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
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:
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)
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.
Hinweis der Redaktion
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).