SURGICAL INFECTIONS Volume 11, Number 6, 2010 Mary Ann Liebert, Inc. DOI: 10.1089/sur.2009.

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Perioperative Use of Antibiotics in Intra-Abdominal Surgical Infections

Apostolos G. Kambaroudis, Savvas Papadopoulos, Michelle Christodoulidou, and Thomas Gerasimidis

Abstract

Background: We created a questionnaire with the aim of evaluating surgeon compliance with the guidelines for antibiotic use in the perioperative period in intra-abdominal surgical infections. We discuss the problems emerging from non-adherence to these guidelines. Methods: In the questionnaire, we tried to correlate the type of intra-abdominal infection with: (1) Time of antibiotic administration commencement; (2) type of antibiotic(s) administered; (c) duration of antibiotic administration; and (4) modication of antibiotic type/duration of administration in the presence of factors increasing the risk of treatment failure. In order to collect and process the data more easily, the patients were divided into four groupsGroup A: Community patients with intra-abdominal surgical infections and simple contamination of the peritoneal cavity according to the Surgical Infection Society (SIS) guidelines; Group B: Community patients with an intra-abdominal surgical infection evolving to secondary peritonitis per SIS guidelines; Group C: Community patients with an intra-abdominal surgical infection with a high risk of surgical site infection; and Group D: Patients with recent hospitalization or nosocomial or postoperative intra-abdominal infection. Results: The questionnaire was sent to the directors of 43 surgical clinics in northern Greece, and 27 answered (63%). In 81.5% of the clinics (median 22; range 1524), depending on the type of infection, empirical antibiotic treatment commenced preoperatively. In Group A, on average, 29.6% of the clinics (median 8; range 516) administer antibiotics for as long as 24 h, and 11.1% (median 3; range 110) use antibiotics not recommended in the SIS guidelines (e.g., third- and fourth-generation cephalosporins, ciprooxacin, imipenem-cilastatin, meropenem, or piperacillin/tazobactam). In Group B, 22.2% of clinics (median 6; range 215) administer antibiotics for three to ve days, and 14.8% (median 4; range 111) use antibiotics outside SIS guidelines. In Group C, 40.7% of clinics (median 11; range 114) administer antibiotics for more than ve days, and 14.8% (median 4; range 1 14) use antibiotics that are outside the SIS guidelines. In Group D, 11.1% of clinics (median 3; range 25) do not cover Enterococcus with the antibiotics administered. Conclusions: There seems to be confusion in determining the situations with simple contamination of the peritoneal cavity, whose treatment requires short-duration antibiotic administration, and in the type of antibiotics administered to various patient groups, elements that lead to prolonged or erroneous administration of antibiotic drugs. Continuous discussion and surgeon training is imperative and may be the best choice to ensure familiarity with antibiotics and their proper use and thus to minimize serious adverse events and treatment failure.

he treatment of intra-abdominal surgical infections includes the reinforcement of the patients general condition, appropriate source control, and complementary antimicrobial therapy. Treatment effects depend on the promptness of diagnosis, the correct timing of the operation, and the effectiveness and soundness of antimicrobial treatment. The perioperative administration of antibiotics is complementary to surgical treatment of intra-abdominal infections,

contributing substantially to the minimizing of complications, morbidity, and death. For a long time, the use of antibiotics was uncontrolled and chaotic. In 1992, the Surgical Infection SocietyEurope (SIS-E), in an effort to reduce the adverse effects of antibiotic abuse, published specic guidelines, which were accepted, among others, by the Hellenic Society of Surgical Infections (HSSI). Unfortunately, despite these guidelines, antibiotic abuse did not abate, resulting in the

Fifth Surgical Clinic of Medical School of Aristotle University of Thessaloniki, Hippokratio Hospital, Hellas, Greece.

535

536 emergence of multi-resistant microbial strains and infections caused by them, which are essentially non-treatable and lifethreatening. As a result, in 2002, the SIS returned to the issue of antibiotic use and published new guidelines, with the necessary amendments required by recent data; and in 2003, the HSSI presented a similar guide [17]. With the aim of evaluating the acceptance and application by surgeons of the guidelines regarding the use of antibiotics in the perioperative period and to discuss the problems arising from noncompliance with these guidelines, we asked the directors of the surgical clinics of northern Greece (Macedonia, Thrace, and Thessaly) to ll out a questionnaire (Table 1). Materials and Methods In a previous roundtable on the treatment of secondary peritonitis that was held during a symposium on surgical infections, it was apparent, from the speakers presentations and the comments of the participants, that there was confusion regarding the usage of antibiotics in intra-abdominal surgical infections and ignorance of the relevant guidelines. After this, and in collaboration with the HSSI, we devised this questionnaire. We tried to correlate the type of intra-abdominal infection with the time antibiotic administration commenced, the type of antibiotic(s) administered, the duration of antibiotic administration, and modication of antibiotic type/ duration of administration in the presence of factors increasing the risk of treatment failure. This questionnaire included an addendum where advanced age (>70 years old), metabolic diseases (diabetes mellitus, renal failure, obesity, cirrhosis, hypoalbuminemia <2 g/dL), immunosuppression (radiation therapy, chemotherapy, corticosteroids), long duration of operation (>3 h), foreign body use (e.g., mesh), tissue ischemia, and abuse of cautery were considered risk factors for surgical site infections (SSIs). Depending on the time of infection treatment and the type of infection and in accordance with the intra-abdominal surgical infection treatment guidelines, we divided the patients into four groups [8,9]: Group A: Community patients with intra-abdominal surgical infections and simple contamination of the peritoneal cavity as described in the SIS guidelines (gastric or duodenal perforation treated within the rst 24 h from symptom onset, intestinal perforationrupture treated within the rst 12 h from symptom onset, acute cholecystitis without gallbladder rupture, acute appendicitis without rupture); Group B: Community patients with intra-abdominal surgical infections evolving to secondary peritonitis per SIS guidelines (gastric or duodenal perforation treated later than 24 h from symptom onset, intestinal perforationrupture treated later than 12 h from symptom onset, acute cholecystitis with gallbladder rupture, acute appendicitis with rupture); Group C: Community patients with intra-abdominal surgical infections at high risk for SSI. Group D: Patients with recent hospitalization or nosocomial or postoperative intra-abdominal infections. During this study, there was continuous communication by telephone with the directors of every clinic that participated in order to conrm proper completion. Additionally, after the data were processed, they were discussed with the participating clinic directors in two special surgical infection symposia.

