Cephalosporins

INTRODUCTION — Beta-lactam antibiotics are among the most commonly prescribed drugs, grouped together based on a shared structural feature, the beta-lactam ring. Cephalosporins are the largest group of beta-lactam antibiotics, cover a broad range of organisms, are generally well-tolerated, are easy to administer, and are thus frequently used.

The classification, spectrum of activity, and pharmacology of the cephalosporins will be reviewed here.

The spectrum of activity of cephalosporins combined with beta-lactamase inhibitors are discussed separately. (See "Combination beta-lactamase inhibitors, carbapenems, and monobactams".)

The mechanisms of action and resistance and major adverse reactions of the beta-lactam antibiotics, and the penicillins and other beta-lactam drugs are also discussed separately. (See "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects" and "Penicillin, antistaphylococcal penicillins, and broad-spectrum penicillins" and "Extended-spectrum beta-lactamases".)

CLASSIFICATION OF CEPHALOSPORINS — Most of the available cephalosporins are semi-synthetic derivatives of cephalosporin C, a compound with antibacterial activity produced by the fungus Cephalosporium. The closely related cephamycin compounds (derived from Streptomyces spp) are regarded as members of the cephalosporin class. In clinical practice, these antibiotics are grouped into five "generations" based upon their spectrum of activity against aerobic and facultative gram-negative bacilli and gram-positive bacteria (table 1):

●First generation (eg, cefazolin)

●Second generation

A. Subgroup with activity against Haemophilus influenzae (eg, cefuroxime)

B. Cephamycin subgroup with activity against Bacteroides spp (eg, cefoxitin and cefotetan)

●Third generation

A. Subgroup with broad gram-negative activity but poor activity against Pseudomonas aeruginosa (eg, cefotaxime and ceftriaxone)

B. Subgroup with broad gram-negative activity including good activity against Pseudomonas aeruginosa (eg, ceftazidime)

●Fourth generation (eg, cefepime)

●Fifth generation (eg, ceftaroline)

Additional advanced cephalosporins include a siderophore cephalosporin (cefiderocol) and cephalosporin combinations with beta-lactamase inhibitors. (See 'Other cephalosporins' below.)

SPECTRUM OF ACTIVITY AND CLINICAL USE

Parenteral agents

First generation — Cephalothin is the oldest of the first-generation cephalosporins and was previously used as the prototype of this group. Cephalothin was active against most gram-positive cocci (including penicillinase-producing staphylococci), but did not have clinically useful activity against enterococci, Listeria, methicillin-resistant staphylococci [1], or penicillin-resistant pneumococci [2-4]. (See "Methicillin-resistant Staphylococcus aureus (MRSA): Microbiology" and "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics".)

Cephalothin was active against most strains of Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae, but had little activity against indole-positive Proteus, Enterobacter, Serratia, and the nonenteric gram-negative bacilli such as Acinetobacter spp and Pseudomonas aeruginosa. Gram-negative cocci (such as the gonococcus and meningococcus) and H. influenzae were generally resistant. Cephalothin was active against most of the common anaerobic pathogens, with certain exceptions such as Bacteroides species, particularly B. fragilis.

Cefazolin has a similar spectrum of activity to cephalothin, is available worldwide, and is now the only parenteral first-generation cephalosporin available in the United States. Cefazolin achieves substantially higher serum levels than cephalothin, and has a longer half-life of elimination. Cefazolin is less stable than cephalothin in vitro to the type A penicillinase of staphylococci [5]; the relevance of this difference for clinical therapy, however, is not certain.

Second generation — Compared with first-generation agents, the second-generation cephalosporins are somewhat less active against staphylococci. In contrast, they have greater activity against certain gram-negative bacilli; specifically, one subgroup of second-generation cephalosporins has enhanced activity against H. influenzae and another, the cephamycins, has enhanced activity against Bacteroides.

Activity against Haemophilus influenzae — In the first subgroup, cefuroxime is available parenterally and orally, and is more active than cefazolin in vitro against strains of Enterobacter and indole-positive Proteus. However, this agent induces the AmpC chromosomal beta-lactamases of these organisms, leading to resistance and failures of clinical therapy [6]. (See "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects", section on 'Mechanisms of bacterial resistance'.)

Cefuroxime is also more active than cefazolin against H. influenzae, and cefuroxime is quite stable to the TEM beta-lactamase in ampicillin-resistant strains. Although cefuroxime is approved for the therapy of H. influenzae meningitis, delayed responses and treatment failures have occurred, and a third-generation cephalosporin is now preferred for therapy of meningitis due to ampicillin-resistant strains [7]. Cefuroxime is also highly active against beta-lactamase-producing Moraxella catarrhalis.

