Cefuroxime 25
Pharmacokinetic and Clinical
Studies on Cefuroxime
by Dr R Norrby, Dr R D Foord, Dr J D Price
and Dr P Hedlund
(Department ofInfectious Diseases,
University ofGoteborg, Sweden, Glaxo Research
Laboratories, Greenford and Medical Department,
Glaxo Holdings, London, England)
Cefuroxime is a new cephalosporin for parenteral
use. It differs from other cephalosporins in its
improved stability to degradation by g-lactamases
from Gram negative bacteria (Richmond &
Wotton 1976) which gives it an unusually broad
antibacterial spectrum (O'Callaghan et al. 1976a,
b, Norrby et al. 1976). Volunteer studies as well
as clinical trials have shown that cefuroxime is
well tolerated, even when administered by the
i.m. route, and that it is clinically effective in
serious infections caused by susceptible pathogens
(Foord 1976, Norrby et al. 1977).
The present report presents data on a large
number of patients treated with cefuroxime. The
pharmacokinetic part of the study includes 4
patients with CNS infections, 2 of whom were
hydrocephal ic children who were given cefuroxime
intraventricularly. These studies were initiated
because cefuroxime is active in vitro against all
pathogens commonly causing CNS infections
including /-lactamase producing strains of
Hmmophilus influenzae (Sykes et al. 1976).
PATIENTS AND METHODS
Patients
Eighty-nine patients, 36 females and 53 males,
were included in the trial, a Phase II and Phase III
study. Two of them were children aged 8 and 10
months, the rest were adults. The mean age of the
adults was 47.6 years (range 19-87 years). All
patients were hospitalized because of confirmed
or suspected bacterial infections which were con-
sidered to require parenteral antibiotic treatment.
Sixteen patients had 2 infections. All adult
patients gave their verbal consent to participate
in the study. The criteria for entering the study,
as well as the treatment schedules, were approved
by the Ethical Committee of the Faculty of
Medicine, University of Goteborg and by the
Swedish Medical Board.
Cefuroxime Treatment
The adult patients were treated with cefuroxime
every 8 or 12 h in doses varying from 0.5-3 g. The
doses were given as i.m. injections each I g of
cefuroxime dissolved in 5 ml of saline; or as
intermittent i.v. infusions via a 4 cm polyethylene
catheter. In these cases cefuroxime was dissolved
in 100 ml of saline and infused over 30 min
followed by a rapid infusion of 100 ml of saline
to wash the vessel. Intravenous bolus injections
were used only in 1 patient. Indwelling catheters
were changed every 48 h.
The 2 children received cefuroxime in a dose of
50 mg in 2.5 ml of saline into the cerebral ventri-
cular system once every 24 h. External poly-
ethylene shunts were used and cefuroxime was
infused over 5 min followed by a rapid infusion
of 5 ml of saline. After each intraventricular dose
the catheter was clamped for 30 min to allow
cefuroxime to diffuse in the ventricular system. In
addition the children also received cefuroxime
i.m. 15 mg/kg body weight 3 times daily, starting
24 h after the first intraventricular dose. In all
patients the sites of injections or infusions were
inspected 3 times daily by the responsible nurses
and pain after i.m. administration as well as
thrombophlebitis after i.v. infusions was re-
corded. Concurrent antibiotic treatment was not
used in any patient.
Routine Laboratory Tests
The following tests were performed in all patients
before and on every third to fifth day during and
after the cefuroxime treatment: hmmoglobin, total
and differential leucocyte count, quantitative
estimation of platelets, erythrocyte sedimentation
rate (ESR) and Coombs' direct and indirect tests;
serum bilirubin, serum alkaline phosphatase,
serum glutamic-oxalacetic transaminases (SGOT)
serum glutamic-pyruvic transaminase (SGPT) and
creatinine; urine microscopy and semiquantitative
determination of blood, glucose, protein and
ketones in urine.
Bacteriological Tests
Samples for bacteriological examination were
taken from sites appropriate to the infections
being treated. When possible, samples were taken
before, every other day during and after cefur-
oxime treatment. Mid-stream urine samples were
taken in all patients before and during the treat-
ment and also afterwards in order to evaluate the
frequency of urinary superinfections. Antibiotic
susceptibility tests were performed with the paper
disc technique of Ericsson & Sherris (1971). The
points used to describe susceptible (S), moderately
susceptible (MS) and resistant (R) organisms
when the isolates were tested against cephalo-
sporins and cefoxitin corresponded to minimal
inhibitory concentrations in solid agar dilution of
<2tg/ml, 2-1 6,ug/ml and> 1 6,tg/ml respectively.
Assays of Cefur-oxime Concentration
In many of the patients serum concentrations and
urine excretion were assayed on the second or
third day of treatment. Samples were drawn
before, and at 0.5, 1, 2, 3, 4, 6 and 8 h after an
26 Proc. roy. Soc. Med. Volume 70 1977 Supplement 9
Table I steel cups. Bacillus subtilis was used as test strain
Concurrent diseases in 89 patients with verified or suspected and the diameters of the zones of inhibition were
bacterial infections treated with cefuroxime read after 18 h of incubation at 280C. Serum half
Concurrent disease No. lives (tj) were calculated graphically from the
Alcoholism 21 f-slope. All samples and standard solutions were
Diabetes mellitus
Narcotic addition
II
2
tested at the same pH and protein concentrations.
Rheumatoid arthritis I
Malignancy 1 RESULT
Total 36 All patients included in the study had severe or
moderately severe acute infections with the
Table 2 exception of 1 patient who was initially thought
Types of infections in 89 patients treated with
to have septicemia but later was diagnosed as a
cefuroxime (16 patients had 2 infections) case of collagenosis. Thirty-six of the patients had
concurrent diseases which might have increased
Type of infection No. patients their susceptibility to infections (Table 1).
Softtissue infection: deep 40
superficial 3 Chronic alcoholism dominated the concurrent
Lower respiratory tract infection 20 diseases and most of these patients had severe
Urinary tract infection 12 deep soft tissue infections. Tables 2 and 3 give the
Septicemia: verified 9
suspected 4 types of infections treated and the bacteriological
Osteitis 5 data. Deep soft tissue infections dominated the
Meningitis 4
Arthritis 3 material and in most of these patients Staphyl-
Other 4 ococcus aureus and/or Streptococcus pyogenes,
No infection (collagenosis) 1
Total 105
group A, were the aetiological agents isolated.
About 80% of the S. aureus strains were peni-
cillinase producing. The group of other infections
consisted of 1 case of bacterial parotitis caused by
i.m. injection or the end of an i.v. infusion. Streptococcus viridans which could be isolated
Urinary excretion was studied in 8 h urine from pus, one case of hepatic abscess and
samples collected between 2 cefuroxime doses. meningitis caused by Klebsiella pneumonie, a
For the assays, a modification of the steel cup staphylococcal pulmonary abscess, and a Salmon-
technique described by Grove & Randall (1955) ella gastroenteritis with arthritis.
was used. Rectangular glass dishes, 30 x 30 cm, Details of the patients with verified septicmmia
with 120 ml of Bacto Penassay agar were used. are given in Table 4. With the exception of patient
On each dish, 2 samples and 1 standard were No. 9 who died in septic shock before adequate
tested, each in 2 dilutions. Six aliquots of each of antibiotic treatment was given, all these patients
the 6 dilutions thus obtained were inoculated in responded favourably to cefuroxime. Of the 4
a randomized order (latin square design) into the patients who were considered improved one (No.

