pharmacology 5 (cell wall inhibitors part 1)

β-lactam antibiotic classes

Penicillins, cephalosporins, carbapenems (imipenem and meropenem), and monobactams (aztreonam)

Mechanism of action of β-lactams

Penetrate the outer cell wall, then bind and inhibit penicillin binding proteins (PBPs)

Penicillin binding proteins (PBPs)

Transpeptidase enzymes required for cross-linking of cell wall precursors; the target of β-lactams

Effect of β-lactam inhibition of cross-linking

Opens channels (pores) through the cell wall, letting fluid into the cell and causing swelling and death

β-lactam activity type

Bactericidal

β-lactam plasma protein binding

Low (exceptions: cefovecin and ceftiofur)

β-lactam distribution

Distribute well to extracellular fluid in most tissues because they are hydrophilic

β-lactam intracellular concentrations

Minimal; not good for intracellular bacteria

Protected sites and β-lactams

Do NOT distribute well to protected sites (CNS, eye, prostate)

β-lactam metabolism

Minimal (exception: ceftiofur)

β-lactam elimination

Glomerular filtration AND tubular secretion (renal elimination)

β-lactam urine concentration

Very high, about 1000x higher than plasma, because active pumps secrete the drugs into urine

β-lactam half-life

Short, so frequent dosing is required (exceptions: cefovecin and ceftiofur crystalline free acid)

Post-antibiotic effect (PAE) of β-lactams

Some PAE against gram-positive bacteria (e.g. penicillin and streptococci)

β-lactam PK/PD parameter

Time-dependent; efficacy depends on time above MIC (T>MIC)

T>MIC target for β-lactams (normal patient)

50% of the dosing interval

T>MIC target for β-lactams against gram-negative bacteria

80% of the dosing interval (more resistant, so time must be higher)

T>MIC target for β-lactams in immunosuppressed or severely ill patients

90-99% of the dosing interval; give frequent doses

Ways to increase T>MIC

Decrease the dosing interval or give a constant rate infusion (CRI) to maintain therapeutic concentration

Benzylpenicillins

Penicillin G; the first β-lactam, first penicillin, and first antibiotic

Penicillin G spectrum

Gram-positive aerobes (Streptococcus species) and anaerobes (including Clostridium(oides)); limited spectrum today

Penicillin G gram-negative activity

Gram-negative bacteria (E. coli, Klebsiella, Pseudomonas) are usually resistant

Penicillin G and β-lactamases

Inactivated by β-lactamases (e.g. Staphylococci 50-60%, Bacteroides fragilis); the antibiotic is useless because binding is reduced

Penicillin G oral absorption

Limited; degraded in gastric acid

Penicillin G IV formulations

Potassium or sodium salt; human products, expensive and unstable

Penicillin G IM/SC formulations

Complexed with procaine or benzathine; longer half-lives, dosed less frequently, extended release, cheap veterinary products

Benzathine penicillin problem

Stays in the body a long time but concentrations stay below the MIC and barely inhibit bacteria; label dose is outdated

Benzathine penicillin dose issue

Old label dose is 6600 IU/kg but 22,000 IU/kg is needed to reach high concentrations to treat bacteria of the body

Benzathine penicillin vs benzylpenicillin

Benzathine penicillin is NOT the same as benzylpenicillin; benzathine formulations do not reach therapeutic concentrations

Penicillin G dosing intervals by formulation

Potassium penicillin q6h, procaine penicillin q12-24h, benzathine penicillin q48h

Procaine reaction

Adverse effect specific to procaine in some penicillin formulations; NOT a penicillin allergy

Procaine mechanism

Sodium channel blocker like lidocaine; makes injections less painful

Procaine penicillin accidentally injected IV

Causes severe cardiovascular and CNS reactions (procaine reaction, e.g. in a horse)

Aminopenicillins

Ampicillin and amoxicillin

Aminopenicillin oral absorption

Good in small animals (amoxicillin > ampicillin); limited to none in large animals

Ampicillin route of use

More commonly used IV/IM/SC

Aminopenicillin spectrum

Increased gram-negative spectrum (lower urinary tract ONLY) while maintaining gram-positive aerobe and anaerobe activity

Aminopenicillin use in small animals

Used VERY frequently; #1 antibacterial in cats, #2 in dogs

Anti-staphylococcal penicillins

Methicillin and oxacillin; active against staphylococci with minimal activity against anything else; highly resistant to β-lactamases; not used clinically

MRSA/MRSP meaning

Methicillin (oxacillin) resistant Staphylococcus aureus/pseudintermedius

MecA gene

Mediates methicillin resistance; encodes PBP 2a, which has very low binding affinity for ALL β-lactams

Staph resistant to methicillin/oxacillin

Implies MecA is present, so resistant to ALL β-lactams (including carbapenems and monobactams) regardless of what the culture says

Cephalosporin classification

1st, 2nd, and 3rd generation (loosely based on spectrum); 4th and 5th are used in human medicine

