Optimizing Therapy for VancomycinResistant Enterococci (VRE)

Peter K. Linden, M.D.1

ABSTRACT

Enterococci are gram-positive, facultative bacteria with low intrinsic virulence but capable of causing a diverse variety of infections such as bacteremia with or without endocarditis, and intra-abdominal, wound, and genitourinary infection. During the past 2 decades the incidence of hospital-acquired enterococcal infection has signicantly risen and is increasingly due to multidrug-resistant strains, primarily to the coacquisition of genetic determinants that encode for the stable expression of high-level b-lactam, aminoglycoside, and glycopeptide resistance. Because enterococci constitute part of the normal colonizing ora, careful clinical interpretation of cultures that grow enterococci is paramount to avoid unnecessary and potentially deleterious antimicrobial therapy. Traditional antimicrobial treatment for ampicillin- and glycopeptide-susceptible enterococcal infection remains a penicillin-, ampicillin-, semisynthetic penicillinbased regimen, or vancomycin in a penicillin-intolerant individual. The need for a bactericidal combination with a cell-wall active agent combined with an aminoglycoside is most supported for native- or prosthetic valve endocarditis but is unproven for the majority of infections due to enterococci. The emergence of vancomycin-resistant enterococci prompted the clinical development of several novel and modied antimicrobial compounds approved for VRE infection (quinupristin-dalfopristin, linezolid) and several approved for non-VRE indications (daptomycin, tigecycline). There is a paucity of comparative clinical trial data with these new agents, although linezolid, based upon its efcacy and tolerability, appears to be the cornerstone of current treatment approaches. Despite a relatively short period of clinical use, enterococcal resistance has now been described for quinupristin-dalfopristin and linezolid and more recently even for daptomycin and tigecycline. Moreover, the optimal treatment of endocarditis due to VRE strains is unknown because, with the exception of daptomycin, current treatment options only yield bacteriostasis. Nonantimicrobial measures to treat VRE infection, such as foreign body removal and percutaneous or surgical drainage of close-spaced infection, reduce both the need for and the duration of anti-enterococcal treatment and the emergence of resistance to the newer antimicrobials.
KEYWORDS: Enterococcus, vancomycin, linezolid, antimicrobial resistance, nosocomial infection

Department of Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Address for correspondence and reprint requests: Peter K. Linden, M.D., Department of Critical Care Medicine, University of Pittsburgh Medical Center, 602 A Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261 (e-mail: lindenpk@ccm.upmc.edu).

Optimizing Antimicrobial Therapy for Serious Infections in the Critically Ill; Guest Editor, David L. Paterson, M.D., Ph.D. Semin Respir Crit Care Med 2007;28:632645. Copyright # 2007 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-2007-996410. ISSN 1069-3424.

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ANTIMICROBIAL RESISTANCE MECHANISMS AMONG ENTEROCCI Intrinsic Resistance Mechanisms Enterococci possess several constitutive, nontransferable resistance mechanisms against a variety of antimicrobials, which limits therapeutic options even for vancomycin-susceptible enterococci and magnies the effect of superimposed intrinsic resistance traits (Table 1). Relative or absolute resistance to the b-lactams (penicillin, ampicillin, antipseudomonal penicillins, cephalo-

Acquired Resistance Mechanisms There are few other species of bacteria that have the proclivity and efciency of the Enterococcus to acquire new and multiple antimicrobial resistance mechanisms3,4 (Table 2). The genomic elements that encode for resistance are carried on plasmid or larger transposon elements, are stable, and often carry multiple resistance determinants that culminate in multidrug-resistant strains. Enterococci acquire resistance to chloramphenicol (mediated by chloramphenicol acetyltransferase), quinolones (by gyrase mutations), rifampin (by mutation of the gene that encodes for RNA polymerase), and tetracyclines (by a variety of mechanisms).8 However, the most clinically important antimicrobials to which enterococci have acquired resistance are discussed in more detail following here.

High-Level b-Lactam Resistance Overproduction and/or mutation of the penicillinbinding protein 5 receptor leading to diminished afnity for b-lactams has increased dramatically in E. faecium

Table 1 Intrinsic Resistance Mechanisms among Enterococci

Antimicrobial Ampicillin, penicillin Aminoglycosides (LL) Clindamycin Erythromycin Tetracyclines Trimethoprim-sulfamethoxasole
LL, low level.

Mechanism(s) Altered binding protein Decreased permeability Altered ribosomal binding Altered ribosomal binding Altered ribosomal binding Efux pump Utilize exogenous folate

Comments

High-level gentamicin strains may be susceptible to high-level streptomycin

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INCIDENCE OF ENTEROCOCCAL INFECTION AND RESISTANCE TRENDS Enterococci have become more common and problematic pathogens over the past 2 decades, with a rise in both the overall incidence of enterococcal infection and multidrug resistance. In a nationwide surveillance study [Surveillance and Control of Pathogens of Epidemiological Importance (SCOPE)] between 1995 and 2002, enterococci were the third most frequent cause of nosocomial bloodstream infection, and high-level vancomycinresistance was present in 60% of Enterococcus faecium strains but only 2% of E. faecalis strains.1 A Centers for Disease Control and Prevention (CDC) surveillance program during the same time period showed that VRE accounted for 27.5% of intensive care unit (ICU) nosocomial bacteremic and nonbacteremic infections.2 The vast majority of E. faecium strains are multidrug resistant with high-level resistance to penicillin and ampicillin (MIC > 128 mg/mL) and high-level resistance to gentamicin (MIC > 1000 mg/mL), which eliminates the potential for bactericidal synergistic treatment. The forces behind this important trend include the increased prevalence and greater longevity of immunocompromised hosts due to native or iatrogenic immunosuppression, the increased use of antimicrobials that are devoid of enterococcal activity (cephalosporins, quinolones) and thus selective for more resistant phenotypes, and, most importantly, the appearance of new resistance mechanisms (i.e., high-level vancomycin resistance), which confer resistance to previously effective antimicrobial classes.

