Optimizing Therapy for Vancomycin- Resistant 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 signiﬁcantly 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 ﬂora, 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 penicillin–based regimen, or vancomycin in a penicillin-intol- erant 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 modiﬁed antimicrobial compounds approved for VRE infection (quinu- pristin-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 efﬁcacy and tolerability, appears to be the cornerstone of current treatment approaches. Despite a relatively short period of clinical use, enter- ococcal 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 1 Department of Critical Care Medicine, University of Pittsburgh Optimizing Antimicrobial Therapy for Serious Infections in the Medical Center, Pittsburgh, Pennsylvania. Critically Ill; Guest Editor, David L. Paterson, M.D., Ph.D. Address for correspondence and reprint requests: Peter K. Linden, Semin Respir Crit Care Med 2007;28:632–645. Copyright # 2007 M.D., Department of Critical Care Medicine, University of Pittsburgh by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, Medical Center, 602 A Scaife Hall, 3550 Terrace St., Pittsburgh, PA NY 10001, USA. Tel: +1(212) 584-4662. 15261 (e-mail: email@example.com). DOI 10.1055/s-2007-996410. ISSN 1069-3424.632
OPTIMIZING THERAPY FOR VANCOMYCIN-RESISTANT ENTEROCOCCI (VRE)/LINDEN 633INCIDENCE OF ENTEROCOCCAL sporins) is expressed in all enterococci due to theINFECTION AND RESISTANCE TRENDS expression of inner-cell-wall penicillin-binding proteinsEnterococci have become more common and problematic (PBPs) with low afﬁnity for these compounds.3 Expo-pathogens over the past 2 decades, with a rise in both the sure of such enterococcal strains to an effective b-lactamoverall incidence of enterococcal infection and multidrug results in inhibitory but not bactericidal activity asresistance. In a nationwide surveillance study [Surveil- measured by time-killing kinetic curves.4lance and Control of Pathogens of Epidemiological Low-level resistance to aminoglycosides is secon-Importance (SCOPE)] between 1995 and 2002, enter- dary to their low penetrability through the outer-perim-ococci were the third most frequent cause of nosocomial eter envelope of the organism, a property that can bebloodstream infection, and high-level vancomycin- overcome with the synergistic activity of an effective cellresistance was present in 60% of Enterococcus faecium wall active agent such as a penicillin or vancomycin.5strains but only 2% of E. faecalis strains.1 A Centers for Although the majority of enterococci exhibit in vitroDisease Control and Prevention (CDC) surveillance susceptibility to trimethoprim/sulfamethoxasole theirprogram during the same time period showed that VRE ability to utilize exogenous folate in vivo precludesaccounted for 27.5% of intensive care unit (ICU) noso- the clinical utility of trimethoprim-sulfamethoxazolecomial bacteremic and nonbacteremic infections.2 The (TMP/SMX) and other agents that impair folate syn-vast majority of E. faecium strains are multidrug resistant thesis.6 A signiﬁcant percentage of enterococci may alsowith high-level resistance to penicillin and ampicillin possess constitutive resistance to macrolides (erythromy-(MIC > 128 mg/mL) and high-level resistance to cin, azithromycin) and lincosamides (clindamycin) pri-gentamicin (MIC > 1000 mg/mL), which eliminates marily mediated by modiﬁcation of the ribosomalthe potential for bactericidal ‘‘synergistic’’ treatment. attachment site.7The forces behind this important trend include theincreased prevalence and greater longevity of immuno-compromised hosts due to native or iatrogenic immuno- Acquired Resistance Mechanismssuppression, the increased use of antimicrobials that There are few other species of bacteria that have theare devoid of enterococcal activity (cephalosporins, proclivity and efﬁciency of the Enterococcus to acquirequinolones) and thus selective for more resistant pheno- new and multiple antimicrobial resistance mechanisms3,4types, and, most importantly, the appearance of new (Table 2). The genomic elements that encode for resist-resistance mechanisms (i.e., high-level vancomycin ance are carried on plasmid or larger transposon elements,resistance), which confer resistance to previously effective are stable, and often carry multiple resistance determi-antimicrobial classes. nants that culminate in multidrug-resistant strains. Enter- ococci acquire resistance to chloramphenicol (mediated by chloramphenicol acetyltransferase), quinolones (by gyraseANTIMICROBIAL RESISTANCE mutations), rifampin (by mutation of the gene that enc-MECHANISMS AMONG ENTEROCCI odes for RNA polymerase), and tetracyclines (by a variety of mechanisms).8 However, the most clinically importantIntrinsic Resistance Mechanisms antimicrobials to which enterococci have acquired resist-Enterococci possess several constitutive, nontransferable ance are discussed in more detail following here.resistance mechanisms against a variety of antimicro-bials, which limits therapeutic options even for vanco-mycin-susceptible enterococci and magniﬁes the effect High-Level b-Lactam Resistanceof superimposed intrinsic resistance traits (Table 1). Overproduction and/or mutation of the penicillin-Relative or absolute resistance to the b-lactams (pen- binding protein 5 receptor leading to diminished afﬁnityicillin, ampicillin, antipseudomonal penicillins, cephalo- for b-lactams has increased dramatically in E. faecium Table 1 Intrinsic Resistance Mechanisms among Enterococci Antimicrobial Mechanism(s) Comments Ampicillin, penicillin Altered binding protein Aminoglycosides (LL) Decreased permeability Altered High-level gentamicin strains may be ribosomal binding susceptible to high-level streptomycin Clindamycin Altered ribosomal binding Erythromycin Altered ribosomal binding Tetracyclines Efﬂux pump Trimethoprim-sulfamethoxasole Utilize exogenous folate LL, low level.
