Published online August 1, 2006
PEDIATRICS Vol. 118 No. 2 August 2006, pp. 717-722 (doi:10.1542/peds.2005-2677)
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Candidiasis (Moniliasis, Thrush)

ARTICLE

The Association of Third-Generation Cephalosporin Use and Invasive Candidiasis in Extremely Low Birth-Weight Infants

C. Michael Cotten, MDa, Scott McDonaldb, Barbara Stoll, MDc, Ronald N. Goldberg, MDa, Kenneth Poole, PhDb, Daniel K. Benjamin, Jr, MD, MPH, PhDa,d on behalf of the National Institute for Child Health and Human Development Neonatal Research Network

a Duke University Department of Pediatrics, Durham, North Carolina
b RTI International, Research Triangle Park, North Carolina
c Emory University Department of Pediatrics, Atlanta, Georgia
d Duke Clinical Research Institute, Durham, North Carolina


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. Previous studies have shown that incidence of invasive candidiasis varies substantially among centers, and previous use of broad-spectrum antibiotics is a risk factor for candidiasis in extremely low birth-weight infants. Differences in center practices, such as antibiotic strategies and the effects of these strategies on center incidence of candidiasis, are not reflected in assessments of an individual's risk of candidiasis. We evaluated the relationship between empirical antibiotic practices for extremely low birth-weight infants and center incidence of candidiasis.

METHODS. We studied a cohort of extremely low birth-weight infants who survived ≥72 hours and were admitted to 1 of 12 tertiary centers between 1998 and 2001. Multivariable logistic regression was used to validate previous broad-spectrum antibiotics use as a risk factor for subsequent candidiasis in individual infants. We calculated correlation coefficients to assess the relationship between center incidence of candidiasis with antibiotic practice patterns.

RESULTS. There were 3702 infants from 12 centers included, and 284 (7.7%) developed invasive candidiasis. Broad-spectrum antibiotics use was associated with candidiasis for individual infants. Center candidiasis incidence ranged from 2.4% to 20.4%. Center incidence of candidiasis was correlated with average broad-spectrum antibiotics use per infant and average use of broad-spectrum antibiotics with negative cultures per infant.

CONCLUSIONS. Center incidences of invasive candidiasis differ substantially, and antibiotic practice differences are possible contributors to center variation in candidiasis risk.

Key Words: antibiotic use • bloodstream infection • candida • candidemia • LBW • extremely low birth weight

Abbreviations: ELBW—extremely low birth weight • BSA—broad-spectrum antibiotic • NEC—necrotizing enterocolitis • CC—correlation coefficient

Neonatal candidiasis is associated with high mortality and increased risk of neurodevelopmental impairment among survivors.1–3 Investigators have identified multiple risk factors for individual infants to develop candidiasis1,4–6 and have noted that the cumulative incidence of candidiasis among preterm infants varies widely between centers.1,4,7,8

Gender, race, birth weight and gestational age of the patient population are sources of center variation that cannot be modified by neonatologists. Variations in the use of many categorically unavoidable "standard treatment" risk factors (mechanical ventilation, use of central lines, parenteral nutrition, and use of antibiotics) exist and may contribute to outcome variations.9 Specifically, it is not known whether center variation in the incidence of candidiasis among extremely low birth-weight (ELBW) infants can be explained simply by nonmodifiable individual patient level risk factors, such as a higher proportion of more premature infants, or whether differences may be explained by modifiable practice variations, such as empirical antibacterial therapy.

Previous work has demonstrated that using potential "best practices" can result in improved outcomes for ELBW infants.10 Identifying center practices that are associated with higher candidiasis incidence may lead to strategies to reduce candidiasis among ELBW infants at high-incidence centers. Our hypotheses were: (1) longer duration of empirical initial antibiotic therapy using any antibiotic regimen is associated with higher incidence of invasive candidiasis, and (2) centers that frequently use broad-spectrum antibiotics (BSAs), such as third-generation cephalosporins, for empirical antibiotic therapy initiated after the third postnatal day have a higher incidence of invasive candidiasis.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The Cohort
Data were collected prospectively from ELBW neonates born weighing 401 to 1000 g from September 1, 1998, to December 31, 2001 at Neonatal Research Network sites. Trained research personnel at participating centers collected sociodemographic, pregnancy, and delivery data soon after birth on all live-born ELBW infants. Maternal and infant data were collected using common definitions developed by the investigators and described in the study Manual of Operations and in previous publications.11 Infant data were collected prospectively from birth until 120 postnatal days, discharge, or death. The registry includes data on late-onset sepsis, infecting organisms, and antibiotic therapy. During the study period, infection surveillance was expanded to include detailed data on maternal intrapartum antibiotic use, results of all blood and cerebrospinal fluid cultures, postnatal age at infection, antibiotic use, presence of indwelling catheters, and other risk factors for infection. Blood cultures were processed by the clinical microbiology laboratories at each center using either the Bactec (Becton Dickinson) or BacT/Alert (Organon Teknika) systems. Decisions to obtain cultures through catheters or peripherally were at the discretion of the bedside clinician. The usual practice among participating centers is to inoculate blood culture bottles with ≥0.5 mL of blood.

