The Lengthening Shadow of MRSA
July 1, 2002 5 minutes read
Abstract & Commentary
Synopsis: The emergence of new clones of exfoliative toxin producing S aureus in Japan may be a harbinger of things to come.
Source: Yamaguchi T, et al. Clonal association of Staphylococcus aureus causing bullous impetigo and the emergence of new methicillin-resistant clonal groups in Kansai district in japan. J Infect Dis. 2002;185:1511-1516.
Between June and September 1999 eighty-eight Staphylococcus aureus strains isolated from skin swabs of outpatients with bullous impetigo were collected from 4 hospitals in Kansai district of Japan. A molecular epidemiological analysis was performed to reveal the clonal association of S aureus strains. Pulsed-field gel electrophoresis (PFGE) with cluster analysis, genetic and phenotypic characterizations, and antimicrobial susceptibility profiling of 88 S aureus strains were undertaken.
Three distinct clonal groups were identified: 2 of them carried the exfoliative toxin (ET) A gene (eta), and the other carried the ETB gene (etb). The former groups represent 2 eta-positive clonal groups that have not been described previously. All the strains in the more dominant eta-positive clonal group and some of the strains in the etb-positive clonal group were methicillin-resistant S aureus (MRSA) showing borderline-to-moderate resistance to b-lactams.
These MRSA strains are emerging as clonal groups that have not been detected in previous epidemiological studies of ET-producing S aureus in Japan. Thus, these new MRSA eta- and etb-positive strains thus pose a significant future threat and may manifest as bullous impetigo and/or staphylococcal scalded-skin syndrome (SSSS).
Comment by Joseph F. John, Jr, MD & Rajiv Naval-Srinivas, MD
Bullous impetigo is a localized skin infection without systemic symptoms caused by exfoliatin toxin-producing staphylococci. SSSS, its more severe cousin, first described by Ritter von Rittershain in 1878. SSSS encompasses a spectrum of clinical features with bullous impetigo being the most common clinical finding. The majority of cases of SSSS in the United States are due to Phage group II with 75% of them belonging to phage type 71. The blister formation is due to exfoliative toxins—ETA, ETB produced by S aureus. The gene producing the toxin ETA, eta, is encoded on the genome of a temperate phage, while the gene for ETB, etb, is encoded on large plasmids. ETA is a serine protease, which cleaves desmoglein 1, a protein connecting epidermal cells.
Not all strains possess genes for exfoliative toxins as these genes are acquired through horizontal transfer during evolution of S aureus. Management of SSSS currently relies on eradication of the exfoliatin-bearing strain from the focus of infection with penicillinase-resistant b-lactam antibiotic, assuming there is no MRSA in the population.
To understand the phenomenon of spreading methicillin resistance, we need to review the molecular biology of methicillin resistance. Methicillin resistance is defined as an oxacillin MIC of > 4 mg/L or a methicillin MIC of > 16 mg/L. Staphylococci have at least 2 essential penicillin binding proteins (PBPs), which have enzymatic activity and are responsible for cross-linking of the peptidoglycan cell wall. MRSA are characterized by the ability to produce an altered penicillin binding protein but, like other S aureus, constitutively produce penicillinase, coagulase, DNase, and enhanced amounts of catalase.
Staphylococci can become resistant to b-lactam agents, cephalosporins, and carbapenems by acquiring a chromosomally mediated mecA gene, which encodes an alternative supplementary target called PBP 2a or PBP 2´ that has low affinity for b-lactams.
The abnormal PBP 2a continues to function when PBP 1, 2, and 3 are inactivated by b-lactam antibiotics and generates a stable peptidoglycan. mecA is located on a large 30-40-kilobase DNA element in the chromosome, flanked by insertion sequence-like elements (IS431 and IS257) that trap additional unrelated drug resistance genetic determinants leading to multiple drug resistance.
Transfer of mec DNA to a susceptible S aureus has occurred in vitro and recently in vivo. The mechanism of transfer of mec DNA from a donor to a recipient is not completely understood. Until recently, horizontal transfer of mec was thought to be relatively rare but a recent population-based study of MRSA from Finland suggests that MRSA may emerge as a community-acquired pathogen as a consequence of horizontal acquisition of mecA gene by a previously susceptible S aureus strain.1
Yamaguchi et al’s study of clonal association of S aureus isolated from bullous impetigo raises the spectre of global emergence of new eta- and etb-positive MRSA. A majority of the 88 isolates were positive for an ET gene and were MRSA while no strains possessed both eta and etb. PFGE analysis separated the 88 isolates into 4 clusters with eta-positive strains found in 3 clusters. The dominant clonal group was sub cluster IIIb composed of eta positive, mecA positive (27/28), coagulase type III that showed borderline-to-moderate resistance to b-lactam antibiotics with a narrow MIC range for each drug. The antibiotic susceptibility pattern of etb-positive MRSA was similar to that of eta-positive MRSA strains. The eta- and etb-positive strains were resistant to gentamicin but sensitive to fusidic acid and minocycline with wide variation in MICs to erythromycin and clarithromycin.
The emergence of the eta-positive MRSA clonal group was postulated by Yamaguchi et al to be due to phage conversion of mecA positive, coagulase type III strain and etb MRSA due to acquisition of mecA gene by etb-positive strains. The emergence of eta- and etb-positive MRSA groups with multiple drug resistance, particularly if proven to be a geographically more dispersed event, could cause serious clinical problems in infants and newborns with SSSS and may manifest differently in adults.
It has now been shown that infections caused by MRSA strains may be more difficult to manage and more expensive to treat.2 The resultant increased vancomycin use could add further to the problem of antibiotic-resistant gram-positive bacteria. A similar study of SSSS in United States would shed more light on the prevalence of eta- and etb-positive MRSA in this hemisphere.
References
1. Salmenlinna, et al. Emerg Infect Dis. 2002; 8(6): 602-607.
2. Abramson M, et al. Infect Control Hosp Epidemiol. 1999;20(6):408-411.
Dr. John, Chief, Medical Subspecialty Services, Ralph H. Johnson Veterans Administration Medical Center; Professor of Medicine, Medical University of South Carolina, Charleston, SC, is Co-Editor of Infectious Disease Alert.
Dr. Rajiv Naval-Srinivas has recently completed his fellowship at the Medical University of South Carolina, Charleston, SC.
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