Review

Introduction: the goals of antimicrobial therapy

Jae-Hoon Song(i)

Antimicrobial agents are generally evaluated in preclinical studies assessing in vitro activity, animal models demon-
strating in vivo bacteriologic efficacy, and clinical trials primarily investigating safety and clinical efficacy. However,
large sample sizes are required to detect any differences in outcomes between antimicrobials in clinical trials, and,
generally, studies are powered to show only clinical equivalence. In addition, diagnosis is often based on clinical
symptoms, rather than microbiological evidence of bacterial infection, and the patients most likely to have resistant
pathogens are often excluded. Clinical efficacy can be achieved in some bacterial infections in which antimicrobials
are suboptimal or even not prescribed. However, bacterial eradication maximizes clinical efficacy and may also
reduce the development and spread of resistant organisms. The goal of antimicrobial therapy is, therefore, to
eradicate bacteria at the site of infection. Bacterial eradication is not usually assessed as a primary endpoint within
the limits of currently recommended clinical trial design. However, pharmacokinetic (PK) (serum concentration
profiles, penetration to site of infection) and pharmacodynamic (PD) (susceptibility, concentration- versus time-
dependent killing, post-antimicrobial effects) criteria can be used to predict bacteriologic efficacy. PK/PD predictions
should be confirmed during all phases of antimicrobial development and throughout clinical use in response to
changing patterns of resistance. A clear rationale for dose recommendations can be determined preclinically based
on PK/PD parameters, and correlated with efficacy, safety and resistance endpoints in clinical trials. The duration of
treatment and dose should be the shortest that will reliably eradicate the pathogen(s), and that is safe and well
tolerated. Currently available agents vary significantly in their ability to achieve PK/PD parameters necessary for
bacteriologic eradication. Recommendations for appropriate antimicrobial therapy should be based on PK/PD
parameters, with the aim of achieving the maximum potential for eradication of both existing and emerging resistant
pathogens.
Int J infect Dis 2003; 7: 51-54

INTRODUCTION pathogens involved in these infections, Streptococcus

pneumoniae, Haemophilus and Movaxella injluenzae,
Infectious disease remains a major cause of death and
cataruhalis, have developed resistance to one or more
morbidity. According to data from the World Health
antimicrobial classes. For example, S. pneumoniae has
Organization (WHO) in 1998, infection was the second
developed resistance to all classes of antimicrobial agent
most common cause of death, causing 25% of deaths
used to treat respiratory tract infections, although
wor1dwide.l However, in developing countries, infectious
resistance prevalences vary between regions and for
diseases accounted for almost half of all deaths.
different antimicrobial agents.
Importantly, infection was responsible for more than
The history of antimicrobial use in respiratory tract
60% of all deaths among children aged O-4 years. The
infection and the emergence of resistance indicates that
WHO data also show that almost 90% of deaths from
there are still serious problems in defining and choosing
infectious diseases were caused by six major diseases, of
which acute respiratory tract infection was the main
3.5-
contributor (Figure l).l
Although the development of antimicrobials has 3.0 -
c
greatly reduced mortality and morbidity from infectious = 2.5-
.G
diseases, at least in the developed world, the emergence z2.0- _
of resistance to antimicrobials threatens to undermine 2 1.5-
these advances. In particular, the global emergence of 5
0” l.O-
bacterial resistance in respiratory tract infections is
0.5 -
of considerable concern. All of the major bacterial
0 I I I I I I
rek~&?~ AIDS Diarrhea1 TB Malaria Measles
(l)Samsung Medical Center, Sungkyunkwan University &Asian-Pacific diseases
infections
Research Foundation for Infectious Diseases (ARFID), Seoul, Korea.

