Staphylococcus aureus infections in children

Abstract

Purpose of review

Staphylococcus aureus is the most common invasive bacterial pathogen infecting children in the U.S. and many parts of the world. This major human pathogen continues to evolve, and recognition of recent trends in epidemiology, therapeutics and future horizons is of high importance.

Recent findings

Over the past decade, a relative rise of methicillin-susceptible S. aureus (MSSA) has occurred, such that methicillin-resistant S. aureus (MRSA) no longer dominates the landscape of invasive disease. Antimicrobial resistance continues to develop, however, and novel therapeutics or preventive modalities are urgently needed. Unfortunately, several recent vaccine attempts proved unsuccessful in humans.

Summary

Recent scientific breakthroughs highlight the opportunity for novel interventions against S. aureus by interfering with virulence rather than by traditional antimicrobial mechanisms. A S. aureus vaccine remains elusive; the reasons for this are multifactorial, and lessons learned from prior unsuccessful attempts may create a path toward an effective preventive. Finally, new diagnostic modalities have the potential to greatly enhance clinical care for invasive S. aureus disease in children.

INTRODUCTION

Thanks in part to successful vaccine development against Streptococcus pneumoniae and Haemophilus influenzae, Staphylococcus aureus is now the leading invasive bacterial pathogen in children in the U.S. and many parts of the world [1■■,2,3]. In fact, current rates of invasive S. aureus disease in children (e.g. bloodstream infection, bone and joint infection) exceed peak rates of pneumococcal and H. influenzae disease at the time that vaccines were developed against those major pathogens [4]. S. aureus may be unrivalled as a pathogen both in terms of the number of failed vaccine attempts against the organism, as well as its protean clinical phenotypes and ability to invade nearly every tissue in the human body. The pathogen also continues to evolve and modulate its virulence, as it progressively gains antibiotic resistance mechanisms among circulating strains causing clinical disease. In this report, we will discuss current opinions and recent data regarding the epidemiology, treatment, prevention and future horizons of invasive S. aureus disease in children.

CHANGING EPIDEMIOLOGY OF PAEDIATRIC INVASIVE STAPHYLOCOCCUS AUREUS STRAINS

On a broad scale, the evolution of clinically relevant, actively circulating strains can be marked by a sequence of ‘eras’. For decades, methicillin-resistant S. aureus (MRSA) was almost exclusively a nosocomial pathogen, while methicillin-susceptible (MSSA) strains caused occasional disease in other-wise healthy hosts in the community [5]. This fundamentally shifted in the mid-1990s with the rise of the epidemic S. aureus clone, USA300, which drove the community-associated MRSA (CA-MRSA) epidemic in the early part of the twenty-first century. This era, while profoundly impactful both at the level of patient care and by its impact on new drug and attempted vaccine development, now appears to be shifting again.

Beginning around 2005, invasive MRSA infection rates began to gradually decline, and over the past decade, a relative rise in virulent MSSA infections has begun to define a new era of invasive S. aureus epidemiology in children [6]. USA300 CA-MRSA strains are no longer the predominant cause of invasive infections in children in the U.S. Rather, a more diverse group of currently circulating S. aureus strains populate the landscape, and the majority of infections now appear to be MSSA, with rates of paediatric bloodstream infection due to MSSA progressively rising since nearly 2009 [3,7■■]. This does not imply, however, that invasive infections due to methicillin-sensitive S. aureus are less severe. Although a variety of studies largely suggested that the USA300 CA-MRSA strain may have led to more severe disease phenotypes than contemporary MSSA comparators, this distinction no longer appears to hold. For example, a large series out of the University of Utah found that from 2009 to 2012, MSSA strains represented nearly 80% of invasive paediatric S. aureus infections, with six predominant strain types and no discernible severity differences comparing MRSA to MSSA [7■■]. This evolution of S. aureus, with a current predominance of MSSA strains, calls into question many current infection control practices, which focus exclusively on prevention of MRSA while ignoring the importance of invasive MSSA [8]. Typical hospital infection control policies mandate contact isolation when MRSA is present, though recent data would suggest an equal importance at preventing the spread of MSSA disease both in and out of the hospital setting [7■■,9■].

