Antibiotics in sepsis

Intensive Care Med (2001) 27: S 33±S 48
Pierre-Yves Bochud
Michel P. Glauser
Thierry Calandra
Antibiotics in sepsis
P.-Y. Bochud ´ M. P. Glauser ´ T. Calandra
Division of Infectious Diseases,
Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Introduction
The management of patients with sepsis, severe sepsis,
or septic shock requires an integrated approach combining the use of rigorous diagnostic measures and the rapid initiation of appropriate antimicrobial therapy and
supportive care. Antimicrobial therapy remains the cornerstone of therapy of patients with sepsis. However,
drainage of abscesses and removal of infected foreign
material or necrotic tissues are also of critical importance for recovery. In recent years several review articles have been published on the treatment of patients
with severe sepsis and septic shock [1, 2, 3]. However,
only few have focused specifically on the antimicrobial
aspect of the patient management. Therefore the aim
of the present article was to use an evidence-based approach to review the literature on antimicrobial therapy
for severe sepsis and septic shock.
In reviewing the literature on this topic we were rapidly confronted with two difficulties. One was the lack
of standard definitions of sepsis, severe sepsis and septic
shock. Until the publication of the definitions of the
Consensus Conference of the American College of
Chest Physicians and the Society of Critical Care Medicine in 1992 [4], the terms sepsis, severe sepsis, and septic shock were ill-defined and often employed interchangeably. The other was the surprising paucity of
large comparative studies on the efficacy and safety of
different antimicrobial regimens in nonneutropenic patients. Whereas the initial studies on treatment of bacteremias published in the 1960s and 1970s included a
majority of nonneutropenic patients, most of the recent
large, clinical trials have been conducted in neutropenic
cancer patients. This emphasis is probably due to the
high frequency of bloodstream infections in neutropenic
cancer patients and the severely compromised host defenses in the context of neutropenia, providing stringent
conditions for testing antimicrobial agents. Therefore
treatment guidelines for patients with severe sepsis and
septic shock have been based for the most part on the
results of large, multicenter studies conducted in neutropenic cancer patients [5, 6].
Treatment guidelines for the use of antimicrobial
agents in the neutropenic host have been published recently [7], but these are unlikely to apply to patients
with severe sepsis or septic shock. Moreover, neutropenic cancer patients account for a minority of patients
with severe sepsis or septic shock and have often been
excluded from septic shock trials [8, 9]. Hence the need
to review, using an evidence-based approach, the literature on antibiotic therapy for patients with severe sepsis
and septic shock.
Methods
Data source
Medline was used to search articles published between 1966 and
October 1999. Keywords were the generic Medical Subject Heading (MeSH) terms sepsis, anti-infective agents, and clinical trials.
ªSepsisº comprised the terms septicemia, sepsis syndrome, septic
shock, bacteremia, fungemia, parasitemia, and viremia. ªAnti-infective agentsº comprised the term antibiotics which was exploded
to include all classes of antibiotics, and all antibiotic names. ªClinical trialº was defined as a pre-planned clinical study of the safety,
efficacy, or optimum dosage schedule, of one or more diagnostic,
therapeutic or prophylactic drugs, devices, or techniques in humans selected according to predetermined criteria of eligibility
and observed for predefined evidence of favorable and unfavorable effects. The MeSH keyword ªagranulocytosisº was used to exclude studies of neutropenic patients. Additional articles were retrieved from review articles or from the reference list of articles
identified by the Medline search. Epidemiological data were ex-
S 34
Fig. 1 A, B Etiology of infections in patients with severe
sepsis and septic shock.
A 1963±1987: Data are derived from 3 studies [22±24]
that included 674 patients.
B 1988±1998: Data are derived
from 18 studies [8, 9, 11±14,
25±36] that included 8,988 patients
tracted from articles identified by a Medline search using the keywords ªepidemiologyº and ªsepsisº, and by a systematic review of
27 clinical trials of anti-inflammatory or mediator-targeted therapies in patients with severe sepsis and septic shock [10, 11, 12, 13,
14].
Selection of articles
Abstracts of all articles meeting 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, and specific infections (AIDS, endocarditis, chronic salmonellosis, viral infections in organ transplant patients, hemorrhagic
fever, viral hepatitis, parasitic infections, and malaria) were excluded if they did not satisfy the inclusion criteria. Articles were selected only if there was unequivocal evidence that patients had clinically or microbiologically documented infections, and if the study
met at least one of the following criteria: (a) 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 [4], (b) sepsis with at least one
organ dysfunction or sign of hypo-perfusion present in more than
50 % of the patients, or (c) an overall mortality greater than 10 %.
This cutoff was chosen because it represents the lower end of the
mortality range of patients with the sepsis syndrome [15]. Medline
search and selection of articles was done by one reviewer (P. Y.B.).
To ensure that articles had been properly selected a random
sample of 25 % of the articles identified by the Medline search
were examined by a second reviewer (T. C.). Agreement between
the two reviewers was assessed using the k test [16]. There was
91 % overall agreement between the two reviewers. The k statistic
was 0.75 indicating that there was substantial agreement between
the two reviewers. Articles for which there was disagreement
were discussed to reach consensus. Levels of evidence and graded
responses to questions were assessed following the criteria proposed by Sackett [17].
Epidemiological features of severe sepsis and septic
shock
Micro-organisms
As shown in Fig. 1A, Gram-negative bacteria caused
the majority of bloodstream infections in the 1960s and
early 1970s [18, 19, 20, 21, 22, 23, 24]. This trend persisted through the middle 1980s, when the proportion of infections caused by Gram-positive bacteria began to increase. Recent data derived from three epidemiological
studies and 15 clinical trials of anti-inflammatory agents
conducted between 1988 and 1998 are summarized in
Fig. 1B [8, 9, 11, 12, 13, 14, 25, 26, 27, 28, 29, 30, 31, 32,
33, 34, 35, 36]. Standard definitions of severe sepsis and
septic shock were used in all these studies. A pathogen
was identified in 71 % of the patients. On average, blood
cultures were positive in 34 % of the patients, ranging
between 9 % and 64 %.
