Enterococcal Infection in Children

Enterococcal Infection in Children Karina M. Butler, MB, BCh, FRCPI From relative obscurity, enterococci have become a leading cause of nosocomial infection. This has been attributed, in part, to the growth in susceptible host populations, increased use of intravascular devices, prolonged hospital stay, and widespread antibiotics use. Furthermore, the facility with which enterococci acquire resistance characteristics coupled with their capacity to survive in the environment renders them uniquely suited as nosocomial opportunists and have resulted in global dissemination of resistant strains. Debate continues as to whether most serious infections arise from a person’s indigenous flora or dissemination of virulent clones. Enterococci are normal inhabitants of the human gastrointestinal tract. Classically associated with endocarditis and wound and urinary tract infections, increasingly they are a cause of nosocomial bacteremia. The rise in incidence of serious enterococcal infection has been particularly evident in neonatal, paediatric intensive care, and haematology/oncology units. Spread of resistant phenotypes has posed a difficult therapeutic challenge. We have been rescued, albeit perhaps only temporarily, by the addition of newer agents, such as linezolid, to the therapeutic armamentarium. However, there is no room for complacency. Linezolid resistance already has been reported. Efforts must continue to focus on prevention of the emergence and dissemination of resistance through policies of rational antibiotic use, infection control and education. Semin Pediatr Infect Dis 17:128-139 © 2006 Elsevier Inc. All rights reserved.

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he two most common species of enterococci causing clinical infection are Enterococcus faecalis and Enterococcus faecium. Together, they account for more than 80 percent of clinical isolates.1 Enterococci are natural inhabitants of the gastrointestinal tract of humans, other mammals, birds, and reptiles. They are a common cause of urinary tract and wound infections. They can disseminate from the gastrointestinal tract to cause cholangitis, peritonitis, and intra-abdominal abscess, often as part of a polymicrobial infection. Bacteremia and endocarditis are other well-recognized clinical manifestations. Enterococci are an infrequent cause of pneumonia, meningitis, and osteomyelitis, usually in the immunocompromised host. Enterococci are relatively avirulent and were considered a rare cause of life-threatening infection. They once ranked low in their overall importance as pediatric pathogens; however, beginning in the late 1970s and continuing today, several factors have combined in their effect to alter this situation. From relative obscurity, enterococci have become a leading cause of nosocomial infection and consistently rank in the top four causes of nosocomial bacteremia in the United

Consultant in Pediatric Infectious Diseases, Our Lady’s Children’s Hospital Crumlin & The Children’s University Hospital, Dublin, Ireland. Address reprint requests to Karina M. Butler, MB, BCh, FRCPI, Consultant in Pediatric Infectious Diseases, Our Lady’s Children’s Hospital Crumlin, Dublin, 12, Ireland. E-mail: [email protected]

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States.1-6 This rise in incidence has, in part, been attributed to changes in medical care during this time: the growth in a susceptible population with more immunocompromised and critically ill patients, the increased use of intravascular devices, more prolonged hospital stays, and the widespread use of antibiotics to which the enterococci are intrinsically resistant. The debate continues, however, as to whether most serious infections arise from a person’s own indigenous flora or whether the rise in incidence of enterococcal infection has been fuelled predominantly by the dissemination of virulent clones with greater invasive potential.7 Although the first reports of enterococci as nosocomial pathogens antedated change in their antimicrobial susceptibility profile,8-10 the ability to acquire resistance characteristics, particularly by E. faecium, facilitated the rise in incidence of enterococcal infection and also led to an increase in the relative importance of E. faecium as a pathogen. The widespread use in hospitals of antibiotics to which enterococci are intrinsically resistant, such as cephalosporins and antistaphylococcal penicillins, promoted their selection over more susceptible organisms. In addition, enterococci can readily acquire resistance to aminopenicillins, to high levels of aminoglycosides, and to glycopeptides. These factors coupled with intrinsic microbiologic characteristics whereby they are hardy organisms, capable of prolonged survival in the environment, renders them uniquely suited as nosocomial opportunists.

Enterococcal infection in children

Microbiology Enterococci are facultative anaerobic, ovoid or slightly elongated, oxidase- and catalase-negative, nonspore-forming grampositive cocci that on Gram stain are seen singly, in pairs, or in short chains. They are capable of surviving harsh environmental conditions such as drying,11 high temperatures,12 and exposure to some antiseptics,13 and they can survive for prolonged periods on inanimate surfaces.14 Since the first use of “entérocoque” to describe a gram-positive diplococcus of intestinal origin, enterococci have undergone numerous name changes and reclassifications, the historical aspects of which have been reviewed by Murray.15 In Lancefield’s serological typing of streptococci, these organisms were classified along with some other nonenterococcal streptococci (ie, Streptococcus bovis and Streptococcus equinus) as group D streptococci. In 1984, based on genetic studies, enterococci were designated as a specific genus.16 Since then, more than 35 species of enterococci have been published (http://www.bacterio.cict.fr/allnamestwo.html). However, Enterococcus faecalis and Enterococcus faecium remain responsible for most clinical infections. Enterococcus avium, Enterococcus casseliflavus/Enterococcus flavescens, Enterococcus durans, Enterococcus raffinosus, Enterococcus gallinarum, and Enterococcus mundtii are less frequent causes of human infection.