KAMBAROUDIS ET AL. The data are presented as percentages and medians and ranges, as this format is considered the simplest and easiest to understand. Results Twenty-seven (63%) surgical clinic directors responded (Appendix 1). Gastric or duodenal perforation Group A. In patients treated during the rst 24 h from symptom onset, 29.6% of clinics (8/27) administer antibiotics during the rst 24 h only, whereas 63% continue administration for two to eight days and 7% of the clinics did not provide the relevant data (Table 1). Second-generation cephalosporins with or without metronidazole and semisynthetic penicillins with a beta-lactamase inhibitor were used by all clinics (Table 2), although 7.4% of them (median 2; range 16) also used third- and fourth-generation cephalosporins with or without metronidazole, quinolones, piperacillin/tazobactam, imipenem-cilastatin, or meropenem, thereby deviating from the SIS guidelines. Group B. In patients treated later than 24 h from symptom onset, the duration of perioperative antibiotic administration was three to ve days in 59.3% of clinics, ve to seven days in 37%, and eight days in 3.7% (Table 1). Second- and thirdgeneration cephalosporins, with or without an antianaerobic agent, semisynthetic penicillins with a beta-lactamase inhibitor, and ertapenem were used by all clinics, but 11.1% of them (median 3; range 111) also used third- and fourth-generation cephalosporins or quinolones combined with antianaerobic antibiotics or piperacillin/tazobactam, imipenem-cilastatin, or meropenem as monotherapy (Table 2). Group C. In high-risk patients, 40.7% of surgical clinics administer antibiotics for ve to seven days, whereas 14.8% (median 4; range 38) deviate from the SIS guidelines, as they do not cover patients for Enterococcus (Tables 1 and 2). Intestinal rupture-perforation Group A. In patients treated during the rst 12 h from symptom onset, 29.6% of surgical clinics administer antibiotics in the rst 24 h according to the SIS guidelines, 66.7% continue administration for two to eight days, whereas 3.7% discontinue antibiotic treatment 48 h after abatement of clinical and laboratory indicators of infection (Table 1). Also, 14.8% of the clinics (median 4; range 17) use third- and fourth-generation cephalosporins or quinolones singly or combined with antianaerobic antibiotics or piperacillin/ tazobactam as monotherapy or combined with antianaerobic antibiotics, deviating from the SIS guidelines (Table 2). Group B. In patients treated later than 12 h from symptom onset, 52% of clinics administer antibiotics for ve to seven days (Table 1). Third- and fourth-generation cephalosporins with or without an antianaerobic agent, ciprooxacin with an antianaerobic agent, or piperacillin/tazobactam or imipenem/cilastatin as monotherapy were administered in 14.8% of clinics (median 4; range 110), deviating from the SIS guidelines (Table 2). Group C. In high-risk patients, 52% of surgical clinics administered antibiotics for ve to seven days and 3.7% for as long as 48 h after clinical and paraclinical indicators of infection have abated. A total of 14.8% of clinics (median 4; range

Table 1. Number (%) of Surgical Clinics Using Various Durations of Treatment Intestinal ruptureperforation Group A Group B Group C Group A Group B Acute cholecystitis Group C Acute appendicitis Group A Group B

Gastricduodenal perforation Group B Group C

Duration

Group A

5 11 10 8

3 6

3 9

537 10 1 1 Summary Group A Range 516 (18.559.3) Range 1122 (40.781.5) Median 26 (96.0) Group B 2 ( 7.4) 19 (70.4) 14 1 14 1

24 h 2 days 23 days 24 days 3 days 34 days 35 days 4 days 45 days 5 days 57 days 7 days 8 days 48 h after signs of infection abate >24 h Not specied (18.5) (40.7) (37.0) ( 3.7) 15 2 1 22 (81.5) 1 ( 3.7) 5 (18.5) 8 (29.6) 11 (40.7) 8 (29.6) 1 ( 3.7) 2 ( 7.4) 2 ( 7.4) 5 (18.5) 2 ( 7.4) 2 ( 7.4) 1 ( 3.7) 3 (11.1) 1 ( 3.7) ( 7.4) (37.0) (51.9) ( 3.7) (11.1) (29.6) (51.9) ( 3.7) ( 3.7) 5 (18.5) 3 (11.1) 2 ( 7.4) 7 (25.9) 3 (11.1) 1 ( 3.7) 1 ( 3.7) 1 ( 3.7) (11.1) (22.2) (55.6) ( 7.4) ( 3.7)

