Beta-Lactams Antimicrobials

Beta-Lactams

• This class antimicrobials is common in veterinary medicine due to safety, efficacy, flexibility, and low cost.
• The family includes beta-lactamase inhibitors (not antimicrobials), penicillins and derivatives, cephalosporins, penems, and monobactams.
• Penems and Monobactams are omitted, and should be avoided in human medication.

Chemistry of Beta-Lactams

• Chemical skeletons contain a four-member beta-lactam ring.
• This ring is a bacterial resistance mechanism target because it is unstable.
• Gastric pH deactivates most beta-lactam antimicrobials, limiting PO administration, except for penicillin V, aminopenicillins, some antistaphylococcal penicillin, most antipseudomonal penicillin, and some cephalosporins.

Mechanism of Action

• Beta-Lactams inhibit bacterial cell wall peptidoglycan synthesis by transpeptidation, targeting penicillin-binding proteins (PBPs).
• Cell lysis occurs in hypo- or iso-osmotic environments when beta-lactams are only effective against rapidly multiplying organisms.
• Spectrum and action differences are due to relative affinity for different PBPs (2-8 in bacteria).
• Beta-lactams must diffuse through the bacterial cell wall to bind PBPs.
• Gram-negative organisms are less susceptible due to an additional lipopolysaccharide layer that decrease antibiotic penetration.
• Aminopenicillins, extended-spectrum penicillins, cephalosporins, penems, and monobactams exhibit good/excellent activity against Gram-negative bacteria.
• These antibiotics poorly penetrate mammalian cells, limiting their use for intracellular pathogens.
• Beta-lactams exhibit time-dependent killing correlating drug concentration exceeding bacterial MIC with efficacy.

Resistance Mechanisms

• Mechanisms include failure of the antibiotic to penetrate outer cell layers.
• Altering PBPs decreases antimicrobial affinity, like with methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus pseudintermedius (MRSP).
• Bacteria can resist via beta-lactamase enzyme production.

Beta-Lactamase Enzymes

• Bacteria produces as many as 50 beta-lactamase enzymes (penicillinases, cephalosporinases, carbapenemases).
• Beta-lactamases hydrolyze the beta-lactam ring's cyclic amide bond, inactivating the antibiotic.
• Penicillinase enzymes: typically hydrolyze penicillins and aminopenicillins; do not inactivate cephalosporins and antistaphylococcal penicillins, but most are inactivated by beta-lactamase inhibitors.
• Cephalosporinases hydrolyze cephalosporins.
• Extended-spectrum beta-lactamases hydrolyze penicillins, their derivatives, and cephalosporins.
• Carbapenemases hydrolyze all beta-lactams.
• Staphylococcal beta-lactamases, synthesized by coagulase-positive Staphylococcus spp., are penicillinases and plasmid-coded.
• Gram-negative bacteria synthesize diverse beta-lactamases that can be chromosomal/plasmid-coded.
• Chromosomal-mediated beta-lactamases can be penicillinase, cephalosporinase, or extended-spectrum beta-lactamases.
• Plasmid-coded beta-lactamases are usually extended-spectrum.

Beta-Lactamase Inhibitors

• Includes clavulanic acid, sulbactam, tazobactam.
• These are only listed with combined beta-lactams on the WHO list.

Pharmacokinetics of Beta-Lactamase Inhibitors

• Clavulanic acid oral bioavailability varies in dogs.
• Bioavailability of IM injection also varies in foals (88% in neonates vs 27% in older foals).
• Clavulanic acid penetrates tissue; its distribution volume is moderate.

Elimination of Beta-Lactamase Inhibitors

• Clavulanic acid is extensively metabolized in dogs, with unknown antimicrobial activity.
• In dogs 34-52% gets excreted in urine (as unchanged drug and metabolites).
• 25% gets excreted in feces, and 16-33% is eliminated through the respiratory tract.
• Urine levels are high but approximately 1/5 those of amoxicillin.

