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Professional Version

Use of Penicillins in Animals


Melissa A. Mercer

, DVM, MS, DACVIM-LA, Virginia Maryland College of Veterinary Medicine

Reviewed/Revised Sep 2022 | Modified Nov 2022
Topic Resources

Penicillins are divided into subclasses based on chemical structure (eg, penicillins, monobactams, and carbapenems), spectrum (narrow, broad, or extended), source (natural, semisynthetic, or synthetic), and susceptibility to beta-lactamase destruction. Manipulation of some drugs has improved the spectrum, resistance to beta-lactamase destruction, or clinical pharmacological characteristics that enhance efficacy.

Classes by Spectrum

All penicillins are ineffective toward cell wall–deficient microorganisms such as Mycoplasma or Chlamydia spp.

Narrow-spectrum Beta-Lactamase–sensitive Penicillins in Animals

The narrow-spectrum beta-lactamase–sensitive group includes naturally occurring penicillin G (benzylpenicillin) in its various pharmaceutical forms and a few biosynthetic acid-stable penicillins intended for oral use (penicillin V [phenoxymethyl-penicillin] and phenethicillin). Penicillins in this class are active against many gram-positive but only a limited number of gram-negative bacteria. These drugs are also effective against anaerobic organisms. They are, however, susceptible to beta-lactamase (penicillinase) hydrolysis.

Penicillin G and its oral congeners (eg, penicillin V) are active against both aerobic and anaerobic gram-positive bacteria and, with a few exceptions (Haemophilus and Neisseria spp and strains of Bacteroides other than B fragilis), are inactive against gram-negative organisms at usual concentrations. Organisms usually sensitive in vitro to penicillin G include streptococci, penicillin-sensitive staphylococci, Trueperella (formerly Arcanobacterium) pyogenes, Clostridium spp, Erysipelothrix rhusiopathiae, Actinomyces bovis, Leptospira Canicola, Bacillus anthracis, Fusiformis nodosus, and Nocardia spp.

Broad-spectrum Beta-Lactamase–sensitive Penicillins in Animals

Broad-spectrum beta-lactamase–sensitive penicillins are derived semisynthetically and are active against many gram-positive and gram-negative bacteria. However, they are readily destroyed by the beta-lactamases (produced by many bacteria). Many members of the group are acid stable and are administered either PO or parenterally. Of those used in veterinary medicine, aminopenicillins (eg, ampicillin and amoxicillin, which may also be produced naturally), are the best known. Ampicillin precursors that are more completely absorbed from the GI tract also belong to this class (eg, hetacillin).

A large number of gram-positive and gram-negative bacteria (but not beta-lactamase–producing strains) are sensitive to the semisynthetic broad-spectrum penicillins (ampicillin and amoxicillin). Susceptible genera include Staphylococcus, Streptococcus, Trueperella, Clostridium, Escherichia, Klebsiella, Shigella, Salmonella, Proteus, and Pasteurella. Although bacterial resistance is widespread, the combination of beta-lactamase inhibitors and broad-spectrum penicillins markedly enhances the spectrum and efficacy against both gram-positive and gram-negative pathogens. Clavulanate-potentiated amoxicillin is an example of such a synergistic association.

Mecillinam, or amdinocillin, is less active than ampicillin against gram-positive bacteria but is highly active against many intestinal organisms (except Proteus spp) that do not produce beta-lactamases. Mecillinam, however, is designated by the FDA as a Qualified Infectious Disease Product for use in humans for the treatment of complicated urinary tract infections. Furthermore, amdinocillin (mecillinam) products have been discontinued in the US and are no longer available.

Broad-spectrum Beta-Lactamase–sensitive Penicillins With Extended Spectra in Animals

Several semisynthetic broad-spectrum beta-lactamase–sensitive penicillins with extended spectra are also active against Pseudomonas aeruginosa, certain Proteus spp, and even strains of Klebsiella, Shigella, and Enterobacter spp in certain cases. Examples include carboxypenicillins (ticarcillin) and ureidopenicillins (includingpiperazine penicillins such as piperacillin). Of these drugs, only ticarcillin is FDA approved for veterinary use as an intrauterine infusion in horses.

The anti-Pseudomonas and other extended-spectrum penicillins are active against most of the usual penicillin-sensitive bacteria. They often have a degree of beta-lactamase resistance and are usually active against one or more characteristic penicillin-resistant organisms. Yet, as a class, they remain susceptible to destruction by beta-lactamases. Examples include the use of ticarcillin and piperacillin against P aeruginosa and several Proteus strains, and the use of piperacillin against P aeruginosa, several Shigella and Proteus strains, and some Citrobacter and Enterobacter spp. Streptococcus faecalis is often resistant to these new extended-spectrum penicillins.

