OVERVIEW OF ANTIMICROBIALS

1. OVERVIEW OF ANTIMICROBIALS Prakash Shah, Pharm.D Clinical Pharmacy Specialist, Infectious Diseases Beaumont Hospital – RO 2012

2. OBJECTIVES • Understand the differences between various classes of antibacterial agents • List various mechanisms of resistance • Define Redman syndrome • List patient risk factors for surgical wound infection • Given a specific antibiotic, list it’s common side effect • Define the optimum administration time of antibiotic for surgical prophylaxis

3. ANTIMICROBIAL ROLE • Three basic roles: A) To treat the infecting organisms whose susceptibility is known B) As empirical treatment for presumed infns C) To prevent infections – Surg prophylaxis

4. PRINCIPLES OF ANTI-INFECTIVE THERAPY COMBINATION THERAPY • To broaden the spectrum of coverage • intra-abdominal infections (amp/metro/gent) • Synergism • Enterococcal endocarditis (pencillin & gentamicin) • Preventing Resistance • TB (INH + rifampin) • Disadvantages of combination therapy • potential additive nephrotoxicity (gent +vanco) • inactivation - aminoglycosides by PCNS in renal pts.

5. PRINCIPLES OF ANTI-INFECTIVE THERAPY Failure of Antimicrobial Therapy • Drug- related: ______________ • Host factors • _________________ • _________________ • _________________ • _________________ • Microorganisms (related) ______________ ___________________________________

6. Antibiotics 1. Reach site of infection 3. Reach Target and Kill Organism Requirements for Antimicrobial Activity Porin Proteins 2. Penetrate Cell PBPs (Proteins) Nucleus Ribosomes Bacterium

7. Mechanism of Resistance4 main types 1_________________________________ 2_________________________________ 3________________________________ _ 4_________________________________

8. Porin Channels (Gram-negatives) Porin channels closed or decreased number Antibiotics Antibiotics Mechanisms of Resistance • Decreased Permeability • Drug Efflux • Drug Inactivation • Altered Target (Proteins) Nucleus Ribosomes Example: Pseudomonas Bacterium

9. Efflux Pump (Proteins) Mechanisms of Resistance • Decreased Permeability • Drug Efflux • Drug Inactivation • Altered Target Antibiotics Nucleus Ribosomes Examples: - Gm(-): Quinolones - S. pneumonia: Quinolones, Macrolides Bacterium

10. S R-CO-NH penem L N COOH O S R-CO-NH B-lactamase opens B-lactam ring N COOH O Antibiotic is inactivated Mechanisms of ResistanceEnzyme inactivation- Beta Lactams Penicillins Cephalosporins Monobactams Carbepenems H. flu M. cat Staph E.coli Kleb Bacteria Produces B-lactamase

11. (Proteins) Mechanisms of Resistance • Decreased Permeability • Drug Efflux • Drug Inactivation • Altered Target Antibiotics Enzymes Nucleus Ribosomes Examples: - Beta-lactamase - AG modifying enzymes Bacterium

12. MOA of B-lactam antibiotics vs. Suscptible S. pneumoniae Mechanism of resistance for DRSP vs. B-lactams Normal Growth of S. pneumoniae Abx Abx Abx Abx Abx Abx Abx 2b 2b 2b 2x 2x 2x 1a 1a 1a Abx Abx Abx 2z 2z 2z 1b 1b 1b 3 3 Abx 3 Abx PBPs Altered PBPs PBPs B-lactam antibiotic binds to PBP and prevents adequate cell- wall formation. Growth is inhibited Antibiotic cannot bind to altered PBPs and cannot inhibit cell-wall formation. Growth continues. PBPs facilitate cell- wall formation for new bacterial cells (cell growth) Abx Alteration in Target SiteAltered penicillin-binding proteins (PBPs)

13. Beta-lactam Allergy • Allergic reaction- principal toxicity of beta-lactams (pcns, cephalosporins) • Allergic reactions occurs in 7-40/1000 treatment cases • About 1/2 of all allergic reactions occurring in hospitalized patients are attributable to beta-lactams

