ANTIMICROBIAL SUSCEPTIBILITY IDENTIFICATION AND TESTING OF A COMMON CLONAL TYPE OF MRSA: COMPARISON OF TEST ACCURACY FROM 2010 AND 2017

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1 TYPE OF MRSA: COMPARISON OF TEST ACCURACY FROM 2010 AND 2017 Sample ES-01 (2017) was a simulated knee joint fluid sample from a 27-year-old male following lower extremity trauma. The sample was sent for organism identification and antimicrobial susceptibility testing (AST) using laboratories' routinely applied diagnostic methods/products. 1-6 The sample contained a Staphylococcus aureus from the USA100 clonal type often associated with hospital-acquired (HA) methicillin-resistant S. aureus (MRSA) infection, although this organism can also be the cause of community-acquired (CA) disease. This challenge organism was also circulated to API subscriber laboratories in 2010 (ES-03), thus allowing a direct comparison of laboratory testing accuracy across seven years. This MRSA has multiple antimicrobial resistances (Tables 1-3), and was distributed as an "ungraded" Educational Sample (ES) to assess the contemporary levels of AST accuracy for disk diffusion (DD) and MIC methods, 1,2 the latter generally performed using FDA-approved commercial devices. The antimicrobial resistances recognized by participants in the 2010 challenge event included mechanisms against β-lactams (meca-based), macrolides, clindamycin, and fluoroquinolones. Organism Identification Responses of S. aureus (875; 98.2%); Staphylococcus, coagulase-positive (7; 0.8%); and Gram-positive organism (4; 0.4%) would be judged as acceptable performance (99.4% overall; 99.1% in 2010). The best identification accuracy to the species level (more than 10 results/method or product) was achieved by BD Phoenix (100.0%) > MicroScan (99.8%) > Vitek 2 (99.0%) > manual biochemical methods (92.3%). The MALDI-TOF method was also highly accurate (100.0%), but results were only received from six laboratories. As stated for ES-03 (2010), S. aureus remains the most commonly isolated pathogen cultured from human infections and can be associated with disease in nearly every organ system. The most frequent infections associated with staphylococci include CA and nosocomial bacteremia, usually secondary to infected intravenous devices, and complicated skin and skin structure infections (csssi) such as furuncles, cellulitis, and abscesses. 7,8 Bones and joints (this sample's infection type), heart valves, and implanted prosthetic devices are additional sites of common deep seated infections caused by S. aureus. CA-MRSA continues to be a significant concern for physicians, as infections due to this pathogen have become more commonly isolated in both the community and hospital setting. 9,10 S. aureus are Gram-positive cocci, usually appearing as clusters on a Gram's stain. It forms large, creamy, raised colonies on routine isolation media (BAP, chocolate agars), which are often pigmented off-white or light yellow and are usually β-haemolytic. 11,12 S. aureus grows both aerobically and anaerobically with a preliminarily identification based on positive reactions for both catalase and coagulase tests. The clumping factor expressed by S. aureus can be detected using the slide

