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1 The Ohio State University Medical Center, Department of Pharmacy, Columbus, OH 43210, USA
2 Wyeth Pharmaceuticals, Collegeville, PA, USA
Correspondence
Debra A. Goff
debbie.goff{at}osumc.edu
Received 10 May 2006
Accepted 13 February 2007
Abbreviations: cIAI; complicated intra-abdominal infection; MRSA, meticillin-resistant Staphylococcus aureus; CA-MRSA, community-associated MRSA; HA-MRSA, healthcare-acquired MRSA; MSSA, meticillin-susceptible S. aureus; SSSI, skin and skin-structure infection.
All MIC testing was done locally following a standard protocol.
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INTRODUCTION |
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 TOP INTRODUCTION METHODSRESULTSDISCUSSIONREFERENCES |
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Isolates of community-associated MRSA (CA-MRSA) have also been identified in recent years, which often possess fundamentally different genetic characteristics and risk factors from HA-MRSA. One important example is the Panton–Valentine leukocidin toxin gene, which has been associated with necrotizing pneumonia (Weber, 2005; Moran et al., 2005).
Future monitoring of the epidemiology of HA-MRSA and CA-MRSA will depend in part on microbial surveillance studies. These provide up-to-date information on the emergence, dissemination, frequency and consequences of microbial resistance and are essential tools in aiding the decision-making process for physicians (Koeth & Miller, 2005). T.E.S.T. (the Tigecycline Evaluation and Surveillance Trial) is a global surveillance study initiated in 2004 to examine the in vitro activity of tigecycline and comparator agents against recent isolates of key Gram-negative and Gram-positive pathogens [including meticillin-susceptible S. aureus (MSSA) and MRSA] from hospitals and the community.
Tigecycline is the first of a new class of antimicrobial agents, the glycylcyclines, which are structurally derived from the tetracycline nucleus. Tigecycline possesses activity against Gram-positive and -negative pathogens, binding to the 30S ribosomal subunit and inhibiting protein synthesis (Bouchillon et al., 2005). Tigecycline does not demonstrate co-resistance with known mechanisms of resistance, including tetracycline resistance (Bergeron et al., 1996). Tigecycline has in vitro activity against drug-resistant phenotypes including vancomycin-resistant enterococci (VRE), penicillin-resistant Streptococcus pneumoniae (PRSP), MSSA and MRSA and extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae (Fritsche et al., 2005; Hoban et al., 2005). It is bacteriostatic against most pathogens, although bactericidal activity has been reported against Streptococcus pneumoniae and Haemophilus influenzae (Zinner, 2005).
This study reports on the relative prevalence of MRSA and MSSA and the occurrence of multidrug resistance (resistance to three or more antimicrobial classes) among S. aureus isolates collected in the continental United States as part of T.E.S.T. This report will also compare the activity of tigecycline and several comparator antimicrobials against these strains of MSSA and MRSA.
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METHODS |
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TOPINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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) across the continental United States between January 2004 and September 2005. Each participating centre was requested to provide at least 25 S. aureus isolates. All isolates were collected from patients aged 1 to 98 years with documented blood, respiratory tract, urine, skin, wound or body fluid infections or infections from other defined sources. Isolates from urine accounted for no more than 25 % of isolates from any one centre. One isolate only was accepted per patient. All isolates were identified on-site by the participating laboratory. Laboratories International for Microbiology Studies, a division of International Health Management Associates, Inc. (Schaumburg, IL, USA), was responsible for organism collection, transport and identification confirmation as well as database development and management.
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. The MIC interpretive criterion for tigecycline (susceptible breakpoint 
0.5 µg ml–1) was derived from the recent US Food and Drug Administration product insert for tigecycline. Determination of intermediate or resistant breakpoints is prevented by the current absence of clinical S. aureus isolates resistant to tigecycline (Wyeth Pharmaceuticals, 2005). S. aureus strains ATCC 25923 and ATCC 29213 were used for quality control of standardized laboratory procedures.
