Antibiotics in Sepsis | Sepsis | Antibiotics

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

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.

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-

29. 12. There was 91 % overall agreement between the two reviewers. A 1963±1987: Data are derived from 3 studies [22±24] that included 674 patients.). 31. respectively. immunology. 13. 12. Articles were selected only if there was unequivocal evidence that patients had clinically or microbiologically documented infections. Mixed bacterial infections occurred in 14 % of the patients. In the present compilation of articles. Articles for which there was disagreement were discussed to reach consensus. 37]. microbiology. Selection of articles Abstracts of all articles meeting the selection criteria were reviewed to exclude irrelevant studies. and by a systematic review of 27 clinical trials of anti-inflammatory or mediator-targeted therapies in patients with severe sepsis and septic shock [10.75 indicating that there was substantial agreement between the two reviewers. blood cultures were positive in 34 % of the patients. hematology. Medline search and selection of articles was done by one reviewer (P. Half of the Gram-positive infections were caused by staphylococci (Staphylococcus aureus: 12 % and coagulase-negative staphylococci: 7 %). viral hepatitis. 9. In fact. The k statistic was 0. Epidemiological features of severe sepsis and septic shock Micro-organisms As shown in Fig. 36]. 34. 33. 11. Most Gram-negative infections were caused by Enterobacteriaceae (29 %) with Escherichia coli (13 %) and Klebsiella pneumoniae (8 %) being the most frequent enteric pathogens. 9. 13. confirming a trend reported in many studies [9. 25±36] that included 8. The most striking finding was that Gram-positive infections were almost as frequent as Gram-negative infections. parasitic infections. ranging between 9 % and 64 %. C. 19.S 34 Fig. 25. catheter management. Agreement between the two reviewers was assessed using the k test [16]. 34].988 patients tracted from articles identified by a Medline search using the keywords ªepidemiologyº and ªsepsisº. 22. B 1988±1998: Data are derived from 18 studies [8. 1 A. chronic infections. 1B [8. animal studies. Recent data derived from three epidemiological studies and 15 clinical trials of anti-inflammatory agents conducted between 1988 and 1998 are summarized in Fig. Enterococci were isolated in 8 % of the patients and pneumococci in 4 %. Gram-positive bacteria and Gram-negative bacteria accounted for 34 % and 42 % of the infections. 23. B Etiology of infections in patients with severe sepsis and septic shock. chronic salmonellosis. 11±14. Pseudomonas aeruginosa (8 %) was the third most frequent agent of Gram- . 32. allergy. viral infections in organ transplant patients. cases of Gram-positive bacteremia outnumbered Gram-negative bacteremia in some studies [12. Levels of evidence and graded responses to questions were assessed following the criteria proposed by Sackett [17]. (b) sepsis with at least one organ dysfunction or sign of hypo-perfusion present in more than 50 % of the patients. Gram-negative bacteria caused the majority of bloodstream infections in the 1960s and early 1970s [18. 30. 33. pharmacology. 14. 35. This cutoff was chosen because it represents the lower end of the mortality range of patients with the sepsis syndrome [15]. 24]. 20. Y. and malaria) were excluded if they did not satisfy the inclusion criteria. Review articles and articles on topics such as antibiotic prophylaxis. 32. 1A. 28. endocarditis. 21. This trend persisted through the middle 1980s.). 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. or (c) an overall mortality greater than 10 %. On average. hemorrhagic fever. 11. 26. 25. 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]. 27. 26. oncology. when the proportion of infections caused by Gram-positive bacteria began to increase. mediators of inflammation. Standard definitions of severe sepsis and septic shock were used in all these studies. 13.B. 14]. and specific infections (AIDS. A pathogen was identified in 71 % of the patients.

