Laura Y. Hardefeldt and John F. Prescott For cephalosporins, the beta‐lactam ring is attached to a six‐membered dihydrothiazine ring with the effect that the cephalosporin nucleus is inherently more resistant to beta‐lactamases than the penicillin nucleus (Figure 8.1). The 7‐aminocephalosporanic acid molecule also provides more sites than the aminopenicillanic acid molecule for manipulation in the production of semisynthetic drugs. Changes at position 7 (R1) alter beta‐lactamase stability and antibacterial properties particularly, whereas changes at position 3 (R2) tend to alter metabolic stability and pharmacokinetic properties. True cephalosporins contain the common 7‐aminocephalosporanic acid of Cephalosporium acremonium, whereas cephamycins are derived from Streptomyces species (cefotetan, cefoxitin) or are synthetic derivatives produced by substituting oxygen for sulfur (latamoxef). In general, cephalosporins have the advantages of beta‐lactamase stability, good activity against target proteins (penicillin‐binding proteins, PBPs), and good ability to penetrate bacterial cell walls. Although they may be active against a wide range of organisms, such activities are not uniform and produce often subtle differences between the different molecules. Pharmacokinetically, they are generally similar and have properties typical of the beta‐lactams, usually requiring parenteral injection, have short (1–2 hour) plasma elimination half‐lives, and are excreted usually through the kidneys in the urine. They are bactericidal, relatively nontoxic, and can be used in many penicillin‐sensitive individuals. One approach to the classification of cephalosporins has been chronological, with the different cephalosporins introduced since 1975 being clustered somewhat arbitrarily as “generations” (Table 8.1). This has implied that each new generation introduced has added another general level of advantage over the previous generation rather than adding some advantage(s) at the expense of another or others. Differences within the generations often appear subtle but are important. Cephalosporins were originally introduced (first generation) for the treatment of penicillinase‐resistant staphylococcal infections with the advantage that these drugs also had a spectrum of activity against Gram‐negatives similar to that of the extended spectrum aminobenzylpenicillins. Alterations of the side chains on the 7‐aminocephalosporanic acid nucleus and the discovery of the cephamycins led to increasing stability to the beta‐lactamases of Gram‐negative bacteria, including Bacteroides fragilis and Pseudomonas aeruginosa. However, this increased stability is usually at the expense of decreasing activity against Gram‐positive bacteria and gives pharmacokinetic differences. Figure 8.1 Structural formula of the cephalosporin nucleus. Table 8.1 Classification of cephalosporins into groups (and generations) based on route of administration and antibacterial activity. By convention, cephalosporins discovered before 1975 are spelled with a “ph” and after 1975 with an “f.” MRSA, methicillin‐resistant Staphylococcus aureus. The “generations” are broadly characterized as detailed in Table 8.1. Third, and subsequent, generations are considered highest priority, critically important antimicrobials for human medicine by the World Health Organization (WHO, 2024), and by most national bodies that have developed specific guidelines for their country (Table 23.2). These antimicrobials should be reserved for cases where there is documented evidence of resistance to antimicrobials of lower WHO classification or for critically ill animals, where there is genuine concern about resistance, while results of microbial culture and susceptibility are pending. The mechanism of action of the cephalosporins is that of beta‐lactam antibiotics (Chapter 7). For susceptibility testing, cephalothin is the class representative drug for first‐generation cephalosporins. For second‐ to fourth‐generation cephalosporins there are no class representatives. For susceptibility testing of Enterobacterales, cefotaxime can usually substitute for ceftazidime, ceftizoxime, and ceftriaxone (and vice versa) and cefamandole for cefonicid and cefuroxime (and vice versa). For P. aeruginosa, cefoperazone will substitute for ceftazidime (and vice versa) and cefotaxime