Chapter e1

Cephalosporins

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The cephalosporins, structurally related to the penicillins, consist of a beta-lactam ring attached to a dihydrothiazoline ring. Substitutions of chemical groups result in varying pharmacologic properties and antimicrobial activities. Cross reactions between penicillins and cephalosporins are thought to be related primarily to similarities in the molecular structure of side chains; for example, penicillin and cefoxitin have similar side chains, as do ampicillin and cephalexin.

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The mechanism of action of cephalosporins is analogous to that of the penicillins: (1) binding to specific penicillin-binding proteins, (2) inhibition of cell wall synthesis, and (3) activation of autolytic enzymes in the cell wall. Resistance to cephalosporins may be due to poor permeability of the drug into bacteria, lack of penicillin-binding proteins, or degradation by beta-lactamases.

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Cephalosporins have been divided into five major groups or “generations” (see eTable 30–4.1) based on their antibacterial activity: First-generation cephalosporins have good activity against aerobic gram-positive organisms and some community-acquired gram-negative organisms (P mirabilis, Escherichia coli, Klebsiella species); second-generation drugs have a slightly extended spectrum against gram-negative bacteria, and some are active against gram-negative anaerobes; and third-generation cephalosporins are active against many gram-negative bacteria. Not all cephalosporins fit neatly into this grouping, and there are exceptions to the general characterization of the drugs in the individual classes; however, the generational classification of cephalosporins is useful for discussion purposes. Cefepime is considered a fourth-generation agent because it is more stable against plasmid-mediated beta-lactamase and has little or no beta-lactamase-inducing capacity. Cefepime compares favorably with ceftazidime with respect to its gram-negative activity; however, its stability versus plasmid-mediated beta-lactamase results in improved coverage against Enterobacter and Citrobacter species. The gram-positive coverage of cefepime approaches that of cefotaxime or ceftriaxone. None of the currently available agents are active against the enterococcus. A fifth-generation cephalosporin, ceftaroline, is uniquely active against methicillin-resistant S aureus and has comparable gram-negative spectrum activity as third-generation agents.

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First-Generation Cephalosporins

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Antimicrobial Activity

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In vitro activity includes coverage of gram-positive cocci, including viridans streptococci, group A hemolytic streptococci, and S aureus. As with all cephalosporins, they are inactive against enterococci and methicillin-resistant staphylococci. Activity against H influenzae is poor, and penicillin-resistant streptococci (both intermediately and highly resistant) are resistant to first-generation cephalosporins. Among gram-negative bacteria, E coli, Klebsiella pneumoniae, and P mirabilis are the most likely susceptible. Anaerobic gram-positive cocci are usually susceptible, but B fragilis is not.

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Pharmacokinetics & Administration

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Oral
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Cephalexin, cephradine, and cefadroxil are generally well absorbed. Cefadroxil, because of its longer half-life, can be given twice daily instead of four times daily.

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Intravenous
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Cefazolin is preferred because its longer half-life allows for less frequent dosing. In kidney disease, it requires dosage adjustment.

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Intramuscular
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Cefazolin can be given intramuscularly; however, the intravenous route is preferred because of the every 8-hour dosing schedule.

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Clinical Uses

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Oral drugs are used for treatment of urinary tract infections, and they can be used for minor skin and soft tissue infections (eg, cellulitis, soft tissue abscess). However, the increase in the incidence of community-associated methicillin-resistant S aureus has limited the use of these agents in some instances.

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Intravenous first-generation cephalosporins are the antibacterial agents of choice for prophylaxis of infection of most clean surgical procedures; however, those institutions with high rates of postoperative surgical site infection due to methicillin-resistant staphylococci should consider the use of alternative agents, such as vancomycin. The second-generation cephalosporins cefoxitin and cefotetan have expanded anaerobic activity and are superior to first-generation agents for prophylaxis of infection following elective colorectal surgery or hysterectomy.

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First-generation cephalosporins do not adequately penetrate into cerebrospinal fluid and are less potent than second- and third-generation agents; thus, they cannot be used in the treatment of meningitis.

