ANNLDO 8(12) 75--84, 1992 I S S N 0738-1751
EDITORIAL BOARD
Editor
H A R O L D C. N E U , M D
Collegeof Physiciansand Surgeons
ColumbiaUniversity,New York, New York
CONTENTS
EDITOR'S NOTE 75
Historical Overview of the
Cephalosporin Spectrum:
Four Generations of
Structural Evolution
Helio S. Sader
Ronald N. Jones 75
Editor's N o t e
Drs. Sader and Jones have provided a his-
torical perspective of the fourth generation
cepahlosporins. Do I agree with all of their
comments? In fact, third- and-fourth gen-
eration cephems are more active against
streptococci than cephalothin or cepha-
losporin, prototype first-generation drugs.
Is this important? Perhaps, since ceftriax-
one or ceftaxime might be better agents for
treating some streptococcal infections. In-
deed, they probably are better for brain ab-
scesses and endocarditis.
I also believe that none of the agents ~ -
ally inhibits Enterobactercloacaeor Acinetc~
bacter. Is the partial activity against
enten:xxx~ of importance for new agents
such as cefpirome and ~ p i m e ? Increasing
problems of enterococcal infections make
this worth evaluation.
Can we go further with cephems? Yes.
Chemically, it is possible to make more po-
tent agents The fourth-generation cepba-
losperins have along at a time when we
need better Gram-positive activity without
loss of Gram-negative activity. I believe that
these agents will play a useful role in hospi-
tal infections over the next few years
while we try to solve the problems of in-
creasing the uptake of cephalosporins
and stability to extended-spectrum heta-
[actamases.
ELSEVIER
V O L U M E 8, N U M B E R 12, D E C E M B E R 1992
Associate Editors
DANIEL AMSTERDAM, PhD
State Universityof New Yorkat Buffalo
and Erie County MedicalCenter
Buffalo,New York
S T E V E N L. BARRIERE, P h a r m D
UCLAMedicalCenter
Los Angeles,California
R O N A L D N . JONES, M D
Universityof Iowa Hospitalsand Clinics
Iowa City, Iowa
Historical Overview of the
Cephalosporin Spectrum: Four
Generations of Structural Evolution
HELIOS. SADER and
RONALD N. JONES
Department of Pathology, University of
Iowa College of Medicine, Iowa City, Iowa
52242
Cephalosporins are currently the most pre-
scribed antimicrobial agent and account
for a significant portion of the health care
budget in the United States and the world.
This phenomenon began in 1945 when
Professor Giuseppe Brotzu initiated his
search for antibiotic-producing microor-
ganisms) He isolated a fungus, Cephalospo-
rium acremonium, from seawater near a
sewage outlet in Kaglara, Sardinia, and
later discovered that this organism inhib-
ited the growth of a variety of Gram-posi-
tive and Gram-negative bacteria. The
active antibacterial factors were isolated
by Abraham and colleagues at Oxford Uni-
versity in the United Kingdon~L2 These
products included cephalosporin C (Fig-
ure 1), which was the origin of 7-amino-
cephalosporinic acid (7-ACA). The first
clinically available cephalosporins were
derived from 7-ACA. In addition to their
broad range of antimicrobial activity,
cephalosporins had the favorable features
of relative acid stability and resistance to
bacterial-mediated penicillinase.2
In this brief overview, we present an
analysis of the in vitro antimicrobial activ-
ity of most parenterai cephalosporins. We
reviewed more than 50 references, includ-
ing some of the most important in vitro
studies and reviews about each com-
CLYDE THORNSBERRY, PhD
Institutesfor MicrobiologyResearch
Nashville,Tennessee
L O W E L L S. Y O U N G , M D
KuzellInstitute for Arthritis and InfectiousDiseases
MedicalResearchInstitute of San ~ a n d s c o
Padfic PresbyterianMedical Center
San Frandsco, California
pound. We utilized only study results de-
rived from well-standardized in vitro test
methods, such as those described by the Na-
tional Committee for Clinical Laboratory
Standards (NCCLS). 3-s
Table 1 summarizes the minimum
inhibitory concentrations of each com-
pound required to inhibit 90% of the
strains tested (MICg0) and the respective
references from which the results were
taken. Most of the results included in this
table originated from multicenter studies
that tested thousands of clinical infection
strains. Several other studies and reviews
were also analyzed in order to evaluate
the variation of the antimicrobial profile
(rarer species) among the compounds. We
also discuss some other factors related to
the in vivo or in vitro activity, including
protein binding and superinfection during
chemotherapy.
The cephalospoHns are_very amenable
to modification of both their biologic and
pharmacologic properties. In general,
modifications at position 3' of the dihy-
drothiazine ring are associated with
changes in the pharmacokinetics, and
modifications at position 7 of the 7-amino-
cephalosporinic acid nucleus are associ-
ated with alteration in the antibacterial
activity. It is also possible to make a substi-
tution at 7-alpba position to alter ~-lac-
tamase stability.6,7
FIRST-GENERATION AGENTS
Cephalothin, the first cephalosporin
available for clinical use in the U.S., was
derived via acylation of 7-ACA with 2-
0378-1751/92/$0.00 + 2.20
 76 THE ANTIMICROBICNEWSLIdTIhR, VOLUME8, NUMBER12, DECEMBER1992