Identification Most enterococci produce no (gamma) or partial (alpha) hemolysis on blood agar. Differentiation from other alpha-hemolytic or nonhemolytic streptococci is performed using biochemical testing. A presumptive identification is made in the clinical laboratory based on type of hemolysis on blood agar, colony size and morphology, Gram stain, L-pyrrolidonyl-␤naphthylamide (PYR), and leucine aminopeptidase (LAP) testing. Enterococci produce PYR, are able to hydrolyze esculin in the presence of 40 percent bile salts (bile-esculin positive), and are capable of growth in 6.5 percent saline, at pH 9.6, and at 10°C and 45°C.

Speciation Biologic testing can be used to differentiate the most common species. E. faecalis, unlike E. faecium, grows in the presence of tellurite, reduces tetrazolium to formazan, and produces acid from sorbitol and glycerol. Motility and pigment studies also are helpful. E. casseliflavus and E. gallinarum are motile, and both E. casseliflavus and E. mundtii produce a yellow pigment. Commercially available panels facilitate the speciation of enterococci, but difficulties with the reliability of these products for some enterococci with atypical characteristics have prompted investigation of other techniques. Several molecular techniques have been used and are being evaluated as a means of rapid, complete, and more reliable identification. Pulsed field gel electrophoresis (PFGE), multilocus sequence typing (MLST), randomly amplified polymorphic DNA (RAPD) analysis, gene sequence analysis, amplified fragment length polymorphism (AFLP) analysis, and real-time polymerase chain reaction (PCR) testing have all been used both for identification purposes and to determine species relatedness17-22 and are of proven use in epidemiologic investigation.23-25 Speciation is not considered necessary for the

129 clinical management of all cases. Although recommended in cases of serious invasive infection, where speciation may influence antibiotic choices, and in the surveillance and investigation of nosocomial infection, when it can be critical for infection control purposes, identification to genus level together with determination of the antimicrobial susceptibility profile is considered adequate for urinary and wound isolates. The complete genomes of isolates of E. faecalis26 and E. faecium (http://www.jgi.doe) have been sequenced, providing hope that novel molecular targets for antimicrobial agents might be identified.

Pathogenicity From the gastrointestinal tract, enterococci can invade and cause infection if the normal host-commensal relationship is disturbed. Host factors that may disrupt the balance include antibiotic use, abdominal surgery, use of vascular and urinary catheters, and alteration of host immune status. Bacterial determinants include production of virulence factors such as adhesins, aggregating and binding substances that facilitate adherence to intestinal, and urinary tract epithelium and heart muscle.27,28 Presence of these and other virulence factors can modulate disease outcome.7 Virulence genes often are clustered on the genome in distinct regions termed pathogenicity islands (PAIs), transfer and deletion of which are frequent. The presence of PAIs are associated with virulent lineages, giving rise to the speculation that important genetic differences may exist between commensal and epidemic infection-derived isolates.7,22,29

Resistance Enterococci are intrinsically resistant to cephalosporins, monobactams, and antistaphylococcal penicillins, and they exhibit low to moderate levels of resistance to clindamycin and aminoglycosides. In addition to having these intrinsic characteristics, enterococci also are adept at acquiring new resistance genes and/or mutations. Even ‘susceptible’ enterococci are inherently several-fold less susceptible to beta-lactam antibiotics, such as penicillin, ampicillin, or piperacillin, than are susceptible streptococci and have minimum inhibitory concentrations (MIC) for penicillin G, ampicillin, amoxicillin, piperacillin, and carbapenems that are 10 to 1000 times greater than those of streptococci.30,31 This is attributed to a decreased affinity of the enterococcal penicillin-binding proteins for beta-lactams. Additionally, some strains exhibit tolerance to beta-lactams. Ampicillin, which generally is more active against enterococci than is penicillin, may be preferred even for the treatment of ‘susceptible’ enterococcal infection. Beta-lactam monotherapy has proved suboptimal for the treatment of endocarditis, and so combination therapy with an aminoglycoside, usually gentamicin, is recommended. Low-to-moderate level resistance to aminoglycosides is intrinsic to enterococci; however, when used together with a cell wall active antibiotic, cellular uptake of the aminoglycoside is facilitated and synergistic activity is obtained. In general, E. faecium are more resistant to beta-lactams than are E. faecalis. E. faecalis and, more rarely, E. faecium, can produce low levels of penicillinase, resulting in reduced sus-

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130 ceptibility to penicillin and ampicillin that can be missed on routine disc susceptibility testing because of an inoculum effect. At low inoculum, strains may appear susceptible because of the low level of production of penicillinase, whereas at high inoculum, with the increased production of penicillinase, they can be recognized as resistant. Thus, The National Committee for Clinical Laboratory Standards (NCCLS) recommends that all isolates from serious invasive infection be tested specifically for the production of beta-lactamase.32 These isolates are treated more effectively with beta-lactamase inhibitor combinations.31 High-level resistance to penicillins, not related to penicillinase but to alteration in penicillin-binding proteins, is encountered more commonly in E. faecium30 and can be either intrinsic or plasmid-mediated. Glycopeptides inhibit cell wall synthesis by gram-positive bacteria through their interaction with the D-alanyl-D-alanine (D-Ala-D-Ala) terminus of the peptidoglycan cell wall precursors. This interaction inhibits the normal polymerization of the peptidoglycan compromising cell wall formation. ‘Resistant’ bacteria produce novel peptidoglycans with decreased affinity for glycopeptides, the production of which is regulated by a number of different gene clusters. Six types of resistance have been characterized on phenotypic and genotypic bases. VanA, B, D, F, and G represent mechanisms of acquired resistance and VanC intrinsic chromosomally mediated resistance. Inducible high-level resistance to both vancomycin and teicoplanin characterizes the VanA phenotype. It depends on the coordinated expression of a cluster of several different genes mediated by transposon 1546 (Tn1546) and closely related elements. Tn1546 is readily transferable, can move between chromosomes and plasmids, and can transfer into unrelated species such as Staphylococcus aureus.33,34 The VanB phenotype, characterized by moderate resistance to vancomycin but not usually to teicoplanin, also is regulated by the presence of a similar but less readily transferable gene cluster. Nontransferable, intrinsic, low-level resistance to vancomycin resulting from the presence of three chromosomal genes in E. gallinarum and E. casseliflavus/E. flavescens characterizes the VanC phenotype. VanD resistance is chromosomally based, nontransferable, and associated with only slightly reduced susceptibility to teicoplanin. VanE and VanG share a common phenotype of low-level resistance to vancomycin while retaining susceptibility to teicoplanin; however, they differ in their genetic organization.35 For purposes of simplicity, in this paper, glycopeptide-resistant enterococci will henceforth be referred to by the common designation vancomycin-resistant enterococci (VRE). The ability of enterococci to adapt to their environments is illustrated further by reports of vancomycin-dependent enterococci. This phenomenon has been observed in some VanA and VanB phenotypes. These isolates not only are resistant to vancomycin and teicoplanin but actually require their presence for growth.36-39 Oxazolidinones are a totally novel class of synthetic antimicrobials that have excellent activity against gram-positive organisms, including methicillin-resistant S. aureus and VRE. Linezolid, the first of this class to enter clinical use, was

