Initial t h e r a p y o f bacterial meningitis with cefuroxime· Experience in 167 children

Initial therapy of bacterial meningitis with cefuroxime: Experience in 167 children. Can J Infect Dis 1992;3(4):162·166. The morbidity and mortality of patients with bacterial meningitis treated initially with eefuroxime were studied and compared with the results of a previous prospective study of patients treated initially with ampicillin plus chloramphenicol in the same institution from 1979 to 1983. A ret rospective chart review was completed in all cases of microbiologically confirmed bacterial meningitis admitted to the Hospital for Sick Children in Toronto. Ontario between Januaty 1. 1984 and August I. 1988. During this period all patients were treated initially with intravenous eefuroxime. The 167 children reviewed ranged in age from six weeks to 17.1 years (median 11.6 months). The case fatality rate was 7.8% and the rate of hearing deficit 13%. There were no statistically significant differences in abnormal neurological outcome (20 versus 20%. respectively). hearing loss (12.9 versus 13%. respec tively). and case fatality rate (6.4 versus 7.8%. respectively) between U1e cohort of 1979-83 and the present study. The rate of hearing loss following meningitis caused by Haemophilus ir1fluenzae type b increased from 7.3 to II. 7% (P~0.26).

A CUTE BACTERIAL MENING ITIS HAS AN INCIDENCE OF 27 TO 100 per 100,000 per year in children younger than five years of age (1).The case fatality rate is 5 to 20%, depending on etiology and age (1 ,2).Between 25 and 50% of survivors suffer long term morbidity (3,4).More recent reports have shown less severe consequences of disease.Fourteen per cent of the survivors of bacterial meningitis and 18% of Haemophilus influenzae type b meningitis survivors suffered long term morbidity (5,6).Hearing loss , language disorders, impaired vision.developmental d elay, m ental retardation.motor deficits and seizures are the most frequent problems.Hearing impairment is reported in lOo/o of cases (range 5 to 30%) (5-7).Cefurox:ime therapy of meningitis due to H influenzae type b has been reported to be associated with both delayed sterilization of cerebrospinal fluid (CSF) and an increased frequency of hearing impairment (8,9).
At the Hospital for Sick Children in Toronto, Ontario during the period July 1. 1984 to March 1, 1989, cefuroxim e was used for initial therapy of all patients admitted with a diagnosis of bacterial meningitis.The medical records of all patients with bacterial meningitis were reviewed to determine whether there was any increase in morbidity or mortality in children treated initially with cefurox:ime, compared with a previous prospective study from 1979-83 from the same institution treated with a different antibiotic regimen (10).

PATIENTS AND METHODS
All patients with microbiologically confirmed bacterial meningitis admitted to the authors' hospital between January 1. 1984 and August 1, 1988 were included in the present study.Cases were identified by review of discharge diagnoses in the health record library and of bacterial cultures of the CSF in the bacteriology department.A patient was considered to have bacterial m e ningitis if CSF culture was positive for H irifluenzae type b.Streptococcus pneumoniae or Neisseria meningitidis.or if the antigens of one of the above pathogens were detected in the CSF by latex agglutination , or if the blood culture was positive and th e white blood cell count in CSF was greater than 1000/mm 3 .The information collected in this retrospective chart review included: age.race.sex, culture results , death and presence of sequelae at discharge and at follow-up .
During this period.all patients admitted with a diagnosis of bacterial m eningitis were treated initially with intravenous cefurox:ime (225 mg/ kg/ day).Thera py was changed to ampicillin or penicillin if susceptible bacteria were identified.If an ampicillin-resistant strain of H influenzae type b was isol ated .cefurox:ime was continued.Uncomplicated cases of meningitis received a seven day course of antibiotics (10).
All patients were sch eduled to have a follow-up visit one month post discharge.at which time an interval history and phys ical examination were performed.Hearing was eval uated by m eans of sound field or visual reinforcement audiometry, depending on the child's age.Hearing impairment was classified as fo llows: mild to moderate.no response at 26 to 55 dB: moderately severe to severe, no response at 56 to 90 dB: and profound, no response at 91 dB or greater.If a h earing p roblem was detected or if the test was inconclusive beca use of young age or lack of cooperation, the patient was followed every th r ee months in the otola ryngology clinic.Ne urodevelopmental an d psychological assessments were a lso scheduled for a ll patients.The n e urodevelopmental evaluation was done in the pediatric neurology clinic within 12 months of discharge.Neurological p a rameters were evaluated by clinical assessment.Investigatio ns such as electroencephalogra phy and co mpu ted tomography scans were only performed if clinically indicated.A psyc hometric evalu ation was performed after two years of age in infants a nd within th e six months after discharge in old er c hildren .The psychological tests appli ed were the Vineland -Griffith a nd the Bayley Scale Development for children younger than 2.5 years of age.and the S tanford-Bin et test for children between two and four years of age.For child r en older t h an five year s the Wide Range Achievement Test a nd the Wechsler Intelligence Scale were performed.A test was conside r ed a bnormal when the score was minus one standard d e viation from th e mean of 100 (standard d eviation 14 to 16) .
Results are expressed in means and proportions and, when appropriate, differences between grou ps were tested with the x 2 test.

