Pharmacology antimicrobials Flashcards
Minimum Inhibitory Concentration (MIC)
The lowest concentration of drug that inhibits visible bacterial growth
MIC90: concentration for inhibiting 90% of the bacteria
Minimum Bactericidal Concentration (MBC)
The lowest concentration of a drug that kills 99.9% of bacteria
Mutant Prevention Concentration (MPC)
The concentration to kill the least susceptible single-step mutant
In theory, kills them all so mutants (ie resistant bacteria) can’t form
bacteriostatic
Stop bacteria from multiplying; don’t kill them
* MBC much larger than the MIC (not always able to reach MBC)
Elimination of infection requires host immune response
* Requires an immunocompetent patient
Not as good for
* Sepsis
* Neonates
* Animals on glucocorticoids
* Animals on cancer chemotherapy
* (anything with not great immune system)
bactericidal
Kill bacteria if concentrations reach MBC for a certain period of time
* MBC at or near the MIC
Preferred for:
* immunosuppressed animals
* Preferred for severely ill patients
* Sepsis
* Neonates
* Animals on glucocorticoids
* Animals on cancer chemotherapy
Bactericidal antimicrobials are NOT always bactericidal
* Static at concentrations below MBC
* Dose dependent
* Bacteria dependent
* Bacteria must be multiplying for bactericidal antibiotic to work
* Combinations of –static and –cidal???
postantibiotic effect (PAE)
Persistent drug effect after plasma concentrations decline below the MIC/MBC
Mechanisms
* Decreased virulence of the bacteria
* Development of abnormal cell wall or septum
* Increased susceptibility to host defenses
* Persistence at sites of infection
Only occurs with some drugs and is bacteria-dependent
pharmokinetic- pharmodynamic interactions
Predict the success of antimicrobial therapies
* Relate concentration of drug to MIC of the pathogen
* Vary by class of drug
* Vary with each pathogen
Guidelines for successful treatment:
* Meeting them increases chance of success
* Not meeting them increases chance of failure
“Drug-Bug” Interactions
time dependent antibiotics
T>MIC: Duration plasma concentration is above the MIC over 24 hours
concentration dependent antibiotics
Cmax:MIC ratio of the maximum plasma concentration (Cmax) to the MIC
concentration/time dependent antibiotics
AUC:MIC: ratio of the AUC (area under curve 0-24h) to the MIC
3 main categories of antibiotic mechanism of action
cell wall: inhibit synthesis
protein synthesis: inhibit 50s or 30s ribsomal subunit
nucleic acids: inhibit synthesis or function
spectrum of activity
Describes the general activity of an antimicrobial
Narrow spectrum
* Implies activity against a limited subset of bacteria
Broad Spectrum
* Implies activity against a wide range of bacteria
* May include mycoplasma, rickettsia, and chlamydia
Tells you that the bacteria CAN BE affected by the antimicrobial
* Individual isolates of bacteria may be resistant to an antimicrobialeven though they are part of its spectrum!
antibacterial spectrum (4 quadrants)
Aerobic bacteria
* Gram (+)
* Gram (-)
Anaerobic bacteria
* Gram (+)
* Gram (-)
Broad Spectrum
* Gets all four quadrants
* Gets other categories
Narrow Spectrum
* 1-2/4 quadrants
antibiotic spectrum (6 quadrants)
Aerobic bacteria (includes facultatice aerobes)
Gram (+)
* Streptococci
* Staphylococci
Gram (-)
* Respiratory pathogens
* Enteric pathogens
Anaerobic bacteria
* Gram (+)
* Gram (-)
additive/indifferent antimicrobial interaction
Typically used to **extend the spectrum **
Does not enhance activity of either
Example:
Horse with pneumonia
Culture – Strep. zooepidemicus (Gm +) and E. coli (Gm -)
Treatment:
Penicillin (for strep) and enrofloxacin (for e coli)
2+2=4
synergistic antimicrobial interaction
Synergism – what we hope for
Combination enhances activity
* Trimethoprim / sulfonamide: Static alone; -cidal together
* Ampicillin / clavulanic acid: CA prevents degradation by β-lactamases
* β-lactams and aminoglycosides: β-lactam increases permeability of cell to aminoglycoside
2+2=6
antagonistic antimicrobial interaction
Antagonism – what we worry about
Activity of the combination is less than the sum
Example: Static plus Cidal
* Penicillin plus tetracycline
Probably depends on the drug/bug
Not necessarily contraindicated, but avoided when possible
2+2=2
IV route of antibiotics
- Highest concentrations
- Highest risk for adverse effects
- Severe systemic illness
- Owner comfort level/animal temperament
IM/SQ route for antibiotics
Bioavailability often complete
* Dehydration/shock may affect absorption
Risk of drug toxicity less than IV
* Injections site reactions
Owner comfort level/animal temperament
oral route for antibiotics
Ileus/colitis
Malabsorption
Drug interactions
transdermal route for antibiotics
DO NOT GIVE to treat systemic infection
topical route for antibiotics
Eyes
Skin
Wounds?
