Gram-negative enteric bacillary meningitis: A twenty-one-year experience

Gram-negative enteric bacillary meningitis: A twenty-one-year experience M a n a s w a t Unhanand, MD, M a h r n o u d M. Mustafa, MD, G e o r g e H. M c C r a c k e n , Jr., MD, a n d John D. Nelson, MD From the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas We reviewed our experience with gram-negative enteric bacillary meningitis In neonates and Infants from 1969 through 1989. Ninety-elght patients were Identified. Their ages were from 1 day to 2 years with a median of 10 days. In 25 patients (26%), predisposing factors were identified, the most common of which were neural tube defects and urinary tract anomalies. The causative agents were Escherichia colt (53%), Klebslella-Enterobacter species (16%), C i t r o b a c t e r dlversus (9%), S a l m o n e l l a species (9%), Proteus mlrabllls (4%), Serratla marc e s c e n s (3%), Bacteroldes fragllls (3%), and A e r o m o n a s species (2%). At the time of diagnosis, Gram-stained smears of cerebrospinal fluid revealed gramnegative bacilli in 61% of patients. The causative organism was cultured from blood obtained from 55% of patients, and 21% had positive urine culture results. The cerebrosplnal fluid leukocyte counts ranged from 0 to 80,600 cells/ram 3, and the cerebrosplnal fluid/serum glucose concentration ratio was less than 0.5 In 72% of patients. Antimlcroblal regimens varied greatly. After initiation of antibiotic therapy, an a v e r a g e of 3 days was n e e d e d for eradication of bacteria from cerebrosplnal fluid. The case-fatality rate was 17%, and 61% of survivors had long-term sequelae that included seizure disorders, hydrocephalus, physical disability, developmental delay, and hearing loss. (J PEDIAIR1993;122:15-21)

Although gram-negative bacilli constitute a major cause of meningitis in newborn infants, the incidence of meningitis caused by these organisms beyond the newborn period is relatively small but apparently increasing. I-s In adults, such an occurrence has been associated with head trauma, neurosurgical procedures, impaired host defense, and gramnegative sepsis. In neonates and young infants, on the other hand, the overall scope of gram-negative enteric bacillary meningitis has not been well characterized. Accordingly, we reviewed our experience during the past 21 years. Our objectives were to determine the patients at risk, predisposing factors, clinical and laboratory findings, complications and therapeutic approaches, and the differences in these variables between neonates and older infants. Submitted for publication Jan. 13, 1992; accepted Aug. 19, 1992. Reprint requests: John D. Nelson, MD, 5323 Harry Hines Blvd., Dallas, TX 75235-9063. 9/20/41978

METHODS The records of neonates and infants admitted to Parkland Memorial Hospital or Children's Medical Center, Dallas, Texas, with the diagnosis of bacterial meningitis during the 21-year period from January 1969 through December 1989 were reviewed. Ninety-eight patients fulfilled the entry criteria for diagnosis by the presence of gram-negative enteric bacilli in cerebrospinal fluid culture or the presence of CSF GNEBM

Cerebrospinalfluid Gram-negative enteric bacillary meningitis

I

[

I

gram-negative enteric bacilli in blood culture with purulent spinal fluid, histologic findings consistent with meningitis, or both. Of 98 patients, 2 fulfilled only the latter criterion. Seven patients had recurrent episodes. Patients with meningitis caused by tlaemophilus influenzae, Pseudomonas aeruginosa, and other nonenteric gram-negative bacilli were excluded from the study. Records were examined for

0022-3476/93/$01.00+00.10

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Table

I. Characteristics of patients by age groups Neonates Characteristic

Age at onset (days)*

Term (n = 49)

Preterm (n = 23)

Age 4-3 m e (n = 48)

Age >3 me (n = 8)

8.8 • 6.5 (1-25) 3214 • 516 i.14:1

8.0_+ 5.8 (I-22) 1888 __-506 1:1.5 32:7:6

52.9 • 20.2 (29-86) -i.6:1 9:4:5

311.4 _+ 271.5 (111-765) -1.7:1 3:1:4

14(61) 5(22) 3(13) 1(4)

