REVIEWS OF INFECTIOUS DISEASES • VOL. 10, NO.2. MARCH-APRIL 1988© 1988 by The University of Chicago. All rights reserved. 0886-0162/88/1002-0009$02.00

Role of Empiric Parenteral Antibiotics Prior to Lumbar Puncturein Suspected Bacterial Meningitis: State of the Art

David A. Talan, Jerome R. Hoffman,Thomas T. Yoshikawa, and Gary D. Overturf

From the Department of Medicine, Division of EmergencyMedicine, Olive View and UCLA Medical Centers, UCLASchool of Medicine; the Geriatric Research, Education and

Clinical Center (GRECC), Veterans Administration; and theDepartment of Pediatrics, UCLA School of Medicine,

Los Angeles, California

The performance of lumbar puncture (LP) in patients with suspected meningitis is oftendelayed if, for example, the clinical presentation suggests a need for prior computed tomo­graphic (CT) scan or if patients are initially examined at settings with limited clinicalfacilities. The role of empiric parenteral antibiotic therapy prior to LP under these cir­cumstances has not been critically analyzed. Review of the literature suggests that in casesof bacterial meningitis (1) the existing data are inadequate to assess the effect of a shortdelay of therapy on mortality and morbidity; (2) a short period of antibiotic therapy priorto LP does not change cerebrospinal fluid (CSF) white blood cell count, protein, or glu­cose; (3) the yield of CSF gram stain and culture may be somewhat reduced by a shortperiod of antibiotic therapy, but these tests often remain positive; and (4) adjunctive tests,including blood cultures and CSF antigen tests, can often independently identify the bac­terial meningopathogen. The available evidence suggests that if bacterial meningitis issuspected and LP must be delayed, intravenous antibiotics are warranted before CSF isobtained.

Bacterial meningitis is a life-threatening but poten­tially treatable disease. Therefore, it is of critical im­portance to establish rapidly the etiologic diagnosisand institute effective antibiotic therapy. In uncom­plicated cases, this can be accomplished in a rela­tively short time by performing a lumbar puncture(LP) and analyzing the CSF for cell count and bac­teria by gram stain. However, circumstances oftenarise in which an LP cannot be performed immedi­ately. LP has been associated with serious compli­cations and death in patients with elevated intra­cranial pressure [1-5]. Thus, in patients with signsassociated with increased intracranial pressure, suchas papilledema or focal neurologic deficits, it maybe necessary to defer an LP until a computed tomo­graphic (CT) scan can be obtained. A recent seriessuggested that the "frequent" practice of obtaininga CT scan prior to LP contributed to a significantdelay in the treatment of bacterial meningitis [6]. Pa-

Received for publication 5 March 1987 and in revised form6 August 1987.

The authors acknowledge the expert manuscript preparationof Ms. Lois McArthur.

Please address requests for reprints to Dr. David A. Talan,Department of Emergency Medicine, Olive View Medical Cen­ter, 14445 Olive View Drive, Sylmar, California 91342.

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tients are commonly seen first in an outpatient set­ting in which there may be inadequate facilities foracute care or inadequate technical or laboratorycapabilities to permit an LP to be done. The timeinvolved in transferring a patient to an appropriatefacility delays the definitive evaluation by LP. In sit­uations such as these, the clinician must decidewhether to treat immediately with empiric parenteralantibiotics or wait to initiate treatment until CSF canbe obtained for analysis and culture.

Because bacterial meningitis is rapidly progressiveand potentially fatal, it has been proposed that, ifthe diagnosis is suspected and the LP will be delayed,intravenous antibiotic therapy should be institutedimmediately without obtaining CSF for microbio­logic studies. McGee and Kaiser [7] state that "thefirst consideration in a patient with the acute pre­sentation of meningitis is therapy, not specific diag­nosis." However, a basic caveat of traditional infec­tious disease practice is that adequate cultures shouldbe obtained prior to the initiation of antibiotic treat­ment so that the etiologic pathogen(s) can be isolatedand appropriate treatment begun. Should the spe­cific bacterial etiology be obscured by prior antibi­otic therapy, causing sterilization of CSF cultures,the patient may be committed unnecessarily to acourse of expensive and potentially toxic therapy. In

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addition to the risk and cost of unnecessary treat­ment of nonbacterial meningitis, there is the chancethat therapy may not be efficacious because of thepresence of organisms such as penicillin- or chlor­amphenicol-resistant pneumococci [8] or ampicillin­or chloramphenicol-resistant Haemophilus influen­zae [9, 10].

Therefore, in cases in which there must be a delayin obtaining eSF, the decision to initiate treatmentprior to an LP in order to maximize therapeutic ef­ficacy comes at the possible expense of a decreaseddiagnostic accuracy. The benefits - or potential detri­ment - of such an approach have not been criticallyanalyzed. To better understand this problem we ad­dressed three questions: Does a delay in administer­ing antibiotics affect mortality and/or morbidity?Does administration of antibiotics prior to an LPobscure the diagnosis of bacterial meningitis? Arethere other methods of diagnosing bacterial menin­gitis if the eSF is made sterile by antibiotics?

