and comparator agents tested against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: Trend analysis of a 6-year period in U.S. medical centers (2005–2010) Diagn Microbiol Infect Dis, 2011 May 3[Epub ahead of print]

59.

Cervera

, Almela

, Martínez-Martínez

et al. Risk factors and management of gram-positive bacteraemia. Int J Antimicrob Agents, 2009; 34,Suppl 4:S26–S30.

60.

Patel

, Pai

, Rodvold

et al. Vancomycin: We can't get there from here. Clin Infect Dis, 2011; 52:969–974.

61.

Hageman

, Patel

, Carey

et al. Investigation and control of vancomycin-intermediate and-resistant Staphylococcus aureus: A guide for health departments and infection control personnel. Atlanta, Georgia: U.S. Centers for Disease Control and Prevention, 2006. www.cdc.gov/ncidod/dhqp/ar_visavrsa_prevention.html. 2011 May 12.

62.

Tenover

. The quest to identify heterogeneously resistant vancomycin-intermediate Staphylococcus aureus strains. Int J Antimicob Agents, 2010; 36:303–306.

63.

Tenover

. Mechanisms of antimicrobial resistance in bacteria. Am J Med, 2006; 119,Suppl 6A:S3–S10.

64.

Tenover

, Biddle

, Lancaster

. Increasing resistance to vancomycin and other glycopeptides in Staphylococcus aureus. Emerg Infect Dis, 2001; 7:327–332.

65.

Walsh

, Bolmstöm

, Qwärnström

et al. Evaluation of current methods for detection of staphylococci with reduced susceptibility to glycopeptides. J Clin Microbiol, 2001; 39:2439–2444.

66.

Plipat

, Livni

, Bertram

, Thomson

Jr . Unstable vancomycin heteroresistance is common among clinical isolates of methicillin-resistant Staphylococcus aureus. J Clin Microbiol, 2005; 43:2494–2496.

67.

Walsh

, Howe

. The prevalence and mechanisms of vancomycin resistance in Staphylococcus aureus. Annu Rev Microbiol, 2002; 56:657–675.

68.

Khatib

, Jose

, Musta

et al. Relevance of vancomycin-intermediate susceptibility and heteroresistance in methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother, 2011 Apr 26[Epub ahead of print].

69.

Cheong

, Harris

, Oman

, Norton

. Challenges in the microbiological diagnosis and management of hVISA infections. Pathology, 2011 May 2[Epub ahead of print].

70.

U.S. Centers for Disease Control and Prevention. CDC reminds clinical laboratories and healthcare infection preventionists of their role in the search and containment of vancomycin-resistant Staphylococcus aureus (VRSA), May 2010. www.bt.cdc.gov/coca/reminders/2010/2010may06.asp. 2010 December 7.

71.

Weigelt

, Itani

, Stevens

et al. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother, 2005; 49:2260–2266.

72.

Itani

, Dryden

, Bhattacharyya

. Efficacy and safety of linezolid versus vancomycin for the treatment of complicated skin and soft-tissue infections proven to be caused by methicillin-resistant Staphylococcus aureus. Am J Surg, 2010; 199:804–816.

73.

Wunderink

, Cammarata

, Oliphant

et al. Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia. Clin Ther, 2003; 25:980–992.

74.

Powers

, Ross

, Lin

et al. Linezolid and vancomycin for methicillin-resistant Staphylococcus aureus nosocomial pneumonia: The subtleties of subgroup analysis. Chest, 2004; 126:314–315.

75.

Sievert

, Rudrik

, Patel

et al. Vancomycin-resistant Staphylococcus aureus in the United States, 2002–2006. Clin Infect Dis, 2008; 46:668–674.

76.

Gold

, Pillai

. Antistaphylococcal agents. Infect Dis Clin North Am, 2009; 23:99–131.

77.

Finks

, Wells

, Dyke

et al. Vancomycin-resistant Staphylococcus aureus, Michigan, USA, 2007. Emerg Infect Dis, 2009; 15:943–945.

78.

Medscape. Vancomycin IV. www.medscape.com/druginfo/pricebrandimage?cid=med&drugid=939&drugname=Vancomycin+IV&monotype=pricebrandimage. 2010 December 7.

79.

Gerson

, Kaplan

, Bruss

et al. Hematologic effects of linezolid: Summary of clinical experience. Antimicrob Agents Chemother, 2002; 46:2723–2726.