HOOC H2NOC\ /S~ OCH3 c,

N HO~CH-C-NH--r~S:"h N--N
C
NH
HC
2H2CH2-002-&
C-N~'~NS/,
~ CH-C-a H'4----~°"h N--N
~/ NH
I
~) UFq#LN.~ L-OH-sJJ fIN
2 -~N j
CH2-ICI-CH3 CO ~ r
1 COOH OH3 I

Cephalosporin
C
COOH O
C:: I
Cefotetan
COOH CH3

CH2CH3
Cefoperazone

N~C--C--NH~--K'S~
~=NN-c H2_C_N. - - w - - ~ S ~ ~l II II II I J / OCH3 O-
H2N/'~S / N %H 3 0 ~ l ' ~ - N ~ - C H2- N ~ , ~ HO--{' \~CH--C-N H - { - ~ / "h N--N
N-- ' II N--N
,N.".
II
--N O O~[~N~~ H2_S~..S.JJ_CH3 \O-C--COOH COOH
I
'oo.o o ~
I
COOH CH3 COOH CH3
Cefazolin Ceftazidime Moxalactam

~ -CH--C-NH~--n"/S~h
I II
I O O~L__~CH
O~H
[ I ! H
N--N
,
N~C~-N
_SJLNN H2N/"~S/ IJllN...OCH
~ I ~ ~
H ~ S " h
!/,
r/~
.I
30#~'~N C'~ooCHH#~
O COOH OH3 COOH O
Cefamandole Cefpirome Cefotaxime

FIGURE 1. Structure of cephalosporin C and eight other representative cephalosporins.

thienylacetyl chloride. 8 The treatment of
cephalothin sodium with pyridine dis-
places the acetate function at the 3-methyl-
ene cephem position, producing
cephaloridine, the second injectable (usu-
ally intramuscular) cephalosporin intro-
duced in the U.S. 9 The clinical successes of
cephalothin and cephaloridine stimulated
efforts to further improve the biological
properties of the basic cephalosporin nu-
cleus by chemical modification. A few
years later cefazolin sodium (Tables ] and
2, Figure 1), a parenteral c o m p o u n d with
improved pharmacoldnetics (q8h dosing)
and greater stability to TEM-1 plasmid-
mediated enzymes was developed by Fu-
jisawa scientists) °
In terms of antimicrobial activity, the
above cited first-generation cepha-
losporins (laGCs) are the most active
cephalosporins against Gram-positive
cocci, including oxacillin-susceptible
staphylococci and Streptococcus spp. How-
ever, these agents have only moderate ac-
tivity against a limited number of aerobic
Gram-negative bacilli, including Es-
cherichia coli, Klebsiella pneumoniae, and in-
dole-negative Proteus. 11-1s OxaciMn-
resistant staphylococci are not discussed
in this review because they should be con-
sidered resistant to all cephalosporins re-
gardiess of generation- 3 The non-penicil-
llnase-producing penicillin-resistant strep-
tococci and enterococci are also resistant
to the laGCs. This antimicrobial spectrum
does not differ among these parenteral 1st"
GCs or their oral counterparts (cephalexin,
cephradine, cephadroxil, cefaclor, loracar-
bef, eefprozil).
SECOND-GENERATION AGENTS
As a group, the second-generation
cephalosporins (2"dGCs)are more potent
than the l a G C s against E. coli, Klebsiella
spp., and Proteus mirabilis (Tables 1 and 2).
Individual members of the 2"aGCs extend
the spectrum of activity of the laGCs to in-
clude most Haemophilus influenzae and
some Enterobacter spp., Serratia spp., in-
dole-positive Proteus, anaerobes, Neisseria
meningitidis, and Neisseria gonorrhoeae.13-16
N o n e of the agents have demonstrated ac-
tivity against Pseudomonas spp. In general,
these agents are less active than the
lStGCs against Gram-positive bacteria.

