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Nat Rev Microbiol. Author manuscript; available in PMC May 16, 2010.
Published in final edited form as:
PMCID: PMC2871281
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Waves of Resistance: Staphylococcus aureus in the Antibiotic Era

Preface

Staphylococcus aureus is notorious for its ability to become resistant to antibiotics. Infections caused by antibiotic-resistant strains often occur in epidemic waves initiated by one or a few successful clones. Methicillin-resistant S. aureus (MRSA) is prominently featured during these epidemics. Historically associated with hospitals and other healthcare settings, MRSA now has emerged as a widespread cause of community infections. So-called community or community-associated MRSA spreads rapidly among healthy individuals. Outbreaks of community MRSA infections have been reported worldwide and community MRSA strains are now epidemic in the United States. There is reason for concern because MRSA often are or can readily become resistant to multiple antibiotics, thus limiting treatment options.

Introduction

Staphylococcus aureus is naturally susceptible to virtually every antibiotic that has ever been developed. Resistance is often acquired by horizontal transfer to genes from outside sources, although chromosomal mutation and antibiotic selection are also important. This exquisite susceptibility of S. aureus led to Alexander Fleming’s discovery of penicillin, ushering in the “antibiotic era.” Penicillin was truly a miracle drug: uniformly fatal infections could be cured. Yet, by the mid-1940s, only a few years after its introduction into clinical practice, penicillin resistance was encountered in hospitals and within a decade it had become a significant problem in the community. S. aureus is remarkable in its ability to acquire resistance to any antibiotic.

A fundamental biological property of S. aureus is the ability to asymptomatically colonize normal people. Approximately 30% of humans are asymptomatic nasal carriers of S. aureus1, 2; i.e., S. aureus is normal flora. S. aureus carriers are at higher risk of infection and they are presumed to be an important source of spread of S. aureus strains among individuals. The primary mode of transmission of S. aureus is by direct contact, usually skin-to-skin contact with a colonized or infected individual, although contact with contaminated objects and surfaces or might also play a role36. Various host factors, including loss of the normal skin barrier, presence of underlying diseases such as diabetes and acquired immunodeficiency syndrome, or defects in neutrophils function predispose to infection.

Infections caused by antibiotic-resistant strains of S. aureus have reached epidemic proportions globally7. The overall burden of staphylococcal disease, particularly that caused by methicillin resistant S. aureus strains (MRSA), is increasing in many countries in both healthcare and community settings813. In the United States the emergence of community-associated MRSA (CA-MRSA) strains as a major cause of skin and soft-tissue infections14, 15 accounts for much of this increase. The rapidity and extent to which CA-MRSA strains have spread has been remarkable. In addition to the United States CA-MRSA strains have been reported from Canada, Asia, South America, Australia, and throughout Europe, including Norway, the Netherlands, Denmark, and Finland, countries with historically low prevalence of MRSA.12, 1629 Globally, CA-MRSA strains have shown a remarkable diversity in the number of different clones that have been identified.

In addition to increasing prevalence and incidence CA-MRSA strains appear to be especially virulent. Overwhelming and tissue-destructive infections, such as necrotizing fasciitis and fulminant, necrotizing pneumonia3032, which have been associated with CA-MRSA strains, were rarely seen prior to their emergence. The factor or factors responsible for this hypervirulent behavior of CA-MRSA are not known, but PVL, which has been epidemiologically associated with severe skin infections and pneumonia caused by methicillin-susceptible S. aureus (MSSA) strains33, has been proposed as a potential leading candidate.

Antibiotics arguably constitute the most concentrated selective pressure ever brought to bear on S. aureus in its long co-evolutionary history with mankind. The consequences of this selective pressure in conjunction with horizontal and vertical gene transfer are the subject of this review. Given their critical importance as therapeutic agents, the story will focus on resistance to penicillins and the structurally related beta-lactam antibiotics.

Epidemic Waves of Antibiotic Resistant Staphylococcus aureus

Emergence of antibiotic resistance by S. aureus can be visualized as a series of waves (Figure 1). The first wave began in the mid-1940s as the proportion of infections caused by penicillin-resistant S. aureus rose in hospitals 34, 35. These strains produced a plasmid-encoded penicillinase that hydrolyzes the beta-lactam ring of penicillin essential for its antimicrobial activity. Penicillin-resistant strains then were observed to cause community infections; by the early 1950s and 1960s they had become pandemic 36. These infections, both in hospitals and the community, were caused primarily by a S. aureus clone known as phage-type 80/81 3639. Pandemic phage-type 80/81 S. aureus infections largely disappeared after the introduction of methicillin 40, but the prevalence of penicillinase-producing strains of other S. aureus lineages has remained high ever since.

Figure 1
A timeline of the four waves of antibiotic resistance in Staphylococcus aureus. Wave 1, which continues today, began shortly after the introduction of penicillin into clinical practice in the 1940s. The first pandemic antibiotic resistant strains, from ...

