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DOI:10.1542/peds.106.4.7122000;106;712-718Pediatrics

Richard Auten and Randall G. FisherDaniel K. Benjamin Jr., Kelly Ross, Ross E. McKinney Jr., Daniel K. Benjamin,

Staphylococcal BacteremiaFungemia With Coagulase-NegativeCandida parapsilosisandCandida albicans

When to Suspect Fungal Infection in Neonates: A Clinical Comparison of

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rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Grove Village, Illinois, 60007. Copyright © 2000 by the American Academy of Pediatrics. Alland trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk publication, it has been published continuously since 1948. PEDIATRICS is owned, published,PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

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When to Suspect Fungal Infection in Neonates: A Clinical Comparison ofCandida albicans and Candida parapsilosis Fungemia With

Coagulase-Negative Staphylococcal Bacteremia

Daniel K. Benjamin, Jr, MD*; Kelly Ross, MD*; Ross E. McKinney, Jr, MD*; Daniel K. Benjamin, PhD‡;Richard Auten, MD*; and Randall G. Fisher, MD*

ABSTRACT. Objectives. To determine the epidemiol-ogy of candidemia in our neonatal intensive care unit; tocompare risk factors, clinical presentation, and outcomesfor neonates infected with Candida albicans, Candida

parapsilosis, and coagulase-negative staphylococcus(CoNS); and to suggest a rational approach to empiricantifungal therapy of neonates at risk for nosocomialinfection.

Design. Retrospective chart review of all neonatal in-tensive care unit patients with systemic candidiasis or

CoNS infection between January 1, 1995 and July 31, 1998at Duke University Medical Center.

Results. Fifty-one patients were reviewed. Nine of 19patients infected with C parapsilosis and 5 of 15 patientsinfected with C albicans died of fungemia. Seventeenneonates had >2 positive cultures for CoNS obtainedwithin 96 hours and 1 died. There was no statisticallysignificant difference in birth weight, gestational age, orage at diagnosis between patient groups; however, can-didemic patients had a sevenfold higher mortality rate.Before diagnosis, candidemic patients had greater expo-sure to systemic steroids, antibiotics, and catecholamineinfusions. Of the 51 patients, 32 received third-genera-tion cephalosporins in the 2 weeks before diagnosis and19 did not. Twenty-nine of the 32 who were treated withthird-generation cephalosporins subsequently devel-oped candidemia, while candidemia occurred in only 5 of19 patients who were not treated with cephalosporins. Atthe time of diagnosis, candidemic patients were morelikely to have required mechanical ventilation and wereless likely to be tolerating enteral feeding. Multivariateclustered logistic regression analysis revealed that candi-demic patients had more exposure to third-generationcephalosporins. Once the clinician was notified of a pos-itive blood culture for Candida , patients infected with C

parapsilosis retained their central catheters longer thanpatients infected with C albicans.

Conclusions. In this retrospective review, we wereable to identify aspects of the clinical presentation and

medication history that may be helpful in differentiatingbetween candidemia and CoNS bacteremia. Those keyfeatures may be used by clinicians to initiate empiricamphotericin B therapy in premature neonates at risk fornosocomial infections. Prolonged use of third-generation

cephalosporins was strongly associated with candidemia.There was no statistically significant difference in themorbidity and mortality between patients infected withC parapsilosis and those infected with C albicans. Ob-served delays in removal of the central venous cathetermay have contributed to finding a mortality rate from C

parapsilosis that was higher than was previouslyreported. Pediatrics 2000;106:712–718; Candida, parapsi-losis, albicans, Staphylococcus epidermidis, neonate, sep-sis, platelets, amphotericin, central line, cephalosporin.

ABBREVIATIONS. NICU, neonatal intensive care unit; CoNS,coagulase-negative staphylococcus; TPN, total parenteral nutri-tion; CSF, cerebrospinal fluid; OR, odds ratio.

Opportunistic infections are an increasinglycommon problem in neonatal intensive careunits (NICUs). Premature neonates often

have compromised skin integrity, gastrointestinaltract disease, chronic malnutrition, central venouscatheters, long-term endotracheal intubation, andother factors that lead to increased risk of acquiring

such infections. Infections with fungi (especially can-didal species) and with coagulase-negative staphylo-cocci (CoNS) are especially prevalent. Signs andsymptoms of infection with any of these organismsare nonspecific and include temperature instability,respiratory distress, abdominal distention, apneaand bradycardia, lethargy, and decreased perfusion.

