Increasing Antibiotic Resistance among Methicillin-Resistant Staphylococcus aureus Strains

Clinical Infectious Diseases, Jun 2008

Vancomycin use has increased dramatically worldwide since the mid-1980s, largely as a result of empirical and directed therapy against burgeoning methicillin-resistant Staphylococcus aureus (MRSA) infections. With limited choices, clinicians have traditionally relied on vancomycin alone in the management of serious MRSA infections and have enjoyed a significant period free of vancomycin resistance in S. aureus. Even now, 5 decades after its introduction, vancomycin resistance among S. aureus strains, as currently defined microbiologically, remains rare. Yet it is becoming clear that vancomycin is losing potency against S. aureus, including MRSA. Serious infections due to MRSA defined as susceptible in the laboratory are not responding well to vancomycin. This is demonstrated by increased mortality seen in patients with MRSA infection and markedly attenuated vancomycin efficacy caused by vancomycin heteroresistance in S. aureus. Therefore, it appears that our definition of vancomycin susceptibility requires further scrutiny as applied to serious MRSA infections, such as bacteremia and pneumonia.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://cid.oxfordjournals.org/content/46/Supplement_5/S360.full.pdf

Increasing Antibiotic Resistance among Methicillin-Resistant Staphylococcus aureus Strains

George Sakoulas ) 1 Robert C. Moellering Jr. 0 0 Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School , Boston, Massachussetts 1 Division of Infectious Diseases, Department of Medicine, Westchester Medical Center and New York Medical College , Valhalla , New York Vancomycin use has increased dramatically worldwide since the mid-1980s, largely as a result of empirical and directed therapy against burgeoning methicillin-resistant Staphylococcus aureus (MRSA) infections. With limited choices, clinicians have traditionally relied on vancomycin alone in the management of serious MRSA infections and have enjoyed a significant period free of vancomycin resistance in S. aureus. Even now, 5 decades after its introduction, vancomycin resistance among S. aureus strains, as currently defined microbiologically, remains rare. Yet it is becoming clear that vancomycin is losing potency against S. aureus, including MRSA. Serious infections due to MRSA defined as susceptible in the laboratory are not responding well to vancomycin. This is demonstrated by increased mortality seen in patients with MRSA infection and markedly attenuated vancomycin efficacy caused by vancomycin heteroresistance in S. aureus. Therefore, it appears that our definition of vancomycin susceptibility requires further scrutiny as applied to serious MRSA infections, such as bacteremia and pneumonia. - Historically, the development of antimicrobial resistance in Staphylococcus aureus has been rapid. Resistance to penicillin in S. aureus was noted only a year after its introduction, and, in the early 1950s, threequarters of S. aureus strains in large hospitals in many countries had become penicillin resistant [1]. Currently, 90%95% of clinical S. aureus strains throughout the world are resistant to penicillin. In 1959, the first antistaphylococcal penicillinmethicillinwas introduced. Within 2 years, the first methicillin-resistant S. aureus (MRSA) strain emerged [2]. Currently, MRSA accounts for 60% of clinical S. aureus strains isolated from intensive care units in the United States [3, 4]. With the rapid emergence of community-associated MRSA, an organism that now causes a majority of the soft-tissue infections in patients presenting to emergency rooms in many parts of the United States, it appears that the antistaphylococcal b-lactams may soon meet the same fate as penicillin with regard to their ability to treat community-associated skin infections [57]. This pattern has continued among the newer agents. Linezolid was introduced clinically in the year 2000, only to result in the first linezolid-resistant MRSA strain being described in the literature a year later [8]. Daptomycin was introduced in 2003, and MRSA resistance to it was first reported within 2 years [9]. What is interesting about vancomycin is that, unlike any of the other antistaphylococcal antimicrobials, resistance to this agent among S. aureus strains took almost 40 years to be recognized, with the first glycopeptide-intermediate S. aureus (GISA) isolate from a pediatric patient in Japan described in 1996 [10]. Highlevel resistance mediated by the vanA gene complex acquired from vancomycin-resistant enterococci (VRE) emerged in Detroit, Michigan, in 2002 and so far has been limited to the United States [11, 12]. The cases for which the clinical details are reported are shown in table 1. It is noteworthy that the vancomycin-resistant phenotype has variable expression, with higher levels of resistance seen in the Michigan strain compared with 8 8 4 in L 2 2 6 c m 1 1 y / 1 1 2 the subsequently found strain from Pennsylvania, perhaps because of a more unstable phenotype or differences in metabolic price (figure 1) [17]. Unlike b-lactam antibiotics, which bind to and interrupt the activity of penicillin-binding proteins (enzymes involved in cellwall synthesis), vancomycin binds with high affinity to the DAla-D-Ala C-terminus of late peptidoglycan precursors and prevents reactions of cell-wall synthesis using these precursors in transglycosylase, transpeptidase, and D,D-carboxypeptidases (figure 2) [17]. Resistance in VRE and vancomycin-resistant S. aureus (VRSA) is due to the presence of operons that encode enzymes that produce the low-affinity precursors D-Ala-D-Lactate or D-Ala-D-Ser and also enzymes that eliminate the competitive high-affinity peptidoglycan precursors normally produced. In GISA strains, none of the operons mediating this mechanism of resistance has been found. Instead, GISA has altered its cellular physiology as a result of cumulative effects of mutations and/or modulation of regulatory systems. This altered physiology appears to change cell-wall metabolism in such a way as to result in increased numbers of D-Ala-D-Ala residues, which serve as dead-end binding sites for vancomycin. This altered cell wall results in a reduced diffusion coefficient of vancomycin, sequestration of vancomycin within the cell wall by these false target (...truncated)


This is a preview of a remote PDF: https://cid.oxfordjournals.org/content/46/Supplement_5/S360.full.pdf

George Sakoulas, Robert C. Moellering Jr.. Increasing Antibiotic Resistance among Methicillin-Resistant Staphylococcus aureus Strains, Clinical Infectious Diseases, 2008, pp. S360-S367, 46/Supplement 5, DOI: 10.1086/533592