UR-11 (2017) SUSCEPTIBILITY FINDING AN ACTIVE ANTIMICROBIAL FOR THERAPY OF MULTIDRUG-RESISTANT (MDR) ENTEROCOCCAL URINARY TRACT INFECTIONS

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1 MULTIDRUG-RESISTANT (MDR) ENTEROCOCCAL URINARY TRACT INFECTIONS Sample UR-11 (2017) was a simulated urine culture with an isolate from a febrile ICU patient with symptoms of a urinary tract infection (UTI). Participants were requested to identify any potential pathogen and to perform antimicrobial susceptibility tests via the methods routinely used by the laboratory. 1-6 This culture contained Enterococcus faecium, a species often associated with multidrugresistance (MDR), particularly in United States (USA) medical centers and in some countries in Western Europe. Previous enterococcal challenge samples from various API programs have featured E. faecium, E. faecalis, and E. gallinarum, each having resistance mechanisms against commonly used agents such as ampicillin, linezolid, and vancomycin. This current sample was forwarded to participants for identification and susceptibility testing, and grading was performed. Actual MICs and inhibitory zone diameters, analyzed by method or susceptibility testing product, are discussed in a separate commentary. Responses of E. faecium, vancomycin-resistant (664, 53.0%); E. faecium (260, 20.7%); growth or Grampositive organism (179, 14.3%); Enterococcus sp. (53, 4.2%); Enterococcus sp., vancomycin-resistant (50, 4.0%); and presumptive Enterococcus sp. (12, 1.0%) were considered acceptable performance, with total identification accuracy at 97.1%. The most common error was identifying the organism as E. faecalis (14, 1.1%). This organism was a very typical example of E. faecium, and all referees had an acceptable response. The clinical isolate was originally derived from a blood culture from a hospitalized patient from Houston, Texas in This organism has a Van A resistance pattern that includes resistance to vancomycin and teicoplanin (both glycopeptides), but the organism also possesses resistances to several other antimicrobial classes including aminopenicillins, oxazolidinones, fluoroquinolones, macrolides, aminoglycosides, and tetracyclines. Organism Identification E. faecium is the second-most-frequent species of the Enterococcus genus isolated from human clinical specimens. E. faecium are Gram-positive cocci that can occur singly, in pairs, or in short chains, and are facultatively anaerobic with an optimum growth temperature range of C. E. faecium isolates grow on standard laboratory isolation media and produce small (1-2 mm) gray/white smooth alpha-hemolytic or non-hemolytic colonies on 5% sheep blood agar plates. All strains are non-motile, catalase negative, can grow in broth with 6.5% NaCl, and will hydrolyze esculin in the presence of 40% bile salts. Most E. faecium isolates hydrolyze leucine-β-naphthylamide (LAP) by producing leucine aminopeptidase (LAPase) and L-pyrrolidonyl-β-naphthylamide (PYR) by producing pyrrolidonyl arylamidase (PYRase). 7 Automated and commercially available identification systems such as Vitek 2, MicroScan, API, and BBL Crystal can be used to accurately identify E. faecium. 7-9 Recently, Matrix-Assisted Laser Desorption / Ionization Time Of Flight (MALDI-TOF) testing has emerged as a rapid, accurate, and cost effective method for identifying bacterial isolates including Enterococcus spp. 10,11