2 agglutination test. S. aureus produces acid from multiple sugar sources, with the distinct exception of xylose, cellobiose, arabinose and raffinose. Identification of S. aureus is reliably achieved using automated commercial identification devices with a high degree of discrimination from other staphylococcal species. Use of chromogenic medias (CHROMagar MRSA, Brilliance MRSA, MRSASelect and chromid MRSA), 13 and technologies such as fluorescence in situ hybridization (FISH) with peptide nucleic acid probes, 14 real-time PCR assays, and MALDI-TOF mass spectrometry all provide highly specific and sensitive identification of S. aureus and/or MRSA concordant with routine testing methods. 15 Antimicrobial Susceptibility Testing (Ungraded) The cefoxitin 30-µg disk test (preferred surrogate for oxacillin disk) or the oxacillin MIC test are the current recommendations for the detection of MRSA (meca-positive) from wild-type methicillin-susceptible strains. The Clinical and Laboratory Standards Institute (CLSI) breakpoint documents 2,3 recommend only the use of the cefoxitin 30-μg disk to predict oxacillin susceptibility, and this result should be extrapolated to resistance for all currently available β-lactam agents, with the exception of the anti-mrsa cephalosporin, ceftaroline. 16 Interpretive zone diameter criteria for the cefoxitin disk test when performed for S. aureus are 22 mm = oxacillin-susceptible and 21 mm = oxacillin-resistant and therefore MRSA. The breakpoint interpretative criteria for oxacillin MIC methods are 4 μg/ml for resistant (MRSA) and 2 μg/ml indicates susceptible (MSSA). The cation-adjusted Mueller-Hinton broth for the reference oxacillin MIC test requires supplementation with 2% NaCl and a full 24 hour incubation of the test panel. The oxacillin MIC test results can be applied as a surrogate for other penicillinase-stable penicillins (cloxacillin, dicloxacillin, methicillin and nafcillin). 1-3 Table 1 lists the expected categorical responses for 35 antimicrobials when tested against this MRSA by reference broth microdilution methods. 1,3-6 Similarly, Table 2 lists the categorical results for 24 agents with accuracy rates for the DD and MIC testing methods. This MRSA USA100 clonal strain was multidrug resistant (MDR) and the DD test was more accurate (99.4%) compared to the combined commercial MIC AST devices (98.9%). The AST accuracy of laboratories participating in the survey of this strain in 2010 (ES-03, 2010) was slightly superior at 99.3% compared to this 2017 challenge at 99.2%, see Table 3. This ES-01 (2017) sample had 9,475 AST results for the 20 tabulated antimicrobials, representing a 26.0% increase in sample size (30.3% increase in vancomycin results, 829 versus 636 MIC results) compared to 2010.

3 Table 1. List of expected susceptibility testing MIC values and categorical results for this HA-MRSA strain (bone and joint infection; USA100) sent as ungraded sample ES-01 (2017). Antimicrobials listed by susceptibility category (Reference MIC in µg/ml) a Susceptible Intermediate Resistant Ceftaroline (1) Chloramphenicol (8-16) Amoxicillin-Clavulanate (>8/4) Dalbavancin (0.06) a Ampicillin (>8) Daptomycin ( ) Azithromycin (>32) Doxycycline (0.12) Cefazolin (>16) Gentamicin ( 1) Cefepime (>16) Linezolid (1-2) Cefotaxime (>32) Minocycline (0.12) Cefoxitin (>8) b Oritavancin (0.015) Ceftriaxone (>8) Q-D ( 0.5) c Ciprofloxacin (>4) Rifampin ( 1) Clindamycin (>2) Tedizolid (0.5) Doripenem (4) Telavancin ( ) Erythromycin (>4) Tetracycline ( 0.25) Imipenem (1-2) Tigecycline ( ) a Levofloxacin (>4) TMP-SMX ( 0.5 / 9.5) c Meropenem (8) Vancomycin (1) Moxifloxacin (>4) Oxacillin (>2) b Penicillin (16 - >16) a. Susceptibility categories determined by CLSI M100-S27 (2017) or by USA-FDA product package insert (tigecycline, dalbavancin). 3,6,43 b. Preferred testing drugs to determine MRSA isolates. Note all β-lactams with the exception of ceftaroline would be considered inactive against this MRSA strain. c. Q-D = Quinupristin-Dalfopristin; and TMP-SMX = Trimethoprim-Sulfamethoxazole