grade D. B 1988±1998: Data are derived from 7 studies [9. 23. 36] that included 5.e. Primary bloodstream infections (i. Together with the Gram stain of specimens obtained from any site suspected of infection. 11±14. 14. leads to lower mortality among patients with Gram-negative bacteremia than among similar patients receiving inappropriate therapy (Table 1) [19. 12. 11. defined as the use of at least one antibiotic active in vitro against the causative bacteria. 43]. 26. 42. Discussion: literature-based recommendations 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. 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 . 26. Abdominal infections and urinary tract infections were the third and fourth most common foci of infections. randomized. A site of infection was identified in 92 % of 2803 patients included in nine studies [14. 41. accounting for 36 % of all infections (Fig. Data derived from seven studies performed between 1988 and 1998 revealed that lung infections were predominant. and nonfatal). 23]. it is probably the single most important information in guiding the choice of antibiotic therapy.S 35 Fig. who were classified in three categories based on the severity of the underlying disease categories (i. 13.e.423 patients negative sepsis. The number of fungal infections are also increasing. 40. Candida was the fourth most common bloodstream pathogen in all recent studies of nosocomial bloodstream infections in the United States [38].. Recommendation Retrospective studies have shown that early administration of appropriate antibiotics reduces the mortality in patients with bloodstream infections caused by Gramnegative bacteria. mainly Candida species. Fungi. and it outnumbered all Gramnegative bacteria [39]. Sites of infection The identification of the primary site of infection is a critical part of the work-up of the septic patient. Hypotension (i. Several retrospective studies conducted in the 1960s and in the 1970s showed that appropriate antimicrobial therapy. The landmark study by McCabe and Jackson [22] included 173 patients with Gram-negative bacillary bacteremia.. rapidly fatal. Similar findings have been reported recently [44]. 22. 2 A. 18. 20. 2A) [21.e. without any other source of infection) were recorded in 20 % of the patients. 35. 2B) [9. controlled trials on the impact of antibiotic treatment versus no treatment on the outcome of patients with sepsis. 23] that included 585 patients. Anaerobes were isolated in a minority of patients (2 %). ultimately fatal. B Sites of infections in patients with severe sepsis and septic shock. 36]. Over the past 30 years significant changes have occurred in the relative frequencies of the site of infections in septic patients. Rationale For obvious reasons there have never been prospective. were the causal agent of sepsis in 5 % of the patients. A 1963±1987: Data are derived from 2 studies [22. 27. 24]. 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..

[45] showed that prompt administration of proper empirical antimicrobial therapy reduced by half the frequency with which shock developed in patients with rapidly fatal.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 Freid and Vosti [20] Rapidly fatal Ultimately fatal Nonfatal Total Bryant et al.003 < 0. grade E.001 *p values are based on the c2 test 30 %. Subsequent studies gave similar results. This explains why there are almost no data on the impact of appropriate antibiotic therapy in patients with Gram-positive sepsis.005 NS 0. 20. ultimately fatal. in a review of 612 episodes of Gram-negative bacteremia Kreger et al.02 0. Rationale While the percentage of patients treated with inappropriate antibiotics ranged between 27 % and 38 % in the initial studies on Gram-negative bacteremias [19. but not in patients with rapidly fatal diseases. compared to 48 % in those who did not receive adequate antibiotics.02 NS 0. 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.001 < 0. Appropriate antibiotic therapy was linked with a reduction in mortality from 48 % to 22 %. 46]. Recommendation By analogy with the observations made in patients with Gram-negative sepsis and despite the lack of substantial clinical data in the literature. 1971 [19] Rapidly fatal Ultimately fatal Nonfatal Total Young et al.001 0.02 0. 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. suggesting that most patients probably presented with severe sepsis or septic shock. 22]. Moreover.05 0. it was less than 15 % in recent trials in which Grampositive bacteria predominated [34. Of note.007 NS NS 0. the impact of appropriate antibiotic treatment on patients' outcome was shown to be statistically significant in patients with nonfatal or ultimately fatal diseases.001 NS < 0. appropriate antibiotic treatment was also found to reduce mortality from 51 % to 28 %. [19]. it is likely that appropriate antibiotic therapy reduces the morbidity and the mortality of Gram-positive sepsis. Clinical studies comparing antibacterial therapy . 1977 [24] Rapidly fatal Ultimately fatal Nonfatal Total Four studies combined Rapidly fatal Ultimately fatal Nonfatal Total n 8/10 10/22 0/49 18/81 21/25 33/78 14/109 68/211 12/14 19/49 11/95 42/158 41/49 62/149 25/253 128/451 82/98 124/289 50/506 256/902 % 80 45 0 22 84 42 13 32 86 39 12 27 84 42 10 28 84 42 10 28 n 2/2 10/16 3/13 15/31 10/11 9/14 9/33 28/58 5/7 13/18 10/35 28/60 17/20 32/48 22/71 71/139 34/40 64/96 44/152 142/288 % 100 63 23 48 91 64 27 48 71 72 29 47 85 67 31 51 85 67 29 49 p* NS NS 0.001 < 0. [24] that included 451 patients with Gram-negative rod bacteremia. or nonfatal diseases. In the study by Freid and Vosti [20] the mortality rate was 32 % in patients who had been treated with appropriate antibacterial agents.001 < 0. In the study by Young et al.

