1. Effective and Appropriate Antimicrobial Therapy for Intra-abdominal Infections
With the increasing prevalence of antimicrobial resistance, it is important to understand the role of antibiotics in leading to patterns of resistance and appropriate use of antimicrobial agents to manage the current treatment challenges.
This presentation will cover the clinical impact of intra-abdominal infections, treatment challenges, and appropriate management in the era of antimicrobial resistance.

2. The Clinical Impact of Intra-abdominal Infection (IAI)
Complicated IAI is a major cause of
morbidity and mortality
Complicated intra-abdominal infections are among the most common infections in general surgery
Even with current management, morbidity rates of 59% and mortality rates of 21% were reported in a retrospective study
Complicated intra-abdominal infections are among the most common infections in general surgery.1,2 They usually are associated with peritonitis or intra-abdominal abscess.1
Even with current management, complicated intra-abdominal infections remain a major cause of morbidity and mortality.3 A retrospective 12-year study conducted between 1981–1993 of 604 patients who underwent surgery for intra-abdominal infection reported postoperative morbidity rates of 59% and postoperative mortality rates of 21% over a 12-year period.4
Solomkin JS et al Ann Surg 2003;237:235–245.
Yellin AE et al Int J Antimicrob Agents 2002;20:165–173.
Fry DE Surg Infect 2001;2(Suppl 1):S3–S11.
Pacelli F et al Arch Surg 1996;131:641–645.

3. Most Common Pathogens in 2 Studies of Community-Acquired IAI
Cattan
(n=317)
Sendt
(n=313)
Gram Positive Cocci
Streptococcus spp.
Enterococcus spp.
Gram Negative Bacilli
Escherichia coli
Klebsiella spp.
Enterobacter spp.
Pseudomonas aeruginosa
Bacteroides fragilis
Other Bacteroides spp.
12% 7%
40% 3% 1% 4% 9% 6%
47% 2%
The table shows the proportions of pathogens in community-acquired intra-abdominal infections from two retrospectively reviewed studies: one conducted in France and one in Germany. The most commonly isolated pathogens at baseline were Enterobacteriaceae such as E. coli and anaerobes such as Bacteroides spp.5
Although Enterococcus is often isolated, its importance as a pathogen in intra-abdominal infections and the need for its routine treatment remain controversial, according to Surgical Infection Society (SIS) guidelines.6 And there is little indication that routine enterococcal coverage is necessary for most patients with community-acquired intra-abdominal infections.6
Adapted from Gerth WC et al EJHP 2004;4:78–83.

4. Role of Enterobacteriaceae and Anaerobes (rodents)
Microbial Synergy in Experimental Intra-abdominal Abscess (in Wistar Rats)
Role of Enterobacteriaceae and Anaerobes (rodents) %
100
Abscesses
Mortality 75 50
Onderdonk et al in the mid-1970s examined the role of different microbial species in the pathophysiology of intra-abdominal infections, using Wistar rats. E. coli, B. fragilis and Enterococci were implanted into the peritoneal cavity singly or in all possible dual combinations. Results were evaluated by mortality rates and the incidence of intra-abdominal abscesses on autopsy following sacrifice after 7 days. Mortality was restricted to recipients of E. coli, thus implicating coliforms in the acute lethality associated with this experimental model. Intra-abdominal abscesses were produced in the majority of the rodents that received the combination of an anaerobe and a facultative organism. Abscesses failed to form with any single strain or with E. coli plus Enterococci.7
These results suggested gram-negative enteric bacteria were found to be responsible primarily for the mortality related to peritonitis, whereas intra-abdominal abscess formation was related to synergy between anaerobes and facultative bacteria.7 25
E. coli
Enterococcus
B. fragilis
E. coli +
Enterococcus
E. coli +
B. fragilis
Enterococcus +
B. fragilis
Onderdonk AB et al Infect Immun 1976;13:22–26.

5. Appropriate Management of Complicated IAI
Adequate resuscitation
Surgical or radiological intervention
Antimicrobial therapy
Important adjunct to surgery and supportive therapy
Should have appropriate coverage against gram-positive and gram-negative, aerobic and anaerobic bacteria
Since complicated intra-abdominal infections are still problems in clinical practice and utilize substantial hospital resources, appropriate management is essential.8-10
Adequate resuscitation and surgical or radiological intervention are usually required as a first option to treat patients with complicated IAI; in addition, antibiotic therapy is an important adjunct to surgery and supportive therapy in the management of these infections.9
Effective antibiotic therapy for complicated intra-abdominal infections should have the appropriate spectrum and activity to cover potential pathogens, which include gram-positive, gram-negative, aerobic and anaerobic organisms.2
Solomkin JS et al Ann Surg 2003;237:235–245.
Mazuski JE et al Surg Infect 2002;3:161–173.
Yellin AE et al Int J Antimicrob Agents 2002;20:165–173.

6. Antimicrobial Resistance: A serious problem facing clinicians in the management of IAI
In nosocomial infections, there is an increasing prevalence of resistant Enterobacteriaceae
ESBL-producing E. coli or K. pneumoniae
Previous fluoroquinolone or cephalosporin use is risk factor
Treatment failure observed with cephalosporins or β-lactam/β-lactamase inhibitor combination
Increasing quinolone-resistance in ESBL-producing isolates
Carbapenem remains drug of choice
Increasing prevalence of Bacteroides fragilis – resistant to clindamycin, cefotetan, cefoxitin and quinolones
Due to increasing antimicrobial resistance, clinicians are now facing many challenges in the management of complicated intra-abdominal infections. For example, the increased prevalence of resistant Enterobacteriaceae is a major concern.11
Rodriguez-Bano et al conducted a case-control study between January 2001 and May 2002 in Spain investigating the risk factors associated with the acquisition of extended-spectrum beta-lactamase (ESBL)-producing E. coli in nonhospitalized patients with suspected community-acquired infections. Diabetes mellitus, previous fluoroquinolone use, a previous hospital admission, recurrent urinary tract infection, and older age in male patients were identified as risk factors by multivariate analysis.11
Paterson et al conducted a prospective observational study between January 1996 and December 1997 of 440 consecutive, sequentially encountered patients with K. pneumoniae bacteremia at 12 hospitals in South Africa, Taiwan, Australia, Argentina, the United States, Belgium and Turkey. Previous administration of ß-lactam antibiotics containing an oxyimino group (cefuroxime, cefotaxime, ceftriaxone, ceftazidime or aztreonam) was associated with bacteremia due to ESBL-producing strains.12
Treatment failure has been observed when cephalosporins or ß-lactam/ß-lactamase inhibitor combination are used for the treatment of serious infections due to ESBL-producing organisms that may be susceptible on the basis of minimum inhibitory concentrations (MICs).13,14 The close association of quinolone resistance in K. pneumoniae with ESBLs is of concern, since ESBL-producing isolates are usually resistant to penicillins, cephalosporins, aminoglycosides and TmP-SmZ.15
Carbapenems remain the drugs of choice for treating infections caused by ESBL-producing organisms, based on in vitro susceptibility and extensive clinical experience.14
Susceptibility profiles for B. fragilis group isolates demonstrate significant resistance to clindamycin, cefotetan, cefoxitin, and quinolones,16,17 and the guidelines recommend not to use these agents alone empirically in cases where B. fragilis is likely to be encountered.8
Rodriguez-Bano J et al J Clin Micro 2004;42:1089– Paterson DL et al Ann Intern Med 2004;140:26–32. Paterson DL et al J Clin Micro 2001;39:2206– Paterson DL Clin Microbiol Infect 2000;6:460–463. Paterson DL et al Clin Infect Dis 2000;30:473–478. Oh H, Edlund C Clin Microbiol Infect 2003;9:512–517. Elsaghier AAF et al J Antimicrob Chemother 2003;51:1436–1437.

