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Cephalosporin
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Cephalosporin
Drug class
Core structure of the cephalosporins
Class identifiers
UseBacterial infection
ATC codeJ01D
Biological targetPenicillin binding proteins
Clinical data
Drugs.comDrug Classes
External links
MeSHD002511
Legal status
In Wikidata
Structure of the classical cephalosporins

The cephalosporins (sg. /ˌsɛfələˈspɔːrɪn, ˌkɛ-, -loʊ-/[1][2]) are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as Cephalosporium.[3]

Together with cephamycins, they constitute a subgroup of β-lactam antibiotics called cephems. Cephalosporins were discovered in 1945, and first sold in 1964.[4]

Discovery

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The aerobic mold which yielded cephalosporin C was found in the sea near a sewage outfall in Su Siccu, by Cagliari harbour in Sardinia, by the Italian pharmacologist Giuseppe Brotzu in July 1945.[5]

Structure

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Cephalosporin contains a 6-membered dihydrothiazine ring. Substitutions at position 3 generally affect pharmacology; substitutions at position 7 affect antibacterial activity, but these cases are not always true.[6]

Medical uses

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Cephalosporins can be indicated for the prophylaxis and treatment of infections caused by bacteria susceptible to this particular form of antibiotic. First-generation cephalosporins are active predominantly against Gram-positive bacteria, such as Staphylococcus and Streptococcus.[7] They are therefore used mostly for skin and soft tissue infections and the prevention of hospital-acquired surgical infections.[8] Successive generations of cephalosporins have increased activity against Gram-negative bacteria, albeit often with reduced activity against Gram-positive organisms.[citation needed]

The antibiotic may be used for patients who are allergic to penicillin due to the different β-lactam antibiotic structure. The drug is able to be excreted in the urine.[7]

Side effects

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Common adverse drug reactions (ADRs) (≥ 1% of patients) associated with the cephalosporin therapy include: diarrhea, nausea, rash, electrolyte disturbances, and pain and inflammation at injection site. Infrequent ADRs (0.1–1% of patients) include vomiting, headache, dizziness, oral and vaginal candidiasis, pseudomembranous colitis, superinfection, eosinophilia, nephrotoxicity, neutropenia, thrombocytopenia, and fever.[citation needed]

Allergic hypersensitivity

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The commonly quoted figure of 10% of patients with allergic hypersensitivity to penicillins or carbapenems also having cross-reactivity with cephalosporins originated from a 1975 study looking at the original cephalosporins,[9] and subsequent "safety first" policy meant this was widely quoted and assumed to apply to all members of the group.[10] Hence, it was commonly stated that they are contraindicated in patients with a history of severe, immediate allergic reactions (urticaria, anaphylaxis, interstitial nephritis, etc.) to penicillins or carbapenems.[11]

The contraindication, however, should be viewed in the light of recent epidemiological work suggesting, for many second-generation (or later) cephalosporins, the cross-reactivity rate with penicillin is much lower, having no significantly increased risk of reactivity over the first generation based on the studies examined.[10][12] The British National Formulary previously issued blanket warnings of 10% cross-reactivity, but, since the September 2008 edition, suggests, in the absence of suitable alternatives, oral cefixime or cefuroxime and injectable cefotaxime, ceftazidime, and ceftriaxone can be used with caution, but the use of cefaclor, cefadroxil, cefalexin, and cefradine should be avoided.[13] A 2012 literature review similarly finds that the risk is negligible with third- and fourth-generation cephalosporins. The risk with first-generation cephalosporins having similar R1 sidechains was also found to be overestimated, with the real value closer to 1%.[14]

MTT side chain

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See also: Disulfiram-like drug
MTT and MTDT sidechains
Methyl­thio­tetrazole
Methyl­thio­dioxo­triazine

Several cephalosporins are associated with hypoprothrombinemia and a disulfiram-like reaction with ethanol.[15][16] These include latamoxef (moxalactam), cefmenoxime, cefoperazone, cefamandole, cefmetazole, and cefotetan. This is thought to be due to the methylthiotetrazole side-chain of these cephalosporins, which blocks the enzyme vitamin K epoxide reductase (likely causing hypothrombinemia) and aldehyde dehydrogenase (causing alcohol intolerance).[17] Thus, consumption of alcohol after taking these cephalosporin orally or intravenously is contraindicated, and in severe cases can lead to death.[18] The methylthiodioxotriazine sidechain found in ceftriaxone has a similar effect. Cephalosporins without these structural elements are believed to be safe with alcohol.[19]

Mechanism of action

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Cephalosporins are bactericidal and, like other β-lactam antibiotics, disrupt the synthesis of the peptidoglycan layer forming the bacterial cell wall. The peptidoglycan layer is important for cell wall structural integrity. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by penicillin-binding proteins (PBPs). PBPs bind to the D-Ala-D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the peptidoglycan. Beta-lactam antibiotics mimic the D-Ala-D-Ala site, thereby irreversibly inhibiting PBP crosslinking of peptidoglycan.[20]

Resistance

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Resistance to cephalosporin antibiotics can involve either reduced affinity of existing PBP components or the acquisition of a supplementary β-lactam-insensitive PBP. Compared to other β-lactam antibiotics (such as penicillins), they are less susceptible to β-lactamases. Currently, some Citrobacter freundii, Enterobacter cloacae, Neisseria gonorrhoeae, and Escherichia coli strains are resistant to cephalosporins. Some Morganella morganii, Proteus vulgaris, Providencia rettgeri, Pseudomonas aeruginosa, Serratia marcescens and Klebsiella pneumoniae strains have also developed resistance to cephalosporins to varying degrees.[21][22]

Classification

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The first cephalosporins were designated first-generation cephalosporins, whereas, later, more extended-spectrum cephalosporins were classified as second-generation cephalosporins. Each newer generation has significantly greater Gram-negative antimicrobial properties than the preceding generation, in most cases with decreased activity against Gram-positive organisms. Fourth-generation cephalosporins, however, have true broad-spectrum activity.[23]

The classification of cephalosporins into "generations" is commonly practised, although the exact categorization is often imprecise. For example, the fourth generation of cephalosporins is not recognized as such in Japan.[citation needed] In Japan, cefaclor is classed as a first-generation cephalosporin, though in the United States it is a second-generation one; and cefbuperazone, cefminox, and cefotetan are classed as second-generation cephalosporins.

First generation

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Cefalotin, cefazolin, cefalexin, cefapirin, cefradine, and cefadroxil are among the drugs belonging to this group.

Second generation

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Cefoxitin, cefuroxime, cefaclor, cefprozil, and cefmetazole are classed as second-generation cephems.

Third generation

[edit]

Ceftazidime, ceftriaxone, and cefotaxime are classed as third-generation cephalosporins. Flomoxef and latamoxef are in a new, related class called oxacephems.[24]

Fourth generation

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Drugs included in this group are cefepime and cefpirome.

