CEPHALOSPORINS

CEPHALOSPORINS

There are presently over 20 different cephalosporin drugs available for either human or veterinary use. Ten separate monographs of cephalosporins that appear to have the most current veterinary use and/or applicability may be found by their generic name.

Pharmacology - The cephalosporin antibiotics are comprised of several different classes of compounds with dissimilar spectrums of activity and pharmacokinetic profiles. All “true” cephalosporins are derived from cephalosporin C which is produced from Cephalosporium acremonium.

Cephalosporins are usually bactericidal against susceptible bacteria and act by inhibiting mucopeptide synthesis in the cell wall resulting in a defective barrier and an osmotically unstable spheroplast. The exact mechanism for this effect has not been definitively determined, but betalactam antibiotics have been shown to bind to several enzymes (carboxypeptidases, transpeptidases, endopeptidases) within the bacterial cytoplasmic membrane that are involved with cell wall synthesis. The different affinities that various beta-lactam antibiotics have for these enzymes (also known as penicillin-binding proteins; PBPs) help explain the differences in spectrums of activity of these drugs that are not explained by the influence of beta-lactamases. Like other beta-lactam antibiotics, cephalosporins are generally considered to be more effective against actively growing bacteria.

The cephalosporin class of antibiotics is usually divided into three classifications or generations. The so-called first generation of cephalosporins include (routes of administration in parentheses): cephalothin (IM/IV), cefazolin (IM/IV), cephapirin (IM/IV/Intramammary), cephradine (IM/IV/PO), cephalexin (PO) and cefadroxil (PO). While there may be differences in MIC’s for individual first generation cephalosporins, their spectrums of activity are quite similar. They possess generally excellent coverage against most gram-positive pathogens and variable to poor coverage against most gram negative pathogens. These drugs are very active in vitro against groups A beta-hemolytic and B Streptococci, non-enterococcal group D Streptococci (S. bovis), Staphylococcus intermedius and aureas, Proteus mirabilis and some strains of E. coli, Klebsiella sp., Actinobacillus, Pasturella, Haemophilus equigenitalis, Shigella and Salmonella. With the exception of Bacteroides fragilis, most anaerobes are very susceptible to the first generation agents. Most species of Corynebacteria are susceptible, but C. equi (Rhodococcus) is usually resistant. Strains of Staphylococcus epidermidis are usually sensitive to the parenterally administered 1st generation drugs, but may have variable susceptibilities to the oral drugs. The following bacteria are regularly resistant to the 1st generation agents: Group D streptococci/enterococci (S. faecalis, S. faecium), Methicillin resistant Staphylococci, indole-positive Proteus sp., Pseudomonas sp., Enterobacter sp., Serratia sp. and Citrobacter sp..

The second generation cephalosporins include: cefaclor (PO), cefamandole (IM/IV), cefonicid (IM/IV), ceforanide (IM/IV) and cefuroxime (PO/IM/IV). Although not true cephalosporins (they are actually cephamycins), cefoxitin (IM/IV) and cefotetan (IM/IV) are usually included in this group, although some references categorize cefotetan as a 3rd generation agent. In addition to the gram positive coverage of the 1st generation agents, these agents have expanded gram negative coverage. Cefoxitin and cefotetan also have good activity against Bacteroides fragilis. Enough variation exists between these agents in regard to their spectrums of activity against most species of gram negative bacteria, that susceptibility testing is generally required to determine sensitivity. The second generation agents have not found widespread use in most veterinary practices, although cefoxitin has been used somewhat.

The third generation cephalosporins retain the gram positive activity of the first and second generation agents, but in comparison, have much expanded gram negative activity. Included in this group are: cefotaxime (IM/IV), moxalactam (actually a 1-oxa-beta-lacatam; IM/IV), cefoperazone (IM/IV), ceftizoxime (IM/IV), ceftazidime (IM/IV), ceftriaxone (IM/IV), ceftiofur (IM) and cefixime (PO). As with the 2nd generation agents, enough variability exists with individual bacterial sensitivities that susceptibility testing is necessary for most bacteria. Usually only ceftazidime and cefoperazone are active against most strains of Pseudomonas aeruginosa. Because of the excellent gram negative coverage of these agents and when compared to the aminoglycosides, their significantly less toxic potential, they have been used on an increasing basis in veterinary medicine. Ceftiofur is approved for use in beef cattle, but its use in other species is hindered by a lack of data on its spectrum of activity or availability of pharmacokinetic profiles.

Uses/Indications - Cephalosporins have been used for a wide range of infections in various species.

Pharmacokinetics (General)- Until recently, only some first generation cephalosporins were absorbed appreciably after oral administration, but this has changed with the availability of cefuroxime axetil (2nd generation) and cefixime (3rd generation). Depending on the drug, absorption may be delayed, unaltered, or increased if administered with food. There are reported species variations in the oral bioavailability of some cephalosporins.

Cephalosporins are widely distributed to most tissues and fluids, including bone, pleural fluid, pericardial fluid and synovial fluid. Higher levels are found in inflamed than in normal bone. Very high levels are found in the urine, but they penetrate poorly into prostatic tissue and aqueous humor. Bile levels can reach therapeutic concentrations with several of the agents as long as biliary obstruction is not present. With the exception of cefuroxime, no first or second generation cephalosporin enters the CSF (even with inflamed meninges) in therapeutically effective levels. Therapeutic concentrations of cefotaxime, moxalactam, cefuroxime, ceftizoxime, ceftazidime and ceftriaxone can be found in the CSF after parenteral dosing in patients with inflamed meninges. Cephalosporins cross the placenta and fetal serum concentrations can be 10% or more of those found in maternal serum. Cephalosporins enter milk in low concentrations. Protein binding of the drugs is widely variable and species specific. Cephalosporins tend to bind to equine and canine plasma proteins less so then to human plasma proteins.

Cephalosporins and their metabolites (if any) are excreted by the kidneys, via tubular secretion and/or glomerular filtration. Some cephalosporins (e.g., cefotaxime, cefazolin, and cephapirin) are partially metabolized by the liver to desacetyl compounds that may have some antibacterial activity.

Contraindications/Precautions/Reproductive Safety - Cephalosporins are contraindicated in patients who have a history of hypersensitivity to them. Because there may be cross-reactivity, use cephalosporins cautiously in patients who are documented hypersensitive to other beta-lactam antibiotics (e.g., penicillins, cefamycins, carbapenems).

Oral systemic antibiotics should not be administered in patients with septicemia, shock or other grave illnesses as absorption of the medication from the GI tract may be significantly delayed or diminished. Parenteral routes (preferably IV) should be used for these cases.