7. Appropriate Antimicrobial Therapy
Considerations in determining appropriate therapy:
Spectrum of activity
Timing and duration of therapy
Dose and dosing frequency
Drug interactions and tolerability
Adequate drug levels
Prior antibiotic treatment
Potential for selecting antibiotic resistance
In the era of antimicrobial resistance, what factors should be considered in determining appropriate antimicrobial therapy?
Appropriate therapy might be defined as antibiotic therapy that covers all suspected pathogens, is administered promptly at the proper dose and dose interval, is well tolerated, and penetrates the site of infection. Appropriate antibiotic therapy should take prior antibiotic therapy into account, and the potential for selecting antibiotic resistance should be considered in choosing the appropriate antibiotic agent.18,19
Raymond DP et al Surg Infect 2002;3:375–385. Moellering RM. In: GL Mandell, JE Bennett, R Dolin, eds. Principles and Practice of Infectious Diseases, 5th ed, 2000.

8. Beneficial Outcomes of Appropriate Antimicrobial Therapy
Improved chance of successful clinical outcome
Reduced mortality
Decreased need for re-operation and second- line therapy
Reduced number of IV antibiotic days
Shorter hospital length of stay
Lower hospital costs
Reduction in the emergence of antimicrobial resistance
Appropriate antimicrobial therapy can be beneficial in many aspects, such as improved chance of successful clinical outcome,20 reduced mortality,21-23 decreased need for re-operation and second-line therapy, reduced number of IV antibiotic days, shorter hospital length of stay,22 lower hospital costs,20,22,23 and most importantly, reduced emergence of antimicrobial resistance.24
The following slides will review some of the potential benefits of appropriate antimicrobial therapy as examples.
Davey P et al. ISPOR 6th Annual International Meeting; Virginia, USA, Bare M et al. ECCMID, Milan, Italy; Burke J et al. Presented at the 39th World Congress of Surgery, Brussels, Belgium; Sendt W et al. Presented at the 12th ECCMID (European Congress of Clinical Microbiology and Infectious Disease), Milan, Italy; Niederman MS et al Crit Care Med 2003;31:608–616.

9. Appropriate Antimicrobial Therapy for IAI: Successful Clinical Outcome
IAI patients with adequate empiric therapy were significantly more likely to have successful clinical outcome*
100.0%
p<0.05
80.0%
81.9%
60.0%
Percentage of patients with
clinical success (%)
58.9%
40.0%
In a prospective observational study, Davey et al (2001) reviewed records of 348 evaluable patients obtained from 1993 to 2000 at three Scottish hospitals to compare the outcome and resource cost associated with appropriate and inappropriate empiric therapy. Patients with acute onset of peritonitis requiring surgery or percutaneous drainage with signs of intra-abdominal infection caused by perforated appendicitis, diverticulitis, ulcer, or bowel; abscess of the appendix or other intra-abdominal area; gangrenous bowel or gangrenous or perforated gallbladder were included. This was accomplished by checking validity of diagnosis, assessing appropriateness of empirical antibiotic treatment, and classifying outcome. The review was conducted independently by two infectious disease specialists.20
Appropriate therapy was defined as positive peritoneal swabs with all bacteria sensitive to at least one empirical drug, or negative or no peritoneal swab where the regimen covered both aerobic and anaerobic bacteria. Inappropriate therapy was defined as positive peritoneal swabs where one or more of the pathogens were resistant to all of the antibiotics used for empiric therapy, or negative or no peritoneal swab where empiric treatment was not effective against both aerobic and anaerobic bacteria.20
Successful outcome was defined as resolution with no change in treatment. Unsuccessful outcome was defined as resolution with downscale, death, or infection.20
A total of 81.9% (195 of 238) of patients who received appropriate therapy had a successful clinical outcome, compared with 58.9% (33 of 56) who received inappropriate therapy (p<0.05).20
20.0%
0.0%
Empiric antibiotic
therapy appropriate
Empiric antibiotic
therapy inappropriate
(n=238)
(n=56)
Davey P et al. Presented at the International Society of Pharmacoeconomics and Outcomes Research Sixth Annual International Meeting; Virginia, USA, 2001.
*Successful outcome was defined as resolution with no change in treatment

10. Appropriate Antimicrobial Therapy for IAI: Reduced Mortality
Mortality was substantially lower for IAI patients who received appropriate empiric therapy
40.0%
30.0%
p<0.05
Mortality (%)
20.0%
23%
This retrospective analysis of patient records (n=365) from two acute-care hospitals in Spain using available hospital databases (discharge, pharmacy, microbiology, and surgery records) was conducted from 1998 to Adult hospitalized patients were identified through ICD-9 discharge codes. The rate of in-hospital death among patients who received inappropriate versus appropriate therapy was evaluated.21
Appropriate therapy was defined as: (1) positive peritoneal swabs where all bacteria isolated were sensitive to at least one of the antibiotics used initially for empiric therapy; or (2) negative or no peritoneal swab and therapy with antibiotics active against Escherichia coli (ß-lactamase producing gram-bacteria) and Bacteroides fragilis (anaerobe). In the statistical analysis, in-hospital mortality for patients with appropriate and inappropriate empiric initial therapy was noted, and associations between in-hospital mortality and therapy appropriateness were determined. Multiple logistic regressions were used to examine associations between in-hospital mortality, age, gender, infection site and process, and comorbid conditions.21
Mortality was substantially higher for patients with intra-abdominal infections who received inappropriate versus appropriate therapy.21
10.0%
12%
0.0%
Appropriate antibiotic
therapy (n=272)
Inappropriate antibiotic
therapy (n=93)
Bare M et al. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases, Milan, Italy; 2002.

11. Appropriate Antimicrobial Therapy for IAI: Decreased Need for Re-operation and Use of Second-Line Therapy
Patients (N=425) given appropriate initial empiric therapy for IAI were less likely to undergo re-operation and require second-line antibiotic therapy 4 5
100 3
Patient died 11 12
Resolved after 80
re-operation 27 60
Resolved with
Percentage (%)
second-line 40 81
therapy
A retrospective, multicenter study of adult hospitalized patients (N=425) with acute onset of intra-abdominal infection requiring surgical intervention for secondary peritonitis was conducted at 20 German hospitals between January 1999 and August The objective was to evaluate the association between initial inappropriate empiric antibiotic therapy and the need for second-line therapy and re-operation among patients undergoing surgery for community-acquired intra-abdominal infections. Cases were identified through computerized patient records using ICD-10 or ICD-9 codes when available; otherwise, a manual review of patient records was conducted.23
Appropriate therapy was defined as positive intra-abdominal swabs or blood cultures where all bacteria were sensitive to at least one empiric drug, or a negative or no intra-abdominal swabs or blood cultures where the regimen covered both aerobic and anaerobic bacteria.23
Inappropriate therapy was defined as positive intra-abdominal swabs or blood cultures where one or more bacteria were resistant to all of the antibiotics used for empiric therapy, or a negative or no intra-abdominal swabs or blood cultures where empiric treatment was not active against both aerobic and anaerobic bacteria.23
Successful outcome was defined as resolution with initial therapy or with a decrease from initial therapy (e.g., from IV to oral, or combination therapy to monotherapy). Unsuccessful outcome was defined as resolution with additional antimicrobial therapy or additional surgical therapy, or in-hospital death.23
There were 425 patients, 183 with positive cultures confirming intra-abdominal infection. Patients with complicated intra-abdominal infection who received inappropriate initial empiric therapy were more likely to undergo re-operation and more likely to require second-line antibiotic therapy.23 57
Resolved with 20
initial or step-
down therapy
Appropriate Initial
Inappropriate Initial
Empiric Antibiotic
Empiric Antibiotic
Therapy
Therapy
Sendt W et al. Presented at the 12th Annual European Congress of Clinical Microbiology and Infectious Diseases, Milan, Italy; 2002.