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THEANTIMICROBICNEWSLETTER,VOLUME8, NUMBER12, DECEMBER1992
However, cefamandole (Figure 1) and ce-
furoxime have the advantage of maintain-
ing the IaGC activity against these
organisms. In addition, they both have a
wider Gram-negative spectrum of activity
and greater stability to [3-1actamases than
the laGCs. They are particularly more ac-
tive than the lStGCs against H. influenzae
(including activity against the B-lactamase-
producing strains), Neisseria spp., En tero-
bacter spp., and indole-positive
Proteus. 17-19 In terms of antimicrobial spec-
trum of in vitro activity, cefonicid and ce-
foranid most resemble cefamandole.
However, those compounds have some
pharmacokinetic advantages (longer se-
rum half-live). In vitro studies demon-
strated that, in comparison with other
lStGCs and 2nck3Cs, both cefonicid and ce-
foranid reach higher peak serum concen-
tration and their concentrations decline at
a slower rate. ~4'~s
The 2~GCs include the cephamycin
subgroup (cefoxitin, cefotetan, cefmeta-
zole), which are also related to cepha-
losperin C, but have two important
structural differences: first, all are charac-
terized by the presence of a methoxy
group on the 7-cephem nucleus; second,
the cephamycins have various substitu-
tions on the 3'-positiort 2°'2!The cephamy-
cins are produced by Streptomyces spp.
(filamentous bacteria), whereas cepha-
losporin C is produced by Cephalosporium
acremonium (fungus). The in vitro antimi-
crobial activity is comparable among the
cephamycin compounds; however, in this
sub-group, cefotetan has a significantly
greater activity against enteric bacilli (Ta-
bles I and 2, Figure 1). The cephamycins
have a broader spectrum of activity
against Gram-negative bacilli than the 1a
GCs and they are very stable to B-lac-
tamases, especially those produced by the
anaerobic Bacteroides spp. These com-
pounds are the most active cepha-
losporins against anaerobes; however,
they have one drawback--they lack high
potency and absolute activity against
Gram-positive aerobic and anaerobic or-
ganisms. 14,22-24
T H I R D - G E N E R A T I O N AGENTS
The third-generation cephalosporins
(3rdGCs) represent a very important devel-
opment in the evolution of [}-lactam antim-
icrobial agents. 2s These compounds
usually incorporate the aminothiazolyl
group and iminomethoxy groups, which
make the cephalosporin molecule [B-lac-
tamase stable and significantly more po-
tent than earlier generation drugs. 6
Moxalactam is an oxa-[~-lactam 3~GC
agent, not a true cephalosporin, since it
has an oxygen instead of a sulfur at the C1
0738-1751/92/$0.00+ 2.20
position (Figure 1). It was included here
because its spectrum of activity and phar-
macokinetic features most resemble those
of the 3~GCs. 26The 3~GCs may be di-
vided into two subgroups: those that dem-
onstrate important activity against
Pseudomonas aerug/nosa, and those with
more modest anti-pseudomonal activity.
The latterj~p'oup is represented by cefo-
taximeY, a' ceftriaxone,29,3°ceftizoxime,31
cefodizime,3z33 and moxalactam, 34"~6
which are compounds that possess very
similar in vitro spectra of antimicrobial ac-
tivity, with a few exceptions. The NCCLS
has included these compounds into the
same "spectrum classes" when testing
some organism groups. 3"4
Since cefotaxime is the 3~GC with the
most clinical experience and widest inter-
national use, it will be used for compari-
son with the other compounds in this
group (Table 2 and Figure 1). Cefotaxime
is slightly less active against Gram-posi-
tive bacteria than the lStGCs (S. aureus
MICs0, 2 gg/ml). However, it has a potent
broad spectrum of activity against aerobic
Gram-negative bacteria that is markedly
superior to that provided by both laGC
and 2ndGC drugs. Cefotaxime inhibits
more than 90% of Enterobacteriaceae, includ-
ing strains producing ]]-lactamases and
m a n y isolates resistant to aminogly-
cosides. The vast majority of E. coli, Pro-
teus spp., and Klebsiella spp. strains are
inhibited by less than 0.5 ~g of cefo-
taxime per ml. The susceptibility of Ser-
ratia marcescens, Enterobacter cloacae, and
Acinetobacter spp. strains are more in-
consistent, and Pseudomonas spp. strains
are usually less susceptible to cefo-
taxime (P. aeruginosa MICs0, 16
~g/ml). 27 Cefotaxime has only moder-
ate activity against anaerobes (partially
enzyme stable), which is inferior to that
of cephamycins against most Gram-
negative anaerobic species but is usu-
ally superior versus the Gram-positive
anaerobic species. ~
In spite of having very similar anti-mi-
crobial spectra, cefotaxime and ceftriaxone
differ in their half-lives, tissue distribu-
tion, and serum protein binding. In addi-
tion, cefotaxime can he metabolized to
desacetylcefotaxime, an active compound
with an activity superior to that of some
older cephalosporins. 37 Ceftriaxone is not
significantly metabolized, but it has a high-
affinity protein binding (>95%) compared
to other 3~lGCs (10 to 40%). Serum protein
binding by antimicrobial agents can affect
pharmacokinetic properties and antimicro-
bial activity. ~ Jones and Barrya9 demon-
strated that the in vitro antimicrobial
activity of ceftriaxone was markedly corn-
© 1992 ELSEVIERSCIENCEPUBLISHINGCO., INC.
77
promised by serum protein binding, re-
suiting in susceptibility categorya changes
(from susceptible to intermediate or resis-
tant) for nearly all staphylococci and some
Gram-negative strains that have ceftriax-
one MICs of 2 to 8 btg/ml. On the con-
trary, cefotaxime or ceftizoxime or
cefodizime or ceftazidime activity was
not adversely influenced by serum. Fur-
thermore, cefotaxime association with
its active metabolite, desacetylcefo-
taxime, showed a tendency toward
greater synergistic or additive activity
and MBC results closer to the MIC.
These characteristics are probably re-
sponsible for the low incidence of Gram-
positive (especially enterococci)
superinfection associated with the use
of cefotaxime. 4° Concerning the other
3'dGCs of this group, cefodizime is
slightly less active than cefotaxime
against Enterobacteriaceae. 32 Moxalactam
is the least active of the 3~GCs against
Gram-positive bacteria and it has vari-
able activity against P. aeruginosa. 34~ In
addition, moxalactam (Tables I and 2)
is the most active 3'dGC against Bactero/-
des frag/l/s, with a potency and spectrum
com Fya'able to that of the 2"dGC cephamy-
cins.~ In fact, the coverage of anaerobic
bacteria among cefoxitin, cefmetazole, ce-
fotetan, and moxalactam is not signifi-
cantly different.
The 3~GCs, which possess the im-por-
tant activity against P. aeruginosa
(Tables I and 2, Figure 1), include cefop-
erazone 41A2and ceftazidime. 43'44Cefopera-
zone is less active than other 3~lGCs
against some Gram-negative bacilli other
than Pseudomonas species. Ceftazidime is
the least active 3rdGC against Gram-posi-
tive cocci, but its spectrum is similar to ce-
fotaxime against most Enterobacteriaceae.
Ceftazidime is the most potent of the
3rdGCs against P. aerug/nosa, with MICg0
varying from 0.5 to 32 F~g/ml in several
studies reviewed by Richards and
Brodgen. 44 Cefoperazone has a greater
overall spectrum against typical patho-
gens than ceftazidime, principally be-
cause of superior Gram-positive and
anaerobic coverage (Table 2).
Despite the great advancement in the
antibacterial activity achieved by the
cephalosporins since the discovery of the
cephalosporin C, even the newer semi-syn-
thetic 3rdGCs appear to have some major
deficiency in their spectra. For example,
the increased activity of ceftazidime rela-
tive to cefotaxime against P. aerug/nosa is
at the expense of weaker activity against
staphylococci and streptococci, organisms
acceptably susceptible to other 3~IGC com-
78 THE ANTIMICROBIC NEWSLETTER, VOLUME 8, NUMBER 12, DECEMBER 1992

