Cephalosporins & Cephamycins

CEPHALOSPORINS & CEPHAMYCINS

Cephalosporins are similar to penicillins, but more stable to many bacterial β lactamases and therefore have a broader spectrum of activity. However, strains of E coli and Klebsiella sp expressing extended-spectrum β lactamases that can hydrolyze most cepha-losporins are a growing clinical concern. Cephalosporins are not active against enterococci and L monocytogenes.

Chemistry

The nucleus of the cephalosporins, 7-aminocephalosporanic acid (Figure 43–6), bears a close resemblance to 6-aminopenicillanic acid (Figure 43–1). The intrinsic antimicrobial activity of natural cephalosporins is low, but the attachment of various R₁ and R₂ groups has yielded hundreds of potent compounds of low toxicity. Cephalosporins can be classified into four major groups or gen-erations, depending mainly on the spectrum of antimicrobial activity.

FIRST-GENERATION  CEPHALOSPORINS

First-generation cephalosporins include cefazolin, cefadroxil,cephalexin, cephalothin, cephapirin, and cephradine. Thesedrugs are very active against gram-positive cocci, such as pneumo-cocci, streptococci, and staphylococci. Traditional cephalosporins are not active against methicillin-resistant strains of staphylococci; how-ever, new compounds have been developed that have activity against methicillin-resistant strains . E coli, K pneumoniae, and Proteus mirabilis are often sensitive, but activity against

P  aeruginosa,  indole-positive  proteus  species,  Enterobacter  sp,S marcescens, Citrobacter sp, and Acinetobacter sp is poor. Anaerobiccocci (eg, peptococci, peptostreptococci) are usually sensitive, but Bacteroides fragilis is not.

Pharmacokinetics & Dosage

A. Oral

Cephalexin, cephradine, and cefadroxil are absorbed from the gut to a variable extent. After oral doses of 500 mg, serum levels are 15–20 mcg/mL. Urine concentration is usually very high, but in most tis-sues levels are variable and generally lower than in serum. Cephalexin and cephradine are given orally in dosages of 0.25–0.5 g four times daily (15–30 mg/kg/d) and cefadroxil in dosages of 0.5–1 g twice daily. Excretion is mainly by glomerular filtration and tubular secre-tion into the urine. Drugs that block tubular secretion, eg, probenecid, may increase serum levels substantially. In patients with impaired renal function, dosage must be reduced (Table 43–2).

B. Parenteral

Cefazolin is the only first-generation parenteral cephalosporin still in general use. After an intravenous infusion of 1 g, the peak level of cefazolin is 90–120 mcg/mL. The usual intravenous dosage of cefazolin for adults is 0.5–2 g intravenously every 8 hours. Cefazolin can also be administered intramuscularly. Excretion is via the kidney, and dose adjustments must be made for impaired renal function.

Clinical Uses

Oral drugs may be used for the treatment of urinary tract infec-tions and staphylococcal or streptococcal infections, including cellulitis or soft tissue abscess. However, oral cephalosporins should not be relied on in serious systemic infections.

Cefazolin penetrates well into most tissues. It is a drug of choice for surgical prophylaxis. Cefazolin may also be a choice in infections for which it is the least toxic drug (eg, penicillinase-producing E coli or K pneumoniae) and in individuals with staphylococcal or streptococcal infections who have a history of penicillin allergy other than immediate hypersensitivity. Cefazolin does not penetrate the central nervous system and cannot be used to treat meningitis. Cefazolin is an alternative to an antistaphylo-coccal penicillin for patients who are allergic to penicillin.

SECOND-GENERATION CEPHALOSPORINS

Members of the second-generation cephalosporins include cefaclor,cefamandole, cefonicid, cefuroxime, cefprozil, loracarbef, and ceforanide; and the structurally related cephamycins cefoxitin, cefmetazole, and cefotetan, which have activity against anaer-obes. This is a heterogeneous group with marked individual differ-ences in activity, pharmacokinetics, and toxicity. In general, they are active against organisms inhibited by first-generation drugs, but in addition they have extended gram-negative coverage. Klebsiella sp (including those resistant to cephalothin) are usuallysensitive. Cefamandole, cefuroxime, cefonicid, ceforanide, and cefaclor are active against H influenzae but not against serratia or B fragilis. In contrast, cefoxitin, cefmetazole, and cefotetan areactive against B fragilis and some serratia strains but are less active against H influenzae. As with first-generation agents, none is active against enterococci or P aeruginosa. Second-generation cepha-losporins may exhibit in vitro activity against Enterobacter sp., but resistant mutants that constitutively express a chromosomal lactamase that hydrolyzes these compounds (and third-generation cephalosporins) are readily selected, and they should not be used to treat enterobacter infections.

