Current challenges in the management of the infected patient

David P. Nicolau
Center for Anti-Infective Research and Development,
Hartford Hospital, Hartford, Connecticut, USA
Correspondence to David P. Nicolau, Director, Center
for Anti-Infective Research and Development, Hartford
Hospital, 80 Seymour Street, Hartford, CT 06074, USA
Tel: +1 860 545 3941; e-mail: dnicola@harthosp.org
Current Opinion in Infectious Diseases 2011,
24 (suppl 1):S1–S10
Purpose of review
Management of hospital-associated infections (HAIs) has been made more challenging
by the increasing proportion of immunocompromised or otherwise severely ill
patients and increasing prevalence of antibiotic-resistant pathogens in this environment.
This review examines strategies to optimize clinical outcomes and lower healthcare
costs for patients with HAIs by focusing on patient-related, pathogen-related, and drug-
related factors.
Recent findings
Factors have converged to increase the risk of infection with antibiotic-resistant
pathogens in the current hospital environment, including the increasing prevalence of
resistant species and number of hospitalized patients with conditions increasingly
susceptible to infection with drug-resistant bacteria. Although the list of bacterial
pathogens associated with HAIs has been fairly constant over time, the prevalence and
resistance profile of these individual species continues to evolve. Periodic antibiograms
should be utilized to access local patterns of resistance within the different hospital
wards. Outcomes for patients with HAIs are optimized with early empiric treatment with
an appropriate regimen, selected on the basis of patient characteristics and local
resistance patterns. Dosing strategies should be utilized to ensure that the efficacy of an
appropriate antibiotic is optimized, by achieving the pharmacodynamic target predictive
of its efficacy. Using these strategies improves quality of care and is associated with
lower overall healthcare costs.
Summary
Bacterial resistance is an increasing problem in the hospital environment, and has been
associated with poorer clinical outcomes and elevated healthcare costs. By using
patient characteristics, local antibiograms, and dosing strategies to achieve an optimal
pharmacodynamic profile, early appropriate empiric therapy can be utilized to improve
clinical outcomes, minimize the development of resistance, and reduce healthcare
costs.

Keywords
antibiotic resistance, antibiotic stewardship, pharmacodynamic, pharmacokinetic

Curr Opin Infect Dis 24 (suppl 1):S1–S10

ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
0951-7375

of resistance in target pathogens or the development of

Introduction
Management of bacterial infections has become increas-
ingly complex, as the general severity of illness or
immune status of hospitalized patients has worsened,
antibiotic resistance has increased, and the pipeline for
new agents is diminishing. Infected patients are treated
in a variety of institutional settings, from community
hospitals to large academic medical centers, but a com-
mon principle of effective treatment is the rapid recog-
nition of infection and the initiation of appropriate
therapy, defined as an antimicrobial with laboratory-
based susceptibility to the infecting pathogen. This
strategy has been shown to reduce infection-related
morbidity and mortality; however, the indiscriminate
use of therapeutic entities may lead to the emergence
0951-7375 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
superinfections (i.e., Clostridium difficile). Hence, when
using antibiotics, it is prudent for the practicing clinician
to be mindful of these benefits as well as the potential
risks. This will not only improve the clinical outcomes of
the infected patient, but will also reduce societal and
healthcare costs associated with therapeutic failure.
Optimizing outcomes
Optimizing infection-related outcomes requires a focus
on three interrelated factors. In simple terms, attention
needs to be directed towards the competency of the
patient, the etiologic pathogen and its susceptibility
profile, and the choice of drug. This review examines
each of these factors, providing a general overview of the

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 S2 Antimicrobial stewardship and infection control programs: meeting new challenges
current state of affairs and guidelines on optimal patient
management and antibiotic use.
Patient (host) factors
As mentioned, the current hospitalized population is
characterized by an increased number of patients with
multiple comorbidities, chronic or severe disease, and/or
who are otherwise immunocompromised [1]. There has
also been a general aging of the US population, and
advanced age is associated with greater risk of comorbidity,
chronic and/or severe disease, polypharmacy, and immu-
nodeficiency. Furthermore, many patients admitted to a
hospital have received prior surgical or medical interven-
tions (i.e., blood products, oncologic, or rheumatologic
medications) that alter patient immunity. Moreover, con-
sideration should be given to the prior use of antibiotic
therapy and thus the increased risk of infection with an
antibiotic-resistant pathogen. In addition, the more severe
the illness for which the patient is hospitalized, the more
likely the patient will have an extended hospital stay,
frequently with use of intubation, parenteral nutrition,
or other medical devices (i.e., central venous or urinary
catheters), all of which increase the risk of a hospital-
acquired infection (HAI) with a drug-resistant pathogen.
