1. Bugs and Drugs: Solving the Antibiotic Dilemma Catherine Davis, Pharm.D. Exempla Saint Joseph Hospital

2. Presentation Overview l Briefly review sensitivity testing l Review advantages/disadvantages of commonly prescribed antibiotics l Provide recommendations for appropriate indications for various antibiotics

3. Drug Expenditures - 2001

4. Challenges in Antimicrobial Selection l Changing resistance patterns l New antibiotics from which to select l National Backorders!!! –Piperacillin/tazobactam –Cefotaxime –Cefotetan –Penicillin –Cefazolin

5. Sensitivity Testing Minimum Inhibitory Concentration l MIC - concentration at which the growth of the organism is inhibited l “breakpoint” is determined based on serum/tissue levels of respective agent l optimum therapy is for peak to achieve > 8 times the MIC l CANNOT compare actual #’s between different classes of antibiotics

6. MIC Interpretation l If the sensitivity report indicates an MIC less than a specific concentration (i.e. <8), antibiotic in question should achieve adequate concentrations to inhibit growth l Review all agents listed as susceptible and select the most narrow spectrum/cost effective agent that will cover the organism

7. Antibiotic Selection: The Right Agent for the Right Patient l Infecting organism l Susceptibility data/local resistance patterns l Site of infection l Duration of hospitalization/prior antibiotics l Allergy history l Age l Renal/Hepatic status l Immunologic status l Pregnancy

8. Antibiotic Classes l Beta-Lactams –penicillins –cephalosporins –carbapenems –monobactams l Quinolones l Aminoglycosides l Glycopeptides l Macrolides l Miscellaneous l VRE Antibiotics

9. Penicillins: Pen VK, Ampicillin, Amoxicillin Advantages l good oral absorption l good gram + coverage –Enterococcus –Streptococcus l inexpensive Disadvantages l frequent dosing l increasing resistance –gram negatives –Strep pneumo l inactivates aminoglycosides

10. Penicillin, Ampicillin, Amoxicillin: Indications for Use l Strep infections known to be PCN sensitive l Enterococcus infections (dose 2 Gms q4h for ampicillin + gentamicin synergy dosed) l Necrotizing fasciitis - PCN 24 MU/day + Clinda 600mg q8h l Renal adjust for CrCl <30 mL/min

11. AntiStaphylococcal PCN’s Nafcillin, Oxacillin, Dicloxacillin Advantages l excellent Staph aureus coverage –best treatment option for serious MSSA infections l narrow spectrum (no gram negative coverage) l Diclox for Staph Disadvantages l frequent dosing (2 Gms q4-6h) l increasing incidence of MRSA (35% at ESJH) l no Enterococcus coverage

12. Beta-Lactamase Inhibitors l Amoxicillin/Clavulanate (Augmentin®) l Ampicillin/Sulbactam (Unasyn®) l Piperacillin/Tazobactam (Zosyn®) l Ticarcillin/Clavulanate (Timentin®)

13. Beta-Lactamase Inhibitors Augmentin, Unasyn, Timentin, Zosyn Advantages l stabilization against beta-lactamases l excellent broad coverage, including anaerobes l Zosyn > Timentin for Pseudomonas l Enterococcus coverage (not Timentin) Disadvantages l GI intolerance (Augmentin) l Superinfections l High cost l frequent dosing l E. coli resistance increasing with Unasyn

14. Unasyn, Zosyn Indications Unasyn Zosyn l Intraabdominal prophylaxis + gentamicin for E. coli l Mixed infection including Enterococcus l 1.5-3 Gms q6h l Severe mixed infection –workhorse ICU drug l Ventilator associated pneumonia +/- AG l Severe diabetic foot infection suspected of involving mixed flora l Narrow as soon as possible l 3.375 Gms q6h

15. Cephalosporins: General Similarities l excellent penetration to tissues, including BBB (ceftriaxone, cefotaxime) l coverage based on “generation” l NO ENTEROCOCCUS ACTIVITY l wide therapeutic index l wide range of uses l *historically comprises one of the largest portions of antibiotic budget

