0095-1137/88/040713-06$02.OO/0
Copyright© 1988, American Society for Microbiology
Fifteen-Year Experience with Bloodstream
Isolates of
Coagulase-Negative Staphylococci in Neonatal Intensive Care
DAVIDG. SIDEBOTTOM,l JONATHAN FREEMAN,2'3 RICHARD PLATT,2 MICHAEL F. EPSTEIN,4
AND DONALD A. GOLDMANN'5*
Divisions ofInfectiousDiseases' andNewborn Medicine4and Infection Control Program,s The Children's Hospital, and Channing Laboratory, Brighamand Women'sHospital,2 Boston, Massachusetts02115, and WestRoxbury Veterans
Administration Hospital, West Roxbury, Massachusetts 021323
Received 6 July1987/Accepted22December 1987
Investigators worldwide, as well as the neonatologists and infection control team at our hospital, have
reported that the incidence of coagulase-negative staphylococcal bacteremia in critically ill neonates has increaseddramaticallyin recentyears.To investigate theseclaims,weexamined the results of all blood cultures obtained from 1970 to 1984 in our neonatal intensive care unit. Throughout thisstudy period,
coagulase-negative staphylococciwereprominent blood culture isolates(crudeoverallincidence of 4.4positivebacteremia
workups per 100 neonatesadmitted; range, 2.5 to6.7), representing 26.3 to 69.6% ofall positivecultures.
Therewas nosignificant increaseinincidenceovertimebyanalysis of linear trend. Detailed analysisof data from 1976 and 1982 (two selected yearsfor which complete information concerning culturing practices and
patient characteristics was available) revealed that these observationswere not explained bychangesin the
frequency of blood culturing. In both 1976 and 1982, the probability that a blood culture would grow
coagulase-negative staphylococci increased steadily from 2 to 3% shortlyafter admission to reach alevel of about 12% inweek 3 ofhospitalization, beforedecliningtoanintermediate level thereafter. Thispattern is moreconsistent withnosocomial bacteremia than with contamination of blood cultures. Contrarytoclinical reports,coagulase-negative staphylococci have beentheprincipal pathogensisolated from blood cultures inour neonatal intensive careunit since atleast 1970, withnomeasurable increaseoverthesubsequent 14years.
Accordingtonumerousrecentstudies,nosocomial
coagu-lase-negative bacteremia is a new and growing problem in
the neonatal intensivecareunit(NICU) (2-6, 11, 13; E. K.
Anday and M. Delivoria-Papadopoulos, Pediatr. Res. 19:195A, abstr. no. 508, 1985; E. K. Anday, G. H. Talbot,
and M. Doorley, Pediatr. Res. 19:286A, abstr. no. 1054,
1985; H. Chawla and M. Curtis-Cohen, Pediatr. Res. 19:289A, abstr. no. 1072, 1985; C. Fabia, M. A. Perlman, E. F. Leon, and M. E. Skalina, Pediatr. Res. 17:312A, abstr. no. 1350, 1983; S. K. Gottschalk, C. R. Schuth, M.
Yazdani, and J. Petri, Pediatr. Res.. 17:314A, abstr. no.
1363, 1983; J. A. Gruskay, I. Nachamkin, S. Baumgart, J. Campos, and M. C. Harris, Pediatr. Res. 20:397A, abstr.no.
1418,1986; M. A. Guiliano, E. F. LaGamma, and J. Bussel, Pediatr. Res. 20:396A, abstr. no. 1414, 1986; S. L. Hall,
R. T. Hall, J. Izueqbu, I. Zerbas, M. Rogolsky, and W. G. Barnes, Pediatr. Res. 20:311A, abstr. no. 914, 1986; B.
Schmidt, M. Corey, L. Ford-Jones, and H. Kirplani, Pe-diatr. Res. 20:402A, abstr. no. 1450, 1986; B. Schmidt, H.
Kirplani, M. Corey, and L. Ford-Jones, Pediatr. Res. 20:403A, abstr. no. 1451, 1986). None of these studies,
however, analyzed older blood culture data ina mannerthat allows accurate evaluation of trends through time. Results
were notadjusted effectively for potentially important
con-founding variables, suchasbirthweightandduration ofstay ofhospitalized babies, which havechanged substantially as a result of improvements in neonatal survival (15) and shifting patterns of NICU bed utilization. Furthermore, previous studies did notmeasurethe frequency with which blood cultures were obtained from neonates nor whether
bloodculturing practices changedovertime.Detailed
epide-miologic analyses, particularly consideration of blood
cul-*Correspondingauthor.
turefrequencies, arecritical ininterpreting data concerning
coagulase-negative staphylococci, which normally colonize the skin andarefrequent blood culture contaminants (1, 9,
18).