Table 3
Pathogens isolated in 69 patients treated with cefuroxime, disc test susceptibility pattern and elimination of bacteria
during cefuroxime treatment
No. strains
Susceptibility (No. strains) eliminated on day
No. CM CX CT No. strains not
Organismn strains S MS R S MS R S MS R 1-3 4-7 8-11 eliminated
Streptococcus pyrogenes (gr. A) 19 19 19 19 19
Streptococcus viridans 1 1 1 1 I
Streptococcus pneumonic 2 2
Staphylococcus aureus 31 31 31 31 18 7 3 3
Staphylococcus epidermidis 2 2 2 2 2
Staphylococcus saprophyticus I I l
Escherichia coli 9 7 I 7 1 1 3 4 2 6 1
Proteus mirabilis 6 4 I 4 2 2 2 3
1 1 2 I
Proteus vulgaris 2 1
Klebsiella pneumonir 9 9
9

9 9 7 0
Harmophilus influenzae 1 1 NT
Streptococcus enteritidis
Staphylococcus san diego 1 I 1
Bacteroidesfragilis 2 1 1 1 2
Total 87 78 2 2 79 3 1 69 7 6 61 13 6 7

CT= cephalothin; CM= cefuroxime; CX=cefoxitin; S= susceptible; MS= moderately susceptible; R= resistant;
NT = not tested
 Cefuroxime 27

