I Antimicrobial therapy for patients with severe sepsis and septic

Transcription

Antimicrobial therapy for patients with severe sepsis and septic
shock: An evidence-based review
Pierre-Yves Bochud, MD; Marc Bonten, MD; Oscar Marchetti, MD; Thierry Calandra, MD, PhD
Objective: In 2003, critical care and infectious disease experts
representing 11 international organizations developed management guidelines for antimicrobial therapy for patients with severe
sepsis and septic shock that would be of practical use for the
bedside clinician, under the auspices of the Surviving Sepsis
Campaign, an international effort to increase awareness and
improve outcome in severe sepsis.
Design: The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based
discussion among subgroups and among the entire committee.
Methods:The modified Delphi methodology used for grading
recommendations built on a 2001 publication sponsored by the
International Sepsis Forum. We undertook a systematic review of
the literature graded along five levels to create recommendation
I
n 2001, the International Sepsis
Forum published guidelines on
the management of patients with
severe sepsis and septic shock, including an evidence-based review on antibiotic therapy (1). The recommendations on antibiotic therapy for sepsis
comprised sections on the epidemiology
of sepsis and the impact of appropriate
antimicrobial therapy on outcome of
Gram-negative, Gram-positive, and fungal sepsis and an evidence-based review of
monotherapy vs. combination therapy for
From The Institute for Systems Biology, Seattle,
WA (PYB); the Department of Internal Medicine, Division of Acute Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, The
Netherlands (MB); Infectious Diseases Service, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (OM, TC).
Supported by grants from the Swiss Foundation for
Medical and Biological Grants to PYB (1121), from the
Swiss National Science Foundation to PYB (81LA65462) and to TC (3100 – 066972), the Bristol-Myers
Squibb Foundation, the Santos-Suarez Foundation for
Medical Research, and the Leenaards Foundation. TC
is a recipient of a career award from the Leenaards
Foundation.
Copyright © 2004 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000143118.41100.14
Crit Care Med 2004 Vol. 32, No. 11 (Suppl.)
grades from A to E, with A being the highest grade. Pediatric
considerations to contrast adult and pediatric management are in
the article by Parker et al. on p. S591.
Conclusion: Since the prompt institution of therapy that is active
against the causative pathogen is one of the most important predictors of outcome, clinicians must establish a system for rapid administration of a rationally chosen drug or combination of drugs when
sepsis or septic shock is suspected. The expanding number of
antibacterial, antifungal, and antiviral agents available provides opportunities for effective empiric and specific therapy. However, to
minimize the promotion of antimicrobial resistance and cost and to
maximize efficacy, detailed knowledge of the likely pathogens and
the properties of the available drugs is necessary for the intensivist.
(Crit Care Med 2004; 32[Suppl.]:S495–S512)
the empirical management of patients
with severe sepsis or septic shock.
Under the auspices of the Surviving
Sepsis Campaign, a joint venture of the
International Sepsis Forum, the Society
of Critical Care Medicine, and the European Society of Intensive Care Medicine,
the International Sepsis Forum guidelines have been updated and extended.
The revised guidelines extend, but do not
entirely replace, the previously published
article (1), as several parts of the initial
document are still up-to-date. As for the
original publication, the revised guidelines were developed using an evidencebased review of the literature. The processes used by the panel of experts to
select and review the relevant literature
are outlined in the Material and Methods
section. The panel elected to focus on the
following topics: 1) impact of appropriate
antibiotic therapy on the outcome of sepsis; 2) impact of pharmacokinetic and
pharmacodynamic principles on treatment outcome; 3) need for prompt initiation of antimicrobial therapy in patients
with severe sepsis and septic shock; 4)
analyses of the efficacy and toxicity of
monotherapy vs. combination therapy as
empirical therapy; 5) indications for empirical use of anti-Gram-positive antibiot-
ics; 6) need for empirical antifungal therapy in patients with severe sepsis; 7)
analyses of the efficacy and safety of conventional vs. lipid formulations of amphotericin B and of azoles and echinocandins vs. amphotericin B for the treatment
of fungal sepsis; and 8) impact of antibiotic cycling on morbidity and mortality of
sepsis.
Materials and Methods
Selection of Panel, Topics of Interest,
and Review Process. The panel was composed of three board-certified infectious
diseases specialists, with expertise in the
fields of antimicrobial therapy, sepsis, intensive care medicine, and infection control, who have been selected by the cochairs of the “Diagnosis and Management
of Infection in the Severe Sepsis” track of
Surviving Sepsis Campaign. The panelists, chairpersons, and directors of the
Surviving Sepsis Campaign discussed the
specific scopes of the guidelines during a
2-day meeting (June 27–28, 2003). Identified topics of interest were distributed
among the panelists based on individual
expertise. Each panelist either alone or in
collaboration with colleagues wrote several sections of the guidelines, which
S495
were assembled by the panel chair and
reviewed and critiqued by the panelists
and track co-chairs.
Data Source. Medline was used to
search articles published between 1966
and July 1, 2003. Medline searches and
selections of articles were performed by
each of the authors. Medical Subject
Heading (MeSH; http://www.nlm.nih.gov/
mesh/meshhome.html) terms used in the
Medline search were sepsis (comprising
the terms septicemia, sepsis syndrome,
septic shock, bacteremia, fungemia, parasitemia, and viremia), pneumonia (comprising the terms bronchopneumonia,
pleuropneumonia, aspiration pneumonia,
bacterial pneumonia, viral pneumonia,
and Pneumocystis carinii pneumonia).
Since no ad hoc MeSH term exists for
intraabdominal infections, we used the
words and MeSH terms intraabdominal,
abdomen, abdominal infection, peritonitis, appendicitis, abdominal abscess to
search for articles on intraabdominal infections. The Medline search was then
narrowed by using the MeSH terms antiinfective agents (comprising the term
antibiotics, which was exploded to include all classes of antibiotics and all
antibiotic names), clinical trials, or
randomized controlled trials, further
limiting the search to human studies
and English literature. The MeSH keywords agranulocytosis, antibiotic prophylaxis, and ambulatory care were
used to exclude studies on neutropenic
patients, antibiotic prophylaxis, and
outpatient therapy. Additional articles
were retrieved from references of articles identified by the Medline search
and of guidelines and review articles on
the following topics: sepsis, community-acquired pneumonia, ventilatorassociated pneumonia, and intraabdominal infections. Epidemiologic data
were extracted from articles identified
by a Medline search using the keywords
epidemiology and sepsis and by a systematic review of 27 clinical trials of
antiinflammatory or mediator-targeted
therapies in patients with severe sepsis
and septic shock (2– 6).
For the section on empirical therapy
for Gram-positive severe sepsis or septic
shock, a Medline search was performed
using the terms empirical combined with
either vancomycin or teicoplanin, which
revealed one and 33 hits, respectively.
Extension of the search to the terms empirical, glycopeptide, and clinical trials
yielded 20 hits. However, none of these
articles included nonneutropenic paS496
tients with Gram-positive infections and
severe sepsis. A Medline search using the
terms clinical trial and either linezolid or
quinupristin/dalfopristin and Synercid
yielded 100 and 41 hits, respectively.
Selection of Articles. Abstracts of all
articles satisfying the selection criteria
were reviewed to exclude irrelevant studies. Review articles and articles on topics
such as antibiotic prophylaxis, pharmacology, microbiology, oncology, hematology, immunology, mediators of inflammation, allergy, catheter management,
animal studies, chronic infections, or
specific infections (acquired immunodeficiency syndrome, endocarditis, chronic
salmonellosis, viral infections in organ
transplant patients, hemorrhagic fever,
viral hepatitis, parasitic infections, and
malaria) were excluded if they did not
fulfill the inclusion criteria. For the comparison of monotherapy vs. combination
therapy, articles on each of the three clinical entities reviewed (i.e., sepsis, pneumonia, and intraabdominal infections)
were selected only if there was unequivocal evidence that patients had either
clinically or microbiologically documented infections and if the study met at
least one of the following criteria: 1) a
definition of sepsis or severe sepsis consistent with the definition of the Consensus Conference of the American College
of Chest Physicians and the Society of
Critical Care Medicine (7); 2) sepsis with
at least one organ dysfunction or sign of
hypoperfusion present in ⬎50% of the
patients; or 3) an overall mortality
⬎10%. This cutoff for mortality was chosen to ensure that articles included a
substantial proportion of patients with
severe sepsis and not simply sepsis. To
ensure that articles on antimicrobial
therapy had been properly selected by one
of the authors (PYB), a random sample of
20% of the articles identified by the Medline search were examined by the panel
chair (TC). Overall agreement between
the two reviewers was 94% for articles on
intraabdominal infections (␬ statistic of
0.71) and 96% for articles on community-acquired pneumonia and ventilatorassociated pneumonia (␬ statistic of 0.81)
corresponding to “substantial” and “almost perfect” agreements, respectively,
according to the criteria proposed by
Sackett et al. (8). Consensus was reached
between the two authors on the articles
for which there was disagreement regarding the inclusion criteria.
Epidemiological Features of
Severe Sepsis and Septic
Shock
Data on secular epidemiologic trends
of the etiological agents and most frequent sites of sepsis have not changed
since the 2001 review and will, therefore,
not be reviewed in detail again (1).
Microorganisms and Sites of Infection. By the mid-1980s, the frequency of
Gram-positive sepsis (mainly caused by
Staphylococcus aureus, coagulase-negative staphylococci, enterococci, and
streptococci) has equaled that of Gramnegative sepsis (mainly caused by Enterobacteriaceae, especially Escherichia coli
and Klebsiella pneumoniae, and by
Pseudomonas aeruginosa). Recent epidemiologic data in the United States and in
Europe indicated that Gram-positive bacteria have now surpassed Gram-negative
bacteria as etiological agents of sepsis (9,
10), confirming a trend observed in many
recent sepsis studies (4, 5, 11–17). Fungi
account for about 5% of all cases of sepsis, severe sepsis, and septic shock (1).
