SUPPLEMENT ARTICLE

Principles of Antibiotic Therapy in Severe Infections:

Optimizing the Therapeutic Approach by Use of
Laboratory and Clinical Data
Stan Deresinski
Division of Infectious Disease and Geographic Medicine, Department of Medicine, Stanford University, Stanford, and Division of Infectious
Diseases, Santa Clara Valley Medical Center, San Jose, and Sequoia Hospital, Redwood City, California

Antimicrobial resistance is strongly associated with adverse patient outcomes and increased resource utilization [1]. The effective clinician in todays hospital
environment must utilize all available laboratory and
clinical data in the selection of the optimal antibiotic
therapy for the critically ill patient. Antibiotics must,
however, be utilized in a manner that ensures not only
a maximally favorable outcome for the individual patient but, also, the minimization of subsequent antimicrobial resistance [2]. Each antibiotic use, whether
appropriate or inappropriate, affects the bacterial ecology by exerting selective pressure and thereby driving
resistance. Thus, all antibiotic use has potential public
health consequences and, in this way, differs from the
use of all other classes of pharmaceutical agents.
When initially faced with a patient with a serious
infection, the clinician most often lacks specific knowledge of the etiologic pathogen and must choose anti-

Reprints or correspondence: Dr. Stan Deresinski, 2900 Whipple Ave., Ste. 115,
Redwood City, CA 94062 (polishmd@earthlink.net).
Clinical Infectious Diseases 2007; 45:S17783
 2007 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2007/4506S3-0004$15.00
DOI: 10.1086/519472

biotics empirically. As the microbiological data and

evolving clinical information become available, antibiotic therapy must be appropriately adjusted, often
allowing a narrowing of its spectrum. Such de-escalation of therapy, along with the ultimate de-escalation
(i.e., discontinuation of therapy as soon as maximum
benefit has been achieved) and assurance of the heterogeneity of antibiotic use, allows for the establishment
of balance between the competing tensions of the individual patient and the public health consequences of
antibiotic use. The implementation of these guidelines
will provide benefit to clinicians and institutions, but,
most of all, it will benefit patients.
Current understanding has allowed the development
of a series of simple principles of antibiotic therapy for
the critically ill patient. Perhaps the most important
principle is the understanding that any delay in the
initiation of adequate antibiotic therapy is potentially
lethal. In addition, inappropriately prolonged antibiotic
therapy may adversely affect both the individual patient
and the more general bacterial ecology. Multiple studies
have demonstrated that survival is significantly improved when the initial choice of antibiotics is appropriate, defined as indicating that all isolated pathogens
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The increasingly daunting problem of antimicrobial resistance has led to an intense focus on optimization of
antibiotic therapy, with simultaneous goals of improving patient outcomes and minimizing the contribution
of that therapy to making the available antibiotics obsolete. Although even appropriate antibiotic therapy
drives resistance, inappropriate therapy may also have adverse effects on the individual patient, as well as on
the bacterial ecology. Recent research has validated the benefit of intelligent utilization of both microbiological
data and clinical assessment in the empirical selection of initial broad-spectrum therapy and in further guidance
of therapeutic decisions throughout the course of illness by use of a systems approach. Thus, the optimal
approach to the critically ill patient with infection involves the initiation of aggressive broad-spectrumempirical
therapy followed by timely responses to microbiological and clinical results as they become available. An
appropriate response to this information often involves de-escalation of therapy or even its discontinuation.

IMPORTANCE OF RAPID INITIATION OF

APPROPRIATE ANTIBIOTIC THERAPY
The impact of the choice of antibiotics is most apparent in
patients who are severely ill. The interaction of appropriate
therapy, severity of illness, and outcome was confirmed in a
retrospective study of 142 patients with ventilator-associated
pneumonia [4]. Empirical antibiotic therapy was judged to have
been appropriate in 44% of patients on day 0 and in 92% of
patients on day 2 [4]. A statistically significant increase in mor-