licensed in the United States in 2000 and in Europe in 2001. It acts through inhibition of bacterial ribosomal protein synthesis. The pathway involves binding to 23S rRNA. Resistance to linezolid typically has been associated with mutation in the 23S rRNA gene, which can occur de novo or following or during exposure to linezolid, or it can be nosocomially acquired.22,40

Epidemiology Enterococci, as their name suggests, are part of the normal enteric flora and are found in high numbers in stools and sewage. They are recovered frequently from the female genital tract and from skin sites. Infants are colonized rapidly after delivery. Enterococci are also widely distributed in the animal kingdom and, thus often are present in soil, water, and foods. Their capacity to withstand harsh environmental conditions renders them welladapted for survival outside their usual hosts. Within the hospital environment, rapid dissemination from a source patient through environmental contamination, contamination of the hands of health care workers, and, on occasion, colonization of health care workers has been demonstrated. Many outbreaks of clonal colonization by E. faecalis and E. faecium have been reported.41-44 In the 1940s, pediatric textbook descriptions of streptococcal disease focused on group A streptococci and Streptococcus pneumoniae, with scant mention given to other “streptococci.”45 In the 1950s, group D streptococci merited a listing as an occasional pathogen in man.46 By the mid-1970s, “group D (enterococcus) hemolytic streptococci” were featured as “infrequent causes of neonatal sepsis,” “common cause of urinary tract infection,” and a “cause of endocarditis.”47 Yet, by the end of the century, as “the third most common cause of nosocomial infection after S. aureus and coagulase-negative staphylococci,” enterococci had earned themselves the title “pathogen of the nineties.”48 This rise in the incidence of enterococcal infection is not confined to adult centers but impacts significantly on patients in neonatal, pediatric intensive care, and hematology/ oncology units. In one large children’s hospital in the United States, enterococci accounted for 0.7 percent of all bacteremic episodes in 1986 compared with 4.8 percent in 1991.49 During the years 1992 to 1997, they were responsible for 6.2 percent of all bloodstream infections in pediatric intensive care units (PICUs).50 In a point prevalence study of nosocomial infection that surveyed 827 neonatal patients in 29 neonatal intensive care units (NICUs) throughout the United States on a single day in 1999, enterococci ranked third after coagulase-negative staphylococci and Candida spp. as the most commonly identified nosocomial pathogens. They accounted for 10.3 percent of pathogens isolated, and caused 15.5 percent of bloodstream infections.51 Traditionally, E. faecalis accounted for virtually all clinical enterococcal infections. E. faecalis caused 91 percent of episodes in one general hospital during the years 1963 to 19778 and 100 percent of enterococcal bacteremia in a neonatal unit from 1980 to 1984.9 The emergence of aminopenicillin and glycopeptide resistance, both of which occur more frequently