14. Antimicrobial Agents • Sulfonamides • Penicillins • Cephalosporins • Aminoglycosides • Macrolides • Lincosamides • Quinolones • Ketolides • Tetracyclines • Glycylcyclines • Glycopeptides • Nitroimidazole • Streptogramins • Oxazolidinones • Nitrofurantoins • Miscellaneous

15. Sulfonamides and Trimethoprim TMP/SMX (Bactrim) • A synergistic combination, very commonly used • MOA - generally bactericidal; it acts by sequential blockade of folic acid enzymes in the synthesis pathway sulfa TMP • PABA----//-------> DHFA-----//---->THFA -- --FA

16. Sulfonamides and Trimethoprim TMP/SMX (Bactrim) • Bactericidal when combined o/w bacteriostatic • Dosage forms - nearly every route (topical, ophthalmic, intestinal sulfas, systemic - IV, PO) • Distribution- Widely distributed • Elimination - Renal • SE- N,V,D, hypersensitivity, hematologic, crystalluria • Use - UTI, CA-MRSA SSTI, PCP,etc

17. PENICILLINS Natural Penicillins (aqueous PCN G, procaine PCN G, Benzathine PCN G and oral PCNs) • MOA - Inhibits PBPs inhibiting bacterial cell wall synthesis • Bactericidal • Distribution - Widely distributed • Elimination - mostly renal • SE - allergic reaxn, rash, GI, hematologic

18. PENICILLINS PENICILLINASE-RESISTANT PENICILLIN Nafcillin, Oxacillin, Methicillin • DOC- For penicillinase producing S. aureus • Widely distributed • Metabolism - Liver • SE - N,V,D, Hematologic, Hypersensitivity reaxn • Use - Cellulitis, Osteomyelitis, Endocarditis, Pneumonia

19. PENICILLINS Aminopenicillins Ampicillin, Amoxicillin • DOC for enterococcus • Distribution - Widely distributed • Elimination - Renal • SE - GI, hematologic, hypersensitivity reaxn • Use- Endocarditis, Meningitis, Otitis Media, UTI

20. PENICILLINS • Antipseudomonal PCNs: carboxypenicillins • Carbenicillin, Ticarcillin (active against serious GNB including PSA, Enterobacter, Serratia, and Proteus) • high sodium content • Antipseudomonal PCNs: Ureidopenicillins • Piperacillin (most potent), • low sodium content • Piperacillin more potent against PSA vs ticarcillin

21. PENICILLINS ß-lactam/ ß-lactamase inhibitor combos • Unasyn (ampicillin/sulbactam) • Zosyn (Piperacillin/tazobactam) • Timentin (Ticarcillin/Clavulanate) The ß-lactamase inhibitors offer an advantage against GPO (MSSA, MSSE) & GNB (E. coli, K.pneumo, N, meningitidis, P. mirabilis, H. flu, M. cat) and Gram-neg anaerobes (B. fragilis, B. fragilis gp)

22. PENICILLINS OVERALL COMPARISON OF ß-LACTAM/ ß-LACTAMASE INHIBITORS • Timentin = Unasyn = Zosyn for Staphylococci • Timentin/Zosyn>Unasyn for enterobacteriaceae (Citrobacter, Enterobacter, E. coli, Klebsiella, Morganella, Proteus, Salmonella, Serratia, etc) • Pseudomonas… Zosyn > Timentin • S. maltophilia… Timentin > Zosyn • Enterococci… Unasyn > Zosyn > Timentin

23. CEPHALOSPORINS • An improved spectrum of antibacterial activity, better PK properties, Concentration-independent • MOA: Bactericidal, binds to PBP enzymes preventing cell wall synthesis • Structurally similar to PCN, 1-7% cross reactivity. • Avoid in patients with high grade allergic reactions to PCNs. • Use cautiously in patients with delayed or mild reactions

24. CEPHALOSPORINS Based on their spectrum of activity, cephs can be broadly categorized into 4 generations • First Generation Cephalosporins - Cefazolin (Ancef, Kefzol) • Second Generation Cephalosporins - cefuroxime, cefamandole, cefotetan, cefoxitin, cefmetazole • Third Generation Cephalosporins - Cefotaxime, Ceftriaxone, Ceftazidime, Ceftizoxime, Cefobid • Fourth Generation Cephalosporins - Cefepime