2 Enterococci grow and survive in many environments and can persist almost anywhere including in soil, food, water, plants, animals, birds, and insects. In humans they are part of the normal flora and are found most often in the gastrointestinal tract, and to a lesser extent in the genitourinary tract and oral cavity. 7,12 Enterococci are known to be important opportunistic pathogens often associated with serious infections including endocarditis. 13 Among the enterococci, E. faecalis and E. faecium are the most frequently observed species causing human infections, and they account for nearly 90% of all enterococcal cultures. Enterococci are known to be the pathogen causing nearly 10% of outpatient urinary tract infections (UTI) and 16% of nosocomial UTIs (such as this specimen). 14 The SENTRY Antimicrobial Surveillance Program has ranked enterococci as the fourth leading pathogen in North America (10.2%) and fifth in Europe (7.2%) from bloodstream infections (BSI). 15 In UTIs, enterococci were the second ranked pathogen overall, ranking after E. coli (47.3%). 14 A higher UTI rate for the enterococci was observed in North America when compared to Europe or Latin America. 14 In a 2013 report from the Centers for Disease Control and Prevention, 16 77% of healthcare-associated infections with E. faecium were resistant to vancomycin, leaving limited treatment options; see Table 1. Table 1. Listing of expected susceptibility testing categorical and MIC results for E. faecium strain sent as sample UR-11 (2017). Antimicrobials listed by CLSI susceptibility category (Reference laboratory MIC in µg/ml) a Susceptible Resistant No criteria b Daptomycin (4) Ampicillin (>16) Clindamycin (>2) Gentamicin (4) c Erythromycin (>16) Dalbavancin (>2) Oritavancin (0.06) Levofloxacin (>4) Moxifloxacin (>4) Quinupristin-Dalfopristin (1) Linezolid (8) Tigecycline (0.03) b Piperacillin-Tazobactam (>16/4) Tedizolid (1) Teicoplanin (>16) Telavancin (>2) Tetracycline (>16) Vancomycin (>16) Streptomycin (>2000) c a. Susceptibility categories determined by CLSI M100-S27 (2017) or USA-FDA product package insert criteria, where appropriate (tigecycline). b. USA-FDA approved agents without susceptibility breakpoint criteria published by CLSI (2017), also see product package inserts for breakpoints not published in CLSI document. 6 c. High-level aminoglycoside resistance screens, MIC >500 µg/ml (gentamicin) or >1000 µg/ml (streptomycin).

3 Antimicrobial Susceptibility Testing Participants were asked to perform antimicrobial susceptibility testing on this E. faecium. This strain was selected to challenge proper identification and to determine antimicrobial coverage across numerous classes of Gram-positive-active antimicrobial agents. The initial reference laboratory antimicrobial susceptibility testing was conducted using standardized reference broth microdilution methods 1 and susceptibility was determined by applying CLSI document M100-S27 breakpoints, 3 where available. The reference laboratory testing reported a total of 19 agents (Table 1) that demonstrated various levels of antimicrobial activity against this strain; however, the usually potent vancomycin was not active, having a MIC value at > 16 µg/ml. Consensus categorical testing accuracy (Table 2) for the presented 15 agents ranged from only 42.9% (linezolid, 7 responses) to 100.0% (five drugs) among disk diffusion (DD) tests. The overall DD and MIC test categorical accuracy were 96.3 and 97.7%, respectively. False-susceptible results for this MDR strain were unusual ( %) except for linezolid, where the DD and MIC methods failed to recognize resistance at rates of 57.1 and 6.4%, respectively. Several antimicrobials were active against this E. faecium, but either were not offered as reporting options (oritavancin, tigecycline) or were tested in insufficient numbers to determine a consensus category to be graded. Also, due to regulatory requirements for PT, the reporting of some agents that either do not have CLSI breakpoints, are not active against Enterococci, or are inactive against UTIs were penalized: cephalosporins (cefaclor, cefazoline, cefepime, cefotaxime, cefoxitin, ceftriaxone, cefuroxime); other β- lactams (ertapenem, oxacillin, ticarcillin-clavulanate); fluoroquinolones (moxifloxacin, ofloxacin); chloramphenicol; trimethoprim-sulfamethoxazole; clindamycin; azithromycin; fosfomycin (for E. faecalis only); and some aminoglycosides (amikacin and tobramycin); for a total of 96 unacceptable responses (1.2% of reported categories). Participants are reminded that ampicillin susceptibility can be used to predict susceptibility to other commonly used penicillin or β-lactam agents such as amoxicillin-clavulanate, ampicillin-sulbactam, penicillin, and piperacillin-tazobactam. Similarly, tetracycline HCl-susceptible results imply susceptibility to doxycycline and minocycline among enterococcal isolates. 2,3 No MIC results were offered to treating physicians for some recently approved potent agents: dalbavancin, telavancin, oritavancin, and tedizolid. Oritavancin and tedizolid were not offered as reporting options due to the lack of breakpoints in the current CLSI document. Oritavancin among the new lipoglycopeptides and daptomycin representing the lipopeptides have proven activity against this