Further generations

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Some state that cephalosporins can be divided into five or even six generations, although the usefulness of this organization system is of limited clinical relevance.[25]

Naming

[edit]

Most first-generation cephalosporins were originally spelled "ceph-" in English-speaking countries. This continues to be the preferred spelling in the United States, Australia, and New Zealand, while European countries (including the United Kingdom) have adopted the International Nonproprietary Names, which are always spelled "cef-". Newer first-generation cephalosporins and all cephalosporins of later generations are spelled "cef-", even in the United States.[citation needed]

Activity

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There exist bacteria which cannot be treated with cephalosporins of generations first through fourth:[26]

Fifth-generation cephalosporins (e.g. ceftaroline) are effective against MRSA, Listeria spp., and Enterococcus faecalis.[27][26]

Overview table

[edit]

Generation
 Name
Approval status
Coverage
 Description
Common Alternate name or spelling Brand
(#) = noncephalosporins similar to generation # H, human; V, veterinary; W, withdrawn; P, Pseudomonas; MR, methicillin-resistant Staphylococcus aureus; An, anaerobe
1 Cefalexin cephalexin Keflex H V Gram-positive: Activity against penicillinase-producing, methicillin-susceptible staphylococci and streptococci (though they are not the drugs of choice for such infections). No activity against methicillin-resistant staphylococci or enterococci.[citation needed]

Gram-negative: Activity against Proteus mirabilis, some Escherichia coli, and Klebsiella pneumoniae ("PEcK"), but have no activity against Bacteroides fragilis, Pseudomonas, Acinetobacter, Enterobacter, indole-positive Proteus, or Serratia.[citation needed]

Cefadroxil cefadroxyl Duricef H
Cefazolin cephazolin Ancef, Kefzol H
Cefapirin cephapirin Cefadryl V
Cefacetrile cephacetrile
Cefaloglycin cephaloglycin
Cefalonium cephalonium
Cefaloridine cephaloradine
Cefalotin cephalothin Keflin
Cefatrizine
Cefazaflur
Cefazedone
Cefradine cephradine Velosef
Cefroxadine
Ceftezole
2 Cefuroxime Altacef, Zefu, Zinnat, Zinacef, Ceftin, Biofuroksym,[28] Xorimax H Gram-positive: Less than first-generation.[citation needed]

Gram-negative: Greater than first-generation: HEN Haemophilus influenzae, Enterobacter aerogenes and some Neisseria + the PEcK described above.[citation needed]

Cefprozil cefproxil Cefzil H
Cefaclor Ceclor, Distaclor, Keflor, Raniclor H
Cefonicid Monocid
Cefuzonam
Cefamandole W
(2) Cefoxitin Mefoxin H An Cephamycins sometimes grouped with second-generation cephalosporins
Cefotetan Cefotan H An
Cefmetazole Zefazone An
Cefminox
Cefbuperazone
Cefotiam Pansporin
Loracarbef Lorabid The carbacephem analog of cefaclor
3 Cefdinir Sefdin, Zinir, Omnicef, Kefnir H Gram-positive: Some members of this group (in particular, those available in an oral formulation, and those with antipseudomonal activity) have decreased activity against gram-positive organisms.

Activity against staphylococci and streptococci is less with the third-generation compounds than with the first- and second-generation compounds.[29]

Gram-negative: Third-generation cephalosporins have a broad spectrum of activity and further increased activity against gram-negative organisms. They may be particularly useful in treating hospital-acquired infections, although increasing levels of extended-spectrum beta-lactamases are reducing the clinical utility of this class of antibiotics. They are also able to penetrate the central nervous system, making them useful against meningitis caused by pneumococci, meningococci, H. influenzae, and susceptible E. coli, Klebsiella, and penicillin-resistant N. gonorrhoeae. Since August 2012, the third-generation cephalosporin, ceftriaxone, is the only recommended treatment for gonorrhea in the United States (in addition to azithromycin or doxycycline for concurrent Chlamydia treatment). Cefixime is no longer recommended as a first-line treatment due to evidence of decreasing susceptibility.[30]

Ceftriaxone Rocephin H
Ceftazidime Meezat, Fortum, Fortaz H P
Cefixime Fixx, Zifi, Suprax H
Cefpodoxime Vantin, PECEF, Simplicef H V
Ceftiofur Naxcel, Excenel H V
Cefotaxime Claforan H
Ceftizoxime Cefizox H
Cefditoren Zostom-O H
Ceftibuten Cedax H
Cefovecin Convenia V
Cefdaloxime
Cefcapene
Cefetamet
Cefmenoxime
Cefodizime
Cefpimizole
Cefteram
Ceftiolene
Cefoperazone Cefobid W[31] P
(3) Latamoxef moxalactam W[31] An oxacephem sometimes grouped with third-generation cephalosporins
4 Cefepime Maxipime H P Gram-positive: They are extended-spectrum agents with similar activity against Gram-positive organisms as first-generation cephalosporins.[citation needed]

Gram-negative: Fourth-generation cephalosporins are zwitterions that can penetrate the outer membrane of Gram-negative bacteria.[32] They also have a greater resistance to β-lactamases than the third-generation cephalosporins. Many can cross the blood–brain barrier and are effective in meningitis. They are also used against Pseudomonas aeruginosa.[citation needed]

Cefiderocol has been called a fourth-generation cephalosporin by only one source as of November 2019.[33]

Cefiderocol Fetroja H
Cefquinome V
Cefclidine
Cefluprenam
Cefoselis
Cefozopran
Cefpirome Cefrom
(4) Flomoxef An oxacephem sometimes grouped with fourth-generation cephalosporins
5 Ceftaroline H MR Ceftobiprole has been described as "fifth-generation" cephalosporin,[34][35] though acceptance for this terminology is not universal. Ceftobiprole has anti-pseudomonal activity and appears to be less susceptible to development of resistance. Ceftaroline has also been described as "fifth-generation" cephalosporin, but does not have the activity against Pseudomonas aeruginosa or vancomycin-resistant enterococci that ceftobiprole has.[36] Ceftolozane is an option for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. It is combined with the β-lactamase inhibitor tazobactam, as multi-drug resistant bacterial infections will generally show resistance to all β-lactam antibiotics unless this enzyme is inhibited.[37][38][39][40][41]
Ceftolozane Zerbaxa H
Ceftobiprole MR
? Cefaloram These cephems have progressed far enough to be named, but have not been assigned to a particular generation. Nitrocefin is a chromogenic cephalosporin substrate, and is used for detection of β-lactamases.[citation needed]
Cefaparole
Cefcanel
Cefedrolor
Cefempidone
Cefetrizole
Cefivitril
Cefmatilen
Cefmepidium
Cefoxazole
Cefrotil
Cefsumide
Ceftioxide
Cefuracetime
Nitrocefin

History

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See also: Discovery and development of cephalosporins

Cephalosporin compounds were first isolated from cultures of Acremonium strictum from a sewer in Sardinia in 1948 by Italian scientist Giuseppe Brotzu.[42] He noticed these cultures produced substances that were effective against Salmonella typhi, the cause of typhoid fever, which had β-lactamase. Guy Newton and Edward Abraham at the Sir William Dunn School of Pathology at the University of Oxford isolated cephalosporin C. The cephalosporin nucleus, 7-aminocephalosporanic acid (7-ACA), was derived from cephalosporin C and proved to be analogous to the penicillin nucleus 6-aminopenicillanic acid (6-APA), but it was not sufficiently potent for clinical use. Modification of the 7-ACA side chains resulted in the development of useful antibiotic agents, and the first agent, cefalotin (cephalothin), was launched by Eli Lilly and Company in 1964.[citation needed]

