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A perspective of cephalosporins in pneumonia. R W Quenzer Chest 1987;92;531-535 DOI 10.1378/chest.92.3.531 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/92/3/531.citation
Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright1987by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692
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L:-
special rePorts A Perspective RonaldW
S
everal important account when situations the most highly effective
not
lead For
Quenzer,
the etiologic at the site
to
agent; of the
emergence
editorial
of
comment
(2) reaches infection; (3)
resistant
see
in Pneumonia
M.D.*
considerations must be taken into selecting antibiotic therapy. In all appropriate drug is one that: (1) is
active against concentration
does
of Cephalosporins
micro-
producing The sented
Since in
organisms; (4) has low toxicity; and (5) can tered by the desired route. The cost ofan
be adminisantibiotic is
also
and
a factor,
but
is secondary
to efficacy
toxicity
factors. The cephalosporin class wide spectrum of bacteria, trations
against
tions,
most
rarely
ratio,
and
of dosage continue
and
ble
has
the
an
and
deserve
current
emergence
newer
the
a
will of
relative
aminoglycosides and
cephalothin,
mono-
became
in
longer
half-life
(ie,
1964.
availa-
injection, levels and
cefazolin),
the
properties and toxicities The second-generation extension against *Associate
of
the
Professor,
oflnfectious
of General Medicine, University of New cine, Albuquerque. Reprint requests: Dr Quenzer, University 2211 Lomas, NE, Albuquerque 87131
also
in the United States or so available thirdmore under investiga-
categories.
antibiotics
rins,
carbapenems,
with
a terminal
requires
OF
(ie,
penicillins,
monobactams)
step
linking
of
in
occur
only
the
inner However,
does
not
cell
cell
Table First-generation
wall
which
synthesis.
The
of the beta-lactam ring (Fig 1). The
if the
cephalosporin
proteins
(PBP),
that
of the result
cephalospointerfering
synthesis
peptidoglycan
membrane
synthesis. binding necessarily
by
act
cephalosporin nucleus consists attached to a dihydrothiazine will
ACTION
can
bind
enzymes
located
catalyze
the
cephalosporin in inhibition
1-Classification
ring activity to on
pep-
to a PBP of bacterial
of Cephalosporins
Second-generation
Third-generation
Cephalothin
Cefoxitin
Cefotaxime
Cefazolin
Cefamandole
Moxalactam
Cephapirin
Cefuroxime
Cefoperazone
Cephradine
Ceforanide
Ceftizoxime
Cephaloridine
Cefotetan
Ceftazidime
Cephalexin
Cefmetazole
Ceftriaxone
Cefadroxil
Cefonicid
Cefmenoxime
Cefotiam
Cefsulodin
microbiologic
spectrum but
Division
more have a
are similar (Table 1). cephalosporins emphasized
antibacterial
Enterobacteriacae,
generation
tidoglycan
Initially,
on intra-muscular higher blood but
reprebroad-
potent,
practical for clinicians to become knowledgeable one agent in each ofthe first-, secondand third-
penicillin-binding
States
less painful of reaching
most about
Beta-lactam
at a range
of their
quinolones
1). are
there are more commonalities in significant differences, it seems
MECHANISM
cephalosporins were limited to two parenteral dosage forms, cephalothin and cephalondine. These were followed by oral as well as new parenteral formulations that are capable
tion (Table 1). Because each generation than
resistant
cephalosporins in the treatment and
(Table
secre-
routes
discussion
B fragilLs
cephalosporins diverse group of
the release ofcefotaxime there are now ten agents with several
1981,
generation
therapeutic-toxic
by all three
carbapenems,
United
against concenof
acceptable
penicillins
in this setting. first cephalosporin, in
the
active effective
in respiratory
schedules. Therefore, to have a principal role
to the
bactams The
to
can be delivered
pneumonia value
pathogens
leads
microorganisms,
is highly reaches
and
spectrum beta-lactam antibiotics. The agents have a broader spectrum of activity and more stability to several ofthe beta-lactamase enzymes than do first- or second-generation cephalosporins.