Cephamycin subgroup (active against Bacteroides) — The cephamycin subgroup of the second-generation cephalosporins includes cefoxitin and cefotetan. This subgroup is active against most strains of E. coli, P. mirabilis, and Klebsiella, like the first-generation cephalosporins. The cephamycins are quite stable to many plasmid-mediated beta-lactamases, but the activity of this group against Enterobacter and indole-positive Proteus is limited by induction of chromosomal cephalosporinases of these species and selection of stably derepressed mutants [6].

Unlike the first-generation cephalosporins, the cephamycins are active against many strains of Bacteroides. The combination of activity against common aerobic and facultative gram-negative bacilli plus Bacteroides has led to the use of the cephamycins in the prophylaxis and therapy of infections in the abdominal and pelvic cavities (where these organisms predominate) [8]. The cephamycins have no clear advantages over the first-generation cephalosporins for infections outside of the abdominal and pelvic areas.

For the Bacteroides fragilis group, overall resistance rates to cephamycins range from 10 to 80 percent, depending on the specific subspecies [9,10]. For comparison, resistance rates to other antibiotics with anaerobic coverage are described elsewhere. (See "Anaerobic bacterial infections".)

Third generation — The third-generation cephalosporin class [11] is marked by stability to the common beta-lactamases of gram-negative bacilli, and these compounds are highly active against Enterobacterales (E. coli, Proteus mirabilis, indole-positive Proteus, Klebsiella, Enterobacter, Serratia, Citrobacter), Neisseria, and H. influenzae. They are the therapy of choice for gram-negative meningitis due to susceptible Enterobacterales. Third-generation cephalosporins may also be useful alternatives to the aminoglycosides in treating gram-negative infections resistant to other beta-lactams, particularly in the patient with renal dysfunction. However, mutants of Enterobacter, indole-positive Proteus, Serratia, and Citrobacter, with stable derepression of the chromosomal beta-lactamase, are resistant to these antibiotics [6,12]. Even if these organisms (Enterobacter, indole-positive Proteus, Serratia, and Citrobacter) test susceptible to cephalosporins, use of a third-generation cephalosporin as a single agent for treatment of serious infections due to these bacteria can lead to the emergence of resistance during therapy.

The third-generation cephalosporins are less active against most gram-positive organisms than the first-generation cephalosporins and are inactive against enterococci, Listeria, methicillin-resistant staphylococci, and Acinetobacter. Cefotaxime and ceftriaxone are usually active against pneumococci with intermediate susceptibility to penicillin, but strains fully resistant to penicillin are often resistant to the third-generation cephalosporins as well. (See "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics".)

Treatment with third-generation cephalosporins may be complicated by superinfection (particularly with enterococci or Candida) or by the emergence of resistance on therapy (particularly when used as single agents for Enterobacter, indole-positive Proteus, or P. aeruginosa infections) [13].

Poor activity against Pseudomonas — One subgroup of the third-generation cephalosporins, cefotaxime and ceftriaxone, has poor activity against P. aeruginosa. Within this subgroup, cefotaxime has the shortest serum half-life (1 hour) because of partial metabolism in the liver to desacetyl-cefotaxime. However, this metabolite also has antibacterial activity and a longer half-life in serum (1.7 hours), allowing dosing every six hours.

Ceftriaxone has the longest serum half-life of this group (6.4 hours) and can be administered once or twice a day. Ceftriaxone has been particularly recommended for the therapy of penicillin-resistant gonorrhea, Lyme disease involving the central nervous system or joints, meningitis due to ampicillin-resistant H. influenzae, and meningitis in children [7,14]. One of the complications of ceftriaxone therapy, however, has been the formation in the biliary tract of "sludge" composed of ceftriaxone crystals, causing the syndrome of biliary pseudolithiasis [15].

Activity against Pseudomonas — The other of the third-generation cephalosporins, ceftazidime, has activity against P. aeruginosa. Ceftazidime is quite stable to the common plasmid-mediated beta-lactamases and is highly active against Enterobacterales, Neisseria, and H. influenzae. Ceftazidime is also particularly active against P. aeruginosa and is an effective therapy for serious infections due to P. aeruginosa when the organism is resistant to the antipseudomonal penicillins or the patient is allergic to penicillin. In addition, it is effective therapy for meningitis caused by P. aeruginosa. As with the antipseudomonal penicillins, however, ceftazidime should generally be given at least initially in combination with an aminoglycoside for treatment of serious P. aeruginosa infection, when susceptibilities are unknown. Ceftazidime has poor activity against gram-positive organisms and should be reserved for use in infections proven or highly suspected to be due to P. aeruginosa.