Table 4
Characteristics of 9 cases of septicmmia treated with cefuroxime
Case Concurrent Outcolme
No. Sex/age Causative organism disease Itifectiousfocus Clinical Bacteriologic acl
9 M 74 Escherichia coli None UTI Died Not eliminated
20 F 56 Hwrmophilus influenzce None Bronchopneumonia Cured Eliminated
23 F 40 Streptococcus pyogeties, Group A None None Improved Eliminated
31 M 57 Escherichia coli None UTI Cured Eliminated
46 F 75 Streptococcus viridans Uterine None Improved Eliminated
malignancy
47 F 77 Streptococcus pyogenes, Group A None Soft tissue infection Cured Eliminated
61 M 30 Streptococcus pnteuimonica Alcoholism Lobar pneumonia Improved Eliminated
67 M 68 Bacteroidesfragiis Thoracic None Cured Eliminated
trauma
85 M 70 Staphtylococcus san diego None Gastroenteritis Improved Persisted

23) developed an acute streptococcal glomerulo-
nephritis with hematuria, proteinuria and reduced
complement titres. Another patient (No. 46)
developed anuria due to a bilateral obstruction of
the ureters by a cancer of the uterus. Patient No.
61 recovered from his septicemia but was found
to have a sterile empyema which had to be
drained. In patient No. 85, the signs of gastro-
enteritis and septicamia vanished but Staphyl-
ococcus san diego persisted in faces and he later
developed sterile arthritis.
The 4 cases of suspected septicemia included 2
young females with typical findings of gonococcal
septicamia, 1 case in whom an Escherichia coli
strain was isolated from blood after cefuroxime
treatment and 1 case of superficial soft tissue
infection caused by S. aureus in whom fever and
the patient's general condition made septicaemia
highly probable.
The majority of the clinical isolates were
susceptible to cefuroxime (Table 2). A comparison
between cefuroxime and cefoxitin revealed no
major differences in susceptibility. One Proteus
vulgaris strain was moderately susceptible to
cefoxitin but resistant to cefuroxime. The reverse
was true for 1 strain of Hamophilis influenza, and
one Bacteroidesfragilis strain was more susceptible
to cefoxitin than to cefuroxime. Cephalothin
seemed less effective than both cefoxitin and
cefuroxime against Gram negative isolates.
Ninety-two percent of the isolates were elimina-
ted during cefuroxime treatment, 70 % during the
first 3 days, 15 % during the 4th-7th days and 7 %
Table 5
Clinical results of cefuroxime treatment
of 105 infections in 89 patients
Clinical result No. patients (%)
Cured 71 (67.6)
Improved 29 (27.6)
Failure 1 (0.9)
Died of infection 2 (1.8)
Treatment not completed 1 (0.9)
No infection 1 (0.9)
during th 8th-il th days. Of the 7 strains which
were not eliminated, 3 were S. aureus from
patients with deep soft tissue infections, 2 were
Gram negative strains from wounds, I was a
Klebsiella pneumonia strain in a patient with a
meningitis and an hepatic abscess, and 2 were
Salmonella strains that persisted in faces.
The clinical results of the cefuroxime treatment
are given in Table 5. Favourable responses were
observed in 95.2% of the patients. The criteria
used for considering a patient cured were absence
of fever, normalized ESR, absence of leucocytosis,
healing of wounds and disappearance of X-ray
changes, when present. The group that was con-
sidered most improved (i.e. fulfilled most but not
all of the above criteria) were mainly patients with
soft tissue infections that had not healed entirely
by the time that there was no further need for
parenteral treatment. Also in this group were
patients with lower respiratory tract infections
who had persisting X-ray changes which, however,
disappeared during the follow-up periods.
The therapy had no effect on the infections in 4
cases. One of these (patient No. 9 Table 4) was
discussed above. The other patient that died had
an hepatic abscess and a meningitis caused by a
Klebsiella pneuimonia? strain susceptible to cefur-
oxime. In this patient the hepatic abscess which
was considered to be the reason for the outcome
of his infection, was not diagnosed until the
autopsy. A third patient died during cefuroxime
treatment but from cardiovascular disease, after
having improved from her bronchopneumonia.
The fourth patient who is listed as a failure has a
suspected septicamia and a cefuroxime susceptible
strain of E. coli was isolated after the end of the
cefuroxime treatment. He responded later to 10
days of gentamicin treatment and the reason for
the failure of the cefuroxime treatment is still
obscure. In one patient, treatment had to be
interrupted after the third dose because of pain
reactions (see below).
Of the patients with CNS infections, the case
with Klebsiella meningitis has been discussed
28 Proc. roy. Soc. Med. Volume 70 1977 Supplement 9
Table 6 the elimination of the pathogens. The treatment
Doses and routes of administration in times ranged from 0.5-25 days with a mean of
87 patients treated with cefuroxime 7 days.
Route ofadministration Cefuroxime was well tolerated although sus-
Dose/24 h and No. patients pected or verified adverse reactions were noted in
(mg and
No. doses) i.m. i.v. as many as 37% of the patients (Table 7). The
500x3 1 1 dominating side effect was increased liver trans-
750x3 42 aminases, which was observed in 21 patients.
1000 x 3 16 10
1500x3 4 6 When these patients were studied in detail it was,
2000 x 2 1 however, found that in 14 patients the abnormal
2000x3 1 4 liver function tests could be explained by previous
3000x3 1
liver diseases and/or abnormal liver function
Total 64 23 before cefuroxime treatment (Table 8). The
i.m. =intramuscular injection; extent of the increases of SGOT and SGPT was
i.v. =intravenous intermittent infusion low and in no case did the abnormal liver function
tests persist during the follow-up periods.
Table 7 Of the other side effects noted, nine were pains
Adverse effects observed in 89 patients after i.m. administration of cefuroxime. Two of
treated with cefuroxime these patients reported severe pains and in one
Adverse effect No. patients patient the treatment had to be stopped after the
Pain after i.m. injection: third injection. In that case the reaction was due
severe 2 to an injection close to the sciatic nerve and should
moderate 7 not be ascribed to cefuroxime. In the other case,
Increased liver transaminases 21
Positive direct Coombs' test 2 the severe pain reaction could partly be explained
Rash I by the fact that the patient was highly pain
Total 33 sensitive. The patients complaining of moderate
or slight pain reactions all described the pain as
Table 8 short-lived with a duration less than 1 min. The
Transaminase increases during cefuroxime treatment in 89 patients
reactions were therefore considered to be due to
the relatively large volumes used when cefuroxime
Total No. patients with transaminase increases 21 was given by the i.m. route. No thrombophlebitis
Relation to route of administration None was seen in the patients that received cefuroxime
Relation to dose of cefuroxime None i.v. A positive direct Coombs' test was noted in
No. patients with previous liver disease 10
No. patients with abnormal liver function tests before
2 patients, neither of whom showed any signs of
cefuroxime treatment 10 hxemolysis. The only skin reaction noted was a
Normalization: maculopapular, confluent, itching rash on the
During cefuroxime treatment
Within 2 weeks after cefuroxime treatment 16
2 fourth day of cefuroxime treatment of a 72-year-
Lost to follow-up 3 old female patient. This reaction was considered
No. patients with maximal transaminase value < 50 units 14 to be due to cefuroxime as she had no other con-
Maximal transaminase value observed (units) Ill current drugs. No other allergic reactions were
Previous liver disease and/or pretreatment abnormal noted, although 8 patients had a previous history
liver function tests 14 of allergic skin reactions in connection with
penicillin therapy. The patients with CNS infec-
tions showed no signs of neurotoxic reactions to
above. The other case with meningitis was a cefuroxime.
female with a pneumococcal meningitis who There were no signs of nephrotoxic reactions to
responded favourably to cefuroxime. The 2 cefuroxime. In 60 patients adequate serum
hydrocephalic children with ventriculitis both had creatinine samples were taken before, during and
growth of Staphylococcus epidermidis in ventricu- after the cefuroxime treatment. The serum
lar cerebrospinal fluid (CSF). After a few intra- creatinine (mg/100 ml±s.d.) in these patients was
ventricular doses of cefuroxime the CSF was 1.22±0.28 before, 1.10±0.20 during and 1.09
sterile in both patients and the clinical symptoms ±0.17 after cefuroxime. Statistically Students'
disappeared. t-test showed the serum creatinine to be higher
In the initial phase of the trial cefuroxime was before than during or after cefuroxime (P<0.05).
used in various doses to evaluate the optimal This difference was considered to be due to the
regimens (Table 6). During the trial it became fact that the first samples were drawn when the
clear that in the majority of the patients a dose of patient had high fever and were often dehydrated.
750 mg i.m. or 1000 mg i.v. 3 times daily was The serum concentration studies revealed that
sufficient for a favourable clinical response and high serum concentrations of cefuroxime were
 Cefuroxime 29