634 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 28, NUMBER 6 2007 Table 2 Acquired Resistance Mechanisms among Enterococci Antimicrobial Mechanism(s) Comments Ampicillin, penicillin (HL) Mutation of pbp-5 95% of E. faecium < 5% E. faecalis Aminoglycoside (HL) Enzyme modiﬁcation Plasmid mediated Some HL-gentamicin R strains may be streptomycin S Quinolones DNA gyrase mutation Chloramphenicol Efﬂux pump Glycopeptide Altered cell wall binding Transposon 1546 Quinupristin/dalfopristin Ribosomal modiﬁcation Efﬂux pump ermB gene vatd, vate gene Linezolid Single point mutation G2476U mutation Daptomycin Unknown Described in E. faecalis, E. faecium, and E. durans HL, high level. but remains uncommon (< 5%) among E. faecalis England in 1986 was a major watershed mark in the strains.9,10 This property is expressed constitutively and evolution of enterococcal antimicrobial resistance and carried by resistance genes located on chromosomal ele- the ﬁnal step toward the subsequent establishment of ments. E. faecium strains with acquired high-level ampi- endemic multidrug-resistant enterococci.15,16 VRE cillin resistance have ampicillin MICs > 128 mg/mL and strains did not ﬁrst appear in the United States until are neither inhibited nor killed by ampicillin, penicillin, 1989, but thereafter their incidence rapidly increased or other b-lactams. The ubiquity of high-level ampicillin from 0.3% of all enterococci in 1989 to 7.9% in 1993.17 resistance has been a major step toward the eventual During this early period the majority of reported VRE evolution of multidrug resistance among E. faecium as isolates were almost exclusively E. faecium, were mono- the superimposition of other resistance traits have or pauciclonal in origin, and predominantly originated appeared in such strains. from ICU patients in tertiary care centers, particularly in the northeastern United States, where both vanA and vanB genotype outbreaks were observed; however, there High-Level Aminoglycoside Resistance was no discernible epidemiologic or clinical differentia- The ﬁrst reports of high-level gentamicin resistant tion between the two types. Local enhancement of (HLGR) strains in the United States were in 1979, contact precautions usually aborted or signiﬁcantly appearing in both E. faecalis and E. faecium.11 More recent modiﬁed such outbreaks. surveillance data from the SCOPE program between the A more contemporaneous surveillance study of years 1997 and 1999 showed 69 to 71% of all U.S. bloodstream isolates has shown a steady decrease in enterococcal strains were HLGR and 40% of all tested vancomycin susceptibility among E. faecium strains vancomycin-resistant enterococci (VRE) strains.12 Enter- from 60% in 1997 to only 39.1% in 2002, whereas the ococci acquire resistance to aminoglycosides via (1) vast majority (96.1 to 99.4%) of E. faecalis strains changes in the ribosomal attachment sites; (2) diminished continue to remain vancomycin susceptible over this aminoglycoside transport into the cell; and (3) 5-year period.18 The incidence of VRE remains highest aminoglycoside-modifying enzymes (adenyltransferase, in the intensive care unit setting. It has increased to a phosphotransferase, and bifunctional acetyl-phospho- greater relative extent on hospital ﬂoors and parahospital transferase). Although the majority of HLGR strains centers such as long-term acute care (LTAC) facilities also exhibit high-level streptomycin resistance, a minority and skilled-care nursing facilities, which often receive retain sensitivity to streptomycin; thus susceptibility test- patients from hospitals with endemic VRE epidemi- ing to high-level streptomycin is worthwhile in HLGR ology.19 strains.13 No reliable bactericidal activity can be achieved with any antimicrobial combination against strains with high-level aminoglycoside resistance.14 Genetic Basis of Vancomycin Resistance Six distinct glycopeptide resistance phenotypes have been discovered: VanA, VanB, VanC, VanD, VanE, VANCOMYCIN AND OTHER and VanG, distinguished based upon gene content, GLYCOPEPTIDE RESISTANCE glycopeptide minimum inhibitory concentrations (MICs), and inducibility and transferability properties20 Epidemiology (Table 3). The vanA and vanB phenotypes uniformly Without question, the appearance of E. faecium strains confer high-level vancomycin resistance (MIC > 64 mg/ with high-level vancomycin resistance in France and mL) and have the highest prevalence and clinical
OPTIMIZING THERAPY FOR VANCOMYCIN-RESISTANT ENTEROCOCCI (VRE)/LINDEN 635Table 3 Level and Type of Vancomycin Resistance in Enterococci Acquired Resistance Level, Type Intrinsic Resistance. Low Level TypeStrain High, Variable, Moderate, Low VanC1/C2/C3Characteristic VanA VanB VanD VanG VanEMIC, mg/L Vancomycin 64–1000 4–1000 64–128 16 8–32 2–32Teicoplanin 16–512 0.5–1 4–64 0.5 0.5 0.5-1Conjugation Positive Positive Negative Positive Negative NegativeMobile element Tn1546 Tn1547 or Tn1549Expression Inducible Inducible Constitutive Inducible Inducible Constititive InducibleLocation Plasmid Plasmid Choromosome Choromosome Choromosome Choromosome choromosome choromosomeModiﬁed target D-Ala-D--Lac D--Ala-D--Lac D--Ala-D--Lac D--Ala-D--Ser D--Ala-D--Ser D--Ala-D--SerD-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 