Staphylococcal and enterococcal infections in the neonatal intensive care unit

Staphylococcal and enterococcal infections in the neonatal intensive care unit

Staphylococcal and Enterococcal Infections in the Neonatal Intensive Care Unit Philip L. Graham III Along with the successes in improving the surviva...

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Staphylococcal and Enterococcal Infections in the Neonatal Intensive Care Unit Philip L. Graham III

Along with the successes in improving the survival of preterm neonates have come changes in the epidemiology o f pathogens that cause healthcare-associated infections. Although gram-negative bacilli and group B streptococci predominated in past years, gram-positive organisms such as staphylococci and enterococci have since taken on greater roles. This shift has been accompanied by difficulties in defining optimal treatments for these pathogens because o f emerging resistance patterns. Copyright 2002, Elsevier Science (USA). All rights reserved.

his article reviews the epidemiology, pathoa n d infection control practices for these infections in the neonatal intensive care unit, particularly multidrug-resistant coagulase-negative staphylococci, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci.

T genesis, treatment,

Coagulase-negative S t a p h y l o c o c c i Epidemiology of CoNS Since the late 1970s and early 1980s, coagulasenegative staphylococci (CONS), particularly Staphylococcus epidermidis, have b e e n recognized as the most c o m m o n cause of bloodstream infection (BSI) in infants in the neonatal intensive care unit (NICU).I.2 Approximately 5% of NICU patients develop b a c t e r e m i a with CoNS that occurs m o s t c o m m o n l y during the third week of hospitalization. 3 T h e incidence of CoNS infections is difficult to precisely ascertain. W h e n these p a t h o g e n s are isolated f r o m a single b l o o d culture, it may be difficult to distinguish true infection f r o m contamination if only 1 b l o o d culture is obtained. Thus, despite the obvious difficulties obtaining 2 blood cultures, m a n y NICUs recognize the i m p o r t a n c e of this practice in From the Division of Infectious Diseases, Department of Pediatrics, Columbia University, New York, NY. Address reprint requests to Philip L. Graham IIl, Fellowin Pediatric Infectious Diseases, Columbia University, Department of Pediatrics, Division of Infectious Diseases, 622 W. 168th St, PH 4 West Rm. 465A, New York, NY 10032; e-mail: [email protected] Copyright 2002, Elsevier Science (USA). All rights reserved. O146-0005/02/2605-0003535. 00/0 doi:10.1053/sper.2002.36265 322

distinguishing infection f r o m contamination and thereby decreasing vancomycin use. T h e increasing survival of extremely low birth weight (ELBW) infants coupled with specific risk factors is responsible for the increased incidence of CoNS infections. 4 Risk factors for infections with CONS, even when adjusted for birth weight, are increased severity of illness as m e a s u r e d by the Score for Neonatal Acute Physiology (SNAP),5 central venous catheters (CVCs), intravenous lipids, 6 parenteral nutrition, 7 length o f hospitalization, s mechanical ventilation, and peripheral catheters inserted within 7 days of bacteremia. 9

Virulence Factors in CoNS Virulence factors include slime, an extracellular glycocalyx capsule? ~ a n d / o r a polysaccharide adhesin xl that are t h o u g h t to mediate adherence to biomaterials. Antibiotic resistance in CoNS is an i m p o r t a n t virulence factor; the vast majority of hospitalacquired strains of CoNS are resistant to multiple agents, including oxacillin, the cephalosporins, and clindamycin.

