Antimicrobial Therapy: Beta-Lactams Flashcards
Beta-Lactams
- Drug class characterized by the Beta-Lactam ring
- penecillins, cephalosporins, carbapenems
- Beta lactamase inhibitors
- Sir Alexander Fleming discovered by mistake
- staphylococcus plate contaminated with penicillium mold which inhibited staphylococcus growth
- Initially ~ 10 years scientific community brushed it off as umimportant … it is not very stable, hard to isolate/mass produce, and why do we need it?
- A team of scientists discovered methods to isolate, stabilize, purify and mass produce
Beta-Lactams:
Pharmacodynamics
MOA: Bind to penicillin binding proteins, enzymes in peptidoglycan biosynthesis in the bacterial cell wall, resulting in cell wall failure
Bactericidal, T>MIC mostly
Weak acids
Variable oral absorption
Variable lipophilicity/penetration into protected environments
Beta-Lactams:
Resistance
- Beta Lactamases -
- break down beta lactam ring and inactivate drug
-
Penicillinases -
- inactivate penicillins
-
Cephalosporinases -
- inactivate some penicillins and cephalosporins
-
Extended Spectrum Beta Lactamases -
- uh oh!
- inactivate most beta lactams, but carbapenems may still be active
-
Carbapenemases -
- inactivate carbapenems - oh no!
Beta-Lactams:
Resistance:
How do we treat these?
-
Penicillinases:
- use cephalosporin for staphylococcus
-
Cephalosporinases:
- use a beta lactamse inhibitor, or later generation cephalosporin
-
ESBLs, Carbapenemases:
- consult a clinical pharmacologist or infectious disease expert, cross your fingers, and wear gloves
Beta Lactams:
Resistance:
Alterations in Penicillin binding Protein
- No place for beta lactams to bind
- Confers resistance across essentially the entire beta lactam class
- If resistance ot oxacillin than resistance to all beta lactams regardless of MICs to specific beta lactams
- E.g. Methicilin resistant Staphylococcus aureus (MRSA), Methicillin resitant Staphylococcus Pseudintermedius (MRSP)
- How do we treat these?
- many still susceptible to ather anitmicrobials
Penecillin Formulations:
Penicillin G
- AKA: benzylpenicillin
- Unstable in acid, no PO administration
- Primary Spectrum:
- gram positive and anaerobes
- Efficacy: T>MIC
- Poor lipophilicity and penetration into protected environments, although inflammation may enhance penetration
- Weak acids (ion trapping)
- Low protein binding
Penicillin Formulations:
Procaine Penicillin G
water insoluble, slow release from injection site, IM/SQ only
Penicillin Formulations:
Potassium Penicillin G
Water soluble, rapid absorption, can be administered IV
Penicillin Formulations:
Penicillin V
is available and is acid stable (po) but essentially never used
Penicillins:
PenG
- primarily eliminated in the urine as active drug
- Anaphylaxis si a possibility, but overall rare
- May cause fatality in non-ruminant herbivores due to bacterial/clostridial overgrowth
Penecillins - Clinical Use:
Procaine Penicillin G
- NEVER administer IV
- Seizures can occur with inadvertant IV or potentially “free” prociane
- Cattle:
- rarely used due to widespread resistance.
