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Journal of Clinical Microbiology, November 1999, p. 3735-3737, Vol. 37, No. 11
Departments of
Pediatrics1 and
Pathology,2 University of Texas Medical
Branch, Galveston, Texas 77555
Received 12 April 1999/Returned for modification 20 May
1999/Accepted 23 July 1999
Systemic candidiasis affects 1.6 to 4.5% of very low birth weight
( Very low birth weight (VLBW)
( Appropriate diagnosis and management of systemic candidiasis in
neonates are controversial (16). The Neonatal Candidiasis Study Group (NCSG) is a consortium of pediatric infectious-disease specialists and neonatologists interested in exploring the
epidemiology, treatment, and prophylaxis of this infection. The NCSG
established a specimen archive to house Candida isolates
involved in neonatal disease. Isolates were submitted to the archive
before therapeutic or prophylactic trials were launched to provide a
baseline of susceptibility patterns as a means to allow detection of
shifts in these patterns following the introduction of new therapies. Evaluation of submitted isolates revealed that species identification was frequently incorrect and that resistance to fluconazole (MIC >8
µg/ml) was already present in nursery isolates.
Participants in the NCSG submitted at least five Candida
isolates to the archive. Isolates were required to be from patients in
the intensive care nursery. However, the isolates were not required to
be from VLBW infants or from infants suffering from invasive disease.
The specimens were streaked onto Sabouraud glucose agar slants and
mailed to the Medical Mycology Research Center at the University of
Texas Medical Branch in Galveston. Upon receipt, the isolates were
checked for purity. Germ tube formation in plasma was assessed to
identify Candida albicans. Non-C. albicans
species were further identified by inoculation of either a Vitek yeast biochemical card or an API 20C strip and a Dalmau plate. Fluconazole MICs were determined by the M27 standard of the National Committee for
Clinical Laboratory Standards (7).
A total of 98 isolates from 90 patients at 17 institutions were
submitted. The median gestational age of the patients was 26 weeks
(range, 23 to 41 weeks), the median birth weight was 820 g (range,
426 to 4,885 g), and the median age at the time of culture was 24 days
(range, 1 to 198 days). Most of the isolates represented invasive
disease. The source of the culture was blood in 56 samples, urine in
14, skin or soft tissue in 9, sputum or tracheal aspirates in 6, cerebrospinal fluid in 4, catheter tips in 3, and other sources in 6. Species included C. albicans (56%); C. parapsilosis (34%); C. tropicalis (5.3%); and
C. guilliermondii, C. glabrata, and C. lusitaniae (collectively comprising the remaining 4.7%).
Seven institutions referred a total of eight isolates (8.2%) that were
misidentified in their clinical laboratories (Table 1). Table 2
provides information about the seven isolates for which the fluconazole
MICs were >8 µg/ml. Two of these isolates were from the blood and
cerebrospinal fluid of the same patient. Two specimens with C. albicans contained two morphotypes, for which the fluconazole MICs
were different (1 and 0.5 µg/ml and 0.25 and 2 µg/ml). The
fluconazole MICs for the C. albicans and C. parapsilosis strains (the most common species isolated) are summarized in Fig. 1.
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Candida Isolates from Neonates:
Frequency of Misidentification and Reduced Fluconazole
Susceptibility
,*
ABSTRACT
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1,500 g) infants. A specimen archive of Candida strains from intensive care nurseries was created; it currently houses 98 isolates from 17 institutions. Eight isolates (8.2%) were
misidentified at the referring institution. The MICs of fluconazole for
seven isolates (7.1%, all non-C. albicans species, one
misidentified initially) were >8 µg/ml.
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1,500 g) infants develop late-onset sepsis (variably defined as
sepsis occurring >3, >4, or >7 days after birth) with high
frequency. Two multicenter studies described late-onset sepsis in 16 and 25% of VLBW infants (6, 19). Nine percent of the
bloodstream isolates in one study were fungi, predominantly
Candida species (19). Systemic candidiasis in
neonates is not limited to bloodstream infection: meningitis, urinary
tract infection, and deep skin infection are other manifestations (4, 12, 17). The incidence of systemic candidiasis in this population is rising. In the 1980s, 1.6 to 4.5% of VLBW infants developed this infection (1, 2, 5, 22), whereas a recent study found that the incidence in one nursery had increased 11-fold between 1981 and 1995 (9).
TABLE 1.
Candida isolates misidentified by the
referring institution
TABLE 2.
Isolates for which the fluconazole MICs were >8 µg/ml
View larger version (17K):
[in a new window]
FIG. 1.
Distribution of fluconazole MICs for the C. albicans and C. parapsilosis strains submitted to the
archive.
