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Perioperative careAntibiotic prophylaxis

Gloria Taliani Department of Clinical Medicine

Sapienza university of Rome

Gloria Taliani, Docente di Malattie InfettiveSapienza Università di Roma

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•Cirrhosis and infections

•Antibiotic prophylaxis

•Upper Gastrointestinal Bleeding

•Elective Variceal ligation/sclerosis

•Endovascular/Surgical procedures

Infections in Cirrhosis

• Bacterial infections are more common in cirrhosis than in the general population, particularly among patients with

– Decompensated cirrhosis

– history of previous infections

– Gastrointestinal Bleeding

– Alcoholic cirrhosis (S aureus, E coli)

1) Fernandez J, et al Hepatology 2002;35:140–148. 2) Borzio M,. Dig Liver Dis 2001;33:41–48.3) Merli M et al. Clin Gastroenterol and Hepatol 2010;8:979–985. 4) Wasmuth HE et al. J Hepatol 2005; 42: 195-201.

Infections in Patients With CirrhosisIncrease Mortality Four-Fold11,987 patients

• MEDIAN age 56 years;

• Males, 68.3%;

• Alcoholic cirrhosis, 46.7%;

• Viral (B or C) cirrhosis, 39%.

(Arvaniti V et al, Gastroenterology 2010; 139: 1246-56)

Bonnel AR et al Clin Gastroenterol and Hepatol 2011

The risk of bacterial infection in

cirrhosis is due to multiple factors:

liver dysfunction, portosystemic

shunting, gut dysbiosis, increased

bacterial translocation, cirrhosis-

associated immune dysfunction

(AID) and genetic factors.

Jalan R et al. Journal of Hepatology 2014; 60: 1310–1324

Cirrhosis Associated Immune Dysfunction Syndrome

Bonnel AR et al Clin Gastroenterol and Hepatol 2011

The risk of bacterial infection in

cirrhosis is due to multiple factors:

liver dysfunction, portosystemic

shunting, gut dysbiosis, increased

bacterial translocation, cirrhosis-

associated immune dysfunction

(AID) and genetic factors.

Jalan R et al. Journal of Hepatology 2014; 60: 1310–1324

Iatrogenic factors

Invasive procedures and catheters

Fequent hospitalization

Cirrhosis Associated Immune Dysfunction Syndrome



•Upper gastrointestinal Bleeding



Dental procedures, antibiotic prophylaxis, and endocarditisamong people with prosthetic heart valves

Rate of infective endocarditis associated with oral streptococci during the three months after invasive dentalprocedures according to different categories of exposure in patients with a prosthetic heart valve.

Tubiana S. et al. BMJ 2017;358: 3776

Dental procedures, antibiotic prophylaxis, and endocarditisamong people with prosthetic heart valves

Rate of infective endocarditis associated with oral streptococci during the three months after invasive dentalprocedures according to different categories of exposure in patients with a prosthetic heart valve.

Tubiana S. et al. BMJ 2017;358: 3776

Dental procedures may contribute to the development of infective endocarditis

in patients with prosthetic heart valves.

However, antibiotic prophylaxis did not significantly reduce

the rate of infective endocarditis associated with oral

streptococci after dental procedures.

Potential Antibiotic Prophylaxis Drowbacks

• Toxicities of Antibiotics

• Drug/Drug Interactions

• Antibiotic Resistance

• Perturbation of the Microbiome

Horton LE et al. Curr Hematol Malig Rep. 2018 doi: 10.1007/s11899-018-0435-0. [Epub ahead of print]

Prevention of InfectionsReduction of mortality

• loss of microbial diversity correlated with risk of life-threatening bacteremia in neutropenic patients

• Several large retrospective studies have shown that the use of broad-spectrumantibiotics is a risk factor for CDI.

Antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding

Overall mortalityBacterial infections

O’Brien-Fleming monitoring boundaries for assessing statistical significance for bacterialinfections and mortality

Risk of bias

1241 Patients in randomised trials comparing antibiotic prophylaxis versus no intervention or placebo

Chavez-Tapia NC et al. Cochrane Database Sys Rev 2010 Sep 8;(9):CD002907.