Infection with an antibiotic-resistant versus antibiotic-
susceptible pathogen has been associated with greater
risk of mortality, increased length of hospital stay, and
higher healthcare and societal costs [2–4]. Risk of infec-
tion with a resistant pathogen increases with advancing
age, immunodeficiency, multiple comorbidities, and prior
antibiotic use. Inappropriate antibiotic therapy is more
likely to occur in patients infected with resistant bacteria,
and the risk of mortality is particularly elevated in immu-
nocompromised patients or those with severe disease
who also experience a delay in the initiation of appro-
priate antibiotic therapy [5,6].
Hence, patient characteristics by themselves and through
interactions with bacterial pathogens and antibiotic
therapy have a major impact on clinical outcomes and
costs. These patient characteristics, including advanced
age; presence of comorbidities (e.g., malnutrition; dia-
betes mellitus; alcoholism; cancer; or chronic heart, lung,
renal, or hepatic disease); immunosuppressive conditions
or use of immunosuppressant drugs; malnutrition; recent
intubation; parenteral nutrition; recent or prolonged hos-
pitalization (5 days); and prior antibiotic use, are
important considerations when determining treatment
for a given patient, and are commonly incorporated in
treatment guidelines for both community-acquired or
hospital-acquired infections [7–9].
Pathogen factors
Hospitalized patients with a suspected bacterial infection
typically receive empiric therapy before diagnostic test
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
results are known. With empiric treatment, clinicians
need to consider the most likely causative pathogen(s)
when prescribing initial therapy. Patient characteristics
and local susceptibility trends, determined through peri-
odic antibiograms, provide important clues as to the like-
lihood of infection with an antibiotic-resistant species.
Institutional antibiograms are important and should be
performed for different institutional departments or units,
because the incidence and susceptibility of pathogenic
bacteria can vary widely for different institutions within
the same geographic area and for different departments
within a given institution [10–12].
When considering nosocomial or HAI-related infec-
tions, the following organisms are commonly identified:
Gram-negative (e.g., Escherichia coli, Klebsiella pneumoniae,
Enterobacter species, Pseudomonas aeruginosa, and certain
Acinetobacter species) and Gram-positive (e.g., Staphyloco-
ccus aureus, Enterococci, and coagulase-negative staphy-
lococci) bacterium [13,14]. Although the bacterial patho-
gens commonly associated with these infections have not
changed much over recent times, variation in their preva-
lence and resistance profiles have been noted by patient
type, institution, institutional department, and infection
site. In addition, Clostridium difficile infections are becom-
ing more common and troublesome than in the past
[15,16]. Table 1 presents the results from a surveillance
of bacterial isolates associated with HAI in the ICU for
1986–2003, illustrating the most commonly isolated
pathogens and their variation by infection site [17].
Although these data provide insight into our national
epidemiologic trends during the study period, it should
be recognized that considerable differences may be
observed over time, both within and among individual
ICUs, as well as across international borders.
Although the organisms causing HAIs have not changed,
their resistance to common antibiotics has. Antibiotic
resistance has become an increasing problem in the
United States and worldwide, and involves both Gram-
negative and Gram-positive bacteria [18–22]. Moreover,
there is now evidence of increasing numbers of strains
that are resistant to multiple antibiotic drugs or drug
classes, so-called multiple-drug resistant (MDR) organ-
isms. Because of this, the selection of empiric and
directed treatment after pathogen identification has
become more difficult in both nosocomial and com-
munity-acquired settings.