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RESULTS |
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TOPINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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. MRSA occurred infrequently in the participating hospital(s) in some states (i.e. 20 % in NH, VT and VA) but was prevalent in others (i.e. all 25 S. aureus isolates collected in KY were MRSA). Although MRSA accounted for 
50 % of S. aureus isolates in 21 states (IL, MI, OH, KS, ND, NE, DC, FL, GA, MD, NC, AL, KY, TN, AR, LA, OK, TX, AZ, NM and WA), the proportion of MRSA and MSSA isolates is approximately equal in many states, with MRSA representing 40–60 % of isolates in 25 states.
Susceptibility data for all S. aureus isolates as well as MSSA and MRSA are presented in Table 3. All isolates were susceptible to tigecycline, linezolid and vancomycin. Minocycline was also highly active: 99.2 % of isolates were susceptible, including 99.3 % of MRSA and 99.0 % of MSSA isolates. Some 91.0 % of all S. aureus isolates were susceptible to imipenem, although in the subset of MRSA isolates only 82.6 % were susceptible by MIC criteria. Four agents (amoxicillin/clavulanate, piperacillin/tazobactam, levofloxacin and ceftriaxone) demonstrated susceptibilities by MIC criteria of between 40 and 90 % against the complete panel of S. aureus isolates; against the subset of MRSA isolates, susceptibility to these agents was low (<32 %). For example, 696 (79.2 %) MRSA isolates across the United States were resistant to levofloxacin, ranging from 47.8 % in LA to 100 % in AZ (Table 4).
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0.25 and an MIC90 of 0.5 µg ml–1 against all isolates. Minocycline was also active against both S. aureus subsets, resulting in an MIC50 and MIC90 of 0.25 µg ml–1 against MSSA and an MIC50 of 0.25 µg ml–1 and an MIC90 of 0.5 µg ml–1 against MRSA. Vancomycin was also active against S. aureus, with an MIC50 of 0.5 µg ml–1 and MIC90 of 1 µg ml–1 against MSSA and MIC50 and MIC90 of 1 µg ml–1 against MRSA. The linezolid MIC50 was 2 µg ml–1 against both MSSA and MRSA; its MIC90 was 2 µg ml–1 for MSSA and 4 µg ml–1 for MRSA.
Considerable variation exists between national and state susceptibility/MIC data. For example, the MIC90 for imipenem against all S. aureus isolates across the country was 4 µg ml–1; however, nine states (IN, OH, ND, DC, FL, NC, LA, UT and WA) reported imipenem MIC90 values 2 doubling dilutions higher than the national average, while 16 states (NH, VT, NJ, IL, KS, NE, GA, VA, WV, AL, KY, MS, TN, NM, CA and OR) reported MIC90 values 2 doubling dilutions lower than the national average (data not shown). This wide range was probably due to regional variations in MRSA occurrence, against which a substantially higher MIC90 for imipenem has been reported in this study (16 µg ml–1).
Only 96 (5.7 %) S. aureus isolates were susceptible to all antimicrobial agents tested; all were MSSA. Multidrug resistance (resistance to three or more antimicrobial classes) was noted in a single isolate in this study. This isolate was collected from a sputum sample collected from a 16-year-old female in New York. It was resistant to all ß-lactams (amoxicillin/clavulanate, ampicillin, penicillin, piperacillin/tazobactam, ceftriaxone and imipenem), fluoroquinolones (levofloxacin) and tetracyclines (minocycline) but was susceptible to tigecycline (MIC 0.5 µg ml–1), linezolid (2 µg ml–1) and vancomycin (2 µg ml–1).
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DISCUSSION |
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TOPINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The three most active agents in vitro against MRSA identified in this study were tigecycline, vancomycin and linezolid, with 100 % susceptibility reported for each. Recent reports of MRSA resistance to linezolid (Wilson et al., 2003; Anderegg et al., 2005; Peeters & Sarria, 2005) and vancomycin (Bozdogan et al., 2003; Chang et al., 2003) highlight the importance of the development of new agents, such as tigecycline, for the appropriate treatment of infections where highly resistant pathogens are suspected or known.
