Beta Lactams & Vancomycin Flashcards
What is the structural difference of gram +ve and gram -ve bacteria?
Gram +ve: (stained blue-black)
1. Thick peptidoglycan & lipoteichoic layer
2. Lacks outer membrane
Gram -ve: (stained pink red)
1. Thin peptidoglycan layer
2. LPS in outer membrane (lipopolysaccharide)
Name the 2 broad types of cell wall synthesis inhibitors.
- Beta-lactams
- Glycopeptides - aka vancomycins
Name the 4 categories of beta lactams.
- Penicillin
- Cephalosporin/Cephamycins
- Carbapenems
- Monobactam
When should antibiotics be administered?
In presence of:
- acute, severe, rapidly spreading infection
No need in case of:
- mild, localised infection in which drainage can be established
What are β-lactam antibiotics?
β-lactam antibiotics consist of the 4-membered β-lactam ring
- fused to either 5 / 6 membered ring via single/double bond
- if fused to nothing => monobactam
MOA of beta-lactams.
TLDR: inhibits cross-linking, aka interferes w transpeptidation
- In cell, transpeptidase catalyses the cross-linking of terminal peptidoglycan proteins in linear polymer chains for cell wall synthesis
- β-lactam ring binds to active site of transpeptidase => prevents cross-linking
- Cell wall weakened => lysis when intracellular pressure increases above surrounding osmotic pressure (in actively growing cell)
Key! If bacteria is static & not actively growing, then the beta lactam doesnt rly have much to interfere w, not as effective
Name the 4 classes of Penicillins.
- Natural Penicillins
- Penicillinase resistant penicillins
- Aminopenicillins (Broad Spectrum) + BL inhibitors
- Anti Pseudomonal penicillins (extended spectrum) + BL inhibitors
NPAA
Name the 2 types of Natural Penicillins & their differences.
- Penicillin G
- low oral bioavailability
- administered parentally (IV or IM) - Penicillin V
- better oral bioavailability than G, cuz more acid stable
Limitation of Natural Penicillin.
- Only useful against bacteria that do not produce β-lactamase!! => thus, useless against most staphs
- β-lactamase/penicillinase will cleave the β-lactam ring and render the antibiotic useless - Not useful against amoebae, plasmodia, fungi or viruses
What is Natural Penicillin useful against?
Useful against β-lactamase negative strains such as:
1. Gram +ve microbes
E.g. streptococci, bacillus diphtheriae
2. Some Gram -ve microbes
E.g. meningococci, gonococci
3. Obligate anaerobes eg. Clostridum spp
Only on non β-lactamase producing bacteria
How is Natural Penicillin excreted?
Renal clearance, excreted in urine
Why is there a need for Penicillinase-resistant penicillins?
They cover penicillinase producing staphylococci, which natural penicillins are helpless against.
(Rmb the beta-lactamases that staphs produce)
How is Penicillinase-resistant penicillin cleared & excreted
Renal clearance, excreted through urine
What is the short coming of penicinillase-resistant penicillin?
Narrow cover antibiotics
- only covers gram +ve bacteria
- no coverage against gram -ves
+
Does not achieve therapeutic levels as it has limited penetration into CSF
What was the 1st gen penicillinase-resistant penicillin and its significance?
Methicillin.
Where MRSA gets its name from. Methicillin-resistant staphylococcus aureus.
- MRSA are staphylococci strain that modified its transpeptidase enzymes such that they have a low affinity to the β-lactam ring
- so transpeptidase in MRSA is not easily inhibited
Why are Penicillinase-resistant penicillins more resistant to penicillinase?
Presence of bulky side chain!
- protects the beta-lactam ring from beta-lactamase
- by limiting their accessibility to the catalytic site of action
Name the commonly used penicillinase-resistant penicillins used today.
- Cloxacillin
- Oxacillin
- Flucloxacillin
- Methicillin (1st gen that is not longer used)
Why are Aminopenicillins and what is their importance?
- Broad Spectrum penicillins
- covers both gram +ve & gram -ve
- (non β-lactamase prducing) - Acid stable => available both orally & via IV
- Commonly used in many diff types of dental infections (cuz of oral admin + broad spec)
- prophylaxis against infective endocarditis
- against aggressive periodotitis
- dental abscesses
Name 2 aminopenicillins.