Resistance is a complex problem affected by various
mechanisms that are expanding and, increasingly, that
are occurring together. Overuse or misuse of antibiotic
agents is a key factor creating selective pressure for the
emergence and amplification of resistant bacteria. Key
mechanisms of antibiotic resistance include production of
b-lactamases that inactivate b-lactam drugs, production

Table 1 Most commonly reported bacterial isolates associated with nosocomial ICU infection based on National Nosocomial
Infections Surveillance System data for 1986–2003
Pneumonia Bloodstream infection
Pathogen (n ¼ 4365)
Gram negative
Escherichia coli 5.0
Klebsiella pneumoniae 7.2
Enterobacter species 10.0
Serratia marcescens 4.7
Pseudomonas aeruginosa 18.1
Acinetobacter species 6.9
Gram positive
Coagulase-negative staphylococci 1.8
Staphylococcus aureus 27.8
Enterococci 1.3
Other 3.2
Reprinted with permission from Gaynes and Edwards [17].
of other enzymes that inactivate nonb-lactam antibiotics,
alteration in drug-binding targets, expression of efflux
pumps (preventing drug access to the intracellular tar-
get), and downregulation or modification of membrane
pores required for drug entry into the cell [18,21,23].
b-Lactamase production is the most important mechan-
ism of resistance among Gram-negative bacilli; the num-
ber of types of these enzymes with broadened activity has
increased, including extended-spectrum b-lactamases
(ESBLs), AmpC-b lactamases, metallo-b-lactamases,
and carbapenemases. This means clinicians frequently
need to treat patients who have been infected with Gram-
negative bacilli resistant to multiple b-lactam antibiotic
subclasses. Other Gram-negative bacteria exhibit MDR
that involves multiple overlapping mechanisms of resist-
ance, especially P. aeruginosa and Acinetobacter baumannii
[24]. It is now a relatively common occurrence in today’s
hospital environment to encounter patients who have
been infected with strains of P. aeruginosa and A. bau-
mannii that are resistant to three or more antibiotic
classes.
The most significant Gram-positive bacterium exhibiting
MDR is S. aureus, and specifically methicillin-resistant
S. aureus (MRSA). Nearly 60% of S. aureus isolates from
hospitalized patients located throughout the United
States are methicillin-resistant, with high rates in both
inpatients and outpatients and somewhat higher rates in
ICUs than in other hospital units [25]. MRSA used to
be confined to nosocomial infections, but increasing
numbers of patients treated as outpatients in emergency
departments or in the community are infected with
MRSA. Surveillance data from the Minnesota Depart-
ment of Health indicated a significant increase in the
proportion of MRSA cases classified as community-
associated from 11% in 2000 to 33% in 2005 (P < .01)
[26]. In a study by Styers et al. [25], MRSA rates were 59,
55, and 48% for strains from non-ICU inpatients, ICU,
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Managing the infected patient Nicolau S3
Percentage of isolates, by infection type
Surgical site infection Urinary tract infection
(n ¼ 2351) (n ¼ 2984) (n ¼ 4109)
3.3 6.5 26.0
4.2 3.0 9.8
4.4 9.0 6.9
2.3 2.0 1.6
3.4 9.5 16.3
2.4 2.1 1.6
42.9 15.9 4.9
14.3 22.5 3.6
14.5 13.9 17.4
4.5 5.8 1.2
and outpatients, respectively. Moreover, these authors
report MRSA rates in outpatient specimens from the
lower respiratory tract, skin and skin tissue, and blood
were 43, 38, and 41%, respectively, compared with rates
of 56, 49, and 49% for inpatient specimens from the same
sources [25].
Community-associated MRSA is a common cause of
skin and soft-tissue infections (SSTIs). Moran et al. [27]
reported that S. aureus was isolated from 76% of individuals
seen in university-affiliated emergency departments for
SSTIs in August 2004, and 59% of these isolates were
resistant to methicillin and various other antibiotics, even
though none of the individuals had established risk factors
for MRSA. This is significant because it means clinicians
treating patients in emergency departments or the com-
munity can no longer assume that oral b-lactam drugs or
macrolides will suffice as treatment. As a result of the
increased prevalence of community-acquired MRSA,
empiric coverage should be directed at this pathogen.
The increasing number of MDR bacterial pathogens is a
challenge, not only for patient care but also in the context
of new drug development. There is a clear need for new
drugs with novel mechanisms of action that can be used
to combat the increasing number of bacteria that are
resistant to multiple classes of currently available agents.