antibiotic-induced mutation. (2) Ampliﬁcation of theto teicoplanin, this agent was never commercially avail- VRE inoculum within the gastrointestinal reservoirable in the United States, and rapid resistance has been usually due to antimicrobial selective pressures. Priordescribed when VanB strains undergo teicoplanin ex- or ongoing antimicrobials may also enhance the risk ofposure.21 Transposon 1546 (Tn1546) contains the vanA VRE colonization by reducing naturally competing gutgene complex which encodes for an eight-peptide se- ﬂora. (3) Natural- or iatrogenic anatomical or immunequence culminating in ligase-mediated modiﬁcation of defects that lead to bloodstream or nonbloodstreamthe cell wall target for vancomycin from a high afﬁnity (tissue) invasion. Perirectal, rectal, or, preferentially,D-alanine-D-alanine linkage to a low afﬁnity D-ala-nine-D-lactate linkage on the cell wall peptidoglycanterminus.22 The vanB gene cluster has partial DNAhomology with the vanA gene cluster and similarlyencodes for ligase modiﬁcation of the vancomycin target.The vanA gene has been shown to be transferable invitro to Staphylococcus aureus, and naturally occurringvanA gene–mediated vancomycin resistance, probablydue to horizontal transposon transmission, has beenreported in four methicillin-resistant S. aureus (MRSA)strains in three patients with protracted vancomycinexposure for MRSA infection and a fourth patientwithout prior vancomycin exposure.23–28Dynamics and Risk Factors for VRE Colonizationand InfectionColonization with VRE is a necessary prerequisite forVRE superinfection, which will arise only when ana-tomical or other predisposing factors become manifest.Similar to the more susceptible enterococcal strains, thenatural colonizing reservoir for VRE is the intestinaltract, with secondary contiguous reservoirs on the skin,genitourinary tract, and oropharynx.29,30 There are threesequential processes leading to detectable VRE coloni-zation and potential subsequent infection with multiplemodiﬁers (Fig. 1): (1) Exposure to enterococci contain-ing the vancomycin-resistant genome via contact with an Figure 1 Sequence of vancomycin-resistant enterococci (VRE)animate or inanimate source. It should be emphasized exposure and antimicrobial ampliﬁcation leading to VRE super-that the vanA gene does not arise from a spontaneous or infection and increased VRE transmission.
636 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 28, NUMBER 6 2007 stool cultures have been the traditional sites to detect Table 4 Clinical and Epidemiological Clues That MDR VRE colonization.31,32 The duration of VRE intestinal Enterococcal Infection Is Present colonization is variable, can last for months to years, and Signiﬁcant and recent antimicrobial exposure may be indeﬁnite, in part subject to the inoculum- Multiple agents detection threshold of the surveillance testing method Third-generation cephalosporins employed.33–35 Spontaneous clearance of intestinal col- Antianaerobic antimicrobials onization only occurs in the minority of patients in Vancomycin several studies analyzing serial cultures in both antimi- Positive rectal-fecal surveillance culture or vancomycin-resistant crobial- and nonantimicrobial-exposed patients. enterococci from a prior clinical site Multiple case control and cohort studies have Intra-abdominal infection (abscess, peritonitis, cholangitis) analyzed risk factors for either VRE colonization, Indwelling catheters in place (bladder, intravascular) VRE superinfection, or both.36–39 Two fundamental High incidence of MDR enterococci in unit, hospital risk factor categories are demographic/illness severity Prior liver transplant, neutropenia, chemotherapy-related variables and the type, intensity, and duration of recent mucositis antimicrobial exposure. Demographic risks include du- MDR, multidrug-resistant. ration of hospital- and ICU length of stay, physical proximity to VRE-colonized patients in the same unit, gens, a careful clinical assessment of whether the re- and hospitalization in units with a high prevalence of ported isolate is a likely cause of the patient’s clinical VRE, ‘‘colonization pressure.’’ Prior administration of syndrome that merits speciﬁc treatment is always war- multiple antibiotics, third-generation cephalosporins, ranted. Realistically, however, it may be difﬁcult to make antimicrobials with anaerobic spectrums (metronidazole, this distinction, particularly in patients who have major clindamycin), and parenteral vancomycin have been comorbid conditions or critical illness that is naturally implicated in case-control analyses of colonization or coupled with colonization or infection due to multidrug- superinfection. Such antimicrobials probably exert a resistant enterococcal strains. Although enterococci are selective effect and amplify otherwise undetectable or of low virulence, it bears emphasis that they are also smaller VRE inocula in the intestines and other secon- quite capable of promulgating the systemic inﬂammatory dary reservoirs. Donskey and colleagues have demon- response syndrome (SIRS), severe sepsis, and septic strated that the density of VRE as measured by serial shock and have been a frequent inciting blood pathogen quantitative stool cultures increased signiﬁcantly when in recent prospective, randomized sepsis trials.42 patients received ! 