80.

Noskin

, Rubin

, Schentag

et al. The burden of Staphylococcus aureus infections on hospitals in the United States: An analysis of the 2000 and 2001 Nationwide Inpatient Sample Database. Arch Intern Med, 2005; 165:1756–1761.

81.

Klevens

, Morrison

, Nadle

et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA, 2007; 298:1763–1771.

82.

De Kraker

, Wolkewitz

, Davey

, Grundmann

. BURDEN Study Group. Clinical impact of antimicrobial resistance in European hospitals: Excess mortality and length of hospital stay related to methicillin-resistant Staphylococcus aureus bloodstream infections. Antimicrob Agents Chemother, 2011; 55:1598–1605.

83.

Cosgrove

, Sakoulas

, Perencevich

et al. Comparison of mortality with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: A meta-analysis. Clin Infect Dis, 2003; 36:53–59.

84.

Engemann

, Carmeli

, Cosgrove

et al. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infection. Clin Infect Dis, 2003; 36:592–598.

85.

Eagye

, Kim

, Laohavaleeson

et al.

Surgical site infections: Does inadequate antibiotic therapy affect patient outcomes?

Surg Infect, 2009; 10:323–331.

86.

Laupland

, Church

, Mucenski

et al. Population-based study of the epidemiology of and the risk factors for invasive Staphylococcus aureus infections. J Infect Dis, 2003; 187:1452–1459.

87.

Jacobsson

, Dashti

, Wahlberg

et al. The epidemiology of and risk factors for invasive Staphylococcus aureus infections in western Sweden. Scand J Infect Dis, 2007; 39:6–15.

88.

Henteleff

, Barie

, Hamilton

et al. members of the Evidence-Based Reviews in Surgery Group. Canadian Association of General Surgeons and American College of Surgeons evidence-based reviews in surgery: Universal screening for methicillin-resistant Staphylococcus aureus in surgical patients. J Am Coll Surg, 2010; 211:833–835.

89.

Ammerlaan

, Kluytmans

, Burkhout

et al. on behalf of the MRSA Eradication Study Group. Eradication of carriage with methicillin-resistant Staphylococcus aureus: Effectiveness of a national guideline. J Antimicrob Chemother, 2011 June 30[Epub ahead of print].

90.

Ammerlaan

, Kluytmans

, Burkhout

et al. on behalf of the MRSA Eradication Study Group. Eradication of carriage with methicillin-resistant Staphylococcus aureus: Determinants of treatment failure. J Antimicrob Chemother, 2011 June 30[Epub ahead of print].

91.

Evans

, Dellit

, Chan

et al. Effect of chlorhexidine whole-body bathing on hospital-acquired infections among trauma patients. Arch Surg, 2010; 145:240–246.

92.

Fukatsu

, Saito

, Matsuda

et al. Influences of type and duration of antimicrobial prophylaxis on an outbreak of methicillin-resistant Staphylococcus aureus and on the incidence of wound infection. Arch Surg, 1997; 132:1320–1326.

93.

Falagas

, Alexiou

, Pappas

, Makris

. Do changes in antimicrobial resistance necessitate reconsideration of surgical antimicrobial prophylaxis strategies? Surg Infect, 2009; 10:557–562.

94.

Chambers

, Worthy

, Myers

et al. Glycopeptide vs. non-glycopeptide antibiotics for prophylaxis of surgical site infections: A systematic review. Surg Infect, 2010; 11:455–462.

95.

Rosenberger

, Politano

, Sawyer

. The Surgical Care Improvement Project and prevention of postoperative infection, including surgical site infection. Surg Infect, 2010; 12:163–168.

96.

Miller

, McKinnell

, Vollmer

, Spellberg

. Impact of methicillin-resistant Staphylococcus aureus prevalence among S. aureus isolates on surgical site infection risk after coronary artery bypass surgery. Infect Control Hosp Epidemiol, 2011; 32:342–350.

97.

Bratzler

, Houck

. for the Surgical Infection Prevention Guideline Writers Workgroup. Antimicrobial prophylaxis for surgery: An advisory statement from the National Surgical Infection Prevention Project. Am J Surg, 2005; 189:395–404.

98.

Finkelstein

, Rabino

, Mashiah

et al. Vancomycin versus cefazolin prophylaxis for cardiac surgery in the setting of a high prevalence of methicillin-resistant staphylococcal infections. J Thoracic Cardiothorac Surg, 2002; 123:326–332.