Tigecycline has previously been shown to be highly active in vitro against S. aureus. Hoban et al. (2005), in an examination of T.E.S.T. database isolates collected globally in 2004, reported an MIC50 of 0.12 µg ml–1 and MIC90 of 0.25 µg ml–1 for tigecycline against both MRSA (n=348) and MSSA (n=489), with 98.9 % of MRSA and 99.8 % of MSSA isolates susceptible. Fritsche et al. (2004) reported an MIC50 of 0.25 µg ml–1 and an MIC90 of 0.5 µg ml–1 for tigecycline against oxacillin-susceptible (n=3196) and -resistant (n=1881) isolates of S. aureus in a clinical study of global isolates collected from patients with community-acquired respiratory tract and cutaneous infections. All isolates in this study were susceptible to tigecycline. Fritsche & Jones (2004) showed similar activity for tigecycline against MSSA and MRSA recovered from nosocomial and community-acquired infections. In this study, 3498 isolates of S. aureus possessed an MIC50 of 0.25 µg ml–1 and an MIC90 of 0.5 µg ml–1, with no differences in MIC noted between MSSA or MRSA subgroups. All isolates were inhibited by tigecycline at 1 µg ml–1.
Recent comparative studies have also demonstrated the clinical efficacy of tigecycline in complicated SSSIs and complicated intra-abdominal infections (cIAIs). In a summary of in vitro data from Phase 3 clinical trials in cSSSIs and cIAIs, Bradford et al. (2005) compared the in vitro activity of tigecycline with that of several other antimicrobial agents. Tigecycline was the most active antimicrobial agent in this study, with an MIC90 of 0.25 µg ml–1 reported for MSSA and MRSA isolates collected from patients with either SSSIs or IAIs. Minocycline was also highly active against MRSA in this study, but in a direct comparison between these two agents, 11 minocycline-resistant MRSA isolates were identified that were susceptible to tigecycline at low concentrations (0.5 µg ml–1) (Bradford et al., 2005).
McAleese et al. (2005) have recently reported a serial passage study in which reduced susceptibility to tigecycline was selected among two strains of S. aureus. These strains were grown in increasing concentrations of tigecycline over a period of 16 days, after which MICs increased by 16-fold for S. aureus strain N315 and 32-fold for strain Mu3. After passage, both strains showed more than 100-fold increases in expression of the gene cluster mepRAB, which encodes the transcription regulator gene mepR, the efflux pump gene mepA and a third protein of unknown function (mepB).
Although several antimicrobial agents possess good in vitro activity against MRSA, most are inactive or only sporadically active against HA-MRSA in vivo. According to Cunha (2005), the list of antimicrobial agents with in vivo activity against MRSA is short, including only quinupristin/dalfopristin, minocycline, daptomycin, linezolid and vancomycin (of these, only daptomycin, linezolid and vancomycin have MRSA indications). These agents are active against HA-MRSA, however; possible treatment options for CA-MRSA include clindamycin and trimethoprim/sulfamethoxazole. Recent clinical studies have shown that tigecycline also demonstrates a high degree of in vivo activity against S. aureus, both MSSA and MRSA. Ellis-Grosse et al. (2005) reported tigecycline microbiological eradication rates of 78.1 and 88.8 % against MRSA (n=32) and MSSA (n=134), respectively, among medically evaluable patients with SSSIs at the test-of-cure visit; patients treated with vancomycin/aztreonam reported eradication rates of 75.8 % for MRSA (n=33) and 90.8 % for MSSA (n=120). Similarly, Babinchak et al. (2005) recently showed equivalent microbiological eradication at test-of-cure visit among patients treated with tigecycline (92.9 %) or imipenem/cilastatin (91.7 %) for cIAIs not infected with MRSA.
Resistance to meticillin among nosocomial S. aureus isolates is imparted through acquisition of a genetic element, the staphylococcal cassette chromosome mecA (SCCmecA), which occurs in several forms. Types I to III impart resistance to ß-lactam antimicrobials, while types II and III also impart resistance to numerous non-ß-lactam antimicrobials (Padmanabhan & Fraser, 2005; Katayama et al., 2000). Risk factors associated with the acquisition of nosocomial MRSA infections include previous hospitalization, increased length of hospital stay, previous exposure to antimicrobial agents (especially fluoroquinolones), enteral feeding and/or surgery (Graffunder & Venezia, 2002).