tality rate was associated with inappropriate therapy only

among patients with a high severity of illness, as judged by
their Logistic Organ Dysfunction (LOD) score [4].
There is also clear evidence that, in the management of patients with severe infection, not only must the chosen antibiotic
regimen be appropriate, but its administration must be
promptly initiated. Kumar et al. [5] retrospectively studied the
impact of delays in initiation of appropriate antimicrobial therapy in 2154 patients with septic shock and found a strong
correlation between delays in initiating antibiotic therapy and
in-hospital mortality (adjusted odds ratio [OR], 1.119 deaths/
1-h delay; P ! .0001). The time to initiation of appropriate antibiotic therapy was the strongest predictor of survival (figure
1). If an effective antibiotic was administered within the first
hour of documented hypotension, the survival rate was 79.9%;
each 1-h delay over the next 6 h decreased average survival
rates by 7.6%. Notably, only 50% of patients received appropriate treatment during the first 6 h [5].
There are multiple steps involved between patient contact
and antibiotic administration, and multiple reasons have been
identified for delays in the administration of antibiotic therapy.
These delays underscore the need for a systematic approach to
the management of patients with serious infections. Reasons
for delay were highlighted in a retrospective study by Iregui et
al. [6] in which 33 (30.8%) of the 107 patients with ventilatorassociated pneumonia had a delay in initiation of appropriate
antibiotic therapy of 24 h. A delay in initiation of appropriate
antibiotic therapy of 24 h was associated with a significantly
greater hospital mortality rate (69.7% vs. 28.4%; P ! .01) [6].
As in other studies, infection with an antibiotic-resistant path-

Figure 1. Early initiation of appropriate antibiotic therapy for septic shock and survival. The survival fraction is the fraction of patients surviving
to hospital discharge after receiving effective therapy initiated within the given time interval. The cumulative effective antimicrobial fraction is the
cumulative fraction of patients having received effective antimicrobials at any given time point. Adapted from Kumar A, Roberts D, Wood KE, Light
B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M. Duration of hypotension before initiation of
effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34(6):158996 [5] (with permission
from Lippincott Williams & Wilkins).
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are susceptible to 1 of the administered antibiotics [3]. Considered more broadly, however, both empirical and definitive
antibiotic therapy, to be considered appropriate, require timely
initiation, administration in appropriate dosages consistent
with pharmacokinetic and pharmacodynamic (PK/PD) information, and appropriate alteration of therapy in response to
clinical responses and microbiological data as they become
available.
Among patients with health careassociated pneumonia, inadequate antimicrobial therapy is most commonly associated
with infection with resistant strains of Pseudomonas aeruginosa,
Staphylococcus aureus, Acinetobacter species, Klebsiella pneumoniae, and Enterobacter species [1]. An important predictor
of the likelihood of inappropriate therapy is, however, the local
prevalence of resistance. As a consequence, clinicians must take
into account institution-specific and, if available, unit-specific
epidemiological profiles and antimicrobial susceptibility patterns. Taking into account the prevalence of resistant organisms,
such as methicillin-resistant S. aureus (MRSA), in the community is of critical importance.

RISK FACTORS FOR INFECTION WITH

MULTIDRUG-RESISTANT (MDR) PATHOGENS
AND CHOICE OF ANTIBIOTIC THERAPY
The guidelines of the American Thoracic Society and the Infectious Diseases Society of America for the management of
health careassociated pneumonia indicate that risk factors
for infection with MDR pathogens include receipt of antimicrobial therapy within the previous 3 months, current hospitalization of 5 days, a high frequency of antibiotic resistance in the community or specific hospital unit, presence of
immunosuppressive disease or receipt of immunosuppressive
therapy, and the presence of factors defining pneumonia as
being health care related [10]. These latter factors include
hospitalization for 2 days within the past 90 days, residence
in a nursing home or extended-care facility, home infusion
therapy (including antibiotics), chronic dialysis within the
past 30 days, home wound care, and a family member with
an MDR-associated infection [10].
The American Thoracic Society/Infectious Diseases Society
of America guidelines recommend broad-spectrum combination therapy with 2 antibiotics as the initial empirical therapy
for patients with health careassociated pneumonia and risk