However. especially in patients with intra-abdominal or pelvic infections. Several arguments would support the use of antibiotic combinations. polymicrobial infections may occur.27. Does appropriate antimicrobial therapy improve the outcome of patients with bloodstream infections and severe sepsis or septic shock ± in patients with candidemia? Answer: yes. In contrast. which might be important.005). Second. treatment started within 72 h of the first positive blood cultures). and two antibiotics may also help to cover a broader range of pathogens. Moreover. suggesting that antifungal therapy reduced mortality. Monotherapy versus combination therapy Historical background and rationale Following the demonstration that early.. Theoretically. a combination of two antibiotics may exert additive or synergistic effects against the infecting organism. 21 %). Early administration did not improve survival. the use of a combination of antibiotics has been shown to reduce the emergence of resistant bacteria [54] and the incidence of superinfections [55]. in a study of 46 patients with candidemia. [56] found that treatment with two antibiotics active against the causative organism was not superior to treatment with one single antibiotic. two-tailed Fisher's exact test). and additional studies are needed to evaluate this question. 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. However. These studies were retrospective and did not include multivariate analyses to take into . suggesting that appropriate antibiotics reduced mortality (p = 0. these early studies provide limited information relevant to the management of patients today.001). treatment initiated ≤48 h or sooner after the onset of candidemia) was found to improve survival (p = 0. In a large. First. clinical and microbiological success rates were evaluated in 20 patients with severe infections due to vancomycinresistant Enterococcus faecium [47]. multicenter. 53]. since treatment is usually initiated empirically in the critically ill patient with sepsis. while 50 patients were treated more than 3 days after documentation of fungal sepsis. compared to 50 % in those treated with a single antibiotic. 25 %) than in the control group (17 of 42. mostly vancomycin. resulting in enhanced antibacterial activity and possibly improved clinical response [51. grade D.e.S 37 to no therapy would be unethical. in a small subset of patients with rapidly fatal disease mortality was 23 % in patients treated with two antibiotics.e. 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. Recommendation Antifungal therapy is recommended for patients with candidemia. early antifungal therapy (i. 40 %). prospective observational study of 427 patients with candidemia 369 patients were treated with antifungal agents. That study compared patients treated with quinupristin-dalfopristin with 40 historical controls treated with other agents. Kreger et al. appropriate antibiotic treatment of Gram-negative bacteremia improves patients' outcome and prevents the development of septic shock. combination therapy broadens the antibacterial spectrum. for unknown reasons [49]. 52. However. In fact. In a review of 612 episodes of Gram-negative bloodstream infections. In an analysis of 444 episodes of bacteremias Anderson et al. The potential advantages of combination therapy were first assessed in a series of retrospective studies performed in the late 1960s and early 1970s. synergism may also allow the use of a reduced dose of the most toxic of the two agents. Rationale Candidemia may cause significant morbidity and serious long-term sequelae and is associated with mortality rates in the range of 40±60 %. while 58 patients did not receive antifungal therapy. Of the 369 patients 319 received early therapy (i. Whether early treatment is associated with better outcome is unknown. the emergence of multiresistant Gram-positive bacteria may give us an opportunity to address that question. However. but this is rarely done in practice. investigators examined whether treatment with two active antibiotics instead of one would improve outcome further.. However. Third. [45] reported equivalent mortality rates in patients treated with antibiotic combinations or with one single agent (22 % vs. An international panel of experts who participated in a consensus conference on the management and prevention of severe Candida infections made similar recommendations [48]. even when patients were stratified by antifungal agents or severity of illness.06) [50]. 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. The mortality directly attributable to infection was lower in the quinupristin-dalfopristin group (5 of 20.