8 (29.6) 1 ( 3.7) 1 ( 3.7) 5 (18.5) 1 ( 3.7) 1 ( 3.7) 2 ( 7.4) 3 (11.1) 2 ( 7.4) 1 ( 3.7)

1 12 1 1

(11.1) (33.3) ( 3.7) (44.4) ( 3.7) ( 3.7)

16 (59.3) 1 ( 3.7) 1 ( 3.7) 4 (14.8) 1 ( 3.7) 1 ( 3.7) 1 ( 3.7) 11 (40.7)

2 ( 7.4) 2 ( 7.4) 15 (55.6) 7 (26.0) 1 ( 3.7)

17 (63.0) 2 ( 7.4)

Totals

Group C

24 h >24 h 35 days

Median 8 (29.6) Median 22 (81.5)

Range 2627 (96100)

Median 26 (96.0)

Range 2627 (96.0100)

Table 2. Type of Antibiotic Given (Number [%] of Clinics) Gastricduodenal perforation Group A 7 (25.9) 15 (56.0) 3 (11.1) 3 (11.1) 12 (44.5) 1 ( 3.7) 4 (14.8) 6 (22.2) 3 (11.1) 6 (22.2) 13 (48.1) 1 ( 3.7) 3 (11.1) 12 (44.4) 2 ( 7.4) 3 (11.1) 8 (29.6) 2 ( 7.4) 14 (51.9) 7 (26.0) 1 ( 3.7) Group B Group C Group A Group B Group C Group A Group B 8 (29.6) 8 (29.6) Intestinal ruptureperforation Acute cholecystitis Group C 7 (26.0) 5 (18.5) 2 ( 7.4) Acute appendicitis Group A 16 (59.3) 8 (29.6) Group B 3 (11.1) 16 (59.3) 1 ( 3.7)

Drug(s)

538 1 ( 3.7) 1 ( 3.7) 4 (14.8) 1 ( 3.7) 2 ( 7.4) 2 ( 7.4) 6 11 1 1 5 (22.2) (40.7) ( 3.7) ( 3.7) (18.5) 3 (11.1) 1 ( 3.7) 3 (11.1) 5 (18.5) 11 (40.7) 1 ( 3.7) 4 (14.8) 3 (11.1) 1 ( 3.7) 4 (14.8) 2 ( 7.4) 7 (26.0) 1 ( 3.7) 2 ( 7.4) 2 ( 7.4) 4 (14.8) 9 (33.3) 1 ( 3.7) 5 (18.5) 1 ( 3.7)

Second-gen. cephalosporin Second-gen. cephalosporin antianaerobic Second-gen. cephalosporin antianaerobic aminoglycoside Second-gen. cephalosporin aminoglycoside Ampicillin/sulbactam Amoxycillin/clavulanic acid Ticarcillin/clavulanic acid aminoglycoside Ticarcillin/clavulanic acid Ertapenem Aztreonam clindamycin Third-gen. cephalosporin Third-gen. cephalosporin antianaerobic Third-gen. cephalosporin antianaerobic aminoglycoside Fourth-gen. cephalosporin Aminoglycoside antianaerobic Piperacillin/tazobactam Piperacillin/tazobactam aminoglycoside Piperacillin/tazobactam metronidazole Ciprooxacin antianaerobic Ciprooxacin antianaerobic aminoglycoside Imipenem-cilastatin Meropenem 8 (29.6) 4 (14.8) 2 ( 7.4) 2 ( 7.4) 1 ( 3.7) 3 (11.1) 6 (22.2) 4 3 1 7 3 1 2 6 3 (11.1) 4 (14.8) 12 (44.4) 1 ( 3.7) 9 (33.3) 1 ( 3.7) 4 (14.8) 2 ( 7.4) (14.8) (11.1) ( 3.7) (25.9) (11.1) ( 3.7) ( 7.4) (22.2) 2 ( 7.4) 1 ( 3.7) 3 (11.1) 2 ( 7.4) 2 ( 7.4) 4 (14.8) 8 (29.6) 4 (14.8) 3 (11.1) 7 (26.0) 2 ( 7.4) 1 ( 3.7) 6 (22.2) 5 (18.5) 2 ( 7.4) 1 ( 3.7) 9 (33.3) 3 (11.1) 3 (11.1) 10 (37.0) 2 ( 7.4) 3 (11.1) 10 (37.0) 2 ( 7.4) 2 ( 7.4) 4 (14.8) 9 (33.3) 1 ( 3.7) 3 (11.1) 3 (11.1) 6 (22.2) 3 (11.1) 10 (37.0) 5 (18.5) 1 ( 3.7) 8 (29.6) 7 (26.0) 3 (11.1)

2 ( 7.4) 1 ( 3.7) 6 (22.2) 2 ( 7.4) 1 ( 3.7) 4 (14.8) 10 (37.0) 1 ( 3.7) 3 (11.1) 12 (44.4) 5 (18.5)

4 (14.8) 7 (26.0) 3 (11.1) 2 ( 7.4) 6 (22.2) 9 (33.3) 5 (18.5) 14 (51.9) 1 ( 3.7) 8 (29.6)

1 ( 3.7) 7 (26.0) 3 (11.1) 4 (14.8) 9 (33.3) 2 ( 7.4) 8 (29.6) 2 ( 7.4) 4 (14.8) 1 ( 3.7)

3 (11.1) 1 ( 3.7) 5 (18.5) 2 ( 7.4) 5 (18.5) 5 (18.5) 2 ( 7.4) 4 (14.8) 6 (22.2) 6 (22.2) 1 ( 3.7)

gen. generation.