4 Van A VRE strain (Table 1). Also note that quinupristin-dalfopristin and tigecycline were potent inhibitors of this E. faecium isolate. Nitrofurantoin was only marginally active. Enterococcal susceptibility testing profiles can enhance accurate species identification, as an isolate that is a VRE, ampicillin-resistant, and quinupristin-dalfopristin-susceptible has a very high likelihood of being an E. faecium. All participants having submitted erroneous species-level identifications, as well as producing susceptible results for vancomycin, should re-examine their methods for technical errors or procedural flaws. Overall, susceptibility testing performance was considered very acceptable, especially among commercial MIC test users; see Table 2. Table 2. Participant performance for selected agents ( 40 responses by one or both tests) listed by disk agar diffusion (DD) and quantitative MIC methods for UR-11 (2017), an Enterococcus faecium UTI culture isolate. Antimicrobial agent Acceptable category a No. % correct No. % correct DD MIC Ampicillin Resistant Ciprofloxacin Resistant Daptomycin Susceptible Erythromycin b Resistant Gentamicin c Susceptible Levofloxacin Resistant Linezolid Resistant Nitrofurantoin Susceptible-Intermediate Norfloxacin Resistant Penicillin Resistant Quinupristin-Dalfopristin Susceptible Rifampin Resistant-Intermediate Streptomycin c Resistant Tetracycline Resistant Vancomycin Resistant a. Correct categorical interpretation was determined by the reference MIC result, using the M07-A10, M100-S27 and USA-FDA breakpoint criteria, or participant consensus (chloramphenicol, gentamicin, norfloxacin, penicillin, rifampin, streptomycin). b. CLSI states "Not routinely reported on isolates from the urinary tract." c. Susceptibility indicates potential synergistic activity in combination with cell wall active agents. Resistance Mechanisms Among the Enterococci E. faecium is dominantly resistant to ampicillin/penicillin due to the presence or overproduction of a lowaffinity penicillin-binding protein (PBP), PBP5. Therefore, the susceptibility result for ampicillin/penicillin

5 can be a useful identification tool, since E. faecalis isolates are commonly susceptible to ampicillin/penicillin. Although rare, resistance in E. faecalis can occur due to the production of β-lactamase enzyme. Overall, enterococcal isolates are intrinsically resistant to several antimicrobial agents and are also prone to acquire exogenous genetic material and/or accumulate target site mutations that confer resistance. The UR-11 isolate had the genome sequenced and screened for resistance genes, which are described in Table 3. Table 3. Antimicrobial resistance genes detected in sample UR-11 (2017) by genome sequencing. Antimicrobial class/agent Lincosamide Clindamycin Streptogramins Quinupristin-dalfopristin Macrolide Erythromycin/azithromycin/clarithromycin Glycopeptides Vancomycin/teicoplanin Lipoglycopeptides Telavancin/dalbavancin Tetracyclines Tetracycline HCl Minocycline Doxycycline Aminoglycoside Tobramycin Amikacin Kanamycin Streptomycin Oxazolidinones Linezolid Tedizolid Resistance gene/mechanism erm(b) erm(b) erm(b); msr(c) vana vana tet(m) tet(m) tet(m) aac(6`) aph(3`)-iii aph(3`)-iii ant(6`)-ia 23S rrna mutation (G2576T) 23S rrna mutation (G2576T) This isolate demonstrated the usual msr(c) gene present in E. faecium, which is embedded in the chromosome and responsible for the intrinsic resistance observed for macrolides. 17 Additional resistance to macrolides can occur due to the presence of a variety of methylase genes, most commonly erm(b),

