This surprising finding overturned the conventional wisdom that the widespread use of methicillin, and the selective pressure that it created, was the driving force responsible for the evolution of methicillin resistance in S.
In the archaic MRSA population we identified resistance genes and mutations to most of the major classes of antibiotics introduced during the s and s, the so-called golden era of antibiotics. Amongst these was a mutation in a ribosomal protein, RpsL, responsible for resistance to streptomycin, the first aminoglycoside antibiotic. Crucially this mutation was found in all the archaic MRSA and was predicted to have arisen around the same time as the methicillin resistance.
From our historical analysis it would appear that it was penicillin prescribing in the s had the unforeseen effect of driving the emergence of MRSA. Notably, streptomycin was first trialled as an anti-tuberculosis therapy in the UK in the mids, and not originally used to treat S. We were however about to become over reliant on antibiotics, and a culture developed where the strict discipline and skills needed to do the sick no harm seemed to relax.
With bacteria developing more and more resistance, and the most common surgical bacteria Staphylococcus aureus evolving, the first culture of Staph aureus found to be resistant to Meticillin was identified under a microscope at Colindale Laboratories in London by the late Professor Patricia Jevons, on October 2nd MRSA has now evolved and spread, is endemic in our hospitals, and now in the community.
The countries in Northern Europe adopted a strict Search and Destroy policy that was developed here in Britain. The Royal Free had an outbreak in and controlled this by using this policy. However, it was believed to be too expensive and consequently more outbreaks occurred until it became endemic. Strict screening and decolonising is carried out before patients are admitted to hospital, if patients have to be admitted as emergencies they are put into isolation. Judicious prescribing of antibiotics is also a key in reducing resistance, using the correct antibiotic at exactly the right dosage and time.
Over use of broad spectrum antibiotics is not only responsible for resistance but for the problems we have with another killer super bug Clostridium difficile. Multi-drug-resistant bacteria are constantly evolving and we need to act to improve clinical practice and use antimicrobials safely, simple infections will be untreatable and surgery as we know it today will not be possible if we do not act with a global response.
We have introduced strict policies here in the UK in an effort to bring this under control. Patients who are going into hospital for surgery are being screened to see if they carry MRSA. If they are found to be carrying it on their skin then they are decolonised with antibacterial wash and an antibiotic cream for the nose.
In the description of these isolates it was noted that methicillin had been used only once previously at this hospital, and that none of the individuals from whom MRSA was isolated had been exposed to the drug. Within 2 years MRSA was being detected elsewhere in Europe, with invasive infections being identified in Denmark [ 4 ]. The genetic basis of methicillin resistance in S. The product of mecA is the peptidoglycan synthesis enzyme penicillin binding protein PBP 2a involved in cross-linking of peptidoglycan in the bacterial cell wall [ 6 , 7 ].
The single locus variant and close relative of STMRSA-I, STMRSA-I was first detected in Denmark in [ 8 ] and has been more successful, spreading globally and persisting as a source of outbreaks in Europe into the late s [ 10 , 11 ], but this too has been superseded by more successful contemporary clones [ 10 ]. Epidemiological evidence has always suggested that MRSA arose as a consequence of the introduction of methicillin into clinical practice.
Here we have used whole genome sequencing of a collection of of the earliest MRSA isolates recovered in Europe between and to reconstruct the evolutionary history of methicillin resistance. Using Bayesian phylogenetic reconstruction we have identified the likely time point at which this early lineage arose and also predicted the time around which SCC mec was acquired. These original isolates have been preserved as freeze-dried cultures, and have not been repeatedly passaged over the years.
One hundred and eighty eight isolates that represented the earliest MRSA were recovered from the ampoules and their genomes sequenced Additional file 1 : Table S1. The S. Following exclusion of mobile genetic elements MGEs and predicted recombination events in the collection, a total of SNPs were identified and used to construct a phylogeny Fig. The population framework revealed a diverse population structure containing several distinct clades.
The mapping of the ST information on to the phylogeny reveals that the ST population is basal to the ST, suggesting that ST emerged from ST, which is consistent with the epidemiological evidence, and supports the hypothesis that this pandemic multidrug-resistant MRSA clone emerged out of the ancestral MRSA genotype [ 8 , 9 ].
Population structure of historic MRSA isolates. The tree was built using a maximum likelihood method using SNPs from the core genome of isolates. Included in the phylogeny is the COL reference isolate to which the sequence reads were mapped. Tree branches are coloured according to their ancestral sequence type population; blue branches indicate the ST population and green branches the ST population.
