Antimicrobial Drug Characterisitcs Flashcards
Beta lactams and aminoglycosides are incompatible ______
In vitro
- clinicians stagger animnoglycoside and penicillin dosings to avoid high in vivo concentrations
How do beta lactams inhibit cell wall synthesis?
Bind to penicillin binding proteins to prevent cross-linkage of peptidoglycan cell wall
How does the cidal action of beta lactams occur?
Osmotic imbalance between hypertonic bacterial cytoplasm and host isotonic environment
- -> protoplasts bulge thru cell wall until cell bursts
- -> if bacteria are in an environment isotonic to their cytoplasm, a static action occurs
________ decreases the activity of beta lactams
Purulent debris
What are the 3 mechanisms of beta lactam resistance?
- degradation by bacterial enzymes
- penicillin binding site alteration
- reduced penetration (seen in gram neg structure = impaired crypticity)
What allows passage of resistance between species of bacteria and between genera?
Plasmids (between species) and transposons (between genera)
Crystalline penicillin G
IV, IM, SQ
- rapid high concentrations
- short duration of plasma concentrations
Procaine penicillin G
IM, SQ
- flip flop kinetics
- lower concentrations, but prolonged duration compared to crystalline pen-G
Benzathene penicillin G
IM
- flip flop kinetics
- extremely low concentrations with prolonged duration
- little benefit in vet med
- increases residue concerns in food animals
Penicillin G adverse reactions
Primary adverse reactions are allergic
- due to degradation product penicilloic acid
- some toxicity associated with salt (potassium pen G) or ester (procaine)
What animals should not be given beta lactams?
Guinea pigs, hamsters, rabbits
- due to hind gut floral disruption
Penicillinase resistant penicillins
Similar to pen G in structure, but not inactivated by penicillinase
- oxacillin or cefoxitin are standard for testing bacteria against drugs of this group due to their better storage stability and reliability
Which penicillinase-resistant penicillin is available for intramammary infusion in dairy cows?
Cloxacillin
Why do broad spec penicillins have better penetration of gram neg bacteria?
Increased crypticity
Which broad spec penicillin is used as an intramammary infusion?
Hetacillin
Which broad spec is absorbed twice as well orally in dogs and cats?
Amoxicillin over amipicillin
Qualitatively compare ampicillin sodium vs ampicillin trihydrate injections
Sodium ampicillin (veterinary) is injectable given by all parenteral routes
- rapid absorption and elimination (every 8 hrs)
- repository ampicillin trihydrate formulation may not be able to reach therapeutic concentrations unless organism is very susceptible (low concentration, prolonged duration)
Ampi and amoxicillin are not effective against ______, even at higher extra label doses
Enteric gram-negative bacteria
- especially true of trihydrate injectable suspensions
Adverse reactions of broad spec penicillins
- large doses of ampicillin causes diarrhea in horses via entry into the bile (type B)
- disrupts flora if given orally to ruminants (okay by injection)
- trihydrate form too irritating for use in horses –> sterile abscesses
Extended spectrum penicillins are also called _________
Anti-pseudomonal
- increased crypticity, but able to bind to altered PBP
Potentiated penicillins
Have a penicillinase inhibitor added to the formulation to release penicillin
- penicillinase inhibitor has no antibacterial properties
- clavulanic acid and sulbactam
- looses stability once hydrated, keep oral tabs in foil
- only works in bacteria resistant via penicillinase
______ are susceptible to potentiated penicillin formulations
Bacteroides fragilis
1st generation cephalosporins
Similar to narrow-spec penicillins except:
- not affected by penicillinase = good Staph activity, used in skin and bone infections!!!
- not reliable against obligate anaerobic bacteria
How does cefazolin differ from other 1st generation cephalosporins?
Is the only injectable 1st gen!!
- better activity against E. coli than other 1st gens
Which 1st gen cephalosporins are approved for intramammary infusion for dairy cows?
Cephapirin
Which cephalosporins have 4 quadrant coverage?
Cefoxitin and cefotetan
- have good anaerobic activity, including B. fragilis
Which cpehalosporin family has a public health concern?
3rd generation
- resistance due to extended spectrum beta lactamases is of increasing public health concern
Which is the only cephalosporin effective against pseudomonas?
Ceftazidime
Which cephalosporin is the drug of choice in treating bacterial meningitis?
3rd generation cephalosporins
- ceftriaxone (expensive) or ceftazidime (more common)
Which cephalosporin family is not effective against carbapenem-resistant enterobacteriaceae?
4th gen, 5th gen, potentiated cephalosporins
Naxcel
Ceftiofur sodium
- comes as a powder, requiring reconstitution
- 4 day withdrawal for slaughter, no milk withdrawal!
- cattle: BRDC, foot rot
- swine, sheep: pneumonia
- horses: respiratory infections
- dogs: UTI
What is the only systemic antibiotic with no milk withdrawal?
Naxcel
Excenel
Ceftiofur HCL
- shelf stable formulation
- swine: respiratory disease, 4 day slaughter withdrawal
- cattle: BRDC, foot rot, acute metritis
- 2 day slaughter withdrawal, no milk withdrawal
- -> exception: spectramast intramammary infusion does have a milk withdrawal of 72 hrs (lactating) or 30 day (dry)
Excede
Ceftiofur crystalline free acid (pure ceftiofur)
- approved for cattle for 1 or 2 doses
- approved in swine for respiratory disease (IM injection in the neck)
- approved in horses for lower respiratory infections –> 2 IM injections 4 days apart
What is the drug of choice for skin and soft tissue infections due to staph, strep, e. coli, pasterurella, and proteus?
