Module 2 (of 3): Antibiotic Review *

1. Module 2 (of 3): Antibiotic Review* Review of selected antimicrobials By Keith Teelucksingh, PharmD Infectious Disease Pharmacist, Kaiser Permanente Vallejo With contributions by Linh Van, PharmD Infectious Disease Pharmacist, Kaiser Permanente Oakland See Notes

2. Goals Build upon pharmacists’ basic knowledge of selected broad-spectrum antibiotics Provide contemporary clinical information on appropriate use, spectrum of activity, clinical pearls and other considerations of selected antibiotics.

3. Objectives Upon completion of this module, the participant will be able to: • Elaborate on the spectrum activity for the β-lactam-related antibiotics, aztreonam, vancomycin, clindamycin, metronidazole and the fluoroquinolones • Discuss the appropriate clinical uses of the broad spectrum β-lactam-related antibiotics and vancomycin

4. Objectives • Describe the appropriate use of the anti-anaerobic agents clindamycin and metronidazole when combined with other anaerobically active antibiotics • Describe the appropriate use of β-lactam agents and vancomycin agents for the treatment of certain bacteria

5. Antibiotics to be Covered • Other • Clindamycin • Metronidazole • Vancomycin • β-Lactams • Penicillins • Cephalosporins • Carbapenems • Monobactams • Aztreonam • Quinolones • Moxifloxacin • Ciprofloxacin

6. Adapted from Brett Heintz, PharmD, BCPS

7. β-Lactams • Natural penicillins: penicillin • Penicillinase-resistant penicillins: nafcillin, dicloxacillin • Aminopenicillins: ampicillin, amoxicillin • Extended spectrum penicillins: pipercillin, ticarcillin • β-lactam/β-lactamase inhibitor combinations: Zosyn®, Unasyn®, Augmentin®, Timentin®

8. Penicillins Penicillin G (IV) • Used for treatment of • Neurosyphilis, endocarditis due to susceptible pathogens • Infections due to penicillin (PCN) susceptible (S) organisms: Group A & B Streptococci, Clostridium perfringes (gas gangrene) • If organism is PCN S (does not produce penicillinase, e.g., Staphylococcus aureus) penicillin, amoxicillin, ampicillin can all be used

9. Penicillins Penicillin G • Side effects • Allergic reactions (rash, blood dyscrasias, anaphylaxis) -> discussed in more detail in Module 3 • Interstitial nephritis • Hyperkalemia • Phlebitis

10. Penicillins Nafcillin • Coverage: Staphylococcus aureus (MSSA)  drug of choice • Not as active versus other Gm + • Does not cover Enterococcus, not as good as penicillin for S. pneumoniae, S. pyogenes • Hepatobiliary clearance • No need to adjust in renal dysfunction Note: Even though nafcillin is not renally eliminated, it still can cause interstitial nephritis

11. Penicillins Nafcillin • When interpreting susceptibilities: • oxacillin = nafcillin • Susceptibility to nafcillin predicts susceptibility to cefazolin/cephalexin

12. Penicillins Nafcillin • Side Effects • Interstitial nephritis • Still monitor serum creatinine if on long course • Neutropenia • Usually seen with longer courses • Phlebitis • Usually occurs when given peripherally • Use central venous catheter or isotonic solution

13. Penicillins Ampicillin/amoxicillin • Drug of choice for Enterococcus spp. infections • If isolate is ampicillin/amoxicillin sensitive • Amoxicillin (PO) • Higher dose used for S. pneumoniae (otitis media, pharyngitis) • Enterococcal UTI • Ampicillin (IV) • Serious infections due to Enterococcus spp. • Listeria (unpasteurized cheeses) infections  typically added for coverage in meningitis

14. Penicillins Ampicillin: clinical applications • Endocarditis/bacteremia • Ampicillin 2g IV q 4h • No one agent is bactericidal against Enterococcus spp. • Bactericidal when combined with aminoglycoside (AG) • If treating endocarditis, addition of AG is strongly recommended • Formal ID consult recommended