AP reducesbacterial infections

and seems to reduce all-cause

mortality, bacterialinfection

mortality, incidenceof rebleeding

events, and lengthof hospitalisation.

Current Indications of Antibiotic Prophylaxis in Cirrhosis

Fernandez J et al. HEPATOLOGY 2012; 55:1551-1561. De Franchis R and Baveno VI Faculty. Journal of Hepatology 2015; 63: 743–752Fernandez J et al. HEPATOLOGY 2016: 63: 2019-2031.

prophylaxis as early as

possible, ideally before or

immediately after

endoscopy

(At least 2 of the following: ascites, severe malnutrition,

encephalopathy or bilirubin>3 mg/dL) has been shown to be more

effective than oral norfloxacin in preventing bacterial infections.

Third-generation cephalosporins recommended in patients with

(1) Advanced cirrhosis

(2) Quinolone prophylaxis.

(3) A recent infection due to a quinolone-resistant organism

In recent infection due to extended-spectrum b-lactamase producing (ESBL)

Enterobacteriaceae prophylaxis should be based on antibiotics active against

multidrug resistant (MDR) bacteria (e.g., intravenous ertapenem 1 g/day).

Individual patient risk characteristics and local antimicrobial susceptibility patterns be

considered when determining appropriate first-line prophylaxis at each center.

The risk of infection rises with

the severity of cirrhosis

Risk of bacterial infection, rebleeding and mortality in acute varicealhemorrhage according to Child-Pugh class and antibiotic prophylaxis

Adjusted OR of infection with antibiotics0.37 (95% CI 0.31-0.74) p=0.005

No effect of antibiotics on risk or rebleeding

(Tandon P et al. Clinical Gastroenterol and Hepatol 2015; 13: 1189-96)

CPA CPB CPC2% 6% 33% Actual mortality

Heterogeneous effect antibiotics across CP classes

62%

35%

By comparative effectiveness methods, adjusted predictedprobability of bacterial infection and mortality in CP class A is very low, regardless of exposure to antibiotics.

In CP class B, prophylaxis reduced infection but not mortality.

In CP class C, prophylaxis reduced infection and mortality.

Infection Rebleeding

Mortality

Risk of INFECTION Risk of DEATH

MELD score was not as useful as CHILD-PUGH in identifying patients with low risk of infection

(Tandon P et al. Clinical Gastroenterol and Hepatol 2015; 13: 1189-96)

Risk of bacterial infection, rebleeding and mortality in acute varicealhemorrhage according to Child-Pugh class and antibiotic prophylaxis

Child-Pugh score versus MELD score

Conejo I et al. Liver Int. 2016; 36: 994–1001

Active alcoholic Child A

patients are at significantly

higher risk of developing

bacterial infections, even

when antibiotic

prophylaxis is given.

Risk of bacterial infection after acute varicealbleeding according to aetiology of cirrhosis

Child–Pugh A and B patients.

Risk of bacterial infection after an acute

variceal bleeding according to aetiology of

cirrhosis and active alcohol consumption

in Child–Pugh A

Antibiotic prophilaxisIn variceal bleeding.

Median CP score 9 (5-14)

Dyson JK et al Aliment Pharmacol Ther 2016 Nov;44(10):1030-1038

Bacterial infections in acute varicealhemorrhage despite antibiotics

Predictors of early bacterial infection in patients who received AVH antibioticprophylaxis (Combined dataset of 371 patients from Canada and Spain)

0.040.02

14% of patients developinfection within 14 days

despite antibiotic prophylaxis.

54% of the 13 culture-positive infections in patients on FQ, were resistant to FQ. 60% of the 25 culture-positive infections in patients on Ceph3 were resistant to beta-lactams including cephalosporins.

