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Cardiac surgery antibiotic prophylaxis and calculated empiric antibiotic therapy Armin Gorski, Khaled Hamouda, Mehmet Özkur, Markus Leistner, Sebastian-Patrick Sommer, Rainer Leyh and Christoph Schimmer Asian Cardiovascular and Thoracic Annals published online 24 July 2014 DOI: 10.1177/0218492314546028 The online version of this article can be found at: http://aan.sagepub.com/content/early/2014/07/23/0218492314546028
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Cardiac surgery antibiotic prophylaxis and calculated empiric antibiotic therapy
Asian Cardiovascular & Thoracic Annals 0(0) 1–7 ß The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492314546028 aan.sagepub.com
¨ zkur, Armin Gorski, Khaled Hamouda, Mehmet O Markus Leistner, Sebastian-Patrick Sommer, Rainer Leyh and Christoph Schimmer
Abstract Background: Ongoing debate exists concerning the optimal choice and duration of antibiotic prophylaxis as well as the reasonable calculated empiric antibiotic therapy for hospital-acquired infections in critically ill cardiac surgery patients. Methods: A nationwide questionnaire was distributed to all German heart surgery centers concerning antibiotic prophylaxis and the calculated empiric antibiotic therapy. Results: The response to the questionnaire was 87.3%. All clinics that responded use antibiotic prophylaxis, 79% perform it not longer than 24 h (single-shot: 23%; 2 doses: 29%; 3 doses: 27%; 4 doses: 13%; and >5 doses: 8%). Cephalosporin was used in 89% of clinics (46% second-generation, 43% first-generation cephalosporin). If sepsis is suspected, the following diagnostics are performed routinely: wound inspection 100%; white blood cell count 100%; radiography 99%; C-reactive protein 97%; microbiological testing of urine 91%, blood 81%, and bronchial secretion 81%; procalcitonin 74%; and echocardiography 75%. The calculated empiric antibiotic therapy (depending on the suspected focus) consists of a multidrug combination with broad-spectrum agents. Conclusion: This survey shows that existing national guidelines and recommendations concerning perioperative antibiotic prophylaxis and calculated empiric antibiotic therapy are well applied in almost all German heart centers.
Keywords Antibiotic prophylaxis, Bacterial infections, Cardiac surgical procedures, Catheters, Indwelling, Drug administration schedule, Surgical wound infection
Introduction Prophylactic intravenous antibiotics should be routinely administered to patients undergoing cardiac surgery.1 However, the optimal choice, dosage, and frequency of perioperative antibiotic prophylaxis in cardiac surgery is controversial. In addition, nosocomial infections after cardiac surgery represent serious complications associated with substantial morbidity, mortality, and economic burden.2–4 Hence there are guidelines concerning antibiotic prophylaxis (duration, antibiotic choice, and calculated empiric antimicrobial therapy in suspected cases of postoperative sepsis). The principles of antibiotic prophylaxis are based on the choice of antimicrobial agent, timing of the first dose, and duration of the prophylactic regimen.1 The majority of published evidence demonstrates that antimicrobial prophylaxis after wound closure is unnecessary,
and most studies comparing single-dose with multipledose prophylaxis have not shown a benefit of additional doses.5 However, there are several reasons why prolonged (24–48 h) prophylactic regimens should be used in cardiac surgery, such as cardiopulmonary bypass and systemic cooling for myocardial protection, invasive devices remaining after surgery, a high risk of bleeding requiring blood transfusion and reexploration, and delayed extubation after surgery. There are few Department of Cardiothoracic and Thoracic Vascular Surgery, University Hospital Wu¨rzburg, Wu¨rzburg, Germany Corresponding author: Christoph Schimmer, MD, Department for Thoracic, Cardiac and Thoracic Vascular Surgery, University Hospital of Wu¨rzburg, Oberdu¨rrbacherstrasse 6, 97080 Wu¨rzburg, Germany. Email: [email protected]
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Asian Cardiovascular & Thoracic Annals 0(0) Table 1. Overview of independent risk factors for nosocomial infection. Author Lola
2
Falagas12
Michalopoulos22
Kollef23
Fowler24
Risk factors
Odds ratio
Diabetes mellitus Duration of mechanical ventilation Presence of complications Readmission to intensive care unit Atrial hypertension Previous vascular surgery Urgent operation Postoperative atrial fibrillation Number of inotropics Transfusion of fresh-frozen plasma Duration of intensive care stay History of immunosuppression Transfusion of >5 units of red blood cells Development of acute renal failure Duration of mechanical ventilation Postoperative empiric antibiotic administration Duration of urinary tract catheterization Female sex Body mass index 30–40 kg m2 Diabetes mellitus Previous myocardial infarction Urgent operative status Hypertension Perfusion time 200–300 min Placement of an intraaortic balloon pump
5.9 1.3 18.6 8.5 51.9 9.5 8.4 6.2 4.3 2.1 1.0 3.6 21.2 49.9 1.2 1.6 1.1 2.1 1.4 1.7 1.4 1.2 1.3 2.0 1.5
data on the pharmacokinetics of antibiotics during cardiopulmonary bypass, therefore, dosing regimens are often based on historical practice.7 Besides these results, many other reports have noted that increasing the duration of antibiotic prophylaxis in cardiac surgery patients did not result in a significant decrease in surgical site infections.8–11 Concerning the international guidelines for antibiotic prophylaxis, there are heterogeneous data. There is no recommendation of singledose administration or for regimen longer than a 48 h. Most guidelines suggest that prophylaxis for 48 h or less may be appropriate for cardiothoracic procedures (evidence level B, class IIa). The independent risk factors for nosocomial infection in cardiac surgery patients have been described (Table 1).2,12–15 There is wide variation in the incidence of hospital-acquired infections in the postoperative period, ranging from 2.7% to 26.8%.12,16 Table 2 gives an overview of the overall incidence, distribution, and mortality rate of nosocomial infections. In cases of clinically suspected sepsis, diagnosis is sometimes difficult because clinical and laboratory signs of inflammation may be caused not only by infection but also by tissue injury and the systemic inflammatory response syndrome associated with cardiopulmonary bypass.2 The choice of empirical therapy depends on the suspected site of infection, the
setting in which the infection developed (home, nursing home, or hospital), medical history, and local microbial-susceptibility patterns. Inappropriate or delayed antibiotic treatment is associated with increased mortality, thus intravenous antibiotic therapy should be started as early as possible and cover all likely pathogens.17 Proper microbiologic work-up is emphasized for knowledge of the local patterns of microbiology and drug susceptibility. Moreover, this is the optimal basis for deescalation in the individual patient. Structured deescalation concepts and strict limitation of treatment duration should lead to reduced selection pressure.1,3,4 The purpose of this study was to assess the choice and duration of antibiotic prophylaxis as well as the diagnostic tools and calculated empiric antibiotic therapy in clinically suspected sepsis at all German surgical heart centers.