References

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Cephalosporin

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Cephalosporins are a class of β-lactam antibiotics that are bactericidal and structurally related to penicillins, originally derived from the fungus (previously known as Cephalosporium). They inhibit bacterial cell wall synthesis by binding to , disrupting cross-linking and leading to bacterial . Discovered in 1945 by Italian scientist Giuseppe Brotzu, who isolated antibiotic-producing strains of Cephalosporium acremonium from seawater near a outlet in , cephalosporins were further developed through collaborative research at the . This effort led to the isolation of cephalosporin C in 1953 and the elucidation of its structure by 1960, paving the way for semi-synthetic derivatives introduced for clinical use in the . Cephalosporins are classified into five generations based on their , resistance to β-lactamases, and clinical applications, with each subsequent generation generally expanding activity against while varying in Gram-positive coverage. First-generation agents, such as and cephalexin, excel against Gram-positive cocci like staphylococci and streptococci but have limited Gram-negative activity. Second-generation cephalosporins, including and , offer improved coverage of Gram-negative organisms and some anaerobes. Third-generation drugs, like and , provide broad-spectrum activity against many Gram-negative pathogens, including some β-lactamase producers, and are often used for serious infections. Fourth-generation cephalosporins, such as cefepime, have enhanced stability against β-lactamases and balanced Gram-positive and Gram-negative efficacy. Fifth-generation agents, including ceftaroline, uniquely target methicillin-resistant Staphylococcus aureus (MRSA) and retain broad Gram-negative activity. Clinically, cephalosporins are employed to treat a wide array of infections, including respiratory tract infections (e.g., pneumonia), urinary tract infections, skin and soft tissue infections, bone and joint infections, and intra-abdominal infections, as well as for surgical prophylaxis. Their selection depends on the generation, site of infection, and local resistance patterns, with parenteral forms used for severe cases and oral options for milder ones. Despite their utility, cross-reactivity with penicillin allergies occurs in about 2-5% of cases, and emerging resistance from β-lactamase production poses ongoing challenges.

Introduction

Definition and General Properties

Cephalosporins are a class of β-lactam antibiotics originally derived from the fungus (previously known as Cephalosporium). They possess a β-lactam ring that is essential for their antimicrobial activity. These antibiotics exhibit bactericidal properties by inhibiting bacterial cell wall synthesis, demonstrating broad-spectrum activity against many Gram-positive and . Certain cephalosporins also show stability against some β-lactamases produced by bacteria, enhancing their efficacy in specific infections. Representative examples include cephalexin, an oral first-generation cephalosporin with a molecular weight of 347.4 g/mol and solubility of approximately 10 mg/mL in at room temperature, suitable for outpatient use. Another is , a parenteral third-generation cephalosporin with a molecular weight of 661.6 g/mol for its sodium salt and solubility of approximately 100-400 mg/mL in , often administered intravenously. Cephalosporins share a structural relation to penicillins through their common β-lactam ring but generally exhibit lower rates of allergic , estimated at less than 2% for IgE-mediated reactions in penicillin-allergic patients, though this can vary based on similarities.

Clinical Importance

Cephalosporins represent one of the most frequently prescribed classes globally, forming a substantial portion of overall utilization in both community and hospital settings. In the United States, outpatient prescriptions for cephalosporins reached 38.9 million in 2023, equating to 116 prescriptions per 1,000 population. In hospital environments, particularly across low- and middle-income countries, third-generation cephalosporins account for 15.5% to 22% of prescriptions as of 2023, underscoring their prominence in treating acute infections. The therapeutic advantages of cephalosporins lie in their broad versatility, enabling effective management of community-acquired infections like and urinary tract infections, as well as nosocomial infections in vulnerable patients. They are particularly valued for prophylactic applications in , where administration has been demonstrated to reduce postoperative morbidity and surgical site infections by up to 50% compared to no prophylaxis. This dual role in empirical therapy and prevention positions cephalosporins as essential tools in clinical practice. From an economic perspective, the global cephalosporin market was valued at USD 19.38 billion in 2023, with projections for continued growth driven by expanding demand in emerging markets. The availability of generic formulations has significantly enhanced cost-effectiveness, with daily treatment costs for generics often one-fourth to one-half lower than brand-name versions, thereby improving access and reducing overall healthcare expenditures in resource-constrained environments. In , cephalosporins are recognized for their critical contributions, with key agents such as and featured on the World Health Organization's Model List of for their proven efficacy against severe bacterial infections. Their appropriate use has played a key role in lowering mortality rates from bacterial diseases by enabling timely and effective treatment, though this impact is tempered by rising resistance patterns that necessitate efforts.

History

Discovery

In 1945, Italian microbiologist Giuseppe Brotzu, professor of hygiene at the , isolated the fungus Cephalosporium acremonium (now classified as Acremonium chrysogenum) from seawater samples collected near a sewage outlet in the harbor of , . Motivated by the regional prevalence of and the need for antibiotics effective against like Salmonella typhi, Brotzu cultured the fungus and observed that its filtrates inhibited the growth of S. typhi as well as . These initial experiments demonstrated the potential of the fungal metabolite as a therapeutic agent, though production yields were low and purification rudimentary. Brotzu published his findings in a 1948 report and forwarded samples of the fungus along with detailed observations to Howard Florey at the University of Oxford. Due to Florey's commitments to penicillin scale-up during postwar reconstruction, the material was redirected to Ernst Chain and Edward P. Abraham at the Sir William Dunn School of Pathology, initiating a key collaboration. The Oxford team replicated Brotzu's cultures and began systematic of the broth in 1948, aiming to identify active principles resistant to bacterial enzymes that degraded penicillin. By 1949, Abraham and his colleague Guy Newton isolated cephalosporin N (also termed penicillin N), a hydrophilic beta-lactam compound structurally related to penicillin, exhibiting activity against both gram-positive and gram-negative bacteria. However, cephalosporin N faced significant early challenges, including chemical instability in solution and susceptibility to hydrolysis by penicillinase enzymes produced by resistant bacteria, which curtailed further development as a direct therapeutic. Attention shifted to other components in the filtrate, leading to the purification of cephalosporin C in 1953—a stable, penicillinase-resistant with a novel bicyclic beta-lactam nucleus but modest potency against clinical pathogens. Throughout the 1950s, the and emerging pharmaceutical collaborators, including , conducted extensive screening of over 400 semi-synthetic derivatives derived from the cephalosporin C nucleus, modifying side chains to enhance antibacterial efficacy and stability. These efforts revealed cephalosporin C's value as a versatile scaffold, overcoming the limitations of earlier isolates and establishing the foundation for a new class of beta-lactam antibiotics.

Development and Commercialization

In the 1960s, pioneered semi-synthetic modifications of the natural cephalosporin nucleus, transforming it from a lab curiosity into viable therapeutic agents. These innovations focused on improving stability and , culminating in the development of first-generation cephalosporins like cephalothin, which received FDA approval in 1964 for parenteral use against Gram-positive infections. The push toward oral formulations accelerated in the late 1960s and early 1970s, with companies such as and Glaxo Laboratories playing key roles in patenting and commercializing absorbable derivatives. A landmark example was cephalexin, an oral first-generation cephalosporin approved by the FDA in 1970, enabling outpatient treatment of mild infections and broadening accessibility beyond hospital settings. By the and , rising bacterial resistance to earlier antibiotics, particularly β-lactamases hydrolyzing first- and second-generation agents, drove the industry toward broader-spectrum cephalosporins. Pharmaceutical firms invested in structural tweaks to enhance Gram-negative coverage while retaining Gram-positive activity, shifting focus from narrow to expanded indications amid global resistance trends. Key milestones marked this progression: third-generation cephalosporins like ceftazidime, developed by Glaxo and FDA-approved in 1985, offered improved penetration against and other resistant Gram-negatives; fourth-generation agents such as cefepime, approved in 1996 by Bristol-Myers Squibb, provided balanced dual coverage and β-lactamase stability; and fifth-generation options including ceftaroline, approved in 2010 by Cerexa (now ), targeted MRSA alongside Gram-negatives. These advancements resulted in over 50 cephalosporins approved globally by 2025, spanning five generations and diverse administration routes. Post-2020 developments addressed multidrug-resistant threats, exemplified by , a siderophore-conjugated cephalosporin approved by the FDA in 2019 for complicated urinary tract infections and expanded in 2020 to hospital-acquired and ventilator-associated in adults with limited alternatives. In 2024, the FDA approved ceftobiprole medocaril (Zevtera), a fifth-generation cephalosporin, for the treatment of bacteremia (including right-sided ), acute bacterial skin and skin structure infections, and community-acquired in adults.