sporins) is expressed in all enterococci due to the expression of inner-cell-wall penicillin-binding proteins (PBPs) with low afnity for these compounds.3 Exposure of such enterococcal strains to an effective b-lactam results in inhibitory but not bactericidal activity as measured by time-killing kinetic curves.4 Low-level resistance to aminoglycosides is secondary to their low penetrability through the outer-perimeter envelope of the organism, a property that can be overcome with the synergistic activity of an effective cell wall active agent such as a penicillin or vancomycin.5 Although the majority of enterococci exhibit in vitro susceptibility to trimethoprim/sulfamethoxasole their ability to utilize exogenous folate in vivo precludes the clinical utility of trimethoprim-sulfamethoxazole (TMP/SMX) and other agents that impair folate synthesis.6 A signicant percentage of enterococci may also possess constitutive resistance to macrolides (erythromycin, azithromycin) and lincosamides (clindamycin) primarily mediated by modication of the ribosomal attachment site.7

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Table 2 Acquired Resistance Mechanisms among Enterococci

Antimicrobial Ampicillin, penicillin (HL) Aminoglycoside (HL) Quinolones Chloramphenicol Glycopeptide Quinupristin/dalfopristin Linezolid Daptomycin
HL, high level.

Mechanism(s) Mutation of pbp-5 Enzyme modication DNA gyrase mutation Efux pump Altered cell wall binding Ribosomal modication Efux pump Single point mutation Unknown

Comments 95% of E. faecium < 5% E. faecalis Plasmid mediated Some HL-gentamicin R strains may be streptomycin S

Transposon 1546 ermB gene vatd, vate gene G2476U mutation Described in E. faecalis, E. faecium, and E. durans

High-Level Aminoglycoside Resistance The rst reports of high-level gentamicin resistant (HLGR) strains in the United States were in 1979, appearing in both E. faecalis and E. faecium.11 More recent surveillance data from the SCOPE program between the years 1997 and 1999 showed 69 to 71% of all U.S. enterococcal strains were HLGR and 40% of all tested vancomycin-resistant enterococci (VRE) strains.12 Enterococci acquire resistance to aminoglycosides via (1) changes in the ribosomal attachment sites; (2) diminished aminoglycoside transport into the cell; and (3) aminoglycoside-modifying enzymes (adenyltransferase, phosphotransferase, and bifunctional acetyl-phosphotransferase). Although the majority of HLGR strains also exhibit high-level streptomycin resistance, a minority retain sensitivity to streptomycin; thus susceptibility testing to high-level streptomycin is worthwhile in HLGR strains.13 No reliable bactericidal activity can be achieved with any antimicrobial combination against strains with high-level aminoglycoside resistance.14

VANCOMYCIN AND OTHER GLYCOPEPTIDE RESISTANCE Epidemiology Without question, the appearance of E. faecium strains with high-level vancomycin resistance in France and

Genetic Basis of Vancomycin Resistance Six distinct glycopeptide resistance phenotypes have been discovered: VanA, VanB, VanC, VanD, VanE, and VanG, distinguished based upon gene content, glycopeptide minimum inhibitory concentrations (MICs), and inducibility and transferability properties20 (Table 3). The vanA and vanB phenotypes uniformly confer high-level vancomycin resistance (MIC > 64 mg/ mL) and have the highest prevalence and clinical

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but remains uncommon (< 5%) among E. faecalis strains.9,10 This property is expressed constitutively and carried by resistance genes located on chromosomal elements. E. faecium strains with acquired high-level ampicillin resistance have ampicillin MICs > 128 mg/mL and are neither inhibited nor killed by ampicillin, penicillin, or other b-lactams. The ubiquity of high-level ampicillin resistance has been a major step toward the eventual evolution of multidrug resistance among E. faecium as the superimposition of other resistance traits have appeared in such strains.

England in 1986 was a major watershed mark in the evolution of enterococcal antimicrobial resistance and the nal step toward the subsequent establishment of endemic multidrug-resistant enterococci.15,16 VRE strains did not rst appear in the United States until 1989, but thereafter their incidence rapidly increased from 0.3% of all enterococci in 1989 to 7.9% in 1993.17 During this early period the majority of reported VRE isolates were almost exclusively E. faecium, were monoor pauciclonal in origin, and predominantly originated from ICU patients in tertiary care centers, particularly in the northeastern United States, where both vanA and vanB genotype outbreaks were observed; however, there was no discernible epidemiologic or clinical differentiation between the two types. Local enhancement of contact precautions usually aborted or signicantly modied such outbreaks. A more contemporaneous surveillance study of bloodstream isolates has shown a steady decrease in vancomycin susceptibility among E. faecium strains from 60% in 1997 to only 39.1% in 2002, whereas the vast majority (96.1 to 99.4%) of E. faecalis strains continue to remain vancomycin susceptible over this 5-year period.18 The incidence of VRE remains highest in the intensive care unit setting. It has increased to a greater relative extent on hospital oors and parahospital centers such as long-term acute care (LTAC) facilities and skilled-care nursing facilities, which often receive patients from hospitals with endemic VRE epidemiology.19

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Table 3 Level and Type of Vancomycin Resistance in Enterococci

Acquired Resistance Level, Type Strain Characteristic MIC, mg/L Vancomycin Teicoplanin Conjugation Mobile element Expression Location Modied target 641000 16512 Positive Tn1546 Inducible Plasmid choromosome
D-Ala-D--Lac