1 antianaerobic antimicrobial, Abundant and recent observational studies sup- whereas this effect was not seen in patients receiving port the association between appropriate empirical antimicrobials with minimal antianaerobic activity.40 antimicrobial therapy and survival.43–45 Thus, for the Interestingly, parenteral vancomycin administration re- severe end of the clinical spectrum, strong consideration sulted in no increase in the stool VRE density. More- should be given to empirical antienterococcal therapy for over, patients with high VRE density coupled with fecal patients whose demographic features and clinical pre- incontinence were also more likely to have positive sentation place them at high risk for enterococcal in- environmental cultures for VRE. The ‘‘VRE-selective’’ fection or sepsis. Clearly a major part of this decision also effects of antimicrobials and other risk factors become includes estimating the likelihood that the enterococcal relatively diminished when the proportion of patients strain could be a multidrug-resistant strain. Such epi- already colonized with VRE is 50% or greater, which demiological and clinical clues, which might prompt may explain some studies where newly introduced anti- empirical enterococcal therapy, are summarized in biotic control measures may only yield modest reduc- Table 4. tions in VRE colonization and infection rates in hyperendemic settings.41 Patients with comorbidities, including oncologic conditions, especially neutropenia, Does the Enterococcus in the Culture Result and prior solid organ transplantation, especially liver Require Antimicrobial Treatment? transplantation, appear to have the highest rates of Microbiological culture data that report the presence of VRE bacteremia and poorest outcomes. enterococci always require some level of clinical discrim- ination to determine whether they merit treatment. Enterococcal isolates from a respiratory specimen (spu- GENERAL ISSUES IN THE TREATMENT OF tum, endotracheal aspirate, bronchoalveolar lavage), and ENTEROCOCCAL INFECTION skin, wound, or mucosal surfaces almost always represent The treatment of serious enterococcal infection is chal- colonization. Urine cultures obtained via indwelling lenging from several aspects. Because enterococci may bladder (Foley) catheters often represent asymptomatic colonize skin, wound, and mucosal surfaces and their bacteriuria. Wound and intra-abdominal drains often isolation is often accompanied by more virulent patho- become colonized with skin ﬂora, including enterococci.
OPTIMIZING THERAPY FOR VANCOMYCIN-RESISTANT ENTEROCOCCI (VRE)/LINDEN 637However, such isolates may be signiﬁcant when the Table 5 Nonantimicrobial Interventions forcharacter of the drainage ﬂuid reveals evidence of Vancomycin-Resistant Enterococcal Infectionsinﬂammatory response (i.e., pyuria or purulence). Site of Infection Nonantimicrobial InterventionAlthough enterococci may be blood culture contami- Bloodstream Catheter removalnants, particularly when specimens are obtained from Consider endovascular infection ifindwelling intravascular catheters, the appropriate clin- no primary source obvious orical bias should be that such cultures represent true patient with risk factors forpathogens in most instances. Finally, simple nonantimi- endocarditis or other endovascularcrobial interventions may obviate the need for antienter- materialococcal therapy, such as removal of intravascular or Closed-space Consider percutaneous or surgicalbladder catheters or superﬁcial wound debridement.46,47 infection drainage, e.g., cholangitis— percutaneous transhepatic drainage or endoscopic retrogradeIs Bactericidal Therapy Required? cholangiopancreatography forThe majority of enterococcal infections are not proven to stent placementrequire bactericidal treatment and can be managed Urinary tract infection Removal of bladder cathetersuccessfully with a single effective agent.48,49 Either or bacteriurianative- or prosthetic-valve endocarditis is the prototyp- Superﬁcial wound Incision and drainage or debridementical enterococcal infection for which bactericidal anti- infectionmicrobial therapy is required, usually achieved with the Suspected foreign May require removal if refractorycombination of a cell wall–active agent such as ampicil- body infection to antimicrobial therapylin, penicillin, or vancomycin combined with an amino- or adjacent to devitalized tissueglycoside such as gentamicin or streptomycin. Othersites of infection for which bactericidal treatment isprobably merited include enterococcal meningitis and considerations is summarized in Table 5. It also bearsenterococcemia in a neutropenic host. emphasis that the inability to address the nonantimicro- However, a bactericidal combination is not pos- bial considerations of such complex VRE infections hassible to achieve with enterococci exhibiting high-level been the principal cofactor leading to the development ofaminoglycoside resistance and almost all strains of VRE strains that have evolved resistance to the recentlyE. faecium strains with high-level vancomycin resistance. approved VRE antimicrobials, quinupristin-dalfopristinUncommon exceptions