6 which was present in this isolate and will confer the macrolide-lincosamide-streptogramin B (MLSB) phenotype. 17 Enterococci are not susceptible to gentamicin and streptomycin at levels observed for other organisms (considered to be a result of a decrease in the permeability of the cell wall); however, the addition of an agent that acts on the cell wall (i.e., peptidoglycan synthesis) markedly increases the uptake of these antimicrobial agents, and this synergistic strategy became the basis for treatment of invasive enterococcal infections. 18,19 All E. faecium strains produce a chromosomally encoded aminoglycoside acetyltransferase, AAC(6 )-Ii, which eliminates synergism between cell wall-active antimicrobials and the aminoglycosides tobramycin, kanamycin, netilmicin, and sisomicin. 20 Therefore, aminoglycosides other than gentamicin and streptomycin are not recommended for synergistic therapy due to the presence of acetyltransferase (intrinsic in E. faecium; AAC(6 )-Ii), phosphotransferases, and methyltransferases (intrinsic in E. faecium). aph-(3 )-III is a common phosphotransferase found among enterococci, which was present in this current isolate as well and confers resistance to kanamycin and amikacin. 21 The occurrence of acquired high-level resistance to aminoglycosides eliminates the potential for synergistic treatments. Although the isolate recovered from the UR-11 sample was susceptible to gentamicin, the production of ANT(6 )-Ia conferred high-level resistance to streptogramin. 13 The glycopeptide resistance observed in this E. faecium isolate was conferred by the presence of vana determinant, which confers a high-level resistance to vancomycin and teicoplanin. vana is typically carried on transposons (e.g., Tn1546), along with other van genes, each with specific functions. 22 Glycopeptide-resistant enterococci produce altered peptidoglycan precursors in which the D-Ala-D-Ala termini are modified to either D-Ala-D-Lactate or D-Ala-D-Serine. These substitutions reduce the binding affinity of the antibiotics for the peptidoglycan precursors. 13 The presence of vana precludes the activity of lipoglycopeptides as well, such as telavancin and dalbavancin. While oritavancin remains more active in vitro than other lipoglycopeptides against vana-carrying enterococci, its in vivo efficacy remains to be determined; 23 see Table 3. Tetracycline resistance is mediated by multiple genes, but follows three general strategies: efflux of the antibiotic, enzymatic inactivation, and ribosomal protection. 24 Efflux pumps (e.g., teta and tetk) confer resistance to tetracycline but not minocycline. Ribosomal protection proteins are cytoplasmic proteins that shield the ribosomes from the action of the tetracycline agents and confer resistance to tetracycline HCl, doxycycline, and minocycline. Examples of ribosomal protection genes are tet(m), tet(o), and tet(s), and the former was detected in the isolate described herein (Table 3). The tet(u) gene was also detected in this E. faecium isolate; however, it has not been associated with a tetracycline resistance phenotype. 25

