Reduced Mortality with Early Infectious Disease Consultation in

Patients with AmpC Gram Negative Bacteremia

Kartik Cherabuddi1; Kairav Shah1; Ken Klinker2

1University of Florida College of Medicine, Gainesville, FL; 2University of Florida College of Pharmacy, Gainesville, FL

BACKGROUND

LIMITATIONS

RESULTS

Infectious diseases (ID) consultation has been shown to reduce mortality in

Staphylococcus aureus bacteremia in multiple studies. The effect of ID consult in

Gram negative bacteremia (GNB) is less well understood. Accurate management

early in the course of illness has shown to improve outcomes in GNB. Therefore, the

objective was to study mortality and source control outcomes of early ID consultation

in AmpC GNB.

METHODS

Single-center, retrospective, cohort study conducted at the University of Florida

Health Shands Hospital from June 2011 to September 2015.

Inclusion Criteria:

• Adult patients ≥ 18 years of age

• Bacteremia with a suspected AmpC producing organism (i.e. Citrobacter spp,

Enterobacter spp, and Serratia spp)

• Phenotypic screening of AmpC beta-lactamase defined by the presence of

cefoxitin resistance

• Cefepime or piperacillin/tazobactam were received as primary therapy >72hours

• Polymicrobial infection were included if the organisms were other

Enterobacteriaceae, Pseudomonas, or Acinetobacter.

Exclusion Criteria:

• Cefoxitin screening reported to be susceptible or intermediate

• Study therapy for less than 72 hours

• Death within 72 hours after initiation of therapy

• Pregnancy

• Based on our data, Early ID consult (<48 hours) has a significant role in the

management of AmpC producing organisms causing bacteremia

• Multivariate Analysis of variables impacting 30-day mortality showed a 2-fold

increase in likelihood of source control with early ID consult

• Early ID Consult is significantly shown to reduce 30-day mortality in patients with

Gram negative bacteremia with AmpC producing organisms even when appropriate

antibiotics are utilized

• Due to limitations of retrospective analyses, additional data are warranted to improve

our understanding of how best to utilize broad spectrum agents against organisms

producing extended spectrum beta-lactamases

References:1. Jacoby, GA. AmpC b-Lactamases. Clin Microbiol Rev. 2009;22:161-182.2. MacDougall C. Beyond Susceptible and Resistant, Part 1: Treatment of Infections Due to Gram-Negative Organisms with Inducible Beta-Lactamases. J Pediatr Pharmacol Ther 2011;16:23-30.3. Chow JW, Fine MJ, Shlaes DM, et al. Enterobacter Bacteremia: Clinical Features and Emergence of Antibiotic Resistance during Therapy. Ann Intern Med 1991;115:585-590.

4. Vardakas KZ, Tansarli GS, Rafailidis PI, et al. Carbapenems versus alternative antibiotics for the treatment of bacteremia due to enterobacteriaceae producing extended-spectrum beta-lactamases: a systematic review and meta-analysis. J Antimicrob Chemother 2012;67:2793-2803.5. Tamma PD, Girdwood SCT, Gopaul R, et al. The Use of Cefepime for Treating AmpC Beta-Lactamase-Producing Enterobacteriaceae. Clin Infect Dis 2013;57:781-788.6. Blanchette LM, Kuti JL, Nicolau DP, et al. Clinical Comparison of Ertapenem and Cefepime for Treatment of Infections Caused by AmpC Beta-Lactamase-Producing Enterobacteriaceae. Scand J Infect Dis 2014;46:803-808.7. Polsfuss S, Bloemberg GV, Giger J, et al. Practical Approach for Reliable Detection of AmpC Beta-Lactamase-Producing Enterobacteriaceae. J Clin Microbiol 2011;49(8):2798-2803.

• Retrospective chart review

• Small sample size without comparator group

• AmpC production identified via screen test based on cefoxitin resistance

Primary Endpoint

• Effect of early ID consult (within 48 hours) on 30-day mortality

Secondary Outcomes

• Clinical improvement at 72 hours and end of therapy (EOT)

• Clinical improvement defined as improvement of systemic signs of infection (WBC, fever, bacteremia, vasopressor use, and source control) and microbiological clearance

• 7-day mortality

84.6

20

90.9

100

57.1

7.7

75

57.1

0

10

20

30

40

50

60

70

80

90

100

Abdominal Urinary Catheter Skin

Perc

ent

(%)

Early ID Consult Late or No ID Consult

p=0.139

p=0.500

p=0.146

Table 1. Patient Demographics 2d. Figure 2. Source Control by Site of infection and Early ID consult

Microbiology Reporting

• Identification and susceptibility testing performed by Vitek 2 (bioMérieux, Durham,

NC)