Cefpodoxime proxetil
What is the drug of choice for SSTI due to staph, strep, and pasturella and for UTI’s due to E. coli?
Cefovecin
- injection once every 7-14 days for 2 injections
- long half life due to protein binding
Monobactam spectrum is limited to
Aerobic gram-neg bacilli
- no activity against gram positives or obligate anaerobes
Which beta lactam has the broadest spectrum of activity of any antibiotic?
Carbapenems
- penetrates BBB and is enhanced in inflammation
High doses of imipenem can cause _______
Seizures
- nephrotoxicity is also seen due to reduction of active drug that reaches the urine, and the metabolite is nephrotoxic
Does meropenem cause nephrotoxicity or seizures?
No
Carbapenem-resistant enterobacteriaceae
Enterobacteriaceae resistant to all beta lactams including the carbapenems
- reported in all 50 states (hospital and nursing homes)
- resistant to all other antimicrobials used in medicine
CRE resistant mechanisms
- carbapenemases
- decreased crypticity
- active efflux pump
Resistance to aminoglycosides
Due to plasmid-controlled aminoglycoside degradation enzymes in periplasmic space of gram neg bacteria
- also includes: decreased uptake into cell, modification of ribosome
Energy dependent phase 1 of aminoglycoside penetration
Oxygen dependent!
- active uptake occurs at cytoplasmic membrane
- process blocked by hyperosmolarity, low pH, and anaerobic conditions
Energy dependent phase 2 of aminoglycoside penetration
Disruption of cytoplasmic membrane, ion leakage is noted before cell death
Synergy between beta lactams and aminoglycosides
Beta lactams break bacterial cell wall, allowing greater entry of aminoglycoside
Neomycin is too toxic to use _______
Parenterally
- used for enteric and topical infection
- is extremely nephrotoxic!!
Gentamicin and amikacin are both veterinary approved for ______
Intra-uterine use in horses
Gentamicin
Want the trough to be < 2 mcg/ml
- avoid glass containers
- peak drawn at 1 hr, trough at 2 half lives (3-6 hrs)
Amikacin
Toxicity: want the trough to be <8 mcg/ml
- is less potent than gentimycin (is a more effective drug overall)
Nonantimicrobial use of gentamicin
Destroys ciliary body when injected into the eye, use to treat glucoma
What are the 3 adverse reactions of all aminoglycosides?
- nephrotoxicity
- ototoxicity
- neuromuscular blockade
Toxcitiy of aminoglycosides is due to prolonged ________
High trough concentrations
What causes nephrotoxicity with aminoglycosides?
Binds covalently to intracellular organelles of proximal renal tubules
- leads to cell damage/death
- covalent binding is responsible for long residues in the kidney tissue
- slaughter withdrawal for extralabel use in cattle at 18 months (is not illegal, but discouraged)
How to avoid aminoglycoside nephrotoxicity
- use 24 hr dosing interval
- keep patient well hydrated
- limit other nephrotoxic drugs
- TDM to optimize efficacy (peak) and minimize toxicity (trough) –> esp. in geriatrics!
- IV calcium gluconate
How does amikacin differ from gentamicin relative to suscepibility and risk of nephrotoxicity?
Gentamicin
- gram neg % susceptibility in the low 90s
Amikacin
- gram neg % susceptibility in the high 90s
- less nephrotoxin than gentamicin
Ways to monitor aminoglycoside therapy to minimize the risk of nephrotoxicity
Increases in serum BUN or creatinine occur too late to be helpful
- perform serial urinalyses and watch for: increasing tubular casts and protein, decreasing SG and increasing glucose
- perform serial urine GGT: creatinine ratios (an increase in more than 3X baseline may indicate imminent toxicity)
Local environments decreasing aminoglycoside activity
- acidic environments
- low oxygen tension (required to have oxygen and active transport to get across cell membrane)
- cellular debris
Macrolides have greater activity in an ________ environment
Alkaline
- also maintain activity in purulent debris!
Macrolide resistance
Either chromosomal or plasmid mediated
- inactivates enzymes, changes in drug permeability, active drug efflux mechanisms
- *cross resistance to other macrolides and lincosamides is common**
What is the drug of choice to treat chlamydia in cats?
Tetracycline
How do the newer macrolides differ in their activity versus older macrolides against gram-neg nonenteric pathogens?
Newer macrolides (ex; tilmicosin) have much greater activity against non-enterics
All medicated feeds with ________ are VFD
Macrolides
What antimicrobial has shown activity against chlamydia and is sometimes used in human medicine for this purpose?
Azithromycin alternative to doxycycline in human genital chlamydiosis
Macolides concentrate ______ due to their weak bases
Intracellularly
- achieve high concentrations in macrophages, prostate, and milk
- do NOT cross BBB
Macrolide - adverse reactions
Individual agent specific
- injection site tissue rxn for vet formulations (esp older macrolides) resulting in sterile abscesses
- hyperthermia due to anhydrosis may occur in foals receiving macrolides for R. pneumonia