ANTIMICROBIAL SUSCEPTIBILITY CHARACTERIZING SUSCEPTIBILITY PATTERNS OF MSSA ASSOCIATED WITH SURGICAL WOUND INFECTIONS

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1 ASSOCIATED WITH SURGICAL WOUND INFECTIONS Specimen ES-02 was designated as a "surgical wound culture" to be identified to the species level and tested for antimicrobial susceptibility. 1-4 The culture contained Staphylococcus aureus, a common cause of skin and skin structure infections (SSSI) and often producing abscesses. Methicillin (oxacillin) resistance has become very common in this species, limiting treatments (especially with orally administered antimicrobial agents), but the methicillin-susceptible strains still prevail. 5,6 This strain was selected for the survey to present a common antimicrobial phenotype pattern of resistance to penicillins mediated by a penicillinase. Other β-lactams were active against this quality control organism, 3 e.g., penicillinase-resistant penicillins, penicillins + β-lactamase inhibitors, many cephalosporins, and the marketed carbapenems (Table 1). Responses of S. aureus (827; 96.6%), staphylococcus coagulase-positive (19; 2.2%), and other acceptable replies (7; 0.8%) were judged as satisfactory, for 99.6% overall acceptable performance. Only three responses of S. aureus, methicillin-resistant were declared as incorrect identification that would have misdirected antimicrobial treatment and local epidemiology. This organism was the commonly used S. aureus QC strain recommended by the CLSI / EUCAST for MIC testing. Well-defined MIC QC ranges have been published for over 30 years; 1,3,4 see Table 1. Organism Identification S. aureus is the most commonly isolated bacterial pathogen cultured from human infections and can be associated with disease in nearly all organ systems. The most frequent infections associated with staphylococci include community-acquired and nosocomial bacteremia (usually secondary to infected intravascular devices), complicated SSSI (csssi), or surgical site infections (SSI). Staphylococcal infections also frequently occur in bone and joints, heart valves, and implanted prosthetic devices. When cultured on routine isolation media for hours at 35 C in a 5% CO 2 atmosphere, S. aureus forms large round colonies which are often pigmented a pale yellow or off-white color, but also can be white. The organism is usually β-haemolytic but can also be non-haemolytic. 7 This species grows aerobically or anaerobically with a preliminary, yet very accurate, identification determined by using Gram's stain morphology, catalase and coagulase tests. Gram s stain of S. aureus reveals a grampositive coccus, usually found in grape-like clusters. The catalase and tube coagulase tests should both provide a positive result. S. aureus expresses clumping factor (bound coagulase) which can be detected using the slide agglutination test. 8 S. aureus produces acid from several sugars, with the exception of xylose, cellobiose, arabinose, and raffinose, and is easily identified using biochemical and MALDI-TOF based automated commercial systems with high discrimination from other staphylococcal species.

2 Table 1. Listing of expected susceptibility testing categorical results for a methicillin-susceptible S. aureus (culture of surgical wound) strain sent as specimen ES-02 (2014). Antimicrobials listed by susceptibility category (Reference MIC [Midpoint of QC range] in µg/ml; breakpoint) a Susceptible Intermediate Resistant Amoxicillin/clavulanate (0.25; b) None Ampicillin (1; use penicillin results) Ampicillin/sulbactam (-; b) Penicillin (0.5, 1; 0.12) Azithromycin (1; 2) Cefazolin (0.5; b) Cefepime (2; b) Cefotaxime (2; b) Cefoxitin (2; 4) Ceftriaxone (2,4; b) Chloramphenicol (4,8; 8) Ciprofloxacin (0.25; 1) Clindamycin (0.12; 0.5) Daptomycin (0.25, 0.5; 1) Erythromycin (0.5; 0.5) Gentamicin (0.25, 0.5; 4) Imipenem (0.03; b) Levofloxacin (0.12, 0.25; 1) Linezolid (2; 4) Moxifloxacin (0.03, 0.06; 0.5) Ofloxacin (0.25, 0.5; 1) Oxacillin (0.25; 2) Quinupristin/dalfopristin (0.5; 1) Rifampin (0.008; 1) Tetracycline (0.25, 0.5; 4) Tigecycline (0.06, 0.12; 0.5) Trimethoprim/sulfamethoxazole ( 0.5; 2) Vancomycin (1; 2) a. Susceptibility categories determined by CLSI M100-S24 (2014), USA-FDA product package insert (tigecycline) or EUCAST (2014), where appropriate (1-4). b. Preferred testing drugs to determine a MRSA isolate. Note that all β-lactams including recently released ceftaroline (ceftobiprole in development) would be considered active against this methicillin-susceptible staphylococcus. Conversely, for a MRSA, only ceftaroline and ceftobiprole would be active among tested β-lactams.