Cephalosporins have been shown to cross the placenta and safe use of them during pregnancy have not been firmly established, but neither have there been any documented teratogenic problems associated with these drugs. However, use only when the potential benefits outweigh the risks.

Adverse Effects/Warnings - Adverse effects with the cephalosporins are usually not serious and have a relatively low frequency of occurrence.

Hypersensitivity reactions unrelated to dose can occur with these agents and can be manifested as rashes, fever, eosinophilia, lymphadenopathy, or full-blown anaphylaxis. The use of cephalosporins in patients documented to be hypersensitive to penicillin-class antibiotics is controversial. In humans, it is estimated that up to 15% of patients hypersensitive to penicillins will also be hypersensitive to cephalosporins. The incidence of cross-reactivity in veterinary patients is unknown.

Cephalosporins can cause pain at the injection site when administered intramuscularly, although this effect is less so with cefazolin than other agents. Sterile abscesses or other severe local tissue reactions are also possible but are much less common. Thrombophlebitis is also possible after IV administration of these drugs.

When given orally, cephalosporins may cause GI effects (anorexia, vomiting, diarrhea). Administering the drug with a small meal may help alleviate these symptoms. Because the cephalosporins may also alter gut flora, antibiotic-associated diarrhea can occur as well as the selection out of resistant bacteria maintaining residence in the colon of the animal.

While it has been demonstrated that the cephalosporins (particularly cephalothin) have the potential for causing nephrotoxicity, at clinically used doses in patients with normal renal function, risks for this adverse effect occurring appear minimal.

High doses or very prolonged use has been associated with neurotoxicity, neutropenia, agranulocytosis, thrombocytopenia, hepatitis, positive Comb’s test, interstitial nephritis, and tubular necrosis. Except for tubular necrosis and neurotoxicity, these effects have an immunologic component.

Some cephalosporins (cefamandole, cefoperazone, moxalactam) that contain a thiomethyltetrazole side chain have been implicated in causing bleeding problems in humans. These drugs are infrequently used in veterinary species at the present time, so any veterinary ramifications of this effect are unclear.

Overdosage/Acute Toxicity - Acute oral cephalosporin overdoses are unlikely to cause significant problems other than GI distress, but other effects are possible.

Drug Interactions - The concurrent use of parenteral aminoglycosides or other nephrotoxic drugs (e.g., amphotericin B) with cephalosporins is controversial. Potentially, cephalosporins could cause additive nephrotoxicity when used with these drugs, but this interaction has only been well documented with cephaloridine. Nevertheless, they should be used together cautiously.

In vitro studies have demonstrated that cephalosporins can have synergistic or additive activity against certain bacteria when used with aminoglycosides, penicillins, or chloramphenicol. However, some clinicians do not recommend using cephalosporins concurrently with bacteriostatic antibiotics (e.g., chloramphenicol), particularly in acute infections where the organism is proliferating rapidly.

Probenecid competitively blocks the tubular secretion of most cephalosporins, thereby increasing serum levels and serum half-lives.

A disulfiram-like reaction (anorexia, nausea, vomiting) has been reported in humans who have  ingested alcohol within 48-72 hours of receiving beta-lactam antibiotics (e.g., cefamandole, cefoperazone, moxalactam, cefotetan) with a thiomethyltetrazole side-chain. Because these antibiotics have been associated with bleeding, they should be used cautiously in patients receiving oral anticoagulants.

Drug/Laboratory Interactions - Except for cefotaxime, cephalosporins may cause false-positive urine glucose determinations when using cupric sulfate solution (Benedict’s Solution, Clinitest®). Tests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected by cephalosporins.

When using the Jaffe reaction to measure serum or urine creatinine, cephalosporins (not ceftazidime or cefotaxime) in high dosages may falsely cause elevated values.

In humans, particularly with azotemia, cephalosporins have caused a false-positive direct Combs’ test. Cephalosporins may also cause falsely elevated 17-ketosteroid values in urine.

Monitoring Parameters - Because cephalosporins usually have minimal toxicity associated with their use, monitoring for efficacy is usually all that is required. Patients with diminished renal function, may require intensified renal monitoring. Serum levels and therapeutic drug monitoring are not routinely done with these agents.

CEFADROXIL

Chemistry - A semisynthetic cephalosporin antibiotic, cefadroxil occurs as a white to yellowishwhite, crystalline powder that is soluble in water and slightly soluble in alcohol. The commercially available product is available as the monohydrate.

Storage/Stability/Compatibility - Cefadroxil tablets, capsules and powder for oral suspension should be stored at room temperature (15-30¡C) in tight containers. After reconstitution, the oral suspension is stable for 14 days when kept refrigerated (2-8¡C).

Pharmacology/Spectrum of Activity - A first generation cephalosporin, cefadroxil exhibits activity against the bacteria usually covered by this class.

Uses/Indications - Cefadroxil is approved for oral therapy in treating susceptible infections of the skin, soft tissue, and genitourinary tract in dogs. It has also been used clinically in cats.

Pharmacokinetics (specific) - Cefadroxil is reportedly well absorbed after oral administration to dogs without regard to feeding state. After an oral dose of 22 mg/kg, peak serum levels of approximately 18.6 micrograms/ml occur within 1-2 hours of dosing. Only about 20% of the drug is bound to canine plasma proteins. The drug is excreted into the urine and has a half-life of about 2 hours. Over 50% of a dose can be recovered unchanged in the urine within 24 hours of dosing.

In cats, the serum half-life has been reported as approximately 3 hours.

Oral absorption of cefadroxil in adult horses after oral suspension was administered was characterized as poor and erratic. In a study done in foals, oral bioavailability ranged from 36-99.8% (mean=58.2%); mean elimination half-life was 3.75 hours after oral dosing.

Doses

Dogs:

For susceptible infections:

a) 22 mg/kg PO bid. Treat skin and soft tissue infections for at least 3 days, and GU infections for at least 7 days. Treat for at least 48 hours after animal is afebrile and asymptomatic. Reevaluate therapy if no response after 3 days of treatment. Maximum therapy is 30 days.

b) 11 - 33 mg/kg PO q8h

c) 20 mg/kg PO bid (q12h)

d) 22 mg/kg PO q8-12h; administer with food if GI upset occurs

Cats:

For susceptible infections:

a) 11 - 33 mg/kg PO q8h

b) 22 mg/kg PO q8-12h; administer with food if GI upset occurs

c) 10 mg/kg PO q12h

d) 20 mg/kg PO q12-24h

CEFAZOLIN SODIUM

Chemistry - An injectable, semi-synthetic cephalosporin antibiotic, cefazolin sodium occurs as a practically odorless or having a faint odor, white to off-white, crystalline powder or lyophilized solid. It is freely soluble in water and very slightly soluble in alcohol. Each gram of the injection contains 2 mEq of sodium. After reconstitution, the solution for injection has a pH of 4.5 - 6 and has a light yellow to yellow color. May also be known as cephazolin sodium.