not available) Superinfections n % Relapse n % Eradication n % Nephrotoxicity n % Mortality due Colonization to infection 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. I+N Clinical success n Mouton et al. Clinical response rates were comparable in patients with nosocomial pneumonia and in those with bacteremia. ± ± ± n. An unknown number of patients were treated with imipenem instead of ceftazidime. 15 % vs. Subgroups analyses also included a relatively small number of patients. ± ± ± n. Likewise.or high-dose isepamicin or amikacin given in combination with ceftazidime [59].a. Clinical response rates were higher when patients were treated with synergistic antibiotic combinations or when peak serum bactericidal activity were greater than 1:8. ± ± ± 0/158 6/155 0 4* 56/61 66/70 92 94 n.a. 24 % p = 0. MER meropenem.68. such as the extended-spectrum penicillins. third.a. but was associated with increased liver toxicity in one study [60].a.a. respectively) as empirical therapy of severe Gram-negative infections in nonneutropenic cancer patients [57]. ticarcillin plus sisomycin or mezlocillin plus sisomycin were found to be equally effective for the treatment of Gram-negative sepsis [58]. The proportion of patients experiencing at least one adverse event was similar in the three treatment groups. More recently 153 adult ICU patients with nosocomial pneumonia or bacteremia were randomized to receive either low. and 8 of 52.30.a. 20 of 41.a.a. [63] (n = 140) IMI Cx+A Cometta et al. 49 %. intensification of therapy did not improve clinical outcome. 60].a. ± ± ± Mouton and Beuscart [64] (n = 237) MER 97/111 C+A 98/118 *p = 0.a. 54 % vs. ± ± ± 11/116 14 11/121 14 13/116 11 10/121 8 n. treating septic patients with three instead of two antibiotics [43. p = 0. the majority of the antibiotics used at that time would no longer be considered appropriate today. Cd+A ceftazidime  amikacin. ± ± ± n. 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.a. Combinations of penicillin or carbenicillin with amikacin showed similar clinical efficacy (55 % and 63 %. ± ± ± 18/142 13 13/138 9 8/142 6 13/138 9 8/148 5 11/138 8 n. However. 10 of 41. 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.04 87 83 7/116 8/121 6 7 n. ± ± ± n. Some investigators went even further.a. [62] (n = 280) IMI I+N Solberg and Sjursen [65] (n = 53) MER Cd  A % Overall mortality n % imipenem + netilmicin. Cx+A cefotaxime + amikacin. 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.a. Most importantly.or fourth-generation cephalosporins. respectively) [61]. ± ± ± account the role played by confounding factors likely to affect mortality. Combinations of an aminoglycoside and an antibiotic with activity against anaerobic bacteria have been used to treat patients with intra-abdominal infections. ± ± ± n. ± ± ± 0/37 1/45 0 2 1/37 0/45 3 0 n. . With the advent of broad-spectrum and bactericidal antibiotics. n. ± ± ± 19/44 15/45 43 33 1/105 4/106 1 4 113/142 80 119/138 86 n. most frequently a b-lactam and an aminoglycoside.a.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. or the carbapenems. ± ± ± n.

± ± ± 0/25 0 3/22*** 14 n. As shown in Table 2.a. [70] (n = 161) CEFTA D+C+T/S Extermann et al. . Of note. the addition of netilmicin to imipenem did not prevent the occurrence of superinfections or of Pseudomonas aeruginosa resistant to imipenem. n. but it increased nephrotoxicity.a. 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). Recommendation Prospective. Thus. not available) Superinfections n % Relapse n % Eradication n % Nephrotoxicity n % 33/38 32/40 87 80 8/33 9/32 24 28 2/33 4/32 6 13 2/33 2/32 6 6 n.a. 65].a. ± ± ± 4/20 7/19 20 37 n. or pneumonia [62]. meropenem also was as efficacious as ceftazidime given either alone or in combination with amikacin [64.a.a.a.a. imipenem was found to be as effective as cefotaxime plus amikacin [63]. D+C+T/S doxcycline + chloramphenicol + trimethoprim/sulfamethoxazole. [69] (n = 97) MOX Conv Arich et al. grade B. In a randomized study of 140 ICU patients with suspected pneumonia or bacteremia. ***p = 0.a.a.a. Netilmicin accounted for almost one-half of the cases of nephrotoxicity that occurred in the combination arm. **p = 0.. ± ± ± n.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. adding an aminoglycoside to imipenem did not improve outcome or prevent the incidence of resistance. ± ± ± n. [67] (n = 47) CEFO C+T White et al. ± n. ± ± ± 3/41 11/47* 7 23 22/25 17/22 88 77 8/25 5/22 32 23 n. [66] (n = 128) CEFTA M+N % Overall mortality n % Mortality due to infection n % cefazolin + tobramycin.a. Rationale Four studies have compared the efficacy and safety of a carbapenem (i. whereas no case of nephrotoxicity was attributed to imipenem monotherapy. ± ± ± 38/41 28/30 93 93 6/41 4/30 15 13 3/56 0/55 5 0 n.05.04. Imipenem monotherapy was compared with a combination of imipenem and netilmicin in 313 patients with severe peritonitis. ± ± ± 50/65 48/63 77 76 13/65 9/63 20 14 n. [68] (n = 128) CEFTA Best guess McCormick et al. Overall success rates were similar in the two treatment groups. Moreover. this is the only study in which the same b-lactam antibiotic was used in both treatment arms. ± ± ± n.a.a. ± ± ± 13/35 37 20/27** 74 n. ± ± ± n. CEFTA ceftazidime. CEFO cefotaxime. ± n.a. ± ± ± n.e. M+N mezlocilin + netilmicin. C+T Regimen Clinical success n Oblinger et al.a. ± ± ± 2/65 8/63* 3 13 *p = 0. ± ± ± n. ± ± ± 1/25 0/22 4 0 n.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. ± ± ± 20/22 14/16 91 88 n. nosocomial bacteremia. Best guess ºbest guessº combination. 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.a.a. Conv conventional therapy.a. ± ± ± n.