4 Table 2. Participant performance for selected agents ( 100 responses by both test methods; except ceftaroline, chloramphenicol and Q-D) listed by agar disk diffusion (DD) and quantitative MIC methods for ES-01 (2017), a methicillin-resistant S. aureus strain (USA100). DD MIC Antimicrobial agent Acceptable category a No. % correct No. % correct Amoxicillin-Clavulanate Resistant Ampicillin Resistant Ampicillin-Sulbactam Resistant Cefazolin Resistant Cefoxitin b Resistant Ceftaroline Susceptible Ceftriaxone Resistant Chloramphenicol Susceptible-Intermediate c Ciprofloxacin Resistant Clindamycin Resistant Daptomycin Susceptible Erythromycin Resistant Gentamicin Susceptible Levofloxacin Resistant Linezolid Susceptible Moxifloxacin Resistant Oxacillin b Resistant Penicillin Resistant Q-D Susceptible Rifampin Susceptible Tetracycline Susceptible Tigecycline Susceptible TMP-SMX Susceptible Vancomycin Susceptible a. Correct categorical interpretation was determined by the reference MIC using the M07-A10 (2015) method and CLSI M100- S27 (2017) or USA-FDA product package insert breakpoint criteria. 1,3,6 b. Underlined values are the agents from which MRSA isolates are best detected. c. Two categories were needed to achieve 80% overall, all-method consensus for determining acceptable performance.

5 Table 3. Comparative accuracy of MIC methods (DD for cefoxitin) for this MRSA sample tested against 20 antimicrobials in 2010 and % Acceptable category/responses (no. tests reported): Antimicrobial agent MRSA screens a Oxacillin 99.7 (627) 99.6 (810) Cefoxitin (DD-test) 95.0 (20) (7) β-lactams Amoxicillin-Clavulanate (228) 98.6 (212) Cefazolin 99.5 (212) 98.4 (183) Ceftriaxone 99.5 (211) 97.5 (161) Imipenem (142) (62) Penicillin 99.3 (403) 99.8 (539) Macrolides b Erythromycin 99.8 (581) 99.7 (764) Clindamycin 99.3 (571) 99.6 (778) Fluoroquinolones Ciprofloxacin 99.8 (433) 99.7 (584) Levofloxacin 99.4 (504) 99.4 (640) Tetracyclines Tetracycline c 99.5 (576) 99.6 (757) Tigecycline (73) (112) Others Chloramphenicol 99.1 (108) 95.3 (64) Daptomycin (98) 99.7 (289) Gentamicin 99.3 (550) 99.0 (676) Linezolid 99.8 (435) 99.4 (616) Rifampin 99.2 (503) 99.2 (601) TMP-SMX 99.3 (580) 99.7 (771) Vancomycin 98.3 (636) 99.3 (829) a. Preferred β-lactam agents to determine MRSA by MIC or disk diffusion methods. 1-5 b. Includes the lincosamide, clindamycin. Erythromycin results predict susceptibilities to azithromycin and clarithromycin. 3-5 c. Tetracycline susceptible results predict susceptibility to doxycycline and minocycline; however, some tetracyclineresistant strains may be susceptible to the other tetracycline derivatives. 3-5 Surrogate antimicrobial "class representatives" are commonly used when testing staphylococci including for the β-lactams (oxacillin MIC or cefoxitin DD), macrolides (erythromycin predicting azithromycin and clarithromycin), and tetracyclines (tetracycline predicting doxycycline and minocycline). False-susceptible very major errors (VME) were observed among the β-lactam AST results, ranging from 0.2% (penicillin) to 5.9% (cefepime). These VME occurrences were observed more often among Vitek 2 users (2.0%) versus MicroScan tests (1.0%), which also included false-susceptibility for the macrolide and fluoroquinolones drug classes. False-resistant major error (ME) results ranged from 0.7% (Vitek 2) to 1.1% (MicroScan). ME was particularly unusual for daptomycin (0.4%), linezolid (0.7%) and tigecycline (0.0%).

