Management of multidrugresistant enterococcal infections

Management of multidrug-resistant enterococcal infections C. A. Arias1,2,3, G. A. Contreras3,4 and B. E. Murray1,5 1) Department of Internal Medicine, Division of Infectious Diseases and Center for the Study of Emerging and Reemerging Pathogens, 2) Center for the Study of Emerging and Reemerging Pathogens, Laboratory for Antimicrobial Research, University of Texas Medical School at Houston, Houston, TX, USA, 3) Molecular Genetics and Antimicrobial Resistance Unit, Universidad El Bosque, Bogota´, Colombia, 4) Division of Pediatric Infectious Diseases, Department of Pediatrics and 5) Department of Microbiology and Molecular Genetics, University of Texas Medical School at Houston, Enterococci are organisms with a remarkable ability to adapt to the environment and acquire antibiotic resistance determinants. The evolution of antimicrobial resistance in these organisms poses enormous challenges for clinicians when faced with patients affected with severe infections. The increased prevalence and dissemination of multidrug-resistant Enterococcus faecium worldwide has resulted in a major decrease in therapeutic options because the majority of E. faecium isolates are now resistant to ampicillin and vancomycin, and exhibit high-level resistance to aminoglycosides, which are three of the traditionally most useful anti-enterococcal antibiotics. Newer antibiotics such as linezolid, daptomycin and tigecycline have good in vitro activity against enterococcal isolates, although their clinical use may be limited in certain clinical scenarios as a result of reduced rates of success, possible underdosing for enterococci and low serum levels, respectively, and also by the emergence of resistance. The experimental agent oritavancin may offer some hope for the treatment of vancomycin-resistant enterococci but clinical data are still lacking. Thus, optimal therapies for the treatment of multidrug- resistant enterococcal infections continue to be based on empirical observations and extrapolations from in vitro and animal data. Clini- cal studies evaluating new strategies, including combination therapies, to treat severe vancomycin-resistant E. faecium infections are urgently needed.
Keywords: Antibiotics, enterococci, resistance, review, vancomycin Clin Microbiol Infect 2010; 16: 555–562 Corresponding author and reprint requests: B. E. Murray, 6431Fannin Street MSB 2.112, Houston, TX 77030, USAE-mail: antibiotic resistance determinants [4]. The emergence of resistance to the most common anti-enterococcal antibiotics has made the treatment of these infections a real challenge Enterococci are common causes of nosocomial infections for clinicians. We review the current and possible future and are ranked second (after staphylococci) as aetiological therapeutic options for the management of infections caused agents of hospital-associated infections in US hospitals, with by multidrug-resistant (MDR) enterococci.
Enterococcus faecalis and Enterococcus faecium currently iso- lated in an approximately 1.5:1 ratio [1]. In Europe, the prev- Therapeutic Choices and Resistance alence of vancomycin resistance in enterococci appears to be increasing, with important regional differences (highest in Greece, UK and Portugal) [2,3]. The ability of enterococci to b-lactams and synergism with aminoglycosides colonize the gastrointestinal (GI) tract of hospitalized humans Enterococci are often tolerant to the activity of penicillin and for long periods is a crucial factor that influences the devel- other b-lactams; this property differentiates enterococci opment of drug resistance. Inside the GI tract, enterococci from most streptococci which, in general, are also suscepti- serve as a reservoir for cycles of transmission and spread of ble to much lower concentrations of b-lactams. Although ª2010 The Authors Journal Compilation ª2010 European Society of Clinical Microbiology and Infectious Diseases Clinical Microbiology and Infection, Volume 16 Number 6, June 2010 rare, resistance to b-lactam antibiotics in E. faecalis is usually In spite of the good in vitro inhibitory activity of ampicillin mediated by the production of a b-lactamase enzyme [5,6].