High, VanA

Variable, VanB

Moderate, VanD

Low VanG VanE

Intrinsic Resistance. Low Level Type VanC1/C2/C3

41000 0.51 Positive Tn1547 or Tn1549 Inducible Plasmid choromosome

D--Ala-D--Lac

64128 464 Negative Constitutive Choromosome

D--Ala-D--Lac

16 0.5 Positive Inducible Choromosome

D--Ala-D--Ser

832 0.5 Negative Inducible Choromosome

D--Ala-D--Ser

232 0.5-1 Negative Constititive Inducible Choromosome

D--Ala-D--Ser

D-Ala-D-Lac, D-alanine-D-lactate; D-Ala-D-ser, D-alanine-D-serine; MIC, minimum inhibitory concentration. (With permission from Couvalin.20)

importance. Although vanB strains retain susceptibility to teicoplanin, this agent was never commercially available in the United States, and rapid resistance has been described when VanB strains undergo teicoplanin exposure.21 Transposon 1546 (Tn1546) contains the vanA gene complex which encodes for an eight-peptide sequence culminating in ligase-mediated modication of the cell wall target for vancomycin from a high afnity D-alanine-D-alanine linkage to a low afnity D-alanine-D-lactate linkage on the cell wall peptidoglycan terminus.22 The vanB gene cluster has partial DNA homology with the vanA gene cluster and similarly encodes for ligase modication of the vancomycin target. The vanA gene has been shown to be transferable in vitro to Staphylococcus aureus, and naturally occurring vanA genemediated vancomycin resistance, probably due to horizontal transposon transmission, has been reported in four methicillin-resistant S. aureus (MRSA) strains in three patients with protracted vancomycin exposure for MRSA infection and a fourth patient without prior vancomycin exposure.2328

Dynamics and Risk Factors for VRE Colonization and Infection Colonization with VRE is a necessary prerequisite for VRE superinfection, which will arise only when anatomical or other predisposing factors become manifest. Similar to the more susceptible enterococcal strains, the natural colonizing reservoir for VRE is the intestinal tract, with secondary contiguous reservoirs on the skin, genitourinary tract, and oropharynx.29,30 There are three sequential processes leading to detectable VRE colonization and potential subsequent infection with multiple modiers (Fig. 1): (1) Exposure to enterococci containing the vancomycin-resistant genome via contact with an animate or inanimate source. It should be emphasized that the vanA gene does not arise from a spontaneous or

Figure 1 Sequence of vancomycin-resistant enterococci (VRE) exposure and antimicrobial amplication leading to VRE superinfection and increased VRE transmission.

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antibiotic-induced mutation. (2) Amplication of the VRE inoculum within the gastrointestinal reservoir usually due to antimicrobial selective pressures. Prior or ongoing antimicrobials may also enhance the risk of VRE colonization by reducing naturally competing gut ora. (3) Natural- or iatrogenic anatomical or immune defects that lead to bloodstream or nonbloodstream (tissue) invasion. Perirectal, rectal, or, preferentially,

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stool cultures have been the traditional sites to detect VRE colonization.31,32 The duration of VRE intestinal colonization is variable, can last for months to years, and may be indenite, in part subject to the inoculumdetection threshold of the surveillance testing method employed.3335 Spontaneous clearance of intestinal colonization only occurs in the minority of patients in several studies analyzing serial cultures in both antimicrobial- and nonantimicrobial-exposed patients. Multiple case control and cohort studies have analyzed risk factors for either VRE colonization, VRE superinfection, or both.3639 Two fundamental risk factor categories are demographic/illness severity variables and the type, intensity, and duration of recent antimicrobial exposure. Demographic risks include duration of hospital- and ICU length of stay, physical proximity to VRE-colonized patients in the same unit, and hospitalization in units with a high prevalence of VRE, colonization pressure. Prior administration of multiple antibiotics, third-generation cephalosporins, antimicrobials with anaerobic spectrums (metronidazole, clindamycin), and parenteral vancomycin have been implicated in case-control analyses of colonization or superinfection. Such antimicrobials probably exert a selective effect and amplify otherwise undetectable or smaller VRE inocula in the intestines and other secondary reservoirs. Donskey and colleagues have demonstrated that the density of VRE as measured by serial quantitative stool cultures increased signicantly when patients received  1 antianaerobic antimicrobial, whereas this effect was not seen in patients receiving antimicrobials with minimal antianaerobic activity.40 Interestingly, parenteral vancomycin administration resulted in no increase in the stool VRE density. Moreover, patients with high VRE density coupled with fecal incontinence were also more likely to have positive environmental cultures for VRE. The VRE-selective effects of antimicrobials and other risk factors become relatively diminished when the proportion of patients already colonized with VRE is 50% or greater, which may explain some studies where newly introduced antibiotic control measures may only yield modest reductions in VRE colonization and infection rates in hyperendemic settings.41 Patients with comorbidities, including oncologic conditions, especially neutropenia, and prior solid organ transplantation, especially liver transplantation, appear to have the highest rates of VRE bacteremia and poorest outcomes.

Table 4 Clinical and Epidemiological Clues That MDR Enterococcal Infection Is Present
Signicant and recent antimicrobial exposure Multiple agents Third-generation cephalosporins Antianaerobic antimicrobials Vancomycin Positive rectal-fecal surveillance culture or vancomycin-resistant enterococci from a prior clinical site Intra-abdominal infection (abscess, peritonitis, cholangitis) Indwelling catheters in place (bladder, intravascular) High incidence of MDR enterococci in unit, hospital Prior liver transplant, neutropenia, chemotherapy-related mucositis
MDR, multidrug-resistant.

gens, a careful clinical assessment of whether the reported isolate is a likely cause of the patients clinical syndrome that merits specic treatment is always warranted. Realistically, however, it may be difcult to make this distinction, particularly in patients who have major comorbid conditions or critical illness that is naturally coupled with colonization or infection due to multidrugresistant enterococcal strains. Although enterococci are of low virulence, it bears emphasis that they are also quite capable of promulgating the systemic inammatory response syndrome (SIRS), severe sepsis, and septic shock and have been a frequent inciting blood pathogen in recent prospective, randomized sepsis trials.42 Abundant and recent observational studies support the association between appropriate empirical antimicrobial therapy and survival.4345 Thus, for the severe end of the clinical spectrum, strong consideration should be given to empirical antienterococcal therapy for patients whose demographic features and clinical presentation place them at high risk for enterococcal infection or sepsis. Clearly a major part of this decision also includes estimating the likelihood that the enterococcal strain could be a multidrug-resistant strain. Such epidemiological and clinical clues, which might prompt empirical enterococcal therapy, are summarized in Table 4.