Effect of Delay in Administration of Antibioticson Mortality and/or Morbidity

Bacterial meningitis is a potentially rapidly fatal dis­ease for which the only form of effective treatmentis specific antimicrobial therapy. Thus, it seems rea­sonable to assume that a delay of even a few hours

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in the administration of antibiotics could have anadverse effect on prognosis. Nevertheless, to answerthis question definitively, a clinical study would berequired in which patients with suspected bacterialmeningitis were randomized to receive antibiotics ei­ther immediately or only after some defined periodof delay. For obvious ethical reasons such a studycannot be done. Therefore, there are no existingstudies that directly examine the effect of any delayof antibiotics on the prognosis of bacterial menin­gitis. Only indirect information relevant to this ques­tion is available. Several studies have compared themortality and morbidity of patients with bacterialmeningitis who present to the hospital after a vari­able duration of symptoms [11-27]. It is importantto note that these studies examine the effect on prog­nosis of a potential delay of therapy of 1-2 days,whereas circumstances that preclude immediateevaluation of suspected meningitis by LP at mostrequire several hours.

Table 1summarizes studies in which mortality wasevaluated in patients with various etiologies of bac­terial meningitis in relation to the duration of symp­toms prior to presentation to the hospital. Moststudies did not demonstrate a statistically significantrelation between mortality and duration of symp­toms [11-16]. In the study by Olsson et al. [17] of43 patients with pneumococcal meningitis, there was

Table 1. Bacterial meningitis: duration of illness vs. mortality.

Mortality (070)

Years of study No. of Duration of illness[reference] patients Organism Overall (days) p*

<2 >2

1949-1973 [11] 349 All 26 24 25 NS1950-1960 [17] 43 PN 65 57 80 NS1952-1964 [12] 53 PN 37 28 31 NS1966-1976 [13] 875 All 11 9 11 NS1966-1976 [14] 164 PN 19 16 18 NS

<1 >1

1950-1960 [18] 107 All 40 47 23 <.051953-1971 [19] 468 HI 8 11 5 <.051971-1976 [20] 207 PN 45 71 50 <.05

Unspecified

1948-1973 [16] 79 PN 11 NS1949-1959 [15] 133 PN 17 NS

NOTE. All = Hemophilus injluenzae, Streptococcus pneumoniae, Neisseria meningitidis, and other bacteria; PN = S. pneu-moniae; HI = H. influenzae.

* P value determined by y} test. NS = not significant (i.e., P >.05).

Antibiotics/Lumbar Puncture in Meningitis

a mortality of 57010 in patients who presented with<2 days of symptoms compared with 80010 in patientswith >2 days of symptoms. However, this associa­tion did not reach statistical significance (X2

, P> .05).This study was remarkable for an unusually highoverall mortality. However, this may have been be­cause of the inclusion of an older population withexclusively pneumococcal meningitis, since both ad­vanced age and a pneumococcal etiology are as­sociated with a poorer prognosis [11]. Also, 72% ofthe patients had a major coexisting illness. Theauthors concluded that "delay in seeking treatmentappears to be primarily responsible for the highermortality in this group of patients."

In contrast to the report by Olsson et al. [17] thestudies by Carpenter and Petersdorf [18], Davis etal. [19], and Baird et al. [20] yielded opposing results;that is, patients with a shorter duration of symptomssuffered a significantly greater mortality. Carpenterand Petersdorf [18] studied 107 children and adultswith various etiologies of meningitis, includingStreptococcus pneumoniae, Neisseria meningitidis,and H. inJluenzae. Seventeen (47%) of 36 patientswho were admitted within the first 24 hours of theirillness subsequently died. On the other hand, patientswho were hospitalized 1-7 days after the onset ofsymptoms had a mortality of only 23% (16 of 71cases, P < .05). The authors speculated that thisdifference in mortality was secondary to the phenom­enon of patients with more severe infections seek­ing earlier hospitalization.

Davis et al. [19] studied 468 children with H in­Jluenzae meningitis. Death occurred in 24 (11%) of220 children whose duration of symptoms prior toadmission was <1 day. This mortality was at leasttwice (5%, 12 of 248) the death rate in children whoseduration of symptoms prior to admission was >1 day(P < .05). In this study, prior treatment with antibi­otics also was associated with a significantly lowermortality. These investigators suggest that theremight be at least two clinical forms of H. inJluenzaemeningitis. One form is "hyperacute" and charac­terized by a short-course, fulminant illness with arapid progression of clinical signs and symptoms.This syndrome is similar to that of severe menin­gococcal meningitis. The other form of H. influen­zae meningitis is a milder illness, with a more gradualonset of symptoms, that is less likely to be recog­nized as meningitis by a physician on the first visitand has a lower mortality. The possibility that priorantibiotic therapy ameliorated the severity of the ill-

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ness and subsequently delayed presentation to thehospital was not mentioned.

