Antimicrobials

1. Antimicrobials Reporter: I1, Lin YH.

2. Introduction • Patients in the ICU are often infected with multiresistant organisms. • Frequently exposed to broad-spectrum antibiotics and invasive procedures • Judicious used of empiric antimicrobial therapy is needed to minimize emergence of resistant organisms. • Choice of antibiotic: suspected source of infection, severity of the illness, local (hospital or ICU) microbiologic flora

3. Chapter Outline ◇ Learning objectives ◇ Antibacterial Antibiotics ◇ Antifungal Drugs ◇Antiviral Drugs ◇ Summary ◇Review Questions

4. Learning Objectives • Recognize the different classes of antimicrobials and their mechanisms of action. • Identify the spectrum of coverage for specific antimicrobials. • Describe possible adverse effects and drug interactions caused by antimicrobials. • Select appropriate antimicrobials for various pathogens.

5. Chapter Outline ◇Learning objectives ◇ Antibacterial Antibiotics • Mechanisms of action and resistance • Spectrum of coverage • Pharmacology and adverse effects ◇ Antifungal Drugs ◇Antiviral Drugs ◇ Summary ◇Review Questions

7. Pharmacology • Basctericidal / bacteriostatic • Mode of action: concentration-dependent / time-dependent killing effect • Minimal inhibitory concentration (MIC) • Postantibiotic effect (PAE) • Syngery / Indifference / Antogonism

11. GRAM-POSITIVE COCCI Micrococcaceae family M. luteus, M. roseus, and M. varians. Micrococcaceae family aureus: S. aureus non-aureus: S. epidermis α-hemolysis: S. pyogenes β-hemolysis: S. agalactiae γ-hemolysis: Enterococcus / non-Enterococcus S. pneumoniae

12. GRAM-POSITIVE RODS Aerobic: Endospore-forming: Bacillus Regular, non-endospore-forming: Listeria Irregular, non-endospore-forming: Corynebacterium Anaerobic: Endospore-forming: clostridium Non-endospore-forming: Actinomycetes

13. GRAM-NEGATIVE • Aerobic cocci: Neisseria-- N. gonorrhoeae, N. meningitidis; Moraxella • Anaerobic cocci: Vellionella • Rods: (1) Enterobacteriaceae: Escherichia coli,Shigella,Salmonella, Klebsiella, Enterobacter, Proteus… (2) Pleomorphic: Haemophilus, Legionella, Pasteurella, Brucella (3) Miscellaneous: Vibrio, Campylobacter, Helicobacter (4) Nonfermenters: Pseudomonas, Acinebacter, Flavobacterium

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15. β-Lactams • Binding to penicillin-binding-protein (PBP) inner cell membrane endogeneous bacterial autolysis • Activity depend on: (1) PBP type (2) degree of affinity to a particular PBP

16. β-Lactams • Resistance: (1)β-Lactamase enzyme: • nosocomial G (-) organisms: encoded on bacterial chromosomes, plasmid mediated, or carried on transposons •G(+): either inducible or constitutive and are ofter plasmid mediated (2) Change permeability of outer membrane (3) Altering their PBP

17. β-Lactams • Penicillin groups: penicillin ring • Cephalosporin groups: cephalosporin ring • Monobactams: Aztreonam • Carbapenems: (1) Imipenem-Cilastatin (Tienam) (2) meropenem (Mepem)

18. β-Lactams : Penicillins • Penicillin G-like drugs: Penicillin G/ Penicillin V • Penicillinase-resistant penicillins: Dicloxacillin / Oxacillin / Methicillin / Nafcillin • Ampicillin-like drugs (Amino-PCNs) Ampicillin / Ampicillin + sulbactam (Unasyn) Amoxicillin / Amoxicillin + clavulanic acid (Augmentin) • Broad-spectrum (antipseudomonal) penicillins: Ticarcillin/ Ticarcillin + Clavulanic Acid ( Timentin ) Piperacillin / Piperacillin + tazobactam (Tazocin )

19. β-Lactams : PCNs • Fallen out as 1st line empiric therapy • Drug of choice for treatment of susceptible pathogens • Most excreted rapidly by kidney (except: Nafcillin) • Hypersensitivity most common side effect • Immunogenicity