Methods A questionnaire was distributed to all German heart surgery centers. A summary of the various guidelines for antibiotic prophylaxis in cardiac surgery is given in Table 3. The guideline ‘‘Prevention, diagnosis, therapy and follow-up care of sepsis’’ of the German Sepsis Society and the German Interdisciplinary Association
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Table 2. Overview of the overall incidence, distribution, and mortality of nosocomial infections. Nosocomial infection
Lola2
Falagas12
Michalopoulos22
Kollef23
Mastoraki25
Bouza13
Overall incidence Surgical site infection: DSWI SSWI SHS Respiratory tract infection Catheter bloodstream infection Urinary tract infection Intraabdominal infection Septicemia/bacteriemia Others Mortality rate with infection without infection p value
13.95% – 3.3% 26.7% 3.3% 13.3% 16.7% 3.3% 3.4% 30% –
2.7% – 9.5% 19% – 38.1% – 19% – 33.3% –
5.0% 16.8% – – – 42% 22.4% 7.5% – – 11.3%
21.7% 25% – – – 34% – 30% – 11% –
5.4% 54.3% 2.1% – – 10.8% 15.2% 4.3% – 10.8% –
26.8% 8.2% 3.5% – – 57% 10.5% 7% – – 11.5%
25% 3.48% –
23.8% 1.2% 0.001
16.8% 3.5% 0.005
11.5% 3.2% 0.001
– – –
– – –
DSWI ¼ deep sternal wound infection, SSWI ¼ superficial sternal wound infection, SHS ¼ saphenous harvest site.
Table 3. Guidelines for the antibiotic prophylaxis in cardiac surgery. Authority
Antibiotic choice
Duration
STS
First-generation cephalosporin
PEG
ACC/AHA
First or 2ndgeneration cephalosporin First or 2ndgeneration cephalosporin Cephalosporin
ASHP
Cephalosporin
There is evidence indicating that antibiotic prophylaxis of 48-h duration is effective, and some evidence that single-dose prophylaxis or 24-h prophylaxis may be as effective as 48-h prophylaxis, but additional studies are necessary to confirm the effectiveness of prophylaxis 48 h is more effective than a 48-h regimen. The duration is based on the consensus of the expert panel because the data do not delineate the optimal duration of prophylaxis. Prophylaxis for 24 h or less may be appropriate for cardiothoracic procedures. The consensus of the workgroup was that administration of prophylaxis for 5 doses: 8%). Cephalosporin was used in 61/69 (89%) heart centers: a second-generation cephalosporin (cefuroxime) in 46%; and a first-generation cephalosporin (cefazolin) in 43%. Ampicillin was used in 2/69 (2%) centers. Table 3 summarizes the different international guidelines regarding antibiotic prophylaxis for cardiac surgery patients. In cases of
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Table 4. Guideline recommendations of diagnostic tools in cases of clinically suspected sepsis. Suspected site of infection
Recommendation
Surgical site infection
When a surgical site infection is suspected, it is recommended to obtain blood cultures and fresh material (tissue) or wound smears to perform Gram staining (evidence level IIIB) When pneumonia is suspected (fresh infiltrates on chest radiograph, leukocytosis or leukopenia and purulent tracheal secretions), it is recommended to obtain secretions from deep airway segments before imitating antimicrobial therapy (evidence level V) If a central venous catheter is deemed to be the likely source of sepsis, it is recommended that the catheter be removed to establish the diagnosis, and the catheter tip sent for microbiological analysis (evidence level V). Before removing the catheter, it is recommended to collect blood cultures through the indwelling catheter and concomitantly via a peripheral vein to compare the results of culture analysis (evidence level IIB) The gold standard for diagnosis of urinary tract infection is a positive medical history typical symptoms, and urine analysis including a quantitative urine culture and its assessment (evidence level IA) Abdominal ultrasound is recommended as first choice to find an intraabdominal focus. If this is unsuccessful, computed tomography is recommended, which may include the use of contrast. In the case of full-blown unequivocal presentation of acute abdomen, emergency laparotomy/ laparoscopy is recommended (evidence level IC) It is recommended to collect blood cultures as soon as possible before instituting antimicrobial therapy (evidence level IC) when sepsis is clinically suspected or when one or more of the following criteria are met: fever, chills/shivering, hypothermia, leukocytosis, left shift in differential blood count, increase in procalcitonin or C-reactive protein levels, and/or neutropenia (evidence level IIB)
Respiratory tract infection
Catheter bloodstream infection
Urinary tract infection
Intraabdominal infection
In addition
Table 5. Results of the questionnaire and the PEG guideline for calculated empiric antibiotic therapy in septic patients. Suspected focus
CEAT (PEG guideline)
CEAT (results of questionnaire)
SSI
Cephalosporin class IIIb/IV þ clindamycin Acylamino penicillin/BLI clindamycin Fluocinolone class II/III þ cephalosporin class II or carbapenem class I þ clindamycin Cephalosporin class IIIb/IV þ Fluocinolone class II/III or fosfomycin Acylamino penicillin/BLI þ fluocinolone class II/III or fosfomycin Carbapenem class I þ fluocinolone class II/III or fosfomycin Glycopeptide or lipopeptid Acylamino penicillin/BLI or Cephalosporin class IIIa/IV or Carbapenem class I Fluocinolone class II/III Cephalosporin class IIIa/IIIb/IV Acylamino penicillin/BLI Carbapenem class I Acylamino penicillin/BLI Cephalosporin class IIIb/IV þ metronidazole Fluocinolone class II/III þ metronidazole Carbapenem class I
Clindamycin (24%) Vancomycin (12%) Piperacillin/tazobactam (6%) Multidrug combination (58%) Piperacillin/tazobactam (54%) Ciprofloxacin (7%) Carbapenems (6%) Multidrug combination (33%) Vancomycin (39%) Piperacillin/tazobactam (15%) Carbapenems (5%) Multidrug combination (41%) Fluoroquinolones (35%) Trimethoprim (18%) Piperacillin/tazobactam (3%) Multidrug combination (44%) Metronidazole (15%) Erythromycin (10%) Carbapenems (7%) Multidrug combination (68%)
RTI
CBI
UTI
IAI
BLI: beta-lactamase-inhibitor; CBI: catheter bloodstream infection; CEAT: calculated empiric antibiotic therapy; IAI: intraabdominal infection; PEG: Paul-Ehrlich-Gesellschaft; RTI: respiratory tract infection; SSI: surgical site infection; UTI: urinary tract infection.