Among Candida species pathogenic to humans, Calbicans has been the species most often associatedwith neonatal infection. Recent reports, however,have suggested an increasing number of infectionsattributable to C parapsilosis associated with com-mon-source outbreaks.1,2 In some NICUs, C parapsi-

losis has become the predominant fungal pathogen.

3,4

In general, animal models and clinical reports havesuggested that C parapsilosis is a less virulent organ-ism than C albicans.5,6 One report showed a sixfoldgreater mortality for patients infected with C albicansthan for those infected with C parapsilosis.4 Undercertain conditions, however, eg, in the presence of intravascular catheters and high intravenous glucoseconcentrations, C parapsilosis may have both a selec-tive advantage and increased virulence relative to Calbicans.7

Infection with CoNS, although clinically difficultto differentiate from fungal infection in the neonate,is less likely to be associated with end-organ involve-

From the *Department of Pediatrics, Duke University, Medical Center,

Durham, North Carolina; and the ‡Department of Economics, Clemson

University, Clemson, South Carolina.

Received for publication Aug 3, 1999; accepted Feb 24, 2000.

Reprint requests to (D.K.B.) Department of Pediatrics, Duke University

Medical Center, Box 3499, Durham, NC 27710. E-mail: danny@abacus.

mc.duke.edu

PEDIATRICS (ISSN 0031 4005). Copyright © 2000 by the American Acad-

emy of Pediatrics.

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ment or mortality. Thirteen different species of CoNSare found as part of the normal human flora, butStaphylococcus epidermidis is the most common signif-icant pathogen.8–10 Colonization precedes infectionwith this species.11 Because the organism is part of normal flora, isolation of the organism in a single

blood culture usually represents contaminationrather than infection.8 When CoNS are recovered onՆ2 blood cultures within 24 hours, infection is morelikely.8 Infected infants rarely die from the disease,

although morbidity (eg, endocarditis and meningitis)can be significant.10

Clinicians caring for a neonate who is deteriorat-ing despite empiric broad-spectrum antimicrobialtherapy face a difficult diagnostic dilemma. If theneonate has systemic candidiasis, amphotericin B isthe treatment of choice. If the patient is infected withCoNS, standard treatment is vancomycin. The use of antibiotics such as vancomycin increases the risk of

both future candidemia14 and the emergence of van-comycin-resistant Gram-positive organisms. We con-ducted a retrospective chart review to see: 1) whetherthe epidemiology of our NICU reflected the apparentnational trend toward increasing isolation of C parap-silosis; 2) whether different risk factors could be iden-tified for the acquisition of C albicans or C parapsilosisversus CoNS; 3) whether morbidity of infection withthese 3 organisms differed; and 4) whether we couldsuggest a rational approach to empiric antifungaltherapy of neonates at risk for nosocomial infection.

METHODS

Microbiology laboratory records from January 1, 1995 to July31, 1998 were reviewed for CoNS bacteremia and candidemia inNICU patients. Inclusion criteria for patients with bacteremiawere the presence of at least 3 positive blood culture results forCoNS within 96 hours, and at least 2 positive blood culture resultsfor CoNS within a 24-hour span. Candidemic patients were in-

cluded based on the presence of at least 1 positive blood cultureresult with either C albicans or C parapsilosis.We analyzed the charts of neonates with CoNS infection or

systemic candidiasis for the following: gestational age, birthweight, age at diagnosis, intravenous dexamethasone before diag-nosis, initiation of antimicrobial therapy, central line access, pres-ence of endotracheal tube, enteral feeds, antibiotics, dextrose con-centration of the total parenteral nutrition (TPN), intravenouslipid administration, intravenous medications, platelet count,white blood cell count, neutrophil count, band count, immature-to-total neutrophil ratio, and acidosis. We reviewed echocardio-gram; head, liver, spleen, and renal ultrasounds; and cerebrospi-nal fluid (CSF) results. We also examined the results of eachinfant’s blood, urine, and CSF culture results, evaluated the lengthof antimicrobial therapy, elapsed time until negative cultures,practices regarding central line removal, survival, and cause of

death.A positive renal ultrasound was defined by a report indicatingthe presence of “nonshadowing echogenic material compatiblewith fungus,” “echogenic foci compatible with fungus balls,”“echogenic debris compatible with fungus,” or “echogenic focicompatible with fungus.” A positive head ultrasound was evi-denced by the presence of ventriculitis, and a positive echocardio-gram required the presence of valvular or mural vegetations. Thedate of diagnosis was the date that the first positive blood culturewas obtained. We defined complete end-organ evaluation as fun-doscopic examination, renal ultrasound, liver and spleen ultra-sound, echocardiogram, and lumbar puncture for CSF culture,Gram-stain, and cell count. We defined continuous cardiovascularsupport drips as the use of epinephrine, dopamine, or dobutaminefor blood pressure support.