The NCSG specimen archive contains a large number of invasive isolates
from infants, with a wide geographic distribution (see footnote 
to
byline of this article). The National Epidemiology of Mycoses Survey,
the only other multicenter study of Candida isolates from
infants, included 147 isolates from intensive care nurseries, but this
survey studied only 34 patients from six institutions (11).
Much of the data from that study is presented in aggregate with isolate
data from surgical intensive care units. Thus, the NCSG specimen
archive is an excellent companion resource focusing on neonatal infection.
Although amphotericin B is considered the treatment of choice in
neonatal systemic candidiasis, fluconazole is used by a substantial number of practitioners (16). Breakpoints for
fluconazole susceptibility testing have been established
through correlation with clinical outcomes (15). Isolates
for which the MIC is 8 µg/ml are considered susceptible, whereas an
MIC of 
64 µg/ml indicates resistance. When the MIC is 16 or 32 µg/ml, the isolate has dose-dependent susceptibility. Data on
fluconazole pharmacokinetics in VLBW infants is sparse, and no data
exist concerning the safety of increasing the dose when the MIC is
elevated (18, 20). In the specimens described in this
report, elevated fluconazole MICs were found only for non-C.
albicans species (Table 2). Although fluconazole resistance in
C. albicans has been described, higher MICs are more common
in non-C. albicans strains (10, 14). There is no
published data correlating outcome to MIC in fluconazole-treated neonates; treatment failures, mostly due to C. albicans,
have been described, but no MICs are included in the reports (3, 8, 21). The distribution of MICs shown in Fig. 1 is comparable to
the distribution published in another large study of adult patients,
suggesting that intensive care nursery isolates reflect those present
in the community at large (15).
Several isolates in the archive were incorrectly identified at the referring institution's clinical laboratory (Table 1). In a recent survey of clinical laboratories in New York, blinded proficiency testing revealed misidentification of C. parapsilosis, C. tropicalis, and C. glabrata in 15% of specimens and C. albicans in 11% (13). Thus, the 8.2% error rate in this archive is not surprising. However, it does raise the specter of possible misidentification of isolates as C. albicans and subsequent complacency about the likelihood of resistance to azoles. Only 28% of clinicians obtain antifungal susceptibility testing data when treating neonates with invasive disease (16). We recommend that clinicians verify the competency of their clinical laboratories for species identification and for susceptibility testing if azole therapy is to be used. Additionally, whenever species identification is potentially critical (e.g., in treatment trials), we recommend that all isolates be submitted to a mycology specialty laboratory.
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ACKNOWLEDGMENTS |
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The NCSG specimen archive was established through a grant from the Pediatric Academic Societies Multicenter Clinical Trials Program.
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FOOTNOTES |
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* Corresponding author. Mailing address: Department of Pediatrics, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0371. Phone: (409) 772-2798. Fax: (409) 747-1753. E-mail: jrowen{at}utmb.edu.
Member of The Neonatal Candidiasis Study Group. Other group members
who submitted isolates are Karen E. Shattuck, University of Texas
Medical Branch, Galveston; Michael J. Horgan and Marilyn A. Kacica,
Albany Medical College, Albany, N.Y.; Donna J. Fisher, Baystate
Medical Center Children's Hospital, Springfield, Mass.; Michele
Estabrook, Case Western Reserve University, Cleveland, Ohio; Paul L. Toubas, Children's Hospital of Oklahoma, Oklahoma City; Lisa Saiman,
Babies & Children's Hospital, Columbia University, New York, N.Y.;
E. Stephen Buescher and M. Gary Karlowicz, Eastern Virginia Medical
School, Norfolk; Frederick Cox and Jatinder Bhatia, Medical College of
Georgia, Augusta; William Albritton and Cindy McEvoy, Children's
Hospital at Sacred Heart, Pensacola, Fla.; Gordon E. Schutze,
University of Arkansas for Medical Sciences and Arkansas Children's
Hospital, Little Rock; Peggy Weintrub, University of California, San
Francisco; Mark J. Abzug, University of Colorado and The Children's
Hospital, Denver; Mobeen H. Rathore and Ana Alvarez, University of
Florida Health Science Center, Jacksonville; Gerard Rabalais and
Kristin Bryant, University of Louisville School of Medicine,
Louisville, Ky.; Roger Faix, University of Michigan, Ann Arbor;
Catherine M. Bendel, University of Minnesota, Minneapolis; Sandor
Feldman, University of Mississippi Medical Center, Jackson; and Wendy
J. Watson, University of Rochester, Rochester, N.Y.
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Journal of Clinical Microbiology, November 1999, p. 3735-3737, Vol. 37, No. 11
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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