Enterococcal infection in children in E. faecium and often are found together with high-level resistance to aminoglycosides, has been associated with an increase in the proportion of infections attributed to E. faecium. In contrast, E. faecium accounted for 11 to 60 percent of bacteremic episodes in reported series spanning 1984 to 2004.49,52-57 Overall, in the United States, among enterococci recovered from blood cultures, the percentage of E. faecalis decreased significantly from 84 percent in 1988/9 to 58 percent in 1994, during which time the percentage of E. faecium increased from 13 to 36.3 percent.58 Results from the 1997 to 1999 SENTRY antimicrobial surveillance program validates the trend; E. faecalis accounted for 57 to 77 percent of isolates from blood, respiratory, wound, and urine infections in Canada, Europe, Latin America, the Asia-Pacific region, and the United States. E. faecium was isolated in 15 to 20 percent of cases in all regions except Latin America, where it accounted for only 5 percent of isolates.1 The dissemination of ampicillin-resistant E. faecium has been dramatic. From Spain, Coque and coworkers reported ampicillin resistance in 17 percent of bloodstream isolates of E. faecium in 1991, 53 percent in 1995, and 75 percent in 2002.53 Furthermore, these isolates were more likely to exhibit resistance to other antimicrobial classes, including quinolones, macrolides, and aminoglycoside, than were ampicillin-susceptible strains isolated during the same time period. Consistent with the Spanish experience, 71 percent of 841 bloodstream isolates reported to the European Antimicrobial Resistance Surveillance Network (EARSS) in 2001 were resistant to aminopenicillins (www.rivm.nl.earss). The proportion of resistance ranged from 40 percent for Iceland to 86 percent for Austria. Conversely, in E. faecalis, aminopenicillin resistance of this nature remains rare: 3 percent of all isolates in 2001 and 1.87 percent in 2004, some possibly a result of misidentification of E. faecium isolates (www. rivm.nl.earss). The acquisition of plasmid-mediated, high-level resistance to glycopeptides in ampicillin-resistant E. faecium was reported first in 1988.59,60 Rapid and extensive dissemination of resistant strains ensued.61-66 Prevalence of glycopeptide resistance has remained significantly higher among strains of E. faecium compared with E. faecalis, being found in 60 percent of E. faecium isolates compared with just 2 percent of E. faecalis isolates during the years 1995 to 2002 in the United States. In the early to mid-1990s, some clinical isolates were resistant to all of the then available antimicrobials. On occasion, physicians faced the challenge of explaining the lack of available effective therapeutic options to affected patients and their families. Although such incidences lent some insight into the difficulties of physicians in the preantibiotic era, they also raised the spectre of a “postantimicrobial era.”67 Such fears, although temporarily allayed by the development of new classes of antimicrobials, are not entirely unfounded and should serve a salutary lesson regarding rational and prudent antimicrobial use. How the rapid dissemination of VRE has occurred has been the subject of many papers. Intriguingly, the mechanisms appear to differ on either side of the Atlantic. In the

131 United States, detection of VRE has been associated primarily with hospital exposure, with relatively few cases detected in community volunteers.68,69 In Europe, however, screening studies have shown a background prevalence of VRE in the community— unrelated to hospital exposure.70 Furthermore these background strains do not necessarily undergo widespread dissemination. The hypothesis has been that the emergence of VRE in Europe was influenced heavily by the use of glycopeptides, specifically avoparcin, in animal feeds with resultant colonization of animals and poultry with glycopeptide resistant strains.71-74 This practice is now banned. In the United States, the emergence of VRE has been linked primarily to hospitalization, vancomycin exposure, and nosocomial spread of clonal strains.53 Introduction of HIPAC/ CDC guidelines75 on the prudent use of vancomycin together with infection control guidance has been followed by some leveling in the rate of spread of VRE in U.S. hospitals.76 Oxazolidinones were to be the answer to resistance in gram-positive organisms and have been a major addition to the antimicrobial armamentarium. However, there is no room for complacency. In 2001, Gonzales reported the isolation of linezolid-resistant E. faecium from five patients.77 Further sporadic case reports followed.78-81 Reassuringly, surveillance programs have shown a low level of resistant isolates, with no consistent trends thus far. In the United States, in 2004, 99.5 percent and 96.4 percent of E. faecalis and E. faecium, respectively, remain susceptible to linezolid.82,83 Yet caution is warranted. From Germany, Klare and coworkers reported the expression of linezolid resistance in ampicillin/glycopeptide-resistant E. faecium strains of the epidemic virulent clonal complex-17 (ie, a clone of E. faecium), expressing VanA phenotype that already has undergone rapid global dissemination22

Clinical Manifestations Enterococci cause ascending urinary tract infection (UTI) and urosepsis and can colonize wounds and cause wound infection. The recovery of Enterococci from wounds such as burns or chronic ulcers must be interpreted with caution as their presence is not synonymous with infection. Other factors must be taken into account before an accurate determination of infection versus colonization can be made. Enterococci have been recognized for some time as being an important cause of endocarditis. In the community setting, enterococcal infections tend to affect those at the extremes of life. In the elderly, especially elderly males, UTI and urosepsis are the most commonly associated clinical conditions. At the other extreme, enterococci cause community acquired neonatal sepsis; however, most cases of neonatal enterococcal bacteremia are seen in older neonates who have had a prolonged stay in the NICU and exposure to antimicrobial agents, reflecting the actual arena of importance for enterococci (ie, as nosocomial opportunists). Bloodstream infections, urosepsis, intra-abdominal sepsis, and, more rarely, meningitis, pneumonia, and bone and joint infection, all have been reported with increased frequency in hospitalized patients.

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Urinary Tract Infections (UTIs) enterococci.1

UTIs are the most common infection caused by In North America, enterococci accounted for 6.6 percent of outpatient urinary isolates from patients aged 1 month to 99 years of age,84 remarkably similar to Farrell’s UK study of 1291 urinary isolates, 6 percent of which were enterococci.85 Felmingham documented a gradual rise in the proportion of enterococcal isolates from urine, rising from 4 percent in 1971 to 12.6 percent in 1990 in hospitalized and from 2 to 5.6 percent in general practice patients, respectively.86 In SENTRY, the frequency of enterococci as uropathogens showed some geographic variation; ranging from 4.2 percent in Latin America to 16.8 percent in Canada.1 The proportion of infections caused by enterococci increases where a history of instrumentation, structural abnormality, or prior antimicrobial use exists. In children, Escherichia coli is the most common urinary tract pathogen, causing 60 to 90 percent of infections. Thereafter, enterococci rank consistently among the next two to three most common pathogens in case series, causing 2 to 8 percent of community acquired UTIs.87-90 In these studies, spanning the years 1985 to 2002, no obvious trend was noted in the proportions of infections caused by enterococci. However, as inclusion criteria differed in each study, no firm conclusions can be drawn. Children with enterococcal UTIs are more likely to have underlying anatomic abnormality than are children with gram-negative UTIs.87,88 Such children had a worse prognosis in terms of recurrence, scarring, and need for surgery compared with all other children with UTIs. They did not, however, have a worse prognosis when compared with children with gram-negative infection who were matched for age and degree of reflux. Thus, enterococcal infection serves as a marker of children who are likely to have underlying abnormality and poor prognosis rather than being an independent risk factor for poor outcome.88 Children in intensive care differ from adult patients in the sites of distribution of nosocomial infection. In adult patients, UTIs are reported most frequently, whereas primary bloodstream infections are found most commonly in children. An age-related increase exists in the frequency of nosocomial UTIs, ranging from 12 percent for those 2 months and younger to 22 percent for those older than 12 years of age. Of these, enterococci accounted for 10.3 percent of uropathogens.50 To date, glycopeptide resistance has not been a notable problem in community-acquired UTIs and has remained relatively rare as a cause of nosocomial UTIs in children.