Critical future work in this area will involve the identification of virulence factors that are conserved across invasive/lethal strains of S. aureus, regardless of MRSA vs. MSSA resistance patterns. For example, the Panton Valentine leucocidin (PVL), thought to be a mediator of the clinical severity and invasion potential associated with USA300 CA-MRSA, is present in only nearly 10% of currently invasive S. aureus strains [7■■]. Identification of those factors that are necessary and sufficient for invasion across distantly related lineages of clinically relevant S. aureus will be central to identifying novel targets of intervention against this major paediatric pathogen.

ADVANCES IN TRADITIONAL ANTISTAPHYLOCOCCAL THERAPEUTICS

The dominance of CA-MRSA, along with multiply-drug-resistant strains of S. pneumoniae and Enterococcus species, as drivers of invasive paediatric infections throughout the early part of this century led to a dramatic response by the drug development industry to identify agents with activity against resistant Gram-positive pathogens, particularly MRSA. This has resulted in a relative surge of recently developed antimicrobials that maintain activity against MRSA and other resistant gram-positive pathogens (Table 1). Daptomycin, initially FDA approved for use in adults in 2003, is a bactericidal agent that provides an alternative to vancomycin for MRSA endocarditis and other invasive (nonpneumonic) infections. Daptomycin is now recommended by the Infectious Diseases Society of America (IDSA) expert guidelines as an equivalent option to vancomycin for the treatment of MRSA bacteraemia in adults [10], but similar recommendations from national guidelines are lagging in paediatric infections.

Table 1.

Recently developed antimicrobials with activity against methicillin-resistant Staphylococcus aureus

Drug name	Initial US approval	Class/Mechanism of action	FDA indications	Paediatric labelling	Comments
Daptomycin	2003	Cyclic lipopeptide; rapid depolarization of cell membrane potential.	cSSSI; SAB including right-sided endocarditis	Dosing recommendations for ≥1 year of age. Not recommended <1 year of ago due to neuromuscular adverse effects in neonatal dogs.	Not indicated for pneumonia due to inactivation by surfactant.
Telavancin	2009	Lipoglycopeptide; inhibits cross-linking of cell wall peptidoglycan	cSSSI (daily infusion; half-life ~8h)	Safety and effectiveness in paediatric patients have not been studied.	Open-label PK study in patients aged 3 months–17 years is underway (NCT02013141)
Ceftaroline	2010	Cephalosporin; disruption of cell wall synthesis via binding to PBP (including PBP2a of MRSA)	ABSSSI and CABP	Safety and effectiveness in paediatric patients have not been established.	Significant PK and safety data are published for children down to 2 months of age (13)
Dalbavancin	2014	Lipoglycopeptide; inhibits cross-linking of cell wall peptidoglycan	ABSSSI (One or two-dose regimens; half-life ~8 days)	Safety and effectiveness in paediatric patients have not been established.	PK and safety appeared similar in adolescents in a small trial (15)
Oritavancin	2014	Lipoglycopeptide; inhibits cross-linking of cell wall peptidoglycan	ABSSSI (Single-dose therapy; half-life ~10 days)	Safety and effectiveness in paediatric patients have not been studied.	Limited PK data available for children aged 2–18 years (16)
Tedizolid	2014	Oxazolidinone; Inhibition of protein synthesis at the 50S ribosomal subunit.	ABSSSI	Safety and effectiveness in paediatric patients have not been established.	PK and safety appeared similar in adolescents in a small trial (17)
Delafloxacin	2017	Fluoroquinolone; inhibition of DNA gyrase and topoisomerase IV.	ABSSSI in adult patients	Use in patients <18 years of age is currently not recommended.	Box warning for tendon rupture and nervous system effects
Omadacycline	2018	Tetracycline; Inhibition of protein synthesis at the 30S ribosomal subunit	ABSSSI and CABP	Due to class effects on tooth development and bone growth, use in patients less <8 years of age is not recommended	Active-controlled safety study in children between 8 and 17 years old with CABP will be conducted

ABSSSI, acute bacterial skin and skin structure infection; CABP, community-acquired bacterial pneumonia; cSSSI, complicated skin and skin structure infection; PBP, penicillin-binding protein; PK, pharmacokinetics.