TABLE 1. MIC90 of the Principal Pathogens Tested against the 18 Parenteral Cephalosporins Discussed in This Review
Organism Cefazolin Cephalothin Cefamandole Cefonicid Ceforanide Cefuroxime Cefoxitin Cefotetan
Citrobacter 8 32 NR NR 1 8 2 2
diversus
Citrobacter 64 128 2 NR >128 8 >32 64
freundii
Enterobacter 64 >128 >128 >128 >128 8 >32 >64
aeYoge-nes
Enterobacter 32 >128 NR NR >128 32 >32 8
agglomerans
Enterobacter >128 >128 64 >128 >128 >32 >32 >64
cloacae
Esherichia coli 8 16 2 1 2 8 8 0.5
Klebsiella 8 16 2 16 2 4 8 0.5
pneumoniae
Morganella >64 >128 64 NR >128 >32 8 16
morganii
Proteus 16 8 2 0.5 1 2 8 0.5
mirabilis
Proteus >128 >128 >64 128 >128 >32 8 1
vulgaris
Providencia >64 >128 4 NR >128 8 >32 8
rettgeri
Serratia >128 >128 >256 >256 >128 >32 >32 8
marcescens
Acinetobacter >64 a >32 >64 NR >32 >32 NR NR
spp.
Haemophilus 32 8 2 1 8 2 8 2
influenzae
Pseudomonas >128 >128 >128 NR >32 >32 >64 >64
aeruginosa
Neisseria NR 1 0.5 0.25 8 NR 0.25 0.25
meningitidis
Enterococcus 16 32 32 >128 >4 >4 >32 a >32a
faecalis
Staphylococcus 2 0.25 4 8 >4 2 4a 16a
aureus
Coag- NR 0.5 NR NR >4 1 NR NR
negative
Staphylococci

