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PEDIATRICS Vol. 108 No. 5 November 2001, pp. 1169-1174
,
,
From the Divisions of * Emergency Medicine and Objective. Despite the lack of
evidence defining a time interval during which cerebrospinal fluid
(CSF) culture yield will not be affected by previous antibiotic
therapy, recent publications cite a "minimum window" of 2 to 3 hours for recovery of bacterial pathogens after parenteral antibiotic
administration. We conducted a retrospective review of children with
bacterial meningitis to describe the rate at which parenteral
antibiotic pretreatment sterilizes CSF cultures.
Methods. The medical records of pediatric patients who
were discharged from a tertiary children's hospital during a 5-year
period with the final diagnosis of bacterial meningitis or suspected
bacterial meningitis were reviewed. The decay in yield of CSF cultures
over time was evaluated in patients with lumbar punctures (LP) delayed until after initiation of parenteral antibiotics and in patients with
serial LPs before and after initiation of parenteral antibiotics.
Results. The pathogens that infected the 128 study
patients were Streptococcus pneumoniae (49),
Neisseria meningitidis (37), group B
Streptococcus (21), Haemophilus
influenzae (8), other organisms (11), and undetermined (3).
Thirty-nine patients (30%) had first LPs after initiation of
parenteral antibiotics, and 55 (43%) had serial LPs before and after
initiation of parenteral antibiotics. After Conclusions. The temptation to initiate antimicrobial
therapy may override the principle of obtaining adequate pretreatment
culture material. The present study demonstrates that CSF sterilization
may occur more rapidly after initiation of parenteral antibiotics than
previously suggested, with complete sterilization of meningococcus
within 2 hours and the beginning of sterilization of pneumococcus by 4 hours into therapy. Lack of adequate culture material may result in
inability to tailor therapy to antimicrobial susceptibility or in
unnecessarily prolonged treatment if the clinical presentation and
laboratory data cannot exclude the possibility of bacterial meningitis.
Infectious
Diseases, Children's Hospital and Health Center; and the § School of
Medicine and Department of Pediatrics, University of California San
Diego, San Diego, California.
ABSTRACT
Top
Abstract
Methods
Results
Discussion
References
50 mg/kg of a
third-generation cephalosporin, 3 of 9 LPs in meningococcal meningitis
were sterile within 1 hour, occurring as early as 15 minutes, and all
were sterile by 2 hours. With pneumococcal disease, the first negative
CSF culture occurred at 4.3 hours, with 5 of 7 cultures negative from 4 to 10 hours after initiation of parenteral antibiotics. Reduced
susceptibility to 
-lactam antibiotics occurred in 11 of 46 pneumococcal isolates. Group B streptococcal cultures were positive
through the first 8 hours after parenteral antibiotics. Blood cultures
were positive in 74% of cases without pretreatment and in 57% to 68%
of cases with negative CSF cultures.
By conservative estimate, culture-confirmed bacterial
meningitis affects 5755 people in the United States each year, nearly half of whom are 18 years of age or younger.1 Even with current antibiotic therapy, the mortality rate is 4% to 15%,
depending on the infecting organism, with hearing loss in 2% to 28%
and mental retardation in 2% to 17%.2
Ideally, the clinical suspicion of bacterial meningitis is supported by
cerebrospinal fluid (CSF) indices consistent with bacterial infection
and confirmed by the recovery of a bacterial pathogen. However, a
clinical practice of initiating antimicrobial therapy before lumbar
puncture (LP) may confound the culture result. Supporting this practice
is the widely held belief that parenteral antibiotic therapy may be
instituted early in suspected bacterial meningitis without compromising
the yield of subsequent CSF cultures. At least 1 text and 1 review
article published after the introduction of the Haemophilus
influenzae type b conjugate vaccine suggest a "minimum" window
of 2 to 3 hours.3,4 However, no published data identify
the duration of a time interval within which previous parenteral
antibiotics will not affect CSF culture results. Our clinical
observation suggested that pretreatment with parenteral antibiotics may
impede the recovery of CSF pathogens more rapidly than suggested in the
literature. Because of the absence of data to define this
interval, we conducted a retrospective review of children with
bacterial meningitis to determine the yield of CSF cultures obtained
shortly after the initiation of parenteral antibiotic therapy.