Lee S. et al. United European Gastroenterol J 2017 Dec;5(8):1090-1099

Bacterial infections in acute varicealhemorrhage despite antibiotics

Predictors of early bacterial infection in patients who received AVH antibioticprophylaxis (Combined dataset of 371 patients from Canada and Spain)

0.040.02

54% of the 13 culture-positive infections in patients on FQ, were resistant to FQ. 60% of the 25 culture-positive infections in patients on Ceph3 were resistant to beta-lactams including cephalosporins.

Lee S. et al. United European Gastroenterol J 2017 Dec;5(8):1090-1099

Risk of Death

14% of patients developinfection within 14 days

despite antibiotic prophylaxis.

MDROrganisms

Methicillin-resistant S. aureus

Vancomycin-resistantenterococci

ESBL-producingEnterobacteriaceae

Carbapenemase-producing

Enterobacteriaceae

Main species S. aureus E. faecium E. coli, K. pneumoniae E. coli, K. pneumoniae

Resistancemechanism

Target modification Target modification β-lactam hydrolysis β-lactam hydrolysis

Resistancegenes

mecA vanA blaCTX-M, blaTEM, blaSHV blaKPC, blaNDM, blaOXA48, blaVIM, blaIMP

Reservoir Oropharynx Intestinal tract Intestinal tract Intestinal tract

Therapeuticoptions

Vancomycin, daptomycin,

linezolid, tigecycline

Daptomycin, linezolid, tigecycline

Carbapenems, piperacillin-

tazobactam, temocillin

Colistin, tigecycline, fosfomycin

Main types of multi-drug-resistant organisms (MDRs).

Fernández J et al. Journal of Hepatology 2016; 65: 1043–1054

<5% in Scandinavia and the Netherlands. >30% in

Greece, Italy and Portugal.

Presence and distribution of resistant bacteria in EuropeEscherichia coli. % of invasive isolates with combined resistance to third-

generation cephalosporins, fluoroquinolones and aminoglycosides

Klebsiella pneumoniae. Distribution of isolates: fullysusceptible and resistant to one, two, three and four

antimicrobial groups (fluoroquinolone, third-generation cephalosporin, aminoglycoside and carbapenems)

Klebsiella pneumoniae. % of invasive isolates with combined resistance to fluoroquinolones, third-generation cephalosporins and aminoglycosides

Pseudomonas aeruginosa.% of invasive isolates with combinedresistance to three or more antimicrobial groups: piperacillin ±

tazobactam, ceftazidime, fluoroquinolones, aminoglycosides and carbapenems)

EARS-Net surveillance data November 2017 for 2016

Resistance percentages are generally higher in southernand south-eastern Europe than in northern Europe

MRSA prevalence decreasedsignificantly at EU/EEA, however it

was >25% in 10/30 Countries

Prudent antibiotic use, comprehensive infection

prevention and control strategies.

Most Gram-negative isolateswere resistant to quinolonesand/or third-generation cephalosporins, typicalcommon prophylactic agents.

Baseline factors associated with 3-month mortality in 203 patients with cirrhosis and

culture-positive bacterial infections

MDR bacterial strains in patientswith cirrhosis according to the

type of resistance

MDR were isolated in 83/313 culture-positive infections (27%)

(Salerno F. et al. Liver Int 2017 Jan;37(1):71-79)

Multivariate analysis

Variables OR 95% CI P Value

Age (years) 1.07 1.03–1.11 .000

HCC 3.55 1.49–8.48 .004

Serum bilirubin (mg/dL) 1.07 1.00–1.14 .047

INR 2.98 1.32–6.72 .008

Isolation of MDR bacteria 2.21 1.02–4.76 .043

Development of renal failure, gastrointestinal bleeding or hepatic encephalopathy.

2.83 1.28–6.23 .01

Child Pugh and MELD scores were excluded to avoid colinearities

Impact of isolation of antimicrobial resistant pathogens on survival from bloodstream infection in cirrhotic patients

Bartoletti M et al. Journal of Hepatology 2014; 61: 51–58

Gram-negative bacteria were the leading pathogens with a high prevalence of MDR and XDR

strains. In addition, 10% of BSIswere caused by Candida spp.