GENERAL ISSUES IN THE TREATMENT OF ENTEROCOCCAL INFECTION The treatment of serious enterococcal infection is challenging from several aspects. Because enterococci may colonize skin, wound, and mucosal surfaces and their isolation is often accompanied by more virulent patho-

Does the Enterococcus in the Culture Result Require Antimicrobial Treatment? Microbiological culture data that report the presence of enterococci always require some level of clinical discrimination to determine whether they merit treatment. Enterococcal isolates from a respiratory specimen (sputum, endotracheal aspirate, bronchoalveolar lavage), and skin, wound, or mucosal surfaces almost always represent colonization. Urine cultures obtained via indwelling bladder (Foley) catheters often represent asymptomatic bacteriuria. Wound and intra-abdominal drains often become colonized with skin ora, including enterococci.

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However, such isolates may be signicant when the character of the drainage uid reveals evidence of inammatory response (i.e., pyuria or purulence). Although enterococci may be blood culture contaminants, particularly when specimens are obtained from indwelling intravascular catheters, the appropriate clinical bias should be that such cultures represent true pathogens in most instances. Finally, simple nonantimicrobial interventions may obviate the need for antienterococcal therapy, such as removal of intravascular or bladder catheters or supercial wound debridement.46,47

Table 5 Nonantimicrobial Interventions for Vancomycin-Resistant Enterococcal Infections

Site of Infection Bloodstream Nonantimicrobial Intervention Catheter removal Consider endovascular infection if no primary source obvious or patient with risk factors for endocarditis or other endovascular Closed-space infection material Consider percutaneous or surgical drainage, e.g., cholangitis percutaneous transhepatic drainage or endoscopic retrograde cholangiopancreatography for stent placement Urinary tract infection or bacteriuria Supercial wound infection Suspected foreign body infection May require removal if refractory to antimicrobial therapy or adjacent to devitalized tissue Removal of bladder catheter Incision and drainage or debridement

Is Bactericidal Therapy Required? The majority of enterococcal infections are not proven to require bactericidal treatment and can be managed successfully with a single effective agent.48,49 Either native- or prosthetic-valve endocarditis is the prototypical enterococcal infection for which bactericidal antimicrobial therapy is required, usually achieved with the combination of a cell wallactive agent such as ampicillin, penicillin, or vancomycin combined with an aminoglycoside such as gentamicin or streptomycin. Other sites of infection for which bactericidal treatment is probably merited include enterococcal meningitis and enterococcemia in a neutropenic host. However, a bactericidal combination is not possible to achieve with enterococci exhibiting high-level aminoglycoside resistance and almost all strains of E. faecium strains with high-level vancomycin resistance. Uncommon exceptions are vancomycin-resistant E. faecalis strains, which retain ampicillin and high-level gentamicin susceptibility. Successful treatment of such cases has been reported with ampicillin and gentamicin, ampicillin ooxacin, penicillin streptomycin, and linezolid gentamicin.50 Limited clinical experience is available for the treatment of vancomycin-resistant enterococcal endocarditis with the newer agents (see later discussion).

considerations is summarized in Table 5. It also bears emphasis that the inability to address the nonantimicrobial considerations of such complex VRE infections has been the principal cofactor leading to the development of VRE strains that have evolved resistance to the recently approved VRE antimicrobials, quinupristin-dalfopristin and linezolid.

Nonantimicrobial Treatment of VRE Infection Many VRE infections may be partially or completely cured with conservative or aggressive nonantimicrobial interventions. Less serious infections such as bladder catheterassociated bacteriuria and urinary tract infection may be adequately treated simply with catheter removal. Postoperative supercial wound infections may also respond to opening the incision and simple drainage or debridement. Closed-space infection such as intra-abdominal abscesses, cholangitis due to biliary obstruction, devitalized tissue, or infected foreign bodies (intravascular catheters, synthetic graft or mesh material, prosthetics) are not infrequently the primary source of VRE bacteremic or nonbacteremic infection. The treatment implications for infections with such anatomical

Specic Antimicrobials for the Treatment of Vancomycin-Resistant Enterococcal Infection Despite the established high prevalence of multidrugresistant enterococcal strains with high-level vancomycin-resistance there is a remarkable paucity of controlled, comparative trial data on its antimicrobial treatment. Major obstacles have been the slow development of novel agents with VRE activity, high levels of comorbidity that confound outcome interpretation, complex surgical infection for which antimicrobial therapy alone is not curative, and the polymicrobial nature of many VRE infections, particularly those occurring in the abdomen. Both approved and nonapproved treatment options for VRE are summarized in Table 6. At present there are only two U.S. Food and Drug Administration (FDA)-approved treatments for VRE (E. faecium) infection: quinupristin/dalfopristin (Q/D, Synercid, King Pharmaceuticals, Inc., Bristol, TN) and linezolid (Zyvox, Pzer, New York, NY) and two other approved agents that have in vitro activity against VRE but are not approved for VRE infection; daptomycin (Cubicin, Cubist Pharmaceuticals, Lexington, MA), which is approved for complicated skinskin structure infection,

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Table 6 Therapeutic Antimicrobial Options for VRE Infection

Antimicrobial(s) High-dose ampicillin or ampicillin-sulbactam Chloramphenicol Tetracycline, doxycycline Novobiocin Nitrofurantoin Teicoplanin Quinupristin/dalfopristin Case series Case reports Anecdotal Small case series Case reports Large case series but noncomparative Reported Evidence Case reports Comments May be effective with VRE strains with ampicillin MIC 3264 mg/mL Resistance reported rifampin or ciprooxacin No longer manufactured Only for urinary tract infections Not active against VanAResistance in VanB reported Bacteriostatic Not active against E. faecalis Resistance reported Linezolid Daptomycin Tigecycline Dalbavancin Telavancin Oritavancin 1. Dose comparative trial 2. Large compassionate use series 1. Case report series In vitro data only In vitro data only In vitro data only In vitro data only Bacteriostatic Resistance reported Bactericidal Resistance reported Bacteriostatic

MIC, minimum inhibitory concentration.