390
page
H influenzae third-generation by a very
not
only
beta-lactamase
Disease;
Chief,
Mexico
School
Division of Medi-
Cefbuperazone ofNew
Mexico
Hospital,
Cefpiramid
CHEST
I 92
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I 3 I SEPTEMBER,
1987
531
Bacterial several penetrate
resistance
to cephalosporins
mechanisms. through
may
occur
by
First ofall, failure ofthe drug the outer wall porin channels
to of
bacteria will restrict the drug from reaching its site on the PBP Gram-positive organisms have permeable cell walls than Gram-negative orga-
some target more
nisms so antibiotic
this is resistance
not
an
important Staphylococcus
for
mechanism of and Strep-
tococcus. A second
mechanism
production by tive organisms
ring
nantly
Dihydrothiazine ring 1. Cephalosporin
FIGURE
as
occurs
penicillinases
or
may
This
may
be very
occur
sensitive
because:
(a) some
to cephalosporins
role in cell wall metabolism, govern cell wall synthesis
(b) other and are
PBPs may
the
cephalosporinases.
The
with a cephalosporin ring causing the ring
open
ofthe
and
result
in inactivation
drug
that
Staphylococcus
have
no
side
the
PBPs that sensitive
do to
negative riplasmic
wall
their
organisms space.
2). This
and
beta-lactamase
as an exoenzyme,
whereas
contain the Characterization
is to
resistance genetically and vary
concentration
sp excrete
cell
(Fig
mechanism of bacterial These enzymes are chromosomes or plasmids
in their location, characterization, enzymatic activity. growth.
from
and Gram-negathat act predomi-
basic reaction ofbeta-lactamase hydrolysis of the beta-lactam is a very important to cephalosporins. mediated through
nucleus.
of resistance
many Gram-positive of beta-lactamases
outall Gram-
enzyme in their peof the beta-lac-
cephalosporins have little to do with the direct antimicrobial effects, and yet, (c) other PBPs that are not only involved with cell wall synthesis and are sensitive
tamases is confusing because ofthe varied classification systems proposed by different investigators. The TEM beta-lactamases are the most common enzymes found
to cephalosporins
in clinical
drug. drug
resist
The killing still require
biotic-PBP binding understood. Mechanism
reaction
of Bacterial
Clinical
and/or
therapy
the
inhibitory
effects
of the
and lyses ofbacteria by a beta-lactam other steps subsequent to the antithat
are
less
completely
Resistance
bacteriologic
of appropriate
nisms;
(b)
nisms;
(c)
non-immune
abscess, necrosis, superinfection (eg, to reach vascular
local obstruction, candidiasis);
to resistance.
tamase situations,
in
defense
disorder
(eg,
foreign material); (d) (e) failure of antibiotic
the site of infection (eg, blood-brain insufficiency); (f) bacterial resistance
antibiotic.
barrier, to the
ber
is that
532
Arrow
Alteration
site
ofbeta-lactamase
attack.
large
Some
in to
amounts
certain greater of beta-
cephalosporins
beta-lactamase other
ofPBPs
of bacterial beta-lactam
(eg,
and
distinct,
range
properties and tissue
gives
peak MIC
blood level should of the infecting Perspective
self-
mechanism
considerable sensitive
species to individual
Characteristics
level
A
important
show
Pharmacokinetie
little
cause
to cephalosporins and other These PBPs are biochemically
are preferentially antibiotics.
is a wide
may
cephalosporins.
in another
resistance antibiotics.
functionally
Selected
indicates
make
beta-
in some also con-
of beta-lac-
small, but be induced
may
or inactivate
There
2.
is
bacteria
an inducible
destruction
macokinetic effect blood
FIGURE
concentration
constitutively.