The most striking finding was that Gram-positive infections were almost as frequent as Gram-negative infections, confirming a trend reported in many studies
[9, 13, 25, 26, 37]. In fact, cases of Gram-positive bacteremia outnumbered Gram-negative bacteremia in some
studies [12, 32, 33, 34]. In the present compilation of articles, Gram-positive bacteria and Gram-negative bacteria accounted for 34 % and 42 % of the infections, respectively. Mixed bacterial infections occurred in 14 %
of the patients. Half of the Gram-positive infections
were caused by staphylococci (Staphylococcus aureus:
12 % and coagulase-negative staphylococci: 7 %). Enterococci were isolated in 8 % of the patients and pneumococci in 4 %. Most Gram-negative infections were
caused by Enterobacteriaceae (29 %) with Escherichia
coli (13 %) and Klebsiella pneumoniae (8 %) being the
most frequent enteric pathogens. Pseudomonas aeruginosa (8 %) was the third most frequent agent of Gram-
S 35
Fig. 2 A, B Sites of infections in
patients with severe sepsis and
septic shock. A 1963±1987:
Data are derived from 2 studies
[22, 23] that included 585 patients. B 1988±1998: Data are
derived from 7 studies [9,
11±14, 26, 36] that included
5,423 patients
negative sepsis. Fungi, mainly Candida species, were the
causal agent of sepsis in 5 % of the patients. The number
of fungal infections are also increasing. Candida was the
fourth most common bloodstream pathogen in all recent studies of nosocomial bloodstream infections in
the United States [38], and it outnumbered all Gramnegative bacteria [39]. Anaerobes were isolated in a minority of patients (2 %).
Discussion: literature-based recommendations
Sites of infection
Recommendation
The identification of the primary site of infection is a
critical part of the work-up of the septic patient. Together with the Gram stain of specimens obtained from any
site suspected of infection, it is probably the single
most important information in guiding the choice of antibiotic therapy. A site of infection was identified in
92 % of 2803 patients included in nine studies [14, 18,
23, 27, 35, 40, 41, 42, 43]. Over the past 30 years significant changes have occurred in the relative frequencies
of the site of infections in septic patients. The abdominal
cavity and the urinary tract were the most frequent sites
of infections (27 % and 21 %, respectively) in studies
conducted in the 1960s and 1970s (Fig. 2A) [21, 23].
Data derived from seven studies performed between
1988 and 1998 revealed that lung infections were predominant, accounting for 36 % of all infections
(Fig. 2B) [9, 11, 12, 13, 14, 26, 36]. Primary bloodstream
infections (i.e., without any other source of infection)
were recorded in 20 % of the patients. Abdominal infections and urinary tract infections were the third and
fourth most common foci of infections. Similar findings
have been reported recently [44].
Retrospective studies have shown that early administration of appropriate antibiotics reduces the mortality in
patients with bloodstream infections caused by Gramnegative bacteria.
Does appropriate antimicrobial therapy improve the
outcome of patients with bloodstream infections and
severe sepsis or septic shock ± in patients with Gramnegative bacteremia?
Answer: yes, grade D.
Rationale
For obvious reasons there have never been prospective,
randomized, controlled trials on the impact of antibiotic
treatment versus no treatment on the outcome of patients with sepsis. Several retrospective studies conducted
in the 1960s and in the 1970s showed that appropriate
antimicrobial therapy, defined as the use of at least one
antibiotic active in vitro against the causative bacteria,
leads to lower mortality among patients with Gram-negative bacteremia than among similar patients receiving
inappropriate therapy (Table 1) [19, 20, 22, 24]. The
landmark study by McCabe and Jackson [22] included
173 patients with Gram-negative bacillary bacteremia,
who were classified in three categories based on the severity of the underlying disease categories (i.e., rapidly
fatal, ultimately fatal, and nonfatal). Hypotension (i.e.,
a blood pressure of less than 90/60 mmHg or a decrease
of more than 70 mmHg in a hypertensive patient) was
present in 37 % patients and the overall mortality was
S 36
Table 1 Impact of the appropriateness of antibiotic therapy
on the mortality of Gram-negative bacteremia
Mortality with appropriate Mortality without
antibiotics
appropriate antibiotics
Category of underlying disease
McCabe and Jackson [22]
Rapidly fatal
Ultimately fatal
Nonfatal
Total
%
n
%
p*
8/10
10/22
0/49
18/81
80
45
0
22
2/2
10/16
3/13
15/31
100
63
23
48
NS
NS
0.001
0.007
21/25
33/78
14/109
68/211
84
42
13
32
10/11
9/14
9/33
28/58
91
64
27
48
NS
NS
0.05
0.02
12/14
19/49
11/95
42/158
86
39
12
27
5/7
13/18
10/35
28/60
71
72
29
47
NS
0.02
0.02
0.005
Young et al. 1977 [24]
Rapidly fatal
Ultimately fatal
Nonfatal
Total
41/49
62/149
25/253
128/451
84
42
10
28
17/20
32/48
22/71
71/139
85
67
31
51
NS
0.003
< 0.001
< 0.001
Four studies combined
Rapidly fatal
Ultimately fatal
Nonfatal
Total
82/98
124/289
50/506
256/902
84
42
10
28
34/40
64/96
44/152
142/288
85
67
29
49
NS
< 0.001
< 0.001
< 0.001
Freid and Vosti [20]
Rapidly fatal
Ultimately fatal
Nonfatal
Total
Bryant et al. 1971 [19]
Rapidly fatal
Ultimately fatal
Nonfatal
Total
*p values are based on the
c2 test
n
30 %, suggesting that most patients probably presented
with severe sepsis or septic shock. Appropriate antibiotic therapy was linked with a reduction in mortality from
48 % to 22 %. Subsequent studies gave similar results. In
the study by Freid and Vosti [20] the mortality rate was
32 % in patients who had been treated with appropriate
antibacterial agents, compared to 48 % in those who
did not receive adequate antibiotics. Proper antibiotic
therapy was associated with a reduction in mortality
from 47 % to 27 % in a retrospective analysis of 218 patients with Gram-negative rod bacteremia by Bryant
et al. [19]. In the study by Young et al. [24] that included
451 patients with Gram-negative rod bacteremia, appropriate antibiotic treatment was also found to reduce
mortality from 51 % to 28 %. Of note, the impact of appropriate antibiotic treatment on patients' outcome
was shown to be statistically significant in patients with
nonfatal or ultimately fatal diseases, but not in patients
with rapidly fatal diseases. Moreover, in a review of 612
episodes of Gram-negative bacteremia Kreger et al.