3 Antimicrobial Susceptibility Testing (Ungraded) Participants were requested to perform antimicrobial susceptibility testing on this S. aureus (MSSA). This strain was selected to challenge proper identification and reporting of results for β-lactams, plus to determine antimicrobial categorical susceptibility and accuracy across numerous classes of agents, especially the newer gram-positive active antimicrobials. The initial reference laboratory antimicrobial susceptibility testing was conducted by standardized reference broth microdilution methods 1 and susceptibility category was determined based on CLSI document M100-S24, USA-FDA product package inserts, or EUCAST breakpoints. 3,4 The reference laboratory reported testing a total of 28 agents (Table 1) that exhibited activity varying from high potency (26 drugs) to resistance for penicillin and ampicillin. These categorical results were consistent with MIC QC ranges found in M100-S24 Table 5A. 3 Consensus categorical susceptibility accuracy data are found in Table 2 for 29 antimicrobials having a significant sample size of participant responses ( 50 results). All listed drugs achieved a categorical consensus ( 80% of results or reference test). Furthermore, several new, potent agents (Table 1) continue to be unreported by a significant number of participants: ceftaroline, fusidic acid, teicoplanin, telavancin, and telithromycin. However, some of these drugs are not available in the USA. The lack of results for ceftaroline (the most active β-lactam against MSSA isolates) was particularly disturbing. The performance by participants using the disk diffusion (DD) method 2 ranged from 89.3% (erythromycin) to 100.0% (16 drugs). The lowest acceptable categorical response rates (<98.0% for DD) were for some β-lactams incorrectly categorized as susceptible for this penicillinase-producing MSSA ( % accuracy) and false-resistant erythromycin and azithromycin results at % (10.7% by DD). The commercial MIC system testing results generally had levels of acceptable performance at 98.0%, except for inappropriately categorized (non-susceptible) results for azithromycin (3.9%), chloramphenicol (7.5%), and imipenem (2.1%); all erroneous results were produced by MicroScan systems. Other false-resistant results were observed for clindamycin (1.7%), erythromycin (1.4%), and vancomycin (1.3%); 87.9% coming from MicroScan. False-susceptibility for penicillin (3.7%) and ampicillin (4.7%) was noted for 26 laboratories, 80.8% using MicroScan products.

4 Table 2. Participant performance for selected agents ( 50 responses by one or both tests except cefoxitin) listed by disk agar diffusion (DD) and quantitative MIC methods for ES-02 (2014), a methicillin-susceptible S. aureus strain (NCTC 12973, ATCC 29213, WDCM 0131, CIP , DSM 2569, JCM 2874). DD MIC Antimicrobial agent Acceptable a category No. % correct No. % correct Amoxicillin/clavulanate Susceptible Ampicillin Resistant Ampicillin/sulbactam Susceptible Azithromycin Susceptible Cefazolin Susceptible Cefepime Susceptible Cefotaxime Susceptible Cefoxitin Susceptible b b Ceftriaxone Susceptible Chloramphenicol Susceptible Ciprofloxacin Susceptible Clindamycin Susceptible Daptomycin Susceptible Erythromycin Susceptible Gentamicin Susceptible Imipenem Susceptible Levofloxacin Susceptible Linezolid Susceptible Moxifloxacin Susceptible Ofloxacin Susceptible Oxacillin Susceptible b b Penicillin Resistant Piperacillin/tazobactam Susceptible Quinupristin/dalfopristin Susceptible Rifampin Susceptible Tetracycline Susceptible Tigecycline Susceptible Trimethoprim/sulfamethoxazole Susceptible Vancomycin Susceptible a. Correct categorical interpretation was determined by the reference MIC using the M07-A9 method and CLSI M100-S24 or USA-FDA (tigecycline) breakpoint criteria. 1,3 b. Underlined values are the antimicrobial agent rates from which methicillin-resistant isolates are best detected among clinical isolates of S. aureus. 1,3

