Preventing C Acnes Infections: Where are we now, and where do we do from here? Wisconsin Orthopedic Society Amy Franta MD University of Wisconsin Department of Orthopedics and Rehabilitation

Safe study

Interesting finding in 2006 but what did it mean?

Where are we in 2018 New name Considered a pathogen Associated with PJI, implant loosening and pain after shoulder arthroplasty Also seen with rotator cuff repair and arthroscopy Nowhere near understanding it New name, cutibacterium acnes-2016 named for cutaneous proprionibacter acnes Pathogen- seem to all agree that it is not only a contaminant Now associate it with failures- 27-70% of cultures at time of revision shoulder positive for PA; about 50% of infections following open RTC repair positive for CA; also happens in arthroscopy… Nowhere near understanding it- colonization and the relevance to infection, best practice on how to diagnose or eradicate c acnes infections

Agenda Prove to you that we are not currently winning the battle with C. Acnes but we are working on it! Evaluate the current data about prevention of C. Acnes colonization/infection Look at future research and discuss some potential recommendations

Background Pilosebaceous unit Commensal organism Lives within pilosebaceous unit (dermis) Aero tolerant, Anaerobic Gram positive bacillus Fastidious (rarely active, replicating)*** 2 key things Lives in the skin not on the skin Rarely active- limits abx Pilosebaceous unit

Role in acne We extract from the dermatology literature, but the strains that cause acne may not be the same ones that cause PJI/surgical infections. By the time we get to the pustles …

What makes C. Acnes unique? Virulence Virulence –once thought to be a low virulent organism but really it was a slow grower, now multiple phenotypes with different virulence. Hemolytic and non-hemolytic strains. Boyle published a paper suggesting that the hemolytic strains were associated with increased pathogenicity however a paper published this year by (Ionnoti’s group) showed no difference infection rates between hemolytic and non-hemolytic strains Colonization- presumably linked to risk of infection

What makes C. Acnes unique? Biofilm aka “the hippie commune” Biofilm-more virulent strains better biofilm formers. As we know this has a significant impact on ability to treat infections. Staph epi

What makes C. Acnes unique? Colonization In the shoulder C Acnes burden greatest at anterior and posterior acromion compared with axilla Remember this is a commensal organism. We hypothesize Colonization- presumably linked to risk of infection, disease (like h pylori) Above the waist problem

Colonization Typically quoted between 42-76% 42% superficial skin swabs positive for CA (post Cefazolin/ but pre skin preparation) Phadnis, et al 47% superficial skin swabs positive for CA (post CHG pre op wash but before skin preparation) –Koh, et al 38 of 40 (95%) patients superficial skin swabs positive for CA one week pre-operatively (no interventions) - Sheer, et al

Current skin preparations do not eliminate C Current skin preparations do not eliminate C. acnes from the cleansed skin or dermis What is worse than colonization is colonization post standard skin preparation

ChloraPrep CHG not able to eradicate C. acnes from the skin and dermis Saltzman, et al (130 patients, 3 different skin preparations, surface cultures) ChloraPrep- 7% cultures positive for CA DuraPrep- 12% cultures positive for CA Povidone-iodine- 15% cultures positive for CA

ChloraPrep AND cefazolin IV Phadnis, et al (50 patients, superficial and dermal swabs) Prior to skin prep- 42% cultures positive for C acnes After skin prep and abx- 14% superficial skin swabs positive for C. acnes After skin prep and immediately after skin incision- 52% of dermal cultures positive for C. acnes Need to decontaminate the sebaceous glands of the dermis This takes us to the meat of the talk looking at the literature about decreasing the burden of C. acnes in shoulder surgery. This talk with focus only on C. Acnes and will not look at other causes of SSI and some of our standard surgical prophylaxis

Decolonization/Prevention of C. Acnes Pre operative skin decolonization 3 main groups benzoyl, combo benzoyl and clinda, doxy Standard skin preparation with CHG do not eliminate C Acnes from the skin Decreasing skin burden MAY decrease risk for wound contamination and delayed infection Bacterial leakage from sebaceous glands released after wounds after skin incision

Benzoyl peroxide- BPO Peroxide family of chemicals Bactericidal No resistance to C. acnes Mechanism not clear Strengths 2.5, 5, and 10% Effects persist 48h? Side effect- skin irritation (typically seen at onset of treatment) Mechanism- sebostatic-debated, comedolytic, inhibits p acnes-from PDR