- PPG administer IM, not SQ due to hematoma formation and drug residue risk
- Horses:
- may cause racing violations due to prociane
Penicillin - Clinical Use:
Potassium Penicillin G
- Most common IV
- Horses:
- give slowely
- potential for potassium toxicity in cardiac arrhythmia and death
- Also can stimulate GIT and result in defecation of soft feces
- give slowely
Penicillin - Clinical Uses
Pen G is overall well tolerated even with high doses
Effective for susceptible bacteria except in protected environments
Often used in conjunction with another antimicrobial
Aminopenicillins:
Amoxicillin
- PO
- More acid stable
- some oral ampicillin formulations exist, but relative to amoxicillin ampicillin has much lower oral bioavailability
- Some formulations for intrammary too
Aminopenicillins:
Ampicillin, Sodium
- IV, IM, SQ
- Can be administered PO, but amoxicillin preferred
- Ampicillin trihydrate is an ampicillin suspension, but is more variable absorption
- DO NOT ADMIN SUSPENSION IV
Aminopenicillins:
Enhance Spectrum
To include some gram negative, but resistant is often noted due to beta lactams
The “amino addition” enhances penetration into gram negative bacteria
Leptospira - can decrease circulating / shedding organisms, but will not eliminate infection
Aminopenicillins
- Addition of beta lactamase inhibitor further enhances spectrum
- irreversible antagonist of many, but not all, beta lactamases
- Little anitmicrobial activity of beta lactamase inhibitors by themselves
Betal Lactamase Inhibitor:
Clavulanate / Clavulanic acid
oral beta lactamase inhibitor
Most commonly combined with amoxicillin
Beta Lactamase Inhibitor:
Sulbactam
injectable beta lactamase inhibitor
Most commonly combined with Ampicillin
Aminopenicillins:
Culture and susceptibility
ampicillin is typically the class represntative drug for amoxicillin
Amoxicillin / clavulanate is typically the marker drug for ampicillin / sulbactam
Aminopenicillins:
Species
- most commonly used in small animal patients
- Amoxicillin and ampicillin are well tolerated
- Some GI adverse effects can occur uncommonly
- Rare anaphylaxis
- Amoxicillin and ampicillin are well tolerated
- GI adverse effects in horses, poor PO bioavailability therefore not used
- Typically not used in cattle
- polyflex approved systemic, amoxi-mast appromed for IMM
- Used in swine, waterers
- Rabbits, Guinea pigs, rats etc. - PO use results in bacterial overgrowth and death
Anti-staphylococcal Penicillins
- Specturm:
- gram postivie aerobes and anaerobes
- These drugs are resistant to beta lactamase
- Used either intramammary or as markers for resistance
- rarely used orally or systemically
- cephalosporins much more widely used
- rarely used orally or systemically
Anti-staphylococcal Penicillins:
Cloxacillin
intramammary
Anti-Staphylococcal Penicillins:
Methicillin
was originally used ot test for PBP mediated resistance of Staphylococcus, but now Oxacillin is used
Anti-pseudomonal Penicillins
- Primarily parenteral, some topical
- Used only for very resistant infections
- Enterobacteriaceae including Pseudomonas
- Used more commonly in exotic animal species
- short half-life in birds, and dosing regimens may not be feasible
- Snakes have longer half-life, more feasible
- Also used in reptiles, amphibians, turtles, but little data supporting its use
Cephalosporins
- Originally isolated form a Fungus:
- Acremonium aka “Cephalosporium”
- Many additional drugs found / developed since originally isolated
Cephalosporins:
MOA
SImialr to penicillins, binding to PBPs and bactericidal
Cephalosporins:
Enhanced Spectrum
Cephalosporins are resistant to inactivation by the penicillinase beta lactamase and are therefore more active against those bacteria producing penicillinase
Stephylococcus are typically resisant to amoxicillin, but susceptible to cephalosporins
Cephalosporins:
Efficacy
T>MIC
Cephalosporins:
Resistance
there are other beta lactamases active against cephalosporins
Alteration of PBP also confers resistance to cephalosporins
MRSA are resistant to cephalosporins as well
Cephalosporins:
Classification
There are many different ways to classify different cephalosporins, probably the most common way is by generations. Typically have some activity against anaerobes, but are not consistent for anareobes except cefoxitin
- First Generation:
- gram positive except Enterococcus,
- some gram negative
- Second Generation:
- additional activity against gram negative,
- some gram positive borrelia
- Cefoxitin has similar activity as 2nd gen, with good anaerobic spectrum
- Third Generation:
- Even greater activity agianst Gram negative, some penetrate BBB, some are lepto positive
- Ceftazidime is the only 1-3rd generation cephalosporin we use with activity against pseudomonas
- Fourth Generation:
- rarely used in vet med
- has activity against Pseudomonas and retains activity against some cephalosporinase producing bacteria
- Fifth generation:
- yeah, dont worry about these
- Not used in vet med
Cephalosporins:
dosing
is drug specific, but oral, IV, IM, SQ, intramammary formulations are available depending on the specific drug
Cephalosporin:
Distribution
most cephalosporins do not penetrate protected environments well
The primary exception are some 3rd generation cephalosporins
weak acids
protein binding varies from low to high
Cephalosporin:
Elimination
most cephalosporins are primarily eliminated as unchanged drug in urine.