Unfortunately, forces have converged to cause pharma-
ceutical companies to invest fewer and fewer resources
towards the development of these new agents [22]. As
such, there is an increasing focus on better use (i.e.,
pharmacodynamic dose optimization, de-escalation of
broad-spectrum empiric therapy) of currently available
agents to lengthen their clinical lifetime and slow the
emergence of further resistance. Other improvements in
infection control are also critical in our attempts to slow
the emergence and spread of antibiotic-resistant patho-
gens within the hospital environment or long-term care
facilities [28–31].
 S4 Antimicrobial stewardship and infection control programs: meeting new challenges
Drug-related factors
The patient population at large is increasingly comprom-
ised, and antibiotic resistance is increasing at the same
time that the development and the subsequent introduc-
tion of new agents is slowing [22,32,33]. In other words,
the host is increasingly challenged, the organisms are
more difficult, and the treatment armamentarium is not
expanding to meet the enhanced medical need. Of the
triad impacting outcomes – host, pathogen, and drug-
related factors – the latter is the only one that is modifi-
able. Healthcare professionals make treatment decisions,
and the choices they make affect outcomes, both in terms
of the immediate patient and reducing emergence of
resistant strains that can subsequently impact other
patients as well. Therefore, it is exceedingly important
that clinicians understand the antibacterial drug arma-
mentarium, from a microbiology, pharmacology, toxicity,
and ecologic perspective.
Early, appropriate therapy
For patients with serious bacterial infections [e.g.,
patients in the ICU with ventilator-associated pneumonia
(VAP) or sepsis], failure to administer an appropriate
antibiotic therapy in a timely manner is associated with
worse hospital-related and infection-related mortality,
infection-related morbidity, length of hospital stay, days
of antibiotic therapy, and healthcare costs, compared
with early appropriate therapy [34–43]. When consider-
ing the reasons for inappropriate therapy, the most com-
mon is unanticipated antibiotic resistance to the selected
therapy [34–36,41,42]. For example, Harbarth et al. [34]
reported that infection with a MDR pathogen was one
characteristic associated with inappropriate treatment in
patients with severe sepsis. Kollef et al. [36] identified
infection with an antibiotic-resistant bacteria as the
primary reason for inadequate antibiotic therapy in their
study of critically ill hospital patients. In a study of
patients transferred from long-term care facilities, 49%
of patients infected with an antibiotic-resistant bacteria
received inappropriate initial antibiotic therapy, com-
pared with only 4% of patients infected with an anti-
biotic-susceptible strain [42].
It is important that the therapeutic regimen is timely as
well as appropriate, and the window of opportunity may
be very small for some patient populations, for example,
as early as within the first hour in the context of sepsis or
septic shock. In a study of patients in the ICU with VAP,
the mortality rate was higher for those who received
delayed appropriate treatment [i.e., after performing
bronchoscopy or obtaining bronchoalveolar lavage
(BAL) results] than for those receiving early adequate
treatment [38]. Moreover, mortality results were similar
for patients who were switched from inadequate to
adequate therapy after bronchoscopy and those who
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
continued to receive inadequate therapy, further demon-
strating the importance of early adequate or appropriate
therapy and the inability to fully rectify an initial error by
a later switch in therapy. Similar results have been
reported in other studies [44]. Similar benefits of appro-
priate therapy have also recently been recognized in non-
VAP infections in ICU patients and non-ICU patients
[45,46].
Balancing effective therapy with resistance
concerns
Although early, appropriate treatment clearly optimizes
outcomes, there is a danger of overtreatment and pro-
motion of antibiotic resistance when a broad-spectrum
antibiotic or antibiotic regimen is utilized beyond what is
required for empiric or directed therapy based on infec-
tion resolution. Clinicians continuously have to ask the
question: when does the need to treat empirically with a
broad-spectrum agent(s) outweigh the need to wait for
culture results. The decision usually hinges on patient
factors that have been associated with increased risk of
infection with a resistant species, together with institu-
tional antibiograms (if available) indicating the likelihood
of resistant species in different units of the hospital. Some
of these patient factors include critical illness with fever,
prior antibiotic use, prolonged mechanical ventilation,
recent surgery, and prolonged hospital stay.
Clinicians are responding to the challenge of treating
patients in an era of increased numbers of MDR patho-
gens, as illustrated by the increased use of broad-spectrum
antibiotics, such as carbapenems. As shown in Fig. 1 [47],
carbapenem usage has increased in the United States by
nearly 90% from 2003 to 2008. This is presumably because
of broad-based coverage of resistant pathogens provided
Figure 1 Rising usage of carbapenems in the United States
(2003–2008)
86% increase
10 000
9079
Carbapenem days of
therapy (thousands)
9000
8000
7000
6000
5000
4869
4000
2003 2004 2005 2006 2007 2008
Year
Adapted from National Sales Perspective audit. IMS. December 2008
[47].