RESULTS
One hundred and sixty-seven infants and children with bacterial meningitis were included in the study.Meningitis was caused by H influenzae type b in 111 patients (63 .3%).Strep pneumoniae in 31 (18%).and N me ningitidis in 25 (14.3%).One hundred and fifty-five patients were a dmitted directly from the clinic or emergency department: 12 were transferred after several days of treatment in other hospitals.Th e ages ranged from six weeks to 17.1 years, with a mean age of 28.3 months (median 11.6).In patients with H irifluenzae m eningitis, the median aO"e was 12 mont11s.and 70% were younger tha n 18 mont11s (Table 1).
The case fatality rate was 7 .8%(13 of 167) .The age of t11e patients who died was between 2.2 and 54.8 mont11s (median 17.8).The fatality rates of m eningitis due to H influenzae and Strep pne umoniae were 9.0 and 9.6%.respectively.No deat11 occurred in t11e 25 patients with meningococcal m eningitis .Of the 13 pa tients who died.nine were brain dead on a rrival at the a u thors• hospital and four were in s hock and died within 48 h .
Of the 12 patients transferred from other centres.four received more than 24 h of antibiotic treatment  Visual deficit (%)

3.5
Other deficits (%) 7.0 before admission.All fo u r cases had H in}Iuenzae meningitis.They were followed for more U1an one year.and only one case wiili a m il d learning disability was detected.These four patients have been excluded from U1e long term neurodevelopmental assessment (Table 2).
Of the 154 patients who survived.123 (80%) were followed for more than n in e months .One or more long term neurodevelopmental sequelae was documented in 25 patients (20.3%) (Table 2) .Twenty-one per cent of patients with H irifl.uenzae men ingitis followed for nine months or more had one or more neurodevelopmental sequelae.Morbidity rates in the patients with meningitis caused by N meningitidis and Strep pneumoniae were 20 and 17% .respectively (Table 2) .Hearing impairment was the most common sequela.occuning in 13% .Hearing loss was moderate to severe in 3 .2% .and bilateral profound in 5 .7% of the survivors.
Of the 27 patients who di d not complete n ine monU1s of follow-up.22 were nom1al at U1e time of discharge and were followed by their family physicians.Three h ad sequelae documented approximately six months after discharge: hypotonia, speech delay and unilateral mil d hearing deficit, respectively.Two patients had sequelae at the time of discharge: speech delay in one and hyperactivity in the other.Of the 27 patients who did not have long term follow-up, 10 had meningococcal In order to determine whether there was a ny in• crease in the mortal ity or morbidity of bacterial m enin• gitis in children who were treated initially wi U1 cefuroxime.findings were compared with those of a previous prospective study at U1e Hospital for Sick Children from 1979 to 1983 at a time when initial therapy consisted of ampicillin plus chloramphenicol (10).This study incl u ded 171 patients with acute bac• terial meningitis fo llowed for more than one year.H irifl.uenzae was isola ted in 124 cases .Strep pneumoniae in 30 and N meningitidis in 17.The mean age was 26.4 monilis (range four clays to 18 years): 74% of patients were younger U1a11 two years.
There was no difference in abnormal outcome during long term follow-up between the two time periods (Table 3).Hearing loss following H in}Iuenzae meningitis had a tendency to increase-11.7%(10 of 85) compared to 7.3% (nine of 124) observed in U1e ampicillin -chloramphenicol group-but U1e difference was not statistically significant (x 2 1.23.P=0.26).(Assuming a type 1 error [alpha] of 0.05 and U1e sample size for each group-the type 2 error [beta] is 50% .)

