A perspective of cephalosporins in pneumonia

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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

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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

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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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