Antibiotics and Anticoagulants

Tissa Hata M.D.Professor of Dermatology

UCSD School of MedicineJuly 7, 2014

Antibiotic Prophylaxis

• Type of Procedure• Type of Patient• What we are prophylaxing against• Type of “Wound” we are working in

Type of Procedure

• MOHS• Excision• Biopsy• Cryotherapy• ED&C• Ablative laser

Type of Patient• Malnutrition• Obesity• Diabetic• Chronic renal insufficiency• Immunosuppression• Tobacco or alcohol use• Advanced Age

Prophylactic Antibiotics for Prevention of Surgical Site Infection

• Depends on wound type• Addressed by several articles • Babcock & Greckin (Dermatol Clin 2003) • Maragh (Dermatol Surg 2005) • Messingham & Arpey (Dermatol Surg 2005) • Dixon & Wilkinson (Dermatol Surg 2006)• Hurst,Grekin, Yu, Neuhaus (Sem Cut Med Surg 2007)• Wright et al ( J am Acad Dermatol 2008)• Rosengren and Dixon (Am J Clin Dermatol 2010)• Rossi and Mariwalla (Dermatol Surg 2012)

Dixon & Wilkinson (Dermatol Surg 2006)

• 3 year prospective study 5091 lesions on 2424 patients

• No prophylactic antibiotics or cessation of anticoagulants

• Overall infection incidence 1.47%

Infection Rate by Procedure

• Curettage 0.73% (3/412)• Skin flap repairs 2.94% (47/1601)• Simple excision and closure 0.54%

(16/2974)• Skin grafts 8.70% (6/69)• Wedge excision of lip or ear 8.57% (3/35)

Infection Rate by Site • Surgery below the knee 6.92% (31/448)• Groin excisional surgery 10% (1/10)• Face 0.81% (18/2209)• Diabetics*, patients on warfarin and/or

ASA, and smokers* without any increase

*5-year prospective study of 7224 lesions subsequently showed diabetics to have an increase in infection of 4.2% 23/551, over 2% without 135/6673 p<0.001. Dixon A. Dermatolog Surg 2009 Jul:35(7): 1035-40. *5-year observation study with 439 smokers with 646 excisions and 3759 non smokers showed no increase in infection, bleeding or wound dehiscience.Br J Dermatol 2000 Feb; 160(2):365-7*Prospective study of 100 subjects in the US showed no increase in infection in diabetics, but increased in smokers. Arch Dermatol. 2007;143(10):1267-1271

Dixon & Wilkinson suggest prophylaxis

• All procedures below the knee and groin• Wedge excisions of lip and ear• All Skin grafts

Advisory Statement 2008.J Am Acad Dermatol 2008 Sep;593) 464-73

Procedure location and surgical techniques requiring prophylaxis

• Lower extremity*• Groin• Wedge excision of lip or ear• Skin flaps on nose*• Skin grafting• Extensive inflammatory skin disease*

Antibiotic prophylaxisWedge excision of lip/ear; flaps on nose; all grafts

No Pen allergy

Cephalexinor

Dicloxacillin

2 g PO

2 g PO

Lesions in groin or lower extremities

No Pen allergy

Cephalexin orTMP-SMX DS or levofloxacin

2 g PO 1 tab PO500 mg PO

Wedge excision of lip/ear; flaps on nose; all grafts

Pen allergy

Clindamycin orAzithromycin/clarithromycin

600 mg PO

500 mg PO

Lesions in groin or lower extremities

Pen allergy

TMP-SMX DS or levofloxacin

1 tab PO500 mg PO

Prophylaxis for Endocarditis

Endocarditis Facts

• Mortality rate as high as 76%• 40% require heart valve replacement within

5-8 years• Less than 10 cases possibly linked to

dermatologic procedures

Bacteremia incidences

Activity or Procedure %Outpatient dermatologic surgery 1.9-3Tooth brushing 24-40Mastication 17-24Tooth extraction 60-90Spontaneous healthy adults 2Vaginal delivery 1-5Incision and drainage of abcess 38

AHA Guidelines 2007

• American Heart Association revised their recommendations ten times since 1955

• Last Update May 2007• Greatly simplified the guidelines• More evidence based• New guidelines recommend prophylaxis in only

the highest risk category

Primary Reasons for Revision of Guidelines

• Endocarditis much more likely to result from frequent exposure to random bacteremia associated with daily activity

• Prophylaxis may prevent an exceedingly small number of cases

• Risk of antibiotic AE exceeds the benefit of prophylactic therapy

• Maintenance of optimal oral health is more important than prophylactic antibiotics

Cardiac conditions in which prophylaxis is recommended

• Prosthetic cardiac valve• Previous endocarditis• Cardiac transplantation recipients who develop

cardiac valvulopathy• Congenital heart disease

– Unrepaired cyanotic CHD, including palliative shunts and conduits– Completely repaired congenital heart defect with prosthetic

material or device, whether placed by surgery or by catheter intervention, during the first 6 months after the procedure

– Repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device

Procedures Requiring Prophylaxis for Endocarditis

• Dental Procedures-All dental procedure that involve manipulation of the gingival tissue or the periapical region of teeth or perforation of the oral mucosa

• Respiratory tract-Incision or biopsy of the respiratory mucosa such as tonsillectomy or adenoidectomy

• GI tract- Not recommended unless active infection

• GU tract-Not recommended unless active infection

Prophylaxis for Skin Procedures

• Recommendations for patients in the high risk category who undergo a surgical procedure that involves infected skin, skin structure or musculoskeletal tissue

Wright et al. Antibiotic prophylaxis in Dermatologic Surgery Advisory Statement 2008.J Am Acad Dermatol 2008, Sep: 59(3); 464-73

Conclusions

• Based on the AHA recommendations, all articles recommend prophylaxis in high risk category during surgery that may involve infected skin

• Recommend prophylaxis in high risk pts during surgery that may involve breach of a mucosal surface

• Advisory Statement 2008 also recommends prophylaxis in high/low risk pt that may involve infected skin and involving any area at high risk for infection

Antibiotic Prophylaxis for Endocarditis

• Should be given 30-60 minutes prior to surgery• No longer recommend a follow-up abx dose• If not, may be given for up to 2 hours after the

procedure

Antibiotic Prophylaxis for EndocarditisNon-oral No Pen

AllergyCephelexin or dicloxacillin

2 g PO2 g PO

Non-oral Pen Allergic

Clindamycin orAzithromycin/clarithromycin

600 mg PO500 mg PO

Oral No Pen Allergy

Amoxicillin 2 g PO

Oral Pen allergic

Clindamycin orAzithromycin/clarithromycin

600 mg PO500 mg PO

Patients at Risk for Prosthetic Joint Infection• First 2 years following joint placement• Previous prosthetic joint infections• Immunocompromised/immunosuppressed patients• Inflammatory arthropathies (eg, RA, SLE)• Drug- or radiation-induced immunosuppression• Insulin-dependent (type 1) diabetes• HIV infection• Malignancy• Malnourishment• Hemophilia

JAAD Advisory Statement 2008

_____________________________________________• Diabetes Type 2• Autoimmune disease• Post-organ transplants• Receiving chemotherapy• Bone Marrow transplant patients• Chronic steroid uses• Obesity• Tobacco exposure or alcohol use• Elderly

AAOS-ADA Clinical Practice Guideline 2012

Derm Advisory Statement for Prosthetic Joint Infection

• High risk patient for joint infection with perforation of oral mucosa

• Any infected site• Noninfected site that is at high risk of

surgical site infection.

Anticoagulants

Warfarin• Metabolized by the CYP2C9 hepatic microsomal

enzyme system• Strongly protein bound, only non-protein bound

fraction is active• Biologic half-life 36-42 hours• Inhibits vitamin K-dependent gamma-

carboxylation of coagulation factors II, VII, IX, X• Inhibit protein C and protein S• Factor VII activity drops at 2 days, but Factor IX,

X, II drop at 4 days• Thus 4-5 days necessary for anticoagulation

Inhibition of gamma-glutamyl carboxylase

Known gamma-Carboxyglutamic Acid-Containing Proteins

Blood Clotting and regulatory proteinsProthrombinFactor VIIFactov IXFactor XProtein CProtein SProtein Z

Bone proteinsOsteocalcin

Matrix Gamma-carboxyglutamic acid protein

Hypercoagulable State

• Hypercoagulable state occurs when patients on long term warfarin are withdrawn as well as when initially starting

• Due to the vitamin K dependent factors returning to normal levels at different rates

• Especially protein C, a normal anticoagulant takes much longer than factor VII, but quicker than prothrombin, Factor IX and X

• This state lasts approximately one week

Aspirin

• Irreversibly acetylates and inactivates cyclooxygenase which catalyzes the conversion of arachidonic acid to thromboxane A2

• Platelets do not synthesize new enzyme, defect persists for the life of the platelet

• Life of platelet 7-10 days

J Dermatol Surg Oncol 1993; 19:578-81.

Previous Recommendations

• Guidelines primarily based on recommendations from 1993 Goldsmith et al

• Discontinue aspirin 7-10 days preoperatively, resume 1 day postoperatively

• Discontinue warfarin 3 days prior and resume 1 day post for low risk

• High risk patients should have perioperative heparin during discontinuation of warfarin

Multiple recent studies now refute these recommendations

• Prospective study of 5950 skin lesions excised in 2394 patients

• The rate of postoperative bleeding was 0·7 % overall and 2·5 % in the 320 patients taking warfarin

• The rate of bleeding was 1·0 % for skin flap repairs, 0·4 % for simple excision and closure, and 5·0 % for skin grafts

A. J. Dixon, M. P.Dixon and J. B. Dixon. BritishJournal of Surgery 2007; 94: 1356–1360

Odds ratio P*

Age > 67 4.7 0.002

Warfarin therapy

2.9 0.006

Flap or graft 2.7 0.004

Ear surgery 2.6 0.012

ASA therapy 1.4 0.349

• 1911 patients at Case Western University• 38% on one anticoagulant or antiplatelet

medication• 8% on two or more• Risk of hemorrhage 0.89%, 17/1911)• Patients on clopidogrel or warfarin were

more likely to have bleeding complications p=0.004, p<0.0001).