INTRA-ABDOMINAL SURGICAL INFECTIONS 19) deviate from the SIS guidelines, as they do not cover these patients for Enterococcus (Tables 1 and 2). Acute cholecystitis Group A: In patients without gallbladder rupture, 18.5% of surgical clinics administer antibiotics for the rst 24 h, according to the SIS guidelines, whereas 81.4% administer antibiotics beyond the rst 24 h postoperatively (Table 1). Third- and fourth-generation cephalosporins and piperacillin/tazobactam as monotherapy and third-generation cephalosporins and uoroquinolones combined with antianaerobic agents, an aminoglycoside, or both were administered in 18.5% of clinics (median 5; range 110) (Table 2). Group B: In patients with gallbladder rupture, 63% of surgical clinics administer antibiotics for ve to seven days (Table 1). Third- and fourth-generation cephalosporins as monotherapy or in combination with antianaerobic agents, an aminoglycoside, or both or piperacillin/tazobactam or uoroquinolones combined with antianaerobic agents, an aminoglycoside, or both were administered by 18.5% of clinics (median 5; range 112), deviating from the SIS guidelines (Table 2). Group C: In high-risk patients, 51.8% of clinics administer antibiotics for ve to seven days, whereas 22.2% (median 6; range 112) deviate from the SIS guidelines, as they do not cover patients for Enterococcus (Tables 1 and 2). Acute appendicitis Group A: In patients without rupture of the appendix, 59.3% of clinics administer antibiotics during the rst 24 h, whereas 40.7% continue for two to seven days, thereby deviating from the SIS guidelines (Table 1). Third- and fourthgeneration cephalosporins and quinolones as monotherapy or combined with metronidazole or piperacillin/tazobactam as monotherapy were administered by 14.8% of clinics (median 4; range 19), a deviation from the SIS guidelines (Table 2). Group B: In patients with appendiceal rupture, 92.6% of clinics administer antibiotics for three to seven days (Table 1). Third- and fourth-generation cephalosporins and uoroquinolones as monotherapy or combined with metronidazole and piperacillin/tazobactam were administered by 18.5% of clinics (median 5; range 16), deviating from the SIS guidelines (Table 2). Group D: In patients with recent hospitalization or nosocomial or postoperative intra-abdominal infection, 74.1% of clinics administer antibiotics for ve to seven days, whereas 11.1% (median 3; range 113) do not cover patients for Enterococcus, and 7.4% report that they followed instructions from an infectious disease specialist (Table 3). Preventive antifungal treatment was administered by 48.2% of the clinics in circumstances strongly suggesting fungal participation in the infection and was not administered by 33.3%, whereas 7.4% followed the instructions from infectious disease specialists in this regard (Table 4). In a mean of 81.5% of surgical clinics (median 22, range 1524), antibiotic treatment commenced preoperatively. The commencement of perioperative antibiotics administration took place: Immediately after the diagnosis of an intra-abdominal infection For Group A patients, administration began immediately in 70.4% (median 19; range 1520) (Table 5). For Group B, the

539 Table 3. Treatment of Nosocomial or Postoperative Intra-Abdominal Infection (Number [%] of Surgical Clinics) Duration (days) 3 35 57 7 >7 Not specied Drug(s) Second-generation cephalosporin Third-generation cephalosporin Fourth-generation cephalosporin Ticarcillin/clavulanic acid Piperacillin/tazobactam Ertapenem Imipenem-cilastatin Meropenem Aminoglycoside antianaerobic Aztreonam clindamycin Second-generation cephalosporin antianaerobic Third-generation cephalosporin antianaerobic Third-generation cephalosporin antianaerobic aminoglycoside Ciprooxacin antianaerobic Fourth-generation cephalosporin antianaerobic aminoglycoside Piperacillin/tazobactam antianaerobic Antibiotic combination anti-staphylococcal Infectious disease specialist consulted 1 1 19 1 2 3 3 3 3 5 11 2 9 3 4 3 5 13 1 ( 3.7) ( 3.7) (70.4) ( 3.7) ( 7.4) (11.1) (11.1) (11.1) (11.1) (18.5) (40.7) ( 7.4) (33.3) (11.1) (14.8) (11.1) (18.5) (14.1) ( 3.7)

