10. Inhibitors of Cell Wall Synthesis Flashcards
What are four inhibitors of cell wall synthesis drugs?
Penicillins
Cephalosporins
Vancomycin
Bacitracin
Who discovered penicillin? When?
Alexander Fleming in 1928
What was the mold Fleming used to fiht bacteria and agaist which bacteria?
Penicillium notalum was isolated to fight staphylococci
What is penicillin’s mechanism of action?
- Bactericidal
- Interferes with last step (transpeptidase) of bacterial cell wall synthesis, causing cell lysis
What kind of bacteria is penicillin effective against?
Rapidly growing organisms that synthesize peptidoglycan cell wall
Describe the two major steps of peptidoglycan cell wall synthesis
- Synthesis of peptidoglycan in single chains
- occurs in cytoplasmic side of cell membrane
- Polymerization and cross linking of single chain peptidoglycan
- polymerization occurs at cell surface
- transpeptidase used in this step to polymerize single units
What are the components of penicillin’s basic structure?
- Thiazolidine ring
- beta-Lactam ring
- Side chain (R group)
- R group variation results in different penicillins
What confers bacterial resistance against penicillin?
- Contain beta-penicillinase or acid that cleaves beta-lactam ring
- hydrolyzes cyclic amide bond of beta-lactam ring
- usually acquired by transfer of plasmids R
- Decreased permeability to drug
- Altered penicillin binding proteins (PBP)
- PBPs are enzymes involved in forming cross linkages between peptidoglycans
What is the antibacterial spectrum of penicillins?
- Natural penicillins
- Extended spectrum penicillins
- Antistaphylococcal penicillins
- Antipseudomonal penicillins
What are two examples of natural penicillins?
Penicillin G
Penicillin V
What are two examples of extended spectrum penicillins?
Ampicillin
Amoxicillin
What are two examples of antipseudomonal spectrum penicillins
Carbenicillin
Ticarcillin
What is the function of beta-lactamase inhibitors?
Allows penicillin efficacy in drugs that have developed penicillin resistance via B-lactamase
What are two beta-lactamase inhibitors?
Clauvulanic acid (product of Steptomyces clavuligerus)
Sulbactam
What is the mechanism of becta-lactamase inhibitors?
Irreversibly binds beta-Lactamase and inactivates them
What are 3 formulations of beta-lactamase inhibitors?
Augmentin
Timentin
Unasyn
Components of augmentin
amoxicillin + clavulanic acid
Components of timentin
ticarillin + clavulanic acid
Components of unasyn
ampicillin + sulbactam
How do beta-lactamase inhibitors effect the efficacy of penicillins?
Improves efficacy
How are penicillins administered?
Oral
IV
IM
Which penicillin is absorbed very well?
Amoxicillin
Which penicillins are difficult to absorb?
Pen G and Ampicillin bc their absorption are impeded by food
Can Pen cross the placenta?
Yes
Does Pen hihgly penetrate the bone and CSF?
NO, minimal penetration
How does kinetics of IM administration of Pen compare ot kinetics of orally administered Pen?
Reach very high blood levels in comparison to oral
Is Pen highly metabolized?
No, minimally
How is Pen excreted?
Kidney
What drug if taken with Pen can inhibit Pen excretion?
Probenecid inhibits Pen excretion
Probenecid treat gouty arthritis
What are adverse reactions of Pen?
- Hypersensitivity
- Diarrhea
- Nephritis
- Neurotoxicity
- PLT dysfunction
- Cation toxicity
How does Pen cause hypersensitivity?
- Penicilloic acid isa hapten for immune rxn
- Urticaria/angioedema to anaphylaxis
- beta-lactam cross reactivity
How does Pen cause diarrhea?
disrupt normla flora composition
How does cation toxicity arise in Pen use?
- K+ and Na+ levels are augmented bc of disruption of their retention
- disruption of Na and K levels result in cardiac side effects
What occurs in acute allergic reactions (< 30mins) to Pen?
- Urticaria
- Angioedema
- Bronchoconstriction
- Shock
What occurs in accelerated (30 mins - 48 hrs) allergic reactions from Pen?