factors for being infected with resistant organisms. The recommended regimens to be considered are an aminoglycoside
OR an antipseudomonal fluoroquinolone plus an antipseudomonal b-lactam (a carbapenem, if extended-spectrum b-lactamaseproducing pathogens or MDR Acinetobacter species are
suspected) PLUS vancomycin or linezolid if MRSA is suspected
[3, 10]. With regard to the treatment of MRSA pneumonia,
however, the guidelines acknowledge that vancomycin may be
an inferior choice. As discussed in detail by Kollef [11] elsewhere in this supplement, vancomycin has significant limitations in the treatment of infections due to S. aureus, because
its activity against this pathogen is steadily decreasing [1215].
Other therapeutic options are currently limited: daptomycin is
unsuitable for use for lung infections because of inactivation
by surfactant, and tigecycline remains under investigation for
this purpose.
Choosing the correct antibiotics is only the start of effective
antimicrobial chemotherapy. Just as important is the attention
that must be paid to PK/PD principles to maximize optimal
antimicrobial effects, minimize the likelihood of emergence of
resistance, and minimize the potential adverse effects of therapy.
Achieving PD targets has been associated with successful bacterial eradication and clinical success, as well as with a reduced
risk of resistance emergence. An example of the importance of
the latter can be seen in the work of Thomas et al. [16], who
evaluated the relationship between antibiotic PK/PD and the
outcomes in 107 patients with nosocomial lower respiratory
tract infection. The results indicated that an area under the
concentration-time curve/minimum inhibitory concentration
(AUC/MIC) of 100 was associated with a significantly lower
risk of emergence of resistant organisms.
EMPIRICAL INITIAL ANTIBIOTIC THERAPY
AND DE-ESCALATION
Kollef and Micek [17] developed an algorithm to help guide
empirical antibiotic therapy, as well as its subsequent de-escalation and discontinuation. Thus, in the presence of severe
infection of possible bacterial etiology, specimens for microbiological analysis should be obtained and empirical broadspectrum antibiotic therapy promptly initiated. The choice of
therapy depends on host factors, including the risk for infection
with antibiotic-resistant pathogens, with guidance from local
susceptibility patterns. Although clinical status and response
should be continually monitored, assessment at 4872 h, a time
when relevant microbiological data are generally available, is a
time of major reevaluation of empirical therapy. If, at that time,
the patients condition has clinically improved and microbiological data indicate the appropriateness of the antibiotic therapy, tailoring the therapy to a narrower spectrum is indicated.
This de-escalation of antibiotic therapy may, in fact, be extended to its discontinuation, if evidence at this time points
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ogen was significantly associated with a longer delay in initiation of appropriate antibiotic therapy (P p .019), but additional contributing factors were delays in writing antibiotic
orders, as well as subsequent delays in the administration of
the antibiotics.
The importance of early initiation of appropriate antibiotic
therapy was confirmed in an analysis of patients with sterilesite MRSA infections [7]. In this retrospective analysis of 549
patients treated over a 3-year period through the end of 2004,
appropriate antibiotic therapy initiated within the first 24 h
after collection of a culture-positive specimen was correlated
with a significantly higher survival rate (33.4% vs. 22.0% among
those who did not receive appropriate antibiotics; P p .015).
Of note is that all survivors received an appropriate antibiotic
within 6 h of the availability of the culture result. An instructive
observation was that the likelihood of administration of inappropriate antibiotic therapy was significantly higher among
patients whose onset of infection occurred !48 h after admission to the hospital than among patients with later onset of
infection, despite the fact that 88.4% of patients with early onset
of infection had risk factors for health careassociated infection
(see below for risk factors), indicating that clinicians failed to
recognize these risks.
Also of note is that the importance of early initiation of
appropriate antimicrobial therapy is not limited to bacterial
infections. Recent studies have found similar improved survival
among patients with candidemia who received antifungal therapy in a timely fashion [8, 9].

S180 CID 2007:45 (Suppl 3) Deresinski

Figure 2. Appropriate empirical antibiotic therapy of ventilator-associated pneumonia: 8 vs. 15 days. In a multicenter, randomized, doubleblind trial involving patients with ventilator-associated pneumonia, the
8-day regimen achieved outcomes better than or equivalent to those
associated with the 15-day regimen. Unfavorable outcome was defined
as death, recurrence of pulmonary infection, or prescription of a new
antibiotic for any reason. ICU, intensive care unit; MDR, multidrug
resistance.

toward an increased risk of recurrence of infection among those

treated with the regimen of shorter duration.
Although the concept of de-escalation seems to be simple,
its systematic and timely implementation often proves difficult
in practice. The experience at one university hospital ICU is
instructive in this regard: although de-escalation was successfully implemented in 69% of cases in which microbiological
data indicated that it was appropriate, there was a mean interval
of 48 h from the time that the relevant microbiological data
were available to the actual time of de-escalation [21]. This
demonstrates the need for systematic approaches to assuring
timely therapeutic de-escalation with information systems allowing real-time linkages between decision support systems,
the clinical microbiology laboratory, the pharmacy, and clinicians. Even with the implementation of such systematic approaches, it is necessary that the prescribing physician make
appropriate changes to therapy as the necessary information
becomes available. The optimal means of achieving this last
step, in particular, is likely to require the establishment of an
effective antimicrobial stewardship program [22].
SYSTEMS APPROACH TO THE OPTIMIZATION
OF ANTIBIOTIC THERAPY
The necessity of formalized systematic approaches to the optimization of antibiotic therapy has become increasingly apparent. The optimal approach requires the development of a
multidisciplinary team with the full support, including necessary monetary support, of an institutions administration.
The Infectious Diseases Society of America has recently published evidence-based guidelines supporting the implementation of a formal program designed to improve antimicrobial
use in the hospital (table 1) [22]. Their recommendations in-