15. Penicillins Pharmacokinetic considerations • Bioavailability (oral) • Amoxicillin, Dicloxacillin > Ampicillin> PCN VK • High concentration in urine • All need to be adjusted in renal dysfunction • Exceptions: nafcillin, dicloxacillin

16. Penicillins Ampicillin/amoxicillin • Side effects (in general, similar to penicillin) • Allergic reactions • Rash • Eosinophilia • Leukopenia

17. Extended Spectrum Penicillins * Piperacillin • Good activity vs. Pseudomonas and Enterococcus • Less active vs. E. coli TicarcillinNF • Good activity vs. Pseudomonas (alternative to piperacillin) • Less active than piperacillin vs. Enterococcus • Not commercially available NF = non formulary  See Notes

18. βL/βLi* combinations Unasyn® (ampicillin/sulbactam) Augmentin® (amoxicillin/clavulanic acid) Zosyn® (piperacillin/tazobactam) Timentin® (ticarcillin/clavulanic acid) NF *βL/βLi = β-lactam/β-lactamaseinhibitor NF = non-formulary

19. βL/βLi combinations • All will cover ampicillin-sensitive Enterococci • All have excellent activity vs. anaerobes • B. fragilis, Prevotella spp. • Unasyn® and Augmentin® do not cover Pseudomonas • Addition of βLi adds activity against: • Bacteroidies (anaerobes), β-lactamase producing Gm – (E. coli, Klebsiella, Serratia) & Gm + (Enterococci, MSSA)

20. βL/βLi combinations * Unasyn® (ampicillin/sulbactam) • Good for Gm + • MSSA/Strep spp./Enterococcus spp. • Uses: Diabetic foot ulcers, cellulitis, community- acquired pneumonia, mild community-acquired GI infections (diverticulitis) • Variable Gm - coverage • E. coli has high resistance • Best in class for Acinetobacter (if isolate S) See Notes

21. βL/βLi combinations Augmentin® (amoxicillin/clavulanic acid) • Gram + coverage similar to Unasyn® • Sometimes more active versus Gram – pathogens such as E. coli and Klebsiella spp. than Unasyn® • Only PO option in class • GI tolerance poor • Uses: diverticulitis, cellulitis • Good oral step-down therapy

22. βL/βLi combinations Zosyn® (piperacillin/tazobactam) • Expanded coverage compared to Unasyn® • Similar to Timentin® may be slightly more active versus certain bacteria (E. coli) • Good activity vs. Pseudomonas • The addition of tazobactam to piperacillin adds NO extra activity vs. Pseudomonas • For confirmed pseudomonal infections, increase dose to 4.5g IV q6h (renal function permitting) to maximize its pharmacodynamic properties vs. Pseudomonas

23. βL/βLi combinations * Zosyn® (piperacillin/tazobactam) • Clinical uses: severe intra-abdominal infections, health care-associated (HCA) infections, including pneumonia/ventilator-associated pneumonia • Use should be reserved for patients with risk factors for nosocomial/drug resistant pathogens: • Skilled nursing facility residents, previous antibiotics exposure, exposure to health care environment, immunocompromised patients See Notes

24. βL/βLi combinations Timentin® (ticarcillin/clavulanicacid)NF • Per previous slide, very similar coverage compared to Zosyn® • May be used as alternative agent for infections due to Stenoptrophomonasmaltophilia NF = non-formulary

25. βL/βLi combinations Side effects: overall, very similar to penicillins • Zosyn® • Thrombocytopenia has been seen with longer courses of therapy and higher doses (i.e., Pseudomonal dosing) • Ticarcillin/Timentin® • Ticarcillin has been shown to impair platelet function  may prolong bleeding time but unclear whether this is clinically significant

26. Carbapenems • The most potent antibiotic in theβ-lactam class • These agents should be used only when no other antibiotic options are available or appropriate • Meropenem (Merrem®) • Ertapenem (Invanz®) • Imipenem/cilastin (Primaxin®) NF • Doripenem (Doribax®) NF NF = non-formulary