6(33) 3(17) I(6) 4(22)

4(50) 3(37.5) -1(12.5)

Birth weight (gm)* M/F ratio 11:8:4 White/black/other ratio Etiologic agent [No. (%)1 Escherichia coli 28(57) Klebsiella-Enterobacter species 5(10) 5(10) Citrobacter diversus Salmonella species 3(6) 3(6) Proteus mirabilis Serratia marcescens 2(4) Aeromonas species 2(4) !(2) Bacteroides fragilis *Values are expressedas mean -+ SD, with range in parentheses.

epidemiologic and demographic information, predisposing factors, clinical findings, laboratory data, antibiotic therapy, acute complications and long-term outcome. Thirtytwo neonates were enrolled in three prospective clinical trials of antibiotic therapy 9m performed at our institution. S t a t i s t i c a l methods. The two-tailed Fisher Exact Test was used. Differences that had a probability of more than 0.05 by the appropriate null hypothesis were considered not significant. Numeric results were expressed as the mean ___ SD. RESULTS Gram-negative enteric bacilli were the fifth most common cause of meningitis, accounting for 3.6% of the 2708 cases in neonates, infants, and children in whom bacterial meningitis had been diagnosed at our institution during the study period from 1969 through 1989 (unpublished data). The other organisms isolated from these patients were H. influenzae type b (59. ! %), Neisseria meningitidis (10.5%), Streptococcus pneumoniae (9.6%), and group B streptococcus (6.5%) in respective ranking. Gram-negative enteric bacilli were isolated from 80 (31%) of 257 neonates with meningitis during the same period. Organisms isolated from the remaining neonatal patients were group B fl-hemolytic streptococcus (53%), other gram-positive cocci (6%), and Listeria monocytogenes (7%). Demographic features. There were 98 patients with GNEBM; 72 patients (73%) were neonates less than 28 days of age at the onset of symptoms, and half of those were younger than 7 days of age. A total of 26 patients (27%) were more than 1 month of age, and 8 of these were older than 3 months. The youngest patient was 20 hours of age and the oldest was 26 months.

--

1(6)

--

--

1(6)

--

--

2(il)

--

Causative organisms. Escherichia coil (53%) was the most common etiologic agent in all age groups (Table I). Klebsiella-Enterobacter species (16%) was an. important but less frequently encountered pathogen. Citrobacter diversus (9%), Salmonella species (9%), and other gramnegative enteric bacilli were infrequently encountered. Bacteroidesfragilis (3%) caused meningitis after trauma or neurosurgical procedures. In postsurgical patients, the most frequent etiologic agents were E. coil (45%) and Klebsiella-Enterobacter species (27%). Predisposing f a c t o r s . Associated conditions that might have led to G N E B M were identified in 25 patients. Surgical problems, especially neural tube defects (6 patients) and urinary tract anomalies (4), were most common. The time interval between the surgical procedure and the onset of meningitis in 11 patients varied from I to 15 days (mean 5.5 days); in 7 patients the interval was less than 7 days. One patient with a ruptured meningomyelocele had thermal instability on the second postoperative day, but a lumbar puncture was not done until 4 days later, when the patient was in a moribund condition; meningitis probably developed before the time recorded. A patient with perianal abscess caused by Klebsiellapneumoniae had incision and drainage performed 14 days before development of meningitis. The drain was not removed until 4 days before development of meningitis caused by the same organism. The overall casefatality rate was 27% (3 of 11 patients) in the postsurgical group and 16% (14 of 87 patients) in nonsurgical patients (p = 0.04). C l i n i c a l features. Thermal instability was the most frequent clinical finding (Table II). Irritability, lethargy, poor feeding, and seizures were also common. Seizures occurred

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T a b l e II. Clinical features of patients with gram-negative enteric bacillary meningitis Neonates Feature

Term

Preterm

Thermal instability 41/44 (93)* Irritability 30/40 (75) Seizure 22/45 (49) Lethargy 18139 (46) Poor feeding or emesis or both 18/39 (46) Respiratory distress 13/39 (33) Jaundice 10/41 (24) Bulging fontanelle 6/33 (18) Nuchal rigidity 2/26 (8) Poor reflexest 6/26 (23) Nystagmus 4/45 (9) Apnea or cyanosis or both 10145 (22) *Denominator= number of patients examined.Numbers in parenthesesare percentages. tPrimitive reflexes(Moro, sucking,grasp reflexes).