7 Oxazolidinones are important agents in the armamentarium against E. faecium, especially MDR isolates such as UR-11. This E. faecium isolate possessed alterations in the 23S rrna at the G2576 position that decreases binding of clinically approved oxazolidinone, linezolid, and tedizolid (Table 3). Other alterations in the 23S rrna can cause oxazolidinone resistance, as well as alterations in the ribosomal proteins L3, L4, and L Additional and transferrable resistance determinants, such as cfr, cfr(b), cfr(c), and optra have been detected as newer mechanisms responsible for decreased susceptibility to linezolid. These plasmid-borne resistance genes have been documented in numerous species of human clinical isolates in several regions worldwide. 26,27 In addition, studies have reported on the concomitant detection of cfr and optra genes in Staphylococcus sciuri and E. faecium. 28,29 The E. faecium isolate also displayed decreased susceptibility to rifampin, nitrofurantoin and fluoroquinolones. Overall, resistance to rifampin and fluoroquinolones in E. faecium has been associated with mutations in the rpob gene and the quinolone resistance determinant region (QRDR), respectively In contrast, nitrofurantoin resistance remains infrequent due to its complex mechanism of action. 33 However, when present, the mechanism of resistance seems to be associated mainly with mutations in nfsa or nfsb, both of which encode for oxygen-insensitive nitroreductases. The lack of reduction of the substance prevents the formation of toxic intermediate compounds. Recently, deletion in ribe, encoding lumazine synthase needed for riboflavin biosynthesis, has also been shown to increase MIC levels in laboratory mutants, although these mutations have so far not been described in clinical isolates. 34,35 Therapeutic Considerations for Serious VRE Infections Treatment options for VRE can be very limited, especially for E. faecium since this organism is usually resistant to ampicillin, piperacillin-tazobactam and other beta-lactam agents that are active against ampicillin-susceptible E. faecalis. The antimicrobial agents most commonly used to treat systemic infections caused by vancomycin-resistant E. faecium are linezolid and daptomycin, and several studies and meta-analyses have compared the efficacy and safety of these two compounds Other antimicrobial agents with in vitro activity against VRE include tedizolid, oritavancin, dalbavancin, telavancin, and tigecycline. 41 However, clinical data on the treatment of VRE infections, especially bloodstream infections, with these agents is very scarce, and none of them has USA-FDA clearance for the treatment of bloodstream infection or bacteremia. Tedizolid is a next-generation parenteral and oral oxazolidinone with in vitro activity against VanA and VanB VRE phenotypes. When tested against VRE, tedizolid (MIC50/90, 0.25/0.5 μg/ml) is four- to eight-fold more active than linezolid (MIC50/90, 2/2 μg/ml). 42 Oritavancin has the broadest spectrum among the available lipoglycopeptides and has demonstrated

8 bactericidal activity against VanA and VanB VRE phenotypes. 43 Dalbavancin and telavancin are active in vitro against VRE expressing VanB phenotype, but have very limited activity against VanA VRE. 44,45 Tigecycline exhibits potent in vitro activity against VRE (MIC50/90, 0.06/0.12 μg/ml) and approximately 20% renal excretion; however, clinical data supporting treatment of UTI is limited. Furthermore, tigecycline is not recommended for the treatment of bacteremic infections due to a high volume of distribution (7-17 L/kg) resulting in low concentrations in serum. 46,47 Other compounds that can be used to treat VRE UTI include the fluoroquinolones (ciprofloxacin, levofloxacin and norfloxacin), quinupristin-dalfopristin, nitrofurantoin, and fosfomycin. Quinupristindalfopristin has bacteriostatic activity against E. faecium (vancomycin-resistant and -susceptible isolates), but is inactive against E. faecalis. Nitrofurantoin and fosfomycin can have good activity against VRE and favorable pharmacokinetic profiles for the treatment of uncomplicated UTI, but are not recommended for the treatment of complicated UTI. 41,48,49 Finally, chloramphenicol was used in the distant past for the treatment of bacteremic VRE infections, but is not currently recommended due to reports of clinical failures (also not active in the urine), development of resistance, and bone marrow toxicity. 50 References 1. CLSI. M07-A10. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard- tenth edition. Wayne, PA: Clinical and Laboratory Standards Institute, CLSI. M02-A12. Performance standards for antimicrobial disk susceptibility tests; Twelfth Edition. Wayne, PA: Clinical and Laboratory Standards Institute, CLSI. M100-S27. Performance standards for antimicrobial susceptibility testing: 27th informational supplement. Wayne, PA: Clinical and Laboratory Standards Institute, EUCAST (2017). Breakpoint tables for interpretation of MICs and zone diameters. Version 7.0, January Available at January USCAST (2017). Breakpoint tables for interpretations of MICs and Zone Diameters, Version 3.0, January Available at March Tygacil. Tygacil Package Insert. Package Insert Accessed at on February 23, Jorgensen JH, Pfaller MA, Carroll KC, et al. Manual of Clinical Microbiology, 11th ed. Washington, D.C.: ASM Press, 2015.

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