antimicrobial therapy Flashcards
Anti“biotic”
-substance produced by
bacteria, and active against other bacteria
Anti“microbial”
-substance (either naturally produced or synthetic) that is active against
microbes, including bacteria, fungi, protozoa
infection site in antimicrobial therapy ex abscess
-depending on where the infection is we have to choose an antibiotic which will get to the site of the infection
-ex> abscess are walled off and hard to get antimicrobials into.
-not likely to be effective are aminoglycosides, B lactams, trimeth/ sulfa.
things to think about when choosing an antimicrobial therapy
- Where is the infection located?
- Will the antimicrobial distribute to the infection site?
-what are the AE of the drug?
-What is the appropriate drug
formulation and dosage regimen?
-Will the antimicrobial be effective in the pathogen’s environment?
-For food animals can you stay
“on label”?
-cost
-parmacodynamics and pharmacokinetis
-risk
goal of antimicrobial therapy
-sufficiently suppress the bacteria and infection so that they can be eliminated by the host’s immune system?
-don’t need to kill all bacteria most of the time.
-just want enough drug so that the infection stops proliferating.
high plasma [ ] in blood
-High plasma drug concentrations are
assumed to be advantageous.
-higher in blood means higher everywhere else
-not always true
-for soft tissue infections (wounds, pyoderma) most bacteria are located ESF so works in equilibrium with plasma so good indicator.
- Exceptions exist: new macrolide drugs
have very low plasma concentrations but
extremely high tissue concentrations: Bind to leukocytes, carried to site of infection (lungs)
MIC
-Minimum Inhibitory Concentration (MIC)
lowest drug concentration that inhibits bacterial growth
Dose to reach target [plasma] of 2-10x the MIC
-determined by microdilution, disk diffusion (qualitative), E-tests.
Minimum Bactericidal Concentration (MBC)
lowest drug concentration to kill 99.9% of the bacteria
Mutant Prevention Concentration (MPC)
MIC of the least-susceptible (i.e. more resistant) single-
step mutant bacterial population
susceptibility testing
-helps guide theraputic decisions. does not gaurantee drug success OR failure.
-predictions can be WRONG: does not account for:
-host immune system, drug distribution, drug efficacy in plasma/ tissues, bacterial growth rate, mixed infections.
Susceptibility Testing Limitations
- Assumes drug concentrations are only reached via
SYSTEMIC administration - LOCAL administration may reach much higher concentrations
Genomics
- Identify key genetic determinants of resistance (e.g., mecA, ampC genes)
- Future diagnostic approach for fast, accurate, and cheap
antimicrobial susceptibility testing?
-uses whole genome sequenxing and metagenomics for AMR detection.
-theres a large disconnet between our understanding of AMR genotype and phenotype.
Bactericidal
Ratio of MBC to MIC is < 4-6
i.e., it’s possible to obtain concentrations in the patient that will kill 99.9% of the bacteria
-Categories are NOT absolute!
Do NOT choose therapy based on cidal vs static!
-ex floroquinolines
Bacteriostatic
Ratio of MBC to MIC is large
i.e., it’s not safe or feasible to administer enough antimicrobial
to kill 99.9% of the bacteria
Categories are NOT absolute!
Do NOT choose therapy based on cidal vs static!
ex. tetracyclines
Post-Antibiotic Effect (PAE)
Bacterial growth remains suppressed after the [antimicrobial] has dropped below MIC. still working even though drug isn’t there anymore.
May be the reason that many dosage regimens are effective, despite not maintaining concentrations > MIC
MAY allow for longer interval between doses
PAE is dependent on the specific combo of antimicrobial & bacteria
PK-PD Integration for Antimicrobials concentration vs time dependent
Bacterial kill-curve studies show that antimicrobials can be:
* Concentration dependent:
AUC0-24 hr: MIC, the more drug and higher exposure you have the better.
Cmax: MIC, bigger the exposure to MIC better it works.
* Time dependent T > MIC, high exposure or concentration isn’t as important as time they spend above MIC of pathogen. And concentration can’t drop below MIC and stay below
approach for time vs concentration dependant therapy
-For concentration (i.e., dose)-dependent killers, more is better.
- For time-dependent killers, dosing more often is better.
Same dose, but divided more times/day
BUT: may be poor client compliance with frequent dose regimens
Infrequent dosing requires “long-acting” form
Slow absorbing (“flip-flop”) formulations
e.g., long acting OTC, CCFA (Excede)
High protein binding (cefovecin)
Beta lactams structure
-penicillin, cephalosporins
-B lactam ring: resistance mechanism breaks down the ring with beta-lactamase’s.
penicillins used in vet med
- Crystalline penicillin G (Na+ or K+)
– Sterile formulations for injection (human drugs) IV!