Decolonization 5% BPO vs 4% chlorhexidine (Sheer, et al) Non surgical healthy volunteers- 2 groups BPO started 48 hours prior to “surgery”, 5 cm strip, twice a day CHG started 24 hours prior to “surgery”, 3 showers CHG in 70 % alcohol used in OR as “prep” 4 skin samples taken in each group over deltopectoral interval 1 week pre op Day of “surgery” (prior to standard skin preparation) After prep and draping in OR 120 min after prep and draping Busy slide but study basically compares at home chg and bpo

BPO vs CHG Sample BPO (# of subjects with P acnes CFUs) CHG A- one week pre op (prior to intervention) 19 of 20 B- day of surgery/intervention 13 of 20 16 of 20 C- immediately after prep and draping 1 of 20 7 of 20 (significant difference between groups) D- 120 min after prep and draping 4 of 20 11 of 20 (significant difference between groups) BPO treatment significantly decreases the presence of P. acnes after pre-operative preparation and the results remain after 120 minutes Sheer, et al

BPO decolonization Sabetta, et al 50 patients prior to first time arthroscopic surgery 5 doses of 5%BPO cream within 2 days of surgery Half dollar size to shoulder and arm pit Skin preparation at the time of surgery- chloroxylenol wash, 3-2% CHG standard IV antibiotics (cefazolin or clindamycin) 12 samples per subject 8 sterile skin swabs Joint aspiration 3 tissue samples Second study looking a pre op at home BPO

BPO treated shoulder Untreated shoulder Cultures taken prior to CHG skin preparation 16% of cultures positive for CA from anterior deltoid 8% positive at axilla 32% of cultures positive for CA from anterior deltoid 28% positive at axilla Cultures taken after CHG skin preparation Skin swab anterior deltoid- 6% Aspiration Tissue (3)- 6%, 2%, 6% Cultures taken during the procedure Anterior deltoid-10% Axilla-10% BPO is an effective way to reduce C. Acnes on skin at beginning and at the end of the surgical procedure Sabetta, et al

Benzoyl peroxide decolonization AAOS 2018 Neer Award Paper (Kolakowski, et al) Randomized to 5% BPO vs 4 % CHG (decolonization) 72 hours pre op, 3 applications 4 samples taken from operative and control (non-operative shoulder) prior to standard skin preparation for shoulder arthroscopy at portal sites (3) and axilla BPO decreases the pre operative P. acnes skin burden at most of the anatomic sites around the shoulder compared to CHG On the other hand- just publish Anterior and posterior saw greater reduction than lateral and axillary sites

BPO and clindamycin 3 products: Onexton, Duac, Benzaclin Dosed 1-2 times per day depending on product Thin layer applied to skin Expensive Most common side effect: skin irritation So if BPO is good could BPO with clindamycin be better?

BPO and clindamycin 78.9% reduction in superficial colonization of CA with > 1 pre operative dose Reducing CA in the dermis before surgery could potentially reduce wound contamination with CA and therefore lower risk of clinical infection with CA Any better than bpo alone, advantage only one dose Reduction in deep colonization from 19.6% to 3.1% Dizay, et al

Doxycycline (oral) Acne vulgaris (dermatology literature) susceptible Azithromycin Fluoroquinolones More than cephalosporins and Vancomycin Rare to see resistance Bacteriostatic, NOT bactericidal (prevents growth rather than killing bacteria) Tetracylclines inhibit protein synthesis by binding reversibly to 30s subunity

Doxycycline Poster 288 AAOS 2018 (Rothman Institute) Randomized: group 1 Doxycycline 100mg BID for 7 days pre-op, group 2 no drug 2% CHG cloth in pre-op Cefazolin or Clindamycin IV pre-op Pre-operative scrub 7.5% povidone- iodine solution 2- CHG 2% in 70% alcohol applicators Punch biopsy of anterior and portal sites 22 of 37 (59.5%) in “no drug” group had a positive culture 16 of 37 (43.2%) in doxycycline group had at least one positive culture No medication side effects Paper did not recommend routine short term use of doxycycline for pre operative decolonization

Pre operative skin preparation Preparation of axillary hair

Hydrogen peroxide Hydrogen peroxide typically broken down to oxygen and water when exposed to light but new stabilized forms available (Crystacide Cream) Benzoyl peroxide broken down into benzoic acid and hydrogen peroxide (active) Same family as bpo

