Surgical prophylaxis in patients colonised with multidrug-resistant Gram-negative bacteria

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Surgical prophylaxis in patients colonised with

multidrug-resistant Gram-negative bacteria

Benedikt Huttner, MD, MS

Division of Infectious Diseases & Infection Control Program Geneva University Hospitals

University of Geneva - Faculty of Medicine

benedikt.huttner@hcuge.ch Symposium #SY037 Saturday, 13.04.2019 14:45-15:45

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Transparency Declaration

• I have received research grants from the Swiss National Science

Foundation (SNF)

• I am a paid consultant to the World Health Organization (WHO)

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Outline

• The title says “multidrug-resistant (MDR) Gram-negative

bacteria”

• Focus mainly on extended-spectrum beta-lactamase producing

Enterobacteriaceae

(ESBL-E)

– Most prevalent MDR Gram-negative bacteria in many settings

– Data already very limited for ESBL-E

• nearly no data for other MDR Gram negatives such as carbapenemase producing Enterobacteriaceae or multidrug-resistant Acinetobacter spp.

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https://ecdc.europa.eu/sites/portal/files/documents/AMR-surveillance-EARS-Net-2017.pdf Bevan et al. J Antimicrob Chemother 2017; 72: 2145–2155

Antimicrobial resistance in Enterobacteriaceae is increasing

2017

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Is the efficacy of surgical

prophylaxis decreasing ?

• Systematic review and meta-analysis

– RCTs assessing efficacy of AP in

preventing postoperative infections

• appendectomy, cesarean section, colorectal surgery, TRBP

• Significant increase in SSIs following

colorectal surgery

– aOR per year, 1.05 (95% CI, 1.03-1.07) • Adjusted for type of antibiotic (cefotetan,

cefoxitin, or cefazolin plus metronidazole) and type of surgery

– no increase for other procedures

Gandra et al. Infect Control Hosp Epidemiol. 2019 Feb;40(2):133-141. TRBP: transrectal biopsy of the prostate

No information regarding causative pathogens (ESBL-E ?)

Results remained significant in a sub-analysis of 22 RCTs with prophylactic antibiotic administration within 60 minutes or at the time of anesthesia induction, patient follow-up of at least 4 weeks, included surgical incision and organ space infections.

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Selection of MDR Gram negative bacteria

by surgical prophylaxis

Baym et al. Science. 2016 Jan 1;351(6268):aad3292.

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• Cohort study in two centers, Denmark (2012-2013)

• Rectal swabs before and 2 days after elective surgery

• Outcome: possible infections caused by ESBL / AmpC-producers

– within 60 days after surgery

– search of the Danish national database

Jakobsen et al. Diagn Microbiol Infect Dis. 2016 Nov;86(3):316-321.

Inclusion criteria Exclusion criteria

• age ≥18 years

• antibiotic prophylaxis with • gentamicin/penicillin G

(surgical gastroenterology) • cefuroxime

(orthopedic surgery)

• gastrointestinal surgery ≤30 days • sepsis

• ileostomy

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Jakobsen et al. Diagn Microbiol Infect Dis. 2016 Nov;86(3):316-321.

• Detection of Enterobacteriacae with transferable ESBL / AmpC

• One single infection with ESBL-E (peritonitis)

• Most patients with two positive swabs: same species, same genotype

Gastroenterology

(gentamicin/penicillin G)

Orthopedic surgery

(cefuroxime)

• 1st swab: 5.8% (26/448)

• 2nd swab: 8.8% (34/385)

• 1

st

_{swab: 6.4% (19/298)}

• 2

nd

_{swab: 7.8% (22/283)}

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Carriage of MDR Gram negative bacteria

as risk factor for SSI

https://www.who.int/gpsc/ssi-infographic.pdf?ua=1

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• Prospective cohort study, 2014-2015

– tertiary-care, academic cancer hospital in Mexico City

• Inclusion criteria

– adult patients

– gynecological or gastrointestinal malignancy

– elective abdominal and pelvic surgical procedure

• Rectal swab for ESBL-E on admission

• Primary outcome

– SSI within 30 days (CDC criteria)

Golzarri et al. Am J Infect Control. 2019 Mar 6. pii: S0196-6553(19)30061-6.

