5/5/2015
Cefoxitin monotherapy versus
cefoxitin-metronidazole
combination therapy for the
treatment of community-acquired
intra-abdominal infection
Jennifer Dela-Pena, PharmD
PGY1 Pharmacy Resident
Detroit Medical Center, Harper University Hospital
Intra-abdominal Infections
• Associated with morbidity and mortality
– Mortality rate: 8.7% – 32%
• Second most common infection in ICU
• 80% are community-acquired intraabdominal infections (CA-IAI)
• 11 million hospital days for appendicitis
Krobot K et al. Eur J Clin Microbiol Infect Dis. 2004; 23:682–687.
Shirah GR et al. Surg Clin N Am. 2014; 94: 1319-1333.
Solomkin JS et al. Clin Infectious Dis. 2010; 50(2): 133-164.
The speaker has no actual or potential conflicts of interest in relation to this presentation.
Types of CA-IAI
Common Organisms in CA-IAI
Enterobacteriaceae
Appendicitis
Pancreatitis
Diverticulitis
Peritonitis
Cholecystitis
Cholangitis
Streptococcus spp.
Shirah GR et al. Surg Clin N Am. 2014; 94: 1319-1333.
Shirah GR et al. Surg Clin N Am. 2014; 94: 1319-1333.
Management: 2010 IDSA Guidelines
Source
Control
Management
IDSA = Infectious Diseases Society of America
Antimicrobial
Therapy
Source Control
Antimicrobial Therapy
Solomkin JS et al. Clin Infectious Dis. 2010; 50(2): 133-164.
Anaerobes
(Bacteroides spp.)
Management: Source Control
• Eliminate infectious foci through surgical
interventions
- Abscess drainage
- Removal of necrotic tissue
• Control factors that increase infection risk
Management
Source Control
Antimicrobial Therapy
Solomkin JS et al. Clin Infectious Dis. 2010; 50(2): 133-164.
1
5/5/2015
Management: Source Control
Publication
Kind of
Inflammation
Number
of
Patients
Initial Source
Control Not
Successful
Management: Antimicrobial Therapy
Mortality
Seiler et al.
Diffuse peritonitis
258
11%
27% (vs. 13%)
Anderson et al.
Severe intraabdominal sepsis
125
48%
90.2% (vs. 19.2%)
Buchler et al.
Diffuse peritonitis
186
11%
25% (vs. 10%)
Wacha et al.
Diffuse peritonitis
355
30%
47% (vs. 14%)
• Impact of appropriate empiric antimicrobial
therapy in CA-IAI
– Increased clinical success
• Step-down to oral therapy
• Resolution of infection
– Decreased duration of hospitalization
Management
Management
Source Control
Source Control
Antimicrobial Therapy
Hecker A et al. Langenbecks Arch Surg. 2014;399(1):11-22.
2010 IDSA Complicated
Intra-abdominal Guidelines
Monotherapy
•
•
•
•
•
Bacteroides Resistance to Cefoxitin
United States Percent Resistance to Cefoxitin 2006-2009
Combination Therapy with
Metronidazole
Cefoxitin
Ertapenem
Moxifloxacin
Tigecycline
Ticarcillin-clavulanic acid
•
•
•
•
•
•
IDSA = Infectious Diseases Society of America
Cefazolin
Cefuroxime
Ceftriaxone
Cefotaxime
Ciprofloxacin
Levofloxacin
Solomkin JS et al. Clin Infectious Dis. 2010; 50(2): 133-164.
Detroit Medical Center Antibiogram
2
16
MEROPENEM
8+4
METRONIDAZOLE
MIC <
mcg/ml
NO. OF
ISOLATES
CEFOXTIN
ORGANISM
CLINDAMYCIN
AMPICILLIN
SULBACTAM
ANAEROBIC BACTERIA
Antimicrobial Therapy
Bare M et al. Int J Technol Assess Health Care. 2006;22(2):242-248.
Krobot K et al. Eur J Clin Microbiol Infect Dis. 2004; 23:682–687.
Nguyen M et al. Clin Infectious Dis. 2000; 30: 870-876.
8
# of isolates
2006-2007 (%)
B. fragilis
1021
4.3
2008-2009 (%)
7.3
B. thetaiotaomicron
418
9.6
20.9
B. ovatus
153
15
14.1
B. vulgatus
136
4.5
5.8
B. distasonis
99
6.5
16.6
B. uniformis
67
13.4
7.1
Other Bacteroides spp.
63
4.3
8
Snydman DR et al. Anaerobe. 2011;17(4):147-151.