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away from the presence of bacterial infection [18]. If, in contrast, the patients condition has failed to improve clinically by
this time, a careful reassessment of the available microbiological
data must be performed, with consideration of the possibility
of infection with a resistant bacterial or nonbacterial pathogen.
The evaluation must also include an assessment of the possible
presence of complications, such as abscess formation, as well
as of the possibility of a noninfectious cause of the patients
septic profile. Once the patients infection is under control,
attention should be paid to discontinuation of antibiotic therapy as soon as maximum benefit has been achieved [2, 18].
The benefits of de-escalation and prompt discontinuation
of antibiotic therapy include cost minimization, a lessening
of the risk of drug-related adverse events, and a reduction in
pressure on the bacterial ecology, thereby diminishing the
likelihood of emergence of resistant pathogens. Examples of
the benefits of early antibiotic discontinuation include a likely
decrease in the incidence of Clostridium difficileassociated
diarrhea and a reduction in the incidence of superinfection
with resistant bacteria and Candida organisms. A clear example of the latter benefit emerged from a study by Singh et
al. [19], who evaluated the impact of a short-course (3 days)
of antibiotic therapy in conjunction with a formal scoring
system designed to determine the diagnosis of nosocomial
pneumonia (the Clinical Pulmonary Infection Score) in 81
patients in the surgical intensive care unit (ICU) who had
pulmonary infiltrates. The likelihood of an infectious cause
of the infiltrates was evaluated on day 3, and patients with
low Clinical Pulmonary Infection Scores were randomized to
have their antibiotic therapy either discontinued or continued
for a duration determined on the basis of their scores. No
adverse consequences, such as increased mortality or length
of stay, were associated with the discontinuation of antibiotic
therapy after 3 days in patients who proved to have a low
likelihood of pneumonia. However, for these low-risk patients, early discontinuation was associated with a significantly
reduced risk of emergence of resistant pathogens, which occurred in only 15% of the patients versus 35% (P p .017) of
those whose therapy was continued beyond 3 days.
Although many of the low-risk patients in the study by Singh
et al. [19] may never have had pulmonary infection at all,
reducing the duration of antibiotic therapy has also proven to
be an effective strategy in patients with proven bacterial pneumonia. Thus, in a randomized trial, Chastre et al. [20] demonstrated similar clinical outcomes, as well as a reduction in
subsequent infection with resistant pathogens among patients
with ventilator-associated pneumonia who received appropriate
antibiotic therapy for 8 days, as opposed to 15 days (figure 2).
A degree of caution is indicated, however, because patients
infected with nonfermenting gram-negative bacilli (mostly P.
aeruginosa) demonstrated a nonstatistically significant trend

Table. 1. Infectious Diseases Society of America guidelines for

antimicrobial stewardship: comprehensive multidisciplinary antimicrobial management program.
Evidence-supported recommendations
Multidisciplinary core team (ID physician, ID pharmacist, clinical
microbiologist, information systems specialist, infection control professional, and epidemiologist)
Prospective audit with intervention and feedback
Formulary restriction and preauthorization
Education and guidelines
Streamlining or de-escalation of therapy
Computer-based surveillance
Insufficient evidence to recommend
Antimicrobial cycling
Combination therapy
NOTE. ID, infectious diseases. From [22].