Thus, a direct correlation or association betweenduration of symptoms and mortality for bacterialmeningitis has not been demonstrated consistently.To a great extent this is due to the inherent limita­tions involved in analyzing an outcome - namelymortality - that may be affected by multiple addi­tional variables such as patient age, associated un­derlying illnesses, etiology and virulence of the in­fecting organism, and prior antibiotic therapy. Inorder to be interpreted, these variables must be iden­tified and studied for their independent importanceby multifactorial analysis. The duration of illnessmay also be difficult to ascertain. In retrospectivestudies such as these, it is often difficult to deter­mine accurately the duration of symptoms by review­ing hospital records. Also, it is impossible to deter­mine when symptoms of meningitis - as opposed tothe prodromal infection - begin.

Several other retrospective studies with similarlimitations have attempted to evaluate the effect ofthe duration of symptoms prior to treatment on mor­bidity rather than mortality. Bohr et al. [13] studiedthe association between the duration of symptomsbefore treatment - specifically, hemiplegia, gaitataxia, intellectual dysfunction, epileptic fits, seri­ous hearing deficits, and vestibular dysfunction­and subsequent morbidity in 875 patients with bac­terial meningitis. There was a positive correlation be­tween the duration of symptoms before treatmentand the rate of sequelae at discharge. These investi­gators also studied late neurologic sequelae in 164patients with pneumococcal meningitis [14]. Patientswho had symptoms for >48 hours prior to admis­sion had a greater incidence of severe sequelae thandid patients who had symptoms for <48 hours. Her­son et al. [21] found that of 73 children with H in­fluenzae meningitis, those with symptoms of >3days' quration were more likely to have died or hadsevere morbidity (defined as blindness, hydrocepha­lus, institutionalization, microcephaly, quadraplegia,severe retardation, or uncontrolled seizures).

Several investigators have studied retrospectivelythe relation between the development of sensorineu­ral hearing loss and the duration of symptoms priorto treatment. Nadol [22] studied the developmentof sensorineural hearing loss in 210 patients with var­ious bacterial etiologies of meningitis who were fol­lowed only during the acute and recuperative phasesof the illness. While the average duration of symp-

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toms was 32 hours in survivors without hearing loss,it was 47 hours in those with hearing loss (either par­tial or complete) (P < .05). Richner et al. [23] re­called children for audiometric testing who hadsuffered H. influenzae meningitis several years ear­lier. He found that while only 2070 of patients whoseH. influenzae meningitis had been treated within 48hours had evidence of sensorineural hearing loss,86% of those who had had symptoms for >48 hourshad demonstrable hearing loss (P < .05).

In contrast to the above data, Dodge et al. [24]reported a prospective evaluation of sensorineuralhearing loss in 185 children with bacterial meningi­tis and found that only 10.3% had persistent bilateralor unilateral hearing loss. This was not correlatedwith the duration of illness. Kaplan et al. [25] re­cently evaluated these data and those of anotherprospective series with regard to neurologic sequelaeand the prior administration of oral antibiotics inchildren with meningitis caused by H. influenzae.Children who were pretreated were more likely tohave paresis and sensorineural hearing loss at follow­up; the duration of illness prior to admission wassignificantly longer for pretreated than for untreatedchildren. While the investigators found no signifi­cant association between duration of illness prior toadmission and deafness (data evaluated by multiplelogistic regression analysis), children who were ill for>1 day prior to admission had a greater relative riskof developing severe sensorineural hearing loss thandid children ill for ~1 day.

Although a delay in definitive antibiotic therapywould seem logically to contribute to a poor out-

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come, the existing literature has not resolved this is­sue. Nevertheless, it is a reasonable concern that evena short delay of antibiotic therapy may be deleteri­ous, particularly for the subpopulation with hyper­acute bacterial meningitis. It is clear that mortalityand morbidity are not consistently predicted by theduration of symptoms prior to presentation, and itmay be difficult clinically to identify a high riskpopulation. However, if there were no risk of ob­scuring the diagnosis and preventing identificationof the bacterial etiology of meningitis, the immedi­ate institution of antibiotics, prior to (delayed) LP,would appear to optimize a desirable therapeuticoutcome.

Effect of Administration of Antibiotics Prior toLumbar Puncture on the Diagnosisof Bacterial Meningitis

The traditional methods of diagnosing bacterialmeningitis include an analysis of CSF cell count, pro­tein, glucose, gram stain, and culture. To what ex­tent are the results of these tests affected by intrave­nous administration of antibiotics several hoursbefore an LP is performed? While no publishedstudy directly addresses this question, the answer canbe extrapolated from data from two sources: clini­cal investigations that have compared the results oftraditional CSF tests in meningitis patients who ei­ther did or did not receive antibiotics in prior out­patient treatment, and studies in which CSF has beenanalyzed serially during the administration of ther­apeutic antibiotics.

