Review of Antimicrobial Agents Part I

1. Review of Antimicrobial AgentsPart I Siriluck Anunnatsiri, MD, MCTM, MPH Infectious Diseases & Tropical Medicine Department of Medicine Khon Kaen University

2. Classification of Antimicrobial Agents • -lactam antibiotics: Penicillins, Cephalosporins, Carbapenems, Monobactams, -lactam/-lactamases inhibitors • Aminoglycosides • Macrolides • Ketolides: Telithromycin, Dirithromycin • Lincosamides: Lincomycin, Clindamycin • Quinolones • Chloramphenicol

3. Classification of Antimicrobial Agents • Tetracyclines, Tigecycline • Sulfamethoxazole/Trimethoprim (SMX/TMP) • Glycopeptides: Vancomycin, Teicoplanin • Oxazolidinones: Linezolid • Fosfomycin • Fusidic acid • Polymyxins: Polymyxin B, Colistin • Metronidazole

4. Classification of Antimicrobial Agents • Lipopeptide: Daptomycin • Streptogramins: Quinupristin-Dalfopristin -lactam antibiotics Aminoglycosides Glycopeptides

5. Structure Spectrum Mechanisms of action Mechanism of resistance Pharmacokinetic Absorption Distribution Metabolism Elimination Pharmacodynamic Drug interaction Side effect Antimicrobial Properties

6. Beta-lactams Antibiotic: Basic Structure Aminoacyl Thiazolidine ring Dihydrothiazine ring Hydroxyethyl

7. Beta-lactams Antibiotic: General Properties • Inhibit cell wall synthesis • Bactericidal effect • Time-dependent bactericidal action • Inoculum effect on antimicrobial activity is more prominent • In GNB - No or short PAE for most -lactam • Share -lactam class allergic reaction except monobactams

8. PD Parameters affecting Antibiotic Potency AUC/MIC >125 for GNB >25-50 for GPC Cmax/MIC >10 > 40-50% of dosing interval

9. Inoculum Effect • The effect of inoculum size on antimicrobial activity • Dense population can be less susceptible to -lactams • Failure to express receptor (PBP) • High concentration of -lactamases • Trend to presence of resistant subpopulation

10. Postantibitic Effect • A persistent suppression of growth after levels have fallen below the MIC

11. Bacterial Cell Wall Synthesis Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155

12. Bacterial Cell Wall Synthesis (Transpeptidase) Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155

13. Beta-lactams Antibiotic : Mechanism of Action Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155

14. Beta-lactams Antibiotic : Mechanism of Resistance • -lactamases destruction of antibiotic • Failure of antibiotic to penetrate the outer membrane of gram-negative to reach PBP target • Efflux of antibiotic across the outer membrane of gram-negative • Low-affinity binding of antibiotic to PBP target

15. Beta-lactams Antibiotic: Adverse Reactions • Hypersensitivity – 3 to 10 % • Irritability, jerking, confusion, seizures– especially with high dose penicillins and imipenem • Leukopenia, neutropenia, thrombocytopenia – therapy > 2 weeks • Interstitial nephritis • Cephalosporin-specific: cefamandole, cefotetan, cefmetazole, cefoperazone, moxalactam • Hypoprothrombinemia - due to reduction in vitamin K-producing bacteria in GI tract

16. Penicillins: Classification • Natural penicillins Penicillin V, Penicillin G • Aminopenicillins Ampicillin, Amoxicillin • Penicillinase-resistant penicillins Cloxacillin, Dicloxacillin, Nafcillin, Methicillin • Carboxypenicillins Carbenicillin, Ticarcillin • Ureidopenicillin Piperacillin, Azlocillin, Mezlocillin

17. Natural Penicillins: Spectrum of Activity Gram-positive Gram-negative S. pneumoniaeNeisseriameningitidis Streptococcus sp. Enterococcus sp. Anaerobes C. diphtheriae Above the diaphragm B. anthracis Clostridiumperfringens L. monocytogenes Other Treponema pallidum Leptospira sp.