– Soluble powder for drinking water (vet drugs non-sterile) - Procaine Penicillin GVM
– “white” injectable penicillin (short acting daily injections or long acting in oil. IM or SC ONLY.
– Oral feed premixes - Benzathine Penicillin GVM
– “Long-acting” injectable penicillin (Duplocillin LA) IM or SC only
-make sure always look at label as there are many different types of penicillin formulations.
penicillin G: mechanism of action
-Act by disrupting synthesis of bacterial cell wall:
* Inhibit the Penicillin-Binding Proteins (PBPs) found
on the outside of bacterial cell membrane
* This interferes with enzymes (transpeptidase) needed
for peptidoglycan synthesis (part of cell wall)
* Causes lysis of growing bacterial cells
– Bactericidal – but only if bacteria is actively growing
Penicillin G: Mechanism of Action in different bacteria types
– Gram (+)
* lots of peptidoglycan in cell wall
* High affinity of PBPs for β-lactams=works good on gram +
– Gram (–)
* Lesser peptidoglycan in cell wall
* Lower affinity of PBPs for β-lactams, doesn’t work as well on gram -, cant penetrate the cell wall.
-dosed in IU. 1 IU = 0.6 ug pen G
penicillin G resistance
- some gram + (staph) have Penicillinase or β-lactamase enzymes so not susceptible to penicillin. (but can be susceptible to cephalosporins)
- Inability of β-lactam to penetrate bacterial cell wall
-gram -: no susceptible to penicillin: Can’t penetrate cell wall
-gram -: not susetable to endogenous b-lactamase producer.
Penicillin G (Benzylpenicillin):
Spectrum of Activity
-Many Gram (+) (ex strep)
(but NOT most Staph,
which make β-lactamase)
-many anaerobes
Gram (+)
* Actinomyces species
* Trueperella pyogenes
* Some Bacillus anthracis,
Corynebacterium, Erysipelothrix
rhusiopathiae, and Listeria spp.
A few Gram (-)
* Some Histophilus & Pasteurella
Most anaerobes
* Fusobacterium, some Clostridium, some Bacteroides
Penicillin G (Benzylpenicillin): resistance bacteria
Most Gram (-)
* Produce β-lactamase
* Can’t penetrate cell wall
* Low affinity PBP
Most Staph spp.
* Produce β-lactamase
Penicillin PK
absorption (oral):
* Poor oral absorption of penicillin G due to rapid hydrolysis in stomach acid
– Exception: Phenoxymethyl penicillin (penicillin V)=acid stable
-penicillin in oral feedmix or water, used locally in gut doesn’t absorb to systemic.
-distribution: weak acid so highly ionized at pH 7.4. low Vd, good plasma concentrations and ESF. more distribution to inflammatory tissues.
-elimination: most in renal tubule. short T1/2 life except benz formulations. (flip flop kinetics)
penicillin PK absorption different formulations
Absorption (parenteral):
* Crystalline (Na+ & K+) pen G:
– Only dosage form that can be used IV
– Rapid absorption after IM or SC injection
- Procaine pen G:
– Procaine salt more slowly absorbed from IM injection site than crystalline forms (especially with oil formulations) - Procaine causes vasoconstriction at injection site
– Results in lower, but more sustained, plasma concentrations
– Injections in neck absorbed more rapidly than in hindquarters - And less carcass damage!
– NEVER USE FOR IV INJECTION (CNS signs) - Benzathine penicillin G:
– Benzathine salt is poorly soluble, very slowly absorbed
-released so slow doesnt reach MIC. high drug residues
penicillin = time dependent antimicrobial
- Efficacy isn’t based on reaching high Cmax
- Need to Keep penicillin conc. > MIC for as long as possible (most of the dosing interval)
– Crystalline penicillin: May require TID / QID dosing
– Procaine Pen G: Once daily dosing
– “LA” procaine/benzathine Pen G: Days between doses - Prolonged absorption (flip flop kinetics)
- NOTE: only useful if plasma concentrations actually
reach pathogen MIC!
Penicillin Adverse Reactions
-Hypersensitivity: Due to R1 side chain, not beta-lactam
* Anaphylaxis / local inflammation (Type I)
* Autoimmune hemolytic anemia (Type II)
* Vasculitis (Type III)
-GI flora changes (diarrhea) most common
* Especially hindgut fermenters (horses, rodents, rabbits)
-Drug residues in food animals (give in injection triangle)
isoxazolyl penicillins vs pen G
- Active against same bacteria as Pen G
– But generally a bit less potent than Pen G
*Impervious to S. aureus penicillinase
– so historically used for Staph infections - Cloxacillin– Dry-Clox intramammary suspension treats shaphylocoocus mastitis in vet med
- Methicillin-resistant Staph aureus & pseudintermedius
(MRSA, MRSP)
Methicillin-resistant Staph aureus & pseudintermedius
(MRSA, MRSP)
: resistant due to different penicillin binding protein. mecA gene. has a LOW AFFINITY FOR ALL B-LACTAM DRUGS (resistant)
Antistaphylococcal Penicillins spectrum
-Many Gram (+)
(including most Staph.)