achieved with all the regimens used (Figs I and 2). 100
The calculated t4 values varied from 0.7-2.6 h
with a mean of 1.4 h. The great variations could
be explained by differences in renal function 50
between patients, but there were no differences
that could be related to the doses given or to the
route of administration. The area under the curve 25
obtained for i.m. administration in comparison to
i.v. administration indicated that cefuroxime is
absorbed to a large extent, if not completely, after
i.m. injection. The mean 0-8 h urinary recovery 10 l
was found to be 84 % of the dose (range 62-115 %).
The 2 patients with meningitis had serum and
CSF concentrations determined at various times. \
In patient No. 76 with a Klebsiella meningitis
(Fig 3), the blood-CSF barrier was severely
inflamed on all sampling occasions. In this patient 2 5
the ratios between cefuroxime concentrations in 2.5
serum and CSF I h after a 2 g dose were found to
be 6.4 on the second day of treatment, 3.5 on the
third and 2.6 on the fourth. On the fourth treat-
ment day, samples were drawn also 5 h after the 1
dose and the serum/CSF ratio was then found to
be 0.56 - a considerably higher cefuroxime con-
centration being found in CSF than in serum. In 0.5-i
patient No. 89 (Fig 4) the meningitis improved 1 2 3 4 5 6 7 8
considerably between the 2 sampling days. In Fig 1 Serum concentrations ofcefuroxime afte i.m.
that patient a lower serum/CSF ratio was found administration
on the first day of cefuroxime treatment (2.5) than
on the 5th day (9.6) when the blood-CSF barrier 150
was considered less inflamed. In this patient a 5 h
sample was obtained only after the first dose and 100
the ratio was then 1.0.
Preliminary results of studies on cefuroxime
elimination from ventricular CSF in the 2 hydro- 50
cephalic children who were given cefuroxime
50 mg in 5 ml intraventricularly, indicate that a
peak concentration of 60 ,tg/ml is achieved about 25
I h after an intraventricular dose and that
cefuroxime is eliminated with a tj of about 8 h.
DISCUSSION 10-
The cephalosporins are broad spectrum anti-
biotics, active against both Gram negative and
Gram positive bacteria. Their clinical usefulness 5
has been limited by a lack of activity against
Streptococcus fa?calis, Pseudomonas ?ruginosa
and ,B-lactamase producing strains of Gram nega- 2.5-
tive bacilli. Many cephalosporins are also less
active against Hamophilis influenza.
Cefuroxime is a new cephalosporin antibiotic
that eliminates some of these drawbacks. Thus, it I
is highly resistant to degradation by ,B-lactamases 1
(Richmond & Wotton 1976) and it is active
against H. influenza,, including the ,B-lactamase
producing strains (Sykes et al. 1976). It lacks 0.5
activity against P. aeruginosa, B. fragilis and some 1 2 3 4 5 6 7 8
strains of indole positive Proteus (O'Callaghan Fig 2 Serum concentrations of cefiiroxime after i.v.
et al. 1976a, b). Norrby et al. (1976) showed intermittent infiusion
30 Proc. ray. Soc. Med. Volume 70 1977 Supplement 9

Cefuroxime concentration (iug/ml) to be more active than cephalothin against E. coli

501 0 Serum and indole negative Proteus strains, which might
DCSF reflect a ,B-lactamase production by these
organisms.
40- t 2000mg of cefuroxime iv. In a high percentage of the infections the
aetiological pathogens were eliminated during
30-
cefuroxime treatment. In 70 % of the cases
bacterial elimination was achieved within 3 days,
indicating that cefuroxime rapidly reaches peri-
20- pheral compartments in therapeutic concentra-
tions. The cases where the bacteria were not
10-