allergy to penicillin, 32% use clindamycin, 9% use vancomycin, and 7% use erythromycin. Standardized screening of methicillin-resistant Staphylococcus aureus (MRSA) is arranged in 56/69 (82%) German surgical
heart centers, decolonization procedures in all patients in 8/69 (12%), and only in MRSA-positive patients in 54/69 (79%). In cases of clinically suspected sepsis, the following diagnostics are performed routinely: wound
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inspection in 100%; white blood count in 100%; radiography in 99%; C-reactive protein levels in 97%; microbiological testing of urine samples in 91%, of blood culture 81%, and of bronchial secretion 81%; procalcitonin levels in 74%; and echocardiography in 75%. Table 4 presents an overview of the guideline ‘‘Prevention, diagnosis, therapy and follow-up care of sepsis’’ of the German Sepsis Society and the German Interdisciplinary Association of Intensive Care and Emergency Medicine concerning the adequate diagnostic tools in cases of clinically suspected sepsis. Table 5 summarize the answers to the questionnaire concerning the calculated empiric antibiotic therapy in all German surgical heart centers in comparison to the guideline ‘‘Prevention, diagnosis, therapy and follow-up care of sepsis’’ of the German Sepsis Society and the German Interdisciplinary Association of Intensive Care and Emergency Medicine concerning the calculated empiric antibiotic therapy in cases of clinically suspected sepsis. From this nationwide survey, it was found that 87.3% of clinics replied to the questionnaire, 100% of these German heart centers use a perioperative antibiotic prophylaxis with a first or second generation cephalosporin, 79% use the routine perioperative antibiotic prophylaxis not longer than 24 h, and almost all German surgical heart centers follow the guidelines for calculated empiric antibiotic therapy of postoperative nosocomial infections, which consists of a multidrug combination with broad-spectrum agents.
Discussion There has been a general move towards using shorter courses of antibiotics for surgical prophylaxis to reduce toxicity, resistant organisms, Clostridium difficile infection, and cost.7 Beckmann and colleagues15 performed a multicenter study, in cooperation with the German Society for Thoracic and Cardiovascular Surgery, the BQS Institute for Quality and Patient Safety, and the National Reference Center for Nosocomial Infection Surveillance, to evaluate current clinical practices in cardiac surgery concerning the prevention and management of sternal wound infections. Similar to our survey, they noted that perioperative antibiotic prophylaxis application periods range from an intraoperative single shot to more than 3 days of treatment. Furthermore, 87% used a first- or second-generation cephalosporin.18 These results are in accordance with the data of our survey. Second-generation cephalosporins have several advantages over other antibiotic choices. They provide broad-spectrum coverage targeting both Gram-positive and Gram-negative organisms, with good tissue penetration. Furthermore, they have a good safety profile with minimal side effects, can be tolerated by penicillin-allergic patients, and have a
lower cost. However, a disadvantage of cephalosporins is the well-established association with Clostridium difficile.19 Several studies described a trend towards prescribing more second-generation cephalosporins because they are more effective than first-generation cephalosporins in cardiac surgery.9,20 Also, the Paul-Ehrlich-Gesellschaft guideline recommends a first- or second-generation cephalosporin as antibiotic prophylaxis in patients undergoing cardiac surgery.3 Many studies have investigated the optimal duration of perioperative antibiotic prophylaxis in patients undergoing cardiac surgery.5,8–11,20,21 It is generally accepted that short-term perioperative antibiotic prophylaxis is as efficacious in preventing postoperative complications as longer-term prophylaxis, but the optimal duration of antibiotic prophylaxis in cardiac surgery is controversial.10 The recommendation from the Paul-Ehrlich-Gesellschaft guideline is based on the consensus of the expert panel because the data do not delineate the optimal duration of prophylaxis. The panel suggested prophylaxis for 24 h or less as appropriate for cardiothoracic procedures (evidence level of IA).3 Even the 2011 American College of Cardiology Foundation/American Heart Association guideline for coronary artery bypass surgery only gives recommendations for preoperative antibiotic prophylaxis, with further intraoperative doses for prolonged surgery.6,7 Nooyen and colleagues9 noted in a prospective randomized comparison study that a single dose of cefuroxime is as effective as a 3-day course in preventing wound infection (sternum: p ¼ 0.35; leg donor site: p ¼ 0.41).9 Bucknell and colleagues11 also showed that single-dose antimicrobial prophylaxis (cefazolin) is as effective as a 48-h regimen. On the other hand, Tamayo and colleagues18 found in a randomized prospective clinical study including 838 adult patients that single-dose cefazolin is associated with a higher surgical site infection rate than a 24-h multiple-dose cefazolin regimen (8.3% vs 3.6%; p ¼ 0.004). Mertz and colleagues10 conducted a systematic review and meta-analysis of the risk of sternal surgical site infections between short-term (>24 h) and longer duration of antibiotic prophylaxis in adult patients undergoing open heart surgery. The authors concluded that antibiotic prophylaxis of >24 h may be more efficacious in preventing sternal surgical site infections compared to shorter regimens. The findings are limited however by the heterogeneity of antibiotic regimens used and the risk of bias in the published studies.10 Lador and colleagues17 also reported, in a systemic review of randomized controlled trials (n ¼ 23), that evidence supports a possible advantage of prophylaxis prolongation up to 48 h postoperatively, but there were no differences between 48 h versus longer regimes for all outcomes. However, the authors indicated that prolonging
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prophylaxis may induce resistant bacteria that may affect the individual patient and surrounding patients. This was not usually assessed in existing trials.20 Gupta and colleagues19 compared 235 adult patients undergoing elective cardiac surgery in a randomized doubleblind study; 2 groups received prophylactic antibiotic therapy for either 48 h or 72 h. The results showed that 48-h prophylactic antibiotic therapy is at least as effective as a 72-h regimen in relation to surgical site infection. Summarizing the data of the international literature, the use of cephalosporins is reasonable for prophylaxis for cardiac surgery for 24 h but not for longer than 48 h.7 The Surgical Infection Prevention Guideline Writers Workgroup5 and other authors stated that for patients with a serious allergy or adverse reaction to b-lactams, vancomycin is appropriate, and clindamycin may be an acceptable alternative.3,4,6,7,16,19,20,23 Concerning MRSA screening and decolonization protocols, the results from our survey show nearly the same data as those from the Beckmann trial (MRSA screening in 81.5%, decolonization procedures in 7.4% of all patients and 85.2% of MRSA-positive patients).18 Bode and colleagues20 showed in a randomized