1st generation cephalosporin spectrum

Best for gram-positive aerobes, including some β-lactamase positive staphylococci

2nd generation cephalosporin spectrum

Increasing gram-negative activity; gram-positive activity similar to 1st generation; best choice for anaerobes

3rd generation cephalosporin spectrum

Best for gram-negative bacteria; still retains gram-positive activity; anaerobic activity variable

Cephalosporin spectrum trend

Gram-positive activity decreases and gram-negative activity increases from 1st to 3rd generation

1st generation cephalosporins

Cefazolin, cefadroxil, and cephalexin

Cefazolin and cephalexin use

VERY commonly prescribed in dogs and cats; better against Staph

2nd generation cephalosporins

Cefoxitin, cefotetan, and cefaclor; otherwise rarely used in veterinary medicine

2nd generation cephalosporin clinical use

Lower GI and dental surgery

3rd generation cephalosporins (veterinary)

Ceftiofur, cefovecin, and cefpodoxime proxetil

3rd generation cephalosporins (human)

Ceftazidime, ceftriaxone, and cefotaxime; highly active against Pseudomonas and CNS infections

Cephalosporin drugs to know

1st gen: cephalexin, cefazolin; 2nd gen: cefoxitin; 3rd gen: ceftiofur, cefpodoxime proxetil, cefovecin

Cephalexin

Oral 1st generation cephalosporin used in dogs and cats

Cephalexin FDA approval

Chewable tablet in dogs (Rilexine); dermatitis caused by non-methicillin/oxacillin resistant staphylococci

Cefazolin

IV 1st generation cephalosporin used in dogs, cats (sometimes horses); extralabel use

Cefazolin clinical use

Surgical prophylaxis

Cefazolin surgical prophylaxis dosing

Administer within 60 minutes of incision and redose q90-120 minutes until wound closure

Cefpodoxime proxetil

3rd generation oral cephalosporin; currently has the most activity against gram-negative bacteria among veterinary cephalosporins

Cefpodoxime proxetil dosing

Longer half-life; once daily dose gives better owner compliance

Cefpodoxime proxetil label

Labeled for dogs for skin and soft tissue infections; used safely in cats and foals

Cefpodoxime proxetil prodrug

The ester improves oral absorption

Cefovecin (Convenia)

3rd generation cephalosporin FDA approved for skin infections in dogs and cats; single subcutaneous dose

Cefovecin duration

Provides therapeutic concentrations for up to 14 days (duration varies for Staph vs Strep)

Cefovecin long half-life cause

High affinity protein binding and urinary reabsorption

Cefovecin use in cats

2 antibacterial in cats; most often chosen when the cat cannot be medicated orally; should be used judiciously

Long-acting antibiotic concerns

Once administered there is no turning back; effects and adverse effects persist longer; not for severe life-threatening infections

Ceftiofur

3rd generation cephalosporin FDA approved in (dogs), horses, chickens, turkeys, cattle, goats, sheep, and swine; main systemic cephalosporin in large animals

Ceftiofur formulations

Ceftiofur sodium (Naxcel), ceftiofur hydrochloride (Excenel), and ceftiofur crystalline free acid (Excede)

Ceftiofur gram-negative dosing

Although 3rd generation, higher doses are needed for gram-negative bacteria

Ceftiofur crystalline free acid (Excede)

Extended-release formulation with a long half-life; exceeds the MIC for 4-10 days; different by species

Excede dosing by species

Single SC dose at the base of the ear in cattle; single IM dose in swine; IM dose in horses repeated once in 4 days

Excede injection site

Needs to be given in sites with good muscle mass

Excede adverse effects

Injection site reactions are common and can be severe (fever, pain, swelling)

Excede given IV

Becomes short acting

Extralabel use of cephalosporins in food animals

Prohibited by FDA in cattle, swine, chickens, and turkeys

Extralabel cephalosporin exceptions in major food animals

Cephapirin intramammary (IMM) and indications not on the label, as long as all other label conditions are met (dose, route, duration of therapy)

Extralabel indication example

Cattle label for Naxcel lists BRD and foot rot, so it can be used for metritis

Extralabel use in minor food-producing species

No FDA prohibition in minor food-producing species

β-lactam toxicity

Relatively rare adverse effects; very safe class

β-lactam hypersensitivity

Anaphylaxis and immune-mediated hemolytic anemia (IMHA)

Penicillin and cephalosporin cross-reactivity

May exist (about 15% in people)

β-lactam CNS toxicity

At very high concentrations can inhibit GABA, causing CNS excitement and seizures

β-lactam GI effects in dogs and cats

Vomiting with high oral doses due to irritation of the gastric mucosa

β-lactam GI effects in horses and rabbits

High incidence of antibiotic associated colitis with oral administration

Rare β-lactam lab effects

Positive Coombs test without anemia; false-positive glucose test on UA if copper-reduction test is used

Rare cephalosporin hematologic effects

Anemia and thrombocytopenia with high doses of some cephalosporins