Hydrogen Peroxide Clinical trial- 2/2017 to 2/2018 (Chalmers) Abstract- Hernandez 2017 ASES closed meeting In Vitro study Used H202 in saline, H2O2 in water, vs 3% topical H202 Within 5 minutes decrease in C .Acnes 3% H2O2 topical solution worked the best

Axillary prep No evidence to suggest that axillary hair removal decreases burden of C. Acnes Marecek (salzman) et al actually have increased bacterial burden after clipping! Compared clipped and unclipped cultures- no difference between cultures after prep

Pre operative Antibiotics Cephalosporin We know Cephalosporins/ pre op abx work to decrease rate of infection. Cephalosporins and PCN have shown strong activity against CA isolates from shoulder operations (Crane) C. acnes. More must be better Cephalosporin plus Vancomycin Cephalosporin plus IV doxycycline Matsen, et al Rao, et al

Ceftriaxone with IV Vancomycin Vancomycin and ceftriaxone IV pre op (Matsen, et al) 10 male patients primary arthroplasty Ceftriaxone 2 gm and Vancomycin 1 gm IV pre-op Double skin preparation Specimens from dermis, fascia, capsule, synovium, and glenoid

Ceftriaxone with IV Vancomycin 30% rate of deep positive cultures for C. Acnes “aggressive prophylaxis with systemic antibiotics and skin preparation may not be successful in eliminating Propionibacterium from the surgical wounds” 7 of 50 positive cultures for P acnes 1/10 dermis 2/10 fascia 1/10 synovium 3/10 glenoid

Cefazolin vs Doxycycline and Cefazolin IV pre-op- (Rao, et al) Anatomic and reverse Cultures from skin edge, dermis, and glenohumeral joint (after skin preparation with alcohol and chlorhexidine and placement of ioban) 38% had one or more positive culture with NO difference between groups Risk factors for positive culture- younger, male No association with BMI or arthroplasty type Skin (30%), Dermis (20%), glenohumeral joint (5%) Not surprised by this study base on what we know of CA and doxycylcine

Intraoperative Intraoperative

Intra-articular Gentamicin Injection Did not specifically look at C. Acnes 507 patients –single surgeon 164 without injection 343 with injection Groups matched for gender, BMI, medical co-morbidities, age 160mg gentamicin in 20 mL of saline Spinal needle inserted prior to closure laterally Lovallo, et al This is the only study I included not specifically looking at CA. Because I found it interesting. Lovallo, et al

After closure of skin, injection performed Figure 1 After closure of skin, injection performed Spinal needle inserted into joint before closure. Journal of Shoulder and Elbow Surgery 2014 23, 1272-1276DOI: (10.1016/j.jse.2013.12.016) Lovallo, et al 2014 Copyright © 2014 Journal of Shoulder and Elbow Surgery Board of Trustees Terms and Conditions

Intra-articular Gentamicin injection Group A without injection – 3% deep infection rate Group B with injection- 0.29% deep infection rate

Vancomycin Powder Minimal shoulder literature (spine) Poor systemic absorption-stays local High local bactericidal levels Effective against C. Acnes Vancomycin powder makes sense but…

Vancomycin topical powder Poster AAOS 801 (Columbia University) Animal (rat) study 2 groups: experimental (10^9 CFU P Acnes and 10g Vancomycin powder) and positive control(10^9 CFU P acnes, no vanco) All rats underwent shoulder hemiarthroplasty ½ sacrificed POD 7 and ½ on POD 42 Samples : rotator cuff, humeral head bone, metal prosthesis

Topical Vancomycin powder Cultures: positive control group 18% and treatment group 15% (all samples) No difference in deep culture rates

Dilute iodine irrigation Minimal literature in the shoulder (hip and knee) 500mL of 1.3 g/L dilute povidone-iodine solution Followed by saline lavage Again I include this b/c it is interesting but no data in the shoulder. Promising studies in hip and knee and spine. I know many surgeon who anecdotaly do this

Post operative Silver containing dressing Sad looking slide- very little post operative literature. No shoulder literature but in vitro studies have shown bactericidal activity properties of a silver-containing dressing against C Acnes for up to 7 days. Silver containing dressing

