Effective and Appropriate Antimicrobial Therapy

for Intra-abdominal Infections

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.

The Clinical Impact ofIntra-abdominal Infection (IAI)

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 IAI is a major cause of morbidity and mortality

Pathogens Cattan(n=317)

Sendt(n=313)

Gram Positive Cocci Streptococcus spp. Enterococcus spp.Gram Negative Bacilli Escherichia coli Klebsiella spp. Enterobacter spp. Pseudomonas aeruginosaBacteroides fragilisOther Bacteroides spp.

12%7%

40%3%1%4%9%6%

7%6%

47%7%4%4%2%6%

Adapted from Gerth WC et al EJHP 2004;4:78–83.

Most Common Pathogens in 2 Studiesof Community-Acquired IAI

0

25

50

75

100

E. coli Enterococcus B. fragilis E. coli +Enterococcus

E. coli + B. fragilis

Enterococcus +B. fragilis

%

Abscesses

Mortality

Microbial Synergy in Experimental Intra-abdominal Abscess (in Wistar Rats)

Onderdonk AB et al Infect Immun 1976;13:22–26.

Role of Enterobacteriaceae and Anaerobes (rodents)

Appropriate Management ofComplicated 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

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.

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

Rodriguez-Bano J et al J Clin Micro 2004;42:1089–1094. Paterson DL et al Ann Intern Med 2004;140:26–32. Paterson DL et al J Clin Micro 2001;39:2206–2212. 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.

Considerations in determining appropriate therapy:

Appropriate Antimicrobial 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 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.

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 resistanceDavey P et al. ISPOR 6th Annual International Meeting; Virginia, USA, 2001. Bare M et al. ECCMID, Milan, Italy; 2002. Burke J et al. Presented at the 39th World Congress of Surgery, Brussels, Belgium; 2001. Sendt W et al. Presented at the 12th ECCMID (European Congress of Clinical Microbiology and Infectious Disease), Milan, Italy; 2002. Niederman MS et al Crit Care Med 2003;31:608–616.

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

IAI patients with adequate empiric therapy were significantly more likely to have successful clinical outcome*

Appropriate Antimicrobial Therapy for IAI: Successful Clinical Outcome

p<0.05

81.9%

58.9%

0.0%

20.0%

40.0%

60.0%

80.0%

100.0%

Empiric antibiotictherapy appropriate

(n=238)

Empiric antibiotictherapy inappropriate

(n=56)

Per

cent

age

of p

atie

nts

with

cl

inic

al s

ucce

ss (

%)

Appropriate Antimicrobial Therapy for IAI: Reduced Mortality

Mortality was substantially lower for IAI patients who received appropriate empiric therapy

Bare M et al. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases, Milan, Italy; 2002.

p<0.05

12%

23%

0.0%

10.0%

20.0%

30.0%

40.0%

Appropriate antibiotic therapy (n=272)

Inappropriate antibiotic therapy (n=93)

Mor

talit

y (%

)

Sendt W et al. Presented at the 12th Annual European Congress of Clinical Microbiology and Infectious Diseases, Milan, Italy; 2002.

Patients (N=425) given appropriate initial empiric therapy for IAI were less likely to undergo re-operation and require second-line antibiotic therapy

Appropriate Antimicrobial Therapy for IAI: Decreased Need for Re-operation and Use of Second-Line Therapy

Patient died

Resolved afterre-operation

Resolved withsecond-linetherapy

Resolved withinitial or step-down therapy

5781

27

12 113

54

0

20

40

60

80

100

Appropriate InitialEmpiric Antibiotic

Therapy

Inappropriate InitialEmpiric Antibiotic

Therapy

Per

cent

age

(%)

Davey P et al. Presented at the International Society of Pharmacoeconomics and Outcomes Research Sixth Annual International Meeting; Virginia, USA, 2001.

10 days

Appropriately treated IAI patients experienced 10 fewer hospital days

Appropriate Antimicrobial Therapy for IAI: Decreased Length of Hospital Stay

(LOS)

22

12

0

5

10

15

20

25

Appropriate EmpiricAntibiotic (n=129)

Inappropriate EmpiricAntibiotic (n=33)

Leng

th o

f Sta

y (D

ays

) p<0.05

“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”

Paterson DL et al Clin Infect Dis 2004;38(Suppl 4):S341–S345.

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 cephalosporinsVancomycin-resistant enterococci (VRE)

Extended-spectrum ß-lactamase–producing Klebsiella species

ß-lactam–resistant Acinetobacter species

Clostridium difficile

QuinolonesMethicillin-resistant Staphylococcus aureus (MRSA)

Quinolone-resistant gram-negative bacilli, including Pseudomonas aeruginosa

Adapted from Paterson DL Clin Infect Dis 2004;38(Suppl 4):S341–S345.

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. *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.

Risk Factors for VRE andAcinetobacter spp.

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

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.

Challenges in the Clinical Management of ESBLs

Community Transmission of ESBLs

Arpin C et al Antimicrob Agents Chemother 2003;47:3506–3514.

