Infection - penicillins
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Infection - penicillins
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Infection - penicillins
- 1. Penicillins
- 2. 2 MOA: Cell wall synthesis inhibitors • PBP • Inhibition of transpeptidase • Production of autolysis Bactericidal Time-dependant Pregnancy Category B
- 3. Members: Natural Penicillin: Penicillin V (PO) & Penicillin G (IV). Synthetic Penicillins: Ampicillin (IV) & Amoxicillin (PO)/clavulanic acid. Penicillinase Resistant: Cloxacillin,Nafcillin. Extended Spectrum: Piperacillin ±tazobactam, Ticarcillin ±Clavulanic acid 3
- 4. Dosage Forms: Amoxicillin: PO Ampicillin: PO Cloxacillin: PO, IV, IM Nafcillin: IV,IM Penicillin G: IV Penicillin V: PO Piperacillin: IV,IM Ticarcillin: IV
- 5. 5 Coverage: • Narrow spectrum agent; mostly aerobic gram positive cocci • Useful against: ß- hemolytic streptococci (Group A, B, C) Treponema pallidum (Syphillis) – Gram negative spirochete N. menigitidis: *note: resistance 1-3% oral anaerobes Enteroccocus (E. facaelis, NOT E. faecium) • NOT useful against: most gram negative organisms Beta-lactamase producing organisms (S. aureus - ~90%) Penicillin (G)/(V)
- 6. 6 Dose Adjustment: Penicllin G: needs renal dose adjustment at CrCl ≤50ml/min
- 7. 7 Coverage: • narrow spectrum agent; mostly Gram positive aerobes, some Gram negative aerobes • covers everything that penicillin does (streptococcus, enterococcus, oral anaerobes) • Gram negative coverage (HiPEEL) - Non-beta-lactamase producing H. influenzae (~25% resistance) Proteus mirabilis E. coli (~30% resistance) • Gram positive coverage better coverage of enterococcus (E.faecalis vs. penicillin) Listeria monocytogenes (HiPEEL) • Useful against: ß- hemolytic streptococci (Group A, B, C), E. faecalis ( <1% resistance), Listeria Amoxicillin/Ampicillin
- 8. 8 Coverage: • broad-spectrum agent • extends spectrum of amoxicillin to cover more gram negatives (E.coli, H. influenzae, Salmonella, Shigella) + gut anaerobes (B. fragilis) • Not useful against: Pseudomonas • “Like pip/tazo (minus Pseudomonal coverage)” Amoxicillin-Clavulanic Acid
- 9. 9 Dose Adjustment: Amoxicillin: needs renal dose adjustment at CrCl ≤30ml/min Ampicillin: needs renal dose adjustment at CrCl ≤50ml/min
- 10. 10 Coverage: • Piperacillin + ß-lactamase inhibitor • Most broad-spectrum penicillin • aerobic Gram positives (including MSSA, E. faecalis), • difficult aerobic Gram negatives (including Pseudomonas, Acinetobacter), • anaerobes (including B. fragilis) • Useful against: Pseudomonas, harder to kill Gram negatives (traditional ß-lactamase producers), most aerobic Gram positives (including MSSA) • NOT useful against: MRSA, E. faecium, ESBL Piperacillin-Tazobactam
- 11. 11 • Active against Pseudomonas aeruginosa and many gram-negative bacilli • Do not cover Klebsiella • + clavulanic acid or tazobactam: Covers penicillinase-producing organisms (for example, most Enterobacteriaceae and Bacteroides species). Coverage: Ticarcillin
- 12. 12 Dose Adjustment: Piperacillin: needs renal dose adjustment at CrCl ≤40ml/min No hepatic Dose Adjustment Ticarcillin: needs renal dose adjustment at CrCl ≤60 ml/min Hepatic: only with concomitant renal dysfunction (CrCl ≤10 ml/min)
- 13. 13 Coverage: • Very narrow spectrum; gram positive aerobes • drug of choice for MSSA • maintains coverage for Streptococci (less so than penicillin/ amoxicillin) • some oral anaerobic coverage (less so than penicillin/amoxicillin) • Not useful against: Enterococci, N. meningitis Cloxacillin
- 14. 14 • Cover penicillinase-producing staphylococci, including methicillinsensitive Staphylococcus aureus (MSSA). Coverage: Nafcillin
- 15. 15 Dose Adjustment: Cloxacillin Nafcillin no need for hepatic or renal dose adjustment
- 16. 16 Mechanism of Resistance: Natural Resistance: Occur in organisms that lack a peptidoglycan cell wall (mycoplasma pneumoniae) Organisms have cell wall that is impermeable to drugs. β-Lactamase activity Decreased permeability to the drug Altered PBPs:
- 17. 17 Hypersensitivity Diarrhea Nephritis Neurotoxicity Hematologic toxicities Contraindications: Hypersensitivity. Side effects:
- 18. Macrolides
- 19. 19 MOA: Protein synthesis inhibition; they inhibit 50S ribosomal subunit Bacteriostatic (bactericidal at higher doses) Concentration dependant.