Pharmacokinetics & Dosage

A. Oral

Cefaclor, cefuroxime axetil, cefprozil, and loracarbef can be given orally. The usual dosage for adults is 10–15 mg/kg/d in two to four divided doses; children should be given 20–40 mg/kg/d up to a maximum of 1 g/d. Except for cefuroxime axetil, these drugs are not predictably active against penicillin-non-susceptible pneumo-cocci and should be used cautiously, if at all, to treat suspected or proved pneumococcal infections. Cefaclor is more susceptible to β-lactamase hydrolysis compared with the other agents, and itsusefulness is correspondingly diminished.

B. Parenteral

After a 1-g intravenous infusion, serum levels are 75–125 mcg/mL for most second-generation cephalosporins. Intramuscular admin-istration is painful and should be avoided. Doses and dosing intervals vary depending on the specific agent (Table 43–2). There are marked differences in half-life, protein binding, and interval between doses. All are renally cleared and require dosage adjust-ment in renal failure.

Clinical Uses

The oral second-generation cephalosporins are active against β-lactamase-producingH influenzaeorMoraxella catarrhalisand havebeen primarily used to treat sinusitis, otitis, and lower respiratory tract infections, in which these organisms have an important role. Because of their activity against anaerobes (including many B fragilis strains), cefoxitin, cefotetan, or cefmetazole can be used to treat mixed anaero-bic infections such as peritonitis, diverticulitis, and pelvic inflamma-tory disease. Cefuroxime is used to treat community-acquired pneumonia because it is active against β-lactamase-producing H influenzae or K pneumoniae and some penicillin-non-susceptiblepneumococci. Although cefuroxime crosses the blood-brain barrier, it is less effective in treatment of meningitis than ceftriaxone or cefo-taxime and should not be used.

THIRD-GENERATION CEPHALOSPORINS

Third-generation agents include cefoperazone, cefotaxime, cef-tazidime, ceftizoxime, ceftriaxone, cefixime, cefpodoxime prox-etil, cefdinir, cefditoren pivoxil, ceftibuten, and moxalactam.

Antimicrobial Activity

Compared with second-generation agents, these drugs have expanded gram-negative coverage, and some are able to cross the blood-brain barrier. Third-generation drugs are active against Citrobacter, S marcescens, and Providencia (although resistance canemerge during treatment of infections caused by these species due to selection of mutants that constitutively produce cephalosporinase). They are also effective against β-lactamase-producing strains of haemophilus and neisseria. Ceftazidime and cefoperazone are the only two drugs with useful activity against P aeruginosa. Like the second-generation drugs, third-generation cephalosporins are hydrolyzed by constitutively produced AmpC β lactamase, and they are not reliably active against Enterobacter species. Serratia, Providencia, and Citrobacter also produce a chromosomallyencoded cephalosporinase that, when constitutively expressed, can confer resistance to third-generation cephalosporins. Ceftizoxime and moxalactam are active against B fragilis. Cefixime, cefdinir,ceftibuten, and cefpodoxime proxetil are oral agents possessing similar activity except that cefixime and ceftibuten are much less active against pneumococci and have poor activity against S aureus.

Pharmacokinetics & Dosage

Intravenous infusion of 1 g of a parenteral cephalosporin produces serum levels of 60–140 mcg/mL. Third-generation cephalosporins penetrate body fluids and tissues well and, with the exception of cefoperazone and all oral cephalosporins, achieve levels in the cerebrospinal fluid sufficient to inhibit most susceptible pathogens.

