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Antimicrobial
Agents
ELSEVIER International Journal of Antimicrobial Agents 26 Suppl. 3 (2005) S170 S175
www.ischemo.org

Principles of appropriate antibiotic use

Michael S. Niederman*
Department of Medicine, Winthrop University Hospital, Mineola, NY, USA and
Department of Medicine, SUNY at Stony Brook, Stony Brook, NY, USA

Abstract
Many antibiotics, including macrolides and quinolones, are used incorrectly in the treatment of presumed respiratory tract infections.
The use of broad-spectrum antibiotics increased considerably in the 1990s, but often this use is inappropriate. Guidelines, such as those
for community-acquired pneumonia, encourage rational therapy and more prudent prescribing. There are strong links between appropriate
use, compliance and resistance as well as between regimen complexity and compliance. These issues provide a platform for thinking
about a short-duration, high-compliance drug therapy with good clinical efficacy. Such therapy will need to be combined with programs
to promote rational antibiotic use, particularly targeting inappropriate prescribing for viral infections and use of agents with a broader
antimicrobial spectrum than is necessary.
© 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
Keywords: Short-course therapy; Compliance; Resistance

1. Introduction
Many antibiotics, including macrolides and quinolones, are
used incorrectly in the treatment of presumed respiratory
tract infections (RTIs). This paper examines current pre-
scribing practices in adult RTIs and discusses the role of
guidelines in promoting rational therapy, using conmmnity-
acquired pneumonia (CAP) as an example. In addition, the
relationship between compliance with prescribed therapy
and antinficrobial resistance is examined.
2. Current antibiotic prescribing practices
In the USA, antibiotics are frequently used in settings where
they may not be needed at all and where it is difficult to
document a benefit. A typical example would be the use of
antibiotics in patients with suspected viral infections.
The National Ambulatory Medical Care Survey con-
ducted in the 1990s showed that although the use of antibi-
otics for the conm~on cold and other upper respiratory tract
infections (URTIs) decreased between 1991 and 1999, the
use of broad-spectrum antibiotics in adults increased from
24% to 48% of antibiotic prescriptions in this setting [1].
By 1998 1999, 22% of all adult prescriptions for broad-
spectrum antibiotics were for RTIs presumed to be caused
* Correspondence address: Department of Medicine, Winthrop Univer-
sity Hospital, 222 Station Plaza North, Suite 509, Mineola, NY 11501,
USA.
E-mail address." MNiederman@Winthrop.gov
by viruses, more than double the figure for 1991 1992. The
increase in broad-spectrum antibiotic use was mainly due to
increased use of macrolides and quinolones for presumed
viral RTIs, although there was a slight increase in the use
of second- and third-generation cephalosporins. No single
class of broad-spectrum antibiotics is used exclusively in
this setting.
Physician education about currently reconmlended antibi-
otic options can improve antibiotic prescribing practices,
as shown by an English study of primary care physicians.
Prescribing practices were assessed before and after a
guidelines workshop that focused on the use of narrow-
spectrum agents and the concept that new agents should
be reserved for complex cases [2]. The study compared
physicians who attended the workshop with a control group
who did not attend. At baseline, narrow-spectrum agents
made up 21.1% of prescriptions, broad-spectrum antibiotics
14.6% and macrolides 4.7%. Both groups of physicians
reduced their use of antibiotics but the reduction was
greater in those physicians who attended the workshop.
Physicians who had not attended the workshop decreased
their use of narrow-spectrum antibiotics and increased their
use of broad-spectrum antibiotics, whilst those attending
the workshop decreased their use of narrow-spectrum
antibiotics to a much smaller extent and decreased their use
of broad-spectrum antibiotics considerably. Physicians who
had attended the workshop used new macrolide antibiotics
in approximately half the number of cases as those who did
not attend the workshop.

0924-8579/$ see front matter © 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
 M.S. Niederman /International Journal of Antimicrobial Agents 26 Suppl. 3 (2005) S170-S175
Even in the presence of a physician who is well versed
on the appropriate use of antibiotics, patient desire for
treatment can play a major role in inappropriate prescribing
practices. A prospective survey of adults with URTIs
who presented at a walk-in clinic found that multivariate
predictors of wanting antibiotics were current smoking
[odds ratio (OR) 2.4] and good previous experience with
antibiotic therapy (OR 3.1)[3]. Multivariate predictors of
antibiotic prescription were the presence of a pharyngeal
exudate, an abnomlal lung examination, an abnormal tym-
panic membrane examination, lymphadenopathy, sinus pain,
patient desire for antibiotics and fever. The investigators
report that although only 46% of patients who wanted
antibiotics actually received them, 29% of patients who did
not want antibiotics also received them. This shows that a
patient' s desire for antibiotics affects prescribing, although
physicians also use clinical judgment in making decisions
about antibiotic therapy.
