PEDIATRICS Vol. 122 No. 4 October 2008, pp. 726-730 (doi:10.1542/peds.2007-3275)
ARTICLE |
Effect of Antibiotic Pretreatment on Cerebrospinal Fluid Profiles of Children With Bacterial Meningitis
a Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts
b Texas Children's Hospital and Baylor College School of Medicine, Houston, Texas
c Rady Children's Hospital San Diego and University of California, San Diego, School of Medicine, San Diego, California
d WakeMed Health and Hospitals, Raleigh, North Carolina
e University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
f Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri
g Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania
h Children's National Medical Center and George Washington University School of Medicine, Washington, DC
i Oakland Children's Hospital and Research Center and University of California, Oakland, School of Medicine, Oakland, California
j A. I. duPont Hospital for Children, Wilmington, Delaware
k Jefferson Medical College, Philadelphia, Pennsylvania
l Children's Memorial Hospital and Northwestern Feinberg School of Medicine, Chicago, Illinois
m Children's Medical Center and Medical College of Georgia, Augusta, Georgia
n Mayo Clinic Jacksonville and Mayo School of Graduate Medical Studies, Jacksonville, Florida
o Phoenix Children's Hospital and University of Arizona College of Medicine, Phoenix, Arizona
p Hasbro Children's Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island
q Seattle Children's and Regional Medical Center and University of Washington School of Medicine, Seattle, Washington
r Children's Hospital Memphis and University of Tennessee Graduate School of Medicine, Memphis, Tennessee
s Children's Hospital of Wisconsin and Medical College of Wisconsin, Milwaukee, Wisconsin
t Children's Healthcare of Atlanta at Scottish Rite, Atlanta, Georgia
u Morgan Stanley Children's Hospital of New York-Presbyterian and Columbia University College of Physicians and Surgeons, New York, New York
v University of California, Davis, Medical Center and University of California, Davis, School of Medicine, Davis, California
w Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California
x Columbus Children's Hospital and Ohio State University, Columbus, Ohio
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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OBJECTIVE. The goal of this study was to evaluate the effect of antibiotic administration before lumbar puncture on cerebrospinal fluid profiles in children with bacterial meningitis.
METHODS. We reviewed the medical records of all children (1 month to 18 years of age) with bacterial meningitis who presented to 20 pediatric emergency departments between 2001 and 2004. Bacterial meningitis was defined by positive cerebrospinal fluid culture results for a bacterial pathogen or cerebrospinal fluid pleocytosis with positive blood culture and/or cerebrospinal fluid latex agglutination results. Probable bacterial meningitis was defined as positive cerebrospinal fluid Gram stain results with negative results of bacterial cultures of blood and cerebrospinal fluid. Antibiotic pretreatment was defined as any antibiotic administered within 72 hours before the lumbar puncture.
RESULTS. We identified 231 patients with bacterial meningitis and another 14 with probable bacterial meningitis. Of those 245 patients, 85 (35%) had received antibiotic pretreatment. After adjustment for patient age, duration and severity of illness at presentation, and bacterial pathogen, longer duration of antibiotic pretreatment was not significantly associated with cerebrospinal fluid white blood cell count, cerebrospinal fluid absolute neutrophil count. However, antibiotic pretreatment was significantly associated with higher cerebrospinal fluid glucose and lower cerebrospinal fluid protein levels. Although these effects became apparent earlier, patients with 
12 hours of pretreatment, compared with patients who either were not pretreated or were pretreated for <12 hours, had significantly higher median cerebrospinal fluid glucose levels (48 mg/dL vs 29 mg/dL) and lower median cerebrospinal fluid protein levels (121 vs 178 mg/dL).
CONCLUSIONS. In patients with bacterial meningitis, antibiotic pretreatment is associated with higher cerebrospinal fluid glucose levels and lower cerebrospinal fluid protein levels, although pretreatment does not modify cerebrospinal fluid white blood cell count or absolute neutrophil count results.