The Institutional Review Board of Children's Hospital San Diego
gave administrative approval for this study. The medical records of all
patients who were discharged from Children's Hospital between January
1, 1992, and December 31, 1996, with the final diagnosis of bacterial
meningitis or suspected bacterial meningitis were identified by a
computerized search for the International Classification of
Diseases, Ninth Revision codes for bacterial meningitis and meningococcal meningitis. Patients were included when they met any 1 of
the following criteria: CSF culture positive for a known bacterial
pathogen; positive CSF antigen study or Gram stain in conjunction with
a CSF leukocyte concentration (WBC) of >10/mm3
(10 × 106/L); blood culture positive with
CSF WBC of >100/mm3 (100 × 106/L); or, in the absence of bacterial isolate,
CSF WBC of >4000/mm3 (4000 × 106/L). The last criterion was chosen because a
CSF WBC of >4000/mm3 (4000 × 106/L) as a single criterion should exclude 93%
to 98% of enteroviral disease.5
Exclusion criteria were positive CSF viral study in the absence of a
known bacterial meningopathogen, neural tube defect, CSF shunt or
catheter, penetrating cranial injury, neurosurgical procedure other
than LP within the previous month, or a medical record that was
unavailable or incomplete.
Each record was abstracted by a single investigator (P.S.) for
demographic and historical data, microbiologic studies, referral pattern, chronologic data, and sequence of interventions. The majority
of the records were reviewed by 1 of the 2 senior investigators, and
all data sheets and accuracy of data entry were reviewed by a second
investigator (J.T.K.). Times of parenteral antibiotic administration
and of CSF collection were obtained from referring office and facility
notes, emergency department (ED) and transport nursing and physician
notes, laboratory reports, inpatient medication administration records,
physician admission orders, and inpatient progress notes. The time
interval of interest was from the initiation of parenteral antibiotic
therapy until the collection of the first pretreated CSF sample or the
first follow-up CSF sample in the case of serial LPs. The time of
medication administration was defined by the start of infusion of the
first dose of any parenteral antibiotic. When multiple chronologic
entries existed concerning a single event, preference was given to the
chart entry created by the individual who most closely witnessed it.
Additional data included previous office or emergency visits, previous
oral antibiotic treatment, results of blood cultures and antigen tests,
and antibiotic susceptibilities of pneumococcal isolates.
Nonsusceptibility was defined as a minimum inhibitory concentration
(MIC) for penicillin of Patients were assigned to the following groups: delayed LP (LPd) group
when the first LP occurred after initiation of parenteral antibiotics,
previous LP (LPp) when the only LP preceded parenteral antibiotics, and
LP pre- and postantibiotic (LPp/p) group when LPs occurred before and
after initiation of parenteral antibiotics. The primary outcome was the
yield of pretreated CSF cultures in the LPd and LPp/p groups by
organism and time from antibiotic administration. Descriptive
statistics were performed using Microsoft Excel (Redmond,
WA), version 2000.
Of 165 cases, 37 were excluded because of ventriculoperitoneal
shunts (14), postoperative infection (2), open neural tube defect with
multiple pathogens (1), and incomplete or unavailable charts (7); 13 received antibiotic therapy for bacterial meningitis but did not meet
the study definition, based on laboratory criteria (12) and presence of
epidural abscess (1). The remaining 128 patients met study criteria by
positive CSF culture (104); CSF pleocytosis with positive CSF Gram
stain, alone (5) or in conjunction with positive antigen test (2); CSF
pleocytosis with positive blood culture, alone (4) or in conjunction
with a positive CSF Gram stain (4), antigen test (3), or both (2); and
by CSF indices alone (4). All patients who were included because of
positive antigen test, Gram stain, or blood culture had CSF WBC of
>200/mm3 (200 × 106/L). In no case was a CSF antigen test the
sole determinant of inclusion or of pathogen identification. Of the 4 patients who met entry criteria by CSF indices alone, 1 orally
pretreated patient had CSF WBC of 9950/mm3
(9950 × 106/L), normal glucose and protein
determinations, and negative Gram stain and culture. Another,
pretreated with cephalexin for 5 days, had CSF WBC of
4825/mm3 (4825 × 106/L), markedly elevated protein concentration,
and group A streptococcal superinfection of varicella. One of the
remaining 2 patients was parenterally pretreated, but both had CSF WBC
of >8000/mm3 (8000 × 106/L), abnormal glucose or protein
concentrations, and no positive microbiologic studies.