The overuse of empirical therapy represents a further
example of inappropriate antibiotic prescribing. However,
it is frequently necessary because very few patients have
a clear etiological diagnosis that allows pathogen-directed
therapy when treatment is first needed. For example, in
a study in which patients with radiographic pneumonia
underwent careful serological testing for Legionella, My-
coplasma, Chlamydia and viruses, approximately half the
patients did not have an etiologic diagnosis even after
extensive diagnostic testing and weeks of follow-up [4].
An additional driver of inappropriate prescribing in
the past was the absence of comprehensive treatment
guidelines. Before the guidelines era, antibiotic prescribing
practices were not always rational. Outpatient data from the
Pneumonia Patient Outcomes Research Team (PORT) study,
which analysed treatment patterns for 927 outpatients and
1328 inpatients at five major medical centers in the USA,
showed that although most patients received an appropriate
macrolide (75%), a large proportion still received non-
macrolide, non-atypical pathogen treatment and only 75%
received monotherapy [5]. In addition, mean duration of
therapy was 12 days. These findings suggest that prior
to the widespread dissemination of guidelines, there was
often inadequate and inappropriate antibiotic use, both of
which could have promoted the development of antibiotic
resistance.
3. The value of treatment guidelines
Guidelines for CAP have many advantages. For example,
they synthesize large amounts of information and define the
strength of existing data using evidence grading. They also
discuss and define relevant management issues, providing
an orderly approach to treatment and help guide accurate
initial empirical therapy. In addition, they provide a standard
against which care can be evaluated and they focus on cost-
effective management. They are probably most useful in
S 171
pointing out defects in current knowledge, directing the
agenda for future research. None the less, guidelines are not
universally accepted. It has been argued that they encourage
management without thought and there is a concern
that deviations may serve as the basis for disciplinary
actions. Although these fears may be unfounded, three
questions still remain. If experts interpret the same data
differently, and different sets of guidelines make different
reconm~endations, how can they be regarded as accurate?
Of what relevance are guidelines if the existing knowledge
(evidence) base is poor? And how strong should new data
be before guidelines are changed and updated?
The first two guidelines for CAP were published by
the American Thoracic Society (ATS) and the Canadian
Infectious Disease Society in 1993. Since then, there have
been additional guidelines from the Infectious Diseases
Society of America (1998, 2000, 2003), the Centers for
Disease Control (2000) and the ATS (2001) in the USA,
the European Respiratory Society (1998) and the British
Thoracic Society (2001).
3.1. Appropriateprescribing for drug-resistant
Streptococcus pneumoniae (DRSP) in CAP
The issue ofpneumococcal resistance in CAP is specifically
addressed in guidelines published since 1998, but earlier
guidelines did not deal with it directly. In general, there
are two rationales for modifying antibiotic therapy if DRSP
risks are present, which are described in detail in the
ATS guidelines: (1) to ensure efficacy for organisms with
higher levels of in vitro resistance; and (2) to manage the
problem of furore resistance, preventing the selection of
resistant pneumococci in the conmmnity. The first rationale
may not be clinically relevant, since there are few data to
suggest that it is necessary to modify antibiotic therapy to
ensure efficacy in the presence of DRSP risks. For example,
penicillin resistance may not even be clinically relevant
unless the minimum inhibitory concentration (MIC) of
the pneumococcus is >4mg/L. To avoid the problem of
emergence of resistance, a highly active antipneumococcal
agent is recommended in patients with DRSP risks. For
example, even if an organism with intem~ediate-level
resistance is present, use of a highly active antinficrobial
regimen can kill the organisms rapidly and completely,
thereby minimizing selection pressure for organisms with
higher levels of resistance. It is also important to identify
patients who are not likely to have resistance, since they
can be effectively treated with a highly focused therapy (e.g.
a macrolide), avoiding unnecessarily broad therapy. In this
way, more potent agents can be reserved for the appropriate
setting. Although the advice to use potent agents only for
patients at risk for resistance is present in all guidelines, it
has been overshadowed by an overemphasis on the clinical
relevance of in vitro resistance.