Key Words: bacterial meningitis • antibiotic pretreatment • cerebrospinal fluid • children
Abbreviations: CSF—cerebrospinal fluid • ANC—absolute neutrophil count • IQR—interquartile range • WBC—white blood cell
Administration of antibiotics to children before the performance of diagnostic lumbar punctures increases the number of false-negative cerebrospinal fluid (CSF) bacterial culture results.1,2 The effects of antibiotic pretreatment on CSF cellular and chemical profiles were studied previously but remain a matter of controversy. Some previous work suggested that antibiotic pretreatment does not affect1,3,4 or has only a small influence on5,6 CSF white blood cell (WBC) profiles in patients with bacterial meningitis. One previous study demonstrated a decrease in CSF protein levels after pretreatment with antibiotics.5 Those previous studies, however, were performed before the introduction of conjugate bacterial vaccines against Haemophilus influenzae type b and Streptococcus pneumoniae, which have transformed the epidemiological features of bacterial meningitis.7,8
Clinical prediction rules for the identification of bacterial meningitis combine clinical and laboratory parameters to estimate the risk of bacterial meningitis. Our group developed9 and then validated10 in a multicenter study the Bacterial Meningitis Score, a clinical prediction rule that accurately identifies children with CSF pleocytosis who are at very low risk of bacterial meningitis. In those studies, we excluded all patients who had received any antibiotic pretreatment, because accurately assigning a diagnosis to pretreated patients with negative bacterial culture results is often difficult. Therefore, the accuracy of the bacterial meningitis score in children with pretreated bacterial meningitis is untested. To explore further the relationship between antibiotic pretreatment and CSF parameters in the era of widespread conjugate vaccination against both H influenzae type b and S pneumoniae, we studied a large cohort of children with bacterial meningitis evaluated in the emergency departments of 20 pediatric centers in the United States.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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We conducted a retrospective cohort study endorsed by the Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Twenty emergency departments in pediatric centers located in diverse geographic areas of the United States participated in the study. Details of the study design were described previously.10 In brief, we identified cases of bacterial meningitis in 2 ways, that is, (1) International Classification of Diseases discharge diagnosis codes revision 9.0 for bacterial meningitis (bacterial meningitis, codes 320.0–320.9, or unspecified meningitis, codes 321.0–322.9) or Neisseria infection (code 036.0) and (2) review of microbiology logs for CSF cultures testing positive for bacterial pathogens. We included all children
29 days and 
18 years of age who presented to the emergency departments of the participating centers between January 2001 and July 2004. We reviewed the medical records of all potential study patients to determine clinical features, including the occurrence and timing of antibiotic pretreatment, and laboratory results.
We defined a case of bacterial meningitis as a patient presenting with a CSF culture testing positive for a bacterial pathogen known to cause bacterial meningitis or CSF pleocytosis (CSF WBC count of 10 cells per µL) with positive blood culture results and/or positive CSF latex agglutination study results. Consistent with clinical practice, we categorized patients with positive CSF Gram-stain results but negative results of bacterial cultures of blood and CSF as having probable bacterial meningitis. We included the patients with probable bacterial meningitis in the bacterial meningitis group in the analysis. We excluded patients with CSF shunts, recent neurosurgery (within 1 month), or suppressed immune systems (either primary or acquired immunodeficiency or immunosuppressive therapy), because the etiologic agents and the inflammatory response may be different from those in a previously healthy population.
We categorized a patient as having pretreated bacterial meningitis if a patient with bacterial meningitis or probable bacterial meningitis was given an antibiotic within 72 hours before the performance of the lumbar puncture. We defined the duration of antibiotic pretreatment as the time between administration of the antibiotic and performance of the lumbar puncture.
