e1-02: Cephalosporins

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. Type 1 allergic cross-reactions between penicillins and cephalosporins are primarily due to similarities in the molecular structure of the R side chains; for example, penicillin and cefoxitin have similar R side chains; ampicillin and cephalexin share similar side chains. Consequently, a patient with a type 1 reaction to penicillin would be more likely to experience a similar reaction with cefoxitin when compared with cephalexin. In contrast, a patient with an allergic reaction to ampicillin would be more likely to have a reaction to cephalexin than cefoxitin.

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 medication into bacteria, lack of penicillin-binding proteins, or degradation by beta-lactamases.

Cephalosporins have been divided into five major groups or “generations” (see eTable 30–1) based on their antibacterial activity: First-generation cephalosporins have good activity against aerobic gram-positive organisms (but not enterococcus) and some community-acquired gram-negative organisms (P mirabilis, Escherichia coli, Klebsiella species); second-generation medications have a slightly extended spectrum against aerobic gram-negative bacteria, and some are active against gram-negative anaerobes (eg, cefoxitin); and third-generation cephalosporins are active against many aerobic gram-negative bacteria. Not all cephalosporins fit neatly into this grouping, and there are exceptions to the general characterization of the medications 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 with 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 over ceftazidime 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 ceftriaxone. Two cephalosporin–beta-lactamase inhibitor combinations are available, ceftazidime-avibactam and ceftolozane-tazobactam, each of which is more likely than the cephalosporin alone to be active against resistant Pseudomonas and ESBL-producing E coli.

Antimicrobial Activity

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

Pharmacokinetics & Administration

A. Oral

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.

B. Intravenous

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

C. Intramuscular

Cefazolin can be given intramuscularly; however, because it must be administered every 8 hours, the intravenous route is preferred.

Clinical Uses

Oral medications are used for treatment of urinary tract infections and minor skin and soft tissue infections (eg, cellulitis, soft tissue abscess). However, the increase in the incidence of community-associated methicillin-resistant S aureus (CA-MRSA) has limited the use of these agents in some instances. Despite this concern, the addition of an agent (trimethoprim-sulfamethoxazole) active against CA-MRSA does not clearly improve outcomes over cephalexin monotherapy in the treatment of cellulitis without abscess.

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, where anaerobic infections are more likely.

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

Second-generation cephalosporins are a heterogeneous group with marked individual differences in activity and pharmacokinetics. In general, second-generation cephalosporins are active against gram-negative organisms inhibited by first-generation cephalosporins with additional aerobic gram-negative activity. Indole-positive Proteus and Klebsiella (including first-generation cephalosporin-resistant strains) as well as M catarrhalis are usually sensitive to 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 anaerobes, including 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.

Pharmacokinetics & Administration

A. Oral

Only cefaclor, cefuroxime axetil, and cefprozil can be given orally. They are less active than amoxicillin against Streptococcus pneumoniae. 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).

B. Intravenous and Intramuscular

Because of differences in medication half-life and protein binding, peak serum levels achieved and dosing intervals vary greatly for this group of medications. Medications with shorter half-lives (cefoxitin) require more frequent dosing than medications with longer half-lives (eg, cefuroxime). Dosage adjustment is required with kidney disease.

Clinical Uses

Cefprozil and cefuroxime axetil have a role in the treatment of sinusitis and otitis media in patients unresponsive to amoxicillin because their activity against beta-lactamase–producing H influenzae and M catarrhalis, similar to the use of amoxicillin clavulanate.

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 increasingly resistant to cefoxitin and cefotetan, alternative agents are preferred for serious intra-abdominal infections.

Antimicrobial Activity

Most of these medications are active against staphylococci 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, cefotaxime, and ceftaroline offer the most reliable antipneumococcal coverage. A major advantage of third-, fourth-, and fifth generation cephalosporins over the first and second generations 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. Nonaeruginosa strains of Pseudomonas are often resistant 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 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. Cefepime has demonstrated equal efficacy to carbapenems for the treatment of Enterobacter, potentially sparing these more broad-spectrum agents. Among the cephalosporins, cefepime is frequently in the treatment of multidrug-resistant P aeruginosa, specifically using an extended-infusion. While cefepime is often active against ESBL-producing organisms, it is clinically less reliable when compared to carbapenems. The extended infusion takes advantage of the time-dependent pharmacodynamics of cefepime, resulting in a useful option, even for those isolates considered to be “resistant” by in vitro microbiology testing methods. Cefiderocol is a siderophore cephalosporin sharing structural similarities with both cefepime and ceftazidime, but with a novel means of accessing the site of action. Cefiderocol uses the bacterial iron transport system to enter the bacterial cell, allowing it to bypass resistance mechanisms, such as porin alterations. Cefiderocol is primarily active against aerobic gram-negative bacteria, including Pseudomonas, and retains activity against beta-lactamases, such as AmpC, ESBL, and KPC-producing Enterobacteriaceae.