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Golzarri et al. Am J Infect Control. 2019 Mar 6. pii: S0196-6553(19)30061-6.

In 16 (64%) of the 25 SSI, the causal

microorganism was isolated • 10 ESBL-producing Escherichia coli • 1 ESBL-producing K. pneumoniae

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Carriage of Extended-spectrum Beta-lactamase–producing

Enterobacteriaceae and the Risk of Surgical Site Infection After Colorectal Surgery: A Prospective Cohort Study

• Prospective cohort study in 3 hospitals

– Israel, Switzerland, Serbia – 2012-2017

• Inclusion criteria for cohort

– age ≥18 years

– undergoing colorectal surgery

– screened for ESBL-E before surgery

– received routine prophylaxis (cephalosporin + metronidazole) – no infection at time of surgery

• Primary outcome

– SSI diagnosis within 30 days of surgery (CDC criteria) – clinic visit 27–33 days post-surgery or phone visit

Dubinsky-Pertzov et al. Clin Infect Dis. 2018 Sep 10. [Epub ahead of print]

Sample size:

1:2 ratio of carriers

to noncarriers

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Characteristics of ESBL-E carriers versus noncarriers

Characteristic ESBL-E carriers

(n=222) ESBL-E noncarriers (n=440) P value Age in years (SD) 63.4 (13.9) 61.6 (18.9) 0.08 Female, % 52.7% 59.1% 0.14 Admission from own home 97.7% 98.6% 0.49

Previous colorectal surgery 34.7% 23.6% 0.03

Diabetes 20.7% 16.6% 0.27 Immunodeficiency 4.5% 7% 0.50 Charlson score >8 22.55 18.4% NS Indication Colorectal cancer IBD Diverticular 67.1% 5.9% 12.2% 80.9% 8.0% 2.3% <0.0001

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• Overall prevalence of ESBL-E

carriage

13.8%

0 5 10 15 20 25 30 35

Belgrade Geneva Tel Aviv

Prevalence of ESBL-E carriage (%)

24.8% (55/220) 11.1% (49/440) P < .001

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Multivariable analysis of the association between SSI

and selected characteristics

Risk factor No SSI

(n=558) SSI (n=104) Adjusted OR 95% CI ESBL-E carriage 167 (29.9%) 55 (52.9%) 2.36 1.50-3.71 NNIS score >0 294 (52.7%) 77 (74.0%) 1.92 1.16-3.18 Stoma after surgery 166 (29.7%) 27 (26.0%) 1.74 0.98-3.09

No significant association with

• age

• cardiovascular disease

• previous colorectal surgery • surgery indication

• mechanical bowel preparation • rectal resection

• retention of drain

mixed-effects models with study site as a random effects variable

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What about colonization and risk of SSI with

carbapenem-resistant Enterobacteriaceae?

Tischendorf et al. Am J Infect Control. 2016 May 1;44(5):539-43.

“overall 16.5% risk of infection with CRE amongst patients colonized with CRE”

(few surgical site infections in this review)

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Targeted surgical prophylaxis in patients colonized

by MDR Gram negatives

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In what situation would you deviate from your standard prophylaxis to

target the MDR Gram negative bacterium (multiple selections possible)

57 year old patient undergoing

A. elective cardiac surgery for valve replacement with intestinal colonization

with E. coli ESBL

B. elective cardiac surgery for valve replacement with intestinal colonization

with K. pneumoniae KPC

C. elective colorectal surgery with intestinal colonization with E. coli ESBL

D. transrectal prostate biopsy with urinary colonization with E. coli NDM-1

E. elective implantation of a vascular prothesis in the inguinal region in a

patient colonized with ESBL-E

F. liver transplantation in a patient colonized with multidrug-resistant

Acinetobacter sp.