The patients ranged in age from 1 day to 16 years (median: 8 months).
Slightly more than half (68 of 128) were girls. Fifty-five patients
(43%) presented directly to the Children's Hospital ED, and the rest
were transferred from other facilities or admitted directly from
physicians' offices. Twenty-nine (41%) of 71 patients who were
transferred from other facilities had received parenteral antibiotics
before LP, compared with 10 (18%) patients who were admitted from the
Children's Hospital ED (intergroup difference [ Final organisms were determined in 125 cases (98%) on the basis of CSF
cultures, blood cultures, and antigen studies of CSF (Table
1), with Streptococcus
pneumoniae (38%), Neisseria meningitidis (29%), and
group B Streptococcus (16%) identified most often. Median
patient ages varied by organism: S pneumoniae, 9 months
(interquartile range [IQR]: 5 months, 19 months); N
meningitidis, 31 months (IQR: 7 months, 58 months); and group B
Streptococcus, 21 days (IQR: 9 days, 31 days). Initial CSF
cultures were positive in 104 (81%). Because many patients were
transferred from other facilities, microbiologic data from sources
other than CSF were not available for all patients. However, results of
initial blood cultures were available for 100 patients, 66 of which
were positive, including 62 (74%) of 84 obtained before any
antibiotics, 2 of 7 obtained after oral pretreatment, and 2 of 9 obtained after parenteral pretreatment. Of the 24 patients with
negative initial LPs, blood culture results were available for 23, with
13 (57%) positive for the presumed pathogen. All 13 positive blood
cultures from the CSF culture-negative group occurred among the 19 with no known antibiotic treatment before blood sampling (68%). Among patients with positive initial CSF cultures, 53 of 77 known blood culture results were positive (69%), including 49 (75%) of 65 without
any pretreatment and 2 each among 7 parenterally and 5 orally
pretreated blood cultures. Despite the apparent differences in blood
culture yields between groups with positive and negative CSF cultures,
the 95% CIs for differences in proportions included 0.
TABLE 1
METHODS
Top
Abstract
Methods
Results
Discussion
References
0.1 µg/mL or a ceftriaxone/cefotaxime MIC
of 1.0 µg/mL.
RESULTS
Top
Abstract
Methods
Results
Discussion
References
]: 
23%; 95%
confidence interval [CI]: 38%, 8%). Reasons for delayed LPs,
determined for the latter group from the ED charts, included
antibiotics given just before LP (3 cases, all with LP within the first
35 minutes), delay for computed tomography (CT; 1 case), misdiagnosis
as retropharyngeal abscess (1), parenteral antibiotics administered by
primary care physician (2), and unsuccessful LP attempts in neonates
(3). Twenty-seven (21%) of the patients had been treated as
outpatients before hospital admission; of these, 20 (74%) had received
oral antibiotics. One additional child received antibiotics from her
family's own supply. A total of 123 (96%) patients survived to
discharge.
Infecting Pathogens and Microbiologic Studies Identifying Organisms
Figure 1 demonstrates the composition of
the study population by timing of LP and CSF yield. LPs were performed
on 39 patients (30%) after initiation of parenteral antibiotics (LPd group), on 34 patients (27%) before parenteral antibiotics (LPp group), and on 55 patients (43%) both before and after initiation of
parenteral antibiotics (LPp/p group). The combined LPp and LPp/p groups
had 82 positive CSF cultures (92%) obtained before parenteral
antibiotic therapy, and the LPd group had 22 positive CSF cultures
(56%; : 36%; 95% CI: 53%, 19%).
