Pharmacologic Studies with Cefaclor, a New Oral Cephalosporin BURT

C

[3-chloro-7-D-

EFACLOR

mido) acid], losporin, vitro

3

-

a new has

a wide

and

drug

is

highly

variety

active influenzae,1’2

tamase-producing picillin.’ on

another

termine excretion tration

of both

resistant

Cefaclor

appears basis

this

The

be

to

de-

serum concentrations and urinary of cefaclor following adminisof either single or multiple doses

to normal

human

acid

and

trarisaminase

calcium, uric and protein-bound

before

and

ages 22-62 13 females,

Methods

years, including five were the subjects

moved

and

within

two

first

males and of these

single-dose

were

collected

From

the

partment of Medicine New 174

York,

of

Medicine, of the City N.Y.

fasting

studies, while

Division of

the drug and remained the study period. The the

10029.

and

volunteers

state all were

Infectious

Diseases,

The Mount University

Sinai of New

the

single-dose

fasting

volunteers Blood was at 0.5, 1, 2, 4,

specimens were the serum was

and

-70#{176}C for was collected then

ingestion. filtered

(PBI)

for

The and

8-24

urine

stored

imre-

assay for hours

was at

im-

-70#{176}C.

One week later the volunteers received 500-mg dose and blood and urine samples

volunteers,

obtained

were

for bloods fastDeSchool York,

as before.

were by sub tilis

specimens

dose

the

8 hours

albumin,

iodine

frozen at days. Urine

drug

fore ingestion of sedentary during

in

acid,

In

ten

and 6 hours. Blood mediately centrifuged;

Bacillus

were

of

phos-

potassium,

study.

Study.

each

acid

alkaline

sodium,

the

Single-Dose

studies. The weight of the volunteers was 63 ± 12 kg (mean ± standard deviation). The volunteers emptied their bladders be-

volunteers

after

mediately normal

(SGPT),

chloride, globulin,

hemocreat-

glut,amic-oxaloacetic (SGOT), glutamic-pyruvic

phosphorous,

the

volunteers.

Eighteen

Volunteers.

had normal urea nitrogen,

phatase,

after Materials

volunteers serum

swallowed 250 mg cefaclor. drawn at time zero and then

cocci.1 was

and

study

cephalosporin, study

All

mine, l)ihrubin, transaminase

more

cephalexin,

Gram-positive of

Gram-

to am-

to than

administered

purpose

cephaactive in

against strains of including /3-lac-

a weight against

The

ing. grams

carboxylic

-

bacteria.1’2

strains

orally

especially

4

-

Gram-negative

Henophilns

active

(phenylglycina-

cephem

-

orally administered been found to be

against

positive

R. MEYERS. M.D.. SHALOM Z. HIRSCHMAN. M.D., GARY WORMSER. M.D.. GARY GARTENBERG. M.D.. and ELINA SRULEVITCH. B.S. New York N.Y.

centration

Study.

study

each

250-

or

of five

In

additional

the

sixth

500-mg

Urine first,

was third, The

urine

collected and fifth Journal

multiple-

after for day

of

cefaclor

Blood samples the first mornand fifth day. was

12 hours

conusing

ingested

tablets

specimen

day,

the

volunteers

every 6 hours for five days. were collected 1 hour after ing dose on the first, third, An

and

assayed for cefaclor the disc method as the test organism.3

iIultJ)le-Dose

either

Serum

a

collected the

last

24 hours on of the study.

of Clinical

Pharmacology

on dose. the

PHARMACOLOGY

OF

of

Results

Single-Dose The

serum

achieved in

4.8 ± viation)

2.7

of

the had

250-mg A

dose

had

centration

of The

Three

of

of

detectable

at

0.5

no

detectable

other

deafter the

ten

one

of

these

serum

con-

throughout volunteers

the had

levels

of 3.2 and 4 ag/ml at 1 hour. The mean concentration of cefaclor was 6.09 ± 2.5 g/m1 at 1 hour after drug dosage and 2.48

1.7

±

g/ml

volunteers

had

of cefaclor Almost

at 2 hours. detectable

None

of the

in serum

con-

of cefaclor

were

achieved

with

the

dose

those

of the

dose (Fig. in the sera both

1B). No drug of two volunteers

volunteers

had

concentrations

of

Again,

was

no drug

of

250-mg

dose

similar

value

life

was

250-mg

was

detectable at 0.5 hour;

appreciable

serum

cefaclor

at

detectable

1

hour.

in the

at

sera

High found

study of

42

total ing

of

of the

first

Fig.