Colonization and Infection With CoNS Evidence suggests that CoNS colonize the skin o f p r e t e r m infants, c o n t a m i n a t e the outside of central venous catheters, and then cause BSIs. Most CoNS infections are t h o u g h t to be endemic, but clonal outbreaks can occur. T h e r e are n u m e r o u s examples of related strains of CoNS causing endemic and epidemic infections, some of which persist for years in an individual NICU. 12 Molecular typing is critical to correctly identify an o u t b r e a k as p h e n o t y p i n g is unreliable, specia-

Seminars in Perinatology, Vol 26, No 5 (October), 2002: pp 322-331


Gram-positive Infections in the NICU

tion by biochemical profiles is inexact, and CoNS are usually multidrug-resistant making antibiogram comparisons unhelpful. CoNS Infections In addition to BSIs, CoNS can cause skin and soft tissue infections, p n e u m o n i a , meningitis, ventriculoperitoneal shunt infections, and right sided endocarditis associated with use o f CVCs or umbilical venous catheters. 1-~CoNS infections are generally m o r e indolent than infections caused by o t h e r pathogens, but can cause a ~rulent course in p r e t e r m infants. In case-control studies of very low birth weight (VLBW) infants m a t c h e d for birth weight and gestational age, sepsis due to CoNS increased the length of hospitalization. 14 Treatment o f C o N S Infections As the majority o f hospital-acquired CoNS isolates are resistant to the semi-synthetic penicillins, vancomycin is usually the d r u g of choice for these infections. If susceptibility testing reveals sensitivity to the semi-synthetic penicillins, eg, oxacillin or nafcillin, they should be used. T h e cephalosporins are almost never active against CONS. C o m b i n a t i o n therapy with rifampin or gentamicin is indicated for difficult to treat infections such as endocarditis. ~-~ If the isolate is resistant to these adjunctive antibiotics and the infection is deep-seated, cure may be difficult to achieve. T r e a t m e n t o f CoNS catheter related BSIs may be a t t e m p t e d without line removal if the patient is clinically stable and bacteremia is not persistent/6

patient contact and after contact with potentially c o n t a m i n a t e d patient care e q u i p m e n t ? 7 As both central a n d peripheral intravascular dexices (IVDs) are an indispensable part of the care of p r e t e r m infants, reducing the risk of infection from these devices is o f p a r a m o u n t importance. Potential sources o f infection associated with IVDs include: skin flora at the insertion site, contamination of the catheter h u b and lumen, and c o n t a m i n a t e d infusates (Fig 1). Reco m m e n d a t i o n s for insertion, maintenance, and use of IVDs are found in Table 1. O t h e r i m p o r t a n t clinical practices that can reduce heahhcare-associated infections include: monitoring of infection rates by infection control teams with feedback to clinicians, p r o p e r storage and p r e p a r a t i o n of enteral feeds, including avoiding the use of p o w d e r e d formulas, discontinuing invasive support devices whenever possible, and early enteral feeding with the goal o f shortening exposure to intravenous lipids and parenteral nutrition.

Staphylococcus Aureus Epidemiology o f S aureus S aureus is a well-known nosocomial p a t h o g e n in NICU patients a n d is associated with substantial morbidity and mortality. I~ Data f r o m the Center for Disease Control's (CDC's) National Nosocomial Infections Surveillance System (NNIS) in 1996 revealed that 7.5% o f late onset sepsis, 16.7% of p n e u m o n i a s , and 22.2 % of surgical site infections in NICUs were caused by S aureus/9

Infection Control o f C o N S Because skin colonization of both infants and healthcare workers (HCWs) is both e n d e m i c a n d probably unavoidable; infection control efforts must be focused on clinical practices shown to reduce infections, modifying risk factors, and on situations where a clonal o u t b r e a k is suspected. T h e good clinical practices that can reduce CoNS infections will also reduce rates of infection f r o m o t h e r pathogens in the NICU. Probably the single most effective infection control measure in the NICU is a p p r o p r i a t e h a n d hygiene. HC-~s should d e g e r m their hands with an alcohol-based h a n d rub before and after every

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Figure 1. Potential sources of infection of an intravascular de~ice, include skin organisms at the insertion site, contamination of the catheter hnb and lumen, and contamination of infusates. (Reprinted with permission of the University of Chicago Press. TM)