Storage/Stability/Compatibility - Cefazolin sodium powder for injection and solutions for injection should be protected from light. The powder for injection should be stored at room temperature (15-30^oC); avoid temperatures above 40^oC. The frozen solution for injection should be stored at temperatures no higher than -20^oC. After reconstitution, the solution is stable for 24 hours when kept at room temperature and 96 hours if refrigerated. If after reconstitution, the solution is immediately frozen in the original container, the preparation is stable for at least 12 weeks when stored at -20^oC.

The following drugs or solutions are reportedly compatible with cephapirin: Amino acids 4.25% / dextrose 25%, D₅W in Ringer’s, D₅W in Lactated Ringer’s, D₅W in sodium chloride 0.2% - 0.9%, D₅W, D₁₀W, Ringer’s Injection, Lactated Ringer’s Injection, normal saline, metronidazole, verapamil HCl and vitamin B-complex.

The following drugs or solutions are reportedly incompatible or only compatible in specific situations with cefazolin: amikacin sulfate, amobarbital sodium, ascorbic acid injection, bleomycin sulfate, calcium chloride/gluconate, cimetidine HCl, erythromycin gluceptate, kanamycin sulfate, lidocaine HCl, oxytetracycline HCl, pentobarbital sodium, polymyxin B sulfate, tetracycline HCl and vitamin B-complex with C injection.

Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used.

Pharmacology/Spectrum of Activity - A first generation cephalosporin, cefazolin exhibits activity against the bacteria usually covered by this class. Because MIC’s occasionally differ for cefazolin when compared to either cephalothin/cephapirin, some clinical microbiologists recommend also testing bacterial susceptibilities for this antibiotic.

Uses/Indications - In the United States, there are no cefazolin products approved for veterinary species, but it has been used clinically in several species when an short-acting injectable first generation cephalosporin is indicated.

Pharmacokinetics (specific) - Cefazolin is not appreciably absorbed after oral administration and must be given parenterally to achieve therapeutic serum levels. Absorbed drug is excreted unchanged by the kidneys into the urine. Elimination half-lives may be significantly prolonged in patients with severely diminished renal function.

Pharmacokinetic parameters for dogs and horses follow:

In dogs, peak levels occur in about 30 minutes after IM administration. The apparent volume of distribution at steady state is 700 ml/kg, total body clearance of 10.4 ml/min/kg with a serum elimination half-life of 48 minutes. Approximately 64% of the clearance can be attributed to renal tubular secretion. The drug is approximately 16-28% bound to plasma proteins in dogs.

In horses, the apparent volume of distribution at steady state is 190 ml/kg, total body clearance of 5.51 ml/min/kg with a serum elimination half-life of 38 minutes when given IV and 84 minutes after IM injection (gluteal muscles). Cefazolin is about 4-8% bound to equine plasma proteins. Because of the significant tubular secretion of the drug, it would be expected that probenecid administration would alter the kinetics of cefazolin. One study performed in horses did not show any effect, but the authors concluded that the dosage of probenecid may have been sub-therapeutic in this species.

In calves, the volume of distribution is 165 ml/kg, and had a terminal elimination half-life of 49-99 minutes after IM administration.

Doses

Dogs:

For susceptible infections:

a) 20 - 25 mg/kg IM, IV q6-8h

b) 10 - 30 mg/kg IM, IV or SQ

c) 11 - 33 mg/kg IV q8h; 22 - 33 mg/kg IM or SQ q8h

For surgical prophylaxis (soft-tissue):

a)                  20 mg/kg IV before and then every 2.5 hours during surgery Cats:

For susceptible infections:

a) 20 - 25 mg/kg IM, IV q6-8h  

b) 10 - 30 mg/kg IM, IV or SQ

c) 11 - 33 mg/kg IV q8h; 22 - 33 mg/kg IM or SQ q8h

Horses:

For susceptible infections:

a) Respiratory tract: 11 mg/kg IV or IM q12h

b) 11 mg/kg IV or IM qid

c) Foals: 20 mg/kg IV q8-12h

CEFOPERAZONE SODIUM

Chemistry - A third generation cephalosporin, cefoperazone sodium contains a piperazine side chain giving it antipseudomonal activity. It occurs as white, crystalline powder and is freely soluble in water and poorly soluble in alcohol. At room temperature, cefoperazone sodium has a maximum solubility in compatible IV solutions of 475 mg/ml (at concentrations >333 mg/ml vigorous and prolonged shaking may be required). Reconstituted solutions of the drug have a pH from 4.5 - 6.5. One gram contains 1.5 mEq of sodium.

Storage/Stability/Compatibility - The sterile powder for injection should be stored at temperatures less than 25^oC and protected from light. Once reconstituted, solutions do not need to be protected from light.

After reconstitution, cefoperazone sodium is generally stable for 24 hours at room temperature and 5 days when refrigerated in a variety of IV solutions (e.g., sterile or bacteriostatic water for injection, dextrose in water/saline/LRS solutions, lactated Ringer’s injection, Normasol R, and saline IV solutions). When frozen at -2 to -10^oC in dextrose, sodium chloride or sterile water for injection, cefoperazone sodium is stable for 3 weeks (dextrose solutions) to 5 weeks (water or saline solutions).

Cefoperazone sodium is reportedly compatible with cimetidine HCl, clindamycin phosphate,

furosemide and heparin sodium, acyclovir sodium, cyclophosphamide, esmolol HCl, famotidine, hydromorphone HCl, magnesium sulfate, and morphine sulfate. It is reportedly incompatible with some TPN mixtures, doxapram HCl, gentamicin sulfate, hetastarch, labetolol HCl, meperidine HCl, odansetron HCl, perphenazine, promethazine, and sargostim. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used.

Pharmacology - Cefoperazone is a third generation injectable cephalosporin agent.

Uses/Indications - Cefoperazone is used to treat serious infections, particularly against susceptible Enterobacteriaceae not susceptible to other less expensive agents or when aminoglycosides are not indicated (due to their potential toxicity).

Pharmacokinetics - Cefoperazone is not absorbed after oral administration and must be given parenterally. It is widely distributed throughout the body; CSF levels are low if meninges are not inflamed. Cefoperazone crosses the placenta and enters maternal milk in low concentrations; no documented adverse effects to offspring have been noted. Unlike most cephalosporins, cefoperazone is principally excreted in the bile and elimination half-lives are approximately 2 hours in humans. Dosage adjustments generally are not required for patients with renal insufficiency.