by this class of agents, including activity against MDR
Pseudomonas, MDR Acinetobacter species, and ESBL-pro-
ducing bacteria [48,49]. However, given the diminishing
number of new drugs entering the market, clinicians need
to be careful that these are not overused or misused,
leading to the emergence of resistance.
As previously stated, although the utilization of broad-
spectrum therapy has been shown to reduce infection-
related morbidity and mortality in a variety of patient
populations, the indiscriminate use and/or the unnecess-
ary prolonged exposure may lead to the emergence of
resistance in target pathogens, the destabilization of gut
flora, and the subsequent development of superinfection
at this or anatomic sites.
Antimicrobial stewardship
Antimicrobial stewardship is an increasingly important
topic in today’s hospital environment, and recent guide-
lines by the Infectious Diseases Society of America and
Society for Healthcare Epidemiology of America provide
recommendations for programs to enhance such steward-
ship [50]. As outlined in the guidelines, the primary goal
of antimicrobial stewardship is ‘to optimize clinical out-
comes while minimizing unintended consequences of
pathogenic organisms (such as C. difficile) and the emer-
gence of resistance’ [50]. A secondary goal is to reduce
healthcare costs, without adversely affecting patient
quality of care. The guidelines note that effective com-
prehensive antimicrobial stewardship programs have
been shown to decrease antimicrobial use by 22–36%,
with associated annual savings of US$ 200 000–900 000.
These benefits have been observed in both larger
academic hospitals and smaller community hospitals.
However, as discussed more fully in the study by
Dr Goff in this supplement, the potential financial
benefits go beyond simply reduction in drug acquisition
or usage costs. Again, the primary focus should be on
improving clinical outcomes, which will typically have
additional benefits in terms of reducing the emergence of
resistance and minimizing length of hospital stay, the
primary driver of increased healthcare costs as discussed
more fully below.
It is important to understand that stewardship is not a
one-time event. Rolling out the program is only the first
step – a successful stewardship program is a continuous
process, and part of that process is not only bringing
clinicians new tools but also providing opportunities for
multidisciplinary education. This educational process
can be very challenging in today’s healthcare environ-
ment due to the ever-changing prescriber base, high
patient caseloads, and reduced protected time for edu-
cational updates. These educational efforts should
include information regarding both the successes and
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Managing the infected patient Nicolau S5
shortcomings of one’s institutional efforts in addition
to future opportunities for improvement.
Another critical component of an effective program is the
development of clinical guidelines and/or pathways for
optimal antibiotic use. A 2001 study by Ibrahim et al. [51]
reported that application of a clinical guideline for VAP
treatment increased the initial administration of adequate
antibiotic therapy and decreased the overall duration of
antibiotic therapy. More recently, we have also reported
the successful implementation of a VAP pathway that
improved clinical and microbiologic outcomes in the face
of emerging pathogen resistance in the ICU setting [52].
In addition, another study also showed that high adher-
ence to an institutional pathway for antibiotic treatment
in ICU patients with VAP (>70% compliance) was asso-
ciated with a shorter duration of treatment for first pneu-
monia episode (6 vs. 10 days, P ¼ .001), a shorter duration
of mechanical ventilation (178 vs. 318 h, P ¼ .017), and a
shorter ICU stay (10 vs. 24 days, P ¼ .001) compared with
low adherence [53]. In other words, failure to utilize
clinical guidelines or pathways lessens the potential for
good microbiologic and clinical outcomes.
Establishing good institutional guidelines should, in part,
be based on local susceptibility patterns within the hos-
pital and the different units, as determined by periodic
antibiograms. As discussed, inadequate antibiotic therapy
is more likely if antibiotic resistance is present. A review
of the literature indicates that the bacterial pathogens
most commonly associated with inadequate antibiotic
therapy of VAP are P. aeruginosa (>35%), S. aureus
(>20%), and Acinetobacter species (approximately 20%)
[54].