Bacterial pneumonia in patients with liver cirrhosis: a possibledefinition of antibiotic prophylaxis associated pneumonia (APAP)

• Previous gastrointestinal bleeding (p= 0.02) and prophylactic antibiotic use (p<.0001) wereassociated with pneumonia.

• Antibiotic prophylaxis does not fulfil the criteriafor HCAP. On the other hand, these cases cannotbe considered as CAP or HAP.

Cuomo G et al. Infect Dis 2018;50: 125-132.

• In the antibiotic prophylaxis-associated pneumonia (APAP) the mortalityrate was close to that of HCAP

In patients on antibiotic

prophylaxis, aggressive

algorithm for diagnosis and

empirical antibiotic therapy

should be formulated by liver

and infectious disease

specialists

An Empirical Broad Spectrum Antibiotic Therapy in Health-Care–Associated Infections Improves Survival in Patients With Cirrhosis

0

5

10

15

20

25

30

35

Overall UTI Pneumonia SBP

60

20

11

2521

3033

In-Hospital mortality according to Antibiotic Treatment

Merli M et al. Hepatology 2016 May; 63: 1632-9

Reduction of mortalitymore evident in sepsis

Broad-Spectrum group had

Lower treatment failure18% vs. 51%; P= 0.001.

Shorter length of hospitalization12.3 ± 7days vs 18 ± 15 days;

P = 0.03.

A broad spectrum antibiotic therapy as empirical treatment in HCA infections improves survival in cirrhosis.

P=0.01

Comparison of risk of bacteremia Between emergency and electivevariceal therapy procedures

Jia Yi et al. Endoscopy International Open 2015; 03: E409–E417

The frequency of bacteremia after emergency EVS/EVL (16 %) is significantly higher than after elective EVS /EVL (12 %).

Currently, prophylactic antibiotics are indicated for all cirrhotic patients at high risk of developing infection :Patients with Child's class C cirrhosis, a recent history of variceal bleeding, a past history of bacterial peritonitis,

or a co-morbid immunosuppression

incidence of bacterial infections in cirrhotic patients undergoingelective endoscopic variceal ligation (EVL)

112 EVL procedures performed in 60 patients [median 2 sessions per patient (range 1–4)].

Primary prophylaxis of variceal bleeding in 47 (78%) patientsSecondary prophylaxis of variceal bleeding in 13 (22%) patients

Before the endoscopicprocedure

24 h after the endoscopicprocedure

P

Value (range) Value (range)

WBC (cells/mmc) 4,200 (1,600–14,500)

4,550 (1,700–14,000)

0.41

C-RP (mg/dL ) 0.4 (0.1–8.7)

0.47 (0.1–9.8)

0.20

PCT (ng/mL) 0.06 (0.03–2.09)

0.1 (0.01–2.56)

0.60

Blood cultures +(After 24 hr)

0 3 (2.7%)*1 CP-A, 2 CP-B

Maimone S. et al. Dig Liver Dis. 2018 doi: 10.1016/j.dld.2017.12.012. [Epub ahead of print]

None of the patients received antibiotic

prophylaxis before or after the intervention.

*: 2 Staphylococcus epidermidis, 1 Streptococcus mitisNo sepsis or any clinical/laboratory

evidence of infection.

Risk of bacteremia afterendoscopic variceal

sclerotherapy (EVS) and endoscopic variceal

ligation (EVL).

Jia Yi et al. Endoscopy International Open 2015; 03: E409–E417

Bacteremia after EVS: 17 % (95 %CI: 11–24 %)

Bacteremia after EVL: 6 % (95 %CI: 2–11 %)

(P= 0.106).

For some procedures, Antibiotic Prophylaxis effectiveness not supported by scientificevidence.

• Endovascular procedures, especially those involving the

insertion of foreign material.

• Laparoscopic and endoscopic surgery.

Antibiotic Prophylaxis for Surgical Procedures: A Systematic

Review.

Swedish Council on Health Technology Assessment.

Stockholm: Swedish Council on Health Technology Assessment

(SBU); 2010 Aug. SBU Yellow Report No. 200.

