PROFILASSI ANTIBIOTICA IN CHIRURGIA ADRIANA CATALDO DIPARTIMENTO CLINICO E DI RICERCA

INMI SPALLANZANI

ROMA

PERIOPERATIVE ANTIBIOTIC PROPHYLAXIS AND SSI

• SSIs: third most common type of hospital-acquired infections

• 17% of total HAI

• Up to 80% of SSIs could be reduced by appropriate PAP administration

Bowater RJ et al Is antibiotic prophylaxis in surgery a generally effective intervention? Testing a generic hypothesis over a set of meta-analyses. Ann Surg. 2009

“Additional research is needed in several areas related to surgical antimicrobial prophylaxis”

LAPAROSCOPIC CHOLECYSTECTOMIES • Antimicrobial prophylaxis not necessary in low-risk patients undergoing

elective laparoscopic cholecystectomies. (Strength of evidence against prophylaxis for low-risk patients = A)

• Recommended in patients with an increased risk of infectious complications. • performance of emergency procedures • diabetes • anticipated procedure duration exceeding 120 minutes • risk of intraoperative gallbladder rupture • age of >70 years • risk of conversion of laparoscopic to open cholecystectomy • ASA classification of ≥3, • episode of biliary colic within 30 days before the procedure • immunosuppression.

Because some of these risk factors cannot be determined before the surgical intervention, it may be

reasonable to give a single dose of antimicrobial prophylaxis to all patients undergoing laparoscopic

cholecystectomy. (Strength of evidence for prophylaxis for high-risk patients = A.)

Included meta-analyses or systematic reviews evaluating prophylactic antibiotics

for laparoscopic cholecystectomy

All of RCTs analysed in these meta-analyses were also reviewed

• 7 meta-analyses, 28 RCTs

• Review of meta-analyses:

• 6 RCTs inappropriate for the meta-analyses • 1 targeted patients with acute cholecystitis

• 1 measured inappropriate outcomes

• 3 were not appropriate for the meta-analyses

• After correcting and excluding inappropriate RCTs RRs were recalculated

• Rates of surgical site, distant and overall infections were all significantly

reduced by antibiotic administration (RR 0.71 (0.51-0.99), 0.37 (0.19-0.73),

0.50 (0.34-0.75), respectively)

TARGETED ANTIBIOTIC PROPHYLAXIS

• FQ most commonly used prophylactic agents for this procedure

• Post-prostate biopsy infections with FQ-R bacteria reported

• Meta-analysis: pooled prevalence of FQ-R 12.8%

• Cumulative incidence proportion of post-biopsy infections • empirical fluoroquinolone-based prophylaxis: 3.3% (95% CI 2.6–4.2%)

• targeted prophylaxis : 0.3% (95% CI 0–0.9%)

Roberts MJ et al, Int J Antimicrob Agents. 2014

M

• Prospective cohort study of patients undergoing elective colorectal surgery

[part of the R-GNOSIS (Resistance in Gram-Negative Organisms:

Studying Intervention Strategies) project]

• Carriers of ESBL-PE have a higher risk of developing SSI than non-carriers

when the routine prophylaxis regimen is used?

• Only patients receiving routine prophylaxis with cephalosporin plus

metronidazole were included

• Rectal swabs were collected 14 days to 1 hour before surgery to detect

colonization with ESBL-PE

• 3600 patients screened

• prevalence of ESBL-PE carriage: 13.8% with a site variation (12.0% in Geneva, 9.4% in Serbia, and 28.8% in Israel)

• 222 carriers served as the exposed group

• unexposed group consisted of 440 non-carriers

• Overall incidence of SSI: 15.7%

• ESBL-PE carriers 24.8%

• non-carriers 11.1%

• unadjusted OR = 2.40, 95% CI: 1.54-3.74

• In multivariable analysis, carriage of ESBL-PE remained an independent

predictor of SSI following colorectal surgery (OR= 2.63, 95% CI = 1.50 - 3.11)

• Deep incisional or organ/space SSI: • 12.2% of carriers

• 5.7% of non-carriers (OR= 2.25 95% CI = 1.27 - 3.99)

• Cultures of the infected site:

• SSI by ESBL-PE in • 7.2% of carriers

• 1.6% of non-carriers (OR= 4.23, 95% CI= 1.70-10.56)

• Multi-centre quality improvement study

• 3 hospitals in Israel, Serbia, and Switzerland in 2012-2017

• Adult patients undergoing elective colorectal surgery screened for ESBL-PE carriage by rectal swab

