Full text of DOI:10.1007/s12019-000-0031-8

O R I G I N A L A R T I C L E
Community-acquired pneumonia (CAP) is a leading
cause of morbidity and mortality, despite effective
therapies. Guidelines for CAP management vary widely
in their approach. Resistance of S pneumoniae to
penicillins and other antibiotics has prompted evalua-
tion of the new fluoroquinolones.
I N T R O D U C T I O N
An Update on
Community-
Acquired
Community-acquired pneumonia (CAP) is an infec-
tion of pulmonary parenchyma associated with
signs and symptoms of a lower respiratory tract
infection, not related to recent hospitalization or res-
idence in a long-term care facility, and is associated
with a radiographic infiltrate unexplained by other
1
causes. The classical approach to treatment of CAP
called for using epidemiologic clues and laboratory
testing to identify likely pathogens and basing
antimicrobial choices on this information. However,
age adjusted mortality rates for influenza and CAP
Pneumonia
in Adults
2
began rising in the late 1970’s. This fact, along with
ongoing controversies regarding treatment led to the
development of several consensus statements. The
two best known guidelines in the United States (US)
are the American Thoracic Society (ATS) guidelines
published in 1993, and the Infectious Diseases Soci-
MARK GOTFRIED, MD
Pulmonary Associates
Phoenix, Ariz
ety of America (IDSA) guidelines published in
Clinical Lecturer
,3
2
000.1 The ATS guidelines called for empirical-
University of Arizona Medical College
Adjunct Associate Professor
University of Illinois, Chicago, Ill
based antibiotic choices determined by the patient’s
age, comorbidity, need for hospitalization, and
3
severity of presentation. The IDSA guidelines
allows for pathogen-directed therapy under certain
conditions, and incorporates newer antimicrobial
medications and more recent resistance data in their
treatment recommendations.1
COLLIN FREEMAN, PharmD, BCPS
Clinical Science Specialist
Bayer Corporation
Clinical Lecturer
University of Kansas School of Pharmacy
Kansas City, Kans
E P I D E M I O L O G Y
CAP is the sixth leading cause of death in the US,
and is the most prevalent fatal infectious disease.1
More than four million cases of CAP occur in the
US each year, a rate of 15 per 1,000 people. The
annual economic cost was recently estimated to be
,4
4
approximately $23 billion per year. A recent meta-
REPRINTS
Collin Freeman, Pharm.D., BCPS, 6015 W. 78 Terrace, Prairie Village, KS
66208 USA
ACKNOWLEDGMENT
Special thanks to David Nicolau, PharmD, and Randy Pryka, PharmD for their
input and editorial comments.
Submitted for publication: September 22, 1999. Accepted: October 27, 1999.
COMP THER. 2000;26(4):283–293
283

analysis reported overall mortality to be 13.7%,
ranging from less than 5% in ambulatory patients to
over 36% in intensive care unit patients. The elder-
other causes, usually leads to the diagnosis of
1
,4,9
CAP.
The chest radiograph also quantifies the
5
severity of the pneumonia, and identifies pneumon-
ic complications, such as lung abscess or pleural
effusion. Bilateral pleural effusions are independent
predictors of short-term mortality in CAP, while
other radiographic signs such as multi-lobar infil-
ly are at particular risk of death from pneumonia
due to comorbid illnesses, decreased host defenses,
aspiration, associated airways disease, and medica-
tions which might impair respiratory function (seda-
6-8
13
tives) or which suppress the immune system.
trates are not. There are no strict guidelines on
when to order a chest radiograph.
C L I N I C A L S I G N S A N D S Y M P T O M S
Diagnostic work-up may include Gram stain and
culture of sputum, blood culture, thoracentesis, and
serologic testing. The role of the Gram stain is dis-
Patients with CAP can present with various symp-
toms including, cough, shortness of breath, chest
4
,9
1,3
pain, malaise, fever, chills, and sweats. Sputum
production may or may not be present. Tachypnea
is an especially disquieting sign.
puted. Material should be obtained from the
lower respiratory tract and screened to ensure that
there are less than 10 squamous epithelial and
greater than 25 polymorphonuclear cells per low
power field. The material should be examined by
qualified laboratory personnel in a timely fashion.