Chemical Structure

Core Molecular Framework

The core molecular framework of cephalosporins is embodied in 7-aminocephalosporanic acid (7-ACA), a bicyclic structure comprising a four-membered β-lactam ring fused to a six-membered dihydrothiazine ring, forming the cephem nucleus. This fusion creates a rigid scaffold that distinguishes cephalosporins within the β-lactam class, with the dihydrothiazine ring providing conformational stability to the overall molecule. Key functional groups on this core include a carboxyl group at position 4 of the dihydrothiazine ring, which contributes to and properties, and an amino group at position 7 of the β-lactam ring, serving as the primary site for during semi-synthetic modifications. The β-lactam ring itself exhibits high reactivity due to the strained amide bond, enabling nucleophilic attack by bacterial enzymes, while the adjacent dihydrothiazine ring modulates this reactivity to enhance chemical stability against . Cephalosporin C, the naturally occurring precursor isolated from fungi, exemplifies this framework with the molecular formula C₁₆H₂₁N₃O₈S and a molecular weight of 415.42 g/mol. In comparison to penicillins, which feature a β-lactam ring fused to a five-membered thiazolidine ring, the six-membered dihydrothiazine ring in cephalosporins introduces greater bulkiness, reducing steric hindrance around the β-lactam and conferring improved resistance to β-lactamase degradation.

Modifications Across Generations

Cephalosporins are structurally modified from the core 7-aminocephalosporanic acid framework primarily at the 7β-acylamino and the 3-position of the dihydrothiazine ring to optimize their pharmacological properties. These alterations define the generational classifications and influence key aspects such as antibacterial potency and resistance profiles. Modifications to the position 7 involve varying acyl groups that significantly impact interactions with bacterial targets. In third-generation cephalosporins, the incorporation of an aminothiazolyl moiety at this position enhances Gram-negative activity by improving binding affinity to and facilitating better penetration into bacterial cells. This structural feature, often combined with a syn-(Z)-methoxyimino group, also confers greater stability against by β-lactamases produced by Gram-negative pathogens, thereby broadening efficacy against resistant strains. At the position 3 side chain, substituents are tailored to modulate absorption and duration of action. Oral first-generation cephalosporins typically feature a at the 3-position, which supports oral . In contrast, parenteral first-generation agents like cephalothin retain the acetoxymethyl group. Third-generation agents like incorporate a complex heterocyclic thiomethyl derivative at position 3 (specifically, a 1,2,4-triazinone-thiomethyl group), which sterically hinders enzymatic degradation and contributes to prolonged systemic exposure through altered clearance pathways. Additional structural innovations appear in later generations to address specific challenges. Fourth-generation cephalosporins, such as cefepime, adopt zwitterionic configurations—bearing both positive and negative charges within the molecule—which enhance stability in renal environments and reduce susceptibility to hydrolysis by certain β-lactamases. Newer agents like introduce conjugation, attaching a moiety to the position 3 side chain to exploit bacterial iron uptake systems for improved intracellular delivery. Structure-activity relationships reveal that these modifications directly correlate with functional outcomes. For instance, the methoxyimino group at position 7 sterically protects the β-lactam ring from nucleophilic attack by β-lactamases, while polar extensions at position 3 enhance membrane permeability across outer bacterial envelopes without compromising core integrity. Such targeted changes underscore the evolution of cephalosporins from narrow-spectrum agents to versatile therapeutics resistant to common resistance mechanisms.

Mechanism of Action

Inhibition of Bacterial Cell Wall Synthesis

Cephalosporins exert their antibacterial effect by binding to (PBPs), which are essential enzymes involved in the final stages of synthesis in the bacterial . In , cephalosporins demonstrate high affinity for PBPs 1A, 1B, 2, and 3, which catalyze transpeptidation and transglycosylation reactions necessary for cross-linking chains. In , their affinity is particularly notable for PBP-2, contributing to the disruption of integrity in these organisms. The binding process involves the reactive β-lactam ring of the cephalosporin molecule, which mimics the D-alanyl-D-alanine terminus of precursors. This ring opens upon interaction with the serine residue of the PBP, leading to where the serine forms a with the β-lactam carbonyl carbon. This acylation irreversibly inhibits the transpeptidase activity of the PBP, preventing the cross-linking of strands. The simplified reaction can be represented as: Cephalosporin+PBP→Acylated PBP (inactive)+H2O\text{Cephalosporin} + \text{PBP} \rightarrow \text{Acylated PBP (inactive)} + \text{H}_2\text{O} As a result of PBP inhibition, uncross-linked precursors accumulate in the periplasmic space, weakening the and activating autolytic enzymes that degrade the existing structure. This leads to osmotic instability and eventual bacterial cell and death. Cephalosporins exhibit time-dependent killing, where efficacy correlates more with the duration of exposure above the rather than peak concentration.

Spectrum of Activity Fundamentals

Cephalosporins exhibit strong antibacterial activity against many , primarily through their binding to (PBPs) essential for synthesis. This interaction is particularly effective against staphylococci and streptococci, where cephalosporins acylate PBPs 1, 2, and 3, leading to inhibition of cross-linking and subsequent bacterial . However, their efficacy is notably weaker against enterococci due to the low affinity of cephalosporins for enterococcal PBPs, especially PBP5, which results in intrinsic resistance and limits clinical utility against these organisms. In , cephalosporin activity is more variable and depends on penetration through the outer membrane via porin channels such as OmpF and OmpC, which allow access to periplasmic PBPs. Early cephalosporins demonstrate reliable coverage against common like and species by binding to their PBPs, but they generally lack activity against owing to poor porin penetration and intrinsic resistance mechanisms in this pathogen. Cephalosporins have limited inherent activity against anaerobes, as many anaerobic species produce cephalosporinases that hydrolyze the beta-lactam ring, rendering the drugs ineffective against pathogens like . They also offer no coverage against such as or viruses, since these lack the targeted by cephalosporins' . Furthermore, susceptibility to beta-lactamases, including plasmid-mediated enzymes like TEM-1, significantly reduces cephalosporin efficacy by hydrolyzing the beta-lactam core, particularly in early variants, and contributes to widespread resistance among both Gram-positive and Gram-negative pathogens.

Pharmacokinetics

Absorption and Distribution

Cephalosporins exhibit variable oral absorption depending on the specific agent and generation, with first-generation compounds like cephalexin demonstrating high of approximately 90-95% following . This rapid absorption occurs primarily in the and is minimally affected by gastric pH or food intake, allowing cephalexin to be administered with or without meals due to its acid stability. In contrast, some second- and third-generation oral cephalosporins, such as or , show bioavailabilities ranging from 50-80%, with food potentially delaying the rate of absorption but not substantially reducing the extent. Parenteral administration via intravenous (IV) or intramuscular (IM) routes achieves complete of 100%, bypassing gastrointestinal barriers and enabling rapid . Once in the bloodstream, cephalosporins distribute primarily to extracellular fluids, including interstitial spaces in tissues such as lungs, kidneys, and soft tissues, due to their hydrophilic nature. The volume of distribution is typically low, ranging from 0.2 to 0.4 L/kg across most agents, reflecting limited penetration into cells and . Protein binding of cephalosporins varies widely from 5% to 90%, influencing the concentration of free, pharmacologically active available for distribution. First-generation agents like cephalexin exhibit low binding (around 15%), promoting higher free fractions, while third-generation cephalosporins such as show high binding (85-95%), which can prolong their but may limit tissue availability. Tissue penetration is generally good into , , and pleural spaces, but cerebrospinal fluid (CSF) access is poor under normal conditions (less than 5% penetration); however, in inflamed during , third-generation agents like achieve 15-30% CSF-to-serum ratios, enabling effective treatment.