The Medline search identified only one randomized. respectively). Ceftazidime was compared with mezlocillin plus netilmicin for the treatment of 128 cirrhotic patients with severe sepsis [66]. ceftazidime was found to more effective that combined therapy with chloramphenicol. 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. 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. 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. 75]. prospective study comparing extended-spectrum penicillin monotherapy with combination therapy. Recommendation Prospective. p = 0. 72.9 and p = 0. The clinical success rate was 88 % with cefotaxime and 73 % with cefazolin plus tobramycin. 14 %. 9 % vs. doxycycline. 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 C. trimethoprim and sulfamethoxazole in patients with severe melioidosis. 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 E. Rationale Five prospective randomized studies have compared monotherapy with a third. randomized controlled studies suggest that monotherapy with third.04). Rationale Aztreonam is a monocyclic b-lactam. hence its designation as monobactam that is active against a broad range .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. neutropenic cancer patients and in patients with peritonitis or nosocomial pneumonia [71. Finally. Bacteriological eradication rates and clinical success rates were similar in the two treatment groups.4. Moxalactam was reported to be as effective as several antibiotic combinations for the treatment of patients with moxalactam-sensitive organisms [69]. reducing mortality from 74 % to 37 % (p = 0. (b) as empirical therapy of sepsis: no. Mortality rates were similar in both treatment groups (17 of 200.009) [70]. 74. suggesting that piperacillin is at least as efficacious as combination therapy for the empirical therapy of sepsis in premature newborns. Clinical success and mortality rates were similar in the two treatment groups (p = 0. 73. grade C. In that study 396 premature neonates at risk of early onset sepsis were treated with piperacillin or with ampicillin plus amikacin. grade C. 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.or fourth-generation cephalosporin with combination therapy (Table 3). a difference that was not statistically significant [67].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.13) [76]. 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]. similar studies have not yet been carried out in patients with severe sepsis or shock. 27 of 196. However. Cefotaxime was compared to cefazolin plus tobramycin in a study of 47 patients with Gramnegative bacteremia. However. 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 fact that monotherapy with carbapenem.e. Recommendation Fluoroquinolones have been shown to be highly effective for the treatment of documented Gram-negative bloodstream infections. ticarcillin-clavulanate. However. 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. or imipenem. There is undoubtedly a need for large. Rationale Fluoroquinolones are effective therapy for bloodstream infections caused by enteric Gram-negative bacteria [80. such as levofloxacin. It has been shown to be as efficacious as. and moxifloxacin show enhanced in vitro activities against Gram-positive bacteria. especially as first-generation fluoroquinolones. Capillary leak syndrome and multiorgan dysfunction are much more frequent in patients with severe sepsis or septic shock than in neutropenic cancer patients. including Enterobacteriaceae and most Pseudomonas aeruginosa. Overall. as it is devoid of activity against Gram-positive bacteria. grade E.or fourth-generation cephalosporins or ureidopenicillins plus b-lactamase inhibitors (i. ceftazidime. Such conditions are likely to influence both the volume of distribution and metabolism of the antibiotics.. only a small number have been conducted in patients with severe sepsis. and patients were then switched to oral therapy at the discretion of the investigator. Limited data are available to evaluate the role of fluoroquinolone antibiotics as a single agent for the treatment of patients with severe sepsis. such as norfloxacin and ciprofloxacin. 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]. Furthermore. Moreover. Other studies are needed to assess the role of fluoroquinolones in this setting. It has no relevant activity against Gram-positive and anaerobic bacteria. many of these studies included fewer than 200 patients. In a multicenter study 157 ICU patients with Gram-negative bacillary infections (78 pneumonias. third. prospective.. or imipenem) given either alone or in combination with an aminoglycoside in a subset of patients (i. 28 urinary tract infections.01) [79]. trovafloxacin. 