12. Appropriately treated IAI patients experienced 10 fewer hospital days
Appropriate Antimicrobial Therapy for IAI: Decreased Length of Hospital Stay (LOS)
Appropriately treated IAI patients experienced 10 fewer hospital days 25
p<0.05 20 22
10 days 15
Length of Stay (Days) 10 12
Davey et al (2001) reviewed records of 348 patients at three Scottish hospitals from 1993 to 1997 to assess appropriateness of empirical antibiotic treatment and classify outcome. Patients with acute onset of peritonitis requiring surgery or percutaneous drainage with signs of intra-abdominal infection caused by perforated appendicitis, diverticulitis, ulcer, or bowel; abscess of the appendix or other intra-abdominal area; gangrenous bowel or gangrenous or perforated gallbladder were included. This was accomplished by checking validity of diagnosis, assessing appropriateness of empirical antibiotic treatment, and classifying outcome. The review was conducted independently by two infectious disease specialists.20
Appropriate therapy was defined as positive peritoneal swabs with all bacteria sensitive to at least one empirical drug, or negative or no peritoneal swab where the regimen covered both aerobic and anaerobic bacteria. Inappropriate therapy was defined as positive peritoneal swabs where one or more of the pathogens were resistant to all of the antibiotics used for empiric therapy, or negative or no peritoneal swab where empiric treatment was not effective against both aerobic and anaerobic bacteria.20
The mean length of hospital stay was 12 days for patients who received appropriate therapy, compared with 22 days for those who received inappropriate therapy (p<0.05). Patients who received inappropriate therapy experienced an average of 10 additional days in the hospital.20
The omission of data from older patients with more severe disease biased this study. The bias was probably towards the null hypothesis that no difference existed in the cost between patients who received appropriate versus inappropriate empiric therapy.20 5
Appropriate Empiric
Inappropriate Empiric
Antibiotic (n=129)
Antibiotic (n=33)
Davey P et al. Presented at the International Society of Pharmacoeconomics and Outcomes Research Sixth Annual International Meeting; Virginia, USA, 2001.

13. “Collateral Damage”
“Collateral damage is ecological adverse effects of antibiotic therapy… that is, the selection of antibiotic-resistant organisms and the unwanted development of colonization or infection with such organisms”
The traditional questions to ask when considering appropriate antimicrobial therapy used to focus on clinical and bacteriological efficacy as well as safety. However, with the increase in resistant antimicrobial strains worldwide, the new addition to this question should be associated with the impact of so-called “collateral damage,” which means ecological adverse effects of antibiotic therapy, that is, the selection of antibiotic-resistant organisms and the unwanted development of colonization or infection with such organisms, according to Paterson et al.25
Paterson DL et al Clin Infect Dis 2004;38(Suppl 4):S341–S345.

14. Selection of Antibiotic-Resistant Pathogens
Summary of potential “collateral damage” from use of cephalosporins and quinolones
Class of agent, pathogen(s) selected for
Third-generation cephalosporins
Vancomycin-resistant enterococci (VRE)
Extended-spectrum ß-lactamase–producing Klebsiella species
ß-lactam–resistant Acinetobacter species
Clostridium difficile
Quinolones
Methicillin-resistant Staphylococcus aureus (MRSA)
Quinolone-resistant gram-negative bacilli, including Pseudomonas aeruginosa
Two antibiotic classes that are commonly linked to “collateral damage” are cephalosporins and quinolones.25 The table in the slide shows the summary of potential “collateral damage” from use of cephalosporins and quinolones.25
Cephalosporins mainly select for vancomycin-resistant enterococci (VRE), extended-spectrum ß-lactamase–producing Klebsiella species, ß-lactam–resistant Acinetobacter species and Clostridium difficile.25 In the era of VRE emergence, several case-control studies have shown that use of third-generation cephalosporins may be a risk factor for infection with VRE.25
And quinolones mainly select for methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant gram-negative bacilli, including Pseudomonas aeruginosa.25
Adapted from Paterson DL Clin Infect Dis 2004;38(Suppl 4):S341–S345.

15. Risk Factors for VRE and
Acinetobacter spp.
In a single-center retrospective study (880 in-patients; 233 VRE cases and 647 matched controls) an increase in VRE* (54 cases/10,000 admissions) was associated with third-generation cephalosporins (p<0.001), I.V. metronidazole (p=0.008), and longer duration of quinolone use (p=0.05).
In vitro results from patients at 15 Brooklyn hospitals showed that cephalosporin use correlated with emergence of a multi-resistant clone of Acinetobacter spp.
Carmeli et al conducted a matched case-control study from October 1993 through December 1997 to compare the effect of prior antibiotic treatment on subsequent isolation of vancomycin-resistant Enterococcus (VRE). During the 51-month study period, 880 patients were included and 233 VRE were isolated. After being matched for hospital location, calendar time, and duration of hospitalization, the variables to predict VRE positives were as follows: main admitting diagnosis, coexisting conditions of diabetes mellitus/organ transplant or hepatobiliary disease, infection or colonization with MRSA or C. difficile within the past year. In the model adjusting for these variables, the effect of being treated with each antibiotic was examined. The incidence of VRE increased from 34 to 88 cases per 10,000 admissions, and two of the key findings were that third-generation cephalosporins and parenteral metronidazole and longer duration of fluoroquinolone usage were highly significant independent risk factors for VRE.26
*VRE = vancomycin-resistant Enterococcus
Carmeli Y et al Emerg Infect Dis 2002;8:802–807.
Landman D et al Arch Intern Med 2002;162:1515–1520.

