2. Inhibitors of Cell Wall Synthesis

Bacterial Cell Wall Characteristics

• Gram +

  • Glycans cross-linked by peptides → THICK Peptidoglycan

  • β-Lactamases

  • Teichoic acids

• Gram -

  • Peptidoglycan (THIN) surrounded by lipoprotein sandwich (Inner and outer plasma membrane)

  • LPS are lipophilic and prevent gram stain penetration

  • Porin channel proteins transport small hydrophilic zwitterions (both + and - charge)

Explain Murein, NAM-NAG and Penicillin-Binding Proteins (PBPs)

• Murein is a PG of repeating NAM and NAG units that crosslink via peptides

• Transpeptidases remove alanine and help crosslink glycine to the previous alanine

  • PBPs = Transpeptidases because Penicillin binds to them and inhibit its activity → Results in loss of cell wall by autolysis → So Penicillin is an antibacterial

    

Characteristics of β-Lactam Rings

• Originates from Penicillin (prototype)

• 5-membered ring

• Substrate for β-lactamase hydrolyzation and breaking of ring

• Unstable structure because it is acid labile → easily destroyed by immune system and stomach acid

What is the basis for Penicillin Hypersensitivity

β-lactam ring undergoes isomerization and then is able to bind a lysyl residue in a protein

• This forms an immunogenic compound that triggers IgG Response

Pharmacokinetics of Penicillin and its derivatives

• Acid labile and binds food proteins → must be administered 1-2hrs before meals

• CSF Penetration is variable but possible

• Plasma protein binding

• Renal excretion of unchanged drug by glomerular filtration and tubular secretion

• Probenecid BLOCKS secretion of penicillin and thus increases half-life

Penicillin Drug categories

• MOA

• Gram + or -

• Susceptible pathogens

• Adverse reactions

• Resistance

• Penicillin G (Prototype)

  • Block last step of cross-linking through β-lactam

  • Drug of choice for gram+ aerobes and anaerobes

    • Staph, Strep, Spirochetes, Treponema pallidum & few gram- such as Neisseria. gonorrhea and H. influenzae

  • Adverse rxns: Hypersensitivity may occur in allergic individuals

  • Resistance: Degradation by β-lactamases and most gram-

• Penicillin V (Oral): same but acid resistant and administered orally

• Penicillinase-resistant penicillin (PRPs/MSSA/methicillin susceptible staph aureus): Methicillin, Oxacillin and Nafcillin

• MRSA Resistant: none

• Aminopenicillins/Broad Spectrum: active against both gram+ and gram- because it gets into gram- through porin channels

  • Amoxicillin and Ampicillin

• Anti-pseudomonas

  • Ticarcillin and Piperacillin

• Combinations:

  • Augmentin: Amoxicillin + Clavulanic Acid (β-lactamase inhibitor)

  • Ampicillin + Sulbactam (β-lactamase inhibitor)

  • Piperacillin + Tazobactam (β-lactamase inhibitor)

  • Ceftazidime + Avibactam (β-lactamase inhibitor)

Explain modes of resistance through PBPs

Mutations in PBP genes result in resistance

• MRSA: results from PBP 2A mutation that has less affinity to β-lactam ring on methycillin, all penicillins and almost all cephalosporins except Ceftaroline

Cephalosporins

• Structure

• MOA

• Produced from what organism

• Generations and how they are different

• Structurally similar to penicillin but ring is 6-membered

• Like penicillin, blocks final cross-linking step

• Produced by fungi

• Adverse reactions:

  • Super strong so superinfections and renal toxicity has been reported

  • Hypersensitivity just like Penicillin

• Generations:

  • 1st Gen (CEF/PH/A): Against gram+, but mostly strep and staph (not MRSA)

    • Cefazolin (injectable) and Cephalexin (oral)

  • 2nd Gen (CEFO): gen1 and gram - anaerobes

    • Cefotetan and Cefoxitin

    • No pseudomona/ MRSA/ Enterococcus coverage

  • 3rd Gen (CEFT): gen2 + pseudomonas coverage

    • Ceftazidime and Ceftriaxone (meningitis cause crosses BBB)

    • No MRSA or Enterococcus coverage

  • 4th Gen (CEFI): same as 3 but more effective for pseudomonas

    • Cefipime

  • 5th Gen (CEFTA): only one that targets MRSA

    • Ceftaroline

Carbapanems (-PENEM)

• Structure

• Derived from

• Against what

• Adverse reactions

• Related to penicillin’s and cephalosporins, have β-lactam ring

• Compound of bacterial origin

• Increased effectiveness against gram - bacteria and increased effectiveness against most β-lactamases