Streptococcus 0.25 0.25 0.25 2 NR 0.25 32 >32

pneumoniae
References 11r 14 11r 12 11,14, 16 14 12 17 24 23, 24
a[f MICs were not based upon a log2 scale from unity (1 lag/ml), the results were rounded to that scale; NR = MIC90 not reported.
bThe organisms were not idenlified to the species level in that study.
CConsensusresults from references 46-49 for oxacillin-susceptible strains.
dMost results were taken from reference 49 because it evaluated a greater number of strains.

pounds (except moxalactam). In fact, the
extended activity against these species has
became a key determinant in evaluating
new cephalosporins, since they are among
the most important causes of contempo-
rary nosocomial infection,45 and com-
pounds that are highly active against
pseudomonads are less active than is desir-
able against the Gram-positive cocci.
In recent years, the success of the
3raGCs has been limited by the rapid de-
velopment of mutant plasmid encoded
TEM or SHV 13-1actamases, which in-
clude these agents as potential sub-
st-rates. Their ineffectiveness against
Citrobacter spp., Enterobacter spp., and P.
aeruginosa with derepressed chromoso-
mal 13-1actamases is another important
problem for the 3~aGCs. These pre-
viously noted and emerging limitations
have stimulated a continuous search for

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 THE ANTIMICROBICNEWSLETrE~ VOLUME8, NUMBER12, DECEMBER1992 79

TABLE 1. Continued
Cefmetazole Cefodizime Ceftaxime Ceftizoxime Ceftriaxone Moxalactam Cefoperazone Ceftazidime Cefepime Cefpirome
0.5 32a 0.25 _<0.12 0.12 _<0.5 2 0.5 0.03 0.25

