Transcript No Slide Title

Effective and Appropriate
Antimicrobial Therapy
for Intra-abdominal Infections
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
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.
Most Common Pathogens in 2 Studies
of Community-Acquired IAI
Pathogens
Gram Positive Cocci
Streptococcus spp.
Enterococcus spp.
Gram Negative Bacilli
Escherichia coli
Klebsiella spp.
Enterobacter spp.
Pseudomonas aeruginosa
Bacteroides fragilis
Other Bacteroides spp.
Adapted from Gerth WC et al EJHP 2004;4:78–83.
Cattan
(n=317)
Sendt
(n=313)
12%
7%
7%
6%
40%
3%
1%
4%
9%
6%
47%
7%
4%
4%
2%
6%
Microbial Synergy in Experimental
Intra-abdominal Abscess (in Wistar Rats)
Role of Enterobacteriaceae and Anaerobes (rodents)
%
100
Mortality
Abscesses
75
50
25
0
E. coli
Enterococcus
B. fragilis
E. coli +
Enterococcus
Onderdonk AB et al Infect Immun 1976;13:22–26.
E. coli +
B. fragilis
Enterococcus +
B. fragilis
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
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.
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
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 secondline therapy
 Reduced number of IV antibiotic days
 Shorter hospital length of stay
 Lower hospital costs
 Reduction in the emergence of antimicrobial
resistance
Davey 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 12 th
ECCMID (European Congress of Clinical Microbiology and Infectious Disease), Milan, Italy; 2002. Niederman MS et al Crit
Care Med 2003;31:608–616.
Appropriate Antimicrobial Therapy for
IAI: Successful Clinical Outcome
Percentage of patients with
clinical success (%)
IAI patients with adequate empiric therapy were significantly
more likely to have successful clinical outcome*
100.0%
80.0%
p<0.05
81.9%
60.0%
58.9%
40.0%
20.0%
0.0%
Empiric antibiotic
therapy appropriate
(n=238)
Empiric antibiotic
therapy inappropriate
(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
Appropriate Antimicrobial Therapy
for IAI: Reduced Mortality
Mortality was substantially lower for IAI patients
who received appropriate empiric therapy
Mortality (%)
40.0%
p<0.05
30.0%
20.0%
10.0%
23%
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.
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
Percentage (%)
100
80
4
3
12
5
11
27
60
40
Patient died
Resolved after
re-operation
Resolved with
second-line
therapy
81
57
20
Resolved with
initial or stepdown therapy
0
Appropriate Initial
Empiric Antibiotic
Therapy
Inappropriate Initial
Empiric Antibiotic
Therapy
Sendt W et al. Presented at the 12th Annual European Congress of Clinical Microbiology and Infectious Diseases,
Milan, Italy; 2002.
Appropriate Antimicrobial Therapy for IAI:
Decreased Length of Hospital Stay (LOS)
Appropriately treated IAI patients experienced
10 fewer hospital days
Length of Stay (Days)
25
p<0.05
20
22
10 days
15
10
12
5
0
Appropriate Empiric
Antibiotic (n=129)
Inappropriate Empiric
Antibiotic (n=33)
Davey P et al. Presented at the International Society of Pharmacoeconomics and Outcomes Research Sixth Annual
International Meeting; Virginia, USA, 2001.
“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 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
Adapted from Paterson DL Clin Infect Dis 2004;38(Suppl 4):S341–S345.
Risk Factors for VRE and
Acinetobacter spp.
 In a single-center retrospective study (880 inpatients; 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.
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
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.
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.
Arpin C et al Antimicrob Agents Chemother 2003;47:3506–3514.
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.
Lautenbach E Arch Intern Med 2002;162:2469–2477.
Correlation of Fluoroquinolone-Resistant
Pathogens to Other Agents
% Resistant
In a hospital-based case-control investigation (N=205):
Antimicrobial susceptibilities of fluoroquinolone-resistant and
fluoroquinolone-susceptible isolates
80
70
60
50
40
30
20
10
0
FQ Susceptible
FQ Resistant
Ampicillinsulbactam
Cafazolin
Ceftriaxone
Sodium
SulfaGentamicin
methoxazoleSulfate
Trimethoprim
Lautenbach E Arch Intern Med 2002;162:2469–2477.
Imipenem
Nitrofurantoin
Tetracycline
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 gramnegative 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.
The Role of Carbapenems
in the Era of
Antimicrobial Resistance
Properties of Carbapenems
 Excellent clinical efficacy
 Broad-spectrum coverage over grampositive and gram-negative aerobic and
anaerobic pathogens*
 Rapidly bactericidal
 Proven tolerability profile
 Low risk for resistance selection
*Ertapenem has minimal activity against non-fermentative gram-negative bacilli
Shah PM, Isaacs R J Antimicrob Chemother 2003;52:331–344.
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
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
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.
Ertapenem: Low Risk for
Resistance Selection
Percent of patients
30%
OASIS I
25%
End of Rx
20%
End of Rx;
or test of cure
OASIS II
15%
10%
5%
0%
%R
%ESBL
Ertapenem
N=348
%R
%ESBL
%R
%ESBL
Piperacillin-Tazobactam Ceftriaxone + Metronidazole
N=153
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, 2003. Poster #789. Friedland I et al. 3rd ACCP,
Santa Margherita, Portofino, Italy, October 16–19, 2003. Poster #57.
Data on file, MSD.
Data from OASIS 1* and 2**:
Imipenem-Resistant P. aeruginosa:
Ertapenem
PiperacillinTazobactam
Ceftriaxone/
Metronidazole
OASIS 1*
0/162 (0.0%)
1/158 (0.6%)
NA
OASIS 2**
2/196 (1.0%)
NA
0/193 (0.0%)
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)
2003 IDSA Guidelines on
Anti-infective Agents for Complicated IAIs
Type of
Therapy
Single Agent
Combination
Regimen
Complicated CommunityAcquired Infections
With
Risk Factor*
Health CareAssociated/
Nosocomial
Infections
Class
Without
Risk Factor*
β-lactam/
β-lactamase
inhibitor
Ampicillin/
Sulbactam
Ticarcillin/Clav.
Piperacillin/Tazobactam
Carbapenem
Ertapenem
Imipenem, Meropenem
Cephalosporinbased
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
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
Shah PM, Isaacs RD J Antimicrob Chemother 2003;52:538–542.
Roehrborn A et al Clin Infect Dis 2001;33:1513–1519.
IAI Patient Types for Ertapenem
 Ruptured appendix
• Complicated intraabdominal 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
 Diverticulitis
 Cholecystitis
 Acute gastric and duodenal
perforation
 Traumatic perforation of the
intestines
 Intra-abdominal abscess
(including liver and spleen)
IAI Patient Types for Imipenem
• 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
 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
IAI Patient Case Study 1 – Previous History
Ertapenem
 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
Imipenem
 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 postoperative peritonitis with multiorgan dysfunction
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
 A 65-year-old male, admitted to
the surgical ICU
 At laparoscopy noted to have a
duodenal perforation with
extensive peritonitis
 Ultrasound: Fluid in the
periappendiceal area, along with
thickening and edema of
appendix
 Postoperatively, on parenteral
nutrition along with antibiotic
therapy of ceftriaxone
2g+metronidazole 500mg /6q a
day
 History of recent antibiotic
treatment with oral ceftriaxone
 Blood cultures obtained
preoperatively grew ESBL+
E. coli
 Patient initially improves but on
day 9 post-op, recurrence of fever
despite antibiotic therapy
 ESBL+ K. pneumoniae were
isolated
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 antibioticresistant 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 (cont’d)
 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
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