6 Other surrogate tests are suggested 4,5 for recently approved lipoglycopeptides (dalbavancin, oritavancin, telavancin) and oxazolidinones (tedizolid), where vancomycin and linezolid results, respectively, can predict the susceptibility of these newly approved agents. DD reagents of these new compounds will not be available, and MIC values will require special reagents/methods and interpretations of endpoints. No results were reported for these new drugs against ES-01 (2017). However, the new MRSA-active intravenous cephalosporin, ceftaroline, was reported as potent (susceptible) by 25 participant laboratories (MicroScan [23 sites], Vitek 2 [2 sites]). Two other less commonly tested and reported anti- Staphylococcal drugs, chloramphenicol and Q-D, are listed in Table 2. Commercial AST device accuracy was acceptable for both of these agents at 95.3% (MicroScan) to 100.0% (Vitek 2, Q-D only). The distribution of AST method use among participants for this ES-01 (2017) staphylococcal sample was: DD (2.2%), BD Phoenix (1.7%), MicroScan (50.2%) and Vitek 2 (45.9%); or 97.8% from MIC-based technologies. Finally, it remains unacceptable to report AST results for antimicrobials that are inactive at the site of infection such as testing/reporting UTI-specific drugs for this MRSA (bone/joint infection) infection. Nitrofurantoin (42 results; 10 from MicroScan and 31 from Vitek 2) as well as norfloxacin categorical responses would be considered errors for a "graded sample". Resistance Mechanisms Among MRSA Methicillin resistance in S. aureus strains is caused by the presence of the meca gene, which encodes an exogenous 76-kDa penicillin-binding protein (PBP) 2a or PBP 2. Methicillin resistance can also be conferred by the related mecc gene, but such isolates are currently rare. 17 meca is carried on a mobile genetic element designated the Staphylococcal Cassette Chromosome mec (SCCmec). 18 SCCmec elements are chromosomally located and can vary in size and genetic composition; at least 12 major types have been described. 19,20 Interestingly, S. aureus apparently acquired meca via horizontal gene transfer from animal-associated staphylococcal species such as S. sciuri or S. fleuretti. 17 β-lactam agents block peptidoglycan synthesis and lead to bacterial death because they bind and inhibit PBPs. PBP2a has a unique structure with low affinity for β-lactams and a reduced rate of β-lactam-mediated acylation. 17 Thus, the production of a PBP2a renders standard antimicrobial therapy with β-lactam agents ineffective. Some of the latest generation cephalosporins (e.g., ceftaroline and ceftobiprole), however, do exhibit activity that includes MRSA isolates carrying meca. 16,21 MRSA isolates can be clustered according to the pulsed-field electrophoresis profile scheme defined by the Centers for Disease Control and Prevention (CDC). 22 A significant portion of the HA-MRSA infections in the United States are caused by the USA100 clone (also known as New York/Japan). 22,23 The epidemiology of MRSA isolates is dynamic, however. For example, the predominant MRSA clone causing HA infections in New York City shifted from USA100 in 1996 to USA300 in Isolates