Only about 25% of sputum samples submitted for
Traditional teaching dictated that one can base
treatment decisions on whether the presentation
was suggestive of a typical organism (high fever,
cough, purulent sputum, sudden onset) or an atypi-
cal organism (gradual onset, non-productive cough,
constitutional symptoms). Today, we realize that
these presentations cannot reliably direct treatment
14
analysis are of good quality. Even when a sample
of good quality is obtained, there is not always con-
cordance with blood culture results. Anaerobic
organisms and atypical pathogens may also be
missed by a Gram stain.
1,9
decisions. In other words, typical pathogens may
present atypically, and vice versa. Varying patho-
genicity of bacterial strains and differing host
responses are possible explanations. Non-classical
presentation of CAP is common in the elderly.10
This presentation may include increased forgetful-
ness, anorexia, and weakness. With a paucity of
classic signs evident, diagnosis may be delayed.
Vital sign abnormalities help to quantify the
severity of CAP and help with decisions on whether
or not to hospitalize. Pulse oximetry should be
obtained on all patients with any abnormality of
vital signs. The most common abnormality on phys-
ical examination is the presence of adventitial lung
sounds. Auscultation of the chest will usually find
nonmusical, discontinuous sounds known as crack-
les or rales. These are best heard with the patient
sitting upright and breathing at normal lung vol-
umes. Asking normal patients to breath from resid-
ual volume to total lung capacity can result in
Sputum culture may reflect colonizing organisms
rather then true pathogens. In addition, a negative
result does not rule out the presence of a bacterial
pathogen. Sputum cultures may be useful when
antimicrobial therapy fails and antimicrobial sus-
ceptibility of a particular pathogen is required.
Blood cultures are still usually obtained from all
hospitalized patients with CAP and are reportedly
useful in 11% of patients.15 The cost-effectiveness of
blood cultures has been questioned since they
rarely alter the antibiotic regimen.
Delayed reporting and poor specificity adversely
affect the useful of many conventional serologic
tests. This testing should be considered for those
with severe disease, not responding to treatment, or
for epidemiologic reasons. In areas of high endemic-
ity, appropriate fungal serologies may need to be
considered (e.g., coccidioidomycoses in the South-
west; histoplasmosis in the Mississippi and Ohio
valley areas). Newer diagnostic techniques such as
polyermase chain reaction (PCR) and other amplifi-
cation techniques are exciting but their role remains
to be determined.
11
abnormal findings about 50% of the time.
No combination of signs and symptoms allow one
to make a diagnosis of CAP with relative certainty.12
However, if chest auscultatory findings are absent
and the patients vital signs are normal, the likeli-
hood of pneumonia is reduced and further diagnos-
tic work-up is probably unwarranted.
Various severity scales have been proposed to
stratify patients by illness severity and to help make
decisions on whether hospitalization is warranted.1
A good scale ideally should take into account the
patient’s age, comorbidities, vital signs, and labora-
tory abnormalities.
D I A G N O S I S
Chest radiographs are still necessary to make an
absolute diagnosis of CAP. A radiographic infiltrate
in the proper clinical setting and unexplained by
284
COMP THER. 2000;26(4)

M I C R O B I O L O G Y
Gram-Positive Anaerobes. These bacteria are
rarely isolated from patients with CAP. Peptostrep-
tococci, Prevotella species, and other oral anaerobes
are more common in adults who have experienced
aspiration pneumonia.8
Gram-Negative Aerobes. Gram-negative aer-
obes normally associated with CAP in adults are
Haemophilus influenzae and Moraxella catarrhalis
(formerly Neisseria catarrhalis and Branhamella
catarrhalis).
The pathogens associated with CAP can be divided
into different categories. Most clinicians categorize
them based upon a combination of microbiological
identification schemes (i.e., Gram- positive or nega-
tive; aerobic or anaerobic), and/or clinical presenta-
tion (i.e., “atypical”).
Gram-Positive Aerobes. The CAP pathogen that
falls under this category is Streptococcus pneumoniae.
For years, this bacterium has been identified as the
,26,27
1
,3,4,16,17
most common pathogen involved in CAP.
In
Haemophilus influenzae. This coccobacillus is
more commonly found as a pathogen in elderly
adults (age ≥ 75 years old), primarily those with
underlying lung disease, as opposed to young
more recent years, concern has risen regarding the
susceptibility of S pneumoniae to penicillin. Epi-
demiology and susceptibility studies published in
the last few years have indicated a growing number
of penicillin-resistant strains of S pneumoniae.1
1
0,28-30
adults.