|
Antibiotic pretreatment in the LPd and LPp/p groups almost always included a third-generation cephalosporin (ceftriaxone, 72%; cefotaxime, 26%), with 98% of known doses at least 50 mg/kg or 1 g. Fifteen patients, all from the LPd group, underwent LPs within 1 hour of parenteral antibiotics with negative CSF cultures in 3 of 9 cases of meningococcal meningitis (Table 2). The earliest instances of sterilization of N meningitidis occurred within 15 and 20 minutes of initiation of infusion of ceftriaxone 175 mg/kg and 50 mg/kg, respectively. One CSF culture remained positive for N meningitidis after 75 mg/kg ceftriaxone intravenously, given in separate doses of 49 mg/kg and 26 mg/kg at 1.5 and 2.3 hours, respectively, before repeat LP. The remaining CSF cultures for N meningitidis were sterile (Fig 2). Culture-negative pneumococcal meningitis occurred as early as 4.3 hours after antibiotics. Five of the positive pretreated pneumococcal cultures occurred with organisms that were nonsusceptible to penicillin and/or ceftriaxone, including 1 obtained 48 hours after outpatient pretreatment with ceftriaxone and amoxicillin-clavulanic acid (MIC for penicillin 2.0 µg/mL and for ceftriaxone 1.0 µg/mL). Another isolate had penicillin and ceftriaxone MICs of 2.5 and 0.5 µg/mL, respectively, and was positive at 1 hour 5 minutes and 43 hours after initiation of parenteral antibiotics. Between 4 and 10 hours after initiation of antibiotics, 5 of 7 cases of pneumococcal meningitis had negative CSF cultures (Fig 2). Early CSF cultures for group B streptococci obtained within 8 hours of parenteral antibiotics were positive. Delayed LPs for group B streptococci obtained from 33.5 hours after antibiotics were sterile with a single exception at 60 hours (Fig 2). Within the LPp/p group, no follow-up cultures were positive when obtained >3 hours after beginning parenteral antibiotic therapy specifically directed against meningitis.
|
|
Twenty-one patients had received oral antibiotics for courses of 1 to
21 days (median: 1 day; IQR: 1 day, 2 days) before LP. When orally
pretreated, only 14 CSF cultures (67%) were positive, including 12 of
17 without parenteral pretreatment (LPp plus LPp/p, 71%) and 2 of 4 in
the LPd group (50%). Without oral or parenteral pretreatment, 70 of
the 72 patients (97%) in the combined LPp and LPp/p groups had
positive cultures. Patients with no oral or parenteral pretreatment had
significantly greater CSF culture yields than patients with any oral
pretreatment (: 31%; 95% CI: 10%, 51%) and orally pretreated
patients with no parenteral pretreatment (: 27%; 95% CI: 5%,
49%). However, the difference in culture yields decreased when
parenterally pretreated patients were included in the comparison (67%
vs 84%; : 17%; 95% CI: 4%, 39%). The 2 cases of CSF
culture-negative meningitis with no known oral or parenteral
pretreatment included Escherichia coli bacteremia with a
traumatic, small-volume initial LP, and a large pleocytosis on
subsequent LP; and presumed bacterial meningitis with no positive cultures and CSF WBC of 11 800/mm3 (11 800 × 106/L).
Of the 49 cases of pneumococcal meningitis, 3 pretreated patients
lacked any positive cultures. Isolates in the remaining 46 included 11 (24%) nonsusceptible to -lactam antibiotics with penicillin MICs of
0.1 µg/mL in 11 and ceftriaxone/cefotaxime MICs of 1.0 µg/mL in
4 (9% of isolates).
| |
DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
References
|
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In our study of antibiotic pretreatment in bacterial meningitis,
negative CSF cultures occurred in 44% of initial LPs performed after
parenteral antibiotics compared with only 8% of those performed before
parenteral antibiotics and only 3% of those with neither oral nor
parenteral pretreatment. Within 1 hour of parenteral antibiotics, 3 of
9 cases of meningococcal meningitis had sterile cultures. None remained
positive >2 hours after receiving 50 mg/kg of a third-generation
cephalosporin. After 4 hours from the initiation of antibiotics, CSF
cultures were usually negative for S pneumoniae, although
positive cultures persisted in the setting of decreased susceptibility
to -lactam antibiotics.