Philip L. Graham

Table 1. Recommendations for Preventing

Intravascular Device Related Infections General Educate all healthcare workers involved with vascular access regarding indications for use, proper insertion technique, and maintenance of IVDs Monitor rates of IVD related infections by infection control team At insertion Degerm hands before insertion or manipulation of IVDs Use maximal barrier precautions (mask, cap, gown, sterile gloves) during insertion of Central Venous Catheters (CVCs) Use aseptic technique including cutaneous antisepsis ideally with chlorhexidine (iodophors and alcohol are also acceptable, but less effective) Use and maintenance Monitor the insertion site on a daily basis Change CVC dressings at least weekly using a sterile semipermeable polyurethane film Do not routinely use topical antibiotics at insertion sites Replace administration sets every 72 hours, or every 24 hours if blood products or lipid mixtures are being infused through them Ensure meticulous attention to sterile technique in preparation of intravenous fluids, blood products, and medications Avoid the use of multidose medication vials that can easily become contaminated Clean the huh or stopcock with 70% alcohol prior to infusion changes or blood drawing Limit opening catheter circuits Remove IVDs as soon as their use is no longer essential Reprinted from MM'WR. 17

Similarly, the National Institute o f Child H e a l t h and Human Development (NICHD) Neonatal Research N e t w o r k r e p o r t e d in 1996 that 9.0% o f cases o f late o n s e t sepsis ( o c c u r r i n g after 3 days o f life) in N I C U patients were attributed to S a u r e u s . 20

Staphylococcal disease was first described in n e w b o r n s in 1773. 21 Since t h e n m a n y o u t b r e a k s in well-baby nurseries a n d N I C U s have b e e n described. T h e earliest m o d e r n e p i d e m i o l o g i c investigation o f a S a u r e u s nursery o u t b r e a k was in 1947. 22 N u m e r o u s a u t h o r s have used phage-typing to identify single strains o f S a u r e u s as the cause o f such outbreaks. I n n o n o u t b r e a k settings, phage-typing usually shows a diversity o f S a u r e u s clones in NICUs. 23 Pulsed field gel electrophoresis (PFGE) has since r e p l a c e d p h a g e -

typing because o f its reproducibility a n d g r e a t e r discriminatory power. 24 A r e c e n t study used PFGE to e x a m i n e the e p i d e m i o l o g y o f S a u r e u s in a N I C U over 1 year a n d f o u n d that it exhibited baseline diversity as well as a t e n d e n c y to u n d e r g o periods in which single clones b e c a m e p r e d o m i n a n t . 25 Methicillin-resistant S a u r e u s

Methicillin-resistant S a u r e u s (MRSA) was first described in 1961 a n d m o r e recently in N I C U settings. Single clones o f MRSA have b e e n frequently identified as sources o f increased rates o f infection. "6 T h e p r i m a r y risk factor for MRSA acquisition in N I C U s is l e n g t h o f stay (LOS); o t h e r risks include antibiotic e x p o s u r e a n d invasive p r o c e d u r e s such as the use o f 1VDs. 27 W h e t h e r MRSA is m o r e virulent than methicillin-sensitive S a u r e u s (MSSA) remains d e b a t e d , b u t the prevailing o p i n i o n is that it is not. 28 H e a l t h c a r e costs associated with MRSA are significant; 1 study f o u n d that hospitalization f o r patients with BSIs caused by MRSA was 4 days l o n g e r a n d $18,000 m o r e expensive than for those with BSIs caused by MSSA. 29 C o l o n i z a t i o n by S a u r e u s

