• No results found

When to Suspect Fungal Infection in Neonates: A Clinical Comparison of Candida albicans and Candida parapsilosis Fungemia With Coagulase-Negative Staphylococcal Bacteremia

N/A
N/A
Protected

Academic year: 2020

Share "When to Suspect Fungal Infection in Neonates: A Clinical Comparison of Candida albicans and Candida parapsilosis Fungemia With Coagulase-Negative Staphylococcal Bacteremia"

Copied!
9
0
0

Loading.... (view fulltext now)

Full text

(1)

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

Candida 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; to compare risk factors, clinical presentation, and outcomes for neonates infected with Candida albicans, Candida parapsilosis, and coagulase-negative staphylococcus (CoNS); and to suggest a rational approach to empiric antifungal therapy of neonates at risk for nosocomial infection.

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, 1998 at Duke University Medical Center.

Results. Fifty-one patients were reviewed. Nine of 19 patients infected withC parapsilosisand 5 of 15 patients infected with C albicans died of fungemia. Seventeen neonates had >2 positive cultures for CoNS obtained within 96 hours and 1 died. There was no statistically significant difference in birth weight, gestational age, or age 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 catecholamine infusions. Of the 51 patients, 32 received third-genera-tion cephalosporins in the 2 weeks before diagnosis and 19 did not. Twenty-nine of the 32 who were treated with third-generation cephalosporins subsequently devel-oped candidemia, while candidemia occurred in only 5 of 19 patients who were not treated with cephalosporins. At the time of diagnosis, candidemic patients were more likely to have required mechanical ventilation and were less likely to be tolerating enteral feeding. Multivariate clustered logistic regression analysis revealed that candi-demic patients had more exposure to third-generation cephalosporins. Once the clinician was notified of a pos-itive blood culture forCandida, patients infected withC parapsilosis retained their central catheters longer than patients infected withC albicans.

Conclusions. In this retrospective review, we were able to identify aspects of the clinical presentation and medication history that may be helpful in differentiating between candidemia and CoNS bacteremia. Those key features may be used by clinicians to initiate empiric amphotericin B therapy in premature neonates at risk for nosocomial infections. Prolonged use of third-generation

cephalosporins was strongly associated with candidemia. There was no statistically significant difference in the morbidity and mortality between patients infected with C parapsilosis and those infected withC albicans. Ob-served delays in removal of the central venous catheter may have contributed to finding a mortality rate fromC parapsilosis that was higher than was previously reported. 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.

O

pportunistic infections are an increasingly

common problem in neonatal intensive care units (NICUs). Premature neonates often have compromised skin integrity, gastrointestinal tract disease, chronic malnutrition, central venous catheters, long-term endotracheal intubation, and other 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 and symptoms of infection with any of these organisms are nonspecific and include temperature instability, respiratory distress, abdominal distention, apnea and bradycardia, lethargy, and decreased perfusion. Among Candidaspecies pathogenic to humans, C albicans has been the species most often associated with neonatal infection. Recent reports, however, have suggested an increasing number of infections attributable to C parapsilosis associated with com-mon-source outbreaks.1,2In some NICUs, C

parapsi-losishas become the predominant fungal pathogen.3,4

In general, animal models and clinical reports have suggested thatC parapsilosisis a less virulent organ-ism than C albicans.5,6 One report showed a sixfold

greater mortality for patients infected withC albicans than for those infected with C parapsilosis.4 Under

certain conditions, however, eg, in the presence of intravascular catheters and high intravenous glucose concentrations,C parapsilosismay have both a selec-tive advantage and increased virulence relaselec-tive toC albicans.7

Infection with CoNS, although clinically difficult to 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

(2)

ment or mortality. Thirteen different species of CoNS are found as part of the normal human flora, but Staphylococcus epidermidisis the most common signif-icant pathogen.8 –10 Colonization precedes infection

with this species.11 Because the organism is part of

normal flora, isolation of the organism in a single blood culture usually represents contamination rather than infection.8When CoNS are recovered on