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Second-Generation Cephalosporins

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Second-generation cephalosporins are a heterogeneous group with marked individual differences in activity and pharmacokinetics. In general, they are active against gram-negative organisms inhibited by first-generation cephalosporins, however, with additional aerobic gram-negative activity. Indole-positive Proteus and Klebsiella (including first-generation cephalosporin-resistant strains) as well as M catarrhalis and Neisseria species are usually sensitive to the parenteral second-generation agents. Cefuroxime is active against H influenzae, including beta-lactamase-producing strains, but has little activity against B fragilis. In contrast, cefoxitin and cefotetan are active against many strains of B fragilis. Against gram-positive organisms, second-generation agents are generally less active than the first-generation cephalosporins (cefuroxime is an exception). Second-generation agents have no activity against P aeruginosa.

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Pharmacokinetics & Administration

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Oral
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Only cefaclor, cefuroxime axetil, and cefprozil can be given orally. Cefuroxime axetil is deesterified to cefuroxime after absorption. Its longer half-life permits twice-daily dosing, and absorption is enhanced when it is taken with food (as is not the case with many other oral antibiotics).

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Intravenous and Intramuscular
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Because of differences in drug half-life and protein binding, peak serum levels achieved and dosing intervals vary greatly for this group of drugs (see eTable 30–4.2). Drugs with shorter half-lives (cefoxitin) require more frequent dosing than drugs with longer half-lives (eg, cefuroxime). Dosage adjustment is required with kidney disease.

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Clinical Uses

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Because of their activity against beta-lactamase–producing H influenzae and M catarrhalis, cefprozil and cefuroxime axetil have a role in the treatment of sinusitis and otitis media in those patients unresponsive to amoxicillin.

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Because of their activity against B fragilis,cefoxitin and cefotetan can be used to treat mixed anaerobic infections, eg, peritonitis and diverticulitis, as well as prophylaxis following colorectal surgery, vaginal or abdominal hysterectomy, and appendectomy. However, since many B fragilis and enteric gram-negative organisms are resistant, alternative agents are preferred for serious intra-abdominal infections.

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Third-, Fourth-, & Fifth-Generation Cephalosporins

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Antimicrobial Activity

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Most of these drugs are active against staphylococci (not methicillin-resistant strains) but less so than first-generation cephalosporins. Ceftazidime, however, has notably weak activity against S aureus and pneumococci. While inactive against enterococci, most third- and fourth-generation cephalosporins inhibit most streptococci (ceftazidime is an exception to this rule). Ceftriaxone and cefotaxime offer the most reliable antipneumococcal coverage. A major advantage of third-, fourth-, and fifth- generation cephalosporins is their expanded gram-negative coverage. In addition to organisms inhibited by other cephalosporins, they are more active against Serratia marcescens, Providencia, Haemophilus, and Neisseria, including beta-lactamase–producing strains. Ceftazidime is unique among all third-generation agents because it is active against P aeruginosa.Acinetobacter, Citrobacter, Enterobacter, and nonaeruginosa strains of Pseudomonas are variably sensitive to third-generation cephalosporins, and Listeria is uniformly resistant. Activity against B fragilis is variable. In contrast to the third-generation agents, cefepime—the only currently available fourth-generation cephalosporin—is more active against Enterobacter and Citrobacter, has activity comparable to that of ceftazidime against P aeruginosa, and has gram-positive activity similar to that of ceftriaxone.

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Cefpodoxime proxetil, cefdinir, cefditoren pivoxil, cefixime, and ceftibuten (the only oral agents in this group) are more active than cefuroxime axetil against gram-negative pathogens. However, none of these oral agents are equal to the parenteral third-generation cephalosporins against these pathogens. All third- and fourth-generation cephalosporins are uniformly active against Streptococcus pyogenes (group A Streptococcus). Cefpodoxime proxetil, cefditoren pivoxil, and cefdinir are active against methicillin-sensitive S aureus, whereas ceftibuten has little activity (none are active against methicillin-resistant strains). Cefdinir, cefditoren pivoxil, and cefpodoxime proxetil are active against penicillin-sensitive strains of Streptococcus pneumoniae (the pneumococcus), but ceftibuten has marginal activity. None of the oral cephalosporins are reliable against intermediately susceptible or penicillin-resistant S pneumoniae. Similar to other members of this class, these drugs are ineffective against enterococci and Listeria monocytogenes. The one available fifth-generation cephalosporin, ceftaroline, is unique in that it represents the only beta-lactam with in vitro activity against methicillin-resistant S aureus. Unlike other beta-lactams, ceftaroline binds PBP2a, a penicillin binding protein encoded by the mecA gene in methicillin-resistant S aureus. The gram-negative spectrum of activity approximates that of ceftriaxone, thus it is inactive against P aeruginosa, Acinetobacter spp, and B fragilis.