Poor outcomes despite appropriate therapy:
treatment timing and dosing issues
The outcome of a bacterial infection may be poor despite
selection of an appropriate antibiotic agent. For example,
as depicted in Fig. 2, a number of studies of patients with
serious infections have reported mortality rates of 15–
40%, even though patients were administered appropri-
ate antimicrobial therapy [38,44,55–58]. Three expla-
nations for continued mortality in the face of appropriate
antimicrobial therapy are continuation of a terminal pro-
cess, treatment delay, or inadequate dosing, leading to
inadequate drug exposure.
In the context of sepsis and septic shock, treatment may
eliminate the instigating pathogen from the bloodstream,
but the sepsis process (i.e., the host response to the insult)
can continue and eventually lead to patient’s death. In
addition, as previously mentioned, the timing of treat-
ment can be an important variable, and a delay in treat-
ment might contribute to a less-than-optimal outcome
 S6 Antimicrobial stewardship and infection control programs: meeting new challenges
Figure 2 Mortality associated with appropriate antimicrobial
therapy in patients with serious infections
Rello et al. [44]
Alvarez-Lerma et al. [55]
Ibrahim et al. [57]
Luna et al. [38]
Garnacho-Montero et al. [56]
Vallés et al. [58]
0 20 40 60 80
Mortality (%)
Data from [38,44,55–58].
despite the use of an appropriate regimen. In earlier
times, clinicians would often initiate empiric treatment
with a relatively narrow-spectrum antibiotic and then
modify treatment as needed when the culture results
became available 3 or 4 days later that revealed a resistant
species. However, we now understand that early appro-
priate therapy is paramount for optimal outcomes, for
both Gram-negative and Gram-positive organisms. For
example, in the case of sepsis or septic shock, the window
of opportunity is the first hour after the process has been
identified – a huge challenge [59]. For S. aureus infec-
tions, data support the importance of appropriate anti-
biotic therapy within 48 h of infection onset [60]. As
antimicrobial susceptibility results are typically not avail-
able this quickly using traditional diagnostic tools, data
such as these highlight the importance of understanding
local resistance patterns and other factors that increase
risk of infection with a resistant species, and making an
appropriate choice for initial empiric therapy.
Lastly, poor outcomes may be observed despite the use of
an appropriate (as defined by laboratory-based suscepti-
bility criteria) antibiotic because the dosing regimen is
insufficient to achieve the necessary level of drug
exposure to ensure antibacterial effects. Tam et al. [61]
studied the treatment of bacteremia due to P. aeruginosa
with piperacillin-tazobactam or other appropriate empiri-
cal (control) therapy within 24 h of positive culture
results. The results showed piperacillin-tazobactam
was associated with a similar 30-day mortality rate as
control treatment when P. aeruginosa with high suscepti-
bility to piperacillin-tazobactam [minimum inhibitory con-
centration (MIC) 16 mg/l] was involved (30 vs. 21%,
P ¼ .673). However, piperacillin-tazobactam therapy was
associated with increased mortality (>80 vs. 20%,
P ¼ .004) when species with reduced piperacillin-tazobac-
tam susceptibility (MIC 32 or 64 mg/l) were involved.
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This illustrates that with organisms closer to the suscepti-
bility breakpoint for a given antibiotic, although they
might still be distinguished as susceptible according to
clinical laboratory standards, conventional doses of the
antibiotic agent may be insufficient to optimize outcomes.
This is true not only for piperacillin-tazobactam but
also for other agents, including other b-lactams, fluoro-
quinolones, and other antibiotic classes [62,63]. We are
beginning to see MRSA with reduced susceptibility to
vancomycin, and one of the ways to approach this is to
push the vancomycin doses higher [64]. However, some
studies have shown that aggressively increasing the van-
100 comycin dose (through concentrations >15 mg/ml) does
not necessarily improve clinical outcomes in patients
with MRSA infections compared with traditional dose
targets (5–15 mg/ml) [65]. Increasing antibiotic doses also
raises the concern about escalating toxicity profiles.
Supplemental strategies to improve
outcomes
It is clear that effective antimicrobial stewardship
means more than simply choosing the correct antimicro-
bial agent. It also means de-escalating an initial broad-
spectrum antimicrobial regimen once culture results
demonstrate a resistant species is not involved [66], as
well as using various approaches to optimize the phar-
macodynamic properties of currently available agents in
an attempt to improve efficacy and minimize the devel-
opment of resistance [67,68]. Switching from intrave-
nous to oral administration or decreasing the treatment
duration after infection resolution are other strategies
that can be used to decrease healthcare-related costs
without compromising outcomes.