Reports of infections caused by MRSA have begun to emerge in recent years among patients not previously exposed to nosocomial MRSA risk factors (Boyce, 2005). Isolates of CA-MRSA possess a novel cassette chromosome, SCCmecA type IV, which is smaller than that found in nosocomial isolates and can be transferred horizontally between isolates (Daum et al., 2002). It is dominated by the ccrAB2 allotype, which is prevalent among emerging community-acquired MRSA strains compared with the less common ccrAB4 allotype (Oliveira et al., 2006). CA-MRSA isolates are typically susceptible to more antimicrobials than HA-MRSA, including clindamycin, trimethoprim/sulfamethoxazole and the aminoglycosides. CA-MRSA also possesses different gene profiles, including Panton–Valentine leukocidin, which can result in increased toxicity (Stevenson et al., 2005). Although the name CA-MRSA refers to colonization or infection in the community rather than actual acquisition (Salgado et al., 2003), CA-MRSA strains are often derived from isolates picked up in healthcare facilities on previous visits or through contact with other individuals who have previously been exposed to HA-MRSA strains. The ability of CA-MRSA to transfer its SCCmecA IV gene horizontally might eventually result in the appearance of SCCmecA IV among HA-MRSA, making these strains even more difficult to distinguish in the future.
MRSA infections can be problematic to treat compared with MSSA infections in part because of the potentially enhanced virulence of MRSA, potentially decreased efficacy of vancomycin against MRSA and/or delays in initiating appropriate antimicrobial therapy (Cosgrove et al., 2003). Engemann et al. (2003) showed that MRSA SSSI patients had significantly longer median durations of hospital stay (8 vs 5 days; P<0.001) and significantly higher mortality (20.7 vs 6.7 %; P<0.001) than SSSI patients infected with MSSA. Treatment cost among MRSA patients can also be higher compared with MSSA patients (MRSA mean cost=$118 415; MSSA mean cost=$73 165). Similarly, Cosgrove et al. (2003) reported a significant increase in mortality associated with MRSA infection compared with MSSA infection (OR=1.93; P<0.001) in a pooled analysis of 31 studies involving S. aureus bacteraemia.
Isolates of MRSA are commonly resistant to multiple antimicrobials, particularly members of the ß-lactam family (Chen & Huang, 2005). The selection of empirical therapy for the treatment of suspected MRSA infection should thus be based on as much clinical information as possible, including the presence of coexisting illness, prior antimicrobial therapy, duration of hospitalization, knowledge of local MRSA incidence and/or evidence of patient colonization (Haddadin et al., 2002). The high prevalence of MRSA reported here calls for extreme caution before commencing empirical therapy for any infection potentially caused by MRSA.
Prevalence of MRSA in those hospitals that submitted isolates varied widely by state in this study, ranging from 12.5 % (3/24) in NH to 100 % (25/25) in KY. Regions with high MRSA prevalences may be indicative of localized clonal MRSA outbreaks, as reported previously both in hospitals (Young et al., 2004) and in the community (Stemper et al., 2004). Such outbreaks are usually identified using pulsed-field gel electrophoresis, multi-locus sequence typing and/or staphylococcal cassette chromosome mec typing to identify genetically related clonal complexes (Gomes et al., 2005). Genotyping is not currently implemented in the T.E.S.T. study; its introduction would undoubtedly enhance its contribution to epidemiological investigations.
This report has shown (using imipenem as an example) that MRSA susceptibility data can vary widely between different states. MIC data for ß-lactams against MRSA must be regarded with caution, as several ß-lactams (i.e. penicillins, carbapenems, cephems, ß-lactam/ß-lactamase inhibitor combinations) can provide false-positive susceptibility results against MRSA isolates that are not clinically effective (CLSI, 2005). Laboratory-derived MIC values may thus not accurately reflect clinical treatment options for MRSA infections. Increasing resistance to established anti-MRSA agents such as linezolid and vancomycin confirms the importance of the development of new antimicrobial agents that are effective against resistant organisms. The excellent in vitro activity of tigecycline against MSSA and MRSA could make it an important tool in the empirical (and targeted) therapy of nosocomial and community infections caused by resistant pathogens such as MRSA.
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ACKNOWLEDGEMENTS |
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