and penicillin against most E. faecalis, previous in vitro and in Non-b-lactamase-mediated resistance to ampicillin and imipe- vivo studies have shown that b-lactam monotherapy is associ- nem has also been reported in E. faecalis and appears to be ated with a poor outcome in patients with endovascular associated with mutations of the pbp4 gene [7]. Conversely, resistance to b-lactams in most clinical isolates of E. faecium therapy that, for many strains, is not achieved with the use of is associated with mutations or overproduction of PBP5, ampicillin or penicillin alone as a result of the tolerance (lack with ampicillin MICs of >256 mg/L in some strains [8]. The of killing) of enterococci to these compounds. Moreover, emergence of b-lactam resistance precludes the use of these certain enterococcal strains are killed only at a specific con- compounds for the treatment of severe enterococcal infec- centration of the b-lactam, above which the killing effect tions with two notable exceptions: (i) infections caused by decreases (designated the Eagle effect [11]), making the b-lactamase-producing E. faecalis may respond to a b-lactam/ success of b-lactam monotherapy unpredictable for severe b-lactamase inhibitor combination (e.g. ampicillin-sulbactam) enterococcal infections. With rare exceptions, synergistic plus an aminoglycoside when treating endocarditis [9,10] and and bactericidal therapy can be reliably achieved with the (ii) strains of E. faecium with MICs of ampicillin of £64 mg/L addition of an aminoglycoside to the b-lactam (or other cell may respond to high-dose ampicillin therapy (18–30 g per wall agent such as vancomycin), as long as the organism does day plus one of the recommended aminoglycosides) because not exhibit high-level resistance (HLR) to the aminoglycoside, sufficient plasma concentrations (>150 mg/L) can be achieved making this combination the standard of care for severe with the high-dose regimen (Fig. 1) [8].
enterococcal infections [12]. Gentamicin and streptomycin Penicillin or ampicillin plus an Non-HLR aminoglycosides E. faecalis Ampicillin plus ceftriaxone (or cefotaxime) HD daptomycin3 plus ampicillin HLR aminoglycosides HD daptomycin3 ± another active agent4Ampicillin plus imipenem (or another active agent)4 Ampicillin MIC ≤ 64 µg/ml HD ampicillin5 plus an aminoglycoside2 Non-HLR aminoglycosides HD ampicillin5 plus HD daptomycin3 Ampicillin MIC ≤ 64 µg/ml Q/D6 plus HD ampicillin or doxycycline with HLR aminoglycosides rifampin HD ampicillin plus imipenem7 Linezolid6 ± another active agent4 E. faecium HD daptomycin3 plus an aminoglycoside5 Ampicillin MIC > 64 µg/ml Q/D6 ± another active agent4 Non-HLR aminoglycosides Linezolid6 ± another active agent4 HD daptomycin3 ± another active agent4 Ampicillin MIC > 64 µg/ml Q/D6 ± another active agent4 HLR aminoglycosides Linezolid6 ± another active agent4 FIG. 1. Suggested therapeutic alternatives in severe infections caused by vancomycin-resistant enterococcal infections. (1) In rare cases of b-lac- tamase-producing isolates, ampicillin-sulbactam (12–24 g/day) is suggested. The use of a continuous infusion is recommended by some experts.
(2) Gentamicin or streptomycin. (3) Consider doses of 8–12 mg/kg day. (4) Agents with potential activity include tigecycline [62,63], doxycycline with rifampin or a fluoroquinolone (if susceptible to each agent). (5) Doses to up to 30 g/day could be considered. (6) Quinupristin-dalfopristin or linezolid are listed in the American Heart Association recommendations for the treatment of vancomycin and ampicillin-resistant Enterococcus faecium. Linezolid has been used with success in a few cases of meningitis as a result of vancomycin-resistant enterococci [61,74]. (7) if imipenem MIC < 32 mg/L. HLR, high-level resistance; HD, high-dose.
ª2010 The AuthorsJournal Compilation ª2010 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 555–562 Arias et al.