5 Combining these results for ES-02 (2014) with those for ES-01 (2013) from MSSA and MRSA challenge strains, the following conclusions about contemporary susceptibility testing of S. aureus can be made: 1. CLSI recommendations to categorize susceptibility to β-lactams, especially the cephalosporins, using the combined oxacillin and cefoxitin test results remains highly accurate. a. Oxacillin MIC performs better than the cefoxitin MIC; b. Cefoxitin DD results were more accurate than the oxacillin DD value; and c. Greatest cephalosporin false-susceptible rates were observed for cefepime (15.5%) and imipenem (8.0%), 96.0% of those results generated by the MicroScan products. 2. False-resistant results occurred more often for the macrolides and chloramphenicol, drugs having breakpoint MIC values near the ECOFF (see Table 1) or midpoint MIC values of the wildtype distribution; 3. Resistance by an MIC method was incorrectly applied when testing these two S. aureus, which were very susceptible to vancomycin ( %) and linezolid (0.2%); and 4. Some commercial systems were more likely to produce false-resistant results or be unable to detect the presence of staphylococcal penicillinase (see text above and Table 2). Treatments of choice for SSTI Skin and soft tissue infections (SSTI) are extremely common and may represent up to 10% of hospital infections. 9 Surgical site infections (SSI), a subset of SSTI, are related to the category of operation (clean versus contaminated) and have been shown to represent about 38% of nosocomial infections in surgery patients. 10,11 Recently, the Infectious Diseases Society of America (IDSA) released its updated practice guidelines for the diagnosis and management of skin and soft tissue infections. 6,12 IDSA has provided an updated algorithm for the treatment of SSI. 6,12 In these guidelines The recommendations for management of SSI include incision, drainage, and adjunctive systemic therapy if there is a significant systemic response to the infection. 6,12 compare therapies for SSI. 6 Unfortunately there have not been any objective studies to The IDSA therapy recommendations for MSSA are an antistaphylococcal penicillin or a first-generation cephalosporin. Vancomycin, linezolid, daptomycin, telavancin, or ceftaroline are recommended for MRSA. 6,12 For infections following surgery where gram-negative bacteria or anaerobes may occur, then a cephalosporin or a fluoroquinolone in combination with metronidazole may be needed. 6,12 Although MRSA are common in SSTI, there are still many S. aureus infections that are caused by MSSA 6,12-14 and it is important to recognize the nuances of MSSA treatment. There is concern that vancomycin may be associated with poorer outcomes in patients with MSSA infections For