The NICU at Duke University has 12 level 2 and 24 level 3nursery beds. The nursery admits an average of 600 infants each

year. Nearly 30% of the infants weigh Ͻ1500 g on admission.Although initial central catheter access is usually obtained viaumbilical vessels, most neonates who require prolonged centralaccess receive percutaneous intravenous central catheters. Whenan infant is evaluated for possible sepsis, the bedside clinician’s

judgment guides the acquisition of cultures and initiation of anti-microbial agents; however, virtually all neonates have 1 peripheral

blood culture obtained and 2 broad-spectrum intravenous antibi-otics are started.

The initial empiric antibiotic regimen for neonates Ͻ10 days of age is ampicillin and gentamicin. Infants Ͼ10 days of age whohave indwelling central catheters are often started on vancomycinrather than on ampicillin. Cefotaxime or ceftazidime are fre-

quently used in neonates Ͼ10 days of age who demonstrate noimprovement with gentamicin (Gram-negative coverage) andGram-positive antimicrobial therapy. For the purpose of this anal-ysis, we considered appropriate empiric antimicrobial therapy to

be the initiation of vancomycin for infants infected with CoNS andamphotericin B for infants infected with Candida species at thetime that the first positive blood cultures were drawn.

Neonates with 1 positive culture for Candida species typicallyundergo complete end-organ evaluation provided their prognosiswarrants evaluation of potential long-term sequelae. Neonateswho are persistently bacteremic may be evaluated for endocarditisor other end-organ damage at the discretion of the bedside clini-cian. Central catheter removal in bacteremic neonates is left to thediscretion of the attending neonatologist, but central catheters areroutinely removed as quickly as possible for candidemic neonates.If the microbiology laboratory identified the species of infecting

organism and the physician then waited at least an additional 24hours (treating with appropriate antimicrobial therapy) to removethe catheter, we documented that as attempted sterilization.

Reported P values are 2-tailed and, except where noted, are based on either Fisher’s exact test or Wilcoxon rank sum test asappropriate. Multivariate analysis was performed using clusteredlogistic regression. For the multivariate analysis, the dependentvariable took on the value of 1 for candidemia, and zero for CoNS.Independent variables were third-generation cephalosporin ad-ministration, antibiotic administration, systemic steroid adminis-tration, cardiovascular drips, ventilatory status, and enteral feed-ing. To evaluate events during the 2 weeks before diagnosis, wecalculated administration of antibiotics and cardiovascular sup-port drips by totaling the number of medications each patientreceived each day during the 14 days before diagnosis.

RESULTS

Candidiasis

Thirty-seven children had positive blood culturesfor Candida species. Nineteen neonates were infectedwith C parapsilosis, 15 neonates were infected with Calbicans, 2 neonates were infected with Candida tropi-calis, and 1 neonate was infected with Candida gla-brata. Of the infants admitted to the NICU whose

birth weight was Ͻ1500 g, 4% developed candi-demia. We reviewed the charts of 34 candidemicpatients.

Infants infected with C albicans and C parapsilosis

had similar birth weight, gestational age, and age atdiagnosis. Before diagnosis, there was no difference between groups in their need for ventilatory supportor parenteral nutrition. Patient platelet countsdropped an average of 13% per day (P ϭ .01) for the7 days before infection with C albicans—a trend thatwas less pronounced with C parapsilosis (P Ͻ .05).Before diagnosis, children infected with C albicanshad a greater rise in their band count (17.2% rise vs11.1%; P Ͻ .001), but a less significant rise in theirneutrophil count (39.9% rise vs 50.9%; P ϭ .0001)than children infected with C parapsilosis. There wasno difference in TPN administration (13/15 [87%] Calbicans vs 17/19 [89%] C parapsilosis), intralipid con-

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centration (12/15 [80%] vs 17/19 [89%]), or dextroseconcentration (18% C albicans vs 16% C parapsilosis;P ϭ .15). Change in white blood cell count did notdiffer significantly between species (P ϭ .087).