Contraindications/Precautions/Reproductive Safety - Only prior allergic reaction to cephalosporins contraindicates cefoperazone’s use. In humans documented hypersensitive to penicillin, up to 16% may also be allergic to cephalosporins. The veterinary significance of this is unclear. Because cefoperazone is excreted in the bile, patients with significant hepatic disease or biliary obstruction may have their serum half-lives increase 2 - 4 times above normal. Dosage adjustment may be necessary. Cefoperazone should be used with caution in patients with preexisting bleeding disorders. It contains a thiomethyltetrazole side-chain which has been associated with causing coagulation abnormalities.

No teratogenic effects were demonstrated in studies in pregnant mice, rats, and monkeys given up to 10 times labeled doses of cefoperazone.

Adverse Effects/Warnings - Cefoperazone is a relatively safe agent. Rarely, hypersensitivity reactions could potentially occur in animals. Because of its thiomethyltetrazole side-chain it may also rarely cause hypoprothrombinemia. Diarrhea secondary to changes in gut flora have been reported.

Some human patients demonstrate mild, transient increases in liver enzymes, serum creatinine and BUN. Clinical significance of these effects is in doubt. If administered via the IM route, pain at the injection site has also been noted.

Overdosage/Acute Toxicity - No specific antidotes are available. Overdoses should be monitored and treated symptomatically and supportively if required.

Drug Interactions - A disulfiram-like reaction (anorexia, nausea, vomiting) has been reported in humans who have ingested alcohol with 48-72 hours of receiving beta-lactam antibiotics with a thiomethyltetrazole side-chain (e.g., cefamandole, cefoperazone, moxalactam, cefotetan). Because these antibiotics have been associated with bleeding, they should be used cautiously in patients receiving oral anticoagulants.

Synergism against some Enterobacteriaceae (e.g., Pseudomonas aeruginosa) may be attained if using cefoperazone with a beta-lactamase inhibitor such as clavulanic acid or with an aminoglycoside (e.g., gentamicin, amikacin). Do not mix cefoperazone in same syringe or IV bag with aminoglycosides as inactivation may occur. Synergy may be unpredictable however and although there have been no reports of additive nephrotoxicity with cefoperazone, some cephalosporins may increase the nephrotoxic potential of aminoglycosides. Probenecid does not have an effect on cefoperazone elimination.

Laboratory Considerations - When using Kirby-Bauer disk diffusion procedures for testing susceptibility, a specific 75 micrograms cefoperazone disk should be used. A cephalosporin-class disk containing cephalothin should not be used to test for cefoperazone susceptibility. An inhibition zone of 21 mm or more indicates susceptibility; 16-20 mm, intermediate; and 15 mm or less, resistant.

When using a dilution susceptibility procedure, an organism with a MIC of 16 micrograms/ml or less is considered susceptible and 64 micrograms/ml or greater is considered resistant. With either method, infections caused by organisms with intermediate susceptibility may be effectively treated if the infection is limited to tissues where the drug is concentrated (e.g., urine, bile) or if a higher than normal dose is used.

In some human patients receiving cefoperazone, a positive direct antiglobulin (Coombs’) test has been reported.

Cefoperazone, like most other cephalosporins, may cause a false-positive urine glucose determination when using the cupric sulfate solution test (e.g., Clinitest®).

Doses

Horses:

For susceptible infections: 30 - 50 mg/kg q8-12h IV or IM (Note: This is a human dose and should be used as a general guideline only)

Monitoring Parameters - 1) Efficacy; 2) PT’s, CBC if bleeding occurs

Client Information - Because cefoperazone use is generally associated with inpatient therapy, little client monitoring is required. They should be alert to either bleeding problems or symptoms associated with hypersensitivity.

CEFOTAXIME SODIUM

Chemistry - A semisynthetic, 3rd generation, aminothiazolyl cephalosporin, cefotaxime sodium occurs as an odorless, white to off-white crystalline powder with a pKa of 3.4. It is sparingly soluble in water and slightly soluble in alcohol. Potency of cefotaxime sodium is expressed in terms of cefotaxime. One gram of cefotaxime (sodium) contains 2.2 mEq of sodium.

Storage/Stability/Compatibility - Cefotaxime sodium sterile powder for injection should be stored at temperatures of less than 30^oC; protect from light. The commercially available frozen injection should be stored at temperatures no greater than -20^oC. Depending on storage conditions, the powder or solutions may darken which may indicate a loss in potency.

All commonly used IV fluids and the following drugs are reportedly compatible with cefotaxime: metronidazole and verapamil. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel; see bibliography).

Pharmacology/Spectrum of Activity - Cefotaxime has a relatively wide spectrum of activity against both gram positive and gram negative bacteria. While less active against Staphylococcus spp. than the first generation agents, it still has significant activity against those and other gram positive cocci. Cefotaxime, like the other 3rd generation agents, has extended coverage of gram negative aerobes particularly in the family Enterobacteriaceae, including Klebsiella sp., E. coli, Salmonella, Serratia marcesans, Proteus sp., and Enterobacter sp.. Cefotaxime’s in vitro activity against Pseudomonas aeruginosa is variable and results are usually disappointing when the drug is used clinically against this organism. Many anaerobes are also susceptible to cefotaxime, including strains of Bacteroides fragilis, Clostridium sp., Fusobacterium sp., Peptococcus sp., and Peptostreptococcus sp..

Because 3rd generation cephalosporins exhibit specific activities against bacteria, a 30 micrograms cefotaxime disk should be used when performing Kirby-Bauer disk susceptibility tests for this antibiotic.

Uses/Indications - In the United States, there are no cefotaxime products approved for veterinary

species, but it has been used clinically in several species when an injectable 3rd generation cephalosporin may be indicated.

Pharmacokinetics (specific) - Cefotaxime is not appreciably absorbed after oral administration and must be given parenterally to attain therapeutic serum levels. After administration, the drug is widely distributed in body tissues, including bone, prostatic fluid (human), aqueous humor, bile, ascitic and pleural fluids. Cefotaxime crosses the placenta and activity in amniotic fluid either equals or exceeds that in maternal serum. Cefotaxime also is distributed into milk in low concentrations. In humans, approximately 13-40% of the drug is bound to plasma proteins.

Unlike the first generation cephalosporins (and most 2nd generation agents), cefotaxime will enter the CSF in therapeutic levels (at high dosages) when the patient’s meninges are inflamed. Cefotaxime is partially metabolized by the liver to desacetylcefotaxime which exhibits some antibacterial activity. Desacetylcefotaxime is partially degraded to inactive metabolites by the liver. Cefotaxime and its metabolites are primarily excreted in the urine. Because tubular secretion is involved in the renal excretion of the drug, probenecid has been demonstrated in several species to prolong the serum half-life of cefotaxime.