- Ampicillin (acid stable, available orally & IV)
- Amoxicillin (better oral absorption than ampicillin, IV)
Limitations of aminopenicillins.
Does not cover:
1. Bacteria that produce beta-lactamase
2. Pseudomonas or Klebsiella
How are aminopenicillins cleared & excreted?
Renal clearance, excreted via urine
- dose adjustment needed in pxs w renal dysfunction
Why are aminopenicillins not only effective against gram +ve bacteria, but also against gram -ve bacteria? (MOA)
- additional hydrophilic group allows penetration into gram -ve bacteria via porins
What is commonly administered w aminopenicillins?
β-lactamase inhibitors!
- addition of β-lactamase inhibitor can extend the spectrum of use to β-lactamase producing strains
E.g. Augmentin = Amoxicillin (aminopenicillin) + Clavulanic acid (β-lactamase inhibitor)
Name the most notorious hospital acquired infections.
Klebsiella & Pseudomonas
- gram -ve bacterias
Name a Anti Pseudomonal Penicillin. How is it administered?
Piperacillin. Administered only via IV
How are Anti-Pseudomonal Penicillins cleared and excreted?
Primarily renal clearance, excreted via urine.
- dose adjustment needed in px w renal dysfunction
Piperacillin is commonly given w _________. Why?
Tazobactam. (β-lactamase inhibitor)
- cuz piperacillin is susceptible to inactivation by bacterial β-lactamase pdn
What is the significance of Anti-Pseudomonas Pencillins?
TLDR: widest coverage (covers pseudomonas & klebsiella & both grams) + wide anaerobic coverage
- has greatest activity against Pseudomonas & Klebsiella: gram -ve bacteria
What are β-lactamase inhibitors?
TLDR: binds irreversibly to β-lactamases, protecting other β-lactam antibiotics from being targeted by β-lactamases
Also: has very weak anti-bacterial properties
Name the 3 common β-lactamase inhibitors
- Clavulanic acid
- Tazobactam
- Sulbactam
Name the 3 common β-lactamase combination drugs.
- Augmentin = amoxicillin + clavulanic acid
- Unasyn = ampicillin + sulbactam
- Zosyn = Piperacillin + Tazobactam
All can administered via IV, additionally, augmentin can be orally administered.
Which penicillin classes are commonly administered w beta-lactamase inhibitors?
Ans: aminopenicillins & anti-pseudomonal penicillins
Not natural penicillins & not penicillinas resistant penicillins (these alr r efficient against beta-lactamase pdc bacteria)
What are the mechanisms of resistance to penicillin?
- Transpeptidase altered, reduced affiinity for the penicillins
- Pdn of β-lactamase, hydrolyses β-lactam ring
- Bacteria decreases porin pdn => decrease in intracellular drug conc
- Presence of efflux pumps
What are the 6 common adverse reactions to penicillin?
- Allergy/Hypersensitivity
- Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) - CDAD: clostridium difficile-associated diarrhoea
- due to ampicillin/augmentin - Neurotoxicity
- due to high dose & renal dysfunction - Hepatotoxicity
- Anosmia
- Seizures, in px w renal failure
List the 6 possible common adverse effects of penicillin.
- Allergy/hypersensitivity
- stevens johnson syndrome(SJS) & toxic epidermal necrolysis(TEN) - CDAD: clostridium difficile-associated diarrhoea
- Neurotoxicity
- Hepatoxicity
- Anosmia
- Seizures, in px w renal impairment
What are some drug drug interactions of penicillin?
- Penicillins/cephalosporins + anti-coagulants (e.g. warfarin) => increased risk of bleeding
- Probenecid inhibit tubular secretion of penicillin (esp amoxicillin) => delays excretion
Which 1st gen Cephalosporin is administered via IV?
Cefazolin
- rest are administered orally
How are Cephalosporins administered?
1-2 gen: mostly orally (except cefazolin)
3 gen onwards: IV/IM
3rd gen cephalosprins and below are..
- more resistant to beta lactamases
- have better CSF distribution
- better activity against anaerobes
What is special about Cefotaxime?