are vancomycin-resistant E. and linezolid.faecalis strains, which retain ampicillin and high-levelgentamicin susceptibility. Successful treatment of suchcases has been reported with ampicillin and gentamicin, Speciﬁc Antimicrobials for the Treatment ofampicillin þ oﬂoxacin, penicillin þ streptomycin, and Vancomycin-Resistant Enterococcal Infectionlinezolid þ gentamicin.50 Limited clinical experience Despite the established high prevalence of multidrug-is available for the treatment of vancomycin-resistant resistant enterococcal strains with high-level vancomy-enterococcal endocarditis with the newer agents (see cin-resistance there is a remarkable paucity of controlled,later discussion). comparative trial data on its antimicrobial treatment. Major obstacles have been the slow development of novel agents with VRE activity, high levels of comor-Nonantimicrobial Treatment of VRE Infection bidity that confound outcome interpretation, complexMany VRE infections may be partially or completely surgical infection for which antimicrobial therapy alonecured with conservative or aggressive nonantimicrobial is not curative, and the polymicrobial nature of manyinterventions. Less serious infections such as bladder VRE infections, particularly those occurring in thecatheter–associated bacteriuria and urinary tract infec- abdomen. Both approved and nonapproved treatmenttion may be adequately treated simply with catheter options for VRE are summarized in Table 6. At presentremoval. Postoperative superﬁcial wound infections there are only two U.S. Food and Drug Administrationmay also respond to opening the incision and simple (FDA)-approved treatments for VRE (E. faecium) in-drainage or debridement. Closed-space infection such as fection: quinupristin/dalfopristin (Q/D, Synercid, Kingintra-abdominal abscesses, cholangitis due to biliary Pharmaceuticals, Inc., Bristol, TN) and linezolid (Zyvox,obstruction, devitalized tissue, or infected foreign bodies Pﬁzer, New York, NY) and two other approved agents(intravascular catheters, synthetic graft or mesh material, that have in vitro activity against VRE but are notprosthetics) are not infrequently the primary source of approved for VRE infection; daptomycin (Cubicin,VRE bacteremic or nonbacteremic infection. The treat- Cubist Pharmaceuticals, Lexington, MA), which is ap-ment implications for infections with such anatomical proved for complicated skin–skin structure infection,
638 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 28, NUMBER 6 2007 Table 6 Therapeutic Antimicrobial Options for VRE Infection Antimicrobial(s) Reported Evidence Comments High-dose ampicillin or Case reports May be effective with VRE strains ampicillin-sulbactam with ampicillin MIC 32–64 mg/mL Chloramphenicol Case series Resistance reported Tetracycline, doxycycline Case reports Æ rifampin or ciproﬂoxacin Novobiocin Anecdotal No longer manufactured Nitrofurantoin Small case series Only for urinary tract infections Teicoplanin Case reports Not active against VanAResistance in VanB reported Quinupristin/dalfopristin Large case series but noncomparative Bacteriostatic Not active against E. faecalis Resistance reported Linezolid 1. Dose comparative trial Bacteriostatic 2. Large compassionate use series Resistance reported Daptomycin 1. Case report þ series Bactericidal Resistance reported Tigecycline In vitro data only Bacteriostatic Dalbavancin In vitro data only VanA strains resistant Telavancin In vitro data only Oritavancin In vitro data only MIC, minimum inhibitory concentration. and S. aureus bacteremia and tigecycline (Tygacil, Wyeth been reported with the use of tetracycline, doxycycline, Pharmaceuticals, Inc., Philadelphia, PA), which is ap- and oral novobiocin combined with either ciproﬂoxacin or proved for complicated skin–skin structure and intra- doxycycline; however, such experience has never been rep- abdominal infection. roduced in larger clinical series of prospective trials.55–58 Prior to the availability of Q/D and linezolid Teicoplanin, a glycopeptide not commercially approval several centers published their experience with available in the United States, does have in vitro activity a variety of available agents or combinations that dem- versus VanB phenotypic enterococci. In a European onstrated in vitro activity. Clinical success was described study of 63 patients with vancomycin-susceptible enter- with high parenteral dosages of ampicillin or ampicillin/ ococcal infection, clinical and microbiological responses sulbactam (18 to 24 g/day), even including endocarditis. were observed in 84% and 87% of cases, respectively.59 Such a strategy appears limited to those uncommon VRE This agent remains unstudied for VanB enterococcal strains with ampicillin MICs of 32 to 64 mg/mL, a target infection, perhaps in part due to the development of range for which plasma ampicillin levels can be achieved teicoplanin resistance among VanB E. faecalis during with high dose therapy.50–52 Because no b-lactamase teicoplanin therapy.60,61 elaboration occurs with VRE, the mechanism of sulbac- Nitrofurantoin has in vitro activity against both tam activity is not known, although a plausible explan- VanA and VanB enterococci.62 Due to its ability to ation is its intrinsic penicillin-binding