ⱖ2 blood cultures within 24 hours, infection is more likely.8Infected 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 antimicrobial therapy face a difficult diagnostic dilemma. If the neonate has systemic candidiasis, amphotericin B is the treatment of choice. If the patient is infected with CoNS, standard treatment is vancomycin. The use of antibiotics such as vancomycin increases the risk of both future candidemia14and the emergence of

van-comycin-resistant Gram-positive organisms. We con-ducted a retrospective chart review to see: 1) whether the epidemiology of our NICU reflected the apparent national trend toward increasing isolation ofC parap-silosis; 2) whether different risk factors could be iden-tified for the acquisition ofC albicansorC parapsilosis versus CoNS; 3) whether morbidity of infection with these 3 organisms differed; and 4) whether we could suggest a rational approach to empiric antifungal therapy of neonates at risk for nosocomial infection.

METHODS

Microbiology laboratory records from January 1, 1995 to July 31, 1998 were reviewed for CoNS bacteremia and candidemia in NICU patients. Inclusion criteria for patients with bacteremia were the presence of at least 3 positive blood culture results for CoNS within 96 hours, and at least 2 positive blood culture results for CoNS within a 24-hour span. Candidemic patients were in-cluded based on the presence of at least 1 positive blood culture result with eitherC albicansorC parapsilosis.

We analyzed the charts of neonates with CoNS infection or systemic candidiasis for the following: gestational age, birth weight, 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), intravenous lipid 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 each infant’s blood, urine, and CSF culture results, evaluated the length of 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 indicating the presence of “nonshadowing echogenic material compatible with fungus,” “echogenic foci compatible with fungus balls,” “echogenic debris compatible with fungus,” or “echogenic foci compatible 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. The date of diagnosis was the date that the first positive blood culture was 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 cardiovascular support drips as the use of epinephrine, dopamine, or dobutamine for blood pressure support.

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

year. Nearly 30% of the infants weigh ⬍1500 g on admission. Although initial central catheter access is usually obtained via umbilical vessels, most neonates who require prolonged central access receive percutaneous intravenous central catheters. When an 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⬍10 days of age is ampicillin and gentamicin. Infants⬎10 days of age who have indwelling central catheters are often started on vancomycin rather than on ampicillin. Cefotaxime or ceftazidime are fre-quently used in neonates⬎10 days of age who demonstrate no improvement with gentamicin (Gram-negative coverage) and Gram-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 and amphotericin B for infants infected with Candidaspecies at the time that the first positive blood cultures were drawn.

Neonates with 1 positive culture forCandidaspecies typically undergo complete end-organ evaluation provided their prognosis warrants evaluation of potential long-term sequelae. Neonates who are persistently bacteremic may be evaluated for endocarditis or other end-organ damage at the discretion of the bedside clini-cian. Central catheter removal in bacteremic neonates is left to the discretion of the attending neonatologist, but central catheters are routinely 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 24 hours (treating with appropriate antimicrobial therapy) to remove the catheter, we documented that as attempted sterilization.

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

RESULTS Candidiasis

Thirty-seven children had positive blood cultures forCandidaspecies. Nineteen neonates were infected withC parapsilosis, 15 neonates were infected withC albicans, 2 neonates were infected withCandida tropi-calis, and 1 neonate was infected with Candida gla-brata. Of the infants admitted to the NICU whose

birth weight was ⬍1500 g, 4% developed

candi-demia. We reviewed the charts of 34 candidemic patients.

(3)

con-centration (12/15 [80%] vs 17/19 [89%]), or dextrose concentration (18% C albicans vs 16% C parapsilosis; P ⫽ .15). Change in white blood cell count did not differ significantly between species (P⫽.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 who had multiple positive blood cultures forCandidadid not differ significantly between the species (P⬎.99). There was no relationship between the number of positive blood cultures for candidiasis and end-or-gan damage (P ⬎.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 without adverse consequences. Central catheters in use in-cluded Broviac catheters, femoral venous catheters, umbilical catheters, percutaneously inserted central catheters, and internal jugular catheters (Table 2). Once the clinician was notified of a positive blood culture forCandida, neonates infected withC albicans had their central catheters removed earlier than did patients infected withC parapsilosis (2.0 days vs 3.6 days;P⬍.001). There were 12 candidemic neonates who had their catheters removed the same day that the clinician was notified of the positive culture, and 11 of them were infected withC albicans.