Neonates eligible for inclusion in this study of late-onset infection were ≤1000-g birth weight and survived beyond postnatal day 3. The institutional review boards at each center approved participation in the registry.

Definitions
Invasive candidiasis was defined as a positive culture from blood or cerebrospinal fluid. It is acknowledged that this definition underestimates the total burden of invasive candidiasis, because cultures from other normally sterile body fluids are not included. We defined BSAs as both third-generation cephalosporins and carbapenems, consistent with previous work.2 Additional analyses were done with cephalosporins and carbapenems considered separately. We defined empirical BSA use as antibiotics prescribed with no positive culture at the time of antibiotic initiation.

Analysis
We used multivariable logistic regression to assess BSA contribution to individual infant risk by using each infant as a unit of measure. We then assessed demographic and treatment variables, including initial antibiotic course lasting >5 days, and any BSA exposure initiated after the third postnatal day. A complete listing of all of the variables tested in the model is included in Table 2 and its legend (noncontributing variables).


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  		TABLE 2 Logistic Regression Analysis of Risk Factors for Invasive Candidiasis Among Infants in 12 NICUs, 1998–2001

 
We evaluated the centers' frequencies of antibiotic courses started on postnatal day 1 that lasted for >5 days, days treated with BSAs per infant, and days treated with BSAs when there was no positive culture during the treatment period per infant and correlated these variables with the incidence of candidiasis at the centers. We also assessed correlations between candidiasis and third-generation cephalosporins alone and carbapenems alone. Center demographic characteristics assessed for correlations with candidiasis included average gestational age and birth weight of day-3 survivors. We also assessed the correlation between the mortality of the first 3 postnatal days and candidiasis and correlations between mortality among infants surviving beyond postnatal day 3 and the antibiotic variables at the centers.

We evaluated potential confounding variables that could possibly contribute to the risk of candidiasis. We assessed correlations between days with central lines (percutaneous, umbilical venous or arterial, Broviac, or other) per ELBW infant with the center incidence of candidiasis. Because incidence of candidiasis is higher among ELBW infants with birth weight <750 g, we assessed correlations between center incidence of candidiasis and center proportion of ELBW infants alive on postnatal day 3 whose birthweight was 401 to 750 g. Because candidiasis risk may be increased with gastrointestinal pathology, we used the incidence of necrotizing enterocolitis (NEC) as a marker of gastrointestinal pathology, and measured the correlation between the incidence of NEC at the centers and the incidence of candidiasis.

Individual centers may have had a rationale based on the incidence of Gram-negative infection or mortality to preferentially use BSAs. We assessed correlations between antibiotic variables and the incidence of Gram-negative infection. In addition, because of high mortality for infants with Gram-negative infection and the possibility that not all Gram-negative infections result in a positive culture, we assessed whether center BSAs use was correlated with center mortality.

We calculated Pearson's product moment correlation for variables with normally distributed incidence and Spearman's rank correlation coefficients for those with nonnormally distributed incidence. All of the data were analyzed using SAS version 8.02 (SAS Institute, Inc, Cary, NC) at RTI International.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
There were 4616 infants from 12 centers enrolled in the network registry in the time period between September 1, 1998 and December 31, 2001. There were 3722 infants who survived beyond postnatal day 3. There were 20 infants with missing data, leaving 3702 infants for analyses. Of the 3702, 284 (7.7%) developed invasive candidiasis. The proportion of study infants of 401 to 750 g birth weight at each center, in whom the incidence and risk of candidiasis is highest,2 is included. The range of the cumulative incidence of candidiasis between centers was 2.4% to 20.4% (Table 1).