Beta-Lactamase–protected Penicillins in Animals

Several naturally occurring and semisynthetic compounds can inhibit many of the beta-lactamase enzymes produced by penicillin-resistant bacteria. When used in combination with broad- or extended-spectrum penicillins, there is a notable synergistic effect because the active penicillin is protected from enzymatic hydrolysis and thus is fully active against a wide variety of previously resistant bacteria. Examples of this chemotherapeutic approach include clavulanate-potentiated amoxicillin and ticarcillin as well as sulbactam-potentiated ampicillin and tazobactam-potentiated piperacillin.

Narrow-spectrum Beta-Lactamase–resistant Penicillins in Animals

The narrow-spectrum beta-lactamase–resistant penicillins group, via substitution on the penicillin nucleus (6-aminopenicillanic acid), is refractory to a greater or lesser degree to the effects of various beta-lactamase enzymes produced by resistant gram-positive organisms, particularly S aureus. However, penicillins in this class are not as active against many gram-positive bacteria as penicillin G and are inactive against almost all gram-negative bacteria. Acid-stable members of this group may be administered PO or locally (eg, intramammary) and include isoxazolyl penicillins, such as oxacillin, cloxacillin, and dicloxacillin. Nafcillin is available as a parenteral preparation. Temocillin is a semisynthetic penicillin that is beta-lactamase stable but also active against nearly all isolates of gram-negative bacteria except Pseudomonas spp; however, it is not available on the US market.

The semisynthetic beta-lactamase–resistant penicillins, such as oxacillin, cloxacillin, and nafcillin, have spectra similar to the other drugs in this group (although often at higher MIC) but also include many of the beta-lactamase–producing strains of staphylococci (especially S aureus and S epidermidis).

Carbapenems in Animals

The carbapenems (imipenem, meropenem, doripenem, and ertapenem) are relatively resistant to beta-lactamase destruction. Imipenem is derived from a compound produced by Streptomyces cattleya. Aztreonam is a related (monobactam) compound but differs from other beta-lactam antimicrobials in that it has a second ring that is not fused to the beta-lactam ring.

The carbapenems are among the most active drugs against a wide variety of bacteria. Their spectrum includes a wide variety of aerobic and anaerobic microorganisms, including most strains of Pseudomonas, Klebsiella, Escherichia coli, streptococci, staphylococci, and Listeria. Anaerobes, including Bacteroides fragilis, are highly susceptible. Of particular note is the efficacy of carbapenems against extended-spectrum beta-lactamase (ESBL)–containing organisms. Some strains of Klebsiella pneumoniae contain carbapenemases (KPC) that render it resistant to carbapenems.

In terms of individual spectrum, ertapenem is considered to be less active than imipenem or meropenem against Pseudomonas, and meropenem is less active than either imipenem or doripenem against Acinetobacter baumannii. In humans, meropenem combined with clavulanic acid is effective against multidrug-resistant Mycobacterium tuberculosis.

Carbapenems are considered critically important antimicrobials by the World Health Organization and should be restricted for use in documented multidrug-resistant infections in both human and veterinary medicine. None of the drugs in this class are FDA approved for use in animals; however, imipenem and meropenem are the mostly commonly used in an extralabel fashion in veterinary medicine.

General Properties

Structure-activity Relationships of Penicillins in Animals

The penicillins, particularly the beta-lactam ring, are somewhat unstable, being sensitive to heat, light, extremes in pH, heavy metals, and oxidizing and reducing agents. Also, they often deteriorate in aqueous solution and require reconstitution with a diluent just before injection. Penicillins are poorly soluble, weak organic acids administered parenterally either as suspensions in water or oil or as water-soluble salts. For example, sodium or potassium salts of penicillin G are highly water-soluble and are absorbed rapidly from injection sites, whereas organic esters in microsuspension such as procaine penicillin G or benzathine penicillin G are gradually absorbed over 1–3 (or even more) days, respectively. The trihydrate forms of the semisynthetic penicillins have greater aqueous solubility than the parent compounds and are usually preferred for both parenteral and oral use.

The beta-lactam nucleus that characterizes penicillins, when cleaved by a beta-lactamase enzyme (penicillinase), produces penicilloic acid derivatives that are inactive but may act as the antigenic determinants for penicillin hypersensitivity. Modification of the 6-aminopenicillanic acid nucleus, either via biosynthetic or semisynthetic means, has produced the array of penicillins used clinically. These differ in their antibacterial spectra, pharmacokinetic characteristics, and susceptibility to microbial enzymatic degradation. There appears to be little to no cross-reactivity in hypersensitivity reactions between penicillins and carbapenems.