The incidence of H influenzae as the
8-20
S
pathogen in adult CAP patients ranges from
pneumoniae strains are now identified by their peni-
cillin minimum inhibitory concentrations (MICs). A
Kirby-Bauer oxacillin disk is usually dropped onto
an agar plate containing confluent growth of S pneu-
moniae and if resistance is found, further suscepti-
bility testing by broth dilution is performed.21 If the
oxacillin MIC is ≤ 0.06 µg/mL, the S pneumoniae iso-
late is considered penicillin susceptible; if the MIC
is 0.125–1.0 µg/mL, then it is considered to be peni-
cillin-intermediately susceptible (or resistant); an
MIC of ≥ 2.0 µg/mL is considered to be penicillin-
resistant. These penicillin susceptibility guidelines
were set by the National Committee of Clinical Lab-
oratory Standards, and were originally designed to
reflect S pneumoniae isolates from patients with
meningitis, rather than pneumonia. Amoxicillin’s
susceptibility breakpoints have been changed to the
following: susceptible ≤ 2.0 µg/mL; intermediately
susceptible 4.0 µg/mL; and resistant ≥ 8.0 µg/mL.
The mechanism of resistance for these S pneumo-
niae strains is not enzyme degradation, (e.g., β-lac-
tamase), but rather an alteration in the target site
in the organism’s cell wall to which β-lactam
antibiotics normally bind, coupled with efflux of
2%–15%.4
,9,17,28,29
Resistance to ampicillin and amox-
icillin by H influenzae due to narrow-spectrum β-lac-
tamases has prompted the use of other antibiotics.
At present, nationwide the US has reported an aver-
age of 30%–40% of H influenzae isolates that are
31
resistant to ampicillin/amoxicillin.
Moraxella catarrhalis. This Gram-negative coccus
is an uncommon pathogen in adult CAP, but is asso-
ciated with other respiratory tract infections such as
otitis media, bronchitis, and sinusitis.32 Neverthe-
less, M catarrhalis may be the causative pathogen in
the adult CAP in 5% or less of cases, but is more
common in patients with pre-existing lung disease,
similar to H influenzae.3 β-Lactamase production is
more common with M catarrhalis than with H
influenzae; current monitoring studies report approxi-
mately ≥ 90% of isolates are β-lactamase positive.3
Atypical Organisms. These pathogens were
originally described as “atypical” because their
uncharacteristic clinical presentation in patients
3-35
2
2
6,37
38
who acquired these pathogens as infections.
An interesting finding of patients with infections
caused by Chlamydia pneumoniae, Mycoplasma pneu-
moniae, or Legionella pneumophila is that coexisting
infection with other bacterial species (e.g., S pneu-
moniae) may often exist.3
2
2
the antibiotic molecules. Therefore, penicillin and
cephalosporin antibiotics are both affected to vary-
ing degrees by this mutation. Other antibiotic
classes are also affected by greater resistance to
actions, even though they do not work through
alternate mechanisms.
8,39
Chlamydia pneumoniae. This pathogen has been
reported to be one of the top four causative
pathogens of CAP, depending upon the study and
the time of year.1
,8,38-41
C pneumoniae is an intracellu-
At present, a majority of adult populations stud-
ied still have penicillin-susceptible S pneumoniae
lar pathogen and does not have a cell wall. There-
fore, antibiotics whose mechanism involves
inhibition of cell wall synthesis (e.g., β-lactams,
vancomycin) are not effective in killing Chlamydia
species. Identification can be difficult, requiring flu-
orescent-antibody staining or some other special
staining (e.g., Giemsa, iodine) since Chlamydia do
not grow on regular media.
23
strains isolated as pathogens, though the percent-
age of penicillin-resistant isolates will likely
increase. Elderly populations in long-term care facil-
ities are at greater risk of penicillin-intermediate
and penicillin-resistant S pneumoniae strains as
24,25
pathogens and colonizers.
COMP THER. 2000;26(4)
285

Mycoplasma pneumoniae. This is another fastidi-
ous pathogen that occurs more commonly in out-
breaks, usually during certain seasons of the year,
and in areas where people live and work in crowd-
ed environments (e.g., university dormitories, mili-
lar time-frame as for other individuals requiring
repeat vaccination.
Influenza vaccination is also important and may
help to prevent severe infectious illness in an elder-
1
,28,51
ly population.
Newer therapy modalities may
3
8,42
tary barracks, etc.).
Mycoplasma is another
also prove useful by making immunization easier to
perform. The influenza neuraminidase-inhibitor,
zanamivir nasal spray, which has activity against
influenza A and B, and may be used for treatment
intracellular pathogen, does not have a cell wall,
and is difficult to culture. Identification is usually
obtained by serologic testing for Mycoplasma anti-
3
8,42
56,57
gen titers using cold agglutinins.
