Antimicrobials 3 Flashcards
tetracyclines mainly used to treat infections with what type of bacteria?
Used mainly to treat infections caused by atypical bacteria in all species
Also effective for many common bacterial infections of livestock
tetracyclines mechanism of action
- Bind to bacterial ribosomes
> inhibit protein synthesis - Bacteriostatic
tetracyclines spectrum of activity?
Small animals:
1st choice for atypicals
Livestock:
Effective against many/some common G+ & G- aerobic & anaerobic pathogens, as well as atypical bacteria
pharmacokinetics of tetracyclines: absorption
Absorption:
* Oral bioavailability varies with drug & species but tends to be low
* Doxycycline has better oral bioavailability than most other
tetracyclines
* Divalent cations in food (e.g., calcium in milk, cheese) can markedly inhibit oral absorption
pharmacokinetics of tetracyclines: distribution
- Most distribute well to the extracellular fluid compartment, except the CNS
- Distribution into cells depends on lipid solubility; doxycycline is the most lipid sol.
> enters host cells well, including prostate & CNS
Tetracyclines bind to multivalent cations such as calcium, and become incorporated into growing bone and teeth
>A food animal residue concern
Pharmacokinetics of tetracycline – Distribution
Tetracyclines bind to multivalent cations such as calcium, and become incorporated into growing bone and teeth
>A food animal residue concern
Pharmacokinetics of tetracycline – Elimination
Most tetracyclines are excreted primarily by glomerular filtration into the urine
Biliary & non-biliary excretion into the intestinal lumen also occurs to an extent depending on lipid solubility of drug
> mainly doxycycline, which is much more lipid soluble than most other tetracyclines and is eliminated almost entirely through the intestinal tract into feces
Enterohepatic recycling can extend drug elimination half life
Pharmacokinetics of tetracycline – Elimination
Most tetracyclines are excreted primarily by glomerular filtration into the urine
Biliary & non-biliary excretion into the intestinal lumen also occurs to an extent depending on lipid solubility of drug
> mainly doxycycline, which is much more lipid soluble than most other tetracyclines and is eliminated almost entirely through the intestinal tract into feces
Enterohepatic recycling can extend drug elimination half life
tetracycline resistance profile and machanisms for resistance
Resistance is widespread
Two main acquired (i.e., plasmid-encoded) mechanisms:
1. Efflux pump
* Removes drug from bacterial cell
* Efflux pump may be overwhelmed by high drug concentration
> explains improved efficacy with topical application in some situations
2. Ribosomal protection protein
- inhibits binding of tetracycline
Adverse effects of tetracyclines:
1) Incorporation into growing teeth & bones
>Discoloration of growing teeth
2) Renal tubular damage
>Use of expired (outdated) drug; administration to dehydrated patients (may be fatal); administration of high dosages
3) Tissue irritation
4) Esophageal lesions from doxycycline in cats
>Broken tablets or undissolved capsules can cause significant esophageal lesions & strictures in cats
Adverse effects of tetracyclines:
1) Incorporation into growing teeth & bones
>Discoloration of growing teeth
2) Renal tubular damage
>Use of expired (outdated) drug; administration to dehydrated patients (may be fatal); administration of high dosages
3) Tissue irritation
4) Esophageal lesions from doxycycline in cats
>Broken tablets or undissolved capsules can cause significant esophageal lesions & strictures in cats
Tetracyclines Flash Card: mechanism of action
Inhibition of protein synthesis (bacteriostatic effect)
Tetracyclines Flash Card: main adverse effects
- Incorporation into growing teeth & long bones
- Nephrotoxicity in dehydrated patients
- Tissue irritation (pain on injection; vomiting oral dose)
- Risk of esophageal damage in cats
- Etc.
Tetracyclines Flash Card: general spectrum
- All species: Atypical bacteria (usually drug of choice)
- Livestock: Broad Spectrum
Tetracyclines Flash Card: health canada prudent use stats
first line
Tetracyclines Flash Card: PK features
Lipid-soluble tetracyclines (e.g., doxycycline) are useful against intracellular pathogens
are sulfonamides very effective alone? why?
Resistance to sulfonamides is now widespread among pathogens of small animals and humans
> largely ineffective when used alone
What are Potentiated sulfonamides? when are they used?
- Effectiveness of the sulfonamide (S) is restored when combined with ‘diaminopyrimidine inhibitors’ such as trimethoprim (TM)
- TMS combinations are widely used in large animal medicine
- Important off-label option for exotic animals
sulfonamides mechanism of action
Folic acid (vitamin B9) is required for DNA, RNA, & protein synthesis
* Mammals acquire all they need from the diet
* Bacteria must synthesize it from PABA
Sulfonamides and trimethoprim inhibit different steps in the bacterial folic acid synthesis pathway:
Sulfonamides
>Resemble PABA
>Competitively inhibit dihydropteroate synthetase
Trimethoprim
>competitively inhibits dihydrofolate reductase
Note: Pus contains huge amounts of PABA, so sulfonamides are ineffective in the presence of pus
sulfonamides spectrum of activity
Small animals: atypical bacteria
Livestock: atypical bacteria, and some broad spectrum effect besides (Effective against many common G+ & G- aerobic & anaerobic pathogens)
Extremely broad spectrum when first marketed (all
bacteria, even some protozoa), but rapid selection for resistance occurred within the first decade of use
Used clinically like tetracyclines:
* Small animals
>Most pathogens are resistant except atypical bacteria, many of which are sensitive
- Livestock
A variety of common pathogens are sensitive
> important 1st-line option - Also used increasingly in humans & small animals for sporadic bacterial cystitis where high concentration of drug in urine overwhelms resistance mechanisms
- Used for bacterial prostatitis due to distribution
pharmacokinetics of sulfonamides
Absorption & Distribution:
* Good oral absorption
* Distribute well to all tissues
* Tissue debris & pus provide PABA > substrate out-competes sulfonamide > reduced efficacy of this class of drugs in presence of pus
Elimination:
* A combination of renal excretion and hepatic metabolism
* Metabolites can accumulate in renal tubules
> renal damage; can be severe in dehydrated patients
sulfonamide resistance profile and mechanisms
- Common among small animal & human pathogens
- Relatively uncommon among livestock pathogens
Bacteria can acquire a plasmid-encoded version of dihydropteroate synthetase that binds PABA better than sulfonamides
Bacteria can also acquire a plasmid-encoded dihydrofolate reductase that does not bind trimethoprim well
The likelihood of a bacterium acquiring modified versions of both enzymes is lower, which is why potentiated sulfonamides are so much more effective than either a sulfa or TM alone
sulfonamides adverse effects
Usually due to the sulfonamide rather than TM
- More allergenic than most drugs (contact dermatitis > not used topically)
- KCS (keratoconjunctivitis sicca or “dry eye”) in dogs
-Sulfas are “lacrimotoxic” in dogs - Nephrotoxicity: precipitation in renal tubules in dehydrated patients > can cause renal failure
TMS Flash Card: mechanism of action
Inhibition of folic acid synthesis
TMS Flash Card: main adverse effects
- Lacrimotoxicity in dogs (KCS)
- Nephrotoxicity in dehydrated patients
- Hypersensitivity (including contact dermatitis)
TMS flash card: general spectrum
- All species: Atypical bacteria, UTIs
- Livestock: Fairly broad spectrum
TMS flash card: health canada prudent use stats
First-line
TMS flash card: PK features
Ineffective in presence of pus
Distribute to all tissues