Data from 30 reviews with 349 included trials, totaling 73.053 participants showed thatmany of the comparisons were supported by low- or very low-certainty evidence and so require further evidence to support future decision making.

Liu Z et al. Cochrane Database of Systematic Reviews 2018, Issue 2. Art. No.: CD012653.

CVC access, HVPG measurement, trans jugular liver biopsy, TIPS, pleural drainage, TACE, loco-regional percutaneous ablative procedures (radio frequency thermal ablation (RFTA), PEI).

The most frequently involved procedures are

TUNNELED CENTRAL VENOUS CATHETER

• There is no difference in infectionrates between catheters placed in the operating room or IR suite 1 even in neutropenic patients 2

• higher rates of infections in certainsubgroups, such as neutropenic and immunocompromised patients, butthere is no robust evidence to support antibiotic prophylaxis in theses populations.

1) Openshaw KL et al. J Vasc Interv Radiol 1994; 5: 111–115: 2) Nouwen JL et al. J Clin Oncol 1999; 17: 1304

Device Infection rate/1000

catheters/days

Reference

Totallyimplantabledevices (Ports)

0.1-0.9

Ng F et al. Clin Oncol2007;19(7):551–556

Hickman catheters 1.8-2.5

Cuffed dialysiscatheters

4.2

Cheong K et al. InternMed J 2004; 34: 234–238

Noncuffed dialysiscatheters

7.1

PICC 8

Fagiuoli S et al. Digestive and Liver Disease 2017; 49: 121–137

Early Endotipsitis is rare (1%). It is usually related to Gram-positive organisms and the

antibiotic therapy must be

long-lasting (at least 3 months) to avoid recurrence (4). In

patients with uncontrolled or recurrent infection liver

transplant should be considered. There is no

evidence for adopting long-term prophylaxis for the

prevention of endotipsitis.(1) Deibert P et al. Digestive Diseases and Sciences 1998;43:1708–13 (2) Gulberg V et al. Hepato-Gastroenterology 2016;46:1126–30 (3) Ghinolfi D et al. Clinical Transplantation 2016;26:699–705 (4) Navaratnam AM et al. World Journal of Hepatology 2015;7:710–6

Votes in Favour: 100%.

Bacteriemia after TIPS (fever >38.5 ◦C, or leucocytosis >15.0003 and positive blood cultures) ranges between 2–25% (1-4) and in a prospective RCT was not influenced by antibiotic prophylaxis [1]. A longer duration of procedure, multiple stenting and the maintenanceof a central venous line are associated with a higher risk of infectionafter TIPS. In patients with uncomplicated procedure, the trans jugularvenous access should be removed at the end of the intervention [1]. A single dose of long acting cephalosporin reduces the incidence of bacterial infection (20–2.6%) justifying its use in anticipated complexprocedures [2].

Is antibiotic prophylaxis

required for the

prevention of TIPS-related

infectious complications?

Antibiotic prophylaxis in transarterial therapy of HCC: A meta-analysis of 210 patients

Fever

Hospital stayHeterogeneity was not observed in any comparison (I²=0%).

No bacteremia or sepsis were reported.

In the trial by Wang et al, one patient in eachgroup developed hyperpyrexia with acute symptoms of toxicity after TACE.

In the Shelgikar trial, no hepatic abscessduring a median follow-up duration of 28 months (Shelgikar).

Wang J et al. Can J Gastroenterol 2012; 26: 85-91

Antibiotic prophylaxis may not be routinelynecessary.

A more judicious use of antibiotics isrecommended for patients who are at

increased risk of infection (prior biliary surgery, biliary obstruction, or gallstones, portal vein

thrombosis, diabetes).

Guidelines interventional radiology practice

• There are no randomized control trials to support the routine use of antibiotic prophylaxis, but many operators use it 1-2

• There is empiric support for use of antibiotic prophylaxis in high-risk patients who have previous bilioenteric anastomosis,

biliary stasis/ductal dilation, severe cirrhosis, immunosuppression, diabetes, and concomitant infection 3.