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According to you what is an acceptable number of patients needed to “treat” with a carbapenem as surgical prophylaxis to prevent one ESBL-SSI ? (single answer)

A. 5

B. 10

C. 15

D. 25

E. 50

F. 100

G. Other

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Global Guidelines for the Prevention of Surgical Site Infection. World Health Organization 2016. https://apps.who.int/iris/bitstream/handle/10665/250680/9789241549882-eng.pdf?sequence=8

2016

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Global Guidelines for the Prevention of Surgical Site Infection. World Health Organization 2016. https://apps.who.int/iris/bitstream/handle/10665/250680/9789241549882-eng.pdf?sequence=8

2016

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https://sfar.org/wp-content/uploads/2018/07/Antibioprophylaxie-RFE-mise-a-jour-2018.pdf SIGN 104 • Antibiotic prophylaxis in surgery

Bam et al. J Am Coll Surg. 2017 Jan;224(1):59-74. Clinical Practice Guidelines for Antimicrobial Prophylaxis in Surgery (AHSP 2013).

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“Resistant organisms — The approach to selecting antimicrobial surgical

prophylaxis for patients known to be colonized or recently infected with

drug-resistant pathogens

must be individualized

.”

“Whether prophylaxis should include coverage for such pathogens depends

on

many factors

including the pathogen, its antimicrobial susceptibility

profile, the host, the planned procedure, and the proximity of the likely

reservoir of the pathogen to the incision and operative sites.”

“Specific prophylaxis for a resistant gram-negative pathogen in a patient with

past infection or colonization may not be necessary for a cutaneous

procedure”

https://www.uptodate.com/contents/antimicrobial-prophylaxis-for-prevention-of-surgical-site-infection-in-adults#H211581 (accessed April 10, 2019)

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Colorectal surgery

Image: https://www.bmj.com/content/343/bmj.d8029

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Ertapenem versus cefotetan prophylaxis in

elective colorectal surgery

• Double-blind randomized non-inferiority trial

– 51 centers USA, 2002-2005

• 1002 adult patients undergoing elective open surgery of the colon

or rectum randomized 1:1

– 1 g of ertapenem iv (single dose)

– 2 g of cefotetan (single dose)

• Primary outcome

– no signs or symptoms of infection at the surgical site and no further need

for antimicrobial therapy or surgery within 4 weeks after surgery

Itani et al. N Engl J Med. 2006 Dec 21;355(25):2640-51.

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• Overall failure rates

– Ertapenem 40.2% – Cefotetan 50.9%

– absolute difference, −10.7% (95% CI, −17.1 to −4.2)

• Microbiologic analysis

– ≥ 1 organism isolated in 30 patients in the ertapenem group and 55 patients in the cefotetan group

– Of tested pathogens that were 16.3% percent in the ertapenem group were resistant to ertapenem and 66.7% in the cefotetan group were resistant to cefotetan

– No data about ESBL-E!

Itani et al. N Engl J Med. 2006 Dec 21;355(25):2640-51.

Ertapenem versus cefotetan prophylaxis in

elective colorectal surgery

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Personalized ertapenem prophylaxis for carriers of extended-spectrum beta-lactamase-producing Enterobacteriaceae undergoing colorectal

surgery (R-GNOSIS WP4)

• Prospective before-after study in 7 surgical wards in 3 hospitals

– Israel, Switzerland, Serbia – 2012-2017

• Adult patients undergoing elective colorectal

– Screening for ESBL-E carriage before surgery (2 weeks - 2 days before)

• Primary outcome

– Any type of SSI within 30 days

Nutman et al. Clin Infect Dis 2019 (accepted for publication)

Ertapenem for ESBL-E carriers (intervention)

Cephalosporin + metronidazole (baseline)

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• 3600 patients screened for ESBL-E carriage

– 498 positive (13.8%; range by center 9.4 % -28.8%)