DISCUSSION
The Hospital for Sick Children has had an established post meningitis follow-up protocol since 1979.All patients in both cohorts were evaluated using the same criteria for hearing test and neurodevelopmental assessment.There was no change in the referral pattern from other hospitals during the late study period versus 1979-83.
The distribution of etiological agents and the age distribution of patients in both cohorts were similar to those described in the literature (9-14).'TWo-thirds of the present cases were caused by H injluenzae type b, and the median age was 11.6 months.As expected, the rate of H irifluenzae type b beta-lactamase positive isolates from sterile sites in the authors' centre was slightly different in the two groups: 22% (59 of 271) for the period 1979-83, and 29.5% (75 of 254) for the period 1984-88 (l 4.149, P=0.041) (personal communication).
There was no statistically significant difference in case fatality rate (6.4 versus 7.8%).incidence of hearing impairment (12.9 versus 12.5%), and occurrence of long term sequelae (20 versus 20%) between the previous study with ampicillin plus chloramphenicol as initial therapy  and the present study  from the same centre.All 167 patients received cefuroxime during the initial 48 to 72 h of therapy.There was an increase in the incidence of hearing impairment when cefuroxime was used as initial therapy, but the difference from the ampicillin plus chloramphenicol cohort was not statistically significant.Cefuroxime has been associated with delayed sterilization of CSF after 18 to 36 h of therapy, a higher rate of neurological deficit at the time of discharge , and hearing loss at six weeks of follow-up post discharge, when compared with a third generation cephalosporin (8,9).Delayed sterilization of CSF has been reported in patients treated with ampicillin, carbenicillin, ceftizoxime and ceftazidime, in addition to cefuroxime (15).A second lumbar puncture after 24 to 48 his not standard practice in the pr esent a uthors' institution.Of the 123 patients with complete follow-up none had a documented relapse of the illness.Risk factors associated 1vith delayed sterilization of CSF included isolation of H mjluenzae and age Jess than six months (8,15).In the later study population, H irifluenzae occurred in 66% of cases.and 24% of patients (27 of 111) were younger than six months of age.One patient in this age group developed a hearing deficit (3.7%).
Although the present study is not a controlled trial, the potential biases in a consecutive cohort study have been addressed.
CAN J INFECT DIS VOL 3 No 4 JULY/ AUGUST 1992 Cefuroxime for bacterial meningitis

TABLE 1
Characteristics of patients with bacterial meningitis treated at the Hospital for Sick Children (Toronto, Ontario) 1984-88

TABLE 2
Outcome of bacterial m e ningitis in 123 children initially treated with c efuroxime and followed for at least nine months These are: change in referral pattern; type of management and follow-up protocol; age; and etiological agent distribution; as well as the proportion of beta-lactamase positive isolates of H influenzae.A trend towards increased hearing impairment in patients with H irifluenzae type b meningitis treated CAN J INFECT DIS VOL 3 No 4 JULY/AUGUST 1992