Introduction of methicillin marks the onset of the second wave of resistance. The first reports of a S. aureus strain that was resistant to methicillin were published in 1961 41, 42. Although the specific gene, mecA, the methicillin resistance determinant which encodes the low affinity penicillin binding protein, PBP 2a (also referred to as PBP 2′), was not identified until more than 20 years later, it was appreciated early on that the resistance mechanism was different from penicillinase-mediated resistance because there was no drug inactivation. Unlike penicillinase-mediated resistance, which is narrow in its spectrum, methicillin resistance is broad beta-lactam antibiotic class resistance to penicillins, cephalosporins, and carbapenems. Among the very earliest of MRSA clinical isolates is the archetypal strain COL, a member of the “archaic” clone of MRSA and perhaps the most studied MRSA strain, which was isolated from a patient in Colindale, United Kingdom in 1960 42. COL is a member of the most successful of all MRSA lineages, which includes both hospital and community-associated strains.

These archaic clone of MRSA strains circulated in hospitals throughout Europe until the 1970s 43. There were isolated reports of MRSA from hospitals in the United States44, 45, but the rest of the world was largely spared and these early MRSA never gained a foothold in the community. By the 1980s for unclear reasons archaic MRSA strains had largely disappeared from European hospitals, marking the end of the second and the beginning of the third wave of antibiotic. Descendants of the archaic MRSA clone (e.g., the Iberian and Rome clones46) and other highly successful MRSA lineages emerged (Table 1) 4749, constituting the third wave of antibiotic resistance. Outbreaks of infections caused by MRSA strains were reported in hospitals in the United States in late 1970s and by the mid-1980s were endemic50, 51. These strains swept the globe leading to the worldwide pandemic of MRSA in hospitals that continues to the present time. Although global in distribution and impact, MRSA was still confined mainly to hospitals and other institutional healthcare settings, such as long-term care facilities. The ever increasing burden of MRSA infections in hospitals led to more usage of vancomycin, the last remaining antibiotic to which MRSA strains were reliably susceptible, and under this intensive selective pressure vancomycin intermediate S. aureus (VISA, which are not inhibited in vitro at vancomycin concentrations below 4 to 8 μg/ml)52 and vancomcyin-resistant S. aureus (VRSA, inhibited only at concentrations of 16 μg/ml or more)53 strains of MRSA emerged.

Table 1
Lineages of common nosocomial MRSA.

The MRSA invasion of the community constitutes the fourth and latest wave of antibiotic resistance. Some of the earliest cases of community-associated MRSA (CA-MRSA) infections occurred in indigenous populations in Western Australia in the early 1990s5456. These MRSA strains were distinguishable from contemporary clones (i.e., genotypes) circulating in Australian hospitals by their pulsed field gel electrophoresis patterns and susceptibility to most antibiotics other than beta-lactams, suggesting that they were either remote, feral descendants of hospital strains or community strains that had acquired mecA by horizontal gene transfer. In the US, the first well-documented cases of MRSA infection that were truly community associated occurred in otherwise healthy children in 1997–99 57. These children had no risk factors for MRSA and all died with overwhelming infection, suggesting that these community MRSA strains were especially virulent. Like their Australian counterparts, these CA-MRSA isolates were unrelated to hospital clones and were susceptible to most antibiotics The CA-MRSA epidemic in the US can be traced to the early 1990s, based on retrospective data from 1993–1995 showing a dramatic increase in MRSA infections in Chicago among children lacking risk factors for hospital-associated MRSA exposure58. CA-MRSA has since been reported in numerous populations including American Indians and Alaska natives 59; Pacific Islanders 60; athletes 4; jail and prison inmates 61; men who have sex with men 62; contacts of patients with CA-MRSA infection 63; military personnel 61; adult emergency room patients 14; and children in day care centers 64. CA-MRSA clones have also gained a foothold in hospitals and are increasingly identified as a cause of hospital-onset and heathcare-associated infections 10, 12, 25, 65, 66.

The epidemic wave of CA-MRSA in the United States, and Canada as well67, 68, is actually two overlapping epidemics. The USA400 clone, which was isolated from the pediatric cases described above, was most prevalent prior to 2001 3, 57, 69. USA400 remains a common cause of community-onset disease in among indigenous populations in Alaska and the Pacific Northwest 70. A second epidemic clone, USA300, which is unrelated to USA400 and has largely displaced it in most other locations, emerged between 1999 and 2001, and now causes the vast majority of CA-MRSA infections in the United States3, 4, 7174.

Outbreaks and epidemics of CA-MRSA now occur worldwide and with a similar epidemiology, although the specific clones that have emerged vary with geographical location. CA-MRSA strains are not merely escapees from healthcare facilities; their genotypes indicate that they are not closely related to endemic hospital clones and these community strains are susceptible to numerous antibiotics to which hospital strains are routinely resistant. Two molecular markers not found in typical hospital MRSA are strongly associated with emergence of CA-MRSA regardless of geographical origin: a specific cassette element encoding mecA and genes encoding Panton-Valentine leukocidin (PVL). These markers are discussed in detail below.