Statistical Analysis

• Categorical variables were compared using Chi-square test or Fisher’s exact

test, as appropriate

• Continuous variables were compared using a Student’s t-test

• All tests were 2-sided and p-value < 0.05 was defined as meeting statistical

significance

• Univariate analysis was conducted to identify factors impacting patient response

variables. Any variables with a p-value < 0.2 were included in the multivariate

analysis

• Statistical tests were performed with JMP® Pro 13 statistical software (Cary, NC)

2c. Figure 1.Source control by site of infection and ID Consult (anytime)

CONCLUSION

Source of Infection

(n,%)

ID Consult

(n = 2)

Late or No ID Consult

(n = 12)p-value

Intraabdominal 0/13 (0) 6/21 (28.6) 0.0337

Pneumonia 2/7 (28.6) 0/8 (0) 0.1044

UTI 0/5 (0) 3/13 (23.1) 0.2393

Catheter-related 0/22 (0) 1/28 (3.6) 0.3706

Skin/Skin structure 0/2 (0) 1/7 (14.3) 0.5708

Endocarditis 0 (0) 1/1 (0) -

Bloodstream 0/2 (0) 0/2 (0) -

Bone/Joint 0 0/1 (100) -

Variable Odds Ratio 95% CI

Early ID Consult (within 48 hours) 0.34 0.06 – 1.68

Source Control 0.05 0.006 – 0.43

• Catheter-related Source control was significantly better (p=0.024) with

ID consultation.

• Source control was not much different for Pneumonia, Bone/Joint,

Endocarditis, Bloodstream (as expected) and has not been displayed

in Figures 1 and 2

Table 3. Mortality by site of infection

2

3.93.8

14.8

0

2

4

6

8

10

12

14

16

7-day Mortality 30-day Mortality

Perc

ent

(%)

Early ID Consult Late or No ID Consult

p=1.0

p=0.0478

Figure 3. 7-day and 30-day Mortality with Early ID Consult

Table 4. Multivariate Analysis of variables impacting 30-day mortality

*CCI = Charlson Comorbidity Index; PBS = Pitt Bacteremia Score

Characteristics Early ID Consult

(n = 51)

Late or No ID Consult

(n = 81)

p-value

Age in yrs (median, IQR) 60 [41 – 68] 56 [41 – 69] 0.9497

Male Gender (n,%) 32 (62.8) 47 (58) 0.5901

CCI* (median, IQR) 3 [1 – 5] 3 [1 – 5] 0.2365

APACHE II (median, IQR) 12 [9 – 14] 11 [8 – 16] 0.9533

PBS* (median, IQR) 2 [1 – 3] 3 [2 – 3] 0.2370

Immunocompromised (n,%) 15 (29.4) 16 (19.8) 0.2024

Admitted to ICU (n,%) 20 (39.2) 35 (43.2) 0.6504

Site of Infection (n,%)

Intra-abdominal 13 (25.5) 21 (25.9) 0.9555

Pneumonia 7 (13.7) 8 (9.9) 0.6541

Urinary Tract Infection 5 (9.8) 13 (16) 0.4974

Catheter-related 22 (43.1) 28 (34.6) 0.3230

Skin/Skin structure 2 (3.9) 7 (8.6) 0.2947

Bone/Joint 0 1 (1.2) 1.0000

Endocarditis 0 (0) 1 (1.2) 1.0000

Bacteremia 2 (3.9) 2 (2.5) 0.6424

Organism (n,%)

Enterobacter spp 38 (74.5) 64 (79)

Citrobacter spp 4 (7.9) 8 (9.9)

Serratia spp 9 (17.6) 9 (11.1)

GNR Polymicrobial (n,%) 11 (21.6) 17 (21) 0.9366

Treatment (n,%)

Cefepime 44 (86.3) 64 (79) 0.2922

Piperacillin/tazobactam 7 (13.3) 17 (21)

Duration of treatment in days

(median, IQR)

15 [10 – 19] 14 [10 – 19] 0.6669

Source Control (n,%) 35 (68.6) 39 (48.1) 0.0210

ID Consults (n,%) 51 (100%) 17 (21%) 2-fold increase in likelihood of source control with early ID consult [2.235 (1.13 – 4.91)]

p=0.457

77.8

14.3

92.9

50

56.3

9.1

68.1

50

0

10

20

30

40

50

60

70

80

90

100

Abdominal Urinary Catheter Skin

Perc

ent

(%)

ID Consult (anytime) No ID Consult

p=0.139

p=0.464

p=0.024

p=0.732

3. Outcomes

1. ID Consults

• 75% (51/68) were obtained within 48 hours of blood culture drawn

2. Source Control

• 2a. ID Consult patients: 67.6% (46/68) received source control

• 2b. Non-ID Consult: 43.8% (28/64) received source control

Outcome Variable Early ID Consult

(n = 51)

Late or No ID Consult

(n = 80)

p-value

Clinical Cure (n,%) 47 (92.2) 68 (83.9) 0.1943

Table 2. Clinical Cure with Early Consult