[45] showed that prompt administration of proper empirical antimicrobial therapy reduced by half the frequency with which shock developed in patients with
rapidly fatal, ultimately fatal, or nonfatal diseases.
Does appropriate antimicrobial therapy improve the
outcome of patients with bloodstream infections and
severe sepsis or septic shock ± in patients with Grampositive bacteremia?
Answer: yes, grade E.
Recommendation
By analogy with the observations made in patients with
Gram-negative sepsis and despite the lack of substantial
clinical data in the literature, it is likely that appropriate
antibiotic therapy reduces the morbidity and the mortality of Gram-positive sepsis.
Rationale
While the percentage of patients treated with inappropriate antibiotics ranged between 27 % and 38 % in the
initial studies on Gram-negative bacteremias [19, 20,
22], it was less than 15 % in recent trials in which Grampositive bacteria predominated [34, 46]. This explains
why there are almost no data on the impact of appropriate antibiotic therapy in patients with Gram-positive
sepsis. Clinical studies comparing antibacterial therapy
S 37
to no therapy would be unethical. However, the emergence of multiresistant Gram-positive bacteria may
give us an opportunity to address that question. In fact,
clinical and microbiological success rates were evaluated
in 20 patients with severe infections due to vancomycinresistant Enterococcus faecium [47]. That study compared patients treated with quinupristin-dalfopristin
with 40 historical controls treated with other agents,
mostly vancomycin. The mortality directly attributable
to infection was lower in the quinupristin-dalfopristin
group (5 of 20, 25 %) than in the control group (17 of
42, 40 %), suggesting that appropriate antibiotics reduced mortality (p = 0.27, two-tailed Fisher's exact test).
Does appropriate antimicrobial therapy improve the
outcome of patients with bloodstream infections and
severe sepsis or septic shock ± in patients with
candidemia?
Answer: yes, grade D.
Recommendation
Antifungal therapy is recommended for patients with
candidemia. An international panel of experts who participated in a consensus conference on the management
and prevention of severe Candida infections made similar recommendations [48]. Whether early treatment is
associated with better outcome is unknown, and additional studies are needed to evaluate this question.
Rationale
Candidemia may cause significant morbidity and serious long-term sequelae and is associated with mortality
rates in the range of 40±60 %. In a large, multicenter,
prospective observational study of 427 patients with
candidemia 369 patients were treated with antifungal
agents, while 58 patients did not receive antifungal therapy, for unknown reasons [49]. The mortality rates after
14 days and after 30 days were 27 % (99 of 369) and
37 % (136 of 369) in patients who received antifungal
therapy and 74 % (43 of 58) and 76 % (44 of 58) in those
who did not (p < 0.001), suggesting that antifungal therapy reduced mortality. However, factors other than antifungal therapy may also have contributed to these differences as the proportion of critically ill and cancer patients was higher in the untreated group than in the
group who benefited from antifungal therapy. Of the
369 patients 319 received early therapy (i.e., treatment
started within 72 h of the first positive blood cultures),
while 50 patients were treated more than 3 days after
documentation of fungal sepsis. Early administration
did not improve survival, even when patients were stratified by antifungal agents or severity of illness. In contrast, in a study of 46 patients with candidemia, early antifungal therapy (i.e., treatment initiated ≤48 h or sooner after the onset of candidemia) was found to improve
survival (p = 0.06) [50].
Monotherapy versus combination therapy
Historical background and rationale
Following the demonstration that early, appropriate antibiotic treatment of Gram-negative bacteremia improves patients' outcome and prevents the development
of septic shock, investigators examined whether treatment with two active antibiotics instead of one would
improve outcome further. Several arguments would
support the use of antibiotic combinations. First, combination therapy broadens the antibacterial spectrum,
which might be important, since treatment is usually initiated empirically in the critically ill patient with sepsis.
Moreover, polymicrobial infections may occur, especially in patients with intra-abdominal or pelvic infections,
and two antibiotics may also help to cover a broader
range of pathogens. Second, a combination of two antibiotics may exert additive or synergistic effects against
the infecting organism, resulting in enhanced antibacterial activity and possibly improved clinical response
[51, 52, 53]. Theoretically, synergism may also allow the
use of a reduced dose of the most toxic of the two
agents, but this is rarely done in practice. Third, the use
of a combination of antibiotics has been shown to reduce the emergence of resistant bacteria [54] and the incidence of superinfections [55].
The potential advantages of combination therapy
were first assessed in a series of retrospective studies
performed in the late 1960s and early 1970s. In an analysis of 444 episodes of bacteremias Anderson et al. [56]
found that treatment with two antibiotics active against
the causative organism was not superior to treatment
with one single antibiotic. However, in a subgroup of patients with rapidly or ultimately fatal diseases the use of
synergistic as opposed to nonsynergistic antibiotic combinations reduced mortality from 78 % to 52 %
(p < 0.005). In a review of 612 episodes of Gram-negative bloodstream infections, Kreger et al. [45] reported
equivalent mortality rates in patients treated with antibiotic combinations or with one single agent (22 % vs.