Most cases of fungal sepsis are caused by
Candida species, which are the fourth
most common bloodstream pathogens in
all recent U.S. studies of nosocomial
bloodstream infections and are associated
with the highest mortality (40%) of all
bloodstream pathogens (18, 19). The incidence of fungal sepsis has increased
three-fold between 1979 and 2000 (10).
However, due to the paucity of published
data on national surveys of fungal infections, it is unclear whether the incidence
of fungal sepsis has increased in a similar
fashion in other parts of the world. Dutch
investigators reported a two-fold increase
in the incidence of candidemia in the
early 1990s (20). In contrast, a Norwegian
survey also conducted in the early 1990s
reported stable incidence of candidemia
and Candida species distribution (21).
Likewise, a recent survey of the incidence
of candidemia in Switzerland has shown
that the incidence of candidemia remained stable between 1991 and 2000
(median, 0.5 episodes/10,000 patientdays) (22). By decreasing order of frequency, the predominant sites of infections in patients with severe sepsis and
septic shock are the lungs, the bloodstream (i.e., without another identifiable
source of infection), the abdomen, the
urinary tract, and the skin and soft tissues.
Need for Prompt Initiation of
Antimicrobial Therapy in
Patients with Severe Sepsis and
Septic Shock
Rationale: Establishing vascular access
and initiating aggressive fluid resuscitation is the first priority when managing
patients with severe sepsis or septic
shock. However, prompt infusion of antimicrobial agents is also a logical strategy
and may require additional vascular access ports. Establishing a supply of premixed antibiotics in an emergency department or critical care unit for such
urgent situations is an appropriate strategy for enhancing the likelihood that antimicrobial agents will be infused
promptly. Staff should be cognizant that
some agents require more lengthy infusion time, whereas others can be rapidly
infused or even administered as a bolus.
Impact of Appropriate Antibiotic
Therapy on Outcome of Sepsis
Recommendations: Initial empirical antiinfective therapy should include one or
more drugs that have activity against the
likely pathogens (bacterial or fungal) and
that penetrate into the presumed source
of the sepsis. The choice of drugs should
be guided by the susceptibility patterns of
microorganisms in the community and
in the hospital.
Grade D
Rationale: Early administration of appropriate antibiotics reduces mortality in patients with Gram-positive and Gramnegative bacteremias. Retrospective studies
conducted in the 1960s and in the 1970s
have shown that appropriate antimicrobial
therapy, defined as the use of at least one
antibiotic active in vitro against the causative bacteria, reduced the mortality of
Gram-negative bacteremia when compared
with patients receiving inappropriate therapy (23–26). In a landmark study of 173
patients with Gram-negative bacteremia,
who were classified in three categories
based on the severity of the underlying disease categories (i.e., rapidly fatal, ultimately
fatal, and nonfatal), McCabe et al. (23) observed that appropriate antibiotic therapy
reduced mortality from 48% to 22%. Four
subsequent studies that included larger
numbers of patients yielded similar results
(24 –27). In a recent prospective study of
2,124 patients with Gram-negative bacteremia, mortality was 34% in 670 patients
who received inappropriate antibiotics and
18% in 1,454 patients who received appropriate antibiotics (p ⬍ .0001) (28). Smaller
recent studies showed that the appropriateness of the antibiotic regimen favorably influenced the outcome of patients infected
with specific Gram-negative bacteria, such
as Enterobacter species (29), P. aeruginosa
(30), and ceftazidime-resistant K. pneumoniae or E. coli (31).
Fewer data have been published on the
impact of appropriate antibiotic therapy
in patients with Gram-positive sepsis
(32). Several studies evaluated the impact
of appropriate antimicrobials in patients
with severe infections due to Gramnegative and Gram-positive bacteria (33–
44). In all but one study (42), appropriate
antibiotic therapy was associated with a
better outcome.
Empirical Antimicrobial Therapy
for Patients with Severe Sepsis
and Septic Shock
The evidence-based review of the literature on empirical antimicrobial therapy for patients with severe sepsis and
septic shock has focused on three clinical
entities: sepsis (i.e., primary or secondary
bloodstream infections), pneumonia
(both community-acquired and hospitalacquired), and intraabdominal infections.
Management guidelines and review articles have been published recently on
these topics (45–53), which should be
used as a supplement to the present article, which focuses on clinical trials of
antimicrobial agents for patients with severe sepsis or septic shock.
A total of 2,065 articles (sepsis, 988;
community-acquired pneumonia and
ventilator-associated pneumonia, 509; intraabdominal infections, 393; Grampositive infections, 175) were identified
using the Medline search strategy described in Material and Methods, of which
1,464 did not meet our inclusion criteria
based on the content of the abstract (Fig.
1). A full text review was performed on
the remaining 614 articles, of which 79
(13%) (sepsis, 37; community-acquired
pneumonia and ventilator-associated
pneumonia, 35; and intraabdominal infections, 7) met the inclusion criteria of
severe sepsis or septic shock. Thus, only a
small proportion of the screened clinical
trials of antibiotic therapy have included
critically ill septic patients with high
mortality. The overall mortality of the
patients in the selected studies was 18%.
Most studies performed before 1990 comprised a limited number of patients (usu-
ally ⬍100 per trial), a majority of these
patients with Gram-negative sepsis, and
did not include intent-to-treat analyses.
Studies performed in the 1990s were
larger, included patients with both Grampositive and Gram-negative sepsis, and in
most instances, included an intent-to-treat
analysis. Given the relatively small number
of studies available and the fact that the
sepsis subset of studies included patients
with various types of infections, including
community-acquired and ventilator-associated pneumonias and intraabdominal infections, all studies were pooled.
Among the 79 studies identified, 67
met the inclusion criteria for severe sepsis and/or septic shock due to bacterial
infections and were grouped in four main
categories: 1) studies comparing different
combination therapies, usually a ␤-lactam antibiotic or a fluoroquinolone plus
an aminoglycoside (n ⫽ 9; sepsis, 4;
pneumonia, 5) (54 – 62); 2) studies comparing a monotherapy with a combination therapy with an aminoglycoside (n ⫽
24; sepsis, 11; pneumonia, 7; intraabdominal infections, 6) (63– 86); 3) studies
comparing single-agent therapies (n ⫽
26; sepsis, 14; pneumonia, 11; intraabdominal infections, 1) (56, 87–111); and
4) miscellaneous studies (n ⫽ 8; pneumonia, 7; sepsis, 1) (112–119).
Monotherapy Vs. Combination
Antibiotic Therapy
Recommendation: Monotherapy is as efficacious as combination therapy with a
␤-lactam and an aminoglycoside as empirical therapy of patients with severe
sepsis or septic shock.
Carbapenem: Grade B. Third- or
fourth-generation cephalosporins: Grade
B. Extended-spectrum carboxypenicillins
or ureidopenicillins combined with ␤-lactamase inhibitors: Grade E
Rationale. The use of antibiotic combinations for the treatment of severe infections relies on the following rationale: 1)
a combination of two antibiotics broadens the antibacterial spectrum, which
may be important as treatment is usually
initiated empirically in critically ill septic
patient; 2) combination of antibiotics
may exert additive or synergistic effects
against the infecting pathogen, resulting
in enhanced antibacterial activity and
possibly better clinical response (120 –
122); 3) the use of a combination of antibiotics may reduce the emergence of
resistant bacteria (123) or of superinfections (124).
S497
Figure 1. Study flow. Studies were searched in Medline as indicated in Material and Methods. Abstracts
were reviewed, and studies that satisfied the inclusion criteria were selected for a full text review.
MRGP, multiple-resistant Gram-positive bacteria.
In the late 1960s and early 1970s, a
series of retrospectives studies examined
the potential benefits of combination
therapy (27, 125). Overall, combination
therapy was not found to be superior to
single-agent therapy, but some benefits
of antibiotic combinations were noted in
subsets of patients, such as those with
rapidly or ultimately fatal diseases. However, the impact of these results for today’s practice is limited given the retrospective nature of these studies and the
facts that it utilized antibiotics that
would no longer be considered appropriate today and that it did not include multivariate analyses. Subsequent studies
evaluated the efficacy of different antibiotic combinations, usually a ␤-lactam
and an aminoglycoside, for the treatment
of Gram-negative infections (54 –59, 61,
62, 126). By and large, there were no
differences between the various antibiotic
regimens in terms of clinical success, microbiological eradication, and mortality
rates. However, in one study of 204 patients with ventilator-associated pneumonia, the clinical cure rate of piperacillin/
tazobactam plus amikacin was superior
to that of ceftazidime plus amikacin (26/
51, 51%, vs. 23/64, 36%; p ⫽ .009), but
mortality was similar in the two treatment groups (8/51, 16%, vs. 13/64, 20%;
p ⫽ .4) (60).
Since the 1980s, the advent of broadspectrum and highly bactericidal antibiS498
otics, such as the extended-spectrum
penicillins, third-generation or fourthgeneration cephalosporins, or the carbapenems, has substantially reduced the
need for aminoglycoside-containing antibiotic combinations. During the last two
decades, most antibiotic studies have,
therefore, compared the efficacy and toxicity of single-agent antibiotic therapies
(i.e., monotherapies) with that of ␤-lactams paired with aminoglycosides (i.e.,
combination therapies). Twenty-four
studies of empirical monotherapy vs.
combination therapy were identified by
the Medline search. The results obtained
with carbapenems, third-generation or
fourth-generation cephalosporins, and
extended-spectrum penicillins with activity against Pseudomonas species are
shown in Table 1.
