Genesis of Methicillin-Resistant Staphylococcus aureus (MRSA), How Treatment of MRSA Infections Has Selected for Vancomycin-Resistant Enterococcus faecium, and the Importance of Antibiotic Management and Infection Control

1204 Genesis of Methicillin-Resistant Staphylococcus aureus (MRSA), How Treatment of MRSA Infections Has Selected for Vancomycin-Resistant Enterococcus faecium, and the Importance of Antibiotic Management and Infection Control Jerome J. Schentag, Judith M. Hyatt, James R. Carr, Joseph A. Paladino, Mary C. Birmingham, Gabrial S. Zimmer, and Thomas J. Cumbo From the School of Pharmacy, State University of New York at Buffalo, and The Clinical Pharmacokinetics Laboratory, Millard Fillmore Health System, Buffalo, New York Scope of Staphylococcal Resistance The dawn of the antimicrobial era in the late 1930s dramatically altered the focus of clinical medicine, at least for the next several decades [1, 2]. With the introduction of the sulfonamides and penicillin, practicing clinicians could remedy many infectious diseases. The early success of anti-infective therapy was evidence that the battle against infectious diseases had been won, and more time and energy could be devoted to chronic diseases. The optimism ultimately proved fallacious because bacteria such as Staphylococcus aureus acquired resistance to penicillin soon after its introduction in the early 1940s. The problem of methicillin-resistant S. aureus (MRSA) broadened to include the concept of multiresistant S. aureus, which is now synonymous with MRSA [2, 3]. MRSA was first observed in the United States in the mid 1980s [4, 5], as exemplified in the epidemiologic data collected by the National Nosocomial Infection Surveillance System. Among S. aureus isolates, resistance increased from 2.4% in 1975 to 29% in 1991 [5]. Institutional surveillance studies conducted over the past 15 – 20 years have chronicled the rise of MRSA [6, 7]. The organism is also endemic in nursing homes, in outpatients who are iv drug abusers, or in those This article is part of a series of papers presented at a satellite symposium of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy. The symposium was entitled ‘‘Emerging Resistance with Gram-Positive Aerobic Infections: Where Do We Go from Here?’’ and was held on 14 September 1996 in New Orleans. Reprints or correspondence: Dr. Jerome J. Schentag, The Clinical Pharmacokinetics Laboratory, Millard Fillmore Health System, 3 Gates Circle, Buffalo, New York 14209. Clinical Infectious Diseases 1998;26:1204–14 q 1998 by The University of Chicago. All rights reserved. 1058–4838/98/2605–0031$03.00 / 9c4c$$my22 04-10-98 02:16:25 undergoing hemodialysis. In hospitals, the first reports of rapidly increasing resistance in S. aureus appeared in large hospitals (ú500 beds) in the mid 1980s [5]. Later, the organism appeared in smaller hospitals and nonteaching hospitals. MRSA — An Import or Homegrown? Most investigators who study the incidence and pathogenesis of MRSA practice in hospitals. Perhaps as a direct consequence, the focus of publications on MRSA epidemiology and transmission has also been on hospitals [5, 7, 8]. Surveillance studies track MRSA where it can be easily found, and in this case the hospital appears to be a highly appropriate target. MRSA is not endemic in healthy individuals living in the community, given that they are not treated with antibiotics [9 – 12]. At Millard Fillmore Hospital, a 600-bed teaching hospital in Buffalo, where the frequency of endemic MRSA is ú40%, our group noted that in the adjoining outpatient community, nasal carriage consists predominantly of methicillin-susceptible S. aureus (MSSA) (authors’ unpublished observations). This finding largely refutes the notion that the MRSA strains infecting Millard Fillmore Hospital’s newly admitted surgical patients are being replenished from an existing community reservoir of MRSA. In the Netherlands, where MRSA is rare and cross-transmission is therefore readily detected by simple procedures such as phage typing, there was 92% homology in MSSA postsurgical wound infections with the patients’ own nasal isolates, and 86% of MSSA infections were due to a unique strain [13]. Postsurgical infections were therefore caused by the patients’ own flora. Further study of the emergence of MRSA should focus on the selective factors that have acted on the MSSA in the pa- cida UC: CID We extensively studied the epidemiology and time course of endemic methicillin-resistant Staphylococcus aureus (MRSA) in the Millard Fillmore Hospital, a 600-bed teaching hospital in Buffalo. The changeover from methicillin-susceptible S. aureus to MRSA begins on the first hospital day, when patients are given cefazolin as presurgical prophylaxis. Under selective antibiotic pressure, colonizing flora change within 24 to 48 hours. For patients remaining hospitalized, subsequent courses of third-generation cephalosporins further select and amplify the colonizing MRSA population. Therefore, managing antibiotic selective pressure might be essential. Other strategies include attention to dosing, so that serum concentrations of drug exceed the minimum inhibitory concentration, and antibiotic cycling. Although there are some promising new antibiotics on the horizon, it is necessary to deal with many resistance patterns by using the combined strategies of infection control and antibiotic management. CID 1998;26 (May) Origins and Management of MRSA and VRE The Link Between Outpatient MSSA Colonization, Inpatient Antibiotics, and MRSA All of the major elements of the link between susceptibility on the outside, antibiotic-mediated shifts in colonization in hospitals, and subsequent infection were described clearly in McGowan’s 1983 review [8]. Although these elements clearly apply to MRSA, it is unfortunate that little was added to the basic knowledge about endemic MRSA, in contrast to epidemic MRSA, during the subsequent 14 years. For a time, studies of endemic resistance in many organisms were subordinated to excitement over the deluge of new cephalosporin and quinolone antibiotics in the mid 1980s. Victory was declared briefly, and drug development ceased. Now, of course, the resistance problem is back with a vengeance. In the case of MRSA, there seems little doubt that the antibiotic selection process acting on MSSA begins after patients reach the hospital environment [8, 15, 21]. Patients arrive with S. aureus as MSSA. The first action that transforms these MSSA to MRSA in hospitalized patients is antibiotic treatment. The action of antibiotics on the endogenous MSSA selects MRSA from the initially heterogeneous culture [22 – 24]. This selection process can act on a phenotypic MSSA, i.e., one that reads as MSSA on an 18-hour incubation screen for identification and susceptibility [23, 25]. In a small subgroup of patients with complications or risk factors, subsequent infections with MRSA are likely to occur following colonization with MRSA [17, 26]. / 9c4c$$my22 04-10-98 02:16:25 Figure 1. Percentage of methicillin-resistant Staphylococcus aureus at Millard Fillmore Hospital (Buffalo), a 600-bed hospital (j), and at (...truncated)