You can’t treat pancreatitis without antibiotics by Dr Emma Goeman

1. The role of antibiotics in the
management of pancreatitis.
Dr Emma Goeman
Advanced Trainee in Infectious Diseases
(Paediatric) & Microbiology
ICPMR, Westmead Hospital
CICM ASM, May 2017
emma.goeman@health.nsw.gov.au

2. Introduction – Acute pancreatitis
• Essentially an aseptic process of
autolysis
• >70-80% caused by gallstones & alcohol
• Rare primary infectious causes
• Secondary infection / infected pancreatic
necrosis thought to be related to
translocation & migration from the
duodenum via pancreatic duct
• Also haematogenous spread

3. Introduction
• 5-10% overall case fatality
• Up to 40% mortality from pancreatic
necrosis
• Mortality rates increase with
superimposed infection
• SIRS response indistinguishable
• Antimicrobial prophylaxis de rigeur
2000s
• Concerns about ABX:
• Toxicity inc C difficile, microbial resistance
(individual and hospital), fungal infection

4. Introduction
• Normal WBC count, CRP, procalcitonin have high negative
predictive values for infectious complications
• Tissue sampling often needed to “rule in” true infection
• Especially if: necrotising disease PLUS persistent organ failure
and/or persistent systemic toxicity
• Surgical debridement or drainage of infected necrotic material
important in management

5. Other interventions of interest in reducing infective
complications
• Early enteral feeding
• Probiotics
• ?increased bowel ischaemia
• Selective gut decontamination
• Animal data supportive of full gut decontamination
• Rectal colonisation > oropharyngeal colonisation predicts pancreatic
microbiology
• No statistically significant overall mortality reduction in human trials
• 1 trial showed narrow mortality benefit when corrected for disease
severity but SGD combined with systemic ABx
Luiten 1998 Intensive Care Med. 1998 May;24(5):438-45.
Sawa J Hepatobiliary Pancreat Surg. 2007;14(5):503-8. Epub 2007 Sep 28.
Luiten Ann Surg. 1995 Jul;222(1):57-65.

6. Microbiology of infected pancreatic necrosis
• Gut flora predominates: Enterobacteriaceae,
enterococci, streptococci, staphylococci, anaerobes
• Danish cohort 78 pts 2005-2011 (Schmidt 2014)
underwent transmural drainage and necrosectomy
• 45% enterococci
• 42% Enterobacteriaceae
• 22% fungi
• Enterococci & fungi assoc with higher mortality
• US data (1990s)
• 35% E coli, 24% Klebsiella pneumoniae, 24% Enterococcus sp,
14% Staphylococci, 11% Pseudomonas
• Suggested Gram negative predominance in biliary
disease & Gram positive in ETOH-associated
pancreatitis
• Yeast: prevalence varies widely 12-37%
Schmidt 2014 Pancreatology. 2014 Nov-Dec;14(6):444-9. doi: 10.1016/j.pan.2014.09.001.
Lumsden 1990 Surg Gynecol Obstet. 1990 May;170(5):459-67.
Mandell & Bennett Principles and Practice of Infectious Diseases

7. Antibiotic “prophylaxis” / pre-emptive
treatment
• Useful in early animal models but conflicting data in
human studies
• Consider antibiotic penetration
• Improved by greater inflammation, reduced by necrosis
• Poor: eg aminoglycosides, ampicillin, first gen
cephalosporins
• Variable (achieves MIC for some relevant organisms): eg
cefotaxime, piperacillin
• Good (achieves MIC for most relevant organisms): eg
quinolones, imipenem, ceftazidime, cefepime,
clindamycin, metronidazole, doxycycline, fluconazole
Ho Arch Surg. 1997;132:187-192.
Barshak, Pancreatic Infection, chapter 78 in Mandell & Bennett 2014 8th edition

8. Antibiotic “prophylaxis” / pre-
emptive treatment
• Early single-centre observational studies suggested
reduction in rates of infected necrosis
• Imipenem appeared to out-perform non-protocol Abx
but confounders; microbiology not reported;
longitudinal retrospective study design
• Four RCTs promising but non-definitive due to
issues with study design and sample size
• (Luiten 1995, Pederzoll 1993, Salnio 1995, & Delcenserie 1996)
• 3/4 reduced “sepsis” rates, 2/4 reduced pancreatic
infection, no difference in need for surgery, 1/4
mortality reduction
Ho Arch Surg. 1997;132:187-192.
Barshak, Pancreatic Infection, chapter 78 in Mandell & Bennett 2014 8th edition

9. Antibiotic “prophylaxis” / pre-emptive
treatment
• Issues with more recent RCTs
• Need for open label Abx prescribing in control patients
• Small numbers of patients with pancreatic necrosis
• High rates of CONS ?contamination
• 2006 Cochrane review concluded decreased
mortality but not infectious pancreatic necrosis
Rokke Scand J Gastroenterol. 2007 Jun;42(6):771-6.
Dellinger Ann Surg. 2007 May;245(5):674-83.
Barshak, Pancreatic Infection, chapter 78 in Mandell & Bennett 2014 8th edition