• Baseline 45/209 (21.5%) SSI versus intervention 47/269 (17.5%)

– aRD -5.0% (95% CI -12.1% -to 2.2%)

– ESBL-E 15/209 patients (7.2%) versus 4/269 patients (1.5%)

• Imperfect adherence to study phases

– Baseline: 8 (3.8%) ertapenem, 7 (3.3%) other antibiotic

– Intervention: 53 (19.7%) routine prophylaxis, 3 (1.1%) other antibiotic or no prophylaxis – “As treated analysis” aRD -7.8% (95% CI:-14.8% to -0.8%)

• NNT 13

– Number needed to screen 45-138

Personalized ertapenem prophylaxis for carriers of extended-spectrum beta-lactamase-producing Enterobacteriaceae undergoing colorectal

surgery (R-GNOSIS WP4)

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2016

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Oral antibiotics (OAB) before elective colorectal surgery

• Neomycin most studied agent

– alone or in combination with other antibiotics

• Potentially active against some MDR Gram negative bacteria

– including ESBL-E

• Some evidence that OAB can reduce the incidence of SSI

– with or without mechanical bowel preparation

– specific impact on infections caused by ESBL-E unclear

Toh et al. JAMA Netw Open. 2018 Oct; 1(6): e183226.

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Colorectal surgery

• It seems reasonable adapt antibiotic prophylaxis for known carriers

of MDR Gram negative bacteria

– Active screening and targeted prophylaxis may be considered even though

the evidence base remains weak

• Perioperative oral antibiotics may also be active against some MDR

Gram negative bacteria

– Already recommended to reduce SSI

– But: unclear what to do if colonization with MDR Gram-negative resistant

to commonly used perioperative oral antibiotics

• Furthermore neomycin testing not readily available in most laboratories

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Urologic interventions

https://www.cancer.gov/images/cdr/live/CDR446226-750.jpg

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66 year old man undergoing transrectal prostate

biopsy with ESBL-E colonization

• Known intestinal and urinary colonization by ESBL producing

– Resistant to ciprofloxacin and cotrimoxazole

– Tested susceptible to

• Fosfomycin • Nitrofurantoin • Amikacin • Ertapenem • Piperacillin/Tazobactam (MIC 2 mg/l)

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66 year old man undergoing transrectal prostate

biopsy with ESBL-E colonization

What prophylaxis would you give ?

A. Fosfomycin

B. Nitrofurantoin

C. Amikacin

D. Ertapenem

E. Piperacillin/Tazobactam

F. Other

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EAU guidelines on urological

infection 2018

“Recent urine culture results including presence of any

multi-resistant organisms, drug allergy, history of C.

difficile associated diarrhoea, recent antibiotic exposure, evidence of symptomatic infection pre-procedure and serum creatinine should be checked.

The panel have decided not to make recommendations for specific agents for particular procedures as there is

considerable variation in Europe and worldwide regarding bacterial pathogens, their susceptibility and availability of antibiotic agents.”

https://uroweb.org/wp-content/uploads/EAU-Guidelines-on-Urological-Infections-2018-large-text.pdf

Peri-Procedural Antibiotic Prophylaxis

Prostate biopsy

“… the choice of regimens and duration of prophylaxis

remains debatable. Most commonly fluorochinolones are

applied. Due to the increase in fluorochinolone resistance recent studies have investigated alternatives like

fosfomycin trometamol or suggest targeted antimicrobial

prophylaxis based on rectal swab. “

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The role of targeted prophylactic antimicrobial therapy before transrectal

ultrasonography‐guided prostate biopsy in reducing infection rates:

a systematic review

9 studies reviewed

Empirical prophylaxis

Targeted prophylaxis

Post-TRUS biopsy

infective complications

4.6%

(95% CI 3.8–5.4%)

0.7%

(95% CI 0.4–1.2%)

Sepsis

2.2%

(95% CI 1.7–2.9%)

0.5%

(95% CI 0.3–0.9%)

Cussans et al. BJU Int. 2016 May;117(5):725-31.

