β-Lactams: Antibacterials

• These notes cover antimicrobials focusing on antibacterials, specifically β-lactams.

Objectives

• List different families of β-lactams.
• Identify the family when a molecule is provided.
• List the main molecules used in veterinary medicine for each β-lactam family.
• Recall the World Health Organization's ranking of medically important antimicrobials for human medicine.
• Recall pharmacokinetic (PK) and pharmacodynamic (PD) properties relevant for treatment.
• Remember the common spectrum and resistance patterns.
• Recall drug interactions and main side effects.
• Recall main formulations used in veterinary medicine.
• Recall main clinical applications when indicated.
• Recall controversies about long-acting 3rd generation cephalosporins labeled in veterinary medicine.
• List regulations in food animals regarding cephalosporins.

β-Lactams

• β-Lactams are safe and effective antimicrobials.
• They have a variety of dosage forms and entail low cost.
• Families include:
  • β-lactamase inhibitors
  • Penicillins and derivatives
  • Cephalosporins
  • Penems
  • Monobactams

β-Lactams: Generalities

• Penicillin, discovered in 1928, is a potent antibacterial substance relatively nontoxic to animals and effective against a variety of Gram-positive bacteria.
• Cephalosporin C was discovered in 1945.

β-Lactams: Chemistry

• β-lactam ring is susceptible to bacterial resistance mechanisms and β-lactamase inhibitors.
• Gastric pH deactivates most β-lactam antimicrobials, limiting PO administration. Exceptions include penicillin V, aminopenicillins, some antistaphylococcal penicillins, most antipseudomonal penicillins, and some cephalosporins.

β-Lactams: Mechanism of Action

• Inhibit penicillin-binding protein (PBP), disrupting bacterial cell wall peptidoglycan synthesis.
• Acetylation of transpeptidase (PBP) occurs.
• Weakening of cell wall leads to cell lysis in hyposmotic/isosmotic environments.
• Effective against rapidly multiplying organisms.
• Poor membrane penetration limits use for intracellular pathogens.
• Susceptibility varies: Gram-positive > Gram-negative, except for aminopenicillins, extended spectrum penicillins, cephalosporins, penems, and monobactams.
• Time-dependent antibiotics require beta-lactams to first diffuse through the bacterial cell wall to bind to PBPs.
• They are time-dependent, so T>MIC.
• Slow bactericidal activity due to slow PBP acetylation.
• Maximum acetylation yields maximum antimicrobial effect.

β-Lactams: Resistance Mechanisms

• Bacteria can produce β-lactamases to hydrolyze the β-lactam ring.
• Failure to reach the site of action occurs due to downregulation, including efflux pumps.
• Decreased affinity to PBP results from a mutation of the enzyme produced by the mecA gene, creating PBP-2a (MRSA).

β-Lactams: Drug Interactions

• Synergistic with aminoglycosides.
• Bacteriostatic antimicrobials, especially chloramphenicol and tetracyclines, should not co-administered.

Penicillin & Derivatives

• Penicillin family includes:
  • Penicillins: Penicillin G (benzylpenicillin), Penicillin V (phenoxymethyl penicillin)
  • Aminopenicillins: Ampicillin, Hetacillin, Amoxicillin
  • Antistaphylococcal penicillins: Isoxazolypenicillins (cloxacillin, dicloxacillin, oxacillin), synthetic derivatives (methicillin, nafcillin)
  • Antipseudomonal penicillins: Carbenicillin, Ticarcillin, Piperacillin
• Gram-positive bacteria and anaerobes are susceptible to penicillins whereas Enterobacteriaceae (β-lactamases) and Pseudomonas are not.

