Dr Indran Balakrishnan Chair, Antimicrobial Stewardship Committee Royal Free London NHS Foundation Trust

Dr Indran Balakrishnan Chair, Antimicrobial Stewardship Committee Royal Free London NHS Foundation Trust

(Scottish Intercollegiate Guidelines Network, 2014, National Healthcare Safety Network, 2012) BUT The breast harbours significant endogenous bacteria (Staphylococci, Propionibacterium acnes) S. epidermidis most common Entering the lactiferous system is akin to entering the respiratory/alimentary/genitourinary tract Breast surgery is therefore more appropriately classified as clean-contaminated surgery (Bartsich et al, 2011, Hardwicke et al, 2013)

Incidence of SSI in breast/axillary surgery is elevated compared to clean procedures Plast Reconstr Surg. 2015 Jun;135(6):1723-39. doi: 10.1097/PRS.0000000000001265. Antibiotic prophylaxis for preventing surgical-site infection in plastic surgery: an evidence-based consensus conference statement from the American Association of Plastic Surgeons. Ariyan S 1, Martin J, Lal A, Cheng D, Borah GL, Chung KC, Conly J, Havlik R, Lee WP, McGrath MH, Pribaz J, Young VL. Meta-analysis of nine studies: Systemic antibiotic prophylaxis is recommended for clean breast surgery

SSI rates following mastectomy and reconstruction have infection rates up to 10x higher than after aesthetic surgery (Pittet et al, 2005)

Ann Plast Surg. 2016 Feb;76(2):174-9. doi: 10.1097/SAP.0000000000000514. Impact of Postoperative Antibiotic Prophylaxis Duration on Surgical Site Infections in Autologous Breast Reconstruction. Drury KE 1, Lanier ST, Khavanin N, Hume KM, Gutowski KA, Thornton BP, Hansen NM, Murphy RX Jr, Fine NA, Kim JY. Retrospective analysis of patients in ASPS TOPS database 583 non-ld autologous reconstructions Two groups based on duration of antibiotic prophylaxis 24h > 24h Cohort characteristics and 30 day outcomes compared Duration of Antibiotics SSI rate P value 24h 5.49% 0.228 >24h 3.20% Antibiotic duration was not predictive of SSI in multivariate regression modelling

No significant difference in SSI rates between patients receiving antibiotics for 24h and >24h in non-ld autologous reconstruction This holds irrespective of reconstruction subtype Consistent with earlier study on microsurgical reconstruction (Liu et al, 2012)

256 patients 2006-09 360 microsurgical reconstructions Overall SSI rate 17.2% (44/256) Duration of Antibiotics SSI rate P value 24h 19.5% 0.47 >24h 15.5%

Pre-operative Single IV dose within 30 minutes before incision Intra-operative Re-dose every 2 half-lives Co-amoxiclav: 4h Teicoplanin (B-lactam allergy): Not applicable Post-operative Not routinely indicated

November 2012

Pre-operative dose No drains: Discontinue within 24h Drains: Role of antibiotics is less clear Limited evidence Documenting a drain in proximity with the implant as reason for continuing antibiotics is SCIP compliant

Ann Plast Surg. 2016 Feb;76(2):174-9. doi: 10.1097/SAP.0000000000000514. Impact of Postoperative Antibiotic Prophylaxis Duration on Surgical Site Infections in Autologous Breast Reconstruction. Drury KE 1, Lanier ST, Khavanin N, Hume KM, Gutowski KA, Thornton BP, Hansen NM, Murphy RX Jr, Fine NA, Kim JY. Retrospective analysis of patients in ASPS TOPS database 453 LD reconstructions Two groups based on duration of antibiotic prophylaxis 24h > 24h Cohort characteristics and 30 day outcomes compared Duration of Antibiotics SSI rate P value 24h 4.41% 0.439 >24h 2.53% Antibiotic duration was not predictive of SSI in multivariate regression modelling