505 of 2219 (22.8%, 95% CI 21.1–24.5) patients fluoroquinolone-resistant Enterobacteriaceae in pre-procedural rectal swabs or stool cultures

NNT: 27 men (95% CI 21.2–34.1) to prevent one post-TRUS biopsy infective complications

No consensus regarding optimal antibiotic regimen

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• Decision-analytic model

• Hypothetical cohort of 66-year-old men

– undergoing TRPB

• Cost-effectiveness of 4

antibiotic prophylaxis strategies

– ciprofloxacin alone – ceftriaxone alone

– ciprofloxacin and ceftriaxone in combination – targeted prophylaxis based on susceptibility

testing

• Assumed resistance prevalence

– Ciprofloxacin 29% – Ceftriaxone 7%

Lee et al. Value Health. 2018 Mar;21(3):310-317.

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Lee et al. Value Health. 2018 Mar;21(3):310-317.

• Directed prophylaxis strategy optimal strategy

– willingness-to-pay threshold of 50’000 USD/QALY gained

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Fosfomycin vs. quinolone-based antibiotic prophylaxis for transrectal ultrasound-guided biopsy of the prostate: a systematic review and meta-analysis

• Five studies comparing fosfomycin and non-fosfomycin identified and included in meta-analysis

– 2 RCTs, 1 pseudo-randomized study

• Overall 1447 patients treated with fosfomycin and 1665 patients with other antibiotics

– OR for post-procedure UTI lower in the fosfomycin cohort (“moderate-quality evidence”)

• OR 0.20 (95% CI 0.13, 0.30),

• Adverse effect profile similar between the two cohorts

Noreikaite et al. Prostate Cancer Prostatic Dis. 2018 Jun;21(2):153-160.

Outcome: Overall UTI

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Urologic procedures

• It seems reasonable adapt antibiotic prophylaxis for known

carriers of MDR Gram negative bacteria

– Active screening and targeted prophylaxis should probably

considered for transrectal prostate biopsy

• Potential carbapenem sparing alternatives

– fosfomycin

– aminoglycosides

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Cardiac surgery

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Enterobacteriaceae producing extended-spectrum β-lactamases (ESBLs) colonization as a risk factor for developing ESBL infections in

pediatric cardiac surgery patients: “retrospective cohort study”

• Retrospective cohort study Rabat, Morocco, 2011-2014

• Paediatric cardiac surgery patients

– Screening for ESBL-E colonization on admission in children with risk

factors (previous hospitalization and/or taking antibiotics)

Cheikh et al. BMC Infect Dis. 2017; 17: 237.

24%

1%

postoperative ESBL infection

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Carbapenem use for surgical prophylaxis in

cardiac surgery in Thailand

• Retrospective study in a tertiary care center in Thailand

• 266 patients ≥15 years

– urgent or scheduled cardiac surgical procedures requiring sternotomy – median age 65 years [IQR 56-72]

• Antibiotic prophylaxis

– 132/266 (49.6%) “standard agents” – 134/266 (50.4%) carbapenems

• Recent hospital stay, recent antibiotic

exposure, presence of intravascular devices not different between groups

– as presumed risk factors for ESBL-E infection

Phuphuakrat et al. J Hosp Infect. 2016 Aug;93(4):362-3.

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Cardiac surgery: conclusions

• In the absence of better data it is probably justifiable to

administer “routine” prophylaxis even in patients colonized

with MDR Gam negative bacteria

– Gram positive coverage more relevant

• There may be certain exceptions

– E.g. outbreak settings, solid organ transplantation (?)

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Other alternatives to carbapenems

https://choosingwiselycanada.org/campaign/antibiotics/

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Cephamycins

• E.g. cefoxitin, cefotetan

• Protected from inactivation by ESBL but not AmpC

• Still commonly used in some settings

• Few data regarding specific effectiveness against postoperative

infections causes by ESBL-E

Tamma et Rodriguez-Bano . Clin Infect Dis. 2017 Apr 1;64(7):972-980.