for ceftriaxone and latamoxef (and vice versa). Cephalosporins are usually active against beta‐hemolytic streptococci and against beta‐lactamase‐producing, but not against methicillin‐resistant, staphyloccci (except fifth‐generation cephalosporins). All enterococci are resistant. Among Enterobacterales, in the absence of acquired resistance, E. coli and Salmonella are susceptible, as are some Proteus and Klebsiella spp. Fourth‐ and fifth‐generation cephalosporins may be effective against Enterobacterales and other Gram‐negative bacteria resistant to earlier generations of cephalosporins because of acquired beta‐lactamase‐based resistance. Susceptibility among common Gram‐negative aerobic species such as Haemophilus and Pasteurella, including beta‐lactamase producers, is usual. Only specific third‐ and fourth‐generation cephalosporins are effective against P. aeruginosa. Mycobacteria are resistant. Against nonspore‐forming anaerobic bacteria, activity is variable and resembles that of aminobenzyl penicillins. B. fragilis is no longer routinely susceptible. The four basic mechanisms of resistance to cephalosporins are PBP modification, reduced permeability, increased efflux, and enzymatic inactivation by beta‐lactamases. Of these, the most important is beta‐lactamase production, with more than 1000 distinct beta‐lactamases now recognized. Their importance is both because of the large number of different beta‐lactamases that have been selected for by the widespread use of third‐ and fourth‐generation cephalosporins and because genes for these beta‐lactamases are often transmissible. The topic has been the subject of a number of excellent reviews (Bush, 2018; Bush and Bradford, 2020). Beta‐lactamases and beta‐lactamase inhibitors are further discussed in Chapter 9. Modification of the PBP targets can occur after transformation of readily transformable fragments of PBP DNA and their homologous recombination with existing PBP genes to produce new “mosaic” PBPs with low affinity for beta‐lactams. This has been extensively described for some important human pathogens, and not well described in animal bacterial pathogens but likely occurs. Other important forms of PBP modification include acquisition of extra “by‐pass” (insensitive) PBP genes by methicillin‐resistant Staphylococcus aureus (MRSA) or by Enterococcus faecium, although this has not yet been described in animal pathogens. This resistance mechanism has resulted in nonsusceptibility of MRSA to cephalosporins, except for fifth‐generation cephalosporins. However, moderate ceftaroline resistance has recently been shown to be particularly high among human MRSA strains in China and Thailand through a novel mutation upstream of PBP genes, but this has not yet been described in animal pathogens. Reduced production of the porins, by which beta‐lactams penetrate Gram‐negative bacteria, has produced resistance to cephalosporins, which in some cases is also the result of a periplasmic beta‐lactamase enzyme. Such reduced uptake may be mediated by an efflux mechanism which gives broad‐spectrum cross‐drug class resistance. There has been an astonishing evolution of these enzymes in response to antimicrobial selection, with subsequent widespread plasmid‐ or transposon‐mediated dissemination through Gram‐negative bacterial populations. Most (class A, C, D molecules) are serine esterases but some (class B) are zinc metalloproteases. Beta‐lactamases and their classification and emergence are discussed in more detail in Chapter 9 (see Table 9.1). The major families or classes of beta‐lactamases are the extended‐spectrum beta‐lactamases (ESBLs), the AmpC cephalosporinases (which include CMY‐2 enzymes), and the now globally emerging carbapenemase‐producing metallo‐beta‐lactamases. The ability of transposable elements to move beta‐lactamases from chromosomes to plasmids (and back again, and between different plasmids), as well as recombination processes involving integrons, means that the earlier designation of beta‐lactamases as either chromosomal or plasmid is increasingly anachronistic. However, the extent or degree of resistance provided by a beta‐lactamase is a function of both its activity and its quantity, which in turn may depend on plasmid copy numbers or the extent to which chromosomal enzymes can be induced. Several thousand naturally