Penicillin

• Highly important antimicrobial.
• Penicillin G has pKa of 2.7, is a weak acid which is hydrolyzed in the acidic environment of the stomach or abomasum, but penicillin V is not hydrolyzed in acid environment.
• Penicillin G is a water-soluble salt (sodium [Na+] or potassium [K+]), called crystalline penicillin, and is not stable.
• Less soluble salt formulations: procaine penicillin G and benzathine penicillin G (the least soluble) are long acting formulations.
• Procaine penicillin G formulations in oil are available in Canada.
• Salts of Penicillin G are quickly absorbed by IM or SC route, and procaine penicillin is slower flip flop kinetics
• Benzathine penicillin G absorbed more slowly risk of subtherapeutic plasma concentrations
• The rate of absorption from IM injections of procaine penicillin G varies depending on the injection site.
• Low to moderate (Vd of 0.2-0.3 L/kg) in most animals.
• Penicillin G: Weak acid highly ionized in plasma.
• Distributed mainly in extracellular fluid and may not reach therapeutic concentrations in sequestered infection sites; however, penetration may be enhanced by inflammation.
• Primarily renal elimination occurs as unchanged drug by glomerular filtration and active renal tubular secretion, so urine concentrations are very high.
• The elimination half-life (t1/2) of penicillin G after IV administration is very short (1h).
• Drug residues
  • Procaine is slowly eliminated violative residues noted in performance horses medicated with penicillin procaine G.
  • Long-acting formulations are a common cause of violative residues in food animals.
  • Benzathine penicillin G slowly eliminated, leaving violative residues at the injection site long after the label withdrawal period. These residues can be 30 to 60 times the MRL at the injection site.
  • Procaine penicillin G formulations can cause violations if injected between muscles into the fascia, or if more than 10 mL are injected per site, or if it is injected SC instead of IM.
• Do not administer with bacteriostatic antimicrobials, in particular chloramphenicol, tetracyclines.
• Synergistic with aminoglycosides.
• Immune-mediated reactions
  • Penicillin hypersensitivity reactions, especially in horses.
  • Anaphylaxis (Type I): after exposure and can be fatal.
  • Autoimmune hemolytic anemia (Type II): usually resolves with discontinuation of penicillin therapy - Intravenous epinephrine, oxygen and respiratory support are recommended.
  • Vasculitis (Type III)
• Penicillins and cephalosporins should not be used as commercial ophthalmic formulations due to risk of contact sensitization
• Gastointestinal upset
• GI upset in all species
• Clostridial spp. intestinal overgrowth in guinea pigs, hamsters and rabbits.

Penicillin: Spectrum of activity & resistance

• Penicillin G has a narrow spectrum, is easily inactivated by β-lactamases and therefore has little efficacy against b-lactamases producer organisms.
• Gram-positive aerobes and most anaerobic bacteria are susceptible.
• Ineffective against those bacteria that are resistant by other mechanisms, e.g. impermeable cell wall

Penicillin: Formulations and Use

• Dosage of penicillin G varies greatly depending on the species, disease, and formulation
• Short elimination half-lives require frequent administration.
• Procaine penicillin G is the most used injectable formulation.
• Some injectable formulations are labeled for low dosages, not recommended for therapeutic used withdrawal time recommendation and no more than 10 mL should injected into one site -Long-acting formulations in oil have extended withdrawal times not to be used in lactating dairy cattle. Premix formulations (PO) to swine and poultry for local treatment of enteritis. Intramammary (IMM) formulation alone or combined with dihydrostreptomycin (aminoglycoside) or novobiocin (aminocoumarin)
• Benzathine penicillin G + Procaine penicillin G are long-lasting preparations therefore slow absorption slow elimination violative residues not recommended and not to be used in lactating dairy cattle.
• Clinical Use
  • Choice against streptococcal diseases and anaerobic infections, given IV for life-threatening situations.
  • Small animals: Bacterial respiratory disease caused by Gram + and anaerobes. Can combine with fluoroquinolones in pneumonia with evidence of sepsis (+ lavage for pyothorax).
  • Ruminants: IMM formulations as treatment or prevention in dry cow. Use only penicillin G Streptococcus agalactiae, + dihydrostreptomycin or novobiocin Streptococcus aureus.