Fourth generation — Cefepime is the fourth-generation cephalosporin currently available. It has a positively charged quaternary ammonium attached to the dihydrothiazone ring, which results in better penetration through the outer membrane of gram-negative bacteria and a lower affinity than the third-generation cephalosporins for certain chromosomal beta-lactamases of gram-negative bacilli.

Cefepime has activity similar to that of cefotaxime and ceftriaxone against pneumococci (including penicillin-intermediate strains) and methicillin-sensitive S. aureus. Like the earlier third-generation agents, it is active against the Enterobacterales, Neisseria, and H. influenzae but has greater activity against the gram-negative enterics that have a broad-spectrum, inducible, chromosomal AmpC beta-lactamase (Enterobacter, indole-positive Proteus, Citrobacter, and Serratia) [16]. The role of cefepime in therapy of infections due to stably-derepressed mutants of these organisms has not yet been fully defined, but some data suggest that it may be effective [17,18]. In a study of 96 patients with infections due to laboratory-confirmed AmpC beta-lactamase-producing organisms, 96 percent of the isolates were susceptible to cefepime [17]. Among patients who received cefepime, the 30-day mortality rate and duration of hospitalization were similar to those observed in a matched subset of patients who received meropenem.

Cefepime is as active as ceftazidime for P. aeruginosa, and is active against some ceftazidime-resistant isolates. As with the antipseudomonal penicillins, cefepime should generally be given in combination with an aminoglycoside for treatment of serious P. aeruginosa infection when susceptibilities are unknown. Accumulated data suggest it can be used for meningitis caused by susceptible gram-negative bacilli [19]. It is not currently recommended for prophylactic use in surgery. Acinetobacter isolates are frequently resistant to cefepime.

Despite these potential advantages over third-generation cephalosporins, especially against organisms with inducible, chromosomal resistance, comparative trials of third- and fourth-generation cephalosporins have not yet been performed.

A review by the United States Food and Drug Administration (FDA) of cefepime safety data was initiated in 2007 following findings of a meta-analysis that raised concern regarding increased all-cause mortality associated with cefepime use (risk ratio 1.26, 95% CI 1.08-1.49) [20]. The FDA reviewed these study data, conducted additional analyses based on other data, and determined that the data do not indicate a higher rate of death in cefepime-treated patients [21]. Cefepime remains an appropriate therapy for its approved indications [22].

Treatment with cefepime may be complicated by superinfection (particularly with enterococci or Candida) [13]. Cefepime use also carries a risk of seizures (specifically nonconvulsive status epilepticus), particularly in patients with renal failure for whom the dose is not appropriately reduced [23]. (See "Beta-lactam antibiotics: Mechanisms of action and resistance and adverse effects", section on 'Neurologic reactions'.)

Fifth generation

●Ceftaroline – This is a fifth-generation cephalosporin whose active metabolite has a spectrum of in vitro activity similar to that of ceftriaxone but with improved gram-positive activity. In particular, ceftaroline has higher affinity for penicillin-binding protein 2a (PBP2a) in methicillin-resistant staphylococci, and has activity against MRSA, as well as vancomycin-intermediate Staphylococcus aureus (VISA) and hetero-VISA. In addition, ceftaroline has activity for Streptococcus pneumoniae that is intermediate or resistant to penicillin or ceftriaxone. Ceftaroline is not active for enterococci nor against AmpC-overproducing or ESBL-producing Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, or B. fragilis. Randomized, double-blind controlled clinical trials have suggested that ceftaroline is noninferior to vancomycin plus aztreonam for treatment of complicated skin and soft tissue infections including those due to MRSA, and to ceftriaxone for therapy of community-acquired pneumonia [24-26]. For MRSA bacteremia, limited observational data suggest efficacy as monotherapy or as part of combination therapy with daptomycin [27-30]. Efficacy is not yet known for hospital-acquired MRSA pneumonia. Clinical use of ceftaroline is discussed elsewhere. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia" and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Methicillin-resistant S. aureus'.)

●Ceftobiprole – This is a cephalosporin available in Canada and some European countries (but not the United States) that is also capable of binding to PBP2a, the protein conferring S. aureus resistance to beta-lactam antibiotics [31]. It can also bind PBP2x in penicillin-resistant S. pneumoniae. It has in vitro activity similar to that of ceftazidime or cefepime against Enterobacterales; it also has activity against enterococci [32,33]. In addition, ceftobiprole appears to have a low potential for selection of resistance [34].

