ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1980, p. 526-529 Vol. 17, No.

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0066-4804/80/04-0526/04$02.00/0

Cefoxitin Penetration into Cerebrospinal Fluid in Patients

with Purulent Meningitis
PAULO A. AYROSA GALVAO,' ANDRE VILLELA LOMAR,' WALDEMAR FRANCISCO,' CID V.
FRANCO DE GODOY,' AND RAGNAR NORRBYIt*
Hospital Emilio Ribas and Department of Microbiology and Immunology, University of Sao Paolo, Sao
Paolo, Brazil,' and Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden2

The penetration of cefoxitin into cerebrospinal fluid (CSF) was studied in 25

patients with purulent meningitis treated with antibiotics other than cefoxitin.

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Each patient received three 2-g doses of cefoxitin at 6-h intervals. Blood and CSF
samples were obtained before and at 2, 4, or 6 h after the first and third doses.
CSF cefoxitin concentrations were found in all patients and varied between 1.2
and 22.0 ,tg/ml, with a majority of the concentrations falling within a range from
1.2 to 6.2 ,ug/ml. The concentrations tended to be higher in CSF samples drawn
after the third cefoxitin dose than in those drawn after the first cefoxitin dose,
indicating an accumulation of cefoxitin in CSF with repeated doses. Peak cefoxitin
concentrations in CSF seemed to occur between 2 and 6 h after intravenous
administration of the drug since the highest concentrations were found in patients
from whom CSF samples were taken 4 h after the doses. In patients with bacterial
meningitis, it should be possible to achieve therapeutic cefoxitin levels in CSF by
using nontoxic doses of the antibiotic.