Beta-Lactamase Inhibitors Drug interactions and Effects

• Penicillin-beta-lactam inhibitor drugs result in a synergistic effect in combination with aminoglycosides.
• Adverse effects are typically beta-lactam antibiotic-related.
• These inhibitors are always combined with beta-lactam antibiotics and have very little antibacterial properties themselves.
• The inhibitors bind irreversibly to Gram-negative/positive bacteria-produced beta-lactamase, which forms an inactive enzyme complex, and allows the co-administered antibiotic to exert its effect.
• Beta-lactamase inhibitors only assist in destructing resistant bacteria producing beta-lactamase enzymes, without affecting other resistance forms.
• They inactivate penicillinase and some cephalosporinases, but do not inactivate all Gram-negative beta-lactamases or carbapenemase.
• Most beta-lactamase synthesized by anaerobes, including Bacteroides fragilis, are susceptible.
• Beta-lactam antibiotic: Clavulanic acid or sulbactam ratio is 2:1 in susceptibility disks, potentially not corresponding to in vivo drug concentrations, which may inaccurately predict testing efficacy.

Formulations of Beta-Lactamase Inhibitors

• Amoxicillin-Clavulanic acid: oral formulations for humans and small animals (Clavamox®, Clavaseptin®).
• Human formulations have differing amoxicillin/clavulanic acid ratios, requiring veterinary product use.
• Sodium ampicillin-sulbactam (Unasyn®) and ticarcillin disodium-clavulanic acid (Timentin®) formulations are for human use (USA/Canada).

Clinical Use of Beta-Lactamase Inhibitors

• Amoxicillin-clavulanic acid: bacterial infections in most tissues (except CNS).
• It is a first-line drug for beta-lactamase-producing staphylococci infections such as superficial bacterial folliculitis in dogs.
• Sodium ampicillin-sulbactam or ticarcillin-clavulanic acid treat sepsis in small animals.
• Sodium ampicillin-sulbactam or ticarcillin-clavulanic acid treat sepsis in valuable foals.

Penicillins

• They include benzylpenicillin (penicillin G) and phenoxymethyl penicillin (penicillin V).
• Penicillin G, the first commercially developed antibiotic, is effective and the initial choice for many bacterial infections.
• Penicillin G is ranked highly important antimicrobials.

Chemistry of Penicillins

• Penicillin G is a weak acid (pKa 2.7) that is rapidly hydrolyzed in stomach acid.
• Penicillin V is not hydrolyzed in this environment.
• Penicillin G is formulated as a water-soluble salt (sodium [Na+] or potassium [K+] penicillin G, also crystalline penicillin), but they are not stable formulations.
• Benzathine penicillin G, and procaine penicillin G are less soluble salt formulations ("long acting").
• Long-acting procaine penicillin G formulations are available in Canada but are oil-based.
• 1 IU of penicillin is 0.6 mcg (1 million IU is 600 mg), and 1 mg of penicillin is 1667 IU.

Pharmacokinetics of Penicillins

• Gastric absorption of penicillin G, poor because of acid hydrolysis, but penicillin V can achieve therapeutic plasma concentrations orally.
• Na+ and K+ salts of penicillin G quickly absorbed via IM/SC reach, but procaine penicillin G is slowly absorbed from IM and produces lower concentrations, though more sustained.
• Benzathine penicillin G is slowly absorbed, producing sustained but subtherapeutic plasma concentrations of penicillin G.
• Procaine penicillin G injection absorption varies, with neck muscle injections causing faster absorption and higher concentrations, versus hindquarters.
• The volume of distribution is low-to-moderate (Vd 0.2-0.3 L/kg) in animals.
• Penicillin G, a weak acid, is highly ionized in plasma with a moderate protein binding degree (25-54%).
• Penicillin distributes mainly into extracellular fluid, without reaching therapeutic concentrations in sequestered infection sites, though penetration may be enhanced by inflammation.
• Eliminated primarily renally as unchanged medication by glomerular filtration/tubular secretion for high urine concentrations.

