Cephalosporins: from cefazolin to cefiderocol

Introduction

Cephalosporins belong to the β-lactam antibiotics, whose mechanism of action involves inhibiting bacterial cell wall synthesis by binding to penicillin-binding proteins. Due to their high activity and low toxicity, cephalosporins are widely used in both hospital and outpatient settings [1]. At the same time, the problem of antibiotic resistance is escalating: microorganisms with multidrug resistance (MDR) and extensively drug-resistant (XDR) strains pose a serious threat in the fight against infectious diseases worldwide. Of particular significance are carbapenem-resistant and non-fermenting Gram-negative strains such as Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Burkholderia cepacia, Proteus mirabilis, Stenotrophomonas maltophilia, and Enterobacter cloacae [2-6].

Given the relevance of this issue, this review traces the evolution of the cephalosporin class from generation to generation in the context of countering antibiotic resistance, including the development of the first siderophore cephalosporin — cefiderocol.

The history of the discovery of cephalosporins and the features of their structure

Cephalosporins are produced by the filamentous fungus Acremonium chrysogenum. The first cephalosporin was described by the Italian pharmacologist Brotzu G. in 1945 in Sardinia. While studying microbial communities in seawater near a sewage outfall, he isolated a strain of Cephalosporium acremonium and discovered that this culture inhibited the growth of Salmonella typhi, which produces β-lactamase. This discovery laid the foundation for the creation of the first laboratory cephalosporin C by the English scientists Newton G.G. and Abraham E.P., which showed activity against Gram-positive cocci and some Gram-negative microorganisms [7].

Subsequently, it turned out that the therapeutic potential of cephalosporin C was limited, which stimulated the search for new, more effective compounds. In 1962, the chemical structure of cephalosporin antibiotics — 7-aminocephalosporanic acid — was established [7]. The same year saw the introduction into clinical practice of the first antibiotic of the cephalosporin class, cephaloridine, active primarily against Gram-positive cocci [7].

The core structure of cephalosporins consists of a bicyclic nucleus comprising a six-membered dihydrothiazine ring fused to a β-lactam ring. Two carbon atoms at positions C3 and C7 provide ample opportunities for introducing variable side chains, allowing the expansion of the antibacterial spectrum and increasing the molecule's stability against β-lactamases [8].

The indications for use of drugs from each of the five generations are determined by their specific antimicrobial activity and pharmacokinetic characteristics. Differences in activity are related to the degree of affinity for penicillin-binding proteins. Cephalosporins demonstrate a broader spectrum of activity compared to standard penicillins, but they are also susceptible to hydrolysis by β-lactamases [8].

Comparative evaluation of cephalosporins depending on generation

Currently, five generations of cephalosporins are distinguished, differing in the time of introduction into practice and the spectrum of antimicrobial activity. From the first to the fourth generation, there is a predominant expansion of the spectrum of action. Fifth-generation drugs are active against "problematic" pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA).

Cephalosporins are divided into parenteral and oral forms [9].

First-generation parenteral cephalosporins include cefazolin and cephalothin; oral forms include cephalexin and cefadroxil. Currently, they are characterized by a narrow spectrum of activity, aimed mainly against Gram-positive cocci. They are not active against MRSA, enterococci, or Listeria [1].

Cefazolin demonstrates effectiveness in treating endocarditis, catheter-associated infections, skin and soft tissue infections, as well as bone and joint infections caused by methicillin-susceptible S. aureus. First-generation drugs are often compared to antistaphylococcal penicillins (ASPs). It has been shown that the use of cefazolin is associated with a lower frequency of antibiotic discontinuation due to adverse reactions, especially cutaneous and renal. However, due to low penetration through the blood-brain barrier (BBB) in CNS infections, ASPs should be preferred [10, 11].

With the development of cephalosporin generations, their activity against Gram-negative flora increases (gonococci, meningococci, H. influenzae, M. catarrhalis, E. coli, P. mirabilis, P. vulgaris, Klebsiella spp.).

Second-generation cephalosporins include parenteral cefuroxime, cefamandole, cefoxitin and oral cefuroxime axetil, cefaclor. Their advantage is increased activity against Gram-negative bacteria: E. coli, H. influenzae, M. catarrhalis, some strains of Klebsiella, Proteus (P. mirabilis, P. vulgaris), and others [1].

The drugs demonstrate activity similar to cefazolin against Gram-positive microorganisms such as Streptococcus spp. and Staphylococcus spp. [12]. Among oral second-generation forms, cefuroxime axetil holds a leading position, being a prodrug that is metabolized in the intestine to active cefuroxime.