Treatment of resistant enterococci are the recommended aminoglycosides for synergistic ther- most active single agent in an animal model of endocarditis apy in combination with a cell wall agent and the use of other compounds of this family is not recommended because of the frequent presence of the aminoglycoside 6¢-acetyltransferase Glycopeptides and lipoglycopeptides (an intrinsic feature of E. faecium, precluding the use of The isolation of vancomycin-resistant enterococci (VRE) has tobramycin, kanamycin, netilmicin and sisomicin) and the aph- steadily increased worldwide subsequent to 1986. A recent (3¢)-IIIa gene that confers HLR to kanamycin and abolishes study from the CDC indicates that, among 983 E. faecium synergism with amikacin. Although enterococci are not isolates analyzed (2006–2007), 80% were resistant to vanco- susceptible to gentamicin and streptomycin at levels used for mycin; conversely, just 6.9% of E. faecalis isolates were other organisms (considered to be a result of a decrease in vancomycin-resistant (n = 1542) [1]. In Europe, the emer- the permeability of the cell wall), the addition of an agent that gence of VRE was initially correlated with the use of the blocks peptidoglycan synthesis markedly increases the uptake glycopeptide avoparcin, which was used as a growth of these antibiotics [13–16]. Nonetheless, in recent years, the promoter in animal husbandry. However, even after the ban acquisition of ribosomal mutations and/or aminoglycoside of avoparcin, the European continent has continued to modifying enzymes that confer HLR to streptomycin or gen- experience an important increase in the isolation of VRE tamicin continue to increase worldwide (although indepen- (E. faecium) from hospitals, indicating that other factors are dent mechanisms, both can occur in the same strain). HLR to promoting the dissemination of VRE in Europe. The streptomycin and gentamicin is defined as growth at concen- increased isolation of vancomycin-resistant E. faecium in hos- pitals worldwide has been attributed to the emergence of a eliminating the synergistic bactericidal effect of the combina- specific genetic lineage designated clonal cluster 17 [22].
tion of the cell wall agent and the aminoglycoside [12–15].
Vancomycin resistance continues to evolve in enterococci The European Committee on Antimicrobial Susceptibility and newer phenotypes have been described. Because of the Testing (EUCAST) has defined HLR to gentamicin as increased presence of gene clusters conferring resistance to MIC > 128 mg/L (EUCAST website: glycopeptides in E. faecium, vancomycin has become almost clinical_breakpoints/ for relevant clinical breakpoints). The obsolete for the treatment of E. faecium infections (at least bifunctional enzyme AAC (6¢)-Ie-APH(2¢¢)-Ia (i.e. the most in the USA).
commonly found enzyme) confers resistance to all available Telavancin is a derivative of vancomycin and also binds to aminoglycosides, except streptomycin. Other enzymes found the D-alanine-D-alanine terminus of peptidoglycan precursors; in enterococci include ANT(6¢)-Ia and APH(2¢¢)-Ic, which unlike vancomycin, telavancin also produces disruption of the confer resistance to streptomycin and gentamicin, respec- bacterial membrane potential leading to increased cell per- tively [13].
meability, which is thought to contribute to the mechanism In addition to the widespread dissemination of genes of bacterial killing [23,24]. Telavancin was recently approved encoding aminoglycoside-modifying enzymes (see above), the by the Food and Drug Administration (FDA) for the treat- use of aminoglycosides is limited in critically ill patients ment of complicated skin and skin structure infections because of their nephrotoxic potential. The combination of (including those caused by vancomycin-susceptible E. faecalis), ceftriaxone (or cefotaxime) and ampicillin has been recently but is not likely to be useful for the treatment of VRE infec- tested as an alternative. The rationale for the use of this tions because effective killing will not be attained at the combination is based on observations that complementary doses recommended [12,25].