16. Challenges in the Clinical Management of ESBLs
Previous administration of oxyimino-containing antibiotics (e.g., cefuroxime, cefotaxime, ceftriaxone, ceftazidime, aztreonam) were associated with bacteremia due to ESBL-producing strain
15 (18%) of 83 ESBL-producing strains isolated in 455 episodes of K. pneumoniae bacteremia were ciprofloxacin resistant
43 of 77 strains (55.8%) of ESBL-producing E. coli and K. pneumoniae were resistant to fluoroquinolones
The incidence of infections due to ESBL-producing Escherichia coli and Klebsiella pneumoniae has remarkably increased in recent years.30
Paterson et al performed a prospective observational study of 440 consecutive, sequentially encountered patients with K. pneumoniae bacteremia at 12 hospitals in South Africa, Taiwan, Australia, Argentina, the U.S., Belgium, and Turkey. A total of 455 episodes of K. pneumoniae bacteremia occurred in 440 patients. Of the episodes of K. pneumoniae bacteremia, 18.7% (85 of 455) were due to ESBL-producing organisms. Seventy-eight of 253 (30.8%) episodes of nosocomial bacteremia were due to ESBL-producing organisms. After adjustment for potentially confounding variables, previous administration of ß-lactam antibiotics containing an oxyimino group member (cefuroxime, cefotaxime, ceftriaxone, ceftazidime, or aztreonam) was associated with bacteremia due to ESBL-producing strains.28
Paterson et al conducted a prospective study of K. pneumoniae bacteremia in 12 hospitals in 7 countries from January 1996 to December Of 452 episodes of bacteremia, ESBL production was detected in 15 (60%) of 25 ciprofloxacin-resistant isolates. In all, 15 (18%) of 83 ESBL-producing strains were ciprofloxacin-resistant.29
Lautenbach et al conducted a retrospective case-control study in two hospitals in the U.S. from June 1997 to September 1998 to identify risk factors for fluoroquinolone resistance in ESBL-producing E. coli and K. pneumoniae infections. Of 77 ESBL-producing E. coli and K. pneumoniae infections, 43 (55.8%) were resistant to fluoroquinolones.30
Paterson DL et al Ann Intern Med 2004;140:26–32.
Paterson DL et a Clin Infect Dis 2000;30:473–478.
Lautenbach E et al Clin Infect Dis 2001;33:1289–1294.

17. Community Transmission of ESBLs
Distribution of ESBL producers
39/2599 (1.5%) detected among the family Enterobacteriaceae
23/887 (2.6%) strains from clinics
11/128 (8.6%) strains from nursing homes
Conclusions:
A variety of ESBLs and ESBL producers are present in the extrahospital setting.
The spread of ESBL-producing organisms to the community seems to be related to previous nosocomial acquisition.
Monitoring patients for ESBL-producing Enterobacteriaceae in general practice is required.
ESBL-producing Enterobacteriaceae are characteristically nosocomial pathogens and are often responsible for outbreaks, mostly in intensive care units (ICUs). When patients hospitalized in ICUs are discharged to a general acute-care unit and then go to a rest, nursing, or retirement home, some of them continue to carry ESBL-producing Enterobacteriaceae. Such continued carriage may contribute to the extrahospital dissemination. ESBLs might be selected from the existing gastrointestinal flora when it is exposed to broad-spectrum antimicrobial agents. However, their occurrence has rarely been reported, probably because detecting ESBLs requires special tests and operator expertise.31
In the survey conducted over a 5-month period in 1999 in the Aquitaine region of France by eight private laboratories, 39 ESBL producers were detected among the 2599 isolates of the family Enterobacteriaceae (1.5%). They consisted of 34 of 1015 (3.3%) strains from institutions, including 23 of 887 (2.6%) strains from clinics and 11 of 128 strains (8.6%) from nursing homes, and 5 of 1584 (0.3%) strains from the community.31
This study shows that a variety of ESBLs and ESBL producers are present in the extrahospital setting. The spread of ESBL-producing organisms to the community seems to be related to previous nosocomial acquisition. And these data stress the need for private laboratories to adequately monitor for ESBL-producing strains of the family Enterobacteriaceae that may be falsely susceptible to broad-spectrum cephalosporins although the infections caused by these organisms are not efficiently treated with such antibiotics.31
Arpin C et al Antimicrob Agents Chemother 2003;47:3506–3514.

18. Fluoroquinolone Resistance
Risk Factors for
Fluoroquinolone Resistance
In a hospital-based case control investigation (n=205):
Multivariable analysis of risk factors for fluoroquinolone resistance in E. coli and K. pneumoniae
Prior fluoroquinolone use
LTCF (Long-term care facility) residence
Prior aminoglycoside use
Older age
Correlation of fluoroquinolone resistance and prior fluoroquinolone use
In subanalysis of the 41 patients who received FQ during the 30 days prior to infection, 35 (85.4%) had an FQ-resistant infection.
Because of the intrinsically low minimum inhibitory concentrations (MICs) of the fluoroquinolones (FQs) to E. coli and K. pneumoniae, it was believed that emergence of FQ resistance in these organisms was rare. However, increasing FQ resistance in these organisms has been reported in recent years. With this alarming situation, Lautenbach et al conducted a hospital-based case-control investigation to identify risk factors for FQ resistance in infections due to E. coli and K. pneumoniae. Eligible cases (FQ-resistant) and controls (FQ-susceptible) were included in the study only if their isolates represented nosocomial acquisition. If any of these organisms was isolated on multiple occasions, only the first episode of infection was reviewed. Of 136 eligible cases, 123 (90.4%) had complete medical records available for review, and of 82 eligible controls, 70 (85.3%) had complete records available.32
On multivariable analysis, the variables noted to be independent risk factors for FQ-resistant infection are: prior FQ use, long-term care facility (LTCF) residence, prior aminoglycoside use, and older age.32
To explore whether certain characteristics of FQ use might be associated with FQ-resistant infection, the investigators subsequently conducted a subanalysis on all patients who received an FQ during the 30 days prior to infection: of the 41 patients who received an FQ, 35 (85.4%) had an FQ-resistant infection.32
Lautenbach E Arch Intern Med 2002;162:2469–2477.

19. Correlation of Fluoroquinolone-Resistant Pathogens to Other Agents
In a hospital-based case-control investigation (N=205):
Antimicrobial susceptibilities of fluoroquinolone-resistant and
fluoroquinolone-susceptible isolates 80
FQ Resistant
FQ Susceptible 70 60 50
% Resistant 40 30
Additionally Lautenbach showed that FQ-resistant isolates were also significantly more likely to demonstrate resistance to other antibiotics. With the exception of nitrofurantoin and imipenem, a significantly greater percentage of FQ-resistant isolates were resistant to other antibiotics for which at least half of all isolates were tested. Thirty-one (25.2%) cases were infected with isolates demonstrating ESBL production.32
In a hospital-based case-control investigation, 123 patients with nosocomial FQ-resistant infections and 70 randomly selected patients with nosocomial FQ- susceptible infections were analyzed to identify risk factors for nosocomial FQ resistance.32 20 10
Ampicillin-
Cafazolin
Ceftriaxone
Sulfa-
Gentamicin
Imipenem
Nitro-
Tetracycline
sulbactam
Sodium
methoxazole-
Sulfate
furantoin
Trimethoprim
Lautenbach E Arch Intern Med 2002;162:2469–2477.

20. Risk Factors for Selecting Pseudomonal Resistance
In a matched case-control study conducted between 1999 and 2000 in France:
Treatment with any fluoroquinolone for acquiring piperacillin-resistant P. aeruginosa may be a risk factor
If treatment with an antibiotic active against gram-negative bacteria is needed, agents with little antipseudomonal activity should be preferred to limit the emergence of multidrug-resistant Pseudomonas aeruginosa (MDRPA)
Pseudomonas aeruginosa is one of the major organisms responsible for drug-resistant nosocomial infections. In order to identify risk factors for acquiring multidrug-resistant P. aeruginosa (MDRPA) in the intensive-care unit, a matched case-control study was conducted between 1999 and 2000 in France. MDRPA was defined as P. aeruginosa with combined decreased susceptibility to piperacillin, ceftazidime, imipenem and ciprofloxacin. During the study period, 370 (14.1%) of 2613 patients were observed with P. aeruginosa, and 39 (10.5%) of these patients had the prevalence of MDRPA infection or colonization. As expected, the time to MDRPA acquisition was long, with a mean of 29 days between ICU admission and MDRPA acquisition.33
Multivariate analysis identified that the receipt of any fluoroquinolone may be a critical risk factor,34 whereas receipt of quinolones without activity against P. aeruginosa conferred protection against the emergence of MDRPA.33
Overall, the study results suggest that when treatment with an antibiotic active against gram-negative bacteria is required, agents with little antipseudomonal activity should be preferred over those with specific antipseudomonal activity to limit the emergence of MDRPA.33
Paramythiotou E et al Clin Infect Diseases 2004;38:670–677.