Distribution of ESBL producers- 39/2599 (1.5%) detected among the family

Enterobacteriaceae23/887 (2.6%) strains from clinics11/128 (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.

Risk Factors for Fluoroquinolone Resistance

Lautenbach E Arch Intern Med 2002;162:2469–2477.

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.

In a hospital-based case control investigation (n=205):

Lautenbach E Arch Intern Med 2002;162:2469–2477.

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

010203040

50607080

Ampicillin-sulbactam

Cafazolin CeftriaxoneSodium

Sulfa-methoxazole-Trimethoprim

GentamicinSulfate

Imipenem Nitro-furantoin

Tetracycline

FQ Resistant

FQ Susceptible

% R

esis

tan

t

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)

Paramythiotou E et al Clin Infect Diseases 2004;38:670–677.

Risk Factors for Selecting Pseudomonal Resistance

In a matched case-control study conducted between 1999 and 2000 in France:

The Role of Carbapenems in the Era of

Antimicrobial Resistance

*Ertapenem has minimal activity against non-fermentative gram-negative bacilli

Shah PM, Isaacs R J Antimicrob Chemother 2003;52:331–344.

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

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

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.

Imipenem: Resistance in Enterobacteriaceae

59 / 1.42 million isolatesUSA 1996–2002, TSN

0 / >220,000 isolatesUSA 1998–2001, TSN

2 / >125,000 isolatesEurope 2000–2001, The

Surveillance Network (TSN) databases

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.

Friedland I et al. Presented at the 13th ECCMID, Glasgow, UK, May 10–13, 2003. Poster #789. Friedland I et al. 3 rd ACCP, Santa Margherita, Portofino, Italy, October 16–19, 2003. Poster #57.Data on file, MSD.

Ertapenem: Low Risk for Resistance Selection

0%

5%

10%

15%

20%

25%

30%

ErtapenemN=348

Piperacillin-TazobactamN=153

Per

cent

of p

atie

nts

% R %ESBL % R %ESBL % R %ESBLCeftriaxone + 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.

End of Rx

End of Rx; or test of cure

OASIS I OASIS II

Data from OASIS 1* and 2**: Imipenem-Resistant P. aeruginosa:

*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)

0/193 (0.0%)NA2/196 (1.0%)OASIS 2**

NA1/158 (0.6%)0/162 (0.0%)OASIS 1*

Ceftriaxone/Metronidazole

Piperacillin-Tazobactam

Ertapenem

Based on discontinuation of therapy (DCOT) and/or test of cure (TOC) swabs

2003 IDSA Guidelines on Anti-infective Agents for Complicated IAIs

Imipenem, MeropenemErtapenemCarbapenem

Ciprofloxacin + MetronidazoleFluoroquinolone

-based

3rd/4th Gen. Cephalosporin + Metronidazole

Cefazolin or Cefuroxime + Metronidazole

Cephalosporin-basedCombinati

on Regimen

Piperacillin/TazobactamAmpicillin/Sulbactam

Ticarcillin/Clav.

β-lactam/β-lactamase

inhibitorSingle Agent

With Risk Factor*

Without Risk Factor*

Health Care-Associated/ Nosocomial Infections

Complicated Community-Acquired Infections

ClassType of Therapy

Solomkin JS et al Clin Infect Dis 2003;37:997–1005.* Higher APACHE II scores, poor nutritional status, significant cardiovascular disease, patients with

immunosuppression

Fluoroquinolone +

Metronidazole

Major Coverage Requirements

• E. coli and other Enterobacteriaceae

• B. fragilis and other anaerobes

• Streptococci

Patient Origination

• IAI acquired outside the hospital

Carbapenem Classifications

• Enterococcus• Enterobacter spp.• Staphylococcus aureus• P. aeruginosa• E. coli and other Enterobacteriaceae

• IAI acquired during hospitalizations (nosocomial)

Group 1 Carbapenem (e.g., ertapenem)

Group 2 Carbapenem(e.g., imipenem, meropenem)

Shah PM, Isaacs RD J Antimicrob Chemother 2003;52:538–542.Roehrborn A et al Clin Infect Dis 2001;33:1513–1519.

Ruptured appendix Diverticulitis Cholecystitis Acute gastric and

duodenal perforation Traumatic perforation of

the intestines Intra-abdominal abscess

(including liver and spleen)

IAI Patient Types for Ertapenem

• 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

IAI Patient Types for Imipenem

*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

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*

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

IAI Patient Case Study 1 – Previous History

Ertapenem 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

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

IAI Patient Case Study 2 – Emergence of ESBL

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

Ertapenem Imipenem

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

Summary

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**

*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

Summary (cont’d)

References1. 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.

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;34:1047-1054.

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 2001. 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 2000-2001 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, 2003. Poster #789.45. Friedland I et al. 3rd International Meeting on Antimicrobial Chemotherapy in Clinical Practice (ACCP), Santa Margherita, Portofino,

Italy, October 16-19, 2003. 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, 2002. Presented at the 43rd ICAAC, Chicago, Illinois, 2003.

References

Copyright © 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.

8-05 INV 2004-W-6307-SS

Please Consult the Summary of Product Characteristics

before Prescribing