Therefore urine concentrations are typically very high
Ceftiofur is metabolized to desfuroylceftiofur, and active metabolite, after systemic administration and desfuroylceftiofur primarily eliminated in urine
Cephalosporins:
Adverse Effects
- PO can result in vomiting diarrhea
- Anaphylactic reactions rare, but may cross react with penicillins
- False positive coombs test for autoimmune disease
- High doses of ceftiofur/cefuroxime associated with anemia, thrombocytopenia
- Bleeding disorders have been reported in dogs, but quite rare
- Many people avoid cephalosporins in patients with bleeding disorders, but overall risk is considered quite low for the cephalosporins used in vet med
- Enhanced risk of seizure reported in predisposed dogs, although the risk seem quite low especially compared to other antimicrobials
First Generation Cephalosporins:
Cephalexin
oral formulations
2-3x daily administration
In general, well tolerated
AE: vomiting, anorexia
Uses: skin and soft tissue infections, UTI, intraocular infections, osteomyelitis, perioperative as appropriate
First Generation Cephalosporin:
Cefazolin
parenteral only
4-8 hour administration
Uses similar to cephalexin
First Generatation Cephalosporin:
Cephapirin
Intramammary formulations
Two different formulations - be sure to use the correct one
Second Generation Cephalosporins:
Cefuroxime
Rarely used PO (dogs)
Has some penetration into prostate and CNS
can be used as outpatient, but not as good as parenteral cefotaxime, ceftriaxone, or ceftazidime
Short Half-life, q6-8h dosing needed
High doses of cefuroxime associated with anemia, thrombocytopenia
Second Generation Cephalosporins:
Cefoxitin
Rarely used
Actually a cephamycin
Will occasionaly be used for surgical prophylaxis for large intestine surgery or if anaerobic bacteria is suspected
Third Generation Cephalosporins:
Cefpodoxime
PO, once daily administration
Labeled for use in dogs (skin), but used similar as cephalexin with better gram negative activity
NO activity against Pseudomonas
Does NOT penetrate protected tissue well
Third Generation Cephalosporins:
Cefovecin
SQ>>IV
Once every 7-14 days in Small animals
Not a sustained release, but large plasma protein binding
Remember only unbound drug is active
NO activity against Pseudomonas
Does NOT penetrate protected tissues well
Third Generation Cephalosporins:
Ceftiofur
- Metabolized to desfuroylceftiofur which is primary active component for systemic administration
- Susceptibility testing is based on ceftiofur though
- Desfuroylceftiofur is less active agianst Staphylococcus compared to ceftiofur, so susceptibilty testing overestimates activity agianst Staphylococcus
- Other bacteria have essentially the same susceptibility to ceftiofur and metabolite
- Penetrate bronchi well, but NOT other protected environments
- Labeled For:
- UTI in dogs
- BRD, foot rot (mastitis for IMM) in cattle
- Respiratory disease in swine, goats, sheep
- Strangles
- Control in early mortality (chicks, poults)
- Used extralabel for many other reasons
Third Generation Cephalosporins:
Ceftiofur:
Sodium Ceftiofur
Naxcel
water soluble solution
Short shelf life (stable 7 days when refrigerated, 12 hours at room temp)
Labeled for beef and dairy cattle, swine, goats, sheep, horses, dogs, day-old chicks/turkey poults
Third generation Cephalosporins:
Ceftiofur:
Ceftiofur hydrochloride
Excenenl RTU EZ
Suspension,
Shelf stable, use within 42 days of opening
Labeled for beed and dairy cattle, swine
Third Generation Cephalosporins:
Ceftiofur
Ceftiofur hydrochloride (Spectramast)
Intrammary use - two formulation
Dry cow
Lactating cow
Third Generation Cephalosporins:
Ceftiofur
Ceftiofur Crystalline Free Acid
Suspension
Shelf stable and sustained release
Use within 12 weeks of opening
Labeled for beef and non-lactating diary cattle, horses, swine
Third Generation Cephalosporins:
Cefotaxime / Ceftriaxone
Uncommon use
Injection only
Good activity agianst gram negative and many gram positive
NOT pseudomonas
Best cephalosporins to protected Blood-brain, prostate, bronchi, ocular barriers
This is the most common reason you would reach for these unless specific C&S states otherwise
Third Generation Cephalosporin:
Ceftazidime:
Uncommon use
Injection only
Similar to cefotaxime/ceftriaxone, except additional activity against Pseudomonas
Carbapenems
Parent drug originally isolated from Streptomyces cattleya
Modified to the drugs currently in use
Carbapenems:
Spectrum
Gram positive, gram negative, aerobic and anaerobic
Activity against some extended spectrum beta lactamases ans Pseudomonas
Carbapenems:
Use
parenteral use only,
Poor penetration into protected tissue
Reserved for resistant infections, and should only be used in consultation with a clinical pharmacologist or infectious disease expert
Carbapenems:
Meropenem
most commonly used
IV, IM, SQ
Carbapenems:
Imipenem / cilastatin
cilastatin added to decrease renal metabolism of imipenem and maintain antimicrobial activity of imipenem in the urine
Less commonly used, need larger volumes, less stable
