Lecture 23
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What is the cause of most complicated skin and skin-structure infections?
MRSA
What are complicated skin and skin-structure infections?
Severe skin infections of deep soft tissue (fascia and/or muscle layers) that require surgical intervention or are in combination w/ underlying disease that makes tx difficult
What is the oral tx for skin infections where MRSA culture and sensitivity are known?
• Trimethoprim/sulfamethoxazole • MInocycline or doxycycline • Fusidic acid • Rifampin
What is the IV tx for serious infections w/ known or presumed MRSA?
• Glycopeptides - New 5th gen cephalosporins (ceftobiprole, ceftaroline)
How does MRSA have resistance?
Very low affinity of al penicillin’s, carbapenems, and almost all cephalosporins for PBP 2a
What do 5th gen cephalosporins have high affinity for?
PBP 2a
What is ceftaroline fosamil used to treat?
• Many gram pos infections resistant to most antibiotics, including MRSA, MSSA, and VRSA • Shown in vitro activity against some types of VRE and S aureus resistant to daptomycin and linezolid • Shown in vitro activity against multi-drug resistant Strep pneumoniae
How is ceftaroline fosamil administered?
• As pro-drug converted by plasma phosphatases to active drug • Administered IV only
What is ceftobiprole medocaril used to treat?
• Many gram pos infections resistant to most antibiotics, including MRSA, MSSA, and VRSA • Shown in vitro activity against S aureus resistant to daptomycin, tigecycline, and linezolid • Shown in vitro activity against multi-drug resistant Strep pneumoniae • Broad gram neg spectrum • Anti-pseudomonal activity
How is ceftobiprole medocaril administered?
• As a pro-drug converted to active drug by esterase or happens non-enzymatically in aqueous environment like blood • Administered IV only
What is vancomycin?
Glycopeptide
What does loss of the sugar portion of vancomycin cause?
Loss of about 1/4 of antibiotic potency
What is the importance of aromatic chlorine substitutions of vancomycin?
• Prevent aromatic ring rotation - Potency decreases if not present
What is the significance of the hepta-peptide of vancomycin?
Required for activity
How is vancomycin synthesized?
Heptapeptide portion is not made via ribosomal synthesis, so unusual amino acids like beta-hydroxytyrosine are incorporated
Why don’t glycopeptide antibiotics have activity against gram neg bacteria?
Have a large size, so can’t penetrate through the outer membrane of gram neg cells and is not taken up by the gram neg porin
What does vancomycin interact w/?
• Peptidoglycan building block formed from Parks nucleotide - Extensive interaction takes place btwn second D-ala and vancomycin via a specific H-bond network
How and why does vancomycin dimerize?
• In an antiparallel orientation w/ building blocks of peptidoglycan • Prevents transglycosidation and transpeptidation (can also bind to growing peptidoglycan after transglycosidation and before transpeptidation)
Does vancomycin have oral bioavailability?
No, given as IV infusion usually over 1 hour
What is the spectrum of vancomycin?
• Gram pos and some gram pos anaerobes (esp clostridium species) • No gram neg
What is vancomycin used to treat?
• Skin infections and complicated skin infections • Endocarditis caused by gram positive • Clostridium difficile (anaerobic) associated diarrhea
How is vancomycin given if it is used to treat clostridium difficile associated diarrhea?
Orally to act locally in gut
What are side effects of vancomycin?
• Nephrotoxicity (rare at normal doses) • Ototoxicity • Upper body rash mediated by histamine release
What is teicoplanin?
Group of at least 5 related chemicals that differ at the alkyl chain