Nine neonates had evidence of end-organ damage(Table 1). The number of infants who suffered evi-dence of end-organ disseminated candidiasis or whohad multiple positive blood cultures for Candida didnot differ significantly between the species (P Ͼ .99).There was no relationship between the number of

positive blood cultures for candidiasis and end-or-gan damage (P Ͼ .99).Twenty-nine candidemic neonates had 33 central

catheters at diagnosis, and in only 1 case were phy-sicians able to salvage the central catheter withoutadverse consequences. Central catheters in use in-cluded Broviac catheters, femoral venous catheters,umbilical catheters, percutaneously inserted centralcatheters, and internal jugular catheters (Table 2).Once the clinician was notified of a positive bloodculture for Candida, neonates infected with C albicanshad their central catheters removed earlier than didpatients infected with C parapsilosis (2.0 days vs 3.6days; P Ͻ .001). There were 12 candidemic neonateswho had their catheters removed the same day thatthe clinician was notified of the positive culture, and11 of them were infected with C albicans.

The day that the clinician was notified of a positive blood culture for Candida species, amphotericin Btherapy was promptly initiated for infants not al-ready on empiric amphotericin B. Notably, 4 of theinitial 34 positive blood cultures for Candida speciestook Ͼ96 hours to grow. Candidemic patients whowere started on amphotericin B Ն3 days after thefirst positive blood culture was drawn had a mortal-ity rate of 50% (3/6 infants). For patients with can-didemia, as the time between obtaining the blood

culture and notification of a positive blood cultureincreased, so did the mortality rate (P ϭ .04). Beforeclinician notification of a positive blood culture,more neonates infected with C albicans (7 of 15; 47%)received empiric amphotericin B than did infantsinfected with C parapsilosis (4 of 19; 21%), but thisdifference did not reach statistical significance.

All 19 neonates who survived were treated with 1mg/kg/day of amphotericin B. Six children infectedwith Candida species were treated for 7 to 14 days.

Each of the 6 neonates had unremarkable evaluationsfor evidence of end-organ damage. Eleven neonates,4 with evidence of disseminated candidiasis, weretreated for 21 to 24 days. Two neonates, 1 with fungalendocarditis and the other with renal mycetoma,were treated for 42 days. None of the 21 patients whosurvived the initial candidemic episode relapsed af-ter treatment. There was no statistically significantdifference in the mortality of children infected with Calbicans or C parapsilosis; 8 of 19 children infected

with C parapsilosis and 5 of 15 children infected withC albicans died secondary to systemic candidiasis(47% vs 33%; P ϭ .73). None of the neonates whodied secondary to systemic candidiasis had a com-plete end-organ evaluation. None of the infants re-quired gastrointestinal surgery for necrotizing en-terocolitis.

CoNS

There were 279 positive blood cultures for CoNS in129 neonates. Only 19 of these patients had a total of at least 3 positive blood cultures for CoNS, 2 of which were drawn within 24 hours and, thus, metinclusion criteria for this study. Two of those neo-nates were concomitantly infected with M furfur and

H anomola, respectively, and were excluded fromanalysis. We, thus, reviewed the charts of 17 patientswith CoNS infection.

Sixteen of the 17 children infected with CoNS hadat least 1 blood culture drawn from a peripheral siteand 1 blood culture drawn from an indwelling cen-tral line (1 of the 17 infants did not have a centralcatheter). One child infected with CoNS had an echo-cardiogram consistent with endocarditis and echo-genic abnormalities on renal ultrasound. None of theinfants had a soft tissue focus of infection. One childdied as a result of CoNS bacteremia. Each of the

initial positive blood cultures for CoNS grew within48 hours.

Sixteen bacteremic infants had central catheters.Children infected with CoNS species retained theircentral catheters longer than did children infectedwith Candida (6.4 vs 4.0 days; P ϭ .007). Attemptswere made to sterilize each of the central catheters,and 2 of 16 (12.5%) were successfully sterilized. Onechild died during attempted sterilization—persistent

bacteremia was documented by positive blood cul-tures for 7 days— despite vancomycin therapy. Only1/13 of the children whose central catheter was re-moved (8%) had a positive blood culture after re-

moval of the catheter.All children infected with CoNS were treated withvancomycin; none of the neonates were infected witha strain that was susceptible to nafcillin. Each of theinfants remained bacteremic for a period of 1 to 9days, despite vancomycin administration. Evidencefor persistent bacteremia included both central andperipheral blood cultures. Duration of antibiotictherapy varied from 5 to 22 days. Fourteen of the 17neonates were given gentamicin for periods of 2 to 22days. No neonate was given rifampin, erythromycin,or clindamycin. None of the 16 children who sur-vived their initial infection had a relapse of CoNS

bacteremia.

