Antibiotic Monotherapy for Intraabdominal Infections
IS BROAD SPECTRUM MONOTHERAPY
ANTIBIOTIC TREATMENT ADEQUATE
FOR INTRAABDOMINAL INFECTIONS ?
Nicolas V. Christou
Associate Professor of Surgery
and Microbiology
McGill University
Antibiotic Monotherapy for Intraabdominal Infections
DIAGNOSIS OF INTRA-ABDOMINAL
INFECTION
History & Physical Examination
Laboratory Tests
Imaging techniques
Antibiotic Monotherapy for Intraabdominal Infections
OUTLINE

Basic principles

Review of antibiotic choices

Presentation of most recent
data on monotherapy

Conclusions
Antibiotic Monotherapy for Intraabdominal Infections
MORTALITY OF INTRA-ABDOMINAL INFECTIONS
Mortality %
60
40
20
0
Localized
Abscess
Localized
Peritonitis
Diffuse
Combined
Suppurative Complicated
Peritonitis
Infection
Antibiotic Monotherapy for Intraabdominal Infections
TREATMENT OF INTRA-ABDOMINAL INFECTIONS

Surgical drainage
and correction of
pathology

broad spectrum
EMPIRIC antibiotic
therapy
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTIC THERAPY OF SURGICAL INFECTIONS
Empiric Antibiotic Therapy:
A single antibiotic or a combination of antibiotics
providing BROAD SPECTRUM coverage
against all possible pathogens.
Definitive Antibiotic Therapy:
Antibiotic administration based on specific
culture and sensitivity results.
Antibiotic Monotherapy for Intraabdominal Infections
HOW DOES ONE PICK APPROPRIATE
EMPIRIC ANTIBIOTIC THERAPY ?
Use an antibiotic
or combination
of antibiotics
that provides
broad spectrum
activity to cover
all suspected
PATHOGENS.
Antibiotic Monotherapy for Intraabdominal Infections
SUSPECTED PATHOGENS IN INTRA-ABDOMINAL INFECTIONS
RVH Data
Gm -ve AEROBES
Other (16%)
P. mirabilis (4%)
Enterobacter (5%)
P. aeruginosa (5%)
K. pneumonia (11%)
E. coli (59%)
Antibiotic Monotherapy for Intraabdominal Infections
SUSPECTED PATHOGENS IN INTRA-ABDOMINAL INFECTIONS
Gm +ve AEROBES
S. epidermidis (6%)
RVH Data
Others (4%)
Corynebacteria (10%)
S. aureus (25%)
Enterococcus (55%)
Antibiotic Monotherapy for Intraabdominal Infections
SUSPECTED PATHOGENS IN INTRA-ABDOMINAL INFECTIONS
RVH Data
ANAEROBES
Others (9%)
Fusobacteria (6%)
B. fragilis (27%)
Bacteroidis sp. (57%)
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTICS FOR SURGICAL INFECTIONS
Penicillins
Aminoglycosides
Cephalosporins Metronidazole
Carbapenems
Clindamycin
Quinolonnes
Vancomycin
Antibiotic Monotherapy for Intraabdominal Infections
PENICILLINS
(Penem nucleus)
 Penicillin G
 Methicillin
 Cloxacillin
 Carboxipenicillins
Basic structure of Penicillins
 Ureidopenicillins
Antibiotic Monotherapy for Intraabdominal Infections
In vitro ACTIVITY of PIPERACILLIN
Minimal Inhibitory Concentration (MIC
90
0
Anaerobic cocci
Fusobacterium