occurring beta‐lactamases have now been described and new variants are continuously emerging. Resistance to beta‐lactams continues to increase and spread globally (Bush and Bradford, 2020). Pathogens may carry multiple different beta‐lactamase genes. The development of aminopenicillins such as ampicillin in the early 1960s importantly broadened the activity of penicillins against Gram‐negative bacteria, particularly Escherichia coli; however, this was followed by the development and spread of plasmid‐mediated beta‐lactamases, notably TEM‐1 (now a common feature of E. coli), as well as SHV‐1 and OXA‐1. Importantly, the first‐generation cephalosporins developed at this time were resistant to staphylococcal beta‐lactamases, which ampicillin was not, and also had a spectrum of activity against Gram‐negative aerobes slightly broader than that of aminopenicillins. However, they were susceptible to the same plasmid‐mediated beta‐lactamases as ampicillin and also lacked its activity against inducible functional group 1 AmpC enzymes. In response to emerging resistance due to beta‐lactamases in the late 1960s, cephalosporins with enhanced beta‐lactamase stability were more readily developed than drugs in the amino‐ or carboxy‐penicillins class. These second‐generation cephalosporins were more stable to TEM‐1 and against some AmpC‐inducible enteric bacteria, such as E. coli. The first cephamycin, cefoxitin, was also found to be uniquely stable to the chromosomal beta‐lactamases of Bacteroides spp., including the anaerobic pathogen B. fragilis, but this feature has increasingly been lost. These drugs remain ineffective against important Gram‐negative aerobic pathogens, such as P. aeruginosa. The third‐generation drugs developed in the 1970s and 1980s, in the search for cephalosporins with improved beta‐lactamase stability, had considerably enhanced activity against Enterobacterales, including TEM‐1, TEM‐2, and SHV‐1 plasmid‐containing strains as well as, in some cases, against P. aeruginosa. Unlike earlier drugs, they had stability against chromosomal beta‐lactamases of Klebsiella spp. and against functional group 1 AmpC‐inducible enteric bacteria because of their weak induction of these enzymes. These enhanced activities were at the expense of activity against staphylococci. Unfortunately, resistance has emerged among the Gram‐negative bacterial targets, through plasmid and transposon transmission, and is becoming increasingly widespread particularly among the Enterobacterales (Enterobacter spp., E. coli, Klebsiella pneumoniae, Morganella morganii, Proteus spp., and Salmonella). Resistance has also spread to Burkholderia spp. and to P. aeruginosa. The major types of beta‐lactamase that are increasing in global prevalence among opportunist pathogens are the plasmid‐encoded functional group 1 cephalosporinases, the group 1e, 2be, 2ber, and 2de ESBLs, the functional groups of 2df, 2de, 2f serine carbapenemases, and the group 3 metallo‐beta‐lactamases (see Table 9.1). Of these, the greatest increase is occurring in the EBSLs. The hyperproduction of AmpC beta‐lactamases occurs most often in bacterial opportunist pathogens that are relatively unusual in animals, notably Enterobacter spp. and Citrobacter freundii. Paradoxically, although third‐generation cephalosporins are weak inducers of these enzymes, they are actually effective in killing organisms producing these enzymes. However, they are ineffective when the enzymes are produced in large amounts by hyperproducers, which are those that have a mutation in the gene for encoding the peptidoglycan recycling enzyme, AmpD. Such “derepressed mutants” resistant to all cephalosporins (and to clavulanic acid and other beta‐lactamase inhibitors) may emerge during therapy of infections caused by these two genera (in sites other than the urinary tract) and may be particularly problematic in hospital settings. More seriously, AmpC hyperproduction can become encoded by high copy number plasmids (FOX, MIR, MOX, CMY‐beta‐lactamase families or types) and mobilized to other Gram‐negative bacteria, notably E. coli and Klebsiella spp. in which the new set of group 1 cephalosporinases may be additive with endogenous nongroup 1 beta‐lactamases (Bush, 2018). In recent years, there has been increasing spread of a family of CMY2‐encoding plasmids in food and