>32 32 a 8 32 0.25 4 64 32 4 8

>32 32 a 1 32 0.25 4 2 32 0.5 0.25

>32 32 a NR 0.5 2 8 4 2 0.5 2

>32 32 a 2 4 32 8 8 8 4 8

1 0.5 0.5 ~0.12 0.12 _<0.5 1 0.5 0.06 -<0.12

2 0.5 0.25 ~0.12 0.12 _~).5 2 0.5 0.06 -<0.12

8 4 4 16 NR 1 4 4 NR 0.5

4 0.015 0.12 ~0.015 0.008 _<0.5 1 <0.12 0.06 _<0.12

2 16 2 _<0.015 4 <0.5 2 0.5 0.5 1

2 8a. 1 0.06 0.12 _<0.5 64 0.5 0.5 0.25

>32 16 8 2 64 8 16 1 1 1

NR 64 128 32 >128 >32 64 8 4 4

4 0.06 0.03 NR 0.12 0.12 <0.25 0.12 0.06 0.03

>64 128 64 >32 >128 >32 16 4 8 16

0.12 _<0.008 _<0.015 ~0.015 0.25 NR 0.015 0.03 _<0.008 ~0.008

>32a >256 >64 >32 >128 >32 64 >32 64 >16

2a 4 4 8 4 16 4 8 2 1

NR NR Ic 8c 8c 16 c 2c 8c Ic Ic

8 0.12 0.06 0.25 0.12 2 <0.25 1 0.5 0.25

24 32 27, 31 31 30 34, 35 41, 42 43 47 47, 49 d

further improvements in the cepha-
losporin molecule.
FOURTH-GENERATION AGENTS
Additional synthetic modifications have
been initiated to achieve a more balanced
spectrum and also greater stability against
the newer extended spectrum ~-lac-
tamases. The result is a fourth genera-
tion of c o m p o u n d s (Tables I and 2, Fig-
ure 1), which includes cefepime 46~ and
cefpirome. 4s,49 The fourth-generation
cephalosporins (4thGCs) have a reduced
affinity for class I ~ l a c t a m a s e s and an
increased outer membrane permeability
when c o m p a r e d to the 3~GCs. A posi-
tively charged quaternary nitrogen at 3"
position seems to be responsible for this
antimicrobial advance, which enhances
the activity against stably derepressed
class I ~-lactamase mutants of Enterobac-
teriaceae a n d P. aeruginosa, s° The 4thGCs