Urticaria
Pruritis
Wheezing
Mild laryngeal edema
Local inflammatory rxns
What occurs in delayed (< 2 days) allergic rxns to Pen?
Skin Rash
Oral glossitis
Furred tongue
Black and brown tongue
Cheilosis
Severe stomatitis with loss of buccal mucosa
Tx for mild allergic rxn to Pen
Benadryl 25-50 mg IV/IM/PO
Tx for severe allergic rxn to Pen
Epinephrine .03-.05 mg
How to determine if pt has allergy to Pen?
Skin test with benzylpenicilloyl-polylysine
What is the dental use of Pen V?
Most frequently used for infection of dental origin
What is the dental use of amoxicillin?
Superior pharmacokinetics
Periodontal infectoin associated with Gram + or Gram - aerobic and anaerobic microorganisms
What is the dental use of Pen G (parenteral)?
Reserved for severe infections
Pharmacokinetics of Pen:
A: ?
D: ?
M: ?
E: ?
A: Oral and parenteral
D: Variable; No CNS entry except with meningitis
M: Minimal
E: Filtratation and excretion: short half life (1-2 hrs)
How was Cephalosporins discovered?
Cephalosporium acremonium was first isolated in 1948 from sea near sewer outlet off Sardinian coast
How does Cephalosporin structure compare to Pen?
Very similar in structure and function but have a dihydrothiazine ring instead of a thiazdolidine ring
How does Cephalosporin resistance to beta-lactamase compare to Pen?
More resistant to beta-lactamase but still susceptible
How are semi-synthetic cephalosporins synthesized?
Synthesized by adding different chemical groups at R1 and R2 to make different varieties of cephalosporins
How have subsequent generations of cephalosporin changed in comparison to previous generations?
Subsequent generations has increased Gram - bacterial susceptibility, increased beta-lactamase resistance and decreased efficacy against Gram +
What are the 3 categories of cephalosporins antibacterial spectrum?
1st generation
2nd genertaion
3rd genertaion
What are the two first genertaion cephalosporins drug and their use?
Cefazolin
Cephalexin
Used for endocarditis
What are two 2nd genertaion cephalosporin drugs?
Cefaclor
Cefoxitin
What is a 3rd genertaion cephalosporin drug and its use?
Ceftriaxone
Used for endocarditis
How has the CNS penetration trend changed with each subsequent cephalosporin generation?
Increased CNS penetration
How is cefazolin administered?
Parenteral
How is Cephalexin administered?
Oral
how od cephalosporins distribute in the body?
Distribute well thorug body fluids
Only 3rd generation Cephalosporins distribute well into the CSF
How are cephalosporins excreted?
Renal elimination
Which cephalosporins are not excreted renally? How are they elminated?
Cefoperazone & Ceftriaxone
Exreted through bile and feces
What is the limitation in the dental use of Cephalosporins?
Good activity against many orofacial pathogen but limited agfainst oral anaerobes
What cephalosporins drugs are used against odontogenic infections? Administration?
Orally active first or second generation Cephalosporins
Which Cephalosporin drugs are used for bacterial endocarditis prophylaxis?
Cephalexin
Cefazolin
What are the adverse effects of Cephalosporins?
Allergy
Disulfram-like effect
Bleeding
Renal, hepatic dysfunction
What is the rate of allergy cross sensitivity b/t cephalosporins and Pen?
15%
What is cephalosporins disulfram like effect?
When taken with alcohol, will cause aldehyde accumulation
Results in respiratory difficulty, nausea and HTN
Why do Cephalosporins cause bleeding?
Anti-Vit K effect
Cephalosporins Pharmacokinetics Summary
- A: ?
- D: ?
- M: ?
- E: ?
- T: ?
- A: Oral and parenteral
- D: Wide; 3rd gen penetrates into CSF
- M: Not extnesively
- E: Renal filtration; 3rd gen by bile/feces
- T: Relatively non-toxic (like Pens);
- Hypersensitivity leads to proximal renal tubular necrosis
- Disulfram like toxicity
