Cephalosporins and Cephamycins Use 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 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).

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).

Resistance to the cephalosporins includes mechanisms described in general for beta-lactam antimicrobials ( see 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.

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.

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.

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.

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.

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 to serve as a guide. Dosage modifications are often required in hepatic and renal disease.

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.

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.

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.

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, www.farad.org) for withdrawal recommendations.