and S. aureus bacteremia and tigecycline (Tygacil, Wyeth Pharmaceuticals, Inc., Philadelphia, PA), which is approved for complicated skinskin structure and intraabdominal infection. Prior to the availability of Q/D and linezolid approval several centers published their experience with a variety of available agents or combinations that demonstrated in vitro activity. Clinical success was described with high parenteral dosages of ampicillin or ampicillin/ sulbactam (18 to 24 g/day), even including endocarditis. Such a strategy appears limited to those uncommon VRE strains with ampicillin MICs of 32 to 64 mg/mL, a target range for which plasma ampicillin levels can be achieved with high dose therapy.5052 Because no b-lactamase elaboration occurs with VRE, the mechanism of sulbactam activity is not known, although a plausible explanation is its intrinsic penicillin-binding protein properties. Chloramphenicol has bacteriostatic activity against enterococci and VRE strains; however, its in vivo efcacy was never established. In a retrospective study of 80 cases of VRE bacteremia, 51 patients were treated with chloramphenicol from which 22/36 (61%) evaluable patients demonstrated a clinical response.53 A microbiological response was also observed in 33/43 (77%) of the microbiologically evaluable patients. No survival benet was observed compared with VRE bacteremic patients in the study cohort who did not receive chloramphenicol. Subsequently at the same center, the prevalence of chloramphenicol resistance among VRE strains over a 10-year period (1991 to 2000) were observed to increase from 0 to 11%, a trend that correlated signicantly with prior chloramphenicol or quinolone exposure.54 Isolated reports of favorable outcome for VRE infection have also

been reported with the use of tetracycline, doxycycline, and oral novobiocin combined with either ciprooxacin or doxycycline; however, such experience has never been reproduced in larger clinical series of prospective trials.5558 Teicoplanin, a glycopeptide not commercially available in the United States, does have in vitro activity versus VanB phenotypic enterococci. In a European study of 63 patients with vancomycin-susceptible enterococcal infection, clinical and microbiological responses were observed in 84% and 87% of cases, respectively.59 This agent remains unstudied for VanB enterococcal infection, perhaps in part due to the development of teicoplanin resistance among VanB E. faecalis during teicoplanin therapy.60,61 Nitrofurantoin has in vitro activity against both VanA and VanB enterococci.62 Due to its ability to achieve high urinary concentrations nitrofurantoin has been shown to be effective in VRE urinary tract infection.46,63 Nitrofurantoin cannot be employed for VRE outside the urinary tract and in patients with a creatinine clearance < 30 mL/min because elevated blood concentrations are associated with hepatic, pulmonary, hematologic, and other toxicities.
QUINUPRISTIN/DALFOPRISTIN

Quinupristin/dalfopristin (Q/D) is a semisynthetic parenteral streptogramin compound, which is derived from its parent natural compound pristinamycin, a product of Streptomyces pristinaspiralis, an oral and topical antistaphylococcal agent that has been in clinical use in Europe since the 1980s. The major properties of this compound are summarized in Table 7. This antimicrobial is a 30:70 mixture of quinupristin and dalfopristin,

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VanA strains resistant

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Table 7 Major Features of Quinupristin/Dalfopristin and Linezolid

Feature Antimicrobial class Peak serum concentrations (mg/L) Elimination half-life (h) Major metabolic routes Major elimination routes Protein binding (%) Mechanism of action Site of action Postantibiotic effect (h) Bactericidal (vs VRE) Cytochrome P-450 inhibition Formulations Dose and administration Dosage adjustment Approved indications Quinupristin/ Dalfopristin Streptogramn 10-12 0.8 (Q) , 0.6 (D) Hepatobiliary Faecal (70-75%) Urinary (19%) 30 (Q) 70 (D) Protein synthesis inhibition 50S ribosome 68 No Yes Parenteral 57.5 mg/kg q 812h None VRE Complicated SSSI Nosocomial pneumonia Major adverse effects Cost ($US per day; 2000 values) Phlebitis (peripheral) Myalgia/arthralgia $300-350 $115 (parenteral) $80 (oral)
D, dalfopristin; Q, quinupristin; qXh, every X hours; SSSI, skin and skin structure infection; VRE, vancomycin-resistant enterocooci. (With permission from Linden.42)

Linezolid Oxazolidinone 15.1 5.5 Peripheral nonoxidative Nonrenal (65%) Urinary (30%) 31 Protein synthesis inhibition 70S initiation complex 1 No No Parenteral oral 600 mg q12 h None

Nosocomial pneumonia Myelosuppression

which are derivatives of streptogramin types B and A, respectively. It is a unique antimicrobial because it acts through sequential ribosomal binding and is internally synergistic to produce a bactericidal effect. Dalfopristin initially binds to the 50S bacterial ribosome, which induces a permanent conformational change that accelerates quinupristin ribosomal binding.64 Protein synthesis is impaired via both the interruption of peptide chain elongation and the inhibition of formed peptide extrusion. SSuch synergism results in bactericidal activity against some important gram-positive species, including Streptococcus pneumoniae, Streptococcus agalacticae, and some strains of Staphylococcus aureus. However, only bacteriostatic activity is present for the majority of E. faecium strains by timekilling curve studies. This effect is primarily mediated by 23S ribosomal modication encoded for by the ermB gene (erythromycin methylase), which reduces quinupristin afnity for its ribosomal binding site and thus limits activity to only the dalfopristin moiety. Such strains are termed MLSb (macrolidelincosamide-streptogramin) phenotypes.65 Erythromycin resistance serves as an excellent surrogate marker for the presence of the MLSb phenotype among enterococci. Q/D is also unique as an antienterococcal agent based upon its marked disparity in in vitro susceptibility between E. faecium (MIC90 1 to 2 mg/mL) and E. faecalis (MIC90 8 to 16 mg/mL). This disparity is most likely due to altered ribosomal binding or presence of an active efux pump.