Clinical trial data on these agents for use in MRSA infections are detailed separately. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections", section on 'Ceftaroline (and ceftobiprole)'.)

Other cephalosporins

●Cefiderocol – This siderophore cephalosporin has activity against multidrug-resistant gram-negative bacteria, including extended-spectrum beta-lactamase- or carbapenemase-producing organisms and multidrug-resistant P. aeruginosa, A. baumannii, Stenotrophomonas maltophilia, and Burkholderia cepacia. In addition to enhanced stability against beta-lactamases, it has a novel mechanism for transport across the outer membrane that can overcome the effect of membrane permeability mutations, as seen in P. aeruginosa [35]. Cefiderocol is thought to have poor gram-positive and anaerobic activity.

In the United States, cefiderocol has been approved by the Food and Drug Administration for use in adults with complicated urinary tract infections (UTIs; including pyelonephritis) and hospital-acquired or ventilator-associated pneumonia due to otherwise highly resistant gram-negative bacteria when there are no alternative treatment regimens [36-38]. Randomized, double-blind trials have reported similar outcomes between cefiderocol and carbapenems for patients with complicated UTIs or nosocomial pneumonia due to gram-negative pathogens [39,40]. Additionally, a randomized, open-label multi-national trial of patients with carbapenem-resistant gram-negative infections (ie, pneumonia, bacteremia or sepsis, complicated UTI) found similar clinical and microbiologic cure rates with cefiderocol versus best available therapy. There were more deaths in the cefiderocol group, but the significance of this finding is uncertain and may have been influenced by the heterogeneous patient-population and high proportion of A. baumannii infections among those who died [41].

Combinations of cephalosporins with beta-lactamase inhibitors are discussed in detail elsewhere. (See "Combination beta-lactamase inhibitors, carbapenems, and monobactams", section on 'Ceftolozane-tazobactam' and "Combination beta-lactamase inhibitors, carbapenems, and monobactams", section on 'Ceftazidime-avibactam'.)

Oral agents — Cephalosporins available for oral use include cephalexin, cefadroxil, cefaclor, cefuroxime axetil, cefprozil, cefixime, cefpodoxime proxetil, ceftibuten, and cefdinir (table 1).

Among the first-generation cephalosporins available for oral use, cefadroxil has a longer serum half-life than cephalexin and is generally given in a dose of 500 to 1000 mg every 12 hours. The oral cephalosporins are poorly active against penicillin-resistant pneumococci [2].

The oral second-generation cephalosporins, cefaclor, cefuroxime axetil, and cefprozil, have improved activity against H. influenzae compared with the first-generation oral cephalosporins and may be useful in treating otitis, sinusitis, and respiratory tract infections.

The oral third-generation cephalosporins, cefixime, cefpodoxime proxetil, ceftibuten, and cefdinir are active against streptococci, H. influenzae (including beta-lactamase producing strains), and M. catarrhalis. They are more active than the other oral cephalosporins against enteric gram-negative bacilli, including E. coli, P. mirabilis, and Klebsiella. However, they have poor activity against most strains of Enterobacter, Acinetobacter, P. aeruginosa, and the anaerobes. Cefixime and ceftibuten have little activity against staphylococci, but cefpodoxime proxetil and cefdinir have more activity. Ceftibuten is also only weakly active against pneumococci. Its spectrum of activity is otherwise similar to those of cefdinir and cefpodoxime.

These antibiotics are relatively stable to many plasmid-mediated beta-lactamases but are much less stable to common chromosomally-mediated cephalosporinases. Although these antibiotics are promoted as oral third-generation cephalosporins, they are less active against the enteric gram-negative bacilli than the parenteral third- or fourth-generation cephalosporins. These antibiotics are recommended as therapy for otitis media, upper and lower respiratory tract infections, and UTIs (cefixime, cefpodoxime, and cefdinir). These indications are shared with the oral second-generation cephalosporins, amoxicillin-clavulanate, and trimethoprim-sulfamethoxazole. Cefixime and ceftibuten have little or no activity against staphylococci in contrast to some of these other agents.

PHARMACOLOGY — Many of the available parenteral cephalosporins have short serum half-lives (generally one hour or less) and should be administered on an every four hour basis when treating serious systemic infections in patients with normal renal function (table 2). Certain cephalosporins have longer serum half-lives and may be dosed less frequently (eg, cefazolin Q8h and ceftriaxone Q24h). All of the cephalosporins except ceftriaxone require dose modification in the presence of severe renal failure (table 2).