variation, beta-lactam
ONH
of other found may
cefoxitin) are known to be a very effective inducer of beta-lactamase, but are minimally susceptible to hydrolysis, while others are much more susceptible to hydrolytic action. An important principle to remem-
and
E.1-
a number
The
some bacteria the enzyme Other
lactamase
one or several concomitant factors: (a) host’s systemic immune defense mechaabnormal local immune defense mecha-
although
as OXA and PSE and Pseudomonads
tribute
amounts. failure
reflects
compromised
isolates,
lactamases, such Enterobacteriaciae
of difference
in
of the cephalosporins concentrations. The
indication
ofthe
peak
be some organism.
of Cephalosporins
phar-
peak
which blood
level.
small multiple By convention,
in Pneumonia
Downloaded from chestjournal.chestpubs.org by guest on July 11, 2011 © 1987 American College of Chest Physicians
tissue
the
The of the the
(Ronald W. Quenzer)
market
in the
1985.
United
Fifty-six
sporins, penicillin cent), broad-spectrum
OCH3
noglycosides
(9.5
was
COONa 3.
N-methylthiotetrazole
side
CH3 chain
The
on cephalosporin
nu-
an
cleus.
blood levels of twoto four-fold organism is thought to be appropriate bacterial
pneumonia
and
most
the
other
MIC of for treatment infections.
possible that, despite a high blood level, may not receive an adequate concentration In order to achieve effective tissue levels, otics tered
which either
ensure
are excreted frequently
tissue
levels
equilibrated
with
efficacy
is still
binding percent
of cephalosporins and the relative
antibiotic
controversial.
while
be large
It is
adminisdoses to
adequate ofthe
blood
therapeutic
The
degree
bound
of protein-
from 15 to 95 activity of the
is still
unknown.
Adverse quent. sitivity
effects
due
The most reactions
gastrointestinal
to
side-effects percent in 5-10
reactions
tion has been treated with
cephalosporins
common in 1-5
reported in cephalosporins.
5-10
are are
and
percent.
infre-
hypersennonspecific Supennfec-
percent of patients Coagulopathy and
disulfiram-like reactions have been observed in several cephalosponns that possess an N-methylthiotetrazole (MTT) group at the 3- position of the dihydrothiazine ring (Fig 3). Moxalactam, cefamandole, cefoperazone, cefmenoxime and cefotetan all contain this MTT side group. Risk factors for bleeding include malnourishment, hyperalimentation, hepatic disease and high-prolonged patients patients
should
receive
receiving
monitored
one
for prolonged
prophylactic of these bleeding
severe renal dosages.
vitamin agents time.
illness, failure, These
The factor corporate element,
cost element of managing
is indeed an extremely the infected patient.
policies have directed but should not subordinate and
toxicity
factors.
The
our
expensive”
half-lives and basis allowing Therefore,
important Federal and
antibiotic
expensive
cephalosporins
the
used.
directly prophyon
a percost of major,
the hospidetermiand labora-
adverse effects or care. Many of the have
longer
serum
greater potency on a weight-to-weight for less frequent and lower dosing.
“Hidden” antimicrobials
total
drug
expense
would
laboratory costs can such as aminoglycosides These
blood levels therapy, but alone, these
drugs
be
be lessened. observed when or vancomycin
regular
require
monitoring
of
and renal function to assure effective yet to avoid toxicity. From this standpoint drugs can become more costly to use than
cephalosporins.
ated
renal
anthem fever
failure,
can
reaction,
for a drug
of unknown
Emergence
and treating complications are very difficult to estimate. costs of an antibiotic-associ-
anaphylactoid
or work-up
fever
Organisms rapidly
severe
that
possess inducible resistance to the
develop
Serratia
marcescens
undetermined,
but
patients
infections
beta-lactamases newer cephalo-
close
with The
during
attention
to these
sec-
extent therapy
of is
organisms
is required.
with
the
atypical
pneumonia
monia
generally
should
than cephalosporins. monia syndromes tive therapeutic immunoincompetency, the
SYNDROMES
usual
monia,
and
associated cloacae
treated
cephalosporins. emerging
PNEUMONIA
tion,
as a
origin?