In 2010, the drug ceftaroline was licensed for treatment of CAP and complicated SSTIs. Designated a fifth-generation cephalosporin, ceftaroline is highly notable as the first beta-lactam antimicrobial with activity against MRSA strains. There is increasing evidence of the utility of ceftaroline for the treatment of severe MRSA SSTI, bacteraemia, endocarditis and orthopaedic infections in adults [11,12]. Recent years have seen the accumulation of substantial experience in the paediatric use of ceftaroline, with significant pharmacokinetic and safety data down to infancy [13].

Newer glycopeptide antimicrobials such as dalbavancin, telavancin and oritavancin are also promising agents based on their much longer half-lives compared with vancomycin, potentially allowing for infusion-based weekly dosing rather than daily home antibiotic dosing via peripherally inserted central catheter (PICC) [14]. Like daptomycin, these agents are now commonly used to treat MRSA infections in adults, but widespread use in paediatrics is lagging significantly behind, in part related to a paucity of pharmacokinetic data, information which is of high importance given the prolonged half-life of these agents. Encouragingly, dalbavancin and oritavancin pharmacokinetics and safety in adolescents appear similar to adults [15,16], though data in younger children are unavailable at present. Finally, tedizolid may emerge as a better-tolerated analogue of linezolid in children, though again, paediatric data are limited beyond some encouraging pharmacokinetic and safety data in adolescents [17].

NOVEL APPROACHES TO ANTISTAPHYLOCOCCAL THERAPEUTICS

The widespread emergence of community-acquired MRSA in the 1990s and 2000s raised considerable concerns that S. aureus might continue to evolve resistance against all currently available antimicrobials. Fortunately, widespread resistance to important antibiotics for invasive staphylococcal infection (e.g. vancomycin and daptomycin) has yet to occur. Accordingly, unlike contemporary MDR Gram-negative pathogens, clinicians still typically have multiple antibiotic options for treating staphylococcal disease. However, treatment failure of invasive S. aureus infections commonly occurs [18■,19], even when the infection isolate has a susceptible MIC to the drug of choice. This phenomenon, which can be broadly referred to as antibiotic tolerance, reflects factors intrinsic to the pathogenesis of staphylococcal infection, as well as the limitations of the current clinical standards for antibiotic susceptibility testing [20].

The hallmark inflammatory lesion of invasive S. aureus infection is the abscess. Abscesses consist of a central bacterial microcolony, or ‘staphylococcal abscess community’, surrounded by viable and necrotic neutrophils. The neutrophilic infiltrate is further surrounded by a thin rim of macrophages, as well as a fibrous abscess capsule that eventually sequesters the lesion from surrounding healthy tissues [21]. Importantly, the staphylococcal abscess community is encased with a coagulase-dependent shell that impedes neutrophil access to the bacteria [22–24]. The staphylococcal coagulases leverage factors of the mammalian clotting system to build this barrier, and FDA-approved drugs that inhibit clotting have shown promise in preclinical models of staphylococcal infection [25]. It is likely that the abscess represents a critical barrier to the free diffusion of antibiotics, although experimental evidence is lacking due to the inherent difficulty in studying spatially heterogenous host-pathogen interactions in infected tissues. Outside of abscess formation, S. aureus exploits a number of host niches to escape immune effectors and antibiotic therapy. For example, staphylococcal invasion of resident macrophages in the liver is a critical determinant of antibiotic failure and subsequent disseminated disease in murine models [26,27]. Surewaard et al. [27] showed that this protective niche could be targeted by creating a liposomal formulation of vancomycin, which more efficiently eliminated intracellular bacteria. In the setting of osteomyelitis, which is one of the most common manifestations of invasive S. aureus infection, staphylococci exist in multiple niches that likely impact antibiotic efficacy. This includes bone marrow abscesses, invasion of necrotic fragments of bone known as sequestra, colonization of the osteocyte-canalicular network in the substructure of bone and growth within biofilms attached directly to the bone surface or to orthopaedic implants [20,28]. Moving forward, a better understanding of the heterogenous host tissue niches occupied by S. aureus during invasive infection will facilitate new developments in antibiotic and adjunctive therapeutic design. In addition, understanding how these host environments impose metabolic constraints on S. aureus that result in the emergence of tolerant subpopulations (e.g. small colony variants or persisters) will fuel new discoveries in antibiotic development [29,30].