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. ceftazidime. critically ill septic patients differ markedly from neutropenic cancer patients.S 41 of Gram-negative bacteria. A prospective randomized study investigated the role of aztreonam as empirical therapy of severe sepsis or septic shock caused by Gram-negative 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. clinical response was achieved in 138 of 166 patients (83 %) treated with ciprofloxacin monotherapy and in 74 of 87 (85 %) treated with aztreonam. gatifloxacin. data are lacking to support their use as single-agent treatment of sepsis. aztreonam monotherapy should not be used in patients with severe sepsis or septic shock. but less nephrotoxic than aminoglycosides in patients with severe Gram-negative infections [78]. However. Comments The data suggest that monotherapy is a safe alternative to combination therapy for the empirical treatment of critically ill septic patients. Aztreonam has been used successfully for the treatment of patients with Gram-negative bacteremia [77]. The efficacy of ciprofloxacin monotherapy was compared with that of several b-lactams (aztreonam. 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]. compared to the wealth of studies performed in febrile neutropenic cancer patients. have limited activity against Grampositive bacteria. but demonstration of activity awaits publication of the results of ongoing studies. this study found that superinfections with Enterococcus faecalis were more frequent in patients treated with aztreonam than in those treated with aminoglycosides. These studies thus suggested that aztreonam is an effective treatment of documented Gram-negative infections. randomized trials to assess .e. However. Ciprofloxacin treatment was given intravenously for a minimum of 2±3 days. 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. However. and their statistical power is therefore limited. ticarcillin-clavulanate. especially as first-generation fluoroquinolones display suboptimal activities against Gram-positive bacteria. However. 81] and therefore are an excellent alternative to blactam antibiotics for the treatment of patients with documented Gram-negative sepsis. resistant strains are selected fairly rapidly. Newer fluoroquinolones. which may result in altered pharmacokinetics and ultimately may affect drug efficacy and toxicity.

or Enterobacter species.. 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]. especially in critically ill septic patients. grade C. 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.34). p = 0. Aminoglycoside-containing regimens have been shown repeatedly to increase the incidence of nephrotoxicity and/or ototoxicity. including bacteremias. netilmicin. Clinical success rates in the intent-to-treat analysis were 65 % (123 of 188) and 70 % (132 of 188). 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. A constant finding in all these studies was the high incidence of . who are already at high risk of developing multiple organ dysfunction.S 42 the efficacy and toxicity of any new antibiotic in patients with severe sepsis and septic shock.47). Of the patients in the cefpirome group 62 % received monotherapy and of those the ceftazidime group 63 %. genitourinary tract infections. 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. In a prospective. Whether up-front empirical therapy should comprise a specific anti-Gram-positive agent is discussed below. Monotherapy should not be regarded as a universal panacea to be used indiscriminately. Favorable clinical response rates were 77 % (30 of 39) and 78 % (25 of 32). 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]. 176 patients were treated with cefpirome and 50 with ceftazidime. respectively. and amikacin) have been shown to be equally effective as empirical monotherapy of Gram-negative sepsis. third. Serratia. Lastly. Both aminoglycosides were accompanied with a high rate of serious adverse events. as antibiotics such as extended-spectrum penicillins. double-blind study. 45 patients with pneumonias or bacteremias were randomized to receive either imipenem or ceftazi- 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. A favorable clinical response was observed in 30 of 34 patients treated with netilmicin (88 %) and in 26 of 33 treated with amikacin (79 %. amikacin or gentamicin was used to treat 174 patients with suspected severe Gram-negative infections [83]. Despite a lack of clearcut advantage. A subsequent randomized multicenter study treated 372 patients with severe sepsis and suspected bacteremias empirically with cefpirome or with ceftazidime [86]. aminoglycoside-induced nephrotoxicity and ototoxicity. gentamicin. 