Metabolism, Excretion, and Half-Life

Cephalosporins generally undergo minimal hepatic metabolism, with the majority of the administered dose excreted unchanged by the kidneys. This limited contributes to their predictable and reduces the risk of active metabolites accumulating. Exceptions include certain third-generation agents like cefoperazone, which exhibits significant biliary , accounting for about 70% of the dose depending on hepatic function, making it suitable for hepatobiliary infections. The primary route of elimination for most cephalosporins is renal, involving both glomerular filtration and active tubular secretion. Typically, 60-90% of the unchanged drug is recovered in the urine within 6-24 hours post-administration, with variations across generations; for instance, first-generation agents like cephalexin achieve nearly 90% urinary recovery. In patients with normal renal function, this efficient clearance ensures rapid elimination, but dosage adjustments are necessary in (CKD) to prevent accumulation. Half-lives of cephalosporins vary by and individual factors, generally ranging from 0.5 to 2 hours in patients with normal renal function, allowing for multiple daily dosing in most cases. For example, the first-generation cefazolin has a serum of approximately 1.8 hours following intravenous administration. Fifth-generation agents like ceftaroline exhibit slightly prolonged half-lives of about 2.6 hours, supporting twice-daily regimens. Renal impairment significantly extends these durations; in anuric patients, ceftriaxone's half-life can increase to 11.4-15.7 hours, necessitating dose reductions in CKD stages 3-5 to maintain therapeutic levels without .

Classification

First-Generation Cephalosporins

First-generation cephalosporins represent the initial class of semisynthetic derivatives developed from the natural antibiotic cephalosporin C, featuring a core β-lactam ring fused to a dihydrothiazine ring with relatively simple modifications at the 7-acylamino side chain, such as phenylacetyl or tetrazolylacetyl groups, which confer their basic pharmacological properties. These agents were introduced in the 1960s and 1970s, prioritizing activity against while offering modest expansion to select Gram-negatives compared to penicillins. Prominent examples include , an intravenous formulation commonly employed for surgical prophylaxis to prevent postoperative infections, and cephalexin, an oral agent frequently used for treating uncomplicated skin and soft tissue infections such as or . Other notable drugs in this class are cephalothin, cephapirin, cephradine, and , which share similar structural simplicity and are administered via oral or parenteral routes depending on the clinical need. Their straightforward acyl side chains, lacking the complex substitutions seen in later generations, contribute to favorable and profiles. The antimicrobial spectrum of first-generation cephalosporins is narrow, with excellent activity against Gram-positive organisms including methicillin-susceptible Staphylococcus aureus (MSSA) and various streptococci species, such as Streptococcus pyogenes and Streptococcus pneumoniae. Coverage against Gram-negative bacteria is limited to certain Enterobacterales, notably Escherichia coli and Proteus mirabilis, but extends minimally to Klebsiella pneumoniae in susceptible strains. These drugs offer several advantages, including low cost, which makes them accessible for routine clinical use, and good tissue penetration into sites like , , and , enhancing their utility in targeted infections. Additionally, they demonstrate stability against some staphylococcal beta-lactamases produced by S. aureus, allowing effective treatment of beta-lactamase-positive strains without the need for inhibitors. Limitations include a lack of coverage against Pseudomonas species and anaerobic bacteria, restricting their application in polymicrobial or complex infections. Typical minimum inhibitory concentrations (MICs) for susceptible S. aureus are ≤2 μg/mL, underscoring their potency against targeted pathogens but highlighting vulnerability to resistance mechanisms like methicillin resistance.

Second-Generation Cephalosporins

Second-generation cephalosporins represent an advancement over first-generation agents by offering enhanced activity against certain Gram-negative bacteria and, in some cases, anaerobes, while maintaining good coverage of Gram-positive organisms. These antibiotics are particularly effective against pathogens such as Haemophilus influenzae and Moraxella catarrhalis, which are common in respiratory tract infections. Key examples include cefuroxime, available in both oral and intravenous formulations and commonly used for treating respiratory infections, and cefoxitin, an intravenous agent noted for its anaerobic activity. The spectrum of activity for second-generation cephalosporins includes improved efficacy against Gram-negative aerobes like H. influenzae, with minimum inhibitory concentrations (MICs) for typically ranging from 1 to 4 μg/mL against susceptible strains. Certain members also provide coverage against anaerobes, particularly through the subclass, which targets species; for instance, demonstrates high activity against , inhibiting 82% of isolates at concentrations of 16 μg/mL or less. This expanded coverage makes them suitable for mixed infections involving both aerobes and anaerobes, such as intra-abdominal or pelvic infections. Structurally, second-generation cephalosporins feature modifications at the 7-position of the beta-lactam ring that enhance resistance to beta-lactamases produced by some . In the cephamycin subclass, exemplified by and , a 7-α-methoxy group is incorporated, which sterically hinders enzymatic and contributes to their stability against beta-lactamases. True cephalosporins in this generation, such as and , lack this but achieve similar resistance through alternative side-chain alterations. These subclasses—true cephalosporins versus s—distinguish variations in anaerobic potency, with cephamycins generally offering superior activity against spp.

Third-Generation Cephalosporins

Third-generation cephalosporins represent an advancement in the cephalosporin class, characterized by expanded activity against Gram-negative bacteria while retaining moderate efficacy against some Gram-positive organisms. These agents are particularly valued for treating serious infections caused by Enterobacteriaceae and Neisseria species, offering deeper penetration into Gram-negative pathogens compared to second-generation counterparts. Their design includes structural modifications, such as increased polarity at the 7-position side chain, which enhance outer membrane permeability in Gram-negative bacteria. Prominent examples include and , both of which exhibit long half-lives enabling convenient dosing regimens for infections. , with a half-life of 6 to 9 hours, is administered once daily via intravenous route and is a mainstay for bacterial due to its excellent penetration. , featuring a half-life of approximately 1 hour but effective in divided doses, is similarly preferred for CNS infections like caused by susceptible pathogens. Ceftazidime stands out among this generation for its specific utility against certain resistant strains, though the class generally shows reduced activity against except in this case. The spectrum of activity emphasizes broad coverage of , including (e.g., , ) and species (e.g., N. gonorrhoeae, N. meningitidis), with some preserved affinity for in Gram-positive cocci like , albeit diminished relative to first-generation agents. These drugs demonstrate high stability against many beta-lactamases produced by , conferring resistance to by common enzymes such as those from . For instance, the (MIC) of against susceptible N. gonorrhoeae strains is typically below 0.25 μg/mL, underscoring its potency in gonococcal infections. In clinical practice, third-generation cephalosporins are often selected as preferred agents for empirical therapy of community-acquired infections, such as or urinary tract infections, where Gram-negative pathogens predominate in outpatient or early settings. This preference stems from their balanced profile against common isolates, aiding timely intervention before culture results are available.