Skin and soft-tissue infections are the most common type of CA-MRSA infection, accounting for approximately 90% of cases, of which 90% are abscesses and/or cellulitis with purulent drainage 14, 15. CA-MRSA strains also appear to be especially virulent with the capacity to cause fulminant, overwhelming infections, such as necrotizing fasciitis, necrotizing pneumonia, bone and joint infections accompanied by septic thromboembolic disease 31, 7577, purpura fulminans with or without Waterhouse-Friderichsen syndrome 78, orbital cellulitis and endophthalmitis 79, infections of the central nervous system 80, 81, and bacteremia and endocarditis 66, 82

Molecular epidemiology of Staphylococcus aureus in the antibiotic era

S. aureus Clonal Complexes

Robust sequence-based molecular methods for genotyping strains of S. aureus, and multilocus sequence typing (MLST) 83 in particular, have made the study of the evolutionary history of S. aureus possible (Box 1). MLST is performed by sequence analysis of approximately 450 bp internal fragments of seven housekeeping genes. Isolates that have identical sequences at all seven genetic loci are considered a clone, and assigned a unique sequence type (ST). Sequence types that differ by single nucleotide polymorphisms at fewer than three loci are considered closely related, and are grouped into clonal complexes (CC) (Figure 2). This is accomplished by application of the eBURST algorithm (http://eburst.mlst.net), which uses multilocus sequence typing data to group closely related strains into a clonal complex. It also predicts the probable founding clone (i.e., sequence type) of each group and recent evolutionary descent of all other strains within the clonal complex from the founder84, 85. The analysis can be further refined to identify specific subclones by the addition of other methods, such as spa typing86 pulsed field gel electrophoresis of genomic DNA, or by the presence of other genetic markers (e.g., toxin genes or specific plasmids).

Box 1. Genotyping is used to identify S. aureus strains and predict phylogeny

Multilocus sequence typing (MLST) is sequence based genotyping method. The method is based on single nucleotide variations (each variant is termed an allele) of 7 housekeeping genes in S. aureus, which provides a discriminatory allelic profile, known as sequence type (ST)83, for each bacterial isolate. MLST, because it indexes variations that accumulate slowly over time can be used to measure long periods of evolution among S. aureus lineages and is highly reproducible. S. aureus isolates having identity at 5 or more of the 7 housekeeping genes/loci based upon MLST are known as a clonal complex (CC)84, 87.

Pulsed-field gel electrophoresis (PFGE)has a somewhat more rapid clock speed than MLST and is suitable for evaluation of more recent evolution among groups of strains. The method relies on separation of SmaI-digested S. aureusgenomic DNA fragments according to size in an agarose gel by by pulsed-field electrophoresis. Related strains are clustered according to an 80% similarity coefficient 99. The CDC has developed a national PFGE database for S. aureus, which uses the “USA” designation (e.g., USA300 for the ST8, PVL-positive community associated MRSA).99

spa typing86 is based upon sequence analysis of variable number tandem repeats in the gene encoding protein A (Spa). Spa typing takes into account point mutations in the the repeat region as well as the number of repeat variations. The method is suitable for investigation of local or global S. aureusoutbreaks. This sequence-based analysis of a single target locus is a relatively inexpensive way of acquiring robust data that can be used to determine both epidemiological and phylogenetic relationships.

Figure 2
An example of multilocus sequence typing scheme and designation of clonal complexes

Studies 47, 83, 8790 of MSSA strains, carriage isolates and hospital and community isolates causing disease, collected worldwide between 1961 through 2004, show that 88% of the strains can be assigned to one of one of 11 clonal complexes (CC1, CC5, CC8, CC9, CC12, CC15, CC22, CC25, CC30, CC45, and CC51/121 47, 84, 8993), (Figure 3A). Percentages of isolates range between 2% and 9% for ten complexes; CC30 is an outlier, accounting for 21% of isolates.

Figure 3
Distribution of antibiotic-susceptible and -resistant S. aureus among clonal complexes

Clonal complexes for contemporary isolates are almost certainly the same as those of strains circulating prior to 1940. For example, the ST5 lineage, the founder of CC5, is estimated to have existed for over 2000 years 94. Furthermore, when Gomes and colleagues 95 genotyped 22 penicillin-susceptible and 77 penicillin-resistant MSSA blood culture isolates dating from 1957 to 1973 by the Statens Serum Institute of Copenhagen, which has collected and maintained every blood culture isolate from patients in Denmark from 1957 to the present, they found that 86% of the isolates fell into 7 clonal complexes, the two most common being CC8 and CC30, which together accounted for 46% of the isolates (Figure 3B). The distributions of penicillin-sensitive and penicillin-resistant isolates were similar. Relatively few isolates were tested and all originated from a single country, which probably accounts for the absence of isolates from CC9, CC12, CC15, or CC22.