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Pharmacokinetics & Administration

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The intravenous third- and fourth-generation agents distribute into extracellular fluid and reach levels in the cerebrospinal fluid exceeding those needed to inhibit susceptible pathogens, particularly in the presence of inflamed meninges. At the present time, the cerebrospinal fluid penetration of ceftaroline is unknown and the drug has not been studied in the treatment of meningitis. The half-lives of these drugs are variable, resulting in differing dosage needs (see eTable 30–4.2). Ceftriaxone is eliminated primarily by biliary excretion, and no dosage adjustment is required in kidney disease. The other drugs are eliminated primarily by the kidney and thus require dosage adjustment in kidney disease.

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Clinical Uses

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Because of their penetration into the cerebrospinal fluid and potent in vitro activity, intravenous third-generation cephalosporins are effective in the treatment of meningitis due to susceptible pneumococci, meningococci, H influenzae, and enteric gram-negative rods. In meningitis in older patients, third-generation cephalosporins should be combined with ampicillin or trimethoprim-sulfamethoxazole until L monocytogenes has been excluded. Ceftazidime has been used to treat meningitis due to Pseudomonas. The dosage for meningitis should be at the upper limits of the recommended range, because cerebrospinal fluid levels of these drugs are only 10–20% of serum levels. Ceftazidime or cefepime is frequently administered empirically in the febrile neutropenic patient. Ceftriaxone is indicated for gonorrhea, chancroid, and more serious forms of Lyme disease. Because of its long half-life and once-daily dosing requirement, ceftriaxone is an attractive option for the outpatient parenteral therapy of infections due to susceptible organisms.

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Cefepime is useful for third-generation cephalosporin–resistant isolates such as Enterobacter and Citrobacter. While cefepime has an extended spectrum of activity compared with third-generation agents, a meta-analysis revealed increased all-cause mortality with this agent when compared with other beta-lactams. Additional analyses have refuted this finding, and cefepime appears no different than any other beta-lactam with respect to mortality risk. Considering its spectrum of activity, including methicillin-resistant S aureus, ceftaroline is useful in the treatment of skin and soft tissue infection due to this pathogen, particularly if gram-negative pathogens are coinfecting.

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Cefdinir, cefditoren pivoxil, and cefpodoxime proxetil are the best third-generation oral agents against pneumococci and S aureus.Cefixime is available in an oral suspension and 400-mg tablets. However, cefixime is no longer considered a drug of choice in the treatment of gonorrhea because of the increased rate cefixime-resistant cases.

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Adverse Effects of Cephalosporins

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Allergy

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Cephalosporins, like penicillins, are sensitizing, and a variety of hypersensitivity reactions occur, including anaphylaxis, fever, skin rashes, nephritis, and hemolytic anemia. The frequency of IgE cross-allergy between cephalosporins and penicillins approximates 5–10%. However, the risk of cross-reactivity is dependent on the specific cephalosporin. Cross reactivity between penicillin and cephalosporins is more common with first-generation agents, when compared with later generations. Persons with a history of anaphylaxis to penicillins should not receive cephalosporins. The likelihood of non–IgE-mediated cross-reactivity between penicillins and cephalosporins is unknown but likely very low. Allergies to a given agent may or may not extend to the entire cephalosporin class.

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Toxicity

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Ceftriaxone has been associated with a dose-dependent biliary sludging syndrome and cholelithiasis due to precipitation of drug when its solubility in bile is exceeded. Long-term administration of 2 g/d or more is a risk factor for this complication. Cefepime may be associated with an increased rate of neurotoxicity, particularly with large doses and concomitant kidney disease.

Ceftaroline fosamil (Teflaro)—a new IV cephalosporin. Med Lett Drugs Ther. 2011 Jan 24;53(1356):5–6.  [PubMed: 21252841] [[XSLOpenURL/ 21252841]]
Cephalosporins for patients with penicillin allergy. Med Lett Drugs Ther. 2012 Dec 24:54(1406):101.   [PubMed: 23282790]

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