Clinical interest in the utility of Q/D for serious VRE infection began in the mid-1990s with a largescale, noncomparative, open-label, emergency use program for multiresistant gram-positive infection, principally vancomycin-resistant E. faecium and MRSA infection refractory or intolerant to vancomycin.66,67 The patient populations in both series had a high prevalence of acute and chronic comorbidities, including diabetes, oncologic conditions, chronic liver disease, dialysis mechanical ventilation, and prior organ transplantation. Q/D was administered at 7.5 mg/kg intravenously every 8 hours to patients with documented VRE bacteremia or nonbacteremic VRE infection, with the duration of treatment determined by the primary treating physicians. The overall success rate dened as both clinical success and bacteriologic eradication was 65.8% in the initial study and 65.6% in the follow-up study. There have been several reports of clinical cure combining Q/D with doxycycline or high-dose ampicillin in endocarditis; however, no larger-scale experience has been performed.6870 As Q/D usage increased both before and after its regulatory approval in 1999, several important clinical limitations became apparent. Peripheral intravenous administration was associated with a high rate of phlebitis necessitating central venous administration. Myalgia and arthralgia unassociated with objective inammatory signs were observed in 7 to 10% of patients in the emergency use program, with much higher rates in

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VRE Complicated SSSI

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LINEZOLID

Linezolid is an oxazolidinone compound, a novel synthetic class that inhibits bacterial protein synthesis in a unique fashion via inhibiting the formation of the 70S initiation complex (50S and 30S ribosomes, mRNA, initiation factors 2 and 3, and fMet-tRNA).75 The major properties of linezolid are summarized in Table 6. Linezolid exhibits a broad gram-positive spectrum but has only bacteriostatic activity against vancomycin-resistant or susceptible enterococci with an MIC90 of 2 mg/mL, which is right at the susceptibility breakpoint. FDA approval was granted in 2000 for vancomycin-resistant E. faecium infection in addition for other indications, including community-acquired and nosocomial pneumonia and complicated skin and skin structure infection. Due to the lack of an approved comparator agent, linezolid was evaluated for patients with clinical and microbiological evidence of serious VRE infection in a blinded, parenteral, dose-comparative trial comparing 66 patients randomized to 200 mg q 12 hours to 79 patients treated with 600 mg q 12 hours.76 Among evaluable patients at end-of-treatment, a modest dose response was observed, with 67% and 52% response rates seen in the high-dose and low-dose groups, respectively. In addition, efcacy and safety were also demonstrated in a large study (n 796 patients) emergency-use program for resistant, or treatment-refractory, or treatment-intolerant patients with serious gram-positive

DAPTOMYCIN

Daptomycin is a novel cyclic lipopeptide compound with a broad gram-positive spectrum and rapid bactericidal

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oncologic patients and liver transplant recipients.71,72 Although the precise reason for this toxicity is unknown a neuropathic cause is suspected. Its higher incidence in populations with diminished metabolism and excretion suggest it is due to either native drug or metabolite accumulation. Phenotypic resistance to Q/D among E. faecium (MIC  4 mg/mL) was observed in six (1.8%) and ve (1.3%) of VRE cases, either during or after treatment, from both published emergency use series.71,72 Clonal dissemination of Q/D-resistant strains despite the absence of Q/D or other streptogramin exposure has been described among pediatric patients.73 Three fundamental resistance mechanisms have been discovered: enzymatic modication (acetylation) of dalfopristin encoded by the vatD or vatE genes, active efux by an adenosine triphosphate (ATP)-binding protein encoded by the msrC or lsa genes, and alteration of the ribosomal target site encoded for by the erm genes.70 Because phenotypic resistance requires the presence of resistance mechanisms to both the quinupristin and the dalfopristin components, at least two or more resistance genes are present. Several surveillance studies have uncovered large Q/D resistance reservoirs among E. faecium isolated from both domestic poultry and livestock in the United States, which may relate to the use of virginiamycin as a growth-promoting food additive in domestic poultry.74

infection.77 Among 549 cases of VRE infection, there was an 81.4% clinical cure rate at end-of-therapy. Because linezolid is a bacteriostatic agent that displays no synergistic activity with other agents its efcacy in VRE native- or prosthetic-valve endocarditis remains questionable. Both clinical success and failure have been reported when linezolid has been used as a rst-line therapy or salvage treatment; however, no large-scale randomized trial experience is yet available.7880 In recent years, linezolid has become the dominant agent for the treatment of serious VRE infection. Multiple cases report of linezolid-resistance (MIC  8 mg/mL) occurring in VRE (E. faecium) and vancomycin-susceptible E. faecalis strains that were susceptible (MIC 1 to 2 mg/mL) at baseline but developed a fourfold or greater rise in MIC to 8 to 32 mg/mL.8185 Common to most cases where linezolid-resistance appeared has been a protracted length of therapy (> 28 days) associated with retained foci of VRE infection such as abscesses, devitalized tissue, or foreign materials. The majority of linezolid-resistant isolates contain a single base-pair mutation in the genome encoding for domain V of the 23S ribosomal binding site (G2476U mutation). The phenotypic level of resistance as determined by elevation in MIC level has been shown to correlate with the gene dose or number of copies of 23S rDNA containing the G2466U mutation.86 Notably this mutation was predicted by earlier in vitro spiral plate serial passage experiments with linezolid.87 Horizontal cross transmission of an identical clone of linezolid-resistant E. faecium among linezolid-naive patients within the same ICU or hospital center have also been described.88,89 A case- controlled analysis revealed that a longer course of linezolid (38 days vs 11 days) and linezolid exposure prior to hospitalization were risk factors for the emergence of linezolid-resistant VRE.90 Thus repeat linezolid susceptibility testing is advisable in patients who have had prior linezolid exposure or persistent isolation of a VRE strain on therapy or in patients treated in a nosocomial setting with prior linezolid resistance. Although gastrointestinal symptoms are the most common reported toxicity, reversible myelosuppression (thrombocytopenia, leukopenia, and/or anemia) has been the most important treatment-limiting side effect with higher rates observed than the original registration studies. Bone marrow examination has shown changes similar to those observed with reversible chloramphenicol toxicity.91,92 Such toxicity is usually observed only with sustained linezolid treatment that exceeds 2 weeks. Other reported toxicities of note include gastrointestinal upset, rare cases of serotonin syndrome, optic- and peripheral neuropathy, and lactic acidosis.9396