27. Carbapenems * • Spectrum of activity • Broadest coverage including Gm+, Gm- (especially drug resistant species -> see below and notes), anaerobic coverage • All cover MSSA, Enterococcus (ampicillin sensitive)*, Streptococcus spp. • Drugs of choice for ESBL* infections • Good empiric coverage for Acinetobacter*, Citrobacter, Pseudomonas* * - except ertapenem  See Notes

28. Carbapenems * • Differences in spectrum of activity • Imipenem ≈ meropenem • Meropenem usually has lower minimum inhibitory concentration (MIC) to Gm - pathogens  not usually clinically significant • Ertapenem • Not clinically active vs. Enterococcus, Pseudomonas, Acinetobacter • Not a good empiric choice for health care associated infections  See Notes

29. Carbapenems • Differences in spectrum of activity: • DoripenemNF • Same coverage as meropenem/imipenem • May be useful for highly multidrug-resistant organisms • Lower MIC to certain pathogens in vitro • Less likely to select for resistance in certain bacterial subpopulations • At present, not much advantage over meropenem for most indications NF = non-formulary

30. Carbapenems • Clinical uses • Severe intra-abdominal infections, heath care-associated infections* including pneumonia, ventilator-associated pneumonia, serious infections due to ESBL-producing organisms, meningitis** • Use should be reserved for patients with risk factors for nosocomial/drug-resistant pathogens (see Zosyn® slide) * - except ertapenem; ** - meropenem only

31. Carbapenems • Side effects • Hypersensitivity/allergic reactions • Uncommon • Low cross-reactivity in patients with penicillin allergy (see Module 3 of this series) • Seizures • Usually associated with imipenem and occurs in patients with poor renal function where dose not adjusted accordingly, previous seizure history may also predispose

32. Carbapenems • Drug interaction • Valproic acid and meropenem decreases valproic acid levels (may apply with all carbapenems). • Monitor valproic acid levels more frequently or use alternative antibiotic.

33. Monobactams Aztreonam (only drug in class, Azactam®): • Monocylic β-lactam ring (traditional β-lactams are bicyclic) i.e., structurally different • Active against Gm - ONLY including Pseudomonas • Gm – coverage similar to ceftazidime (they have structurally similar side chains) • Side effects: rash • Can be safely used in patients with Type I penicillin allergy • Caution if patient has ceftazidime allergy (see Module 3)  Currently on backorder; use only when no other options are available

34. *Program Learning* • What is the drug of choice for ampicillin-sensitive Enterococcus? Besides the drug of choice, what other beta-lactam(s) would work? • Which penicillins cover MRSA? • What are the penicillins that would cover MSSA?

35. *Program Learning Answers* • What is the drug of choice for ampicillin sensitive Enterococcus? Besides the drug of choice, what other beta-lactam(s) would work? Ampicillin is the drug of choice. Amoxicillin, penicillin, piperacillin, ticarcillin, imipenem, meropenem would also be appropriate choices. No cephalosporin covers Enterococcus. Ertapenem has variable activity. Aztreonam has no gm + coverage.

36. *Program Learning Answers* Which penicillins cover MRSA? None. No β-lactam agent covers MRSA. What are the penicillins that would cover MSSA? Nafcillin, dicloxacillin, Zosyn®, Timentin®, Augmentin®, Unasyn®. If isolate is PCN-susceptible (this indicates that isolate does not produce penicillinase), then also can use penicillin, amoxicillin or ampicillin.

37. *Program Learning Answers* • A patient with resistant Pseudomonas aeruginosa wound infection has been on meropenem in-house and the MD plans to give ertapenem as a home IV infusion. His rationale is that ertapenem is a once daily medication as opposed to three times daily for meropenem. Is this appropriate? Why?