Carbapenems. In five prospective, randomized, controlled studies, monotherapy with imipenem-cilastatin or
meropenem was shown to be as effective
as a combination of a ␤-lactam (cefuroxime, ceftazidime, or imipenem) and
an aminoglycoside (gentamicin, amikacin, or netilmicin) (Table 1) (64 – 66, 74,
75). It is worth mentioning that the same
␤-lactam antibiotic (imipenem) was used
in both treatment arms in only one of
these studies, in which the success rates,
the occurrence of superinfections, and of
P. aeruginosa resistant to the carbapenem were similar in the imipenem and
in the imipenem plus netilmicin treatment groups (65). However, nephrotoxicity was significantly more frequent in the
aminoglycoside-containing treatment
arm. In three studies of severe sepsis or
intraabdominal sepsis, imipenem was
found to be at least as efficacious as and
less nephrotoxic (one study) than a combination of gentamicin or tobramycin
and clindamycin or metronidazole (63,
81, 82).
Third-Generation and Fourth-Generation Cephalosporins. In ten prospective,
randomized, controlled studies, monotherapy with a third- or fourth-generation cephalosporin (cefotaxime, moxalactam, cefoperazone, or ceftazidime) was as
effective as combination therapy with a
␤-lactam (usually an extended-spectrum
penicillin or a cephalosporin) and an aminoglycoside (67–71, 77, 78) or clindamycin and an aminoglycoside (76, 83, 84). In
four of the ten studies, clinical success
rates were significantly higher in the
monotherapy treatment groups (69, 76 –
78). However, it is difficult to draw firm
conclusions from these observations as
different ␤-lactams were used in the
monotherapy and combination therapy
treatment groups in all but one study.
Mortality rates were similar in the monotherapy and combination therapy treatment groups in nine of the ten studies. A
trend toward a lower mortality in the
monotherapy treatment arm was observed in one trial (77). As expected,
nephrotoxicity was higher in the aminoglycoside-containing regimen in seven
of the ten studies, reaching statistical significance in five.
Extended-Spectrum Penicillins with
Anti-Pseudomonas Activity. In four prospective, randomized, controlled studies,
extended-spectrum carboxypenicillins (ticarcillin) or ureidopenicillins (piperacillin) used either alone or in combination
with a ␤-lactamase inhibitor (clavulanic
acid or tazobactam) were found to be as
effective as amoxicillin-clavulanate, piperacillin, piperacillin-tazobactam, or clindamycin combined with an aminoglycoside (gentamicin, amikacin, or
netilmicin) as empirical antibiotic therapy for patients with intraabdominal infections, pneumonia, or neonatal sepsis
(72, 79, 85, 86) (Table 1). However, as
noted for the carbapenem or cephalosporin studies, in three of these four studies,
different ␤-lactam antibiotics were used
in the monotherapy and combination
therapy treatment groups. In a study of
206 patients with intraabdominal sepsis,
clinical success, and mortality and nephrotoxicity rates were similar in patients
treated with piperacillin-tazobactam or
with piperacillin-tazobactam plus amikacin (86).
Fluoroquinolones. One study showed
that monotherapy with ciprofloxacin was
as effective as therapy with a ␤-lactam
and/or an aminoglycoside for the treatment of patients with documented Gramnegative sepsis (80). However, given that
first-generation fluoroquinolones exhibit
suboptimal activities against Grampositive bacteria, this class of antibiotics
should not be used as empirical singleagent therapy in patients with severe sepsis.
Comments. The evidence-based review of the literature tends to suggest
that monotherapy with a broad-spectrum
␤-lactam antibiotic is as efficacious and
less nephrotoxic than a combination of a
␤-lactam and an aminoglycoside as empirical therapy for critically ill patients
presenting with severe sepsis or septic
shock. However, monotherapy should not
be regarded as a universal remedy to be
used indiscriminately for several reasons.
Compared with the abundant literature
on empirical therapy for febrile neutropenia, few studies have been conducted in
shock. Moreover, many of the clinical trials reviewed here included ⬍200 patients, and the statistical power was,
therefore, limited. Furthermore, rarely
was the same ␤-lactam antibiotic used in
the control and experimental treatment
groups, thus limiting the conclusions
that could be drawn about the apparent
equivalent efficacy of the two regimens.
There is clearly a need for large, prospective, randomized trials to assess the efficacy and toxicity of new antibiotics in
critically ill septic patients.
One should keep in mind that the
choice of empirical antibiotic therapy
depends on several factors related to
the patient’s history (including drug intolerance), underlying diseases, and
susceptibility patterns of microorganisms of the hospital environment and
patient’s community. The initial selection of an empirical antimicrobial regimen should be broad enough to cover
all likely pathogens. Despite a lack of
clearcut advantage, clinicians may still
prefer to rely initially on a ␤-lactam and
aminoglycoside combination, especially
in the context of high level of antibiotic
resistance or when treating patients
with suspected Pseudomonas infection,
even though the benefit of combination
therapy for the latter indication remains controversial. Yet, the benefit
from additive or synergistic effects of
antibiotic combination and the possible
prevention of emerging resistant bacteria must be weighed against the risk of
increased toxicity. Indeed, aminoglycoside-containing regimens have been
shown repeatedly to increase the risk of
nephrotoxicity or ototoxicity.
Single-Agent Antibiotic
Therapies
Recommendation: Third-generation and
fourth-generation cephalosporins, carbapenems, and extended-spectrum carboxypenicillins or ureidopenicillins combined with ␤-lactamase inhibitors are
equally effective as empirical antibiotic
therapy in patients with severe sepsis.
Third- or fourth-generation cephalosporins: Grade A. Carbapenem: Grade B.
Extended-spectrum carboxypenicillins or
ureidopenicillins combined with ␤-lactamase inhibitors: Grade C.
Carbapenems, Third-Generation, or
Fourth-Generation Cephalosporins. Six
prospective, randomized, clinical trials
(of which five included between 150 and
400 patients) were identified that investigated the efficacy and safety of a carbapenem (imipenem or meropenem), a
third-generation cephalosporin (ceftazidime or cefotaxime combined with metronidazole), a ureidopenicillin with a
␤-lactamase inhibitor (piperacillin-tazobactam), or another carbapenem (Table 2) (92, 95–97, 99, 107, 111). In all but
one study, virtually identical clinical response rates and overall mortality were
observed in patients treated with either
imipenem or meropenem or control
␤-lactam antibiotics. In a smaller clinical
trial of 94 patients with intraabdominal
sepsis, the clinical response rate of patients treated with meropenem was superior to that of those treated with cefotaxime plus metronidazole (111).
In summary, as one might have anticipated given the fairly comparable antimicrobial spectrum of activity of most
third-generation and fourth-generation
cephalosporins, the studies conducted
with these agents for the treatment of
patients with severe sepsis and community-acquired or nosocomial (including
ventilator-associated) pneumonia or miscellaneous types of infections have
yielded very comparable results (Table 2)
(91,93,94,98,101–104,108). Response
rates for the various cephalosporins were
in the range of 65% to 85% in most
studies, except for slightly lower response
rates for ceftriaxone and cefotaxime in
two smaller studies (101, 104).
Aminoglycosides, Monobactams, or
Fluoroquinolones. In the late 1970s and
early 1980s, three studies compared the
efficacy and safety of different aminoglycosides (gentamicin vs. tobramycin, gentamicin vs. amikacin, and netilmicin vs.
amikacin) as single-agent therapy for
Gram-negative sepsis (87– 89). Clinical
responses rates, overall mortality, and
nephrotoxicity were similar among the
various aminoglycosides compared in
these studies. A high incidence of aminoglycoside-induced nephrotoxicity and
ototoxicity were noted in these studies,
which is a major concern in critically ill
septic patients already at high risk of developing organ failures due to the circulatory collapse associated with severe sepsis or septic shock. In two small studies,
aztreonam was found to be as effective
and less toxic than aminoglycosides as
empirical monotherapy of patients with
severe Gram-negative sepsis (90, 100).
However, today, aminoglycosides or a
monobactam antibiotic such as aztreonam should not be used as single-agent
empirical therapy of severe sepsis because
of their narrow antibacterial activity and
risk of toxicity (aminoglycosides).