“Stepwise antisepsis” Koh, et al Swab 6- superficial skin after subQ closure and irrigation with povidone iodine Swab 5- deep after implant placement and irrigation with cefazolin and gent in 2 L saline Swab 4- deep after ioban drapping, incision, and disarticulation Swab 1- superficial skin-after home CHG but before IV abx Swab 2-skin after abx (cefazolin and gent) and skin prep with CHG scrub brush Swab 3- skin after standard CHG prep times 2

Where do we go from here? First establish link between C. Acnes colonization and infection/ outcomes More shoulder specific data on Vancomycin powder, iodine irrigation Oral doxycycline- 30 days vs 7 days Take our in vitro studies to in vivo studies and our animal studies to human studies looking at vancomycin powder, silver dressing, hydrogen peroxide After that disappointing slide…where do we go from here, role of more post op research Take a look at our dermatology colleagues- UV light (blue light)

Recommendations Follow our current practices to prevent SSIs Appropriate antibiotics Pre operative skin preparation Changing gloves MRSA/MSSA screening Addition of BPO pre operatively should be considered for shoulder surgery to decrease C. Acnes burden Consider bpo- safe, inexpensive, effective. Wash vs cream- skin irritation

Consider intrawound applications Intra-articular injection gentamicin Vancomycin powder Povidone-iodine irrigation Dismiss aggressive IV pre op abx.

references Rao, et al. JBJS 100 (11): 958-964, Jun 2018. Preoperative Doxycycline Does Not Reduce Propionibacterium Acnes in Shoulder Arthroplasty Matsen, et al. Propionibacterium can be isolated from deep cultures obtained at primary surgery despite intravenous antimicrobial prophylaxis. JSES. 2015 Jun;24 (6) : 844-7 Matsen, et al. Origin of Propionibacterium in Surgical Wounds and Evidence-based Approach for Culturing Propionibacterium form Surgical Sites. JBJS 95 (e181):1-7, 2013. Koh,et al. Propionibacterium acnes in primary shoulder arthroplasty: rates of colonization, patient risk factors, and efficacy of perioperative antibiotics. JSES. 25 (5): 846-52, May 2016. Sheer, et al. Topical benzoyl peroxide application on the shoulder reduces Propionibacterium acnes: a randomized study. JSES. 2018 June; 27, 957-961 Sabetta, et al. Efficacy of topical benzoyl peroxide on the reduction of Propionibacterium acnes during shoulder surgery. JSES. 2015; 24: 995-1004 Lovello, et al. Intraoperative intra-articular injection of gentamicin: will it decrease the risk of infection in total shoulder arthroplasty? JSES. 2014; 23: 1272-1276 Levy, et al. Propionibacterium acnes: an underestimated etiology in the pathogenesis of osteoarthritis? JSES. 2013; 22: 505-511 Lee, et al. Propionibacterium persists in the skin despite standard surgical preparation. JBJS. 2014; 96: 1447-50 Chuang, et al. The incidence of Propionibacterium acnes in shoulder arthroscopy. Arthroscopy. 2015; 31 (9): 1702-1707 Sethi, et al. Presence of Propionibacterium acnes in primary shoulder arthroscopy: results of aspiration and tissue cultures. JSES. 2015; 24: 796-803 Phadnis, et al. Frequent isolation of Propionibacterium acnes from the shoulder dermis despite skin preparation and prophylactic antibiotics. JSES. 2016; 25: 304-310 Dizay, et al Clark et al. Preventing infection in shoulder surgery. JSES. 2018; 27: 1333-1341 Mahylis, et al. Hemolytic strains of Propionibacterium acnes do not demonstrate greater pathogenicity in periprosthetic shoulder infections. JSES. 2018; 27: 1097-1104

abstracts 2017 ASES Closed meeting Paper 21 Bactericidal efficacy of hydrogen peroxide on Propionibacterium acnes. Hernandez, et al 2018 AAOS Poster 801Topical Vancomycin to Eradicate P. Acnes after Shoulder Arthroplasty: An In-vivo Animal Study. Qayyum, et al. Poster 802 Benzoyl Peroxide effectively decreases preoperative Propionibactium acnes shoulder burden. Kolakowski, et al. Poster 288 Preoperative Doxycycline Does Not Decolonize P. Acnes from the Skin of the Shoulder: A Randomized Controlled Trial. Namdari, et al. Rothman Institue. Poster 300 (published JBJS) Rao, et al

Thank You Special thanks to Dr Zdeblick and the Department of Orthopedics and Rehabiliation