Although CSF culture is the standard for diagnosing bacterial meningitis, delay in LP may occur for several reasons. Hemodynamic instability and infection at the site of proposed puncture are recognized contraindications. Some clinicians may precede LP with CT for fear of precipitating cerebral herniation.6 However, one review of the literature found herniation unlikely in pediatric bacterial meningitis in the absence of neurologic abnormality or coma.7 One report described LP-related herniation despite normal CT findings (images not provided).8 However, the clinical signs may have represented an early opportunity to institute treatment for intracranial hypertension. Febrile pediatric patients also may be treated with parenteral antibiotics and transferred to tertiary facilities without previous LP either because of a lack of technical expertise or because of an assumption that the yield of CSF cultures obtained several hours later will not be compromised. Despite the lack of evidence, a widely used text published in 1998 refers to a "minimum window of 2 to 3 hours ... when CSF cultures are not adversely affected" and states that "in the pediatric population a single dose of antibiotic before transport is unlikely to prevent bacterial identification."3
The clinician may face additional pressures to administer parenteral antibiotics before definitive studies are performed. Although potential diagnostic delays are not conclusively associated with worsened outcome,9 reported time intervals from presentation to antibiotics averaging 2 to 3 hours for pediatric bacterial meningitis10-12 have prompted recommendations for changes in clinical management practices to shorten this interval.12,13 "Expert" opinion on the expected time to antibiotics is widely divergent.11 Therefore, physicians who are concerned about cerebral herniation or delays in therapy may elect to defer LP and may be falsely reassured that the bacterial pathogen and its antibiotic susceptibility can be determined at a later time. However, CSF culture recovered the pathogen in only 81% of our study patients and 92% even in the absence of parenteral antibiotic pretreatment. Furthermore, data that associate delayed sterilization with adverse outcomes also seem to implicate patient age, disease severity, and bacterial concentrations as causal factors.14,15
Previous antibiotic therapy is unlikely to alter the biochemical and cellular abnormalities of CSF sufficiently to prevent the recognition of bacterial meningitis,16,17 but oral antibiotic pretreatment will decrease CSF bacterial concentrations and yields of Gram stain and culture.17,18 Recovery of H influenzae is possible in 43% of CSF samples obtained 4 to 12 hours after 75 mg/kg ceftriaxone19 and in 2% to 3% performed 18 to 36 hours after initiation of ceftriaxone,20 cefotaxime,21 and meropenem.21 However, no data directly address shorter time intervals within which parenteral antibiotics will not impair CSF culture recovery.
CSF sterilization as a result of antibiotic pretreatment may result in
unwarranted or unnecessarily prolonged treatment if the clinical
presentation and other laboratory investigations cannot exclude the
possibility of bacterial meningitis. Of the 12 cases with
culture-negative pleocytosis that failed to meet our study criteria, at
least 7 were pretreated patients who received 7 days of parenteral
antibiotics for this reason, including 1 whose LP was completed within
5 minutes after antibiotics. Previous -lactam administration is
unlikely to prevent recognition of organisms with reduced
susceptibility. However, pretreatment with multiple antibiotics that
target resistant organisms may preclude the use of simpler and less
toxic regimens, if cultures subsequently fail to yield a bacterial
pathogen.
The increasing prevalence of nonsusceptible pneumococcal isolates in
invasive infections22 and meningitis23 is a
significant concern. During a 3-year period, reduced susceptibility to
penicillin increased by 50% and that to ceftriaxone increased 3-fold
(and by 9 times for meningitis).22,23 Our study revealed
nonsusceptibility to -lactam antibiotics in 22% of all cases of
pneumococcal meningitis. Antibiotic-resistant meningococci are not a
significant problem in the United States, with intermediate resistance
remaining stable at approximately 3% of isolates between
199124 and 1997.25 However, reports of
rapidly increasing penicillin resistance in Spain,26
penicillinase production,27,28 the acquisition of
-lactamase-encoding plasmids,28 and high-level
chloramphenicol resistance29 predict that knowledge of
antibiotic susceptibility will become increasingly important in guiding
therapy for meningococcal disease.
