Cell Wall Active Antimicrobials Flashcards
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
4th generation Cephalosporin clinical uses
Ex: Cefepime (IV)
Clinical uses • Nosocomial infections • Febrile neutropenia • Pseudomonas infections • ESBL producing GNR (some) • Mixed Gram-positive and negative infections
5th generation Cephalosporin spectrum
Ex: Ceftaroline (IV)
Spectrum • S. aureus • MRSA • MRSE • Strep • Good Gram-negative • NO pseudomonas
5th generation Cephalosporin clinical uses
Ex: Ceftaroline (IV)
- Pneumonia (Community-acquired)
- SSTI
- Many others to come
Classes of organisms Cephalosporin does NOT have activity against
NONE have activity against o Enterococci o Listeria o Chlamydia o Mycoplasma
CNS penetration of Cephalosporin
o None in all 1st generation
o Almost all in 2nd generation
o Excellent: ceftriaxone, ceftazadime, cefepime
Carbapenems: spectrum
Ex: Meropenem (IV)
Broad Spectrum
o Gram-positive
o Gram-negative (including Extended Spectrum Beta-lactamases [ESBL] producers)
o Pseudomonas (Doripenem > rest; NOT ertapenem)
o Anaerobes
Carbapenems: do NOT cover these organisms
o MRSA o MRSE o E. faecium (including VRE) o C. difficile o Stenotrophomonas o Burkholderia o Ertapenem misses pseudomonas and acinetobacter
Properties of carbapenems
o Small molecules (able to pass through Gram-negative porins)
o Resistant to many beta-lactamases
o Affinity for PBP from a wide range of bacteria
Carbapenems: clinical uses
Serious infections in critically ill patients • Nosocomial infections • Pseudomonas infections Meningitis/CNS (meropenem) Mixed infections • Intra-abdominal • Severe skin and soft tissue
Monobactam (Aztreonam): spectrum
o Gram-negatives (including Pseudomonas)
o No gram-positive or anaerobes
Monobactam (Aztreonam): clinical uses
o Safe to use with penicillin hypersensitivity
o Niche role: Pseudomonas infections when we cannot use a beta-lactam due to allergy
o Could be used for other GNF aerobes
Glycopeptide (Vancomycin): mechanism of action
o Binds to D-alanyl-D-alanine portion of peptide precursor unit
o Prevent formation of peptidoglycan cross links
o Results in autolysis BUT cell death is slow
Glycopeptide (Vancomycin): pharmacology
o Huge molecule = hard to get into CNS
o Poor GI tract absorption
• Oral vancomycin used only for C. difficile because stays in GI tract
o Higher dosing due to increasing MRSA MIC’s
Glycopeptide (Vancomycin): spectrum
Gram-positive bacteria • Aerobic and anaerobic GPC • Most GPR (but not all) Important activity against: • MRSA • MRSE • Enterococci (not VRE – vancomycin resistant) • Streptococci (including penicillin and cephalosporin resistant S. pneumoniae)
Glycopeptide (Vancomycin): clinical uses
o MRSA and MRSE serious infections
o Enterococcal infections
o Alternative to beta-lactam when severe allergy present
o Penicillin and cephalosporin-resistant S. pneumoniae in meningitis and other serious pneumococcal infections
o Oral form to treat C difficile
Cyclic Lipopeptides (Daptomycin): Mechanism of action
o Lipid portion inserts into cytoplasmic membrane
o Loss of membrane potential and ion conduction channel → cell death
o Rapid cidal activity
Cyclic Lipopeptides (Daptomycin): pharmacology
o Once daily dosing
Cyclic Lipopeptides (Daptomycin): spectrum
Gram-positive bacteria: • MRSA and MRSE • VRE • Pneumococci • Other streptococci
Cyclic Lipopeptides (Daptomycin): clinical uses
o Serious infections due to MRSA, MRSE, VRE
o Do NOT use for pneumonia because drug is inhibited by pulmonary surfactant
Penicillins: Adverse Reactions
o Rash o Hypersensitivity o Diarrhea o Interstitial nephritis o Nafcillin = neutropenia, phlebitis o Ticarcillin/Piperacillin = high salt load o Generally well tolerated
Cephalosporins: Adverse Reactions
o Generally well tolerated
o Rash (cross reaction with penicillins in 3-7%)
o Diarrhea
o Ceftriaxone = biliary sludging with prolonged use
o Cefepime = mental status changes (be careful in elderly)
Carbapenems: Adverse Reactions
o Rash and hypersensitivity (cross reaction with penicillins)
o Diarrhea
o Seizure and risk with imipenem (especially when improperly dose-adjusted for renal impairment)
Monobactam (Aztreonam): Adverse Reactions
o Rash and hypersensitivity
Vanomycin: Adverse Reactions
o Neutropenia o Nephrotoxin (when combined with other nephrotoxins) o Ototoxicity (rare) o “Red Man’s Syndrome” • Histamine release from rapid infusion • Rash and itching head and neck
Daptomycin: Adverse Reactions
o Myopathy
Concentration vs. Time-dependent Killing
Time-dependent killing
o Time above MIC is the parameter that predicts efficacy
o Beta-lactams
Concentration-dependent killing
o Peak/MIC and AUC/MIC ratios are the parameters that predict efficacy
o Aminoglycosides