Fourth-Generation Cephalosporins

Fourth-generation cephalosporins represent an advancement in the cephalosporin class, characterized by their broad-spectrum activity that balances enhanced Gram-negative coverage with restored potency against Gram-positive bacteria, while offering improved stability against certain beta-lactamases. Key representatives include cefepime and cefpirome, both administered intravenously for serious infections such as febrile neutropenia in immunocompromised patients. Cefepime, in particular, is frequently used as empirical therapy in hospital settings for its rapid bactericidal effects against pathogens like Pseudomonas aeruginosa. These agents feature zwitterionic structures, with a positively charged quaternary ammonium group on the acyl side chain that confers a net neutral charge, facilitating faster penetration through the outer membrane of Gram-negative bacteria compared to earlier generations. This structural feature enhances their overall stability and efficacy in diverse clinical scenarios. The spectrum of activity for fourth-generation cephalosporins encompasses a wide range of Gram-negative organisms, including Pseudomonas aeruginosa and Enterobacteriaceae, alongside Gram-positive pathogens such as methicillin-susceptible Staphylococcus aureus (MSSA), staphylococci, and Streptococcus species. This balanced profile arises from their ability to bind multiple penicillin-binding proteins (PBPs), particularly PBP2 and PBP3 in Gram-negative bacteria, which restores Gram-positive activity diminished in third-generation agents while maintaining strong anti-Pseudomonal effects. Cefpirome similarly demonstrates potent activity against Enterobacteriaceae, S. aureus, and P. aeruginosa, making it suitable for moderate to severe nosocomial infections. For instance, against P. aeruginosa, cefepime exhibits minimum inhibitory concentrations (MICs) typically ranging from 0.75 to 16 μg/mL, with an MIC90 of 8 μg/mL in clinical isolates, underscoring its utility in treating susceptible strains. A primary advantage of fourth-generation cephalosporins is their resistance to hydrolysis by AmpC beta-lactamases, produced by certain and species, due to the zwitterionic configuration and side-chain modifications that reduce enzymatic degradation. Cefepime, as a weak inducer of AmpC enzymes, withstands effectively, providing reliable activity against AmpC-derepressed strains where third-generation cephalosporins fail. However, limitations include the absence of oral formulations, restricting their use to parenteral administration in hospital or outpatient infusion settings. Additionally, emerging concerns with extended-spectrum beta-lactamase (ESBL)-producing organisms have been noted, as some ESBL variants can hydrolyze these agents, potentially compromising efficacy in regions with high resistance prevalence.

Fifth-Generation Cephalosporins

Fifth-generation cephalosporins are a class of β-lactam antibiotics distinguished by their enhanced activity against (MRSA) and certain multidrug-resistant , addressing gaps in coverage from prior generations. These agents were developed to combat evolving bacterial resistance, with key representatives including ceftaroline, , and , each approved by regulatory agencies between 2010 and 2024 for specific severe infections. Their mechanism involves binding to (PBPs), including PBP2a in MRSA, which restores bactericidal activity against strains resistant to earlier cephalosporins. Ceftaroline fosamil, the first fifth-generation cephalosporin approved by the U.S. Food and Drug Administration (FDA) in 2010, is indicated for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) in adults and pediatric patients. It exhibits potent activity against Gram-positive pathogens, including MRSA and vancomycin-intermediate S. aureus (VISA), with minimum inhibitory concentrations (MICs) typically ranging from 0.5 to 1 μg/mL for MRSA isolates. Against Gram-negatives, ceftaroline covers common respiratory and skin pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, but shows reduced efficacy against extended-spectrum β-lactamase (ESBL)-producing Enterobacterales and lacks reliable activity against Pseudomonas aeruginosa or carbapenemase producers. Administered intravenously, ceftaroline's prodrug form enhances solubility, allowing for once- or twice-daily dosing in clinical practice. Ceftobiprole medocaril, approved by the European Medicines Agency (EMA) in 2008 and by the FDA in April 2024 as Zevtera, expands treatment options for S. aureus bacteremia (SAB), including right-sided endocarditis, ABSSSI, and CABP in adults. This intravenous agent demonstrates broad-spectrum coverage similar to ceftaroline, with strong anti-MRSA activity (FDA breakpoint ≤2 μg/mL for S. aureus) and efficacy against VISA, while also targeting Gram-negatives like Enterobacterales and some non-fermenters including P. aeruginosa. In preclinical models of osteomyelitis, ceftobiprole cleared MRSA infections where MICs were ≤1 μg/mL, highlighting its bactericidal potential in deep-seated infections. Unlike earlier cephalosporins, ceftobiprole's dual affinity for PBP2a and other PBPs enables its role in monotherapy for complicated infections previously requiring combination therapy. Cefiderocol, approved by the FDA in 2019, represents a novel subclass of fifth-generation cephalosporins utilizing a cephalosporin mechanism to actively transport the drug into via iron uptake pathways, enhancing penetration in multidrug-resistant (MDR) strains. It is indicated for complicated urinary tract infections (cUTIs) and hospital-acquired or ventilator-associated (HABP/VABP) caused by susceptible Gram-negatives, including carbapenem-resistant Enterobacterales, , and P. aeruginosa. Cefiderocol's spectrum focuses on MDR Gram-negatives, with MIC90 values of 0.5–4 μg/mL for Enterobacterales, but it has limited Gram-positive coverage, including weaker activity against MRSA compared to ceftaroline or . This agent's stability against many β-lactamases, including metallo-β-lactamases, positions it as a key option for infections resistant to , though it is reserved for cases where alternatives are unsuitable due to resistance patterns.

Naming Conventions and Comparative Table

Cephalosporins follow (INN) conventions established by the , employing the stem "cef-" to denote derivatives of 7-aminocephalosporanic acid used as systemic antibiotics. Earlier first-generation agents, particularly oral formulations, may retain the "ceph-" prefix, as seen in cephalexin, while parenteral and later-generation drugs uniformly use "cef-". Generation-specific naming patterns are not rigidly standardized but often provide mnemonic cues; for instance, third-generation cephalosporins frequently incorporate elements like "tri-" (e.g., ) or "tax-" (e.g., ) to reflect their expanded spectrum. These naming conventions facilitate identification of antimicrobial profiles, with generations broadly classified by evolving spectrum of activity, beta-lactamase resistance, and clinical applications. The following table compares the five generations, highlighting key examples, coverage against Gram-positive and (qualitatively based on typical minimum inhibitory concentrations, or MICs, where low MIC indicates good activity, e.g., ≤2 μg/mL for susceptible strains), stability to (including extended-spectrum beta-lactamases, or ESBLs), and primary uses. Data are derived from established pharmacological reviews.
GenerationKey ExamplesGram-Positive CoverageGram-Negative CoverageBeta-Lactamase StabilityCommon Uses
FirstCefazolin, CephalexinExcellent (low MICs against MSSA, streptococci; e.g., MIC90 0.5–2 μg/mL for S. aureus)Poor (high MICs against most Enterobacteriaceae; limited to some E. coli)Low (hydrolyzed by penicillinases and early beta-lactamases)Surgical prophylaxis, uncomplicated skin/soft tissue infections, urinary tract infections
SecondCefuroxime, CefoxitinGood (moderate MICs against MSSA, streptococci; reduced vs. first generation)Moderate (improved MICs against H. influenzae, Moraxella; e.g., MIC90 1–4 μg/mL for E. coli)Moderate (resistant to some plasmid-mediated beta-lactamases; variable anaerobes)Respiratory tract infections, intra-abdominal infections, gonorrhea
ThirdCeftriaxone, CefotaximeFair (higher MICs against staphylococci; good for streptococci)Excellent (low MICs against Enterobacteriaceae, Neisseria; e.g., MIC90 0.03–0.5 μg/mL for E. coli)High against chromosomal beta-lactamases; low against ESBLsMeningitis, serious Gram-negative infections, gonorrhea, Lyme disease
FourthCefepimeGood (low-moderate MICs against MSSA, streptococci; restored vs. third)Excellent (broad, including Pseudomonas; e.g., MIC90 0.5–8 μg/mL for P. aeruginosa)High (stable to AmpC and extended-spectrum enzymes)Febrile neutropenia, hospital-acquired pneumonia, intra-abdominal infections
FifthCeftarolineExcellent (low MICs against MRSA, streptococci; e.g., MIC90 0.5–1 μg/mL for MRSA)Good (moderate MICs against Enterobacteriaceae; limited Pseudomonas)High (resistant to ESBLs and MRSA-specific enzymes)Community-acquired pneumonia, complicated skin infections (including MRSA)
Fifth-generation agents represent the most recent standard classification, emphasizing anti-MRSA activity through structural modifications. An advanced cephalosporin, , exploits bacterial iron transport systems for enhanced Gram-negative penetration and stability against carbapenemases, positioning it as a "sixth-like" agent for multidrug-resistant infections, though not formally classified as such.

