Glycopeptide Antibiotics, Polymixins, Gramicidins, Nitroimidazoles

Question 1

Glycopeptide ABs

Mechanism of Action
Resistance
Spectrum

Answer 1

MoA
Inhibition of cell wall cross linkage
Recognition and binding (drug resembles enzyme) to D
Alanine residues on end of peptide chain–> prevention
of transpeptidase action

Resistance
C Terminal of D Alanine residue replaced by D Lactate
or D Serine–> AB can no longer recognise and bind

Cell wall thickening–> increased # binding sites–> drug
sequestered in cell wall

Spectrum
Aerobic and anaerobic bacteria; MRSA included
Not effective against G- as ABs are large polycations–>
can’t diffuse across outer membrane of G-s

Question 2

Glycopeptide ABs

Pharmacokinetics
SE
Uses

Answer 2

Large molecules–> not absorbed orally. Parenteral
Distribution mostly in EC space
Can enter CNS when inflammation +
Eliminated renally

SE
Red Man Syndrome (Vancomycin): direct histamine
release from mast cells. Can also be seen with
opiates and curare

Nephro and Ototoxic esp long term–> monitoring of
plasma levels recommended

Uses
   Osteomyelitis 
   MRSA Infections
   Endocarditis
   Meningitis
   2nd choice for C. Difficile

Question 3

Glycopeptide ABs

Drug Names and Characteristics

Answer 3

Vancomycin
T1/2: 6 hrs
More tissue tociv than teicoplanin

Teicoplanin
Mixture of 6 related compounds
Stronger PPB–> longer T1/2

Question 4

Lipoglycopeptides

MoA
Indications
Drug Names

Answer 4

MoA
Inhibit peptidoglycan synthesis; increase permeability
via damaging bacterial cell membrane

Indications
Multiresistant G+ skin and soft tissue infections

Drugs
Telavancin
Oritavancin: T1/2: 16 days–> single dose sufficient

Question 5

Lipopeptides

MoA
Spectum
SE

Answer 5

Integrates into cell membrane and dimerises–> channel formation–> depolarisation and K efflux.

In humans equilibrium potential of the cell is that of K. In bacteria equilibrium potential of K would severely depolarise the cell–> ‘selective toxicity’

Spectrum
G+ incl vancomycin resistant strains

SE
Damages sarcolemmas (like statins and fibrins)–>
monitor CK

Question 6

Lipopeptides

Pharmacokinetics
Indications
Drug Name

Answer 6

Not absorbed orally
Renal elimination

Multiresistant G+ infections
Do not use in pneumonia as surfactant inactivates drug

Daptomycin

Question 7

Polymixins

MoA
Resistance
Spectrum

Answer 7

Are polypeptide ABs

MoA
Are surface active amphipathic agents; act as cationic
detergents; have strong interaction with
phospholipids–> damage/ dissolve plasma membrane

Also bind and inactivate lipopolysaccharide (endotoxin)

Resistance
Rare as drugs not freq used due to their SEs

Spectrum
Only G- bacteria
(Wall of G+s too thick to allow access to cell membrane)

Question 8

Polymixins

Pharmacokinetics
SE
Indications

Answer 8

Not absorbed orally
Excreted renally

SE
Neurotoxic (solubilise lipids from axonal membrane)
Nephrotoxic (solubilise lipids from renal tubules)
–> don’t give with other nephrotoxic drugs such as:
Aminoglycosides, cyclosporin, NSAIDs, ACE Inhib

Indications
Topically: Ophthalmic, otic, skin infections
Inhaled for CF and pneumonia
Hail mary for severe MDR G- systemic infections

Question 9

Polymixins

Drug Names

Answer 9

Polymixin B
B referring to micture of polymyxin B1 and B2

Polymixin E

Question 10

Gramicidine

Answer 10

Polypeptide ABs composed of alternating L and D AAs.
Alteration is vital for formation of beta helix

MoA
Chain assembles into beta helix inside hydrophobic
interior of cell lipid bilayer

Dimerises to form elongated channel–> Disruption of
Na and pH

Spectrum
Mainly against G+

SE
Haemolysis therefore not used systemically

Indication
Topically as eye/ear drops

Question 11

Nitroimidazoles

Mechanism of Action
Mechanisms of Resistance

Answer 11

MoA
Prodrug undergoes non enzymatic reduction by
ferredoxin

Reactive metabolite covalently binds to DNA and
proteins. Attack of anaerobic energy producing mech
of bacteria and protozoa

MoR: Resistance common in bacteria. Not as much in
protozoa as would require mutation in both alleles

Low ferrodoxin levels
Reduced O2 scavenging–> O2 reduced rather than
drug
NADPH dep reduction: NO2–> NH2

Question 12

Nitroimidazoles

Spectrum
Pharmacokinetics
SE

Answer 12

Spectrum
Anaerobic bacteria: Clostridium, bacterioids
Microaerophilic protozoa: Entamoeba, Trichomonas
Microaerophilic bacteria: Ex H. Pylori

Pharmacokinetics
Good oral absorption; good distribution even into
bones, abscesses, can cross BBB

SE
Inhibit aldehyde dehydrogenase–> disulfiram like
Headache
Metallic taste, dry mouth
Potentiate coumarin like effect; inhibit enzyme

Question 13

Nitroimidazoles

Indications
Drug Names

Answer 13

Anaerobic Infections ex abscesses
1st choice for pseudomembranous colitis
Trichomonas vaginalis
Giardiasis
H. Pylori erradication

Metranidizole
Tinidazole