CC8 and CC30 have given rise to epidemics during each of the four waves of antibiotic resistance. The first well-characterized pandemic of antibiotic resistant S. aureus attributable to a single clone was caused by phage type 80/81 strains, which belong to CC30 96. Originally isolated in Australia in 1953 39, phage type 80/81 strains were penicillin-resistant and caused both hospital and community outbreaks on a global scale96. Phage type 80/81 strains are prevalent in strain collections dating back to 1927; these strains were considered to be highly transmissible and particularly virulent, and were also among the first to be identified as penicillin resistant 37. Phage type 80/81 isolates in a collection dating to the 1950s and 1960s have been shown almost uniformly to possess genes for PVL96, which is reminiscent of the association of PVL and resistance to methicillin in the contemporary epidemic CA-MRSA strains. For unknown reasons, phage type 80/81 strains virtually disappeared in the early 1960s, coincident with the first use of semi-synthetic penicillins, which are resistant to penicillinase. Modern descendents of the ST30/CC30 lineage include the PVL-positive southwest Pacific (SWP) clone of CA-MRSA in Australia and hospital associated ST36 EMRSA16 clone, a major cause of nosocomial infections and bacteremia in the both Australia and the United Kingdom 9698.

MRSA Clonal Complexes

The very first MRSA clinical isolates, of which COL is an example, were ST250 and members of CC8. ST250 MRSA strains circulated in the UK and Europe prior to the 1970s, but never established a presence in the United States, and had largely disappeared by the 1980s. However, other highly successful clones emerged, including the ST247 Iberian/EMRSA5 clone, which is closely related to ST250. No fewer than nine other endemic nosocomial clones are descendants of the ST8 founder of this lineage. The CA-MRSA strain USA300 (which is PVL-positive) that is prevalent in the US is also ST8 99.

MSRA strains generally been concentrated into a subset of the S. aureus clonal complexes, including CC1, CC5, CC8, CC22, CC30, and CC45, although as discussed below CA-MRSA have exhibited some diversity. These clonal complexes were widespread prior to emergence of methicillin resistance 43, 95, indicating that superior epidemicity preceded acquisition of drug resistance and that the adaptations and innovations that make clones successful also may favor their adaptation to antibiotic selective pressures.

Staphylococcal Chromosome Cassette mec, SCCmec

The discovery by Hiramatsu and colleagues that mecA is always found within a mobile cassette element was a great advance for understanding the biology of methicillin resistance and provided an additional tool for determining evolutionary relationships among MRSA 100. This element, SCCmec (staphylococcal chromosome cassette mec) is integrated into orfX, a S. aureus gene of unknown function (Figure 4). To date eight SCCmec allotypes, designated I through VIII 49, 100104, have been described (Table 2) along with numerous subtypes and more are likely to be identified as sequence data become available for more MRSA strains (see http://www.staphylococcus.net/for additional descriptions and information). Similar elements are present in coagulase-negative staphylococci, which are commensual organisms that are normal skin flora of humans and other mammals 105. gene complexes, mec and ccr (the recombination/excision locus that encodes the gene or genes that mediates integration and excision of the whole cassette into orfX), are used to classify SCCmec types (Table 2). There are also other differences among the various SCCmecs, particularly in insertion sequences and antimicrobial resistance genes, but as these are themselves mobile elements, they have not proven useful in classification of major types, although they are useful in defining subtypes. class A mec gene complex (class A mec) is the prototype complex. It contains PBP 2a-encoding mecA, the complete mecR1 and mecI regulatory genes upstream of mecA, and the hypervariable region (HVR) and insertion sequence IS431 downstream of mecA. The class B mec gene complex is composed of mecA, a truncated mecR1 resulting from the insertion of IS1272 upstream of mecA, HVR, and IS431 downstream of mecA. The class C mec gene complex contains mecA and truncated mecR1 by the insertion of IS431 upstream of mecA, HVR, and IS431 downstream of mecA. There are two distinct class C mec gene complexes. In the class C1 mec gene complex, the IS431 elements upstream and downstream of mecA both have the same orientation. In the class C2 mec gene complex, the orientation of IS431 upstream of mecA is reversed. C1 and C2 are regarded as different mec gene complexes since they have likely evolved independently. The mecA, mecR1, and mecI sequences are highly conserved with >99% nucleotide sequence identity. The ccr complex consists of two adjacent genes ccrA and ccrB in SCCmec I–IV, VI, and VIII, and ccrC in V and VII. MRSA strains isolated prior to 1990, all nosocomial isolates, contained predominantly SCCmecI–III. Community MRSA isolates overwhelming contain SCCmecIV or SCCmecIV subtypes or, less commonly, SCCmecV 28, 106. SCCmec IV is increasingly identified in contemporary hospital MRSA strains as well.

Figure 4
Comparison of methicillin-resistance cassettes typical of hospital- or community MRSA
Table 2
Comparison of SCCmec allotypes.