We compared proportions by using 
2 analysis. We compared group medians by using the Mann-Whitney U test (2 groups) or the Kruskal-Wallis test (3 groups). We used multivariate linear regression to determine the relationship between duration of antibiotic pretreatment and each of the following CSF parameters: CSF WBC count, CSF absolute neutrophil count (ANC), CSF protein level, and CSF glucose level. In each case, we adjusted for the following 4 clinically important covariates in the multivariate analyses: patient age, duration of fever, hypotension requiring vasoactive medication, and respiratory failure requiring intubation. We selected the covariates based on our a priori belief that these parameters have associations with patients' inflammatory responses to bacterial meningitis, as reflected in CSF findings. First, bacterial pathogens are known to differ according to the age of the patient.7 Second, the duration of fever or illness may affect both the CSF inflammatory response and the likelihood of being pretreated with antibiotics.11 Finally, previous work showed that patients with more severe infections such as meningococcal disease have reduced CSF neutrophil responses.12
Patients with missing information regarding either the main predictor (duration of antibiotic pretreatment) or any of the covariates were not included in the multivariate analyses. We then performed a threshold analysis for antibiotic effect by using the median for each of the 4 CSF parameters at 3 clinically sensible cutoff points (4, 12, and 24 hours of antibiotic pretreatment). We used SPSS 15.0 (SPSS, Chicago, IL) for all analyses.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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We identified a total of 255 patients with bacterial meningitis. We excluded 10 patients because of the presence of a CSF shunt or recent neurosurgery. Of the remaining 245 patients with bacterial meningitis, 14 (5.7%) were categorized as having had probable bacterial meningitis on the basis of positive Gram-stain results alone (and are included in the bacterial meningitis group in subsequent references and analyses). Of the 245 study patients, 159 (65%) had nonpretreated bacterial meningitis, 85 (35%) had pretreated bacterial meningitis, and 1 (0.4%) lacked data about antibiotic pretreatment. Of the 14 patients with probable bacterial meningitis, 9 had been pretreated with antibiotics before lumbar puncture. The children with pretreated bacterial meningitis were slightly older than those with nonpretreated bacterial meningitis, although this difference did not reach statistical significance (age of patients with pretreated bacterial meningitis: median: 0.8 years; interquartile range [IQR]: 0.3–4.1 years; age of patients with nonpretreated bacterial meningitis: median: 0.4 years; IQR: 0.2–3.8 years; P = .09).
Of the 85 patients who received antibiotic pretreatment, 20 (24%) received orally administered antibiotics alone, 59 (69%) parenterally administered antibiotics alone, and 6 (7%) parenterally and orally administered antibiotics. The duration of antibiotic pretreatment varied according to the route of administration (orally administered alone: median: 24 hours; IQR: 24–54 hours; parenterally administered alone: median: 4 hours; IQR: 1–24 hours; both orally and parenterally administered: median: 24 hours; IQR: 10.5–60 hours; P < .001) (Fig 1). Of the 25 patients who were pretreated for <4 hours before lumbar puncture, 24 (96%) were given parenterally administered ceftriaxone. Fourteen patients had missing information about the duration of antibiotic pretreatment.
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We first examined the effect of antibiotic pretreatment on CSF Gram-stain results and bacterial culture positivity among the 231 patients with definite bacterial meningitis (Table 1). Although the rates of positive CSF Gram-stain results did not differ according to pretreatment status, those who had received any antibiotic pretreatment before blood or CSF specimens were obtained for culture had lower rates of corresponding positive culture results than did patients who had not received any antibiotic treatment (Table 1). Because blood and CSF culture specimens were not always obtained simultaneously, the pretreatment status sometimes differed according to culture source. Of the 85 patients who received antibiotics before lumbar puncture, 46 (54%) had blood culture specimens obtained before the administration of antibiotics. For 16 (35%) of the 46 patients, the bacterial meningitis pathogen was identified on the basis of blood culture results alone.
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We then examined the effect of antibiotic pretreatment on CSF profiles with adjustment for clinically important covariates (patient age, duration of fever, hypotension requiring vasoactive medications, and respiratory failure requiring intubation). The duration of antibiotic pretreatment was not associated with either CSF WBC count (β = –0.15; P = .20) or CSF ANC (β = –0.16; P = .21). However, we identified an association between duration of antibiotic pretreatment and both CSF glucose level (β = 0.19; P = .04) and CSF protein level (β = –0.31; P = .01). The results of the analyses were similar when we excluded the 14 patients with probable bacterial meningitis defined on the basis of positive Gram-stain results alone (data not shown).