Bloodstream Infection Enterococci are not a common cause of bacteremia in healthy children.91 Enterococci are a rare cause of early onset and community acquired, late-onset sepsis in neonates, of UTIassociated bacteremia (usually in children with a history of antibiotic exposure), and of endocarditis. More commonly, enterococcal bacteremia is a nosocomial infection. Enterococci are a cause of late-onset neonatal sepsis and of bacteremia and sepsis in compromised, seriously ill children such as

patients in hematology/oncology and intensive care units and those with intravascular catheters.

Neonatal Sepsis Enterococci are a relatively rare cause of early-onset neonatal sepsis, in the developed92,93 and developing world,94 whereas they account for as many as 3 percent of cases of late-onset sepsis with higher rates occurring during outbreak periods.6,95,96 In 1990, Dobson and coworkers10 reported 56 cases of enterococcal sepsis in a single large NICU between 1977 and 1986. An increase in the incidence of enterococci as a cause of late-onset sepsis after 1983 was documented. Affected infants were more premature and of lower birth weight than were infants with early-onset sepsis, and the nosocomial origin of infection was noted.10 Enterococci show marked propensity to cause nosocomial outbreaks of neonatal infection.6,9,91 The presenting features of enterococcal sepsis such as fever, apnea, bradycardia, and respiratory deterioration are nonspecific and characteristic of neonatal sepsis. Dobson observed a high incidence of catheter-related infection (23%), meningitis and pneumonia (15% each), and coincident necrotising enterocolitis.10 In 1996, McNeeley and coworkers,96 in their review of 138 episodes of enterococcal bacteremia, compared the incidence over two sequential decades, 1974 to 1983 and 1984 to 1993. More than three times the number of episodes were documented in the second decade, at a time when no change in the incidence of group B streptococcal bacteremia occurred. The increase related primarily to an increased incidence of nosocomial, lateonset sepsis; the mean age of onset of infection increased from 16.1 days in the first decade to 45.3 days in the second. Enterococci frequently were part of a polymicrobial infection. Risk factors for enterococcal bacteremia include prolonged hospital stay, exposure to antibiotics, central venous catheter use, and necrotising enterocolitis.96 VRE outbreaks also have been documented in the NICU setting, and nosocomial transmission has been demonstrated.97-100

Older Children Boulanger and colleagues32 reviewed 50 cases of enterococcal bacteremia in infants (n ⫽ 18) and children (n ⫽ 32) hospitalized between 1985 and 1989; 82 percent were nosocomial in origin, and 92 percent were in children with significant underlying problems or who had recently undergone surgery.91 Community-acquired infection occurred in only seven children, six of whom had a comorbid condition. Infection was polymicrobial in 13 (26%). Prior surgery and antimicrobial exposure were common findings in this population.91 Over a similar time period, 1986 to 1991, Christie and coworkers reviewed 83 episodes in 80 children. Nosocomial acquisition (69%), comorbidity (81%), and polymicrobial bacteremia (38%) were seen commonly. Thirty-one percent of episodes were community acquired, only 19 percent of which were in children older than 3 months of age. Invasive procedures (central lines, ventilation, drainage tubes) and antimicrobial exposure were common antecedents.49 E. faecalis predominated in each of the aforemen-

Enterococcal infection in children tioned studies, accounting for 86 percent and 83 percent isolates, respectively. Resistance to ampicillin (⬍1%) and vancomycin (⬍3%) was a rare occurence. In the United Kingdom, Das and colleagues54 reviewed 75 episodes of enterococcal bacteremia in children who attended Birmingham Children’s Hospital between 1995 and 1997. The common features of serious underlying disease (89%), prior antimicrobial use (64%), nosocomial acquisition (63%), and polymicrobial infection (35%) again were highlighted.54 Both Christie and Das noted the importance of central catheters as a source of infection. Other important sources included the gastrointestinal and biliary tract, heart, and skin and soft tissues.49,54 In the Birmingham study, E. faecalis and E. faecium were isolated at equal frequency, each accounting for 49.3 percent of isolates; 89 percent of E. faecium were resistant to ampicillin in contrast to only 8 percent of E. faecalis strains.54 Clinical features of bacteremia included fever (78%), elevated white blood cell count (44%), septic shock (12%), and disseminated coagulation (6%).49