Reported inci-
as well as prophylaxis.
dence of this pathogen in CAP varies, ranging from
A supplement on immunization against pneumo-
coccal disease and influenza in the American Journal
of Health-system Pharmacy, may prove valuable read-
ing to health-care professionals.58
1,43,44
2%–30%.
Legionella pneumophila. L pneumophila is an
infrequent cause of CAP. It is more often associated
with outbreaks, usually contaminating air coolant
systems because Legionella are hydrophilic.45
L
A N T I M I C R O B I A L T H E R A P Y
pneumophila also is an intracellular pathogen, with-
out a cell wall and requires PCR antigen testing of
urine or some other body fluid for early detection.45
A special yeast and charcoal growth media is neces-
sary for isolation and growth in the laboratory. Inci-
dence rates of Legionella pneumonia have generally
Treatment of infectious diseases involves the triad
of the patient, the medication, and the microorgan-
isms. These factors must all be considered when
choosing when and what antimicrobial therapy
should be utilized. In addition, issues like pharma-
coeconomics and pathogenic resistance need also to
be considered.
If the decision is to prescribe an antimicrobial,
then the following factors should be considered to
determine which medication(s) is/are most beneficial:
1. Inherent activity against the known or pre-
sumed pathogen(s)
2. Slow emergence of resistance
3. Optimal pharmacokinetic and pharmacodynam-
ic characteristics
4. Good penetration to the site of infection and
rapid killing
45,46
been reported in the 1%–5% range,
retrospective study reported a rate of 16%.
although one
47
P R E V E N T A T I V E T H E R A P Y
Preventative therapy for disease states has come to
the forefront of US medicine. In the case of infec-
tious diseases and respiratory pathogens, vaccines
that have been available for decades and newly
developed vaccines are receiving more acceptance
and use as cost-effective therapies to reduce mor-
28,48-50
bidity and mortality.
The 23-valent pneumococcal vaccine has received
a great deal of praise and mention in medical litera-
ture as an effective method of preventing S pneumo-
5. Well tolerated (low incidence and severity of
adverse effects)
6. History of good clinical response rates
Empirically knowing the susceptibility patterns of
microbial pathogens in a clinician’s area/region,
which antimicrobial cover the particular
organism(s), and facts about the patient, such as site
of the infection, age, drug allergies, kidney and liver
function, help to increase the chances of a success-
ful clinical outcome.
The β-Lactams. This class includes the peni-
cillins, cephalosporins, and carbapenems. These
antibiotics kill bacteria by binding to certain pro-
teins within the bacteria’s cell wall that will eventu-
ally lead to poor structure and lysis of the cell.59
Penicillins. The most common medications in this
group used in treating CAP are listed in Table 1.
They are classified based upon their activity against
certain bacteria.
1,28,48,51
niae infection.
Those populations who should
receive pneumococcal vaccine include immunocom-
promised individuals (e.g., spleenectomized, HIV-
positive organ transplant recipients, severe
cardiovascular and/or pulmonary disease, etc.) and
5
1
people ≥ 65 years of age. Repeat vaccination for
immunocompromised individuals and the elderly is
52
recommended at 5 years. Elderly patients’ abilities
to mount sufficient pneumococcal antibodies from
the 23-valent vaccine is still unclear, with one study
finding a sufficient reaction to the vaccine,53 while
another reported an insufficient antibody
54
response. A survey in 1997 of the elderly (age ≥ 65
years) in the US found that only 45% of persons in
this age group had received a pneumococcal vacci-
5
5
nation. Although the efficacy of repeat pneumo-
coccal vaccination for the elderly has not been
studied, recommendations generally call for a simi-
In addition, β-lactamase inhibitors that have simi-
lar chemical structures to the β-lactams are com-
286
COMP THER. 2000;26(4)

TABLE 1
Penicillin G/Penicillin V*
Table 1 for the advantages and disadvantages of
these antibiotics.