Detroit Medical Center Guidelines
CA-IAI Empiric Therapy
4
PERCENT SUSCEPTIBLE
BACTEROIDES FRAGILIS
30
93
43
73
100
92
BACTEROIDES SPECIES
42
91
38
41
98
100
FUSOBACTERIUM
SPECIES
15
100
100
93
100
89
PREVOTELLA SPECIES
11
91
82
91
100
--
Cefoxitin ± Metronidazole
2
5/5/2015
Methods
Purpose
• To evaluate clinical outcomes in patients who
received cefoxitin monotherapy or cefoxitin
and metronidazole combination therapy for
the treatment of CA-IAI
Hypothesis
• No significant differences in clinical outcomes
between the treatment regimens
Study
Design
• Retrospective, multi-site
cohort study
IRB
Approval
• Detroit Medical Center
• Wayne State University
Methods: Patient Eligibility
Inclusion
• Admission to DMC
hospital between
January 2010 and July
2014
• Age 18-89 years old
• Cefoxitin or cefoxitin/
metronidazole therapy
for CA-IAI
Methods: Primary Outcomes
Clinical Success
• Absence of
persisting or
worsening signs
of infection per
treating physician
Clinical Failure
• Escalation of
antimicrobial
treatment
• Worsening
infection per
treating physician
• 30-day all-cause
mortality
Exclusion
• Non-intra-abdominal
source of infection
• Healthcare-associated
infection
• Antibiotics other than
study regimen on
admission
• Gram-negative
aerobes resistant to
cefoxitin
Methods: Secondary Outcomes
•
•
•
•
Duration of antimicrobial treatment
Duration of hospitalization
Admission to ICU
Re-admission within 30 days related to
initial infection
3
5/5/2015
Methods: Statistical Analysis
Results: Study Population
N=681
• 128 patients total to reach 80% power
• Software: SPSS
• Normality test performed on all data
Patients
Screened
N = 131
– Descriptive statistics
– Mann-Whitney U Test
– Fisher's Exact Test
– Chi-squared Test
– P-value < 0.05 significant
N=69
Cefoxitin
Results: Baseline Characteristics
Cefoxitin/
Metronidazole
(N=62)
P-value
Age (yr) - median (IQR)
52 (43-59)
52 (44-60)
NS
Male gender - n (%)
30 (43.5)
34 (54.8)
NS
41 (67.2)
15 (24.6)
0 (0.0)
5 (8.2)
35 (70.0)
9 (18.0)
2 (4.0)
4 (8.0)
NS
NS
NS
NS
Caucasian
African American
Hispanic
Other
Excluded
N=62
Cefoxitin/Metronidazole
Results: Baseline Characteristics
Cefoxitin
(N=69)
Race - n (%)
N=550
Included
IQR – Interquartile range
Cefoxitin
(N=69)
Cefoxitin/
Metronidazole
(N=62)
P-value
Charlson Index - median (IQR)
Liver disease - n (%)
CKD - n (%)
Diabetes - n (%)
MI - n (%)
CHF - n (%)
0 (0-0)
1 (1.4)
2 (2.9)
1 (1.4)
0 (0)
0 (0)
0 (0-2)
0 (0)
2 (3.2)
1 (1.6)
1 (1.6)
1 (1.6)
NS
NS
NS
NS
NS
NS
APACHE II - median (IQR)
4 (2-6)
4 (2-7)
NS
ID consult - n (%)
4 (5.8)
8 (12.9)
NS
Bacteremia - n (%)
1 (2.9)
2 (3.2)
NS
Abscess - n (%)
7 (10.1)
12 (19.4)
NS
IQR – Interquartile range
Results: Day 1 of Infection
Results: Source of CA-IAI
Cefoxitin
(N=69)
Cefoxitin/
Metronidazole
(N=62)
P-value
80.2 (63.9-106.5)
65.7 (58.0-85.1)
0.009
WBC (per mm3) - median (IQR)
12.2 (9.5-14.7)
13.1 (10.6-16.9)
NS
Temp ( ̊C) - median (IQR)
37.2 (36.8-37.6)
37.3 (37.0-38.0)
NS
CrCl (ml/min) - median (IQR)
Overall
(N=131)
Cefoxitin
(N=69)
Cefoxitin/
Metronidazole
(N=62)
Diverticulitis - n (%)
46 (35.1)
7 (10.1)
39 (62.9)
Cholecystitis - n (%)
41 (31.3)
37 (53.6)
4 (6.5)
Appendicitis - n (%)
25 (19.1)
15 (21.7)
10 (16.1)
Pancreatitis - n (%)
10 (7.6)
6 (8.7)
4 (6.5)
Other - n (%)
6 (4.6)
3 (4.3)
3 (4.8)
Cholangitis - n (%)
3 (2.3)
1 (1.4)
2 (3.2)
4
5/5/2015
Results: Surgical Intervention
Results: Cultures
91.3%
n = 63
P < 0.001
Cultures
41.9%
n = 26
No Cultures
N=69
N=62
Results: Organisms in Cultures
Primary Outcome: Clinical Success
98.6%
n = 68
Cefoxitin
(N=26)
Cefoxitin/
Metronidazole
(N=18)
P-value
No growth - n (%)
16 (61.5)
10 (55.6)
NS
Polymicrobial - n (%)
6 (23.1)
4 (22.2)
NS
E. coli - n (%)
4 (15.4)
4 (22.2)
NS
K. Pneumoniae - n (%)
1 (3.8)
2 (11.1)
NS