In the USA, acceptable treatment regimens for outpa-
tients with DRSP risks include cephalosporins, selected
S 172 M.S. Niederman/International Journal of Antimicrobial Agents 26 Suppl. 3 (2005) S170-S175
Table 1
Acceptable outpatient therapy choices if risk factors for drug-resistant
Streptococcus pneumoniae are present
Class Agent(s)
Cephalosporins a Cefpodoxime, cefuroxime, short-term ceftriaxone
Penicillins a Amoxicillin/clavulanic acid, high-dose ampicillin
Antipneumococcal Gatifloxacin, levofloxacin, moxifloxacin
quinolones
Ketolides Telithromycin
Oxazolidinones Linezolid B
a If either a cephalosporin or penicillin is used, a macrolide should be
added to treat for possible atypical pathogen co-infection.
b Although linezolid is not recommended in existing guidelines, this may
change with community-acquired methicillin-resistant Staphylococcus
aureus (MRSA). The role of the ketolides in empirical therapy of
community-acquired pneumonia is still being defined.
penicillins and antipneumococcal quinolones (Table 1). In
those with DRSP risks, if a macrolide is used it should
always be combined with a selected [3-1actam agent, but
the macrolide component is needed to cover for the pos-
sibility of atypical pathogen co-infection. However, in the
UK, where pneumococcus is the most common causative
organism and atypical pathogens are less conm~on in the
elderly, coverage for atypical pathogens is not generally
in guidelines, unless there is an epidemic involving these
organisms [6]. Instead, recommended outpatient treatment
is high-dose amoxicillin, and macrolides are reconmlended
as alternative therapy in patients who are allergic to
penicillins. In the USA, [3-1actam monotherapy is no longer
reconm~ended in any of the current guidelines.
Reports that have validated the outpatient guideline
reconmlendations are scarce. In 1997, Gleason et al. [7]
published the results of an analysis of data for 864
outpatients in the PORT database: 546 patients with
uncomplicated infection (<60 years, no co-morbidity) and
318 with complicated infection (>60 years and/or co-
morbidity). In 339 patients with uncomplicated infection,
treatment was according to guidelines available at the time
(ATS 1993 guidelines), whilst in 207 it was inconsis-
tent with the guidelines. Among those treated according
to guidelines, 94% received macrolides, whilst among
those whose treatment was inconsistent with guidelines
26% received amoxicillin. When treatment complied with
guidelines, costs were three-fold lower but the outcome was
the same (hospitalization rate, return to work, quality of
life). Among patients with complicated infection, 56 were
treated according to guidelines (29% with trimethoprinff
sulphamethoxazole (TMP/SMX), 29% with cefuroxime,
29% with amoxicillin/clavulanic acid) and 262 were treated
in a manner inconsistent with the guidelines (51% with
erythromycin only, 67% with any macrolide). Treatment
according to guidelines resulted in 10-fold higher costs,
with a trend to more hospitalization and higher mortality,
although other outcomes were similar. However, it is
important to bear in mind that while very few patients with
complicated infection were treated according to guidelines,
many received TMP/SMX, which is no longer considered
a good choice. In addition, those doing well in the
complicated group often received a macrolide, and these
findings suggest that there may indeed be a benefit from
using a regimen that routinely covers for atypical pathogens
in all groups of outpatients.
4. Prescribing practices leading to antibiotic
resistance
Four main factors are driving the current problem of
increasing antinficrobial resistance. First, using the wrong
drug for the wrong patient, for example using a broad-
spectrum antibiotic in a low-risk patient. Guidelines should
help address this problem. Second, antibiotic consumption,
including not only unnecessary usage, but probably all
usage can help select for resistant organisms. Less con-
sumption is likely to result only from a renewed focus on
appropriate use. Third, proper dosing, because suboptimal
concentrations, even of the correct agent, can lead to
resistance. And finally, non-compliance with the prescribed
regimen.
From currently available data, it appears that quinolone
overutilization is already a major problem in North Amer-
ica. Of 100 consecutive patients who were discharged from
the emergency department of a major academic medical
center on quinolone therapy, 81 were receiving treatment
inappropriately [8]. These included clinical situations where
there was another more appropriate first-line agent (53%) or
a lack of documented infection (33%), and the inappropriate
therapy applied across all infection indications. Of the 19
patients receiving appropriate therapy, only 1 was given
the medication at the correct dose and for the proper
duration. In a prospective study of CAP initially treated
in the emergency departments of six Canadian hospitals
and then on an outpatient basis, the guideline-reconm~ended
treatment was a macrolide or doxycycline [9]. Quinolone
therapy was only reconmlended in patients with chronic
obstructive pulmonary disease (COPD) who had received
antibiotics or steroids in the last 3 months. However, 33% of
the 768 patients received a quinolone (levoftoxacin) and
55% received a macrolide. Predictors of levoftoxacin use
were older age, COPD, antibiotic use on presentation,
site of care and low physician patient volume. In only
49% of patients receiving levofloxacin was such treatment
considered appropriate.