25. First Generation Cephalosporins Better activity against gram-positive bacteria and less gram-neg activity • Use: Cellulitis, UTI, Osteo, Surgical prophylaxis • eg. Cefazolin (Kefzol, Ancef)- very well tolerated, longer t1/2 allows less frequent dosing • Cost: $

26. CEPHALOSPORINS Second Generation Cephalosporins • 2 groups within this generation of cephs - different spectrum of activity & SE profile • “true” cephs - cefamandole, cefuroxime - similar to 1st gen against GPC, MSSA. Incr activity against some GN bacteria • Use: RTI (community acquired), UTI • WBH: Cefuroxime • Cost: $

27. Second Generation Cephalosporins (contd) Cephamycins - cefoxitin, cefotetan, cefmetazole - Less active against GPC but better against GN bacteria and active against most anaerobes • Use: Intra-abdominal infns, Surg Prophylaxis,etc • SE: MTT side chain predisposes patient to hypoprothrombinemia and bleeding by disturbing synthesis of Vit-k dependent clotting factors in pts with certain risk factors. • RF - renal, hepatic dzs, poor nutrition, elderly, cancer, wafarin

28. Third Generation Cephalosporins • Improved activity against hospital acquired gram-neg bacteria including Pseudomonas aeur. (ceftazidime>cefoperazone) • Should be avoided for Enterobacter sp. (may become resistant on therapy) • Less active against staph than 1st & 2nd gen • Highly active against Strep. Pneumoniae (Ceftriaxone & Cefotaxime) • None active against MRSA, Enterococci, etc.

29. Third Generation Cephalosporins Uses Cefotaxime: CAP, bacterial meningitis, other infns Ceftriaxone: CAP, bacterial meningitis, Osteo • long t1/2 , biliary elimination, high PB Ceftazidime: Very active against PSA, poor against gram-positive. Low protein binding, renally eliminated

30. Fourth Generation Cephalosporin Cefepime • Rapidly crosses the outer membrane of GNB • Excellent activity against Enterobacteriaceae and Pseudomonas aeruginosa = ceftazidime • Better Gram-positive activity than ceftazidime • Weak inducer of β-lactamases so less likely to produce resistance unlike ceftazidime • Widely distributed in the body

31. Cefepime • Renally excreted • Substituted for aminoglycosides (gent/tobra) to avoid toxicity • Dosed twice a day except when treating Pseudomonas • Uses: CAP, Nosocomia pneumonia, Febrile neutropenic patients, Meningitis, Skin and skin structure infections,UTI

32. Ceftaroline(Teflaro) • Broad-spectrum cephalosporin with GN as well as GP activity including MRSA • FDA approved in Oct 2010 • Indications: ABSSSI, CABP • Plan to restrict to ID only • Usual dose: 600 mg q 12 hours (IV) over 1 hour & renal adjustment required • SE: GI, HA, rash

33. Cost Comparison

34. CEPHALOSPORINS ADVERSE EFFECTS • Overall, Cephs have a low incidence of SE • Thrombophlebitis: 1-5% • Hypersensitivity reaxns: Anaphylaxis (rare) • Rash: 1-3% • Hematologic reaxns: eosinophilia, neutropenia, thrombocytosis, hypoprothrombinemia • GI: Diarrhea (2-5%), biliary tract sludge • Nephrotoxicity: Rare

35. CEPHALOSPORINS ADVERSE EFFECTS • Cefamandole, cefotetan, cefoperzone, moxalactam, cefmetazole have methylthiotetrazole (MTT) side-chain • Associated with hypoprothrombinemia and bleeding in patients with risk factors (renal dzs, hepatic dzs, poor nutrition, elderly, cancer, wafarin)

36. Cephalosporins(Oral) 1st gen: Cefadroxil(Duricef) Cephalexin (Keflex) 2nd gen: Cefaclor (Raniclor) Cefprozil(Cefzil) Cefuroxime (Ceftin) 3rd gen: Cefdinir (Omnicef) Cefditoren Spectracef) Cefixime (Suprax) Cefpodoxime (Vantin) Ceftibuten (Cedax)

37. Aztreonam • A monobactam • None to minimal cross reactivity with other β-lactam agents like penicillin or cephalosporins • Similar activity as ceftazidime • No gram-positive activity, only gram-neg activity including Pseudomonas aeruginosa • Widely distributed • Renally eliminated