Streptococcus - n (%)
6 (23.1)
3 (16.7)
NS
Bacteroides - n (%)
6 (23.1)
4 (22.2)
NS
0 (0)
2 (11.1)
NS
Other - n (%)
98.4%
n = 61
P > 0.99
N=69
Primary Outcome: Clinical Failure
Overall - n (%)
Secondary Outcomes
Cefoxitin
(N=69)
Cefoxitin/
Metronidazole
(N=62)
P-value
1 (1.4)
1 (1.6)
NS
Escalation of therapy - n (%)
1 (1.4)
1 (1.6)
NS
Worsening of symptoms - n (%)
1 (1.4)
1 (1.6)
0 (0)
0 (0)
30-day all-cause mortality - n (%)
N=62
Cefoxitin
(N=69)
Duration of cefoxitin therapy (days) median (IQR)
2.9 (2.0-3.5)
Cefoxitin/
Metronidazole P-value
(N=62)
3.0 (2.3-4.9)
NS
Total duration of therapy (days) median (IQR)
3.6 (2.7-8.1)
10 (8.5-13.0)
-
Discharged on antibiotic - n (%)
26 (37)
46 (74)
NS
< 0.001
< 0.001
5
5/5/2015
Secondary Outcomes
Cefoxitin
(N=69)
Admission to ICU - n (%)
Discussion
Cefoxitin/
Metronidazole
(N=62)
• Majority of patients did not have cultures
P-value
0 (0)
1 (1.6)
NS
Length of stay (days) - median (IQR)
3.2 (2.5-4.7)
4.0 (2.6-5.2)
0.027
Re-admission within 30 days - n (%)
2 (2.9)
4 (6.5)
NS
– Cultures not necessary in CA-IAI if therapy
active against common organisms
– Change in therapy not required if clinical
response occurs
Solomkin JS et al. Clin Infectious Dis. 2010; 50(2): 133-164.
Discussion
Limitations
• Cefoxitin/Metronidazole therapy
•
•
•
•
– Feasibility of source control based on type of
CA-IAI
– More likely to be discharged on antibiotic
– Longer duration of therapy
Retrospective
Diagnosis per treating physician
Intra-operative antibiotics documentation
Lack of susceptibility testing for anaerobes
Conclusion
Future Directions
• No significant differences in clinical
outcomes between monotherapy and
combination therapy
• Addition of metronidazole to cefoxitin not
warranted for empiric treatment of CA-IAI
• Re-assess DMC CA-IAI empiric guidelines
for combination therapy
• Cefoxitin/Metronidazole therapy
– Short vs. long duration
6
5/5/2015
Learning Question #1
Learning Question #1
1. Which organisms are most commonly
associated with community-acquired intraabdominal infections?
1. Which organisms are most commonly
associated with community-acquired intraabdominal infections?
A. Enterobacteriacae, Staphylococcus aureus and
Enterococcus faecalis
B. Enterobacteriacae, Streptococcus spp. and
anaerobes
C. Staphylococcus aureus, Enterococcus faecalis and
anaerobic organisms
D. Streptococcus spp., Enterococcus faecalis,
Stenotrophomonas maltophilia
A. Enterobacteriacae, Staphylococcus aureus and
Enterococcus faecalis
B. Enterobacteriacae, Streptococcus spp. and
anaerobes
C. Staphylococcus aureus, Enterococcus faecalis and
anaerobic organisms
D. Streptococcus spp., Enterococcus faecalis,
Stenotrophomonas maltophilia
Learning Question #2
Learning Question #2
2. According to the 2010 Infectious Diseases
Society of America guidelines, which of the
following can be used as initial empiric
monotherapy of CA-IAI?
2. According to the 2010 Infectious Diseases
Society of America guidelines, which of the
following can be used as initial empiric
monotherapy of CA-IAI?
A. moxifloxacin
B. ceftriaxone
C. cefazolin
D. levofloxacin
Acknowledgements
Kyle Murray, PharmD, BCPS
Clinical Pharmacist Specialist
Infectious Diseases and Critical Care
Huron Valley-Sinai Hospital
Commerce Township, MI
Jing Zhao, PharmD
Clinical Pharmacist Specialist
Infectious Diseases
Harper University Hospital
Detroit, MI
A. moxifloxacin
B. ceftriaxone
C. cefazolin
D. levofloxacin
Cefoxitin monotherapy versus
cefoxitin-metronidazole
combination therapy for the
treatment of community-acquired
intra-abdominal infection
Jennifer Dela-Pena, PharmD
PGY1 Pharmacy Resident
Detroit Medical Center, Harper University Hospital
The speaker has no actual or potential conflicts of interest in relation to this presentation.
7