17/23 6/23 15/23 12/23 14/23 3/23 10/23 2/12 0/10 6/12 1/23 10/23

A g e >4 mo

(74) (26) (65) (52) (61) (13) (43) (17) (0) (50) (4) (43)

23/26 (88) 17/25 (68) 1o/25 (40) 11/26 (42) 18/26 (69) 3/25 (12)

Term

Ptelerm

patients

6728 _+ 627 (0-40,000) 78 ___ 19 (20-100) 1.2 + 1.2 22.4 + 21.1 (0-65) 392.9 ___456.5 (42-1,900) 23/35(92) 22/36(61) 20/35(57) 3.4 (1-18)

7016 _ 10,521 (0-33,700) 80 + 18 (25-99) 1.2 _ 1.0 21.9 + 17.7 (2-68) 352.3 _+ 231.7 (I 43-976) 9/! I (82) 12/16(75) 10/14(71) 2.7 (!-6)

0/25 (0) (55)

12/22 4/16 2/22 1/25

(25) (9) (4) 4/25 (16)

T a b l e III. Analysis of cerebrospinal fluid at time of diagnosis Neonates Findings

WBCs/mm 3. PMNs (%)* Glucose (mmol/L)* (mg/dl) Protein (mg/dl)* CSF/blood glucose ratio <0.5t CSF protein ~200 mg/mlt Positive Gram staint Mean duration (days) of positive cultures:]:

All

7204 +_ 12,153 (0-80,600) 79 --- 20 (1-100) 1.3 _+ 1.2 23 __+21 (0-77) 335 +_ 347 (17-1,900) 44/53(83) 47/76(62) 40/66(61) 2.0 (I-18)

PMNs, Polymorphonuclearleukocytes;WBCs,white bloodcells. *Values expressedas mean +_SD, with range in parentheses. tNo. positive/No,tested,with percentagesin parentheses. ~:Rangein parentheses.

in 51% of patients and were noted before diagnosis in 49% of those patients. Respiratory distress, apnea, and jaundice were less frequently encountered. Stiff neck and bulging fontanelle were rarely present in neonates but were more common in older infants. The mean duration of symptoms before diagnosis was 1.7 days (range 1 to 11 days). Laboratory findings. Peripheral leukocyte counts obtained at the time of diagnosis varied widely; mean leukocyte counts were >10,000/mm 3 in all groups. Neutrophil and band-form counts varied from none to 79% and from none to 50%, respectively. Immature neutrophil/total neutrophil ratio greater than 0.20 was identified in 58% of patients. Absolute neutrophil counts < 1000/mm 3 were noted

in 10 (12%) of 86 patients, and platelet counts <100,000/ mm 3 were observed in 12 (21%) of 56 patients. The CSF leukocyte counts in 87 patients ranged from none to 80,600/mm 3, with a polymorphonuclear cell predominance (>__50%) in 89% of cases (Table III). The C S F glucose concentration ranged from none to 4.3 m m o l / L (none to 77 mg/dl), and the CSF protein concentration ranged from 17 to 1900 mg/dl. In 47 (62%) of 76 patients the CSF protein value was >200 mg/dl at diagnosis. A total of 74 (88%) of 84 patients had a CSF glucose concentration <2.8 mmol/L (<50 mg/dl), and 44 (72%) of 61 patients had CSF/blood glucose concentration ratios less than 0.5. Gram-stained smears of CSF revealed gram-negative