All of the cephalosporins achieve therapeutic levels in pleural, pericardial, peritoneal, and synovial fluids, and urine. Biliary concentrations exceed serum levels (in the absence of obstruction) and are particularly high for cefazolin and ceftriaxone.

First- and second-generation cephalosporins (except cefuroxime) penetrate the cerebrospinal fluid (CSF) barrier poorly and should not be used to treat infections of the central nervous system. The third-generation cephalosporins achieve much more reliable CSF levels in patients with meningeal irritation. Peak CSF concentrations of several cephalosporins given at meningeal doses are shown in the table (table 3). Cefotaxime, ceftriaxone, and ceftazidime are approved for the treatment of bacterial meningitis.

Fatal reactions due to calcium-ceftriaxone precipitates in the lungs and kidneys of neonates have been reported. Ceftriaxone should not be reconstituted or mixed with a calcium-containing product (eg, Ringer's or Hartmann's solution or parenteral nutrition). In addition, ceftriaxone should be avoided in infants aged ≤28 days if they are receiving or expected to receive intravenous calcium-containing products. However, ceftriaxone and calcium-containing products may be used concomitantly in patients aged >28 days, provided that the infusion lines are thoroughly flushed between infusions [42].

SUMMARY AND RECOMMENDATIONS

●Classification of parenteral cephalosporins – In clinical practice, cephalosporins are grouped into five "generations" based upon their spectrum of activity against aerobic and facultative gram-negative bacilli and gram-positive bacteria (table 1).

●Parenteral cephalosporins

•First-generation – These cephalosporins, including cefazolin, are active against most gram-positive cocci except for enterococci, methicillin-resistant staphylococci, and penicillin-resistant pneumococci. They are also active against most strains of Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. (See 'First generation' above.)

•Second-generation – This group includes two subgroups. One subgroup has activity against Haemophilus influenzae and Moraxella catarrhalis. The other subgroup consists of the cephamycins, which are active against many strains of Bacteroides. (See 'Second generation' above.)

•Third-generation – Members of this group have less activity against most gram-positive organisms than first-generation agents but are highly active against Enterobacterales, Neisseria, and H. influenzae. Ceftazidime is also active against Pseudomonas aeruginosa. (See 'Third generation' above.)

•Fourth generation – The only fourth-generation cephalosporin, cefepime, has similar activity as the third-generation cephalosporins and also includes activity against P. aeruginosa. It has greater activity than earlier generations against enteric gram-negative bacilli that have an inducible chromosomal beta-lactamase. (See 'Fourth generation' above.)

•Fifth generation – The novel fifth-generation cephalosporin, ceftaroline, has activity against methicillin-resistant staphylococci, penicillin-resistant pneumococci, and enteric gram-negative rods. It is not active against extended-spectrum beta-lactamase (ESBL)- or Amp-C-producing Enterobacterales, P. aeruginosa, Acinetobacter baumannii, or Bacteroides fragilis. (See 'Fifth generation' above.)

•Siderophore cephalosporin – A novel siderophore cephalosporin, cefiderocol, does not belong to any of the above groups. It has activity against multidrug-resistant gram-negative bacteria, including ESBL- or carbapenemase-producing organisms and multidrug-resistant P. aeruginosa, A. baumannii, Stenotrophomonas maltophilia, and Burkholderia cepacia. (See 'Other cephalosporins' above.)

●Parenteral dosing and administration – Many of the available parenteral cephalosporins have short serum half-lives and require frequent administration. All of the cephalosporins except ceftriaxone require dose modification in the presence of severe renal failure. Doses are listed in the table (table 2). (See 'Pharmacology' above.)

●Tissue penetration of parenteral formulations – All of the parenteral cephalosporins achieve therapeutic levels in pleural, pericardial, peritoneal, and synovial fluids, and urine. First- and second-generation cephalosporins enter into cerebrospinal fluid (CSF) poorly. Third-generation cephalosporins achieve more reliable CSF levels in patients with meningeal irritation (table 3). (See 'Pharmacology' above.)

●Oral cephalosporins – These are also divided into different generations, and their spectra of activity generally mirror those parenteral agents of the corresponding generation (table 1). However, oral third-generation drugs are less active against enteric gram-negative bacteria than the parenteral third-generation cephalosporins. Second- and third-generation oral cephalosporins have similar indications, namely otitis media, respiratory tract infections, and urinary tract infections (UTIs). (See 'Oral agents' above.)