ond- or third-generation this problem of resistance and
ex-
masquerading
sporins. This phenomenon is most closely with Pseudomonas aeruginosa, Enterobacter and
of
of Resistance
Patients
attention to this the importance of
injectable
are
tory, costs ofdiagnosing and treating complications, and costs of hospital
K, and all should be
Cos’rs
33 percent
the per-gram (acquisition) the only, nor is it the
The costs ofdiagnosing antimicrobial treatment What are the additional
TOXICITY
all others (3.7 in the hospital
for nonsurgical
cephalosporins
in
vancomycin
and usage
determinant of the overall cost of treating talized infected patient. Other important nants are “hidden costs” of the pharmacy
“more
in sales for cephalo-
ampicillin (2.6 per(10.8 percent), ami-
therapy,
10. 7 percent
However, is not
was
percent) of the
disease
newer
basis. antibiotic
are to therapeutic
may vary antimicrobial
it is protein
the of
the tissues ofthe drug. most antibi-
rapidly should or at sufficienfly
levels. However, the exact duration concentration is not clear. The relationship of protein-binding
efficacy
gram
billion
clindamycin,
(13.6 percent
and
$1.3 sales
percent), penicillins
percent),
for infectious
for surgery, laxis.
was
of these (3.8
and metronidazole percent). Fifty-six
FIGURE
States
percent
community-acquired syndrome be
treated
with
However, there in which cephalosporins agents:
pneu-
or chronic are
pneu-
agents
other
four
pneuattrac-
are
pneumonia associated with gastric aspiration, hospitaliza-
aged. CHEST
I
92
I
3
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I
SEPTEMBER.
1987
533
in Immunocompromised
Pneumonia
Except operative,
when a cellular bacteria are
agents
of
hosts. ratia,
immune the most
pneumonia
in
the
common
immunocompromised
Gram-negative
is the most common patients. Rational
selected
based
immunologic monas and Serratia
the
cephalosporins lactamases
either
or minimally
or possess type that allow resistance
therapy with aminoglycoside
a cephalosporin combined
is the
microorganisms of usual
Streptococcus and
may
be appropristatus of the and precise mi-
of aspiration pharyngeal
viridans,
Bacteroides
enhance
pneumonia and gastric
microaerophilic non-fragilis
bacterial for
colonize tionally, the
groups
concentration
aged
organisms ‘freatment
for
Gram-
more broad-spectrum with a newer cephalosporin combined with penicillin or clindamycin. Cephalosporims (ie, cefoxitin, cefotetan) that have good to excellent activity
against
most
Nosocoinial The lance
responsible infection monia 534
there
are
no
comparative
Pneumonia
1984 (NNIS)
counted tions,
B fragilLi,
including
anaerobes,
may be used alone, but studies to support this.
National program
for 17.8 exceeded for rate confers
Nosocomial showed
percent only
Infection Surveilpneumonia ac-
ofall hospital-acquired by urinary tract
38.5 percent. was 16.6 percent. the
that
highest
percent), percent),
The
surgical Nosocomial
mortality
rate
infecinfections wound pneuat
25-50
infections.
recognition,
Efforts
as well
to
as more
regimens will have a major impact morbidity and mortality. Gramaerobes make up about 60 percent of the
The NNIS
frequency
of
various
is P aeruginosa
data
(16.9
Kiebsiella (11.6 percent), Enterobacter (9.4 E coli (6.4 percent), Serratia (5.8 percent),
Proteus Conditions
(4.2
percent) or diseases
and that
(12.9
S aureus in particular
percent).
predispose
to
Gram-negative aerobic bacillary pneumonia are longed hospital stay, recent antibiotic exposure, rious illness, immunosuppression, debilitation, tracheal
proseand
intubation.