We further explored the relationship between the duration of antibiotic pretreatment and the observed effects on CSF profiles by using clinically sensible time cutoff points (Table 2). At 4 hours of pretreatment, the glucose level was higher (P = .045) and the protein level was lower (P = .24), compared with patients who received no pretreatment, although the differences in CSF protein levels did not achieve statistical significance. However, when we compared patients who had received no or <12 hours of pretreatment with patients who had been pretreated for 12 hours, the median CSF glucose level was significantly higher (P = .005) in pretreated patients and the median CSF protein level was significantly lower (P = .008). No significant differences in CSF WBC count or CSF ANC results were noted at any of the time points. The effects of antibiotic pretreatment on the CSF parameters tested were very similar for a threshold of 24 hours of pretreatment and for a threshold of 12 hours of pretreatment (differences in CSF glucose levels: P = .005; differences in CSF protein levels: P = .009). When we adjusted for patient age, duration of fever, hypotension, and respiratory failure in a multivariate analysis, CSF glucose and protein levels both became significantly different after 12 hours of antibiotic pretreatment.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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This study examined the effect of antibiotic pretreatment on CSF profiles in the era of widespread use of bacterial conjugate vaccines against H influenzae type b and S pneumoniae. In our cohort of 245 children with bacterial meningitis, more than one third received antibiotics before the initial lumbar puncture was performed. We found that antibiotic pretreatment did not significantly affect CSF WBC count or CSF ANC. However, antibiotic pretreatment was associated with higher CSF glucose levels and lower CSF protein levels and a lower rate of CSF culture positivity. Although these effects on CSF parameters became apparent after 4 hours of pretreatment, glucose and protein levels were significantly higher and lower, respectively, after
12 hours of pretreatment, after adjustment for other factors that might affect CSF profiles. Numerous previous investigations investigated the relationship between antibiotic pretreatment and CSF profiles.1–6 No consistent effect of antibiotic therapy was suggested by all of those studies, which might be attributable in part to the differences in definitions and patient populations among the studies. Our study differed from those studies in several important ways. First, all previously published studies were performed before the introduction of universal H influenzae type b immunization, whereas our study reflects the epidemiological features of bacterial meningitis in the setting of nearly universal H influenzae type b and conjugate pneumococcal vaccination (in the United States). One previous group defined bacterial meningitis by using CSF parameters (elevated CSF WBC count, low CSF glucose level, and elevated CSF protein level) without requiring positive blood or CSF culture results,1 potentially obscuring any impact of pretreatment on those parameters. Because of this concern, we conducted our analyses with only patients who had microbiologic confirmation of bacterial meningitis or positive CSF Gram-stain results. Furthermore, by seeking a threshold duration of antibiotic pretreatment at which changes became apparent, we were able to detect differences in CSF protein levels (as shown by others5) and glucose profiles that could not be appreciated by simply comparing patients who received pretreatment and those who did not receive pretreatment. Finally, we applied multivariate statistical methods to determine the independent contribution of antibiotic pretreatment after adjustment for other clinically important variables.