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Unhanand et aL

The Journal of Pediatrics January 1993

T a b l e IV. Clinical outcome by age groups Neonates Outcome

Term

Preterm

Age ;>I mo

Total

Death 7/49 (14) 5/23 (22) 5/26 (19) 17/98 (17) Survival* CNS sequelae 18132 (56) 6/11 (55) 10116 (62) 34159 (58) Normal at >6 mo follow-up 14/32 (44) 5/11 (45) 6/16 (38) 25159 (42) Recurrence of meningitist 3/32 (9) 0/11 (0) 4/16 (25) 7/59 (t2) Valuesare expressedas number positive/total,with percentagein parentheses. CNS, Central nervoussystem. *Twenty-twopatients not evaluated;somewere not followedup by examination,and some had an underlyingillnessthat could lead to neurologicsequelae. tRecurrence of meningitisevaluatedin only the patientswho livedin Dallas,Tex.

bacilli in 61% of those with a positive CSF culture result. The Gram stain was negative in all with a sterile CSF culture. There were six C S F specimens with culture-proven gram-negative enteric bacilli in which gram-positive or gram-negative cocci were reported on smear. Of 77 culturepositive C S F specimens, 5 (6%) had normal CSF leukocyte counts and normal CSF glucose and protein values (two term neonates, two preterm neonates, and a 9-month-old infant). Duration of positive results on CSF cultures after the start of antibiotic therapy ranged from 1 to 18 days (mean 2.9 days; median 2.0 days). Blood cultures were positive in 46 (55%) of 83 patients. Urine culture results were positive in 9 (21%) of 44 patients, 7 (78%) of whom also had positive blood culture results. It cannot be determined whether bacteremia or bacteriuria came first. In all cases the blood and urine isolates were the same as the organisms isolated from CSF. Therapy and outcome. The 98 patients were treated with 51 different antimicrobial regimens. Most of the patients were treated with multiple antibiotics. The most frequent initial treatment regimens were as follows: (1) ampicillin alone (14 patients) or in combination with an aminoglycoside (79); (2) cefotaxime or moxalactam alone (25) or in combination with an aminoglycoside (1 I) or with ampicillin (11); and (3) penicillin combined with an aminoglycoside (1 I). Duration of therapy was 7 to 43 days (mean 23 days; median 22 days) in surviving patients. The great diversity of antimicrobial agents, administered singly and in combination by various routes and with alterations of the initial antimicrobial regimen for clinical or laboratory reasons, made comparison of the different therapeutic regimens impossible. No definite conclusion can be made with regard to efficacy of antibiotic therapy. Twenty-eight patients received lumbar intrathecal or intraventricular therapy with various antibiotics, including aminoglycosides, ampicillin, polymyxin B, and colistimethate, in addition to parenteral therapy. Two patients received two drugs intrathecally, and one patient received

intrathecal gentamicin and intraventricular methicillin. The case-fatality and morbidity rates in these patients were 12% (3/26) and 52% (12/23), respectively. There were no significant differences in clinical outcome for these patients compared with patients who received parenteral antibiotic therapy alone. Acute complications included ventriculitis in 20% of neonates and in 14% of older infants. The diagnosis of ventriculitis was made by positive CSF findings from a ventrieular tap, and by cranial computed tomography in recent years. Subdural effusion occurred in 13% and 14% of neonates and infants, respectively. Brain abscess occurred in eight patients; C. diversus was the most common etiologic agent (four patients). The causative organisms in the other four patients were E. coli, Enterobacter-Klebsiella species, Salmonella species, and B.fragilis. The syndrome of excess antidiuretic hormone secretion was diagnosed in 13% of patients. Twelve (17%) of 72 neonates and 5 (19%) of 26 infants died (Table IV). Among the survivors, 34 (58%) of 59 patients had permanent neurologic sequelae and 25 (42%) were physically normal, with no hydrocephalus or history of seizures, for 6 months after the episode of meningitis. Twenty-two patients who were not followed in our institution or had underlying problems that could influence neurologie outcome, such as intraventricular hemorrhage grade 3, CNS anomalies, or anoxic brain damage, were not included in long-term clinical evaluations. DeveloPmental and behavioral assessment and auditory evaluation were not uniformly performed, but 26 of the patients were enrolled in prospective clinical trials9-11 at our institution and their evaluations were complete. Neurologic sequelae. Hydrocephalus developed in 16 (27%) of 59 patients (Table V); a seizure disorder developed in 21 (36%) of 56 patients, and long-term anticonvulsant therapy was required. Of 59 patients, 18 (31%) acquired permanent spastic paralysis and 13 (22%) had severe mental and neurologic damage requiring constant care; 37% of the patients had development delay, Of whom 59% had se-

