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Cephalosporins and Cephamycins Use in Animals


Melissa A. Mercer

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

Reviewed/Revised Sep 2022 | Modified Nov 2022
Topic Resources

The cephalosporins, and the closely related cephamycins, are similar to penicillins in several respects, sharing pharmacological group features.

Classes and Antibacterial Spectra

Cephalosporins include cephamycins, which differ from other cephalosporins in that they contain a 7-alpha-methoxy group, which imparts resistance to extended-spectrum beta-lactamases. The early cephalosporins differed mainly with respect to pharmacokinetic characteristics. Whereas penicillins were classified based on source (natural vs semisynthetic) and spectra, cephalosporins are classified by generation (1–4). Later generations are more resistant to beta-lactam destruction and are often characterized by extended but variable spectra.

First-generation Cephalosporins in Animals

First-generation cephalosporins include cephaloridine, cephapirin, cefazolin, cephalexin, cephradine, and cefadroxil. Cephalosporins in this group are usually quite active against many gram-positive bacteria but are only moderately active against gram-negative organisms. They are ineffective against Enterococcus spp, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus. Susceptible gram-negative bacteria include Escherichia coli and Proteus, Klebsiella, Salmonella, Shigella, and Enterobacter spp. Cefazolin is more effective against E coli than cephalexin, to which it is minimally susceptible. Although generally less susceptible to beta-lactamase destruction than penicillins, cephalosporins are susceptible to cephalosporinases and are not as effective against anaerobes as are the penicillins.

Second-generation Cephalosporins in Animals

Second-generation cephalosporins include cefamandole, cefoxitin (a cephamycin), cefotiam, cefachlor, cefuroxime, and ceforanide. These agents are generally active against both gram-positive and gram-negative bacteria. Moreover, they are relatively resistant to beta-lactamases compared with first-generation drugs. They are not effective against Enterococcus spp, Salmonella spp, methicillin-resistant Staphylococcus spp, P aeruginosa (with the frequent exception of cefoxitin), Actinobacter spp, and many obligate anaerobes (again, cefoxitin is an exception).

Third- and Fourth-generation Cephalosporins in Animals

The third-generation cephalosporins include ceftiofur, ceftriaxone, cefsulodin, cefotaxime, cefoperazone, moxalactam (not a true cephalosporin), and several others, including cefpodoxime and cefovecin, approved for use in dogs and for use in dogs and cats, respectively. Cefepime is a fourth-generation cephalosporin. The spectrum of third- and fourth-generation cephalosporins varies and should be confirmed based on bacteriologic culture and antimicrobial susceptibility testing before use. The spectrum of veterinary third-generation cephalosporins should not be considered extended in that efficacy often does not include Pseudomonas or other problematic coliforms.

Ceftiofur is a third-generation cephalosporin with a gram-negative spectrum that is more similar to that of first-generation cephalosporins. Ceftiofur has been specifically approved for use in cattle with bronchopneumonia, especially if due to Mannheimia haemolytica or Pasteurella multocida. Although it is approved for use in dogs to treat urinary tract infections (injectable), other more convenient drugs are generally used. Cefpodoxime and cefovecin are particularly effective against Staphylococcus pseudintermedius, yet retain fair efficacy toward gram-negative organisms such as E coli, Klebsiella, and Proteus.

Some drugs approved for use in people have only moderate activity against gram-positive bacteria (again, enterococci are resistant) but have extensive activity against a wide variety of gram-negative bacteria, including Pseudomonas spp, Proteus vulgaris, Enterobacter spp, and Citrobacter spp (eg, cefotaxime and ceftazidime). Third- and fourth-generation cephalosporins were designed to be increasingly resistant to beta-lactamases. However, differences in chemical structure have been overcome by the formation of extended-spectrum beta-lactamases that target third- and fourth-generation drugs (but not, as a general rule, cephamycins).

General Properties

The physical and chemical properties of the cephalosporins are similar to those of the penicillins, although the cephalosporins are somewhat more stable to pH and temperature changes. Cephalosporins are weak acids derived from 7-aminocephalosporanic acid. They are used either as the free base form for PO administration (if acid stable) or as sodium salts in aqueous solution for parenteral delivery (sodium salt of cephalothin contains 2.4 mEq of sodium/g). Cephalosporins also contain a beta-lactam nucleus susceptible to beta-lactamase (cephalosporinase) hydrolysis. These beta-lactamases may or may not also target penicillins. Modifications of the 7-aminocephalosporanic acid nucleus and substitutions on the side chains via semisynthetic means have produced differences among cephalosporins in antibacterial spectra, beta-lactamase sensitivities, and pharmacokinetics.