99.

Sweet

, Roh

, Silva

. Intra-wound application of vancomycin for prophylaxis in instrumented thoracolumbar fusions: Efficacy, drug levels, and patient outcomes. Spine, 2011 Feb 7[Epub ahead of print].

100.

Buttaro

, Guala

, Comba

et al. Incidence of deep infection in aseptic revision THA using vancomycin-impregnated impacted bone allograft. Hip Int, 2010; 20:535–541.

101.

Furuya

, Dick

, Perencevich

et al. Central line bundle implementation in US intensive care units and impact on bloodstream infections. PLoS One, 2011; 6:e15452.

102.

Sihler

, Chenoweth

, Zalewski

et al. Catheter-related vs. catheter-associated blood stream infections in the intensive care unit: Incidence, microbiology, and implications. Surg Infect, 2010; 11:529–534.

103.

U.S. Centers for Disease Control and Prevention. Vital signs: Central line-associated blood stream infections—United States, 2001, 2008, and 2009. MMWR Morb Mortal Wkly Rep, 2011; 60:243–248.

104.

Edwards

, Peterson

, Mu

et al. National Healthcare Safety Network (NHSN) report: Data summary for 2006 through 2008, issued December 2009. Am J Infect Control, 2009; 37:783–805.

105.

May

, Stafford

, Bulger

et al. Surgical Infection Society. Treatment of complicated skin and soft tissue infections. Surg Infect, 2009; 10:467–499.

106.

May

. Skin and soft tissue infections: The new Surgical Infection Society guidelines. Surg Infect, 2011; 12:179–184.

107.

DeLeo

, Otto

, Kreiswirth

, Chambers

. Community-associated meticillin-resistant Staphylococcus aureus. Lancet, 2011; 375:1557–1568.

108.

Collage

, Rosengart

. Abdominal wall infections with in situ mesh. Surg Infect, 2010; 11:311–318.

109.

Rybak

, Lomaestro

, Rotschaefer

et al. Vancomycin therapeutic guidelines: A summary of consensus recommendations from the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis, 2009; 49:325–327.

110.

Liu

, Bayer

, Cosgrove

et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis, 2011; 52:e18–e55.

111.

Gonzalez

, Rubio

, Romero-Vivas

et al. Bacteremic pneumonia due to Staphylococcus aureus: A comparison of disease caused by methicillin-resistant and methicillin-susceptible organisms. Clin Infect Dis, 1999; 29:1171–1177.

112.

Cruciani

, Gatti

, Lazzarini

et al. Penetration of vancomycin into human lung tissue. J Antimicrob Chemother, 1996; 38:865–869.

113.

Stryjewski

, Szczech

, Benjamin

et al. Use of vancomycin or first-generation cephalosporins for the treatment of hemodialysis-dependent patients with methicillin-susceptible Staphylococcus aureus bacteremia. Clin Infect Dis, 2007; 44:190–196.

114.

Chang

, Peacock

Jr , Musher

et al. Staphylococcus aureus bacteremia: Recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine, 2003; 82:333–339.

115.

Weigelt

, Itani

, Stevens

et al. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother, 2005; 49:2260–2266.

116.

Itani

, Dryden

, Bhattacharyya

. Efficacy and safety of linezolid vs. vancomycin for the treatment of complicated skin and soft-tissue infections proven to be caused by methicillin-resistant Staphylococcus aureus. Am J Surg, 2010; 199:804–816.

117.

Wunderink

, Cammarata

, Oliphant

et al. Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia. Clin Ther, 2003; 25:980–992.

118.

Powers

, Ross

, Lin

et al. Linezolid and vancomycin for methicillin-resistant Staphylococcus aureus nosocomial pneumonia: The subtleties of subgroup analysis. Chest, 2004; 126:314–315.

119.

Gold

, Pillai

. Antistaphylococcal agents. Infect Dis Clin North Am, 2009; 23:99–131.

120.

Gerson

, Kaplan

, Bruss

et al. Hematologic effects of linezolid: Summary of clinical experience. Antimicrob Agents Chemother, 2002; 46:2723–2726.

121.

Sánchez García

, De la Torre

, Morales

et al. Clinical outbreak of linezolid-resistant Staphylococcus aureus in an intensive care unit. JAMA, 2010; 303:2260–2264.

122.