20. Penicillin: a. GPC: Streptococci, Treotococcus pneumoniae, Enterococci b. Anaerobics: except Bacteroides fragilis c. Treptonema pallidum (syphilis) • Ampicillin / ampicillin-like drugs :  GNB  Hydrolyzed by many β-Lactamase Unasyn / Augmentin a) Ampicillin: ‧ GPC: Liesteria monocytogenes & many Entecoccus spp. ‧ Community-acquired Enterobacteriaceaeand Neiserria spp. b) Amoxicillin: analog, superior oral bioavailability

21. New generation of penicillins: (1) β-lactam + β-lactamase inhibitor: a) Unasyn: Community acquired soft-tissue infection, intra- abdomen or pelvic infection, polymicrobial RI. b) Augmentin: UTI, otitis media, sinusitis, bite wounds. (empiric coverage against β-lactamase-producing staphylococci, H. influenzae, Neisseria gonorrhoeae, Moraxella catarrhalis, Bacteroides, and Klebsiella spp.) (2) Antipseudomonal penicillins: GP + GN a) Timentin & Tazocin: polymicrobial soft-tissue infection intra-abdomen or pelvic infection, LRI. b) Timentin Stenotrophomonas maltophilia; Tazocin p. aeruginosa.

22. β-Lactams: Cephalosporins 2.5 generation- Cephamycins cefmetazole, ceftetan, cefoxitin

23. Similar mechanism to PCNs • Side chain Coverage spectrum, pharmacokinetics, side effect • Resistance: Enterobacter, Pseudomonas, Serratia, Citrobacter spp. • Not effect against enterococci or ORSA • Most renally excreted • Side effect: a) Hypersensitivity b) MTT side chain (N-methylthiotetrazole): ( 2nd- Cefamandole, Cefmetazole, Cefotetan)  caugulopathy (vit. K dependent CF) ; disulfiram-like reaction with ethanol flushing, sensation of warmth, giddiness, nausea, and occasionally tachycardia

24. β-Lactams: Cephalosporins • Against GPC 1st > 2nd > cephamycins > 3rd • Against GNB 1st < 2nd < cephamycins < 3rd

25. 1st-generation cephalosporins • Activity: a) Against most GPC, including β-Lactamase producine strains b) CAI-GNB, E. coli, Klebsiella spp. c) Typically resistance: B. fragilis, P. aeruginosa, Enterobacter spp. d) No BBB penetration • Cefazolin (Veterin ): Longest T1/2 (1.7h)  q8h; most effective to E. coli

26. 2nd-generation cephalosporins • Expanded coverage to GNB • No BBB penetration • Cefuroxime (Zinacef): a) very active against MSSA and Streptococcal species b) β-Lactamase stable

27. 3rd-generation cephalosporins • More active in GNB but less active in GPC (especially S. aureus) • Drug of choice for GNB meningitis • Lead to superinfection with fungi.and enterococci(induce production of β-Lactamase. Ex: p. aerugnosa, Citrobacter species…) • Anti-pseudomonal cephalosprins a) Ceftazidime (Kefadin) b) Cefoperazone (Cefobid) • Broad-spectrum cephalosporins: bac. Meningitis a) Ceftriaxone ( Rocephin= Sintrix) b) Cefotaxime

28. 4th-generation cephalosporins • Anti-pseudomonas + Broad-spectrum 3rd • Less BBB peneration • Cefepime (Maxipime) a) Enhanced stability against GNBβ-Lactamase ( Enterocobecter spp. Klebsiella…) b) significant activity against GPC: S.aureus, pneumococci c) Neutropenic fever: monotherapy

29. Penicillin groups: penicillin ring • Cephalosporin groups: cephalosporin ring • Monobactams: Aztreonam • Carbapenems: (1) Imipenem-Cilastatin (Tienam) (2) meropenem (Mepem)

30. β-Lactams : Monobactams • Aztreonam a) only binds PBPs of aerobic G(-) bac. (many strains of P.aeruginosa) b) completely ineffective to all G(+) bac. c) useful in allergic to PCNs

31. β-Lactams : Carbapenems • Tienam/ mepem Widest spectrum: 1) anaerobes, 2) most GPC (except Enterococcus faecium and ORSA) 3) most GNB (except: Stenotrophomonas maltophilia and Burkholderia cepacia ) • Special stereochemical characteristics  β-lactamase stable • Hypersensitivity similar with PCNs • Seizure attack with predisposing factors (e.g., advanced age, renal insufficiency, Hx. of seizure)