Bacteroides
B. fragilis
Enterococci
S. epedermidis
Streptococci
S. aureus
Acinetobacter
Moerganella
Citrobacter
Seratia
Proteus
P. aeruginosa
Klebsiella
Enterobacter
E. coli
10
20
30
40
in µg/ml) of Antibiotic
50
60
70
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTICS FOR SURGICAL INFECTIONS
"More Recent" therapy
UreidoPenicillin
(Antianaerobic
Agent)
eg Piperacillin
1-2 g q8h
(eg Clindamycin
600 mg q8h)
Antibiotic Monotherapy for Intraabdominal Infections
AMINOGLYCOSIDES
(gentamycin)
 Gentamycin
 Tobramycin
 Netilmicin
 Amikacin
Excellent Gm- activity
Antibiotic Monotherapy for Intraabdominal Infections
In vitro Activity of Aminoglycosides - GENTAMYCIN
Minimal Inhibitory Concentration (MIC90 in µg/ml) of Antibiotic
0
Anaerobic cocci
Fusobacterium
Bacteroides
B. fragilis
Enterococci
S. epedermidis
Streptococci
S. aureus
Acinetobacter
Moerganella
Citrobacter
Seratia
Proteus
P. aeruginosa
Klebsiella
Enterobacter
E. coli
20
40
60
80
100
120
140
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTICS FOR SURGICAL INFECTIONS
"Gold Standard" therapy
Aminoglycoside
+
Antianaerobic
Agent
eg Gentamycin
2-3 mg/kg q8h
eg Clindamycin
600 mg q8h
Antibiotic Monotherapy for Intraabdominal Infections
Aminoglycoside Use - Caution
 Ototoxicity
Occurs in up to 30% of
cases and often is not
reversible.
Nephrotoxicity
Occurs in up to 5% of
cases and is often
reversible.
Antibiotic Monotherapy for Intraabdominal Infections
CEPHALOSPORINS
First Generation
eg. Cephazolin
Penam nucleus
Second Generation
eg. Cefoxitin
R
R1
Cephem nucleus
Third Generation
eg. Cefotaxime
Antibiotic Monotherapy for Intraabdominal Infections
In vitro ACTIVITY of 2nd GENERATION CEPHALOSPORINS
- CEFOXITIN
Minimal Inhibitory Concentration (MIC90 in µg/ml) of Antibiotic
0
Anaerobic cocci
Fusobacterium
Bacteroides
B. fragilis
Enterococci
S. epedermidis
Streptococci
S. aureus
Acinetobacter
Moerganella
Citrobacter
Seratia
Proteus
P. aeruginosa
Klebsiella
Enterobacter
E. coli
20
40
60
80
100
120
140
Antibiotic Monotherapy for Intraabdominal Infections
In vitro ACTIVITY of 3rd GENERATION CEPHALOSPORINS
- CEFOTAXIME
Minimal Inhibitory Concentration (MIC90 in µg/ml) of Antibiotic
0
Anaerobic cocci
Fusobacterium
Bacteroides
B. fragilis
Enterococci
S. epedermidis
Streptococci
S. aureus
Acinetobacter
Moerganella
Citrobacter
Seratia
Proteus
P. aeruginosa
Klebsiella
Enterobacter
E. coli
5
10
15
20
25
30
35
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTICS FOR SURGICAL INFECTIONS
"More Recent" therapy
rd
3 Generation
Cephalosporin
+
Antianaerobic
Agent
eg Cefoperazone
1-2 g q12h
eg Clindamycin
600 mg q8h
Antibiotic Monotherapy for Intraabdominal Infections
QUINOLONES
Basic Structure of Quinolones