Address correspondence to Dr J.-H. Song, Division of Infectious n Over age 5 years q Under age 5 years
Diseases, Samsung Medical Center, 50 Ilwon Dong, Kangnam-Ku,
Seoul 135-710, Korea.
Figure 1. Leading causes of mortality due to infectious
E-mail: jhsong@smc.samsung.co.kr diseases. Redrawn with permission from the WHO.’
S2 International Journal of Infectious Diseases I Volume 7, Supplement 1,2003
the best (most appropriate) antimicrobials for clinical
therapy. In order to achieve successful therapy of respira-
tory tract infection, we need to define clear goals for
‘success’, and an evidence-based approach for deter-
mining the potential of different therapies to achieve
these goals. This supplement outlines the importance of
bacterial eradication as the primary goal of antimicrobial
therapy (see J. Garau, this issue). Pharmacokinetic (PK)
and pharmacodynamic (PD) analyses can be used
to predict bacterial eradication and applied to the
assessment and choice of agents currently used for the
treatment of respiratory tract infections as well as
the development of improved formulations and new
antimicrobials (see M. R. Jacobs and R. Dagan, this
issue). Finally, the need for changes in prescribing
practice, driven by PK/PD predictions of bacterial
eradication to maximize clinical outcomes and minimize
the emergence and spread of resistance, is examined
(see K. Klugman, this issue).
APPROPRIATE PRESCRIBING AND
DRUG DEVELOPMENT
The continued development and spread of antimicrobial-
resistant bacterial strains creates an urgent need for the
development of new antimicrobials and the appropriate
use of currently available agents. Few new antimicrobials
are now reaching the market; development timelines are
lengthy, often more than a decade, and new agents are
untried in clinical practice. There are many examples
showing that the safety profile of a new agent cannot be
guaranteed based on the profiles of other antimicrobials
in the same class. In addition, for new agents developed
from existing antimicrobial classes, cross-resistance with
other members of the class may also be a problem. The
continued development of currently available agents
through the introduction of new formulations and
doses is attractive, as it is likely to be much faster than
developing new antimicrobials, and has the advantage
of a known efficacy and safety record. However, new
formulations/doses must be able to overcome existing
bacterial resistance.
LIMITATIONS OF CLINICAL ASSESSMENT
OF ANTIMICROBIAL EFFICACY
Before the use of current antimicrobials can be
optimized, a satisfactory way to assess their efficacy
must be found. Antimicrobials are usually assessed
formally in clinical trials, and prescribing recommen-
dations are often made based on these trials. Although
clinical trials constitute the accepted way of proving the
therapeutic efficacy of antimicrobials, their limitations
must always be borne in mind, in order to avoid reach-
ing unsupported conclusions.
Study design and sample size are problems in many
clinical trials. Trials of new agents in comparison to the
established therapy are often designed to show non-
inferiority only, rather than superiority. This is because
more than 700 patients are needed in each of the two
arms of the trial in order to show that one agent has a
clinical success rate that is 5% better than another
agent. In practice, this number of patients is difficult to
obtain in many clinical trials, and their statistical power,
therefore, tends to be weak. Data from small clinical
trials must always be interpreted carefully. Furthermore,
statistically similar outcomes between two antimicro-
bials in a trial that was designed to show non-inferiority
do not mean that the two agents tested have equivalent
efficacy-only that the study was not powered to show
any difference in efficacy.
The primary problem with clinical trials is that most
do not assess antimicrobial efficacy, i.e. the ability of
the antimicrobial to eradicate the bacterial infection.
Instead, clinical trials generally assess only clinical cure.
Data on bacteriologic outcome, if determined, are usually
only available from a small number of patients, and the
number of antimicrobial-resistant bacterial isolates
is often too low to allow the assessment of efficacy.
In addition, if included, bacteriologic outcomes may
actually be ‘presumed bacteriologic success or failure’;
that is, the patient had a bacterial pathogen isolated
at baseline, and was a clinical cure, or failure, in the
absence of a follow-up microbiologically evaluable
sample. Another limitation is that, in most trials, patients
are enrolled based on a clinical diagnosis, and in the case
of respiratory tract infections, patients who do not have
a bacterial infection will almost certainly be included.
The importance of bacteriologic evaluation in clinical
trials cannot be overemphasized.
The perceived value of the clinical assessment of
antimicrobials is perpetuated in clinical guidelines.
For example, neither the Infectious Diseases Society
of America2 nor the American Thoracic Society3
guidelines for the management of community-acquired
pneumonia indicate that sputum culture is required for
outpatients, while both recommend clinical response as
a measure of the efficacy of the empirical antimicrobial
chosen.
Although clinical assessment may seem to be more
practical than bacteriologic evaluation, on its own it may
result in a false interpretation of therapeutic success.
Marchant et al reviewed the results of randomized,
double-blind trials of antimicrobials in acute otitis
media to determine bacteriologic and associated clinical
success rates.4 They found that, for a drug with a
bacteriologic efficacy of lOO%, the calculated clinical
efficacy was 93% for acute bacterial otitis media, and for
a drug with a bacteriologic efficacy of 27% (equivalent
to spontaneous resolution with no antimicrobial therapy),
the calculated clinical efficacy was 71%. Thus, an agent
that has little antimicrobial activity will appear to be
reasonably effective if only clinical criteria are used
(Figure 2). The authors of this study named this the
‘Pollyanna phenomenon’, after the over-optimistic
heroine of the eponymous novel.
 Introduction: the goals of antimicrobial therapy / Song S3