32. ★ ★ ★ ★ Amikacin (Amikin)/ Gentamicin/ Neomycin / Netromycin ★

33. Aminoglycosides • Amikacin (Amikin)/ Gentamicin/ Neomycin / Netromycin • Bactericidal for numerous G(+) & G(-) bacteria • Not active in 1) oxygen-poor environment 2) low PH  ineffective to anaerobes and abscesses • Usually with β-Lactam antibiotics to GNB • Synergy with PCNs to streptococcal, enterococcal endocarditis

34. Aminoglycosides • Interfering with protein synthesis during aerobic metabolism. • Good potensy: concentration-dependent killing effect and time-dependent PAE on G(+) and G(-) organisms • Potency depend on 1) susceptibility to aminoglycoside-inactivating enzyme 2) permeability to cell wall

35. Freeze initiation Block peptide bond formation Misreading of mRNA

36. Aminoglycosides • Excreted rapidly by normally functioning kidney TBW-dependent distribution: ↑dose in pregnancy, burns, ascites, septic shock  ↓dose in renal insufficiency • Adverse effect: 1) Nephrotoxicity reversible but possible permanent renal failure monitor renal function during therapy 2) ototoxicity  prolonged use (>14 days) , renal insufficiency, concurrent use with other ototoxic agents.

37. Fluoroquinolones: Ciprofloxacin (Ciproxin) Levofloxacin (Cravit ) / Nofloxacin ( Noxacin ) ★ ★ ★ ★ ★ ★

38. Fluoroquinolones • Ciprofloxacin (Ciproxin) / Levofloxacin (Cravit ) / Nofloxacin ( Noxacin ) • 快速且完全自腸胃道吸收 • Synergic effect with some β-lactam antibiotics • Active against: 1) Most GNB : Enterobacteriaceae, H. influenza, P. aeruginosa… 2) Many GPC • 目前為一對P. aeruginosa有效的口服抗生素 • Resistance: mutations in DNA gyrase

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40. Glycopeptides (Vancomycin ) • Bactericidal against most G(+) bacteria • Bacteriostatic to enterococci VRE↑ • Indication: 1) Serious infection with resistance to β-lactam-resistance G(+) bac. 2) Allergy with β-lactam antibiotics 3) Orally treatment of C. difficile colitis that lift-threatening 4) Endocarditis prophylaxis 5) prophylaxis in prosthetic implant 6) empiric use for suspected pneumococcal spp. meningitis • Histamine-related reaction: red men syndrome

41. Macrolides • Erythromycin/ Azithromycin / Clarithromycin (Klaricid) / Clindamycin • Bateriostatic • High tissue concentration but unreliable CSF penetration • Hepatic elimination • Resistance: alteration of ribosomal binding sites • Increase plasma level of theophylline, wafarin…

42. Sulfonamide • Buktar: Trimethoprim + Sulfomethoxazol • Bacteriostatic antibiotics with a wide spectrum against most G(+)& many G(-) organisms. • Uncomplicated UTI, nocardiosis (土壤絲菌病）,chancroid（軟下疳） 1) combine with pyrimethamine  toxoplasmosis, 2) substitute for penicillin in prophylaxis of rheumatic fever 3) prophylaxis against susceptible meningococcal strains, in ulcerative colitis (as sulfasalazine), in burns (as silver sulfadiazine or mafenide), in chloroquine-resistant Plasmodium falciparum infection, and in combination with trimethoprim

44. Nitromidazole (Metronidazole) • Active only against protozoa, such as Giardia lamblia（腸梨形蟲）, Entamoeba histolytica(痢疾阿米巴), and Trichomonas vaginalis（陰道滴蟲）, and strictly anaerobic bacteria (Bacteroides fragilis). (Not active against aerobic or microaerophilic bacteria.) • Drug of choice in Clostridium difficile colitis. • Drug of choice for bacterial vaginosis. It has also been used successfully in Crohn's disease • penetrates into the CSF in high concentrations • Disulfiram-like reaction may occur if alcohol is ingested

45. Others • Antituberculous antibiotics: Rifampin • Tetracyclin