12 (44.4) 1 ( 3.7) 1 ( 3.7) 2 ( 7.4) 2 ( 7.4)

gure was 81.5% (median 22; range 1824). For Group C, this plan was used in 88.9% of clinics (median 24; range 2224). For Group D, immediate treatment was used in 88.9% of clinics. During induction to anesthesia In Group A patients, antibiotics were delivered during induction in 14.8% of clinics (median 4; range 310). In Group B, this gure was 11.1% (median 3; range 25), whereas in Group C, it was 7.4% (median 2; range 23), and in Group D, it was 7.4% (n 2). Intraoperatively In Group A patients, intraoperative administration was used in 18.5% of clinics (median 5; range 25). In Group B, such treatment was used in 7.4.1% of clinics (median 2; range Table 4. Coverage in Patients with Nosocomial or Postoperative Intra-Abdominal Infections (Number [%] of Clinics) Coverage of Enterococcus Yes No Prophylactic coverage of fungi Yes No Infectious disease specialist consulted No answer 12 (45.0) 15 (55.0) 13 9 2 3 (48.1) (33.3) ( 7.4) (11.1)

540

KAMBAROUDIS ET AL. Table 5. Timing of Commencement of Antibiotic Administration (Number [%] of Clinics)

Group A Gastricduodenal perforation treated within 24 h Intestinal rupture treated within 12 h Acute cholecystitis without gallbladder rupture Acute appendicitis without appendiceal rupture Gastricduodenal perforation treated after 24 h Intestinal rupture treated after 12 h Acute cholecystitis with gallbladder rupture Acute appendicitis with appendiceal rupture Gastricduodenal perforation in high-risk patient Intestinal rupture treated after 12 h in high-risk patient Acute cholecystitis in high-risk patient Nosocomial or postoperative intra-abdominal infection Median (range)

Preoperative 19 20 19 15 22 24 22 18 22 24 22 24 22 (70.4) (74.1) (70.4) (55.6) (81.5) (88.9) (81.5) (66.7) (81.5) (88.9) (81.5) (88.9) (1524)

Induction of anesthesia 3 4 3 10 3 2 2 5 3 2 2 2 3 (11.1) (14.8) (11.1) (37) (11.1) ( 7.4) ( 7.4) (18.5) (11.1) ( 7.4) ( 7.4) ( 7.4) ( 210)

Intraoperatively 5 3 5 2 2 1 3 4 2 1 3 1 2 (18.5) (11.1) (18.5) ( 7.4) ( 7.4) ( 3.7) (11.1) (14.8) ( 7.4) ( 3.7) (11.1) ( 3.7) ( 15)

C D

14). In Group C, intraoperative administration was applied in 3.7% of clinics (median 1; range 13). In Group D, it was used in 3.7% of clinics (Table 5). Discussion Antimicrobial agents, without doubt, are one of the greatest achievements of modern mankind. Their emergence, especially with the advent of penicillin, was met with great enthusiasm and excessive optimism. The quick emergence of resistant strains, initially staphylococcal and subsequently enterococcal and gram-negative ones, led to intense skepticism and reconsideration. It was understood that abuse and erroneous administration of these agents are the main elements that lead to resistance problems. Today, despite many references in the literature to the appropriate use of antibiotics in the surgical patient during perioperative chemoprophylaxis and empirical or etiologic treatment of surgical and postoperative infections, the clinician often encounters difculties in agent selection and administration. These difculties are aggravated by the plethora of medications available with the same or similar effects and the vagueness of available information regarding the pharmaceutical value and use of the agents. We believe that every effort in setting guidelines on antimicrobial agent usage and reducing their abuse adds another page to the chapter on proper antibiotic usage. According to the guidelines of both the SIS and the HSSI, gastric or duodenal perforation treated within 24 h of symptom onset, intestinal rupture or perforation treated within 12 h of symptom onset, acute or gangrenous appendicitis without appendiceal rupture, and acute or gangrenous cholecystitis without gallbladder rupture are considered localized inammations that cause simple contamination of the peritoneal cavity, not an infection. Through the analysis of mostly Grade I studies, those experts recommend that perioperative antibiotic administration not exceed 24 h. The HSSI recommends that perioperative chemotherapy last ve to seven days for biliary tract infection (acute cholecystitis/cholangiitis) and two or three days for gangrenous nonruptured appendicitis [10]. The HSSI rst published its guidelines for antibiotic use in 2003. Taking into consideration the widespread use of antibiotics in Greek hospitals, the special conditions of the Greek area regarding multiresistant strains, and the confusion among surgeons about perioperative antibiotic use, the HSSI

considered that some deviation from international guidelines should be included in the rst organized step in perioperative antibiotic use, in light of the Greek reality; e.g., perioperative antibiotic administration for ve to seven days in acute cholecystitischolangiitis and two or three days in gangrenous nonperforated appendicitis. Gastric or duodenal perforation treated later than 24 h from symptom onset, intestinal perforationrupture operated on later than 12 h from symptom onset, acute or gangrenous appendicitis with appendiceal rupture, and acute or gangrenous cholecystitis with gallbladder rupture are considered intra-abdominal infections that lead to generalized infection of the peritoneal cavity (secondary peritonitis). The guidelines for the perioperative use of antibiotics in these cases were based chiey on Grade II studies, because the disease characteristics do not easily allow the planning of blinded randomized trials. The guidelines recommend that the duration of antibiotic treatment be four to seven days [817]. However, there are studies recommending that the duration of perioperative chemotherapy be correlated with the intraoperative ndings at the initial operation or the abatement of clinical and paraclinical indicators of infection. Despite the seeming divergence of the experts on this issue, it is stressed emphatically that the persistence of infection signs or their recurrence beyond four to six days after initial surgery is an indication for diagnostic re-evaluation of the extent of the initial infection or of the presentation of a new distant infection. Consequently, a change in antimicrobial therapy is called for. Regarding the type of antibiotics that should be used in the perioperative period for proper coverage of patients with intra-abdominal infections, the SIS guidelines recommend the following: 1) Patients presenting from their homes with an intraabdominal infection without recent hospitalization or antibiotic administration (community infection) have suffered infection by microorganisms from their own alimentary tracts. These infections usually are mixed, with aerobic microbial strains adequately covered by second-generation cephalosporins (cefuroxime, cefamandole, ceforadine, cefoxitin) or aminopenicillins with b-lactamase inhibitors (ampicillin/sulbactam, amoxicillin/clavulanic acid) and anaerobic strains covered by metronidazole, clindamycin, carboxypenicillins with b-lactamase inhibitors (ticarcillin/