saturation and inhibition of E. faecalis PBPs by ceftriaxone Oritavancin is a glycopeptide semisynthetic derivative of and ampicillin can result in a synergistic effect [17,18]. Clini- chloroeremomycin with the interesting property that it cal support for this concept has been documented in a retains activity against VRE. In a clinical trial evaluating the nonrandomized trial that involved 13 hospitals in Spain [19]; efficacy of oritavancin for skin and soft tissue infections of note, this synergistic effect was not observed with (mostly caused by staphylococci and streptococci), this anti- E. faecium isolates. Additionally, the success of ampicillin, biotic was comparable to vancomycin (approximately 78%) imipenem plus vancomycin for the management of E. faecalis [26,27]. Recent data using solid-state nuclear magnetic reso- nance imaging suggest that the increased activity of oritavan- reported. In experimental endocarditis caused by vancomy- cin against VRE isolates (E. faecium) is a result of the cin-resistant E. faecium, the combination of ampicillin and presence of binding sites other than to the D-Ala-D-Ala ter- imipenem produced a statistically significant decrease in minus of peptidoglycan precursors [28]. Oritavancin also bacterial counts from vegetations (5-log10) compared to the appears to disrupt membrane potential and permeability ª2010 The Authors Journal Compilation ª2010 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 555–562 Clinical Microbiology and Infection, Volume 16 Number 6, June 2010 [29]. In experimental endocarditis (rabbit) caused by strains and the addition of another active agent may have a clinical of vancomycin-resistant E. faecalis (VanA or VanB pheno- benefit, perhaps by preventing the emergence of resistant type), an intramuscular regimen of 20 mg/kg produced a sig- mutants, and should be carefully weighed in the face of nificant reduction in the bacterial counts of vegetations severe endovascular infections (Fig. 1).
compared to controls. Nonetheless, mutants with increased oritavancin MICs were selected in the VanA-type strains (approximately 10)7), although the addition of gentamicin Linezolid is an oxazolidinone antibiotic that inhibits bacterial prevented the selection of mutants and provided a synergis- ribosomal protein synthesis [44]. Clinically relevant linezolid tic effect [30,31].
resistance in enterococci is mostly mediated by mutations in domain V of the 23S rRNA, which appear to alter the inter- action of the antibiotic with its target [45,46]. Even though Daptomycin is a lipopeptide antibiotic [32] that has FDA- linezolid has an FDA approval for some VRE infections and European Medicines Agency (EMEA)-approved indica- (Table 1) and is recommended by the American Heart Asso- tions for the treatment of complicated skin and soft tissue ciation [47] for the treatment of endocarditis as a result of infections caused by susceptible Gram-positive organisms multidrug-resistant enterococci, the use of linezolid in severe (they do not include VRE, and EUCAST daptomycin break- enterococcal infections is a matter of controversy, mainly points for enterococci have not been set) and bacteraemia because of the lack of a bactericidal effect and a paucity of caused by Staphylococcus aureus. The mechanism of action prospective randomized clinical trials. In 2003, an open-label, involves the interaction of the antibiotic with the cytoplasmic noncomparative and nonrandomized study that evaluated the membrane via the calcium-dependent insertion of its hydro- efficacy of linezolid for Gram-positive infections found that phobic moiety leading to alteration of membrane potential the clinical cure and microbiologic eradication rates for and permeability [33]. Daptomycin has concentration-depen- vancomycin-resistant E. faecium bacteraemia were 78% and dent bactericidal activity against enterococci in in vitro models 85%, respectively [46]; in the case of bacteraemia as a result and the pharmacodynamic parameters that correlate best of endocarditis, the percentages of clinical and microbiologi- with antimicrobial activity appear to be the area under the cal success were lower (76% and 63%, respectively). In this curve/MIC and peak concentration/MIC ratios [34,35]; in vitro study, however, a significant number of the patients were synergism with rifampin (against E. faecium), fosfomycin lost to follow up and only a small sample size was available (against E. faecalis) and gentamicin (against E. faecalis) has for evaluation; thus, the actual efficacy of linezolid may have been described [36–38].