The three epidemic waves of MRSA correspond to evolutionary changes in SCCmec. The early MRSA strains, COL and other CC8 strains that circulated in the UK and Denmark in the early 1960s, all carried type I SCCmec. These clones were replaced in the 1980s by new, and arguably more successful, lineages that eventually became established in hospitals throughout the world. These clones, predominantly CC5 and CC8, carried type II or III SCCmecs (e.g., New York/Japan EMRSA, EMRSA-16 in Australia and the United Kingdom, Brazilian clone, Hungarian clone), or the type IA variant of the archaic SCCmec type I (Iberian clone). Why types II and III were more successful than type I SCCmec is not known, but it could be that the recombinase genes, which are defective in type I SCCmec but functional in types II and III100, limited the potential for horizontal gene transfer of type I SCCmec into new genomes.

What gave rise to the most recent worldwide epidemic wave of community MRSA, is the “invention” of SCCmecIV, which appears to have evolved from type I SCCmec, although it has type 2 ccrAB 107. Originally identified in the community-associated MW2/USA400 strain, the first occurrence of type IV SCCmec in S. aureus may have been in the ST5 “Pediatric” clone that was circulating in hospitals in the late 1980s and 1990s 108. The ultimate origins of mecA and SCCmec elements may never be known, but there is good evidence suggesting that coagulase-negative staphylococci are the sources 109111.

The success of SCCmecIV is borne out by two observations. First, it is the most widely distributed among S. aureus isolates. It has been found in 9 distinct MRSA clonal complexes or sequence types, compared to only 2 such lineages for type I, 3 for type II, and 2 for type III 107. Second, CA-MRSA strains containing SCCmecIV have growth rates faster than hospital MRSA strains carrying other SCCmec types and these growth rates are no different from MSSA isolates 106. In a rabbit bacteremia model fitness and virulence of USA300, which carries SCCmec type IVa, was indistinguishable from its isogenic methicillin-susceptible variant 112. Thus, the type IV methicillin-resistance cassette appears to exact little or no cost in fitness for the organism.

Epidemiology of Community-Associated MRSA

As mentioned above, the earliest reported cases of CA-MRSA infection in the US were caused by a USA400 strain, MW2 57. MW2 is closely related to the PVL-negative clone, WA-1, which is an important CA-MRSA in Australia and to the MSSA strain 476 in the United Kingdom.55 USA400 has been supplanted by USA300, which is by far the most frequent cause of CA-MRSA infections in the US 113. The USA300 clone seems to be particularly well adapted to the community with reports of CA-MRSA infections caused by USA300 or its close relatives in Australia and Denmark and outbreaks of CA-MRSA in Columbia114116. USA300 strains can also cause healthcare-associated infections65, 66, 117, 118

While there is evidence of international spread of these USA300 and USA400,18, 23, 119, 120 CA-MRSA strains unrelated to either have been responsible for infections outside of the United States. ST80 in is the predominant clone circulating in Europe, ST59 in Taiwan, and ST30 in Eastern Australia, demonstrating that CA-MRSA strains have evolved in separate geographical regions 2123. There also can be considerable strain diversity in CA-MRSA from country to country. For example in Australia 45 distinct clones of CA-MRSA have been identified23; many of these are related to well-known MRSA lineages, but others appear to be novel. Diversity of CA-MRSA isolates has been noted by others as well18, 27, 114, 119, 120. In the United Kingdom the vast majority of CA-MRSA infections are caused by EMRSA-15 (ST22) and EMRSA-16 (ST36), which are also important hospital clones121; ST80 is also present, but it accounts only for a small proportion of isolates122. A CA-MRSA strain, ST 398, of swine origin and transmissible to humans has also been described123, 124.

The epidemiology of CA-MRSA is quite similar regardless of country of origin. Isolates tend not to be multiple drug-resistant, SCCmec types IV and V are typically present, and infections of skin and soft tissue are the most common. The presence of PVL among CA-MRSA isolates is more variable. For example in Australia and the United Kingdom most CA-MRSA clones do not produce PVL23, 121 and prevalence of PVL among the more common CA-MRSA isolates from Denmark ranged from 17% to 100%120. On the other hand isolates of clones that typically do not carry PVL genes, e.g., EMRSA-15 and EMRSA-16, have been found on occasion to be PVL-positive121.

Nasal carriage of MRSA has increased in parallel with the emergence of MRSA as a community pathogen, which is not unexpected given that approximately 30% of people have asymptomatic nasal colonization with S. aureus. Between 2001 and 2004 carriage of MRSA strains in a US population based study approximately doubled from 0.8% to 1.5% 2 and the percentage of community-associated MRSA genotypes increased from7% to 24.2% 88. Although the sites of carriage (e.g., nasal versus groin versus other) and the relationship between carriage of CA-MRSA strains and disease is not entirely clear, CA-MRSA strains, especially USA300, appear to be more easily transmitted than other strains,125 which could account for increasing carriage rates in the community. Thus, no individual or group can be considered not at risk for CA-MRSA infection.

