Seek and Destroy: General Principles and Antibiotic Choices in Treating Dental Infections Kelly W. Jones, Pharm.D., BCPS McLeod Family Medicine Center kjones@mcleodhealth.org 11/7/2018

Two types of antibiotics Time-dependent killers Penicillin, cephalosporin, imipenem clindamycin, macrolides, TMP/SMX, tetracyclines Accumulation at the site of infection is important at inhibiting bacterial growth Concentration-dependent killers Quinolones, Aminoglycosides, Metronidazole “qAm” 11/7/2018

Time-dependant Killers Macrolides Clindamycin Cephalosporin Tetracycline Penicillin MIC 11/7/2018

Concentration-dependant Killers Quinolones Aminoglycosides Metronidazole MIC 11/7/2018

Dosing Issues Three times a day and four times a day dosing is a set up for adherence problems. Use total daily dose twice a day. Cephalexin (Keflex®) 250 mg capsule (#30 cost $14) 500 mg capsule (#30 cost $14) 750 mg capsule (#30 cost $100) 125 mg/5 ml; 250 mg/5 ml each in 100 and 200 ml Each of these are ~$18 11/7/2018 For cost information: www.drugstore.com

Dosing Issues Three times a day and four times a day dosing is a set up for adherence problems. Use total daily dose twice a day. Cephalexin (Keflex®) 250 mg capsule (#30 cost $14) 500 mg capsule (#30 cost $14) 750 mg capsule (#30 cost $100) 125 mg/5 ml; 250 mg/5 ml each in 100 and 200 ml Each of these are ~$18 11/7/2018

Dosing Issues Keflex® 750 mg is branded drug. Why? Has indication for BID use or as JCAHO wants you to write: twice daily use. Therefore write: Cefalexin 500 mg capsules, take 2 capsules twice daily. 1 gm twice a day! You can do this with Penicillin 11/7/2018

You may be wondering? Why can you give an antibiotic that is a time-dependent killer less often? Pharmacokinetic principle: As you increase the dose and the serum concentration, you can stay above the MIC until the next dose - dose dependent. 11/7/2018

Time-dependant Killers Cephalexin 1 gm 2nd dose MIC 12 hours 11/7/2018

Dosing Issues: Concentration Killers “qAm” More is better! Examples: Fluoroquinolone Levofloxacin 250 mg (#10 cost $120) 500 mg (#10 cost $168) 750 mg (#10 cost $260) 5 day therapy for CAP Metronidazole for trichomonas infection 2 gram single dose is better than 500 mg bid for 7 days 11/7/2018

Administration IV PO 100% bioavailable Best for the sickest patient, they often poorly absorbs oral drugs PO Several classes of drugs have excellent bioavailability similar to their IV dose TMP/SMX, FQ, metronidazole Mayo Clin Proc 1998;73:995 11/7/2018

Research Question of 2010 How long do we treat? Otitis media 5 days Uncomplicated UTI’s 3 days with all drugs Uncomplicated pyelonephritis 7 days with FQ Strep throat 10 days 11/7/2018

How long do we treat? Prostatitis CAP Bronchitis 6 weeks with TMP/SMX; 2-4 weeks FQ CAP 7 to 14 days (14 if in hospital) Bronchitis 0 days, Do not treat! Treatment is recommended for smokers and chronic lung disease patients 11/7/2018

Dental Infections How long do we treat? ???? Treat as cellulitis - 7 to 10 days 11/7/2018

Common Oral Dental Antibiotics Penicillin (Pen-Vee K®) Amoxicillin (Amoxil®) Amoxicillin/clavulanate (Augmentin®) Clindamycin (Cleocin®) Cephalexin (Keflex®) What about cefdinir? Erythromycin/Azithromycin/Clarithromycin Metronidazole (Flagyl®) IV Ampicillin/Sulbactam (Unasyn®) 11/7/2018

How to select an antibiotic! CSI-like Where is the infection? What are the bugs? Guess the organism based on epidemiology research What is the best antibiotic? Initial antibiotic choice is always empiric therapy 11/7/2018

Where is the infection? Mouth Reversible pulpitis Irreversible pulpitis Absess Cellulitis Pericoronitis Periodontal Disease Antibiotic are best utilized in situations of regional spread 11/7/2018

What are the bugs? Dominant isolates are anaerobic bacteria. Streptococcus mutans are thought to cause initial caries infection Alpha-hemolytic streptococci, a.k.a. Streptococcus viridans Can coexhist with staph Streptococcus anginosis 11/7/2018

What are the bugs? Others Gram +: Peptostreptococci Gram negative: Bacteroides Prevotella (Bacteroides melaninogenicus) Porphyromonas Fusobacterium nucleatum Infections through the fascial planes usually are polymicrobial (average 4-6 organisms). 11/7/2018