-,-
.11

0 2 4 6 8 4O 6 8
t
2
Day
tf Day3
34
L -&-i a&

tt
56
1
2 4 68 Time (h)
Day4

Fig 3 Concentrations of cefuroxime in serum and

eliminated were 5 with necrotic wound infections,
2 with Salmonella infections and 1 with an
undiagnosed hepatic abscess. In all of these cases
it was not surprising that the pathogens persisted.
Cefuroxime seemed to exert a low ecological
pressure as only 2 cases of superinfections were
noted, I funguria and 1 case of growth of P.
wruginosa in a wound close to the anus. In both
cerebrospinalfluid(CSF) in patient No. 76. patients the organisms vanished after the end of
Klebsiella meningitis cefuroxime treatment and were considered to be
of no clinical importance.
Cefuroxime was clinically effective and 95 % of
the patients were considered to be cured or
improved. The doses of cefuroxime required for a
satisfactory clinical result were low and in a
majority of the patients 0.75 g i.m. or 1 g i.v. three
times daily was sufficient. With these doses
adequate serum and urine concentrations were
achieved and because of the relatively high tj, 8 h
dose intervals seemed optimal.
Cephalosporins are not normally used for the
treatment of CNS infections. Clinical failures
have been reported with cephalothin (Almond
1969, Mangi et al. 1973). With cephaloridine,
better therapeutic results have been reported, but
in most cases cephaloridine was given both
systemically and intraventricularly (Love et al.
1970). Despite these experiences with cephalo-
sporins in meningitis, it was nonetheless con-
sidered clinically justified to try cefuroxime in 2
Fig 4 Concentrations ofcefuroxime in serum and cases of severe bacterial meningitis, I caused by
cerebrospinalfluid(CSF) inpatient No. 89. Klebsiella and 1 by S. pneumoniu. In the first case
Pneumococcal mmningitis
the patient died from meningitis as the hepatic
abscess from which it derived was not diagnosed.
relatively high susceptibility of S. facalis when a The clinical response to therapy in the second
low bacterial inoculum was used but this has not patient was better and she was considered cured.
been verified. In both patients surprisingly high concentrations
The pathogens isolated from the patients in this of cefuroxime were assayed in CSF. The data
study were tested for susceptibility to cefuroxime, obtained in the second patient, when concentra-
cephalothin and cefoxitin, the last being a tions were assayed during the recovery phase,
cephamycin with a spectrum similar to that of indicated that an inflammatory reaction in the
cefuroxime but with better activity against blood-CFS barrier permits high CSF concentra-
B. fragilis and indole positive Proteus strains tions of the drug. Cefuroxime was also given by
(Brumfitt et al. 1974, Tally et al. 1975). Cefoxitin the intraventricular route to 2 hydrocephalic
and cefuroxime seemed equally active in these children with ventriculitis. They responded
conditions with the exception of a few strains that favourably to therapy and high concentrations of
were more susceptible to one drug than to the cefuroxime were obtained in CSF. Study of the
other. Both cefuroxime and cefoxitin were found pharmacokinetics of the elimination of cefuroxime
 Cefuroxime 31

