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Find information on animal health topics, written for the veterinary professional.


By Dawn Merton Boothe, DVM, PhD, Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University

The penicillins are among the earliest classes of antibacterial drugs. 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 β-lactamase destruction. Manipulation of some drugs has improved the spectrum, resistance to β-lactamase destruction, or clinical pharmacologic characteristics that enhance efficacy.

Classes by Spectrum

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

Narrow-spectrum β-Lactamase–sensitive Penicillins:

This 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 β-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 (Arcanobacterium) pyogenes, Clostridium spp, Erysipelothrix rhusiopathiae, Actinomyces bovis, Leptospira Canicola, Bacillus anthracis, Fusiformis nodosus, and Nocardia spp.

Broad-spectrum β-Lactamase–sensitive Penicillins:

Penicillins in this class are derived semisynthetically and are active against many gram-positive and gram-negative bacteria. However, they are readily destroyed by the β-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. Several ampicillin precursors more completely absorbed from the GI tract also belong to this class (eg, hetacillin, pivampicillin, talampicillin).

A large number of gram-positive and gram-negative bacteria (but not β-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 β-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 excellent example of such a synergistic association.

Mecillinam is less active than ampicillin against gram-positive bacteria but is highly active against many intestinal organisms (except Proteus spp) that do not produce β-lactamases.

Broad-spectrum β-Lactamase–sensitive Penicillins with Extended Spectra:

Several semisynthetic broad-spectrum penicillins are also active against Pseudomonas aeruginosa, certain Proteus spp, and even strains of Klebsiella, Shigella, and Enterobacter spp in certain cases. Examples of this class include carboxypenicillins (carbenicillin, its acid-stable indanyl ester, and ticarcillin), ureido-penicillins (azlocillin and mezlocillin), and piperazine penicillins (piperacillin).

The anti-Pseudomonas and other extended-spectrum penicillins are active against most of the usual penicillin-sensitive bacteria. They often have a degree of β-lactamase resistance and are usually active against one or more characteristic penicillin-resistant organisms. Yet, as a class, they remain susceptible to destruction by β-lactamases. Examples include the use of carbenicillin, 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. Imipenem and meropenem are relatively resistant to β-lactamase destruction. Their spectrum includes a wide variety of aerobic and anaerobic microorganisms, including most strains of Pseudomonas, streptococci, enterococci, staphylococci, and Listeria. Anaerobes, including Bacteroides fragilis, are highly susceptible.

β-Lactamase–protected Penicillins:

Several naturally occurring and semisynthetic compounds can inhibit many of the β-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 β-Lactamase–resistant Penicillins:

This group, through substitution on the penicillin nucleus (6-aminopenicillanic acid), is refractory to a greater or lesser degree to the effects of various β-lactamase enzymes produced by resistant gram-positive organisms, particularly Staphylococcus 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 given orally and include isoxazolyl penicillins, such as oxacillin, cloxacillin, dicloxacillin, and flucloxacillin. Methicillin and nafcillin are available as parenteral preparations. Temocillin is a semisynthetic penicillin that is β-lactamase stable but also active against nearly all isolates of gram-negative bacteria except Pseudomonas spp.

The semisynthetic β-lactamase–resistant penicillins, such as oxacillin, cloxacillin, floxacillin, and nafcillin, have spectra similar to those noted above (although often at higher MIC) but also include many of the β-lactamase–producing strains of staphylococci (especially S aureus and S epidermidis).


Imipenem and meropenem are among the most active drugs against a wide variety of bacteria. Imipenem is derived from a compound produced by Streptomyces cattleya. Aztreonam is a related (monobactam) compound but differs from other β-lactams in that it has a second ring that is not fused to the β-lactam ring.

General Properties

Structure-activity Relationships:

The penicillins, particularly the β-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 β-lactam nucleus that characterizes penicillins, when cleaved by a β-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 by 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.

Pharmacokinetic Features

The pharmacokinetics of the many penicillins differ substantially. The general guidelines below emphasize singularly significant aspects.


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, but effective concentrations are likely to be achieved only in the urine. Serum concentrations of penicillins generally peak within 2 hr of PO administration. Penicillins may also be absorbed after intrauterine infusion. There is no information regarding bioavailability of human generic products when used off-label in veterinary patients.