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 80
TABLE 2. Spectrum Analysis for Eight Representative Cephalosporins versus Critical Pathogen Groups a
Organisms Cefazolin Cefamandole
Staphylococci +++ +++
Streptococci b +++ +++
Enterococci - +
E. coli, Klebsiella, and ++ +++
P. mirabilis
Citrobacter, - +
Enterobacter , a n d
Serratia
Other enteric bacilli - -
Haemophilus, M . ++ ++
catarrhalis, and
Ne/sser/a
Pseudomonas - -
deru girtosa
B. fragilis - -
Gram-positive ++ ++
anerobes
a = <50% coverage of strains tested; + = 50-80%; ++ = 81-95%; +++ = >95%.
bIncludes only oxacillin-susceptible isolates.
have also demonstrated an excellent af-
finity for the lethal Gram-negative peni-
cillin-bindingproteins (PBPs). sl In
addition to improving activity against
Gram-negative bacteria, compared to
the 3~GCs, these compounds (espe-
cially cefpirome, Tables 1 and 2) im-
prove u p o n the 3'dGC activity against
Gram-positive cocci (S. aureus cefpi-
rome MICs0, 0.5 ~tg/ml).
Cefepime and cefpirome have similar
in vitro spectra of antimicrobial activity,
but some differences have been noted. Ce-
fpirome is slightly more active than ce-
fepime against Gram-positive bacteria
(Fable 1). In terms of in vitro activity
against Staphylococcus spp., cefpirome is
more comparable to laGCs while ce-
fepime is more similar to cefotaxime. They
are both very active against streptococci
and more potent than the 3~GCs against
the enterococci (Table 2). This acceptable
activity against Gram-positive organisms,
especially enterococci, may be associated
with a low incidence of superinfection
caused by these organisms.4° The 4thGc
are the most active cephalosporins against
Enterobacteriaceae and their activity against
P. aeruginosa is comparable to that of cefop-
erazone or ceftazidime. However, their ac-
tivity and spectra against Bacteroides spp.
are limited, thus requiring use of an an-
aerobic-active co-dru~ for empiric therapy
of surgical infections,s2
As we have pointed out above, the an-
timicmbial activity can be adversely af-
fected by serum protein binding (>95%).
Serum bactericidal activity (SBA) determi-
© 1992 ELSEVIERSCIENCEPUBLISHINGCO., INC.
THEANTIMICROBICNEWSLETI'ER,VOLUME8, NUMBER12, DECEMBER1992
Cefotetan Moxalactam Cefotaxime
++ ++ +++
++ ++ +++
- - + +
+++ +++ +++
+ +++ ++
+ +++ +++
++ +++ +++
- + + ++
++ ++ ++
++ ++ +++
nation is an important tool for comparing
pharmacodynamic characteristics of differ-
ent antimicroblal agents because these
techniques allow integration of pharma-
cokinetic and host factor (serum) antimi-
crobiai qualities,s3 SBA studies comparing
broad-spectrum antimicrobial agents54
have shown that cefpirome provides a
more potent SBA than those of other
broad-spectrum cephalosporins, such as
ceftazidime and ceftriaxone when tested
against S. aureus and E. doacae. Against P.
aeruginosa the best results were achieved
by ceftazidime and cefpirome. Cefepime
has also demonstrated good tissue pene-
tration and SBA against E. cloacae and P.
aeruginosa, but not against S. aureus, ss
In conclusion, we have observed a great
advancement in the antimicrobial activity
(Tables 1 and 2) and pharmacokinetic
properties of the cephalosporins since the
7-ACA molecule (Figure 1) was first dis-
covered more than 30 years ago. 1'2 First
we noticed a gradual improvement in the
activity against Gram-negative organisms
at the expense of weaker potency and
spectra (Table 2) as compared to the activ-
ity against Gram-positive bacteria. Re-
cently, the 4thGCs seem finally to have
achieved a highly active and balanced
aerobic antimicrobial spectra only to lose
activity against pathogens important to
the surgical service, e.g., anaerobic Gram-
negative bacilli. These compounds were
shown to be the most active cepha-
losporins against Enterobacteriaceae and as
active as the anti-pseudomonas 3~GCs
against Pseudomonas spp., a fact that al-
Cefoperazone C e f ~ z i d i m e Cefpirome
+++ ++ +++
+++ ++ +++
- +
++ +++ +++
++ ++ +++
+++ +++ +++
++ +++ +++
++ ++
+++ ++ +++
lows their use against some 3rdGC-resis-
tant isolates, probably with an aminogly-
coside co-drug. Furthermore, they have
demonstrated lStGC-like activity against
S. aureus, particularly cefpirome.
Despite the progress already achieved,
the search for more potent and stable
cephalosporin molecules must continue,
since new alterations in ~lactamases or
other bacterial mechanisms of resistance