Cefoxitin has been found to give concentra- sion was 3.6 days (range, 1 to 10 days). CSF was
tions in cerebrospinal fluid (CSF) which are macroscopically purulent in all patients, with leuko-
similar to those obtained with ampicillin both in cyte counts varying between 512 and 28,160 cells per
individuals with and in individuals without men- mm3. There was a dominance of polymorphonuclear
ingeal inflammation (3, 5). It has been used creasedleukocytes (54 to 95%; mean, 77%). There were in-
therapeutically in very few patients with men- ratios betweenconcentrations of protein in CSF, and the
CSF and blood glucose were decreased
ingitis, and published data (5) of two patients in all patients. The causative
with gram-negative meningitis do not allow the in 19 patients (Table 1). Thepathogens
were isolated
remaining six patients
conclusion that cefoxitin is effective in the treat- had negative CSF cultures. The leukocyte counts in
ment of meningitis since both of these patients CSF from these patients varied between 512 and 8,188
also received other antibiotics. However, since cells per mm3 (mean, 3,588 cells per mm3), with 54 to
cefoxitin has a very broad antibacterial spec- 94% polymorphonuclear leukocytes (mean, 80%).
trum, cases of bacterial meningitis caused by Antibiotic treatment. None of the patients re-
pathogens which are resistant to most other sion. ceived antibiotic treatment within 72 h before admis-
Twenty-four of the patients received an initial
antibiotics but susceptible to cefoxitin are likely antibiotic
to appear. The present study was undertaken to treatment with ampicillin in daily doses
evaluate the CSF penetration of cefoxitin in varying between 12 and 16 g, and one patient received
benzylpenicillin at a dose of 14.4 g/day. After 24 to 48
patients with bacterial meningitis treated with h, when the bacterial etiology was known, treatment
other antibiotics. was changed to other antibiotics in some patients. In
addition to the above antibiotics, all patients received
MATERIALS AND METHODS three doses of cefoxitin (Mefoxin; Merck Sharp &
Pa,tients. Twenty-five patients with bacterial men- Dohme, Rahway, N.J.) administered as intravenous
ingitis were included in the study. They were all ad- bolus injections over 3 to 5 min at 6-h intervals. These
mitted to one hospital in Sao Paolo. The mean age doses were administered concurrently with the first
was 32 years (range, 19 to 67 years). Five patients were three doses of ampicillin or benzylpenicillin.
females, and 20 were males. Upon admission, all pa- Assays of cefoxitin concentrations. Cefoxitin
tients had clinical signs of meningitis with headache, concentrations in serum and CSF were studied in
fever, and nuchal rigidity. Two patients were uncon- samples drawn before the first cefoxitin dose and at 2,
scious. The mean duration of symptoms upon admis- 4, or 6 h after the first and third cefoxitin doses. The
patients were randomly allocated to the three sam-
pling times by using an allocation list. For cefoxitin
t Address reprint requests to: Dr. Ragnar Norrby, Depart- assays, a paper disk diffusion technique was used.
ment of Infectious Diseases, East Hospital, S-416 85 Gothen- Brain heart infusion agar was inoculated with a strain
burg, Sweden. of Staphylococcus aureus (MB 2786; Merck Sharp &
526
VOL. 17, 1980
TABLE 1. Etiology ofpurulent meningitis
Etiology No. of patients
Streptococcus pneumoniae .....
Staphylococcus aureus ....
Neisseria meningitidis .........
Haemophilus influenzae ....
Proteus spp ........... ...
Negative culture ...............
Dohme) and poured into plates (100 by 15 mm), 5 ml/
plate. On each plate, two paper disks dipped in a
serum or CSF sample were placed together with two
disks saturated with a standard solution of cefoxitin
containing 5 ,ug/ml. Each test included a standard
series of cefoxitin in twofold dilutions from 20 to 1.25
pg/mi. After incubation overnight at 37°C, the inhi-
bition zones were measured and the cefoxitin concen-
trations were calculated from a standard curve. Sam-
ples with inhibition zones larger than the one obtained
with the 20-pg/ml standard were diluted in 1% phos-
phate buffer, pH 6.0, and retested. Standard curves
obtained with cefotoxin, diluted in pooled human se-
rum or 1% phosphate buffer, pH 6.0, did not differ
from each other. The test strain had a minimum
inhibitory concentration for ampicillin and benzylpen-
icillin of more than 200 jig/ml, and these antibiotics
were not found to interfere with the cefoxitin assays
when added to the standards in concentrations of up
to 200 jg/ml.
RESULTS
The serum and CSF concentrations of cefoxi-
tin are given in Table 2. All samples taken before
the first dose contained no detectable antibiotic
activity. When the patients within each of the
three sampling groups, i.e., 2, 4, and 6 h after
cefoxitin administration, were compared, consid-
erable variations were found in both serum and
CSF concentrations. These variations were
probably due to differences in age, weight, renal
function, and the degree of meningeal inflam-
mation. However, it was not considered ethical
to overcome this problem by increasing the num-
ber of CSF samples in each patient.
In all patients, cefoxitin gave detectable CSF
concentrations which varied from 1.2 to 22.0 Ag/
ml. Most patients had concentrations below 7
,ug/ml, and concentrations above that level were
found in only six samples from four patients.
Two of these patients had pneumococcal men-
ingitis, one of whom died, and two had menin-
gococcal meninlgitis. The cell and protein con-
tents in CSF from these four cases were not
higher than those in the other 21 patients. In the
total material, there was no relation between the
degree of meningeal inflammation and the CSF
concentrations of cefoxitin. Thus, patient no. 19,
who had 28,160 leukocytes per mm3 of CSF, had
somewhat lower concentrations than did patient
no. 22, who had only 512 cells per mm3.
CEFOXITIN PENETRATION INTO CSF 527
When the CSF concentrations achieved after
the third cefoxitin dose were compared with
9 those obtained after the first dose, 16 patients
2 had higher absolute concentrations and 15 had
5 higher concentrations in relation to concurrent
1 serum levels in the sample taken after the third
2 dose. By the Student t test for paired differences,
6 this difference was significant (P < 0.05) both in
the total material and in the group of patients
sampled at 2 h after cefoxitin administration.
Due to pronounced individual variations, it was
difficult to compare the CSF concentrations ob-
tained after 2, 4, and 6 h in the three groups of
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patients. However, a tendency toward higher
concentrations at 4 and 6 h was noted. This
difference was not statistically significant if the
absolute CSF concentrations were compared,
but the concentrations in relation to concurrent
serum concentrations were significantly (P <
0.01) higher at 4 and 6 h than those at 2 h after
the first cefoxitin doses and also higher at 6 h
than at 2 h after the third cefoxitin doses (t test
of the mean). These results indicated that the
peak CSF concentration of cefoxitin occurred
from 2 to 6 h after intravenous administration of
the drug.
All patients were followed for adverse reac-
tions to cefoxitin, the only reported one being a
pain reaction at the infusion site in one patient.
Two of the patients with pneumococcal menin-
gitis died of their infections, and the deaths were
considered definitely not related to the cefoxitin
administration. Since cefoxitin was not used
therapeutically, no evaluation was made of the
outcome of the treatment.
DISCUSSION
The increasing frequency of antibiotic resist-
ance among bacterial species causing meningitis,
e.g., Haemophilus influenzae (2, 9), has created
a need for new antibiotics which can be used for
the treatment of purulent meningitis. Cefoxitin,
a cephamycin for parenteral use, has an antibac-
terial spectrum which is broad and which covers
most bacterial species causing meningitis, in-
cluding Escherichia coli, Klebsiella, Proteus
spp. and beta-lactamase-producing strains of
Haemophilus influenzae (8). However, the
miniimum inhibitory concentrations of cefoxitin
for these pathogens are in the range of 0.5 to 8
,ug/ml, and a prerequisite for the use of cefoxitin
therapeutically would be that the antibiotic have
a good penetrability over the blood-CSF barrier.
Previous studies in animals and humans have
demonstrated that cefoxitin gives CSF concen-
trations which are low if the meninges are intact
and relatively high in the presence of meningeal
inflammation (3-5). In patients with normal
528 GALVAO ET AL. ANTIMICROB. AGENTS CHEMOTHER.
TABLE 2. Concentrations in serum and CSF of cefoxitin administered 2 g intravenously at 6-h intervals
Cefoxitin concn (yg/ml) in: Serum/CSF concn ratio
Patient no. Sampling time (h) Serum CSF
Dose 1 Dose 3
Dose 1 Dose 3 Dose I Dose 3
3 2 12.5 8.4 2.5 4.8 5.0 1.8
4 2 17.0 8.2 1.8 2.9 9.4 2.9
5 2 12.0 5.8 1.4 2.3 8.6 2.5
6 2 12.5 10.0 1.2 5.0 10.4 2.0
8 2 28.0 20.0 2.1 5.8 13.3 3.4
11 2 28.0 35.0 13.2 17.2 2.1 2.0
15 2 22.0 7.9 4.8 2.2 4.6 3.6
8.0 7.8 2.5 2.0 3.2 3.9