Inthis study, wesoughttoconfirm theclinical impression that coagulase-negative staphylococci have become more
frequentblood culture isolates inrecentyears. Ourfindings
are based on a review of the results of blood cultures obtained in our NICU over a 15-year period, including
consideration of the potential impact of changes in birth weight, length of hospital stay, and blood-culturing prac-tices.
(Presentedin partatameetingof theSociety for Pediatric Research,6May 1986, Washington, D.C.)
MATERIALS AND METHODS
Study population.TheChildren'sHospitalNICU isalevel III referral nursery administered and staffed by the Joint Program inNeonatology of Harvard Medical School. This studyis based on results ofblood culturesobtained in this NICUoverthe15-year periodbeginningin 1970. Inaddition, the years 1976 and 1982 were selected for more detailed investigation.Theseyears werechosenbecause therewas a sudden increase in the clinical diagnosis of nosocomial coagulase-negative staphylococcalbacteremia in the NICU in1982,and 1976wasthe earliestcomparisonyearfor which dataconcerning patientsandallblood cultures(both positive and negative) were available. The names, medical record numbers,birthweights, admission and discharge dates,and outcomesweretaken from theNICU logbookfor 1976and 1982. The medicalrecordnumbers,datesdefining lengthsof hospital stay, andoutcomeswerevalidated froma comput-erized list obtained from the administrative offices of the hospital.
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Microbiologic data. Specimens of blood for culture were
obtainedby thephysicians of the infants for clinical indica-tions;surveillance blood cultureswerenotperformed. Blood cultures generally were obtained percutaneously following
NICU policy, exceptfor blood cultures taken through
um-bilical cathetersimmediatelyafterplacement. Cultures were
processed in a conventional two-bottle broth blood culture system by standard procedures (12). Results were taken
from the original data in logbooks maintained in the Chil-dren's Hospital microbiology laboratory since 1970.
Definition of positive blood culture. To obtain data that
were independent of arbitrary clinical interpretation, we
listed as positive all blood cultures that were not sterile. Blood cultures that grew a single morphologic type or
species of coagulase-negative staphylococcus as the sole
isolatewerecounted aspositive for that organism. Cultures
growing multiple strains of coagulase-negative staphylo-cocci, Corynebacterium sp.,Bacillus sp., or any
combina-tion of these organisms wereclassified asprobably contam-inated and excluded from further analyses. Strain identity
was determined by the laboratory technologist responsible
for eachblood culture and hisorhersupervisoronthe basis
of colony morphology, antibiotic susceptibility testing
re-sults, and species determination; plasmid typing and bacte-riophage typingwere notperformed. Since strains of
coagu-lase-negative staphylococci that have the same colony
morphology, antibiogram, and species identificationcanstill
be distinct, these procedures undoubtedly resulted in the misclassification ofsome mixedcultures.
Definitionofaworkup foranepisodeof suspected bactere-mia (bacterebactere-mia workup). Two factors determined the
num-ber ofblood culturesobtainedduring the workup ofaclinical
episode ofsuspected bacteremia: the blood volume of the baby and the differing propensity of individual house officers and attending physicians to obtain multiple blood cultures
per episode. To avoid introducing artifacts resulting from
varying numbers of blood cultures per workup, the fre-quency with which blood cultures were obtained and the
incidenceofpositive blood cultureswerecalculatedby 48-h
intervals after the onset ofeach clinical episode. Thus, in this study only the first blood culture obtained in each bacteremia workup was counted; additional blood cultures
drawnduring the subsequent 48 h were excluded from the tally. The result of this method of enumerating the frequency of blood culturesisacountofthenumberof clinicalepisodes ofsuspected bacteremia during whichablood culturemight
have been positive.
Similarly, multiple blood cultures growing the same
spe-cies or type of coagulase-negative staphylococcus drawn within48 hofaninitialpositive culturewere considered to represent the same bacteremia workup and were also
ex-cluded from the analysis. This resulted in a count ofthe numberof clinicalepisodes of suspected bacteremia during whichoneor moreblood culturesactuallywerepositive for
coagulase-negative staphylococci.