Elimination, Residues, and Interactions of Penicillins

• Penicillin G has a short half-life after IV administration (1 hour).
• Oral penicillin V has a 3.7-hour half-life.
• Long-acting penicillin's have slow absorption from injection sites.
• Procaine residues in performance horses result from slow elimination of Procaine
• Penicillin long-acting poses violative residue problems and is a common cause for residue violations in food animals.
• Benzathine penicillin G formulations slowly eliminate, which leaves residues at injection site long after withdrawal.
• Label doses have resulted in violative residues 30–60x the limit, even labeling withdrawal times.
• Procaine penicillin G can cause violations if injected into the fascia between semimembranosus/semitendinosus muscles, if more than 10ml/site, or if administered SC vs. IM.
• As penicillin action relies on actively dividing bacteria, avoid administering with bacteriostatic antimicrobials like chloramphenicol or tetracyclines.

Penicillins, Aminoglycosides, Adverse Effects, and Reactions

• Beta-lactam disruption of bacterial cell walls leads to increased aminoglycoside intracellular uptake, which leads to bacterial killing increases.
• There is additive/synergistic activity with aminoglycosides in vivo, though penicillins/aminoglycosides should not be mixed to avoid activating/precipitation.
• Penicillin carries hypersensitivity reactions, especially in horses:
  • Anaphylaxis (Type I): fatal, from prior penicillin exposure.
  • Autoimmune hemolytic anemia (Type II): discontinuing use usually resolves problem, intravenous epinephrine and oxygen administration and are indicated.
  • Vasculitis (Type III Hypersensitivity)
• Penicillin and cephalosporins are 15% cross-reactive in sensitive individuals.
• Penicillin is not used as ophthalmic solutions due to risk of contact sensitization.
• Procaine may cause extreme CNS stimulation when procaine penicillin products are IV administered, and cattle typically do not survive this unless diazepam is administered just prior. Intramuscular injections are needed with procaine.

Electrolyte Imbalances, GI Issues, Spectrum, and Resistance of Penicillins

• Fluid-based penicillin can cause electrolyte imbalances.
• Potassium penicillin G has 1.7 mEq of potassium per million units, so administer by slow IV to prevent cardiac arrhythmias.
• GI upset can occur in all species, and Clostridial spp. can overtake the intestines, which is occasionally fatal.
• Penicillin G, a narrow-spectrum agent, is effective towards aerobic Gram-positive and most anaerobic bacteria.
• Penicillin G is inactive if there are any beta-lactamases.

Susceptibility and Resistance to Penicillin G

• Gram-positive, Aerobic, facultative anaerobes commonly susceptible:
  • Beta-hemolytic Streptococci
  • Beta-lactamase negative Staphylococci
  • Erysipelothrix rhusiopathiae
  • Actinomyces spp.
  • Trueperella pyogenes
  • Some Bacillus anthracis
  • Corynebacterium spp.
• Gram-positive, Anaerobes commonly susceptible:
  • Clostridium spp.
  • No value for intracellular bacteria
• Gram-negative, Little activity against the general aerobes:
  • Notable is Leptospira spp
  • Aerobic Pseudomonas are resistant
• Gram-negative, common anaerobes:
  • Fusobacterium necrophorum
• Beta-lactamase producing Bacteroides spp are resistant, as well has Mycoplasma intrinsically because of their lack of a cell wall.

Dosing, Formulations, and Clinical Use of Penicillin

• Exact penicillin G dosage depends on the species, diagnosis, and exact compound.
• Sodium and potassium penicillin G are only available for IV and possible IM or SC, which is due to short elimination half lives.
• Potassium penicillin is administered frequently, using a CRI.
• Procaine and benzathine penicillin G, which is for oil administration, have extended intervals.
• Food Use - Long Acting is discouraged due to its tendency to lead to antimicrobial residue.
• Procaine penicillin G is the injectable formulation used most for penicillin.

Aminopenicillins

• They include the compounds: ampicillin, hetacillin, amoxicillin.
• Aminopenicillins are ranked as highly important antimicrobials.

