CEPHALOSPORINS (GENERAL INFORMATION)
Pharmacology - CEPHALOSPORINS (GENERAL INFORMATION)The cephalosporin antibiotics are comprised of several different classes ofcompounds with dissimilar spectrums of activity and pharmacokinetic profiles. All "true"cephalosporins are derived from cephalosporin C which is produced from Cephalosporiumacremonium.
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 wallsynthesis. The different affinities that various beta-lactam antibiotics have for these enzymes (alsoknown as penicillin-binding proteins; PBPs) help explain the differences in spectrums of activity ofthese drugs that are not explained by the influence of beta-lactamases. Like other beta-lactamantibiotics, cephalosporins are generally considered to be more effective against actively growingbacteria.
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 firstgeneration cephalosporins, their spectrums of activity are quite similar. They possess generallyexcellent coverage against most gram-positive pathogens and variable to poor coverage against mostgram 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 andaureas, 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 Corynebacteriaare susceptible, but C. equi (Rhodococcus) is usually resistant. Strains of Staphylococcusepidermidis are usually sensitive to the parenterally administered 1st generation drugs, but mayhave variable susceptibilities to the oral drugs. The following bacteria are regularly resistant to the1st generation agents: Group D streptococci/enterococci (S. faecalis, S. faecium), Methicillin-resistant Staphylococci, indole-positive Proteus sp., Pseudomonas sp., Enterobacter sp., Serratiasp. 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 (theyare actually cephamycins), cefoxitin (IM/IV) and cefotetan (IM/IV) are usually included in thisgroup, although some references categorize cefotetan as a 3rd generation agent. In addition to thegram positive coverage of the 1st generation agents, these agents have expanded gram negativecoverage. Cefoxitin and cefotetan also have good activity against Bacteroides fragilis. Enoughvariation exists between these agents in regard to their spectrums of activity against most species ofgram negative bacteria, that susceptibility testing is generally required to determine sensitivity. Thesecond generation agents have not found widespread use in most veterinary practices, althoughcefoxitin has been used somewhat.
The third generation cephalosporins retain the gram positive activity of the first and secondgeneration agents, but in comparison, have much expanded gram negative activity. Included in thisgroup 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) andcefixime (PO). As with the 2nd generation agents, enough variability exists with individual bacterialsensitivities that susceptibility testing is necessary for most bacteria. Usually only ceftazidime andcefoperazone are active against most strains of Pseudomonas aeruginosa. Because of the excellentgram negative coverage of these agents and when compared to the aminoglycosides, theirsignificantly 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 dataon its spectrum of activity or availability of pharmacokinetic profiles.
Uses, IndicationsCephalosporins have been used for a wide range of infections in variousspecies. 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 wereabsorbed appreciably after oral administration, but this has changed with the availability of cefuroxime axetil (2nd generation) and cefixime (3rd generation). Depending on the drug, absorptionmay be delayed, unaltered, or increased if administered with food. There are reported speciesvariations in the oral bioavailability of some cephalosporins which are detailed under each individualdrug'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. Veryhigh levels are found in the urine, but they penetrate poorly into prostatic tissue and aqueoushumor. Bile levels can reach therapeutic concentrations with several of the agents as long as biliaryobstruction is not present. With the exception of cefuroxime, no first or second generationcephalosporin enters the CSF (even with inflamed meninges) in therapeutically effective levels.
Therapeutic concentrations of cefotaxime, moxalactam, cefuroxime, ceftizoxime, ceftazidime andceftriaxone 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 thosefound in maternal serum. Cephalosporins enter milk in low concentrations. Protein binding of thedrugs is widely variable and species specific. Cephalosporins tend to bind to equine and canineplasma proteins less so then to human plasma proteins.
Cephalosporins and their metabolites (if any) are excreted by the kidneys, via tubular secretionand/or glomerular filtration. Some cephalosporins (e.g., cefotaxime, cefazolin, and cephapirin) arepartially metabolized by the liver to desacetyl compounds that may have some antibacterial activity.
Contraindications, Precautions, Reproductive SafetyCephalosporins are contraindicated inpatients who have a history of hypersensitivity to them. Because there may be cross-reactivity, usecephalosporins cautiously in patients who are documented hypersensitive to other beta-lactamantibiotics (e.g., penicillins, cefamycins, carbapenems).
Oral systemic antibiotics should not be administered in patients with septicemia, shock or othergrave illnesses as absorption of the medication from the GI tract may be significantly delayed ordiminished. Parenteral routes (preferably IV) should be used for these cases.
Cephalosporins have been shown to cross the placenta and safe use of them during pregnancyhave not been firmly established, but neither have there been any documented teratogenic problemsassociated with these drugs. However, use only when the potential benefits outweigh the risks.
Adverse Effects, WarningsAdverse effects with the cephalosporins are usually not serious andhave a relatively low frequency of occurrence.
Hypersensitivity reactions unrelated to dose can occur with these agents and can be manifested asrashes, fever, eosinophilia, lymphadenopathy, or full-blown anaphylaxis. The use of cephalosporinsin patients documented to be hypersensitive to penicillin-class antibiotics is controversial. Inhumans, it is estimated that up to 15% of patients hypersensitive to penicillins will also behypersensitive to cephalosporins. The incidence of cross-reactivity in veterinary patients isunknown.
Cephalosporins can cause pain at the injection site when administered intramuscularly, althoughthis effect is less so with cefazolin than other agents. Sterile abscesses or other severe local tissuereactions are also possible but are much less common. Thrombophlebitis is also possible after IVadministration 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 thecephalosporins 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 tubularnecrosis. Except for tubular necrosis and neurotoxicity, these effects have an immunologic component.
Some cephalosporins (cefamandole, cefoperazone, moxalactam) that contain a thiomethyltetrazoleside chain have been implicated in causing bleeding problems in humans. These drugs areinfrequently used in veterinary species at the present time, so any veterinary ramifications of thiseffect are unclear.
Overdosage, Acute ToxicityAcute oral cephalosporin overdoses are unlikely to cause significantproblems other than GI distress, but other effects are possible (see Adverse effects section).
Drug InteractionsThe concurrent use of parenteral aminoglycosides or other nephrotoxicdrugs (e.g., amphotericin B) with cephalosporins is controversial. Potentially, cephalosporinscould cause additive nephrotoxicity when used with these drugs, but this interaction has only beenwell documented with cephaloridine (no longer marketed). Nevertheless, they should be usedtogether cautiously.
In vitro studies have demonstrated that cephalosporins can have synergistic or additive activityagainst 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 isproliferating rapidly.
Probenecid competitively blocks the tubular secretion of most cephalosporins, thereby increasingserum levels and serum half-lives.
A disulfiram-like reaction (anorexia, nausea, vomiting) has been reported in humans who haveingested alcohol with 48-72 hours of receiving beta-lactam antibiotics (e.g., cefamandole, cefoperazone, moxalactam, cefotetan) with a thiomethyltetrazole side-chain. Because these antibioticshave been associated with bleeding, they should be used cautiously in patients receiving oral anticoagulants.
Drug/Laboratory Interactions - Except for cefotaxime, cephalosporins may cause false-positiveurine glucose determinations when using cupric sulfate solution (Benedict's Solution,
Clinitest®). Tests utilizing glucose oxidase (Tes-Tape®, Clinistix®) are not affected bycephalosporins.
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 withtheir use, monitoring for efficacy is usually all that is required. Patients with diminished renalfunction, may require intensified renal monitoring. Serum levels and therapeutic drug monitoringare not routinely done with these agents.