Epidemiologic analyses. The incidence of bacteremia
work-ups during which at least one culture was positive for coagulase-negative staphylococciwascalculatedper admis-siontothe NICUfor the15-yearperiod from 1970to 1984. For 1976 and 1982, incidence densities were calculated as
numbersofbacteremia workupsperformed and the number of bacteremia workups with positive cultures per 1,000
patient days (10). For stratified analyses, infants were
grouped bybirthweight intoseven strata(500 to749g,750 to999g, 1,000to 1,249g,1,250to1,499g, 1,500to1,749g,
1,750 to 1,999 g, and >2,000 g). Summary estimates of
relative risk of events over strata of birth weight were calculatedbyMantel-Haenszelprocedures forrelative risks in a cohort studywith test-based 95% confidence intervals (10, 16, 17),andlinear trend analysiswasdone bystandard methods fromthe same sources.
In the final aspect of the analysis, the probability that a blood culture would be positive for coagulase-negative staphylococci according to week of hospitalization was investigated. Since the basis of this analysis was blood cultures rather than patients or patient days, all culture results from infants of all birth weights were restratified according tothe hospital week during which theblood was obtained for culture.
RESULTS
Incidence ofbacteremia workups with blood cultures posi-tive for coagulase-negative staphylococci, 1970 to 1984. The numberof bacteremiaworkups during which a blood culture was positive for coagulase-negative staphylococci and the number of admissions to the NICU for the 15-yearperiod from1970 to1984arepresented inTable 1. The crudeoverall incidence was 4.4 positive workups per 100 admissions (range,2.5/100to6.7/100), and therewas nochange over the 15 yearsby linear trend analysis. Linear trend analysiswas repeatedexcluding the first5years (1970 to 1974)whenthe numberof beds was known but the number of admissions per year was approximated, and the result was the same.
TABLE 1. Incidenceperadmission ofbacteremia workups with blood culturespositiveforcoagulase-negativestaphylococci,
andproportionof all workupspositiveforany micro-organismyieldingcoagulase-negativestaphylococci,
TheChildren's Hospital NICU, 1970to
1984"
Proportion ofpositive Workups positivefor
No.of workups yielding coagulase-negative Yr infants coagulase-negative staphylococci/100
admitted staphylococci/
admissions
total (%)
1970 200b 10/23(43.5) 5.0
1971 200b 5/16(31.3) 2.5
1972 200b 9/18(50.0) 4.5
1973 250b5/19(26.3) 2.5
1974 200 10/20(50.0) 5.0
1975 204 8/19(42.1) 3.9
1976 256 15/33(45.5) 5.9
1977 325 13/32(40.6) 4.0
1978 317 9/18(50.0) 2.8
1979 346 16/34(47.1) 4.6
1980 330 15/26(57.7) 4.5
1981 354 16/33(48.5) 4.5
1982 413 16/23(69.6) 3.9
1983 376 17/33(51.5) 4.5
1984 330 22/33(66.7) 6.7
Crude overall 4,251 186/380C(48.9) 4.4
aTherewasnosignificant changeovertime in the numberofworkupswith
culturespositiveforcoagulase-negative staphylococciper100infant
admis-sionsbyanalysisof linear trend. Thisanalysiswasrepeated, omittingthedata
from the first5years,and the resultswerethesame.
b Theexactnumberof babies admitted from 1970to1975was notrecorded
separatelyfor thisNICU,but the size oftheunit and the occupancyratewere relativelyunchangedfrom 1970to1975.
cOfthe totalof 380workups withpositivebloodcultures, 48.91% were
coagulase-negative staphylococci, 17.6% were gram-negative bacilli, 7.9%
wereStaphylococcus aureus, 7.1%weregroup Bstreptococci,7.1%werea
orviridansstreptococci,and11.3%wereothersinglepathogens.
Coagulase-negativestaphylococciwereisolated fom blood drawn from central catheters
inonly6of the 186workupsobservedover15years.
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Thereisnoteven ahintfrom these data ofasecularincrease
in the number of clinical episodes of suspected bacteremia with a blood culture positive for coagulase-negative
staph-ylococci during the study period.
Coagulase-negative staphylococci were isolated from
blood obtained through central lines in only 6 of the 186 workups with positive cultures observed over the 15-year
study period. In only three workups was a central line
culture the only positive culture obtained.