Coant et al30 reported positive blood cultures in up to 97% of patients with bacterial meningitis in the 2- to 24-month age range. However, these data pertain to a subset of patients with positive CSF cultures when H influenzae was the predominant pathogen. In our study, 74% of available blood cultures obtained before antibiotics were positive compared with only 57% when the CSF culture was negative. Similarly, Klugman et al21 found positive blood cultures associated with 58% of positive CSF cultures. Although CSF antigen tests may identify bacterial pathogens in 87% of cases of partially treated meningitis,31 the antibiotic sensitivity will remain unknown. Such tests did not contribute to the diagnosis in our patients, and their diagnostic utility has been questioned by others.32 Other diagnostic modalities, such as the polymerase chain reaction assay, may prove useful for the identification of bacterial species and antimicrobial resistance.33 However, the technique does not yet enjoy widespread acceptance, and its yield is adversely affected by previous antibiotic therapy.34
The limitations of this study include its dependence on the accuracy and completeness of the medical record for chronologic data and culture results. Even with complete chronologic data, it often is impossible to determine the rapidity of antibiotic infusion and whether the time documented represents the beginning or end of infusion. Such data also are subject to inaccuracy in the calibration of timepieces used in clinical settings35 and in the documentation of time intervals by clinical personnel.36 The strict study criteria may have excluded patients who had bacterial meningitis and minimal CSF changes37 and who would have received a full course of parenteral antibiotic treatment on the basis of clinical judgment. However, we opted to miss possible cases of true sterilization to avoid inclusion of cases of nonbacterial meningitis. Because the intentions of the treating physicians were unknown, pretreated patients may have differed in disease severity or presentation. Patients who present with clinically and biochemically more severe disease and greater CSF bacterial burdens may have delayed sterilization.14,38,39 Conversely, an atypical presentation with milder disease may be associated with more rapid sterilization. The study sample does not permit assessment of the role of reduced susceptibility in early CSF sterilization. The lack of uniformity in antibiotic choice, dosage, and route of administration poses some difficulty in interpretation, but it does reflect the range of therapies given as pretreatment in diverse clinical settings. A prospective study in humans would face the ethical barrier of delaying initial LPs in suspected bacterial meningitis or the practical difficulty of frequent CSF sampling after antibiotic administration. Consent would be problematic, and any sampling method or device could alter antimicrobial efficacy and the resultant microbiologic data.
Recent published opinion suggests that antibiotic administration before LP is unlikely to hinder the recovery of a bacterial meningopathogen.3 However, no previous publication directly supports this assumption. The present study demonstrates that CSF sterilization occurs more rapidly after initiation of parenteral antibiotics than previously suggested. We demonstrated that CSF cultures may be sterilized within 1 hour of parenteral antibiotic therapy for meningococcal meningitis and within 4 hours for pneumococcal meningitis. As the use of the pneumococcal conjugate vaccine increases, the proportion of children with meningococcal meningitis will increase, leading to substantial increases in the proportion of CSF cultures that are negative within 1 hour of antibiotic therapy. Therefore, if technically feasible, hemodynamically stable patients with suspected meningitis and no evidence of cerebral edema or herniation syndromes should undergo lumbar puncture before the administration of parenteral antibiotics.
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ACKNOWLEDGMENT |
|---|
We thank Ian McCaslin, MD, for review of the manuscript.
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FOOTNOTES |
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Reprints not available.
Received for publication Dec 12, 2000; accepted Jun 25, 2001.
This work was presented orally at the Annual Meeting of the Ambulatory Pediatric Association (Region IX and X); February 11, 2001; Carmel, CA, and in poster format at the Annual Meeting of the Pediatric Academic Societies, May 1, 2001; Baltimore, MD.
Address correspondence to John T. Kanegaye, MD, Division of Emergency Medicine, Children's Hospital San Diego, 3020 Children's Way (MC 5075), San Diego, CA 92123. E-mail: jkanegaye{at}chsd.org
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ABBREVIATIONS |
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CSF, cerebrospinal fluid; LP, lumbar puncture; CSF WBC, cerebrospinal fluid leukocyte concentration; ED, emergency department; MIC, minimum inhibitory concentration; LPd, delayed LP group; LPp, prior LP group; LPp/p, LP pre- and postantibiotic group; CI, confidence interval; IQR, interquartile range; CT, computed tomography.
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REFERENCES |
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Methods
Results
Discussion
References
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part II: current management and therapeutic research.
Ann Emerg Med
1993;
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