protein properties. achieve high urinary concentrations nitrofurantoin has Chloramphenicol has bacteriostatic activity against been shown to be effective in VRE urinary tract enterococci and VRE strains; however, its in vivo efﬁcacy infection.46,63 Nitrofurantoin cannot be employed for was never established. In a retrospective study of 80 cases VRE outside the urinary tract and in patients with a of VRE bacteremia, 51 patients were treated with chlor- creatinine clearance < 30 mL/min because elevated amphenicol from which 22/36 (61%) evaluable patients blood concentrations are associated with hepatic, pul- demonstrated a clinical response.53 A microbiological monary, hematologic, and other toxicities. response was also observed in 33/43 (77%) of the micro- biologically evaluable patients. No survival beneﬁt was QUINUPRISTIN/DALFOPRISTIN observed compared with VRE bacteremic patients in the Quinupristin/dalfopristin (Q/D) is a semisynthetic study cohort who did not receive chloramphenicol. Sub- parenteral streptogramin compound, which is derived sequently at the same center, the prevalence of chloram- from its parent natural compound pristinamycin, a phenicol resistance among VRE strains over a 10-year product of Streptomyces pristinaspiralis, an oral and top- period (1991 to 2000) were observed to increase from 0 to ical antistaphylococcal agent that has been in clinical use 11%, a trend that correlated signiﬁcantly with prior in Europe since the 1980s. The major properties of this chloramphenicol or quinolone exposure.54 Isolated re- compound are summarized in Table 7. This antimicro- ports of favorable outcome for VRE infection have also bial is a 30:70 mixture of quinupristin and dalfopristin,
OPTIMIZING THERAPY FOR VANCOMYCIN-RESISTANT ENTEROCOCCI (VRE)/LINDEN 639Table 7 Major Features of Quinupristin/Dalfopristin and LinezolidFeature Quinupristin/ Dalfopristin LinezolidAntimicrobial class Streptogramn OxazolidinonePeak serum concentrations (mg/L) 10-12 15.1Elimination half-life (h) 0.8 (Q) , 0.6 (D) 5.5Major metabolic routes Hepatobiliary Peripheral nonoxidativeMajor elimination routes Faecal (70-75%) Nonrenal (65%) Urinary (19%) Urinary (30%)Protein binding (%) 30 (Q) 70 (D) 31Mechanism of action Protein synthesis inhibition Protein synthesis inhibitionSite of action 50S ribosome 70S initiation complexPostantibiotic effect (h) 6–8 1Bactericidal (vs VRE) No NoCytochrome P-450 inhibition Yes NoFormulations Parenteral Parenteral þ oralDose and administration 5–7.5 mg/kg q 8–12h 600 mg q12 hDosage adjustment None NoneApproved indications VRE VRE Complicated SSSI Complicated SSSI Nosocomial pneumonia Nosocomial pneumoniaMajor adverse effects Phlebitis (peripheral) Myelosuppression Myalgia/arthralgiaCost ($US per day; 2000 values) $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)which are derivatives of streptogramin types B and A, Clinical interest in the utility of Q/D for seriousrespectively. It is a unique antimicrobial because it acts VRE infection began in the mid-1990s with a large-through sequential ribosomal binding and is internally scale, noncomparative, open-label, emergency usesynergistic to produce a bactericidal effect. Dalfopristin program for multiresistant gram-positive infection, prin-initially binds to the 50S bacterial ribosome, which in- cipally vancomycin-resistant E. faecium and MRSA in-duces a permanent conformational change that acceler- fection refractory or intolerant to vancomycin.66,67 Theates quinupristin ribosomal binding.64 Protein synthesis patient populations in both series had a high prevalenceis impaired via both the interruption of peptide chain of acute and chronic comorbidities, including diabetes,elongation and the inhibition of formed peptide extru- oncologic conditions, chronic liver disease, dialysis me-sion. SSuch synergism results in bactericidal activity chanical ventilation, and prior organ transplantation.against some important gram-positive species, including Q/D was administered at 7.5 mg/kg intravenously everyStreptococcus pneumoniae, Streptococcus agalacticae, and 8 hours to patients with documented VRE bacteremia orsome strains of Staphylococcus aureus. However, only nonbacteremic VRE infection, with the duration ofbacteriostatic activity is present for the majority of E. treatment determined by the primary treating physi-faecium strains by time–killing curve studies. This effect is cians. The overall success rate deﬁned as both clinicalprimarily mediated by 23S ribosomal modiﬁcation success and bacteriologic eradication was 65.8% in theencoded for by the ermB gene (erythromycin methylase), initial study and 65.6% in the follow-up study. Therewhich reduces quinupristin afﬁnity for its ribosomal have been several reports of clinical cure combining Q/Dbinding site and thus limits activity to only the dalfopris- with doxycycline or high-dose ampicillin in endocarditis;tin moiety. Such strains are termed MLSb (macrolide- however, no larger-scale experience has been per-lincosamide-streptogramin) phenotypes.65 Erythromycin formed.68–70resistance serves as an excellent surrogate marker for the As Q/D usage increased both before and after itspresence of the MLSb phenotype among enterococci. regulatory approval in 1999, several important clinicalQ/D is also unique as an antienterococcal agent based limitations became apparent. Peripheral intravenousupon its marked disparity in in vitro susceptibility be- administration was associated with a high rate oftween E. faecium (MIC90 ¼ 1 to 2 mg/mL) and E. faecalis phlebitis necessitating central venous administration.(MIC90 ¼ 8 to 16 mg/mL). This disparity is most likely Myalgia and arthralgia unassociated with objectivedue to altered ribosomal binding or presence of an active inﬂammatory signs were observed in 7 to 10% of patientsefﬂux pump. in the emergency use program, with much higher rates in