from the CSF in these children is so far only treatment. Various doses of cefuroxime were
preliminary, but indicates that cefuroxime is used, and it was concluded that an i.m. dose of
eliminated slowly, with a tj of about 8 h. 750 mg or an i.v. dose of 1000 mg 3 times daily is
Although relatively frequent adverse effects sufficient for a good clinical result in the majority
were observed in the patients treated with of infections. Pharmacokinetic studies revealed
cefuroxime, it was nonetheless considered to be that with these doses, sufficiently high serum and
a safe drug. The most commonly observed side urine concentrations were achieved and- that with
effect was a moderate increase in liver trans- a mean half life in serum of 1.4 h, dose intervals
aminases, which in the majority of the cases could longer than 8 h should not be necessary.
be explained by previous liver diseases in the Four of the patients had CNS infections, 2
patients. In no case did the increased trans- cases of bacterial meningitis and 2 hydrocephalic
aminases cause discontinuation of the cefuroxime children with ventriculitis. In 3 of these patients
treatment. In all cases the liver tests normalized cefuroxime eradicated the pathogens and clinical
during or shortly after treatment. Transaminase cures were obtained. The fourth patient died of
increases have previously been reported during meningitis as the focus of the infection, an hepatic
cephalosporin therapy (Martin & Wellman 1967, abscess, was not discovered. The concentrations
Shemonsky et al. 1975). The finding of a positive of cefuroxime assayed in cerebrospinal fluid from
direct Coombs' test in 2 patients accords with the 2 cases of meningitis indicated that very high
what has been reported for other cephalosporins cefuroxime concentrations are achieved when the
(Moltan et al. 1967). Only 1 case of hypersensi- blood-CSF barrier is inflamed. The 2 children
tivity reaction ascribed to cefuroxime was noted received cefuroxime by the intraventricular route
and 8 patients with a history of skin reactions and no neurotoxic reactions were observed. Pre-
during penicillin therapy did not react to liminary results of studies on the elimination of
cefuroxime. cefuroxime from the ventricular system of these
The local tolerance of cefuroxime was good and patients indicate that the drug is eliminated
only slight or moderate pains after i.m. adminis- slowly, with a half life of about 8 h. Elimination
tration were noted. These could be ascribed to the from the CSF is via the choroid plexus and it
relatively large injection volumes used. No seems unlikely that an active transport of
thrombophlebitis was observed after i.v. infusion. cefuroxime from the CSF occurs.
Thus, cefuroxime can easily be administered by A considerable number of patients showed
the i.m. route which gives it an important increased liver transaminases during cefuroxime
advantage over most other cephalosporins. treatment. In the majority of cases these findings
As a significant number of nephrotoxic reactions could be explained by previous liver diseases and
have been reported after therapy with cepha- in all cases the liver function tests normalized
loridine and cephalothin (Foord 1975) it is during or shortly after the cefuroxime treatment.
important to investigate every new cephalosporin Pains at the injection sites after i.m. administra-
for signs of nephrotoxicity. No effects by cefur- tion were noted in 9 patients. These reactions
oxime on the renal function of the patients in this were considered to be due to the relatively large
study were noted. It should, however, be stressed volumes used and not to an irritation caused by
that these patients were all carefully monitored to cefuroxime itself. Other side effects noted were 2
avoid overdosages and that the doses used in most cases of positive direct Coombs' test and I case
cases were moderate. It cannot therefore be of allergic skin reaction. No nephrotoxic reactions
stated that cefuroxime is completely safe with to cefuroxime were observed.
regard to nephrotoxic reactions and it seems It was concluded that cefuroxime is an impor-
justified to follow the renal function of all tant innovation. Its broader antibacterial spectrum
patients treated with the drug until further increases the primary indications for cephalo-
clinical experience has been gained. sporins and it seems clinically and bacterio-
logically effective without any serious side effects.
Summary In particular it may have a special role for the
Cefuroxime is a new cephalosporin antibiotic with treatment of bacterial meningitis, partly because
a broader antibacterial spectrum than the existing it seems to penetrate well through inflamed
cephalosporins. This is the result of an increased meninges and partly because it has the most
stability to degradation by ,B-lactamases from favourable spectrum with respect to potential
Gram negative bacilli. Eighty-nine patients with pathogens causing virulent meningitis.
acute bacterial infections were treated with
cefuroxime. Clinically and bacteriologically excel-
lent results were achieved, 95 % of the patients Almond