All staphylococcal disease begins with colonization. Hospitalized n e w b o r n s rapidly acquire S a u r e u s o n their umbilicus followed by their nares. As m a n y at 5 0 % t o 70% o f infants in nurseries a n d N I C U s are c o l o n i z e d by the first week o f life. S a u r e u s transiently colonizes the a n t e r i o r nares o f 30% to 50% o f healthy adults, a n d persistently colonizes 10% to 20%. 3o Persistent carriage is d e f i n e d as the r e p e a t e d isolation o f 1 strain o f S aureus, while in transient carriers, different strains are isolated over time. T h e majority o f staphylococcal colonization in patients occurs via H C W s whose h a n d s have b e e n transiently c o l o n i z e d f r o m their own reservoirs o f S a u r e u s o r f r o m c o n t a c t with c o l o n i z e d / i n f e c t e d patients. 31 MSSA colonization o f the nares, umbilical stump, a n d skin is a n o r m a l process, yet it may serve as a source for invasive infection. Staphylococcal infection occurs 10 times m o r e frequently in otherwise healthy infants w h o are c o l o n i z e d with S aureus. 32 T h e relationship between colonization a n d infection is n o t completely u n d e r s t o o d , b u t is related to factors in-

Gram-positive Infections in the N I C U

trinsic to the host as well as to the strain o f S a u r e u s . Host factors associated with an increased risk of infection include defects in chemotaxis, opsonization, and leukocyte function, or the presence of foreign bodies such as IVDs? ;~ S a u r e u s expresses several virulence determinants, which include surface proteins that p r o m o t e colonization and exoproteins that facilitate invasion. 31 Using molecular typing, investigators have shown that greater than 80% o f bacteremias caused by S a u r e u s in hospitalized adults were p r e c e d e d by colonization of the anterior nares with the same strain. 34

Staphylococcal Disease T h e spectrum of staphylococcal disease in NICU patients is broad. Skin disease can range from impetigo, cellulitis, and wound infections to toxin-mediated diseases such as staphylococcal scalded skin syndrome (SSSS) and toxic shock syndrome (TSS). T h e a p p e a r a n c e of several patients in a N1CU with skin findings including vesicles with clear yellow fluid and crusting should alert the neonatologist to an outbreak of S a u r e u s in the unit. SSSS begins as a tender erythematous e x a n t h e m that progresses to bullae, which enlarge, and can slough with light r u b b i n g o f the skin (the Nikolsky sign). SSSS is caused by a strain of S a u r e u s that colonizes or infects the infant and then produces an exfoliative toxin that disrupts the granulosa layer of the skin and causes intraepidermal disruption. 3-', While this syndrome usually presents in full-term infants, clusters of the disease have b e e n described in NICUs. -~6 Some S a u r e u s strains p r o d u c e the toxic shock syndrome toxin (TSST), which acts as a superantigen. TSST broadly activates T ceils causing an exaggerated i m m u n e response, causing TSS. This syndrome is characterized by the sudden onset of fever, shock, multiorgan system failure, and desquamation of the skin after a diffuse erythematous exanthem. TSS is rare in the neonatal period and is associated with an u n d r a i n e d foci of S a u r e u s infection. 37 S a u r e u s is a c o m m o n causative agent of p u r u l e n t conjunctivitis, which responds to topical therapy. Staphylococcal breast abscess and mastitis are often found in lactating mothers, but can occur in neonates with physiologic breast tissue enlargement. :~8 S a u r e u s is a c o m m o n cause o f bacteremia and