companion animals. For example, hospital‐acquired infection in multidrug‐resistant E. coli producing the cephamycinase‐encoding gene CMY2 was described over 20 years ago in dogs with nosocomial infections in a veterinary hospital in the United States (Sanchez et al., 2002), with the same isolate being detected in the environment of the intensive care unit and surgical wards. Many of these isolates were also resistant to florfenicol, and the floR and blaCMY2 genes were found to be transferable, probably by a transposon. Additional resistance to spectinomycin and sulfonamides in the isolates was also provided by integrons (Sanchez et al., 2002). CMY2 AmpC beta‐lactamase plasmids appear to be common in, and to move between, E. coli and Salmonella isolated from food animals and people. In Salmonella, the plasmid‐encoded blaCMY2 gene was identified in numerous Salmonella isolated from swine (Elnekave et al., 2019). The blaCMY2 genes are also common in ceftiofur‐resistant E. coli isolates from diseased swine (Hayer et al., 2020). In Canada, there was a dramatic rise in CMY‐2 producing S. Heidelberg in chickens associated with extra‐label use of ceftiofur in eggs and day‐old poults, with spread of infection into people (Dutil et al., 2010); this fell equally dramatically once ceftiofur was no longer (temporarily) used for this purpose (Primeau et al., 2022). The blaCMY2 gene is the main extended‐spectrum cephalosporin resistance determinant in E. coli isolated from Canadian turkeys (Moffat et al., 2020). Extended‐spectrum beta‐lactamases contain the greatest number of distinct beta‐lactamase enzymes that are variants of the broad‐spectrum TEM and SHV beta‐lactamases, all of which are plasmid or transposon mediated. Currently, there are over 200 TEM‐type and over 165 SHV‐type ESBLs (see Table 9.1). These enzymes produce resistance by hydrolyzing the oxyimino‐aminothiazole‐containing beta‐lactams (aztreonam, cefotaxime, ceftazidime, and to some extent cefepime, as well as earlier generation cephalosporins). By contrast, the alpha‐methoxy‐cephalosporins (cefoxitin, cefotetan, latamoxef) and imipenem are stable to these enzymes. There are differences between different ESBLs in the rate at which they hydrolyze different cephalosporins. For example, TEM‐12 and SHV‐2 ESBLs hydrolyze cephalosporins slowly so that infections may respond to third‐generation cephalosporin treatment; however, a second single nucleotide mutation in the TEM‐12 beta‐lactamase gene will produce high‐level resistance. Other plasmid‐mediated ESBLs not closely related to the TEM and SHV families include the CTX‐M family that preferentially hydrolyze cefotaxime (and cefepime). The CTX‐M family also encodes for numerous distinct enzymes, including the cefotaximases of the SFO‐1 and BES‐1 types, and the PER, VEB, TLA‐1 and GES/IBC types that preferentially hydrolyze ceftazidime. There is rapidly increasing documentation of third‐generation cephalosporin beta‐lactamase‐producing Enterobacterales infections in animals (Timofte et al., 2016; Elnekave et al., 2019; Hayer et al., 2020; Moffat et al., 2020; Anderson et al., 2023). Since the turn of the century, CTX‐M beta‐lactamases have become the most prominent of the ESBLs in E. coli globally, with some types such as CTX‐M‐15 becoming more dominant because of clonal expansion of strains such as ST131, which, besides expanded virulence attributes, carry additional resistance genes (Chong et al., 2018; Zogg et al., 2018; Isgren et al., 2019). Fecal colonization by CTX‐M beta‐lactamase‐encoding E. coli is becoming globally relatively common in both humans and animals; humans and animals may share the same strains or mobile genetic elements containing CTX‐M genes (Toombs‐Ruane et al., 2020). In human medicine, infections caused by ESBL‐producing bacteria are seen most often in severely ill hospitalized patients in the intensive care unit, but outbreaks have also been described in nursing homes, pediatric units, and other hospital settings. These outbreaks present very important infection control issues in hospitals. A common approach to control is not only to institute rigorous infection control procedures and monitoring but also to restrict use of extended‐spectrum beta‐lactams by switching to other drug classes for empirical therapy of serious infections (see Chapter 6). Many