- 20. Members, dosage form & Pregnancy Category Clarithromycin: PO (Cat C) Erythromycin: PO, IV (Cat B) Azithromycin: PO, IV (Cat B)
- 21. 21 Relatively broad-spectrum • Gram positives: Streptococci (note increasing resistance with S. pneumoniae ~20%) • some Gram negatives (A & C only): H. influenzae, M. cattarhalis • atypicals • NO anaerobic coverage • Not useful for: MRSA, enterococcus Coverage
- 22. 22 Dose Adjustment: Clarithromycin needs renal dose adjustment at CrCl <30ml/min Erythromycin: No renal or hepatic Dose Adjustment Azithromycin: No renal Dose Adjustment (use w/ caution w/ GFR <10ml/min)
- 23. 23 Mechanism of resistance: 1) the inability of the organism to take up the antibiotic, 2) the presence of efflux pumps, 3) a decreased affinity of the 50S ribosomal subunit for the antibiotic. 4) the presence of plasmid-associated erythromycin esterases in gram-negative organisms such as Enterobacteriaceae.
- 24. 24 Side Effects: 1. Gastric distress and motility 2. Cholestatic jaundice 3. Ototoxicity Contraindications: Severe hepatic failure & QT prolongation (Clarithromycin)
- 25. Monobactams
- 26. 26 Members : Aztreonam • MOA : cell wall synthesis inhibitors • Coverage : gram negative aerobic including P.aeruginosa and Enterobacteriaceae, lack activity against gram positive organisms and anaerobes • Bactericidal • time dependent
- 27. • Dosage form : IM, IV, inhalation • Pregnancy category: B needs renal dose adjustment at CrCl <30ml/min
- 28. 28 •Elevated hepatic transaminases. •GI: diarrhea, N/V. •Pain at site of injection, Phlebitis. •Neutropenia, eosinophilia, thrombocytopenia. •C/I: hypersensitivity Adverse effects:
- 29. Chloramphenicol
- 30. 30 • MOA: inhibit protein synthesis at the peptidyl transferase rxn (50S ribosomal unit) • Coverage: active against chlamydiae, rickettsiae, spirochetes, and anaerobes. • bacteriostatic, but depending on the dose and organism, it may be bactericidal. • Time-dependent • Resistance: 1) presence of enzymes that inactivate chloramphenicol. 2) decreased ability to penetrate the organism and ribosomal binding site alterations.
- 31. 31 • Dosage form: IV • Pregnancy category C • S:E Anemia, Grey baby syndrome, bone marrow suppression • C/I: Hypersensitivity, blood dyscrasias (box warning) • No renal or hepatic dose adjustment needed.
Editor's Notes
- MOA: The penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage), resulting in exposure of the osmotically less stable membrane. Cell lysis can then occur, either through osmotic pressure or through the activation of autolysins. Penicillins are only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall. Consequently, they are inactive against organisms devoid of this structure, such as mycobacteria, protozoa, fungi, and viruses. Penicillin-binding proteins: Penicillins also inactivate numerous proteins on the bacterial cell membrane. These penicillin-binding proteins (PBPs) are bacterial enzymes involved in the synthesis of the cell wall and in the maintenance of the morphologic features of the bacterium. Exposure to these antibiotics can therefore not only prevent cell wall synthesis but also lead to morphologic changes or lysis of susceptible bacteria. Alterations in some of these PBPs provide the organism with resistance to the penicillins. [Note: Methicillinresistant Staphylococcus aureus (MRSA) arose because of such an alteration.] Inhibition of transpeptidase: Some PBPs catalyze formation of the cross-linkages between peptidoglycan chains. Penicillins inhibit this transpeptidase-catalyzed reaction, thus hindering the formation of cross-links essential for cell wall integrity. Production of autolysins: Many bacteria, particularly the gram positive cocci, produce degradative enzymes (autolysins) that participate in the normal remodeling of the bacterial cell wall. In the presence of a penicillin, the degradative action of the autolysins proceeds in the absence of cell wall synthesis. Thus, the antibacterial effect of a penicillin is the result of both inhibition of cell wall synthesis and destruction of the existing cell wall by autolysins.
- β-Lactamase activity: This family of enzymes hydrolyzes the cyclic amide bond of the β-lactam ring, which results in loss of bactericidal activity. β-Lactamases either are constitutive, mostly produced by the bacterial chromosome or, more commonly, are acquired by the transfer of plasmids. Decreased permeability to the drug: Decreased penetration of the antibiotic through the outer cell membrane of the bacteria prevents the drug from reaching the target PBPs. The presence of an efflux pump can also reduce the amount of intracellular drug (for example, Klebsiella pneumoniae). Altered PBPs: Modified PBPs have a lower affinity for β-lactam antibiotics, requiring clinically unattainable concentrations of the drug to effect inhibition of bacterial growth. This explains MRSA resistance to most commercially available β-lactams.
- Mechanism of action The macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, thus inhibiting translocation steps of protein synthesis. They may also interfere with other steps, such as transpeptidation.
- • Niche: RTIs, Legionella\
- a decreased affinity of the 50S ribosomal subunit for the antibiotic, resulting from the methylation of an adenine in the 23S bacterial ribosomal RNA in gram-positive organisms Resistance to erythromycin has been increasing, thereby limiting its clinical use (particularly for S. pneumoniae).