TABLE 1. Evidence of End-Organ Dissemination and Mortal-ity in 34 Candidemic Patients and 17 Patients With CoNS Bacte-

remiaC albicans(n ϭ 15)

C parapsilosis(n ϭ 19)

CoNS(n ϭ 17)

Abnormal renalultrasound

2/11 5/10 1/8

Abnormalechocardiogram

1/11 0/15 1/11

Abnormal liver/spleenultrasound

0/8 0/9 0/8

Abnormal fundoscopicexamination

0/10 0/8 0/13

Abnormal CSF 0/3 0/9 0/8Abnormal head

ultrasound1/10 0/13 0/7

Number of deaths 5/15 8/19 1/17

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Univariate Analysis Comparing Candidiasis and CoNSBacteremia

Children infected with C albicans, C parapsilosis,and CoNS had similar birth weight, gestational age,and age at diagnosis (Table 2). On the day of diag-nosis, neonates infected with Candida species weremore likely to be on a ventilator than were childreninfected with CoNS (32/34 vs 41/17; P ϭ .01). Neo-nates infected with Candida species were also lesslikely to be taking enteral feeds (8/34 vs 10/17; P ϭ.03). During the 2 weeks before diagnosis, 20/34 of

the neonates infected with Candida species (56%) and6/17 of the neonates infected with CoNS (35%) werereceiving systemic steroids. Children infected withCandida species were 7 times more likely to die fromsepsis than were children infected with CoNS (13/34vs 1/17; P ϭ .02).

Appropriate empiric therapy on the day that bloodcultures were obtained (which subsequently turnedpositive for either CoNS or Candida species) varied between patient groups. On the day the first positive blood culture was obtained in patients with CoNS, 13of 17 (76%) neonates were either receiving or werestarted on appropriate empiric antimicrobial therapy

(vancomycin). Fewer candidemic patients, 11 of 34(32%), were started on appropriate empiric ampho-tericin B (P Ͻ .01).

For the 2 weeks before the time of diagnosis, can-didemic patients differed from patients bacteremicwith CoNS in several respects by univariate analysis(Table 2). Candidemic infants were less likely to have

been started on appropriate antimicrobial therapy(odds ratio [OR]: 6.8) and were more likely to beintubated (OR: 8.7), intolerant of enteral feeds (OR:4.6), and to be receiving third-generation cephalo-sporins (OR: 27.1).

The 34 candidemic infants had 44 negative bloodcultures drawn in the 2 weeks before diagnosis (1.3

blood cultures per infant). This was significantlymore (P Ͻ .001) than the 4 negative blood culturesdrawn in the 17 bacteremic infants before their infec-tions with CoNS.

Thirty-two of the 51 patients analyzed receivedthird-generation cephalosporins and 29 of those 32patients were subsequently infected with Candidaspecies. This was a substantially higher rate of can-didemia than patients who did not receive intrave-nous third-generation cephalosporins (P ϭ .02; Fig1). Children infected with C parapsilosis were more

likely to have received long-term (Ͼ3 days) empiricthird-generation cephalosporin coverage than werepatients infected with CoNS (OR: 27.4; P Ͻ .001) orthose infected with C albicans (OR: 4.7; P Ͻ .05).

Multivariate Analysis Comparing Candidiasis andCoNS Bacteremia

We evaluated third-generation cephalosporin ad-ministration, administration of all other antibiotics,ventilation status, enteral feeding, cardiovascularsupport drips, and systemic steroids in the 2 weeks

before diagnosis using multivariate clustered logisticregression (Table 3). Patients who developed candi-

demia were more likely to have received third-gen-eration cephalosporins (OR: 21.3, P ϭ .001). Thethird-generation cephalosporin use in the infantswas predominantly empiric; only 1 child had a doc-umented blood, urine, or CSF culture that supportedthe use of a third-generation cephalosporin.

DISCUSSION

Two of the most common nosocomial infections inthe hospitalized neonate are CoNS bacteremia andcandidemia.17–19 The clinical presentation of thenewborn with sepsis caused by CoNS and Candida isnonspecific. Before diagnosis, patients infected witheither CoNS or Candida species can often present

TABLE 2. Patient Demographics and Risk Factors

Candidemic Patientsn ϭ 34

CoNS Patientsn ϭ 17

UnivariateAnalysisP Value

OR (95%Confidence

Interval)