16. Cephalosporins: First Generations l most active against gram positives –cellulitis l good coverage against selected gram negatives (E. coli, Proteus, Klebsiella) –Good option for pyelonephritis l excellent for surgical prophylaxis (cefazolin) l Cefazolin (Ancef®) 1 Gm q8h l Cephalexin (Keflex®) higher MIC’s to Staph

17. Cephalosporins: Second Generations l less gram positive coverage l additional gram negative coverage, respiratory pathogens (Hemophilus, Moraxella) - cefuroxime (Zinacef®, Ceftin®) l anaerobes (anti-anaerobic agents - cefotetan, cefoxitin, cefmetazole) –~ 75% anaerobic coverage –intraabdominal, GYN prophylaxis

18. Cefotetan (Cefotan®), Cefoxitin (Mefoxin®): Indications for Use l Surgical Prophylaxis for intraabdominal infections (Cefotan 1 Gm q12h) l Intraabdominal infections from community (no Enterococcus coverage) l Diabetic foot infections (E. coli, anaerobes)

19. Cephalosporins: Third+ Generations l additional gram negative (nosocomial) coverage, some gram positive, anaerobic coverage l Pseudomonas coverage (ceftazidime, cefepime) l excellent BBB penetration (ceftriaxone, cefotaxime and others) l Good coverage against Strep and Staph (except ceftazidime)

20. Third Generation Ceph’s: Indication for Use l Cefepime (Maxipime®), ceftazidime (Fortaz®) –Neutropenic Fever (cefepime 2 Gms q12h) –Pseudomonas infections l Cefotaxime (Claforan®), ceftriaxone (Rocephin®) –Meningitis (cefotaxime 2 Gms q8h) –CAP (cefotaxime 1 Gm q8-12h) –Endocarditis with HACEK organisms or PCN intermediate Strep (cefotaxime 2 Gms q8h)

21. Oral Cephalosporins l 1st Generation: cephalexin (Keflex®) –500 mg TID-QID –UTI l 2nd Generation: None Formulary –Ceftin®, Cefzil®, Lorabid® l 3rd Generation: cefpodoxime (Vantin®) –Oral transition for CAP, STD’s –100 - 200 mg BID

22. Carbapenems l Imipenem/Cilastatin (Primaxin®) –excellent broad spectrum coverage but increasing Pseudomonas resistance –reserve for resistant organisms, seriously ill patients or PCN allergy –potential for seizures - adjust for renal status –beta-lactamase inducer –500 mg q6-8h l Meropenem (Merrem®) –less seizure risk –fewer indications

23. Carbapenems: Ertapenem (Invanz®) l Recently approved agent for community infections l Intraabdominal or complicated skin and skin structure infections l No Enterococcus or Pseudomonas coverage l 1 Gm IV q24h l Adjust for CrCl <30 mL/min (500 mg qd)

24. Monobactam: Aztreonam (Azactam®) l ONLY gram-negative coverage l moderate Pseudomonas activity l safe to use in PCN allergic patients l excellent safety profile l 1 -2 Gms q8h l Adjust for CrCl <30 mL/min

25. Quinolones Another Class with Generations l excellent tissue penetration l excellent bioavailabilty l convenient dosing l some resistance to Pseudomonas developing l potential for overuse due to many factors l avoid with sucralfate, separate from antacids

26. Quinolones: “First Generations” l Norfloxacin, Ciprofloxacin l primarily gram negative, including Pseudomonas l some atypical l poor gram positive, no anaerobic l Cipro - interactions with theophylline, warfarin, phenytoin

27. Quinolones: “Second Generations” l Levofloxacin, Lomefloxacin, Gatifloxacin, Moxifloxacin l additional gram positive and atypical coverage, including Strep pneumoniae l moderate gram negative l excellent bioavailability l Levofloxacin - warfarin interactions l Moxifloxacin - no Pseudomonas coverage, good anaerobic coverage (KP formulary)