These types of quinolone utilization behavior will prob-
ably only drive more resistance. Guidelines are intended to
ensure that the right treatment is given to the right patient,
but they are not often followed, and this in turn can lead to
inappropriate antibiotic usage, usually with an agent that is
broader spectrum than is needed.
 M.S. Niederman /International Journal of Antimicrobial Agents 26 Suppl. 3 (2005) S170-S175 S 173

Recent use of [3-1actams or macrolides increases the risk no longer effective. This type of usage may select for
of penicillin resistance and probably of macrolide resistance resistance, and the AECB population may be the adult
as well. A retrospective cohort study of 303 patients with reservoir for pneumococcal resistance.
pneumococcal bacteremia, 98 of whom had penicillin non- To avoid the development of pneumococcal resistance,
susceptible Streptococcus pneumoniae (PNSP; two-thirds it may be necessary to take a history of recent antibiotic
intermediate resistance, one-third high-level resistance), usage. Because prior therapy (within at least the last
determined the relationship between antibiotic use in the 3 months) with [3-1actams, macrolides and quinolones can
last 1 month and 6 months and PNSP bacteremia [10]. lead to resistance to these agents, it may be prudent to
The use of [3-1actams, sulfonamides and macrolides, but choose an antibiotic that differs from that used previously,
not quinolones, in the past 1 month and 6 months was even if it worked well last time. This is a form of 'patient-
associated with PNSP bacteremia. The longer the duration specific antibiotic rotation', a concept that needs to be
of [3-1actam therapy, the greater the frequency of PNSP, and validated with prospectively collected data. If this concept
multiple courses of [3-1actams and macrolides also increased is correct, then there may be no single drug that is always
the risk compared with one course. best for RTIs, and best practice may involve an active eflbrt
Although this study suggests that quinolones do not lead to introduce antibiotic heterogeneity.
to PNSP, other data show a link between quinolone usage
and quinolone-resistant pneumococci. Anderson et al. [11]
showed that levofloxacin treatment in the last 4 months
5. The impact of compliance on antibiotic resistance
in immunocompromised patients with CAP increased the
risk for levofloxacin-resistant pneumococcal CAP, but not The impact of compliance and completion of therapy on
PNSR In another study, four patients with pneumococcal
antibiotic resistance is an area that is just now being
pneumonia failed therapy with oral levofloxacin, one
understood and may be a target for future eflbrts. In an
of whom died [12]. Two patients initially had resistant
analysis of 76 studies of medication compliance (not only
organisms (they had received prior quinolone therapy) and
antibiotics) conducted between 1986 and 2000, dose-taking
two acquired resistance during therapy (initial MICs of
compliance was 71% and dose-timing compliance was 59%.
1 mg/L and 4 mg/L increased to MICs of 8-16 rag/L). Other
Dose-taking compliance decreased as daily dose frequency
quinolones, such as gatifloxacin and moxifloxacin, are gen-
increased, and dose-timing compliance also decreased with
erally more active against pneumococci than levofloxacin,
more daily doses (Table 2) [13].
and possibly may be less likely to promote quinolone
When therapy is given only once a day, compliance
resistance. However, these data collectively lead to the
can approach 100% and it also improves with reduced
conclusion that alternative, non-quinolone therapy for CAP
duration of treatment (<7 days) [14]. Patients with lower
should be considered if the patient has recently received
RTIs usually comply with treatment because they perceive
quinolone therapy. In addition, testing pneumococci for
their infection as severe and so see a high cost in not taking
quinolone susceptibility is advisable.
their medication. Compliance mistakes can be multiple and
Two issues are not reflected by the levofloxacin resistance
include not filling the prescription in the first place, not
data: multistep mutants that are still reported as sensitive;
starting therapy, delaying therapy, omitting doses, missing
and, over the course of time, there may be a 'MIC
doses (or not taking them at the right time) and stopping
drift', with the median MIC values rising even though
therapy early. Factors that influence compliance include
the percentage of resistant organisms has not increased.
patient education, drug price, duration of therapy, frequency
The breakpoint for levofloxacin sensitivity is very high,
of dosing, convenience and formulation, packaging and
which means that organisms with a significant increase in
adverse effects.
median MIC will still be considered sensitive. This may
manifest itself as consistent reporting of very high levels
Table 2
of levofloxacin sensitivity, followed by a sudden drop as Rate of compliance with any medication among outpatients, by frequency
MIC values rise gradually from the sensitive to the resistant of regimen [ 13]
range.