Retrospective matched cohort study Implant reconstruction 2008-12 (Toronto) 208 patients, 647 procedures Total (N=188) <24H Abx Abx until drain removal

Duration of Antibiotics SSI rate (%) Single pre-op dose (cefazolin or clindamycin) >24h cefalexin 10 12 P=0.8 Only pre-operative radiotherapy was associated with infection (P=0.003)

Concerns that ADM are a separate risk factor for SSI Implant under a non-vascularized dermal construct Poorly perfused mastectomy skin flaps Compromised lymphatic drainage Increased dead space Infection rates up to 31% have been reported(phillips et al, 2014)

Retrospective study of 96 patients operated on over 3 years Immediate or delayed expander-based reconstruction using Allo-Derm allogenic acellular dermal matrix 17/06/2007 30/9/2009 Experimental cohort 1 st time interval 48h post-operative antibiotics N=88 breasts 10/01/2009 18/11/2009 Control cohort 24 h post-operative antibiotics N=19 breasts SSI Rate (%) 7.9 31.6 3.2 P = 0.002 19/11/2009 30/8/2010 Experimental cohort 1 st time interval 48h post-operative antibiotics N=31 breasts

Conclusions Minimum of 48h post-operative antibiotics Much larger study needed to determine exactly how long

Numbers 2 experimental cohorts ( 48h post-op antibiotics) N=88, 31 1 control cohort ( 24h post-op antibiotics) N=19 Uncontrolled variables Time course between mastectomy and reconstruction Nodal dissection Operative history Unilateral or bilateral reconstruction

Antibiotic regimens Pre-operative 1 of 1 st generation cephalosporin Vancomycin Clindamycin Post-operative 1 st generation cephalosporin (62%) Vancomycin (23.8%) Clindamycin (13.1%) Ciprofloxacin (1.2%)

<24h 48h Day 16 MSSA Day 17 MRSA Day 19 S. epidermidis Day 20 Enterococcus Day 22 MSSA Day 28 MSSA Day 14 MSSA Day 17 Serratia Day 37 Mycobacterium abscessus Day 38 Pseudomonas Day 50 MRSA Day 72 Mycobacterium abscessus Day 127 Culture negative Day 134 Culture negative Day refers to duration after surgery that the tissue expander was removed Note: 48h post-operative antibiotics cohort had a high incidence (> 50%) of atypical, multiresistant pathogens that would be more difficult to treat Independent risk factor for implant loss

112 TE-IBR patients, 180 breasts Randomized into 2 groups prospectively 62 received antibiotics for 24h 50 received antibiotics until drain removal Duration of Antibiotics SSI rate 24h 19.4% Until drain removal 22.0% P value 0.82

Several hypotheses Infection Haematoma Granulomatous response to free silicone Bacterial biofilm

Bacteria are enclosed within a polysaccharide matrix May elude standard microbiological sampling Confers resistance against antibiotics, host defenses and antiseptics Chronic inflammatory response

Pre-incision dose of antibiotic Extending duration post-operatively does not result in reduced superficial or periprosthetic infections (Khan, 2010) Pocket irrigation (Giordano et al, 2013) Povidone-iodine Cefuroxime Gentamicin Clinical application of topical ointments is unclear Future: Implant coating with surfaces that are either resistant to bacterial adhesion or antimicrobial

Incidence of infection Cosmetic implant surgery: 2.0-2.5% Reconstructive implant surgery: up to 35.4% Higher incidence of infection Atypical pathogens Independent risk factor for implant loss

Implant is positioned under a poorly vascularized mastectomy skin flap Often hospitalized after surgery Closed suction drains Peri-operative antibiotics Neo-adjuvant radiotherapy and chemotherapy