-anarobes
Isoaxyzyl penicillins
Beta-lactam antimicrobials:
Aminopenicillins
-spectrum: active agaisnt all bacteria that pen G is, but amino groups allow better penetration through the outer layer of gram-neg bacteria (esp. amoxicillin)
-some gram neg, all gram pos (not staph), anaerobes
-still susceptible to degradation by enzymes.
forms:
* Ampicillin
* Amoxicillin:
Ampicillin
-Aminopenicillins
– Trihydrate salt injectable suspension (PolyflexVM)
* For IM/SC (not IV) use in cattle, swine, dogs, cats
– Many human sterile crystalline Na+ (IV injection) and oral forms
Amoxicillin
-aminopenicillin
– Many veterinary oral tablets / suspensions
* With/without clavulanic acid
* Indications: wide variety of infections in dogs/cats
– Soluble powder for medicated water
* Swine & poultry
aminopenicilin PK
Absorption:
* Oral: Both ampicillin & amoxicillin are acid-stable
* Ampicillin oral F is ~ ½ that of amoxicillin
– Amoxicillin: both fed or fasting state is OK, good on stomach.
- Injectable:
– Ampicillin trihydrate – slowly absorbed (SC, IM)
– Ampicillin sodium – rapid, can be given IV
-short 1/2 life. BID dosing orally. 2 but 3 is better a day.
SID for ampicillin trihydrate after IM
-time dependent antimicrobials
aminopenicillins adervse effects
Adverse events:
* Hypersensitivity (due to R1 side chain)
– Slightly less than Pen G?
– Cross-reactivity in patients with Pen G hypersensitivity? probably not seen due to different side chains. you will just switch to a non B-lactam
* Oral adverse events (vomit, diarrhea)– Intestinal flora disruption:
Beta-lactam antimicrobials:
Carboxypenicillins (anti-pseudomonal penicillins)
-piperacillin
– All human formulations
– Usually administered IV so only used in clinic in serios cases.
* With β-lactamase inhibitor like tazobactam
– Expensive
Anti-pseudomonal penicillins:
Spectrum of Activity
Active against Gram (-)
* Except β-lactamase producers
Active against Pseudomonas
* Can penetrate its cell wall
- anaerobes
BUT: ↓ activity against Gram (+)
-only used in clinic
Beta-lactam antimicrobials:
β-lactamase inhibitors
- Clavulanic acid
– In many oral tablet and suspensions for small animals
(Clavamox, Clavaseptin, Aventiclav) - Human formulations: Different ratio of Amox: Clav
β-lactamase inhibitors:
Mechanism of Action
-by providing B-lactamase inhibitors with penicillins they will not be susceptible to B lactamase enzymes. so always the penicillin to bind to binding protein.
-Irreversibly binds to & inactivates β- lactamase enzymes
– Allows β-lactam antimicrobial included in the
formulation to bind with PBP
β-lactamase inhibitors:
Spectrum of Activity
When included with amoxicillin:
* Most Gram (+)
– Including most β-lactamase producing Staph
(unless methicillin-resistant → altered PBP)
* Many Gram (-)
* Many anaerobes
-can add and in the MIC will make resistant microbials turn to susceptible microbials
β-lactamase Inhibitors
(with aminopenicillin) specutrum
-some gram -
-gram + (except MR-staph)
-anaerobes
β-lactamase inhibitors: PK
Almost the same as amoxicillin…
* Quickly & extensively absorbed after oral
administration
* Renal excretion
* T1/2 elim similar to amoxicillin
Minimal Adverse Events
* If ADE do occur, probaly due to aminopenicillin
portion (not β-lactamase inhibitor)
Carbapenems (extended-spectrum penicillins)
- Imipenem
Extremely wide spectrum of activity: - Gram (+)
- Gram (-)
- Anaerobes
- Impervious to β-lactamase enzymes
DRUG OF LAST RESORT IN HUMAN MEDICINE, so DONT USE
Beta-lactam antimicrobials:
Cephalosporins
-same B-lactam ring
-cephalexin (rilexine or cefaseptin tablets)
-cetiofur (EXCEDE is crystalline free acid)
-cefovecin (Convenia injectable solution)
-cefpodoxime (Simplicef tablets)
* Cephapirin
* Cefazolin (human formulation sterile injectable) used perioperative, give before surgery or during
CEPHALEXIN
-cephlosporin
* Now only oral tablets
* Indicated for canine
superficial pyoderma
caused by susceptible
strains of Staphylococcus
pseudintermedius
Cephalosporins: Mechanism of Action
More β-lactam drugs: so same as penicillin!