Efficacy Bacteria associated with endodontic abscesses reported to be susceptible to several antibiotics (level 3 [lacking direct] evidence) based on cultures of 98 species of bacteria aseptically aspirated by needle from endodontic abscesses Amoxicillin 91% Amoxicillin/clavulanate 100% Clindamycin 96% Penicillin V 85% Metronidazole 45% Metronidazole with penicillin V 93% Metronidazole with amoxicillin 99% 11/7/2018 J Endod 2003 Jan;29(1):44

Consensus Statement no evidence to recommend one antibiotic regimen over another for management of systemic complications of acute apical abscess Based on systematic review and meta-analysis 14 trials 11/7/2018

What is the best antibiotic? Natural penicillin Coverage Gram +, anaerobes But no staph Products: IV - Aqueous Pen G, benzathine Pen G PO - Pen VK, Vee Tids Dose: 1 gram twice daily ( 2-500 mg tabs) Children: 50 mg/kg/day divided into 2 doses 11/7/2018

Penicillinase-resistant penicillins Examples: IV - methicillin, nafcillin PO - cloxacillin, dicloxacillin Coverage Gram + including staph, anaerobes 11/7/2018

Methicillin-resistant Staph Aureus 95% of staph was resistant to penicillin by 1953 MRSA was first isolated in 1968 Methicillin was developed in 1960 incidence of infection MRSA has risen from < 10% of all infecting staph aureus infections in the hospital in 1983 to 64% in 2004 to 70% in the intensive care units in 2008 MRSA is prevalent 11/7/2018

MRSA Drugs for treatment of community-acquired MRSA Tetracycline 500 mg qid Doxycycline 100 mg bid Minocycline 100 mg bid TMP/SMX 320 mg bid of trimethoprim (2 DS bid) Clindamycin 300 to 450 mg tid Levofloxacin 750 mg daily Moxifloxacin 400 mg daily Linezolid 600 mg bid 11/7/2018

MRSA You can always add a second antibiotic: Synergy with: Rifampin 300 mg twice daily $65 for 30 caps 11/7/2018

Practice Recommendations JFP 2008;57(9):588-2 MRSA abscesses are best managed by incision and drainage alone (90% cure rate vs 84% with antibiotics, level A evidence). If incision and drainage fail within 7 days, add an oral antibiotic. Eradication of MRSA from the nasal passages is not useful in preventing the spread of the infection in communities (level B evidence). In one military study, 121 men with MRSA colonization needed to be treated with nasal mupirocin to prevent one MRSA infection (Antimicrob Agents Chemother. 2007;51:3591-8) 11/7/2018

Extended-spectrum penicillin Aminopenicillins Examples: IV - Ampicillin PO - Ampicillin, amoxicillin Coverage Gram + (no staph), enterococcus, anaerobes, basic gram - 34% of Prevotella species are resistant to amoxicillin 11/7/2018

Amoxicillin Availability - should be $12 or less for most 250 mg capsule 500 mg capsule 500 tablet 875 mg tablet ($27 for #30) Chewables 125 mg, 250 mg Suspension 250 mg/5 ml 400 mg/5 ml 11/7/2018

New Drug Formulation Amoxicillin (Moxatag®) Once-daily form, for Strep pharyngitis and tonsillitis Pulsys delivers stacccato pulses (3) over 6 hrs 775 mg tablet 1 immediate release, 2 delay-release 10 day course is $90 11/7/2018

Extended-spectrum penicillin Antipseudomonal penicillins Examples: IV - ticarcillin, pipercillin PO - carbenicillin Coverage Gram + (no staph), broad gram neg, anaerobes 11/7/2018

Extended-spectrum penicillin Beta-lactamase inhibitor penicillin Examples: IV - ticarcillin-clavulanate (Timentin®), pipercillin-tazobactam (Zosyn®), ampicillin-sulbactam (Unasyn®) PO - Amoxicillin-clavulanate (Augmentin®) Coverage Gram +, broad gram -, anaerobes 11/7/2018

Augmentin® - now generic Chewable 400-57mg ($60/#20) Suspension (~$50 to $60) 250-62.5mg/5ml 75ml, 100 ml, 150 ml Bottle 600-42.9mg/5ml, 75ml Bottle Tablets 250-125mg ($100/#20) 500-125mg ($46/#20) 875-125mg ($32/#20) 11/7/2018

Cephalosporins Minimal utility for dental infections First generation Examples: IV - Cefazolin (Ancef®) PO - Cephalexin (Keflex®) Coverage Broad Gram +, including staph No anaerobe coverage 11/7/2018

Cephalosporins Second generation Examples: Coverage IV - cefuroxime (Zinacef®), cefoxitin (Mefoxin®) PO - Cefaclor (Ceclor®), cefpodoxime proxetil, cefuroxime axetil, cefprozil, loracarbef Coverage Broad gram +, basic gram - Some have minimal anaerobe coverage 11/7/2018

