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The cephalosporins, and the closely related cephamycins, are similar to penicillins in several respects, sharing pharmacologic group features.
Classes
Cephalosporins include cephamycins. The early cephalosporins differed mainly with respect to pharmacokinetic characteristics. Cephalosporins are classified by generations (1–4); later generations are more resistant to β-lactam destruction and are characterized by extended spectra. They may also be classified by groups based on spectra and susceptibility to β-lactamases, as well as oral administration.
First-Generation Cephalosporins
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. Although generally less susceptible to β-lactamase destruction compared to penicillins, they are susceptible to cephalosporinases. They are not as effective against anaerobes as are the penicillins.
Second-Generation Cephalosporins
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-lactamase. They are ineffective against enterococci, Pseudomonas aeruginosa (with the exception of cefoxicin), Actinobacter spp, and many obligate anaerobes (again, cefoxicin is an exception).
Third and Fourth-Generation Cephalosporins
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. Many have only moderate activity against gram-positive bacteria but are active against a wide variety of gram-negative bacteria, including in certain instances Pseudomonas spp, Proteus vulgaris, Enterobacter spp, and Citrobacter spp. Cefpodoxime and cefovecin are very effective against Staphylococcus intermedius. Cephalosporins are usually highly resistant to β-lactamase enzymes. However, microbes increasingly are developing resistance through production of extended spectrum β-lactamases that target third- and fourth-generation drugs. 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. Ceftiofur has been specifically approved for use in cattle with bronchopneumonia, especially if caused by Mannheimia haemolytica or P multocida.
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 sodium/g). Cephalosporins also contain a β-lactam nucleus that is susceptible to β-lactamase (cephalosporinase) hydrolysis. These β-lactamases may or may not also attack 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.
Antimicrobial Activity
Bacterial Resistance
Resistance to the cephalosporins includes mechanisms described in general for β-lactams (see Antibacterial Agents: 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.
Antibacterial Spectra
The first generation cephalosporins are generally effective against most gram-positive aerobic cocci and several of the gram-negative bacteria, including E coli and Proteus, Klebsiella, Salmonella, Shigella, and Enterobacter spp. Cefazolin is more effective against E coli compared to cephalexin. Cephalosporinase-producing organisms are not susceptible. The second-generation cephalosporins have greater activity against gram-negative organisms but are somewhat less active against gram-positive species. An exception is cefoxitin, which has excellent efficacy against gram-positive bacteria and potentially Pseudomonas spp. It is difficult to identify trends among third- and fourth-generation cephalosporins. Some (eg, cefotaxime, ceftazidime) have an extensive gram-negative spectrum, which may include P aeruginosa. Ceftiofur is a third-generation cephalosporin with a gram-negative spectrum that is more similar to first-generation cephalosporins. However, unlike first- generation cephalosporins, efficacy against Staphylococcus spp is not predictable. Cefpodoxime and cefovicin are particularly effective against Staphylococcus intermedius, while retaining fair efficacy toward gram-negative organisms such as E coli, Klebsiella, and Proteus. The later generation cephalosporins may be effective against anaerobic bacteria, except for Bacteroides fragilis, which is susceptible only to certain cephalosporins (eg, cefoxitin). The newest members of this group are also highly resistant to β-lactamase, although cephalosporins (and to a lesser degree cephamycins) are susceptible to destruction by extended spectrum β-lactamases.
Pharmacokinetic Features
Limited information regarding cephalosporins is available in animals.
Absorption
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%. 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.
Distribution
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 Staphyloccocus intermedius and E coli for up to 14 days.
Biotransformation
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 that can contribute significantly to efficacy. Few of the other cephalosporins are metabolized to any appreciable extent.
Excretion
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, dose rates should be reduced. 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.
Pharmacokinetic Values
Plasma half-lives are often 30–120 min, but there are exceptions, the most notable being cefovecin. Third-generation cephalosporins tend to have longer plasma half-lives in humans, but this is not always the case in other animals—substantial species differences exist. A selection of pharmacokinetic values for cephalosporins is listed in see Antibacterial Agents: Elimination, Distribution, and Clearance of Cephalosporins to serve as a guide. Dosage modifications are often required in hepatic and renal disease.
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Table 4
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| Elimination, Distribution, and Clearance of Cephalosporins |
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Cephalosporin
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Species
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Elimination Half-life (min)
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Volume of Distribution (mL/kg)
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Clearance (mL/kg/min)
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Cefazolin
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Horses
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45
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188
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5.5
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Cefotaxime
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Sheep
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25
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134
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9.0
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Cefpodoxime
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Dog
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300
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150
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Cefovecin
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Dog
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5.5 days
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90
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Cephalexin
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Dogs
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84
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—
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—
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Cefadroxil
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Dogs
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120
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—
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—
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Cats
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150–180
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—
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—
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Ceftiofur
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Cattle
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~360
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—
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—
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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 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 dogs and cats, respectively. Cephalosporins are particularly useful for treating 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 the management of osteomyelitis, prostatitis, and arthritis. Oral cephalosporins are also usually effective in the management of urinary tract infections, except those due to Pseudomonas aeruginosa. Cephapirin benzathine is used for dry-cow therapy, and cephapirin sodium is used in treatment of mastitis.
A selection of general dosages for some cephalosporins is listed in see Antibacterial Agents: Dosages of Cephalosporins a. The dose rate and frequency should be adjusted as needed for the individual animal.
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Table 5
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| Dosages of Cephalosporins a
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Cephalosporin
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Dosage, Route, and Frequency
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Cephalexin
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20–60 mg/kg, PO, bid-tid
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Cephapirin
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30 mg/kg, IM or IV, every 4–6 hr
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Cefazolin
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20–25 mg/kg, IM or IV, tid-qid
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Cefpodoxime
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8 mg/kg, SC, every 14 days
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Cefovecin
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5–10 mg/kg, PO sid-bid
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Cephalexin
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10–30 mg/kg, PO, tid-qid
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Cefadroxil
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22 mg/kg, PO, bid
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Ceftiofur
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1.1–2.2 mg/kg, IM, sid
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a All for use in small animals, except ceftiofur, which is for use in cattle.
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Special Clinical Concerns
Adverse Effects and Toxicity
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.
Interactions
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.
Effects on Laboratory Tests
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.
Drug Withdrawal and Milk Discard Times
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 Antibacterial Agents: Drug Withdrawal and Milk Discard Times of Cephalosporins). An exception exists for ceftiofur, whose withdrawal time varies with the product.
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Table 6
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Drug Withdrawal and Milk Discard Times of Cephalosporins |
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Cephalosporin
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Withdrawal Time
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Milk Discard Time
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Ceftiofur
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2–16 days, depending on formulation
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Sodium cephapirin (intramammary)
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4 days before slaughter
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4 days
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Benzathine cephapirin (dry-cow treatment)
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42 days after latest infusion
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3 days after calving—milk not used for food
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Last full review/revision March 2012 by Dawn Merton Boothe, DVM, PhD, DACVIM, DACVCP
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