More recently, five studies, of which
four enrolled only patients with severe
community-acquired or nosocomial
pneumonias, showed that fluoroquinolones (ciprofloxacin, four studies; levofloxacin, one study) were as efficacious as
␤-lactam antibiotics (imipenem in four
studies; various ␤-lactams with or without an aminoglycoside in one study) for
the treatment of patients with severe sepsis caused predominantly by Gramnegative bacteria (Table 2) (56, 105, 106,
109, 110). Of note, a large number of
patients (ranging between 250 and 400)
were randomized in three of the four
pneumonia studies. However, given the
limited activity of first-generation fluoroquinolones (i.e., norfloxacin and ciprofloxacin) against Gram-positive bacteria
and the possibility of resistance among
Gram-negative bacteria, these antibiotics
cannot be recommended as empirical
monotherapy for patients with severe
sepsis or septic shock of unknown etiology, including patients with communityacquired or healthcare-associated pneumonia. The most recent, so-called
respiratory fluoroquinolones (i.e., levoS499
Table 1. Monotherapy versus combination antibiotic therapy as empirical treatment of severe sepsis and septic shock
Authors and Yr of
Publication
Type of
Infection
Experimental
Therapy
Control
Therapy
Success (%)
(Exp. vs. Control)
Carbapenems vs. ␤-lactams or antianaerobes combined with an aminoglycoside
Solomkin et al. 1985 (63)
SEPSIS
Imipenem
Poenaru et al. 1990 (81)
ABDOM
Imipenem
Gentamicin ⫹ clindamycin
28/37 (76) vs. 27/37 (73)
Tobramycin ⫹ clindamycin
—
or metronidazole
Solomkin et al. 1990 (82)
ABDOM
Imipenem
67/81 (83) vs. 57/81 (70)
Mouton et al. 1990 (64)
SEPSIS
Imipenem
Cefotaxime ⫹ amikacin
58/70 (83) vs. 54/70 (77)
a
SEPSIS
Imipenem
Imipenem ⫹ netilmycin
113/142 (80) vs. 119/138 (86)
Cometta et al. 1994 (65)
Sieger et al. 1997 (74)
HAP
Meropenem
Ceftazidime ⫹ amikacin
76/106 (72) vs. 62/105 (59)
Jaspers et al. 1998 (66)
SEPSIS
Meropenem
Cefuroxime ⫹ gentamicin
27/39 (69) vs. 25/40 (63)
⫹/⫺ metronidazole
Alvarez-Lerma et al. 2001 (75)
HAP
Meropenem
Ceftazidime ⫹ amikacin
47/69 (68) vs. 39/71 (55)
Third- or fourth-generation cephalosporins vs. ␤-lactams or antianaerobes combined with an aminoglycoside
Arich et al. 1987 (67)
SEPSIS
Cefotaxime
Cefazolin ⫹ tobramycin
22/25 (88) vs. 17/22 (77)
Schentag et al. 1983 (83)
ABDOM
Moxalactam
37/49 (76) vs. 36/49 (73)
a
Oblinger et al. 1982 (68)
SEPSIS
Moxalactam
33/38 (87) vs. 32/40 (80)
Conventional therapy
Mangi et al. 1988 (76)
HAP
Cefoperazone
Clindamycin or cefazolin
41/46 (89) vs. 44/61 (72)
and gentamicin
Greenberg et al. 1994 (84)
ABDOM
CefoperazoneClindamycin ⫹ gentamicin
33/47 (70) vs. 15/29 (52)
sulbactam
b
Fernandez-Guerrero et al. 1991 (77) HAP
Cefotaxime
217/275 (79) vs. 193/273 (71)
Combination therapy
Croce et al. 1993 (78)
HAP
Ceftazidime or
Ceftazidime or cefoperazone 22/39 (56) vs. 22/70 (31)
cephoperazone
⫹ gentamicin
Rubinstein et al. 1995 (69)
SEPSIS
Ceftazidime
Ceftriaxone ⫹ tobramycin
227/306 (74) vs. 179/274 (65)
d
Extermann et al. 1995 (70)
SEPSIS
Ceftazidime
38/41 (93) vs. 28/30 (93)
“Best guess” combination
McCormick et al. 1997 (71)
SEPSIS
Ceftazidime
Mezlocilin ⫹ netilmicin
50/65 (77) vs. 48/63 (76)
Antipseudomonas penicillins vs. ␤-lactams or anti-anaerobes combined with an aminoglycoside
Fink 1991 (85)
ABDOM
Ticarcillin-clavulanate Gentamicin ⫹ clindamycin
15/20 (75) vs. 16/25 (64)
Hammerberg et al. 1989 (72)
SEPSIS
Piperacillin
Ampicillin ⫹ amikacin
—
Speich et al. 1998 (79)
CAP ⫹ HAP
PiperacillinAmoxiclav ⫹ netilmicin or
37/41 (90) vs. 36/43 (84)
tazobactam
gentamicin
Dupont et al. 2000 (86)
ABDOM
PiperacillinPiperacillin-tazobactam ⫹
44/99 (44) vs. 55/105 (52)
tazobactam
amikacin
Miscellaneous monotherapies versus ␤-lactams combined with an aminoglycoside
f
Korvick et al. 1992 (73)
SEPSIS
␤-lactam ⫹ aminoglycoside
—
␤-lactam or
aminoglycoside
alone
Manhold et al. 1998 (80)
HAP
Ciprofloxacin
Ceftazidime ⫹ gentamicin
—
p
1.000
—
.094
.527
.155
.061
.637
.121
.446
1.000
.547
.052
.143
.030
.015
.023
1.000
1.000
.525
—
.521
.266
—
—
p, two-tailed Fisher’s exact test; ABDOM, intraabdominal infections; CAP, community-acquired pneumonia; HAP, hospital-acquired pneumonia
(ventilator-associated or not).
a
Conventional therapy included a ␤-lactam (i.e., penicillin, ampicillin, ticarcillin, nafcillin, cefamandole, cefoxitin) given either alone or in combination
with an aminoglycoside (tobramycin or amikacin); bcombination therapy comprised a ␤-lactam (a cephalosporin or a “broad-spectrum” penicillin) with an
aminoglycoside (gentamicin, tobramycin, or amikacin); cinfection-related mortality; dbest guess combination usually include a ␤-lactam with an
aminoglycoside (not specified); f␤-lactam included a cephalosporin, imipenem, or an extended-spectrum penicillin; aminoglycosides included gentamicin,
tobramycin, amikacin, or kanamycin.
floxacin, gatifloxacin, moxifloxacin, or
gemifloxacin) exhibit enhanced in vitro
activities against Gram-positive bacteria.
Numerous studies have shown that these
agents are highly efficacious as singleagent therapy of community-acquired
pneumonia in the outpatient or inpatient
setting (48, 50, 127). When used for the
treatment of severe community-acquired
or nosocomial infections in intensive care
unit (ICU) patients in whom Pseudomonas infection is a concern, ciprofloxacin
or the respiratory fluoroquinolones
should preferentially be combined with
an anti-Pseudomonas antibiotic (i.e., a
carbapenem, a third- or fourth-generation cephalosporin, or an extendedS500
spectrum penicillin) with or without an
aminoglycoside.
Empirical Use of Anti-GramPositive Antibiotics in Patients
with Severe Sepsis
Recommendation: Empirical use of glycopeptide antibiotics (vancomycin, teicoplanin), oxazolidinones (linezolid), or
streptogramins (quinupristin/dalfopristin) in patients with severe sepsis or septic shock is justified in patients with hypersensitivity to ␤-lactams or in
institutions with resistant Gram-positive
bacteria (i.e., methicillin-resistant staphylococci, penicillin-resistant pneumo-
cocci, or ampicillin-resistant enterococci) in the community or in the
hospital.
Grade E
Rationale: Antimicrobial coverage of both
Gram-positive and Gram-negative bacteria is mandatory in the empirical treatment of critically ill patients with severe
sepsis. Naturally, many broad-spectrum
antibiotics reliably cover both pathogens
and, therefore, can be used for empirical
therapy. The choice of empirical treatment, however, should depend on the local epidemiology of pathogens associated
with infections and their antimicrobial
Table 1. Continued.
Mortality (%) (Exp. vs. Control)
6/37 (16) vs. 4/37 (11)
4/52 (8) vs. 9/52 (17)
11/81 (14) vs. 14/81 (17)
7/70 (10) vs. 7/70 (10)
18/142 (13) vs. 13/138 (9)
13/104 (13) vs. 23/107 (21)
3/39 (8) vs. 4/40 (10)
p
Nephrotoxicity (%) (Exp. vs. Control)
p
.736
.235
1/37 (3) vs. 10/27 (27)
—
.007
—
.664
1.000
.448
.100
1.000
—
1/105 (1) vs. 4/102 (4)
0/158 (0) vs. 6/149 (4)
0/104 (0) vs. 2/105 (2)
2/39 (5) vs. 5/35 (13)
—
.369
.014
.498
.432
0/69 (0) vs. 2/69 (3)
.497
16/69 (23) vs. 20/71 (28)
.564
8/25 (32) vs. 5/22 (23)
7/49 (14) vs. 6/49 (12)
8/33 (24) vs. 9/32 (28)
9/61 (15) vs. 13/71 (18)
.530
1.000
.783
.645
0/25 (0) vs. 3/19 (14)
6/49 (12) vs. 14/35 (29)
3/41 (7) vs. 11/36 (23)
6/61 (10) vs. 12/66 (15)
.095
.078
.046
.447
6/47 (13) vs. 3/29 (10)
1.000
0/47 (0) vs. 1/28 (3)
.382
36/275 (13) vs. 52/273 (19)
c
2/39 (5) vs. 7/70 (10)
.063
.485
0/275 (0) vs. 7/266 (3)
5/39 (13) vs. 25/45 (36)
.007
.013
31/306 (10) vs. 33/274 (12)
6/41 (15) vs. 4/30 (13)
13/65 (20) vs. 9/63 (14)
.508
1.000
.484
0/306 (0) vs. 9/265 (3)
—
2/65 (3) vs. 8/55 (13)
.001
—
.053
3/20 (15) vs. 5/25 (20)
17/200 (9) vs. 27/196 (14)
1/41 (2) vs. 6/43 (14)
.716
.110
.110
19/99 (19) vs. 22/105 (21)
.862
24/118 (20) vs. 20/112 (18)
.738
—
—
13/28 (46) vs. 6/23 (26)
.158
—
—
susceptibility. It is, therefore, essential to
get frequent feedbacks from the microbiology laboratory on antibiotic susceptibilities trends. Major changes in the relative
importance of Gram-positive and Gramnegative infections among critically ill
patients have occurred during the last 10
yrs. While Gram-negative bacteria predominated until the middle 1980s, Grampositive bacteria now account for at least
one-half of the infections occurring in
patients with severe sepsis (128, 129).
Moreover, methicillin-resistant S. aureus
(MRSA) and methicillin-resistant Staphylococcus epidermidis are responsible for
a majority of staphylococcal infections in
some institutions. The frequency of penCrit Care Med 2004 Vol. 32, No. 11 (Suppl.)