Frequencyof blood culturing, 1976versus1982. The
num-bers ofbacteremia workups performed in 1976 and 1982are
presented in Table 2. Rates are expressed in terms of neonates who survived their hospitalization, since the
ma-jority of those who died did sowithin the firstdayortwoof life(median time of deathwas duringday 2), and thus most of the babies who died were not eligible for even a single
bacteremiaworkup. In bothyears,therewasastronglinear trend(P < 10-6) toward increasing numbers of bacteremia workups with decreasing birth weights ofneonates.
Survi-vorswith birth weights under 750ghadatleast fourtimesas many workups during which blood cultures were obtained
than did survivors with birth weights over 2,000 g. When
these calculationswererepeated withall admissions instead
ofonly the survivors, significant linear trends (P < 0.05) were still noted, although the slopeswere muchlesssteep. The data in Table 2 appeared to indicate that smaller babies experienced more clinical episodes of suspected
bacteremia that resulted in bacteremia workups, but our
previous work suggested that the apparent increase in the number of workups with decreasing birth weight was
ex-plained bydifferences in duration ofexposuretothehospital (7a; J. Freeman, D. A. Goldmann, R. Platt,D. G. Sidebot-tom, and M. F. Epstein, Pediatr. Res. 20:378A, abstr. no.
1306, 1986; J. Freeman, M. F. Epstein, R. Platt, D. G. Sidebottom, D. A. Goldmann, Pediatr. Res. 20:378A, abstr.
no. 1305, 1986). In Table 3 are presented the incidence
densities according tobirth weight of bacteremia workups (workupsper 1,000 patient days) for all admissions in 1976
and 1982. This adjustment simultaneously corrects for the difference in duration ofhospital stay between the tiniest babiesandlargerbabies and also has the effect of correcting for the difference in duration of hospital stay between neonates who survived and those who died.
After this adjustment, there was no longer a significant
overall linear trend(P= 0.08) in the incidence of bacteremia
workups with decreasing birth weight (Table 3). In fact,
TABLE 2. Number ofbacteremia workups performedonall survivors, TheChildren's Hospital NICU, 1976and 1982e
No. ofworkups/no.of survivors(ratio) Birthwt(g)
1976 1982
500-749 12/3(4.0) 32/5(6.4)
750-999 19/5(3.8) 60/21 (2.9)
1,000-1,249 22/12(1.8) 21/19(1.1)
1,250-1,499 19/13 (1.5) 16/18(0.9)
1,500-1,749 26/12(2.2) 24/23(1.0)
1,750-1,999 29/20(1.5) 23/27(0.9)
>2,000 125/121(1.0) 156/244(0.6)
Crudeoverall 252/186(1.4) 332/357(0.9)
aInbothyears,therewas astronglinear trend (P<10-6)towardincreasing
numbersofbacteremiaworkups with decreasing birth weights ofneonates.
Whenthesecalculationswererepeated with all admissions insteadofonlythe
survivors, significantlinear trends(P<0.05)werestillnoted, although the
slopesweremuchlesssteep.
TABLE 3. Incidence densities of bacteremiaworkupsper1,000 days, by birth weight, The Children'sHospitalNICU,
1976 and 1982e
No.ofworkups/no.ofhospitaldays
Birth wt(g) (incidencedensity)
1976 1982
500-749 13/192(67.8) 33/535(61.7)
750-999 24/274(87.6) 63/1,034(60.9)
1,000-1,249 38/424 (89.6) 26/424(61.3) 1,250-1,499 22/461 (47.7) 16/213(75.1) 1,500-1,749 27/369(73.2) 12/179(67.0) 1,750-1,999 33/304(108.6) 27/455 (59.3) >2,000 147/1,564(94.0) 176/1,880(93.6) Crude overall 304/3,588 (84.7) 353/4,720 (74.8)
a The Mantel-Haenszeladjusted summary relative risk ofhavinga
bacte-remia workup in1976compared with 1982was1.20(95% confidenceinterval,
1.02to1.41),indicatingaslightlygreaterlikelihood ofhavingabacteremia
workup during the earlier time period. Incidence density is a standard
measureof thefrequency with whichan eventoccursin adefinedperiod of
person-time (10).
there was actually a slight linear trend (P < 0.05) in the opposite direction in 1982. Thatis, per hospital day in 1982, physicians weremorelikelyto haveobtained blood cultures from larger, notsmaller, neonates. However, becausetiny babies had muchlonger hospitalstaysthanlargerneonates, they had many more bacteremia workups per hospital ad-mission (Table 3).
