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Bugs and Drugs: Solving the Antibiotic Dilemma

Bugs and Drugs: Solving the Antibiotic Dilemma. Catherine Davis, Pharm.D. Exempla Saint Joseph Hospital. Presentation Overview. Briefly review sensitivity testing Review advantages/disadvantages of commonly prescribed antibiotics

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Bugs and Drugs: Solving the Antibiotic Dilemma

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

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

  3. Drug Expenditures - 2001

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

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

  6. MIC Interpretation • 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 • 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 • Infecting organism • Susceptibility data/local resistance patterns • Site of infection • Duration of hospitalization/prior antibiotics • Allergy history • Age • Renal/Hepatic status • Immunologic status • Pregnancy

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

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

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

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

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

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

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

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

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

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

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

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

  20. Third Generation Ceph’s:Indication for Use • Cefepime (Maxipime®), ceftazidime (Fortaz®) • Neutropenic Fever (cefepime 2 Gms q12h) • Pseudomonas infections • 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 • 1st Generation: cephalexin (Keflex®) • 500 mg TID-QID • UTI • 2nd Generation: None Formulary • Ceftin®, Cefzil®, Lorabid® • 3rd Generation: cefpodoxime (Vantin®) • Oral transition for CAP, STD’s • 100 - 200 mg BID

  22. Carbapenems • 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 • Meropenem (Merrem®) • less seizure risk • fewer indications

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

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

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

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

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

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

  29. Aminoglycosides:Gentamicin, Tobramycin, Amikacin • excellent gram negative coverage • amikacin > tobramycin > gentamicin • synergistic activity • low levels for gram positive synergy (1 mg/kg) • therapeutic levels for gram negative synergy • (5-7mg/kg once daily) • NO Anaerobes - requires 02 to get into cell • dosing strategies dependent on indication • toxicities well defined

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

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

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

  33. Miscellaneous • 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 • Not effective against non-albicans strains • 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 • Systemic infections: 800 mg load, 400 mg qd • UTI: 100 mg qd x5 days • Excellent bioavailability

  35. Antibiotic Costs

  36. New Agents for VRE: • 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 P450 3A4 interaction • Non-Formulary

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

  38. Cost Comparison

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

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

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