INTRA-ABDOMINAL SURGICAL INFECTIONS clavulanic acid), ureidopenicillins (piperacillin/ tazobactam), and, to a lesser extent, by antianaerobic second-generation cephalosporins (cefoxitin, cefotetan). Aminoglycosides are considered in acute severe conditions, renal status permitting, and their blood concentrations can be controlled. Enterococci are not a particular problem for this group of patients, and not covering them with specic antibiotics does not alter the rates of successful treatment. The surgical treatment of these infections can be augmented by the usual antibiotics in the perioperative period. This means that we can choose monotherapy with an antianaerobic second-generation cephalosporin (cefoxitin), ampicillin/sulbactam, amoxicillin/clavulanic acid, ertapenem, ticarcillin/clavulanic acid, or a combination of a second-generation cephalosporin plus metronidazole or aminoglycoside plus metronidazole in special cases. 2) Patients with a community intra-abdominal infection who are older or in poor general condition are in danger from postoperative enterococcal infection if not covered perioperatively by antibiotics effective against it. This means that these patients are not treated adequately by cephalosporins or aminoglycosides or a combination only. It is recommended to use ampicillin/sulbactam, amoxicillin/ clavulanic acid, ertapenem, ticarcillin/clavulanic acid, or aztreonam plus clindamycin in cases of allergy to specic antibiotic groups. 3) Patients with an intra-abdominal infection and recent hospitalization or living in communal housing or with a postoperative infection should receive stronger antibiotics. Recommended as such are piperacillin/tazobactam, imipenem-cilastatin, meropenem as monotherapy, and aztreonam plus clindamycin, ciprooxacin plus metronidazole, or third- and fourth-generation cephalosporin plus metronidazole or clindamycin as combination therapy. These patients also are in danger of enterococcal infection if not covered perioperatively with appropriate antibiotics. Patients with postoperative or tertiary peritonitis certainly need coverage against Pseudomonas and Staphylococcus, and frequently inability to control infection is attributable to fungi. So, if there is a high index of suspicion of a fungal contribution to the infection, early empiric (preemptive) antifungal therapy is necessary [1836]. As already mentioned, 27 surgical clinic directors (63% of the northern Greece surgical clinics) responded to the questionnaire. This percentage does not reduce the value of the conclusions, because in discussions in prior symposia, which the directors who did not participate in the study attended, it was agreed that the main reason for non-participation was their awareness of improper antibiotic use at their institutions and their fear of an audit. Their participation thus would simply have reinforced our conclusions. To what extent is antibiotic management in northern Greek surgical clinics in compliance with these guidelines, which were adopted by the HSSI as well as the SIS? From the analysis of our data and comparison with the SIS guidelines, the following conclusions can be drawn. Gastric-duodenal perforation In patients treated within 24 h (Group A), the duration of perioperative chemotherapy does not comply with the SIS

541 guidelines at 63% of the responding surgical clinics (duration two to eight days). Regarding the antibiotics used, 7.4% of clinics (median 2; range 16) deviate from the guidelines (administration of third- and fourth-generation cephalosporins, ciprooxacin, or imipenem-cilastatin). In patients treated after 24 h (Group B), the duration of perioperative chemotherapy is in accordance with the guidelines. Regarding the type of antibiotics, however, 11.1% of clinics (median 3; range 111) deviate from the guidelines by using third-generation cephalosporins as monotherapy or combined with antianaerobic agents and 33% of clinics by using ciprooxacin plus metronidazole or imipenem-cilastatin. In high-risk patients (Group C), 14.8% of surgical clinics (median 4, range 38) do not cover Enterococcus with the antibiotics administered. Intestinal rupture In Group A, only 29.6% of the surgical clinics administer antibiotics for 24 h. The remaining 70.4% deviate from the guidelines by treating patients for two to seven days. Regarding the type of antibiotic administered, 14.8% of clinics (median 4; range 17) do not comply with the guidelines, using third-generation cephalosporins as monotherapy or combined with metronidazole or clindamycin, the combination of ciprooxacin/metronidazole or imipenem-cilastatin, or piperacillin/tazobactam with antianaerobic agents. In Group B, the duration of perioperative chemotherapy is in accordance with the guidelines. A total of 14.8% of clinics (median 4; range 110) administered third- and fourthgeneration cephalosporins with or without an antianaerobic agent, ciprooxacin with an antianaerobic agent, or piperacillin/tazobactam or imipenem-cilastatin as monotherapy (Table 5). In Group C, the duration of perioperative chemotherapy is in accordance with the guidelines, but 14.8% of clinics (median 4, range 19) do not cover Enterococcus with the antibiotics administered. Acute cholecystitis In patients without gallbladder rupture (Group A), 81.4% of surgical clinics administer antibiotics beyond the rst 24 h, whereas 18.5% (median 5; range 110) administer third- and fourth-generation cephalosporins or piperacillin/tazobactam as monotherapy and third-generation cephalosporin or uoroquinolones plus an antianaerobic agent, an aminoglycoside, or both. In patients with gallbladder rupture (Group B), 18.5% of surgical clinics (median 5, range 112) administer third- and fourth-generation cephalosporins as monotherapy or combined with an antianaerobic agent or an aminoglycoside, piperacillin/tazobactam, or uoroquinolone plus an antianaerobic agent, an aminoglycoside, or both. In Group C, 22.2% of surgical clinics (median 6; range 112) do not cover Enterococcus. Acute appendicitis In patients without appendiceal rupture (Group A), 40.7% of surgical clinics administer antibiotics for two to seven days, whereas 14.8% (median 4; range 19) administer third- and fourth-generation cephalosporins or uoroquinolones as monotherapy or combined with metronidazole