Virulence of Community-Associated MRSA

Compared to infections caused by healthcare-associated MRSA strains and community MSSA, CA-MRSA infections have been associated with fulminant and lethal infections and worse clinical outcomes30, 77, 126, giving rise to the clinical impression that CA-MRSA strains, especially USA300, are more virulent than other strains. Much of what the information about the unique virulence properties of CA-MRSA is based on studies of USA300 strains, the most extensively investigated clone. The USA300 core genome (chromosome excluding mobile genetic elements) is quite similar to that of the early MRSA strain, COL 127. Yet, studies in animal models indicate that USA300 is more virulent than COL128, 129. Expression of virulence factors by USA300 is high and USA300 130, 131 and closely related strains are more lethal than more distant relatives and cause more extensive disease in animal models of infection129, 130. The major difference between COL and USA300 genomes resides in mobile genetic elements, which include prophages, plasmids, pathogenicity islands, and transposons, acquired through horizontal gene transfer. These elements encode factors that may impact transmission, antibiotic resistance, and virulence. Prophages ΦSa2 and ΦSa3, which are present in USA300 strains and not in COL, could contribute to the noted differences in virulence between these two lineages. Prophage ΦSa2 contains lukS-PV and lukF-PV, which encode PVL. Prophage ΦSa3 encodes staphylokinase, staphylococcal complement inhibitor (SCIN), and S. aureus chemotaxis inhibitory protein (CHIPS), all of which are modulators of the innate immune system 132, 133. ΦSa3 is present in strains other than CA-MRSA. A pathogenicity island, SaPI5, similar to the one that is in COL, is present in USA300. SaPI5 encodes two additional superantigens not present in COL, SEQ and SEK, which also are found in other MRSA and MSSA lineages. S. aureus produces many other molecules that promote host colonization, facilitate evasion of the innate immune system, and/or alter immune responses (Tables 36) 131, 134, 135. Most of these molecules are not unique to CA-MRSA. The virulence factors more commonly found in CA-MRSA compared to other strains, those that are linked by epidemiology to CA-MRSA infections, or those that have been studied in animal models of CA-MRSA infection are discussed below.

Table 3
Virulence factors of Staphylococcus aureus that interfere with bacterial killing.
Table 6
Superantigens produced by Staphylococcus aureus.

Panton-Valentine leukocidin (PVL)

PVL has been studied extensively since its discovery by Panton and Valentine 70 years ago136. The role of PVL in the marked epidemicity and enhanced virulence of CA-MRSA is subject of debate. PVL is comprised of two subunits, LukS-PV and LukF-PV 137 that are encoded by prophage ΦSa2 138 that is acquired by horizontal gene transfer. LukS-PV and LukF-PV are secreted by the bacterium. These subunits bind to specific membrane receptors, yet to be identified, and associate to form pores in the membrane of host leukocytes139, 140. At high concentrations (200 nM) PVL causes lytic cell death, but at sublytic concentrations (5 nM), PVL appears to partially activate neutrophils in a phenomenon often called priming, as they release potent mediators of inflammation, such as leukotriene B4, interleukin-8, and neutophil granule contents through exocytosis 141143. In addition, PVL primes neutrophils for enhanced release of reactive oxygen species upon stimulation with the widely used neutrophil agonist N-formylpeptide (fMLP) 144. Thus, PVL could contribute to pathogenesis by causing an exaggerated inflammatory response and injury to the host. Several lines of evidence, largely circumstantial, indicate that PVL is associated with severe skin infections and severe necrotic hemorrhagic pneumonia 33, 145, 146. Both the phage type 80/81 penicillin-resistant strains that were associated with numerous outbreaks and severe disease in the 1950s and USA300, now the leading cause of skin and soft tissue infections in the United States and a cause of extremely severe infections, produce PVL. The epidemiologic association between PVL and emergence of genetically unrelated (i.e., different and unrelated sequence types) CA-MRSA strains that are geographically dispersed is striking.

There are other observations, however, that call into question the presumption that PVL is driving the CA-MRSA epidemic. It is found infrequently in other common and quite successful community strains. For example, PVL genes are present in only ~1–10% of MSSA clinical isolates 89, 147, 148. And although USA300 and USA400 are both PVL-positive, it is USA300 that has become the predominant CA-MRSA clone in the US. This suggests that factors other than PVL are important for the recent emergence of CA-MRSA.