If an antibiotic, irrespective of its class, is used repeatedly Regimen Mean compliance (%)
frequency Dose taking a Dose timing
to treat conmmnity RTIs, resistance to that agent is
likely to develop. Acute exacerbation of chronic bron-
1 dose/day (qd) 79 74
chitis (AECB) provides an excellent example of induced
2 doses/day (bid) 69 58
antibiotic resistance. Patients with AECB are generally
3 doses/day (tid) 65 46
older, chronically colonized in their airway, and frequently
4 doses/day (qid) 51 40
treated with corticosteroids (and are therefore slightly
All regimens 71 59
inmmnosuppressed). This population is then often treated
repeatedly with the same antibiotic regimen until it is a qd vs. tid, P - 0 . 0 0 8 ; qd vs. qid, P <0.001; bid vs. qid, P-0.001.
S 174 M.S. Niederman/International Journal of Antimicrobial Agents 26 Suppl. 3 (2005) S170-S175
Table 3
Short-course therapy for community-acquired pneumonia [ 15]
Regimen a
Azithromycin 500mg single dose on first day; 250mg on Days 2 ~ b [16]
Azithromycin 500 mg/day for 3 days [16]
Clarithromycin 250 mg bid for 10 days [17]
Azithromycin 500 mg/day for 3 days [17]
Azithromycin 1.5 g single dose [18]
Azithromycin 500 mg/day for 3 days [18]
Amoxicillin 15 mg/kg po q8h for 3 days [19]
Amoxicillin 15 mg/kg po q8h for 5 days [19]
a bid, twice daily; po, orally; q8h, every 8 h.
b Due to atypical pathogens.
c Afebrile in ~<96h.
d Cure plus improvement.
e Cure, defined as afebrile within 72 h and disappearance of other clinical signs or symptoms and
complete or partial radiographic regression within 2 weeks.
One way to optimize compliance is to avoid pro-
longed and unnecessary therapy. However, when the 2001
ATS CAP guidelines were developed there were surpris-
ingly little data to define the optimal duration of therapy.
More recently, a review discussed this topic and provided
information about the use of short-duration therapy for CAP
(Table 3) [15].
6. Short-course therapy
Azithromycin is proven for short-course therapy for CAP
because of its prolonged half-life and post-antibiotic
effect. Thus, a 3-day azithromycin regimen demonstrates
equivalent efficacy to 5-day azithromycin [16] and 10-day
clarithromycin [17] regimens, and there has been continued
interest in developing even shorter duration therapy with
long-acting macrolides. Short-course amoxicillin therapy
has been used in pediatric CAP with favorable results [19].
The 3-day regimen was associated with less non-compliance
than a 5-day regimen (P < 0.001). This may have a direct
impact on patient well-being, since in the 5-day regimen
group non-compliance was associated with more failures
(P < 0.0001).
For many CAP patients, duration of therapy can be
5-7 days, or even less with oral azithromycin because the
tissues are front-loaded with sufficient antibiotic to keep
drug concentrations above the MIC over the 5-7 days.
In defining optimal duration, therapy should be tailored
to clinical response: treatment should be maintained for
4 8 - 7 2 h after the patient is afebrile, for a mininmm of
5 days; response may be slower with more severe illness.
Such short-duration regimens can even be used to treat
pneumococcal bacteremia, although the clinical response
patterns with bacteremia may be slower. The identity of the
pathogen may not matter provided that there is good clinical
Satisfactory
clinical response
80% (32/40) c
88% (36/41)
95% (84/88) d
94% (83/88)
97.9% (47/48) e
97.9% (47/48)
79% (791/1000) d
80% (798/1000)
response, the pathogen is sensitive to the therapy used, the
proper dose of the correct therapy is given, and there is no
extrapulmonary infection such as meningitis or empyema.
However, such regimens are not suitable for Staphylococcus
aureus or Pseudomonas aeruginosa infections.
7. Conclusions
These issues set an appropriate background for thinking
about a short-duration drug with good efficacy and tolerance
for the therapy of common conmmnity RTIs. Such therapy
will need to be combined with a campaign to promote
appropriate antimicrobial use, particularly targeting inap-
propriate application of agents with a broader spectrum of
coverage than is absolutely necessary.
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