Returning to the overall number of bacteremia workups per survivorgivenin Table2, itappearedfrom these crude data that the number of bacteremia workups might have declined substantially over time, from 1.4 per survivor in 1976 to 0.9 per survivor in 1982, a 36% decrease. After adjustment for duration of hospitalization and birth weight (Table 3), there was a 20% smaller chance of having a bacteremia workup in 1982-a less impressive but still statistically significant decrease. Therefore, this analysis, which documents a slight decrease in the frequency of culturingin 1982,does not explaintheapparent increase in coagulase-negative staphylococcal bacteremia reported by ourneonatologists in thatyear.
Comparison ofthe results from the analyses presentedin Tables2 and 3 indicates that incidence density is themore informative type ofanalysis and suggests that the simple attackrate analysis presentedinTable 2, even with exclu-sion ofthe deaths, is less valuable in studyingevents in a hospitalnursery.
Frequency of positive bacteremia workups, 1976 versus 1982.Theresultsofallblood cultures obtained frompatients inTheChildren'sHospital NICU in1976 and1982,stratified by birth
weight,
areshown in Tables4and5. When 1982 wascompared
with1976,
therewas nosignificant
increase in the incidence of bacteremia workups with blood cultures posi-tive forcoagulase-negative staphylococci. There was, how-ever, astatistically
significant decrease in the incidence of bacteremia workups with blood cultures positive forother organisms in1982compared with1976(Table 5), whichmay have led tothe incorrectperceptionthatcoagulase-negative staphylococci hadbecome a more frequent causeof bacte-remia.Probability that a blood culture would be positive for coagulase-negative staphylococci by week of hospitalization. The probability that ablood culture obtained in the NICU would be positive for coagulase-negative staphylococci by
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TABLE 4. Incidencedensitiesofbacteremia workups with blood cultures positiveforcoagulase-negative staphylococci(workups
with apositive culture per 1,000 days), by birth weight, The Children'sHospital NICU, 1976 and 1982"
No. ofpositive workups/no. of hospital days
Birth wt (g) (incidence density)
1976 1982
500-749 0/192 (0.0) 3/535 (5.6)
750-999 5/274 (18.2) 8/1,034 (7.7)
1,000-1,249 2/424(4.7) 1/424(2.3)
1,250-1,499 1/461 (2.2) 1/213 (4.7)
1,500-1,749 1/369(2.7) 0/179(0.0)
1,750-1,999 1/304 (3.3) 0/455 (0.0)
>2,000 5/1,564 (3.2) 3/1,880(1.6) Crude overall 15/3,588 (4.2) 16/4,720 (3.4)
aTheMantel-Haenszeladjusted summary relative risk ofhavingablood
culture positive for coagulase-negative staphylococci during a bacteremia
workup in 1976 compared with 1982 was 1.78(95% confidence interval, 0.86
to 3.69), indicating a slightly, but not significantly, greater likelihood of having
apositive bacteremia workup in the earlier timeperiod.
week ofhospitalization ispresented in Fig. 1. In both 1976 and1982,theprobability ofablood culturebeing positive for coagulase-negative staphylococci was lowest (2 to 3%) in week1ofhospitalization, with little change between the first 2days and the subsequent 5 days of week1 in thehospital. After week 1, inboth 1976and 1982 the probability that a blood culture would be positive for coagulase-negative staphylococci increasedweekly, peaked in week3 of hospi-talization at a level of about 12%, and then gradually returned to lower levels by week 6 or 7 of hospital stay. Since the time patterns were similar in the two years, the datawerecombined andarepresented
graphically
inFig.