Birth weight (g*) 1178 (Ϯ893) 1094 (Ϯ589) .66Gestational age (wk*) 27.6 (Ϯ4.8) 28.2 (Ϯ3.5) .15Age at diagnosis (d*) 24 (Ϯ18) 31 (Ϯ19) .19Intubated (n) 32 (94%) 11 (65%) .01 8.7 (1,5,49.5)NPO (n) 26 (76%) 7 (41%) .03 4.6 (1.3,16)Antibiotics (# per patient d) 1.47 1.0 Ͻ.001Inotropic drugs (% of patient d) 37% 14% Ͻ.001Systemic steroids (% of patient d) 27% 13% Ͻ.001Number of patients receiving third-

generation cephalosporins29 3 Ͻ.001 27.1 (5.6,130)

Third-generation cephalosporin usein the 2 wk before diagnosis

4.4 d per patient .8 days per patient Ͻ.001

Patients who were not onappropriate empiricantimicrobial therapy

23 4 Ͻ.01 6.8 (1.8,25.8)

Central catheters at diagnosis (n) 33 22Broviac 1 4Percutaneously inserted central

catheter16 10

Umbilical 9 1Femoral 6 4Internal jugular 1 0

* Ϯ standard deviation.








with a clinical picture of slow deterioration.20 Thispresentation of slow deterioration contrasts with ne-onates who experience septic shock secondary toGram-negative rods or virulent Gram-positive or-ganisms. The primary objectives of this study were todetermine: 1) the epidemiology of candidemia in ourNICU; 2) whether different risk factors could beidentified for the acquisition of C albicans, C parapsi-losis, and CoNS; 3) whether the morbidity of infec-tion with these 3 organisms differed; and 4) whetherwe could suggest a rational approach to initiation of

empiric antifungal therapy of neonates at risk fornosocomial infection.

CoNS Bacteremia and Candidemia

Univariate analyses comparing candidemic neo-nates with matched controls have shown steroidsand antibiotic administration to be linked with can-didemia. Previous multivariate analysis has linkedantibiotic administration and subsequent neonatalcandidemia.12

There were no differences among patient groupsin birth weight, gestational age, or age at diagnosis.These similarities provided an opportunity to usepatients infected with CoNS as a comparison group

in evaluating risk factors for candidemia. We electedto include infants with at least 3 positive blood cul-tures for CoNS in an effort to select infants most

likely to have true bacteremia and subsequent morbidity and mortality. We intentionally excluded in-fants with cultures likely to reflect contamination.Requiring multiple positive blood cultures to makethe diagnosis of CoNS infection is supported by themicrobiologic literature and ensures that all patientsincluded in the analysis have true infection withCoNS.8 Given that we attempted to analyze the ne-onates most likely to have significant bacteremia, anypotential selection bias attributable to such rigorousinclusion criteria would be likely to bias our resultsregarding potential risk factors toward the null hy-pothesis.

The groups differed significantly before diagnosisin several respects (Table 2). Our results indicatethat, at the time at diagnosis, neonates with candi-demia required more intensive care support andwere more ill-appearing than infants infected withCoNS. Furthermore, our data suggest (Tables 2 and3) that clinicians attempting to differentiate prospec-tively between candidemia and CoNS bacteremiashould consider ventilatory status, inability to toler-ate enteral feeding, previous steroid exposure, andlong-term antibiotic exposure as conferring addi-tional risk for candidiasis. Previous exposure to athird-generation cephalosporin was strongly associ-

ated with candidemia by multivariate analysis in thisretrospective study (OR: 21.4).Virtually all of the cephalosporin use in this re-

view was empiric. Not only was there substantialdifference in the use of third-generation cephalospo-rins between infants who developed candidemia and

bacteremia, there was also a significant difference inthe children infected with C parapsilosis and C albi-cans. A significant number of the neonates infectedwith C parapsilosis received over 1 week of empiriccoverage with third-generation cephalosporins.When evaluating the epidemiology of fungemia intheir NICU, clinicians faced with Candida speciesother than C albicans should consider their choice of

Fig 1. Empiric third-generationcephalosporin use in neonates be-fore diagnosis with candidemia orCoNS bacteremia. For candidemicpatients, the top and bottom lines of the box represent the 25th and 75thpercentiles, respectively, of expo-sure in the 2 weeks before diagnosis.The line bisecting the box representsthe median amount of exposure,and the T-bar represents the maxi-

mum exposure. There were only 3patients exposed to third-generationcephalosporins subsequently in-fected with CoNS; therefore, the25th, 50th, and 75th percentiles arecaptured by the line at zero expo-sure, and the exposed patients in the

box and whisker plot are repre-sented individually.