1/20 (5) vs. 0/25 (0)
50/200 (25) vs. 43/153 (22)
0/44 (0) vs. 2/43 (4)
3/99 (3) vs. 3/102 (3)
icillin-resistant S. pneumoniae is also increasing in many areas of the world. Yet,
the relevance of reduced susceptibility of
Streptococcus pneumoniae to penicillin
on clinical outcome of patients treated
with ␤-lactam antibiotics is uncertain,
especially for respiratory tract infections
(130). Clinical failures, however, have
been reported in patients with bacterial
meningitis caused by a penicillin-resistant S. pneumoniae treated with ceftriaxone (131). Does this epidemiologic context justify the empirical use of
glycopeptides (vancomycin or teicoplanin), oxazolidinones (linezolid), or
streptrogramins (quinupristin/dalfopris-
.444
.480
.494
1.000
tin) on a routine basis in all patients with
severe sepsis and septic shock?
Glycopeptides. To the best of our
knowledge, randomized trials comparing
empirical treatment with or without
Gram-positive coverage (including glycopeptides) have never been performed in
adult nonneutropenic patients and such
an approach would probably be judged as
unethical. None of the articles retrieved
by the Medline search included a comparison of empirical treatment with or without Gram-positive patients in nonneutropenic adults with severe sepsis. Although
the indiscriminate use of glycopeptides
for presumed Gram-positive infections in
patients with severe sepsis or septic shock
S501
Table 2. Comparison of monotherapies as empirical treatment of severe sepsis and septic shock
Authors and Yr of
Publication
Type of
Infection
Experimental
Therapy
Control Therapy
Carbapenems versus third-generation cephalosporins or carbapenems
Norrby et al. 1993 (92)
SEPSIS
Imipenem
Ceftazidime
Kempf et al. 1996 (111)
ABDOM
Meropenem
Cefotaxime ⫹
metronidazole
Colardyn and Faulkner 1996 (95) SEPSIS
Meropenem
Imipenem
Mehtar et al. 1997 (96)
SEPSIS
Meropenem
Ceftazidime ⫹
metronidazole
Garau et al. 1997 (97)
SEPSIS
Meropenem
Imipenem
a
HAP
Imipenem
Piperacillin-tazobactam
Jaccard et al. 1998 (107)
Verwaest 2000 (99)
SEPSIS
Meropenem
Imipenem
Third- or fourth-generation cephalosporins vs. a third-generation cephalosporin
Mangi et al. 1988 (91)
SEPSIS
Cefoperazone
Ceftazidime
Reeves et al. 1989 (101)
HAP
Ceftriaxone
Cefotaxime
Mangi et al. 1992 (102)
HAP
Ceftriaxone
Cefoperazone
Thomas et al. 1992 (103)
HAP
Cefotaxime
Ceftriaxone
Norrby and Geddes 1993 (93)
SEPSIS
Cefpirome
Ceftazidime
Barckow et al. 1993 (104)
CAP ⫹ HAP Cefepime
Cefotaxime
Schrank et al. 1995 (94)
SEPSIS
Cefepime
Ceftazidime
Norrby et al. 1998 (98)
SEPSIS
Cefpirome
Ceftazidime
Grossman et al. 1999 (108)
CAP
Cefepime
Ceftriaxone
Fluoroquinolones vs. ␤-lactams
b
CAP ⫹ HAP Ciprofloxacin
Imipenem
Fink et al. 1994 (105)
Siami et al. 1995 (106)
CAP ⫹ HAP Ciprofloxacin
Imipenem
Krumpe et al. 1999 (56)
SEPSIS
Ciprofloxacin
Several ␤-lactams
Torres et al. 2000 (109)
HAP
Ciprofloxacin
Imipenem
West et al. 2003 (110)
HAP
Levofloxacin
Imipenem followed by
(IV then oral)
oral ciprofloxacin
Success (%)
(Exp. vs. Control)
p
Mortality (%)
(Exp. vs. Control)
p
27 /197 (64) vs. 124/196 (63)
41 /43 (95) vs. 30/40 (75)
.834
.012
20/197 (10) vs. 31/196 (16)
3/43 (7) vs. 5/40 (13)
.101
.473
68 /90 (76) vs. 67/87 (77)
46 /48 (96) vs. 40/43 (93)
.861
.664
24/106 (23) vs. 17/98 (17)
10/68 (15) vs. 11/63 (17)
.385
.812
55 /66 (83) vs. 49/67 (73)
56 /79 (71) vs. 62/75 (83)
67 /87 (77) vs. 62/91 (68)
.208
.091
.240
22/76 (29) vs. 26/75 (35)
6/79 (8) vs. 7/75 (9)
22/107 (21) vs. 14/105 (13)
.488
.777
.201
48 /62 (77) vs. 54/63 (86)
.256
12 /25 (48) vs. 19/26 (73)
.089
35 /50 (70) vs. 48/60 (80)
.269
8 /12 (67) vs. 10/15 (67)
1.000
131 /176 (74) vs. 34/50 (68)
.372
27 /37 (73) vs. 10/18 (56)
.231
11 /13 (85) vs. 12/15 (80)
1.000
123 /188 (65) vs. 132/188 (70) .377
53 /67 (79) vs. 46/61 (75)
.676
23/62 (37) vs. 24/63 (38)
2/25 (8) vs. 4/26 (15)
12/50 (24) vs. 10/60 (17)
1/12 (8) vs. 5/15 (33)
28/282 (10) vs. 10/80 (13)
13/37 (35) vs. 4/18 (22)
1/13 (8) vs. 2/15 (13)
15/188 (8) vs. 23/188 (12)
7/76 (9) vs. 7/75 (9)
1.000
.668
.351
.182
.536
.372
1.000
.231
1.000
92 /202 (46) vs. 90/200 (45)
.921
17 /24 (71) vs. 14 /21 (67)
1.000
138 /166 (83) vs. 74/87 (85)
.858
40 /57 (70) vs. 34/52 (65)
.683
135 /204 (66) vs. 143/206 (69) .526
43/202 (21) vs. 38/200 (19)
2/24 (8) vs. 3/21 (14)
26/207 (13) vs. 13/99 (13)
8/41 (20) vs. 4/34 (12)
38/220 (17) vs. 32/218 (15)
.620
.652
.857
.529
.515
p, two-tailed Fisher’s exact test; CAP, community-acquired pneumonia; HAP, hospital-acquired pneumonia (ventilator-associated or not).
a
Infection-related mortality; bsame study as Snydam et al. 1994.
should be avoided, their use is appropriate in severely ill patients in the following
circumstances: 1) endemic levels of
MRSA; 2) documented hypersensitivity to
␤-lactam antibiotics; and 3) treatment of
bacterial meningitis in areas with high
levels of penicillin-resistance of S. pneumoniae. Naturally, “endemic” and “high”
levels of resistance are subjective, and no
studies have been performed to determine the level of resistance above which
the empirical use of antibiotics active
against these resistant pathogens is warranted. There probably is an inverse relationship between the severity of sepsis
and the willingness to accept a risk not to
cover an antibiotic-resistant pathogen
empirically. However, the possible clinical benefit associated with the empirical
use of glycopeptides should be weighed
against the risks of selecting resistant microorganisms and of increased toxicity,
especially when vancomycin is used in
combination with an aminoglycoside or
other nephrotoxic agents. To further reduce the risk of emergence of vancomycin-resistant staphylococci, empirical
vancomycin therapy should be rapidly
discontinued in patients in whom Grampositive infections have been ruled out.
Finally, it is rarely, if ever, appropriate to
use vancomycin alone as empirical therapy since most cases require additional
S502
Gram-negative coverage, at least until
microbiological results are available.
Empirical use of either vancomycin or
teicoplanin has been common practice in
the management of neutropenic patients
with fever, in whom coagulase-negative
staphylococci and viridans streptococci
are predominant pathogens. Although
some studies have suggested that the use
of glycopeptides at the initiation of empirical therapy might be beneficial, a recent prospective, randomized, doubleblind trial failed to demonstrate clinical
benefits (132). Prolonged courses of vancomycin therapy have been associated
with the development of vancomycinresistance S. aureus, either through reduced cell wall permeability (133) or
through acquisition of the vanA gene
from vancomycin-resistant enterococci
(VRE) (134).
Linezolid and Quinupristin/Dalfopristin. Linezolid and quinupristin/dalfopristin are recently introduced antibiotics for
the treatment of Gram-positive infections. Linezolid is a new oxazolidinone
antibiotic with activity against staphylococci (including MRSA), and Enterococcus faecium and Enterococcus faecalis
(including strains resistant to vancomycin) (135). Indications for the empirical
use of linezolid are similar to that of
glycopeptides plus two other indications,
namely the need for empirical coverage of
VRE and documented hypersensitivity to
glycopeptides. The use of linezolid is approved for infections with VRE (including
bacteremia), community-acquired and
nosocomial pneumonia caused by S.
pneumoniae or S. aureus (including
MRSA), and skin and soft tissue infections caused by Gram-positive bacteria.
Four randomized trials comparing the
efficacy of linezolid with alternative treatment in adult nonneutropenic patients
have been identified (Table 3). In an
open-labeled randomized trial, San Pedro
and coworkers (136) compared linezolid
(sequential intravenous-to-oral therapy)
with ceftriaxone IV followed by oral cefpodoxime for patients hospitalized with
community-acquired pneumonia. Episodes of community-acquired pneumonia
were primarily caused by S. pneumoniae,
and overall clinical cure rates were
higher for linezolid-treated patients, especially for patients with S. pneumoniae
bacteremia (93.1% vs. 68.2%; p ⫽ .021).