double-blind placebo-controlled multicenter trial that the number of surgical site Staphylococcus aureus infections acquired in the hospital can be reduced by rapid screening and decolonizing of nasal carriers on admission. On the other hand, treating all patients with mupirocin carriers a potential risk of increasing antibiotic resistance, which has cost and public health implications in the longer term. The diagnosis of postoperative infection is sometimes difficult because clinical and laboratory signs of inflammation may be caused not only by infection but also by tissue injury, and mainly by the systemic inflammatory response syndrome associated with cardiopulmonary bypass.2 Furthermore, interpretation of microbiological findings in critically ill patients is difficult because often microorganisms are identified that satisfy merely the definition of colonization.3 Therefore, the value of the different diagnostic tools in cardiac surgery patients with clinically suspected sepsis remains unclear. Many studies examined the rate and impact of nosocomial infections on patient outcomes following cardiac surgery.2,12–16,23,25 Michalopoulos and colleagues22 analyzed 2122 adult patients who underwent open heart surgery with the use of extracorporal circulation, and identified a rate of nosocomial infection of 5.0% and a mortality rate of 16.8% among patients with infection. Falagas and colleagues12 focused on the effect of off-pump coronary artery bypass and evaluated an infection rate of 2.7%. To decrease the overall high rates of mortality in patients with sepsis, the Surviving Sepsis Campaign
developed evidence-based guidelines for management of sepsis. The working group demonstrated that the use of a multifaceted performance improvement initiative was successful in changing sepsis treatment behavior, as demonstrated by a significant increase in compliance with sepsis performance measures (from 18.4% to 36.1%, p ¼ 0.008). This was associated with a significant reduction in hospital mortality over the duration of a 2-year study (from 37% to 30.8%, p ¼ 0.001).25 In 2010, the German Sepsis Society in collaboration with 17 German medical scientific societies published the 1st revision of the S2k guideline: ‘‘Prevention, diagnosis, therapy and follow-up care of sepsis’’. This guideline provides state-of-the-art information on the effective and appropriate medical care of critically ill patients with severe sepsis or septic shock.3 Nosocomial pneumonia is a frequent complication of hospital care. Most data relate to ventilator-associated pneumonia. However, infections on general wards are also increasing. A central issue is infections with multidrug-resistant pathogens which are difficult to treat, particularly in the empirical setting, potentially leading to inappropriate use of antimicrobial therapy.16 Michalopoulos and colleagues22 and Kollef and colleagues23 found in a prospective case-control study of cardiac surgery patients that the majority of nosocomial infections were respiratory tract infections (45.7% and 34%, respectively). Ventilator-associated pneumonia must be differentiated from pneumonia that requires ventilation assistance.3 Data regarding ventilator-associated pneumonia in patients undergoing cardiac surgery are scare, and usually come from single institutions.16 The proportion of nosocomial pneumonia in the overall postoperative infection rate ranges from 10.8% to 57%.16,23 Surgical site infections are the second most common cause of nosocomial infections.5 Fowler and colleagues24 analyzed 331,429 coronary artery bypass cases and identified a rate of major surgical site infection (defined as superficial and deep sternal wound infections and venous graft harvest site) in 3.51% and a mortality rate of 17.3% among patients with infection. The limitation of our study is the fact that only 87.3% of all German heart surgical centers participated in the survey. Therefore, the results might be biased. Nevertheless, the principal conclusion of this study is that all German heart surgical centers prescribe prophylactic antibiotics in the context of cardiac surgery as well as early adequate antimicrobial therapy in cases of hospital-acquired infection; 79% of all German heart centers use routine perioperative antibiotic prophylaxis with a cephalosporin for no longer than 24 h. Usually, the calculated empiric antibiotic therapy in cases of clinically suspected sepsis consists of a multidrug combination with broad-spectrum agents.
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Funding This research received no specific grant from any funding agency in the public, commerical, or not-for-profit sectors.
Conflict of interest statement None declared.
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11. Bucknell SJ, Mohajeri M, Low J, McDonald M and Hill DG. Single- versus multiple-dose antibiotics prophylaxis for cardiac surgery. Aust NZ J Surg 2000; 70: 409–411. 12. Falagas M, Rosmarakis ES, Rellos K, Michalopoulos A, Samonis G and Prapas SN. Microbiologically documented nosocomial infections after coronary artery bypass surgery without cardiopulmonary bypass. J Thorac Cardiovasc Surg 2006; 132: 481–490. 13. Bouza E, Hortal J, Munoz P, et al. Postoperative infections after major heart surgery and prevention of ventilator-associated pneumonia: a one-day European prevalence study (ESGNI-008). J Hosp Infect 2006; 64: 224–230. 14. Angus DC and van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013; 369: 840–851. 15. Beckmann A, Doebler K, Schaefer E, Koetting J, Gastmeier P and Graf K. Sternal surgical site infection prevention—is there any room for improvement? Eur J Cardiothorac Surg 2011; 40: 347–351. 16. Inkster T. Antibiotic prophylaxis for cardiac surgery: a shift away from traditional cephalosporins? J Cardiothorac Vasc Anesth 2009; 23: 933–935. 17. Lador A, Nasir H, Mansur N, et al. Antibiotic prophylaxis in cardiac surgery: systematic review and meta-analysis. J Antimicrob Chemother 2012; 67: 541–550. 18. Tamayo E, Gualis J and Flo´rez S. Comparative study of single-dose and 24-hour multiple-dose antibiotic prophylaxis for cardiac surgery. J Thorac Cardiovasc Surg 2008; 136: 1522–1527. 19. Gupta A, Hote MP, Choudhury M, Kapil A and Bisoi AK. Comparison of 48 h and 72 h of prophylactic antibiotic therapy in adult cardiac surgery: a randomized double blind controlled trial. J Antimicrob Chemother 2010; 65: 1036–1041. 20. Bode LG, Kluytmans JA, Wertheim HF, et al. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N Engl J Med 2010; 362: 9–17. 21. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med 2010; 38: 367–374. 22. Michalopoulos A, Geroulanos S, Rosmarakis ES and Falagas ME. Frequency, characteristics, and predictors of microbiologically documented nosocomial infections after cardiac surgery. Eur J Cardiothorac Surg 2006; 29: 456–460. 23. Kollef MH, Sharpless L, Vlasnik J, Pasque C, Murphy D and Fraser VJ. The impact of nosocomial infections on patient outcomes following cardiac surgery. Chest 1997; 112: 666–675. 24. Fowler VG Jr, O’Brien SM, Muhlbaier LH, Corey GR, Ferguson TB and Peterson ED. Clinical predictors of major infections after cardiac surgery. Circulation 2005; 112: 358–365. 25. Mastoraki S, Michalopoulos A, Kriaras I and Geroulanos S. Cefuroxime as antibiotic prophylaxis in coronary artery bypass grafting surgery. Interact Cardiovasc Thorac Surg 2007; 6: 442–446.