21. The Role of Carbapenems in the Era of Antimicrobial Resistance
Group 2 carbapenems, like imipenem and meropenem, have been reliable drugs of choice for severe nosocomial infections and have been reserved in many cases due in large part to their activity against non-fermentative gram-negative bacilli such as P. aeruginosa and Acinetobacter spp.35
With the introduction of ertapenem, the first Group 1 carbapenem with proven clinical efficacy and broad-spectrum coverage against common gram-positive and gram-negative aerobic and anaerobic pathogens but minimal activity against non-fermenters, we would like to think of the appropriate roles of Group 1 and Group 2 carbapenems in the era of increasing antimicrobial resistance as being for infections where pseudomonal infection is suspected and not suspected, respectively.36

22. Properties of Carbapenems
Excellent clinical efficacy
Broad-spectrum coverage over gram-positive and gram-negative aerobic and anaerobic pathogens*
Rapidly bactericidal
Proven tolerability profile
Low risk for resistance selection
Option 1
All carbapenems in general share the similar properties of having excellent clinical efficacy, broad-spectrum coverage of gram-positive and gram-negative aerobic and anaerobic organisms, rapid bactericidal activity, proven tolerability profile and low risk for resistance selection.36
With the major difference of the spectrum coverage lacking activity against non-fermenters, ertapenem may seem unlikely to be a specific selector of imipenem/meropenem resistance in these species.35
*Ertapenem has minimal activity against non-fermentative gram-negative bacilli
Shah PM, Isaacs R J Antimicrob Chemother 2003;52:331–344.

23. Carbapenems: Low Risk for Resistance Selection
Enterobacteriaceae
Resistance to carbapenems remains rare
as proven with > 18 years of imipenem use
carbapenem is drug of choice in treating ESBL-producing gram-negative bacilli
-lactamase (ESBL and AmpC) alone cannot cause resistance to carbapenem
Resistance of Klebsiella to ertapenem
requires both hyper-production of -lactamase (e.g., ESBL or AmpC) PLUS chromosomal mutation (extreme impermeability or efflux mutations)
Little inoculum effect
As proven with the usage of imipenem/cilastatin over 18 years, resistance to carbapenems against Enterobacteriaceae has remained rare. Despite the spread of ESBLs and increasing resistance to cephalosporins and fluoroquinolones, carbapenems are still drugs of choice for ESBL gram-negative bacilli, according to Gold and Moellering.37
This may be backed up by carbapenems’ resistance mechanisms. To confer resistance to carbapenems against Enterobacteriaceae requires a combination of extreme impermeability and hyper-production of -lactamase (e.g., ESBL or AmpC), unlike with cephalosporins, which require only a high level of -lactamase production. And since impermeability is a chromosomal mutation that occurs at a low frequency in vivo, these mutants have a survival disadvantage of lacking the permeability of essential nutrients to enter these organisms.38 Carbapenems have little inoculum effect.
In an in vitro study, ertapenem, imipenen, and meropenem were evaluated for an inoculum effect. A differential spectrophotometic assay was conducted to determine E. coli clinical isolates that produce either ß-lactamase and K. pneumoniae clinical isolates or an uncharacterized ESBL. When the innoculum level was increased 10-fold, increasing the amount of ß-lactamase present, the MIC range of carbapenem increased to no greater than 1μg/mL. In contrast, MIC increase with non-carbapenem ß-lactams was generally greater, resulting in resistance in many cases.39
Dorso KL et al assessed the bactericidal activity of ertapenem against ESBL-producing E. coli in an in vitro time-kill kinetics study comparing to piperacillin-tazobactam, cefepime and ceftriaxone. At higher inocula (107 colony-forming units/mL), only ertapenem was bactericidal against an ESBL+ strain of E. coli.40
Gold HS, Moellering RC N Engl J Med 1996;335:1445–1452.
Fung-Tomc JC et al Antimicrob Agents Chemother 1996;40:1289–1293.
Kohler J et al Antimicrob Agents Chemother 1999;43:1170–1176.
Dorso KL et al Presented at the 23rd International Congress of Chemotherapy (ICC), South Africa, 2003.

24. Imipenem: Resistance in Enterobacteriaceae
Europe 2000–2001, The Surveillance Network (TSN) databases
2 / >125,000 isolates
USA 1998–2001, TSN
0 / >220,000 isolates
USA 1996–2002, TSN
59 / 1.42 million isolates
This table shows evidence that imipenem resistance remains extremely rare in Enterobacteriaceae, despite the fact that antimicrobial resistance is increasing in many species of Enterobacteriaceae.41
Wenzel et al analyzed data from The Surveillance Network (TSN) database collected from 2000 to 2001 in four European countries, the U.S., and Canada (N=670) to report the in vitro antimicrobial susceptibilities gram-negative bacteria isolated from hospitalized patients. All members of the Enterobacteriaceae family tested were susceptible to imipenem, with the exception of one isolate of Proteus mirabilis from France and one isolate of Morganella morganii from Canada.42
Karlowsky et al studied TSN data to determine the in vitro activities of 14 commonly tested antimicrobial agents against 10 of the most common clinically relevant Enterobacteriaceae species isolated from hospitalized U.S. patients from 1998 to Essentially all of the isolates studied were susceptible to imipenem, and imipenem susceptibility was 100% for all Enterobacteriaceae in all four years studied.41
Livermore states that imipenem retains “near universal” activity against Enterobacteriaceae, citing the fact that among 1.42 million Enterobacteriaceae isolates reported in the TSN database, just 59 (0.005%) were imipenem-resistant.43
Karlowsky JA et al Antimicrob Agents Chemother 2003;47:1672–1680.
Wenzel RP et al Antimicrob Agents Chemother 2003;47:3089–3098.
Livermore DM Ann Med 2003;35:226–234.