MICs may underestimateactivity of topically/locally applied antibacterial drugs! (MICs are based on plasma concentrations)
site of infections: ISF
For most pathogens, the site of infection is the ISF
* Protein binding is major determinant of drug distribution to the ISF
* Low protein bound drugs have good distribution
* Highly protein bound drugs have limited distribution (>80%)
In general, MICs adequately predict success for infections in the ISF
site of infection: protected sites
CNS, eye, prostate, bronchus, testes
* Protective barriers that consist of tights junctions between the endothelial cells
* Limited drug movement into these areas
* Lipid solubility or active transport
Significance during inflammation: more able to get to site through increased permeability
MIC testing will overestimate activity of antibiotics!
* need to give higher dose over longer duration
intracellular infections
Examples: R. equi, Salmonella sp., Babesia
Lipophilic drugs have better penetration into cells than do hydrophilic drugs
site of infection: abscesses and granulomas
Drug diffusion slow
* Lower Cmax
* Slower equilibrium
Lower blood supply to the area
Treatment unsuccessful without DRAINAGE!!!
* If you can DRAIN and LAVAGE the abscess, antibacterials may not be necessary…
If you can’t drain:
* Choose more lipophilic drugs
* Treat for long periods
most common bacteria in equine respiratory disease
Streptococcus zooepidemicus
most common bacteria in canine skin dz
Staphylococcus pseudintermedius
most common bacteria in Feline bacterial cystitis
E. coli
beta lactam antibiotics
Penicillins
Cephalosporins
Carbapenems
* Imipenem and meropenem
Monobactams
* Aztreonam
beta lactam antibiotic types
Penicillins
Cephalosporins
Carbapenems
* Imipenem and meropenem
Monobactams
* Aztreonam
beta lactam mechanism of action
Penetrate the outer cell wall
Bind to and inhibit penicillin binding proteins (PBPs)
* Transpeptidase enzymes required for cross-linking of cell wall precursors
Inhibition of cross-linking
* Opens channels through the cell wall to create pores
* Allows fluid into the cell, causing cell swelling and death
bactericidal
beta lactams pharmokinetics
Low plasma protein binding
* Distribute well to the extracellular fluid in most tissues
* Exceptions: cefovecin, ceftiofur
Hydrophilic
* Minimal intracellular concentrations
* Do not distribute well to protected sites (CNS, eye, prostate)
Metabolism
* Minimal
* Exceptions: ceftiofur
Elimination
* Glomerular filtration and tubular secretion
* Very high concentrations in urine!!! (use for UTI)
* 1000x higher than plasma!!!
Short half-life and require frequent dosing
* Exceptions: cefovecin, ceftiofur crystalline free acid
Some post antibiotic effect (PAE) against gram-positive bacteria
* Penicillin and Streptococci
**Time-dependent **
* T>MIC 50% of the dosing interval (Minimum- Some people say 80% for Gm (-))
* If immunosuppressed: T>MIC 90-99%, Constant rate infusions
beta lactams plasma protein binding
Low plasma protein binding
Distribute well to the extracellular fluid in most tissues
Exceptions: cefovecin, ceftiofur
beta lactams hydrophobic or hydrophilic?
hydrophilic
Minimal intracellular concentrations
Do not distribute well to protected sites (CNS, eye, prostate)
beta lactams metabolism
Minimal
Exceptions: ceftiofur
beta lactams elimination
Glomerular filtration and tubular secretion
Very high concentrations in urine!!!
1000x higher than plasma!!!