Table 2. Effect of prior outpatient antibiotic treatment on cerebrospinal gram-stain smears and cultures.

Reference

Positive smear Positi're culture

Organism Treated (010) Untreated (%) Treated (%) Untreated (%)

HI 84 92HI 82 90 94 98All 41 69§ 50 n§All 35 53§ 59 88§All 68 73 62 63All 68 84§ 68 95§All 37 54§

NOTE. HI = Hemophilus injluenzae; All = H. injluenzae, Streptococcus pneumoniae, Neisseria meningitidis, and other bacteria.* Includes only cases with positive CSF cultures.t Includes only cases with positive blood or CSF cultures, positive CIE or LA, or positive gram stain.t Includes only cases "typical" of bacterial meningitis (Le., increased CSF white blood cell count, increased protein, decreased glucose).§ P <.05.II Includes all cases of meningitis with CSF white blood cell count>10/mm3

•

Antibiotics/Lumbar Puncture in Meningitis

The term partially treated meningitis has been ap­plied to those patients with bacterial meningitis whohave received some form of antibiotic therapy (usu­ally oral) prior to a diagnostic LP; several investiga­tors have studied the effect of partial treatment onCSF parameters in such patients [19, 25, 28-32].Studies of this nature are somewhat difficult to evalu­ate because of differing criteria used to define bac­terial meningitis. Because CSF culture is the goldstandard for the diagnosis of bacterial meningitis,any attempt to study the effect of prior antibioticson the yield of CSF cultures must also evaluate thosepatients who have negative CSF cultures. Thus, someinvestigations included patients with negative CSFculture but in whom CSF protein, glucose, whiteblood cell count, and differential are "typical" or"consistent" with bacterial meningitis; others haveincluded all patients with >10 white blood cells/mm3

in the CSF. This is problematic because a variablenumber of cases of nonbacterial meningitis will beincluded depending upon the stringency of defi­nition.

With an appreciation of the confounding method­ologic problems in these studies, it is still possible todraw some conclusions. Table 2 summarizes studiesthat have analyzed the effect of prior outpatient an­tibiotic therapy on CSF gram-stained smears and cul­tures. The studies by Harter [28], Dalton and Alli­son [29], Winkelstein [30], and Jarvis and Saxena[31] defined meningitis by a positive culture (CSFor blood) or smear or negative cultures and smearbut "typical" CSF parameters consistent with bac­terial meningitis. Criteria for typical CSF parametersvaried but in general included an elevated whiteblood cell count with a predominance of polymor­phonuclear cells, elevated CSF protein, and de­creased CSF glucose. Converse et al. [32] definedmeningitis by a CSF white blood cell count of >10cell/mm3

• Davis et al. [19] included only cases ofbac­terial meningitis with positive CSF cultures, whileKaplan et al. [25] included only cases with positiveblood or CSF cultures, positive counterimmuno­electrophoresis (CIE) or latex agglutination (LA),or positive gram stain.

In general, partial (oral antibiotic) treatment re­sulted in a decrease in the number of positive CSFcultures of 40"/0-330"/0, and a decrease in CSF gramstains of 70"/0-410"/0. It is important to note that anti­biotic treatment can also alter the accuracy of thegram-stain results; dead or injured gram-positive or­ganisms may appear to be gram-negative [33]. These

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studies did not consistently reveal that the identifi­cation of a specific bacterial agent of meningitis wasmore difficult than that of any other specific bacte­ria following antibiotic therapy. In the patients withpositive CSF cultures, the CSF cell counts, protein,and glucose were similar in patients with or withoutpartial treatment. Because of the methodologic prob­lems described above, it is difficult to draw conclu­sions regarding the effect of prior treatment on CSFparameters in culture-negative patients.

From these data it can be assumed that if prioradministration of oral antibiotics decreases the yieldof CSF gram stains and culture, then the adminis­tration of intravenous antibiotics prior to LP wouldhave a similar effect. Experimental studies using rab­bit meningitis models suggest that CSF cultureswould remain positive following treatment with ~­

lactam antibiotics for 8-12 hours [34].Several studies in humans have also reported the