"True Quinolones"
Norfloxacin
Ciprofloxacin
Enoxacin
Classified according to
modifications at X2 and X8
positions.
Perfloxacin
Ofloxacin
Antibiotic Monotherapy for Intraabdominal Infections
In vitro activity of QUINOLONES
Minimal Inhibitory Concentration (MIC
90
0
Anaerobic cocci
Fusobacterium
Bacteroides
B. fragilis
Enterococci
S. epedermidis
Streptococci
S. aureus
Acinetobacter
Moerganella
Citrobacter
Seratia
Proteus
P. aeruginosa
Klebsiella
Enterobacter
E. coli
5
10
15
20
in µg/ml) of Antibiotic
25
30
35
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTIC "EFFICACY" STUDIES:
INTRAABDOMINAL INFECTIONS
Cephalosporin
based Rx
52-96% range
Aminoglycoside
based Rx
61-95% range
0
20
40
60
Success Rate %
80
100
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTIC "EFFICACY" STUDIES:
INTRAABDOMINAL INFECTIONS
Problems in Study Design
exclusion
lack
criteria not rigid
of "illness stratification"
results
reporting
Antibiotic Monotherapy for Intraabdominal Infections
CARBAPENEMS
Imipenem
- approved for use
Meropenem
- phase III clinical trials
Antibiotic Monotherapy for Intraabdominal Infections
In vitro activity of IMIPENEM
Minimal Inhibitory Concentration (MIC90 in µg/ml) of Antibiotic
0
Anaerobic cocci
Fusobacterium
Bacteroides
B. fragilis
Enterococci
S. epedermidis
Streptococci
S. aureus
Acinetobacter
P. species
Citrobacter
Seratia
Proteus
P. aeruginosa
Klebsiella
Enterobacter
E. coli
10
20
30
40
50
60
70
Antibiotic Monotherapy for Intraabdominal Infections
COMPARATIVE ACTIVITIES OF VARIOUS ANTIBIOTICS
Enterobacter cloacae
Tobram ycin
Ceftazidim e
Ceftazidim e
Piperacillin
Piperacillin
Im ipenem
Im ipenem
0
2
4
6
8
10
12
14
16
Acinetobacter calcoaceticus
Tobram ycin
0
5
10
MIC (90) µg/ml
Tobram ycin
P. aeruginosa
Piperacillin
Piperacillin
Im ipenem
Im ipenem
4
6
8
10 12 14 16 18 20
MIC (90) µg/ml
25
30
35
40
S. faecalis
Am picillin
Ceftazidim e
2
20
MIC (90) µg/ml
Ceftazidim e
0
15
0
20
40
60
80
100 120 140
MIC (90) µg/ml
Antibiotic Monotherapy for Intraabdominal Infections
A Multicenter Comparative Trial of Imipenem/Cilastatin vs
Tobramycin/Clindamycin for Intraabdominal Infections
Prospective, randomized, open design
290 Patients Entered
143 - Tobra/Clinda
147 - Imipenem
81 Patients Evaluable
81 Patients Evaluable
Antibiotic Monotherapy for Intraabdominal Infections
Statistical Considerations
 Assumed failure rate = 25%
 Assumed nonevaluability rate = 30%
 Sample size to detect a 50% difference in
outcome with = .05 and ß = .20
 Adequate sample size: n=300
2
 Logistic Regression Analysis, X , and
Student's t-tests
Antibiotic Monotherapy for Intraabdominal Infections
Criteria for Eligibility