Retrospective chart review 902 consecutive immediate implant-based reconstructions 2007-2011 Peri-operative antibiotics given until drains were removed Cefalexin 96.2% Clindamycin 3.8% Infectious complications in 103 (11.4%) 54 (5.74% of total) required explantation 2 (0.22% of total) required radiological drainage of abscess 13 excluded no specimens sent for culture

43 infected IBR included for analysis Permanent implants: 5 Acellular dermal matrix (Alloderm): 38 (88.4%) Reconstructions salvaged: 21(51.2%) Oral Antibiotics (all patients) Cefalexin: 39.5% Co-amoxiclav: 30.2% Clarithromycin: 9.3% Clindamycin: 7.0% Quinolones: 9.3% Co-trimoxazole: 4.65% Preculture IV Antibiotics (all patients) Vancomycin: 56% Cefazolin: 23% Piperacillin/tazobactam: 9% Ampicillin/sulbactam: 6% Clindamycin: 6%

Time to infection: 7-89 days (mean: 30.7) Culture analysis on 43 implants Bacterial growth in 30 (69.7%) Group B Streptococcus Morganella morganii MRSA Enterobacter sp E. coli Enterococcus sp Pseudomonas sp Serratia marcescens MSSA S. epidermidis

Equivalence of Gram positive and Gram negative organisms Importance of early effective treatment of S. epidermidis Biofilm impedes antibiotic activity Co-amoxiclav or flucloxacillin are not the best agents for either prophylaxis or empiric treatment

Microbiology Appropriate spectrum Pharmacokinetics Half-life Intra-operative re-dosing every 2 half-lives Tissue penetration Safety Allergic reactions Adverse reactions Minor (GI upset) Major (C. difficile associated diarrhoea, PMC) Multiresistant healthcare-associated infections MRSA, VRE, MDR-GNR Reduction in antibiotic susceptibility in both patient and hospital flora Risks increase with duration of antibiotic exposure Hippocrates (460-375 BC)

Resistance to antibiotics risks health 'catastrophe' to rank with terrorism and climate change CMO Dame Sally Davies Mar 2013 Press release Prime Minister warns of global threat of antibiotic resistance From: Department of Health and Prime Minister's Office, 10 Downing Street First published: 2 July 2014

The White House Office of the Press Secretary For Immediate Release March 27, 2015 FACT SHEET: Obama Administration Releases National Action Plan to Combat Antibiotic-Resistant Bacteria Antibiotic resistance now 'global threat', WHO warns By Pippa Stephens Health reporter, BBC News 30 April 2014

Change antibiotic prophylaxis regimen for implant breast reconstruction Better cover for likely pathogens S. epidermidis Enterobacteriaceae and Pseudomonas Appropriate timing and duration Short-comings with co-amoxiclav > 80% resistance amongst S. epidermidis 30% resistance with E. coli Higher with other Enterobacteriaceae No activity at all against P. aeruginosa Short half life of 2-3h Requires intra-operative re-dosing every 4h Short-comings with flucloxacillin > 80% resistance amongst S. epidermidis No Gram negative activity Short half-life (2h) Requires intra-operative re-dosing every 4h

Single doses pre-incision: Teicoplanin 10 mg/kg IV Gentamicin 5 mg/kg IV These doses provide cover for 24h No post-operative doses unless infection suspected Acellular dermal matrix consider 1 further dose as above (48h cover)

Group B Streptococcus Morganella morganii MRSA Enterobacter sp E. coli Enterococcus sp Pseudomonas sp Serratia marcescens MSSA S. epidermidis 1 st Line Teicoplanin 10 mg/kg (Max: 800 mg) IV Piperacillin/tazobactam 4.5 g QDS IV If patient septic add Gentamicin (dose as per Trust Aminoglycoside Policy) Penicillin Allergy Teicoplanin 10 mg/kg (Max: 800 mg) IV Ciprofloxacin 400 mg bd IV If patient septic add Gentamicin (dose as per Trust Aminoglycoside Policy) Review with clinical response and cultures