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Cardiac surgery antibiotic prophylaxis and calculated empiric antibiotic therapy Armin Gorski, Khaled Hamouda, Mehmet Özkur, Markus Leistner, Sebastian-Patrick Sommer, Rainer Leyh and Christoph Schimmer Asian Cardiovascular and Thoracic Annals published online 24 July 2014 DOI: 10.1177/0218492314546028 The online version of this article can be found at: http://aan.sagepub.com/content/early/2014/07/23/0218492314546028
Published by: http://www.sagepublications.com
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The Asian Society for Cardiovascular Surgery
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Original Article
Cardiac surgery antibiotic prophylaxis and calculated empiric antibiotic therapy
Asian Cardiovascular & Thoracic Annals 0(0) 1–7 ß The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0218492314546028 aan.sagepub.com
¨ zkur, Armin Gorski, Khaled Hamouda, Mehmet O Markus Leistner, Sebastian-Patrick Sommer, Rainer Leyh and Christoph Schimmer
Abstract Background: Ongoing debate exists concerning the optimal choice and duration of antibiotic prophylaxis as well as the reasonable calculated empiric antibiotic therapy for hospital-acquired infections in critically ill cardiac surgery patients. Methods: A nationwide questionnaire was distributed to all German heart surgery centers concerning antibiotic prophylaxis and the calculated empiric antibiotic therapy. Results: The response to the questionnaire was 87.3%. All clinics that responded use antibiotic prophylaxis, 79% perform it not longer than 24 h (single-shot: 23%; 2 doses: 29%; 3 doses: 27%; 4 doses: 13%; and >5 doses: 8%). Cephalosporin was used in 89% of clinics (46% second-generation, 43% first-generation cephalosporin). If sepsis is suspected, the following diagnostics are performed routinely: wound inspection 100%; white blood cell count 100%; radiography 99%; C-reactive protein 97%; microbiological testing of urine 91%, blood 81%, and bronchial secretion 81%; procalcitonin 74%; and echocardiography 75%. The calculated empiric antibiotic therapy (depending on the suspected focus) consists of a multidrug combination with broad-spectrum agents. Conclusion: This survey shows that existing national guidelines and recommendations concerning perioperative antibiotic prophylaxis and calculated empiric antibiotic therapy are well applied in almost all German heart centers.
Keywords Antibiotic prophylaxis, Bacterial infections, Cardiac surgical procedures, Catheters, Indwelling, Drug administration schedule, Surgical wound infection
Introduction Prophylactic intravenous antibiotics should be routinely administered to patients undergoing cardiac surgery.1 However, the optimal choice, dosage, and frequency of perioperative antibiotic prophylaxis in cardiac surgery is controversial. In addition, nosocomial infections after cardiac surgery represent serious complications associated with substantial morbidity, mortality, and economic burden.2–4 Hence there are guidelines concerning antibiotic prophylaxis (duration, antibiotic choice, and calculated empiric antimicrobial therapy in suspected cases of postoperative sepsis). The principles of antibiotic prophylaxis are based on the choice of antimicrobial agent, timing of the first dose, and duration of the prophylactic regimen.1 The majority of published evidence demonstrates that antimicrobial prophylaxis after wound closure is unnecessary,
and most studies comparing single-dose with multipledose prophylaxis have not shown a benefit of additional doses.5 However, there are several reasons why prolonged (24–48 h) prophylactic regimens should be used in cardiac surgery, such as cardiopulmonary bypass and systemic cooling for myocardial protection, invasive devices remaining after surgery, a high risk of bleeding requiring blood transfusion and reexploration, and delayed extubation after surgery. There are few Department of Cardiothoracic and Thoracic Vascular Surgery, University Hospital Wu¨rzburg, Wu¨rzburg, Germany Corresponding author: Christoph Schimmer, MD, Department for Thoracic, Cardiac and Thoracic Vascular Surgery, University Hospital of Wu¨rzburg, Oberdu¨rrbacherstrasse 6, 97080 Wu¨rzburg, Germany. Email: [email protected]
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Asian Cardiovascular & Thoracic Annals 0(0) Table 1. Overview of independent risk factors for nosocomial infection. Author Lola
2
Falagas12
Michalopoulos22
Kollef23
Fowler24
Risk factors
Odds ratio
Diabetes mellitus Duration of mechanical ventilation Presence of complications Readmission to intensive care unit Atrial hypertension Previous vascular surgery Urgent operation Postoperative atrial fibrillation Number of inotropics Transfusion of fresh-frozen plasma Duration of intensive care stay History of immunosuppression Transfusion of >5 units of red blood cells Development of acute renal failure Duration of mechanical ventilation Postoperative empiric antibiotic administration Duration of urinary tract catheterization Female sex Body mass index 30–40 kg m2 Diabetes mellitus Previous myocardial infarction Urgent operative status Hypertension Perfusion time 200–300 min Placement of an intraaortic balloon pump
5.9 1.3 18.6 8.5 51.9 9.5 8.4 6.2 4.3 2.1 1.0 3.6 21.2 49.9 1.2 1.6 1.1 2.1 1.4 1.7 1.4 1.2 1.3 2.0 1.5
data on the pharmacokinetics of antibiotics during cardiopulmonary bypass, therefore, dosing regimens are often based on historical practice.7 Besides these results, many other reports have noted that increasing the duration of antibiotic prophylaxis in cardiac surgery patients did not result in a significant decrease in surgical site infections.8–11 Concerning the international guidelines for antibiotic prophylaxis, there are heterogeneous data. There is no recommendation of singledose administration or for regimen longer than a 48 h. Most guidelines suggest that prophylaxis for 48 h or less may be appropriate for cardiothoracic procedures (evidence level B, class IIa). The independent risk factors for nosocomial infection in cardiac surgery patients have been described (Table 1).2,12–15 There is wide variation in the incidence of hospital-acquired infections in the postoperative period, ranging from 2.7% to 26.8%.12,16 Table 2 gives an overview of the overall incidence, distribution, and mortality rate of nosocomial infections. In cases of clinically suspected sepsis, diagnosis is sometimes difficult because clinical and laboratory signs of inflammation may be caused not only by infection but also by tissue injury and the systemic inflammatory response syndrome associated with cardiopulmonary bypass.2 The choice of empirical therapy depends on the suspected site of infection, the
