Cell Wall Active Antimicrobials Flashcards
(50 cards)
list the types of drugs active against bacterial cell walls
Penicillins Cephalosporins Monobactam Glycopeptides Cyclic lipopeptides
Explain the mechanism of action for drugs that are active against the bacterial cell wall.
Beta-lactams
o Structure: thiazolidine ring, beta-lactam ring, and acyl side chain
o Acyl side chain gives different activity, susceptiblility to beta-lactamase enzymes, and pharmacokinectic properties
Includes:
• Penicillins
• Cephalosporins
• Carbapenems
• Monobactams
MOA:
• Penetrates bacteria and binds to bacterial enzymes called Penicillin Binding Proteins (PSPs)
• Gram-negative bacteria: must first pass through porin before penetrating the peptidoglycan and binding PBP
• Gram-positive bacteria: antibiotic diffuses directly across peptidoglycan and binds PBPs
• Inhibits transpeptidation → no peptidoglycan cross-linking
• Loss of cell wall integrity → cell autolysis (inhibition of the inhibitor for autolysis)
o Beta-lactams are cidal antibiotics
Glycopeptide
o Inhibit synthesis of peptidoglycan (act at earlier stage in cell wall synthesis)
o Ex: vancomycin
Cyclic lipopeptide
o Bind to cell membrane of Gram-positive organisms
o Ex: daptomycin
Lipoglycopeptide
o Telavancin
Describe the major mechanisms by which bacteria develop resistance to cell wall active agents.
Enzyme inactivation
o Beta-lactamases can inactivate drugs like penicillins and cephalosporins
o Example of resistant enterobacteriacae
• Klebsiella producing carbapenemase
• KPC and NDM-1 (new Delhi Metallo-beta-lactamase-1)
• Most common in Kebsiella
• Also in E. coli and other enterobacteriaeae
• Resistance to all antibiotics except polymyxins, tigecycline, and rarely aminoglycosides
Alteration in target site
o Altered Penicillin Binding Proteins (PBPs)
• With susceptible bacteria: antibiotic binds PBPs → bacteria cannot make adequate cell wall → growth stops
• With resistant bacteria: antibiotic cannot bind → bacterial growth continues
Altered bacterial membrane
o Ex: change charge/structure of membrane porins → antibiotic can’t penetrate outer membrane of Gram-negatives
Efflux pumps
o Antibiotic permeates cell but is actively pumped back out
o Gram-negative enteric bacilli
o S. pneumonia vs macrolides (relatively new)
o Antibiotics: tetracyclines, quinolones, macrolides
Environmental
o Oxygen tension
• Metronidazole = only in anaerobic environment
• Must get reduced to active form
• Aminoglycosides = enter bacteria through aerobic uptake mechanism
• Can’t enter (so can’t function) in anaerobic environment
More than one
Penicillins: Pharmacology
o Time-dependent killing
o Short half life → frequent dosing
• Exception = benathine penicillin G (IM form so longer acting)
o Location
• Oxacillin = good CNS penetration
• Penicillin G not very lipid soluble, but high doses can get it into CSF
Penicillins: sub-groups
- -Natural penicillins (Penicllin G IV form and Penicillin G benzathine IM form)
- -Aminopenicillins (Amoxicillin)
- -Semi-synthetic penicillins (dicloxacillin, oxacillin)
- -Extended spectrum Penicillins (Piperacillin)
- -Penicillins + beta-lactamase inhibitors (amoxicillin-clavulanic acid; piperacillin-tazobactam)
Natural Penicillins: spectrum
Gram-positives o Streptococci, enterococci, pneumococci o Peptostreptococcus o Listeria, Clostrida Gram-negatives o Pasturella, Neisseria meningitides Spirochets o T. pallidum (syphilis), Borrelia spp (Lyme)
Natural Penicillins: Clinical uses
Streptococcal infections o Pharyngitis to cellulitis to endocarditis Enterococcal infections Meningococcal infections Syphilis (all stages) Gas gangrene (Clostridia perfringens) o Plus clindamycin to decrease organism toxin production Periodontal infections
Aminopenicillins: spectrum
