Waves of resistance: Staphylococcus aureus in the antibiotic era

Abstract

Staphylococcus aureus is notorious for its ability to become resistant to antibiotics. Infections that are caused by antibiotic-resistant strains often occur in epidemic waves that are initiated by one or a few successful clones. Methicillin-resistant S. aureus (MRSA) features prominently in these epidemics. Historically associated with hospitals and other health care settings, MRSA has now emerged as a widespread cause of community infections. Community or community-associated MRSA (CA-MRSA) can spread rapidly among healthy individuals. Outbreaks of CA-MRSA infections have been reported worldwide, and CA-MRSA strains are now epidemic in the United States. Here, we review the molecular epidemiology of the epidemic waves of penicillin- and methicillin-resistant strains of S. aureus that have occurred since 1940, with a focus on the clinical and molecular epidemiology of CA-MRSA.

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 lineage named phage type 80/81 (Φ80/81), were penicillin resistant and produced PVL (Panton-Valentine leucocidin). Wave 2 began almost immediately upon the introduction of methicillin into clinical practice with isolation of the first MRSA (Archaic clone), which contained type I SCCmec (MRSA-I) and extended into the 1970s in the form of the Iberian clone. Wave 3 began in the mid-to-late 1970s with emergence of new MRSA strains, which contained novel SCCmec, types, II and III (MRSA-II and III), marking the on-going worldwide pandemic of MRSA in hospitals and healthcare facilities. The upsurge in vancomycin usage for treatment of MRSA infections eventually led to emergence of vancomycin intermediate S. aureus (VISA) strains. Wave 4, which began in the mid-to-late 1990s, marks the emergence of MRSA strains in the community. Community MRSA strains where susceptible to most antibiotics other than beeta-lacams, were unrelated to hospital strains, contained a novel, smaller, more mobile type IV SCCmec (MRSA-IV), and a variety of virulence factors, including PVL. Vancomycin-resistant S. aureus (VRSA) strains, of which 10 or so have been isolated exclusively in healthcare settings, were first identified 2002.

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

Approximately 450 nucleotides of seven chromosomal “housekeeping” genes (arcC, carbamate kinase; aroE, shikimate dehydrogenase; glpF, glycerol kinase; gmk, guanylate kinase; pta, phosphate acetyltransferase; tpiA, triose phosphate isomerase yqiL, acetyl-CoA acetyltransferase), selected for their presumed absence of selective pressure and therefore relatively stable in nucleotide sequence, are sequenced. Each unique sequence within a gene locus is assigned a unique number. The numbers are concatenated in left-to-right in the order shown to provide a seven interger series of numbers, which is assigned a number designating this sequence type (ST). Strains which are identical at all seven loci are classified as the same ST. Strains differing at one or two loci, are related, but as they are not identical, are assigned different STs. Closely related STs are grouped into a clonal complex. In the example shown, ST1, ST5, and ST8 differ at most loci and thus are not closely related. ST250 and ST247 differ from each other at one locus and from ST8 at one or two loci, respectively. Thus, ST8, ST250, and ST247 are closely related and from a clonal complex, CC8, so designated because analysis of sequence identities and differences in a large collection of strains indicates ST8 is the founder of this clonal complex, the ancestor of both ST247 and ST250, and that ST247 is a descendant of ST250.

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

a) MSSA (blue) versus MRSA (red) clonal complexes. b) Penicillin-susceptible S. aureus (PSSA, blue) versus penicillin-resistant S. aureus (PRSA, red) clonal complexes. Data in (a) were collected from 6 continents (1961–2004) and those in (b) are from a single study of 99 isolates collected in Copenhagen from 1957–73. See text for details.

Figure 4. Comparison of methicillin-resistance cassettes typical of hospital- or community MRSA

Type II mec (SCCmecII) is most abundant in hospitals whereas Type IV mec (SCCmecIV) is present in the most abundant CA-MRSA strains. Transposon Tn554 encodes resistance to macrolide-lincosomide-streptogramin B antibiotics and spectinomycin. SCCmecII encodes resistance to multiple antibiotics whereas SCCmecIV encodes resistance to methicillin alone. IS431, insertion sequence 431. See text for additional details.