sepsis in the NICU patient. Because NICU patients are often d e p e n d e n t on IVDs for nutrition, the question of when to remove such devices during a bacteremic episode is a c o m m o n m a n a g e m e n t problem. Neonates who do not have their IVDs removed within 24 hours o f developing a catheter associated S a u r e u s bacteremia have significantly higher rates of metastatic sites of infection and worse outcomes, s0 Neonates with p r o l o n g e d S a u r e u s bacteremia after catheter removal should be assumed to have endocarditis, or a n o t h e r c o m m o n site of metastatic infection such as the bones or lungs. S a u r e u s is an infrequent cause o f p n e u m o n i a in the NICU patient. It can be associated either with distant sites of infection, which seed the hmgs via bacteremia, or m o r e commonly, by bacteria which descend f r o m the u p p e r airway and cause alveolar infection. Staphylococcal p n e u m o n i a s are often associated with e m p y e m a formation and with residual p u l m o n a r y abnormalities such as pneumatoceles. In addition to adequate antimicrobial therapy, these infections often require drainage of associated pleural effusions and empyemas. 4~ Osteomvelitis caused by S a u r e u s occurs either xia h e m a t o g e n o u s seeding of b o n e during bacteremia or via direct inoculation of colonizing skin flora during p r o c e d u r e s such as heel punctures. 4~ The pathophysiolo~, of osteomyelitis in neonates differs f r o m older children. Infection develops at the metaphysis, but because neonates have blood vessels that penetrate the growth plate and because the periosteum is relatively thin, infection can track into the growth plate adversely affecting growth. 42 Septic arthritis can occur xia direct extension from a site o f osteomvelitis or by h e m a t o g e n o u s seeding. Septic arthritis must always be drained in addition to administering antibiotics. Diagnosis of osteomyelitis and septic arthritis may be difficult; p r o m p t radiographic imaging and a high index of suspicion are n e e d e d when a neonate has lack of mobility in an extremity or unexplained irritabiliw. Cellulitis, which can overlie an osteomyelitis, or swelling of an extremity should also p r o m p t consideration of this diagnosis. S a u r e u s endocarditis in the neonatal period is rare, but increasing due to use of invasive support devices and surgical palliation of complex congenital heart disease. 4:~ Endocarditis may be especially difficult to diagnose in the neonatal


Philip L. Graham

period, but prolonged bacteremia, hematuria, heart failure, and new murmurs should all lead the neonatologist toward early echocardiography. When S a u r e u s is the causative agent of endocarditis, central catheters must be removed and an extended treatment course with 2 or 3 antibiotics administered. Treatment o f S a u r e u s Infections S a u r e u s possesses several virulence factors that must be taken into account when planning treatment. It secretes enzymes such as hyaluronidase that facilitate tissue invasion, as well as protein A and coagulase that inhibit phagocytosis. While surface proteins such as peptioglycan cause neutrophil migration to the site of infection, S a u reus can persist intracellularly. 44 This combination of virulence factors causes staphylococcal infections to often be deep-seated and require surgical drainage to achieve cure. After surgical drainage, antibiotic therapy must be tailored to the site of infection and the specific resistance pattern of the infecting organism. Preterm infants have varying degrees of glomerular function, so doses must be individualized by gestational age, chronologic age, and by serum antibiotic levels where appropriate. Over 95% of S a u r e u s isolates produce an enzyme that hydrolyzes the/3-1actam ring of penicillin which makes this drug inactive in the treatment of staphylococcal infections. Semi-synthetic penicillins such as oxacillin and nafcillin are not susceptible to this hydrolysis and therefore are the drugs of choice when the infecting organism is sensitive. First generation cephalosporins such as cefazolin and combinations of /3-1actam agents and/3-1actam inhibitors such as ampicllin/sulbactam or piperacillin/tazobactam are also active against MSSA. First generation cephalosporins do not penetrate the CSF well and should not be used for treatment of meningitis/ventriculitis. T h e m e c A gene that encodes for an altered penicillin-blinding protein confers methicillin resistance. MRSA isolates are resistant to all penicillins and cephalosporins making vancomycin the drug of choice for these infections. The oxazaolindone, linezolid, is also active against MRSA. It must be r e m e m b e r e d that vancomycin is an inferior anti-staphylococcal drug, and that the semi-synthetic penicillins are the treatment