1. Serum

concentration

+ S.D.) after 250-mg (A) and April

1978

of cefaclor

was

after

excreted

oral administration 500-mg (B) doses.

of

single

of

excreted

was

excreted

during

per

cent dur-

The

dose

first

the

when

The

average

first 7.3

morning ig/ml for

of cefaclor

g/ml total

dose

was cent

and

Similarly,

19 41

of

the on

on

the

study, the third

in

1 and

5 of

32 per

of 250

mg

recovered on was recovered per per

higher dose was recovered

covered

recovered days

Thus, dose

day

cent,

on

cent

of the

of 500 in urine

mg on

27 second

the

the higher dose. of the daily ad-

ccfaclor

II).

after

1, B).

from 4.47 to dose and from

between

6 hours 20 per day,

ranged lower

days

2, A and 1 hour

for amount of

decreased

on

(Fig. levels

1

dose of either 6 hours were

determined

dose the

ex-

24 hours.

Study

study

serum

10.16 the

was

first

concentrations

5 of the

449

8 hours

of cefaclor

hour after the first morning 250 or 500 mg given every similar

was

administered

the

during

serum

dose

conthe

the next 16 hours. to 48 per cent of

Multiple-Dose

cent,

dur-

1.6

the

cent, during 45 per cent

in urine

day

during

only

a 500-mg cent

administered

creted

istered hours

(mean

was

dose

per

and 5.4 per Thus, only the

urine

next 16 hours. The average of cefaclor in urine during 43

day. 2

dose

250-mg dose was per cent of the

However,

8 hours

third

1

half-

500-mg

in

the

administered

ing the centration

every day,

0.5

a

the

of cefaclor were I). The average

dose

time.

the study (Table of the administered

HOURS

for

cefaclor

administered this

urine

2

the

minutes;

the

concentrations urine (Table

ministered

I

45

from

serum

from

minutes

first 8 hours after 364 g/ml. Forty-three

8.12 to However,

0.5

was

the

3, and

0

The

determined

derived

in

quite

E

4 hours.

cefaclor

study.

dose

centrations

above

volunteers

half-life

g/ml;

concentrations

at 4 hours. twofold increases

500-mg

the

GLOB

concentration

concentra-

hour;

cefaclor

two

are

concentration

drug. no

cefaclor

volunteers study.

1A.

cefaclor

g/ml (mean ± standard was achieved by 0.5 hour

ingestion of

of

a single

Fig.

volunteers tion

concentrations

after

shown

Study

CEFA

per day, (Table

cent and

cent given

the first on the the

fifth

adminevery 6 the first was

re-

22

per

II). 175

MEYERS,

HIRSCHMAN,

WORMSER,

TABLE Excretion

Urine Time

AL.

I

Concentration

and

ET

of Cefaclor

After

Cefacl

tion (hr) Excretion mean

±

% total

S.D. dose

Concentration mean ± range

(mg) (mean

S.D.

±

total

Concentration mean ± range

is a broad

to

S.D.

(mg)

dose

(mean

sporins, strains

oral 176

serum

administration

S.D.)

449

±

456

1.6

than

those

lexin,

and

the

1.25-1030

9.45

27

±

4

5.4

±

27

54

±

76 ±

15

±

154

0-140

0-490

111

240

45

48

found

for

cefadroxil,

cephradine.

Figure

comparative

serum

cepha3

shows

concentrations

active than cephaloand

sp., and fecalis,

Proteus mirab’ilis.’ Enterobacter sp.,

indole-positive sp. are resistant other orally

more active some GramEscherichia

orally

Proteus, and to cefaclor

-

E 0’

0 -J (1

w 0

administered

However, administered

in

contrast cephalo-

highly active influenzae1’2

against includ-

3

135

5 DAY S

/3-lactamase-proFig. 2. Serum

strains.1

The

412

10.4

derivative spectrum.

also appears to be latter drugs against bacteria including

ampieillin-resistant

ducing

±

penicillin-susceptible aureus and streptococci.”4

eefaclor is of Hemophilus

ing

27

dose

eephradine,

eefadroxil-against Staphylococcus

the

250

±

4 ± ±

(g/inl)

S.D.

be more administered

sporins-cephalexin,

to

±

43

0-1100

cephalosporin antibacterial

Cefaclor appears three other orally

and

213

30

364

(g/ml)

Discussion

cephalosporins.”2’4 to the other

76

±

(1ig/ml)

% total

Pseudomonas

±

43

Total amount recovered average (mg)

0-24

sp.,

107

(g/ml)

±

%

Serratia

S.D.)