Experimental evidence does not provide a clear picture. Voyich et al. found that USA300 and USA400 wild-type and isogenic PVL-deletion strains (Δpvl) strains caused virtually identical courses of infection in mouse abscess and sepsis models and that there was no difference in neutrophil phagocytosis or lysis after uptake, although because these experiments were conducted with culture supernates the results could reflect the action of multiple lytic factors149. Similar results in a rat pneumonia model were reported by Montgomery and Daum150. Bubeck Wardenburg et al. showed that USA300 and USA400 wild-type and isogenic PVL-deletion strains were equally virulent in these mouse abscess and pneumonia models 151, 152. Diep et al. used two rabbit bacteremia models to compare hematogenous dissemination of wild-type and Δpvl CA-MRSA strains to major organs 153. Although PVL did not promote seeding of lungs, spleen or blood by USA300, there was a modest, transient contribution of PVL to colonization of the kidneys. However, in series of experiments using the same USA300 wild-type and mutant (Δpvl) strain pair as Voyich et al 149, Brown et al found that the parent was more virulent than the Δpvl mutant in murine pneumonia and abscess models and that disease caused by the wild-type strain was attenuated by immunization with recombinant LukF-PV or LukS-PV 154. In addition, Labandeira-Rey et al found evidence suggesting that PVL may play a role in murine model of staphylococcal pneumonia 155. Direct instillation of high doses of purified toxin provoked an inflammatory response in the lung and reduced survival. These investigators, using a laboratory strain transduced with PVL-encoding bacteriophage to establish infection, reported worse outcome for the PVL-producing variant. However, in addition to presence or absence of PVL, this laboratory construct has major alterations in global gene expression that confounded interpretation of the data. As PVL has no impact on protein or gene expression in USA300 or USA400 153, it is possible that factors other than PVL accounted for the experimental results. The data in aggregate suggest that the contribution of PVL to CA-MRSA pathogenesis may be relatively minor or perhaps dependent on an as yet unidentified bacterial factor or host-susceptibility component.

Alpha-hemolysin (Hla or alpha-toxin)

This pore-forming toxin causes destruction of a wide-range of host cells, including epithelial cells, erythrocytes, fibroblasts, and monocytes and is lethal in animal models when injected in purified form 156. Alpha-hemolysin is ubiquitous among clinical isolates, although some strains lack an active alpha-toxin. Recent studies by Bubeck Wardenburg et al 151 demonstrated that alpha-hemolysin is essential for USA300 and USA400 to cause lethal pneumonia in a murine model. Toxin levels produced by these strains in vitro correlate with severity of lung disease 130, 151, 157.

Alpha-type phenol-soluble modulins (PSMa)

Alpha-type phenol-soluble modulins (PSMα) from a novel group of peptides in S. aureus that have some similarity to phenol-soluble modulins (PSMs) of S. epidermidis 131. High expression of PSMα could contribute to the enhanced virulence of CA-MRSA; PSMs are produced at much higher levels in vitro by prominent CA-MRSA strains, including USA300 and USA400, compared to hospital MRSA strains 131. PSMα peptides recruit, activate, and ultimately lyse human neutrophils, thus promoting S. aureus pathogenesis and contribute significantly to USA300 and USA400 virulence in mouse abscess and sepsis models. The studies by Wang et al131 are the first to identify molecules of CA-MRSA that account at least in part for the enhanced virulence of USA300 and USA400.

Arginine catabolic mobile element (ACME)

ACME is a 30.9 kilobase segment of DNA that appears to be unique to USA300 112. This element is adjacent to SCCmecIV and is mobilized by the recombinases encoded on SCCmec. This DNA element contains two potential virulence factors including a cluster of arc genes that encode an arginine deiminase pathway and Opp-3, which encodes an oligopeptide permease operon158, 159. Deletion of ACME but not SCCmec has been shown to decrease fitness of USA300 in a rabbit bacteremia model 112. Thus, ACME could contribute to the fitness and epidemic spread of USA300.

Although mobile genetic elements such as ACME are likely to play a role in transmission of CA-MRSA, there are differences in virulence potential and human disease manifestation even among similar USA300 isolates. For example, Kennedy et al used comparative whole genome sequencing to determine whether USA300 arose by convergent evolution toward a hypervirulent phenotype or from a recent common ancestor of high virulence potential 113. Eleven USA300, which included those from a wide range of clinical syndromes and from different geographic locations in the US, were examined. The strains differed by only a few single nucleotide polymorphisms (SNPs), ranging from 11 to 408 in number compared to the USA300 reference strain FPR3757 genome. Phylogenetic analysis indicated that eight of the strains, differing on average by 32 SNPs from the reference strain and 50 SNPs from each other, clustered together with the reference strain and had descended from a recent common ancestor. These 9 closely related isolates comprise the epidemic USA300 clone; 8 of the 9 were ACME positive and all contained the same SCCmec type IVa subtype. The two other strains, both of which lacked ACME and carried a different SCCmec subtype, type IVb, were outliers. Unexpectedly, the virulence of the more closely related isolates was variable in animal infection models. Some of these isolates had caused dramatically different disease syndromes in humans (e.g., necrotizing pneumonia versus abscess in isolates that differ by only 23 SNPs), which serves to underscore the importance of host factors in disease presentation and severity.