1.DISCUSSION
Numerous
investigators,
as well as neonatologists and infection control officers inour owninstitution, have claimed that coagulase-negative staphylococci have emergedas im-portant bloodstream pathogens in the NICU only in the current decade(2-6,
13). This clinicalperception
is notTABLE 5. Incidence densities of bacteremiaworkups with blood culturespositive formicroorganisms other than
coagulase-negative staphylococci(workupswithapositive cultureper1,000days), bybirthweight, The
Children's Hospital NICU, 1976and1982"
No.ofepisodes/no.ofhospitaldays
Birthwt(g) (incidence density)
1976 1982
500-749 3/192 (15.6) 2/535 (3.7)
750-999 0/274 (0.0) 1/1,034 (1.0)
1,000-1,249 5/424 (11.8) 1/424 (2.3)
1,250-1,499 2/461 (4.3) 0/213 (0.0)
1,500-1,749 0/369 (0.0) 0/179 (0.0)
1,750-1,999 2/304 (6.5) 0/455 (0.0)
>2,000 6/1,564 (3.8) 3/1,880 (1.6)
Crudeoverall 18/3,588 (5.0) 7/4,720 (1.5) aTheMantel-Haenszel adjusted summary relative risk of havingablood
culturepositive fororganisms otherthancoagulase-negative staphylococci
duringabacteremia workup in 1976compared with 1982 was 3.78(95%
confidenceinterval,1.59 to9.00),indicatingasignificantly greater likelihood
ofhaving apositive workup fororganisms other than coagulase-negative
staphylococci duringtheearlier timeperiod.
0.16
0.14
0.12
~-> 0.10
t 0.08
où
CL
0.060.04
0.02
OL
O 1 2 3 4 5
Hospital Week
6'
9 10FIG. 1. Probability that a blood culture would be positive for coagulase-negative staphylococci, byweek ofhospitalization, The Children's Hospital NICU, 1976 and 1982 combined. The bars represent the68% confidence interval, corresponding to one stan-dard deviation.
supported by our 15-year review of the results of blood culturesobtained from babiesin theNICUatThe Children's Hospital in Boston. Coagulase-negative staphylococcihave beenfrequent blood culture isolates sinceatleast 1970, and we noted nochange in theadjustedrates ofblood cultures growingthese organisms over anextendedperiod.
Although this 15-yearsurvey provided valuable informa-tion regarding coagulase-negative staphylococci in the NICU,morerefinedanalyseswerenecessary toexamine the potential confounding effects of concurrent changes in the hospitalized neonatal population. In recentyears, therehas beenanextraordinary improvement in the survival ofvery low birthweight (lessthan1,000 g)infants, who tendtohave prolonged hospitalstays(15). Thus, therehasbeenashift in NICU bedutilizationtoward occupancybybabies who have the highest overall risk of developing nosocomial blood-streaminfections.Inaddition, theremayhave been concur-rent changes in the apparent incidence of positive blood culturesifphysiciansaltered theirblood-culturing practices tofit theperceived needs of this evolving NICU population. For example, more frequent blood culturing might lead to improveddetection ofcasesof bacteremiathat weremissed previouslyor,alternatively, might simplyresult inimproved documentationof blood culture contamination.
Toaddress thesecritical issues, weperformed adetailed
analysis
of blood culture data obtained in 1976 and 1982. Bacteremiaworkups
wereperformed slightly
lessfrequently in 1982 than in 1976, afterappropriate
adjustments were made for birthweightand duration ofhospitalization(Table 3),and therewere nosignificant
increases intheincidenceof bacteremia workups yielding coagulase-negative staphylo-cocci (Table 4), thus confirming the results of the crude 15-yearsurvey (Table 1).Sincethe datapresentedin this studyarebasedsolelyon the results of blood cultures, they must be interpreted
cautiously
by theclinician. Interpretation ofblood cultures that are positive for coagulase-negative staphylococci is particularly difficult becausetheseorganisms liveontheskin and mucous membranes as commensals and may contami-nate blood cultures during the collection process. Otherinvestigators
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tion from true bacteremia (bloodstream invasion) with coag-ulase-negative staphylococci. Twogroups have studied en-tire hospital populations composed primarily of adult patientsand have concluded thatonly about 6%ofpatients with coagulase-negative staphylococci isolated from blood culturesactually had bacterial invasion ofthebloodstreamat thetime the cultures were drawn(9, 18).
Conclusions based on studies ofblood cultures obtained from babies in NICUs have been quite different. In such studies (2-6, 13), 26 to 77% of infants with coagulase-negative staphylococci recoveredfrom blood cultures were judgedtohave been trulybacteremic. That is, when coagu-lase-negative staphylococci are found when blood is cul-tured,currentliteraturesuggeststhata neonateisfrom4to 13 timesaslikely tobe bacteremicas anadult.