Isolates from Denmark are highlighted in blue shading and isolates described in the Jevons study are outlined in the dashed box , and a zoomed in view of the phylogeny is displayed in b. The coloured branch labels indicate the three individuals who supplied the original isolates in the Jevons study. Highlighted in the expanded view Fig. The isolation source and resistance profiles of these isolates are shown in Additional file 2 : Table S2.
These isolates are genetically very closely related, differing by seven SNPs only. Present within this cluster are additional isolates from the Public Health England collection originating between and Full epidemiological data are not available for these, but two of these isolates were identified in the same region as the hospital where the original Jevons study isolates originated.
The genetic distance between isolates and their phylogenetic relationships suggests there was transmission within the hospital between patients A and C and nurse B, and that they were also transmitted beyond the hospital as part of a local outbreak.
Although all of the Jevons isolates are confined to a single clade, other isolates from the early s are distributed throughout the entire phylogeny Fig. This suggests that the earliest MRSA circulating in the UK were not from a single recently emerged clone, but were representatives of an established population.
These derive from onwards, and include the youngest isolates within the collection from the late s. The Danish isolates are found in three clusters distributed throughout the phylogeny Fig. Distribution of antibiotic resistance determinants in the archetypal MRSA clone.
The identity of genetic determinants are listed at the top and divided into acquired genes red text ; left hand side , and core mutations green text ; right hand side. And for the core gene mutations are: streptomycin substitution of arginine for a lysine at residue 56 K56R of the ribosomal protein rpsL ; fusidic acid, substitution of a proline for a leucine at residue PL of the transcription elongation factor fusA ; trimethoprim, substitution of an tyrosine for a phenylalanine at residue 99 F99Y of the dihydrofolate reductase dfrA.
The type I element carries mecA as its only resistance gene in combination with a truncated gene encoding the MecRI regulatory proteins together known as a class B mec gene complex with type 1 chromosomal recombinases ccrA1 and ccrB1. The original description of SCC mec type I identified the presence of a frameshift mutation in ccrB1 which disrupts the translation of this site-specific recombinase [ 13 ]; the mutation occurs after codon and is caused by a single base deletion in a poly-A hexamer resulting in a pentamer sequence.
The remaining 16 isolates lacking complete SCC mec elements were distributed throughout the phylogeny, suggesting that these represent methicillin-sensitive S. In addition to methicillin resistance, the first MRSA described were also resistant to penicillin, streptomycin and tetracycline [ 3 ]. Analysis of the genomes of these isolates identified blaZ and tetK genes conferring resistance to penicillin and tetracycline, respectively, but failed to identify the str, aadE or aad9 genes associated with streptomycin resistance in S.
In the absence of an acquired resistance gene, the core genome was examined for mutations potentially responsible for resistance to streptomycin. In Mycobacterium tuberculosis , mutations in the ribosomal protein RpsL were shown to confer streptomycin resistance, including the substitution of an arginine for a lysine residue at residue 43 [ 14 ].
Alignment of the M. Comparison with RpsL sequences in the public sequence databases showed that in S. This demonstrates that the non-synonymous substitution resulting in an arginine for a lysine residue at residue 56 K56R occurred most likely very early during emergence of the archetypal MRSA population. In silico analysis of the resistomes of the isolates revealed genetic resistance determinants to numerous other antibiotics, including penicillin blaZ , erythromycin ermA and linA , kanamycin aadD , gentamicin and kanamycin aacA - aphD , spectinomycin and streptomycin aad9 , and chloramphenicol catA1 , catA2 and catA3 , fusidic acid fusA PL and trimethoprim dfrA F99Y , as well as genes associated with decreased susceptibility to disinfectants qacA and qacC.
The frequency and widespread dispersal of these determinants reveal the strong selective pressure exerted by antibiotics on the archetypal MRSA clone over an extensive period. Examining their distribution in the context of the phylogeny shows that some of these traits have been co-acquired Fig.
To determine if the methicillin resistance emerged once or multiple times in the archetypal MRSA population, we examined the variation within the SCC mec type I elements. In total, variant sites were identified in elements present in the collection. Analysis of the distribution of the variation within the elements suggested that some could be attributed to homologous recombination. Excluding these predicted recombination regions, 39 core variants sites across The maximum SNP distance distinguishing any two elements was eight SNPs, and phylogenetic analysis revealed that the elements present in the historic MRSA clone were closely related Additional file 3 : Figure S1 and shared a common evolutionary origin.