fraditionally, an aminoglycoside in conjunction with an anti-staphylococcal agent has constituted appropriate initial excellent
therapy evidence
generation
in this situation. that monotherapy
cephalosporin
There with
is as efficacious
is now a third-
as combina-
tion therapy in non-neutropenic patients. At best, curative therapy for nosocomial Gram-negative pneumonia is 65-85 percent. Cefotaxime and ceftriaxone have better activity than against Staphylococcus ceftazidime shows monas and Serratia. frequently resistant the
new
with Serious
third-generation Streptococcus,
is now
the
against Pseudocakoaceticus is Imipenem,
drug
an aminoglycoside Gram-negative
agents while
ofchoice
as an pneumonias
for this alternate due to
Serratia or Enterobacter may still combination therapy with an aminoglycoside a broad-spectrum penicillin or third-generation
quire plus be
other and
superior activity Acinetobacter to all cephalosporins.
carbapenem,
cephalosporin.
hypopharyngeal may need to be
early
pneumonias.
stomach
and
nosocomial
and
from
P aeruginosa,
a propensity
to colonize their in these situations
nosocomial
treatment. gastrointherapy may organisms to system. Addipatients or
major
effective treatment on hospital-associated negative bacillary
organism, agent.
predominate,
in the
have
are flora.
Streptococ-
more pathogenic Bacteroides the upper gastrointestinal hospitalized or institutionalized
debilitated
negative region.
ther-
the other available and Serratia sp.
so moderate-dose penicillin is appropriate Gastric or intestinal motility disorders, testinal surgery or cimetidine/ranitidine
allow
An
Syndrome
representatives
cus
to
betamono-
conventional
Modification ofthis empiric regimen ate depending on the immunologic patient, epidemiologic circumstances, crobial sensitivity data.
The
sensitive
1 chromosomal to develop,
is more active than against P aeruginosa
Mendelson’s
and
is to be discouraged. with a broad-spectrum
or cephalosporin
apy. Ceftazidime cephalosporins
pathogen must be
epidemiologic
of the prevention
pathogens
Because most Pseudomany Enterobacter and
and
resistant
Serthe
are
whereas
Gram-positive empiric therapy
existing
circumstances. Acinetobacter
are
penicillin
on
Enterobacter, Legionella pathogens,
S aureus in these
effect
defect is singularly common etiologic
Pseudomonas, Klebsiella, E coli, Acinetobacter and
most
percent
Hosts
avoided
due
transferable
Combined to the
or drug
resistance Pneumonia
Bacterial
Eleven
beta-lactam problem
in the
percent
of
therapy inducible
should and
in
United
antagonism.
Elderly
of the
population
the
States is over 65 years ofage. This group consumes 30 percent ofthe health care dollars due partially increased
re-
over to an
prevalence,
morbidity and mortality of inAerobic Gram-negative bacillary organisms (ie, H influenza, Klebsiella, Enterobacter, E coli, Legionella) are more often the etiologic agents than in younger patients. This is because 30-50 percent
fectious
diseases.
ofaged
patients
homes
have
live
bacilli.
residing pharyngeal
in hospitals
or skilled
colonization
Appropriate
empiric
broad in spectrum or be organism(s) as ascertained
based
nursing
Gram-nega-
therapy
must
be
on a most probable examining acceptable
from
samples
with
respiratory
secretion
pectoration procedures
and more commonly by (ie, nasotracheal aspiration,
obtained
rarely
by
ex-
minor invasive transtracheal
bronchoscopy).
aspiration,
A
Perspective
of Cephalospolins
in Pneumonia
Downloaded from chestjournal.chestpubs.org by guest on July 11, 2011 © 1987 American College of Chest Physicians
(Ronald
W. Quenzer)
Many can
antimicrobials
potentiate.
noglycosides at 2 percent.
have
adverse
The
nephrotoxicity
ranges These
from 5-10 complications
greater in the Carbenicillin
effects
that
reported
age
from
ami-
and ototoxicity be significantly
percent may
more
nearly
5 mEq
Na/g
which
generation
drug
as initial
cephalosporin therapy
microbiologic antibiotic
in the unless
specimen
aged.