25. Ertapenem: Low Risk for Resistance Selection
30%
OASIS I
OASIS II
25%
End of Rx
20%
End of Rx;
or test of cure
Percent of patients
15%
10% 5% 0%
This slide presents the results of the OASIS 1 and OASIS 2 bowel colonization sub-studies.
Two rectal swabs (cotton-tipped) were collected at baseline, DCOT (discontinuation of study therapy) and TOC (test of cure, 2 weeks following DCOT). These rectal swabs were placed in transport medium and shipped to Merck Research Laboratories, where they were planted on selective media [MacConkey agar plate containing ertapenem (ETP, 0.5 µg/ml), MacConkey agar plate containing ceftriaxone (CRO, 1 µg/ml), MacConkey agar plate containing ceftazidime (CTZ, 1µg/ml)] to isolate gram-negative bacilli. The gram-negative bacilli on any selective medium were identified, and MICs to a range of antimicrobials, including imipenem (IPM), were determined by broth microdilution (following NCCLS guidelines) and E-test.44,45
In OASIS 1, of 370 patients who received >1 dose of therapy, 152 in the ertapenem group and 153 in the piperacillin-tazobactam group were assessable for the presence of resistant faecal enterics in the sub-analysis. In the OASIS 2 bowel colonization sub-study, a total of 196 ertapenem-treated and 193 ceftriaxone plus metronidazole-treated patients were evaluable.43 In OASIS 1 at baseline, a resistant Enterobacteriaceae isolate was found in one patient in the piperacillin-tazobactam group but none in ertapenem group. At both discontinuation of study therapy and test of cure study time points, only one ertapenem-treated patient (<1%) at each time point had an ertapenem-resistant Enterobacteriaceae. In contrast, at the discontinuation of study therapy study time point, 18 patients (11.8%) in the piperacillin-tazobactam group showed resistant Enterobacteriaceae to piperacillin-tazobactam, and 21 patients (13.7%) at discontinuation and/or test of cure.44
In OASIS 2 at baseline, an ertapenem-resistant Enterobacteriaceae isolate was found in one patient in the ertapenem group and 4 ceftriaxone-resistant Enterobacteriaceae in ceftriaxone plus metronidazole-treated group. At both discontinuation of study therapy and test of cure study time points, there was no emergence of ertapenem-resistant Enterobacteriaceae in the ertapenem-treated group (same resistant isolate at baseline and DCOT/TOC). In contrast, 31 patients (16.1%) at the discontinuation of study therapy and 50 patients (25.9%) at DCOT and/or TOC in the ceftriaxone plus metronidazole-treated group showed ceftriaxone-resistant Enterobacteriaceae. It is noteworthy that ceftriaxone-resistant Enterobacteriaceae significantly increased in the ceftriaxone group not only during the therapy but also two weeks post-therapy (p<0.001).45
The primary endpoint of the OASIS I study was to compare the efficacy of ertapenem to the clinical response assessment of piperacillin-tazobactam at test of cure (2 weeks post therapy). The results were 90% and 94% for ertapenem and piperacillin-tazobactam, respectively.
The primary endpoint of the OASIS II study was to compare the efficacy of ertapenem to the clinical response of ceftriaxone+metronidazole at test of cure (2 weeks post-therapy). The results were 97% for both ertapenem and ceftriaxone+metronidazole.
% R
%ESBL
% R
%ESBL
% R
%ESBL
Ertapenem
N=348
Piperacillin-Tazobactam
N=153
Ceftriaxone + Metronidazole
N=193
OASIS = Optimising Intra-Abdominal Surgery with INVANZ™ study
% R: Enterobacteriaceae resistant to study drug
% ESBL: ESBL-producing E. coli and Klebsiella spp.
Friedland I et al. Presented at the 13th ECCMID, Glasgow, UK, May 10–13, Poster #789. Friedland I et al. 3rd ACCP, Santa Margherita, Portofino, Italy, October 16–19, Poster #57.
Data on file, MSD.

26. Data from OASIS 1* and 2**: Imipenem-Resistant P. aeruginosa:
Ertapenem
Piperacillin-
Tazobactam
Ceftriaxone/
Metronidazole
OASIS 1*
0/162 (0.0%)
1/158 (0.6%) NA
OASIS 2**
2/196 (1.0%) NA
0/193 (0.0%)
In the OASIS 1 bowel colonization sub-study, imipenem-resistant P. aeruginosa was detected in one patient in the piperacillin/tazobactam group at discontinuation of therapy, while it was not detected in the ertapenem group at DCOT. In OASIS 2, imipenem-resistant P. aeruginosa was detected in two patients in the ertapenem group (p=NS) during study therapy and in none in the ceftriaxone group.44,45
These results demonstrated that little or no emergence of imipenem-resistant P. aeruginosa existed in the ertapenem-treated patient group.44,45
Based on discontinuation of therapy (DCOT) and/or test of cure (TOC) swabs
*Friedland I et al. 13th ECCMID, Glasgow, UK, May 10–13, 2003
**Friedland I et al. 3rd ACCP, Santa Margherita, Italy, October 16–19, 2003 (Poster #57)

27. 2003 IDSA Guidelines on Anti-infective Agents for Complicated IAIs
Type of Therapy
Class
Complicated Community-Acquired Infections
Health Care-Associated/ Nosocomial Infections
Without
Risk Factor*
With
Risk Factor*
Single Agent
β-lactam/ β-lactamase inhibitor
Ampicillin/ Sulbactam Ticarcillin/Clav.
Piperacillin/Tazobactam
Carbapenem
Ertapenem
Imipenem, Meropenem
Combination Regimen
In both Infectious Disease Society of America (IDSA) and Surgical Infection Society (SIS) guidelines on anti-infective agents for complicated intra-abdominal infections, patients with intra-abdominal infections acquired outside the hospital are divided into those with and those without risk factors for post-operative mortality.6
Likewise, the usage of ertapenem and imipenem has been differentiated based on this classification. Ertapenem is recommended for complicated intra-abdominal infections acquired outside the hospital, without the risk for multi-resistant flora such as Pseudomonas aeruginosa. Other carbapenems such as imipenem and meropenem are mostly for post-operative (nosocomial) intra-abdominal infections with the risk for multi-resistant flora such as Pseudomonas aeruginosa.6,8,9
Both guidelines state that unnecessary use of expanded gram-negative bacterial-spectrum agents (e.g., agents with pseudomonal coverage) could contribute to the emergence of antimicrobial resistance. Thus, appropriate usage of antibiotics and shortened durations of therapy are strongly recommended.6,8
Cephalosporin-based
Cefazolin or Cefuroxime + Metronidazole
3rd/4th Gen. Cephalosporin + Metronidazole
Fluoroquinolone -based
Fluoroquinolone + Metronidazole
Ciprofloxacin + Metronidazole
Solomkin JS et al Clin Infect Dis 2003;37:997–1005.
* Higher APACHE II scores, poor nutritional status, significant cardiovascular disease, patients with immunosuppression

28. Carbapenem Classifications
Group 1 Carbapenem
(e.g., ertapenem)
Group 2 Carbapenem
(e.g., imipenem, meropenem)
Patient Origination
IAI acquired outside the hospital
IAI acquired during hospitalizations (nosocomial)
Major Coverage Requirements
E. coli and other Enterobacteriaceae
B. fragilis and other anaerobes
Streptococci
Enterococcus
Enterobacter spp.
Staphylococcus aureus
P. aeruginosa
E. coli and other Enterobacteriaceae
With the different features of carbapenems, a new classification of carbapenems has been proposed.35
The Group 1 carbapenem (currently only ertapenem is available) is for the treatment of complicated intra-abdominal infections acquired primarily outside the hospital, which require the bacterial coverage of primarily Enterobacteriaceae such as E. coli, and anaerobes such as Bacteroides fragilis. By comparison, Group 2 carbapenems such as imipenem and meropenem are for the treatment of complicated intra-abdominal infections acquired during hospitalizations, which require the bacterial coverage of Enterococcus, Enterobacter spp. Staphylococcus aureus and coagulase-negative staphylococci (CNS), Pseudomonas spp., and E. coli.35,36,47
Shah PM, Isaacs RD J Antimicrob Chemother 2003;52:538–542.
Roehrborn A et al Clin Infect Dis 2001;33:1513–1519.