38. *Program Learning Answers* Not appropriate because ertapenem does not cover Pseudomonas. The carbapenems with activity against Pseudomonas are imipenem, meropenem and doripenem.

39. Cephalosporins • These compounds are structurally related to the penicillins due to presence of β-lactam ring. This will only focus on cephalosporins used commonly in the inpatient setting • 1st generation • 2nd generation • 3rd generation • 4th generation

40. Cephalosporins • No cephalosporins cover Enterococcus • No cephalosporins cover MRSA • None are active versus ESBL-producing organisms • All cephalosporins, including 3rd generation, are rendered inactive • Cefepime still may be used for certain infections but should consult with ID clinician before using

41. Cephalosporins 1st generation • Cefazolin (Ancef®) • Proteus, E. coli, Klebsiella (PEK), MSSA, Streptococcus spp. • Better for Streptococcus spp. than nafcillin (cellulitis) • Cephalexin (Keflex®), cefadroxil (Duricef®) • Both with similar coverage to cefazolin • Both are well absorbed orally • Cefadroxil - less frequent dosing

42. Cephalosporins 1st generation • Uses • Cefazolin • Cellulitis, MSSA infections, surgical prophylaxis • Cephalexin, cefadroxil • UTI, skin/soft tissue infections due to MSSA or Strep spp.

43. Cephalosporins 2nd generation • Cefuroxime (PO/IV), cefaclor (PO) • Coverage: PEK (see 1st generation slide) + Haemophilus, Neisseria = HNPEK • More gram negative coverage, less Staph coverage • Cephamycins (IV): cefotetan, cefoxitin • Only cephalosporins that cover anaerobes • Both active vs. B. fragilis be aware that resistance is increasing • Used for pelvic inflammatory disease, surgical prophylaxis in ObGyn and colorectal surgery

44. Cephalosporins * 3rd generation • Ceftriaxone (Rocephin®), cefotaxime (IV only) • HNPEK + Serratia = HNPEKS • Not as reliable for Staph • Good Pneumococcus activity, good meningeal penetration • Multiple uses: UTI, SBP, meningitis, pneumonia • Cefpodoxime, cefdinir, cefixime (all PO) • Cefixime use should be reserved for treatment of STDs

45. Cephalosporins 3rd generation • Ceftriaxone • Has numerous indications but only a few require doses higher than 1g: • 2g IV q24h (endocarditis and osteomyelitis) • 2g IV q12h (meningitis) • No adjustment needed for renal dysfunction

46. Cephalosporins 3rd generation • Ceftazidime (Fortaz®) • Coverage is broadened compared with others in 3rd generation to include Pseudomonas • Only other cephalosporin which covers Pseudomonas is cefepime • Not so good for Staphylococcus, Streptococcus • Used for empiric treatment of febrile neutropenia, has decent meningeal penetration

47. Cephalosporins 4th generation • Cefepime (Maxipime®)NF • Similar to ceftazidime, covers Pseudomonas and may be slightly more active vs. some Gm – organisms • Better Gm + coverage than ceftazidime but still not as good as 1st generation cephalosporins • Used in febrile neutropenia, health care-associated infections, meningitis • May be used in certain infections/situations when treating ESBL infections consult ID clinician NF = non-formulary

48. Cephalosporins • Side effects • Similar to penicillins • Allergic reactions • Blood dyscrasias • Rare

49. *Program Learning* • Which cephalosporins do not need renal adjustment? • How is ceftriaxone dosed for these disease states? • Community-acquired pneumonia, endocarditis, osteomyelitis, meningitis • Which cephalosporins have anaerobic coverage? • Which cephalosporins cover Pseudomonas?

50. *Program Learning Answers* • Which cephalosporins do not need renal adjustment? Ceftriaxone only. All other cephalospsorins need to be adjusted for renal dysfunction. • How is ceftriaxone dosed for these disease states? CAP: 1g iv q24h, Endocarditis/Osteomyelitis: 2g iv q24h, Meningitis: 2g iv q12h