3rd gen cephalosporin that covers pseudomonas, enterobacteriaceae, neisseria gonorrhea
What is special about Cefepime?
4th gen Cephalosporin, covers pseudomonas
What is special about Ceftaroline
5th gen Cephalosporin. covers MRSA
Name the Cephalosporins that are 3rd gen and above.
3rd gens: cefotaxime, ceftazidime, ceftriaxone
4th gen: cefepime
5th gen: ceftaroline
What is Ceftriaxone?
- 3rd gen cephalosporin
- used in pxs w renal impairment, since its the only cephalosporin that is excreted hepatically
Adverse effects of Cephalosporins?
- Cross-hypersensitivity w penicillins
- Thrombophlebitis (increased risk of blood clot formation) /increased bleeding
- GIT: CDAD
Carbapenems are the first line agent against..
- ESBLs. Extended spectrum beta-lactamase producing gram neg bacteria
- good coverage against anaerobic bacteria too
How are Carbapenems administrated?
IV.
Name the 3 Carbapenem drugs
- Imipenem & Cilastatin (Tienam)
- Meropenem
- Ertapenem
What is Cilastatin?
DHP1 inhibitor => so that more Imipenem avail
- cuz Imipenem is rapidly hydrolyzed by DHP1 found in the brush border of proximal renal tubule
*not a beta-lactamase inhibitor!!
Name the Carbapenems that are stable against hydrolysis by DHP1
Meropenem & Ertapenem.
- Imipenem is quickly hydrolysed in proximal renal tubule, thus, administered w Cilastatin to recover more of the active form
How are Carbapenems cleared and excreted?
Renal clearance, excreted in urine
Do Carbapenems cover Pseudomonas?
Imipenem and Meropenem have coverage against Psuedomonas.
Ertapenem NO COVERAGE against pseudomonas aeroginosa & enterococcus spp
Briefly list the adverse effects of carbapenems.
- GIT-related symptoms
- nausea, vomiting (occurs more w Tienam) - Rashes
- Neurotoxicity
- Cross-hypersensitivity w penicillin
Monobactam acts against..
- Gram neg bacteria & 2. β-lactamase producing gram neg bacteria
* no activity against +ves & anaerobes
E.g.
- enterobacteriaceae
- Pseudomonas
- klebsiella
- E. Coli
Name the only Monobactam.
Aztreonam
Monobactams have no activity against..
Gram positive bacteria & anaerobes
Administration of Aztreonam.
IM/IV
- penetrates BBB in inflamed meninges
Adverse effects of Aztreonam
- generally well tolerated
- occasional skin rashes
- little or no cross-sensitivity w penicillins
Aztreonam is cleared and excreted via
Renal clearance, excreted in urine
- dose reduction req in renal impairment pxs
What does Vancomycin target to prevent cell wall synthesis (MOA)
- targets transglycosylases
- unlike beta lactams that target transpeptidases
What are Vancomycins used against (coverage)
Effective only against gram +ves.
- staph aureus (both MSSA & MRSA)
- Streptococci (both penicillin resistant & sensitive strains)
- Clostridium spp (administered orally)
- Enterococcus
- Bacillus spp
Administration of Vancomycin.
IV for systemic treatment
Oral for CDAD or more severe AAPMC (antibiotic-associated pseudo-membranous colitis)
Vancomycin is cleared and excreted via..
Renal clearance, excreted via urine
- dose adjustment in px w renal impairment
What bacterial species are resistant to Vancomycin?
Gram neg bacilli & mycobacteria
Briefly list the adverse reactions of taking Vancomycin.
- Red man syndrome
- occurs when Vancomycin is administered too quickly
- due to histamine release in the face & upper torso - Nephro & Oto toxicity
- esp if px has renal impairment
- similar to aminoglycosides - Thrombophlebitis w fever & chills
- Cat C for pregnancy in parenteral formulations
Name 2 instances of Vancomycin resistance
- Enterococcal resistance (VRE)
- S. Aureus => reduced/intermediate susceptibility (VRSA)
- major concern as it is until recently where vancomycin was the only AB that staph was reliably susceptible