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  		TABLE 1 Cumulative Incidence of Invasive Candidiasis at Centers, 1998–2001

 
Individual Risk Factors
Risk factors for invasive candidiasis in individual infants were assessed. Results from the logistic regression are depicted in Table 2. Treatment with BSAs was associated with an increased risk of invasive candidiasis. Risk-adjusted center odds of candidiasis varied widely, with 6 of 11 centers having higher odds of candidiasis than the reference center. The reference center had the lowest incidence of candidiasis and the largest subject population. As expected, lower gestational age increased candidiasis odds. Initial antibiotic course >5 days was not significant at the individual infant level. Maternal hypertension was protective, whereas rupture of membranes >24 hours was associated with increased candidiasis odds. In a separate multivariable analysis with a conditional logistic regression model that included an individual center, using blood culture as the unit of measure, exposure to BSAs in the 7 days before culture was significantly associated with candidiasis (hazard ratio: 1.675; P = .0012).

Correlations: Center Demographics and Candidiasis
Demographics varied substantially among centers, but centers average gestational age and birth weight were weakly correlated with incidence of candidiasis. Center mortality before or after postnatal day 3 did not correlate with incidence of candidiasis (Table 3).


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  		TABLE 3 Correlations Among Center Characteristics, Initial Antibiotic Courses, BSA Use, and Candidiasis

 
Correlations: Center Antibiotics and Candidiasis
Initial antibiotic courses starting on postnatal day 1 and lasting >5 days ranged from 26.9% to 69.3% (Table 3). The use of initial antibiotic courses >5 days, overall use, and use with negative cultures were weakly correlated with incidence of candidiasis after postnatal day 3. Center BSAs use after postnatal day 3 varied widely and was significantly correlated with the center incidence of candidiasis. With cephalosporins alone, the correlation between average cephalosporin days and candidiasis was 0.67 (P = .017). The correlation coefficient between candidiasis and the average days of cephalosporin use with negative cultures was 0.68 (P = .015). Carbapenem use was rare in this cohort and ranged from 0 days to an average of 1.15 days per infant. Correlation coefficients were not significantly different without carbapenem data. Carbapenem use alone was not significantly correlated with incidence of candidiasis.

Correlations: Central Lines and Other Possible Confounders
Central line days per infant in each center (range, median days: 13–27.5 days) were also not correlated with candidiasis (correlation coefficient [CC]: 0.21; P = .51), although the center with the highest median line days was also the center with highest incidence of candidiasis (Table 3). The proportion of postnatal day 3 ELBW survivors whose birthweight fell between 401 and 750 g (range: 32.14%–56.29%) at a center was not correlated with center incidence of candidiasis (CC: 0.34; P = .28). Incidence of NEC (range: 6.21%–16.06%) was not correlated with candidiasis (CC: –0.15; P = .64)

Correlations: BSA Use With Gram-Negative Infections
To assess whether centers had a rationale for the prevalent use of BSAs based on a high incidence of Gram-negative infections, we assessed correlations between BSAs use and the incidence of Gram-negative infections (Table 3). The center incidences of Gram-negative bacterial infections (range: 5.9%–16.8%) were correlated with neither the incidence of candidiasis at the center (CC: –0.07; P = .84), nor the use of BSAs by the center (CC: –0.07; P = .83).

Correlations: BSA Use and Mortality
Correlations between center mortality among infants surviving beyond postnatal day 3 (range: 9%–26.8%) and average BSAs days per infant and average BSAs days with negative cultures per infant were weakly positive (CCs: 0.505 and 0.511, respectively) but not significant (both P = .09; Table 3).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The analysis of antibiotic practices among centers identified correlations between the use by centers of BSAs, consisting largely of third-generation cephalosporins, and the incidence of invasive candidiasis among ELBW infants. Prolonged initial courses of antibiotics showed a trend toward positive correlation, as did center demographics, with centers with postnatal day-3 survivors of lower gestational age and birth weight with a trend toward higher incidence of candidiasis.

Invasive candidiasis and other nosocomial bloodstream infections are persistent problems in neonatal intensive care and have not decreased substantially in the ELBW infant population over the past decade. Our analysis of risk factors in individual infants confirmed previous studies identifying BSAs as a risk factor.2 The analysis also indicated that older gestational age was protective. We speculate that more mature infants are at lower risk most likely because of the maturation of the immune system and other barriers to infection. including skin integrity.4 Cesarean section delivery was not associated with risk of candidiasis; however, maternal hypertension was protective. Previous analyses of Candida colonization have found cesarean section delivery to be associated with reduced odds of Candida colonization5 but not candidemia.4 The report by Saiman et al4 on candidemia included 35 subjects with infection, whereas our report included 284 infants with candidemia, increasing the likelihood of identifying risk factors of borderline significance not noted with smaller sample sizes. The analysis by Saiman et al4 did not include assessment of maternal hypertension. It may be that infants born by cesarean delivery without concurrent infection or suspected maternal infection are not colonized as often as those delivered by cesarean section to women with signs and symptoms of infection.