The day that the clinician was notified of a positive blood culture for Candida species, amphotericin B therapy was promptly initiated for infants not al-ready on empiric amphotericin B. Notably, 4 of the initial 34 positive blood cultures forCandidaspecies took⬎96 hours to grow. Candidemic patients who were started on amphotericin B ⱖ3 days after the first 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 culture increased, so did the mortality rate (P⫽.04). Before clinician notification of a positive blood culture, more neonates infected withC albicans(7 of 15; 47%) received empiric amphotericin B than did infants infected with C parapsilosis (4 of 19; 21%), but this difference did not reach statistical significance.

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

Each of the 6 neonates had unremarkable evaluations for evidence of end-organ damage. Eleven neonates, 4 with evidence of disseminated candidiasis, were treated for 21 to 24 days. Two neonates, 1 with fungal endocarditis and the other with renal mycetoma, were treated for 42 days. None of the 21 patients who survived the initial candidemic episode relapsed af-ter treatment. There was no statistically significant difference in the mortality of children infected withC albicans or C parapsilosis; 8 of 19 children infected withC parapsilosisand 5 of 15 children infected with C albicans died secondary to systemic candidiasis (47% vs 33%; P ⫽ .73). None of the neonates who died 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 in 129 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, met inclusion criteria for this study. Two of those neo-nates were concomitantly infected withM furfurand H anomola, respectively, and were excluded from analysis. We, thus, reviewed the charts of 17 patients with CoNS infection.

Sixteen of the 17 children infected with CoNS had at least 1 blood culture drawn from a peripheral site and 1 blood culture drawn from an indwelling cen-tral line (1 of the 17 infants did not have a cencen-tral catheter). One child infected with CoNS had an cardiogram consistent with endocarditis and echo-genic abnormalities on renal ultrasound. None of the infants had a soft tissue focus of infection. One child died as a result of CoNS bacteremia. Each of the initial positive blood cultures for CoNS grew within 48 hours.

Sixteen bacteremic infants had central catheters. Children infected with CoNS species retained their central catheters longer than did children infected with Candida (6.4 vs 4.0 days; P ⫽ .007). Attempts were made to sterilize each of the central catheters, and 2 of 16 (12.5%) were successfully sterilized. One child died during attempted sterilization—persistent bacteremia was documented by positive blood cul-tures for 7 days— despite vancomycin therapy. Only 1/13 of the children whose central catheter was moved (8%) had a positive blood culture after re-moval of the catheter.

All children infected with CoNS were treated with vancomycin; none of the neonates were infected with a strain that was susceptible to nafcillin. Each of the infants remained bacteremic for a period of 1 to 9 days, despite vancomycin administration. Evidence for persistent bacteremia included both central and peripheral blood cultures. Duration of antibiotic therapy varied from 5 to 22 days. Fourteen of the 17 neonates were given gentamicin for periods of 2 to 22 days. 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-remia

C albicans

(n⫽15)

C parapsilosis

(n⫽19)

CoNS (n⫽17) Abnormal renal

ultrasound

2/11 5/10 1/8

Abnormal echocardiogram

1/11 0/15 1/11

Abnormal liver/spleen ultrasound

0/8 0/9 0/8

Abnormal fundoscopic examination

0/10 0/8 0/13

Abnormal CSF 0/3 0/9 0/8

Abnormal head ultrasound

1/10 0/13 0/7

(4)

Univariate Analysis Comparing Candidiasis and CoNS Bacteremia

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 were more likely to be on a ventilator than were children infected with CoNS (32/34 vs 41/17;P⫽ .01). Neo-nates infected with Candida species were also less likely to be taking enteral feeds (8/34 vs 10/17;P⫽ .03). During the 2 weeks before diagnosis, 20/34 of the neonates infected withCandidaspecies (56%) and 6/17 of the neonates infected with CoNS (35%) were receiving systemic steroids. Children infected with Candidaspecies were 7 times more likely to die from sepsis than were children infected with CoNS (13/34 vs 1/17;P⫽ .02).