Medical Uses

Primary Indications

Cephalosporins serve as first-line or empirical therapy in numerous clinical scenarios due to their broad-spectrum activity against gram-positive and . They are particularly valued in settings requiring rapid initiation of treatment to prevent complications, such as surgical site infections or severe community-acquired infections. Selection often depends on the generation, with first-generation agents favored for gram-positive coverage and higher generations for enhanced gram-negative activity. In surgical prophylaxis, first-generation cephalosporins like are recommended as the primary agent for the majority of procedures, including cardiac, orthopedic, and gastrointestinal surgeries to reduce postoperative infection risk. These guidelines emphasize timely administration to optimize efficacy while minimizing resistance development. For community-acquired infections, cephalosporins are commonly employed in uncomplicated cases. Oral cephalexin, a first-generation agent, is indicated for mild skin and soft tissue infections caused by methicillin-sensitive or streptococci, as per guidelines for non-purulent . Third-generation options like are alternatives for acute uncomplicated cystitis in patients unable to tolerate preferred therapies, providing effective coverage against common uropathogens. In respiratory tract infections, second-generation is used empirically for in outpatient settings with moderate severity, targeting and . In hospital settings, cephalosporins play a key role in managing serious infections. Ceftriaxone, a third-generation cephalosporin, is the empirical choice for bacterial in adults and children, offering broad coverage against likely pathogens like and . For intra-abdominal infections, second-generation is recommended as monotherapy for mild-to-moderate community-acquired cases, effective against anaerobes and enteric gram-negatives. In or , fourth-generation cefepime is often selected for in high-risk patients, providing antipseudomonal activity in hospital-acquired scenarios. Special indications include , where intravenous is preferred for neurologic manifestations such as or , ensuring penetration into the . For , remains the standard single-dose treatment for uncomplicated urogenital, rectal, and pharyngeal infections, addressing rising resistance concerns. As of 2025, the IDSA has updated UTI guidelines to simplify definitions, confining uncomplicated cases to infections, while WHO guidelines reaffirm for empiric treatment. Current IDSA and WHO guidelines, as of 2025, underscore the importance of to narrower-spectrum agents once results are available, promoting antimicrobial stewardship to curb resistance while maintaining efficacy.

Administration and Dosing Considerations

Cephalosporins are administered via oral, intravenous (IV), or intramuscular () routes, depending on the generation and the specific agent. First- and second-generation cephalosporins, such as cephalexin and , are commonly given orally at doses of 250-500 mg every 6-12 hours for adults with mild to moderate infections. Third- through fifth-generation agents, like and cefepime, are primarily administered IV or IM due to their broader spectrum and need for higher , with typical adult doses ranging from 1-2 g daily for . Dosing regimens are tailored to infection severity, patient age, and weight. In pediatric patients, doses are weight-based, often 25-50 mg/kg/day divided every 6-12 hours for first-generation agents in mild infections, increasing to 50-100 mg/kg/day for severe cases. For example, cefazolin is dosed at 50-100 mg/kg/day IV in children, divided every 8 hours. Renal function significantly influences dosing, as cephalosporins are primarily excreted by the kidneys. Adjustments are recommended when creatinine clearance (CrCl) falls below 50 mL/min; for instance, with CrCl <30 mL/min, doses may be halved or intervals extended, such as reducing cephalexin to 250-500 mg every 12-24 hours. In severe impairment (CrCl <10 mL/min), further reductions or monitoring are advised to prevent accumulation. Drug interactions can alter cephalosporin and efficacy. Probenecid inhibits renal tubular secretion, prolonging and increasing serum levels of most cephalosporins, which may allow for dose reduction in some cases. Concurrent use with aminoglycosides provides synergistic antibacterial activity but heightens risk, necessitating close renal function monitoring. Certain agents like contain a methylthiotetrazole that can induce a disulfiram-like reaction with alcohol, causing flushing, , and if consumed within 72 hours of administration. Therapeutic drug monitoring is not routinely required for cephalosporins due to their favorable safety profile but may be beneficial in obese patients or those who are critically ill, where altered can lead to subtherapeutic levels or . In such scenarios, plasma concentrations are assessed to guide adjustments, particularly for extended-spectrum agents.

Adverse Effects

Common and Gastrointestinal Effects

Common adverse effects of cephalosporins primarily involve the , with symptoms such as , , , and occurring in 1% to 10% of patients. These effects are typically mild and self-limiting, contributing to an overall rate of approximately 5% in outpatient settings based on real-world data from therapy. Gastrointestinal disturbances are more frequent with oral formulations due to direct exposure of the gut mucosa. The mechanisms underlying these effects include direct of the gastrointestinal lining by the and disruption of the normal gut , which alters bacterial balance and promotes osmotic or motility changes. For instance, broad-spectrum cephalosporins can reduce beneficial anaerobes, leading to overgrowth of opportunistic pathogens and subsequent symptoms like loose stools. Management strategies focus on supportive care, such as administering doses with food to mitigate and spacing administrations to reduce peak concentrations in the gut. , including strains like and , have been shown to prevent antibiotic-associated by restoring microbial diversity, with meta-analyses indicating a of about 50% in affected patients. Rare superinfections, such as oral or vaginal , may require treatment if symptoms persist. Cephalosporins have been associated with an elevated risk of Clostridium difficile in susceptible individuals.

Hypersensitivity Reactions

Hypersensitivity reactions to cephalosporins encompass both immediate IgE-mediated responses and delayed T-cell-mediated reactions, with the former posing risks of severe outcomes such as and urticaria. IgE-mediated reactions typically manifest within minutes to hours of exposure and occur in approximately 1-3% of patients receiving cephalosporins, though is rarer at less than 0.1% of exposures. Fatal is exceptionally uncommon, with an incidence of 0.0001% (0.1 cases per 100,000 exposures). T-cell-mediated reactions, often presenting as maculopapular rashes, affect 1-3% of exposed individuals and develop days after administration. Cross-reactivity between cephalosporins and penicillins occurs in 1-10% of cases among penicillin-allergic patients, largely attributable to structural similarities in the R1 of the beta-lactam ring. This risk diminishes for second- and later-generation cephalosporins, where divergent R1 s reduce the likelihood of shared epitopes, often lowering to around 2%. A allergy elevates the odds of cephalosporin by 2- to 3-fold, making prior beta-lactam reactions a key risk factor. Other contributors include female sex and advanced age, though these are less pronounced. Diagnostic evaluation for suspected cephalosporin hypersensitivity relies on detailed history assessment followed by skin prick and intradermal testing using major determinants like benzylpenicilloyl poly-L-lysine, particularly for immediate reactions. If skin tests are negative, graded drug provocation testing is recommended to confirm tolerance. Delabeling protocols, outlined in the 2023 Australasian Society of Clinical Immunology and Allergy (ASCIA) consensus and aligned with American Academy of Allergy, Asthma & Immunology (AAAAI) guidelines, emphasize proactive evaluation to verify true , as many reported reactions are non-immunologic and safe re-administration is feasible in over 90% of cases. This approach mitigates unnecessary avoidance and supports appropriate stewardship.