Percutaneous tumor ablation

1) Livraghi T et al. 2003; 226: 441–451; 2) Moon E. et al. Semin Intervent Radiol 2010; 27: 327-373) Goldberg SN et al. J Vasc Interv Radiol 2009; 20: S377–S390

Risk of infection in patients with cirrhosis undergoing EndoscopicRetrograde Cholangio-Pancreatography (ERCP)?

• ERCP is a procedure carrying a high risk of infectious cholangitis, bacteraemia and pancreatitis in the general population; Antibiotic prophylaxis for patientsundergoing elective ERCP prevents cholangitis, septicaemia, bacteraemia but has

no impact on overall reduction in mortality (I).

Brand M et al. Cochrane Database Syst Rev 2010 Oct 6;(10):CD007345Hirota WK et al. Gastrointest Endosc 2003; 58: 475-82; Inamdar S et al Liver Int 2016; 36: 1457-63.

Outcome: SepsisOutcome: Mortality

Antibiotic prophylaxis for hernia repair

17 trials (7843 participants in total) reported SSI data presenting a single comparison of antibiotic prophylaxis with placebo or no treatment.

Available trial evidence reports that antibiotic prophylaxis probably reduces SSI risk (RR 0.67, 95% CI 0.54 to 0.84) with moderate-certainty evidence.

Sanchez-Manuel FJ et al. Antibiotic prophylaxis for hernia repair. Cochrane Databaseof Systematic Reviews 2012, Issue 2. [DOI: 10.1002/14651858.CD003769.pub4

Antibiotic prophylaxis for preventing SSIs in patients undergoing electivelaparoscopic cholecystectomy

• 11 trials (1664 participants) reported SSI data presenting a single comparison of antibiotic prophylaxis with placebo or no-prophylaxis.

• It is uncertain whether antibiotic prophylaxis reduces SSI risk (very low-certaintyevidence; downgraded twice for risk of bias and once for imprecision - assessedby overview authors).

Sanabria A et al. Antibiotic prophylaxis for patients undergoing elective laparoscopic cholecystectomy. Cochrane Database of Systematic Reviews 2010, Issue 12. [DOI: 10.1002/14651858.CD005265.pub2

Surgical site preparation

Dumville JC, et al. Preoperative skin antiseptics for preventingsurgicalwound infections after clean surgery. Cochrane Databaseof

Systematic Reviews 2015, Issue 4. [DOI:10.1002/ 14651858. CD003949.pub4

WHO Surgical Site Infection Prevention Guidelines, 2016

Overall, a moderate quality of evidence shows that alcohol-based antiseptic solutions are more

effective compared to aqueous solutions in reducing the risk of SSI.

Surgical Site Infections in cirrhotic patientsINFECTIONS ASSOCIATED WITH INVASIVE PROCEDURES

Statement

At present there is no evidence supporting a need for a different schedule of perioperative prophylaxis in

cirrhotic patients. It is recommended to adhere to current Italian (PNLG 2008) guidelines for perioperative

prophylaxis.

Further scientific efforts in this setting are required in the near future (III B).Fagiuoli S et al.Dig Liver Dis. 2014; 46: 204-12

Mechanisms of Bacterial

Translocation in Cirrhosis

Yan and Garcia-Tsao. Expert Opin Pharmacother 2016; 17: 689-701

Targeting Bacterial translocation in cirrhosis

Bacterialovergrowth

Alterationintestinal motility

Impairedintestinal barrier

Impaired immunity

Antibiotic Prophylaxis in cirrhotic patientsundergoing invasive procedures

• The benefits of AP outweigh the risks for those at high-risk, and possibly for those at moderate-risk.

• There are clearly concerns about the promotion of antibioticresistance and the overall costs of healthcare

• What is required is a synthesis of the existing evidence, followed by an honest balancing of the risks and benefits.

Because many factors are beyond the control, a “magic bullet” strategy is often followed to compensate for the difficulty in controlling risk factors.

Agarwal N et al.Infect Control Hosp Epidemiol 2018 Feb 13:1-2. [Epub ahead of print]

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