Tally

, DeBruin

. Development of daptomycin for gram-positive infections. J Antimicrob Chemother, 2000; 46:523–526.

123.

Bassetti

, Nicco

, Ginocchio

et al. High-dose daptomycin in documented Staphylococcus aureus infections. Int J Antimicrob Agents, 2010; 36:459–461.

124.

Nailor

, Sobel

. Antibiotics for gram-positive bacterial infections: Vancomycin, teicoplanin, quinupristin/dalfopristin, oxazolidinones, daptomycin, dalbavancin, and telavancin. Infect Dis Clin North Am, 2009; 23:965–982.

125.

Miller

, Gray

, Leblanc

et al. Acute eosinophilic pneumonia secondary to daptomycin: A report of three cases. Clin Infect Dis, 2010; 50:e63–e68.

126.

Nannini

, Murray

, Arias

. Resistance or decreased susceptibility to glycopeptides, daptomycin, and linezolid in methicillin-resistant Staphylococcus aureus. Curr Opin Pharmacol, 2010; 10:516–521.

127.

Rose

, Rybak

. Tigecycline: First of a new class of antimicrobial agents. Pharmacotherapy, 2006; 26:1099–1110.

128.

Ellis-Grosse

, Babinchak

, Dartois

et al. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: Results of 2 double-blind Phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis, 2005; 41,Suppl 5:S341–S353.

129.

Towfigh

, Pasternak

, Poirier

et al. A multicentre, open-label, randomized comparative study of tigecycline versus ceftriaxone sodium plus metronidazole for the treatment of hospitalized subjects with complicated intra-abdominal infections. Clin Microbiol Infect, 2010; 16:1274–1281.

130.

Food and Drug Administration. U.S. Department of Health and Human Services. FDA Drug Safety Communication: Increased risk of death with Tygacil (tigecycline) compared to other antibiotics used to treat similar infections, September 1, 2010. www.fda.gov/Drugs/DrugSafety/ucm224370.htm. 2010 December 7.

131.

Cai

, Wang

, Liang

et al. Systematic review and meta-analysis of the effectiveness and safety of tigecycline for treatment of infectious disease. Antimicrob Agents Chemother, 2011; 55:1162–1172.

132.

Guskey

, Tsuji

. A comparative review of the lipoglycopeptides: Oritavancin, dalbavancin, and telavancin. Pharmacotherapy, 2010; 30:80–94.

133.

Stryjewski

, Chu

, O'Riordan

et al. Telavancin versus standard therapy for treatment of complicated skin and skin structure infections caused by gram-positive bacteria: FAST 2 study. Antimicrob Agents Chemother, 2006; 50:862–867.

134.

Jauregui

, Babazadeh

, Seltzer

et al. Randomized, double-blind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections. Clin Infect Dis, 2005; 41:407–415.

135.

Siberry

, Tekle

, Carroll

, Dick

. Failure of clindamycin treatment of methicillin-resistant Staphylococcus aureus expressing inducible clindamycin resistance in vitro. Clin Infect Dis, 2003; 37:1257–1260.

136.

Sincak

, Schmidt

. Iclaprim, a novel diaminopyrimidine for the treatment of resistant gram-positive infections. Ann Pharmacother, 2009; 43:1107–1114.

137.

Dauner

, Nelson

, Taketa

. Ceftobiprole: A novel, broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Am J Health Syst Pharm, 2010; 67:983–993.

138.

Steed

, Rybak

. Ceftaroline: A new cephalosporin with activity against resistant gram-positive pathogens. Pharmacotherapy, 2010; 30:375–389.

139.

Noel

, Bush

, Bagchi

et al. A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skin structure infections. Clin Infect Dis, 2008; 46:647–655.

140.

Corey

, Wilcox

, Talbot

et al. CANVAS 1: The first Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. J Antimicrob Chemother, 2010; 65,Suppl 4:iv41–iv51.

141.

Wilcox

, Corey

, Talbot

et al. CANVAS 2: The second Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. J Antimicrob Chemother, 2010; 65,Suppl 4:iv53–iv65.

142.

Altemeier

, Hummel

, Hill

. Staphylococcal enterocolitis following antibiotic therapy. Ann Surg, 1963; 157:847–857.

143.

Lin

, Kotler

, Schlievert

, Sordillo

. Staphylococcal enterocolitis: Forgotten but not gone? Dig Dis Sci, 2010; 55:1200–1207.