21 %). However, in a small subset of patients with rapidly fatal disease mortality was 23 % in patients treated
with two antibiotics, compared to 50 % in those treated
with a single antibiotic. However, these early studies
provide limited information relevant to the management of patients today. These studies were retrospective
and did not include multivariate analyses to take into
S 38
Table 2 Studies comparing carbapenem monotherapy with a combination of a b-lactam and an aminoglycoside as empirical therapy
of severe sepsis (IMI imipenem, Cx+A cefotaxime + amikacin, I+N
Clinical
success
Mouton
et al. [63]
(n = 140)
IMI
Cx+A
Cometta
et al. [62]
(n = 280)
IMI
I+N
Solberg
and
Sjursen
[65]
(n = 53)
MER
Cd  A
imipenem + netilmicin, MER meropenem, Cd+A ceftazidime  amikacin, n.a. not available)
Overall
mortality
Mortality due Colonization
to infection
Superinfections
Relapse
Eradication
Nephrotoxicity
n
%
n
%
n
%
n
%
n
%
n
%
n
%
n
%
58/70
54/70
83
77
7/70
7/70
10
10
3/70
2/70
4
3
7/44
6/45
16
13
4/44
7/45
9
16
n.a.
±
±
±
19/44
15/45
43
33
1/105
4/106
1
4
113/142 80
119/138 86
n.a.
±
±
±
18/142 13
13/138 9
8/142 6
13/138 9
8/148 5
11/138 8
n.a.
±
±
±
n.a.
±
±
±
0/158
6/155
0
4*
56/61
66/70
92
94
n.a.
±
±
±
n.a.
±
±
±
n.a.
±
±
±
0/37
1/45
0
2
1/37
0/45
3
0
n.a.
±
±
±
n.a.
±
±
±
87
83
7/116
8/121
6
7
n.a.
±
±
±
n.a.
±
±
±
n.a.
±
±
±
11/116 14
11/121 14
n.a.
±
±
±
Mouton
and Beuscart [64]
(n = 237)
MER
97/111
C+A
98/118
13/116 11
10/121 8
*p = 0.04
account the role played by confounding factors likely to
affect mortality. Subgroups analyses also included a relatively small number of patients. Most importantly, the
majority of the antibiotics used at that time would no
longer be considered appropriate today.
Subsequent studies performed in the late 1970s and
early 1980s then evaluated the efficacy of various antibiotic combinations for the treatment of Gram-negative
infections, most frequently a b-lactam and an aminoglycoside. Combinations of penicillin or carbenicillin with
amikacin showed similar clinical efficacy (55 % and
63 %, respectively) as empirical therapy of severe
Gram-negative infections in nonneutropenic cancer patients [57]. Likewise, ticarcillin plus sisomycin or mezlocillin plus sisomycin were found to be equally effective for the treatment of Gram-negative sepsis [58].
Clinical response rates were higher when patients were
treated with synergistic antibiotic combinations or
when peak serum bactericidal activity were greater
than 1:8. More recently 153 adult ICU patients with
nosocomial pneumonia or bacteremia were randomized
to receive either low- or high-dose isepamicin or amikacin given in combination with ceftazidime [59]. An unknown number of patients were treated with imipenem
instead of ceftazidime. Clinical response rates were
comparable in patients with nosocomial pneumonia
and in those with bacteremia. The proportion of patients experiencing at least one adverse event was similar
in the three treatment groups. Some investigators went
even further, treating septic patients with three instead
of two antibiotics [43, 60]. However, intensification of
therapy did not improve clinical outcome, but was associated with increased liver toxicity in one study [60].
Combinations of an aminoglycoside and an antibiotic
with activity against anaerobic bacteria have been used
to treat patients with intra-abdominal infections. Clinical response and mortality were comparable among
93 patients with intra-abdominal sepsis who were treated either with clindamycin plus gentamicin or with
chloramphenicol plus gentamicin (28 of 52, 54 % vs. 20
of 41, 49 %, p = 0.68, and 8 of 52, 15 % vs. 10 of 41,
24 % p = 0.30, respectively) [61].
With the advent of broad-spectrum and bactericidal
antibiotics, such as the extended-spectrum penicillins,
third- or fourth-generation cephalosporins, or the carbapenems, the need for aminoglycoside-containing antibiotic combinations has subsided. In recent years studies have compared the efficacy and toxicity of a single
broad-spectrum antibiotic with those of a b-lactam
paired with an aminoglycoside.
S 39
Table 3 Studies comparing monotherapy with a third or a fourthgeneration cephalosporin with a combination of a b-lactam and
an aminoglycoside as empirical therapy of severe sepsis (MOX
moxalactam, Conv conventional therapy, CEFO cefotaxime, C+T
Regimen
cefazolin + tobramycin, CEFTA ceftazidime, D+C+T/S doxcycline
+ chloramphenicol + trimethoprim/sulfamethoxazole, Best guess
ºbest guessº combination, M+N mezlocilin + netilmicin, n.a. not
available)
Clinical success
Overall
mortality
Mortality due
to infection
Superinfections
Relapse
n
%
n
%
n
%
n
%
n
Oblinger
et al. [69]
(n = 97)
MOX
Conv
33/38
32/40
87
80
8/33
9/32
24
28
2/33
4/32
6
13
2/33
2/32
6
6
Arich
et al. [67]
(n = 47)
CEFO
C+T
22/25
17/22
88
77
8/25
5/22
32
23
n.a.
±
±
±
1/25
0/22
n.a.
±
±
±
13/35 37
20/27** 74
n.a.
±
±
±
38/41
28/30
93
93
6/41
4/30
15
13
3/56
0/55
50/65
48/63
77
76
13/65
9/63
20
14
n.a.
±
White
et al. [70]
(n = 161)
CEFTA
D+C+T/S
Extermann
et al. [68]
(n = 128)
CEFTA
Best guess
McCormick
et al. [66]
(n = 128)
CEFTA
M+N
Eradication
Nephrotoxicity
%
n
%
n
%
n.a.
±
±
±
n.a.
±
±
±
3/41
11/47*
7
23
4
0
n.a.
±
±
±
n.a.
±
±
±
n.a.
±
±
±
4/20
7/19
20
37
n.a.
±
±
±
n.a.
±
±
±
5
0
n.a.
±
±
±
n.a.
±
±
±
20/22
14/16
91
88
n.a.
±
±
±
±
±
n.a.
±
±
±
n.a.
±
n.a.
±
n.a.