continued positivity of CSF cultures in some patientsrelatively early after the initiation of antibiotic ther­apy [35-48]. Wilson and Haltalin [35] studied 62 chil­dren with H. inJluenzae meningitis who had repeatLP performed 26 hours (mean) after initiation ofintravenous ampicillin therapy. Fourteen (23%) of62 children continued to have positive CSF culturesthat could not be attributed to antibiotic resistance.Ten of these 14 positive isolates could only be grownon Levinthal medium and not on standard chocolateagar medium. These children had a poorer clinicaloutcome with a higher frequency of neurologic se­quelae. Feldman [36] studied 27 children with cul­ture-positive bacterial meningitis caused by H. in­f/uenzae (19 cases, one of which was a relapse), groupB streptococci (five cases), S. pneumoniae (threecases), and N. meningitidis (one case). Patients hadinitial LP followed by a repeat LP 24 hours after ini­tiation of intravenous ampicillin or penicillin, aloneor in combination with chloramphenicol. Persistentpositive CSF cultures (using standard microbiologicmethods) were present in four (180"/0) of22 patients.Three isolates were H. inf/uenzae and one was groupB streptococci. The author examined CSF bacteriaconcentration and found that patients with persis­tent positive cultures had high initial bacterial con­centrations. These patients also had organisms withhigh ("resistant") MICs to ampicillin and penicillinbut not to chloramphenicol when a correspondinglylarge inoculum was used for in vitro susceptibilitytesting. Despite this, antibiotic therapy was eventu­ally effective. Overturf et al. [37] reported that, de-

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spite good antibiotic susceptibility and a favorableclinical outcome, nine (38070) of 24 patients withH. influenzae meningitis treated with carbenicillinand one (6%) of 17 patients treated with ampicillinhad positive CSF cultures on standard culture mediaafter 12-24 hours of therapy. After 2-3 days ofther­apy, however, all CSF cultures were sterile. Barsonet al. [38] reported on 50 children with bacterialmeningitis due to H. influenzae (42 cases), S. pneu­moniae (four cases), N. meningitidis (three cases),and Streptococcus agalactiae (l case), who had LPrepeated 10.5-18 hours after starting treatment. Eight(33070) of 24 children treated with ceftriaxone andeight (40%) of 20 children treated with ampicillinand chloramphenicol had persistently positive cul­tures. In all except one case the persistent pathogenwas H. influenzae. Repeat CSF cultures were morelikely to be positive in cases with initial CSF bac­terial colony counts of ~107 cfu/mL. In a series inwhich LP was repeated earliest, specimens were ob­tained 4-12 hours after the initiation of therapy [39].Del Rio et al. studied 78 cases of bacterial meningi­tis caused by H. influenzae (54 cases), S. pneumo­niae (nine cases), and N. meningitidis (nine cases).Nine (43 %) of 21 patients treated with ceftriaxoneand 11 (58%) of 19 patients treated with ampicillinor chloramphenicol had persistent positive CSF cul­tures at 4-12 hours. In all patients except one, thepersistent pathogen was H. influenzae. There wasno significant difference between CSF bacterial con­centration or susceptibility in those CSF specimensin which cultures remained positive and those inwhich they did not; clinical outcome was similar, de­spite the presence or absence of positive cultures.

These studies demonstrate that intravenous anti­biotics will significantly decrease the frequency ofpositive cultures after initiation of therapy. However,even after 24 hours, as many as 38% may have posi­tive cultures. As antibiotic killing of bacteria pro­ceeds at a rate of (\)1.0 log/hour [34] one would pre­dict that if LP were performed after only 1-2 hoursof intravenous antibiotics, it would be possible toobtain positive CSF cultures in the majority of pa­tients. A study to address this question directly wouldbe feasible if, in patients with presumed bacterialmeningitis, CSF were sampled for culture at serialhours after parenteral antibiotics are initiated.

Because CSF white blood cell count, protein, andglucose will not be affected to a significant degree,administration of antibiotics prior to LP will notusually obscure the physician's initial impression of

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bacterial meningitis. Nevertheless, since the yield ofCSF culture and gram stain may be reduced, if thesetests are relied upon alone, it might be impossibleto make a definitive diagnosis of bacterial meningi­tis and identify the specific bacterial pathogen.

Alternative Diagnostic Methods If CSFIs Made Sterile by Antibiotics

At present three tests other than CSF culture andgram stain are available to establish the specific bac­terial etiology in cases of meningitis. These are bloodcultures, CSF counterimmunoelectrophoresis (CIE),and CSF latex agglutination (LA) and coagglutina­tion (CoLA). Blood cultures can be obtained easilyprior to the initiation of antibiotic therapy, evenwhen LP must be delayed. In (\)50% of cases of bac­terial meningitis, blood cultures are positive for theetiologic agent (see table 3) [11, 12, 15, 17, 19, 31,49, 50]. The yield of positive cultures depends to agreat extent on the specific bacterial pathogen andits tendency to disseminate via the blood stream.Some cases of bacterial meningitis may occur as aresult of local extension and thus are associated withnegative blood cultures. Swartz and Dodge [49] re­ported positive blood cultures in 79% of cases ofH. influenzae meningitis, 56% of cases of S. pneu­moniae meningitis, 33% of cases of N. meningitidismeningitis, 29070 of cases of f3-hemolytic streptococ­cal meningitis, and only 17% of cases of Staphylo­coccus aureus meningitis. On the other hand, Fin­land and Barnes [50] noted positive blood culturesin 63070- 86070 of cases of bacterial meningitis causedby these organisms. Thus, in patients with clinicaland other laboratory findings suggestive of menin-

Table 3. Frequency of positive blood cultures in casesof bacterial meningitis.