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25 2
Mean 2 17.5 12.9 3.7 5.3 7.1 2.8
SD 7.7 9.9 4.0 5.0 3.9 0.8
2 4 13.0 16.0 NDb 2.5 ND 6.4
7 4 2.0 17.0 1.5 11.0 1.3 1.5
16 4 16.0 22.0 15.0 15.0 1.1 1.5
19 4 3.8 9.6 2.0 4.0 1.9 2.4
20 4 7.8 5.0 5.8 6.0 1.3 0.8
22 4 2.7 8.0 2.2 6.2 1.2 1.3
23 4 1.5 2.0 4.0 3.6 0.4 0.6
Mean 4 6.7 11.4 5.1 6.9 1.2 2.1
SD 5.8 7.2 5.1 4.5 0.5 2.0
1 6 1.8 2.5 2.9 3.5 0.6 0.7
9 6 2.3 2.1 2.7 3.9 0.9 0.5
10 6 2.2 1.8 1.8 1.2 1.2 1.5
12 6 9.0 35.0 3.2 22.0 9.1 1.6
13 6 4.0 3.4 2.7 1.2 1.5 2.8
14 6 8.0 3.4 3.3 1.5 2.4 2.3
17 6 5.0 2.4 5.8 4.8 0.9 0.5
18 6 4.0 3.8 3.2 3.6 1.3 1.1
21 6 3.4 3.3 2.8 3.1 1.2 1.1
24 6 3.8 4.0 2.3 3.2 1.7 1.3
Mean 6 6.4 6.2 3.1 4.8 2.1 1.3
SD 8.2 10.2 1.1 6.2 2.5 0.8
aSD, Standard deviation.
bND, Not determined.
CSF findings, Liu et al. (3) found very low, if cefoxitin concentrations in the CSF of 11 pa-
any, concentrations of cefoxitin in CSF after tients without meningitis after single cefoxitin
single doses. After multiple 2-g doses with or doses with or without probenicid but rather high
without probenicid, the CSF concentrations concentrations after three doses of 4 g each. In
were between 0.6 and 5.0 ,g/ml at 1 h after patients with meningeal inflammation, they
administration. These concentrations were found high CSF concentrations (4.6 to 57 ,ug/ml)
equal to or even better than those obtained with at 1 to 1.5 h after single or multiple doses of 2 to
ampicillin or cefamandole in the same study. It 4 g of cefoxitin. In these patients there was no
is noteworthy that the concentrations in this obvious correlation between the protein content
study were assayed relatively early after the of CSF and the penetrability of cefoxitin. In
cefoxitin doses and probably before the peak neither of the above studies did probenecid in-
concentration occurred in lumbar CSF (1, 6). In crease the passage of cefoxitin over the blood-
another study, Nair et al. (5) found no detectable CSF barrier.
VOL. 17, 1980
Our results were in good correlation with those
obtained by Nair et al. (5) in patients with
meningitis. The pharmacokinetics of the CSF
penetration seemed to be characterized by a
peak concentration at between 2 and 6 h after
the administration of the 2-g doses. The concen-
trations obtained after the third dose tended to
be higher, both absolutely and relatively to the
concurrent serum concentrations, than those ob-
tained after the first cefoxitin dose, indicating an
accumulation in CSF of cefoxitin with repeated
doses. Our results, in combination with those of
others, indicate that cefoxitin has a good pene-
trability into CSF of patients with bacterial men-
ingitis and that it might be considered in selected
cases of purulent meningitis when the suscepti-
bility pattern indicates its usefulness. However,
the 2-g, 6-h regimen used by us is probably too
low of a dose to attain CSF concentrations of
cefoxitin which are well above the minimum
inhibitory concentrations for bacteria classified
as susceptible to cefoxitin; therefore, daily doses
of 12 to 18 g of cefoxitin will probably be required
in the therapeutic situation. These doses are
somewhat higher than those recommended by
the manufacturers of cefoxitin, but should im-
pose no risks of serious adverse reactions since
cefoxitin seems to have a high degree of safety
(7).
CEFOXITIN PENETRATION INTO CSF 529
LITERATURE CITED
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K. Saz. 1974. Haemophilus influenzae resistant to am-
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3. Liu, C., D. R. Hinthorn, G. R. Hodges, J. L. Harms,
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mangaud. 1979. Penetration of cefoxitin into cerebro-
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