The use of third-generation cephalosporins as empirical antibiotic therapy varies substantially between nurseries. Although used in some nurseries, empirical cephalosporin use has never been shown to be more effective than the use of more narrow spectra antibiotics, such as aminoglycosides. In our retrospective analysis, more prevalent BSAs use was not associated with better survival at the center level. Cephalosporin use has been associated with intestinal colonization with Candida among neonates,5 and colonization is a risk factor for candidiasis.5,12 Correlations between the use of BSAs and candida intestinal colonization incidence will be useful. The lack of correlation between central line days per infant with candidiasis suggests that central line practices, although identified as an individual risk factor, do not vary as much among centers as does the use of BSAs.

This analysis of center differences is a unique contribution to the analysis of risk factors in the nursery. Although previous use of cephalosporins has been shown to distinguish infants with candidiasis from infants with other infections,2,6 it is unknown whether the wide variation in the incidence of candidiasis observed between nurseries is avoidable with reduced empirical cephalosporin use. These data, however, at both the individual and center level, support the hypothesis that the risk of invasive candidiasis is related to decisions made by the physician: specifically, the choices in length and type of empirical antibacterial therapy.1,13 Despite numerous published guidelines on the appropriate use of antibiotics and repeated warnings about the dangers of antibiotic resistance, physicians continue to use antibiotics both inappropriately and excessively.14 Overuse of cephalosporins may also result in increased incidence of extended spectrum ß-lactamase producing multidrug resistant Gram-negative bacteria.15 Reducing empirical BSA use, as well as increasing attention to infection control strategies, might reduce the risk of candidiasis among ELBW infants.16

Limitations
There are several limitations to this study. We have limited information on the impact of carbapenems and other broad-spectrum antibiotics, such as piperacillin-tazobactam, because these agents were used infrequently in this cohort. We did not analyze other center practices that could possibly be risk factors for candidiasis, including hand washing, unit staffing practices, or colonization rates among staff or infants. Postnatal steroid use was not included in the analysis. Timing of steroid use relative to timing of infection was not collected. This limitation is tempered by the fact that previous multivariable regression analyses have not shown an association between steroid use and Candida species colonization or invasive candidiasis.2,5 Data were unavailable on other possible confounders, including days of hyperalimentation, timing of use of H2 blockers before and after candidiasis, and use of intralipids. No center reported an outbreak of candidiasis or reported using fluconazole prophylaxis during the study period.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Demographic risk factors for candidiasis, such as prematurity, cannot be altered by neonatologists; however, practice patterns that contribute to risk can be changed. This study demonstrates increased individual risk of candidiasis with empirical broad-spectrum antibiotic use and suggests an association between candidiasis and the patterns of empirical BSAs use by centers. Further study is needed to determine causation and whether restricting the use of third-generation cephalosporins will reduce candidiasis risk without increasing mortality or morbidity.


   ACKNOWLEDGMENTS
 
This study was supported by National Institutes of Health grants U10 HD27904, U10 HD21364, U10 HD27851, U10 HD34167, U10 HD27856, U10 HD27880, U10 HD34216, U10 HD27853, U10 HD21397, U10 HD27881, U10 HD21415, U10 HD40689, U10 HD 21373, U10 HD21385, U10 HD27871, and U01 HD36790. Dr Benjamin received support from HD-044799-01 and Drs Cotten and Goldberg received support from National Institutes of Health grant 1U10H040492-01.

The following centers (primary investigator; coordinator) participated in the National Institute for Child Health and Human Development Neonatal Research Network during study subject enrollment: Brown University (William Oh, MD; Angelita Hensman, BSN, RNC), Case Western Reserve University (Avroy A. Fanaroff, MB, BCh; Nancy Newman BA, RN), Emory Universtiy (Barbara J. Stoll, MD; Ellen Hale, RN, BS), Harvard University (Ann R. Stark, MD; Kerri Fournier, RN), Indiana University (James A. Lemons, MD; Diana Dawn Appel, RN, BSN), Stanford University (David K. Stevenson, MD; Bethany Ball, BS CCRC), University of Alabama at Birmingham (Waldemar A. Carlo, MD; Monica Collins, RN, BSN), University of Cincinnati (Edward F. Donovan, MD; Marcia Mersmann, RN), University of Miami (Charles R. Bauer, MD; Amy Mur Worth, BSN), University of New Mexico (Lu-Ann Papile, MD; Conra Backstrom, RN), University of Tennessee at Memphis (Sheldon B. Korones, MD; Tina Hudson, RN), University of Texas-Dallas (Abbot R. Laptook, MD; Susie Madison, RN), University of Texas-Houston (Jon E. Tyson, MD, MPH; Georgia McDavid, RN), Wayne State University (Seetha Shankaran, MD; Gerry Muran, BSN), Yale University (Richard A. Ehrenkranz; Pat Gettner RN), National Institute for Child Health and Human Development (Linda L. Wright, MD; Beth McClure, MEd), and Steering Committee Chairman Alan H. Jobe, MD, PhD.