  • Reserved for life-threatening diseases with resistance

• Names:

  • Imipenem (prototype) + Cilastatin (Renal dehydropeptidase inhibitor /DHPI)

  • Also Meropenem, Doreipenem, Ertapenem → These do not require a DHPI

• Adverse effects:

  • Renal disease requires decreasing dose due to decreased renal clearance

  • Toxicity leads to CNS toxicity (seizures in elderly)

  • Can only be prescribed by

Monobactam (AM)

• Structure

• Against what

• Adverse reactions

• Name

• Structure: Monocyclic β-lactam

• Narrow Spectrum: Similar to 3rd gen cephalosporins including pseudomonas, but not gram + and anaerobes

  • Highly resistant to β-lactamases

• Adverse effects: Superinfections and GI disturbances

• Aztreonam: used when pt can’t tolerate aminoglycosides due to renal insufficiency and when resistant to 3rd gen cephalosporins

Bacitracin

• Structure

• MOA

• Against

• Adverse effects

• Structure: cyclic peptide

• MOA: Inhibits bacterial cell wall formation

• Against gram + bacteria and mostly used as a topical ointment, derm or ophthalmic

• Adverse effects:

  • Poor absorption

  • Excretion by glomerular filtration

  • IM use discontinued due to toxicity

Vancomycin

• Structure

• MOA

• Against

• Resistance

• Adverse effects

• Structure: glycopeptide, acid labile and hydrophilic (IV use only)

• MOA: Hydrogen bonds to D-ala and prevents transpeptidase from binding and cross linking of NAM-NAG units

  • Bypasses PBP2 mutations so it can kill MRSA

    

  • Also blocks trans-glycosylase mediated polymerization

• Against:

  • Narrow spectrum: gram + bacteria including MSSA and MRSA; too large to kill gram -

  • Drug of choice for: MRSA, endocarditis, sepsis, pneumonia, osteomyelitis and cellulitis

• Resistance:

  • Vancomycin Intermediate S. aureus (VISA) and Vancomycin Resistance S. aureus (VRSA)

  • Vancomycin Resistant Enterococcus (VRE): substitutes D-ala with D-lactate so vancomycin cannot block cross-linking

• Adverse effects

  • Renal elimination dependent on creatinine clearance

  • Red man syndrome: pseudo-allergy due to rapid IV infusion

  • Nephrotoxicity and ototoxicity

Daptomycin

• Structure

• MOA

• Against

• Resistance

• Adverse effects

• Structure: cyclic peptide

• MOA: Depolarizes bacterial cell membrane by binding Ca2+ and causes ion leakage, leading to cell death (NOT LYSIS)

  

• Against: Gram +, MRSA, VRSA, VISA, VRE

  • Same use as vancomycin: skin, eye, osteomyelitis, bacteremia, sepsis, endocarditis

• Resistance: bacteria find a way to reset membrane potential

• Adverse effects:

  • Don’t use for pneumonia: Inactivated by lung surfactants

  • Myopathies and rhabdomyolysis:

    • Stop taking statins at the same time because risk for myopathy increases

Fosfomycin

• Structure

• MOA

• Against

• Structure: phosphoenolpyruvate analog

• MOA: Inhibits transferase in early stage of bacterial cell wall synthesis

• Against both gram + and negative

  • Synergistic with β-lactams, aminoglycosides and fluoroquinones

  • Use for UTI’s, one dose for females and 9-21 Sundays for males

Cycloserine

• Structure

• MOA

• Against

• Adverse effects

• Structure: structural analog of D-ala

• MOA: transpeptidase binds it instead of D-ala, prevents cross-linking

• Against both gram + and - bacteria

  • Only used as a second-line treatment for treatment of tuberculosis resistant to first-line agents

  • Administered orally, can enter CSF

• Adverse effects: Dose-related CNS toxicity and peripheral neuropathies

Polymyxin B

• Structure

• MOA

• Against

• Adverse effects

• Combinations

• Structure: group of cationic basic peptides

• MOA: Imitates cationic detergents and disrupts cell membrane, causing leakage

  • Similar MOA to Daptomycin

• Against only gram - bacteria

• Adverse effects:

  • Only B polymyxin is available in the USA

  • Restricted for topical use only

• Combinations:

  • Polymyxin B + Trimethoprim = for both gram - and gram +

  • Polymyxin B + Hydrocortisone

Triple antibiotic has what 3 drugs

Neomycin, Bacitracin and Polymyxin B