Specific Toxicities and Risks

Certain cephalosporins, particularly second-generation agents such as cefamandole, cefoperazone, and moxalactam, contain an N-methylthiotetrazole (NMTT or MTT) at the 3-position of the beta-lactam ring, which is associated with hypoprothrombinemia through inhibition of in the liver, thereby disrupting the recycling of and impairing the synthesis of vitamin K-dependent clotting factors II, VII, IX, and X. This manifests as prolonged and increased bleeding risk, with an incidence of 10-30% reported in patients receiving high doses, especially those with , renal impairment, or concurrent . Prophylactic vitamin K supplementation is often recommended for at-risk patients to mitigate this effect. Cephalosporins pose a risk for (CDI), comparable to other beta-lactam antibiotics, due to their disruption of the and selection for toxin-producing strains, with an overall incidence of approximately 7-8 cases per 10,000 patient-days in hospitalized settings. Third-generation cephalosporins, owing to their broad-spectrum activity, are associated with a heightened CDI risk compared to narrower-spectrum agents, contributing to outbreaks in healthcare facilities where their use is prevalent. Other rare non-allergic toxicities include with high-dose cefepime, occurring in less than 1% of cases and typically reversible upon discontinuation, particularly when combined with other nephrotoxic agents like . Cefepime has been linked to seizures and in patients with renal failure, where drug accumulation exceeds safe plasma levels, with reported in up to 23% of such high-risk cases but generally resolving with dose adjustment or . Hematologic effects, such as (1-3%) and transient thrombocytosis, are occasionally observed and typically benign. Recent studies from 2022 have highlighted that prolonged cephalosporin use induces significant intestinal , characterized by reduced bacterial diversity and overgrowth of pathogenic taxa, which can exacerbate and increase susceptibility to secondary infections in animal models. This persists beyond treatment cessation, underscoring the need for to limit extended courses.

Antimicrobial Resistance

Bacterial Resistance Mechanisms

Bacteria evade cephalosporins through several molecular mechanisms that disrupt the antibiotic's ability to inhibit cell wall synthesis. The most prevalent is the production of , enzymes that hydrolyze the beta-lactam ring in cephalosporins, rendering them inactive. Extended-spectrum (ESBLs), particularly CTX-M variants, are serine-based enzymes that efficiently hydrolyze third- and fourth-generation cephalosporins, such as and , leading to resistance in including and . AmpC , which can be chromosomally encoded or plasmid-mediated, also hydrolyze cephalosporins, especially second- and third-generation agents, and are commonly found in species like , , and . , such as Klebsiella pneumoniae carbapenemase (KPC), a class A serine , further extend this hydrolysis to include advanced cephalosporins and , contributing to severe resistance in Gram-negative pathogens. Alterations in (PBPs), the molecular targets of cephalosporins, represent another key resistance strategy. In methicillin-resistant Staphylococcus aureus (MRSA), the acquisition of the gene encodes PBP2a, a low-affinity PBP with a modified that prevents effective binding by most beta-lactams, including cephalosporins, thereby allowing continued cross-linking during synthesis. This mechanism confers high-level resistance to first- through fourth-generation cephalosporins in MRSA strains. Fifth-generation cephalosporins, such as ceftaroline and , were developed to overcome this by exhibiting higher affinity for PBP2a, though mutations in PBP2a can further reduce their efficacy. In , resistance is frequently augmented by impaired drug influx and active efflux. Loss of outer membrane porins, such as OprD in P. aeruginosa, restricts the entry of cephalosporins into the periplasmic space, where PBPs are located; mutations including deletions, insertions, or downregulation of OprD can increase minimum inhibitory concentrations (MICs) for agents like cefepime and ceftazidime by reducing permeability. Concurrently, efflux pumps like the MexAB-OprM system in and AcrAB-TolC in actively expel cephalosporins from the cell, lowering intracellular concentrations and synergizing with production to elevate resistance levels. These non-enzymatic mechanisms are particularly prominent in environmental and nosocomial isolates of Gram-negatives. Biofilm formation provides an additional layer of tolerance to cephalosporins by encasing bacterial communities in an extracellular matrix of polysaccharides, proteins, and extracellular DNA, which physically impedes antibiotic diffusion and binds cephalosporins, reducing their bioavailability at target sites. Within biofilms, persister cells exhibit metabolic dormancy, rendering them insensitive to cephalosporins that rely on active cell processes for lethality, and can survive exposures up to 1,000-fold higher than planktonic cells. Biofilms also accelerate the horizontal transfer of resistance determinants, such as ESBL-encoding plasmids, through enhanced conjugation rates—up to 16,000-fold greater than in free-floating bacteria—facilitating rapid dissemination; for instance, blaCTX-M genes on conjugative plasmids drive ESBL spread in E. coli. Recent 2024 surveillance data highlight this dissemination, reporting ESBL production in 54.8% of clinical E. coli isolates from northeastern Thailand, predominantly via plasmid-mediated mechanisms.

Clinical Implications and Strategies

The increasing prevalence of to cephalosporins poses significant challenges in clinical settings, particularly among . According to the World Health Organization's Global Antibiotic Resistance Surveillance Report 2025, more than 40% of infections and over 55% of infections worldwide are resistant to third-generation cephalosporins, with resistance rates exceeding 30% in hospital-acquired infections across multiple regions. This trend has prompted a shift in treatment paradigms for methicillin-resistant Staphylococcus aureus (MRSA), where earlier cephalosporin generations are ineffective, leading to greater reliance on fifth-generation agents like ceftaroline and , which retain activity against MRSA strains. Clinically, cephalosporin resistance contributes to higher rates of treatment failure and increased mortality. Infections caused by extended-spectrum beta-lactamase (ESBL)-producing organisms, which confer resistance to third- and fourth-generation cephalosporins, are associated with a relative risk of all-cause mortality 1.7 times higher than non-ESBL infections in bacteremia cases, equating to substantially elevated fatality rates—often exceeding 30% in severe cases. For instance, inappropriate empirical use of cephalosporins in ESBL infections can lead to delays in effective therapy, necessitating combination regimens such as cephalosporins with inhibitors or alternatives like aminoglycosides to improve outcomes. To mitigate these implications, key strategies include antimicrobial stewardship programs, which promote judicious use of cephalosporins through guidelines like those from the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). These programs emphasize routine susceptibility testing with updated breakpoints—for example, EUCAST's lower thresholds for third-generation cephalosporins against —to guide therapy and reduce selective pressure for resistance. When resistance is suspected, alternatives such as (e.g., ) or cephalosporin-beta-lactamase inhibitor combinations (e.g., ceftazidime-avibactam) are recommended for ESBL-producing Gram-negatives, with evidence showing improved clinical success rates in settings. Looking ahead, ongoing research focuses on innovative approaches to combat cephalosporin resistance. Vaccine development targets prevalent resistant pathogens, with candidates like vaccines against K. pneumoniae outer membrane proteins showing promise in preclinical trials since 2020, such as murine models demonstrating protection against . trials, particularly for multidrug-resistant Gram-negatives post-2020, have shown promise in compassionate-use cases and phase II studies, achieving microbiological clearance in over 70% of treated patients with cephalosporin-resistant infections. Surveillance initiatives, such as WHO's Global Antimicrobial Resistance and Use Surveillance System (), continue to track resistance trends, informing global policies to curb the spread.

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