• Phase 1 patients received standard prophylaxis with cephalosporin plus metronidazole, regardless of carrier status

• Phase 2, ESBL-PE carriers received targeted prophylaxis with ertapenem (1 gram)

• Primary outcome: SSI within 30 days using CDC definitions

• 3626 patients screened

• 15.3% ESBL-PE carriers (total 433, 222 in Phase 1 and 211 in Phase 2)

• SSI rate 23.4% in Phase 1 and 13.7% in Phase 2 (p=0.007)

• Deep SSI 12.6% and 8.5%, respectively (p=0.171)

• Multivariable analysis (included diverticular disease and NNIS Risk Index score):

ertapenem prophylaxis significantly reduced SSI risk (OR 0.5, 95% CI 0.3-0.8)

• Study underpowered to detect differences in deep SSI rates, but a similar trend

was observed (OR 0.8, 95% CI 0.4-1.5)

VANCOMYCIN?

• Routine use of vancomycin not recommended for any procedure

• Vancomycin may be included

• cluster of MRSA cases (e.g., mediastinitis after cardiac procedures) or MR coagulase-negative

staphylococci SSIs

• known MRSA colonization or at high risk for MRSA colonization in the absence of surveillance

data (e.g.,patients with recent hospitalization, nursing-home residents, hemodialysis patients)

Elliott RA et al. Eur J Health Econ 2010; 11:57-66

Aim: to esplore whether there is a threshold of MRSA prevalence at which switching to routine glycopeptide-based antibiotic prophylaxis becomes cost-effective

The model suggests that, where the MRSA

infection rate is >= 25% and the rate of other

infections with cephalosporin prophylaxis is

>=20%, the combination of cephalosporin

plus vancomycin is the optimal antibiotic

prophylaxis for hip arthroplasty patients

GLYCOPEPTIDES VERSUS Β-LACTAMS FOR THE PREVENTION OF SURGICAL SITE INFECTIONS IN CARDIOVASCULAR AND ORTHOPEDIC SURGERY: A META-ANALYSIS

• To compare the efficacy of glycopeptides and β-lactams in preventing SSIs in cardiac, vascular, and orthopedic surgery

• 14 studies included

• No difference in overall SSI

• Compared with β-lactams, glycopeptides reduced the risk of resistant staphylococcal SSIs by 48% and enterococcal SSIs by 64%

• Subgroup analysis of cardiac procedures showed superiority of β-lactams in preventing superficial and deep chest SSIs, susceptible staphylococcal SSIs, and respiratory tract infections

Saleh A et al. Ann Surg. 2015

MRSA DECOLONISATION

S. aureus decolonization of the anterior nares decreases SSI rates in many surgical patients

Evidence supporting the importance of screening and decolonization of S. aureus carriers

undergoing surgery pertains cardiac and orthopaedic surgery patients

• Perl TM et al. N Engl J Med. 2002

• Konvalinka A et alsp Infect. 2006

• Bode LG et al N Engl J Med. 2010

• Rao N et al Clin Orthop Relat Res 2008

• 7 quasi-experimental studies both nasal decolonization and glycopeptide prophylaxis

• 2 decolonized MRSA carriers only, 2 MRSA and MSSA carriers, and 3 all pts

• MRSA carriers received vancomycin for prophylaxis in 4 studies, vancomycin and cefazolin in 2 studies, and teicoplanin in 1 study

• 2 cardiac operations, 3 total joint arthroplasties, 2 general orthopedic surgical procedures

Glycopeptide prophylaxis was a risk factor for MSSA SSI

Glycopeptide prophylaxis not associated with significantly decreased SSI by Gram positive bacteria or by S aureus

• 8 RCTs, 4 quasi-experimental, 3 retrospective cohort studies • 8 cardiac operations, 5 total joint arthroplasties, and 2 both • 12 vancomycin, 3 teicoplanin • 6 studies combination of a glycopeptide plus another

antimicrobial agent (rifampin, clindamycin, cefuroxime, cefazolin, ticarcillin/clavulante) vs β lactam antibiotic only

Combination prophylaxis was significantly protective against

Gram positive surgical site infections (pooled relative risk 0.22,

0.09 to 0.55)

Glycopeptide prophylaxis for all patients to prevent SSI by Gram positive bacteria

TIMING

• Prospective cohort study, all consecutive adult patients undergoing elective cardiac surgery

• Population was stratified in patients whose antimicrobial prophylaxis administration violated or not the vancomycin timing protocol (i.e., when the first skin incision was performed before the end of vancomycin infusion)