Pharmacokinetic parameters in certain veterinary species follow: In dogs, the apparent volume of distribution at steady state is 480 ml/kg, and a total body clearance of 10.5 ml/min/kg after intravenous injection. Serum elimination half-lives of 45 minutes when given IV, 50 minutes after IM injection, and 103 minutes after SQ injection have been noted. Bioavailability is about 87% after IM injection and approximately 100% after SQ injection.

In cats, total body clearance is approximately 3 ml/min/kg after intravenous injection and the serum elimination half-life is about 1 hour. Bioavailability is about 93-98% after IM injection.

Doses

Dogs:

For susceptible infections:

a) For acute pancreatitis: 6 - 40 mg/kg IV or IM qid

b) 27.5 - 55 mg/kg IM, IV or SQ q8h

c) 25 - 50 mg/kg IV, IM or SQ q8h

Cats:

For susceptible infections:

a) 27.5 - 55 mg/kg IM, IV or SQ q8h

b) 25 - 50 mg/kg IV, IM or SQ q8h

c) 25 - 50 mg/kg IV, IM or SQ q8h

Horses:

For susceptible infections:

a) Foals:20 - 30 mg/kg IV q6h

Birds:

For susceptible infections:

a) For most birds: 50 - 100 mg/kg IM tid; may be used with aminoglycosides, but nephrotoxicity may occur. Reconstituted vial good for 13 weeks if frozen.

b) 75 - 100 mg/kg IM or IV q6-8h

Reptiles:

For susceptible infections:

a) 20 - 40 mg/kg IM once daily for 7-14 days.

CEFOXITIN SODIUM

Chemistry - Actually a cephamycin, cefoxitin sodium is a semisynthetic antibiotic that is derived from cephamycin C which is produced by Streptomyces lactamdurans. It occurs as a white to offwhite, somewhat hygroscopic powder or granules with a slight characteristic odor. It is very soluble in water and slightly soluble in alcohol. Each gram of cefoxitin sodium contains 2.3 mEq of sodium.

Storage/Stability/Compatibility - Cefoxitin sodium powder for injection should be stored at temperatures less than 30^oC and should not be exposed to temperatures greater than 50^oC. The frozen solution for injection should be stored at temperatures no higher than -20^oC.

After reconstitution, the solution is stable for 24 hours when kept at room temperature and from 48 hours to 1 week if refrigerated. If after reconstitution the solution is immediately frozen in the original container, the preparation is stable up to 30 weeks when stored at -20^oC. Stability is dependent on the diluent used and the reader should refer to the package insert or other specialized references for more information. The powder or reconstituted solution may darken, but this apparently does not affect the potency of the product.

All commonly used IV fluids and the following drugs are reportedly compatible with cefoxitin: amikacin sulfate, cimetidine HCl, gentamicin sulfate, kanamycin sulfate, mannitol, metronidazole, mutivitamin infusion concentrate, sodium bicarbonate, tobramycin sulfate and vitamin B-complex with C. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used.

Pharmacology/Spectrum of Activity - Although not a true cephalosporin, cefoxitin is usually classified as a 2nd generation agent. Cefoxitin has activity against gram positive cocci, but less so on a per weight basis than the 1st generation agents. Unlike the first generation agents, it has good activity against many strains of E. coli, Klebsiella and Proteus that may be resistant to the first generation agents. In human medicine, cefoxitin’s activity against many strains of Bacteroides fragilis has placed it in a significant therapeutic role. While Bacteroides fragilis has been isolated from anerobic infections in veterinary patients, it may not be as significant a pathogen in veterinary species as in humans. Because 2nd generation cephalosporins exhibit specific activities against bacteria, a 30-micrograms cefoxitin disk should be used when performing Kirby-Bauer disk susceptibility tests for this antibiotic.

Uses/Indications - In the United States, there are no cefoxitin products approved for veterinary species, but it has been used clinically in several species when an injectable second generation cephalosporin may be indicated.

Pharmacokinetics (specific) - Cefoxitin is not appreciably absorbed after oral administration and must be given parenterally to achieve therapeutic serum levels. The absorbed drug is primarily excreted unchanged by the kidneys into the urine via both tubular secretion and glomerular filtration. In humans, approximately 2% of a dose is metabolized to descarbamylcefoxitin, which is inactive. Elimination half-lives may be significantly prolonged in patients with severely diminished renal function.

In horses, the apparent volume of distribution at steady state is 110 ml/kg, total body clearance of 4.32 ml/min/kg with a serum elimination half-life of 49 minutes.

In calves, the volume of distribution is 318 ml/kg, and has a terminal elimination half-life of 67 minutes after IV dosing, and 81 minutes after IM administration. Cefoxitin is approximately 50% bound to calf plasma proteins. Probenecid (40 mg/kg) has been demonstrated to significantly prolong elimination half-lives.

Doses

Dogs:

For susceptible infections:

a) 6 - 20 mg/kg SQ, IM, IV tid; for meningitis: 6 - 40 mg/kg IV tid-qid

b) 11 - 22 mg/kg IV q8h

c) 10 - 20 mg/kg IV q8h

d) 30 mg/kg IV q8h

Cats:

For susceptible infections:

a) 11 - 22 mg/kg IV q8h

b) 10 - 20 mg/kg IV q8h

c) 30 mg/kg IV q8h

Horses:

For susceptible infections:

a) Foals: 20 mg/kg IV q4-6h

CEFTIOFUR SODIUM

CEFTIOFUR HCL

Chemistry - Ceftiofur sodium and HCl are semisynthetic 3rd generation cephalosporins.

Storage/Stability/Compatibility - Unreconstituted ceftiofur sodium powder for reconstitution should be stored in the refrigerator (2^o-8^oC). Protect from light. Color of the cake may vary from off-white to tan, but this does not affect potency. After reconstitution with bacteriostatic water for injection or sterile water for injection, the solution is stable for up to 7 days when refrigerated and for 12 hours at room temperature (15-30^oC). According to the manufacturer, if a precipitate should form while being stored refrigerated during this time, the product may be used if it goes back into solution after warming. If not, contact the manufacturer. Frozen reconstituted solutions are stable for up to 8 weeks. Thawing may be done at room temperature or by swirling the vial under running warm or hot water.

The HCl product should be stored at controlled room temperature (20^o-25^oC; 68^o-77^oF) and protected from freezing. It should be shaken well before use.

Pharmacology/Spectrum of Activity - Ceftiofur inhibits cell wall synthesis (at stage three) of susceptible multiplying bacteria. Ceftiofur exhibits a spectrum of activity similar to that of cefotaxime.