Aminopenicillins

• The aminopenicillin family includes ampicillin, hetacillin, amoxicillin, and they are highly important antimicrobials.
• They are hydrolyzed by β-lactamases but not inactivated in gastric acid, and they can penetrate the outer layer of Gram-negative bacteria.
• Hetacillin acts as a pro-drug (ampicillin + acetone)
• Sodium ampicillin is more water-soluble when compared to ampicillin trihydrate.
• Ampicillin sodium can be given IM or SC.
• vs ampicillin trihydrate IM (flip-flop kinetics)
• Do not produce therapeutic concentrations when administered PO to horses and ruminants. vs ampicillin trihydrate.
• They have moderate protein binding.
• Primarily excreted by urine (unchanged) and have a short half-life.
• They have a broad spectrum of effect so they have activity against Gram - and Gram + because of the better penetration of the outer layer of Gram-.
• Amoxicillin has greater activity against Gram-.
• β-lactamase-producing pathogens hydrolyze the aminopenicillin.
• • β-lactamase inhibitors extend the spectrum to include B-lactamase producing Staphylococcus spp., E coli spp. Klebsiella spp., and Proteus spp.
• Aminoglycosides inactivate aminopenicillins via precipitation
• Synergism: b-lactamase inhibitors.
• Antagonism: bacteriostatic drugs
• Clinical use -Ampicillin and amoxicillin in veterinary products or human generic formulations as oral tablets and suspensions -Ampicillin is only available as humal capsules -Amoxicillin-clavulanic acid is only available as as oral formulations (tablets or suspension) for humans and small animals -Sodium ampicillin ( administer every 6 to 8 hrs ) is is available as an aqueous formulation of IV, IM or SC. -Ampicillin tryhydrate is poorly soluble, slow-release aqueous suspension given IM or SC every 12 hours. IN cATTLE, every 24 hours -Hetacillin is available as mammary infussion for cattle
• Surgical prophylaxis. in cases of sepsis, first line small animals ,urinary/bacterial/superficial use, amoxicillin for bacterial cystitis
• Ampicillin -trihydrate bacterial pneumonia in cattle hetacillin or amoxicillin intramammary mastitis

Beta-lactamase inhibitors

• clavulanic acid, sulbactam and tazobactam
• High on on the medical importance scale used for humans Used with B LActam they have drum combinations Clavulanoc acid is used with amoxacillin, sulbactam is used with ampicillin and ticarcillin is used with piperacillin all are B lactamase inhibitors
• Clavulonic acid ,penetrate in the issue and are used for glomular filtration ,metabolizes into fecas
• They destroy bacteriaa resistance but dont icrease the resistace
• inactivate gram postiive and synthesise in most bateria are exceptive
• Used with clavulonic bacteria the ratio should be 2 to 1 for susceptibility Theses is use for in small animals and infections

Antistaphylococcal penicillins

• Highly important antimicrobial Gram positive, dont reach gram negative, and methicillin the reason the anti-drug
• High inistability, and pharmacodunamocs and very resitiant, methicillisn
• the indicators are multi rugs resitince if they are used
• can be used for ELDU, clax, diclox and cloxi

Anti Pseudomonal penicillin

• Are combined when a B lactamase inhibitor is used
• Good in Gram + and aneribes can be used against pseudomans
• Not use in humans unless there are more options left

CEPHALOSPORINS

• For pareneteral used in humans a lot, and great reistance
• there is cefadrin an ceafiexic for veterinary care
• all the cephalosporins is used a lot and not so muc in other cases
• the higher priority cephalosporis are a bit mire hard to see
• to a few animals its only use for cephalosporins
• Can cause vomiting or diarrhea from oral administration.

Penems

• Are very last thing in bacteria use
• Stable B Lac
• Hard to find
• Used if needed but cause sesure on imipenem

Monobactams

• are only for humans
• There is a lot of resitince