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activity that is currently approved for complicated skinskin structure infection and S. aureus bacteremia, including right-sided endocarditis.97 Its apparent mechanism of action includes attachment to the exterior of the bacterial cytoplasmic membrane with membrane penetration of a lipophilic tail with disruption of the transmembrane potential due to ion efux, an effect that is both concentration- and calcium iondependent and leads to nonlytic bacterial cell death. In vitro studies have shown nearly uniform activity against vancomycinresistant E. faecium and E. faecalis strains with an MIC 90 of 24 mg/mL.98,99 In one recent study examining only VRE strains that were either linezolid- or Q/Dresistant, daptomycin demonstrated susceptibility using a 4 mg/mL provisional breakpoint.100 The MIC breakpoint is 4 mg/mL for vancomycin-susceptible E. faecalis; however, there is no established breakpoint for vancomycin-susceptible or -resistant E. faecium. Regardless of the testing method (E-test, disk diffusion, or broth dilution) the zone size or MIC result can be signicantly elevated by a two- to eightfold magnitude with inadequate calcium supplementation. To the present time, clinical experience with daptomycin for serious VRE infection remains quite limited. The optimal dosing for enterococcal infection is not yet established; however, daily dosing at 6 mg/kg in the absence of renal insufciency has been the most common dosing scheme. A randomized phase 3 trial versus linezolid in VRE infection was aborted due to enrollment difculties. In a study of nine neutropenic patients with VRE bacteremia treated with daptomycin at 4 mg/kg/day or 6 mg/kg/day, a clinical and/or microbiological response was observed in only 4/9 (44%).101 In a second report a similar response rate of 5/11 (45%) was observed in patients with VRE bacteremia and endocarditis treated with 6 mg/kg/day of daptomycin.102 Unfortunately, daptomycin resistance has been reported during treatment for vancomycin-resistant E. faecalis, E. faecium, and E. durans infection with a rise in the MIC to  8 mg/mL.103106
TIGECYCLINE

tee for Clinical Laboratory Standards (NCCLS) breakpoints for vancomycin-resistant E. faecium strains are not yet established.108,109 Although clinical experience with tigecycline for VRE infection is not yet available it appears to be a promising option, particularly for intra-abdominal sites, where it has shown comparable efcacy to meropenem in non-VRE monomicrobial and polymicrobial infection.
NOVEL GLYCOPEPTIDES (ORITAVANCIN, DALBAVANCIN, TELAVANCIN)

REFERENCES
1. Centers for Disease Control and Prevention. National Nosocomial Infection Surveillance (NNIS) system: report, data summary from January 1992 through June 2003, issued August 2003. Am J Infect Control 2003;31:481498 2. Wisplinghoff H, Bischoff T, Tallent SM, Seiferd H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004;39:309317 3. Moellering RC Jr. The Garrod Lecture. The Enterococcus: a classic example of the impact of antimicrobial resistance on therapeutic options. J Antimicrob Chemother 1991;28:112 4. Murray BE. The life and times of the Enterococcus. Clin Microbiol Rev 1990;3:4665 5. Hodges TL, Zighelboim-Daum S, Eliopoulos GM, Wennersten C, Moellering RC Jr. Antimicrobial susceptibility changes in Enterococcus faecalis following various penicillin exposure regimens. Antimicrob Agents Chemother 1992;36:121125

Tigecycline is the rst approved agent of the glycylcycline class, a group closely related to the tetracyclines but synthetically modied to achieve an enhanced spectrum of activity against MRSA, other multiresistant grampositive species, and many gram-negative bacilli.107 Tigecycline is currently approved for complicated skinskin structure and intra-abdominal infection based upon phase 3 studies showing comparability to standard comparator regimens. Vancomycin-resistant enterococci were not included in these registration trials. However, daptomycin exhibits very low MICs for both vancomycin-susceptible and vancomycin-resistant versus clinical strains of E. faecium and E. faecalis (MIC90 0.012 mg/mL), although National Commit-

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Several new glycopeptide derivatives have in vitro bactericidal activity against VRE. Dalbavancin is a longacting (half-life 7 to 10 days) derivative of teicoplanin, which has received approval for the treatment of complicated skinskin structure infection; however, similarly to teicoplanin, this agent lacks in vitro activity against the more prevalent VanA enterococcal strains.110 Oritavancin is a semisynthetic glycopeptide that blocks peptidoglycan synthesis and exerts bactericidal activity across a broad gram-positive spectrum.111 It has superior activity against vanA and vanB enterococci compared with dalbavancin and telavancin, with concentrationdependent bactericidal activity against both E. faecium and E. faecalis strains (MIC90 1 to 2 mg/mL) and is synergistic with ampicillin against the majority of isolates.112 This agent has completed phase 3 trials in cSSSI (complicated skin-skin structure infection); however, concerns pertaining to its long half-life, high protein binding, and reports of spontaneous resistance may limit its development. Telavancin, a long-acting lipoglycopeptide with multiple sites of action at the cell membrane and cell wall has shown noninferiority versus standard therapy in gram-positive cSSSI, including MRSA; however, clinical data for VRE are not yet available.113,114