of the third‐generation cephalosporin beta‐lactamase‐producing bacteria described in companion animals have been obtained from veterinary hospitals (Timofte et al., 2016; Walther et al., 2017), likely reflecting the spread of flexibly resistant clones within hospital environments. However, numerous studies globally have shown that ESBL‐producing Enterobacterales in animals continue to expand outside hospitals into primary care clinical settings (Chong et al., 2018; Zogg et al., 2018; Chen et al., 2019; Weese et al., 2022). The emergence and threatening rise of extended‐spectrum cephalosporinases in food animal species reflects the increasing use of third‐generation cephalosporins, as well as the complex ecology of resistance (Chapter 3), and poses a significant public health threat as some of these bacteria are zoonotic and can transmit to humans via various routes (Gelalcha and Dego., 2022). Metallo‐beta‐lactamases have emerged in the last decade as important beta‐lactamases particularly of nonfermenting Gram‐negative bacteria (Aeromonas spp., P. aeruginosa). The genes for these enzymes (IMP, OXA‐48, SPM, VIM types) can be transferred through plasmids to Enterobacterales such as Enterobacter and Klebsiella. Enzymes of the IMP and VIM types can degrade virtually all beta‐lactams, including the carbapenems. Some of these beta‐lactamases are carried on integrons that encode multiple drug resistance genes (Weldhagen, 2004). The movement of some metallo‐beta‐lactamase (MBL) genes onto transmissible plasmids and their dissemination globally has raised enormous concern. There are reports of blaNDM in food and companion animals (Chen et al., 2019; Elias et al., 2020; Ramirez‐Castillo et al., 2023). The basic pharmacokinetic and drug disposition characteristics of cephalosporins are typical of beta‐lactams (Chapter 7), with a plasma elimination half‐life of 1–2 hours. Some drugs, however, such as cefotetan and ceftriaxone have significantly longer half‐lives. Second‐ and third‐generation oral cephalosporins are well absorbed after oral administration, which may be enhanced by formulations as prodrugs to be later metabolized to the active compound within the body (e.g., cefpodoxime proxetil). Some fourth‐generation cephalosporins can be administered orally to monogastrates. Clearance is through the kidney in most cases although drugs with high molecular weight and protein binding, such as cefoperazone, are largely excreted in the bile. Cephalosporins are among the safest antimicrobial drugs. They have the safety associated with penicillins, although individual drugs may have specific adverse effects. For example, hypoprothrombinemia and platelet abnormalities causing bleeding disorders have been noted with some newer cephalosporins. The broad spectrum of antibacterial activity of second‐ to fourth‐generation drugs may cause overgrowth by inherently resistant bacteria including Clostridiodes difficile which no longer have to compete with susceptible members of the microbial flora. Gastrointestinal disturbances are therefore also among adverse effects, particularly with drugs excreted through the bile. Human patients allergic to penicillin are sometimes (5–8%) also allergic to cephalosporins. Many second‐ and third‐generation drugs are painful on injection and therefore administered IV, but orally administered third‐generation cephalosporins are now available. As with all beta‐lactams, the aim of treatment is to maintain serum and tissue concentrations of drug ≥ MIC for the majority of or the entire dosing interval, preferably at the target site of infection. In recent years, long‐acting formulations of third‐generation cephalosporins have been introduced for injection in both food and companion animals, which produce serum concentrations exceeding MIC for periods of 4–14 days, depending on the particular formulation and the bacterial pathogen. These have the advantage of efficiency in treating food animals and of ensuring “compliance” in companion animals but the disadvantage of using a high‐priority, critically important antimicrobial in cases where they are often not indicated (i.e., for beta‐hemolytic streptococcal infections where susceptibility to penicillin is predictable). In addition, and importantly, the long therapeutic plasma concentrations are followed by a substantial