38. Aztreonam • Good safety record • Used in place of gent/tobra to avoid their toxicities • Uses: Variety of infections - cystitits, pyelo, lower resp tract infns, septicemia, intra-abdominal infns, etc. usually with another agent • Most expensive abx on the formulary • Use monitored • (~$140/day vs $5/day for gent)

39. Carbapenems Primaxin (imipenem/cilastatin) • MOA: Binds to PBP causing cell death • Combined 1:1 with cilastatin (dehydropeptidase inhibitor) to prevent hydrolysis of imipenem • Broad spectrum agent: GN, GP, Anaerobes • β-lactamase inducer • Widely distributed • Renally excreted

40. PrimaxinImipenem/Cilastatin • Fungal superinfection is a possibility • Cross-reactivity with penicillins • SE: Seizures (0.4 -1.5%), N, V • Monitored antibiotic at WBH • Uses: Polymicrobial infections, Resistant organisms • Cost: $$$

41. Meropenem/Doripenem • Broad spectrum antibiotic similar to Primaxin except it has increased activity against GN organisms • Pseudomonas susceptible to meropenem when it may be resistant to Primaxin (imipenem) • Cleared by the kidneys • Less epileptogenic (?) • Cost:$$$

42. Ertapenem (Invanz) • Once daily carbapenem • Broad-spectrum agent including anaerobes • No activity against Pseudomonas, Enterococcus or Acinetobacter species • Given once daily – frequently used as an out-patient drug • Side effect profile similar to other carbapenems • Cost:$$

43. Doripenem(Doribax) • Newest member of the carbapenems • Broad-spectrum antibiotic similar to meropenem • FDA approved for cUTI and cIAI…..and likely to be approved for HAP • Typically 1 hour infusion (may give over 4 hrs) • Less epileptogenic (?) • Cost:$$$

44. Aminoglycosides(amikacin, gentamicin, tobramycin, neomycin, streptomycin) • MOA: Binds to bacterial ribosomes and preventing the initiation of protein synthesis causing cell death • Very active against GNB including PSA. Active against S. aureus, Enterococci when combined • Synergistic with penicillins, nafcillin, vanco • Distributes in most fluids and renally eliminated • SE: Nephrotoxicity ( when combined with vancomycin), Ototoxicity, Neuromuscular blockade

45. Neuromuscular Blockade • Risk is increased in patients receiving NMBA used in anesthesia, hypocalcemia, hypomagnesemia, botulism, myasthenia gravis • Can be reversed by administration of IV calcium gluconate • Variable response with neostigmine

46. Aminoglycosides • Uses: Gram-negative infections either alone or combined…. (usually combined) • Gram-positive infections (Viridans strep, Enterococcus, Staphyloccus) when combined with penicillin, nafcillin, vancomycin • Can be given as a single daily dose or conventional dosing • Need to monitor levels for efficacy and toxicity

47. MacrolidesErythromycin, Azithromycin, Clarithromycin • MOA - Inhibition of bacterial protein synthesis • Bacteriostatic for most part • Active against certain gram-positive and gram-negative organisms (S. pneumoniae, Viridans group, N. meningitidis, N. gonorrhoeae, Atypical organisms) • Distributed widely • SE: GI, thrombophlebitis, QT prolongation • Use: Resp Infns (community-acquired), genitourinary, Chlamydial infns, etc

48. Clindamycin • MOA: Inhibition of protein synthesis • Active against GP organisms and anaerobes • Bacteriostatic, bactericidal against some bacteria • Widely distributed including bone except in CSF • Metabolized by the liver • SE: Diarrhea (20%), Pseudomembranous colitis (PMC) due to overgrowth of C. difficile • Use: Anaerobic infections, Alternate for Gram-positive infns (MRSA, Strep infns, not Enterococci)

49. Clindamycin • Use in combination in the treatment of necrotizing streptococcal soft tissue infections (flesh-eating bacteria) • Active in presence of high inoculum streptococcal infections • Limits toxin production providing increased efficacy

50. Quinolones Agent Trade Name • Norfloxacin Noroxin • Ciprofloxacin Cipro • Levofloxacin Levaquin • Moxifloxacin Avelox