542 and piperacillin/tazobactam. In patients with appendiceal rupture (Group B), 18.5% of clinics (median 5; range 16) administer third- and fourth-generation cephalosporins or uoroquinolones as monotherapy or combined with metronidazole and piperacillin/tazobactam. In patients with recent hospitalization or nosocomial or postoperative intra-abdominal infection (Group D), 11.1% of clinics (median 3; range 113) do not cover patients for Enterococcus. Preemptive antifungal therapy on suspicion of fungal participation in the infection is employed by 48.2% of the clinics. The time of antibiotic treatment commencement is important because the risk of a surgical infection rises two-fold to three-fold if the antibiotic is administered before the incision and six-fold if it is administered too early (e.g., more than 2 h before incision)[31,37]. From our study data, 7.4% (median 2; range 15) of surgical clinics administer antibiotics after the surgical incision; i.e., intraoperatively. It seems from these data that: 1. The patient group with an intra-abdominal infection with simple contamination of the peritoneal cavity is not separated from the patient group with secondary peritonitis. In most surgical clinics, the patients of the rst group are treated as if they suffered from a generalized peritoneal infection, and the duration of antibiotic treatment is two to seven days. 2. A high percentage of surgical clinics use advanced antibiotics, resulting in a higher treatment cost and a markedly higher likelihood of multiresistant strain emergence, as is already happening with Pseudomonas, Escherichia coli, Acinetobacter, and Klebsiella. 3. A high percentage of clinics do not consider Enterococcus as a potential participant in a postoperative infection and therefore do not cover patients for it. 4. A high percentage of surgical clinics do not appreciate the importance of fungi in infection in patients with postoperative or tertiary peritonitis. 5. Infectious disease specialists are consulted only rarely, particularly in special patient groups. These data were discussed in the two surgical infections symposia under the auspices of HSSI, with the main subject being the management of antibiotics perioperatively during the treatment of intra-abdominal surgical infections. Additionally, the data were presented in the subsequent PanHellenic Congress on Surgical Infections. Finally, the propositions evolved were included in a special HSSI issue with antibiotic use guidelines in surgical patients and a special issue of the Health Ministry Center for Disease Control. It was also agreed to undertake a random, without warning, audit regarding antibiotic use in surgical clinics in a specic time frame. It is considered necessary for every surgical clinic to appoint a specic person to control antibiotic administration and to create a special form for using restricted antibiotic groups. Conclusion It must be accepted that in conditions characterized by simple contamination of the peritoneal cavity, surgical treatment must be accompanied by brief (24 h) administration of antimicrobial agents. There must be a continuous effort to