Penicillin-susceptible Penicillin-resistant
S. Dneumoniae S. oneumoniae
70- 69
65 ’
3 co-
48 48
.g so- 42
%40-
” 30-
P 20- 17
IO-
40 n ll-ll-
- ’ Amoxicillin- ’ Cefixime ’ Amoxicillin- ’ Cefixime ’
30 1 clavulanate clavulanate
J
20 I n Pre-therapy 0 Post-therapy
Bacteriologic Clinical
efficacy efficacy

Figure 2. Success of antimicrobial treatment for acute Figure 3. Nasopharyngeal carriage of penicillin-susceptible
bacterial otitis media based on bacteriologic and clinical and penicillin-resistant 5. pneumoniae before and after
criteria. Redrawn with permission from Marchant et al.4 treatment with amoxicillin-clavulanate or cefixime. Data
obtained from Dabernat et aLg

THE GOALS OF ANTIMICROBIAL THERAPY
The primary goal of antimicrobial therapy should be
bacterial eradication. Antimicrobials that maximize
bacterial eradication will also maximize clinical cures
(see J. Garau, this issue). The direct association of
bacteriologic success and clinical success has been
clearly shown by Dagan et a1.‘jT7In their series of 123
patients with acute otitis media,6 a high clinical success
rate (97%) was achieved in those whose middle ear fluid
was culture negative on day 4-5 after starting anti-
microbial treatment. In contrast, the clinical success
rate was only two-thirds of this (63%) in those children
whose middle ear fluid was culture positive. A significant
association between high bacterial eradication and high
clinical cure has also been demonstrated in acute
exacerbations of chronic bronchitis.8
Bacteriologic success is also critical to prevent the
emergence of resistance (see J. Garau, this issue). For
example, Dabernat et al found that, in nasopharyngeal
samples from children with acute otitis media treated
with cefixime or amoxicillin-clavulanate, the proportion
of S. pneumoniae strains resistant to penicillin was
higher at the end of treatment (56.0%, 65/116 S. pneu-
moniae strains) and at follow-up (50.3%, 69/137) than
at inclusion (38.8%) 87/224).9 Cefixime did not decrease
penicillin-resistant S.pneumoniae carriage after treatment,
whereas amoxicillin-clavulanate significantly decreased
the carriage of these strains, with only 17/42 patients still
carrying penicillin-resistant S.pneumoniae after therapy
(Figure 3).9
The WHO acknowledges the evidence supporting
bacterial eradication, issuing the following statement in
2000: ‘The most effective strategy against antimicrobial
resistance is to get the job done right the first time-to
unequivocally destroy microbes-thereby defeating
resistance before it starts.‘lO In other words, the old
philosophy of saving the best agents for last is wrong,
and the most effective antimicrobials should be used
from the start to eradicate all bacterial pathogens and
thus minimize the selection of resistant strains.
PREDICTING BACTERIAL ERADICATION
If bacterial eradication is the primary goal of anti-
microbial therapy, and clinical trials cannot provide us
with the data to determine which agents will achieve
this goal, how do we proceed towards appropriate
prescribing? Studies in both animals and humans
indicate that the relationship between pharmacokinetics
and pharmacodynamics (PK/PD) can be used to predict
antimicrobial bacteriologic efficacy (see M. R. Jacobs,
this issue).
Antimicrobials cause either time-dependent killing
(e.g. penicillins, cephalosporins, and most macrolides) or
concentration-dependent killing (e.g. azalides and
fluoroquinolones). For agents causing time-dependent
killing, the PK/PD parameter predictive of bacterial
eradication is the duration of the dosing interval for
which antimicrobial concentrations at the site of in-
fection exceed the MIC of the infecting pathogen,
or time above MIC (T > MIC). Mortality in animal
models infected with S. pneumoniae is minimized when
the T > MIC is 25-40% for penicillins and 40-50% for
cephalosporins. r1,12For agents, such as the fluoroquino-
lanes, with concentration-dependent killing, the ratio
of the area under the concentration-time curve (AUC)
and the MIC, or the ratio of the maximum plasma
concentration (CL,,) and the MIC, are predictive of
bacterial eradication.rr-l3 For fluoroquinolones, an
AUC/MIC ratio of 25 is predictive of bacterial eradica-
tion for S. pneumoniae, although ratios of >125 are
required to eradicate Gram-negative pathogens, or in
immunocompromised patients.11,13
S4 International Journal of Infectious Diseases I Volume 7, Supplement 1,2003

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