setting in which the infection developed (home, nursing home, or hospital), medical history, and local microbial-susceptibility patterns. Inappropriate or delayed antibiotic treatment is associated with increased mortality, thus intravenous antibiotic therapy should be started as early as possible and cover all likely pathogens.17 Proper microbiologic work-up is emphasized for knowledge of the local patterns of microbiology and drug susceptibility. Moreover, this is the optimal basis for deescalation in the individual patient. Structured deescalation concepts and strict limitation of treatment duration should lead to reduced selection pressure.1,3,4 The purpose of this study was to assess the choice and duration of antibiotic prophylaxis as well as the diagnostic tools and calculated empiric antibiotic therapy in clinically suspected sepsis at all German surgical heart centers.
Methods A questionnaire was distributed to all German heart surgery centers. A summary of the various guidelines for antibiotic prophylaxis in cardiac surgery is given in Table 3. The guideline ‘‘Prevention, diagnosis, therapy and follow-up care of sepsis’’ of the German Sepsis Society and the German Interdisciplinary Association
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Table 2. Overview of the overall incidence, distribution, and mortality of nosocomial infections. Nosocomial infection
Lola2
Falagas12
Michalopoulos22
Kollef23
Mastoraki25
Bouza13
Overall incidence Surgical site infection: DSWI SSWI SHS Respiratory tract infection Catheter bloodstream infection Urinary tract infection Intraabdominal infection Septicemia/bacteriemia Others Mortality rate with infection without infection p value
13.95% – 3.3% 26.7% 3.3% 13.3% 16.7% 3.3% 3.4% 30% –
2.7% – 9.5% 19% – 38.1% – 19% – 33.3% –
5.0% 16.8% – – – 42% 22.4% 7.5% – – 11.3%
21.7% 25% – – – 34% – 30% – 11% –
5.4% 54.3% 2.1% – – 10.8% 15.2% 4.3% – 10.8% –
26.8% 8.2% 3.5% – – 57% 10.5% 7% – – 11.5%
25% 3.48% –
23.8% 1.2% 0.001
16.8% 3.5% 0.005
11.5% 3.2% 0.001
– – –
– – –
DSWI ¼ deep sternal wound infection, SSWI ¼ superficial sternal wound infection, SHS ¼ saphenous harvest site.
Table 3. Guidelines for the antibiotic prophylaxis in cardiac surgery. Authority
Antibiotic choice
Duration
STS
First-generation cephalosporin
PEG
ACC/AHA
First or 2ndgeneration cephalosporin First or 2ndgeneration cephalosporin Cephalosporin
ASHP
Cephalosporin
There is evidence indicating that antibiotic prophylaxis of 48-h duration is effective, and some evidence that single-dose prophylaxis or 24-h prophylaxis may be as effective as 48-h prophylaxis, but additional studies are necessary to confirm the effectiveness of prophylaxis 48 h is more effective than a 48-h regimen. The duration is based on the consensus of the expert panel because the data do not delineate the optimal duration of prophylaxis. Prophylaxis for 24 h or less may be appropriate for cardiothoracic procedures. The consensus of the workgroup was that administration of prophylaxis for 5 doses: 8%). Cephalosporin was used in 61/69 (89%) heart centers: a second-generation cephalosporin (cefuroxime) in 46%; and a first-generation cephalosporin (cefazolin) in 43%. Ampicillin was used in 2/69 (2%) centers. Table 3 summarizes the different international guidelines regarding antibiotic prophylaxis for cardiac surgery patients. In cases of
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Table 4. Guideline recommendations of diagnostic tools in cases of clinically suspected sepsis. Suspected site of infection
Recommendation
Surgical site infection
When a surgical site infection is suspected, it is recommended to obtain blood cultures and fresh material (tissue) or wound smears to perform Gram staining (evidence level IIIB) When pneumonia is suspected (fresh infiltrates on chest radiograph, leukocytosis or leukopenia and purulent tracheal secretions), it is recommended to obtain secretions from deep airway segments before imitating antimicrobial therapy (evidence level V) If a central venous catheter is deemed to be the likely source of sepsis, it is recommended that the catheter be removed to establish the diagnosis, and the catheter tip sent for microbiological analysis (evidence level V). Before removing the catheter, it is recommended to collect blood cultures through the indwelling catheter and concomitantly via a peripheral vein to compare the results of culture analysis (evidence level IIB) The gold standard for diagnosis of urinary tract infection is a positive medical history typical symptoms, and urine analysis including a quantitative urine culture and its assessment (evidence level IA) Abdominal ultrasound is recommended as first choice to find an intraabdominal focus. If this is unsuccessful, computed tomography is recommended, which may include the use of contrast. In the case of full-blown unequivocal presentation of acute abdomen, emergency laparotomy/ laparoscopy is recommended (evidence level IC) It is recommended to collect blood cultures as soon as possible before instituting antimicrobial therapy (evidence level IC) when sepsis is clinically suspected or when one or more of the following criteria are met: fever, chills/shivering, hypothermia, leukocytosis, left shift in differential blood count, increase in procalcitonin or C-reactive protein levels, and/or neutropenia (evidence level IIB)
Respiratory tract infection
Catheter bloodstream infection
Urinary tract infection
Intraabdominal infection
In addition
Table 5. Results of the questionnaire and the PEG guideline for calculated empiric antibiotic therapy in septic patients. Suspected focus
CEAT (PEG guideline)
CEAT (results of questionnaire)
SSI
Cephalosporin class IIIb/IV þ clindamycin Acylamino penicillin/BLI clindamycin Fluocinolone class II/III þ cephalosporin class II or carbapenem class I þ clindamycin Cephalosporin class IIIb/IV þ Fluocinolone class II/III or fosfomycin Acylamino penicillin/BLI þ fluocinolone class II/III or fosfomycin Carbapenem class I þ fluocinolone class II/III or fosfomycin Glycopeptide or lipopeptid Acylamino penicillin/BLI or Cephalosporin class IIIa/IV or Carbapenem class I Fluocinolone class II/III Cephalosporin class IIIa/IIIb/IV Acylamino penicillin/BLI Carbapenem class I Acylamino penicillin/BLI Cephalosporin class IIIb/IV þ metronidazole Fluocinolone class II/III þ metronidazole Carbapenem class I