TABLE 3. Multivariate Analysis of Historical Risk Factorsand Clinical Presentation Comparing Candidemic and BacteremicPatients

Risk Factor OR* 95%Confidence

Interval

P Value

Third-generation cephalosporinadministration

21.4 3.4–134.2 .001

All antibiotics other thancephalosporins

1.2 .8–1.6 .31

Intubated 7.1 .9–58.7 .07Tolerating enteral feeding .3 .1–1.2 .09Steroid administration 1.5 .5–4.3 .50Cardiovascular support dips 1.1 .5–2.4 .81

* Some caution must be applied when interpreting the ORs in thisstudy given the high rate of exposure among the cases. As the ORsincrease, they can overstate the estimated risk ratio by increasingamounts.









empiric antibiotics as a potential source of Candidaspecies selection pressure.

It is biologically plausible that the long-term, fre-quent, empiric use of third-generation cephalospo-rins in this group of patients is causally related to therelatively high rate of candidemia in our NICU. Be-cause of the retrospective nature of this study, how-ever, cause and effect cannot be determined. It is alsopossible that the administration of third-generationcephalosporins is a marker for candidemia, in that

physicians may have been prompted to administerthese antibiotics empirically because the patientswere experiencing signs and symptoms of unrespon-sive infection, or because the patients were moreseverely ill than others and at higher risk for devel-oping fungal infection. Regardless, our data suggestthat amphotericin B is a reasonable choice for em-piric therapy in a newborn with birth weight Ͻ1500g who is deteriorating despite usual empiric antibac-terial treatment (Table 4).

End-Organ Evaluation With One Positive Culture

Most of the neonates with end-organ damage sec-ondary to candidemia in this review (5 of 9) had only1 positive blood culture for Candida species. The 5patients who developed end-organ damage despitehaving only 1 positive culture included 1 neonatewith fungal endocarditis and 1 neonate with ventric-ulitis. These data suggest that a single positive bloodculture for Candida should be considered sufficientevidence to investigate or to treat presumptively, forend-organ damage.

We had relatively few patients with evidence of end-organ damage; however, the patients who diedsecondary to disseminated candidiasis were usuallycritically ill at the time of diagnosis and died severaldays later. Because of their clinical instability and

poor prognosis, these critically ill patients usuallydid not undergo lumbar puncture, ultrasonographicevaluation, or fundoscopic examination. The neo-nates who were evaluated for evidence of end-organdamage were a select group of more stable infantswith candidemia, most of whom survived. The lackof complete end-organ evaluation did not seem tohave an adverse effect on this cohort of patients. Thismay be explained by the small sample size of 21surviving patients or by the fact that most patients(all but 6) received Ն21 mg/kg of amphotericin Bafter negative blood cultures.

Central Catheter Removal and Mortality Attributable toCoNS and C parapsilosis

CoNS bacteremia produce an extracellular slime thatenhances adherence to catheter surfaces and protectsthem from immune responses and antimicrobialagents.9,15 Despite this protective mechanism, CoNS

bacteremia often can be successfully treated withoutcentral catheter removal; some authors have reported a70% catheter salvage rate in CoNS infection.16 We be-lieve that the high failure rate of central catheter steril-

ization in our study is attributable to the selection biasinherent in our patient sample that was comprised of children who had persistent bacteremia. Although apatient with a single positive blood culture for CoNSmay well respond to medical therapy, our study indi-cates that once a patient has had 3 positive cultures forCoNS within 96 hours, the clinician should stronglyconsider central catheter removal.

In patients with fungemia, prompt removal of cen-tral catheters is more crucial; morbidity and mortal-ity can be significantly reduced.18 Although in vitrostudies suggest that C parapsilosis is less virulent thanis C albicans, we found no difference in the rate of dissemination, end-organ damage, or mortality be-tween Candida species (Table 1). The mortality rateattributable to C parapsilosis is strikingly high in thisstudy, compared with those seen in previous publi-cations regarding C parapsilosis in neonates.4 Clini-cians tended to remove central catheters morequickly when told that the patient was infected withC albicans; this may explain the high mortality ratewe observed in patients infected with C parapsilosis.Outcome in candidemic neonates may be moreclosely related to the timeliness of central catheterremoval than to the species of the infecting organism.