±
±
±
0/25
0
3/22*** 14
2/65
8/63*
3
13
*p = 0.04, **p = 0.05, ***p = 0.06
Is monotherapy ± with a carbapenem ± as efficacious as
combination therapy with b-lactam and aminoglycoside
as empirical therapy of patients with severe sepsis or
septic shock?
Answer: yes, grade B.
Recommendation
Prospective, randomized controlled studies suggest that
monotherapy with carbapenem antibiotics is as effective
as combination therapy with a b-lactam and an aminoglycoside for the empirical treatment of nonneutropenic patients with severe sepsis.
Rationale
Four studies have compared the efficacy and safety of a
carbapenem (i.e., imipenem-cilastatin or meropenem)
to that of a b-lactam paired with an aminoglycoside as
empirical therapy of patients with severe sepsis or septic
shock (Table 2). Imipenem monotherapy was compared
with a combination of imipenem and netilmicin in
313 patients with severe peritonitis, nosocomial bacteremia, or pneumonia [62]. Of note, this is the only study in
which the same b-lactam antibiotic was used in both
treatment arms. Overall success rates were similar in
the two treatment groups. Netilmicin accounted for almost one-half of the cases of nephrotoxicity that occurred in the combination arm, whereas no case of
nephrotoxicity was attributed to imipenem monotherapy. Moreover, the addition of netilmicin to imipenem
did not prevent the occurrence of superinfections or of
Pseudomonas aeruginosa resistant to imipenem. Thus,
adding an aminoglycoside to imipenem did not improve
outcome or prevent the incidence of resistance, but it increased nephrotoxicity. In a randomized study of 140
ICU patients with suspected pneumonia or bacteremia,
imipenem was found to be as effective as cefotaxime
plus amikacin [63]. As shown in Table 2, meropenem
also was as efficacious as ceftazidime given either alone
or in combination with amikacin [64, 65].
S 40
Is monotherapy ± with a 3rd or 4th generation
cephalosporin ± as efficacious as combination therapy
with b-lactam and aminoglycoside as empirical therapy
of patients with severe sepsis or septic shock?
Answer: yes, grade C.
Recommendation
Prospective, randomized controlled studies suggest that
monotherapy with third- or fourth-generation cephalosporins is as effective as combination therapy with a blactam and an aminoglycoside for the empirical treatment of nonneutropenic patients with severe sepsis.
Rationale
Five prospective randomized studies have compared
monotherapy with a third- or fourth-generation cephalosporin with combination therapy (Table 3). Ceftazidime was compared with mezlocillin plus netilmicin for
the treatment of 128 cirrhotic patients with severe sepsis
[66]. Clinical success and mortality rates were similar in
the two treatment groups (p = 0.9 and p = 0.4, respectively). However, renal failure occurred in 13 % of the
patients treated with mezlocillin and netilmicin but in
only 3 % of those who received ceftazidime monotherapy (p = 0.04). Cefotaxime was compared to cefazolin
plus tobramycin in a study of 47 patients with Gramnegative bacteremia. The clinical success rate was 88 %
with cefotaxime and 73 % with cefazolin plus tobramycin, a difference that was not statistically significant
[67]. In a multicenter study 128 patients with severe sepsis or septic shock were randomized to receive either
single-agent therapy with ceftazidime or combined therapy to be freely chosen by the investigator [68]. Bacteriological eradication rates and clinical success rates were
similar in the two treatment groups. Moxalactam was
reported to be as effective as several antibiotic combinations for the treatment of patients with moxalactam-sensitive organisms [69]. Finally, ceftazidime was found to
more effective that combined therapy with chloramphenicol, doxycycline, trimethoprim and sulfamethoxazole in patients with severe melioidosis, reducing mortality from 74 % to 37 % (p = 0.009) [70].
Is monotherapy ± with an extended-spectrum penicillin ±
as efficacious as combination therapy with b-lactam and
aminoglycoside as empirical therapy of patients with
severe sepsis or septic shock?
Answer: uncertain, grade E.
Recommendation
Extended-spectrum carboxypenicillins or ureidopenicillins combined with b-lactamase inhibitors have been
shown to be effective for the treatment of suspected infections in febrile, neutropenic cancer patients and in
patients with peritonitis or nosocomial pneumonia [71,
72, 73, 74, 75]. However, similar studies have not yet
been carried out in patients with severe sepsis or shock.
Rationale
Extended-spectrum carboxypenicillins or ureidopenicillins combined with b-lactamase inhibitors (such as ticarcillin-clavulanate or piperacillin-tazobactam) show excellent in vitro activity against a broad range of Gramnegative and Gram-positive bacteria as well as against
anaerobes making them candidates for single-agent
therapy. The Medline search identified only one randomized, prospective study comparing extended-spectrum penicillin monotherapy with combination therapy.
In that study 396 premature neonates at risk of early onset sepsis were treated with piperacillin or with ampicillin plus amikacin. Mortality rates were similar in both
treatment groups (17 of 200, 9 % vs. 27 of 196, 14 %,
p = 0.13) [76], suggesting that piperacillin is at least as
efficacious as combination therapy for the empirical
therapy of sepsis in premature newborns.
Is monotherapy ± with a monobactam ± as efficacious as
combination therapy with b-lactam and aminoglycoside
as empirical therapy of patients with severe sepsis or
septic shock?
Answer: (a) for the treatment of patients with documented Gram-negative sepsis: yes, grade C; (b) as empirical therapy of sepsis: no, grade C.
Recommendation
Monotherapy with aztreonam appears to be as effective
as combination of a b-lactam and an aminoglycoside for
the treatment of patients with documented Gram-negative sepsis. The fact that aztreonam lacks any appreciable activity against Gram-positive or anaerobic bacteria
precludes its use as empirical single-agent therapy in patients with severe sepsis.
Rationale
Aztreonam is a monocyclic b-lactam, hence its designation as monobactam that is active against a broad range
S 41
of Gram-negative bacteria, including Enterobacteriaceae and most Pseudomonas aeruginosa. It has no relevant
activity against Gram-positive and anaerobic bacteria.