   FOOTNOTES
 
Accepted Mar 20, 2006.

Address correspondence to C. Michael Cotten, MD, PO Box 3179, Duke University, Durham, NC 27710. E-mail: cotte010{at}mc.duke.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Stoll BJ, Hansen N, Fanaroff AA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics. 2002;110 :285 –291[Abstract/Free Full Text]
  2. Benjamin DK Jr., Stoll BJ, Fanaroff AA, et al. Neonatal Candidiasis among infants < 1000g birthweight: risk factors, mortality, and neuro-developmental outcomes at 18–22 months. Pediatrics. 2006;117 :84 –92[CrossRef][ISI][Medline]
  3. Stoll BJ, Hansen NI, Adams-Chapman I, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA. 2004;292 :2357 –2365[Abstract/Free Full Text]
  4. Saiman L, Ludington E, Pfaller M, et al. Risk factors for candidemia in Neonatal Intensive Care Unit patients. The National Epidemiology of Mycosis Survey study group. Pediatr Infect Dis J. 2000;19 :319 –324[CrossRef][ISI][Medline]
  5. Saiman L, Ludington E, Dawson JD, et al. Risk factors for Candida species colonization of neonatal intensive care unit patients. Pediatr Infect Dis J. 2001;20 :1119 –1124[CrossRef][ISI][Medline]
  6. Benjamin DK Jr, Ross K, Benjamin DK, McKinney RE Jr, Auten R, Fisher RG. When to suspect fungal infections in neonates: a clinical comparison of Candida albicans and Candida parapsilosis fungemia with coagulase-negative staphylococcal bacteremia. Pediatrics. 2000;106 :712 –718[Abstract/Free Full Text]
  7. Rangel-Frausto MS, Wiblin T, Blumberg HM, et al. National epidemiology of Mycoses Survey (NEMIS): variations in rates of bloodstream infections because ofCandida species in seven surgical intensive care units and six neonatal intensive care units. Clin Infect Dis. 1999;29 :253 –258[ISI][Medline]
  8. Makhoul IR, Kassis I, Smolkin T, Tamir A, Sujov P. Review of 49 neonates with acquired fungal sepsis: further characterization. Pediatrics. 2001;107 :61 –66[Abstract/Free Full Text]
  9. Van Marter LJ, Allred EN, Pagano M, et al. Do clinical markers of barotraumas and oxygen toxicity explain interhospital variation in rates of chronic lung disease? Pediatrics. 2000;105 :1194 –1201[Abstract/Free Full Text]
  10. Horbar JD, Rogowski J, Plsek PE, et al. Collaborative quality improvement for neonatal intensive care. Pediatrics. 2001;107 :14 –22[Abstract/Free Full Text]
  11. Lemons JA, Bauer CR, Oh W, et al. Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1995 through December 1996. Pediatrics. 2001;107(1) . Available at: www.pediatrics.org/cgi/content/full/107/1/e1
  12. Pappu-Katikaneni LD, Rao KP, Banister E. Gastrointestinal colonization with yeast species and Candida septicemia in very low birth weight infants. Mycoses. 1990;33 :20 –23[ISI][Medline]
  13. Isaacs D. Rationing antibiotic use in neonatal units. Arch Dis Child Fetal Neonatal Ed. 2000;82 :F1 –F2[Free Full Text]
  14. Goldmann DA, Weinstein RA, Wenzel RP, et al. Strategies to prevent and control the emergence and spread of antimicrobial-resistant microorganisms in hospitals: a challenge to hospital leadership. JAMA. 1996;275 :234 –240[Abstract]
  15. Gupta A, Ampofo K, Rubenstein D, Saiman L. Extended spectrum beta lactamase-producing Klebsiella pneumoniae infections: a review of the literature. J Perinatol. 2003;23 :439 –443[CrossRef][Medline]
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



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