Empiric Treatment of Very Low Birth Weight Infants

With Amphotericin BSome of the relative increase in mortality attribut-

able to C parapsilosis may also be attributable to a lackof early clinical recognition of candidemia. Earlyclinical recognition of C albicans would prompt ear-lier empiric treatment of infected infants; earliertreatment of C albicans infections could result in sim-ilar mortality rates among species despite greaterintrinsic virulence of C albicans. There was a ten-dency for patients infected with C albicans to receiveamphotericin B earlier than neonates infected with C

parapsilosis. Over the last several years, clinicianshave used thrombocytopenia as a diagnostic aid in

initiating empiric amphotericin B therapy.19,21

Pa-tients infected with C parapsilosis had a somewhatless pronounced fall in platelet counts than did pa-tients infected with C albicans.

Early empiric treatment is imperative to successfulmanagement of candidemia in immune-compromisedpatients. In contrast to the high sensitivity of bloodcultures in detecting bacteremia, the sensitivity of

blood cultures in diagnosing candidemia is as low as50% to 80%.22 Neonates with systemic candidiasis hadsignificantly more negative blood cultures drawn theweek before diagnosis than did infants bacteremic withCoNS. In fact, 3 of the neonates in this study died

before the administration of amphotericin B.

TABLE 4. Historical and Clinical Features Consistent WithCandidemia in Very Low Birth Weight Infants

Historical features1. Admission to an intensive care unit with a substantial rate

of candidemia2. Significant history of broad-spectrum antibiotic coverage*3. Administration of a third-generation cephalosporin*4. Negative blood culture result*5. Falling platelet count, sustained Ͼ3 d6. Systemic steroids*

Clinical features7. NPO8. Intubated9. Cardiovascular instability requiring pressor support

* In the 2 weeks before diagnosis.








Notably, although empiric coverage with vanco-mycin was initiated for most of the children infectedwith CoNS, relatively few of the children with can-didemia were receiving empiric antifungal coverage.It is striking how often a low-grade pathogen (CoNS)was treated empirically, while a pathogen that con-fers substantial mortality (Candida species) was not.This practice bias may stem from the erroneous be-liefs that: 1) bacterial infections are always morethreatening than other pathogens, and 2) empiric

treatment with amphotericin B carries significant riskand is, therefore, not to be embarked on withoutstrong evidence of fungal infection. Much of theconcern about the toxicity of amphotericin B derivesfrom clinical experience with a poorly purified prod-uct in the late 1950s and early 1960s.23 In fact, short-term amphotericin B therapy is particularly well-tolerated in neonates,24–26 who seem to be spared theinfusion reactions still fairly common in older chil-dren and adults.

Although the mortality rate of all patients infectedwith Candida species was 38%, the rate was 50% forpatients started on amphotericin B Ͼ2 days after thefirst positive blood culture. Given the high mortalityrate of candidemia, we would encourage clinicians toconsider empiric coverage with amphotericin B invery low birth weight infants who show signs of nosocomial sepsis unresponsive to empiric antibiotictherapy and who have 6 of the historical and clinicalfeatures given in Table 4.

The presence or absence of 6 of the features listedin Table 4 was a fairly reliable predictor of fungalinfection in this retrospective cohort: 28 of the 34candidemic neonates (82%) satisfied these criteria. Incontrast, only 3 of 17 bacteremic neonates (18%) metthe same criteria.

Because of variability in sensitivity of Candida to

fluconazole, we would advocate the use of empiricamphotericin B. Because 4 of the 34 initial positive

blood cultures for Candida species took Ͼ96 hours togrow, and the half-life of amphotericin B is substan-tial, we would consider 3 to 5 daily doses of empirictherapy for high-risk neonates.

CONCLUSION

Empiric use of third-generation cephalosporinswas associated with the development of candidemiain this review. A single positive blood culture withCandida species should prompt a complete end-organevaluation. Although C parapsilosis may be a less

virulent organism than C albicans in vitro, promptremoval of the central catheter remains a criticalcomponent in the care of neonates with any type of candidemia. Empiric treatment with amphotericin Bshould be considered in high-risk, very low birthweight, ill neonates who fail to respond promptly toempiric antibacterial treatment.

ACKNOWLEDGMENTS

We thank Robert H. Smith, MD; Leigh G. Donowitz, MD; LauraK. Smith; Beth New; and Tammy Lyons for their assistance.

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DOI:10.1542/peds.106.4.7122000;106;712-718Pediatrics

Richard Auten and Randall G. FisherDaniel K. Benjamin Jr., Kelly Ross, Ross E. McKinney Jr., Daniel K. Benjamin,

Staphylococcal BacteremiaFungemia With Coagulase-NegativeCandida parapsilosisandCandida albicans

When to Suspect Fungal Infection in Neonates: A Clinical Comparison of

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