Aztreonam has been used successfully for the treatment
of patients with Gram-negative bacteremia [77]. It has
been shown to be as efficacious as, but less nephrotoxic
than aminoglycosides in patients with severe Gram-negative infections [78]. However, this study found that superinfections with Enterococcus faecalis were more frequent in patients treated with aztreonam than in those
treated with aminoglycosides. A prospective randomized study investigated the role of aztreonam as empirical therapy of severe sepsis or septic shock caused by
Gram-negative bacteria. In a multicenter study 157
ICU patients with Gram-negative bacillary infections
(78 pneumonias, 28 urinary tract infections, 23 peritonitis and 40 bacteremias) were randomized to be treated
either with aztreonam alone or with a combination of
amikacin with or without a broad-spectrum b-lactam.
Clinical cure was achieved in 44 of 48 patients (92 %)
who received aztreonam and in 25 of 34 patients (73 %)
who received amikacin and b-lactam (p = 0.01) [79].
These studies thus suggested that aztreonam is an effective treatment of documented Gram-negative infections. However, aztreonam monotherapy should not be
used in patients with severe sepsis or septic shock, as it
is devoid of activity against Gram-positive bacteria.
Is monotherapy ± with a quinolone ± as efficacious as
combination therapy with b-lactam and aminoglycoside
as empirical therapy of patients with severe sepsis or
septic shock
Answer: uncertain, grade E.
Recommendation
Fluoroquinolones have been shown to be highly effective for the treatment of documented Gram-negative
bloodstream infections. However, data are lacking to
support their use as single-agent treatment of sepsis, especially as first-generation fluoroquinolones display
suboptimal activities against Gram-positive bacteria.
Furthermore, resistant strains are selected fairly rapidly.
Rationale
Fluoroquinolones are effective therapy for bloodstream
infections caused by enteric Gram-negative bacteria
[80, 81] and therefore are an excellent alternative to blactam antibiotics for the treatment of patients with documented Gram-negative sepsis. Limited data are available to evaluate the role of fluoroquinolone antibiotics
as a single agent for the treatment of patients with severe sepsis. The efficacy of ciprofloxacin monotherapy
was compared with that of several b-lactams (aztreonam, ceftazidime, ticarcillin-clavulanate, or imipenem)
given either alone or in combination with an aminoglycoside in a subset of patients (i.e., with an Acute Physiology and Chronic Health Evaluation II score of ≤20 or
less) enrolled in a multicenter study of 540 patients
with severe infections [82]. Ciprofloxacin treatment
was given intravenously for a minimum of 2±3 days,
and patients were then switched to oral therapy at the
discretion of the investigator. Overall, clinical response
was achieved in 138 of 166 patients (83 %) treated with
ciprofloxacin monotherapy and in 74 of 87 (85 %) treated with aztreonam, ceftazidime, ticarcillin-clavulanate,
or imipenem. Other studies are needed to assess the
role of fluoroquinolones in this setting, especially as
first-generation fluoroquinolones, such as norfloxacin
and ciprofloxacin, have limited activity against Grampositive bacteria. Newer fluoroquinolones, such as levofloxacin, trovafloxacin, gatifloxacin, and moxifloxacin
show enhanced in vitro activities against Gram-positive
bacteria, but demonstration of activity awaits publication of the results of ongoing studies.
Comments
The data suggest that monotherapy is a safe alternative
to combination therapy for the empirical treatment of
critically ill septic patients. However, compared to the
wealth of studies performed in febrile neutropenic cancer patients, only a small number have been conducted
in patients with severe sepsis. Moreover, many of these
studies included fewer than 200 patients, and their statistical power is therefore limited. The fact that monotherapy with carbapenem, third- or fourth-generation
cephalosporins or ureidopenicillins plus b-lactamase inhibitors (i.e., piperacillin-tazobactam) have been shown
to be as effective as b-lactam antibiotics paired with an
aminoglycoside in large multicenter studies in severely
compromised neutropenic patients certainly lends further support to the present recommendations [7]. However, critically ill septic patients differ markedly from
neutropenic cancer patients. Capillary leak syndrome
and multiorgan dysfunction are much more frequent in
patients with severe sepsis or septic shock than in neutropenic cancer patients. Such conditions are likely to
influence both the volume of distribution and metabolism of the antibiotics, which may result in altered pharmacokinetics and ultimately may affect drug efficacy
and toxicity. One should therefore be concerned that
treatment guidelines for the most severely ill septic patients tend to rely heavily on the results of trials accomplished in the neutropenic host. There is undoubtedly a
need for large, prospective, randomized trials to assess
S 42
the efficacy and toxicity of any new antibiotic in patients
with severe sepsis and septic shock.
Monotherapy should not be regarded as a universal
panacea to be used indiscriminately. Despite a lack of
clearcut advantage, some clinicians may still prefer to
rely on b-lactam and aminoglycoside combinations to
treat patients with nosocomial pneumonia or those
with infections caused by Pseudomonas, Serratia, or Enterobacter species. The potential benefit from additive
or synergistic effects and the possible prevention of
emerging resistant bacteria must be weighed against
the risk of increased toxicity. Aminoglycoside-containing regimens have been shown repeatedly to increase
the incidence of nephrotoxicity and/or ototoxicity. Furthermore, the concept that adding an aminoglycoside
may prevent the emergence of resistance has been challenged by the results of a recent study in patients with
severe nosocomial infections [62]. Pseudomonas aeruginosa resistant to imipenem have been found to be as
frequent in patients treated with netilmicin and imipenem as in those treated with imipenem alone. Whether
up-front empirical therapy should comprise a specific
anti-Gram-positive agent is discussed below.
aminoglycoside-induced nephrotoxicity and ototoxicity.
These serious adverse events are a major concern, especially in critically ill septic patients, who are already at
high risk of developing multiple organ dysfunction. Today aminoglycosides should not be used as single-agent
empirical therapy of severe sepsis, as antibiotics such as
extended-spectrum penicillins, third- or fourth-generation cephalosporins, or carbapenems have a broader
spectrum of activity and are less toxic than aminoglycosides.