28. Levofloxacin (Levaquin®) Indications for Use l CAP, especially patients with comorbidities –Doxycycline for pts with no comorbidities l Complicated UTI infections (resistant to first generation ceph’s, sulfa) l Gram negative infections in patient allergic to PCN (+/- AG or anaerobic coverage) l Not preferred for cellulitis (750 mg dose) l 500 mg IV/PO qd (adjust for CrCl < 50) l Add metronidazole for anaerobes

29. Aminoglycosides: Gentamicin, Tobramycin, Amikacin l excellent gram negative coverage –amikacin > tobramycin > gentamicin l synergistic activity –low levels for gram positive synergy (1 mg/kg) –therapeutic levels for gram negative synergy l (5-7mg/kg once daily) l NO Anaerobes - requires 0 2 to get into cell l dosing strategies dependent on indication l toxicities well defined

30. Glycopeptides: Vancomycin l excellent gram positive l reserve for resistant organisms, PCN/Ceph allergic patients l VRE l GISA?? l nephrotoxicity no longer a real concern l only monitor trough’s except for select situations l oral ONLY for Flagyl failures

31. Macrolides: erythro-, clarithro-, azithromycin l moderate gram positives (Strep developing resistance - now up to 35%) l good atypical l use for lower respiratory tract infections l erythro and clarithro interactions –theophylline, warfarin (+ azithro) l azithromycin - STD coverage (1 Gm x1) –CAP: 250 - 500 mg qd x 5-7 days

32. Antianaerobic Agents l Metronidazole (Flagyl®) –excellent anaerobic, first line C. difficile –500 mg q12h except C. diff and bowel preps l half-life = 8 hours –Excellent bioavailability –warfarin interaction, disulfiram reactions l Clindamycin (Cleocin®) –gram positive, anaerobic (600 mg IV q8h max) –Use with PCN for nec fasciitis (Gp A Strep) –? Pseudomembranous colitic

33. Miscellaneous l SMX/TMP (Septra®, Bactrim®) –excellent tissue penetration, broad uses –gram positive and “easy” gram negative –warfarin interaction –Some GI intolerance in elderly

34. Antifungals: Fluconazole l Not effective against non-albicans strains l Indications for use –C. albicans from sterile body site –C. albicans from multiple non-sterile sites (urine, wound, sputum) –Prophylaxis for recurrent intraabdominal rupture or anastomotic leak l Systemic infections: 800 mg load, 400 mg qd l UTI: 100 mg qd x5 days l Excellent bioavailability

35. Antibiotic Costs

36. New Agents for VRE: l Quinupristin/Dalfopristin (Synercid®) –Streptogramin antibiotics –Effective against VREF (not E. faecalis), Staph aureus (MRSA and MSSA) –Dosing: 7.5 mg/kg q8h –Infusion related ADR’s - central line preferred –Potential to elevate liver enzymes –Cyt P 450 3A4 interaction l Non-Formulary

37. New Agents for VRE Linezolid (Zyvox®) l Oxazolidinone antibiotic l Effective against E. faecalis & E. faecium, MRSA, MSSA, Strep pneumo l IV, PO, Suspension - 100% absorption l 600 mg BID l Thrombocytopenia (> 2 weeks duration of therapy), GI intolerance l MAOI - weak inhibitor l Dopamine, epinephrine - adjust dose down

38. Cost Comparison

39. Linezolid (Zyvox®): Indications for Use l VREF –likely will be considered preferred therapy in place of Synercid® –need to carefully evaluate for potential colonization l MRSA Infections ONLY for Vanco intolerant patients –after trial of continuous infusion +/- Benadryl if possible l ID Consult

40. Resistance: A National Concern l Often result of inappropriate or overuse of antibiotics l Significant financial impact on healthcare l Selecting out multi-drug resistance l Narrow coverage as soon as possible l ? Rotation of preferred classes of antibiotics l Don’t treat colonizations or contaminations