29. IAI Patient Types for Ertapenem
Ruptured appendix
Diverticulitis
Cholecystitis
Acute gastric and duodenal perforation
Traumatic perforation of the intestines
Intra-abdominal abscess (including liver and spleen)
Complicated intra-abdominal infections associated with secondary peritonitis
Without risk factors*
*Risk factors (e.g.)
high APACHE II scores (>10)
poor nutritional status
significant cardiovascular disease
inability to obtain adequate control of the source of infection
use of corticosteroid therapy
This slide summarizes the patient types for ertapenem and imipenem.
Ertapenem is recommended for complicated intra-abdominal infections associated with secondary peritonitis with or without abscess formation, which can be diagnosed as: acute appendicitis (ruptured or perforated appendix) and periappendiceal abscess; acute diverticulitis with perforation and/or abscess; cholecystitis (including gangrenous) with either rupture or perforation; acute gastric and duodenal perforation; traumatic perforation of the intestines; and intra-abdominal abscess (including liver and spleen).46

30. IAI Patient Types for Imipenem
Patients with immunosuppression
e.g., medical therapy for transplantation
Patients at risk for nosocomial infections caused by resistant organisms
e.g., prolonged length of hospital stay, prior antibiotic therapy
Patients with complicated pancreatitis
pancreatic abscess and/or necrotizing pancreatitis
Postoperative peritonitis, tertiary peritonitis, and pancreatitis with risk factors*
*Risk factors (e.g.)
high APACHE II scores (>10)
poor nutritional status
significant cardiovascular disease
inability to obtain adequate control of the source of infection
use of corticosteroid therapy
By comparison, imipenem is recommended for the treatment of severe intra-abdominal infections caused by multi-resistant nosocomial isolates, which lead to postoperative peritonitis, tertiary peritonitis, and complicated pancreatitis. Imipenem is recommended for patients with immunosuppression due to medical therapy for transplantation, patients at risk for nosocomial infections due to prolonged length of hospital stay and history of prior antibiotic therapy, and patients with pancreatic abscess and/or necrotizing pancreatitis.8

31. IAI Patient Case Study 1 – Previous History
Ertapenem
Imipenem
A 36-year-old male experiencing bloating, abdominal distention, nausea, and vomiting
A double-barrel sigmoidostomy was inserted the previous month due to extensive perianal fistulas and abscess formation
Ultrasound: Significant colon enlargement, evacuation obstruction in the colostomy area, suspected kinking, and colon wall thickening
Has not received any previous antibiotic medication
Diagnosed as perforated colon with secondary peritonitis
A 72-year-old female, transferred to the surgical ICU, controlled with mechanical ventilation
Perforation of the sigmoid colon due to diverticulitis with localized peritonitis
6 days after initial treatment (surgical intervention + antimicrobial therapy with piperacillin-tazobactam 13.5g/day), showed rapid clinical deterioration
Diagnosed as severe post-operative peritonitis with multi-organ dysfunction
This slide shows two different intra-abdominal infection patient case studies: the one on the left is more suited for ertapenem, while the one on the right is more suited for imipenem. This case study features the patients with or without previous antibiotic medication.

32. IAI Patient Case Study 2 – Emergence of ESBL
Ertapenem
Imipenem
A 44-year-old male, brought to the emergency department
Onset of chills during the past 24 hours, experienced mild nausea and abdominal pain 2 days ago
Ultrasound: Fluid in the periappendiceal area, along with thickening and edema of appendix
History of recent antibiotic treatment with oral ceftriaxone
Blood cultures obtained preoperatively grew ESBL E. coli
A 65-year-old male, admitted to the surgical ICU
At laparoscopy noted to have a duodenal perforation with extensive peritonitis
Postoperatively, on parenteral nutrition along with antibiotic therapy of ceftriaxone 2g+metronidazole 500mg /6q a day
Patient initially improves but on day 9 post-op, recurrence of fever despite antibiotic therapy
ESBL+ K. pneumoniae were isolated
This slide presents two different intra-abdominal infection patient case studies: the one on the left is more suited for ertapenem, while the one on the right is more suited for imipenem. This case study features patients suspected of having and/or presenting with ESBL-producing organisms either transmitted from community or hospital.

33. Summary
Intra-abdominal infection is still a major cause of morbidity and mortality
Principles of management of intra-abdominal infections include adequate surgical procedures as well as antimicrobial therapy
Due to the increasing prevalence of antibiotic-resistant strains of bacteria, it is important to understand
the role of antibiotics in leading to resistance
the potential of more judicious antibiotic usage in minimizing resistance selection and colonization

34. Summary (cont’d) Ongoing surveillance study: SMART**
INVANZTM† (ertapenem) and TIENAMTM† (imipenem) in general share the similar properties of carbapenems with broad-spectrum coverage and excellent clinical efficacy*
INVANZ and TIENAM have demonstrated a low risk for resistance selection
Each agent is well suited for different patient types
INVANZ for the treatment of complicated intra-abdominal infections associated with secondary peritonitis with or without abscess formation
TIENAM for the treatment of postoperative peritonitis, tertiary peritonitis and complicated pancreatitis
Ongoing surveillance study: SMART**
In general, ertapenem and imipenem share the similar properties of carbapenems. With the major difference of its spectrum coverage lacking activity against non-fermenters, ertapenem may have an advantage as it seems unlikely to be a specific selector of imipenem/meropenem resistance in these species.35
In summary, while any potent new antimicrobial must be used prudently and appropriately, an ongoing global antimicrobial surveillance study, SMART (Study for Monitoring Antimicrobial Resistance Trends)* will play a role in monitoring the resistance trend of carbapenems as well as other agents (e.g., piperacillin-tazobactam, ceftriaxone) among Enterobacteriaceae causing intra-abdominal infections.48
*SMART is an ongoing global antimicrobial resistance surveillance study focusing on disease-based isolate collection. The objective of the study is to determine susceptible rates among Enterobacteriaceae that cause intra-abdominal infections.48
*Ertapenem has minimal activity against non-fermentative gram-negative bacilli
**Study for Monitoring Antimicrobial Resistance Trends
†Trademarks of Merck & Co., Inc., Whitehouse Station, NJ, USA