Antibiotics can be classified by their pharmacodynamic
profile. The three general pharmacokinetic/pharmacody-
namic parameters most predictive of antibiotic efficacy
are duration of time a drug concentration remains above
the MIC (T > MIC), ratio of the maximal drug concen-
tration to the MIC (Cmax : MIC), or ratio of the area under
the drug concentration time curve at 24 h to the MIC
(AUC0–24 : MIC) [67–69]. Agents whose efficacy is best
predicted by T > MIC are called time-dependent agents,
whereas those whose efficacy is best predicted by Cmax : -
MIC or AUC : MIC are concentration-dependent drugs.
Optimal drug exposure and clinical outcomes, including
minimization of drug resistance, can best be achieved by
understanding the pharmacodynamic parameter best cor-
relating with efficacy for a given drug, and then dosing to
achieve that measure.
b-Lactams are among the most frequently administered
antimicrobials in hospitals, cephalosporins and penicillins
for more general usage and, increasingly, carbapenems to

satisfy the need for appropriate empiric therapy in
the setting of growing resistance. b-Lactams are time-
dependent agents whose efficacy is best predicted by
T > MIC [68]. The optimal T > MIC varies by b-lactam
class: 60–70% for cephalosporins and 40% for carbape-
nems. Optimal efficacy for a carbapenem is best achieved
by dosing in a manner that ensures that the concentration
of the drug at the target site remains above that of the
MIC for at least 40% of the dosing interval, typically
defined as a 24-h period. Strategies to increase the
T > MIC include increasing the dose, increasing the
dosing frequency (without a subsequent increase in the
dose), or extending the infusion time of intravenous
agents. Dose-escalation techniques (increasing the dose
or dosing interval) are relatively ineffective strategies to
increase T > MIC and b-lactam efficacy [68,70]. Although
some increase in T > MIC or exposure may be achieved,
it is usually nonproportional, small, and insufficient to
achieve optimal T > MIC or drug exposure. For example,
doubling the drug dose typically does not mean a dou-
bling of the T > MIC, and hence does not lead to a
meaningful improvement in efficacy, but it does double
the cost and potential toxicity associated with a given
therapy. To improve drug exposure, one can use a once-
daily compound with sufficient potency that optimizes
the pharmacodynamic profile, or for the shorter half-life
b-lactams, a strategy to increase the T > MIC is to
increase the infusion duration of intravenous agents.
By lengthening the infusion time, the T > MIC can be
increased, while using the same dose and dosing interval.
By playing with these parameters, an optimal T > MIC
can be achieved in a reproducible manner that does not
increase drug costs. Moreover, because of the inherent
safety of b-lactams in the clinical setting, the strategy of
prolonged infusion can be combined with higher b-lac-
tam doses when desiring better coverage of pathogens
with reduced susceptibility. This is a potentially exciting
opportunity allowing clinicians to best avail themselves
of the existing drug armamentarium to optimize clinical
outcomes and minimize resistance in the context of a
diminishing drug pipeline.
Bacterial resistance and increasing
healthcare costs
Infections caused by resistant versus susceptible bacterial
species are associated with higher mortality, longer hos-
pital stays, and increased healthcare costs [3]. A recent
study by Evans et al. [71] compared cost and hospital
length of stay data for 604 surgical admissions treated for
at least one Gram-negative rod infection caused by
susceptible species (n ¼ 467) or a species resistant to at
least one major antibiotic class (n ¼ 137). Infection with a
resistant versus susceptible Gram-negative rod was
associated with longer median hospital length of stay
(29 vs. 13 days, P < .0001) and longer median ICU length
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Managing the infected patient Nicolau S7
of stay (13 vs. 1 day, P < .0001), and higher median
hospital costs (US$ 80 500 vs. 29 604, P < .0001) and
higher median antibiotic costs (US$ 2607 vs. 758,
P < .0001). Hence, infection with a resistant species
increased the total cost of hospital care by more than
2.5-fold.
