Third Generation Cephalosporins

Continuing Education Activity

Third-generation cephalosporins are medications used in the management and treatment of gram-negative and gram-positive organisms. They are in the beta-lactam class of drugs. This activity describes the indications, action, and contraindications for third-generation cephalosporins as a valuable agent in the management of gram-negative meningitis, Lyme disease, Pseudomonas pneumonia, gram-negative sepsis, Streptococcal endocarditis, melioidosis, penicillinase-producing Neisseria gonorrhea, chancroid, and gram-negative osteomyelitis. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional healthcare team in the treatment of patients with gram-positive and gram-negative infections and related conditions.


  • Identify the mechanism of action of third-generation cephalosporins.
  • Describe the adverse effects and contraindications of third-generation cephalosporins.
  • Review the toxicity of third-generation cephalosporins.
  • Summarize interprofessional team strategies for improving care coordination and communication to advance third-generation cephalosporins, and improve outcomes, including antibiotic stewardship and how it affects antimicrobial selection as it pertains to improving care coordination among the interprofessional team when initiating antibiotic therapy with third-generation cephalosporins.


Cephalosporins, along with penicillin, belong to the beta-lactam group of bactericidal antibiotics.[1] Based on the timeline of drug discovery and their antimicrobial properties, these antibiotic agents are grouped into different generations, first through fifth.[2] In general, as we move from first to third, the microbicidal activity of cephalosporins decreases against gram-positive organisms but increase against gram-negative bacilli. Furthermore, the resistance against beta-lactamases increases from first to fifth generations.[3]

In terms of antibacterial activity, the first-generation cephalosporins are solely active against gram-positive organisms, and second-generation has improved activity against gram-negative and some anaerobes but less activity against gram-positive microbes. On the contrary, the third-generation cephalosporins are broad-spectrum antimicrobial agents with activity against both gram-negative and gram-positive organisms. Nevertheless, they are more active against gram-negative bacteria and organisms that are resistant to the first and second regeneration cephalosporins. Furthermore, these agents seem to be less active against several gram-positive bacteria, such as Streptococcus and Staphylococcus species.

Third-generation cephalosporins show more stability to beta-lactamases than first or second generations, especially those produced by Klebsiella, Haemophilus influenzae, and Escherichia coli. As an empiric therapy, third-generation cephalosporins include indications for central nervous system (CNS) infections, including meningitis as they can cross the blood-brain barrier, genitourinary tract infections, bone and joint infections, community-acquired pneumonia, and skin and soft tissue Infections.

For specific therapy, they are active against gram-negative meningitis, Lyme disease, Pseudomonas pneumonia, gram-negative sepsis, Streptococcal endocarditis, melioidosis, penicillinase-producing Neisseria gonorrhea, chancroid, and gram-negative osteomyelitis.[4] Of note, third-generation cephalosporins are usually not active against Chlamydia trachomatis.[5]

These compounds are also useful in combination with other groups of antibiotics such as penicillins, aminoglycosides, quinolones, or beta-lactamase inhibitors. For example, the ceftazidime-avibactam combination has been used successfully in infections with Enterobacteriaceae infections, intra-abdominal and urinary tract infections, sepsis, pneumonia, and respiratory infections by Pseudomonas aeruginosa in cystic fibrosis patients.[6][7][8][9]  Ceftriaxone, combined with azithromycin, is the first-line treatment against gonorrhea.[10] Cefotaxime or ceftriaxone is given along with vancomycin for bacterial meningitis as empirical treatment, but also covers most of the specific organisms implicated in this pathology.[11]

The fourth-generation cephalosporins, while retaining their activity against gram-negative like third-generation, also have improved gram-positive activity. The novel fifth-generation cephalosporins are active against methicillin-resistant Staphylococcus aureus (MRSA) and various other beta-lactamase-producing organisms.[12]