Ampicillin/Amoxicillin. These medications are also
losing their activity against the newer penicillin
highly-resistant S pneumoniae strains, but may be
just as effective against the intermediately-suscepti-
ble strains of S pneumoniae if higher doses can be
used. Atypical pathogens are still resistant to these
and other β-lactams. Also, many strains of H
influenzae and M catarrhalis are resistant due to nar-
row-spectrum β-lactamases. The addition of β-lacta-
mase inhibitors (clavulanic acid with amoxicillin;
sulbactam with ampicillin) has returned some of
the spectrum that was lost by some β-lactamase
producing strains of these bacteria. Most oral anaer-
obes like peptostreptococci still tend to be suscepti-
ble to ampicillin and amoxicillin. Tables 2 and 3
contain a list of advantages and disadvantages for
these antibiotics.
•
Losing activity against S pneumoniae but still
effective against most clinical isolates
•
•
Not effective against the “atypical” pathogens
H influenzae and M catarrhalis are often
resistant
Not effective against most Gram-negative bac-
teria (e.g., Klebsiella pneumoniae)
Majority of anaerobic Gram-positives are still
susceptible
•
•
Advantages
—
—
—
Less expensive than many other antimicro-
bials for CAP
Still effective for most S pneumoniae isolates
depending on geographic location
Available in intravenous or oral
formulations
Cephalosporins. This section will focus on the oral
cephalosporins. These β-lactams are also not effec-
tive against the “atypical” pathogens Mycoplasma,
Chlamydia, Legionella. These antibiotics can be
divided into two categories: the first generation, and
the extended-spectrum group. The first generation
includes cephalexin, cephradine, and cefadroxil.
This group typically has activity against most S
pneumoniae strains, but their activity against H
influenzae and M catarrhalis is unreliable (i.e., higher
MICs) as the extended-spectrum cephalosporins.6
The oral extended-spectrum cephalosporins
include cefaclor, loracarbef, cefuroxime axetil,
cefixime, cefprozil, cefpodoxime proxetil,
ceftibuten, and cefdinir. These medications are
dosed less frequently than their first generation
counterparts, and their activity against H influenzae
Disadvantages
—
Ineffective for most M catarrhalis and H
influenzae isolates
—
Many respiratory pathogens are resistant
(
e.g., M pneumoniae, C pneumoniae)
—
—
—
Dosing frequency decreases compliance
Adverse effects (diarrhea) and allergies
Oral medications tend to have poor activity
against Enterobacteriaceae and M catarrhalis
3-65
*
Adapted from Wright AJ. The penicillins. Mayo
Clin Proc. 1999;74:290-307.
bined with some of the penicillins to serve as “sui-
cide-inhibitors” against certain β-lactamases and
restore some of the parent penicillin’s spectrum.
The currently licensed β-lactamase inhibitors
include clavulanic acid, sulbactam, and tazobactam.
Interestingly, these β-lactamase inhibitors can also
increase the production of the β-lactamase enzyme
63-66
and M catarrhalis is also more reliable.
The extended-spectrum group has variable activi-
ty against S pneumoniae depending on the strain’s
susceptibility to penicillin. Cefpodoxime, cefurox-
ime, and cefprozil seem to have better activity
against the penicillin-intermediately susceptible
strains than the other other oral cephalosporins, but
60-62
by the bacteria to variable degrees.
23,67
Penicillin G/Penicillin V. These penicillins are
gradually losing their activity against S pneumoniae
but remain effective against most clinical isolates.
Higher doses of penicillins may be just as effective
at eradicating the intermediately susceptible strains
of S pneumoniae (MIC of 0.125–1.0 µg/mL). They
are not effective against the “atypical” pathogens
like Chlamydia or Mycoplasma. Also, H influenzae
and M catarrhalis are typically resistant. However,
the majority of anaerobic Gram-positive bacteria
this can vary from location to location.
See Table
4 for a list of the oral cephalosporins currently
approved in the US and their general advantages
and disadvantages.
The parenteral cephalosporins, cefotaxime and
ceftriaxone, have been advocated as being reliable
against penicillin-intermediate S pneumoniae infec-
tions, including CAP.68 Cefepime may also retain its
activity against the penicillin-intermediate strains of
28
S pneumoniae, but ceftizoxime apparently has a sig-
(
e.g., peptostreptococci) are still susceptible. See
nificant loss of activity against these strains.68
COMP THER. 2000;26(4)
287

TABLE 2
TABLE 4
Advantages and Disadvantages of
Oral Cephalosporins*
Ampicillin/Amoxicillin in treating CAP*
1
•
st Generation
Cephalexin, cephradine, and cefadroxil
Advantages
•
•
Less expensive
Extended spectrum
Still effective for most S pneumoniae and possi-
bly H influenzae
Available in intravenous or oral formulations
•
Cefaclor, loracarbef, cefuroxime axetil,
cefixime, cefprozil, cefpodoxime proxetil,
ceftibuten, and cefdinir
•
(
ampicillin)
General Properties
Disadvantages
•
Losing activity against S pneumoniae but still
effective against most clinical isolates
•
•
•
Many respiratory pathogens are resistant
Dosing frequency decreases compliance
Adverse effects (diarrhea) and allergies
–
Most are effective against penicillin-inter-
mediate S pneumoniae, but still not effective
against highly resistant isolates
*
Adapted from Wright AJ. The penicillins. Mayo
–
Ceftriaxone and cefotaxime are still very
effective against penicillin-intermediate S
pneumoniae
Clin Proc. 1999;74:290-307.