A second factor that contributes to antibiotic failure for susceptible staphylococcal isolates is the inability of standard antimicrobial susceptibility testing (AST) methods using rich bacterial media to fully recapitulate the complex in-vivo host environment during infection. Invading bacteria encounter myriad physiologic alterations in vivo, such as tissue hypoxia, limited nutrient availability, the presence of antimicrobial peptides, pH differences, changes in buffering capacity and altered osmolarity, among others. Accordingly, some investigators have sought to perform AST in media that faithfully model the host environment [31,32,33■,34,35]. Such media compositions range from bodily fluids (e.g. urine or bronchoalveolar lavage fluid), to media with altered nutrient, pH or cation concentrations, to media containing antimicrobial peptides or immune cells. Modelling of the host environment during AST is a critical area for future research, and this effort will benefit from new developments for rapid AST profiling [36–41].

Another important emerging approach to develop new treatments for S. aureus infection is the repurposing of drugs already approved for other clinical indications. To this end, several recent studies have highlighted compounds with ‘antivirulence’ activity against S. aureus [42]. Antivirulence compounds are defined as those that target bacterial virulence factors or pathways that regulate virulence rather than directly inhibiting the growth of, or killing, bacteria. Potential advantages of such compounds include that they might be less prone to select for drug resistance, they can be combined with traditional antimicrobial agents to improve treatment outcomes, and they can mitigate tissue damage and dysfunction induced by bacteria. One example of antivirulence compounds for treatment of staphylococcal infection are so-called ‘quorum-quenching’ drugs, which target the accessory gene regulator (Agr) locus to inhibit multiple classes of virulence factors in S. aureus [42–45]. Examples of staphylococcal quorum quenching antivirulence compounds include the FDA-approved NSAID diflunisal [46], auto-inducing peptide analogues [44], savirin [47], Solonamide B [48], the fungal metabolite apicidin [49] and compounds produced by coagulase-negative staphylococci [50,51]. Other antivirulence compounds target bacterial stress responses that are necessary for survival in host tissues in the setting of inflammatory responses. For example, lipid-lowering squalene synthase inhibitors can also inhibit the production of the antioxidant staphyloxanthin, which is the golden carotenoid pigment for which S. aureus is named [52]. Finally, passive immunoprophylaxis with monoclonal antibodies that block staphylococcal toxins is a highly active area of research that is poised to deliver new antivirulence therapies. These strategies are discussed further in the following section.

PREVENTION OF STAPHYLOCOCCUS AUREUS DISEASE: VACCINE DEVELOPMENT

Few, if any, pathogens have resulted in as many unsuccessful vaccine attempts as S. aureus. The first known reported attempt at a staphylococcal vaccine construct was a whole-cell vaccine developed in 1902 [53]. Over the subsequent 119 years, many other putative vaccines were developed, with a surge in attempts in recent years. As of the time of this writing, however, S. aureus has eluded all passive and active immunization attempts to date. A clear need for a S. aureus vaccine exists, as current rates of invasive S. aureus infections in children exceed the rates of invasive H. influenzae type B and S. pneumoniae before vaccines were deployed against these other important invasive bacterial pathogens [4].

Current opinions in the field are that prior staphylococcal vaccine attempts have been unsuccessful in humans for a combination of reasons. First, many gaps still exist in our understanding of what defines functional immunity against S. aureus in the human host. Animal and in-vitro models are crucial for fundamental understanding of key aspects of S. aureus bacteriology and metabolism [54], but inferences regarding virulence factors and targets of the host response have shown to translate relatively poorly. Similarly, the field lacks a reliable serologic correlate of protection against S. aureus. Previous, successful bacterial vaccine development (e.g. Hib and pneumococcus) involved clear markers of functional immunity, such as opsonophagocytic assays that reliably translated to efficacy. Further, it remains unclear which of the many S. aureus virulence factors are actually produced in the setting of invasive human infection, are necessary for pathogenesis and intervenable by immunization. Traditional assessments have focused on immunodominant epitopes, while the most important antigens may be relatively less immunogenic. These gaps result in a poor understanding of which specific antigen(s) should be targeted in an ideal S. aureus vaccine.