beta lactam half life
Short half-life and require frequent dosing
* Exceptions: cefovecin, ceftiofur crystalline free acid
Some PAE against gram-positive bacteria
* Penicillin and Streptococci
beta lactam time dependency
T>MIC 50% of the dosing interval
Minimum- Some people say 80% for Gm (-)
If immunosuppressed: T>MIC 90-99%, Constant rate infusions
penicillin G
first beta lactam
Oral absorption limited
* Degraded in gastric acid
IV formulations
* Potassium or sodium salt
* Human products ($$$)
IM/SC formulations
* Complexed with procaine or benzathine
* Longer half-lives and can be dosed less frequently
* Veterinary products (cheap)
benzylpenicillins
Still effective against
* Streptococcus species
* Anaerobes (Clostridia)
* Gram-negative bacteria are usually resistant (E. coli, Klebsiella, Pseudomonas)
Inactivated by β-lactamases
* Staphylococci +/-
* Bacteroides fragilis (anaerobe)
Spectrum: Gram-positives, Streptococci, Anaerobes
aminopenicillins
Ampicillin, amoxicillin
Good oral absorption in small animals
* Amoxicillin (oral) > ampicillin
* Ampicillin more commonly used IV/IM/SC
Limited to no oral absorption in large animals
Increased spectrum against gram-negative bacteria
Lower urinary tract
Still maintain activity against Gram-positives and anaerobes
Used VERY frequently in small animals (#1 in cats #2 in dogs)
Methicillin (oxacillin) resistant Staph. (MRSA/MRSP)
Bacteria reported resistant to oxacillin should also be considered to be resistant to all other β-lactam antibiotics
drugs in methicillin class not used clinically
cephalosporin 1st generation
Active against gram-positive bacteria, including some beta-lactamase positive staphylococci
* Includes cefazolin, cefadroxil and cephalexin
Cefazolin has the most activity against gram-negative bacteria
Cephalexin (oral) VERY commonly prescribed for dogs for staph pseudointermedius
1st generation have A in name
2nd generation cephalosporins
rarely used in clinical practice
3rd generation cephalosporins
Have the most activity against gram-negative bacteria
Still retain activity against gram-positives (but lesser)
Not used clinically - injudicious
Includes ceftiofur, cefovecin, cefpodoxime proxetil
* Human drugs
* Ceftazidime and cefotaxime – Pseudomonas, CNS infections
4th generation cephalosporins
Includes cefepime and cefquinome
* Broad-spectrum
* Cefquinome is currently available in Europe and the UK for veterinary use
* Approval for BRD denied by FDA
Rarely used in veterinary medicine (US) in any species
prob not on test
cephalexin
1st gen cephalosporin
Oral use in dogs and cats
FDA approved chewable tablet in dogs (Rilexine®)
Dermatitis caused by non-methicillin/oxacillin resistant staphylococci
cefazolin
cephalosporin 1st generation
IV use in dogs, cats (sometimes horses)
Extralabel use
Surgical prophylaxis*
* Administer within 60 minutes of incision
* Dose q90-120 minutes until wound closure
Cefpodoxime proxetil
3rd gen cephalosporin
Labeled for use in dogs (Has been used safely in cats, foals)
Skin and soft tissue infections
Longer half-life = Once daily dose
* Better owner compliance
Prodrug
* Ester improves oral absorption
simplicef
cefovecin
3rd gen cephalosporin
FDA approved for the treatment of skin infections in dogs and cats
Single subcutaneous dose (Long half-life due to high affinity protein binding!)
Provides therapeutic concentrations for up to 14 days
not fast acting, adverse effects also last 2 weeks
Convenia®
ceftiofur
3rd gen cephalosporin
FDA approved for use in (dogs), horses, chickens, turkeys, cattle, goats, sheep and swine
Main cephalosporin used systemically in large animals
3rd generation, but…Higher doses needed for Gm-negative bacteria!!!
Three formulations available
* Ceftiofur sodium (Naxcel®) powder
* Ceftiofur hydrochloride (Excenel®) liquid
* Ceftiofur crystalline free acid (Excede®)
Ceftiofur crystalline free acid (Excede®)
3rd gen cephalosporin
FDA approved for use in (dogs), horses, chickens, turkeys, cattle, goats, sheep and swine
Main cephalosporin used systemically in large animals
3rd generation, but…Higher doses needed for Gm-negative bacteria!!!
Long-acting: Long half-life due to extended release formulation!
Single SC dose at the base of the ear in cattle
Single IM dose in swine
IM dose in horses, repeated once in 4 days
* Injection site reactions common!
extralabel use of cephalosporins in food animals
Prohibited by FDA in major food producing species (Cattle, swine, chickens and turkeys)
Exceptions:
* Cephapirin: can use for indications not on the label
* All other label indications met (dose, route, duration of therapy, etc.)
* No prohibition in minor food-producing species (Sheep, goats, honeybees, fish, wildlife, etc.)
beta lactam antibiotic adverse effects
Relatively rare
Hypersensitivity reactions (anaphylaxis, IMHA)
* Cross-reactivity between penicillins and cephalosporins may exist (15% in people)
At very high concentrations, can inhibit GABA
* Cause CNS excitement and seizures
Procaine reactions (reaction to procaine in formulation, not penicillin)
* DONT GIVE PROCAINE PENICILLIN IV TO HORSE
Gastrointestinal effects
* Dogs and cats: Vomiting with high oral doses due to irritation of the gastric mucosa
* Horses and rabbits: High incidence of antibiotic associated colitis with oral administration
beta lactam drug interactions
Aminoglycosides
Synergism!!!
Inactivation!!!
* Chemical inactivation when mixed
* Does not precipitate
Does not happen in vivo
* Diluted by plasma
methicillin resistance
Mediated via the MecA gene
Encodes for penicillin binding protein (PBP) 2a
Very low binding affinity for all β-lactam antibiotics
resistant to all β-lactams!!!
* Includes carbapenems and monobactams
B lactam mechanism of resistance
enzyme degredation- beta lactamases
break beta lactam ring
ex: staphs
b lactamase inhibitors
combine with b lactam antibiotics
blocks b lactamases
clavulanic acid, sulbactam (not absorbed orally), tazobactam
ex: clavamox (better choice for staphs)