Catheter-Associated Bacteremia Enterococci are a frequent cause of intravascular catheterrelated bloodstream infections. In children, these infections usually occur in the intensive care setting, where temporary central venous catheters (CVCs) often are implicated, or in patients with tunnelled devices (eg, oncology patients or infants dependent on total parenteral nutrition with short gut syndrome), settings in which catheter preservation often is of the utmost importance. In 2002, Sandoe and coworkers56 reported their experience of treating 61 episodes of enterococcal catheter-related infections, only seven of which were in children or adolescents. Catheter salvage was attempted in 13 cases. Of four patients treated with both an appropriate cell wall agent and an aminoglycoside, all were cured, in contrast to only one of nine others. They concluded, albeit on very small numbers, that CVC salvage is feasible if appropriate antimicrobials are used.56 Line salvage can be a critically important issue for infants and children where technical difficulties may limit replacement options. In general, if the CVC is temporary, removal of the line is recommended. For tunnelled lines, provided that the patient is hemodynamically stable and the course is uncomplicated, line salvage can be attempted.101 Two approaches are used: (1) infusion of antibiotics through the infected line, ensuring rotation of antibiotics through the different ports, or (2) use of an antibiotic lock therapy in addition to systemic antibiotics. In my experience, instilling an antibiotic lock (teicoplanin or vancomycin) into each lumen on a daily basis for 5 to 14 days coupled with peripherally administered antibiotics usually is successful in treating CVC-associated enterococcal infection. Criteria for line removal include hemodynamic instability, persistent bacteremia despite the administration of appropriate antimicrobial therapy, or the presence of complications, including septic thrombosis, metastatic seeding, or endocarditis.

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Endocarditis Although enterococci rank third after streptococci and staphylococci as a cause of endocarditis in adults102 and children103 and account for 5 to 18 percent of all adult cases,104-106 endocarditis remains a rare complication of enterococcal bacteremia. Endocarditis tends to occur at the extremes of life, with more that half of all cases occurring in adults older than the age of 60. The clinical presentation usually is of a subacute nature, similar to that of viridans streptococci. Enterococcal endocarditis of native valves occurs more often in an older population than does nonenterococcal infection, is associated with heart failure rather than embolic events, and has a relatively low short-term mortality rate.104,105 Prosthetic valve infection caused by enterococci is associated with higher rates of abscess formation than is nonenterococcal infection but is similar in terms of need for surgical intervention and outcome.107 VRE endocarditis involving both native and prosthetic valves has been reported in adults108 and in a neonate.97 The clinical features of VRE endocarditis are the same as those of susceptible enterococcal infection. However, as might be anticipated, affected patients are those at most risk for acquisition of VRE (eg, those who are hospitalized, immunocompromised, or attend a dialysis center or have other types of comorbidity).108 Enterococcal endocarditis is a rare finding in children. In Japan, enterococci were the causative organisms in only one of 188 cases complicating congenital heart disease, 113 of whom were children.109 In Canada enterococci were implicated as part of a polymicrobial infection in only one of 56 cases of endocarditis in patients younger than 18 years of age.110 In most pediatric series, endocarditis complicating bacteremia has been reported in fewer than 5 percent of cases.49,54,91 Endocarditis should be suspected in an infant or child with enterococcal infection if there is underlying congenital heart disease or if persistent bacteremia is present despite the administration of appropriate antimicrobial therapy and the removal of potential sources of persistent infection such as intravascular lines.

Intra-abdominal Infection Most of what is written with regard to enterococci and abdominal sepsis relates to pathogenic studies in animals and clinical studies in adult patients. The importance of the pathogenic role of enterococci in intra-abdominal sepsis has been debated.111 Enterococci are isolated regularly along with other enteric organisms from such infections,112-116 despite which, treatment with antibiotic combinations that lack specific anti-enterococcal activity (eg, cephalosporin and metronidazole), is often successful.117 This success lends support to the argument that enterococci are not the prime invaders but act synergistically with other more pathogenic organisms to produce infection.118-120 Conversely, researchers have argued that this approach may predispose the patient to the emergence of enterococcal superinfection,115,121 which can be a particular hazard for immunocompromised patients or those with preceding antimicrobial treatment.122 It is potentially less of a problem with appendiceal infections, as enterococci are isolated less commonly in this situation.115

134 Thus, selection of an antimicrobial regimen with anti-enterococcal activity is prudent for seriously ill or compromised patients with intra-abdominal sepsis.123 Enterococci have been isolated in pure culture in spontaneous peritonitis and in patients on peritoneal dialysis and are, on occasion, the only organisms isolated from an intra-abdominal abscess or biliary infection. In children with enterococcal bloodstream infection, the gastrointestinal tract was cited as the focus in 14 to 16 percent of cases.49,54 In neonates, those figures reached 21 to more than 50 percent.10,96 Gastrointestinal compromise is an important risk factor for development of enterococcal infection. Neonatal necrotising enterocolitis (NEC) and neonatal abdominal surgery are frequent antecedents to the development of intra-abdominal enterococcal sepsis. As with the adult patient, the experience of successful treatment with regimens lacking specific enterococcal activity (eg, cefotaxime, metronidazole, and gentamicin for NEC) is recognized. However, such regimens may promote selection of enterococci and contribute to the overall increase in enterococcal infections seen in neonatal units.