500mg

Excretion

8-24

coli, Kiebsiella Streptococcus

or dose

250mg

0-8

Cefaclor than the negative

Doses

aiter

administra-

Cefaelor with a

Single

concentrations of cefaclor

achieved

with

were

lower

+

S.!).)

morning 500 mg

concentration

of cefaclor

(mean

ingestion of first dose after doses of 250 mg (A) or (B) given every 6 hours for five days. 1

The

hour

after

Journal

of

Clinical

Pharmacology

PHARMACOLOGY

OF

CEFACLOB

g/m1 half-life

for cefadroxil.7 of cefaclor

than those ministered The

of the other cephalosporin

serum

dose

all strains

pyo genes,

w

C-) 2

0

to

serum concentration 2 hours after a

0

sufficient lin-resistant The

HOURS Fig. 3. Serum concentrations of cefadroril,7 cephalexin,5’6 cephradine,7 and cefaclor after single oral doses of 500 my of each drug.

achieved after four eephalosporin serum

level

hour

following

lower

than

found were

for 15.2

500-mg oral derivatives.

of cefaclor the

g/ml

of the

concentration

drug

serum

cephradine

Urine

Excretion

of

strains

of

Escherichia

in the

and

than

even the MBC sp.2 Forty-three ministered dose of bacter

were

much

was

3

Mean

% 5

Mean

1978

S.D. daily

±

total

% total April

±

total

S.D. daily

with

Multiple

Daily

Doses daily

dose

500mg

±

S.D. daily

318

±

345

812

±

426

S.D.)

31.8

±

34.5

40.6

±

21.3

196

±

94

(mean

±

S.D.)

19.6

±

9.41

186

±

(mean

±

S.D.)

18.6

±

(mg) dose

6-hourly

±

(mg) dose

greater

strains of Enteroper cent of the adcefaelor was excreted

(mean

(mg) dose

minifor

for

250mg

%

the (MIC)

II

6-hourly Mean

and high

found

cefaelor

strains

Cefaclor

1

Kleb-

8 hours after either dose. The concentration

of

urine during the 250-mg or 500-mg

susceptible

Day

80 per

coli,

was

of Cefaclor

oral

over

at 1

14.9

cefaclor

a 500-mg

to inhibit

of

of penicil-

and Hemophilus influenzae of Proteus mirabilis.2 Very

sp.,

at be

aureus.2

after

sufficient

found would

cent

of eefaelor in urine far exceeded mal inhibitory concentration

TABLE Daily

cent

2 hours

concentrations

levels and

were

all strains

of 18 g/ml Peak

92 per

concentrations

at

siella

doses of the The peak

of 12.8

ingestion

cephalexin.5’6 g/ml for

serum

aureus

of cefaclor 500-mg dose

Staphylococcus

dose

and

However,

cefaclor and requires for inhibition.2 The

to inhibit

achieved

34

Strepto-

streptococci,

Staphylococcus

is more resistant higher concentrations

mg the

of penicillin-sus-

pneumoniae.2

penicillin-resistant

z

cefaclor

aureus,

viridans

Streptococcus

ad-

dose of 250 2 hours after

Staphylococcus

coccus

I-

of

an oral even at

to inhibit

ceptible

I-

three orally derivatives.

concentrations

achieved after were sufficient z 0

Indeed, the serum appears to be shorter

530

±

134

26.5

±

6.7

138

444

±

179

13.8

22.2

±

8.9

177

MEYERS,

in

urine

during

the

able to the 45 viously reported The after mg

first

achieved

at

multiple

doses

of

250

over

both

the

higher

urinary

pathways

the

may

multiple

have

doses

of

metabolism and is

as unaltered dogs istered

in only oral

rats

unchanged

in

peared

to

metabolic

be

or

by

the of rats, that

almost

unchanged

primarily

by However,

in

cefaclor more

in dogs

labile

to

in rats

or mice. Seventy-five per cent of the oral dose of radiolabeled cefaclor was absorbed from the gastrointestinal tract in dogs, and

the

biotic Biliary

bioavailability was approximately excretion played

in the and

elimination kidney

greater vial

fluid

not

also

These

in

from

the

sufficient found hibit

and

cefaclor cephalosporin marked

show healthy

Only

is

treatment

blood.8

bacteria. other derivatives

unteers of 250 trations

antimicrobial

where may

play

role. The drug appears to trials of its efficacy in the patients

with

various

types

1 hour and 500

after mg,

concentrations

was voldoses concenwere

single oral respectively. declined

doses The

rapidly

no drug was detected at 4 hours. high concentrations of cefaclor were during

the

first

8 hours

gestion of the

of the drug. Forty-three total dose was excreted

during

the

first

cumulation

8 hours.

of

multiple-dose

drug

after

in-

per cent in urine

There

in

and Very found

was

serum

no

ac-

during

the

studies.