It has a broad range of in vitro activity against a variety of pathogens, including many species of Pasturella, Streptococcus, Staphylococcus, Salmonella, and E.coli.

Uses/Indications - Ceftiofur sodium/HCl is indicated for treatment of bovine respiratory disease (shipping fever, pneumonia) associated with Pasturella hemolytica, Pasturella multocida and Haemophilus somnus in lactating or non-lactating cattle and ceftiofur sodium is indicated in horses for respiratory disease associated with Strep zooepidimicus. Ceftiofur HCl is also approved for foot rot in cattle.

Ceftiofur could potentially be of usefulness in small animal infections as well, but little  published data is available to recommend its use.

Pharmacokinetics (specific) - In cattle, ceftiofur sodium and HCl have practically equivalent pharmacokinetic parameters. Peak levels of ceftiofur are slightly higher after IM injection, but areas under the curve are practically equal as well as elimination half-lives (approx. 9-12 hours).

Doses

Cattle:

For labeled indications:

a) Ceftiofur sodium (Naxcel®): 1.1 - 2.2 mg/kg IM once daily for 3 treatments; may give additional doses on 4th and 5th day if response is not satisfactory. Reconstitute 1 g vial with 20 ml and the 4 g vial with 80 ml of either Bacteriostatic Water for Injection or Sterile Water for Injection.

b) Ceftiofur HCL (Excenell®): 1.1 - 2.2 mg/kg IM or SQ once daily for 3 treatments; may give additional doses on 4th and 5th day if response is not satisfactory. For BRD only: May inject 2.2 mg/kg IM or SQ every other day (days 1 and 3; 48 hour interval). Do not inject more than 15 ml per IM injection site.  

Horses:

For respiratory disease associated with Strep zooepidimicus:

a) Naxcel®: 2.2 - 4.4 mg/kg (2 - 4 ml reconstituted sterile solution per 100 lb. of body weight) with a maximum of 10 ml administered per injection site. Repeat treatment at 24 hour intervals, continued for 48 hours after symptoms have disappeared. Do not exceed 10 days of treatment.

Dogs:

For susceptible infections:

a) Range from 2.2 mg/kg subQ once daily for 5-14 days for treatment of UTI to 4.4 - 5.5 mg/kg subQ once daily. Use with caution.

Reptiles:

For susceptible infections:

a) For chelonians: 4 mg/kg IM once daily for 2 weeks. Commonly used in respiratory infections.

CEFTRIAXONE SODIUM

Chemistry - A third generation cephalosporin, ceftriaxone sodium occurs as white to yellowishorange crystalline powder. It is soluble in water (400 mg/ml at 25¡C). Potencies of commercial products are expressed in terms of ceftriaxone. One gram of ceftriaxone sodium contains 3.6 mEq of sodium.

Storage/Stability/Compatibility - The sterile powder for reconstitution should be stored at, or below 25^oC and protected from light. After reconstituting with either 0.9% sodium chloride or D₅W, ceftriaxone solutions (at concentrations of approximately 100 mg/ml) are stable for 3 days at room temperature and for 10 days when refrigerated. Solutions of concentrations of 250 mg/ml are stable for 24 hours at room temperature and 3 days when refrigerated. At concentrations of 10-40 mg/ml solutions frozen at -20^oC are stable for 26 weeks. The manufacturer does not recommend admixing any other anti-infective drugs with ceftriaxone sodium.

Pharmacology - Ceftriaxone is a third generation injectable cephalosporin agent.

Uses/Indications - Ceftriaxone is used to treat serious infections, particularly against susceptible Enterobacteriaceae that are not susceptible to other less expensive agents or when aminoglycosides

are not indicated (due to their potential toxicity). Its long half life, good CNS penetration, and activity against Borrelia burgdorferi also has made it a potential choice for treating Lyme’s disease.

Pharmacokinetics - Ceftriaxone is not absorbed after oral administration and must be given parenterally. It is widely distributed throughout the body; CSF levels are higher when meninges are

inflamed. Ceftriaxone crosses the placenta and enters maternal milk in low concentrations; no documented adverse effects to offspring have been noted. Ceftriaxone is excreted by both renal and

non-renal mechanisms and in humans, elimination half-lives are approximately 6-11 hours. Dosage adjustments generally are not required for patients with renal insufficiency (unless severely uremic) or with hepatic impairment.

Contraindications/Precautions/Reproductive Safety - Only prior allergic reaction to cephalosporins contraindicates ceftriaxone’s use. In humans documented hypersensitive to penicillin, up to 16% may also be allergic to cephalosporins. The veterinary significance of this is unclear.

Although bleeding times have only been reported rarely in humans, ceftriaxone should be used with caution in patients with vitamin K utilization or synthesis abnormalities (e.g., severe hepatic disease).

No teratogenic effects were demonstrated in studies in pregnant mice and rats given up to 20 times

labeled doses of ceftriaxone.

Adverse Effects/Warnings - Because veterinary usage of ceftriaxone is very limited, an accurate adverse effect profile has not been determined. The following adverse effects have been reported in humans and may or may not apply to veterinary patients: hematologic effects, including eosinophilia (6%), thrombocytosis (5%), leukopenia (2%) and more rarely, anemia, neutropenia, lymphopenia and thrombocytopenia. Approximately 2-4% of humans get diarrhea. Very high dosages (100 mg/kg/day) in dogs have caused a ‘sludge’ in bile. Hypersensitivity reactions (usually a rash) have been noted. Increased serum concentrations of liver enzymes, BUN, creatinine, and urine casts have been described in about 1-3% of patients. When given IM, pain may be noted at the injection site.

Overdosage/Acute Toxicity - Limited information available; overdoses should be monitored and treated symptomatically and supportively if required.

Drug Interactions - Synergism against some Enterobacteriaceae (e.g., Pseudomonas aeruginosa) may be attained if using cefoperazone with an aminoglycoside (e.g., gentamicin, amikacin). Organisms with a high degree of resistance to both ceftriaxone and the aminoglycoside are unlikely to be affected when the two drugs are used together. Probenecid does not have an effect on ceftriaxone elimination.

Laboratory Considerations - When using Kirby-Bauer disk diffusion procedures for testing susceptibility, a specific 30 micrograms ceftriaxone disk should be used. A cephalosporin-class disk containing cephalothin should not be used to test for ceftriaxone susceptibility. An inhibition zone of 18 mm or more indicates susceptibility; 14-17 mm, intermediate; and 13 mm or less, resistant.

When using a dilution susceptibility procedure, an organism with a MIC of 16 micrograms/ml or less is considered susceptible and 64 micrograms/ml or greater is considered resistant. With either method, infections caused by organisms with intermediate susceptibility may be effectively treated if the infection is limited to tissues where the drug is concentrated or if a higher than normal dose is used.