Are there differences between third-generation and
fourth-generation cephalosporins and carbapenem
antibiotics as empirical therapy of patients with severe
sepsis or septic shock?
Answer: no, grade C.
Recommendation
Third-generation and fourth-generation cephalosporins
and carbapenem antibiotics are equally effective as empirical therapy in patients with severe sepsis.
Studies comparing single-agent therapeutic strategies
Aminoglycosides were among the first antibiotics to be
studied as single-agents for the treatment of Gram-negative infections. In the late 1970s and early 1980s several
studies compared the efficacy and safety of various aminoglycosides. In a prospective, double-blind study, amikacin or gentamicin was used to treat 174 patients with
suspected severe Gram-negative infections [83]. Favorable clinical response rates were 77 % (30 of 39) and
78 % (25 of 32), respectively. Both aminoglycosides
were accompanied with a high rate of serious adverse
events. Definite nephrotoxicity and ototoxicity occurred in 5 of 62 (8 %) and 2 of 32 (6 %) patients treated
with amikacin and in 7 of 62 (11 %) and 3 of 30 (10 %)
patients treated with gentamicin. Netilmicin and amikacin were used to treat 80 patients with severe sepsis due
to Gram-negative bacteria, including bacteremias, genitourinary tract infections, and pneumonias [84]. A favorable clinical response was observed in 30 of 34 patients treated with netilmicin (88 %) and in 26 of 33 treated with amikacin (79 %, p = 0.34). The frequency of
nephrotoxicity was 38 % with netilmicin (13 of 34) and
28 % with amikacin (8 of 29) and that of ototoxicity
was 9 % (3 of 34) and 24 % (7 of 29) respectively, but
the difference was not statistically significant (p = 0.42
and 0.16, respectively). Overall, the various aminoglycosides (i.e., gentamicin, tobramycin, netilmicin, and amikacin) have been shown to be equally effective as empirical monotherapy of Gram-negative sepsis. A constant
finding in all these studies was the high incidence of
Rationale
Four studies have compared the efficacy and safety of a
third-generation cephalosporin to that of a fourth-generation cephalosporin or a carbapenem. An analysis
was carried out on 226 patients with microbiologically
confirmed septicemia selected from a pool of 15 phase
II and phase III studies of cefpirome [85]; 176 patients
were treated with cefpirome and 50 with ceftazidime.
A satisfactory clinical response was found in 131 of 176
(74 %) cefpirome recipients and in 34 of 50 (68 %)
ceftazidime recipients (p = 0.47). A subsequent randomized multicenter study treated 372 patients with severe sepsis and suspected bacteremias empirically with
cefpirome or with ceftazidime [86]. The study protocol
allowed the addition of metronidazole, an aminoglycoside, or a glycopeptide antibiotic whenever indicated.
Of the patients in the cefpirome group 62 % received
monotherapy and of those the ceftazidime group 63 %.
Clinical success rates in the intent-to-treat analysis
were 65 % (123 of 188) and 70 % (132 of 188), respectively. These two studies showed that cefpirome and
ceftazidime are equally effective for the treatment of
patients with severe sepsis. Ceftazidime and cefepime
have also been found to be equally effective in a small
study of 28 severely ill patients with suspected Gramnegative bacteremia [87].
Lastly, 45 patients with pneumonias or bacteremias
were randomized to receive either imipenem or ceftazi-
S 43
dime therapy. A favorable clinical response was observed in 17 of 21 (81 %) patients receiving ceftazidime
and in 16 of 24 (67 %) receiving imipenem (p = 0.33)
[88]. Despite limited statistical power due to the small
number of patients enrolled, these four studies suggest
that third- and fourth-generation cephalosporins and
carbapenem antibiotics are equally effective as empirical therapy in patients with severe sepsis.
Are there clinical conditions justifying the use of
empirical anti-Gram-positive therapy in patients with
severe sepsis?
Answer: yes, grade E.
Recommendation
The indiscriminate use of vancomycin or teicoplanin for
presumed Gram-positive infections in patients with severe sepsis and septic shock should be avoided. Glycopeptides are appropriate in severely ill patients with
catheter-related infections or in centers in which methicillin-resistant staphylococci predominate. However,
the possible clinical benefit associated with the empirical use of vancomycin or teicoplanin should be weighed
against the risks of selecting resistant organisms and of
increased toxicity, especially when vancomycin is given
in combination with an aminoglycoside [89] or other
nephrotoxic agent. To further reduce the risk of the
emergence of vancomycin-resistant staphylococci or enterococci, empirical vancomycin therapy should also be
rapidly discontinued in patients in whom Gram-positive
infections has been ruled out. Finally, it is rarely, if ever,
appropriate to use vancomycin alone as empirical therapy since most cases require additional Gram-negative
coverage, at least until microbiological results are available.
Rationale
In recent years many institutions have experienced a
major change in the cause of bacterial infections occurring in ICU patients with sepsis. While Gram-negative
bacteria predominated until the middle 1980s, Grampositive bacteria now account for approximately onehalf of the infections occurring in patients with severe
sepsis and septic shock [20]. Moreover, methicillin-resistant S. aureus and methicillin-resistant coagulase-negative staphylococci are responsible for a majority of staphylococcal infections in some institutions. The frequency of penicillin-resistant S. pneumoniae is also increasing in many areas of the world. Does this epidemiological context justify the empirical use of glycopeptide
antibiotics (i.e., vancomycin and teicoplanin) on a routine basis in all patients with severe sepsis and septic
shock? The literature does not offer an answer to that
question. To our knowledge, no study has prospectively
examined the role of glycopeptide antibiotics in the
management of nonneutropenic patients with severe
sepsis. All recent studies have been performed in neutropenic cancer patients, in whom viridans streptococci
and coagulase-negative staphylococci are a frequent
cause of infection [7]. Controversy still exists as to the
need for empirical specific anti-Gram-positive therapy
at the onset of fever in neutropenic cancer patients [90,
91, 92]. Although some studies have suggested that the
empirical use of vancomycin or teicoplanin at the initiation of empirical therapy is preferable, others have
yielded data that do not support that concept. Prospective studies are ongoing to further address that question.