Appropriate empiric therapy on the day that blood cultures were obtained (which subsequently turned positive for either CoNS or Candida species) varied between patient groups. On the day the first positive blood culture was obtained in patients with CoNS, 13 of 17 (76%) neonates were either receiving or were started on appropriate empiric antimicrobial therapy (vancomycin). Fewer candidemic patients, 11 of 34 (32%), were started on appropriate empiric ampho-tericin B (P⬍ .01).

For the 2 weeks before the time of diagnosis, can-didemic patients differed from patients bacteremic with 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 be intubated (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 blood cultures drawn in the 2 weeks before diagnosis (1.3

blood cultures per infant). This was significantly more (P ⬍ .001) than the 4 negative blood cultures drawn in the 17 bacteremic infants before their infec-tions with CoNS.

Thirty-two of the 51 patients analyzed received third-generation cephalosporins and 29 of those 32 patients were subsequently infected with Candida species. This was a substantially higher rate of can-didemia than patients who did not receive intrave-nous third-generation cephalosporins (P ⫽ .02; Fig 1). Children infected with C parapsilosis were more likely to have received long-term (⬎3 days) empiric third-generation cephalosporin coverage than were patients infected with CoNS (OR: 27.4;P ⬍.001) or those infected withC albicans(OR: 4.7;P⬍ .05).

Multivariate Analysis Comparing Candidiasis and CoNS Bacteremia

We evaluated third-generation cephalosporin ad-ministration, administration of all other antibiotics, ventilation status, enteral feeding, cardiovascular support drips, and systemic steroids in the 2 weeks before diagnosis using multivariate clustered logistic regression (Table 3). Patients who developed candi-demia were more likely to have received third-gen-eration cephalosporins (OR: 21.3, P ⫽ .001). The third-generation cephalosporin use in the infants was predominantly empiric; only 1 child had a doc-umented blood, urine, or CSF culture that supported the use of a third-generation cephalosporin.

DISCUSSION

Two of the most common nosocomial infections in the hospitalized neonate are CoNS bacteremia and candidemia.17–19 The clinical presentation of the

newborn with sepsis caused by CoNS andCandidais nonspecific. Before diagnosis, patients infected with either CoNS or Candida species can often present

TABLE 2. Patient Demographics and Risk Factors

Candidemic Patients

n⫽34

CoNS Patients

n⫽17

Univariate Analysis

PValue

OR (95% Confidence

Interval)

Birth weight (g*) 1178 (⫾893) 1094 (⫾589) .66

Gestational age (wk*) 27.6 (⫾4.8) 28.2 (⫾3.5) .15

Age at diagnosis (d*) 24 (⫾18) 31 (⫾19) .19

Intubated (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 ⬍.001

Inotropic drugs (% of patient d) 37% 14% ⬍.001

Systemic steroids (% of patient d) 27% 13% ⬍.001

Number of patients receiving third-generation cephalosporins

29 3 ⬍.001 27.1 (5.6,130)

Third-generation cephalosporin use in the 2 wk before diagnosis

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

Patients who were not on appropriate empiric antimicrobial therapy

23 4 ⬍.01 6.8 (1.8,25.8)

Central catheters at diagnosis (n) 33 22

Broviac 1 4

Percutaneously inserted central catheter

16 10

Umbilical 9 1

Femoral 6 4

Internal jugular 1 0

(5)

with a clinical picture of slow deterioration.20 This

presentation of slow deterioration contrasts with ne-onates who experience septic shock secondary to Gram-negative rods or virulent Gram-positive or-ganisms. The primary objectives of this study were to determine: 1) the epidemiology of candidemia in our NICU; 2) whether different risk factors could be identified for the acquisition ofC albicans, C parapsi-losis, and CoNS; 3) whether the morbidity of infec-tion with these 3 organisms differed; and 4) whether we could suggest a rational approach to initiation of empiric antifungal therapy of neonates at risk for nosocomial infection.

CoNS Bacteremia and Candidemia

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

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

in evaluating risk factors for candidemia. We elected to 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 mor-bidity and mortality. We intentionally excluded in-fants with cultures likely to reflect contamination. Requiring multiple positive blood cultures to make the diagnosis of CoNS infection is supported by the microbiologic literature and ensures that all patients included in the analysis have true infection with CoNS.8Given that we attempted to analyze the

ne-onates most likely to have significant bacteremia, any potential selection bias attributable to such rigorous inclusion criteria would be likely to bias our results regarding potential risk factors toward the null hy-pothesis.