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. respectively). In the late 1970s and early 1980s several studies compared the efficacy and safety of various aminoglycosides.e. Rationale Four studies have compared the efficacy and safety of a third-generation cephalosporin to that of a fourth-generation cephalosporin or a carbapenem. respectively. The study protocol allowed the addition of metronidazole. tobramycin. Today aminoglycosides should not be used as single-agent empirical therapy of severe sepsis.16. an aminoglycoside. but the difference was not statistically significant (p = 0. the various aminoglycosides (i. Furthermore. A satisfactory clinical response was found in 131 of 176 (74 %) cefpirome recipients and in 34 of 50 (68 %) ceftazidime recipients (p = 0.42 and 0. or carbapenems have a broader spectrum of activity and are less toxic than aminoglycosides. or a glycopeptide antibiotic whenever indicated. Recommendation Third-generation and fourth-generation cephalosporins and carbapenem antibiotics are equally effective as empirical therapy in patients with severe sepsis. 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.or fourth-generation cephalosporins. These serious adverse events are a major concern. 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. and pneumonias [84]. Netilmicin and amikacin were used to treat 80 patients with severe sepsis due to Gram-negative bacteria. Overall. These two studies showed that cefpirome and ceftazidime are equally effective for the treatment of patients with severe sepsis.

96]. Clinical manifestations of candidiasis are usually not specific. Rationale In recent years many institutions have experienced a major change in the cause of bacterial infections occurring in ICU patients with sepsis.. it is rarely. in whom viridans streptococci and coagulase-negative staphylococci are a frequent cause of infection [7]. Recommendation The indiscriminate use of vancomycin or teicoplanin for presumed Gram-positive infections in patients with severe sepsis and septic shock should be avoided. A recent survey of bloodstream infections found ICUs to have the highest incidence of candidemia. it is unclear whether all these fungal isolates were the causal agent of infections rather than colonizing micro-organisms. especially when vancomycin is given in combination with an aminoglycoside [89] or other nephrotoxic agent. Although some studies have suggested that the empirical use of vancomycin or teicoplanin at the initiation of empirical therapy is preferable. While Gram-negative bacteria predominated until the middle 1980s.and fourth-generation cephalosporins and carbapenem antibiotics are equally effective as empirical therapy in patients with severe sepsis. appropriate to use vancomycin alone as empirical therapy since most cases require additional Gram-negative coverage. aureus and methicillin-resistant coagulase-negative staphylococci are responsible for a majority of staphylococcal infections in some institutions. 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. All recent studies have been performed in neutropenic cancer patients. if ever. Are antifungal agents indicated as empirical therapy of patients with severe sepsis or septic shock? Answer: no. pneumoniae is also increasing in many areas of the world. 94. Controversy still exists as to the need for empirical specific anti-Gram-positive therapy at the onset of fever in neutropenic cancer patients [90. and standard culture techniques and tests for detection of Candida antigens or metabolites lack sensitivity. others have yielded data that do not support that concept. 91. However. Prospective studies are ongoing to further address that question. 92]. 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. such as fluconazole. 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]. 1B). no study has prospectively examined the role of glycopeptide antibiotics in the management of nonneutropenic patients with severe sepsis. accounting for 45 % of all episodes of fungemia [97]. at least until microbiological results are available. Glycopeptides are appropriate in severely ill patients with catheter-related infections or in centers in which methicillin-resistant staphylococci predominate. recent epidemiological studies and multicenter trials have shown that fungi account for only 5 % of all cases of severe sepsis or septic shock (Fig.33) [88]. 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. Moreover. Grampositive bacteria now account for approximately onehalf of the infections occurring in patients with severe sepsis and septic shock [20]. Finally.e. Despite limited statistical power due to the small number of patients enrolled. To our knowledge. Recommendation Antifungal agents. 95. should not be used on a routine basis as empirical therapy in patients with severe sepsis and septic shock. Are there clinical conditions justifying the use of empirical anti-Gram-positive therapy in patients with severe sepsis? Answer: yes. Does this epidemiological context justify the empirical use of glycopeptide antibiotics (i.S 43 dime therapy. grade E. A favorable clinical response was observed in 17 of 21 (81 %) patients receiving ceftazidime and in 16 of 24 (67 %) receiving imipenem (p = 0. The frequency of penicillin-resistant S. 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. methicillin-resistant S. However. grade E. empirical vancomycin therapy should also be rapidly discontinued in patients in whom Gram-positive infections has been ruled out. these four studies suggest that third. To further reduce the risk of the emergence of vancomycin-resistant staphylococci or enterococci. which would not justify the use of antifungal therapy on a routine ba- .