Ref- Organ- No. of cases with positive blood cultures/erence ism no. of cases with bacterial meningitis (010)

11 All 72/242 (30)12 PN 22/40 (55)15 All 60/133 (45)17 PN 23/43 (53)19 HI 152/349 (44)31 All 52/105 (50)49 All 79/153 (52)50 All 289/371 (78)

NOTE. All = Hemophilus injluenzae, Streptococcus pneu­moniae, Neisseria meningitidis, and other bacteria; PNS. pneumoniae; HI = H. injluenzae.

Antibiotics/Lumbar Puncture in Meningitis

gitis to whom antibiotics are administered afterblood samples are obtained for culture but beforean LP is performed, the presence of bacteremia willestablish a presumptive diagnosis of bacterial menin­gitis.

CIE, LA, and CoLA are laboratory tests that canidentify CSF antigens of the commonest bacterialmeningopathogens - i.e., H. influenzae, S. pneumo­niae, and N. meningitidis. Currently, prepared an­tisera against these organisms have an acceptable sen­sitivity and specificity. In various studies CIE iscapable of detecting antigen in 50070-90070 of patientswith meningococcal meningitis, 50%-100% of pa­tients with pneumococcal meningitis, and 77070-90070of patients with H. influenzae type b meningitis,[51-61]. Nonspecific reactions are rare. Gram stainis similarly sensitive but may be difficult to inter­pret after antibiotic therapy is initiated. Recent re­ports suggest that LA and CoLA are much moresensitive than CIE with similar specificity [51, 54,62-64]. CIE, LA, and CoLA can be particularly use­ful in patients with meningitis in whom antibioticshave been administered (either orally or parenterally)before a diagnostic LP is performed. Bacterial anti­gens may persist in the CSF for several days afterantibiotic therapy. Bortolussi et al. [51] reported that,on repeat lumbar puncture, all patients with initiallypositive LA had a persistently positive test from 1to 6 days after the initiation of intravenous antibi­otic therapy for various etiologies of bacterial menin­gitis. This has been confirmed by other authors [54,64]. Thus, the yield from CIE, LA, and CoLA wouldbe essentially unaffected if antibiotics were admin­istered several hours prior to obtaining spinal fluid.

CIE, LA, and CoLA have limitations that mustbe considered. While a positive test using these tech­niques is very helpful, a negative test does not neces­sarily exclude the diagnosis of bacterial meningitis.Currently there is no consistently reliable antiserumto detect the polysaccharide of N. meningitidis sero­group B, a serogroup that is responsible for (\)50%of meningococcal meningitis in the United States.Pneumococcal serotypes 7 and 14 are also not reli­ably detected. Because S. pneumoniae and N. menin­gitidis account for the vast majority of adult bac­terial meningitis, CIE, LA, and CoLA are much lessreliable in adults than in children in whom H. influ­enzae is the commonest pathogen. CIE, LA, andCoLA assays are not useful in diagnosing gram-neg­ative bacillary, staphylococcal, and listerial menin­gitis. These organisms are more commonly isolated

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from immunocompromised hosts with meningitis,those patients with meningitis associated with endo­carditis, or those patients developing meningitis fol­lowing surgery; therefore, in such patients, CIE, LA,and CoLA should not be relied upon to establisha diagnosis. Most importantly, although CIE, LA,and CoLA may identify the bacterial pathogen, theydo not provide direct information about the antibi­otic susceptibility of the organism.

Other tests that may be helpful but that are lessavailable include the enzyme-linked immunosorbentassay (ELISA) for capsular antigen and the limuluslysate assay for endotoxin. ELISA has compared wellto CIE and LA for the detection of H. influenzaetype b and pneumococcal antigen [65, 66]. The limu­Ius lysate assay detects endotoxin from gram-negativebacillary organisms (e.g., Escherichia coli, Klebsiellapneumoniae, and Pseudomonas aeruginosa) as wellas H. influenzae and N. meningitidis [67,68]. Mostreports indicate that the test is rapid and reliable.However, in one study by McCracken and Sarff [69],the limulus test failed to diagnose culture-positivegram-negative bacterial meningitis in 31OJ(} of thecases in neonates.

Discussion

The performance of LP in patients with suspectedmeningitis may be delayed when clinical situationsdictate a need for prior CT scan. The risks of LPand the indications for CT scanning prior to LP havebeen debated. There have been several reports ofacute neurologic deterioration immediately follow­ing LP in patients with increased intracranial pres­sure or intracranial mass lesions. Duffy [1] followedfor one year 30 patients with raised intracranial pres­sure who had neurologic deterioration during or fol­lowing LP. These patients were subsequently foundto have intracranial mass lesions or infarction. Thir­teen of these patients had loss of consciousness dur­ing or immediately after LP; the neurologic statusof the others deteriorated to various degrees over thenext 12 hours. The same author noted neurologicdeterioration following LP in seven of 55 patientswith subarachnoid hemorrhage [2]. All six patientswho were subsequently investigated had evidence ofherniation confirmed by necropsy or CT scan.Garfield, who described one of the largest series ofbrain abscess cases, demonstrated that in 140 patientsin whom LP was performed, 41 had "significant de­terioration in the level of consciousness" during the

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48 hours following the procedure [3]. Careyet al.[4] reported eight of 62 patients with brain abscesswho died within 36 hours following LP.