The groups differed significantly before diagnosis in several respects (Table 2). Our results indicate that, at the time at diagnosis, neonates with candi-demia required more intensive care support and were more ill-appearing than infants infected with CoNS. Furthermore, our data suggest (Tables 2 and 3) that clinicians attempting to differentiate prospec-tively between candidemia and CoNS bacteremia should consider ventilatory status, inability to toler-ate enteral feeding, previous steroid exposure, and long-term antibiotic exposure as conferring addi-tional risk for candidiasis. Previous exposure to a third-generation cephalosporin was strongly associ-ated with candidemia by multivariate analysis in this retrospective study (OR: 21.4).

Virtually all of the cephalosporin use in this re-view was empiric. Not only was there substantial difference in the use of third-generation cephalospo-rins between infants who developed candidemia and bacteremia, there was also a significant difference in the children infected with C parapsilosis and C albi-cans. A significant number of the neonates infected with C parapsilosis received over 1 week of empiric

coverage with third-generation cephalosporins.

When evaluating the epidemiology of fungemia in their NICU, clinicians faced with Candida species other thanC albicansshould consider their choice of Fig 1. Empiric third-generation

cephalosporin use in neonates be-fore diagnosis with candidemia or CoNS bacteremia. For candidemic patients, the top and bottom lines of the box represent the 25th and 75th percentiles, respectively, of expo-sure in the 2 weeks before diagnosis. The line bisecting the box represents the median amount of exposure, and the T-bar represents the maxi-mum exposure. There were only 3 patients exposed to third-generation cephalosporins subsequently in-fected with CoNS; therefore, the 25th, 50th, and 75th percentiles are captured 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 Factors and Clinical Presentation Comparing Candidemic and Bacteremic Patients

Risk Factor OR* 95% Confidence

Interval

PValue

Third-generation cephalosporin administration

21.4 3.4–134.2 .001

All antibiotics other than cephalosporins

1.2 .8–1.6 .31

Intubated 7.1 .9–58.7 .07

(6)

empiric antibiotics as a potential source of Candida species 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 the relatively 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 also possible that the administration of third-generation cephalosporins is a marker for candidemia, in that physicians may have been prompted to administer these antibiotics empirically because the patients were experiencing signs and symptoms of unrespon-sive infection, or because the patients were more severely ill than others and at higher risk for devel-oping fungal infection. Regardless, our data suggest that amphotericin B is a reasonable choice for em-piric therapy in a newborn with birth weight⬍1500 g 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 only 1 positive blood culture for Candida species. The 5 patients who developed end-organ damage despite having only 1 positive culture included 1 neonate with fungal endocarditis and 1 neonate with ventric-ulitis. These data suggest that a single positive blood culture for Candida should be considered sufficient evidence to investigate or to treat presumptively, for end-organ damage.

We had relatively few patients with evidence of end-organ damage; however, the patients who died secondary to disseminated candidiasis were usually critically ill at the time of diagnosis and died several days later. Because of their clinical instability and poor prognosis, these critically ill patients usually did not undergo lumbar puncture, ultrasonographic evaluation, or fundoscopic examination. The neo-nates who were evaluated for evidence of end-organ damage were a select group of more stable infants with candidemia, most of whom survived. The lack of complete end-organ evaluation did not seem to have an adverse effect on this cohort of patients. This may be explained by the small sample size of 21 surviving patients or by the fact that most patients (all but 6) received ⱖ21 mg/kg of amphotericin B after negative blood cultures.

Central Catheter Removal and Mortality Attributable to CoNS andC parapsilosis

CoNS bacteremia produce an extracellular slime that enhances adherence to catheter surfaces and protects them from immune responses and antimicrobial agents.9,15 Despite this protective mechanism, CoNS

bacteremia often can be successfully treated without central catheter removal; some authors have reported a 70% catheter salvage rate in CoNS infection.16We

be-lieve that the high failure rate of central catheter steril-ization in our study is attributable to the selection bias inherent in our patient sample that was comprised of children who had persistent bacteremia. Although a patient with a single positive blood culture for CoNS may well respond to medical therapy, our study indi-cates that once a patient has had 3 positive cultures for CoNS within 96 hours, the clinician should strongly consider central catheter removal.