> 18 years

No drug hypersensitivity

Normal renal function

Suspected Intraabdominal
Infection
Antibiotic Monotherapy for Intraabdominal Infections
Criteria for Exclusion
 Simple Appendicitis
 Simple Cholecystitis
 Traumatic bowel perforation < 12h
 Perforated peptic ulcer < 24 h
 Exploration with negative bacterial
cultures
Antibiotic Monotherapy for Intraabdominal Infections
Reasons for Exclusion of 128 Patients
M iscelaneous
Tobra/Clinda n=61
Imipenem n=67
Inadequate OR
M edication errors
<12 h perforation
Survival < 48h
No Intervention
No Infection
0
10
20
30
Number of Patients
40
Antibiotic Monotherapy for Intraabdominal Infections
"ILLNESS" STRATIFICATION
% Mortality
APACHE II
100
80
A severity of disease
classification system
based on acute and
chronic physiologic
response variables
such as :
60
40
20
 Pulse, Pressure etc
0
0-4
5-9
10-14 15-19 20-24 25-29 30-34
APACHE II Ranges
35+
 Oxygenation, pH
 Glascow Coma Scale
Antibiotic Monotherapy for Intraabdominal Infections
Drug Therapy
 Imipenem/Cilastatin 500 mg i.v. q6h
 Tobramycin 1.5 mg/kg i.v. with interval adjusted
for serum creatinine,
+
Clindamycin 600 mg i.v. q8h
 Tobramycin levels aimed at : peak > 6 µg/ml and
trough < 2 µg/ml
Antibiotic Monotherapy for Intraabdominal Infections
Outcome Scoring
 Local Intra-abdominal
Infection
 Hospitalization
Antibiotic Monotherapy for Intraabdominal Infections
Definition of Rx Success
 Initial study driven
antibiotic therapy and an
adequate operation cured
the intraabdominal
infection.
Antibiotic Monotherapy for Intraabdominal Infections
Definition of Rx Failure

Survival of < 7 days

Second intervention showed
recurrence with initial
organisms

Wound Infection developed
Antibiotic Monotherapy for Intraabdominal Infections
Demographics of Evaluable Patients - I
Sex (M:F)
Age
<50
50-59
60-69
70-79
>79
Tobra/Clinda
Imipenem
49:32
51:30
23
10
24
17
7
33
16
13
13
6
Antibiotic Monotherapy for Intraabdominal Infections
Demographics of Evaluable Patients -II
Tobra/Clinda
Imipenem
Cirrhosis
Diabetes
Malnutrition
Alcoholism
Malignancy
0
4
8
Number of Patients
12
16
Antibiotic Monotherapy for Intraabdominal Infections
Disease Processes Encountered at Initial Operation
Other
Post-Op
Colon
Appendix
Small Bowel
Tobra/Clinda
Imipenem
Biliary
Stom/Duod
0
4
8
12
16
Number of Patients
20
24
Antibiotic Monotherapy for Intraabdominal Infections
Mean APACHE II Scores Encountered at Admission
Other
Post-Op
Colon
Tobra/Clinda
Imipenem
Appendix
Small Bowel
Biliary
Stom/Duod
0
4
8
12
16
Mean APACHE II Score
20
24
Antibiotic Monotherapy for Intraabdominal Infections
Organisms Encountered in Intra-Abdominal Foci
Gm -ve aerobes
E. coli
Enterobacter spp.
Klebsiella spp.
P. aeruginosa
Proteus spp.
S. marcencens
Tobra/Clinda
Imipenem
Citrobacter spp.
M. morgagni
Others
0
5
10
15
20
25
30
Number of Patients
35
40
45
50
Antibiotic Monotherapy for Intraabdominal Infections
Organisms Encountered in Intra-Abdominal Foci
Gm +ve aerobes
Alpha Strep
Enterococci
ß-Streptococci
S. aureus
Tobra/Clinda
Imipenem
S. epidermides
Candida
0
5
10
15
Number of Patients
20
25
Antibiotic Monotherapy for Intraabdominal Infections
Organisms Encountered in Intra-Abdominal Foci
Anaerobes
B. fragilis
Bacteroides spp.
Clostridium spp.
Peptococci
Fusobacterium spp.
Tobra/Clinda
Imipenem
Lactobacillus
Eubacterium spp.
Others
0
5
10
15
Number of Patients
20
25
Antibiotic Monotherapy for Intraabdominal Infections
Microbiologic Patterns of Encountered Infections
Mixed
Gm-ve rods only
Gm+ cocci only
Tobra/Clinda
Imipenem
Anaerobes Only
0
10
20
30
40
Number of Patients
50
60
Antibiotic Monotherapy for Intraabdominal Infections
Activity of Study Agents: Gm-ve Bacteria
E.coli
Tobra/Clinda
Imipenem
Enterobacter
Klebsiella
Proteus spp.
P. aeruginosa
Citrobacter
spp.
Others
0
4
8
MIC 90 (µg/ml) of Antibiotic
12
16
Antibiotic Monotherapy for Intraabdominal Infections
Activity of Study Agents: Anaerobic Bacteria
B. fragilis
Clindamycin
Imipenem
Bacteroides
spp.
Clostridium
Spp.
Enterococci
0
4
8
12
16
20
MIC 90 (µg/ml) of Antibiotic
24
28
32
Antibiotic Monotherapy for Intraabdominal Infections
Overall Deaths, Failures and Predicted Deaths
# patients
60

