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Previous Article | Next Article 
Journal of Clinical Microbiology, January 2001, p. 274-278, Vol. 39, No. 1
Laboratoire de Microbiologie
Médicale1 and Département
d'Information Médicale,3 Institut Jean
Godinot, 51056 Rheims Cedex, and Laboratoire de
Microbiologie Médicale, Institut Curie, 75231 Paris Cedex
05,2 France
Received 3 April 2000/Returned for modification 1 September
2000/Accepted 31 October 2000
We carried out a prospective study in two French Comprehensive
Cancer Centers (95 and 184 beds, respectively) to assess the validity
of a test based on the earlier positivity of central venous blood
cultures in comparison with peripheral blood cultures for predicting
catheter-related bacteremia. The differences between the times to
positivity for the 21 patients with clinical catheter-related bacteremia and the differences between the times to positivity for the
nine patients with bacteremia due to another source were compared by
the median test. The difference between the median values was
significant (P = 0.0003). A receiver operating
characteristic curve was constructed to determine the optimum threshold
of the test, which appeared to be at the cutoff point of Patients with cancer often need
long-term intravascular devices (IVD), which can be externalized
indwelling central venous catheters or subcutaneously implanted venous
access systems. The use of IVD has improved the management of
critically ill patients, but catheter-related bacteremia (CRB) is a
frequent and potentially life-threatening complication (1, 8, 9,
12, 23). Several cancer centers have shown that CRB occurs in 10 to 20% of hospitalized patients with cancer (13, 16, 17).
In cancer patients, it is preferable not to remove the IVD if the
microorganism species allows it to be left in place, and several
authors showed the efficacy of antibiotic treatment of port-associated
bacteremia without IVD removal (26).
For several years, blood culture has benefited from the advantages of
new semiautomatic methods. Time to positivity seems to correlate with
the inoculum introduced into a bottle and can be accurately assessed by
following indices of growth every 10 to 15 min (21, 28).
Lastly, the authors of two recent interesting studies showed that
earlier positivity of central venous blood cultures in comparison with
peripheral blood cultures is highly predictive of CRB (4,
5).
We carried out the present prospective study at the Institut Jean
Godinot (Rheims) and the Institut Curie (Paris), French Comprehensive
Cancer Centers, with 95 and 184 beds, respectively. The first step was
to assess the validity of the test for the diagnosis of CRB by
comparing the times to positivity of blood cultures drawn
simultaneously from a peripheral vein and from the central IVD. The
second step was to show the test's usefulness for cancer patients with
bacteremia from an unknown source.
Preliminary study in vitro.
To study the link between the
microbial inoculum and the times to positivity of blood cultures, we
performed several measurements with clinical isolates of the following
four species of microorganisms (three strains each): Escherichia
coli, Pseudomonas aeruginosa, Staphylococcus
epidermidis, and Candida albicans. For the first three,
bacteria were cultured at 37°C for 16 h in 10 ml of peptone water per colony (Sanofi Pasteur, Marnes la Coquette, France). C. albicans was cultured in 3 ml of glucose-buffered broth per colony
(Sanofi Pasteur). Next, 10-fold serial dilutions were performed in 30 ml of saline. Aerobic bottles were then inoculated with 10 ml of each
dilution and were placed in the automated blood culture system. The
initial inoculum was counted on blood agar.
Diagnosis of CRB.
The criteria of CRB diagnosis were derived
from those described by Raad and Bodey (25) and were based
on the clinical symptoms and/or results of a quantitative IVD tip
culture, taking into account the presence of bacteremia or fungemia in
all patients.
0095-1137/01/$04.00+0 DOI: 10.1128/JCM.39.1.274-278.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Validity of Earlier Positivity of Central Venous Blood Cultures
in Comparison with Peripheral Blood Cultures for Diagnosing
Catheter-Related Bacteremia in Cancer Patients
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
+3 h, with 100% specificity and 81% sensitivity. The positive and negative predictive values obtained with this cutoff point confirmed the efficacy of the test for predicting the presence or absence of catheter-related bacteremia in cancer patients. The cutoff point was
then used to post-classify the 68 episodes of bacteremia from an
unknown source. The characteristics and clinical course of both the
positive and negative post-classified episodes did not show that the
test was clearly useful for a large number of clinical presentations.
