Elephant Formulary

© 2003-17 Susan K. Mikota DVM and Donald C. Plumb, Pharm.D. Published by
Elephant Care International

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*Adverse Effect Noted

Elephant specific information, if available, is in blue.

Note: 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. For a more detailed review of cephalosporins in veterinary medicine, the reader is referred to the following article: Caprile, K.A. 1988. The Cephalosporin Antimicrobial Agents: A Comprehensive Review. J Vet Pharmacol Ther 11 (1):1-32.

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 beta-lactam 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. FDA-approved indications/species, as well as non-approved uses are listed in the Uses/Indications and Dosage sections for each individual drug.

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 which are detailed under each individual drug’s monograph.

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 (see Adverse effects section).

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 (no longer marketed). 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 with 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.

a) Adverse effect noted: There are no published pharmacokinetic studies on cephalosporins in elephants. Potential side effects (renal and hepatic problems) have been noted when a second generation cephalosporin was used IV (specific drug not cited).

See also Cetiofur sodium

Elephant References:
a) Schmidt, M.J: Senior Research Veterinarian, Washington Park Zoo, Portland, Oregon, personal communication, 1986. In: Olsen,J.H., 1999. Antibiotic therapy in elephants. In: Fowler,M.E. and Miller R.E. (Editors), Zoo and Wild Animal Medicine: Current Therapy 4. W.B. Saunders, Philadelphia, PA,USA p. 538.