Despite a spectrum of antimicrobial activity similar to cefaclor, cefuroxime demonstrates higher clinical efficacy against Streptococcus spp. and Staphylococcus spp. [1, 13]. Furthermore, cefuroxime is more active against Moraxella catarrhalis and Haemophilus spp., as it is resistant to hydrolysis by their β-lactamases, whereas cefaclor is susceptible to degradation by these enzymes. Like first-generation cephalosporins, second-generation drugs are not active against MRSA, P. aeruginosa, Serratia marcescens, Providencia, Morganella, Acinetobacter spp., nor against most anaerobes [13, 14].

Third-generation cephalosporins are among the most frequently used in clinical practice. Parenteral representatives include cefotaxime, ceftriaxone, ceftazidime, cefoperazone; oral ones include cefixime, cefditoren, ceftibuten.

Their primary antimicrobial activity is directed against Gram-negative flora resistant to first- and second-generation cephalosporins; however, they are less active against some Gram-positive bacteria such as Streptococcus and Staphylococcus spp., and also possess low anti-anaerobic activity.

Third-generation cephalosporins retain susceptibility against penicillin-susceptible strains of S. pneumoniae, which explains their widespread use in treating upper and lower respiratory tract infections [11, 15, 16]. Cefotaxime and ceftriaxone demonstrate good activity against pneumococci [17].

Two third-generation representatives — cefoperazone and ceftazidime — exhibit activity against Pseudomonas aeruginosa, which is not characteristic of previous generations [18].

The use of third-generation cephalosporins for infections caused by bacteria producing AmpC β-lactamases (e.g., Enterobacter spp. and K. aerogenes) is not recommended due to potential resistance induction. Nevertheless, data exist on their comparable clinical efficacy with fourth-generation cephalosporins or carbapenems, which are typically prescribed for such infections [19].

Ceftriaxone (in combination with azithromycin) is considered a first-line treatment for gonorrhea [20]. Third-generation cephalosporins are widely used in treating meningitis due to their ability to penetrate the BBB. They are the drugs of choice for preventing spontaneous bacterial peritonitis, although recent data suggest a decline in their effectiveness [15, 21].

Cefotaxime is characterized by a broad therapeutic index, good penetration into cerebrospinal fluid, and a lower risk of nephrotoxicity, making it the most commonly used third-generation cephalosporin for early neonatal sepsis [8, 22].

Fourth-generation cephalosporins (cefepime, cefpirome) combine the spectrum of action of their predecessors. They retain activity against Gram-negative bacteria, including the family Enterobacteriaceae and P. aeruginosa, even strains resistant to third-generation cephalosporins. This advantage is due to higher affinity for penicillin-binding proteins and structural features: the simultaneous presence of negative and positive charges, facilitating penetration through the outer membrane of Gram-negative bacteria [23].

Furthermore, fourth-generation cephalosporins possess improved activity against Gram-positive microorganisms (cefpirome surpasses cefepime), but remain inactive against MRSA and enterococci [23].

Fifth-generation drugs were specifically developed to combat bacterial strains with MDR. These include ceftobiprole, ceftaroline, and ceftolozane. Ceftobiprole, used for treating community-acquired pneumonia, is effective against MRSA. Ceftolozane in combination with the β-lactamase inhibitor tazobactam (ceftolozane/tazobactam) is widely used for infections caused by carbapenem-resistant Enterobacterales and P. aeruginosa. Ceftaroline is active against MRSA and other β-lactamase-producing microorganisms, including penicillin-resistant streptococci and β-lactamase-producing Enterococcus faecalis. Ceftaroline is ineffective against Pseudomonas aeruginosa [24].

Cefiderocol

Among the new cephalosporins, cefiderocol stands out, approved by the FDA in October 2019 for treating complicated urinary tract infections, and in September 2020 for treating nosocomial pneumonia associated with mechanical ventilation. Cefiderocol is the first siderophore cephalosporin intended for treating infections caused by MDR Gram-negative bacteria, including carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, Burkholderia spp., S. maltophilia, and Elizabethkingia meningoseptica. Cefiderocol has no clinically significant activity against Gram-positive cocci and anaerobes [25-28].

The cefiderocol molecule consists of a side chain at the C-7 position identical to that of ceftazidime, and a side chain at the C-3 position similar to cefepime, but containing a chlorocatechol moiety at the end, which enables chelation of ferric iron, turning the antibiotic into a siderophore (Greek for "iron carrier"). Siderophores are chelators of ferric iron involved in its transport into the bacterial cell. Iron is an essential micronutrient required for bacterial survival. During an infectious process, innate immunity activates mechanisms that limit iron availability to pathogens. Under iron-deficient conditions, bacteria enhance iron transport, including in the form of the cefiderocol-iron complex.