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Table V. Neurologic sequelae by age groups Neonates Term (n = 32)

Age >4 mo (n = 46)

Pteterm (n = 11)

Total (n = 59)

Sequelae

No.

%

No.

%

No.

%

No.

%

Hydrocephalus Seizure disorder Cerebral palsy Developmental delay Hearing loss

9 9 6 8 5

28 28 !9 25 16

4 4 5 6 2

36 36 45 55 18

3 8 7 8 3

19 50 44 50 19

!6 21 18 22 10

27 36 31 37 17

Table VI. Relationship between etiologic agents and clinical outcome Etiologic agents

Acute complication

Sequelae"

Case-fatality rate

Recurrence rate

Escherichia coli 19/53 (36) 13/30 (43) 10/53 (19) 3/30 (10) Klebsiella-Enterobacter species 6/17 (35) 6/9 (67) 2/17 (12) I/9 (11) Otrobacter diversus 7/9J" (78) 4/5 (80) 0/9 (0) 0/9 (0) Salmonella species 6/11 (55) 5/7 (71) 1/I1 (9) 3/7 (43) Proteus mirabilis 3/4 (75) 3/4 (75) 0/4 (0) 0/4 (0) Serratia marcescens 0/3 (0) 2/2 (100) I/3 (33) 0/3 (0) Aeromonasspecies I/2 (50) 0/2 (0) 2/2 (100) 0/2 (0) Bacteroidesfragilis 2/3 (67) 3/3 (I00) 0/3 (0) 0/3 (0) Values are expressedas number of patients ~-ithparticularclinicaloutcome/numberof patients examined.Numbers in parenthesesare percentages. *Only patientswho had follow-upexaminationsunderwent evaluationof outcome. tBrain abscessdevelopedin four of nine patients in this group.

vere mental retardation. In 17% of the patients a hearing deficit was documented. Factors associated significantly with sequelae included a platelet count <100,000/mm 3 ( p - - 0 . 0 3 ) , a C S F leukocyte count >2000/mm 3 (p = 0.003), a CSF/blood glucose concentration ratio <0.5 (/7 = 0.04), a CSF protein concentration >__200 mg/dl (p = 0.004), and a positive C S F culture for >__48 hours after the start of treatment (p = 0.001). The relationship between different etiologic agents and clinical outcome is shown in Table VI. Seven of nine patients with meningitis caused by C. diversus had acute complications, including four with brain abscess. Recurrent episodes of meningitis occurred in three of nine patients with Salmonella meningitis. Infection recurred after therapy in 3 (5.8%) of 52 patients with E. call meningitis and in I (6.3%) of 16 patients with Klebsiella-Enterobacter meningitis. Among the three patients with recurrent Salmonella meningitis, the first was treated with cefuroxime for 4 days, followed by ampicillin for I0 days. The organism was susceptible to both antibiotics, but the patient had a relapse 6 days after treatment was discontinued. The second patient was treated with ampicillin for 26 days, followed by chloramphenicol for 9 days and intrathecal administration of polymyxin B. The organism was also susceptible to all antibiotics used, but meningitis recurred 33 days later. The

third patient was treated with ampicillin and amikacin for 21 days; the antimicrobial susceptibility was unknown. The patient had recurrent Salmonella meningitis 40 days later. The two patients with E. call meningitis were initially treated for 21 days with ampicillin and gentamicin, to which the strains were susceptible in vitro; however, relapse occurred at 7 and 10 days, respectively, after completion of therapy. The other patient with E. coli meningitis received ampicillin and cefotaxime for 7 days, followed by cefotaximP alone for 14 days, and had a relapse 15 days later. The patient with Klebsiella meningitis was initially treated with gentamicin and chloramphenicol for 15 days (susceptibility unknown) and intrathecal administration gentamicin for 6 days. Meningitis recurred 8 days after the end of therapy. DISCUSSION Because patients with gram-negative bacillary meningitis are seen relatively rarely by individual physicians or in individual hospitals, we analyzed our entire experience to assess the clinical and laboratory findings in our patient population. This consisted of neonates who had disease before leaving the hospital, and older infants referred to our medical center to receive intensive care management because of complications. In the former group were many low birth weight, preterm infants who had predisposing factors