18. Penicillinase-Resistant Penicillins: Spectrum Gram-positive MSSA MSSE Streptococcus sp.

19. Aminopenicillins: Spectrum of Activity Gram-positive Gram-negative Streptococcus sp. Proteus mirabilis Enterococcus sp. Salmonella sp. L. monocytogenes Shigella C. diphtheriae some E. coli H. influenzae N. meningitidis Anaerobes Above the diaphragm Clostridiumperfringens

20. Carboxypenicillins: Spectrum of Activity Gram-positiveGram-negative Streptococcus sp. Proteus mirabilis C. diphtheriae Salmonella sp. Shigella E. coli H. influenzae Neisseria sp. Anaerobes Enterobacter sp. Fairly good activity P. aeruginosa Citrobacter sp. Serratia sp.

21. Ureidopenicillins: Spectrum of Activity Gram-positiveGram-negative Streptococcus sp. Proteus mirabilis Enterococcus sp. Salmonella sp. L. monocytogenes Shigella E. coli Klebsiella sp. H. influenzae Neisseria sp. Anaerobes Enterobacter sp. Fairly good activity P. aeruginosa S. marcescens

22. Penicillins: Pharmacology • Administration – Oral, IV, IM • Varying oral absorption 40% for Ampicillin  75% for Amoxicillin • Varying protein binding • 17% for aminopenicillin  97% for dicloxacillin • More free drugs in the presence of probenecid • Mainly excrete via renal tubular cells, which can be blocked by probenecid.

23. Penicillins: Pharmacology • Dose adjustment is needed when CCr < 10-20 ml/min, on hemodialysis or CVVH • Biliary excretion is important only for nafcillin and antipseudomonal penicillins. • Well distributed to most tissues, high concentration in urine and bile • Relatively insoluble in lipid and penetrate cells relatively poorly

24. Cephalosporins: Classification

25. 1st Generation Cephalosporins: SpectrumBest activity against gram-positive aerobes, with limited activity against a few gram-negative aerobesGram-positiveGram-negativeMSSA EnterobacteriaceaeStreptococcus sp. 2nd Generation Cephalosporins/Cephamycins: Spectrum • More active against gram-negative aerobes • Cephamycin group has activity against gram-negative anaerobes including Bacteroides fragilis

26. 3rd Generation Cephalosporins: Spectrum • Increase potency against gram-negative aerobes • Ceftriaxone and cefotaxime have the best activity against MSSA and Streptococcus sp. • Ceftazidime, moxalactam, cefixime, and ceftibuten have less activity against MSSA • Ceftazidime, cefoperazone, and cefsulodin have activity against P. aeruginosa.

27. 4th Generation Cephalosporins: Spectrum • Extended spectrum of activity • gram-positives: similar to ceftriaxone • gram-negatives: Enterobacteriaceae including cephalosporinase-producer, P. aeruginosa. • Stability against -lactamases; poor inducer of extended-spectrum  -lactamases

28. Cephalosporins: Pharmacology • Polar, water-soluble compounds • Administration – IM, IV, oral, intraperitoneum • High oral bioavailability • Varying protein binding – 10% -> 98% • Largely confined to extracellular compartment, relatively poor intracellular concentration • Good CNS penetration – Only 3rd & 4th gen. cephalosporins • Almost excrete via renal tubular secretion, except ceftriaxone and cefoperazone are largely eliminated via biliary route

29. Carbapenems • Imipenem • N-formimidoyl derivative of thienamycin • Need to combine with cilastatin to prevent renal dehydropeptidase I hydrolysis and nephrotoxic effect • Meropenem, Ertapenem • -1-methyl, 2-thio pyrrolidinyl derivative of thienamycin

30. Carbapenems: Spectrum of Activity • Most broad spectrum of activity of all antimicrobials • Have activity against gram-positive and gram-negative aerobes, anaerobes, Nocardia sp., rapid-growing mycobacteria • Bacteria not covered by carbapenems include MRSA, MRSE, E. faecium, C. difficile, S. maltophilia, B. cepacia • Ertapenem not active against P. aeruginosa and Acinetobacter sp.

31. Carbapenems: Pharmacology • Absorbed poorly after oral ingestion • T1/2: • Imipenem, Meropenem 1 hr • Ertapenem 4 hr • Well distributed to body compartment and penetrate well into the most tissues • Excrete via renal, dosage adjustment is required in patient with impaired renal function. • Need supplement dose in patient performing CVVH, hemodialysis

32. -Lactam/-Lactamase Inhibitor • Ampicillin/sulbactam (A/S) • Amoxicillin/clavulanate (A/C) • Ticarcillin/clavulanate (T/C) • Piperacillin/tazobactam (P/T) • Cefoperazone/sulbactam (C/S)

33. -Lactam/-Lactamase Inhibitor: Spectrum • Maintain spectrum of -Lactams but enhance activity against -Lactamase (Ambler class A) producing organisms • Activity against MSSA, Streptococcus sp., Enterococcus sp. (Except C/S),-Lactamase producing Enterobactericeae, P. aeruginosa (Only P/T, C/S), Anaerobes.