PREVENTION OF ANTIMICROBIAL
RESISTANCESOME ADDITIONAL
RECENT APPROACHES
The Centers for Disease Control and Prevention have published
a 12-step program designed to slow the march of antimicrobial
resistance, focusing on the effective use of devices, accurate
diagnoses, the careful use of antimicrobials, and prevention of
pathogen transmission [29]. Highlighting the importance of
infection control measures as a means of limiting infections
due to antibiotic-resistant pathogens, Huang et al. [30] examined the impact of 4 infection control measures on the incidence of MRSA bacteremia in a single hospital. The use of
routine surveillance cultures and patient isolation was associated with a significantly reduced incidence of MRSA bacteremia
(a 75% reduction in ICU patients [P p .007] and a 40% reduction in non-ICU patients [P p .008]) [31]. The absence of
a contemporaneous decrease in the incidence of methicillinsusceptible staphylococcal bacteremia was consistent with the
conclusion that the decrease in MRSA infections was the result
of the study intervention.
Continuing the focus on MRSA infections and infection control practices, Girou et al. [31] found that good compliance
with hand hygiene practices at the bedside of the patient was
a strong predictor of reduced MRSA prevalence. The relationship between hand hygiene and resistance rates was significant
even after adjustment for the length of stay in the hospital and
the number of hand hygiene opportunities per hour of care,
which the authors suggested was a surrogate for nursing workload and, to a lesser extent, severity of infection [31].
Finally, the routine use of mupirocin ointment and chlorhexidine baths for patients with nasal carriage of MRSA was
associated with a significant reduction in nosocomial MRSA
infections in ICU patients [32]. From January 1999 to December 2003, ICU patients with nasal carriage of MRSA received
2% mupirocin ointment intranasally 3 times daily for 5 days
and a chlorhexidine bath once daily for 3 days. A total of 2200
patients underwent screening, and 364 were found to have nasal
carriage of MRSA. The rates of nosocomial MRSA infection
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clude the establishment of a multidisciplinary team whose core

consists of an infectious diseases physician, an infectious diseases pharmacist, a clinical microbiologist, an information system specialist, an infection control professional, and an epidemiologist. The basic strategies that may be considered for
implementation are prospective audit, with intervention as necessary, together with individualized feedback and formulary
restriction with preauthorization. These strategies are not mutually exclusive. Additional elements of the program may include clinician education (in addition to the individualized realtime feedback) and the development of antibiotic use
guidelines, as well as the implementation of a program of
streamlining and de-escalation of therapy [22]. A frequently
suggested approach, antibiotic cycling, is not positively endorsed, because of an assessment that there is insufficient evidence for its support. In fact, there may be sufficient available
evidence, both theoretical and empirical, to recommend against
antibiotic cycling [2326]. In contrast, mathematical modeling
and limited clinical experience indicate that a more effective
approach to slowing the progression of antimicrobial resistance
is to assure heterogeneity of antibiotic use [23, 27].
It should be noted that one commonly used approach, the
establishment of a restrictive formulary, is in opposition to the
heterogeneous use of antibiotics and, if strictly enforced, may
actually exacerbate the problem of antibiotic resistance. Restrictive formularies are problematic for institutions with outpatient programs, because of the implementation of Medicare
Part D, which necessitates the availability of medications in the
program chosen by the participant. Another approach, the routine use of definitive pathogen-directed combination therapy,
is appealing in theory, but data supporting a positive impact
on the emergence of resistant pathogens are not available.
The effects of the implementation of some of these elements
of antimicrobial stewardship were recently examined in a ques-

tionnaire study by Zillich et al. [28] that involved 448 US

hospitals. The effect of 5 independent variables (dissemination
of clinical practice guidelines for antimicrobial use, implementation of guidelines, use of antimicrobial-related information
technology, use of decision support tools, and communication
to prescribers about antimicrobial use) on antimicrobial resistance rates was analyzed [28]. The results indicated that implementation of antibiotic use guidelines by hospitals and optimization of empirical antibiotic prophylaxis were associated
with lower rates of resistance (P ! .01 ); in contrast, the other
control measures were associated with greater rates of resistance, as was the use of restrictive formularies (P p .05) [28].

steadily declined during the intervention period, from 8.3% in

1999 to 6.3% in 2000, 4.3% in 2001, 3.6% in 2002, and 2.8%
in 2003. The difference between the rates in 1999 and 2003
was statistically significant (P p .001) [32].
Thus, it seems likely that rigorous institution of robust process-of-care improvements that include both antimicrobial stewardship and effective infection control procedures can result
in a lower likelihood of bacterial resistance and improved clinical outcomes.
CONCLUSIONS

Acknowledgments
Supplement sponsorship. This article was published as part of a supplement entitled Bugging the Bugs: Novel Approaches in the Strategic
Management of Resistant Staphylococcus aureus Infections, jointly sponsored by the Dannemiller Memorial Educational Foundation and Emeritus
Educational Sciences and supported by an educational grant from OrthoMcNeil, Inc., administered by Ortho-McNeil Janssen Scientific Affairs, LLC.
Potential conflicts of interest. S.D. is a consultant for Schering-Plough
and Ortho-McNeil, and is on the speakers bureaus for Merck, OrthoMcNeil, Schering-Plough, Pfizer, Wyeth, and Cubist.

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