Our study has some important limitations. First, our study was retrospective and is subject to the limitations of retrospective data gathering. However, we had minimal missing data and included only objective parameters that were likely to be recorded accurately in the medical records. Second, the route of antibiotic pretreatment was strongly related to the duration of pretreatment, because all except 1 patient who had been pretreated for <4 hours had received parenterally administered ceftriaxone, rather than orally administered antibiotics. The study had insufficient power, however, to separate statistically the effects of oral versus parenteral antibiotic pretreatment, beyond the duration of pretreatment. We did not detect any significant changes in WBC counts or ANCs with increasing duration of antibiotic treatment. Although the study might have been underpowered to detect true differences in CSF WBC counts or CSF ANCs according to pretreatment duration, demonstration of significant differences in these CSF parameters would only reinforce our conclusion not to apply bacterial meningitis prediction rules to pretreated patients. The most important potential limitation, however, is that our study could not evaluate the effect of antibiotic pretreatment on the CSF profiles of children with negative CSF Gram-stain results and negative blood and CSF culture results, who might have had bacterial meningitis but whose cultures yielded negative results because of antibiotic pretreatment. Because accurate assignment of pretreated patients with negative culture and Gram-stain results into bacterial or aseptic meningitis groups was not feasible, such patients were excluded from this analysis. Some of those patients might in fact have had bacterial meningitis. It is conceivable, but undeterminable, that the effect of antibiotic pretreatment on the CSF profiles of those patients is different from the effect on the profiles of patients who retain microbiologic evidence of bacterial meningitis.
There are important implications of this study. We have demonstrated that antibiotic pretreatment of children with bacterial meningitis affects CSF profiles, specifically resulting in increases in CSF glucose levels and decreases in CSF protein levels that become apparent within several hours of pretreatment, in addition to the decreased rate of CSF culture positivity. Therefore, the CSF profiles of children who have received antibiotic pretreatment before lumbar puncture should be interpreted with caution. In particular, predictive models that discriminate bacterial from aseptic meningitis often include CSF parameters such as glucose and/or protein levels,9,10,13–16 including the Bacterial Meningitis Score developed by our group.9,10 Our results suggest that predictive models that rely on these variables should not be applied to patients who have received antibiotics before lumbar puncture.
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ACKNOWLEDGMENTS |
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This work was supported by an Ambulatory Pediatric Association Young Investigator Grant and a National Research Service Award (grant T32 HD40128-01, Research Training in Pediatric Emergency Medicine, to Dr Nigrovic).
We thank other members of the study group, including those who helped with chart abstraction, data entry, and database management, as follows: Elizabeth R. Alpern, MD MSCE (Children's Hospital of Philadelphia and University of Pennsylvania), Troy Bush (Texas Children's Hospital and Baylor College of Medicine), Joseph M. Campos, PhD (Children's National Medical Center), Christopher R. Cannavino, MD (Rady Children's Hospital San Diego and University of California, San Diego, School of Medicine), Murray Edelberg, PhD (Carlisle, MA), Kim Fisher, PhD (Center for Pediatric Research, University of Tennessee), Marissa Hauptman, MPH (New York University School of Medicine), Paul Ishimine, MD (Rady Children's Hospital San Diego and University of California, San Diego, School of Medicine), Daniel M. Kaplan (Children's National Medical Center), John Leake, MD, and R. Ian McCaslin, MD, MPH (Rady Children's Hospital San Diego and University of California, San Diego, School of Medicine), Umair Salim (Center for Pediatric Research, University of Tennessee), James Wilde, MD (Children's Medical Center Augusta and Medical College of Georgia), and Xiaohi Zhao (Brookline, MA).
We thank the members of the Pediatric Emergency Medicine Collaborative Research Committee for their critical review and endorsement of the study protocol.
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FOOTNOTES |
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Accepted Jan 7, 2008.
Address correspondence to Lise E. Nigrovic, MD, MPH, Division of Emergency Medicine, Children's Hospital Boston, 300 Longwood Ave, Boston, MA 02115. E-mail: lise.nigrovic{at}childrens.harvard.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
| What's Known on This Subject Administration of antibiotics to children before diagnostic lumbar punctures increases the number of false-negative CSF bacterial cultures. The effect of antibiotic pretreatment on CSF cellular and chemical profiles has been studied but remains a matter of controversy.
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| What This Study Adds We demonstrate that antibiotic pretreatment of children with bacterial meningitis affects CSF profiles, specifically resulting in increases in CSF glucose levels and decreases in CSF protein levels, which become apparent within several hours of pretreatment.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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