Our analysis of the evolutionary events surrounding the emergence of methicillin resistance in the archetypal MRSA lineage focused on a subset of isolates that had precise dates and places of origin which could be linked to original submission records Additional file 2 : Table S1.
This enabled us to generate a robust Bayesian phylogeny and temporal calibration. All of the canonical SNPs associated with the SCC mec genotypes could be singularly mapped onto nodes of the core phylogeny, suggesting that the variation observed in the SCC mec elements had occurred during expansion of the ST and ST populations.
On the basis of this, we propose that a type I SCC mec element was acquired once in a single primordial development of methicillin resistance Fig. In total, ten genotypes were observed, and the genetic events that distinguish each genotype from the founder genotype are indicated. The tree is centred on the majority genotype inferred as the founder population, and colour-coded according to their genotype.
Black asterisks indicate isolates that lack the type I SCC me c element. The sizes of the circles illustrate the relative sizes of the genotype populations. The key below the tree describes the canonical SNPs differentiating SCC mec type I genotypes and the number of variants with that genotype. Tips of the tree are constrained by isolation dates; the time scale is shown below the tree.
The branches of the tree are coloured according to the genotype of the SCC mec type I element present in that strain illustrated in a. Internal branches are coloured according to parsimonious reconstruction of the predicted genotype.
Where terminal branches are black and highlighted by a black asterisk , this indicates the absence of an SCC mec element, which is predicted to reflect loss of the element. An arrow indicates the point in the phylogenetic reconstruction where an ancestral type I SCC mec element was acquired.
From the analysis the estimated mutation rate of population is 1. This substitution rate falls within the reported ranges of multiple successful S. Our efforts in infection control have yielded only partial success in dealing with staphylococci and even here the organism seems to show a remarkable ability to thwart our efforts. The recent emergence of CA-MRSA means that staphylococci now have a way to get in through the back door as they circumvent infection control interventions largely directed to hospital-acquired, not community-acquired infections.
To date, immunization has been the only way to eradicate infectious diseases such as smallpox and possibly polio, but this remains an elusive goal for S. The failure of a potentially effective vaccine in a recent Phase III trial after an apparently successful initial trial clearly illustrates this fact. The past 50 years could have been called the half century of MRSA, as these organisms, with a genome of fewer than open reading frames, have spread throughout the world and defied our most vigorous efforts to contain them.
I am a scientist, not a gambler, but if I were a betting man, short of the development of an effective antistaphylococcal vaccine, I would bet on the staphylococcus to successfully complete the second half of the century of MRSA. This is a situation in which I would be happy to be wrong! Google Scholar. Google Preview. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide.
Sign In or Create an Account. Sign In. Advanced Search. Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Origins of MRSA. Epidemiology of MRSA. Non-human reservoirs of MRSA. MRSA—evolving antimicrobial resistance. New therapeutic approaches. Transparency declarations. MRSA: the first half century.
Moellering, Jr Robert C. Oxford Academic. Cite Cite Robert C. Select Format Select format. Permissions Icon Permissions. Abstract Fifty years ago methicillin-resistant Staphylococcus aureus MRSA first revealed themselves to the medical community, having been described in a landmark article published in the British Medical Journal.
Google Scholar Crossref. Search ADS. Origin and molecular evolution of the determinant of methicillin resistance in staphylococci. Reconstruction of the phenotypes of methicillin-resistant Staphylococcus aureus by replacement of the staphylococcal cassette chromosome mec with a plasmid-borne copy of Staphylococcus sciuri pbpD gene. Ubiquitous presence of a mecA homologue in natural isolates of Staphylococcus sciuri.
Methicillin-resistant Staphylococcus aureus : the European landscape. Google Scholar PubMed. Community-associated methicillin-resistant Staphylococcus aureus : epidemiology and clinical consequences of an emerging epidemic. A clinician's guide to community MRSA—its evolving antimicrobial resistance and implications for therapy. Community-associated methicillin-resistant Staphylococcus aureus. Disproportionate increase from — in S.
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Methicillin-resistant coagulase-negative staphylococci in the community: high homology of SCCmec IVa between Staphylococcus epidermidis and major clones of methicillin-resistant Staphylococcus aureus. Panton-Valentine leukocidin-positive and toxic shock syndrome toxin 1-positive methicillin-resistant Staphylococcus aureus : a French multicenter prospective study in Molecular epidemiology of Panton-Valentine leukocidin-positive Staphylococcus aureus in Spain: emergence of the USA clone in an autochthonous population.
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