6 example, therapy with nafcillin or cefazolin were independently associated with a 79% lower adjusted rate of mortality compared to vancomycin, and switching from vancomycin to nafcillin or cefazolin was highly protective against mortality. 19 Further, differences in tolerability in patients who received the antistaphylococcal penicillin, nafcillin and the first-generation cephalosporin, cefazolin have been shown. 20 Treatment with nafcillin was demonstrated to result in a higher rate of premature discontinuation and drug-emergent events than cefazolin. 20 Also, there have been concerns in the literature that cefazolin may have failed in some cases due to it being more labile to the S. aureus β-lactamase than the antistaphylococcal penicillins. 21 The anti-mrsa cephalosporin ceftaroline is active against MRSA and is intrinsically more active (8- to 16-fold) when compared to other cephalosporins tested against MSSA (ceftaroline MIC 90, 0.25 µg/ml; ceftriaxone MIC 90, 4µg/mL). 22,23 The majority of MSSA are resistant to penicillin due to production of a penicillinase. Penicillin is highly active against MSSA strains lacking β-lactamase production. However, care should be taken to ensure that the strain is not a weak β-lactamase producer by testing following enzyme induction. 1,3 Recently (2014) two new antistaphylococcal agents were approved for marketing in the USA by the FDA (the oxazolidinone, tedizolid; and the long-acting lipoglycopeptide, dalbavancin). These agents provide some unique advantages in terms of dosing, and we will have to wait to see how these compounds are incorporated into staphylococcal treatment regimens for outpatients as well as hospitalized patients with SSTIs of varying severity. References 1. Clinical and Laboratory Standards Institute M07-A9. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard: ninth edition. Clinical and Laboratory Standards Institute, Wayne, PA. 2. Clinical and Laboratory Standards Institute M02-A11. Performance standards for antimicrobial disk susceptibility tests; approved standard: eleventh edition. Clinical and Laboratory Standards Institute, Wayne, PA. 3. Clinical and Laboratory Standards Institute M100-S24. Performance standards for antimicrobial susceptibility testing: 24th informational supplement. Clinical and Laboratory Standards Institute, Wayne, PA. 4. European Committee on Antimicrobial Susceptibility Testing Breakpoint tables for interpretation of MICs and zone diameters. Version 4.0, January Available at Accessed January 1, Moellering RC, Jr MRSA: the first half century. J. Antimicrob. Chemother. 67: 4-11.

7 6. Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan SL, Montoya JG, Wade JC Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin. Infect. Dis. 59: e Versalovic J, Carroll KC, Funke G, Jorgensen J, Landry ML, Warnock DW Manual of Clinical Microbiology, 10th ed. ASM Press, Washington D.C. 8. Clinical Microbiology Procedures Handbook, 3rd ed L. S. Garcia. ASM Press, Washington, D.C. 9. Giordano P, Weber K, Gesin G, Kubert J Skin and skin structure infections: treatment with newer generation fluoroquinolones. Ther. Clin. Risk Manag. 3: Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR Guideline for Prevention of Surgical Site Infection, Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am. J. Infect. Control. 27: ; quiz ; discussion Gaynes RP, Culver DH, Horan TC, Edwards JR, Richards C, Tolson JS Surgical site infection (SSI) rates in the United States, : the National Nosocomial Infections Surveillance System basic SSI risk index. Clin. Infect. Dis. 33 Suppl 2: S Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan SL, Montoya JG, Wade JC Executive summary: practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of america. Clin. Infect. Dis. 59: Friedland HD, O'Neal T, Biek D, Eckburg PB, Rank DR, Llorens L, Smith A, Witherell GW, Laudano JB, Thye D CANVAS 1 and 2: analysis of clinical response at day 3 in two phase 3 trials of ceftaroline fosamil versus vancomycin plus aztreonam in treatment of acute bacterial skin and skin structure infections. Antimicrob. Agents Chemother. 56: Dryden MS Skin and soft tissue infection: microbiology and epidemiology. Int. J. Antimicrob. Agents 34 Suppl 1: S Lodise TP, Lomaestro B, Graves J, Drusano GL Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob. Agents Chemother. 52: Chang FY, Peacock JE, Jr., Musher DM, Triplett P, MacDonald BB, Mylotte JM, O'Donnell A, Wagener MM, Yu VL Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine 82: Stryjewski ME, Szczech LA, Benjamin DK, Jr., Inrig JK, Kanafani ZA, Engemann JJ, Chu VH, Joyce MJ, Reller LB, Corey GR, Fowler VG, Jr Use of vancomycin or first-generation

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