The presence of a carbon atom at the C1 position is critical to the potency and spectrum of the carbapenems. This quality plus the types and positions of side chains aids in their resistance to beta-lactamases. Imipenem, the first carbapenem developed for treatment of complex microbial infections, is subject to inactivation by dehydropeptidase I present in the renal brush border. Therefore, imipenem is typically combined with a dehydropeptidase inhibitor such as cilastatin. The addition of a methyl group to the 1beta position is protective against dehydropeptidase destruction, and therefore newer carbapenems (ie, meropenem, doripenem, and ertapenem) contain this modification.

Pharmacokinetic Features

The pharmacokinetics of the many penicillins differ substantially. These general guidelines emphasize singularly important aspects.

Absorption of Penicillins in Animals

Most penicillins in aqueous solution are rapidly absorbed from parenteral sites. Absorption is delayed when the inorganic penicillin salts are suspended in vegetable oil vehicles or when the sparingly soluble repository organic salts (eg, procaine penicillin G and benzathine penicillin G) are administered parenterally. Although prolonged absorption results in longer persistence of plasma and tissue drug concentrations, peak concentrations may not be sufficiently high to be effective against organisms unless MICs are low. The penicillin G repositol salts should never be injected IV. Only selected penicillins are acid stable and can be administered PO at standard doses.

Absorption from the upper GI tract differs markedly in amount and rate among the various penicillins. Penicillin V must be given at high oral doses. The aminopenicillins are orally bioavailable, although food impairs the absorption of ampicillin. Paracellular (as opposed to transcellular) transport may play a major role in oral absorption. The indanyl form of carbenicillin is orally bioavailable; however, effective concentrations are likely to be achieved only in the urine. Serum concentrations of penicillins generally peak within 2 hours after PO administration. Penicillins may also be absorbed after intrauterine infusion. Information regarding bioavailability of human generic products when used in veterinary patients (ie, in an extralabel fashion) is lacking.

Carbapenems have low oral bioavailability and limited ability to cross gastrointestinal membranes and therefore are only available in parenteral forms. Although all carbapenems may be administered IV, imipenem and ertapenem may also be administered IM.

Distribution of Penicillins in Animals

After absorption, penicillins are widely distributed in body fluids and tissues. The volume of distribution tends to reflect extracellular compartmentalization, although some penicillins (including carbapenems) penetrate tissues quite well. Potentially therapeutic concentrations of the various penicillins are generally found in the liver, bile, kidneys, intestines, muscle, and lungs; however, only very low concentrations are found in poorly perfused areas such as the cornea, bronchial secretions, cartilage, and bone. The diethylamino salt of penicillin G produces particularly high concentrations in pulmonary tissue.

The penicillins usually do not readily cross the normal blood-brain, placental, mammary, or prostatic barriers unless massive doses are given or inflammation is present. Penicillins may be substrates for P-glycoprotein efflux from the CNS. Selected penicillins are able to penetrate nonchronic abscesses and pleural, peritoneal, or synovial fluids. Penicillins are reversibly and loosely bound to plasma proteins. The extent of this binding varies with particular penicillins and their concentration (eg, ampicillin is usually ~20% bound, and cloxacillin may be ~80% bound). Protein binding varies dramatically among the carbapenems, with meropenem being ~2% protein bound, imipenem being ~20% protein bound, and ertapenem being ~90%–95% protein bound. Pregnancy increases the volume of distribution, which has the effect of lowering the concentration of drug produced via a given dose.

Biotransformation of Penicillins in Animals

Penicillins are generally excreted unchanged; however, fractions of a given dose may undergo metabolic transformations via unknown mechanisms (usually < 20% metabolized). Penicilloic acid derivatives that are formed tend to be allergenic.

Excretion of Penicillins in Animals

Most (60%–90%) of a parenterally administered penicillin is eliminated in the urine within a short time (eg, up to 90% of penicillin G within 6 hours), which results in high concentrations in urine. Approximately 20% of renal excretion occurs via glomerular filtration and ~80% via active tubular secretion—a process that may be deliberately inhibited (to prolong effective concentrations in the body) by probenecid and other weak organic acids. Anuria may increase the half-life of penicillin G (normally ~30 min) to 10 hours. Carbapenems are also eliminated via the renal route, and renal disorders increase the elimination half-life and may require dose adjustment. The biliary route also may be a major excretory pathway for the broad-spectrum semisynthetic penicillins. Clearance is considerably lower in neonates than in adults. Penicillins are also eliminated in milk, although often only in trace amounts in the normal udder, and may persist for up to 90 hours. Penicillin residues in milk also have been found after intrauterine infusion.