Ceftriaxone, like most other cephalosporins, may cause a false-positive urine glucose determination when using the cupric sulfate solution test (e.g., Clinitest®).

Ceftriaxone in very high concentrations (50 micrograms/ml or greater) may cause falsely elevated serum creatinine levels when manual methods of testing are used. Automated methods do not appear to be affected.

Doses

Dogs/Cats:

For resistant cases of Lyme Disease when response to other antibiotics is not noted:

a) 20 mg/kg IV or SubQ q12h for 7-10 days

Horses:

For susceptible infections: 25 - 50 mg/kg q12h IV or IM (Note: This is a human dose and should be used as a general guideline only)

Monitoring Parameters - 1) Efficacy; 2) If long term therapy, occasional CBC, renal function (BUN, Serum Creatinine, urinalysis) and liver enzymes (AST, ALT) may be considered.

CEPHALEXIN

Chemistry - A semi-synthetic oral cephalosporin, cephalexin (as the monohydrate) occurs as a white to off-white, crystalline powder. It is slightly soluble in water and practically insoluble in alcohol.

Storage/Stability/Compatibility - Cephalexin tablets, capsules, and powder for oral suspension should be stored at room temperature (15-30^oC) in tight containers. After reconstitution, the oral suspension is stable for 2 weeks.

Pharmacology/Spectrum of Activity - A first generation cephalosporin, cephalexin exhibits activity against the bacteria usually covered by this class.

Uses/Indications - There are no approved cephalexin products for veterinary use in the United States. It has been used clinically in dogs, cats, horses and birds, however.

Pharmacokinetics (specific) - After oral administration, cephalexin is rapidly and completely absorbed in humans. Cephalexin (base) must be converted to the HCl before absorption can occur and, therefore, absorption can be delayed. There is a form of cephalexin HCl commercially available for oral use which apparently is absorbed more rapidly, but the clinical significance of this is in question.

In a study done in dogs and cats, peak serum levels reached 18.6 micrograms/ml about 1.8 hours after a mean oral dose of 12.7 mg/kg in dogs, and 18.7 micrograms/ml, 2.6 hours after an oral dose of 22.9 mg/kg in cats. Elimination half-lives ranged from 1-2 hours in both species. Bioavailability was about 75% in both species after oral administration. In the U.K., an oily suspension of the sodium salt is apparently available for IM or SQ injection in animals. In calves, the sodium salt had a 74% bioavailability after IM injection and a serum half-life of about 90 minutes.

Adverse Effects/Warnings - In addition to the adverse effects listed in the general statement on the cephalosporins, cephalexin has reportedly caused salivation, tachypnea and excitability in dogs, and emesis and fever in cats. Nephrotoxicity occurs rarely during therapy with cephalexin, but patients with renal dysfunction, receiving other nephrotoxic drugs or are geriatric may be more susceptible. Interstitial nephritis, a hypersensitivity reaction, has been reported with many of the cephalosporins including cephalexin. The incidence of these effects is not known.

Doses

Dogs:

For susceptible infections:

a) 11 - 33 mg/kg PO q8h

b) 22 mg/kg PO q8h; administer with food if GI upset occurs

c) 10 - 30 mg/kg PO q8h

d) 30 mg/kg PO q12h

e) For Staph. osteomyelitis: 30 mg/kg PO q12h

Cats:

For susceptible infections:

a) 11 - 33 mg/kg PO q8h

b) 22 mg/kg PO q8h; administer with food if GI upset occurs

c) 10 - 30 mg/kg PO q8h

d) 30 mg/kg PO q12h

Horses:

For susceptible infections:

a) 25 mg/kg PO qid

b) 22 - 33 mg/kg PO q6h

Birds:

For susceptible infections:

a) 35 - 50 mg/kg PO qid (using suspension); most preps are well accepted.

b) 40 - 100 mg/kg q6h PO

CEPHALOTHIN SODIUM

Chemistry - An injectable semi-synthetic cephalosporin antibiotic, cephalothin sodium occurs as a practically odorless, white to off-white, crystalline powder. It is freely soluble in water and very slightly soluble in alcohol. Each gram of the injection contains 2.8 mEq of sodium. After reconstitution the solution for injection has a pH of 6.0-8.5.

Storage/Stability/Compatibility - The sterile powder for injection and reconstitution should be stored at room temperature. After reconstituting with sterile water for injection, cephalothin sodium neutral is stable for 12 hours at room temperature and 96 hours when refrigerated. Precipitates may occur with refrigerated solutions, but can be redissolved with warming and agitation. Solutions may darken, particularly at room temperature, but this does not indicate any loss of potency. In the frozen state, cephalothin sodium solutions are relatively stable.

The following drugs or solutions are reportedly compatible with cephalothin: D₂₅W/Amino Acids 4.25%, D₅W in Lactated Ringer’s, D₅W in sodium chloride 0.2% - 0.9%, D₅W, D₁₀W, Lactated Ringer’s Injection, normal saline, ascorbic acid injection, chloramphenicol sodium succinate, clindamycin phosphate, cytarabine, fluorouracil, heparin sodium, hydrocortisone sodium succinate, magnesium sulfate, metaraminol bitartrate, methotrexate, nitrofurantoin sodium, oxacillin sodium, phytonadione, polymyxin B sulfate, potassium chloride, sodium bicarbonate and vitamin B complex with C.

The following drugs or solutions are reportedly incompatible or only compatible in specific situations with cephalothin: amikacin sulfate, aminophylline, bleomycin sulfate, calcium chloride/ gluconate, cimetidine HCl, dopamine HCl, doxorubicin HCl, erythromycin lactobionate, gentamicin sulfate, isoproterenol HCl, kanamycin sulfate, norepinephrine bitartrate, oxytetracycline HCl, penicillin G potassium/sodium, phenobarbital sodium, prochlorperazine edisylate and tetracycline HCl.

Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used.

Pharmacology/Spectrum of Activity - A first generation cephalosporin, cephalothin exhibits activity against the bacteria usually covered by this class.

Uses/Indications - In the United States, there are no cephalothin products approved for veterinary species, but it has been used clinically in several species when a relatively short-acting, injectable, first generation cephalosporin is indicated.

Pharmacokinetics (specific) - Cephalothin is not appreciably absorbed after oral administration and must be given parenterally to achieve therapeutic serum levels. Absorbed drug is partially metabolized by the liver and kidneys to desacetylcephalothin which is about 25% as active an antibacterial as the parent compound. In humans, about 60-95% of the drug is excreted unchanged into the urine and 27-54% of a dose is excreted as the desacetyl metabolite. Elimination half-lives may be significantly prolonged in patients with severely diminished renal function.  Pharmacokinetic parameters for dogs and horses follow:

In dogs, the apparent volume of distribution at steady state is 435 ml/kg, total body clearance of 11.6 - 15 ml/min/kg with a serum elimination half-life of 42-51 minutes.