20

Unhanand et al.

for systemic bacterial infections, including surgical procedures. The interval between the surgical procedure and the initial bacterial isolation from the CSF was shorter than previously reported, It'14 especially in adult patients. This difference is presumably a result of two factors. First, the underlying neurosurgical conditions of pediatric patients in this study involved anatomic skin-dura or dura-arachnoid disruption that allowed bacterial access to the central nervous system before or during surgery. Second, the meningeal barrier in neonates may offer less protection to offending bacteria than that in older children or adults. 15"17 Nevertheless, most previous studies t2"14 have reported a lower case-fatality rate in postoperative cases than in spontaneous meningitis. We found that the case-fatality rate in postsurgical meningitis was only slightly higher than in those with nonsurgical disease. The second most common predisposing factor to GNEBM was urinary tract anomalies. These findings suggest that urine culture of specimens from neonates and infants with suspected meningitis may be useful in detecting the primary site of the gram-negative infection and urinary tract anomalies in some patients. Clinical features were similar in neonates and older infants except that meningeal signs such as nuchal rigidity and bulging fontanelle were less commonly present in neonates.IS, 19 The mean duration of clinical symptoms before diagnosis was 1.7 days. One factor that made the diagnosis of GNEBM less delayed than described previously9, II, 13,20 was the early onset of seizures, which in almost half the cases were present before or at the time of diagnosis. Hematologic findings were also similar in all age groups; leukocytosis and increased immature forms predominated. Leukopenia, neutropenia, and thrombocytopenia were occasionally present. Neutropenia and thrombocytopenia correlated significantly with increased mortality rates. Thrombocytopenia also correlated significantly with morbidity, but patients with abnormal immature neutrophil/ total neutrophil ratios did not have significantly greater mortality and morbidity rates. Initial CSF examinations in all age groups were abnormal, with high leukocyte counts and polymorphonuclear cells, decreased glucose concentrations, and increased protein concentrations. However, 6% of the initial CSF specimens with positive culture results had normal leukocyte counts and normal glucose and protein concentrations. High CSF leukocyte counts and protein concentrations and low glucose concentrations were all associated with higher morbidity rates but not higher case-fatality rates. Consistent with a previous study21 from this institution, early sterilization of CSF from infants with GNEBM is associated with an improved prognosis. The mean duration of positive CSF culture results in surviving patients was 3 days. Of 42 patients with persistent gram-negative organisms for