7 belonging to the USA100 clone are associated with the multilocus sequence type (MLST) 5 and carry SCCmec type II (ST5-MRSA-II), while USA300 are ST8 and carry the SCCmec IV (ST8-MRSA-IV). USA100 isolates usually display resistance phenotypes to additional antimicrobials, including erythromycin, levofloxacin and clindamycin; see Table 2. These various resistance phenotypes can be explained by the presence of additional genes within the SCCmec type II element or on other insertion sequences or plasmids. SCCmec type II can carry integrated plasmid or transposon elements, such as pub110 and Tn554. pub110 contains the ant(4 ) gene, which confers resistance to kanamycin, spectinomycin, bleomycin and tobramycin, while Tn554 harbors erma, which is responsible for the inducible macrolide, lincosamides and streptogramin resistance (MLSB) phenotype. 18 Resistance to other antimicrobials, such as tetracycline, gentamicin and trimethoprim/sulfamethoxazole, can emerge by acquisition of resistance determinants residing on plasmids, often associated with transposons or insertion sequences. 26 For one example of the complexity of the USA100 resistance genotype, see Kuroda et al., who used whole-genome sequencing to uncover the full complement of antimicrobial resistance genes present within two USA100 isolates. 27 In contrast, USA300 isolates tend to be more susceptible, but will typically exhibit β-lactam (meca) and macrolide (msra) resistance phenotypes. However, resistance to other antibiotic classes is sometimes observed. 24,28 Therapeutic Considerations for Serious MRSA Infections S. aureus is a common cause of skin and soft tissue infections Superficial infections can be treated with topical agents such as mupirocin and small localized abscesses by incision and drainage. 29,31 Antimicrobial therapy with systemic agents is given when there is extensive infection involving multiple sites, when the infection is in a site which is difficult to drain, or if the infection is rapidly progressing. 29,31 Hospital admissions with cutaneous infections have been increasing along with an emergence of resistance to many commonly used agents. 31,32 Currently many HA and CA strains are MRSA, thus requiring empiric therapy to provide coverage for this possibility. 29,31 For less severe infections, oral medications such as trimethoprim-sulfamethoxazole, doxycycline, minocycline, clindamycin, or linezolid can be considered. 29,31,33 In severe infections, empiric intravenous therapy is required and vancomycin is typically first line therapy, although there have been numerous concerns raised related to its potency or toxicity. 29,31,34 Vancomycin use is further complicated by the use of therapeutic drug monitoring of trough levels (typically ug/ml trough level is targeted). 29,33 Daptomycin, linezolid and tigecycline are alternative agents which can be selected. 29,33 Other newer agents to consider are ceftaroline, dalbavancin, oritavancin, telavancin, or tedizolid. 29,31,33,35-39 Ceftaroline is a cephalosporin which was designed to have activity against PBP2a. 40 Ceftaroline is the only USA- FDA approved β-lactam which is effective against MRSA. Dalbavancin and oritavancin are semisynthetic

8 lipoglycopeptides that have broad-spectrum Gram-positive activity, and both have a clinical indication for acute bacterial skin and soft tissue infections (ABSSSI) caused by S. aureus (MSSA and MRSA). These two agents have a similar mechanism of action to that of vancomycin which involves binding to the terminal D-Ala-D-Ala in the peptidoglycan chain, thus inhibiting cell wall cross-linking. 35,41,42 Moreover, the advantage for these two lipoglycopeptides is their prolonged serum half-life which allows for the use of a single-dose regimen. 35,42-44 Additionally approved for use in ABSSSI, another potent lipoglycopeptide telavancin can be applied once daily. 45 Also, the novel oxazolidinone tedizolid (both intravenous and oral formulations) has been shown to maintain in vitro activity against a limited number of strains exhibiting linezolid resistance due to the chloramphenicol-florfenicol resistance (cfr) gene in strains lacking chromosomal resistance mutations. 46 Currently physicians have numerous treatment options for therapy of infections caused by MRSA. References 1. Clinical and Laboratory Standards Institute M07-A10. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard. Tenth edition. Wayne, PA: CLSI; Clinical and Laboratory Standards Institute M02-A12. Performance standards for antimicrobial disk susceptibility tests. Twelfth Edition. Wayne, PA: CLSI; Clinical and Laboratory Standards Institute M100-S27. Performance standards for antimicrobial susceptibility testing: 27th informational supplement. Wayne, PA: CLSI; EUCAST. Breakpoint tables for interpretation of MICs and zone diameters. Version 7.0, January Available at Accessed January USCAST. Breakpoint tables for interpretations of MICs and Zone Diameters, Version 3.0, January Available at Accessed March Tygacil Available at Accessed February 23, Miller LG, Eisenberg DF, Liu H, Chang CL, Wang Y, Luthra R, et al. Incidence of skin and soft tissue infections in ambulatory and inpatient settings, BMC Infect Dis. 2015;15: Balachandra S, Pardos de la Gandara M, Salvato S, Urban T, Parola C, Khalida C, et al. Recurrent furunculosis caused by a community-acquired Staphylococcus aureus strain belonging to the USA300 clone. Microb Drug Resist. 2015;21: Choo EJ, Chambers HF. Treatment of methicillin-resistant Staphylococcus aureus bacteremia. Infection & chemotherapy. 2016;48:

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