Therefore,
would the
be an clinical
would
direct
a thirdappropriate situation
a more
or
narrow
agent.
The
diagnosis
of
roentgenogram,
rests
pneumonia
examination
of the
secretions, and assessment pleural fluid cultures, when the etiologic agent, negative pneumonias
of the positive,
on
lower
the
important select
questions the
most
must
or for
of Gramon blood
that an infection several general
be considered
appropriate
the
patient
have
but
of the very
to empirically
antimicrobial(s).
an
immunocompromised disease
would
fibrosis immune
to
state? predispose
S aureus defects to
underlying Chronic
First,
lung
has
disease
obstructive
to H influenza
or P aeruginosa, varied opportunistic
any
would
pathogens
and
put
important him
predominant
surveillance
Gram-positive
or
(her)
pneumonia experience
at
synwith
cultures?
is useful information for evaluating nosocomial tions. Fifth, does the patient’s sputum smear
This infecreveal a
Gram-negative
flora
with rare squamous cell contamination. If not, this sample is useless in directing antimicrobial therapy. Cephalosporins have a definite place in the therapy of pneumonia in the immunocompromised victim of gastric aspiration, the hospitalized
host, the patient
and
utility
the
aged.
These
agents
have
of patients with atypical pneumonia
and and
or lung cystic
systemic infections.
SUGGESTED
little
if any
in
community-acquired syndrome or chronic
READING
Hewitt WL. The cephalosporins and cephamycins: In: Remington JS, Swartz MN, eds. Current infectious diseases, vol 2. New York: McGraw-Hill, Neu
the patient recenfly received antibiotic therapy? This would select for more resistant organisms. Second, does
that
respiratory
patient. Blood are definitive
but only 20 percent will show positive
been decided tract exists,
experienced
pneumonias.
chest
cultures. Once it has lower respiratory
patient
risk for atypical or chronic Fourth, what is the recent
the therapy pneumonia,
CONCLUSION
the
exposure(s)
nosocomial
elderly. contains
toxicity
has
epidemiologic increased dromes?
can precipitate heart failure. Long-acting sulfa drugs may potentiate the hypoglycemic effects of oral diabetic agents. Erythromycin may induce theophylline toxicity in COPD patients. Tetracyclines and isoniazid show
Third,
HC.
The
new
beta-lactamase-stable
a perspective.
topics
clinical
in
1981
cephalosporins.
Ann
In-
tern Med 1982; 97:408 Neu HC. The emergence ofbacterial resistance and its influence on empiric therapy. Rev Inf Dis 1983; 55:59 Nikaido H. Nonspecific transport through the outer membrane. In: Inauye M, ed. Bacterial outermembrane. NewYork: John Wiley and Sons, Inc. 1979 Sanders CC, SandersJr WE. The cephalosporins and cephamycins. In: Peterson PK, VerhoefJ, eds. The antimicrobial agents, Annual 1. New York: Elsevier, 1986 Spratt BC. Biochemical and genetical approaches to the mechanism ofaction ofpenicillin. Philos ‘frans R Soc London Biol 1980; 289:273 Tomasz A. The mechanism of irreversible antimicrobial effects of penicillins: How the beta-lactam antibiotics kill and lyse bacteria. Ann Rev Microbiol 1979; 33:113
CHEST
I 92 I 3 I
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SEPTEMBER.
1987
535
A perspective of cephalosporins in pneumonia. R W Quenzer Chest 1987;92; 531-535 DOI 10.1378/chest.92.3.531 This information is current as of July 11, 2011 Updated Information & Services Updated Information and services can be found at: http://chestjournal.chestpubs.org/content/92/3/531.citation Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.chestpubs.org/site/misc/reprints.xhtml Reprints Information about ordering reprints can be found online: http://www.chestpubs.org/site/misc/reprints.xhtml Citation Alerts Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to the right of the online article. Images in PowerPoint format Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online figure for directions.
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