•
•
Not effective against the “atypical” pathogens
H influenzae and M catarrhalis are usually
susceptible
Effective against most Gram-negative bacteria
(e.g., Klebsiella)
TABLE 3
Advantages and Disadvantages of
Amoxicillin/Clavulanate in treating CAP*
•
Advantages
•
Improved activity against H influenzae and M
Cephalosporin Advantages
catarrhalis
•
•
Older antimicrobials are less expensive
Still effective for most S pneumoniae, H influen-
zae, and M catarrhalis
–
Still not effective against the “atypical”
pathogens
•
New dosage strength helps improve
compliance
•
•
Available in parenteral and oral dosage forms,
including suspensions
Newer medications have daily or twice-daily
dosing
Disadvantages
•
•
•
Incidence of diarrhea is increased due to
clavulanate component
May induce greater amount of β-lactamases to
be produced by some bacteria
Not currently available intravenous (use ampi-
cillin/sulbactam instead?)
Cephalosporin Disadvantages
•
•
Atypical pathogens are still resistant
Older antimicrobials dosing frequency
decreases compliance
•
•
Allergies to β-lactams
Newer medications tend to be relatively
expensive
*
Adapted from Wright AJ. The penicillins. Mayo
Clin Proc. 1999;74:290-307; Weber DA, Sanders
CC. Diverse potential of β-lactamase inhibitors to
induce class I enzymes. Antimicrob Agents
Chemother. 1990;34:156-158; and Sanders CC,
Sanders WE Jr. Type I β-lactamases of gram-neg-
ative bacteria: interactions with β-lactam antibi-
otics. J Infect Dis. 1986;154:792-800.
*
Adapted from references 63-68.
against the penicillin-intermediate and resistant
70
strains of S pneumoniae. However, macrolides are
normally active against the “atypical” pathogens. H
influenzae is not typically susceptible to ery-
thromycin, but may be more susceptible to
azithromycin and in some cases to the hydroxy-
Macrolides. These antimicrobials are considered
to be bacteriostatic and act by binding to the 50s
ribosomal subunit, crippling bacterial replication.
6
9
69
metabolite of clarithromycin. Since it is clar-
Erythromycin, dirithromycin, azithromycin, and
clarithromycin fall into this antibiotic group.
Macrolide antibiotics are also losing their activity
ithromycin’s hydroxy-metabolite that has activity
against H influenzae, clarithromycin’s degree of anti-
H influenzae activity in vivo is dependent upon the
288
COMP THER. 2000;26(4)

TABLE 5
Macrolides/Azalides*
TABLE 6
Tetracyclines*
General Properties
General Properties
•
Losing activity against S pneumoniae but still
effective against most clinical isolates
• Losing activity against S pneumoniae but still
effective against most clinical isolates
•
•
Effective against the “atypical” pathogens
• Effective against the “atypical” pathogens
• Not effective against most Gram-negative bac-
teria or anaerobes
H influenzae and M catarrhalis are not usually
sensitive based upon achievable plasma con-
centrations, but patients do tend to respond
clinically to clarithromycin or azithromycin
Not effective against Gram-negative CAP bac-
teria or anaerobes
•
H influenzae and M catarrhalis are variably
sensitive
•
–
Better for doxycycline and minocycline
Advantages
Advantages
•
•
•
•
Relatively inexpensive compared to newer
antibiotics for CAP
Still effective for most S pneumoniae and possi-
bly H influenzae and M catarrhalis
•
•
•
•
Erythromycin is less expensive than many
newer antibiotics
Still effective for most S pneumoniae and possi-
bly H influenzae
Available in parenteral or oral forms (ery-
thromycin & azithromycin)
New medications are dosed daily or twice-
daily
Available in parenteral and oral dosage forms
(doxycycline and minocycline)
Doxycycline and minocycline are dosed daily
or twice-daily
Disadvantages
Disadvantages
•
More respiratory pathogens are becoming
resistant
•
More respiratory pathogens (S pneumoniae, H
influenzae) are becoming resistant
•
Contraindications (children, pregnancy) and
interactions (polyvalent cations, e.g., calcium,
magnesium, iron, etc.)