Chemistry and Formulations

• Aminopenicillins may be hydrolyzed by ß-lactamases, but are unaffected by gastric acid.
• Hetacillin is a combination of ampicillin and acetone, so it is a prodrug of ampicillin.
• Sodium ampicillin is water-soluble, while ampicillin trihydrate is poorly soluble.
• Aminopenicillins are better at penetrating the outer layer of Gram-negative bacteria than penicillin G, and amoxicillin does this more easily than ampicillin.

Pharmacokinetics of Aminopenicillins

-Small animals: PO amoxicillin is effective, while PO aminopenicillins is not.

• Dogs: Amoxicillin has twice ampicillin's bioavailability (60-80% vs. 30-40%), is unaffected feeding, instead of giving ampicillin 1-2 hours before.
• PO aminopenicillins do not deliver significant concentrations in horses and ruminants.
• IM and SC aminopenicillins (sodium) are effective.
• IM administration of ampicillin trihydrate produces relatively low concentrations that extend for a longer time (flip-flop kinetics), which is due to erratic absorption and low plasma concentrations.
• The penetration of aminopenicillins is high in synovial and other fluids.
• VD is low, generally.
• Ampicillin is lower than amoxicillin, although both are highly protein bound.
• The drug excretes unchanged in the urine.
• Amoxicillin and ampicillin generally have half lives that are short IV.

Interactions of and Spectrum of Aminopenicillins

• Aminopencillins have the same drug interactions and adverse effects as penicillin G
• Broad-spectrum activity; beta-lactamase-producing pathogens hydrolyze.
• Better penetration activity against Gram-negative bacteria (like E. coli, Salmonella, Pasteurella), but this can be acquired easily.
• Most anaerobes are resistant.

Formulations/Administration of Aminopenicillins

• Generally are not given to calves (due to diarrhea), and other small mammals due to intestinal disruptions.
• Available as human tablets/suspension form.
• Amoxi-clav is also a good oral form for pets.
• Ampicillin is found generally as generics or human oral solutions.
• Ampicillin is found in a Polyflex trihydrate suspension.

Antipseudomonal Penicillins

• This section is extended spectrum penicillins.
• The common compounds include: carbenicillin, ticarcillin, pipercillin,
• They rank restricted by the WHO.
• Should be avoided in veterinary practices, if possible.

Metabolism/Resistance of Antipseudomonal Penicillins

• This should be given by the parenteral system.
• Can penetrate Pseudo and negative bacteria because of its range.
• They may lose function as beta-lactam medications.
• Combined beta-catam inhibs.

Cephalosporins

• Cephalosporins are organized via generations based on their antibacterial activity
• Convention has it that “Ph” is used to group and classify pre-1975 drugs, while “f” follows
• Cephalosporins 1st and 2nd generation are ranked highly important antimicrobials.
• Cephalosporins 3rd and 4th generation are ranked highest priority critically important antimicrobials
• USES CAN AND SHOULD follow logical bases
• Extralabel use should be avoided.

Cephalosporin Types and Formulations

• Cephalosporins, they are broad (similar to penicillin), used primarily in the liver.
• Cephalosporins are available as sodium versions through common versions.
• Cefpodoxime proxetil is a prodrug that is de-esterified in the gastrointestinal tract to release the active drug, cefpodoxime.
• Ceftiofur is formulated as sodium solution, hydrochloride formulation and ceftiofur crystalline free acid.

Pharmacokinetics, Safety, and Resistance

• P.O. for dogs and cats, horse infants.
• Generally effective with the IM and SC.
• Protein usage needs considerations.
• Effects are generally similar to penicillins.
• May result in immune reactions of various types.
• Can cause nephrotoxicity.
• Beta-lactamase resistance may become widespread.

Clinical Cephalosporins

• Generation 1 (good alternative with staph/strep for pyoderma, mastitis), with all these medications having the same factors, so choose with what you know (formulation, economy, etc.)
• Generation 2 isn't used frequently in veterinary medicine
• Ceftiofur, Cefpodoxine, can be first line drugs
• Beta Lactamase concerns are elevated in multiple drug resistance