CEFTRIAXONE (THIRD GENERATION CEPHALOSPORIN) Introduction Cephalosporins are similar to penicillins, but more stable to many bacterial b-lactamases

and therefore have a broader spectrum of activity. However, strains of E coli and Klebsiella species expressing extended-spectrum b-lactamases that can hydrolyze most cephalosporins are becoming a problem. Cephalosporins are not active against enterococci and L monocytogenes. Classification by generations is based on general features of antimicrobial activity EXAMPLES USEFUL SPECTRUM a First Generation Cefazolin (ANCEF, ZOLICEF, others) Streptococci b; Staphylococcus aureus. c Cephalexin monohydrate (KEFTAB) Cefadroxil (DURACEF) Cephradine (VELOSEF) Second Generation Cefuroxime (ZINACEF) Escherichia coli, Klebsiella, Proteus, Haemophilus influenzae, Moraxella catarrhalis. Not as active against gram-positive organisms as first-generation Cefuroxime axetil (CEFTIN) agents. Cefprozil (CEFZIL) Inferior activity against S. aureus compared to cefuroxime but with added activity Cefmetazole (ZEFAZONE) against Bacteroides fragilis and other Bacteroides spp. Loracarbef (LORABID)

Third Generation Cefotaxime (CLAFORAN) Ceftriaxone (ROCEPHIN) Cefdinir (OMNICEF) Cefditoren pivoxil (SPECTRACEF) Ceftibuten (CEDAX) Cefpodoxime proxetil (VANTIN) Ceftizoxime (CEFIZOX)

Enterobacteriaceae d; Pseudomonas aeruginosa e; Serratia; Neisseria gonorrhoeae; activity for S. aureus, Streptococcus pneumoniae, and Streptococcus pyogenes f comparable to first-generation agents. Activity against Bacteroides spp. inferior to that of cefoxitin and cefotetan.

Cefoperazone (CEFOBID) Active against Pseudomonas Ceftazidime (FORTAZ, others) Fourth Generation Cefepine (MAXIPINE) Comparable to third-generation but more resistant to some -lactamases. a All cephalosporins lack activity against enterococci, Listeria monocytogenes, Legionella spp., methicillin-resistant S. aureus, Xanthomonas maltophilia, and Acinetobacter species. b Except for penicillin-resistant strains. c Except for methicillin-resistant strains. d Resistance to cephalosporins may be induced rapidly during therapy by de-repression of bacterial chromosomal -lactamases, which destroy the cephalosporins. e Ceftazidime only. f Ceftazidime lacks significant gram-positive activity. Cefotaxime is most active in class against S. aureus and S. pyogenes. Antimicrobial Activity y Compared with second-generation agents, these drugs have expanded gram-negative coverage, and some are able to cross the blood-brain barrier. y Active against citrobacter, S marcescens, and providencia (though resistance can emerge during treatment of infections caused by these species due to selection of mutants that constitutively produce cephalosporinase). They are also effective against blactamase-producing strains of haemophilus and neisseria. y Ceftazidime and cefoperazone are the only two drugs with useful activity against P aeruginosa. y Like the second-generation drugs, third-generation cephalosporins are hydrolyzable by constitutively produced AmpC blactamase, and they are not reliably active against enterobacter species. Serratia, providencia, and citrobacter also produce a chromosomally encoded cephalosporinase that, when constitutively expressed, can confer resistance to third-generation cephalosporins. y Ceftizoxime and moxalactam are active against B fragilis. y Cefixime, cefdinir, ceftibuten, and cefpodoxime proxetil are oral agents possessing similar activity except that cefixime and ceftibuten are much less active against pneumococci (and completely inactive against penicillin-resistant strains) and have poor activity against S aureus. Pharmacokinetics & Dosage y Intravenous infusion of 1 g of a parenteral cephalosporin produces serum levels of 60-140 mcg/mL. y Cephalosporins penetrate body fluids and tissues well and, with the exception of cefoperazone and all oral cephalosorins, achieve levels in the cerebrospinal fluid sufficient to inhibit most pathogens, including gram-negative rods, except pseudomonas. y Ceftriaxone (half-life 7-8 hours) can be injected once every 24 hours at a dosage of 15-50 mg/kg/d. A single daily 1-g dose is sufficient for most serious infections, with 4 g once daily recommended for treatment of meningitis. y Cefoperazone (half-life 2 hours) can be injected every 8-12 hours in a dosage of 25-100 mg/kg/d. The remaining drugs in the group (half-life 1-1.7 hours) can be injected every 6-8 hours in dosages between 2 and 12 g/d, depending on the severity of infection.