Mechanism of Action

Peptidoglycans are the exoskeleton of bacteria that provides structural integrity and shape to the cells and protects them from bursting out.[13] Peptidoglycans are cross-linked in the final step of bacterial cell wall synthesis to make peptidoglycan polymers with the help of membrane-anchored enzymes (i.e., transpeptidases, carboxypeptidases, and endopeptidases), collectively called penicillin-binding proteins (PBPs).[14] Most bacteria possess at least one PBP, and they are the target of different beta-lactam antibiotics like cephalosporins, penicillins, carbapenems, and monobactams. The beta-lactam ring structure of third-generation cephalosporins mimics the “D-Ala-D-Ala” moiety of the natural substrate of PBPs. Structural binding of cephalosporin antibiotics to the active site of PBPs in bacterial cell walls leads to inhibition of their enzymatic activity and leads to defective peptidoglycan synthesis; this results in an inability to construct a functional cell wall and subsequent death of the bacterial cells by osmotic lysis.[15]


Third-generation cephalosporins administration can be oral, intramuscular, or intravenous. Well-absorbed oral compounds include: cefixime, ceftibuten, cefdinir, cefpodoxime, and cefditoren and are useful in out-patient settings. Except for ceftibuten and cefdinir, all the oral compounds are esters and are hydrolyzed by esterases in the gastrointestinal tract for absorption.[16] These drugs have high oral bioavailability with established therapeutic plasma concentrations and low potential for toxicity.

Pharmacokinetically, some third-generation compounds are poorly absorbed in the gastrointestinal tract and are administered only intramuscularly or intravenously. These agents are ceftriaxone, ceftazidime, and cefotaxime. Ceftriaxone has high protein binding capacity and has the longest-half life of antibiotics in this generation, administered as a once-daily dose.[17] Ceftazidime is also useful as an inhalational agent in bronchiectasis, ventilator-associated pneumonia, and post-transplant airway infections.[18] There are also documented accounts of intraventricular administration of third-generation cephalosporins in the brain for meningitis.[19]

Cephalosporins have excellent penetration into most body fluids and the extracellular fluid of most tissues, especially in the presence of inflammation (which increases diffusion). Adequate penetrations of third-generation cephalosporins such as cefotaxime and ceftriaxone in cerebrospinal fluid (CSF) are achievable and thus are pharmacokinetically suitable for the treatment of meningitis. Like the other cephalosporin classes, the third-generation agents have poor penetration into the intracellular compartment and vitreous humor. Most cephalosporins are excreted primarily in the urine. Therefore their doses require adjustment in patients with renal insufficiency. Cefoperazone and ceftriaxone, which have significant biliary excretion, do not require dose adjustment, but the FDA discontinued cefoperazone from the market in the USA.[20]

Adverse Effects

As with most beta-lactam antibiotics, third-generation cephalosporins are generally well tolerated and characteristically have a low toxicity profile. However, some toxicity profiles may be particularly severe. For instance, reports exist of coagulopathies leading to bleeding with the use of third-generation cephalosporins. For example, because cefoperazone contains the N-methyl-thio-tetrazole (NMTT) side chain, which inhibits vitamin K-dependent carboxylation, administration of cefoperazone and other NMTT-containing cefalosporins can induce alterations in the hepatic glutathione redox state, an increase in oxidized glutathione, and, in turn, inhibition of microsomal reduction of vitamin K epoxide with hypoprothrombinemia and bleeding.[21] Again, moxalactam, another third-generation cephalosporin, was discontinued from the market for causing fatal bleeding in patients.[22]

Not unlike other classes and subclasses of antibiotics, the use of third-generation cephalosporins may expose the patient to the risk of superinfection. There are also reports of pseudomembranous colitis induced by Clostridium difficile with the use of third-generation cephalosporins.[23]

Hypersensitivity reactions have been noted, though serious allergic reactions are uncommon. Immune-mediated hemolytic anemias and thrombocytopenias are possible, where cephalosporins act as a hapten and may elicit antibody reactions.[24]

Other rare reactions to some third-generation cephalosporins include seizures and disulfiram-like reactions. Concerning neurotoxicity, apart from the well-known epileptogenic activity, cephalosporin-induced neurotoxicity may occur in a variety of clinical presentations, including myoclonus, asterixis, and encephalopathy. The pathogenetic mechanism is not well understood, but it is probably related to the competitive antagonism of gamma-aminobutyric acid (GABA). Although extremely rare, the possibility of a ceftriaxone-induced encephalopathy featuring limb weakness or numbness, memory impairment, and behavioral problems, has been reported.[25] Clinically, the symptoms manifest after 1 to 7 days of antibiotic therapy and usually resolve within 2 to 7 days after discontinuation of the medication. On the other hand, there are no reports of nephrotoxicity with third-generation cephalosporins. Ceftriaxone binds calcium in the bile and can form stones, which eventually lead to biliary pseudolithiasis.[26]

Cephalosporins are in the high-risk category of medications that may cause Steven-johnson syndrome or toxic epidermal necrolysis as this syndrome may occur with cefdinir and ceftriaxone.[27] Other more common but less severe adverse effects include stomach discomfort, nausea or vomiting, diarrhea, fungal infection, rash or itching, and injection site reactions.