tail of subtherapeutic plasma concentrations that can serve to select resistant strains. Cephalosporins are an important class of antimicrobial agents with widespread potential use. First‐generation cephalosporins have a spectrum of activity and clinical use similar to that of extended‐spectrum aminobenzyl penicillins, with the important addition of resistance to certain staphylococcal beta‐lactamases. First‐generation cephalosporins are therefore used in the treatment of canine S. pseudintermedius skin infections and urinary tract infections, as well as bovine S. aureus and streptococcal mastitis. Ceftiofur is approved for the treatment of Gram‐negative respiratory pathogens in food animals and Streptococcus zooepidemicus in horses. Some formulations are also approved for the treatment of foot rot in cattle. However, second‐ and some third‐generation parenteral cephalosporins are used to treat infections caused by bacteria resistant to first‐generation drugs. For example, ceftiofur, which has antimicrobial characteristics between second‐ and third‐generation cephalosporins, is used (extra‐label) in animals to treat systemic infections caused by Gram‐negative aerobes, including E. coli, Pasteurella and Salmonella infections, but with particular focus on the more susceptible bacteria, such as those involved in respiratory disease, as well as anaerobic bacteria. Cefovecin is used for treatment of susceptible skin and urinary tract infections in dogs and susceptible skin infections in cats. Cefpodoxime proxetil is an oral formulation for skin infections in dogs. Cefoxitin has a special place in the treatment of mixed aerobic‐anaerobic infections, such as animals with peritonitis. The antipseudomonal, group 6 cephalosporins are used exclusively in the treatment of P. aeruginosa infections. Other third‐, fourth‐, and fifth‐generation cephalosporins are usually (but not always) reserved, in human medicine, for the treatment of hospital‐based bacterial infections resistant to earlier generations of cephalosporins or alternative antimicrobial drugs. The broad spectrum and bactericidal activity (at concentrations ≥4 × MIC) may be a drawback of newer cephalosporins, since these characteristics are associated with resistant bacterial superinfection and gastrointestinal disturbance. Widespread use of third‐generation cephalosporins in human and veterinary medicine may have been one of the important factors underlying the resistance crisis in medicine and has been associated with the striking emergence and dissemination of multiple forms of beta‐lactamases observed in recent years. This may also apply to the use of cefovecin in dogs. The fifth edition of this book stated that second‐ and third‐generation cephalosporins are not first‐choice antimicrobial agents in animals but rather should be reserved for use where susceptibility testing indicates that alternatives are not available. This remains the opinion of the authors, but these drugs are increasingly widely used in veterinary medicine as first‐choice antimicrobials. This use is under increasing scrutiny by the medical profession, public health officials, and governments. There has been a remarkable rise in resistance through ESBLs in Enterobacterales from both food and companion animals (including food‐borne pathogens, such as Salmonella) associated with the increased use of later generation cephalosporins. The association between ceftiofur use in eggs or day‐old broiler chicks with CMY‐2 beta‐lactamase‐producing Salmonella and E. coli, and the spread of resistant S. Heidelberg into the human population documented in Canada and the US, led to drug label changes and bans on such use. One response to the rise of ESBLs in the US was the prohibition in 2012 by the Food and Drug Administration of the extra‐label use of cephalosporins in food animals (Food and Drug Administration, 2012). This prohibition extends to use for disease prevention, use at unapproved doses, frequencies, durations, or routes of administration, and use of human or companion animal drugs. Ceftiofur can be used for an extra‐label disease treatment (e.g., Gram‐negative sepsis) as long as the label dosage regimen is followed. The ban does not extend to the extra‐label use of cephapirin products in food‐producing species or extra‐label use in food‐producing minor species (e.g., ducks, rabbits). In Denmark, voluntary discontinuation of cephalosporin use in swine in 2010 was associated with a decline in ESBL‐resistant E. coli in pigs at slaughter. There are severe restrictions on the use of third‐ and later generation cephalosporins in some countries in Europe, including Denmark, France, and The Netherlands. For example, in France there is a legal requirement for both clinical examination and susceptibility testing before using highest priority, critically important antimicrobials such as third‐generation cephalosporins (ANSES‐ANMV, 2018). This includes the demonstration that lower World Health Organization (2016) category antimicrobials are ineffective. This regulation has considerably reduced the use of these drugs by veterinarians. Stewardship issues are discussed further in Section 3 of this book. First‐generation cephalosporins have high activity against Gram‐positive bacteria, including penicillinase‐producing S. aureus and S. pseudintermedius; moderate activity against certain nontransferable, beta‐lactamase‐producing, Gram‐negative Enterobacterales and fastidious Gram negatives; and no activity against Enterobacter spp., P. aeruginosa, and Serratia spp., among others. Antimicrobial activity of oral first‐generation cephalosporins is similar to that of aminopenicillins with the addition of resistance to the beta‐lactamase of S. aureus. For susceptibility testing, cephalexin should be used as the class drug in dogs rather than cephalothin, which has been used in the past. Cefazolin may also be tested since it is more active against Gram‐negative bacteria. Acquired resistance is common in Gram negatives and is particularly important in Enterobacterales. Methicillin‐resistant S. aureus and methicillin‐resistant S. pseudintermedius (MRSP), discussed in Chapter 7, are resistant to all cephalosporins except those in the fifth generation. Apart from MRSA and MRSP, which are increasingly detected in companion animals, pigs, and horses, acquired resistance is rare in Gram‐positive bacteria. Canine isolates of MRSA and MRSP are commonly multidrug resistant (Morris et al., 2017). Antimicrobial susceptibility categories given below are guidelines only; bacterial susceptibility in veterinary medicine may vary by region and species, and over time (Chapter 2).
8
Beta‐lactam Antibiotics: Cephalosporins
General Considerations
Classification
Generation
Route of Administration
Characteristics
Examples
First
Parenteral
Resistant to staphylococcal beta‐lactamase; sensitive to enterobacterial beta‐lactamase; moderately active
Cephacetrile, cephaloridine, cephalothin, cephapirin, cephazolin
Oral
Resistant to staphylococcal beta‐lactamase; moderately resistant to some enterobacterial beta‐lactamase; moderately active
Cefadroxil, cephadrine, cephalexin
Second
Parenteral
Resistant to many beta‐lactamases; moderately active
Cefaclor, cefotetan, cefoxitin, cefuroxime, cefamandole
Third
Parenteral
Resistant to many beta‐lactamases; highly active
Cefotaxime, ceftiofur, ceftriaxone, latamoxef
Oral
Resistant to many beta‐lactamases; highly active
Cefetamet, cefixime, cefpodoxime
Parenteral
Resistant to many beta‐lactamases; active against Pseudomonas aeruginosa
Cefoperazone, cefovecin, cefsulodin, ceftazidime
Fourth
Parenteral
Resistant staphylococcal, enterobacterial and pseudomonal beta‐lactamases; highly active
Cefepime, cefquinome, cefpirome
Fifth
Parenteral
Broad‐spectrum activity including MRSA and extensively resistant strains such as vancomycin‐intermediate S. aureus (VISA), heteroresistant VISA and vancomycin‐resistant S. aureus; highly active
Ceftraroline, ceftobiprole
Antimicrobial Activity
Resistance to Cephalosporins
Penicillin‐binding Protein Modifications
Reduced Permeability and Increased Efflux
Beta‐lactamase Inactivation
First‐generation Cephalosporin Beta‐lactamases
Second‐generation Cephalosporin Beta‐lactamases
Third‐generation Cephalosporin Beta‐lactamases
AmpC Hyperproducers
Extended‐spectrum Beta‐lactamases
Group 3 Metallo‐beta‐lactamases
Pharmacokinetic Properties
Toxicity and Adverse Effects
Dosage Considerations
Clinical Usage
First‐generation Cephalosporins: Cefacetrile, Cephaloridine, Cefazolin, Cephapirin, Cephradine, Cephalothin, Cefadroxil, Cephradine, Cephalexin, and Cephaloglycin
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