Clindamycin (24%) Vancomycin (12%) Piperacillin/tazobactam (6%) Multidrug combination (58%) Piperacillin/tazobactam (54%) Ciprofloxacin (7%) Carbapenems (6%) Multidrug combination (33%) Vancomycin (39%) Piperacillin/tazobactam (15%) Carbapenems (5%) Multidrug combination (41%) Fluoroquinolones (35%) Trimethoprim (18%) Piperacillin/tazobactam (3%) Multidrug combination (44%) Metronidazole (15%) Erythromycin (10%) Carbapenems (7%) Multidrug combination (68%)
RTI
CBI
UTI
IAI
BLI: beta-lactamase-inhibitor; CBI: catheter bloodstream infection; CEAT: calculated empiric antibiotic therapy; IAI: intraabdominal infection; PEG: Paul-Ehrlich-Gesellschaft; RTI: respiratory tract infection; SSI: surgical site infection; UTI: urinary tract infection.
allergy to penicillin, 32% use clindamycin, 9% use vancomycin, and 7% use erythromycin. Standardized screening of methicillin-resistant Staphylococcus aureus (MRSA) is arranged in 56/69 (82%) German surgical
heart centers, decolonization procedures in all patients in 8/69 (12%), and only in MRSA-positive patients in 54/69 (79%). In cases of clinically suspected sepsis, the following diagnostics are performed routinely: wound
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inspection in 100%; white blood count in 100%; radiography in 99%; C-reactive protein levels in 97%; microbiological testing of urine samples in 91%, of blood culture 81%, and of bronchial secretion 81%; procalcitonin levels in 74%; and echocardiography in 75%. Table 4 presents an overview of the guideline ‘‘Prevention, diagnosis, therapy and follow-up care of sepsis’’ of the German Sepsis Society and the German Interdisciplinary Association of Intensive Care and Emergency Medicine concerning the adequate diagnostic tools in cases of clinically suspected sepsis. Table 5 summarize the answers to the questionnaire concerning the calculated empiric antibiotic therapy in all German surgical heart centers in comparison to the guideline ‘‘Prevention, diagnosis, therapy and follow-up care of sepsis’’ of the German Sepsis Society and the German Interdisciplinary Association of Intensive Care and Emergency Medicine concerning the calculated empiric antibiotic therapy in cases of clinically suspected sepsis. From this nationwide survey, it was found that 87.3% of clinics replied to the questionnaire, 100% of these German heart centers use a perioperative antibiotic prophylaxis with a first or second generation cephalosporin, 79% use the routine perioperative antibiotic prophylaxis not longer than 24 h, and almost all German surgical heart centers follow the guidelines for calculated empiric antibiotic therapy of postoperative nosocomial infections, which consists of a multidrug combination with broad-spectrum agents.
Discussion There has been a general move towards using shorter courses of antibiotics for surgical prophylaxis to reduce toxicity, resistant organisms, Clostridium difficile infection, and cost.7 Beckmann and colleagues15 performed a multicenter study, in cooperation with the German Society for Thoracic and Cardiovascular Surgery, the BQS Institute for Quality and Patient Safety, and the National Reference Center for Nosocomial Infection Surveillance, to evaluate current clinical practices in cardiac surgery concerning the prevention and management of sternal wound infections. Similar to our survey, they noted that perioperative antibiotic prophylaxis application periods range from an intraoperative single shot to more than 3 days of treatment. Furthermore, 87% used a first- or second-generation cephalosporin.18 These results are in accordance with the data of our survey. Second-generation cephalosporins have several advantages over other antibiotic choices. They provide broad-spectrum coverage targeting both Gram-positive and Gram-negative organisms, with good tissue penetration. Furthermore, they have a good safety profile with minimal side effects, can be tolerated by penicillin-allergic patients, and have a
lower cost. However, a disadvantage of cephalosporins is the well-established association with Clostridium difficile.19 Several studies described a trend towards prescribing more second-generation cephalosporins because they are more effective than first-generation cephalosporins in cardiac surgery.9,20 Also, the Paul-Ehrlich-Gesellschaft guideline recommends a first- or second-generation cephalosporin as antibiotic prophylaxis in patients undergoing cardiac surgery.3 Many studies have investigated the optimal duration of perioperative antibiotic prophylaxis in patients undergoing cardiac surgery.5,8–11,20,21 It is generally accepted that short-term perioperative antibiotic prophylaxis is as efficacious in preventing postoperative complications as longer-term prophylaxis, but the optimal duration of antibiotic prophylaxis in cardiac surgery is controversial.10 The recommendation from the Paul-Ehrlich-Gesellschaft guideline is based on the consensus of the expert panel because the data do not delineate the optimal duration of prophylaxis. The panel suggested prophylaxis for 24 h or less as appropriate for cardiothoracic procedures (evidence level of IA).3 Even the 2011 American College of Cardiology Foundation/American Heart Association guideline for coronary artery bypass surgery only gives recommendations for preoperative antibiotic prophylaxis, with further intraoperative doses for prolonged surgery.6,7 Nooyen and colleagues9 noted in a prospective randomized comparison study that a single dose of cefuroxime is as effective as a 3-day course in preventing wound infection (sternum: p ¼ 0.35; leg donor site: p ¼ 0.41).9 Bucknell and colleagues11 also showed that single-dose antimicrobial prophylaxis (cefazolin) is as effective as a 48-h regimen. On the other hand, Tamayo and colleagues18 found in a randomized prospective clinical study including 838 adult patients that single-dose cefazolin is associated with a higher surgical site infection rate than a 24-h multiple-dose cefazolin regimen (8.3% vs 3.6%; p ¼ 0.004). Mertz and colleagues10 conducted a systematic review and meta-analysis of the risk of sternal surgical site infections between short-term (>24 h) and longer duration of antibiotic prophylaxis in adult patients undergoing open heart surgery. The authors concluded that antibiotic prophylaxis of >24 h may be more efficacious in preventing sternal surgical site infections compared to shorter regimens. The findings are limited however by the heterogeneity of antibiotic regimens used and the risk of bias in the published studies.10 Lador and colleagues17 also reported, in a systemic review of randomized controlled trials (n ¼ 23), that evidence supports a possible advantage of prophylaxis prolongation up to 48 h postoperatively, but there were no differences between 48 h versus longer regimes for all outcomes. However, the authors indicated that prolonging