Antimicrobial Activity

Bacterial Resistance to Cephalosporins and Cephamycins in Animals

Resistance to the cephalosporins includes mechanisms described in general for beta-lactam antimicrobials ( see Antimicrobial Activity Antimicrobial Activity Beta-lactam antimicrobials, named after the active chemical component of the drug (the 4-member beta-lactam ring), include the 6-membered ring-structured penicillins, monobactams, and carbapenems... read more Antimicrobial Activity ). Cephalosporins generally are stable against the plasmid-mediated beta-lactamases produced by gram-positive bacteria such as Staphylococcus aureus. Several types of inducible beta-lactamases produced by gram-negative organisms may be mediated by either plasmids or chromosomally and may hydrolyze either or both penicillins and cephalosporins (cross-resistance). Second- and particularly third-generation cephalosporins have greater stability against beta-lactamases produced by gram-negative bacteria.

Extended-spectrum beta-lactamases (ESBLs) have been increasingly identified in a number of bacteria, mainly Enterobacteriaceae(including E coli) and Klebsiella spp; however, ESBL production has also been increasing in Salmonella spp. The ESBLs are plasma-mediated enzymes that hydrolyze the oxyimino side chain on extended-spectrum cephalosporins, including third- and fourth-generation drugs such as cefotaxime, ceftriazone, and ceftazidime. Plasmids encoding ESBL genes also often encode for other resistance genes that may affect other classes of antimicrobials. The presence of ESBLs can be determined on susceptibility testing based on resistance to these drugs but susceptibility to clavulanic acid, tazobactam, or sulbactam.

Pharmacokinetic Features

Limited information regarding the pharmacokinetics of cephalosporins in animals is available.

Absorption of Cephalosporins and Cephamycins in Animals

Only a few cephalosporins are acid stable and thus effective when administered PO (eg, cephalexin, cephradine, cefadroxil, cefpodoxime, and cefachlor). They are usually well absorbed, and bioavailability is 75%–90% in small animals. Although cefpodoxime has acceptable bioavailability in neonatal foals, older foals and adult horses have poor bioavailability of any of the oral cephalosporins. There is no information regarding bioavailability of human generic products when used in an extralabel fashion in veterinary patients. The others are administered either IV or IM, with plasma concentrations peaking ~30 minutes after injection.

Ceftiofur crystalline-free acid and cefovecin are the two sustained-release formulations approved for veterinary use. Cefovecin is sustained release in small animals due to its intrinsic long elimination half-life, whereas ceftiofur crystalline-free acid is sustained release due to its vehicle.

Distribution of Cephalosporins and Cephamycins in Animals

Cephalosporins are distributed into most body fluids and tissues, including kidneys, lungs, joints, bone, soft tissues, pericardial fluid, and the biliary tract; however, in general, the volume of distribution is < 0.3 L/kg. This low volume of distribution suggests that distribution primarily remains in the extracellular fluid. However, poor penetration into the CSF, even in inflammation, is a notable feature of the standard cephalosporins. Cephalosporins are substrates for P-glycoprotein efflux from the CNS. The third-generation cephalosporins (eg, moxalactam) may achieve good penetration into the CSF.

The degree of plasma-protein binding is variable (eg, 20% for cefadroxil and 80% for cefazolin). The high degree of protein binding of cefovecin (90% in dogs; 99% in cats) contributes to its long elimination half-life (5.5 days in dogs, 6.9 days in cats). However, drug concentrations in transudate remain above the MIC90 of both Staphylococcus intermedius and E coli for up to 14 days. Third- or fourth-generation cephalosporins are often able to penetrate the blood-brain barrier and are frequently indicated in bacterial meningitis due to susceptible pathogens. In general, cephalosporins poorly penetrate the ocular humor.

Biotransformation of Cephalosporins and Cephamycins in Animals

Several cephalosporins (eg, cephalothin, cephapirin, ceftiofur, cephacetrile, and cefotaxime) are actively deacetylated, primarily in the liver but also in other tissues. The deacetylated derivatives are much less active, with the exception of ceftiofur. Ceftiofur is metabolized to several active metabolites, including an acetylated metabolite (desfuroylceftiofur), that can contribute substantially to efficacy. However, esfuroylceftiofur is less active than ceftiofur against S aureus and Proteus spp. Few of the other cephalosporins are metabolized to any appreciable extent.

Excretion of Cephalosporins and Cephamycins in Animals

Most cephalosporins, including cefpodoxime and cefovecin, are rapidly renally excreted. Tubular secretion predominates, although glomerular filtration is important in some cases (cephalexin and cefazolin). In the case of renal failure, dosages might be decreased, although the need for doing so is not clear because there is a low risk of adverse effects at high concentrations. Biliary elimination of the newer cephalosporins (eg, cefoperazone) may be appreciable. Therefore, hepatic insufficiency may lead to drug accumulation. Generally, these beta-lactam antimicrobials maintain effective blood concentrations for only 6–8 hours. Exceptions include ceftiofur, cefpodoxime, and cefovecin.