Meningitis Although sporadic case reports dot the literature,124-129 enterococci are a rare cause of meningitis, accounting for 0 to 3 percent of cases.130-132 In Bingen’s study of 1084 cases of bacterial meningitis in children in France, enterococci did not appear among listed pathogens.133 Enterococcal meningitis can develop spontaneously or postoperatively. Although all ages can be affected, most cases occur in the first decade, more than 50 percent of which are in the first year of life. Most children in whom it occurs are either neonates or have underlying neurosurgical conditions (eg, ventriculo-peritoneal shunts) or other comorbidity. Of 54 cases in children, Pintado found that the median age at onset was younger for infants with spontaneous meningitis compared with those with postoperative infection (1 month versus 11 months; P ⫽ 0.22).134 Prematurity was the most common underlying condition in children. The clinical presentation is the same as that for bacterial meningitis caused by other organisms and as such is influenced by the age of presentation. The mortality rate for children, similar to that of adults, was 27 percent for spontaneous and 9 percent for postoperative infection.134

Therapy Optimum therapy of enterococcal infections depends on the susceptibility of the isolate and the site of infection. It is important that the microbiology laboratory is fully conversant with the nuances of enterococcal susceptibility testing; ␤-lactamase-production, antibiotic synergy, and even vancomycin resistance may be overlooked if specialized techniques are not used and correctly interpreted. In general, monotherapy is adequate for treatment of uncomplicated urinary tract or soft tissue infection. Ampicillin or penicillin remains the agent of choice for such infection.

K.M. Butler Nitrofurantoin is an alternative for the treatment of UTIs. For ␤-lactamase-producing isolates, amoxicillin-clavulanate or nitrofurantoin is preferable to ampicillin or penicillin. For strains with both high-level penicillin resistance and nitrofurantoin resistance, treatment options include a glycopeptide (vancomycin or teicoplanin) or linezolid. UTIs with glycopeptide-resistant strains remain relatively infrequent. These strains frequently retain susceptibility to nitrofurantoin, which can be useful in this situation. Where nitrofurantoin resistance coexists or for complicated infections, linezolid is the preferred option. Combination therapy with both a cell wall active agent and an aminoglycoside is necessary for treatment of endocarditis. For susceptible isolates, ampicillin or penicillin together with gentamicin, given in combination for the full course of therapy, is preferred. Some experts favor ampicillin over penicillin. Vancomycin is recommended for penicillin-allergic patients. If high-level penicillin resistance exists, a glycopeptide, vancomycin, or teicoplanin can be substituted. Vancomycin levels are obtained routinely to monitor therapy. However, treating endocarditis with teicoplanin requires confirming the adequacy of the trough levels because treatment failures have been associated with suboptimum levels. High-level resistance to gentamicin (MIC ⬎2000 ␮g/mL) eliminates the potential for synergy and negates its benefit. Monotherapy with either ampicillin or vancomycin, depending on the isolate’s susceptibility, remains the only option, with the attendant increase in risk of relapse. All treatment for endocarditis should be administered intravenously. The duration of therapy is 4 to 6 weeks. Four weeks is recommended for those with symptoms of less than 3 months duration who have received combination therapy with ampicillin or penicillin and gentamicin. Six weeks of therapy is recommended for those treated with vancomycin or with ampicillin monotherapy or those who have symptoms of more than 6 weeks’ duration.103 In patients with prosthetic valves or other prosthetic materials, the treatment duration should be a minimum of 6 weeks.103 Unless high-level resistance to gentamicin is present, combination therapy should continue for the entire course of treatment. The need for combination therapy in uncomplicated bacteremia is less certain. The choice of antimicrobial agents remains the same with ampicillin or penicillin, the first-line agents for susceptible strains. Penicillin-resistant isolates can be treated with a glycopeptide. Use of combination therapy with gentamicin may be prudent until clearance of bacteremia is documented and endocarditis is excluded. Linezolid now offers an alternative to the glycopeptides for treatment of ampicillin-resistant strains and for use in the penicillin-allergic patient; however, the economic cost can be prohibitive, as it is several times more costly than is vancomycin. No evidence base exists to guide providers in the use of combination versus monotherapy for enterococcal meningitis. Pintado, in a retrospective study of enterococcal meningitis in which antimicrobial data were available for 117 pa-

Enterococcal infection in children tients, found that combination therapy with a cell wall active agent and an aminoglycoside was used in 44 (38%) cases. Sixty-five (57%) patients received some form of dual antienterococcal therapy. In this study, the mortality rate was not influenced by use of combination therapy. The strength of this conclusion is limited severely by the retrospective nature of the study, the characteristics of the population, the diversity of isolate susceptibility patterns, and the variability of antibiotic combinations used.134 In the absence of evidence, some experts recommend using combination therapy based on the bacteriostatic nature of beta-lactam and glycopeptide activity against enterococci and the severity of the infection. Others recommend using combination therapy until cerebrospinal fluid sterility is documented and completing therapy thereafter with high-dose ampicillin or penicillin. A total treatment duration of 14 to 21 days is recommended.

Treatment of Glycopeptide-Resistant Enterococci (GRE, VRE) VRE colonization has been demonstrated in numerous different pediatric settings, including pediatric intensive care,135 neonatal intensive care,98,99,136 oncology,25,137-139 and liver transplant140 units. Risk factors for colonization include hospitalization, duration of stay, and antimicrobial exposure (third-generation cephalosporins, metronidazole, and vancomycin have all been implicated).25,139,141,142 Colonization generally is very prolonged, lasting months rather than weeks.137 An important note is that treatment is not indicated for colonized cases. No single regimen has proven successful in eradicating VRE colonization. Fortunately, even in the setting of clonal outbreaks, the actual incidence of infection has been relatively low, up to 8 percent of colonized patients. Infections have included catheter-related bacteremia,25,137 peritonitis,25,140 endocarditis,97 meningitis,134 and UTI.137,143 When possible, any source of persistent infection (eg, intravascular or peritoneal dialysis catheters) should be removed and abscesses drained. The selection of antimicrobial agents depends on antimicrobial susceptibility data, which are determined by the strain phenotype (VanA, VanB, etc.) and presence of resistance determinants to other antimicrobial classes. Some VanA strains, usually E. faecalis, although resistant to glycopeptides, retain susceptibility to ␤-lactams and to gentamicin. When this is the case, ampicillin or penicillin, usually in combination with gentamicin, can be used. VanB phenotypes are resistant to vancomycin but retain susceptibility to teicoplanin. Teicoplanin has been used successfully in this setting, but caution is warranted because treatment failures and emergence of resistance to teicoplanin have been described. High-level resistance to gentamicin, if present, precludes benefit from its use. Susceptibility may be retained to streptomycin, which can be substituted for gentamicin in the treatment of serious infections. Glycopeptide-resistant E. faecium strains now typically are resistant to ampicillin and also may exhibit high levels of resistance to gentamicin. Quinupristin-dalfopristin (Synercid®) is a combined streptogrammin antibiotic that inhibits