of choice for MSSA. Thus, if empiric treatment was begun with vancomycin and the infecting organism is shown to be sensitive to the semisynthetic penicillins, treatment should be optimized by changing to one of these agents. T h e r e have been several reports o f patients with MRSA isolates with reduced sensitivity to vancomycin (vancomycin intermediate S a u r e u s or VISA), but n o n e have yet been reported in NICUs. 45 In addition to surgical drainage of infected sites, several adjunctive antibiotics can be helpful in treating serious staphylococcal infections. Rifampin penetrates well into cells, bone, and the CSF and can aid in clearance of deep-seated infections. Because resistance to rifampin occurs easily through a single mutation, it should never be used as a single agent. The intravenous formulation of rifampin often causes indwelling catheters to lose patency. If the patient is able to absorb enteral medications, oral rifampin is a good treatment option. Gentamicin acts synergistically with both the ~ l a c t a m agents and vancomycin and is beneficial in staphylococcal endocarditis. Infection Control for S a u r e u s

Control of MSSA represents unique challenges as colonization is expected, endemic infections are tolerated, and surveillance efforts generally focus on multi-drug resistant pathogens. Most infection control strategies for preventing S a u reus infections focus on epidemic periods when 1 clone causes the majority of disease in the unit. However, preventing infections from endemic flora is also important. Good clinical practices and IVD care discussed above as infection control measures for CoNS apply equally to preventing S a u r e u s infections. Epidemic infections with single clones of S a u r e u s are an indication that routine infection control practices have failed. Routine surveillance cultures of NICU patients have fallen out o f favor secondary to expense and lack of utility.4 6 However, targeted surveillance and typing with PFGE during periods of increased incidence can identify patient to patient transmission caused by breakdowns in infection control practices and colonized patients who can serve as reservoirs for the spread of infection to other patients. NICU patients with long-term hospitalizations or infants transferred from other NICUs

Gram-positive Infections in the NICU

m i g h t be a subpopulation in which surveillance cultures would be cost-effective. T h e results of such cultures could direct preemptive segregation of colonized older patients f r o m younger, m o r e vulnerable p r e m a t u r e infants. In addition, if rates of infection increase, HCWs can be cultured to identify those colonized who can then be treated to eliminate carriage. 47 Routine culture surveys of HCWs are not helpful, as they c a n n o t discriminate between those who will disseminate their flora to patients and those who will not. After d e t e r m i n i n g colonization status, patients can be appropriately c o h o r t e d and treated. T r e a t m e n t with intranasal m u p i r o c i n of all patients can control o u t b r e a k s - this has proven especially helpful with MRSA. 48 Unfortunately, inappropriate widespread use of mupirocin has resulted in resistance, so this strategy must be used judiciously. 49 Targeted t r e a t m e n t may be m o r e a p p r o p r i a t e when colonization rates are low. Contact precautions will help prevent spread of MRSA in a NICU when initial cases are detected.

Enterococcus Epidemiology of Enterococcus spp.

Enterococcus faecalis and Enterococcus faecium are generally considered to be low virulence pathogens, but their epidemiology has changed over the past 30 years. They are now a leading cause of hospital-acquired bacteremia in adults and an increasingly c o m m o n cause of infections in NICU patients. Data f r o m the National Nosocomial Infections Surveillance (NNIS) System in 1996 revealed that 6.2% of late onset sepsis, 4.6% of pneumonias, and 8.9% of surgical site infections in NICUs were caused by enterococci. a9 Similarly, the Pediatric Prevention Network point-prevalence survey published in 2001 reported that 10.3% of bloodstream infections a n d 16.7% o f urinary tract infections were attributed to enterococci. 5~ Data from several studies show that UTIs attributable to enterococci rose from 2% in the 1970s to 14% in the 1990s. 51 Enterococci are part of the n o r m a l adult bowel and vaginal flora and can be acquired by neonates during delivery. In addition, nosocomial patient-to-patient transmission has been demonstrated. 52 Risk factors for colonization in-


clude LOS, use of IVDs, and antibiotic use. 5-~ T h e first r e p o r t e d NICU o u t b r e a k of E faecium was in 19845a and of Efaecalis in 1987. 55 While colonization with enterococci is a normal process, p r e t e r m infants can develop infections from this e n d o g e n o u s flora.