We therefore suggest restricting it to febrile neutropenic cancer
patients for whom clinical signs of infection are slight or absent and
when the test is positive.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Inclusion criteria for patients and episodes. All patients had cancer and were hospitalized for their cancer treatment or for palliative care. They all had a long-term IVD and one sign of fever, shown by a temperature of >38.5°C or <36°C once or >38°C twice within a 2- to 3-h interval (24). In some cases they exhibited other clinical signs, such as chills and/or hypotension. Some patients had neutropenia (<500 G/liter). We considered only one episode per patient. Patients were considered by clinicians to be cured when their temperature returned to normal within 24 h of IVD removal or within 72 h of a suitable antibiotic treatment when the IVD was left in place. When the course of the bacteremia could not be observed or when the patient had been transferred to another hospital or had been discharged and was at home, the episode could not be evaluated and the patient was considered lost to follow-up. For each episode, one or multiple simultaneous sets of blood cultures were tested. Each set consisted of a peripheral aerobic culture paired with a central aerobic culture and a peripheral anaerobic culture paired with a central anaerobic culture.
Blood culture techniques. The systems used were the BacT/Alert (Organon Teknika Corp., Durham, N.C.) and the BACTEC 9000 (Becton Dickinson Co., Sparks, Md.) (21, 28). With both systems, continued noninvasive monitoring of each bottle allows the detection of positive cultures with a computer-driven algorithm that monitors the initial, increased, and/or total level of CO2 produced by microbial growth. The exact amount of blood inoculated into each bottle, which varied from 5 to 8 ml, was determined by weight. Each bottle was weighed before and after blood inoculation. Pre-sampling bottle weight was obtained by calculating the mean weight of 100 bottles from each batch (in the BACTEC system) or by asking the manufacturer (BacT/Alert; Organon Teknika) to specify the pre-sampling weight. The volume in each filled bottle was then calculated by subtracting the weight of the uninoculated bottle from the weight of the filled bottle. Weights were adjusted for caps and labels. When the weight of the inoculated blood in one bottle of a pair of aerobic or anaerobic blood cultures was more than three times that of the other, the pair was excluded. After inoculation, all bottles were incubated at 37°C for 6 days.
For each episode for which multiple sets of blood cultures were positive, we considered only the pair of the set containing the earliest positive aerobic or anaerobic culture. The definitions proposed by the Centers for Disease Control and Prevention, Atlanta, Ga., were used for positive bloodstream cultures and contaminants (6, 15). The time to positivity of each sample, and the difference between the time to positivity of peripheral aerobic and central aerobic blood cultures or of peripheral anaerobic and central anaerobic cultures (
TP), were calculated and expressed in hours and decimal fractions.
Positive samples were Gram stained, and microorganisms were cultured in
the appropriate media for identification, using conventional methods.
Susceptibility testing allowed us to compare samples of the same species.
Statistical methods.
To determine the optimal threshold of
the test, a receiver operating characteristic (ROC) curve
(19) was constructed with the TP values obtained for
the patients having CRB and the values obtained for the patients having
bacteremia due to another source. The PROC LOGISTIC of the SAS Software
(SAS Institute Inc., Cary, N.C.) was used. Differences between the
TP values obtained for patients having CRB and for those having
bacteremia due to another source were calculated by the median test.
Positive and negative predictive values were also calculated by taking
into account the values for the prevalence of CRB shown in three U.S.
cancer centers (13, 16, 17) and in one of our own hospitals.
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RESULTS |
|---|
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
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Preliminary study. In the preliminary study in vitro, the trend curves obtained with the microorganisms tested confirmed the inverse linear relationship between the microbial inoculum and the time to positivity of the culture for each strain. However, the slopes of the curves of E. coli, P. aeruginosa, and S. epidermidis were similar, but the curve of C. albicans was not as steep.
Assessment of the validity of the test. This prospective study was carried out from 14 June 1995 to 17 December 1996. We counted 213 infectious episodes, 106 of which were excluded (3 for inappropriate weight of the inoculated blood in one of a paired bottles, 1 for different microorganisms in each paired bottle, and 102 for positivity of only one of the paired bottles, including 32 classified as contaminants). Of the remaining 107 episodes, 21 corresponded to patients having CRB, 9 corresponded to patients having bacteremia due to another source, and 77 corresponded to patients having bacteremia from an unknown source.