There are unique difficulties in studying blood culture results fromprematureinfants.Thetiniestprematureinfants
(birth weights
less than 1,500 g) nowgenerallysurvive, and since the blood volume of thesetiny
babies issosmall, they may need to be transfused repeatedly to compensate for multiple phlebotomy. Neonatologists naturally attempt to limit transfusions and their associateddangers,soitis usual to obtain but asingle blood culture perbacteremia workup fromthese smallest babies. Whereas investigators studying adultpatients
usually have been abletocomparethe results oftwo or more sets of blood cultures obtainedduring
the same clinical episode of suspected bacteremia, neonatolo-gists mustplacegreaterrelianceonclinicalcriteria,such as apnea, bradycardia, temperature instability, orfeeding diffi-culties. These clinical manifestations of illness tend to benonspecific
in the neonatalpopulation.Since there isnoabsolute standardcapable of distinguish-ing blood culture contamination from bacteremia with coag-ulase-negative staphylococci in the neonate, we cannot determineprecisely howmanyofthepositivecultures in our study
population
represent true bloodstream invasion. The neonatologists in our NICU do not obtain blood cultures unless apatient
has a clinical syndrome compatible withbacteremia,
but isolation of coagulase-negative staphylo-cocci fromasingle
blood culture under these circumstances neither rules out contaminationnorestablishes a definitivediagnosis. Nevertheless,
ourdatasuggestthatalarger
num-ber of the babies who had
coagulase-negative
staphylococci isolated from blood cultures did, in fact, have bacteremia. Detailedanalysis
of blood culture results during 1976 and 1982 revealed that theprobability
that a culture would bepositive
forcoagulase-negative staphylococci
roseweekly
from admissiontopeak in week3ofhospitalizationand thenfell
slowly
backtoalower levelby week6 or 7(Fig. 1). This pattern is not consistent with mere blood culture contami-nation but is typical of that seen with other nosocomial infections (7),including
coagulase-negative bacteremia as defined by ourselves and otherinvestigators (2-7, 7a, 8, 9, 13, 14;J. Freeman, D. A. Goldmann, R. Platt, D. G.Side-bottom,
andM. F.Epstein, Pediatr.Res.20:378A, abstr.no. 1306, 1986; J. Freeman, M. F. Epstein, R. Platt, D. G.Sidebottom,
and D. A.Goldmann,
Pediatr. Res. 20:378A, abstr. no. 1305, 1986).The very low rates ofpositive bloodculturesobservedin the first weekof lifeprovide further evidence that contami-nation of blood cultures is not a major problem in this
population.
Since approximately one-half of NICU babies havenotyetdevelopedskincolonizationinthe first 2days oflife,
contaminationofblood cultureswould not be expected inthisperiod (8). However,werecontaminationasignificantproblem,
aprecipitous increaseinpositivecultures would beexpected as coagulase-negative staphylococci rapidly colo-nized the skin. Previously published results of nose and umbilicus cultures (8)aswell asunpublished results of skin cultures obtained from neonates in our NICU over the past 2 years have revealed that more than 90% of babies are colonized withcoagulase-negative staphylococci by the third hospital day. Heavy skincolonization is almostuniversalby days 5 to 7. The continuing low probability that a blood culture would grow coagulase-negative staphylococci throughoutthefirst week oflifein the face of theincreasing presenceof organismson theskinsuggests that themajority of positive cultures documented in this study cannot be attributed tocontamination.
The marked divergence between clinical reports and our microbiologic data probablystemsfromthearbitrarycriteria used by clinicians to interpret blood culture data from newborn infants, particularly when coagulase-negative staphylococci areisolated. Recentreportsconcerning coag-ulase-negative staphylococcal infections in neonates have increasedthe awarenessofourclinicalstaff, and coagulase-negative staphylococci that might have been dismissed as contaminants in the 1970s are morelikely tobe considered true pathogens in the 1980s. Also, the real decrease in incidence of bacteremia workups positive for other orga-nisms has led to a relative increasein the proportion of all positive bacteremia workups that yield coagulase-negative staphylococci (Tables4and5),andthis
changing
proportion
may have contributed to the clinical impression that there was an epidemic. In addition, improvements inthe careofcritically
illnewborns haveshifted the NICUpatient popu-lation towardverylow birthweight
babies withlonghospital stays. It is possible thatneonatologists
are morelikely
to "believe"positive
blood cultures iftheyareobtainedfrom suchdesperately ill, very prematureinfants. These hypoth-eses will require furtherinvestigation,
but it is clear that coagulase-negativestaphylococci
have been common and constantisolates from neonatal blood cultures sinceatleast 1970.LITERATURE CITED
1. Archer, G. L. 1985.Coagulase-negative staphylococci in blood cultures: the clinician's dilemma.Infect. Control 6:477-478. 2. Battisti, O., R. Mitchison, and P. O. Davies. 1981. Changing
blood cultureisolates inareferral neonatalintensivecareunit. Arch. Dis. Child. 56:775-778.