10. Antibiotic “prophylaxis” / pre-emptive
treatment
• Rokke 2007 Norwegian RCT – underpowered, low
recruitment
• 73 pts randomised to early imipenem vs no Abx
• No difference in mortality, LOS, surgery, need for ICU
• Imipenem group had lower complication (12 versus 22 patients)
(p=0.035) & infection rates
• Dellinger 2007 US RCT
• 100 pts with severe necrotising pancreatitis randomised
to meropenem or placebo
• No difference in pancreatic / peripancreatic infections,
mortality (20 vs 18%, p=0.799), or need for surgical
intervention.
Rokke Scand J Gastroenterol. 2007 Jun;42(6):771-6.
Dellinger Ann Surg. 2007 May;245(5):674-83.
Barshak, Pancreatic Infection, chapter 78 in Mandell & Bennett 2014 8th edition

11. Antibiotic “prophylaxis” / pre-emptive
treatment• Cochrane review 2010, 7 studies, 404 patients
• All ABX:
• Mortality: 8.4% vs 14.4% controls (NS)
• Infected pancreatic necrosis: 19.7% vs 24.4% controls (NS)
• Non pancreatic infection rates: 23.7 vs 36% (NS)
• Overall infections: 37.5 vs 51.9% (NS)
• Beta-lactams:
• Mortality: 9.4% vs 15% (NS)
• Infected pancreatic necrosis: 16.8% vs 24.2% (NS)
• Non-pancreatic infections: 21 vs 32.5% (NS)
• Overall infections: 34.4% vs 52.8% (NS)
• Imipenem:
• Mortality: 9% vs 13.4%
• Pancreatic infection: RR 0.34 (95% CI 0.13-0.84) p= 0.02
• Overall infections: 25.6 vs 52.4
Cochrane Database Syst Rev. 2010 May 12;(5):CD002941. doi:
10.1002/14651858.CD002941.pub3.

13. • 78 trials, 7366 participants
• Primary outcome: short term mortality
• No evidence of difference with any
interventions
• 18 antibiotic trials included
2017

14. Short term
mortality
ACUTE
PANCREATITIS
(ALL)
ANTIBIOTICS VS
CONTROL

15. Serious adverse
events
(proportion)
ACUTE PANCREATITIS (ALL)
ANTIBIOTICS VS CONTROL

16. Serious
adverse
events
(number))
ACUTE
PANCREATITIS
(ALL)
ANTIBIOTICS
VS CONTROL

17. ANTIBIOTICS
VERSUS CONTROL
COMPARISON ODDS RATIO CONFIDENCE
INTERVAL
ORGAN FAILURE 36/133 VS 38/125 0.78 [0.44, 1.38]
INFECTED
PANCREATIC
NECROSIS
47/358 VS 54/356 0.82 [0.53, 1.25]
SEPSIS 4/30 VS 8/30 0.42 [0.11, 1.60]
TOTAL ADVERSE
EVENTS
(PROPORTION)
81/212 VS
109/217
0.51 [0.32, 0.80]
TOTAL ADVERSE
EVENTS
(NUMBER)
- 0.75 [0.58, 0.95]
ACUTE PANCREATITIS
(ALL)

18. ANTIBIOTICS
VERSUS CONTROL
COMPARISON ODDS RATIO CONFIDENCE
INTERVAL
SHORT TERM
MORTALITY
41/351 VS 45/332 0.82 [0.52, 1.30]
SERIOUS ADVERSE
EVENTS
(PROPORTION)
29/142 VS 31/139 0.84 [0.46, 1.54]
SERIOUS ADVERSE
EVENTS (NUMBER)
- 0.79 [0.59, 1.06]
ORGAN FAILURE 32/ 110 VS 33/101 0.78 [0.42, 1.45]
INFECTED
PANCREATIC
NECROSIS
34/213 VS 37/213 0.85 [0.51, 1.42]
SEPSIS 4/30 VS 8/30 0.42 [0.11, 1.60]
ACUTE
NECROTISING
PANCREATITIS

19. ANTIBIOTICS
VERSUS CONTROL
COMPARISON ODDS RATIO CONFIDENCE
INTERVAL
SHORT TERM
MORTALITY
46/272 vs 54/270 0.82 [0.53, 1.27]
SERIOUS ADVERSE
EVENTS
(PROPORTION)
19/83 vs 26/81 0.56 [0.27, 1.18]
SERIOUS ADVERSE
EVENTS (NUMBER)
- 0.81 [0.52, 1.25]
ORGAN FAILURE 20/69 vs 20/68 0.89 [0.40, 1.99]
INFECTED
PANCREATIC
NECROSIS
24/172 vs 30/169 0.73 [0.41, 1.33]
SEVERE ACUTE
PANCREATITIS