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(1969) New EnglandJournal ofMedicine 281, 218
being cured or improved and 92 % of the isolated BrumfittHW,R Kosmidis J, Hamilton-Miller J M T & Gilchrist J N G
pathogens being eliminated during cefuroxime (1974) Antimicrobial Agents and Chemotherapy 6, 290
32 Proc. roy. Soc. Med. Volume 70 1977 Supplement 9
Ericsson H M & Sherris J C (1971) Acta Pathologica et Dr J Kosmidis (Athens) said that after giving
Microbiologica Scandinavica B 217 (Suppl.), 67
Foord R D cefuroxime to a patient with normal meninges it
(1975) Journal ofAntimicrobial Chemitherapy 1, (Suppl. 1) 119 was not detectable 3 h later in the CSF, although
(1976) Antimicrobial Agents and Cheqitoerapy 9, 741 it had high levels in serum. Although this was
Grove D C & Randall W A (1955) Assay methods of antibiotics.
In: Medical Encyclopedia, Ch. 4. New York only 1 case, it confirmed the expectation that the
Love W C, McKenzie P, Lawson J H, Pinkerton I W, drug would not pass readily through normal
Jamieson W M, Stevenson J, Roberts W & Christie A B
(1970) Postgraduate MedicalJournal4o, (Suppl. 1) 155 meninges. He asked Dr Norrby for the cell
Mangi R J, Kundargi R S, Quintiliani R & Andriole V T numbers present in the 2 patients that he had
(1973) Annals of lnternal Medicine 78, 347
Martin W J & Wellman W E (1967) Postgraduate Medicine 42 350 described.
Molton L, Reidenberg M M & Eichman M F
(1967) New England Journal ofMedicine 277, 123 Dr Norrby said that the figure was about 2 x 103
Norrby R Brorsson J & Seeberg S
(1976) Antimicrobial Agents and Chemotherapy 9, 506 in the acute phase in both patients and about 500
Norrby R, Foord R D & Hedlund P in the later phase in the second patient. There
(1977) Journal of AntimicrobiaI Chemotherapy 3, 355
O'Callaghan C H, Sykes R B, Griffiths A & Thornton J E were marked inflammatory reactions.
(1976a) Antimicrobial Agents and Chemotherapy 9, 511
O'Callaghan C H, Sykes R B, Ryan D M, ]Foord R D
& Muggleton P W (1 976b) Journal of Antibiotics 29, 29 Dr G F Rahim (Birmingham) asked Professor
Richmond M H & Wotton S Simon whether any of his blisters became infected
(1976) Antimicrobial Agents and Chemotherapy 10, 219 before complete healing, and what happened to
Sykes R B, Griffiths A & O'Callaghan C H
(1976) Proceedings ofthe Sixteenth Interscience Conference on the cefuroxime in blister fluid after 24 h.
Antimicrobial Agents and Chemotherapy, Chicago 1976 (Abstract)
Tally F P, Jacobus N V, Bartlett J q & Gorbach S L
(1975) Antimicrobial Agents and Chemotherapy 7, 128 Professor Simon said that no infection of skin
blisters had occurred at any time. At the end of
continuous i.v. infusion, drug concentration in
skin blisters fell more slowly than in serum.
Professor Modai (Paris) had studied the passage
of cefuroxime into the CSF in virulent meningitis
2 days after the beginning of the disease. Samples
from 4 patients 30 min after an i.v. injection of 1 g
DISCUSSION of cefuroxime had produced levels of I ,tg/ml in
Dr J R T Gabriel (London) asked whether CSF, but never more.
cefuroxime was more closely bound to serum
proteins than the other 4 cephalosporins studied Dr Norrby said that he would have expected such
by Professor Simon. a result. In his first patient there was a con-
siderably higher concentration 5 h after the dose
Professor Simon said that the figures for protein than 1 h afterwards, and these samples were taken
binding were cefuroxime 40%; cefazolin 87%; 1 and 5 h after the completion of the 30 min
cephalothin 70 % and cephradine 15 %. infusion, that is to say 1.5 h after its beginning.
Several 3-lactam antibiotics had been claimed to
Dr J R T Gabriel (London) asked why it had a have poor penetration through an intact blood-
higher concentration in the blister fluid studies if CSF barrier, but he thought that peak concen-
it was less closely bound to protein than the other trations should be looked for at 3-5 h after dosing.
cephalosporins. Since both of these patients had been allergic to
penicillin, they were treated with cefuroxime
Professor Simon said that tissue penetration and alone.
penetration into body fluids was not only depen-
dent on protein binding but also on molecular Dr E Rubinstein (Tel-Hashomer) asked Professor
size, molecular weight and other factors so far Simon if his control graph was for fluid taken
unexplained. from normal blisters.
Dr A J Kuzemko (Peterborough) asked whether Professor Simon confirmed that it was. He has
cefuroxime passed into normal cerebrospinal prepared standard curves from blister fluid taken
fluid. from untreated individuals, but in studying drugs
with low protein binding there was a difference
Dr Norrby said that the question would be dis- between the serum standard curve and the skin
cussed further at the Conference, but he would not blister fluid standard curve. It was important to
expect more than 10 % of the peak serum con- have a special standard curve for drugs with high
centration to be achieved in a peak CSF concen- protein binding, because the difference in protein
tration with this ,B-lactam antibiotic. content could be decisive.