Demonchy et al. Int J Antimicrob Agents. 2018 Jun;51(6):836-841.

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Temocillin

• Derivative of ticarcillin

• Introduced in the early 1980s

• Not widely used because of lack of activity against

– Gram-positive organisms

– anaerobes

– P. aeruginosa

• Protected from inactivation by most of Ambler class A (including

ESBLs and KPC) and class C β-lactamases

• Little impact on intestinal anaerobes

• No good data for surgical prophylaxis

Woerther et al. Int J Antimicrob Agents. 2018 Dec;52(6):762-770.

De Vries-Hospers et al. Drugs. 1985;29 Suppl 5:227-33.

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Decolonization of MDR Gram-negative bacteria

https://www.wsj.com/articles/the-ultimate-battle-against-mrsa-1473699288

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Humphreys et al. J Hosp Infect. 2016 Nov;94(3):295-304.

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• The panel does not recommend routine decolonization of

3GCephRE carriers

– Grading: conditional recommendation against the intervention

• The panel does not recommend routine decolonization of CRE

carriers

– Grading: conditional recommendation against the intervention

• Carbapenem-resistant Acinetobacter baumannii

– Evidence is insufficient to provide a recommendation for or against any

intervention.

Taconnelli et al. Clin Microbiol Infect. 2019 Jan 29. [Epub ahead of print]

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WP3: Randomized, open-label, multicenter phase 2 trial

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PRIMARY OUTCOME: DETECTION OF ESBL-E / CPE AT V4 (STOOL CULTURE)

Huttner et al. Clin Microbiol Infect. 2019 Jan 4. pii: S1198-743X(18)30796-1.

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Huttner et al. J Antimicrob Chemother. 2013 Oct;68(10):2375-82.

Huttner et al. Clin Microbiol Infect. 2019 Jan 4. pii: S1198-743X(18)30796-1.

ITT population

OR for decolonization 1.7 (95% CI 0·4-6·4 ) FMT is probably not a “miracle drug” for decolonization of MDRO

• still be worth exploring for some patients

• different approaches: higher amount FMT, no antibiotics,… ?

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ESBL :

In patients colonized by Enterobacteriaceae producing ESBL, the prophylactic use of Ertapenem (1g IV) or Amikacin (15mg/kg IV) is justified only in colorectal, vascular (scarpa approach) or urological surgery.

Surgical prophylaxis and MDR Gram negative bacteria Local practice in our hospital

In colorectal surgery: active screening before intervention

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Conclusion

• Patients colonized with MDR Gram negative bacteria have a higher risk of

infection including surgical site infections

• It seems reasonable to adapt prophylaxis in certain types of surgery where

Gram-negatives predominate as cause of SSI or certain high-risk

procedures

– Colorectal surgery, urologic interventions, solid organ transplantation… – Carbapenem overuse for prophylaxis should be avoided

– The evidence base remains very weak => better studies are needed

• Decolonization before surgery can currently not routinely be

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Thank you!

Special thanks to Stephan Harbarth for his input

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Personalized ertapenem prophylaxis for carriers of extended-spectrum beta-lactamase-producing Enterobacteriaceae undergoing colorectal surgery (R-GNOSIS WP4)

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Bode et al. N Engl J Med. 2010 Jan 7;362(1):9-17.

• Randomized, double-blind, placebo-controlled clinical trial • Screening for S. aureus nasal

carriage

• Randomization

• decolonization with either mupirocin–chlorhexidine • placebo

• Three university hospitals and two general hospitals in the Netherlands (2005-2007) Hospital-associated S. aureus infections

• 3.4% (17 of 504 patients) mupirocin–chlorhexidine • 7.7% (32 of 413 patients) placebo

• RR 0.42 (95% CI 0.23 to 0.75)