The half-lives of these drugs and the necessary dosing intervals vary greatly: 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 2 g every 12 hours recommended for treatment of meningitis. Cefoperazone (half-life 2 hours) can be infused 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 infused every 6–8 hours in dosages between 2 and 12 g/d, depending on the severity of infection. Cefixime can be given orally (200 mg twice daily or 400 mg once daily) for urinary tract infections and as a single 400 mg dose for uncompli-cated gonococcal urethritis and cervicitis. 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. The excretion of cefoperazone and ceftriaxone is mainly through the biliary tract, and no dosage adjustment is required in renal insufficiency. The others are excreted by the kidney and therefore require dosage adjustment in renal insufficiency.

Clinical Uses

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 β lactamases, however, are not susceptible. Third-generation cephalosporins should be avoided in treatment of enterobacter infections—even if the clinical isolate appears susceptible in vitro—because of emergence of resistance. Ceftriaxone and cefotaxime are approved for treatment of meningitis, including meningitis caused by pneu-mococci, meningococci, H influenzae, and susceptible enteric gram-negative rods, but not by L monocytogenes. Ceftriaxone and cefotaxime are the most active cephalosporins against penicillin-non-susceptible strains of pneumococci and are recommended for empirical therapy of serious infections that may be caused by these strains. Meningitis caused by strains of pneumococci with penicil-lin MICs > 1 mcg/mL may not respond even to these agents, and addition of vancomycin is recommended. Other potential indica-tions 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. In neutropenic, febrile immunocom-promised patients, ceftazidime is often used in combination with other antibiotics.

FOURTH-GENERATION CEPHALOSPORINS

Cefepime is an example of a so-called fourth-generation cephalosporin. It is more resistant to hydrolysis by chromosomallactamases (eg, those produced by Enterobacter). However, like the third-generation compounds, it is hydrolyzed by extended

spectrum     β       lactamases. Cefepime    has    good  activity       against aeruginosa, Enterobacteriaceae, S aureus, and S pneumoniae. Itis highly active against Haemophilus and Neisseria sp. It penetrates well into cerebrospinal fluid. It is cleared by the kidneys and has a half-life of 2 hours, and its pharmacokinetic properties are very similar to those of ceftazidime. Unlike ceftazidime, however, cefepime has good activity against most penicillin-non-susceptible strains of streptococci, and it is useful in treatment of entero-bacter infections.

Cephalosporins Active against Methicillin-Resistant Staphylococci

Beta-lactam antibiotics with activity against methicillin-resistant staphylococci are currently under development. Ceftaroline fosamil, the prodrug of the active metabolite ceftaroline, is the first such drug to be approved for clinical use in the USA. Ceftaroline has increased binding to penicillin-binding protein 2a, which mediates methicillin resistance in staphylococci, resulting in bactericidal activity against these strains. It has some activity against enterococci and a broad gram-negative spectrum, although it is not active against extended-spectrum β-lactamase-producing strains. Since clinical experience with this and similar investiga-tional drugs is limited, their role in therapy is not yet defined.

ADVERSE EFFECTS OF CEPHALOSPORINS

A. Allergy

Cephalosporins are sensitizing and may elicit a variety of hyper-sensitivity reactions that are identical to those of penicillins, including anaphylaxis, fever, skin rashes, nephritis, granulocy-topenia, and hemolytic anemia. However, the chemical nucleus of cephalosporins is sufficiently different from that of penicillins so that some individuals with a history of penicillin allergy may tolerate cephalosporins. The frequency of cross-allergenicity between the two groups of drugs is uncertain but is probably around 5–10%. Cross-allergenicity appears to be more common with penicillins and early generation cephalosporins compared with later generation cephalosporins. However, patients with a history of anaphylaxis to penicillins should not receive cephalosporins.

B. Toxicity

Local irritation can produce pain after intramuscular injection and thrombophlebitis after intravenous injection. Renal toxicity, including interstitial nephritis and tubular necrosis, has been dem-onstrated with several cephalosporins and caused the withdrawal of cephaloridine from clinical use.

Cephalosporins that contain a methylthiotetrazole group (cefa-mandole, cefmetazole, cefotetan, and cefoperazone) may cause hypoprothrombinemia and bleeding disorders. Oral administra-tion of vitamin K₁, 10 mg twice weekly, can prevent this. Drugs with the methylthiotetrazole ring can also cause severe disulfiram-like reactions; consequently, alcohol and alcohol-containing medications must be avoided.