35. References
1. Solomkin JS et al, for the Protocol 017 Study Group. Ertapenem versus piperacillin/tazobactam in the treatment of complicated intraabdominal infections: Results of a double-blind, randomized comparative phase III trial. Ann Surg 2003;237:235–245.
2. Yellin AE et al. Ertapenem monotherapy versus combination therapy with ceftriaxone plus metronidazole for treatment of complicated intra-abdominal infections in adults. Int J Antimicrob Agents 2002;20:165–173.
3. Fry DE. Basic aspects of and general problems in surgical infections. Surg Infect 2001;2(Suppl 1):S3–S11.
4. Pacelli F et al. Prognosis in intra-abdominal infections: Multivariate analysis on 604 patients. Arch Surg 1996;131:641–645.
5. Gerth WC et al. Economic considerations when choosing parenteral antibiotic treatment for complicated community-acquired intra-abdominal infections. EJHP 2004;4:78–83.
6. Mazuski JE et al. The Surgical Infection Society guidelines on antimicrobial therapy for intra-abdominal infections: Evidence for the recommendations. Surg Infect 2002;3:175–233.
7. Onderdonk AB et al. Microbial synergy in experimental intra-abdominal abscess. Infect Immun 1976;13:22–26.
8. Solomkin JS et al. Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections. Clin Infect DIs 2003;37:997–1005.
9. Mazuski JE et al. The Surgical Infection Society guidelines on antimicrobial therapy for intra-abdominal infections: An executive summary. Surg Infect 2002;3:161–173.
10. Cattan P et al. Outcomes of empiric antibiotic therapy for hospitalized patients with community-acquired intra-abdominal infection. Presented at the 11th Annual European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Istanbul, Turkey; 2001.
11. Rodriguez-Bano J et al. Epidemiology and clinical features of infections caused by extended-spectrum beta-lactamase-producing Escherichia coli in nonhospitalized patients. J Clin Microbiol 2004;42:1089–1094.
12. Paterson DL et al. International prospective study of Klebsiella pneumoniae bacteremia: Implications of extended-spectrum ß-lactamase production in nosocomial infections. Ann Intern Med 2004;140:26–32.
13. Paterson DL et al. Outcome of cephalosporin treatment for serious infections due to apparently susceptible organisms producing extended-spectrum beta-lactamases: Implications for the clinical microbiology laboratory. J Clin Microbiol 2001;39:2206–2212.
14. Paterson DL. Recommendations for treatment of severe infections caused by Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs). Clin Microbiol Infect 2000;6:460–463.
15. Paterson DL et al. Epidemiology of ciprofloxacin resistance and its relationship to extended-spectrum ß-lactamase production in Klebsiella pneumoniae isolates causing bacteremia. Clin Infect Dis 2000;30:473–478.
16. Oh H, Edlund C. Mechanism of quinolone resistance in anaerobic bacteria. Clin Microbiol Infect 2003;9:512–517.
17. Elsaghier AAF et al. Bacteraemia due to Bacteroides fragilis with reduced susceptibility to metronidazole. J Antimicrob Chemother 2003;51:1436–1437.
18. Moellering RC. Principles of anti-infective therapy. In: GL Mandell, JE Bennett, R Dolin, eds. Principles and Practice of Infectious Diseases. 5th ed., Churchill Livingstone, Philadelphia, PA, 2000, pp. 223–235.
19. Raymond DP et al. Preventing antimicrobial-resistant bacterial infections in surgical patients. Surg Infect 2002;3(4):375–385.
20. Davey P et al. How important is appropriate empirical antibiotic treatment for intra-abdominal infections? Presented at the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) Sixth Annual International Meeting; Virginia, USA, 2001.
21. Bare M et al. Excess mortality associated with inappropriate initial empiric antibiotic therapy in patients undergoing surgery for intra-abdominal infection. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Milan, Italy; 2002.
22. Burke J et al. Effect of adequate empiric antibiotic therapy on outcomes among patients with complicated intra-abdominal infections. Presented at the 39th World Congress of Surgery, Brussels, Belgium; 2001.
23. Sendt W et al. Association between inappropriate initial empiric antibiotic therapy and the need for reoperation and second-line therapy among German patients undergoing surgery for community-acquired intra-abdominal infections. Presented at the 12th Annual European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Milan, Italy; 2002.
24. Niederman MS. Appropriate use of antimicrobial agents: Challenges and strategies for improvement. Crit Care Med 2003;31:608–616.

36. References
25. Paterson DL. “Collateral damage” from cephalosporin or quinolone antibiotic therapy. Clin Infect Dis 2004;38(Suppl 4):S341–S345.
26. Carmeli Y et al. Antecedent treatment with different antibiotic agents as a risk factor for vancomycin-resistant Enterococcus. Emerg Infect Diseases 2002;8:802–807.
27. Landman D et al. Citywide clonal outbreak of multiresistant Acinetobacter baumannii and Pseudomonas aeruginosa in Brooklyn, NY. Arch Intern Med 2002;162:1515–1520.
28. Paterson DL et al. International prospective study of Klebsiella pneumoniae bacteremia: Implications of extended-spectrum beta-lactamase production in nosocomial infections. Ann Intern Med 2004;140:26–32.
29. Paterson DL et al. Epidemiology of ciprofloxacin resistance and its relationship to extended-spectrum beta-lactamase production in Klebsiella pneumoniae isolates causing bacteremia. Clin Infect Dis 2000;30;473–478.
30. Lautenbach E et al. Epidemiological investigation of fluoroquinolone resistance in infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. Clin Infect Dis 2001;33:1288–1294.
31. Arpin C et al. Extended-spectrum ß-lactamase-producing Enterobacteriaceae in community and private health care center. Antimicrob Agents Chemother 2003;47:3506―3514.
32. Lautenbach E et al. Risk factors for fluoroquinolone resistance in nosocomial Escherichia coli and Klebsiella pneumoniae infections. Arch Intern Med 2002;162:2469–2477.
33. Paramythiotou E et al. Acquisition of multi-drug resistant Pseudomonas aeruginosa in patients in intensive care units: Role of antibiotics with antipseudomonal activity. Clin Infect Diseases 2004;38:670–677.
34. Trouillet JL et al. Pseudomonas aeruginosa ventilator-associated pneumonia: Comparison of episodes due to piperacillin-resistant versus piperacillin-susceptible organisms. Clin Infect Dis 2002;34:
35. Livermore DM et al. Properties and potential of ertapenem. J Antimicrob Chemother 2003;52:331–344.
36. Shah PM, Isaacs RD. Ertapenem, the first of a new group of carbapenems. J Antimicrob Chemother 2003;52:538–542.
37. Gold HS, Moellering RC. Antimicrobial drug resistance. N Engl J Med 1996;335:1445–1453.
38. Fung-Tomc JC et al. Differences in the resistant variants of Enterobacter cloacae selected by extended-spectrum cephalosporins. Antimicrob Agents Chemother 1996;40:1289―1293.
39. Kohler J et al. In vitro activities of the potent, broad-spectrum carbapenem MK-0826 (L-749,345) against broad-spectrum beta-lactamase- and extended spectrum beta-lactamase-producing Klebsiella pneumoniae and Escherichia coli clinical isolates. Antimicrob Agents Chemother 1999;43:1170–1176.
40. Dorso KL et al. In vitro killing of gram-negative enteric pathogens by ertapenem and other beta-lactams: Effect of inoculum size and serum. Presented at the 23rd International Congress of Chemotherapy (ICC), South Africa, 2003.
41. Karlowsky JA et al. Trends in antimicrobial susceptibilities among Enterobacteriaceae isolated from hospitalized patients in the United States from 1998 to Antimicrob Agents Chemother 2003;47:1672–1680.
42. Wenzel RP et al. In vitro susceptibilites of gram-negative bacteria isolated from hospitalized patients in four European countries, Canada, and the United States in to expanded-spectrum cephalosporins and comparator antimicrobials: Implications for therapy. Antimicrob Agents Chemother 2003;47:3089–3098.
43. Livermore DM. The threat from the pink corner. Ann Med 2003;35(4):226–234.
44. Friedland I et al. Presented at the 13th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), Glasgow, UK, May 10-13, Poster #789.
45. Friedland I et al. 3rd International Meeting on Antimicrobial Chemotherapy in Clinical Practice (ACCP), Santa Margherita, Portofino, Italy, October 16-19, Poster #30.
46. Data on file, MSD
47. Roehrborn A et al. The microbiology of postoperative peritonitis. Clin Infect Dis 2001;33:1513–1519.
48. Friedland I et al. Antimicrobial susceptibility in Enterobacteriaceae causing intraabdominal infections: Results from SMART in the US and Asia, Presented at the 43rd ICAAC, Chicago, Illinois, 2003.

37. Please Consult the Summary of Product Characteristics before Prescribing
Copyright © 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.
8-05 INV 2004-W-6307-SS