Are antifungal agents indicated as empirical therapy of
patients with severe sepsis or septic shock?
Answer: no, grade E.
Recommendation
Antifungal agents, such as fluconazole, should not be
used on a routine basis as empirical therapy in patients
with severe sepsis and septic shock.
Rationale
Since the middle 1980s fungi have emerged worldwide
as an increasingly frequent cause of nosocomial infections in critically ill patients and are associated with significant morbidity and high mortality [93, 94, 95, 96]. A
recent survey of bloodstream infections found ICUs to
have the highest incidence of candidemia, accounting
for 45 % of all episodes of fungemia [97]. A 1-day point
prevalence study carried out in 1417 ICUs in western
European countries isolated fungi in 17 % of all ICU-acquired infections [98]. However, it is unclear whether all
these fungal isolates were the causal agent of infections
rather than colonizing micro-organisms. Clinical manifestations of candidiasis are usually not specific, and
standard culture techniques and tests for detection of
Candida antigens or metabolites lack sensitivity. Taken
together these facts might support the empirical use of
antifungal agents for the treatment of the critically ill
ICU patient with severe sepsis or septic shock. However, recent epidemiological studies and multicenter trials
have shown that fungi account for only 5 % of all cases
of severe sepsis or septic shock (Fig. 1B), which would
not justify the use of antifungal therapy on a routine ba-
S 44
sis. Since Candida infections from species other than C.
albicans are increasing, along with the resistance to azoles, one should even be more cautious with the use of
this class of antifungal agents.
Are azoles as effective as amphotericin B for the
treatment of patients with candidemia?
Answer: yes, grade A.
Recommendation
Fluconazole is as effective as and less toxic than amphotericin B for the treatment of candidemia in nonneutropenic patients. However, if the patient has been
treated previously with fluconazole, it might be prudent
to begin therapy with amphotericin B while waiting for
the identification of the Candida species and for the results of susceptibility testing. Infections caused by Candida strains other than C. albicans with reduced susceptibility to azoles are more commonly seen in patients
who have received previous antifungal therapy, including azoles, than in those who did not. Among the other
Candida strains, C. krusei is intrinsically resistant to
fluconazole, and C. glabrata is relatively resistant to
fluconazole. Many investigators consider amphothericin
B the agent of choice to treat unstable patients with candidemia [48]. Whether 5-fluorocytosine should be combined with amphotericin B in these patients is debatable. No data have shown that combining these agents
improve outcome of patients with candidemia.
Rationale
A recent study has shown that Candida is the fourth
most frequent cause of bloodstream infections [99]. Between one-fourth and one-half of all episodes of candidemia occur in ICUs. Seven comparative studies compared the efficacy of fluconazole and amphotericin B
for the treatment of candidemia. A large multicenter
study treated 206 nonneutropenic patients with candidemia with fluconazole (400 mg per day) or with amphotericin B (0.5±0.6 mg/kg per day). Most of these patients had catheter-related candidemia. Fluconazole
was as effective as amphotericin B (success rate were
72 % and 79 %, respectively) [100]. The proportion of
patients with hypokalemia and elevated blood urea nitrogen or serum creatinine were significantly lower in
the fluconazole group than in the amphotericin B group
(p < 0.001 and p = 0.006). In a large multicenter, prospective observational study of the morbidity and mortality of candidemia, intravenous amphotericin B was
given to 227 patients and fluconazole to 67 patients
[49]. Mortality at day 30 was not significantly different
in patients treated with amphotericin B and in those
treated with fluconazole (31 % vs. 27 %, p = 0.6). Another randomized study treated 50 patients with fluconazole and 53 with amphotericin B. Clinical success
rate (24 of 42, 57 % vs. 26 of 42, 62 %, respectively,
p = 0.82) and mortality at day 14 (13 of 50, 26 % vs. 11
of 53, 21 %, respectively, p = 0.69) were comparable in
the two treatment groups [101]. Two smaller studies
yielded analogous results. Fluconazole was found to be
as effective as amphotericin B in 90 ICU patients with
cancer and systemic Candida infections (i.e., bloodstream infections, pneumonia or peritonitis; clinical response rates: 33 of 45, 73 % vs. 32 of 45, 71 %, p = 0.8)
[102]. The efficacy and safety of fluconazole was compared to that of amphotercin B for the treatment of disseminated fungal sepsis in neonates [103]. Case fatality
rates were 33 % (4 of 12) in the fluconazole group and
45 % (5 of 11) in the amphotericin B group (p = 0.68).
Adverse effects were less frequent in neonates treated
with fluconazole than in those who received amphotericin B. In all studies there were fewer adverse events, especially nephrotoxicity, hypokalemia, fever, and chills,
with fluconazole than with amphotericin B.
There is a lack of dose-finding studies on which to
base a recommendation on what dose of antifungal
agents to use for the treatment of patients with candidemia. A dose of 400 mg/d has been used in most fluconazole studies. Whether higher daily doses of fluconazole would be more effective is unclear. One study of
65 patients with fungemia due to C. albicans found a
clinical response rate of 60 % in patients treated with
5 mg/kg fluconazole once daily and one of 83 % in those
who received a daily dose of 10 mg/kg [104]. Of note, 18
of 20 international experts who participated in a consensus conference on the management of Candida infections would use a daily dose of 400 mg fluconazole to
treat stable patients with candidemia; in patients who
are unstable or deteriorating, one-half of the experts
would use a dose of 800 mg fluconazole while the other
one-half would use amphotericin B [48]. However, these
opinions were based primarily on personal experience.
Prospective randomized trials are needed to address
these issues.
Acknowledgements We are grateful to Dr. Jacques Cornuz for assistance in the literature search and statistical analysis, and to Prof.
Jonathan Cohen for critical reading of the manuscript. This work
was supported by grants from the Swiss National Science Foundation to T. C. (32-49129.96). T. C. is recipient of a career award
from the Swiss National Science Foundation (32-48916.96).
M. P.G. is recipient of a career award from the Bristol-Myers
Squibb Foundation.
S 45
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