In two double-blind, randomized trials, a
combination of linezolid and aztreonam
was compared with vancomycin and aztreonam for the treatment of patients
with hospital-acquired pneumonia (119,
137). Although equivalence of activity
was found in both trials, a subsequent
retrospective analysis of the combined
Table 3. Clinical studies of linezolid in patients with Gram-positive infections
Authors and Yr of
Publication
Rubinstein et al. 2001 (119)
Stevens et al. 2002 (139)
San Pedro et al. 2002 (136)
Wunderink et al. 2003 (137)
Wunderink et al. 2003 (138)
Type of
Infection
Experimental
Therapy
Control
Therapy
Success (%)
(Exp. vs. Control)
p
Linezolid ⫹ Vancomycin ⫹ 71/107 (66.4)a vs. 62/91 (68.1)a
aztreonam
aztreonam 86/161 (53)b vs. 74/142 (52)b
Known/suspected MRSA Linezolid
Vancomcyin 109/192 (57)b vs. 93/169 (55)b
infections
Documented MRSA
41/56 (73) vs. 38/52 (73)
infections
CAP due to S.
Linezolid
Ceftriaxon/
316/381 (83) vs. 280/366 (76)
pneumoniae
cefpodoxim
HAP
Linezolid ⫹ Vancomycin ⫹ 135/256 (53)b vs. 128/245 (52)b
aztreonam
aztreonam 114 /168 (68)a vs. 111/171 (65)a
Documented SA HAP
Linezolid ⫹ Linezolid ⫹ 70/136 (51.5)a vs. 59/136 (43.4)a
(n ⫽ 339)
aztreonam
aztreonam
Documented MRSA HAP
36/61 (59.0)a vs. 22/62 (35.5)a
(n ⫽ 160)
SA HAP diagnosed by
47/92 (51)a vs. 39/90 (43)a
invasive procedure
(n ⫽ 223)
MRSA HAP diagnosed by
19/33 (58)a vs. 13/39 (33)a
invasive procedure
(n ⫽ 95)
HAP
NS
.908
NS
Survival (%)
(Exp. vs. Control)
p
36/203 (18)b vs. 49/193 (25)
b
40/240 (17) vs. 30/220 (14)
.067
b
NS
NS
.04
NS
NS
366/381 (4) vs. 347/366 (5)
NS
257/321 (80)b vs. 241/302 (80)b
145/157 (92)a vs. 150 /166 (90)a
131/168 (78) vs. 121/171 (71)
NS
NS
⬍.01
60/75 (80) vs. 54/85 (64)
.025
NS
86/109 (79) vs. 82/114 (72)
NS
34/40 (85) vs. 37/55 (67)
.05
.04
HAP, hospital-acquired pneumonia (ventilator-associated or not); MRSA, methicillin-resistant Staphylococcus aureus; SA, Staphylococcus aureus.
a
In the clinically evaluable population; bIntention-to-treat analysis.
dataset revealed that initial therapy with
linezolid was associated with significantly
better survival and clinical cure rates in
patients with nosocomial pneumonia due
to MRSA (138). Finally, in an openlabeled randomized trial, Stevens and coworkers (139) compared the efficacy of
linezolid with that of vancomycin for the
treatment of patients with suspected
MRSA. Linezolid and vancomycin had
similar efficacy, both in an intention-totreat analysis and in a subgroup of patients with documented MRSA infections.
Most patients, however, had skin or soft
tissue infections and probably did not fulfill the criteria of severe sepsis. No clinical data are available on the use of linezolid for bacterial meningitis in areas of
high levels of penicillin-resistant S. pneumoniae.
Resistance to linezolid is based on specific point mutations in the 23S ribosomal RNA of the 50S subunit of the
ribosome preventing binding of linezolid
(135). Resistance development of VRE
and S. aureus during therapy was associated with the presence of indwelling prosthetic devices and prolonged courses of
antimicrobial therapy (140, 141). Moreover, nosocomial spread of linezolidresistant VRE has been reported as well
(142). Therefore, empirical linezolid therapy should be rapidly discontinued in patients in whom Gram-positive infections
have been ruled out.
Quinupristin/dalfopristin is an injectable streptogramin available for the
treatment of Gram-positive infections
caused by S. aureus (including MRSA)
and E. faecium (including VRE), but it
has no activity against E. faecalis. Two
randomized clinical trials of quinupristin/dalfopristin have been identified
(Table 4). Fagon and coworkers (118)
compared quinupristin/dalfopristin
with vancomycin (aztreonam was allowed in both treatment arms) in patients with Gram-positive nosocomial
pneumonia. The second study was a
combined report of two nearly identical
open-label randomized trials in which
patients with Gram-positive skin and
skin structure infections were treated
with quinupristin/dalfopristin or with
one of three comparator antibiotics (cefazolin, vancomycin, or oxacillin) (143).
In both studies, clinical cure rates of
quinupristin/dalfopristin and of control
antibiotics were similar. However, only
a few patients fulfilled the criteria of
severe sepsis in the latter study (143). A
formal head-to-head comparison of linezolid and quinupristin/dalfopristin has
not been performed. Therefore, empirical therapy with quinupristin/dalfopristin should be limited to severely ill
patients with a high likelihood of infection caused by vancomycin-resistant E.
faecium or MRSA and to patients with
documented or presumed hypersensitivity to linezolid. The indiscriminate
use of linezolid or of quinupristin/
dalfopristin for presumed Gram-positive infections in patients with severe
sepsis or septic shock should be
avoided. The possible clinical benefit
associated with the empirical use of
these agents should be weighed against
the risks of selection of resistant microorganisms, toxicity, and increased
treatment costs. Finally, it is rarely, if
ever, appropriate to use linezolid or
quinupristin/dalfopristin alone as empirical therapy of severe sepsis or septic
shock, since Gram-negative coverage is
needed, at least until microbiological
results become available.
Modification of Empirical
Antimicrobial Therapy Based on
Culture Results
Recommendation: Modification of empirical antimicrobial therapy with the aim to
restrict the number of antibiotics and
narrow the spectrum of antimicrobial
therapy is an important and responsible
strategy for minimizing the development
of resistant pathogens and for containing
of costs.
Grade E
To the best of our knowledge no studies have been performed in which patients were randomized either to continue to receive empirical broadspectrum antibiotic therapy or to be
switched to a narrow-spectrum antibiotic
regimen selected on the basis of susceptibility data of the causative pathogen. In
a before-after study design, Ibrahim and
coworkers (144) assessed the effects of a
clinical guideline on the appropriateness
of empirical therapy in patients with ventilator-associated pneumonia. The clinical guideline consisted of empirical therapy with imipenem, ciprofloxacin, and
vancomycin, followed by narrowing of
antibiotic therapy when a microbiological
cause of infection was identified and discontinuation of antibiotic therapy after 7
days when the clinical condition allowed.
Implementation of the clinical guideline
S503
Table 4. Clinical studies of quinupristin/dalfopristin in patients with Gram-positive infections
Authors and Yr of
Publication
Fagon et al. 2000 (118)
Nichols et al. 1999 (143)
Type of
Infection
HAP
Complicated Grampositive skin and
structure infections
Experimental
Therapy
Control
Therapy
Success (%)
(Exp. vs. Control)
Quinup/Dalfop ⫹ Vancomycin ⫹
aztreonam
aztreonam
49/87 (56)a vs. 49/84 (58)a
Quinup/Dalfop
65/150 (43) vs. 67/148 (45)
68.2%a vs. 70.7%
Cefazolin or
vancomycin
or oxacillin
b
p
Survival (%)
(Exp. vs. Control)
p
NS
b
NS
NS
NS
b
b
38/150 (25) vs. 116/148 (22)
HAP, hospital-acquired pneumonia (ventilator-associated or not).
a
In the clinically evaluable population.
was associated with higher appropriateness of empirical therapy and a reduction
in the mean duration of therapy. However, the number of patients in whom
antibiotics were narrowed was not reported.
In fact, there are arguments both in
favor and against such an approach. On
the one hand, narrowing of the antimicrobial spectrum may reduce the risk of
selecting resistant microorganisms and
treatment costs. On the other hand, microbiological documentation of the etiology of sepsis is lacking in a significant
proportion of sepsis cases, making it difficult, if at all possible, to narrow the
antibiotic coverage based on clinical criteria only.
Recommendations: The antimicrobial
regimen should always be reassessed after
48 –72 hrs on the basis of microbiological
and clinical data with the aim of using a
narrow-spectrum antibiotic to recant the
development of resistance, to reduce toxicity, and to reduce costs. Once a causative pathogen is identified, there is no
evidence that combination therapy is
more effective monotherapy. The duration of therapy should typically be 7–10
days and guided by clinical response.
Grade E
Recommendations: If the presenting clinical syndrome is determined to be due to a
noninfectious cause, antimicrobial therapy
should be stopped promptly to minimize
the development of resistant pathogens and
superinfection with other pathogenic organisms.
Grade E
Antibiotic Cycling
Recommendations: At the present time,
there is insufficient evidence to recommend the use of antibiotic cycling as a
strategy to reduce the development of
antibiotic resistance.
S504
Grade C
Rationale: Antibiotic cycling has been
proposed as a strategy to minimize the
development of antibiotic resistance and
thus to improve the patient’s outcome.