Failures
Deaths
50

40
Predicted
30
20
10




0
0 -4
5 - 9
10 - 14
15 - 16
20 - 24
APACHE II Range
# Enrolled
24
39
36
36
18
Antibiotic Monotherapy for Intraabdominal Infections
Analysis of Deaths - I
Tobra/CLinda (n=14)
Imipenem (n=11)
Death within 7
days
Death with Rx
Failure
Death with Rx
Success
0
2
# Patients
4
6
Antibiotic Monotherapy for Intraabdominal Infections
Analysis of Deaths - II
Tobra/CLinda (n=14)
Imipenem (n=11)
Death within 7
days
Death with Rx
Failure
Death with Rx
Success
0
4
8
12
16
APACHE II Score
20
24
Antibiotic Monotherapy for Intraabdominal Infections
Analysis of Deaths - III
Tobra/CLinda (n=14)
Imipenem (n=11)
Death within 7
days
Death with Rx
Failure
Death with Rx
Success
0
10
20
30
Survival Time (days)
40
50
Antibiotic Monotherapy for Intraabdominal Infections
Failure as a Function of APACHE II and Antibiotic
Regimen: All Patients
25
Tobra/Clinda
20
Cumulative
Failures
X2 = 4.1 p=0.0429
15
Imipenem
10
5
0
0
5
10
15
20
25
APACHE II Score
30
35
40
Antibiotic Monotherapy for Intraabdominal Infections
Failure as a Function of APACHE II and Antibiotic
Regimen: Gm-ve Organisms
20
Tobra/Clinda
15
Cumulative
Failures
X 2 = 5.65 p=0.0175
10
Imipenem
5
0
0
5
10
15
20
25
APACHE II Score
30
35
40
Antibiotic Monotherapy for Intraabdominal Infections
Reasons for Failure
Reccurent Abscess
Fasciitis
Dead with "sepsis"
Wound Infection
Tobra/Clinda (n=24)
Imipenem (n=14)
Adverse Reaction
Initial Resistance
0
2
4
# Failures
6
8
Antibiotic Monotherapy for Intraabdominal Infections
Tobramycin Levels
Peak Maximum
(µg/ml + sd)
Days to Max Peak
(days + sd)
-
Successes
Failures
6.4 + 1.9
-
6.1 +- 1.7
3.8 +- 2.6

4.6 +- 5.2
Variable times to adequate Tobramycin levels
Antibiotic Monotherapy for Intraabdominal Infections
Data in support of MONOTHERAPY
for surgical infections
Results of a Multicenter Trial Comparing
Imipenem/Cilastatin to Tobramycin/Clindamycin
for Intra-abdominal Infections.
Solomkin JS, Dellinger EP, Christou NV, Busuttil RW
Ann. Surg 212:581-591, 1990.
Imipenem vs Tobramycin-Antianaerobe
Antibiotic therapy in Intra-abdominal
Infections.
Poenaru D, De Santis M, Christou NV
Can. J. Surg. 33:415-422, 1990.
Antibiotic Monotherapy for Intraabdominal Infections
ANTIBIOTIC OF CHOICE FOR
INTA-ABDOMINAL INFECTIONS
Carbapenem
MonoRx
eg Imipenem
500 mg q6h