Other studies, .however, suggest that even in thepresence of papilledema the risk of herniation afterLP is small. Korein et al. [5] reported possible com­plications following LP in seven of 59 patients withraised intracranial pressure without papilledema andin one of 70 patients with papilledema (85 % ofwhom also had increased intracranial pressure).These data and a review of 348 additional cases fromthe literature revealed possible complications in only1.2% of patients with papilledema on whom LP wasperformed. Thus, it is clear that rapid and severe neu­rologic deterioration has been associated with theperformance of LP; because of the close temporalrelation, these reports strongly suggest that LP wasthe cause of the deterioration. The frequency withwhich these complications occur in various settings,however, cannot be easily assessed.

Because of reports such as these, it has beenrecommended that LP not be performed in the pres­ence of signs of increased intracranial pressure orintracranial mass lesions. With the advent of CTscanning, these contraindications for LP have be­come indications for CT scan prior to LP. The ex­act role of CT scan prior to LP is particularly ger­mane with regard to the evaluation of patients withsuspected meningitis because the findings of fever,headache, and stiff neck are features also commonto the diagnoses of intracranial abscess (includingsubdural empyema) and subarachnoid hemorrhage.However, which clinical signs should preclude LPis not completely clear.

In the series reported by Duffy [1] of the 30 pa­tients whose neurologic status deteriorated after LP,five were subsequently diagnosed with cerebral ab­scess that was treated initially as meningitis. Thesefive deteriorated after repeat LP. While all of theother 25 patients had either papilledema or otherevidence of an intracranial space-occupying lesion,in only one of the five with suspected meningitis andactual brain abscess were focal neurologic signsreported; none of the five apparently had papill­edema. In Duffy's series of patients with subarach­noid hemorrhage, five of the seven who worsenedafter LP were initially grade 2- defined as moderate­to-severe headache, nuchal rigidity, and no neuro­logic deficit other than cranial nerve palsies [2].There was no mention of the presence or absenceof papilledema in these patients. These observations

Talan et al.

led Duffy to suggest that LP not be performed whenthere is a history of progressive headaches associatedwith changes in mental status and the presence offocal neurologic signs or papilledema. He expressedcaution about the use of LP when a syndrome sug­gestive of cerebral abscess was present - such as anear, nose, or sinus infection - followed by signs ofmeningitis. He also suggested that CT scan be theinitial investigation prior to LP in all cases of sus­pected subarachnoid hemorrhage.

Garfield [3] noted that convulsions, hemisphericsigns, or papilledema were present in 68% of his se­ries of 200 patients with brain abscess, comparedwith 30% of his series of 50 patients with nontuber­culous bacterial meningitis. Based on this findinghe stated that, in the presence of these signs, LP iscontraindicated. A current neurology textbook byAdams and Victor [70] states that "in patients withsuspected (raised) intracranial pressure, LP shouldbe preceded by CT scan whenever possible." McGeeand Kaiser [7] state that LP is contraindicated in thepresence of papilledema or focal findings (exceptophthalmoplegia) until a CT scan has excluded thepossibility of a mass lesion.

Although general guidelines can be given, the ex­act indications for CT scan prior to LP in a givenpatient suspected of meningitis are not clear. More­over, the available data indicate that overt clinicalsigns are not always manifest when intracranial hy­pertension or mass lesions exist. Focal neurologicfindings have been noted in 15%-30% of patientswith proven bacterial meningitis [71], although thepercentage of patients with suspected meningitis whohave these findings may be less. Because of these un­certainties, the ready availability of CT scans, andthe present medicolegal climate, the CT scan is of­ten employed and, perhaps, overutilized prior to LPin the evaluation of patients with suspected menin­gitis. It is our opinion that the CT scanning is par­ticularly overutilized in the pediatric population, inwhich the likelihood of brain abscess and subarach­noid hemorrhage is very small relative to the fre­quency of meningitis. Further studies are needed todetermine the value or detriment of CT scan per­formed prior to LP in cases of suspected meningitis.

Another situation that may result in delay of LPis the initial evaluation of a patient at a setting whereLP cannot be performed. Even at our urban centers,patients are frequently referred to us with suspectedmeningitis in whom LP has not been performed. Pa­tients are seen at offices, clinics, and urgent care

Antibiotics/Lumbar Puncture in Meningids

centers that may not have the LP t~quipmentavail­able, may not have the time or the laboratory facili­ties to initiate a septic workup, or may not have thecapability to manage an acutely ill patient. Further­more, the urgency for rapid transport of the patientto an acute-care facility may preclude further diag­nostic evaluation, Le., LP. It is our opinion that inseverely ill patients, obtaining CSF is of low prioritycompared with initiating treatment and ensuring thatpatients are expeditiously moved to an acute-carehospital.