Dr E Rubinstein (Tel-Hashomer) had had a
similar experience with a method used to detect
antibiotic either free or bound to protein.
Professor S Rosachino (Milan) said that since
meningitis was an important disease, clinical
experience should be increased beyond the 2 cases
so far reported. He doubted whether the dosage
of 50 mg given in hydrocephalus would be
appropriate for normal meningitis sufferers.
Dr Norrby said firstly that he did not favour
intrathecal administration of antibiotics, because
he did not believe that the drug reached the
ventricular system and stayed there. Secondly, in
children with minor and major hydrocephalus,
the doses were 25 and 75 mg; 50 mg was used for
moderate cases. He thought these doses gave a
sufficient concentration. He believed that there
would be further reports on patients with
meningitis, but he did not recommend routine
use of cefuroxime in this condition, only further
studies on the subject.
Dr J G McVie (Glasgow) asked about daily serum
levels in the first patient with meningitis.
Cefuroxime 33
Dr Norrby said that it had been difficult to
monitor this patient closely. A higher dose of the
drug would not have saved him, because they had
not detected the hepatic abscess. But it might be
of interest that serum levels did appear to fall
slightly in the final stages.
Dr R Corocher (Verona) asked if any modification
had occurred with bilirubin transport during
cefuroxime treatment.
Dr Norrby had not studied the question, but
certainly bilirubin was normal in all patients.
They had a high proportion of narcotic and
alcohol addicts which he thought accounted for
the transaminase increases. Some such increase
might be observed even in patients on placebo.
Dr I Nakayama (Tokyo) asked Professor Simon if
he had compared i.m. injection with i.v. adminis-
tration and what phases had been used in his
2-compartment model.
Professor Simon had studied i.v. administration
only. The half-life in the model related to the
f-phase as the slow phase of elimination.