y Cefixime can be given orally (200 mg twice daily or 400 mg once daily) for respiratory or urinary tract infections. y The adult dose for cefpodoxime proxetil or cefditoren pivoxil is 200-400 mg twice daily; for ceftibuten, 400 mg once daily; and for cefdinir, 300 mg/12 h. y The excretion of cefoperazone and ceftriaxone is mainly through the biliary tract, and no dosage adjustment is required in renal insufficiency. y The others are excreted by the kidney and therefore require dosage adjustment in renal insufficiency. Mechanisms of Bacterial Resistance to the Cephalosporins. y Resistance to the cephalosporins may be related to the inability of the antibiotic to reach its sites of action or to alterations in the penicillin-binding proteins (PBPs) that are targets of the cephalosporins such that the antibiotics bind to bacterial enzymes (blactamases) that can hydrolyze the b-lactam ring and inactivate the cephalosporin. y The most prevalent mechanism of resistance to cephalosporins is destruction of the cephalosporins by hydrolysis of the b-lactam ring. Many gram-positive microorganisms release relatively large amounts of b-lactamase into the surrounding medium. Although gram-negative bacteria seem to produce less b-lactamase, the location of their enzyme in the periplasmic space may make it more effective in destroying cephalosporins as they diffuse to their targets on the inner membrane, as is the case for the penicillins. y The cephalosporins have variable susceptibility to b-lactamase. For example, of the first-generation agents, cefazolin is more susceptible to hydrolysis by b-lactamase from S. aureus than is cephalothin (no longer marketed). Cefoxitin, cefuroxime, and the third-generation cephalosporins are more resistant to hydrolysis by the b-lactamases produced by gram-negative bacteria than first-generation cephalosporins. y Third-generation cephalosporins are susceptible to hydrolysis by inducible, chromosomally encoded (type I) b-lactamases. Induction of type I b-lactamases by treatment of infections owing to aerobic gram-negative bacilli (especially Enterobacter spp., Citrobacter freundii, Morganella, Serratia, Providencia, and P. aeruginosa) with second- or third-generation cephalosporins and/or imipenem may result in resistance to all third-generation cephalosporins. y The fourth-generation cephalosporins, such as cefepime, are poor inducers of type I b-lactamases and are less susceptible to hydrolysis by type I b-lactamases than are the third-generation agents. These type I b-lactamases are not detected in routine laboratory testing until a mutation occurs that makes their expression constitutive. Clinical Uses y Third-generation cephalosporins are used to treat a wide variety of serious infections caused by organisms that are resistant to most other drugs. Strains expressing extended-spectrum b-lactamases, however, are not susceptible. y Third-generation cephalosporins should be avoided in treatment of enterobacter infectionseven if the clinical isolate appears susceptible in vitrobecause of emergence of resistance. y Ceftriaxone and cefotaxime are approved for treatment of meningitis, including meningitis caused by pneumococci, meningococci, H influenzae, and susceptible enteric gram-negative rods, but not by L monocytogenes. Ceftriaxone and cefotaxime are the most active cephalosporins against penicillin-resistant strains of pneumococci and are recommended for empirical therapy of serious infections that may be caused by these strains. y Meningitis caused by highly penicillin-resistant strains of pneumococci (ie, those susceptible only to penicillin MICs > 1 mcg/mL) may not respond even to these agents, and addition of vancomycin is recommended. y Other potential indications include empirical therapy of sepsis of unknown cause in both the immunocompetent and the immunocompromised patient and treatment of infections for which a cephalosporin is the least toxic drug available. y In neutropenic, febrile immunocompromised patients, third-generation cephalosporins are often used in combination with an aminoglycoside. Adverse Reactions y Hypersensitivity reactions to the cephalosporins are the most common side effects, and there is no evidence that any single cephalosporin is more or less likely to cause such sensitization anaphylaxis, bronchospasm, and urticaria are observed. More commonly, maculopapular rash develops, usually after several days of therapy; this may or may not be accompanied by fever and eosinophilia. y Patients with a history of a mild or a temporally distant reaction to penicillin appear to be at low risk of rash or other allergic reaction following the administration of a cephalosporin. However, patients who have had a recent severe, immediate reaction to a penicillin should be given a cephalosporin with great caution, if at all. y The cephalosporins have been implicated as potentially nephrotoxic agents, although they are not nearly as toxic to the kidney as are the aminoglycosides or the polymyxins. Renal tubular necrosis has followed the administration of cephaloridine in doses greater than 4 g/day; this agent is no longer available in the United States. Other cephalosporins are much less toxic and, when used by themselves in recommended doses, rarely produce significant renal toxicity. High doses of cephalothin (no longer available in the United States) have produced acute tubular necrosis in certain instances, and usual doses (8 to 12 g/day) have caused nephrotoxicity in patients with preexisting renal disease. There is good evidence that the concurrent administration of cephalothin and gentamicin or tobramycin act synergistically to cause nephrotoxicity, especially in patients older than 60 years of age. y Diarrhea can result from the administration of cephalosporins and may be more frequent with cefoperazone, perhaps because of its greater biliary excretion. y Intolerance to alcohol (a disulfiram-like reaction) has been noted with cephalosporins that contain the MTT group, including cefamandole (no longer available in the United States), cefotetan, moxalactam, and cefoperazone. Serious bleeding related either to hypoprothrombinemia owing to the MTT group, thrombocytopenia, and/or platelet dysfunction has been reported with several b-lactam antibiotics.