Cephalosporins Third generation Examples: Coverage IV - ceftriaxone, ceftizoxime, cefotaxime PO - cefixime, ceftebutin, cefdinir (Omnicef®) Coverage Broad Gram +, broad gram - Ceftazidime (Fortaz®) - only gram -, but includes pseudomonas Oral drugs loose gram + reliability 11/7/2018

Cephalosporins Fourth generation Examples: Coverage IV - cefepime (Maxipime®) PO - none Coverage Broad Gram +, broad gram -, including pseudomonas Poor anaerobe coverage Fifth generation cephalosporin due out soon - ceftaroline Added MRSA coverage 11/7/2018

Dental Principle Cephalosporin - best for general cellulitis Cephalexin (Keflex®) Cefdinir (Omnicef®) 300 mg capsule - $36 for #20 125 mg/5 ml, 60 ml, $48 IV or IM Ceftriaxone (Rocephin®) If you decide to use a cephalosporin, it is best to add metronidazole for anaerobe coverage. 11/7/2018

Macrolides Examples: Coverage IV - azithromycin, erythromycin PO - azithromycin, clarithromycin, erythromycin, dirithromycin Coverage Broad gram +, minimal gram - (h.flu?), atypicals no anaerobes 11/7/2018

Azithromycin Review Z-pak (generic $26) Tri-pak ($44) Zmax 1 gm powder for oral suspension Suspension 100mg/5ml, 15 ml ($50 - brand name only) 250 mg/5ml, 15 ml, 22.5 ml, 30 ml - $32 600 mg tablet 11/7/2018

Clarithromycin (Biaxin®) Tablets 250 mg ($100/#30) 500 mg 500 mg, 24 hr tablet ($160/#30) Suspension 125 mg/5 ml, 50 ml, 100 ml 250 mg/5 ml, 50 ml ($40), 100 ml ($80) New FDA alert: do not give with colchicine 11/7/2018

Sulfonamides Examples: TMP/SMX Coverage IV - trimethoprim/sulfamethoxazole PO - trimethoprim/sulfamethoxazole, erythromycin/sulfamethoxazole (Pediazole®) Coverage Great staph drug, alternative for strep and does NOT cover S pyogenes (group A, beta-hemolytic) or enterococcus Good gram - with some pseudomonal coverage no anaerobes Poor-man’s regimen - add metronidazole 11/7/2018

Clindamycin (Cleocin®) Coverage broad gram +, broad anaerobe IV dose is larger than the oral dose Great for the penicillin allergy patient Dosing PO 150 mg capsule (generic $25/#30) 300 mg capsule (generic $80/#30) 11/7/2018

You can always add….. Metronidazole Coverage Dose twice daily PO Broad anaerobe coverage Dose twice daily PO Tablets ($12/#30) 250 mg 500 mg 750 mg ($200/#30) - 24 hour tablet 11/7/2018

Fluoroquinolones First generation quinolone Nalidixic acid (NegGram) Second generation fluoroquinolone IV and PO - ciprofloxacin Others - ofloxacin, norfloxacin, lomefloxacin, enoxacin Coverage Gram - only 11/7/2018

Fluoroquinolones Third generation fluoroquinolone IV and PO Levofloxacin, {gatifloxacin}, gemifloxacin moxifloxacin (respiratory quinolone) Coverage Broad gram + Broad gram - NO anaerobes 11/7/2018

SBE Prophylaxis - In who? ACC/AHA Task Force Update 2008 Prosthetic cardiac valve Previous infective endocarditis Congenital heart disease (CHD) 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 Prosthetic material for valve repair Cardiac transplantation recipients who develop cardiac valvulopathy 11/7/2018 J Am Coll Cardiol 2008;52(8):676-85

SBE Prophylaxis - Dental Procedure? Dental procedures that involve manipulation of the gingival tissue Periapical region of the teeth Perforation of the oral mucosa No longer required for: Routine anesthetic injections X-ray Bleeding from trauma to the lips or oral mucosa 11/7/2018

SBE Prophylaxis - With what? Adults amoxicillin 2 g PO 1 hour before procedure. Children amoxicillin 50 mg/kg If by IV, administer ampicillin 2 g for adults and 50 mg/kg for children within 30 minutes before the procedure. For patients allergic to penicillin Adult - Clindamycin 600 mg PO/IV 1 hour before the procedure. Children -Clindamycin 20 mg/kg PO/IV. Alternatively, azithromycin or clarithromycin 500 mg PO 1 hour before the procedure may be administered for adults and 15 mg/kg PO may be administered for pediatric patients. 11/7/2018

E-mail: kjones@mcleodhealth.org Questions??? E-mail: kjones@mcleodhealth.org 11/7/2018