In situations such as these in which LP is delayedand bacterial meningitis is suspected, the clinicianmust decide whether or not to treat immediately withempiric parenteral antibiotics. While no study cur­rently exists that directly addresse~, the potential ad­vantages or disadvantages of giving immediate an­tibiotic therapy prior to LP, and while the indirectdata regarding this issue are inconclusive, it wouldbe reasonable to assume that a delay of therapy maybe deleterious. Moreover, direct and indirect evidencecurrently available suggests that immediate antibi­otic therapy shortly before LP is unlikely to seriouslyhamper the clinician's ability to diagnose the spe­cific etiology of bacterial meningitis. By combiningthe results of preantibiotic blood cultures, subse­quent CSF cultures, and CSF, CIE, LA, or CoLA,it should be possible to make an etiologic diagnosisin the large majority of patients with bacterial menin­gitis, despite a short period of prior antibiotictherapy.

With regard to epidemiologic considerations, it isimportant to note that rv75f1Jo of all cases of bac­terial meningitis occur in children less than 10 yearsof age, and approximately two-thirds of these casesare due to H. injluenzae. Compared to other menin­gopathogens, H. injluenzae appt~ars to be easier togrow from early postantibiotic CSF cultures, is morefrequently cultured from blood, and is identifiedwith greater sensitivity by CSF, CIE, LA, and CoLA.Thus, particularly in the pediatric population - inwhich most cases of suspected bacterial meningitisoccur - it is extremely unlikely that a single dose ofparenteral antibiotic would prevent the identifica­tion of the offending bacteria. In other populations,such as neonates, adults, and imrnunocompromisedpatients, the sensitivity of blood cultures and im­munologic tests for meningopathogens that com­monly infect these groups is less secure; thus, thereis a greater justification for obtaining CSF either be-

373

fore antibiotics are given or at least within 1-2 hoursof initiating therapy.

The necessity to establish a specific etiologic bac­terial diagnosis is diminished because of the im­proved broad-spectrum coverage of new antibiotics,such as the third-generation cephalosporins. Yet, bac­terial identification and antibiotic-sensitivity test­ing remain desirable because of the emergence ofantibiotic resistance among common meningopatho­gens - such as ampicillin- or chloramphenicol-resis­tant H. influenzae and penicillin- or chlorampheni­col-resistant pneumococci [8-10] - and the increasingnumber of immunocompromised and postsurgicalpatients who develop meningitis with unusual bac­teria such as Listeria monocytogenes and gram-neg­ative organisms. In cases in which LP is delayed, thebacterial pathogen and its antibiotic susceptibilitycan usually be established, even after antibiotics areadministered, by blood cultures and subsequent CSFcultures. In cases in which cultures are sterile, CIEor LA may identify the bacterial pathogen, but theantibiotic sensitivity of the organism will not beknown. In this situation, treatment can be basedupon the known epidemiology of bacterial menin­gitis. Only rarely will both cultures and immunologictests not reveal the causative bacteria and mandatecontinued empiric broad-spectrum antibiotic cover­age. Appropriate empiric antimicrobial regimens andappropriate dosages have been recommended pre­viously [71]. Initiation of a combined regimen ofchloramphenicol and ampicillin in children less than5 years of age and a regimen of ampicillin or peni­cillin G alone in older children and adults is sufficientfor disease suspected to be caused by community­acquired meningopathogens. Alternatively, a singleinitial dose of a number of third-generation cepha­losporins (cefotaxime, ceftizoxime, ceftazidime, orceftriaxone) could be utilized for these patients. Ini­tial empiric therapy must be sufficiently broadenedto include coverage for community-acquired menin­gopathogens, staphylococci, L. monocytogenes, andgram-negative organisms (including Pseudomonasaeruginosa) in immunosuppressed hosts or in pa­tients recovering from neurosurgical procedures (e.g.,a regimen of vancomycin and a third-generationcephalosporin).

Conclusion

Should empiric parenteral antibiotics be adminis-

374

tered prior to LP, the risk of obscuring the diagnosisof bacterial meningitis is small, as is the risk thatthe patient would receive inadequate antibiotic treat­ment. Evidence found in this review supports therecommendation that, if bacterial meningitis is sus­pected and LP will be delayed, intravenous antibi­otics should be given immediately after blood sam­ples are drawn for culture. Further research needsto be done to determine the conditions that lead todelays in the evaluation of patients with suspectedbacterial meningitis, the role of CT scanning in theinitial evaluation of these patients, and the effectsof early therapy on the ability to identify bacterialmeningopathogens.

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