Treatment in the Era of Community-Associated MRSA

CA-MRSA has had a profound impact on empirical therapy of suspected staphylococcal infection. Most beta-lactam antibiotics, including all orally available agents, no longer can be assumed to be effective for a variety of common staphylococcal infections and skin and soft-tissue infections in particular. In regions where CA-MRSA is prevalent antimicrobial therapy, if it is indicated for treatment of staphylococcal infection, should be active against MRSA strains. Yet, there are few clinical data to support the use of agents other than vancomycin, daptomycin, or linezolid. The oral agents that are recommended for treatment of CA-MRSA skin and soft tissue infections, despite lack of rigorous clinical studies, include clindamycin, long-acting tetracyclines (doxycycline and minocycline), TMP-SMX, and, as adjunctive agents to be used in combination, rifampin and fusidic160162.

Surgical incision and drainage is the treatment of choice for cutaneous abscesses; adjunctive antimicrobial therapy is of little or no benefit in most cases 14, 15, 163, 164. Antibiotic therapy after drainage of CA-MRSA abscesses is not routinely recommended unless the patient has severe or extensive disease, or has rapid progression in the presence of associated cellulitis; has signs and symptoms of systemic illness; is very old or very young or has medical comorbidities or immune suppression (e.g., diabetes mellitus, HIV infections, neoplastic disease); or has an abscess in area that is difficult to drain or an abscess that is associated with septic phlebitis 160.

Vancomycin is still is the preferred drug for treatment of serious MRSA infections. However, prolonged, persistent, or recurrent bacteremia during therapy 165, 166, high rates of microbiological and clinical failures 167, nephrotoxicity 168, and increasing prevalence of non-susceptible strains 169, 170 limit its effectiveness. Randomized clinical trials of alterative agents such as linezolid and daptomycin show that they are comparable, or more precisely, non-inferior, but not superior, to standard therapy 171176. and drug toxicity remain concerns regardless the choice of agent.

One or more compounds under development are likely to become available for treatment of MRSA infections in the near future 177, 178. Telavancin, dalbavancin, and oritavancin are vancomycin derivatives that rapidly kill S. aureus in a concentration-dependent manner in vitro. Whether more rapid killing will translate into improved efficacy over vancomycin for more serious infections, such as endocarditis or bacteremia, remains to be determined. Carbapenems and cephalosporins that bind PBP 2a, the penicillin-binding protein that mediates methicillin resistance, with much higher affinity than the currently available beta-lactams, have been developed 179. Two cephalosporins, ceftobiprole and ceftaroline 180, 181, have been shown to be clinically effective for treatment of MRSA skin and soft infections. An issue with these and the other anti-MRSA beta-lactams under development is that they are very broad spectrum for the targeted treatment of MRSA infection. Further studies are needed to define their eventual role in therapy of MRSA infections.

The vancomycin-derivatives and anti-MRSA beta-lactams, which can only be administered intravenously, do not address the need for orally active agents. Orally bioavailable oxazolidinones active against MRSA are in early stages of development 182.

Several non-traditional approaches to treatment and prevention of MRSA infections have been or are under investigation. These include lysostaphin 183, antimicrobial peptides 184 and other natural products (e.g., tea tree oil) 185, and anti-staphylococcal vaccines 186. There are major challenges in the development of these agents, including prohibitively expensive cost, potential for hypersensitivity with repeated administration of protein products, short half lives with systemic administration, and short-lived or partially protective immunity with vaccines, as was the case with an anticapsular vaccine that proved to be ineffective 187. These are years away from the clinic, if they make it at all. Prudent use of agents that are now available is essential to avoid further erosion of the antimicrobial armamentarium.

Concluding Remarks

S. aureus is an extraordinarily adaptable pathogen with a proven ability to develop resistance. Especially concerning is the steadily erosion in the effectiveness of beta-lactam antibiotics during a relatively brief 60-year time period. Although details vary the basic themes of each successive wave of antibiotic resistance are similar. Resistance, often as a consequence of horizontal gene transfer, is initially encountered in hospitals and healthcare institutions, where the selective pressures for resistance are greatest. Resistant strains are contained within hospitals temporarily, but eventually though a series of modifications and adjustments, invariably find their way into or arise from within the community to emerge as fully fit and virulent pathogens. Understanding of the forces that direct the evolution of virulent and drug-resistant organisms is imperfect, but overuse and misuse of antibiotics is clearly a contributing factor. Discovery and development of new antimicrobials, while necessary, is unlikely to solve the problem of drug resistance for very long. New technologies leading to improved and more rapid diagnostics, a better understanding of pathogenesis of staphylococcal disease, and non-antimicrobial approaches to prevention and treatment of infection will also be needed to forestall the coming of the post-antibiotic era.

Table 4
Hemolysins and anti-platelet factors produced by Staphylococcus aureus.
Table 5
Leucocidins and anti-phagocytic factors produced by Staphylococcus aureus.

Acknowledgments

This article was supported in part by the Intramural Research Program of the NIAID, NIH (FRD) and by NIH, NIAID grant number R01 AI070289 (HFC).

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