Pharmacokinetic Parameters of Cephalosporins and Cephamycins in Animals


Plasma half-lives of cephalosporins are quite variable, being as short as 30–120 minutes but generally longer than those of penicillins. For example, the half-life of the approved cephalexin product in dogs after administration PO is 7.3 hours (9 hours if given with food). Third-generation cephalosporins tend to have longer plasma half-lives in people; however, this is not always the case in other animals—substantial species differences exist. A selection of pharmacokinetic values for cephalosporins is listed in the table Elimination, Distribution, and Clearance of Cephalosporins Elimination, Distribution, and Clearance of Cephalosporins Elimination, Distribution, and Clearance of Cephalosporins to serve as a guide. Dosage modifications are often required in hepatic and renal disease.

Therapeutic Indications and Dose Rates

First-generation cephalosporins have proved useful, particularly for infections involving Staphylococcus spp (eg, oral cephalexin for dermatitis) and for surgical prophylaxis (eg, cefazolin). However, their efficacy appears to be declining because of emerging resistance, including methicillin-resistant organisms. Ceftiofur is approved for use in a variety of production animals. It is approved for bovine respiratory disease principally due to Pasteurella spp and in urinary tract infections in dogs. Use of ceftiofur for treatment of soft-tissue infections in dogs is not recommended because proper dosages and safety have not been documented. Cefpodoxime (PO) has been approved for use in dogs, and cefovecin (SC) has been approved for use in dogs and cats.

Cephalosporins are particularly useful to treat infections of soft tissue and bone due to bacteria that are resistant to other commonly used antimicrobials. Cefazolin (IV) has been administered prophylactically 1 hour before surgery. More than most penicillins, cephalosporins may penetrate tissues and fluids sufficiently (CSF being an exception for most) to be effective in management of osteomyelitis, prostatitis, and arthritis.

Orally administered cephalosporins can be effective in management of urinary tract infections, except those due to P aeruginosa. Cephalexin should be anticipated to be ineffective against E coli. Cephapirin benzathine is used for dry-cow treatment, and cephapirin sodium is used to treat mastitis in lactating cattle. Except for cephapirin, extralabel use of cephalosporins is prohibited in major food-producing animal species (cattle, swine, chickens, and turkeys). Although not expressly prohibited in minor food-producing animal species, cephalosporins should be viewed as restricted-class antimicrobials due to their critical importance in human medicine.


A selection of general dosages for some cephalosporins is listed in Dosages of Cephalosporins Dosages of Cephalosporins Dosages of Cephalosporins . The dose rate and frequency should be adjusted as needed for the individual animal.

Special Clinical Concerns

Adverse Effects and Toxicity of Cephalosporins and Cephamycins in Animals

The approved cephalosporins are relatively nontoxic and have a relatively high therapeutic index. Cephalosporins injections IM can be painful, and repeated IV administration may lead to local phlebitis. Nausea, vomiting, and diarrhea may occasionally occur. Antimicrobial-induced colitis due to perturbations in GI flora has been reported. Hypersensitivity reactions of several forms have occurred, with cross-reactivity to penicillin allergies possible. Superinfection may arise with the use of cephalosporins, and Pseudomonas or Candida spp are likely opportunistic pathogens. Cephalosporins do have nephrotoxic potential via immune complex deposition in the glomerular basement membrane or direct toxicity causing acute tubular necrosis; however, these effects are rarely seen at clinically relevant doses.

Interactions With Cephalosporins and Cephamycins in Animals

In vitro incompatibilities are quite common for cephalosporin and cephamycin preparations; an exception exists when mixing with weak bases such as aminoglycosides. Potential pharmacokinetic interactions are similar to those of the penicillin group. Cephalosporins can be synergistic against a number of pathogens.

Effects of Cephalosporins and Cephamycins on Laboratory Tests in Animals

Several laboratory determinations may be altered by the cephalosporins. Activities of ALP, AST, ALT, and lactate dehydrogenase as well as BUN concentration may be increased. False-positive Coombs test results and urine glucose test results are also possible. Hypernatremia may be caused by the sodium salts of various cephalosporins.

Drug Withdrawal and Milk Discard Times of Cephalosporins and Cephamycins in Animals

Although prolonged tissue residues for most cephalosporins are not anticipated, withdrawal times are not available for most of the cephalosporins because they are not approved for use in food-producing animals in most countries. In the US, cephalosporins (excluding cephapirin) are prohibited from extralabel drug use (ELDU) except for indication in major species (cattle, swine, chickens and turkeys). This includes deviations from the approved dose, treatment duration, frequency, or administration route on the product label; the use of a product in an unapproved major species or animal production class; and the use of the product for the purpose of disease prevention. In the US, ELDU is permissible in minor species (including small ruminants, camelids, and game birds). Withdrawal times can vary between products, so it is imperative to follow the label meat and milk withdrawal times for the particular product used.

For instances of permissible 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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