Ex. Amoxicillin
Same as penicillin plus most E. coli, Proteus mirabilis, Hemophilus
o Unless beta-lactamase producing
Penicillin Spectrum: Gram-positives o Streptococci, enterococci, pneumococci o Peptostreptococcus o Listeria, Clostrida Gram-negatives o Pasturella, Neisseria meningitides Spirochets o T. pallidum (syphilis), Borrelia spp (Lyme)
Aminopenicillins: Clinical use
- Upper and lower respiratory tract
- UTI
- Enterococcal infections
- Listeria
- Endocarditis prophylaxis
Semi-synthetic penicillins: Spectrum
Penicillinase-resistant
Ex: dicloxacillin, oxacillin
Spectrum
• Staphylococci
• Streptococci
• NO Gram-negatives or anaerobes
Semi-synthetic penicillins: Clinical use
- Staphylococcal infections (Drug of choice)
* Oxacillin = preferred drug for serious Staphylococcal infections
Extended spectrum penicillins: Spectrum
• Ex: Piperacillin
Spectrum • Gram-negative aerobes • Pseudomonas • Piperacillin covers enterococci • Still good for Strept and Staph
Extended spectrum penicillins: Clinical use
- Rarely used in this form
- Instead = used beta-lactamase inhibitor combination forms
- Pseudomonas infections
- Polymicrobial infections (in combination with others)
- Nosocomial infections
Penicillins + beta-lactamase inhibitors: Spectrum
Ex: amoxicillin-clavulanic acid; piperacillin-tazobactam
Function:
• Beta-lactamase inhibitor binds beta-lactamase → out of action
• Parent penicillin can now work
Spectrum • Same as parent penicillin PLUS beta-lactamase producers: o S. aureus o E. coli o H. influenza o Moraxella catarrhalis o Klebsiella o Bacteroides plus other anaerobes o Others
Penicillins + beta-lactamase inhibitors: Clinical use
- Upper and lower respiratory tract
- Head and neck
- Cellultis/abscess
- Intra-abdominal infections
- Animal and human bites (amoxicillin/clavulanic)
- Nosocomial infections including Pseudomonas (Piperacillin/tazobactam)
List the representative drug(s) from each generation of Cephalosporin
o 1st: Cephalexin (oral), Cefazolin (IV) o 2nd: Cefoxitin o 3rd: Ceftriaxone o 4th: Cefepime (IV) o 5th: Ceftaroline (IV)
1st generation Cephalosporin spectrum
Cephalexin (oral), Cefazolin (IV)
Spectrum:
• Gram-positive cocci (Streptococci, Staphylococci)
• E. coli
• Klebsiella
1st generation Cephalosporin clinical uses
Cephalexin (oral), Cefazolin (IV)
- Clinical uses:
- Skin and soft tissue infections due to Staph and Strep
- Surgical prophylaxis
2nd generation Cephalosporin spectrum
Cefuroxime group
o Spectrum= same as 1st generation + Hemophilus and Moraxella
Cephamycin group (includes Cefoxitin) o Spectrum = same as 1st generation + anaerobes and more aerobic GNR
2nd generation Cephalosporin clinical uses
Cefuroxime group
o Clinical uses = upper and lower respiratory tract infections,
Cephamycin group (includes Cefoxitin) o Clinical uses = intra-abdominal and pelvic infections
3rd generation Cephalosporin spectrum
Ex. Ceftriaxone
Broad spectrum:
• Excellent Gram-negative aerobe activity
• Excellent streptococcal activity
• Good for S. aureus
• Excellent N. gonorrheae (Ceftriaxone)
• Ceftazadime = excellent for pseudomonas, poor for staph and strep
3rd generation Cephalosporin clinical uses
Ex. Ceftriaxone
Clinical uses
• Meningitis (ceftriaxone)
• Community acquired pneumonia (ceftriaxone)
• Viridans strep endocarditis (ceftriaxone)
• UTI (ceftriaxone)
• Gonorrhea (ceftriaxone IM, cefexime)
• Intra-abdominal (ceftriaxone + a drug for anaerobes)
• Pseudomonas (ceftazadime)
3rd generation Cephalosporin pharmacology
- Long half-life so once daily dosing
- Dosed 2x daily for CNS infections (excellent CNS penetration)
- Biliary excretion
4th generation Cephalosporin spectrum
Ex: Cefepime (IV)
Spectrum • S. aureus • Streptococci • GNR aerobes • Pseudomonas • NO anaerobe