Significant recent data suggest that the toxins of S. aureus represent a promising target for intervention against this organism [55], for several reasons. First, S. aureus expresses numerous host-evasion (and specifically antibody-evasion) mechanisms on the cell surface [56], such as staphylococcal protein A (SpA), which inhibits normal antibody function by binding the Fc antibody region with high affinity as well as facilitating B cell apoptosis [57,58]. Antibodies targeting toxins and acting extracellularly, may be relatively spared from S. aureus’ wealth of antiantibody mechanisms. Second, the pore-forming family of toxins [e.g. alpha-haemolysin (Hla), PVL, LukAB, LukED], a crucial component of staphylococcal evasion of innate host defenses, potently disrupt innate host immunity by a variety of mechanisms including the lysis of phagocytes [59]. Importantly, these toxins (particularly Hla and LukAB) are known to be produced in the setting of invasive human infection and targeted by the adaptive host response [60–62].

Recent findings suggest that the pore-forming toxins warrant continued investigation as potential targets of intervention, particularly for the amelioration or prevention of invasive disease and bloodstream infections [55]. This intervention could occur via active immunization against toxoid constructs, as recently demonstrated in animal models for LukAB [63■,64], PVL and Hla [65], or via passive immunization with neutralizing antibodies (i.e. monoclonal or oligoclonal preparations) in high-risk hosts [62,66,67].

Multivalent (i.e. simultaneously targeting a variety of important antigens) vaccine constructs are likely to be a necessary approach given the complexity of this organism. Moreover, a worthwhile goal is likely not the eradication of this organism nor prevention of colonization or even cutaneous infection, but rather amelioration of severe, invasive S. aureus disease and the associated morbidity and mortality. Numerous novel constructs and putative vaccines are in development (Table 2), many of which align with the priorities mentioned above, and ongoing work will determine whether the as-yet-insurmountable challenge of preventing S. aureus disease by vaccination will soon be overcome.

Table 2.

Staphylococcus aureus vaccine candidates currently in human trials, as of May 2021

Specific Components	Name / Description	Manufacturer	Status of Development
Toxins/Leukocidins
Two pore-forming toxins: toxoid of α-toxin, and recombinant PVL subunit (rLukS-PV)	Two-component toxoid / subunit	Nabi Biopharmaceuticals	Phase 1 safety and immunogenicity complete
Human mAb targeting α-toxin	AR-301 (mAb)	Aridis Pharmaceuticals	Ongoing trial in ventilator-associated pneumonia (VAP), healthcare-associated bacterial pneumonia (HABP) and community-acquired pneumonia (CAP)
5-valent mAB against α-toxin, PVL, HlgAB, HlbCD, LukED; and mAb against LukAB	ASN100 (mAb combination)	Arsanis	VAP; discontinued
Anti-Hla mAb	Suvratoxumab	AstraZeneca	SAATELLITE trial for VAP
Surface adhesins or capsular polysaccharides
rAls3p-N (Candidal adhesin)	NDV-3A	NovaDigm Therapeutics	Phase 2, prevention of S. aureus colonization– complete. (A separate Phase 2a trial in patients with Hyper IgE syndrome was discontinued due to adverse effects)
Capsular polysaccharides conjugated to tetanus toxin, α-toxoid, clumping factor A	4C-Staph	Novartis/GlaxoSmithKline	Phase 1 Safety and immunogenicity–complete
Nutritional transporters
IsdB-N2, MntC, Hla, SEB, SpA	Five-component recombinant antigen	Chengdu Olymvax Biopharmaceuticals	Open-label phase 1b safety and immunogenicity; Ongoing
Not disclosed
Five recombinant antigens, bioconjugated and adjuvanted; components not publicly disclosed	Sa-5Ag	GlaxoSmithKline	Phase 1 safety and immunogenicity, patients with recent SSTI; Ongoing

FUTURE HORIZONS AND OPPORTUNITIES

There are many exciting opportunities on the horizon to improve the diagnosis and treatment of staphylococcal infections. As noted above, continued innovation of AST methods will improve prediction of antibiotic success vs. failure in an increasingly medically complex population. Basic science investigations into the many niches that S. aureus can occupy in host tissues and how these niches impact antigen display, virulence factor production and bacterial metabolism, will improve efforts to predict and therapeutically target antibiotic failure.

