Cephalosporins and Cephamycins
The cephalosporins, and the closely related cephamycins, are similar to penicillins in several respects, sharing pharmacologic group features.
Cephalosporins include cephamycins, the latter of which differ from other cephalosporins in that they contain a 7-alpha-methoxy group, which imparts resistance to extended-spectrum β-lactamases.. The early cephalosporins differed mainly with respect to pharmacokinetic characteristics. Whereas penicillins were classified based on source (natural versus semisynthetic) and spectra, cephalosporins are classified by generations (1–4). Later generations are more resistant to β-lactam destruction and are often characterized by extended but variable spectra.
This group includes cephalothin (no longer marketed in the USA), 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 enterococci. Susceptible gram-negative bacteria include Escherichia coli and Proteus, Klebsiella, Salmonella, Shigella, and Enterobacter spp. Cefazolin is more effective against E coli than cephalexin, the latter of which is minimally susceptible. Although generally less susceptible to β-lactamase destruction than penicillins, they are susceptible to cephalosporinases. They are not as effective against anaerobes as are the penicillins.
This group includes 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 β-lactamases compared with first-generation drugs. They are ineffective against enterococci, Pseudomonas 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 culture and 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 has been specifically approved for use in cattle with bronchopneumonia, especially if caused by 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, while retaining 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, ceftazidime). Third- and fourth-generation cephalosporins were designed to be increasingly resistant to β-lactamases. However, differences in chemical structure have been overcome by the formation of extended-spectrum β-lactamases that target third- and fourth-generation drugs (but not, as a general rule, cephamycins). Ceftiofur is a third-generation cephalosporin with a gram-negative spectrum that is more similar to that of first-generation cephalosporins.
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 sodium/g). Cephalosporins also contain a β-lactam nucleus susceptible to β-lactamase (cephalosporinase) hydrolysis. These β-lactamases may or may not also target penicillins. Modifications of the 7-aminocephalosporanic acid nucleus and substitutions on the sidechains by semisynthetic means have produced differences among cephalosporins in antibacterial spectra, β-lactamase sensitivities, and pharmacokinetics.
Resistance to the cephalosporins includes mechanisms described in general for β-lactams (see Antimicrobial Activity). Cephalosporins generally are stable against the plasmid-mediated β-lactamases produced by gram-positive bacteria such as Staphylococcus aureus. Several types of inducible β-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 gram-negative β-lactamases. However, third- and fourth-generation drugs are susceptible to extended-spectrum β-lactamases, the presence of which on susceptibility testing is indicated based on resistance to these drugs but susceptibility to clavulanic acid.
Limited information regarding the pharmacokinetics of cephalosporins in animals is available.
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 values are 75%–90%. There is no information regarding bioavailability of human generic products when used off-label in veterinary patients. The others are administered either IV or IM, with plasma concentrations peaking ~30 min after injection. Ceftiofur is available in a sustained-release form; its duration of action is extended by administration at the base of the ear in food animals.
Cephalosporins are distributed into most body fluids and tissues, including kidneys, lungs, joints, bone, soft tissues, and the biliary tract, but in general, the volume of distribution is <0.3 L/kg. 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% dogs, 99% 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 caused by susceptible pathogens.
Several cephalosporins (such as 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, that can contribute significantly to efficacy. Few of the other cephalosporins are metabolized to any appreciable extent.
Most cephalosporins, including cefpodoxime and cefovecin, are renally excreted. Tubular secretion predominates, although glomerular filtration is important in some cases (cephalexin and cefazolin). In renal failure, dosages might be reduced, although the need for doing so is not clear. Biliary elimination of the newer cephalosporins (eg, cefoperazone) may be significant. Generally, these β-lactam antibiotics maintain effective blood concentrations for only 6–8 hr. Exceptions include ceftiofur, cefpodoxime, and cefovecin.
Plasma half-lives of cephalosporins are quite variable, being as short as 30–120 min, but generally are longer than those of penicillins. For example, the half-life of the approved cephalexin product in dogs is 7.3 hr (9 hr if given with food). Third-generation cephalosporins tend to have longer plasma half-lives in people, but this is not always the case in other animals—substantial species differences exist. A selection of pharmacokinetic values for cephalosporins is listed in Elimination, Distribution, and Clearance of Cephalosporins to serve as a guide. Dosage modifications are often required in hepatic and renal disease.
Elimination, Distribution, and Clearance of Cephalosporins
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 food animals. It is approved for bovine respiratory disease principally caused by 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) and cefovecin (SC) also have been approved for use in dogs and in dogs and cats, respectively. Cephalosporins are particularly useful to treat infections of soft tissue and bone due to bacteria that are resistant to other commonly used antibiotics. Cefazolin (IV) has been used prophylactically 1 hr 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. Oral cephalosporins can be effective in management of urinary tract infections, except those due to Pseudomonas aeruginosa. Cephalexin should be anticipated to be ineffective against E coli. Cephapirin benzathine is used for dry-cow therapy, and cephapirin sodium is used to treat mastitis. Except for cephapirin, extra-label use of cephalosporins is banned in major food animal species.
A selection of general dosages for some cephalosporins is listed in Dosages of Cephalosporins. The dose rate and frequency should be adjusted as needed for the individual animal.
Dosages of Cephalosporins
The approved cephalosporins are relatively nontoxic. IM injections can be painful, and repeated IV administration may lead to local phlebitis. Nausea, vomiting, and diarrhea may occasionally be seen. Hypersensitivity reactions of several forms have been seen, with cross-reactivity to penicillin allergies possible. Superinfection may arise with the use of cephalosporins, and Pseudomonas or Candida spp are likely opportunistic pathogens.
Several laboratory determinations may be altered by the cephalosporins. Alkaline phosphatase, AST, ALT, lactate dehydrogenase, and BUN may be increased. A false-positive Coombs’ test and a false-positive urine glucose may occur. 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 animals in most countries (see Table: Drug Withdrawal and Milk Discard Times of Cephalosporins). An exception exists for ceftiofur, the withdrawal time of which varies with the product.