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prophylaxis may induce resistant bacteria that may affect the individual patient and surrounding patients. This was not usually assessed in existing trials.20 Gupta and colleagues19 compared 235 adult patients undergoing elective cardiac surgery in a randomized doubleblind study; 2 groups received prophylactic antibiotic therapy for either 48 h or 72 h. The results showed that 48-h prophylactic antibiotic therapy is at least as effective as a 72-h regimen in relation to surgical site infection. Summarizing the data of the international literature, the use of cephalosporins is reasonable for prophylaxis for cardiac surgery for 24 h but not for longer than 48 h.7 The Surgical Infection Prevention Guideline Writers Workgroup5 and other authors stated that for patients with a serious allergy or adverse reaction to b-lactams, vancomycin is appropriate, and clindamycin may be an acceptable alternative.3,4,6,7,16,19,20,23 Concerning MRSA screening and decolonization protocols, the results from our survey show nearly the same data as those from the Beckmann trial (MRSA screening in 81.5%, decolonization procedures in 7.4% of all patients and 85.2% of MRSA-positive patients).18 Bode and colleagues20 showed in a randomized double-blind placebo-controlled multicenter trial that the number of surgical site Staphylococcus aureus infections acquired in the hospital can be reduced by rapid screening and decolonizing of nasal carriers on admission. On the other hand, treating all patients with mupirocin carriers a potential risk of increasing antibiotic resistance, which has cost and public health implications in the longer term. The diagnosis of postoperative infection is sometimes difficult because clinical and laboratory signs of inflammation may be caused not only by infection but also by tissue injury, and mainly by the systemic inflammatory response syndrome associated with cardiopulmonary bypass.2 Furthermore, interpretation of microbiological findings in critically ill patients is difficult because often microorganisms are identified that satisfy merely the definition of colonization.3 Therefore, the value of the different diagnostic tools in cardiac surgery patients with clinically suspected sepsis remains unclear. Many studies examined the rate and impact of nosocomial infections on patient outcomes following cardiac surgery.2,12–16,23,25 Michalopoulos and colleagues22 analyzed 2122 adult patients who underwent open heart surgery with the use of extracorporal circulation, and identified a rate of nosocomial infection of 5.0% and a mortality rate of 16.8% among patients with infection. Falagas and colleagues12 focused on the effect of off-pump coronary artery bypass and evaluated an infection rate of 2.7%. To decrease the overall high rates of mortality in patients with sepsis, the Surviving Sepsis Campaign
developed evidence-based guidelines for management of sepsis. The working group demonstrated that the use of a multifaceted performance improvement initiative was successful in changing sepsis treatment behavior, as demonstrated by a significant increase in compliance with sepsis performance measures (from 18.4% to 36.1%, p ¼ 0.008). This was associated with a significant reduction in hospital mortality over the duration of a 2-year study (from 37% to 30.8%, p ¼ 0.001).25 In 2010, the German Sepsis Society in collaboration with 17 German medical scientific societies published the 1st revision of the S2k guideline: ‘‘Prevention, diagnosis, therapy and follow-up care of sepsis’’. This guideline provides state-of-the-art information on the effective and appropriate medical care of critically ill patients with severe sepsis or septic shock.3 Nosocomial pneumonia is a frequent complication of hospital care. Most data relate to ventilator-associated pneumonia. However, infections on general wards are also increasing. A central issue is infections with multidrug-resistant pathogens which are difficult to treat, particularly in the empirical setting, potentially leading to inappropriate use of antimicrobial therapy.16 Michalopoulos and colleagues22 and Kollef and colleagues23 found in a prospective case-control study of cardiac surgery patients that the majority of nosocomial infections were respiratory tract infections (45.7% and 34%, respectively). Ventilator-associated pneumonia must be differentiated from pneumonia that requires ventilation assistance.3 Data regarding ventilator-associated pneumonia in patients undergoing cardiac surgery are scare, and usually come from single institutions.16 The proportion of nosocomial pneumonia in the overall postoperative infection rate ranges from 10.8% to 57%.16,23 Surgical site infections are the second most common cause of nosocomial infections.5 Fowler and colleagues24 analyzed 331,429 coronary artery bypass cases and identified a rate of major surgical site infection (defined as superficial and deep sternal wound infections and venous graft harvest site) in 3.51% and a mortality rate of 17.3% among patients with infection. The limitation of our study is the fact that only 87.3% of all German heart surgical centers participated in the survey. Therefore, the results might be biased. Nevertheless, the principal conclusion of this study is that all German heart surgical centers prescribe prophylactic antibiotics in the context of cardiac surgery as well as early adequate antimicrobial therapy in cases of hospital-acquired infection; 79% of all German heart centers use routine perioperative antibiotic prophylaxis with a cephalosporin for no longer than 24 h. Usually, the calculated empiric antibiotic therapy in cases of clinically suspected sepsis consists of a multidrug combination with broad-spectrum agents.
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Funding This research received no specific grant from any funding agency in the public, commerical, or not-for-profit sectors.
Conflict of interest statement None declared.
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