•
Adverse effects (GI upset) and drug interac-
tions (p450) with clarithromycin and ery-
thromycin
*Adapted from references 71-73.
•
New antimicrobials are more expensive
GI, gastrointestinal.
Adapted from references 69-71.
but have no activity against anaerobes.72,73 Their
advantages and disadvantages are displayed in
Table 6.
*
amount of hydroxy-clarithromycin formed from
hepatic oxidative metabolism. In general, in vitro
activity of azithromycin and clarithromycin on H
influenzae, is decreasing. Macrolides are also not
active against anaerobes. Table 5 lists this class’s
general advantages and disadvantages.
Fluoroquinolones. Fluoroquinolones are bacte-
ricidal antimicrobials and inhibit enzymes involved
in the supercoiling of susceptible bacterias’ DNA.74
The latest fluoroquinolones include levofloxacin,
sparfloxacin, gatifloxacin, and moxifloxacin. In June
1999, shortly after strong warnings and restrictions
in the European market, the US Food and Drug
Administration (FDA) sent letters to physicians and
pharmacists that warned of possible hepatotoxicity
with trovafloxacin. The FDA restricted the use of
trovafloxacin to inpatient (hospital or long-term care
facility) use only for nosocomial pneumonia, com-
munity-acquired pneumonia, complicated intraab-
dominal infections, gynecologic and pelvic
infection, or complicated skin and skin structure
infections (including diabetic foot infections). Also
in 1999, the makers of grepafloxacin voluntarily
removed this antimicrobial from the market due to
reports of cardiotoxicity.
7
0
Ketides are a new antimicrobial class, closely relat-
ed to the macrolides and azalides. Telithromycin is
one example of this new class and is expected to be
approved within the next one or two years in the US.
Tetracyclines. Tetracyclines act by binding to
the 30s ribosomal subunit, interfering with bacterial
7
1
replication. They are also losing their activity
against the penicillin-resistant S pneumoniae strains,
and their activity against H influenzae and M
catarrhalis is also variable. However, doxycycline
and minocycline tend to be more active than the
72,73
parent compound, tetracycline.
These antimicro-
bials are also active against “atypical” pathogens,
COMP THER. 2000;26(4)
289

Most of these newer fluoroquinolones have better
activity against Gram-positive bacteria compared to
their older counterparts. Another advantage to the
fluoroquinolones is they are unaffected by the cur-
rent mechanisms of resistance that are found in
TABLE 7
Fluoroquinolones*
Older
Newer
Investigational
Sitafloxacin
Gemifloxacin
Ciprofloxacin Levofloxacin
7
5
penicillin-resistant strains of S pneumoniae. Their
activity against atypical pathogens varies depending
upon the individual fluoroquinolone. H influenzae
and M catarrhalis strains display very low MICs to
all of the fluoroquinolones that are currently mar-
Ofloxacin
Sparfloxacin
Trovafloxacin
Moxifloxacin
Gatifloxacin
7
6
keted or in development. Their activity against
oral anaerobic pathogens is often poor, but newer
fluoroquinolones like moxifloxacin may have appre-
General Properties
•
Activity against S pneumoniae is fair to
78
ciable activity against these bacteria.
excellent
Moxifloxacin, gatifloxacin, and the soon-to-be-
marketed gemifloxacin have good-to-excellent in
vitro activity against all of the major community
bacterial and atypical pathogens normally encoun-
•
Variably effective against the “atypical”
pathogens but generally susceptible
H influenzae and M catarrhalis are sensitive
Effective against most Gram-negative bacteria
Most fluoroquinolones are not effective against
anaerobes
•
•
•
76,78-80
tered in CAP, and can be dosed once daily.
See
Table 7 for a summary of the fluoroquinolones that
may be used in treating CAP.