• ASA, NSAID and vitamin E not significant

Bordeaux JS, Martires KJ et al. Prospective evaluation of dermatologic surgery complications including patients on multiple antiplatelet and anticoagulant medications. J Am Acad Dermatolog 2011;65: 576-83.

• Risk of Hemorrhage: Partial repair>flap repair> graft repair> complex repair>intermediate repair

• All complications resolved without sequelae• Conclusions were the rate of complications

were low, and anticoagulants should be continued

Bordeaux JS, Martires KJ et al. Prospective evaluation of dermatologic surgery complications including patients on multiple antiplatelet and anticoagulant medications. J Am Acad Dermatolog 2011;65: 576-83.

Postoperative hemorrhage risk after outpatient dermatologic surgery

procedures• 2418 subjects undergoing dermatologic surgery• 51% received one or more anticoagulant

medications• 11 post operative hemorrhages• Warfarin had greatest risk 4/161 but was still <3%• 1/58 Warfarin+OA, 3/881 ASA, 0/67

clopidogrel+ASA, 0/56 clopidogrel, 3/1184 no anticoag

O'Neill JL, Taheri A, Solomon JA, Pearce DJ. Postoperative hemorrhage risk after outpatient dermatologic surgery procedures. Dermatol Surg. 2014 Jan;40(1):74-6

Complications of cutaneous surgery in patients taking clopidogrel-containing

anticoagulation• 220 patient taking clopidogrel underwent 363 surgical

procedures• Clopidogrel-containing anticoagulation was 6x more likely

than ASA to result in severe complications after MOHS• Pts on Clopidogrel and ASA together verses ASA alone

were 8x more likely after MOHS to have severe complications

• Pts on clopidogrel are at an increased risk of complications

Cook-Norris RH1, Michaels JD, Weaver AL, Phillips PK, Brewer JD, Roenigk RK, Otley CC. J Am Acad Dermatol 2011;65:584-91

Novel Oral Anticoagulants

• Dabigatran (Pradaxa)• Rivaroxaban(Xarelto)• Apixaban (Elquis)

Fig 1 Simplified coagulation cascade highlighting the biological targets of the novel oral anticoagulants. The intrinsic and extrinsic pathways converge to activate factor Xa, which in turn activates thrombin. Rivaroxaban and apixaban are factor Xa inhibit...

Molly Plovanich , Arash Mostaghimi

Novel oral anticoagulants: What dermatologists need to know

Journal of the American Academy of Dermatology, Volume 72, Issue 3, 2015, 535 - 540

http://dx.doi.org/10.1016/j.jaad.2014.11.013

Mechanism of Action Novel Anticoagulants

Pharmacokinetics of Novel Oral Anticoagulants

Risks of New Oral Anticoagulants Unknown

• Strengths are predictability of pharmacokinetics allow for no monitoring

• Shorter half life• Negatives include no monitoring currently

available• No “antidote” in event of overdose• No current data out on these NOAs with

dermatologic surgery

Dermatol Surg 2000; 26:785-789

Risk of Thrombotic complications related to discontinuation of warfarin

• Rates of thromboemblism range from 5.8 to 47% within 1 month of stopping warfarin

• A retrospective literature review of patients undergoing dental surgery and warfarin stopped had 5 out of 493 patients with significant embolic complications (4 deaths)

Dermatol Surg 2007;33:1189-1197

Dermatologic Surgery Risk of Thrombotic complications related to discontinuation of

warfarin and aspirin

• Study by Kirkorian and Marmur• Survey mailed to 720 members of the

American College of Mohs (ACMMSCO)• 271 responded (38%)• 126 had thrombotic events

Dermatol Surg 2007;33:1189-1197

Types of thrombotic complicationsThrombotic EventStroke 39TIA 25Myocardial Infarction 19Unstable angina 17Death 15Deep Venous Thrombosis 7Pulmonary embolus 4

What about discontinuing clopidogrel?

• Alam and Goldberg report one patient who stopped clopidogrel and had acute thrombosis of the prosthetic aortic valve

• Another with acute MI on post op day 1• Otley reported pt with thomboembolic stroke• McFadden reported 2 patients who developed late

thrombosis in stents after discontinuing clopidogrel

Cook-Norris RH1, Michaels JD, Weaver AL, Phillips PK, Brewer JD, Roenigk RK, Otley CC. J Am Acad Dermatol 2011;65:584-91

Conclusions• Based on the serious nature of thrombotic complications,

and low risk of serious hemorrhagic complications most agree on the following:

• Patients on warfarin should have therapy continued throughout the procedure and the INR should be within the accepted therapeutic range(usually less than 3)

• Good informed consent• Patients on ASA or clopidogrel if medically necessary

should be continued, if not medically necessary surgeon may choose to continue or discontinue

• Prescribing physician should be involved in any decision to discontinue

• Compression bandages should be applied for 48 hours after surgery

Thank you!