This unique chemical structure and penetration mechanism confer upon cefiderocol stability against major antibiotic resistance mechanisms, including loss of porin channels, overexpression of efflux pumps, and inactivation by β-lactamases.

The activity of cefiderocol against metallo-β-lactamases is of particular interest, as currently, there are no other β-lactam antibiotics active against carbapenemases produced by Enterobacterales or non-fermenting microorganisms [25-29]. However, despite the advantages of its mechanism of action, cases of resistance to cefiderocol have already been reported. In a study by Karakonstantis S. et al. (2022), resistance mechanisms were identified, including mutations affecting the target (PBP-3), as well as mutations altering the expression of receptor genes for cefiderocol (most commonly affecting the cirA and fiu genes in Enterobacterales, piuA and piuD in P. aeruginosa, and pirA and piuA in A. baumannii) [30-35].

Despite high activity against most β-lactamases, reduced efficacy has been noted against some specific enzymes (NDM, OXA-427) [30-35].

Pharmacokinetics

Cephalosporins are divided into drugs with typical and atypical pharmacokinetics. Typical pharmacokinetics implies poor gastrointestinal absorption, good tissue penetration, a short half-life (1-2 hours), no hepatic metabolism, and excretion unchanged in urine [1, 9, 14].

Atypical pharmacokinetics is characteristic of oral cephalosporins and differs by rapid and complete absorption, although food intake usually slows absorption. An exception is cefuroxime axetil, for which food aids the biotransformation of the prodrug into the active form. Third-generation cephalosporins penetrate the BBB well, which underlies their use in meningitis.

Drugs with a long half-life (3-4 hours) include cefixime and ceftibuten. The longest half-life is characteristic of ceftriaxone — from 6.5 to 8 hours. An atypical excretion route is observed for cefoperazone and ceftriaxone, which are eliminated in bile up to 70% and 40%, respectively [1, 9, 14, 36].

Adverse reactions

Cephalosporins are characterized by a low toxicity profile and are generally well-tolerated. Most adverse reactions are dose-dependent. These include allergic reactions (including Stevens-Johnson syndrome), occurring less frequently than with penicillins. In particular, cefazolin may be an alternative in patients with penicillin allergy. Cross-reactivity is thought to be due to the common R1 side chain, which is absent in cefazolin. A study by Norvell M.R. et al. (2023) showed that using cefazolin for perioperative antibiotic prophylaxis in total joint arthroplasty in patients with β-lactam allergy was associated with a reduced rate of postoperative surgical site infections compared to clindamycin/vancomycin, typically prescribed as alternatives [37, 38].

The development of coagulopathies has been described with the use of cefamandole, cefotetan, and cefoperazone. A key factor in the pathogenesis of coagulopathy is considered to be the presence of the N-methylthiotetrazole (NMTT) side chain, which inhibits vitamin K-dependent carboxylation, leading to impaired synthesis of clotting factors. Cefotaxime less frequently causes coagulopathies [15, 39, 40].

Due to the presence of the methylthiotetrazole moiety, cefamandole, cefmetazole, cefotetan, and cefoperazone can inhibit aldehyde dehydrogenase, potentially leading to a disulfiram-like reaction [15, 39-42].

The use of cefepime may be associated with neurotoxicity, manifesting as confusion, delirium, myoclonus, and seizures. This is presumably related to the drug's ability to penetrate the BBB and competitively interact with γ-aminobutyric acid receptors [15, 39-43]. Cases of neutropenia have been described [44]. For second-, third-, and fourth-generation cephalosporins, the development of pseudomembranous colitis associated with Clostridioides difficile is possible. Nephrotoxicity is most pronounced with fifth-generation drugs [15, 39].

Conclusion

Cephalosporins hold an important place in the treatment of bacterial infections in patients of all age groups, including infections caused by "problematic" pathogens. Favorable pharmacokinetic parameters and a low risk of adverse reactions have led to their widespread use in clinical practice, especially in multi-specialty hospitals.

In recent years, the innovative cephalosporin cefiderocol has entered the clinical arsenal in the US and Europe — the first representative of the siderophore cephalosporins, showing activity against carbapenem-resistant and non-fermenting Gram-negative bacteria with difficult-to-overcome resistance mechanisms. Due to its unique structure and mechanism of action, cefiderocol is stable against major antibiotic resistance mechanisms (porin loss, efflux, β-lactamase hydrolysis). Nevertheless, reports of cefiderocol-resistant strains have already emerged.

Thus, on the one hand, the advent of new antibiotics opens optimistic prospects for treating severe infections; on the other hand, reports of resistance development within the first years of clinical use underscore the necessity of a rational and balanced approach to the use of any representative of this unique class of drugs.