•
Some are available in parenteral and oral
dosage forms
C A P T R E A T M E N T G U I D E L I N E S
The British Thoracic Society (BTS), the ATS, the
IDSA, the Canadian Infectious Diseases Society, and
the Canadian Thoracic Society have all published
guidelines regarding the management of CAP in the
last seven years, and will likely update these guide-
Fluoroquinolone Advantages
•
•
•
•
•
Improved bioavailability with newer medica-
tions compared to older quinolones
Reduced drug interaction profile with newer
antimicrobials
Improved microbiologic activity, even against
penicillin-resistant S pneumoniae
Improved pharmacokinetics, allowing for
once-daily dosing with newer medications
Potent oral dosage forms for older and newer
antimicrobials
1
,3,81,82
lines in the months or years to come.
These
guidelines all differ in their management recom-
mendations. This is not surprising, since data sup-
porting decisions in infectious diseases are often
unreliable due to confounding factors during clini-
cal studies (age, comorbidity, antimicrobial dosing,
immune status, and function, etc.) and patient pop-
ulations which are too small to detect an apprecia-
ble difference between treatment groups. Indeed,
infectious diseases are often short, self-limiting dis-
ease-states in which the outcome is nominal: cure
or death. This fact also complicates CAP healthcare
economic studies, unlike long-term illnesses such as
diabetes mellitus or hypertension. Publication of
various CAP management guidelines has also
increased commentary about their merits and detri-
Fluoroquinolone Disadvantages
•
Increased acquisition cost compared to some
other antimicrobials used for CAP
•
New and different adverse effects for each
medications
*Adapted from references 74-80.
times, the “better treatment” rests in the perspec-
tive of who truly benefits, i.e., the patient, the
health-care provider(s), the health system, or the
ultimate payor. Coupled with therapeutic options
are the routine pressures that physicians face, par-
ticularly from health-care system managers and the
patients, themselves.87
Another product of the current US health-care
system is the use of treatment pathways for com-
mon disease states/problems. Pneumonia pathways
are prevalent in many institutional and outpatient
8
3-86
ments.
A visual example comparing how the
three major guidelines differ in terms of treatment
can be seen in Table 8.
D I S C U S S I O N
Despite our best efforts, CAP is still a leading cause
of morbidity and mortality in the world. Imperfec-
tions of clinical studies and the ambiguity of treat-
ment regimens has led to confusion on how to
diagnose and most effectively treat CAP. Often
290
COMP THER. 2000;26(4)

TABLE 8
point that only the very susceptible subpopulations
of bacteria are eradicated, leaving behind the
heartier, more resistant strains. Therefore, under
dosing a patient may lead to an even greater prob-
lem (i.e., bacterial resistant subpopulation
regrowth) than overdosing.
Community-Acquired Pneumonia Guidelines Empiric
Antibiotic Therapy for Outpatients: A Comparison*
British Thoracic
Society
Amoxicillin or Penicillin
Alternative: Erythromycin
American Thoracic
Society
C O N C L U S I O N
•
< 60 years old,
no comorbidities
Macrolide or Tetracycline
Management of CAP patients continues to provide
new challenges as time, healthcare costs, and
increasing pathogen resistance force new guidelines
to be developed, and old guidelines to be revised.
To keep CAP morbidity and mortality outcomes
low, requires continued revisitation of the subject
and updating of every clinician’s personal knowl-
edge base of the effectiveness of various manage-
ment strategies. Withholding antibiotics from
patients without confirmed respiratory tract infec-
tions is difficult, but should be done to preserve our
antimicrobial armamentarium for patients who
truly need them. Proper diagnosis is key in deci-
sion-making of when to treat a patient for CAP, as
well as which therapy to use. Empiric therapy
should be based on local susceptibility data, in addi-
tion to factors such as possible adverse effects, drug
interactions, and comorbidity. Increased resistance
of S pneumoniae will require better use of preven-
tive measures and newer antimicrobial medications
like the fluoroquinolones to better ensure clinical
success and decrease the chance for regrowth of
more resistant pathogens. CT
•
> 60 years old or Cephalosporin, or
comorbidity
Sulfamethoxazole/
trimethoprim, or
β-lactam/β-lactamase
inhibitor ± a macrolide
Macrolide, or
Fluoroquinolone, or
Doxycycline
Infectious Diseases
Society of America
Canadian Infectious
Diseases Society/
Canadian Thoracic
Society
•
outpatient, no
comorbidities
Macrolide or Doxycycline
•
chronic obstruc-
tive lung disease,
no antibiotics or
steroids
Newer macrolide or
Doxycycline
•
*
chronic obstruc-
tive lung disease
New Fluoroquinolone, or
extended spectrum
Cephalosporin+
+
other risk
factors
Macrolide, or
β-lactam/β-lactamase
inhibitor ± macrolide
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