640 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 28, NUMBER 6 2007 oncologic patients and liver transplant recipients.71,72 infection.77 Among 549 cases of VRE infection, there Although the precise reason for this toxicity is unknown was an 81.4% clinical cure rate at end-of-therapy. a neuropathic cause is suspected. Its higher incidence in Because linezolid is a bacteriostatic agent that displays populations with diminished metabolism and excretion no synergistic activity with other agents its efﬁcacy in suggest it is due to either native drug or metabolite VRE native- or prosthetic-valve endocarditis remains accumulation. Phenotypic resistance to Q/D among questionable. Both clinical success and failure have been E. faecium (MIC ! 4 mg/mL) was observed in six reported when linezolid has been used as a ﬁrst-line (1.8%) and ﬁve (1.3%) of VRE cases, either during or therapy or salvage treatment; however, no large-scale after treatment, from both published emergency use randomized trial experience is yet available.78–80 In series.71,72 Clonal dissemination of Q/D-resistant recent years, linezolid has become the dominant agent strains despite the absence of Q/D or other streptogra- for the treatment of serious VRE infection. Multiple min exposure has been described among pediatric pa- cases report of linezolid-resistance (MIC ! 8 mg/mL) tients.73 Three fundamental resistance mechanisms have occurring in VRE (E. faecium) and vancomycin-suscep- been discovered: enzymatic modiﬁcation (acetylation) of tible E. faecalis strains that were susceptible (MIC 1 to dalfopristin encoded by the vatD or vatE genes, active 2 mg/mL) at baseline but developed a fourfold or greater efﬂux by an adenosine triphosphate (ATP)-binding rise in MIC to 8 to 32 mg/mL.81–85 Common to most protein encoded by the msrC or lsa genes, and alteration cases where linezolid-resistance appeared has been a of the ribosomal target site encoded for by the erm protracted length of therapy (> 28 days) associated genes.70 Because phenotypic resistance requires the with retained foci of VRE infection such as abscesses, presence of resistance mechanisms to both the quinu- devitalized tissue, or foreign materials. The majority of pristin and the dalfopristin components, at least two or linezolid-resistant isolates contain a single base-pair more resistance genes are present. Several surveillance mutation in the genome encoding for domain V of the studies have uncovered large Q/D resistance reservoirs 23S ribosomal binding site (G2476U mutation). The among E. faecium isolated from both domestic poultry phenotypic level of resistance as determined by elevation and livestock in the United States, which may relate to in MIC level has been shown to correlate with the ‘‘gene the use of virginiamycin as a growth-promoting food dose’’ or number of copies of 23S rDNA containing the additive in domestic poultry.74 G2466U mutation.86 Notably this mutation was pre- dicted by earlier in vitro spiral plate serial passage LINEZOLID experiments with linezolid.87 Horizontal cross trans- Linezolid is an oxazolidinone compound, a novel syn- mission of an identical clone of linezolid-resistant thetic class that inhibits bacterial protein synthesis in a E. faecium among linezolid-naive patients within the unique fashion via inhibiting the formation of the 70S same ICU or hospital center have also been de- initiation complex (50S and 30S ribosomes, mRNA, scribed.88,89 A case- controlled analysis revealed that a initiation factors 2 and 3, and fMet-tRNA).75 The major longer course of linezolid (38 days vs 11 days) and properties of linezolid are summarized in Table 6. Line- linezolid exposure prior to hospitalization were risk zolid exhibits a broad gram-positive spectrum but has factors for the emergence of linezolid-resistant VRE.90 only bacteriostatic activity against vancomycin-resistant Thus repeat linezolid susceptibility testing is advisable in or susceptible enterococci with an MIC90 of 2 mg/mL, patients who have had prior linezolid exposure or per- which is right at the susceptibility breakpoint. FDA sistent isolation of a VRE strain on therapy or in patients approval was granted in 2000 for vancomycin-resistant treated in a nosocomial setting with prior linezolid E. faecium infection in addition for other indications, resistance. Although gastrointestinal symptoms are the including community-acquired and nosocomial pneu- most common reported toxicity, reversible myelosup- monia and complicated skin and skin structure infection. pression (thrombocytopenia, leukopenia, and/or anemia) Due to the lack of an approved comparator agent, has