20. Additional data – what about timing
Manes Am J Gastroenterol. 2006 Jun;101(6):1348-53.
• Early (day 1) versus late (day 4) meropenem
• Pancreatic infection 13.3% vs 31% (NS)
• Extra-pancreatic infection 16.6% vs 44.8% (p<0.05)
• No mortality benefit

22. Australian antimicrobial resistance data 2015
(AGAR) – Gram negatives
• 7,330 isolates analysed – Enterobacteriaceae,
Pseudomonas aeruginosa & Acinetobacter species
• Enterobacteriaceae 89.6%
• Overall 75% community onset, 25% hospital onset
• Hospital onset > community onset: Enterobacter cloacae,
Serratia marcescens
• Mortality:
• 10.6% community-onset
• 18.6% hospital-onset
• Average length of stay 7d
• Principal clinical manifestation (known for 5083
episodes):
• Urinary tract infection 43%
• Biliary tract infection 16%
• Intra-abdominal infection other than biliary tract 10%
AGAR GROUP, June 2016, Gram-negative Sepsis Outcome Programme (GNSOP), 2015 Antimicrobial Susceptibility Report

23. Australian
antimicrobial
resistance data 2015
(AGAR)
AGAR GROUP, June 2016, Gram-negative Sepsis
Outcome Programme (GNSOP), 2015 Antimicrobial
Susceptibility Report
E. coli
K. pneumoniae
P. aeruginosa
Mortality by
antibiotic
use –
hospital
onset sepsis

24. Australian
antimicrobial
resistance data
2015 (AGAR)
AGAR GROUP, June 2016, Gram-negative Sepsis
Outcome Programme (GNSOP), 2015 Antimicrobial
Susceptibility Report
E. cloacae
K. oxytoca
P. mirabilis
Mortality by
antibiotic
use –
hospital
onset sepsis

25. Australian antimicrobial resistance data 2015
(AGAR) – Gram negatives
%I/R Ampicillin Amox-clav Pip-tazo
E coli 57% 22% 6%
K pneumoniae N/A 9% 6%
E cloacae
complex
N/A N/A 20%
P. aeruginosa N/A N/A 13%
AGAR GROUP, June 2016, Gram-negative Sepsis Outcome Programme (GNSOP), 2015 Antimicrobial Susceptibility Report

26. Australian antimicrobial resistance data 2015
(AGAR) – Gram negatives
%I/R Cephazolin Ceftriaxone Meropenem Gentamicin Ciprofloxacin
E coli
22% 11 0 8 16
K
pneumoniae
11% 6 0.3 5 9
E cloacae
complex
97% 26 3 7 7
P. aeruginosa
N/A N/A 8 3 9
AGAR GROUP, June 2016, Gram-negative Sepsis Outcome Programme (GNSOP), 2015 Antimicrobial Susceptibility Report

27. Australian antimicrobial resistance data 2015
(AGAR)
• Extended spectrum beta-lactamase (ESBL) production:
• E. coli 11.5% (majority ST131)
• Klebsiella pneumoniae 7.7%
• Carbapenemase production (eg. metallo beta
lactamase/ MBL)
• 0.30% among Enterobacteriaceae & Pseudomonas aeruginosa
• Most commonly blaIMP-4
• Plasmid mediated quinolone resistance
• E coli 15.8%
• Klebsiella pneumoniae 9.1%
• Enterobacter cloacae 7.4%
AGAR GROUP, June 2016, Gram-negative Sepsis Outcome Programme (GNSOP), 2015 Antimicrobial Susceptibility Report

28. Australian antimicrobial resistance data 2015
(AGAR) - Enterococcus
• 1014 isolates / episodes
• 50:50 community to hospital onset
• Hospital E faecium > E faecalis (72 vs 28%)
• Community E faecalis > E faecium (65 vs 35%)
• 30 day all cause mortality 20% (E faecium 26%, E faecalis 16%)
• VRE faecium mortality 29% vs vancomycin susceptible E faecium 23%
(NS)
• VRE prevalence
• 0.9% E faecalis
• 50% E faecium
AGAR GROUP, June 2016, Australian Enterococcal Sepsis Outcome Program (AESOP) 2015 Final Report

29. Clinical bottom line / Conclusions
• No significant mortality / adverse event benefit from pre-emptive
/ prophylactic antibiotics for acute pancreatitis, including severe /
necrotic disease
• Trends to benefit
• Data heterogeneous and variable quality
• Predicting infected necrosis is challenging
• Circumstantially better data for carbapenems than BLBLIs
• Stack up risk factors
• Know your local microbial epidemiology
• Pursue peripheral and tissue diagnostics
• Treat established infected pancreatic necrosis and extrapancreatic
infection
• Apply the “if it was your mother” test??
• Primum non nocere