The Journal of Pediatrics January 1993

more than 48 hours despite effective antibiotic therapy, 25 had a significantly higher incidence of permanent neurologic sequelae than did patients with early sterilization of CSF. Several studies5, 12,22, 23 have reported the association of higher mortality rates with bacteremia, but this was not the case in our study. Despite advances in antimicrobial therapy and effective intensive care, the mortality and morbidity rates for GNEBM remain substantial. Recent studies24,25 have increased our understanding of the pathophysiology of bacterial meningitis. Further studies in newborn infants are needed to assess the value of dexamethasone therapy and other interventions that might improve the outcome of patients with GNEBM. We thank Helen T. Kusmiesz, who reviewed the name records of patients with a diagnosis of meningitis.We also thank Marva L. Brown for the preparation of all charts from Children's Medical Center at Dallas. REFERENCES 1. Finland M, Barnes MW. Acute bacterial meningitisat Boston City Hospital during 12 selected years, 1935-1972. J Infect Dis 1977;136:400-15. 2. Cherubin CE, Marr JS, Sierra MF, Becker S. Listeria and gram-negative bacillary meningitis in New York City, 19721979. Am J Med 1981;71:199-209. 3. Crane LR, Lerner AM. Nontraumatic gram-negative bacillary meningitis in the Detroit Medical Center, 1964-1974. Medicine (Baltimore) 1978;57:197-209. 4. Gorse GJ, Thrupp LD, Nudleman KL, Wyle FA, Hawkins B, Cesario TC. Bacterial meningitis in the elderly. Arch Intern Med 1984;144:1603-7. 5. Mangi RJ, Quintiliani, Andriole VT. Gram-negative bacillary meningitis. Am J Med 1975;59:829-36. 6. Fraser DW, Henke CE, Felman RA. Changing patterns of bacterial meningitis in Olmsted County, Minnesota, 19351970. J Infect Dis 1973;128:300-7. 7. Kaiser AB, McGee ZA. Aminoglycosidetherapy of gramnegative bacillary meningitis. N Engl J Med 1975;293:121520. 8. McCracken GH Jr, Mize SG. A controlled study of intrathecal antibiotic therapy in gram-negative enteric meningitis of infancy. J PEO~AXR1976;89:66-72. 9. McCracken GH Jr, Mize SG, Threlkeld N. Intraventricular gentamicin therapy in gram-negative bacillary meningitis in infancy. Lancet 1980;1:787-91. 10. McCracken GH Jr, Sarff LD, Glode MP, et al. Relation between Escherichia coil K1 capsular polysaccharide antigen and clinical outcome in neonatal meningitis. Lancet 1974;2: 246-50. 11. Ehrlichman RJ. Clinical conferences at the Johns Hopkins Hospital: gram-negative bacillary meningitis. Johns Hopkins Medical Journal 1978;143:60-3. 12. Berk SL, McCabe WR. Meningitis caused by gram-negative bacilli. Ann Intern Med 1980;93:253-60. 13. Mancebo J, Domingo P, Blanch L, Coil P, Net A, Nolla J. Postneurosurgical and spontaneous gram-negative bacillary meningitis in adults. Seand J Infect Dis 1986;18:533-8. 14. Gower DJ, Barrows AA Ill, Kelly DL Jr, Pegram S Jr. Gram-

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negative bacillary meningitis in adults: review of 39 cases. South Med J 1986;79:1499-502. Manesis JG, Stanosheck J. Escherichia coil meningitis in adults. Arch Neurol 1965;13:214-6. Otila E. Studies on the cerebrospinal fluid in the premature infants. Acta Paediatr Scand 1948;35(suppl8):3-9. Groover RV, Sutherland JM, Landing BH. Purulent meningitis in newborn infants. N Engl.J Meal 1961;264:1115-21. Berman PH, Banker BQ. Neonatal meningitis: a clinical and pathological study of 29 cases. Pediatrics 1966;38:6-24. Overall JC Jr. Neonatal bacterial meningitis. J PI~DIATR ! 970;76:499-51I. McCracken GH Jr, Threlkeld N, Mize S, et al. Moxalactam therapy for neonatal meningitis clue to gram-negative enteric bacilli. JAMA 1984;252:1427-32. McCracken GH Jr. The rate of bacteriologic response to an-

22.

23.

24.

25.

21

timicrobial therapy in neonatal meningitis. Am J Dis Child 1972;123:547-53. Thompson AJ, Williams EB Jr, Williams ED, Anderson JM. Klebsiellapneurnoniae meningitis.Arch Intern Med 1952;89: 405-20. Hodges GR, Perkins RL. Acute bacterial meningitis: an analysis of factors influencing prognosis. Am J Med Sci 1975; 270:427-40. Saez-Llorens X, Ramilo O, Mustafa MM, Mertsola J, McCracken GH Jr. Molecular pathophysiologyof bacterial meningitis: current concepts and therapeutic implications. J PEDIA'rR 1990;I 16:671-83. Tunkel AR, WispelweyB, Scheld WM. Bacterial meningitis: recent advances in pathology and treatment. Ann Intern Med 1990;! 12:610-23.

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