In patients with fungemia, prompt removal of cen-tral catheters is more crucial; morbidity and mortal-ity can be significantly reduced.18Although in vitro

studies suggest thatC parapsilosisis less virulent than is C albicans, we found no difference in the rate of dissemination, end-organ damage, or mortality be-tween Candidaspecies (Table 1). The mortality rate attributable toC parapsilosisis strikingly high in this study, compared with those seen in previous publi-cations regarding C parapsilosis in neonates.4

Clini-cians tended to remove central catheters more quickly when told that the patient was infected with C albicans; this may explain the high mortality rate we observed in patients infected withC parapsilosis. Outcome in candidemic neonates may be more closely related to the timeliness of central catheter removal than to the species of the infecting organism.

Empiric Treatment of Very Low Birth Weight Infants With Amphotericin B

Some of the relative increase in mortality attribut-able toC parapsilosismay also be attributable to a lack of early clinical recognition of candidemia. Early clinical recognition of C albicanswould prompt ear-lier empiric treatment of infected infants; earear-lier treatment ofC albicansinfections could result in sim-ilar mortality rates among species despite greater intrinsic virulence of C albicans. There was a ten-dency for patients infected withC albicansto receive amphotericin B earlier than neonates infected withC parapsilosis. Over the last several years, clinicians have used thrombocytopenia as a diagnostic aid in initiating empiric amphotericin B therapy.19,21

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

Early empiric treatment is imperative to successful management of candidemia in immune-compromised patients. In contrast to the high sensitivity of blood cultures in detecting bacteremia, the sensitivity of blood cultures in diagnosing candidemia is as low as 50% to 80%.22Neonates with systemic candidiasis had

significantly more negative blood cultures drawn the week before diagnosis than did infants bacteremic with CoNS. In fact, 3 of the neonates in this study died before the administration of amphotericin B.

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

Historical features

1. Admission to an intensive care unit with a substantial rate of candidemia

2. Significant history of broad-spectrum antibiotic coverage* 3. Administration of a third-generation cephalosporin* 4. Negative blood culture result*

5. Falling platelet count, sustained⬎3 d 6. Systemic steroids*

Clinical features 7. NPO 8. Intubated

9. Cardiovascular instability requiring pressor support

(7)

Notably, although empiric coverage with vanco-mycin was initiated for most of the children infected with 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 (Candidaspecies) was not. This practice bias may stem from the erroneous be-liefs that: 1) bacterial infections are always more threatening than other pathogens, and 2) empiric treatment with amphotericin B carries significant risk and is, therefore, not to be embarked on without strong evidence of fungal infection. Much of the concern about the toxicity of amphotericin B derives from clinical experience with a poorly purified prod-uct in the late 1950s and early 1960s.23In fact,

short-term amphotericin B therapy is particularly well-tolerated in neonates,24 –26who seem to be spared the

infusion reactions still fairly common in older chil-dren and adults.

Although the mortality rate of all patients infected with Candidaspecies was 38%, the rate was 50% for patients started on amphotericin B⬎2 days after the first positive blood culture. Given the high mortality rate of candidemia, we would encourage clinicians to consider empiric coverage with amphotericin B in very low birth weight infants who show signs of nosocomial sepsis unresponsive to empiric antibiotic therapy and who have 6 of the historical and clinical features given in Table 4.

The presence or absence of 6 of the features listed in Table 4 was a fairly reliable predictor of fungal infection in this retrospective cohort: 28 of the 34 candidemic neonates (82%) satisfied these criteria. In contrast, only 3 of 17 bacteremic neonates (18%) met the same criteria.

Because of variability in sensitivity of Candida to fluconazole, we would advocate the use of empiric amphotericin B. Because 4 of the 34 initial positive blood cultures forCandidaspecies took⬎96 hours to grow, and the half-life of amphotericin B is substan-tial, we would consider 3 to 5 daily doses of empiric therapy for high-risk neonates.