been overestimated [46]. A small meta-analysis performed to Emergence of daptomycin-resistant strains with treatment assess the available data related with the efficacy of linezolid failures has been documented with standard daptomycin in the treatment of endocarditis indicated that seven out of dose monotherapy (6 mg/kg) and it has been postulated that eight cases of enterococcal endocarditis were cured or the use of higher doses (up to 12 mg/kg) is likely to be more achieved resolution of the infectious episode. The previous effective against enterococcal isolates, which, in general, exhi- use of an unsuccessful therapy and/or allergy to other antibi- bit higher MICs than staphylococci or streptococci. Addition- otics were the principal reasons for the use of linezolid ther- ally, the combination of daptomycin with other agents may offer certain clinical advantages in the setting of enterococcal TABLE 1. Antibiotic options for the treatment of ampicillin- endocarditis [36,37]. Combinations of high-dose daptomycin and vancomycin-resistant enterococcal infections (8 mg/kg) plus ampicillin plus gentamicin and daptomycin plus gentamicin plus rifampin have been reported to have success- Administration approved potential clinical use fully achieved cure in two patients with vancomycin-resistant E. faecium endocarditis [39,40]. More recently, two case reports have documented the successful combination of high-dose daptomycin with tigecycline in the treatment of endocarditis [41,42]. Furthermore, in a case of meningitis caused by MDR E. faecium, clinical cure with intravenous daptomycin and tigecycline plus intrathecal daptomycin was *Only Enterococcus faecium.
 Not recommended as monotherapy.
achieved in a paediatric patient [43]. In conclusion, higher àOnly Enterococcus faecalis.
§ doses of daptomycin should be considered as an alternative Only for uncomplicated urinary tract infections.
–Only if susceptible and as part of a combination regimen.
for the treatment of endovascular enterococcal infections ª2010 The AuthorsJournal Compilation ª2010 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 555–562 Arias et al.
Treatment of resistant enterococci apy in this study [48]. A shortcoming of this study is related gentamicin, rifampin, ampicillin, imipenem or levofloxacin), to publication bias because positive results are much more when possible, although clinical data are still lacking and the likely to be reported than treatment failures (although lin- use of this antibiotic is often hampered by side effects that ezolid failures in the treatment of enterococcal endocarditis may lead to the discontinuation of therapy. Of note, the have also been well documented). In view of the paucity of American Heart Association lists Q/D as an option for the solid clinical evidence, and, until further data are available, treatment of MDR E. faecium endocarditis (Fig. 1).
we suggest that linezolid be used with caution in the treat- ment of VRE endocarditis, and only when resistance, side effects or allergy prevent the use of combinations of b-lac- Tigecycline is a broad-spectrum antibiotic derived from tams and aminoglycosides, high-dose daptomycin plus other minocycline [63] which is FDA and EMEA approved for skin active agents or quinupristin-dalfopristin- based regimens and soft tissue infections, including those with vancomycin- (Fig. 1) [49–51]. Nonetheless, as a result of the good phar- susceptible E. faecalis. Tigecycline inhibits protein synthesis macokinetic profile of linezolid in the central nervous system upon interaction with the bacterial 30S ribosomal subunit (CNS), this antibiotic may be a good first choice for the [64] and only one case of tigecycline-resistant E. faecalis has treatment of enterococcal meningitis or related CNS infec- been documented, although the exact mechanism of resis- tions [52,53], especially when caused by vancomycin-resistant tance has not yet been elucidated [65]. In the management of soft tissue infections (including those with vancomycin-sus- ceptible E. faecalis), tigecycline showed a microbiological eradication rate of 87.5%, similar to vancomycin plus aztreo- Quinupristin-dalfopristin (Q/D) is a streptogramin antibiotic nam (91.7%) [66]. In a trial evaluating the treatment of com- only active against E. faecium [54]; most E. faecalis are resis- plicated abdominal infections, tigecycline and imipenem- tant as a result of the presence of a gene designated lsa, cilastatin exhibited similar rates of microbiological