TIMING PROTOCOL VIOLATION AND SSI

• Vancomycin prophylaxis timing protocol violated in 305 (41%) out of 741 enrolled patients

• SSIs in 3% of patients without violation (13/436)

• SSIs in 15.4% of patients with a violation (47/305) (P < 0.0001)

PROPHLYLAXIS IN PATIENTS WITH REPORTED BETA-LACTAM ALLERGY

PROPHYLAXIS IN PATIENTS WITH REPORTED BETA-LACTAM ALLERGY

• Second-line antibiotic therapy in patients with self reported b-lactam allergy (SRBA)

• therapies often broader

• more toxic

• less effective

• Only 1%–3% of pts with SRBA, are found to have true penicillin allergy after confirmation with positive skin testing

• Good evidence that cephalosporins, including cefazolin, may be safely used without further screening among individuals with SRBA

• Assess the impact of structured allergy histories on patients with SRBA undergoing elective surgical procedures

• Structured allergy histories performed by a pharmacist and reviewed with an infectious diseases physician

• Patients deemed safe to proceed with cefazolin prophylaxis if they did not describe a history of type I-mediated or severe reaction

• Antibiotic prophylaxis orders were scheduled into the computerized order entry system

485 patients with SRBA

• 24% reported a type I-mediated allergy history

• 55% received cefazolin prophylaxis and none subsequently experienced an adverse reaction

• After intervention implementation, the overall use of alternative antibiotic prophylaxis among those with SRBA decreased from 81.9% to 55.9%

IMPACT OF PAP

• Use of PAP important contribute to the total amount of antibiotics used in hospitals

• ~15% of all antibiotics in hospitals are prescribed for surgical prophylaxis

• Important impact on antibiotic resistance and CDI rate

SURGICAL ANTIBIOTIC PROPHYLAXIS AND THE RISK FOR ANTIBIOTIC-RESISTANT AND C. DIFFICILE INFECTIONS

• Associations between antibiotic prophylaxis duration and C. difficile among

patients undergoing coronary artery bypass grafting

• Adjusted analyses: extended prophylaxis (vs standard prophylaxis) associated

with significantly increased C. difficile risk (OR, 1.43; CI, 1.07-1.92)

Poeran J J Thorac Cardiovasc Surg. 2016

Kirkwood KA et al, J Thorac Cardiovasc Surg. 2018

• Patients with CDI more likely to have received > 48 h of postoperative antibiotic prophylaxis

• Less likely to have received second-generation cephalosprins as postoperative antibiotic prophylaxis

Kirkwood KA et al, J Thorac Cardiovasc Surg. 2018

SYSTEMATIC REVIEW AND EVIDENCE-BASED GUIDANCE ON PERIOPERATIVE ANTIBIOTIC PROPHYLAXIS

The objectives of this project were:

• to identify the effectiveness of key modalities of perioperative antibiotic prophylaxis from a systematic review

• to develop five key PAP modalities and process indicators for monitoring their implementation on the basis of scientific evidence and expert opinion.

KEY MODALITIES OF THE EFFECTIVENESS OF PAP

POTENTIAL BARRIERS TO EU-WIDE IMPLEMENTATION OF KEY PAP MODALITIES

• lack of education

• psychological barriers

• lack of awareness regarding local antimicrobial resistance patterns

• hierarchical problems

• lack of professional regulations

• Studies reported non-compliance with PAP guidelines ranging from 5 to 88%

• Reasons for this wide spread and persistent noncompliance remain opaque and are discordant with the urgent international need to optimize use of antimicrobial agents

• Australian teaching hospital

• Twenty surgeons and anesthetists participated in in-depth semistructured interviews on SAP prescribing. Results were analyzed using the framework approach

• 3 key relationship dynamics influenced antibiotic prescribing decisions

1. RELATIONSHIP BETWEEN THE SURGEON AND THE ANESTHETIST

• Challenging a surgeon’s opinion about antibiotic choice was described as difficult, particularly from a more junior position

• Ownership of antibiotic prophylaxis decision: grey area

2. HIERARCHY WITHIN AND BETWEEN SURGICAL AND ANESTHETIST TEAMS • Challenging decisions made by more senior doctors is perceived as

conferring interpersonal risk to junior doctors, which therefore makes appropriate SAP prescribing influence difficult in situations where a consultant makes a decision that is not based on evidence

3. WHO’S ON YOUR TEAM? THE ANTIMICROBIAL STEWARDSHIP/INFECTIOUS DISEASES/SURGEON RELATIONSHIP