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76. Moellering RC. Linezolid: the rst oxazolidinone antimicrobial. Ann Intern Med 2003;138:135142 77. Pharmacia and Upjohn. Linezolid for the Treatment of Vancomycin Resistant Enterococcal Infections: A DoubleBlind Trial Comparing 600 mg Linezolid Every 12 Hours with 200 mg Linezolid Every 12 Hours (study report M/ 1260/0054A). Peapack, NJ: Pharmacia Upjohn; 1999 78. Birmingham MC, Raynes CR, Meagher AK, Flavin SM, Batts DH, Schentag JJ. Linezolid for the treatment of multidrug-resistant gram-positive infections: experience from a compassionate use program. Clin Infect Dis 2003; 36:159168 79. Stevens MP, Edmond MB. Endocarditis due to vancomycin-resistant enterococci: case report and review of the literature. Clin Infect Dis 2005;41:11341142 80. Archuleta S, Murphy B, Keller MJ. Successful treatment of vancomycin-resistant Enterococcus faecium endocarditis with linezolid in a renal transplant recipient with human immunodeciency virus infection. Transpl Infect Dis 2004;6:117119 81. Babcock HM, Ritchie DJ, Christiansen E, Starlin R, Little R, Stanley S. Successful treatment of vancomycin-resistant Enterococcus endocarditis with oral linezolid. Clin Infect Dis 2001;32:13731375 82. Zimmer SM, Caliendo AM, Thigpen MC, Somani J. Failure of linezolid treatment for enterococcal endocarditis. Clin Infect Dis 2003;37:e29e30 83. Tsigrelis C, Singh KV, Coutinho TD, Murray BE, Baddour LM. Vancomycin-resistant Enterococcus faecalis endocarditis: linezolid failure and strain characterization of virulence factors. J Clin Microbiol 2007;45:631635 84. Gonzales RD, Schreckenberger PC, Graham MB, et al. Infections due to vancomycin-resistant Enterococcus faecium resistant to linezolid. Lancet 2001;357:1179 85. Seedat J, Zick G, Klare I, et al. Rapid emergence of resistance to linezolid during linezolid therapy of an Enterococcus faecium infection. Antimicrob Agents Chemother 2006;50:42174219 86. Marra AR, Major Y, Edmond MD. Central venous catheter colonization by linezolid-resistant, vancomycin-susceptible Enterococcus faecalis. J Clin Microbiol 2006;44:19151916 87. Rahim S, Pillai SK, Gold HS, Venkataraman L, Inglima K, Press RA. Linezolid-resistant, vancomycin-resistant Enterococcus faecium infection in patients without prior exposure to linezolid. Clin Infect Dis 2003;36:E146148 88. Swaney SM, Shinabarger DL, Schaadt RD, Bock JH, Slightom JL, Zurenko GE. Oxazolidinone resistance is associated with a mutation in the peptidyl transferase region of 23S rRNA [abstract C-104]. In: Program and Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego. Washington, DC: American Society for Microbiology; 1998:9899 89. Herrero IA, Issa NC, Patel R. Nosocomial spread of linezolid-resistant vancomycin-resistant Enterococcus faecium. N Engl J Med 2002;346:867869 90. Marshall SH, Donskey CJ, Hutton-Thomas R, Salata RA, Rice LB. Gene dosage and linezolid resistance in Enterococcus faecium and Enterococcus faecalis. Antimicrob Agents Chemother 2002;46:33343336 91. Pai MP, Rodvold KA, Schreckenbefger PC, Gonezales RD, Petrolatti JM, Quinn JP. Risk factors associated with the development of infection with linezolid- and vancomycinresistant Enterococcus faecium. Clin Infect Dis 2002;35: 12691272

92. Green SL, Maddox JC, Huttenbach ED. Linezolid and reversible myelosuppression. JAMA 2001;285:1291 93. Halpern M. Linezolid-induced pancytopenia. Clin Infect Dis 2002;35:347348 94. Wigen CL, Goetz MB. Serotonin syndrome and linezolid. Clin Infect Dis 2002;34:16511652 95. Saijo T, Hayashi K, Yamada H, Wakakura M. Linezolidinduced optic neuropathy. Am J Ophthalmol 2005;139: 11141116 96. Bressler AM, Zimmer SM, Gilmore JL, Somani J. Peripheral neuropathy associated with prolonged use of linezolid. Lancet Infect Dis 2004;4:528531 97. Apodaca AA, Rakita RM. Linezolid-induced lactic acidosis. N Engl J Med 2003;348:8687 98. Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant grampositive pathogens. Clin Infect Dis 2004;38:9941000 99. Pfaller MA, Sader HS, Jones RN. Evaluation of the in vitro activity of daptomycin against 19615 clinical isolates of gram positive cocci collected in North American hospitals (20022005). Diagn Microbiol Infect Dis 2007;57:459 465 100. Jorgensen JH, Crawford SA, Kelly CC, Patterson JE. In vitro activity of daptomycin against vancomycin-resistant enterococci of various Van types and comparison of susceptibility testing methods. Antimicrob Agents Chemother 2003;47:37603763 101. Anastasiou DM, Thorne GM, Luperchio SA, Alder JD. In vitro activity of daptomycin against clinical isolates with reduced susceptibility to linezolid and quinupristin/dalfopristin. Int J Antimicrob Agents 2006;28:385388 102. Poutsiaka DD, Skifngeron S, Miller KB, Hadley S, Snydman DR. Daptomycin in the treatment of vancomycin-resistant Enterococcus faecium bacteremia in neutropenic patients. J Infect 2007;54:567571 103. Segreti JA, Crank CW, Finney MS. Daptomycin for the treatment of gram-positive bacteremia and infective endocarditis: a retrospective case series of 31 patients. Pharmacotherapy 2006;26:347352 104. Long JK, Choueiri TK, Hall GS, Avery RK, Sekeres MA. Daptomycin-resistant Enterococcus faecium in a patient with acute myeloid leukemia. Mayop Clin Proc 2005;80: 12151216 105. Munoz-Price LS, Lolans K, Quinn JP. Emergence of resistance to daptomycin during treatment of vancomycinresistant Enterococcus faecalis infection. Clin Infect Dis 2005; 41:565566 106. Lewis JS II, Owens A, Cadena J, et al. Emergence of daptomycin resistance in Enterococcus faecium during daptomycin therapy. Antimicrob Agents Chemother 2005;49: 16641665 107. Green MR, Anasetti C, Sandin RL, Rolfe NE, Greene JN. Development of daptomycin resistance in a bone marrow transplant patient with vancomycin-resistant Enterococcus durans. J Oncol Pharm Pract 2006;12:179181 108. Stein GE, Craig WA. Tigecycline: a critical analysis. Clin Infect Dis 2006;43:518524 109. Sader HS, Jones RN, Stilwell MG, Dowzicky MJ, Fritsche TR. Tigecycline activity tested against 26,474 bloodstream infection isolates: a collection from 6 continents. Diagn Microbiol Infect Dis 2005;52:181186 110. Streit JM, Sader HS, Fritsche TR, Jones RN. Dalbabancin activity against selected populations of antimicrobial resistant

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