eradication whose function has not been established [55]. Q/D inhibits for vancomycin-susceptible E. faecalis (78.8% and 74.5%, protein synthesis by interacting with the 50S ribosomal sub- respectively) [67]. Some in vitro models suggest that syner- unit [56,57] and several mechanisms of resistance have been gism of tigecycline combined with vancomycin, gentamicin, documented in enterococci [58,59]. The efficacy and safety doxycycline (in a doxycycline-resistant strain of E. faecium) of Q/D was evaluated in a prospective, multicentre noncom- or rifampin can be achieved for certain strains of E. faecalis parative study for the treatment of vancomycin-resistant and E. faecium compared to tigecycline alone [68]. Recently, E. faecium infections for which no appropriate alternative successful therapy of endocarditis with the combination of antibiotic therapy was available. An overall clinical response tigecycline plus daptomycin has been documented in two was observed in 65.6% of patients and varied according to cases of enterococcal endocarditis [67,68]. A serious draw- enrollment indication (e.g. 80% for urinary tract infections back of the use of tigecycline monotherapy for the treatment and 72% for bacteraemia of unknown origin). Arthralgia and of bacteraemia and endocarditis is the low serum levels myalgia were the most common adverse events, which, in obtained with this antibiotic [68,69]; thus, the use of this some cases, led to the discontinuation of therapy [60]. Q/D compound as monotherapy for severe enterococal infections has also been used as part of a combination regimen in the is discouraged. Tigecycline may play a role in combination treatment of E. faecium endocarditis. In one patient with therapies with bactericidal agents (Fig. 1); however, prospec- infective endocarditis, sterilization of the blood was only tive, clinical data to support this use are still lacking.
obtained after the addition of doxycycline and rifampin to Q/D [61]. Microbiological eradication in E. faecium endocar- Other antibiotics with anti-enterococcal activity ditis in a cancer patient was also achieved after the use of a Nitrofurantoin and fosfomycin tromethamine are useful alter- regimen that included high-dose ampicillin (32 g/day) and natives for the management of lower uncomplicated urinary Q/D [61,62]. The use of Q/D as part of a combination tract infections as a result of enterococci [71] (fosfomycin is regimen was also shown to be effective in a rabbit model of FDA approved for urinary tract infections caused by vanco- endocarditis where the combination of Q/D with imipenem mycin-susceptible E. faecalis). Similarly, chloramphenicol has or levofloxacin caused a greater decrease in CFU isolated been used for the treatment of VRE infections; chlorampheni- from vegetations than Q/D alone [62]. Although Q/D has an col was used in 51 patients with VRE bloodstream infections, FDA indication for treatment of vancomycin-resistant E. fae- of whom 61% had a favourable clinical response and 79% cium (Table 1), we suggest that it may be preferable to use exhibited microbiological eradication with no major side Q/D as part of a combination regimen (i.e. with doxycycline, effects [72,73]. Also, the tetracycline group of antibiotics has ª2010 The Authors Journal Compilation ª2010 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 555–562 Clinical Microbiology and Infection, Volume 16 Number 6, June 2010 been used as part of combination therapies in the treatment ated with healthcare-associated infections: annual summary of data of severe MDR enterococcal infections. As mentioned above, reported to the National Healthcare Safety Network at the Centersfor Disease Control and Prevention, 2006–2007. Infect Control Hosp the combination of Q/D plus doxycycline and rifampin was Epidemiol 2008; 29: 996–1011. See Erratum 2009 Jan;30(1):107 successfully used to treat a patient with endocarditis as 2. Brown DF, Hope R, Livermore DM et al. Non-susceptibility trends a result of E. faecium [74]; similarly, chloramphenicol plus among enterococci and non-pneumococcal streptococci from bacte-raemias in the UK and Ireland, 2001–06. J Antimicrob Chemother 2008; minocycline was used in patient with prosthetic valve endo- 62 (suppl 2): ii75–ii85.
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ª2010 The AuthorsJournal Compilation ª2010 European Society of Clinical Microbiology and Infectious Diseases, CMI, 16, 555–562


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