References 1.

2.

in is

a new oral cephalosporin, to 18 normal human,

in either single or multiple and 500 mg. Mean serum of 6.09 and 12.8 g/ml

achieved of 250

levels 0

Bill,

N.

J.,

and in

Washington,

parison cephradine,

of

vitro and

Agents

Chemother.

Meyers, B. R., and microbial activity new ceplialosporin. 85 (1978). Meyers, B. R., Hirschman,

in vitro J. Clin.

Antimicrob.

A.:

cephalexin, Antirnicrob. (1977).

Z.:

S. of

iii

Agents

human

Anti-

cefaclor,

Pharmacol.

B., Ynncovitz, Pharmacological

Z.:

Com-

of

Hirschman,

Ribner, S.

J.

activity cefaclor. 11:470

cefamandole

with

un-

cefaclor

is well

a 18:

S., and studies volunteers.

Chemother.

9:140

4.

Buck, R. E., and Price, K. E.: Cefadroxil, a new’ broad spectrum cephalosporin. Antimicrob. Agents Chemother. 11:324

5.

Meyers, L.: arid

6.

Nicholas, P., Meyers, B. B., and Hirschman, S. Z.: Cephalexin: pharmacologic evaluation following oral and pareiiteral administration. J. Gun. P/iarmacol. 13:463 (1973).

volunteers

tract of

orally

bronchitis influenzae

(1976).

human

The

chronic

treatment

infections.

Cefaelor, administered

Syno-

eliminated

that

serum and Gram-positive

of

cefaclor

in the

Summary

liver levels

those found cephalexin

gastrointestinal

over

cent. role

significant to hand,

concentrations

both in susceptible

negative

in

important warrant clinical

kidney.5’#{176}

studies

absorbed

drug.

contained

comparable the other

by the

anti-

radiocarbon found

metabolized

changed

178

of the that

intact

60 per only a minor

contained

than

of cefaclor blood. On

its

of the

with

in urine

ap-

than

Thus,

useful

of Heniophilus

serum

renal

of the adminwas recovered

considerably

degradation

to

in

Thus,

influenzae.

an

of

AL.

the

et al.8 found

mice.

urine.8

for for

a study

14C-cefaclor

and

500

fifth day. metabolic

In

per cent of eefaclor

ET

be especially

strains

were

induced

Sullivan

21.5 dose

1 hour

doses,

the that

been

antibiotic

excretion

to

eliminated

may

pre-

appeared

cefaclor. of

dogs,

cefaclor

lower

first suggest

Hernophilus

we

no evidence However,

of cefaclor

from findings

compar-

period

was drug.

and

excretion

decrease These

either

a five-day

and there of the

WOEMSEB,

of patients

levels

cefaclor

mice,

8 hours,

per cent excretion for cephalexin.8

serum

comparable, accumulation

the

HIRSCHMAN,

and

that

antibiotic

are

urine and

to inGram-

advantage

of

in

administered appears activity

to against

be

(1977).

Clin.

B. R., Kaplan, K., and Weinstein, Cephalexin: microbiological effects pharmacologic parameters in man. Pharm.

The

Journal

Therap.

of

10:810

Clinical

(1969).

Pharmacology

PHARMACOLOGY 7.

Pfeffer, Perche

M.,

human

De

Jackson, Menezes,

oral

clinical

cefadroxil,

cephalexin

Antimicrob.

Agents

A.,

Ximines, J., J.: Comparative pharmacology and

Chemot

OF

and of

April

Sullivan, Quay,

1978

H. R., J. P.,

Due,

and

of

14C-cefaclor,

a cephalosporin laboratory

Chemother.

anti-

ani10:

11:331

(1977). 8.

lism

biotic, in three species of mals. Antimicrob. Agents 630 (1976).

cephradine.

her.

CEFACLOR

S. L., Kau, D. L. K., Miller, W. M.: Metabo-

Address man, M.D., New

York,

reprint The N.Y.

requests to: Shalom Z. HirschMount Sinai School of Medicine, 10029.

179