The rationale is that the cyclic exposure
to different classes of antibiotics should
prevent emergence of resistance by exposing the microbial flora to homogeneous selective antibiotic pressure during
a limited period of time. This concept is
based on several assumptions. First, it is
assumed that antibiotic-resistant microorganisms have a growth disadvantage
when the selective antibiotic pressure is
withdrawn. Therefore, development of resistance during exposure to a given antibiotic will be counterbalanced during periods of nonexposure. Second, should
resistance develop during one period, exposure to another class of antibiotics in
the following cycle will eliminate the resistant microorganisms. For this to occur, it presupposes the absence of crossresistance (i.e., that the mechanism of
resistance be different among different
classes of antibiotics). However, besides
these theoretical considerations, antibiotics are just one of many factors that
have an impact on the development of
resistance. For example, changes in the
numbers of patients introducing resistant
microorganisms into the unit or changes
in compliance with hygienic measures
will also affect the emergence of antibiotic resistance. The effectiveness of infection control programs can be influenced
by changes in the workload of healthcare
workers or understaffing, which both will
lead to more contacts between patients
and healthcare workers and less adherence to hand hygiene and thus to more
transmission of pathogens (145–147).
Whether the theoretical benefits of antibiotic cycling hold true in daily practice
can only be tested in studies in which
there is careful control of confounding
variables.
The “real-life” experience with antibiotic cycling is sparse, and interpretation
of findings is seriously hampered by numerous methodologic problems in study
design. These included a nonstructured
antibiotic cycling scheme (148), evaluation of changes in empirical therapy in a
before-after design (149), use of multiple
antibiotics for cycling and different cycling intervals (148, 150), presence of important confounding factors, such as reduction in the antibiotic use (151), or
changes in infection control strategies
(152).
Clinical Data. The impact of antibiotic
cycling on a patient’s outcome has been
analyzed in three studies. Kollef and coworkers (149) compared the effects of replacing ceftazidime by ciprofloxacin in
the empirical treatment of suspected
Gram-negative infections in two 6-month
periods. The incidence of ventilatorassociated pneumonia (VAP) decreased
from 11.6% to 6.7% (p ⫽ .028), as did the
incidences of VAP and bacteremia due to
antibiotic-resistant Gram-negative bacteria (4% to 0.9%, p ⫽ .013, and 1.7% to
0.3%, p ⫽ .12, respectively). However,
outcome parameters such as survival and
length of stay remained unaffected. In
another trial, Raymond and coworkers
(152) compared a 1-yr period of nonprotocol-driven antibiotic use with a subsequent 1-yr period of rotating empirical
antibiotic assignment. Different classes of
antibiotics were used for different indications (pneumonia vs. peritonitis or sepsis
of unknown origin) with rotation of antibiotic combinations after 4 months. Infection rates with resistant Gram-positive
and Gram-negative bacteria significantly
decreased, survival in the ICU increased,
and antibiotic rotation was identified as
an independent predictor for survival in
logistic regression analysis. Yet, other
confounding factors were changed as
well. An antibiotic surveillance team was
instituted in the second half of the first
study period, and alcohol hand dispensers
were distributed at the start of the second
period. In the third study, Gruson and
coworkers (151) investigated whether a
new program of antibiotic use had an
impact on the incidence of VAP caused by
antibiotic-resistant bacteria in a beforeafter study. In the second part of the
study, ceftazidime and ciprofloxacin use
were restricted, antibiotics were rotated
without favoring any one antibiotic, and
each antibiotic prescription was determined by one of the two investigators. In
addition to these measures, a policy of
shorter duration of aminoglycoside therapy was implemented and compliance
with protocol was stimulated by daily
meetings between of one of the two investigators with critical care physicians,
weekly meetings with nurses to identify
nosocomial problems, monthly evaluation of antibiotic consumption, and
three-monthly evaluation of changes in
resistance patterns. The rotation protocol
included the variable use of a ␤-lactam
antibiotic (cefepime or piperacillintazobactam or imipenem or ticarcillin
during periods of at least 1 month) and
an aminoglycoside (amikacin or tobramycin, netilmicin or isepamicin) for lateonset VAP. For early-onset VAP, prescription was rotated on a monthly basis using
either amoxicillin-clavulanic acid, cefotaxime, ceftriaxone, or cefpirome in combination with an aminoglycoside or fosfomycin. Importantly, implementation of
all these measures reduced overall antibiotic use by ⬎50%. In addition, antibiotic resistance levels of isolated pathogens decreased, both for antibiotic use
that had been reduced (i.e., ciprofloxacin
and ceftazidime) and for antibiotics use
that had been increased (i.e., cefepime
and piperacillin-tazobactam). Incidences
of microbiologically confirmed VAP decreased from 22.1% to 15.7% (p ⬍ .01)
among patients requiring mechanical
ventilation for ⬎48 hrs, but ICU mortality did not change (40.6% to 37.2%; p ⫽
NS).
In summary, none of these studies
have taken into account the most important factors contributing to the development of dynamics of antibiotic resistance
in the hospital settings (i.e., relative importance of introduction, cross-transmission, and endogenous acquisition by selective antibiotic pressure), precluding a
reliable assessment of the role played by
antibiotic cycling. Furthermore, the optimal choice of antibiotics and cycle intervals remain to be determined (153,
154).
Empirical Use of Anti-Fungal
Agents in Patients with Severe
Sepsis or Septic Shock
Recommendation: Empirical antifungal
therapy should not be used on a routine
basis in patients with severe sepsis or
septic shock, but it may be justified in
selected subsets of septic patients at high
risk for invasive candidiasis (155).
Grade E
Rationale: Since the 1980s, fungi have
emerged worldwide as an increasingly
frequent cause of nosocomial infections
in critically ill patients and are associated
with significant morbidity and mortality
(156 –159). Candida was the fourth most
frequent cause of bloodstream infections
in U.S. hospitals in the 1990s (18). About
one third of all episodes of candidemia
occur in medical, surgical, or pediatric
ICUs (22, 160). Fungi were isolated from
17% of the patients with ICU-acquired
infections in a 1-day point prevalence
study conducted in 1,417 ICUs in western
European countries (129). However, it is
unclear whether all these fungal isolates
were the etiological agent of infections or
simply colonizing microorganisms. Clinical manifestations of candidiasis are usually not specific, and standard culture
techniques lack sensitivity. Detection of
Candida antigens (mannan and ␤-glucan), metabolites (arabinitol and enolase), or antibodies (anti-mannan) and
amplification of fungal DNA by polymerase chain reaction have been or are currently under investigation. The facts that
Candida infections are difficult to diagnose and associated with severe morbidity and high mortality are arguments in
favor of the empirical or preemptive use
of antifungal agents in critically ill ICU
patients at high risk of candidiasis. The
likelihood of fungal sepsis is increased in
patients who have been treated with several broad-spectrum antibiotics, who are
colonized with Candida at multiple sites,
who have damaged physiologic barriers
(i.e., recurrent gastrointestinal perforations or anastomotic leakages, acute necrotizing pancreatitis, chemotherapyinduced mucositis, vascular access
devices, and total parenteral nutrition),
or who are immunosuppressed (i.e., cancer patients with neutropenia, or hematopoietic stem cells or solid organ transplant recipients) (155, 161). However,
recent epidemiologic studies and multicenter trials have shown that fungi account for only 5% of all cases of severe
sepsis or septic shock, which does not
justify the use of antifungal therapy on a
routine basis, but only in selected subsets
of septic patients at high risk for invasive
candidiasis.
Treatment of Candidemia
Recommendation: Azoles (fluconazole)
and echinocandins (caspofungin) are as
efficacious as and less toxic than amphotericin B deoxycholate for the treatment
of patients with candidemia. Albeit better
tolerated, there is no evidence that lipid
formulations of amphotericin B are superior to amphotericin B deoxycholate for
the treatment of candidemia.
Azoles: Grade A; Echinocandins: Grade B;
Lipid formulations of amphotericin B:
Grade E
Rationale: Candidemia is associated with
significant morbidity, prolonged hospital
stay, long-term sequelae, and high crude
mortality rates (40% to 60%) (162, 163).
Moreover, the presence of disseminated
infection is an independent prognostic
factor of fatal outcome in patients with
candidiasis (164), and antifungal therapy
has been shown to reduce mortality (165,
166). Therefore, recent management
guidelines have recommended that all patients with candidemia be treated with
antifungal agents (155, 167).
For decades, amphotericin B deoxycholate, a fungicidal compound targeting
ergosterol in the cell membrane of a
broad spectrum of fungi, has been the
agent of choice for the empirical therapy
of invasive fungal infections. However,
nephrotoxicity and infusion-related adverse events, especially fever and rigors,
are frequent adverse events of conventional amphotericin B therapy that have
limited its use.
In the late 1980s, the advent of azoles
constituted a major progress in the management of invasive mycoses. This class
of drugs inhibits the synthesis of ergosterol. Fluconazole and itraconazole became available in the early 1990s. Different clinical studies compared the efficacy
of fluconazole and amphotericin B deoxycholate for the treatment of candidemia.
Azoles. In a multicenter study of 206
nonneutropenic patients with candidemia, fluconazole (400 mg/day) was
shown to be as efficacious (success rates
were 72% and 79%, respectively) as and
better tolerated than amphotericin B deoxycholate (0.5– 0.6 mg/kg/day) (168).