CONCLUSION

Empiric use of third-generation cephalosporins was associated with the development of candidemia in this review. A single positive blood culture with Candidaspecies should prompt a complete end-organ evaluation. Although C parapsilosis may be a less virulent organism than C albicans in vitro, prompt removal of the central catheter remains a critical component in the care of neonates with any type of candidemia. Empiric treatment with amphotericin B should be considered in high-risk, very low birth weight, ill neonates who fail to respond promptly to empiric antibacterial treatment.

ACKNOWLEDGMENTS

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

REFERENCES

1. Welbel SF, McNeil MM, Kuykendall RJ, et al.Candida parapsilosis blood-stream infections is neonatal intensive care unit patients: epidemiologic

and laboratory confirmation of a common source outbreak.Pediatr Infect Dis J. 1996;15:998 –1002

2. Saxen H, Virtanen M, Carlson P, et al. NeonatalCandida parapsilosis outbreak with a high case fatality rate. Pediatr Infect Dis J. 1997;14: 776 –781

3. Levy I, Rubin LG, Vasishtha S, Tucci V, Sood SK. Emergence ofCandida parapsilosisas the predominant species causing candidemia in children. Clin Infect Dis. 1998;26:1086 –1088

4. Kossoff EH, Buescher ES, Karlowicz MG. Candidemia in a neonatal intensive care unit: trends during fifteen years and clinical features of 111 cases.Pediatr Infect Dis J. 1998;17:504 –508

5. Faix RG. Invasive neonatal candidiasis: comparison of albicans and parapsilosis infection.Pediatr Infect Dis J. 1992;11:88 –93

6. Weems JJ. Candida parapsilosis: epidemiology, pathogenecity, clinical manifestations, and antimicrobial susceptibility.Clin Infect Dis. 1992;14: 756 –766

7. Critchley IA, Douglas LJ. Differential adhesion of pathogenicCandida species to epithelial and inert surfaces.FEMS Microbiol Lett. 1985;28: 199 –203

8. Zaidi AKM, Harrell LJ, Rost JR, Reller LB. Assesment of similarity among coagulase-negative staphylococci from sequential blood cultures of neonates and children by pulse-field gel electrophoresis.J Infect Dis. 1996;174:1010 –1014

9. Hall RT, Hall SL, Barnes WG, Izuegbu MR, Zorbas I. Characteristics of coagulase-negative staphylococci from infants with bacteremia.Pediatr Infect Dis J. 1987;6:377–383

10. Noel GJ, Edelson P.Staphylococcus epidermidisbacteremia in neonates: further observations and the occurrence of focal infection.Pediatrics. 1984;74:832– 837

11. D’Angio CT, McGowan KL, Baumgart S, St Geme J, Harris MC. Surface colonization with coagulase-negative staphylococci in premature neo-nates.J Pediatr. 1989;114:1029 –1034

12. Weese-Mayer DE, Fondriest DW, Brouillette RT, Shulman ST. Risk factors associated with candidemia in the neonatal intensive care unit: a case-control study.Pediatr Infect Dis J. 1987;6:90 –196

13. Jarvis WR: Epidemiology of nosocomial fungal infections, with empha-sis onCandidaspecies.Clin Infect Dis. 1995;20:1526 –1530

14. Stoll BJ, Gordon T, Korones SB, et al. Late onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network.J Pediatr. 1996; 129:63–71

15. Gray ED, Peters G, Verstegen M, Regelman W. Effect of extracellular substance from Staphylococcus epidermidison the human cellular im-mune response.Lancet. 1984:365–367

16. Flynn PM, Shenep JL, Stokes DC, Barrett FF. In situ management of confirmed central venous catheter-related bacteremia.Pediatr Infect Dis J. 1987;6:729 –734

17. Weber DJ, Rutala WA, Samsa GP, Wilson MB, Hoffman KK. Relative frequency of nosocomial pathogens at a university hospital during the decade 1980 to 1989.Am J Infect Control. 1992;20:192–197

18. Eppes SC, Troutman JL, Gutman LT. Outcome of treatment of candi-demia in children whose central catheters were removed or retained. Pediatr Infect Dis J. 1989;8:99 –104

19. Butler KM, Baker CJ.Candida: an increasingly important pathogen in the nursery.Pediatr Clin North Am. 1988;35:543–563