34. -Lactam/-Lactamase Inhibitor: Pharmacology • Clavulanate, Sulbactam – Moderately well absorbed • Good tissue distribution • Penetration into inflamed meninges • Clavulanate, Sulbactam – Poor • Tazobactam – Good in animal model • Excretion • Clavulanate – Lung, feces, urine • Sulbactam, Tazobactam - Urine

35. Monobactams • Aztreonam • Bind primarily to PBP 3 in Enterobacteriaceae, P. aeruginosa, and other gram-negative aerobes • No activity against gram-positive or anaerobic bacteria • Low incidence of drug hypersensitivity; no cross-reaction with other -Lactams • Weak -Lactamase inducer

36. Aminoglycosides: Basic Chemical Structure Aminocyclitol Ring

37. Aminoglycosides: Classification

38. Aminoglycosides: Mechanism of Action

39. Aminoglycosides: Mechanism of Resistance Adenyltransferase Acetyltransferases Phosphotransferases

40. Aminoglycosides: Spectrum of Activity • Gram-Negative Aerobes • Enterobacteriaceae, P. aeruginosa, Acinetobacter sp.- Kanamycin & Gentamicin groups • F. tularensis, Brucella sp., Y. pestis - Streptomycin, gentamicin • N. gonorrhoeae - Spectinomycin • Mycobacteria • M. tuberculosis – Streptomycin, kanamycin, amikacin • Non-tuberculous – Amikacin, streptomycin

41. Aminoglycosides: Spectrum of Activity • Gram-Positive Aerobes(In vitro synergy) S. aureus, S. epidermidis, viridans streptococci, Enterococcussp. • Nocardia sp. - Amikacin • E. histolytica, C. parvum - Paromomycin

42. Aminoglycosides: Pharmacology • Bactericidal effect • Concentration dependent killing • Little influence by inoculum effect • Presence of PAE effect • Administration – IV, IM, intrathecal, intraperitoneum, inhale, oral (neomycin, paromomycin), topical • Low level of protein binding (10%), high water solubility, lipid insolubility

43. Aminoglycosides: Pharmacology • 99% of drug is excreted unchanged by glomerular filtration • 5% of excreted drug is reabsorbed at renal proximal tubule

44. Once-Daily Aminoglycosides • Equal efficacy compared to multiple-dose administration • May lower but not eliminate risk of drug-induced nephrotoxicity and ototoxicity • Simple, less time consuming, and more cost effective • Does not worsen neuromuscular function in critically ill ventilated patients • Probably should not be used in enterococcal endocarditis • Need further study in pregnancy, cystic fibrosis, GNB meningitis, endocarditis, and osteomyelitis

45. Aminoglycosides: Adverse Effects • Neuromuscular blockage • Nephrotoxicity • Reversible if detection early • Risk factors: prolonged trough level, volume depletion, hypotension, underlying renal dysfunction, elderly, other nephrotoxins • Ototoxicity • Cumulative dose • 8th cranial nerve damage - irreversible • Vestibular toxicity: dizziness, vertigo, ataxia • Auditory toxicity: tinnitus, decreased hearing (high frequency)

46. Glycopeptides • Vancomycin • Teicoplanin

47. Glycopeptides: Mechanism of Action Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155

48. Glycopeptides: Mechanism of Resistance in S. aureus Hiramatsu K. Lancet Infect Dis 2001; 1: 147-155

49. Glycopeptide-resistant S. aureus NCCLS = The National Committee for Clinical Laboratory Studies BSAC = The British Society for Antimicrobial Chemotherapy

50. Glycopeptide-resistant S. aureus • Recommend using MIC determination for confirmation of VISA, GISA, or VRSA isolates • Heteroresistance phenomenon: Hetero-VRSA • Only a subpopulation of S. aureus can grow on vancomycin-containing agar (>8 g/ml) • Precursor of VISA/VRSA isolates • Population analysis is needed to identify hetero-VRSA