Construction of the ROC curve showed that theTP threshold with
100% specificity and 81% sensitivity was +3 h (Table
1 and Fig. 1). The
positive and negative predictive values were calculated, with a TP
of 3 h, taking into account the values for the prevalence of CRB
shown in three U.S. cancer centers (13, 16, 17), ranging
from 10.5 to 19.7%, and taking into account our own hospital
prevalence data of 1.45%. Positive predictive values were 100% for
each hospital, and negative predictive values ranged from 95.6 to
97.8% for the three U.S. cancer centers; the value was 99.7% for our
own data.
|
|
TP values obtained for the 21 patients having CRB ranged from
54.4 to +60.4 h (median = +9 h), and the TP values obtained for the 9 patients having bacteremia due to another source ranged from
41 to +0.3 h (median = 0 h). The difference between the median values was significant (P = 0.0003).
Study of microorganism distribution showed that cutaneous
microorganisms occurred only among the 21 CRB patients. They comprised S. aureus in nine episodes, coagulase-negative staphylococci
in seven episodes, and Candida sp. in two episodes,
which constituted 81.8% (18 out of 22) of all microorganisms. The
other microorganisms were environmental (P. aeruginosa, Acinetobacter sp., and Bacillus sp.) except for one (Klebsiella sp.). Fourteen patients with
CRB had their IVD removed, received appropriate antibiotic treatment, and were cured. Five patients were cured out of the seven having CRB
who did not have IVD removed. Death, which occurred for the two uncured
patients, was not related to CRB but was caused by myocardial
infarction in one case and concerned a patient on palliative care in
the other.
Among the nine patients having bacteremia due to another source, we
counted 10 microorganisms, none of which was cutaneous. These
microorganisms were Enterobacteriaceae species in six cases, Streptococcus sp. in two cases, and Streptococcus
pneumoniae in one case. One case involved two
Enterobacteriaceae species in the same blood sample. None of
these nine patients had IVD removed, and seven were cured. Death was
caused by pneumococcal pneumonia in one patient, and the other patient
who died was on palliative care.
Episodes with bacteremia from an unknown source.
The TP
cutoff point of +3 h was used to post-classify the 77 episodes of
bacteremia from an unknown source. Forty-four episodes with a TP of
+3.0 h (range, +128.2 to +3.0) were classified as positive, and 33 episodes with a TP of <+3.0 h (range, +2.8 to 17.0) were
classified as negative. Nine patients were lost to follow-up because
they left the hospital before their clinical course could be observed.
These nine patients who were not included in the study corresponded to
five positive and four negative post-classified episodes. This left a
total of 68 episodes that were followed up (39 positive and 29 negative). The positive episodes included many more cutaneous
microorganisms than the negative episodes (27 out of 41 [66%] versus
11 out of 32 [34%]; P = 0.0075).
24 h, and the IVD was left in place in
27 of them. Fifteen, among whom were six non-neutropenic patients
without any other infection, of the 27 were cured within 72 h of a
suitable antibiotic treatment and never relapsed. We paid special
attention to the positive post-classified episode caused by an
Enterobacter sp., which affected one patient with no
neutropenia or other infection. Careful study of the later clinical
course of this patient showed that he did not relapse, even though the
IVD was not removed. Six patients died. Four deaths were due to an
infection other than CRB, and two concerned patients who were on
palliative care. The remaining six patients were cured within >72 h
but three of them had an infection other than CRB. Of the other three
comprised patients without neutropenia or any other infection, one of
them was on palliative care and the two others were cured within 96 and
120 h, respectively, without relapse.
The characteristics and course of the 29 negative post-classified
bacteremia cases from an unknown source were also studied. Four of the
six patients with clinical IVD infection had IVD removed and were
cured. Of these, one non-neutropenic patient had bacteremia caused by
both coagulase-negative staphylococci and S. pneumoniae and
also had another infection by a microorganism different from the one in
the bloodstream. The three other patients had neither neutropenia nor
any other infection and were cured within 24 h. In these three
patients, bacteremia was caused by pathogenic microorganisms (an
Enterobacter sp. in one case and S. aureus in two
cases). The two other patients with clinical IVD infection who did not have IVD removed were cured after more than 72 h, but both had an
infection other than CRB and one had neutropenia.
In this group of 29 negative post-classified bacteremia cases from an
unknown source, 2 of the 23 patients without clinical IVD infection had
no neutropenia or any other infection and did not have IVD removed but
were not cured within 72 h. However, one of them, who had
Listeria sp., was cured within 96 h and did not
relapse, but the other, who had CNS infection, was on palliative care.