Cephalosporins are contraindicated in patients with a known allergy to the cephalosporin group of antibiotics. Moreover, cephalosporins share molecular similarity with penicillins and could lead to allergic reactions in 10% of patients with known allergy to penicillins. Cephalosporins, along with penicillins, are also contraindicated in patients who have a history of severe anaphylactic reactions with these agents.

Ceftriaxone has the affinity for binding to albumin by replacing bilirubin and is contraindicated in jaundiced neonates at risk for bilirubin encephalopathy.[28] Although not contraindicated, considerable attention is necessary while using cephalosporins along with warfarin, as this combination has correlations with an increased risk of bleeding.[29] As a precautionary measure, patients should avoid alcohol consumption while on third-generation agents to avert disulfiram-like reactions. Because third-generation cephalosporins are pregnancy category B medications under the prior FDA rating system, they are not contraindicated in pregnancy.


Before instituting treatment with cephalosporins, clinicians should obtain appropriate specimens for culture and isolation of the causative organism and the determination of its susceptibility to the antibiotics. Therapy may commence before receiving the results of susceptibility testing. Clinicians prescribe oral cephalosporins in the outpatient settings are safe while parenteral agents like ceftriaxone, which get infused intravenously, are always done under a hospital in-patient setting and are subject to active monitoring.

Coagulation profile should be evaluated in patients with a known risk of bleeding while on third-generation cephalosporins.[22] Although cephalosporins are potentially useful in penicillin-allergic patients, they require careful observation for any potential adverse reactions.


This group of cephalosporins does not have any other particular toxicity other than those already mentioned in the adverse effects section. In case of any suspicion of toxicity, appropriate laboratory tests and clinical evaluation should take place on an individual basis, and the decision on withdrawal of the drug and subsequent treatment initiated swiftly.

Enhancing Healthcare Team Outcomes

Effective management of bacterial infection requires increased awareness among physicians for the optimal choice of cephalosporins and the duration and frequency of administration based on their pharmacokinetic and pharmacodynamic profiles. Antibiotic resistance is a global health emergency, and extended-spectrum beta-lactamase-producing organisms that are resistant to third-generation cephalosporins are on the rise, and the use of these agents must be done very cautiously by avoiding unwarranted prescriptions from the side of the physician[30][31][32]. A consult with a microbiologist/infectious disease specialist (e.g., antimicrobial stewardship programs) and a board-certified infectious disease pharmacist regarding the choice of antibiotic for the particular patient, the type of infection at hand, profile of the microorganism elucidated including its sensitivity/resistance patterns, their experience with similar infections in other patients in the hospital or in the region can invariably lead to a better treatment protocol. Nurse practitioners assist in close monitoring of the patients for adverse drug reactions, and immediate withdrawal of the culprit drug can reduce the complexity of management. Indeed, an interprofessional collaboration aimed at the prevention and rapid recognition of cefalosporin-induced toxicity (e.g., neurotoxicity and bleeding) is mandatory, especially in high-risk patients such as the elderly. Pharmacists can assist by avoiding the over-the-counter sale of third-generation cephalosporins as such practices can lead to the development of resistant organisms in the community. They can also ensure the safety of the patients by meticulously evaluating other medications ordered along with that may cause drug-to-drug interactions in a patient. Effective communication between interprofessional teams, hospital supervisory boards/authorities in reporting any newly developed resistant organisms, or peculiar clinical presentation of an infectious pathogen will be worthwhile in tackling the healthcare costs, leads to efficient patient-care and helps the evolution of novel treatment regimes. [Level V]

Finally, but importantly, patient education is also of paramount importance as it is imperative to continue the full course of antibiotics to eradicate the pathogen to improve infection cure rates and avoid the development of any resistance or treatment failures. 

Article Details

Article Author

Vijay Arumugham

Article Editor:

Marco Cascella


3/28/2021 12:59:40 AM



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