As noted earlier, part of the reason for the increased costs
associated with resistant pathogens is due to initial
inadequate antibiotic therapy. This has led to a general
strategy in many institutions to ‘hit hard and fast’ with a
broad-spectrum agent(s) when a resistant species is likely
to be involved [72], with step-down or modification of
therapy if and when culture data prove otherwise. Various
components of care contribute to overall costs, but drug
acquisition and usage costs are only a small contributor.
Although a reduction in antimicrobial costs is the most
common justification for implementing an antimicrobial
stewardship program [73], a number of studies have
demonstrated that drug acquisition costs are a relatively
small and often insignificant portion of total healthcare
costs, in the range of about 5% (Fig. 3) [74–78]. In terms
of both patient outcomes and healthcare costs, it is
typically more important to treat as early as possible with
an appropriate regimen, even if more expensive, than to
begin with inadequate therapy that leads to longer hos-
pital stay and poorer patient outcomes – as well as
increasing the risk of resistance.
These points are illustrated in a recent 2010 study
reported by our center that looked at hospital costs
associated with the use of a clinical pathway imple-
mented in ICUs to optimize antibiotic regimen selection
for patients with VAP [79]. VAP-related length of
stay, hospitalization costs, and antibiotic costs were com-
pared between patients treated using the pathway and a
Figure 3 Antibiotics as percentage of total healthcare costs for
various types of bacterial infection
Community-acquired
pneumonia [74]
Hospital-acquired
pneumonia [75]
Abdominal trauma [76]
Diabetic foot [77]
Burn [78]
0 20 40 60 80 100
Total costs (%)
antibiotic cost; healthcare cost. Data from [74–78].
 S8 Antimicrobial stewardship and infection control programs: meeting new challenges
historical control group treated according to prescriber
preference. Results showed patients in the clinical path-
way group were more frequently aggressively dosed with
more costly antibiotics as empiric therapy, including
more frequent use of combination therapy targeting
P. aeruginosa (93 vs. 12%, P < .001) and triple-drug
therapy targeting both MRSA and P. aeruginosa (79 vs.
4%, P < .001). Despite this, VAP hospitalization cost
was lower for the clinical pathway versus control group
(US$ 47 033 vs. 90 585, P < .001). These data showed
hospital costs were similar for the two groups over the first
week of VAP (US$ 24 501 vs. 28 106), but were signifi-
cantly lower for the clinical pathway group during week 2
(US$ 12 231 vs. 20 947, P < .001). Patients treated with
the clinical pathway also had shorter lengths of ICU stay
after VAP, shorter total hospital lengths of stay after VAP,
and a lower infection-related mortality rate (9 vs. 21%).
Costs for VAP-associated antibiotics accounted for 1.49%
of total hospital costs for patients in the clinical pathway
group and 0.64% in the control group. There was no
significant difference in mean antibiotic drug costs
between the treatment groups (US$ 766 vs. 934, P ¼ .45).
Conclusion
Optimal outcomes for bacterial infections are best
achieved by early empiric therapy with an appropriate
regimen, making modifications as necessary after the
availability of culture results. Selection of the initial
empiric therapy should be based on patient character-
istics and data from local antibiograms combined with
pharmacodynamic dosing strategies to optimize anti-
biotic exposures. In terms of financial costs, the costs
saved by avoiding treatment failure are generally much
greater than the costs spent on antibiotic therapy. As
illustrated by our economic study of VAP management,
drug-acquisition cost is an important but often small
component of overall healthcare costs for patients with
serious bacterial infections. In addition, we demonstrated
that the utilization of more potent antimicrobial regimens
combined with a de-escalation strategy in our VAP popu-
lation resulted in improved clinical and microbiologic
outcomes. As shown in our publication, clinicians can
use less-expensive, less-potent antimicrobial therapies
for longer periods and get inferior outcomes, or one could
administer optimally designed regimens that improve the
quality of care and lower healthcare costs. Lastly,
although strong infection control programs should be
advocated to enhance awareness and minimize the spread
of resistant pathogens, the only modifiable factor in the
context of the host–bug–drug triad is the choice of the
antibiotic, dose, and duration. In the era of increasing
resistance, an aging/compromised patient population,
and a dwindling pipeline of novel agents, the imple-
mentation of antibiotic stewardship practices is para-
mount if good clinical outcomes are to be sustained.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Acknowledgement
This supplement was supported through an educational grant from
Merck & Co., Inc.
The author declares no conflicts of interest.
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