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
|
|---|
Despite the valid guidelines issued for good practice in central venous catheterization (14, 22), CRB still occurs and is a serious infectious problem, particularly among cancer patients who need long-term catheterization (1, 13, 16, 17). For these patients, unnecessary removal of an IVD must be avoided. Until now, no easy cheap laboratory test has been available to help clinicians diagnose CRB and decide whether to remove the catheter.
The first part of this prospective study assessed the validity of the
use of TP as an indicator of CRB. This validity was easily obtained
with the new automated blood culture systems and with the TP values
obtained for patients with CRB or patients with bacteremia due to
another source. The results obtained are in agreement with the
definitions chosen for the study (25) and confirm the
correct classification of the episodes. The TP cutoff point of +3
h was close to the one of +2 h found by others in similar studies
(4, 5). The laboratory test by which TP is obtained is
easy to carry out, and its results seem to be very helpful to
clinicians for the diagnosis of CRB, with 100% specificity and high
sensitivity (81%). The positive and negative predictive values
obtained with this TP cutoff point of +3 h confirmed the efficacy
of the test for predicting the presence or absence of CRB in cancer patients.
In the second part of this study, the usefulness of the TP cutoff
point of +3 h based on the clinical course of the 68 post-classified episodes of bacteremia from an unknown source was more difficult to
evaluate. The characteristics and course of the infections which
occurred for the 39 positive and 29 negative post-classified episodes
showed that in many cases, the test was no better than appreciation of
the clinical and microbiological presentation.
There were many more cutaneous microorganisms among the positive
post-classified episodes than among the negative ones (66% versus
34%), and the difference was significant (P = 0.0075). The 10 patients with a positive test (TP +3 h) and clinical IVD
infection exhibited characteristics and a clinical course which
corresponded to the criteria used to define a CRB. In these cases, the
test seemed of little benefit.
The study of the usefulness of the test may have been easiest for the patients with no clinical catheter-related infection and no neutropenia or any other infection and whose IVD was not removed. But in these cases, the test did not appear to yield better results than clinical observation. It is noteworthy that even without IVD removal, a large proportion of the positive post-classified episodes without clinical IVD infection were cured after suitable antibiotic treatment based on both the clinical symptoms and the microbiological data.
CRB is known to be frequently caused by CNS, a microorganism known for
its low pathogenicity and its high probability of cure without IVD
removal (3) but is less often described when caused by
pathogenic microorganisms (26). Therefore, it seems
extremely difficult to draw any conclusions about episodes affecting
patients with neutropenia and/or another infection. It is noteworthy
that the positive post-classified episode caused by an
Enterobacter sp., which affected one patient with no
neutropenia or other infection, was cured within 24 h and that the
patient did not relapse, even though the IVD was not removed.
Clinical results did not agree with those of the test for negative post-classified episodes showing IVD infection. Study of the clinical course of negative post-classified episodes without clinical IVD infection involved many difficulties. Firstly, for patients whose IVD was removed and who had either an infection other than CRB or neutropenia, the return to a normal temperature could have been due either to antibiotic treatment for the other infection or to the end of their neutropenia. Secondly, for patients whose IVD was not removed, the time to cure of the fever was due to their clinical status, especially when they were neutropenic, whether or not they had an infection other than CRB.
Analysis of the results for the 68 undetermined episodes shows the slight usefulness of the time-to-positivity test when the clinical presentation is obvious. For cancer patients, the clinical symptoms, the presence or absence of a clinical IVD infection, and the microorganism species causing the bacteremia appear to provide sufficient information in most cases. Despite the high specificity and sensitivity of this attractive test, we therefore suggest limiting its use to febrile neutropenic cancer patients, especially when it is positive, and when clinical signs of IVD infection are slight or absent. In this way, the test could provide additional information for clinicians who hesitate to remove a very effective IVD, especially when the bacteremia is caused by a pathogenic microorganism.
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ACKNOWLEDGMENTS |
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We are grateful to F. Cuzon, A. Crevoisier, J. Elart, V. Fournier-Boutault, S. Lecuru, and C. Mestrude for technical assistance.
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FOOTNOTES |
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* Corresponding author. Mailing address: Laboratoire de Microbiologie, Institut Jean Godinot, 1 rue du Général Koenig, BP 171, 51056 Rheims Cedex, France. Phone: 33 3 26 50 42 93. Fax: 33 3 26 50 42 94. E-mail: veronique.bussy{at}reims.fnclcc.fr.
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Materials and Methods
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Discussion
References
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