In horses, the apparent volume of distribution at steady state is 145 ml/kg, total body clearance of 13 ml/min/kg with a serum elimination half-life of 15 minutes when given IV and 49 minutes after IM injection. Cephalothin is about 20% bound to equine plasma proteins.

Doses - IM injection may be very painful.

Dogs:

For susceptible infections:

a) 35 mg/kg IM, SQ q8h

b) 10 - 30 mg/kg IV or IM q6-8h

c) 10 - 30 mg/kg IM, IV or SQ

d) 11 - 33 mg/kg IV q8h; 22 - 33 mg/kg IM or SQ q8h

For surgical prophylaxis (soft-tissue):

a) 40 mg/kg IV before and then every 1.5 hours during surgery

Cats:

For susceptible infections:

a) 35 mg/kg IM, SQ q8h

b) 10 - 30 mg/kg IV or IM q6-8h

c) 10 - 30 mg/kg IM, IV or SQ

d) 11 - 33 mg/kg IV q8h; 22 - 33 mg/kg IM or SQ q8h

Cattle:

For susceptible infections:

a) 55 mg/kg SQ q6h

Horses:

For susceptible infections:

a) 11 - 18 mg/kg IM or IV qid

b) Foals: 20 - 30 mg/kg IV q6h

c) 18 mg/kg IM or IV q6h

Birds:

For susceptible infections:

a) 100 mg/kg IM qid

Reptiles:

For susceptible infections in most species:

a) 20 - 40 mg/kg IM q12 hours

CEPHAPIRIN SODIUM

CEPHAPIRIN BENZATHINE

Chemistry - An injectable semi-synthetic cephalosporin antibiotic, cephapirin sodium occurs as a white to off-white, crystalline powder having a faint odor. It is very soluble in water and slightly soluble in alcohol. Each gram of the injection contains 2.36 mEq of sodium. After reconstitution the solution for injection has a pH of 6.5-8.5. May also be known as cefapirin sodium.

Storage/Stability/Compatibility - The sterile powder for injection and reconstitution should be stored at room temperature and is stable for 24 months in dry state. After reconstituting with sterile water for injection in concentrations of 50 - 400 mg/ml, cephapirin is stable for 12 hours at room temperature. After reconstituting with bacteriostatic water for injection in concentrations of 250 - 400 mg/ml, cephapirin is stable for 48 hours at room temperature. After reconstituting with sodium chloride 0.9% injection or dextrose 5% in water in concentrations of 20 - 100 mg/ml, cephapirin is stable for 24 hours at room temperature. All of the above solutions are stable for 10 days when stored at 4^oC (refrigeration) and may be stable longer when solutions are frozen. Solutions may become yellow, but this does not indicate any loss of potency.

Cephapirin mastitis tubes should be stored at room temperature (15-30^oC); avoid excessive heat. The following drugs or solutions are reportedly compatible with cephapirin: D5W in Ringer’s,

D5W in Lactated Ringer’s, D5W in sodium chloride 0.2% - 0.9%, D₅W, D₁₀W, D₂₀W, Ringer’s Injection, Lactated Ringer’s Injection, normal saline, bleomycin sulfate, calcium chloride/gluconate, chloramphenicol sodium succinate, diphenhydramine HCl, ergonovine maleate, heparin sodium, hydrocortisone sodium phosphate/succinate, metaraminol bitartrate, oxacillin sodium, penicillin G potassium/sodium, phenobarbital sodium, phytonadione, potassium chloride, sodium bicarbonate, succinylcholine chloride, verapamil HCl, vitamin B-complex with C and warfarin sodium.

The following drugs or solutions are reportedly incompatible or only compatible in specific situations with cephapirin: Mannitol 20%, amikacin sulfate, aminophylline, ascorbic acid injection, epinephrine HCl, erythromycin gluceptate, gentamicin sulfate, kanamycin sulfate, nitrofurantoin sodium, norepinephrine bitartrate, oxytetracycline HCl, phenytoin sodium, tetracycline HCl, and thiopental sodium.

Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used.

Pharmacology/Spectrum of Activity - A first generation cephalosporin, cephapirin exhibits activityagainst the bacteria usually covered by this class. A cephalothin disk is usually used to determine bacterial susceptibility to this antibiotic when using the Kirby-Bauer method.

Uses/Indications - In the United States, there are no parenterally administered cephapirin products approved for veterinary species, but it has been used clinically in several species when a relatively short-acting injectable first generation cephalosporin is indicated.

An intramammary cephapirin sodium product is approved for use in the treatment of mastitis in lactating dairy cows and cephapirin benzathine is approved in dry cows.

Pharmacokinetics (specific) - Cephapirin is not appreciably absorbed after oral administration. In horses, the bioavailability is about 95% after IM injection. The apparent volumes of distribution have been reported as 0.32 L/kg in dogs, 0.335 - 0.399 L/kg in cattle and 0.17 - 0.188 L/kg in horses. The total body clearance of cephapirin is 8.9 ml/min/kg in dogs, 12.66 ml/min/kg in cattle and about 7.8 - 10 ml/min/kg in horses. Serum elimination half-life is about 25 minutes in dogs, 64 - 70 minutes in cattle and 25-55 minutes in horses. Probenecid has been demonstrated to reduce the renal clearance of the drug.

Doses

Dogs:

For susceptible infections:

a) 10 - 30 mg/kg IV or IM q6-8h

b) 10 - 30 mg/kg IV, IM, SQ q8h

c) 11 - 33 mg/kg IV q8h; 22 - 33 mg/kg IM or SQ q8h

Cats:

For susceptible infections:

a) 11 - 33 mg/kg IV q8h; 22 - 33 mg/kg IM or SQ q8h

b) 10 - 30 mg/kg IV, IM, SQ q8h

c) 10 - 30 mg/kg IV or IM q6-8h

Cattle:

For mastitis:

a) Lactating cow: After milking out udder, clean and dry teat area. Swab teat tip with alcohol wipe and allow to dry. Insert tip of syringe into teat canal; push plunger to instill entire contents. Massage quarter and do not milk out for 12 hours. May repeat dose q12h.

b) Dry Cow: Same basic directions as above, but should be done at the time of drying off and not later than 30 days prior to calving.

Horses:

For susceptible infections:

a) 20 mg/kg IM q8h or q12h if administered with probenecid (50 mg/kg intragastrically).

b) Foals: 20 - 30 mg/kg IV q6h

c) 20 mg/kg IM q8h