Fluconazole was found to be as effective as amphotericin B in 90 ICU patients with cancer and systemic Candida infections (i.S 44 sis. Mortality at day 30 was not significantly different in patients treated with amphotericin B and in those treated with fluconazole (31 % vs.6 mg/kg per day). glabrata is relatively resistant to fluconazole.82) and mortality at day 14 (13 of 50. One study of 65 patients with fungemia due to C. This work was supported by grants from the Swiss National Science Foundation to T. than in those who did not. 32 of 45. Since Candida infections from species other than C. P.006). 71 %. if the patient has been treated previously with fluconazole. Recommendation Fluconazole is as effective as and less toxic than amphotericin B for the treatment of candidemia in nonneutropenic patients. Whether higher daily doses of fluconazole would be more effective is unclear. 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. (32-49129. pneumonia or peritonitis. albicans with reduced susceptibility to azoles are more commonly seen in patients who have received previous antifungal therapy.. Rationale A recent study has shown that Candida is the fourth most frequent cause of bloodstream infections [99]. Infections caused by Candida strains other than C. A dose of 400 mg/d has been used in most fluconazole studies. 11 of 53. and chills. Prospective randomized trials are needed to address these issues. Are azoles as effective as amphotericin B for the treatment of patients with candidemia? Answer: yes.69) were comparable in the two treatment groups [101]. 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. 73 % vs. and to Prof. Seven comparative studies compared the efficacy of fluconazole and amphotericin B for the treatment of candidemia. is recipient of a career award from the Swiss National Science Foundation (32-48916.96). In all studies there were fewer adverse events.6). 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. 57 % vs. is recipient of a career award from the Bristol-Myers Squibb Foundation. p = 0. . However. hypokalemia. bloodstream infections. Whether 5-fluorocytosine should be combined with amphotericin B in these patients is debatable. Clinical success rate (24 of 42. 21 %. p = 0. one-half of the experts would use a dose of 800 mg fluconazole while the other one-half would use amphotericin B [48]. grade A. Of note. C. T. fever. Another randomized study treated 50 patients with fluconazole and 53 with amphotericin B. albicans are increasing. However.8) [102].96).001 and p = 0. Jonathan Cohen for critical reading of the manuscript. 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. along with the resistance to azoles. Fluconazole was as effective as amphotericin B (success rate were 72 % and 79 %. 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]. The efficacy and safety of fluconazole was compared to that of amphotercin B for the treatment of disseminated fungal sepsis in neonates [103]. p = 0. Many investigators consider amphothericin B the agent of choice to treat unstable patients with candidemia [48]. Between one-fourth and one-half of all episodes of candidemia occur in ICUs. C. 26 % vs. Acknowledgements We are grateful to Dr. Most of these patients had catheter-related candidemia. with fluconazole than with amphotericin B. p = 0. 27 %. respectively. Case fatality rates were 33 % (4 of 12) in the fluconazole group and 45 % (5 of 11) in the amphotericin B group (p = 0. 62 %. M. clinical response rates: 33 of 45.G.e. and C. C. No data have shown that combining these agents improve outcome of patients with candidemia. respectively. Two smaller studies yielded analogous results. intravenous amphotericin B was given to 227 patients and fluconazole to 67 patients [49]. one should even be more cautious with the use of this class of antifungal agents. these opinions were based primarily on personal experience. including azoles. Jacques Cornuz for assistance in the literature search and statistical analysis. Among the other Candida strains. especially nephrotoxicity. respectively) [100]. prospective observational study of the morbidity and mortality of candidemia. In a large multicenter.5±0. Adverse effects were less frequent in neonates treated with fluconazole than in those who received amphotericin B. in patients who are unstable or deteriorating. 26 of 42. krusei is intrinsically resistant to fluconazole.68). A large multicenter study treated 206 nonneutropenic patients with candidemia with fluconazole (400 mg per day) or with amphotericin B (0.

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