An6biotic Resistant Enterococci T h e enterococci are intrinsically resistant to the cephalosporins, clindamycin, trimethoprim-sulfamethoxazole, and to low levels of aminoglycosides. They also exhibit tolerance to antibiotics active against the cell wall, eg, ampicillin, necessitating c o m b i n a t i o n therapy when bactericidal activity is n e e d e d ) 6 Some enterococci have acquired resistance to o t h e r classes of antibiotics including: high levels of the aminoglycosides, the/3-1actam agents, and vancomycin. W h e n the enterococci acquire aminoglycoside modifying enzymes that cause high-level resistance to b o t h gentamicin and streptomycin, bactericidal activity is difficult to achieve. 57/3-1actam resistance in E faecium occurs via altered penicillin binding proteins. Some Efaecalis strains p r o d u c e a penicillinase that does not a p p e a r to cause clinically significant levels of resistance. 5s Vancomycin resistance in enterococci is a significant p r o b l e m in hospitalized adults. Acquired vancomycin resistance usually occurs via the p r o d u c t i o n o f altered cell wall precursors that do not bind vancomycin. During 1999, the prevalence of vancomycin resistance a m o n g enterococci isolated from adult ICU patients increased by 40%, when c o m p a r e d with the prevalence from the 5 year period f r o m 1994-1998. 59 Although E faecalis is responsible for 80% of enterococcal infections, E faecium strains acc o u n t for 98% of vancomycin resistant cases. 6~ Risk factors for acquisition o f vancomycin resistant enterococci (VRE) include vancomycin use, cephalosporin use, and e x t e n d e d LOS. 61 In contrast, the Pediatric Prevention Network pointprevalence survey in 2001 did not detect any infections caused by VRE suggesting that effective control of VRE is obtainable in N I C U populations. 50

Enterococcal Disease Enterococci can cause bacteremia as well as urinary tract infections (UTIs), endocarditis,


Philip L. Graham

w o u n d infections, and central nervous system (CNS) infections. 62 These bacteria have b e c o m e frequent causes of late onset bacteremia and sepsis in NICU patients. While early onset disease is similar to that caused by group B streptococcus, late-onset enterococcal sepsis is most often healthcare-associated and may be polymicrobial. Affected infants generally have had complicated medical courses with p r o l o n g e d LOS, low birth weight, prior antibiotic therapy, and multiple invasive procedures. 6~ Late-onset enterococcal sepsis is often related to focal sites of infection or necrotizing enterocolitis. Successful treatment of these infections usually requires drainage of abscesses and removal of infected catheters in addition to appropriate antibiotic therapy. 64 Endocarditis is rare in the neonatal period and enterococcal endocarditis is even rarer. 65 However, p r o l o n g e d enterococcal bacteremia after catheter removal is an indication for early echocardiography, as the treatment of enterococcal endocarditis requires p r o l o n g e d bactericidal combination therapy that must be started as soon as possible. Most CNS infections caused by enterococci are related to underlying pathology such as hydrocephalus, neural tube defects, or ventricular shunts; however, neonates can develop enterococcal meningitis in the absence of these risk factors. 66 Treatment o f Enterococcal Infections