Looking ahead, we suggest two areas of focus that could transform the care of patients suffering from S. aureus infection. First, as the electronic health record (EHR) becomes more sophisticated and integrated with patient metadata, there is an opportunity to discover factors that predict susceptibility to, or protection from infectious diseases. For example, multiple studies from the investigative team lead by Dr Vance Fowler have identified loci that predict enhanced susceptibility to staphylococcal disease in murine and human infection [68,69■■,70,71]. More recently, the MRSA Systems Immunobiology Group performed whole exome sequencing on a well matched cohort of prospectively enrolled patients with persistent or resolving MRSA bacteraemia. A single nucleotide polymorphism in the intronic region of DNMT3A was found to differentiate between persistent and resolving S. aureus bacteraemia. Mechanistically, DNMT3A variants were predicted to alter the host response to infection via methylation of key regulatory genes and reduced IL-10 production [69■■]. This study is paradigmatic of ‘bedside-to-bench’ research studies that leverage well constructed patient cohorts, EHR variables and genomic data to predict susceptibility to infectious diseases and resultant complications. As tools to mine the EHR and DNA databases become more sophisticated, it is possible to predict genetically encoded disease patterns using tools such as pheWAS (phenome-wide association studies) and phenotypic risk scoring [72,73]. Such tools and databases could also enable personalized antibiotic dosing regimens to maximize safety and efficacy.

A second area of focus for future research to transform management of S. aureus infection is the development of new diagnostic modalities that specifically detect viable bacteria or immune responses to S. aureus. Although rapid molecular diagnostics have improved the time to diagnosis for typical presentations of S. aureus disease, there remains a need for improved detection of invasive infection in those patients who have been pretreated with antibiotics, or in whom recrudescent infection is suspected following initial antibiotic therapy. In these cases, cultures are often negative, and diagnosis by traditional molecular diagnostics may require invasive procedures to obtain new specimens. One exciting development in both preclinical models and early human clinical trials is the development of new imaging modalities to specifically detect the presence of viable bacteria. For example, studies in animal models have shown the power of creating imaging probes to detect the activity of specific staphylococcal virulence factors such as staphylocoagulase or nuclease [74,75]. Similarly, labelling specific metabolites that are selectively imported by bacteria can enable the creation of pathogen-specific imaging probes [76–78]. Finally, chemically modifying antibiotics for use as PET probes has shown promise in the diagnosis of infection and monitoring of treatment responses [79–81]. These approaches might hold considerable value for patients with posttraumatic or postsurgical staphylococcal infection, wherein it can be difficult to distinguish sterile inflammation from ongoing infection.

Finally, the adaptive host response to invasive staphylococcal infections may also be leveraged as a diagnostic opportunity. Presence of specific antibodies targeting those factors strongly associated with invasive disease, rather than colonization or noninvasive infections, may assist with the diagnosis of invasive infections (e.g. osteomyelitis, septic arthritis or visceral abscesses) that may be culture-negative due to antimicrobial pretreatment or inadequate diagnostic specimens. Pilot data suggest that antibodies against the leukocidin LukAB, which is ubiquitous among clinical isolates and abundantly produced in the setting of invasive disease, may be promising in this regard [82]. Similarly, antiglucosaminidase antibodies have shown promise as a serologic diagnostic for S. aureus osteomyelitis [83]. Notably, the lack of antiglucosaminidase antibodies was associated with worsened clinical outcomes and higher mortality, suggesting a fundamental role of this aspect of the adaptive response in S. aureus infection [84].

CONCLUSION

Despite myriad scientific breakthroughs, discoveries and novel therapeutics, S. aureus remains a scourge and a major human pathogen causing a wide variety of clinical phenotypes. Notably, the organism continues to evolve, both in terms of its dominant circulating lineages (and the virulence factors contained therein), and regarding antimicrobial resistance. USA300 CA-MRSA is no longer the dominant clone driving invasive paediatric infections, and a relative rise of MSSA (every bit as severe as MRSA) is the hallmark in recent years. The identification and development of novel preventives and therapeutics will be paramount in attempting to keep pace with this highly successful organism.

KEY POINTS.

• Currently, circulating invasive strains of S. aureus continue to evolve, and the USA300 CA-MRSA epidemic clone is no longer dominant; in fact, MSSA is more frequent in recent series, though equally as severe as invasive MRSA.

• Numerous new antistaphylococcal antimicrobials have been developed in recent years, though paediatric data remain limited.

• Recent scientific breakthroughs highlight the opportunity for novel interventions against S. aureus by interfering with virulence rather than by traditional antimicrobial mechanisms.

• A S. aureus vaccine remains elusive; the reasons for this are multifactorial, and lessons learned from prior unsuccessful attempts may create a path towards an effective preventive.