been the most important treatment-limiting side linezolid was evaluated for patients with clinical and effect with higher rates observed than the original regis- microbiological evidence of serious VRE infection in a tration studies. Bone marrow examination has shown blinded, parenteral, dose-comparative trial comparing changes similar to those observed with reversible chlor- 66 patients randomized to 200 mg q 12 hours to amphenicol toxicity.91,92 Such toxicity is usually observed 79 patients treated with 600 mg q 12 hours.76 Among only with sustained linezolid treatment that exceeds evaluable patients at end-of-treatment, a modest dose 2 weeks. Other reported toxicities of note include response was observed, with 67% and 52% response rates gastrointestinal upset, rare cases of serotonin syndrome, seen in the high-dose and low-dose groups, respectively. optic- and peripheral neuropathy, and lactic acidosis.93–96 In addition, efﬁcacy and safety were also demonstrated in a large study (n ¼ 796 patients) emergency-use DAPTOMYCIN program for resistant, or treatment-refractory, or treat- Daptomycin is a novel cyclic lipopeptide compound with ment-intolerant patients with serious gram-positive a broad gram-positive spectrum and rapid bactericidal
OPTIMIZING THERAPY FOR VANCOMYCIN-RESISTANT ENTEROCOCCI (VRE)/LINDEN 641activity that is currently approved for complicated tee for Clinical Laboratory Standards (NCCLS) break-skin–skin structure infection and S. aureus bacteremia, points for vancomycin-resistant E. faecium strains are notincluding right-sided endocarditis.97 Its apparent yet established.108,109 Although clinical experience withmechanism of action includes attachment to the exterior tigecycline for VRE infection is not yet availableof the bacterial cytoplasmic membrane with membrane it appears to be a promising option, particularly forpenetration of a lipophilic tail with disruption of the intra-abdominal sites, where it has shown comparabletransmembrane potential due to ion efﬂux, an effect that efﬁcacy to meropenem in non-VRE monomicrobial andis both concentration- and calcium ion–dependent and polymicrobial infection.leads to nonlytic bacterial cell death. In vitro studieshave shown nearly uniform activity against vancomycin- NOVEL GLYCOPEPTIDES (ORITAVANCIN, DALBAVANCIN,resistant E. faecium and E. faecalis strains with an MIC TELAVANCIN)90 of 2–4 mg/mL.98,99 In one recent study examining Several new glycopeptide derivatives have in vitro bac-only VRE strains that were either linezolid- or Q/D- tericidal activity against VRE. Dalbavancin is a long-resistant, daptomycin demonstrated susceptibility using acting (half-life 7 to 10 days) derivative of teicoplanin,a 4 mg/mL provisional breakpoint.100 The MIC break- which has received approval for the treatment of com-point is 4 mg/mL for vancomycin-susceptible E. faecalis; plicated skin–skin structure infection; however, similarlyhowever, there is no established breakpoint for vanco- to teicoplanin, this agent lacks in vitro activity againstmycin-susceptible or -resistant E. faecium. Regardless the more prevalent VanA enterococcal strains.110of the testing method (E-test, disk diffusion, or broth Oritavancin is a semisynthetic glycopeptide that blocksdilution) the zone size or MIC result can be signiﬁ- peptidoglycan synthesis and exerts bactericidal activitycantly elevated by a two- to eightfold magnitude with across a broad gram-positive spectrum.111 It has superiorinadequate calcium supplementation. To the present activity against vanA and vanB enterococci comparedtime, clinical experience with daptomycin for serious with dalbavancin and telavancin, with concentration-VRE infection remains quite limited. The optimal dependent bactericidal activity against both E. faeciumdosing for enterococcal infection is not yet established; and E. faecalis strains (MIC90 ¼ 1 to 2 mg/mL) and ishowever, daily dosing at 6 mg/kg in the absence of renal synergistic with ampicillin against the majority of iso-insufﬁciency has been the most common dosing scheme. lates.112 This agent has completed phase 3 trials in cSSSIA randomized phase 3 trial versus linezolid in VRE (complicated skin-skin structure infection); however,infection was aborted due to enrollment difﬁculties. concerns pertaining to its long half-life, high proteinIn a study of nine neutropenic patients with VRE binding, and reports of spontaneous resistance maybacteremia treated with daptomycin at 4 mg/kg/day limit its development.or 6 mg/kg/day, a clinical and/or microbiological re- Telavancin, a long-acting lipoglycopeptide withsponse was observed in only 4/9 (44%).101 In a second multiple sites of action at the cell membrane and cellreport a similar response rate of 5/11 (45%) was wall has shown noninferiority versus standard therapy inobserved in patients with VRE bacteremia and endo- gram-positive cSSSI, including MRSA; however, clin-carditis treated with 6 mg/kg/day of daptomycin.102 ical data for VRE are not yet available.113,114Unfortunately, daptomycin resistance has been re-ported during treatment for vancomycin-resistantE. faecalis, E. faecium, and E. durans infection with a REFERENCESrise in the MIC to ! 8 mg/mL.103–106 1. 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