20. St Geme JW III.Staphylococcus epidermidisand other coagulase-negative staphylococci. In: Long S, ed.Principles and Practice of Pediatric Infectious Diseases. New York, NY: Churchill Livingstone, Inc; 1997:795 21. Benjamin DK Jr, Benjamin DK, Fisher RJ, McKinney RE Jr. Candidal

mycetoma in the neonatal kidney.Pediatrics. 1999;104:1126 –1129 22. Pizzo PA, Robichaud KJ, Gill FA, Witebsky FG. Empiric antibiotic and

antifungal therapy for cancer patients with prolonged fever and gran-ulocytopenia.Am J Med. 1982;72:101–110

23. Hoperich PD. Clinical use of amphotericin B and derivatives: lore, mystique, and fact.Clin Infect Dis. 1992;14(suppl 1):S114 –S119 24. Johnson DE, Thompson TR, Green TP, Ferrieri P. Systemic candidiasis

in very low-birth-weight infants (less than 1500 grams).Pediatrics. 1984; 73:138 –143

25. Ward RM, Sattler FR, Dalton AS Jr. Assessment of antifungal therapy in an 800-gram infant with candidal arthritis and osteomyelitis.Pediatrics. 1983;72:234 –238

(8)

2000;106;712

Pediatrics

Richard Auten and Randall G. Fisher

Daniel K. Benjamin, Jr., Kelly Ross, Ross E. McKinney, Jr., Daniel K. Benjamin,

Staphylococcal Bacteremia

Fungemia With Coagulase-Negative

Candida parapsilosis

and

Candida albicans

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

Services

Updated Information &

http://pediatrics.aappublications.org/content/106/4/712

including high resolution figures, can be found at:

References

http://pediatrics.aappublications.org/content/106/4/712#BIBL

This article cites 23 articles, 5 of which you can access for free at:

Subspecialty Collections

b

http://www.aappublications.org/cgi/collection/infectious_diseases_su Infectious Disease

following collection(s):

This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtml

in its entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or

Reprints

http://www.aappublications.org/site/misc/reprints.xhtml

(9)

2000;106;712

Pediatrics

Richard Auten and Randall G. Fisher

Daniel K. Benjamin, Jr., Kelly Ross, Ross E. McKinney, Jr., Daniel K. Benjamin,

Staphylococcal Bacteremia

Fungemia With Coagulase-Negative

Candida parapsilosis

and

Candida albicans

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

http://pediatrics.aappublications.org/content/106/4/712

located on the World Wide Web at:

The online version of this article, along with updated information and services, is

by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Figure

TABLE 1.Evidence of End-Organ Dissemination and Mortal-ity in 34 Candidemic Patients and 17 Patients With CoNS Bacte-remia
TABLE 2.Patient Demographics and Risk Factors
TABLE 3.Multivariate Analysis of Historical Risk Factorsand Clinical Presentation Comparing Candidemic and BacteremicPatients

References

Related documents

Efficacy of Patrapinda Sweda and Matra Basti (Combined Therapy) in the Management of Sandhivata (Osteo Arthritis). Source of support: Nil, Conflict of interest:

Accordingly, this study was focused on the main objective of assessing the impact of domestic gender-based violence on female students’ academic achievement in the case of Agemsa

Hind tibia weakly widened towards apex, about 10.5 times as long as its maximum subapical width, 1.1 times as long as hind tarsus.. Basitarsus of hind tarsus 2.25 times as long

Between September 2002 and December 2002, a subgroup Bb with 25 patients was randomly compared with patients receiving classical vaginal hysterectomy with general anesthetic

BCN: Breast Care Nurse; CBT: Cognitive Behavioural Therapy; CEAC: Cost- Effectiveness Acceptability Curves; CRF: Case Report Form; CSRI: Client Service Receipt Inventory; DCIS:

According to the Identity Process Theory (IPT), physical functioning in terms of the body’s ability to perform everyday activities is the most important aspect of identity in

Joachim Merz, Henning Stolze und Markus Zwick, 2006, Wirkungen alternativer Steuerreformmodelle auf die Einkommensverteilung von Freien und anderen Berufen, FFB-Diskussionspapier

The above graph shows the effect of various frequency value of vibration with changing the length of exciter at 0 to 7 mm using with MR Damper &magnetic field... According to