3. Baumgart, S.,S. E.Hall, J.M.Campos,and R. A. Polin. 1983. Sepsis with coagulase-negative staphylococci in critically ill newborns.Am.J. Dis. Child. 137:461-463.
4. Cainen, G., P. Campognone, and G. Peter. 1984. Coagulase-negative staphylococcal bacteremia in newborns. Clin. Pediatr. 23:542-544.
5. Donowitz,L.J.,C. E.Haley,W.W.Gregory,and R. P. Wenzel. 1987. Neonatalintensive care unit bacteremia: emergence of gram-positive bacteria as major pathogens. Am. J. Infect. Control 15:141-147.
6. Fleer, A., R. C. Senders, M. R. Visser, R. P. Bilmer, L.J. Gerards, C. A.
Kraaieveld,
and J. Verhoff. 1983. Septicemia duetocoagulase-negative staphylococciinaneonatalintensive careunit: clinical andbacteriological featuresandcontaminated parenteral fluids as a source of sepsis. Pediatr. Infect. Dis. 2:426-431.7. Freeman, J., andJ. E. McGowanJr. 1981. Day-specific inci-dence of nosocomial infection estimated from a prevalence survey. Am. J.Epidemiol. 114:888-901.
7a.Freeman,J., R. Platt, D. G. Sidebottom, J. M. Leclair, M.-F. Epstein,and D. A.Goldmann. 1987.Coagulase-negative staphy-lococcal bacteremia inthechangingneonatalintensivecareunit population. J.Am. Med. Assoc.258:2548-2552.
on April 11, 2020 by guest
http://jcm.asm.org/
8. Goldmann, D. A., J. Leclair, and A. Macone. 1978. Bacterial colonization of neonates admitted to an intensive care environ-ment. J. Pediatr. 93:288-293.
9. Kirchhoff, L. V., and J. N. Sheagren. 1985. Epidemiology and clinical significance of blood cultures positive for coagulase-negative staphylococcus. Infect. Control 6:479-486.
10. Kleinbaum, D. G., L. L. Kupper, and H. Morgenstern. 1982. Epidemiologic research: principles and quantitative methods. Lifetime Learning Publications, Belmont, Calif.
11. Kumar, M. L., H. B. Jenson, and B. B. Dahms. 1985. Fatal Staphylococcus epidermidisinfections in very low-birth-weight infants with cytomegalovirus infection. Pediatrics 76:110-112. 12. Lennette, E. H., A. Balows, W. J. Hausler, Jr., and H. J.
Shadomy (ed.). 1985. Manual of clinical microbiology, 4thed. American Society for Microbiology, Washington, D.C. 13. Munson, D. P., T. R. Thompson, D. E. Johnson, F. S. Rhame, N.
VanDrunen, and P. Ferrieri. 1982.Coagulase-negative staphy-lococcal septicemia: experience in a newborn intensive care
unit.J. Pediatr. 101:602-605.
14. Noel, G. J., andP.J. Edelson. 1984.Staphylococcusepidermidis bacteremia in neonates: further observations and the occur-rence offocal infection.Pediatrics 14:832-837.
15. Paneth, N., J. L. Kiely,S. Wallenstein, M. Marcus, J. Pakter, and M. Susser. 1982. Newborn intensive care and neonatal mortality in low-birth-weight infants. N. Engl. J. Med. 307: 149-155.
16. Rothman, K. J., and J. D. Boice, Jr. 1979. Epidemiologic analysis withaprogrammable calculator. Department ofHealth, Education, andWelfare, Washington, D.C.
17. Snedecor, G. W., and W. G. Cochran.1980.Statistical methods, 7th ed. Iowa State University Press, Ames.
18. Weinstein, M. P., B. L. Reller, J. R. Murphy, and K. A. Lichtenstein. 1983. The clinical significance of positive blood cultures: acomprehensive analysis of 500 episodes of bactere-mia and fungemia in adults. I. Laboratory and epidemiologic observations.Rev. Infect. Dis. 5:35-53.