can emerge with the continued wide-
spread use of these and other broad-spec-
trum [3-lactam compounds.
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Index to V o l u m e 8
Ac/net0baaer spp., 12:77, 79; 3:21 Carbacephems, 8/9:62
Agar dilution method, 8/9:54 chemical stability of, 8/9:62
Aminoglycosides, Enterococci resistance to, testing potential for future development, 8/9:62-63
of, 10/11:67, 69-71 Cefaclor, 1:3
Amoxicillin, 10/11:66 MIC, 8/9:61
Ampidnin, 1:3, 5 pharmacokinetic disposition, 3:22
Entenxx~cus resistance to, testing of, 10/11:65, Cefamandole, 12:77
66,67,68-69 MIC90 for, 12:78, 79
NCCLS susceptibility tests, with Haemophilus test spectrum analysis for, 12:79
medium, re-evaluation of, 4/5:31-35 Cefazolin
prophylaxis of surgical wound infec!ion by, 3:19 MIC90 for, 12:78, 79
Amsterdam D, 2:9-16 prophylaxis of surgical wound infection b~ 3:19
Anaerobic bacteria, susceptibility testing of spectrum analysis for, 12:79
E test for, 1:4-5 S. aureus resistant to, 3:18
importance of, 7:49-52 Cefixime, pharmacokinetic disposition, 3:22
review of current methods and future prospects, Cefmetazole, 12:77, 80
8/9"33-58 MICg0 for, 12:78, 79
Antimicrobial agents, See also specific agent Cefodizime, 12:77
history of, 2:9-10 Cefomdd, MICg0 for, 12:78, 79
t~le in surgical sound L,dectiot~prevention, and in Cefoperazone, 12:80
vivo model of prophylaxis, 3:17-20 spectrum analysis for, 12:79
Azabache DB, 6:37--44 Ceforanide, MIC90 for, 12:78, 79
Aztreonam, 1:5; 10/11:67 Cefotaxime, 1:4, 5; 12:77
spectrum analysis for, 12:79
Cefotetan, 12:77, 80
MIC90 for, 12:78, 79
Bacter0/d~s spectrum analysis for, 12:79
fragilis, 12:77, 79 Cefoxitin, 1:5; 12:77, 80
susceptil~lity testing, 1:4; 7:49 MIC90 fc~, 12:78, 79
spp., 12:77, 80 Cefpirome, 12:80
Barriere SL, 3:21-23; 4/5:25--31 spectrum analysis for, 12:79
13-1actam antibiotics Cefpodoxime, 3:21
carbacephems, 8/9:58--63, See a/so Carbacephems clinical trials on, 3:22-23
history of, 8/9:59-60 pharmacokinetic disposilion, 3:22
pharmacokinetics, 3:21 Cefprozil (Cefzil), 3:21
ring, 8/9:60-62 clinical trials on, 3:22
13-Lactamase,2:15; 3:18 pharmacokinetic disposilSon, 3:21, 22
Broth micredilution method, susceptibility testing Ceftazidime, 1:5-6; 12:80
with, 8/9:54--55 spectrum analysis for, 12:79
Ceftizoxime, 12:77
Ceftriaxone, 1:4; 12:77
Cefuroxime, 1:3, 4, 6; 12:77
Campylohacterjejuni, susceptibility testing, E test for, MICg0 for, 12:78, 79
1:6 pharmacokinet ic di sposi lion, 3:21, 22
© 1992 ELSEVIERSCIENCE PUBLISHING CO., INC.
Clin Microbiol Infect Dis 9:677-685, 1990.
53. Schimpff SC, Drusano GL, Standiford
HC: Serum bactericidal test in volun-
teers--a review. Eur J Clin Microbiol In-
fect Dis 5:71-78, 1986.
54. Paradis D, Vallee F, AUard S, et al: Com-
parative s t u d y of pharmacokinetics and
serum bactericidal activities of cefpirome,
ceftazidime, ceftriaxone, imipenem, and
dprofloxacin. Antimicrob Agents Chemo-
ther 36:2085-2092, 1992.
55. Kalman D, Barriere S, Johnson BL Jr:. Phar-
macokinetics disposition of bactericidal
activities of cefepime, ceftazidime, and ce-
foperazone in serum and blister fluid. An-
timicrob Agents C h e m o t h e r 36:453-457,
1992.
Cefzit See Cefprozil
Cephalexin
MIC, 8/9:61
pharmacokinetic disposition, 3:22
Cephalosporin(s), 10/11:67
early, compariscm of, 8/9:61
historical ov~view of, 12:75-82
MIC, 12:75, 76, 78-79
modifying nudeus of, carbacephems from,
8/9:62, See a/so Carbacephems
oral, new, 3".21-23
resistance to, 8/9:53
spectrum analysis for, 12:79
structure of, 12:76
susceptibility testing, 2:15
Cephalosporin C, 12:77
Cephalesporium acremonium 12:77
Cephalothin, 1:3, 6; 12:76
activity, 8/9:61
MICg0 for, 12:78, 79
Cephem, chemical stability of, 8/9:62
Cherubin CE, 6:37--44
Children, admihistration of new oral cepha-
losporins in, 3:21
Chlorampherdcol, 1:3
Ciprofloxacin, 1:3, 4, 5; 4/5:29
anttmicrobial activity, 4/5:27
clinical uses, 4/5:28
Enterucoccus resistance to, testing of, 10/11: 66, 67
pharmacokinetics, 4/5:28
Citrobacter, 12:79
diversus, 3:21; 12:78
freundii, 12:78
Citron DM, 8/9:53-58
Clindamycin, 1:3, 4, 5; 4/5:27, 28; 10/11:67
resistance to
in Peptostreptococcus species, assessment of, use
of E-test for, 7:45--49
in Streptococcus pneumoniae and Streptococcus
pyogenes, 6:37-44
Clostridium sl0p., 1:4
Cos/s, related to oral cephalosporins and other an-
timicrobials, 3:23
Croco JL, 7:45--49
0738-1751/92/$0.00 + 2.20