KAMBAROUDIS ET AL. minimize the duration of antibiotic treatment, in order to reduce the pressure of resistant strain emergence. The persistence or recurrence of the infection signs beyond three or four days from the initial operation means in all probability a recurrence of the original infection or a new infection site and mandates diagnostic re-evaluation of the patient, not continuation or immediate change of the antimicrobial treatment. Finally, the most potent and most specialized antibiotics should be reserved for cases in which they are absolutely necessary. Continuous discussion and surgeon training by a specic scientic team is considered vital and probably is the best choice in order for surgeons to become connoisseurs of antibiotics and their proper use and thereby reduce serious adverse effects. The periodic update of the guidelines for antibiotic use should be the responsibility of this team, in addition to the continuous evaluation of their application, in order to increase the percentage of proper antibiotic management and to reduce the rate of emergence of multiresistant strains, side effects, and overall cost. Author Disclosure Statement No conicting nancial interests exist. References
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13. Michalopoulos A, Tzelepis G, Geroulanos S. Antimicrobial Chemoprophylaxis and Therapy in Surgery and Emergency Medicine. Athens. H. Tzevelekakis Editions. 1997. 14. Guide to Antimicrobial Therapy and Prophylaxis for the Hospitalized Patient. Athens. Central Committee for Surgical Infections. 2001. 15. Bohnen JM, Solomkin JS, Dellinger EP. Guidelines for clinical care: Anti-infective agents for intra-abdominal infections: A Surgical Infection Society policy statement. Arch Surg 1992;127:8389. 16. Smith TC, Pierson ML. The emergence of vancomycin resistance in Staphylococcus aureus. N Engl J Med 1999;340:493501. 17. Fridkin SK, Jarvis WR. Epidemiology of nosocomial fungal infections. Clin Microbiol Rev 1996;9:499511. 18. Schein M, Assalia A, Bachus H. Minimal antibiotic therapy after emergency abdominal surgery: A prospective study. Br J Surg 1994;81:989991. 19. Christou NV, Turgeon P, Wassef R, et al. Management of intra-abdominal infections: The case for intraoperative cultures and comprehensive broad-spectrum antibiotic coverage. Arch Surg 1996;131:11931201. 20. Mercer-Jones MA, Hadjiminas DJ, Heinzelmann M. Continuous antibiotic treatment for experimental abdominal sepsis: Effects on organ inammatory cytokine expression and neutrophil sequestration. Br J Surg 1998;85: 385389. 21. Roehrborn A, Wacha H, Schoeffel U, et al. Coverage of enterococci in community-acquired secondary peritonitis: Results of a randomized trial. Surg Infect 2000,1:95107. 22. Wacha H, Hau T, Dittmer R, et al. Risk factors associated with intra-abdominal infections: A prospective multicenter study. Langenbecks Arch Surg 1999;384:2432. 23. Burnett RJ, Haverstock DC, Dellinger EP, et al. Denition of the role of enterococcus in intra-abdominal infection: Analysis of a prospective randomized trial. Surgery 1995;118:716 723. 24. Lark R, Chenoweth C, Saint S. Four year prospective evaluation of nosocomial bacteremia: Epidemiology, microbiology and patient outcome. Diagn Microbiol Infect Dis 2000;38:131140. 25. Kamparoudis A., Karakantzas D., Kazdovasili P. Chemoprophylaxis: Is it necessary or not in appendectomy? Med Commun 1990;2:3336. 26. Taylor E, Dev V, Shah D, et al. Complicated appendicitis: Is there a minimum intravenous antibiotic requirement? A prospective randomized trial. Am Surg 2000;66:887890.

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Address correspondence to: Dr. Apostolos G. Kambaroudis 5th Surgical Clinic Hippokratio Hospital Medical School of Aristotle University of Thessaloniki Konstantinoupoleos st 49, P.C. 54642 Thessaloniki, Greece E-mail: kambarou@med.auth.gr

(Appendix follows ?)

544 Appendix. Surgical Clinics who responded to the questionnaire

1. Fifth Surgical Clinic A.U.Th.*, Hippokrateion General Hospital, Thessaloniki (Director: Prof. T. Gerasimidis), 2. Surgical Clinic, Kastoria General Hospital (Director: P. Papadiamantopoulos), 3. Third Surgical Clinical A.U.Th.*, AHEPA General Hospital, Thessaloniki (Director: Prof. O. Gamvros), 4. Surgical Clinic, second I.K.A. General Hospital, Thessaloniki (Director H. Hristakis), 5. Second Surgical Clinic, Theageneio Hospital, Thessaloniki (Director: G. Hrisas), 6. Second Surgical Clinic, Papanikolaou General Hospital, Thessaloniki (Director: G. Hristianopoulos), 7. Surgical Clinic, Kilkis General Hospital (Director: N. Ioannidis), 8. First Surgical Clinic, Kavala General Hospital (Director: K. Hristodoulidis), 9. Surgical Clinic, Grevena General Hospital (Director A. Mitselis) 10. Surgical Clinic, Karditsa General Hospital (Director: H. Koumbouras), 11. Fourth Surgical Clinic A.U.Th.*, Papanikolaou General Hospital, Thessaloniki (Director: D. Betsis, 12. Second Surgical Clinic A.U.Th.*, G. Gennimatas General Hospital, Thessaloniki (Director: Prof. K. Atmatzidis), 13. Surgical Clinic, Volos General Hospital (Director: A. Lioupis),

KAMBAROUDIS ET AL.

14. First Surgical Hospital, Drama General Hospital (Director: E. Molis), 15. First Surgical Clinic, Hippokrateion General Hospital, Thessaloniki (Director: G. Hatzitheocharis) 16. Surgical Clinic, Veroia General Hospital (Director: T. Chatziathanasiou), 17. First Surgical Clinic D.U.Th.**, Alexandroupoli University Hospital (Director: Prof. K. Manolas), 18. Surgical Clinic, Trikala General Hospital (Director: Tsianos), 19. Surgical Clinic of University of Thessaly, Larisa University Hospital (Director: Prof. K. Chatzitheolou), 20. Surgical Clinic, Giannitsa General Hospital (Director: A. Doumalas), 21. First Propedeutic Surgical Clinic A.U.Th., AHEPA General Hospital, Thessaloniki (Director: N. Harlaftis) 22. Surgical Clinic, Edessa General Hospital (Director: Th. Chrysidis), 23. Surgical Clinic, Agios Pavlos General Hospital, Thessaloniki (Director: Fronis), 24. Surgical Clinic, Polygyros General Hospital (Director: Kasinos), 25. Surgical Clinic, Xanthi General Hospital (Director: A. Chiotis), 26. Surgical Clinic, Papanikolaou General Hospital (Director: N. Makrantonakis), 27. Surgical Clinic, Theageneio General Hospital, Thessaloniki (Director: Oikonomou)

* Aristotle University of Thessaloniki. ** Democritus University of Thrace.