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 as active as the parenteral third-generation cephalosporins against these pathogens. All third- and fourth-generation cephalosporins are uniformly active against S pyogenes (group A Streptococcus). Cefpodoxime proxetil, cefditoren pivoxil, and cefdinir are active against methicillin-susceptible S aureus, whereas ceftibuten has limited activity (none are active against methicillin-resistant strains). Cefdinir, cefditoren pivoxil, and cefpodoxime proxetil are active against penicillin-susceptible strains of S 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 medications are ineffective against enterococci and Listeria monocytogenes. The one available fifth-generation cephalosporin ceftaroline is unique in that it represents the only beta-lactam available in the United States with in vitro activity against methicillin-resistant S aureus. (Ceftobiprole has activity against methicillin-resistant S aureus but is only available commercially outside of the United States.) 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 of ceftobiprole approximates that of ceftriaxone; thus, it is inactive against P aeruginosa, Acinetobacter species (spp), and B fragilis.

Pharmacokinetics & Administration

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 and cefiderocol are unknown; however, successful use of ceftaroline in the treatment of complicated methicillin-resistant S aureus central nervous system infections, such as meningitis, has been reported. Cefiderocol is primarily excreted in the urine as unchanged drug and approved for the treatment of complicated urinary tract infections at a dose of 2 g every 8 hours as a 3-hour extended intravenous infusion.

The half-lives of the third-, fourth-, and fifth-generation agents vary, resulting in differing dosage frequency. Ceftriaxone has the longest half-life and differs from the others in that it is eliminated primarily by biliary excretion; no dosage adjustment is required in kidney disease.

Clinical Uses

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 certain enteric gram-negative bacilli. In older patients with meningitis, third-generation cephalosporins empirically should be combined with ampicillin or trimethoprim-sulfamethoxazole to cover L monocytogenes. 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 medications are only 10–20% of serum levels. Ceftazidime or cefepime is frequently administered empirically for febrile neutropenia due to their activity against Pseudomonas and most enteric Enterobacteriaceae. 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 widely used in the outpatient parenteral therapy of infections due to susceptible organisms.

Cefepime is useful for third-generation cephalosporin–resistant isolates such as Enterobacter and Citrobacter. Considering its spectrum of activity, including methicillin-resistant S aureus, ceftaroline is useful in the treatment of skin and soft tissue infections due to this pathogen, particularly with coinfecting gram-negative pathogens. Cefiderocol is the only available cephalosporin without a coformulated beta-lactamase inhibitor that retains activity against resistant gram-negative organisms, including Pseudomonas, Acinetobacter baumannii, Stenotrophomonas maltophilia, and carbapenem-resistant Enterobacteriaceae (CRE).

Cefdinir, cefditoren pivoxil, and cefpodoxime proxetil are the most active oral third-generation agents against pneumococci and S aureus. Cefixime is available in an oral suspension and 400-mg tablets. While cefixime has been used in the treatment of gonorrhea (rather than ceftriaxone), proof of cure is necessary.

Similar to the penicillin–beta-lactamase inhibitor combinations, two cephalosporin–beta-lactamase inhibitor combinations are available, ceftazidime-avibactam and ceftolozane-tazobactam. The addition of avibactam to ceftazidime results in activity against ceftazidime-resistant Enterobacteriaceae and Pseudomonas, including ESBL, AmpC, and KPC enzymes. Similarly, the combination of ceftolozane and tazobactam increases coverage of some AmpC beta-lactamases and multidrug-resistant P aeruginosa. Both agents distribute comparably to other cephalosporins and are eliminated by the kidneys. The dose of ceftazidime-avibactam is 2 g of ceftazidime (with 500 mg avibactam) as a 2-hour infusion every 8 hours. Ceftazidime-avibactam is approved for the treatment of complicated urinary tract infections, including pyelonephritis, intra-abdominal infections (in combination with metronidazole), and hospital-acquired and ventilator-associated pneumonia. The dose of ceftolozane-tazobactam is 1 g of ceftolozane (with 500 mg tazobactam) every 8 hours given as a 1-hour infusion for intra-abdominal infections (in combination with metronidazole) and urinary tract infections, including pyelonephritis. An increased dose of 2 g of ceftolozane (with 1 g tazobactam) every 8 hours given as a 1-hour infusion is recommended for the treatment of hospital-acquired or ventilator-associated pneumonia. Importantly, neither agent is active against anaerobes, including B fragilis; thus, the addition of metronidazole is needed for the treatment of intra-abdominal infections. The scope of adverse events and drug interactions is comparable to the other later generation cephalosporins.

Allergy

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. Cephalosporin allergy in penicillin-allergic patients is attributable to cross-reactive antibodies to R1 or R2 side-chain similarity to penicillin or amoxicillin. 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.

Toxicity

Ceftriaxone has been associated with a dose-dependent biliary sludging syndrome and cholelithiasis due to precipitation of medication when its solubility in bile is exceeded. Long-term administration of 2 g/day 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.