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, but 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. Pregnancy increases the volume of distribution, which has the effect of lowering the concentration of drug produced by a given dose.


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


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 hr), which results in high concentrations in urine. Approximately 20% of renal excretion occurs by glomerular filtration and ~80% by 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 hr. 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 hr. Penicillin residues in milk also have been found after intrauterine infusion.

Pharmacokinetic Values:

Selected pharmacokinetic values for some penicillins in a few species are listed in 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 hr in dogs, suggesting that an 8-hr dosing interval is appropriate. Formulations that prolong absorption after IM administration are appropriate for time-dependent drugs, assuming peak concentrations surpass the MIC of the infecting microbes. Dosage modifications may be necessary because of age or disease. However, the general safety of β-lactams may negate the need for dose adjustment in all but profound renal disease.

Elimination, Distribution, and Clearance of Penicillins



Elimination Half-life (min)

Volume of Distribution (mL/kg)

Clearance (mL/kg/min)

Penicillin G
























Therapeutic Indications and Dose Rates

The penicillins are commonly used to treat or prevent local and systemic infections caused by 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 therapy. 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 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 T>MIC for circumstances presented in the individual animal.

Dosages of Penicillins


Dosage, Route, and Frequency

Sodium penicillin G

10,000–20,000 IU/kg, IV or IM, qid

Potassium penicillin G

25,000 IU/kg, PO, qid

Procaine penicillin G

10,000–30,000 IU/kg, IM or SC, once to twice daily

Benzathine penicillin G

10,000–40,000 IU/kg, IM (horses) or SC (cattle), every 48–72 hr

Penicillin V

15,000 IU/kg or 8–10 mg/kg, PO, tid-qid


10–25 mg/kg, IM or PO, qid


5–10 mg/kg, IV, IM, or SC, bid-tid; 10–25 mg/kg, PO, bid-qid


4–10 mg/kg, IM, once to twice daily; 10–20 mg/kg, PO, bid-qid (dogs)

Sodium carbenicillin

10–20 mg/kg, IV or IM, bid-qid

Potassium clavulanate:amoxicillin (1:4)

10–20 mg/kg (amoxicillin) and 2.5–5 mg/kg (clavulanate), PO, bid-qid

Probenecid (prolongs blood concentrations of penicillins that have short plasma half-lives or that are costly)

1–2 mg/1,000 IU penicillin G (dogs), PO, qid

Amoxicillin-clavulanic acid

10–20 mg/kg, PO, bid-qid


1–7 mg/kg, IV or IM, bid-tid


12–24 mg/kg, IV or SC, bid-tid

Ticarcillin (with or without clavulanic acid)

40–110 mg/kg, IM or IV, tid-qid

Special Clinical Concerns

Adverse Effects and Toxicity:

Organ toxicity is rare. Hypersensitivity reactions to penicillin as a hapten reflects, in part, formation of penicillinoic 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 should be administered IV with some caution, especially if hyperkalemia is present. The sodium salt of penicillin G may also contribute to the sodium load in congestive heart failure.


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 depressing vitamin K production by gut flora. Absorption of ampicillin is impaired by the presence of food. β-lactams in general interact chemically with the aminoglycosides and should not be mixed in vitro. Ampicillin and penicillin G are incompatible with many other drugs and solutions and should not be mixed.

Effects on Laboratory Tests:

Laboratory determinations may be altered, depending on the penicillin used. Alkaline phosphatase, AST, ALT, and eosinophil count may be increased. A false-positive Coombs’ test may also result after penicillin therapy. A positive test 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:

Regulatory requirements for withdrawal times for food animals and milk discard times vary among countries. These must be followed carefully to prevent food residues and consequent public health implications. The times listed in Drug Withdrawal and Milk Discard Times of Penicillins serve only as general guidelines.

Drug Withdrawal and Milk Discard Times of Penicillins



Withdrawal Time (days)

Milk Discard Time (days)

Procaine penicillin G


10 (at label dosage)

30 (at 20,000 IU/kg, bid)






Benzathine penicillin G






Preruminant calves






a All administered IM

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