135 protein synthesis at two different target sites. Marked geographic variability exists in resistance prevalence, with higher rates in Europe than in the United States.1 In the United States, quinupristin-dalfopristin retains activity against most glycopeptide resistant strains of E. faecium but not E. faecalis. It has been used successfully to treat resistant E. faecium infection in children.144,145 Loeffler reviewed the safety and efficacy of quinupristin-dalfopristin used to treat 131 episodes of infection in 127 patients younger than 18 years of age. Adverse events occurred in 8 percent and were mild; pain and rash, observed in 2 percent of recipients, were the most frequent events encountered. Therapy was discontinued in only one patient because of side effects.145 In contrast, treatment-limiting myalgia and arthralgia were reported in four of 11 children who received quinupristin-dalfopristin after undergoing organ transplantation.146 The restriction of its activity to E. faecium, the need for parenteral therapy, and its side-effect profile have limited its overall use in children. Glycopeptide-resistant E. faecalis and E. faecium generally retain susceptibility to linezolid, a novel oxazolidinone antimicrobial. Experience with its use in children,97,147-150 even in premature infants,97 is accumulating that is favorable. One particular advantage is its excellent bioavailability so that rapid substitution of oral for parenteral therapy is feasible. Its efficacy has been well documented in the treatment of bacteremia, UTIs, skin and soft-tissue infections, and pneumonia. Good penetration into osteoarticular and meningeal sites indicates its potential utility in treating resistant gram-positive infection of cerebrospinal fluid, bone, and joints. Anecdotal success in the treatment of endocarditis has been reported, although caution has been advocated in this regard because of its inherently bacteriostatic nature. Linezolid generally is well-tolerated, the most commonly reported adverse events being diarrhea/loose stools, vomiting, rash, and fever.147 Dose-dependent neutropenia and thrombocytopenia have been reported in adults151 but appear to be less problematic in children.152 Of some concern are the emerging reports of reversible optic neuropathy153-155 and irreversible peripheral neuropathy156,157 in adults who have received prolonged therapy. This finding may relate to inhibition of mitochondrial protein synthesis.158 Long-term use should be avoided when possible. Infectious Disease or Clinical Microbiology service consultation is strongly advised for anyone undertaking the treatment of a patient with a serious VRE infection. Selection of the optimum therapeutic regimen requires good understanding of both the microbiological characteristics of the isolate and the pharmacokinetics of the available agents.

Prevention In 1995, in response to the emerging threat of VRE, the Hospital Infection Control Practices Advisory Committee issued recommendations to curtail the spread of VRE.75 The guidelines adopted a three-pronged approach: education of health care professionals regarding the problem of antimicrobial resistance; prudent use of vancomycin in hospitals; and an infection control strategy of surveillance, detection, and

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136 response with cohorting and isolation of VRE-colonized patients. The leveling in the rate of rise of VRE as a proportion of all enterococcal isolates has been attributed, in part, to these guidelines. From a pediatric perspective success in implementation of the guidelines in difficult situations also has been achieved42; however, consideration also must be given to the psychological impact of isolation on children, for what can be prolonged periods. A more rational approach may be developed as our understanding of VRE increases. Genotypic identification of epidemic strains of outbreak isolates allowed for the selective implementation of infection control measures with successful outbreak control in The Netherlands.159 Such an approach may be of importance, particularly in Europe, where there is a significant background prevalence of nonepidemic VRE strains in the community. Guidelines that emphasize the need for a risk-assessment approach in determining need for isolation and cohorting of patients for the control of glycopeptide-resistant enterococci recently have been published by the combined working party of the Hospital Infection Society, the Infection Control Nurses Association, and the British Society for Antimicrobial Chemotherapy.160

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Conclusion Enterococci are normal commensals of the human gastrointestinal tract. They have demonstrated ability to readily adapt to their environment. Most infections are endogenously acquired, but cross-infection between hospitalized patients does occur. They are uniquely suited to their role as nosocomial opportunists, facilitated by their hardy nature that permits prolonged survival on hands and inanimate surfaces. Basically poorly pathogenic, the real threat from enterococci lies in their ability to acquire antimicrobial resistance and to disseminate rapidly. The transfer of resistant determinants from E. faecium to S. aureus, a more sinister and lethal pathogen, already has occurred. This transfer underscores the fragility of our control over the world of microbes and gives ironic resonance to the words of William Stewart, U.S. Surgeon General, who, in 1969, somewhat prematurely declared to the U.S. Congress that it was “time to close the books on infectious disease.” Rather, it is more apt to heed the words of Jeffrey Koplan, then director of the Centers for Disease Control and Prevention, who in prefacing the document “Preventing Emerging Infectious Diseases: A Strategy for the 21st Century,” noted that “the battle between humans and microbes will continue long past our lifetimes and those of our children.”161

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