Similar findings were made in a prospecS505
tive observational candidemia study in
which 227 patients were treated with amphotericin B deoxycholate (median daily
dose, 0.5– 0.7 mg/kg) and 67 patients
with fluconazole (median daily dose, 200
mg) (165) and in several other smaller
comparative studies (169 –171). Noncomparative studies yielded similar success
rates for fluconazole (172–178). In summary, fluconazole (400 mg/day) was
found to be as effective as and better
tolerated than amphotericin B deoxycholate (used at a dose of 0.3–1.2 mg/kg/
day) for the treatment of candidemia or
invasive candidiasis. Whether higher
doses of fluconazole would be associated
with better response rates is unknown. In
a study of 65 patients with Candida albicans bloodstream infections, clinical response rates were 60% and 83% for patients treated with 5 or 10 mg/kg/day of
fluconazole (179). The favorable efficacytoxicity profile of fluconazole led to a
rapidly increasing use of this azole for
prophylaxis and treatment of invasive
candidiasis. As anticipated, in the late
1990s an increasing incidence of infections due to non-C. albicans species with
reduced dose-dependent susceptibility
(Candida glabrata) or intrinsic resistance
(Candida krusei) to azoles was observed
in some U.S. centers (18, 180). The use of
high doses (800 –1200 mg) of fluconazole
has been advocated for the empirical
treatment of candidemia when infections
with azole-resistant Candida species are
suspected, but efficacy data from comparative trials are lacking. However, for most
experts, amphotericin B remained clearly
the first choice for empirical therapy of
invasive candidiasis in the preechinocandin area (155, 167). This may have
changed since the advent of the echinocandins.
Itraconazole, an azole with improved
in vitro activity against fluconazoleresistant Candida species, has been available since the early 1990s. However, a
poor bioavailability of the oral formulation of itraconazole has been a major
limitation for its use in critically ill patients. Recently, an intravenous form of
itraconazole has been developed, but
there are very few data on the efficacy of
IV itraconazole for the treatment of candidemia.
Voriconazole, a member of the newest
generation of antifungal triazoles, has
been shown to exhibit excellent in vitro
and in vivo activities against Candida species (181). In patients with oropharyngeal
and/or esophageal candidiasis, voriconS506
azole was found to be at least as effective
as fluconazole (182). Moreover, voriconazole salvage therapy showed an overall
treatment success rate of 55% and 61%
in patients with refractory systemic or
esophageal candidiasis, respectively
(183). A large multicenter study comparing voriconazole with sequential use of
amphotericin B deoxycholate followed by
fluconazole in nonneutropenic patients
with candidemia has recently been completed, and the first results of that trial
indicate that voriconazole is as effective
as and was better tolerated than amphotericin B/fluconazole. Posaconazole and
ravuconazole are two other triazoles in
clinical development.
Echinocandins. Echinocandins are a
new class of antifungal agents that act by
inhibiting the synthesis of ␤-(1, 3)-Dglucan, a component of the fungal cell
wall (184). Caspofungin, the first representative of this new family of antifungal
agents, is active against Candida (C. albicans and non-C. albicans) and Aspergillus species. In immunosuppressed,
mostly human immunodeficiency viruspositive patients with oropharyngeal and
esophageal candidiasis, caspofungin was
observed to be as effective as and better
tolerated than amphotericin B deoxycholate (185, 186). In a large multicenter
trial that included 239 patients (of whom
24 were neutropenic) with invasive candidiasis (80% of the patients had candidemia), caspofungin (70-mg loading
dose, followed by 50 mg daily) was at least
as efficacious as and less toxic than amphotericin B deoxycholate (0.6 –1.0 mg/
kg/day) (success rates, 73% vs. 62%; discontinuation for adverse events, 3% vs.
23%) (187). Of note, the success rates of
caspofungin against C. glabrata and C.
krusei were comparable with those obtained in azole-susceptible Candida species. Micafungin and anidulafungin are
two other echinocandins that are currently in clinical development.
In summary, azoles (fluconazole) and
echinocandins (caspofungin) have been
shown to be as efficacious as and better
tolerated than amphotericin B deoxycholate for the treatment of patients with
candidemia and invasive candidiasis.
Limited information is available on the
efficacy of these agents in neutropenic
patients. Amphotericin B and caspofungin are the antifungal agents of choice for
the treatment of infections caused by fluconazole-resistant non-C. albicans species. The place of the newest triazole voriconazole with improved in vitro activity
against resistant strains awaits the results
of a recently completed large multicenter
study in patients with candidemia. Given
the poor prognosis of fungal sepsis, clinicians have shown great interest for the
use of combinations of antifungal agents
of different classes for the treatment of
critically ill patients with invasive mycoses. However, up to now, there have been
relatively few in vitro or in vivo studies of
combinations of antifungal agents. While
awaiting the results of prospective, randomized clinical trials demonstrating
that combinations of antifungals are superior to and reasonably not more toxic
than treatment with single agents, the
undiscriminating use of these costly
treatment regimens should be discouraged.
Lipid Formulations of Amphotericin
B. Nephrotoxicity and infusion-related
reactions are frequent adverse events of
treatment with amphotericin B deoxycholate, and treatment interruptions because of toxicity may have a negative impact on efficacy. In noncomparative
studies, continuous infusion of amphotericin B deoxycholate over 24 hrs has
been shown to limit infusion-related reactions and nephrotoxicity and did not
seem to affect efficacy (188, 189). Yet, the
influence of this mode of administration
of amphotericin B on treatment efficacy
remains to be demonstrated, as it results
in a marked alteration of drug pharmacokinetics. Lipid formulations have been
developed to improve the toxicity and
possibly also the efficacy profile of amphotericin B. Three lipid formulations
with different pharmacologic properties
are available: liposomal amphotericin B,
amphotericin B lipid complex, and amphotericin B colloidal dispersion. They
have been primarily used for the treatment of cancer patients with neutropenia
and persistent fever or with invasive aspergillosis. In large, multicenter clinical
trials, the lipid formulations were shown
to be as efficacious as and usually better
tolerated than amphotericin B deoxycholate (190 –197). Yet, there were differences between the lipid preparations in
terms of adverse events. Infusion-related
reactions were significantly less frequent
with liposomal amphotericin B (5% to
20%) than with amphotericin B lipid
complex (40% to 80%) or colloidal dispersion of amphotericin B (50% to 80%).
Therefore, liposomal amphotericin B has
been used as the control treatment regimen in most recent studies of empirical
antifungal therapy for persistent fever in
neutropenic cancer patients (193, 198).
Lipid formulations are considerably more
expensive than conventional amphotericin B, which has had a negative impact
on their use.
There are few data on the direct comparison of the efficacy and toxicity of amphotericin B deoxycholate and the lipid
formulations for the treatment of patients with invasive candidiasis. Small
noncomparative studies suggest that lipid
formulations of amphotericin B are as
efficacious as but better tolerated than
conventional amphotericin B (199 –202).
Their high costs, the paucity of clinical
data, and the existence of alternative antifungal therapies (azoles and echinocandins) explain why the use of lipid formulations has been limited in patients with
invasive candidiasis (155).
Recommendation: Third- or fourthgeneration cephalosporins: Grade A. Carbapenem: Grade B. Extended-spectrum
carboxypenicillins or ureidopenicillins
combined with ␤-lactamase inhibitors:
Grade C
5. Empirical use of glycopeptide antibiotics (vancomycin, teicoplanin), oxazolidinones (linezolid), or streptogramins (quinupristin/dalfopristin) in
shock is justified in patients with hypersensitivity to ␤-lactams or in institutions with resistant Gram-positive
bacteria (i.e., methicillin-resistant
staphylococci, penicillin-resistant
pneumococci, or ampicillin-resistant
enterococci) in the community or in
the hospital.
Recommendation: Grade E
Summary Recommendations
1. Antibiotic therapy should be started
within the first hour of recognition of
severe sepsis, after appropriate cultures have been obtained.
2. Initial empirical antiinfective therapy
should include one or more drugs that
have activity against the likely pathogens (bacterial or fungal) and that
penetrate into the presumed source of
sepsis. The choice of drugs should be
guided by the susceptibility patterns of
microorganisms in the community
and in the hospital.
Recommendation: Grade D
3. Monotherapy is as efficacious as combination therapy with a ␤-lactam and
an aminoglycoside as empirical therapy of patients with severe sepsis or
septic shock.
Recommendation: Carbapenem: Grade B.
Third- or fourth-generation cephalosporins: Grade B. Extended-spectrum carboxypenicillins or ureidopenicillins combined with ␤-lactamase inhibitors: Grade
E.
4. Third-generation and fourth-generation cephalosporins, carbapenems,
and extended-spectrum carboxypenicillins or ureidopenicillins combined
with ␤-lactamase inhibitors are
equally effective as empirical antibiotic therapy in patients with severe
sepsis.
6. Modification of empirical antimicrobial therapy with the aim to restrict
the number of antibiotics and narrow
the spectrum of antimicrobial therapy
is an important and responsible strategy for minimizing the development
of resistant pathogens and for containing costs.
7. The antimicrobial regimen should always be reassessed after 48 –72 hrs on
the basis of microbiological and clinical data with the aim to use a narrowspectrum antibiotic to prevent the development of resistance, to reduce
toxicity, and to reduce costs. Once a
causative pathogen is identified, there
is no evidence that combination therapy is more effective monotherapy.
The duration of therapy should typically be 7–10 days and guided by clinical response.
8. If the presenting clinical syndrome is
determined to be due to a noninfectious cause, antimicrobial therapy
should be stopped promptly to minimize the development of resistant
pathogens and superinfection with
other pathogenic organisms.
9. At the present time, there is insufficient evidence to recommend the use
of antibiotic cycling as a strategy to
reduce the development of antibiotic
resistance.
Recommendation: Grade C
10. Empirical antifungal therapy should
not be used on a routine basis in
shock, but it may be justified in selected subsets of septic patients at
high risk for invasive candidiasis
(155).
11. Azoles (fluconazole) and echinocandins (caspofungin) are as efficacious
as and less toxic than amphotericin B
deoxycholate for the treatment of patients with candidemia. Albeit better
tolerated, there is no evidence that
lipid formulations of amphotericin B
are superior to amphotericin B deoxycholate for the treatment of candidemia.
Recommendation: Azoles: Grade A. Echinocandins: Grade B. Lipid formulations
of amphotericin B: Grade E.
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I Antimicrobial therapy for patients with severe sepsis and septic

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