* Act by disrupting synthesis of bacterial cell wall
* Inhibit the Penicillin-Binding Proteins
* Interferes with cell wall peptidoglycan synthesis
General advantages of cephalosporins:
* Stable against (some) beta-lactamase enzymes
* Good affinity for target proteins (PBPs)
* Good ability to penetrate bacterial cell wall
– Including Gram (-) abit more gram - coverage
emerging resistance to cephlasporins
- Different β-lactamase enzymes:
– Extended-spectrum β-lactamase enzymes (ESBL)
– AmpC cephalosporinases
– Metallo- β-lactamase enzymes - Modify the PBPs (mecA gene, others) **cant use for mrsa its all B-lactams
- Reduce cellular concentrations:
– ↓ bacterial cell wall permeability
– Induction of efflux pumps
cephlasporin spectrum of activity
Gram (+)
* Strep spp.
* Staph. aureus, pseudintermedius
* Many other Gram (+)
some Gram (-)
* Many enterbacteriaciae
– E. coli, Salmonella, Klebsiella
– Histophilus, Mannheimia, Pasteurella
Most anaerobes
resistant to cephlosporins
Gram (+)
* Meth-resistant Staph spp.
– Altered PBP
* Enterococcus – inherently
resistant to cephalosporins
Gram (-)
* Many enteric pathogens with ESBL activity
* Rhodococcus equi
* Pseudomonas (except Gr. 6&7)
- Mycobacteria
Anaerobes: Bacteroides - except cefoxitin
Cephalosporins distributions
Oral absorption: generally good
* SimplicefTM: Cefpodoxime proxetil → prodrug
Parenteral absorption: Depends on the formulation
* Cefazolin: Extremely rapid
– Can go IV
* Ceftiofur sodium (Excenel) – very rapid
– Can go IV (but only labelled for IM/SC)
* Ceftiofur HCl (Excenel RTU EZ) – slower
* Ceftiofur crystalline free acid (Excede) – very slow
(long-acting formulation)
Cephalosporins: PK
Distribution: Low Vd
-Metabolism occurs for some cephalosporins:
* Ceftiofur → desfuroylceftiofur (less active metabolite)
* Cephapirin → deacetylated in the liver
Renal elimination (most cephalosporins)
* Glomerular filtration + Tubular secretion
Short half-life (1 – 2 h) with exeptions
Cephalosporins: PK exceptions
Protein-binding & T1/2 elim
Cefpodoxime & (especially) cefovecin:
* Extremely highly protein bound (>95%)
- Cefpodoxime T½ = 5-6 HOURS in dogs
- Cefovecin T½ = 5.5 - 6.9 DAYS after SC administration
in dogs and cats
– ↓ clearance in kidney due to high protein binding
– Result = one dose every 2 weeks
Ceftiofur T1/2 elim varies by formulation:
* Ceftiofur sodium (Excenel) = 2 – 3 h in cattle
- Ceftiofur HCl (Excenel RTU) = 20 h in pigs
- Ceftiofur crystalline free acid (Excede):
– 40+ h in cattle
– 50 h in pigs
cephalosporins adverse effects
Mostly the same as penicillins
* Hypersensitivity: same as penicillin. ex. eruption of skin.
-more reactivity between older amino and cephs.
- GI upset
– Vomit (esp. cephalexin), diarrhea
– Loss of normal GI flora can lead to bacterial overgrowth - Coagulopathies / blood dyscrasias (also rare) but goes away when drug is stopped
– Ceftiofur: thrombocytopenia
– Cephalexin: IMT
Cephalosporins: Concerns about AMR
-problem with compounded versions and extralabel uses.
– Can’t alter the dose, route, frequency, or duration
– Can use in minor species
– Can use for different indication
* BUT: Cannot use for prevention
-some extralabel uses are prohibited: ovo chick injections, bio bullets in cattle (banned USA)
cephalosporins are inherently ineffective against which UTI pathogen?
enterococcus
Emergence of
Vancomycin-Resistant Enterococci (VRE)
-Enterococcus: Inherent resistance to cephalosporins
* Risk factors for VRE colonization and infection include prolonged hospital stays, exposure to intensive care
units, transplants, hematologic malignancies, and exposure to antibiotics.
– Exposure to cephalosporins is particularly important
-if treated with cephosporin people are 3x more likey to get a Vancomycin-Resistant Enterococci infection.
Cetiofur
Cephalosporin type drug
Excede crystalline
Exenel in salt form
Cefovectin
Convenia
Cephalosporin