Therapy of enterococcal infections depends on the site of infection and the resistance pattern of the isolate. Ampicillin-sensitive enterococcal infections should be treated with either ampicillin m o n o t h e r a p y in the case of UTIs or combination therapy with an aminoglycoside for more serious infections. If the isolate is susceptible to ampicillin, but has high-level aminoglycoside resistance, therapy with ampicillin will need to be continued at high doses for p r o l o n g e d periods. The cephalosporins and trimethoprim-sulfamethoxazole should never be used for enterococcal infections, even if the laboratory reports in vitro sensitivity. Ampicillin-resistant, vancomycin-sensitive stains can be treated with vancomycin with or without a synergistic aminoglycoside depending on the site of infection. VRE represents the largest therapeutic challenge in treating enterococcal infections. Until

recently there were no reliable treatment options for these infections. Linezolid was approved for adult use in April 2000 and its spectrum of activity includes vancomycin susceptible and resistant E faecalis and E faecium, making it the drug of choice for serious VRE i n f e c t i o n s , 67 including CNS infections. 6s Pharmacokinetic (PK) studies are o n g o i n g for pre-term and term neonates. Based on preliminary PK data, linezolid dosages of 10 m g / k g / d o s e q8h are reco m m e n d e d for infants. 6s O f note, there have been several case reports of linezolid resistance and thrombocytopenia with prolonged use (>21 days) of this agent. 69 Infection Control for VRE

While the enterococci may be part of the normally acquired bowel flora of neonates, VRE is not, and infection control practices can contain its spread. CDC guidelines for control of VRE focus on prevention of its emergence, detection in the microbiology laboratory, and controlling nosocomial transmission. Vancomycin use should be limited to treatm e n t of serious infections caused by /3-1actam resistant gram-positive organisms and certain cases of late onset sepsis p e n d i n g culture results 7~ (Table 2). It has been difficult to control the use of vancomycin in NICUs as the majority of late-onset sepsis episodes in VLBW infants are caused by CoNS resistant to oxacillin. However, limiting vancomycin use is critical not only to control the emergence of VRE but also to avoid

Table 2. Prudent Vancomycin Use in the NICU Vancomycin should used: For the treatment of serious infections caused by /3-1actam-resistant gram-positive organisms For the treatment of gram-positive infections in patients with serious allergies to /3-1actam antibiotics Vancomycin should not be used: For surgical prophylaxis except in institutions with high rates of MRSA In response to a single blood culture positive for CoNS if other cultures are negative For continued empiric use in patients whose cultures are negative for j3-1actam-resistant grampositive organisms For prophylaxis of indwelling catheters For eradication of MRSA colonization For routine prophylaxis of low birth weight infants Reprinted from MMWR.7~

Gram-positive Infections in the NICU

the likely e m e r g e n c e of CoNS isolates with reduced susceptibility to vancomycin. In examining one strategy to reduce the use of vancomycin, investigators e x a m i n e d the effect of using oxacillin as empiric anti-staphylococcal coverage in the place of vancomycin. This study f o u n d that of 477 cases of late-onset sepsis over a 10 year period, 277 were caused by CONS, but only 4 of these led to death within 48 hours, and that mortality did not increase during a time period when oxacillin replaced vancomycin as empiric gram-positive coverage. 7t Further studies are n e e d e d to define the subset of NICU patients that can have vancomycin therapy deferred p e n d i n g culture results. As the use o f e x t e n d e d spectrum cephalosporins, eg, cefotaxime and ceftazidime, have b e e n linked to the e m e r g e n c e of both VRE and resistant gram-negative bacilli, their use should be limited. 72 W h e n VRE is detected in a NICU patient, contact precautions must be i m p l e m e n t e d including, the use of gloves and gowns for all patient contact and contact with patient care equipment, the use of dedicated noncritical medical devices (eg, stethoscopes), as well as single rooms or cohorting with any o t h e r VRE c o l o n i z e d / infected patients. H a n d hygiene in staff and parents should be reemphasized. If multiple cases of VRE infections occur, or if a NICU has its first case of VRE detected, surveillance cultures of all patients to detect colonized infants who may serve as reservoirs followed by cohorting may stop ongoing transmission. Because colonization of the gastrointestinal tract may be persistent despite treatment, colonized infants should remain isolated for the duration of their hospitalizations. Because enterococci c o n t a m i n a t e the e n v i r o n m e n t easily and persistently, cleaning procedures must be meticulous. 73

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