Pharmacokinetic Values of Penicillins in Animals


Selected pharmacokinetic values for some penicillins in a few species are listed in Elimination, Distribution, and Clearance of Penicillins Elimination, Distribution, and Clearance of Penicillins Elimination, Distribution, and Clearance of Penicillins . Penicillins, in general, have very short elimination half-lives, which is problematic for time-dependent drugs. For example, ~90% of amoxicillin will be eliminated within 4 hours in dogs, suggesting that an 8-hour dosing interval is appropriate. Formulations that prolong absorption after IM administration are appropriate for time-dependent drugs, assuming peak concentrations surpass the minimum inhibitory concentration (MIC) of the infecting microbes. Dosage modifications may be necessary because of age or disease. However, the general safety of beta-lactam antimicrobials may negate the need for dose adjustment in all but profound renal disease. It should be noted that the species, age, physiologic status (eg, sick or pregnant), formulation, dose, route, and frequency (eg, single vs multiple doses) may affect pharmacokinetic parameters.

Therapeutic Indications and Dose Rates

Therapeutic indications for penicillins include local and systemic infections due to susceptible bacteria. Several acute infectious disease syndromes are specifically responsive. Because of their synergistic interaction with other antimicrobials, they are often used as part of combination treatment. Penicillins also are used topically in the eye and ear as well as on the skin; intramammary administration is common for treatment or prevention of bovine mastitis. Amoxicillin with or without clavulanic acid is among the first-choice antimicrobials for treatment of canine or feline urinary tract infections.


A selection of general dosages for some penicillins is listed in the table Dosages of Penicillins Dosages of Penicillins Dosages of Penicillins . The dose rate and frequency should be adjusted as indicated by changes in MICs in target antimicrobial populations and as necessary to achieve and maintain an appropriate time above MIC for circumstances in the individual animal.

Special Clinical Concerns

Adverse Effects and Toxicity of Penicillins in Animals

Organ toxicity from penicillins is rare in animals; however, nephrotoxicity is a risk with carbapenem treatment. Imipenem is subject to metabolism by dehydropeptidase I present in the renal brush border leading to accumulation of toxic metabolites and renal tubular necrosis. Therefore, imipenem is typically combined with a dehydropeptidase inhibitor such as cilastatin. Imipenem may also lower seizure threshold in patients with CNS disorders such as epilepsy and head trauma. The newer carbapenems, such as meropenem, have less nephrotoxic potential. Hypersensitivity reactions to penicillin as a hapten reflects, in part, formation of penicilloic acid. Hypersensitivity (particularly in cattle) includes skin reactions, angioedema, drug fever, serum sickness, vasculitis, eosinophilia, and anaphylaxis. Cross-sensitivity among penicillins is well recognized.

Intrathecal administration may result in convulsions. Guinea pigs, chinchillas, birds, snakes, and turtles are sensitive to procaine penicillin. The use of broad-spectrum penicillins may lead to superinfection, and GI disturbances may occur after PO administration of ampicillin. Potassium penicillin G contains approximately 1.7 mEq/million units of penicillin and should be administered IV with some caution, especially in the case of hyperkalemia. The sodium salt of penicillin G may also contribute to the sodium load in congestive heart failure. Rapid IV administration of carbapenems may result in seizure activity.

Interactions With Penicillins in Animals

Active renal tubular secretion is delayed in the presence of selected organic ions, including salicylates, phenylbutazone, sulfonamides, and other weak acids. Gut-active penicillins potentiate the action of anticoagulants by decreasing vitamin K production by gut flora. Absorption of ampicillin is impaired by the presence of food. Beta-lactam antimicrobials in general interact chemically with the aminoglycosides and should not be mixed in vitro. Procaine, in procaine penicillin G, is metabolized to para-aminobenzoic acid (PABA), which may inactivate sulfonamide antimicrobials. Ampicillin and penicillin G are incompatible with many other drugs and solutions and should not be mixed.

Effects of Penicillins on Laboratory Tests of Animals

Laboratory determinations may be altered, depending on the penicillin used. Activities of alkaline phosphatase (ALP), AST, and ALT as well as eosinophil count may be increased. False-positive Coombs test results may also occur after penicillin treatment. A positive test result for urine glucose and protein is also possible. Procaine is detectable in the urine of horses for several days after administration of procaine penicillin; withdrawal time before competition may be up to 6 days.

Drug Withdrawal and Milk Discard Times for Penicillins in Animals

Regulatory requirements for drug withdrawal times for production animals and milk discard times vary among countries. These must be followed carefully to prevent food residues and consequent public health implications. Withdrawal times can vary between products, even for the same drug. Therefore, when using products according to label recommendations, it is imperative to follow the label meat and milk withdrawal times for the particular product used.

For instances of extralabel drug use (ELDU), it is recommended to contact a country-specific advisory program to obtain evidence-based withdrawal recommendations extrapolated from known species pharmacokinetics. In the US, veterinarians may contact the Food Animal Residue Avoidance Databank (FARAD, for withdrawal recommendations.

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