Continuing Education Activity

Third-generation cephalosporins are medications used in the management and treatment of gram-negative and gram-positive organisms. They are encompassed among 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.

Objectives:

• Identify the mechanism of action of third-generation cephalosporins.

• Describe the potential adverse effects 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 starting antibiotic therapy with third-generation cephalosporins.

Indications

Cephalosporins, along with penicillin, belong to the beta-lactam group of bactericidal antibiotics.[1] Historically, cephalosporins have been discovered by the Italian scientist Giuseppe Brotzu (1895-1976) in 1945, who isolated a mixture of compounds from the mold Acremonium (previously called Cephalosporium).[2] Later on, in 1955, the British scientists Edward Abraham (1913–1999) and Guy Newton (1919-1969) discovered, purified, and described the structure of cephalosporin C as a minor component of the mixture of antibiotics produced by Acremonium.[3] Cephalosporin C possessed only modest antibacterial activity and was produced in negligible quantities until 1960 when the era of semisynthetic cephalosporins began.

Structurally, these antibiotics contain a six-member dihydrothiazine ring fused to the beta-lactam portion. The substituents at C3, C4, and C7 are key factors for their antimicrobial activity. Furthermore, the carboxyl group at C4 needs to remain unchanged, and the acylamido side chain at C7 (7-aminocephalosporanic nucleus) has a pivotal role in the hydrophilic/hydrophobic features of these compounds.

Cephalosporins are produced by structural modification in the laboratory. Based on the timeline of drug development and their antimicrobial properties, these antibiotic agents are grouped into different generations, first through fifth.[4] The distinction concerns the structure of the molecules and implies important therapeutic implications. In general, moving from the first to the third generation, the microbicidal activity of cephalosporins decreases against gram-positive organisms but increases against gram-negative bacilli. Notably, the resistance against beta-lactamases increases from the first to the fifth generation.[5]

In terms of antibacterial activity, first-generation cephalosporins such as cefadroxil, cefazolin, and cephalexin are solely active against gram-positive organisms. Furthermore, second-generation (e.g., cefaclor, cefotetan, cefamandole, and loracarbef) has improved activity against gram-negative and some anaerobes, although there is less activity against gram-positive microbes.

The third-generation class of cephalosporins is the most commonly prescribed group. These cephalosporins are semisynthetic analogs with different chemical substitutions on the C7 acylamido chain. The class includes ceftriaxone, cefdinir, cefixime, cefixime, cefditoren, cefpodoxime, ceftazidime, cefoperazone, ceftizoxime, ceftibuten, and others. They 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 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. In other words, they are active against some gram-positive strains, although not as active as the first-generation cephalosporins. Interestingly, third-generation cephalosporins show more stability to beta-lactamases than first or second generations, especially those produced by Klebsiella, Haemophilus influenzae, and Escherichia coli. Cefoperazone and ceftazidime are active against Pseudomonas aeruginosa, while the rest of the class is not. Despite the rising prevalence of gram-positive organisms in spontaneous bacterial peritonitis (SBP), third-generation cephalosporins appear to furnish adequate empirical treatment in patients with healthcare-associated and community-acquired SBP without hepatocellular carcinoma.[6]

Agents of this class are used for prophylaxis and/or therapy:

• Prophylaxis: They are recommended for first-line prophylaxis against SBP, biliary infections, neurosurgery-related infections, and post-urologic procedures infections. Moreover, these drugs are recommended as alternative prophylactic antibiotics for neutropenic infections and infective endocarditis.
• Therapy:
  • For Empiric therapy of central nervous system (CNS) infections, including meningitis, as they can cross the blood-brain barrier (BBB), genitourinary tract infections, bone, and joint infections, as well as 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.[7] Of note, third-generation cephalosporins are usually not active against Chlamydia trachomatis.[8]

These compounds are also useful in combination with other antibiotics such as penicillins, aminoglycosides, quinolones, or beta-lactamase inhibitors. For example, the ceftazidime-avibactam combination has been used successfully in Enterobacteriaceae infections, intra-abdominal and urinary tract infections, sepsis, pneumonia, and respiratory infections by Pseudomonas aeruginosa in cystic fibrosis patients.[9][10][11][12] Ceftriaxone, combined with azithromycin, is the first-line treatment against gonorrhea.[13] 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.[14] Finally, combined with amikacin or imipenem, a third-generation cephalosporin can successfully treat the primarily opportunistic infection, Nocardiosis.[15]

In brief, the third-generation cephalosporins are used for:

• Spontaneous bacterial peritonitis [16], although there is increasing resistance to these agents.[17]
• Sexually transmitted infections (gonorrhea, pelvic inflammatory disease, epididymitis, proctitis).
• Moderate-to-severe diabetic foot infections.
• Empiric therapy of acute lower respiratory infections including community-acquired pneumonia (CAP) in adults and children.
• Empiric therapy of CAP in patients requiring intensive care unit (ICU) admission.
• Empiric treatment for suspected infection in Human Immunodeficiency Virus (HIV) patients (outpatients).
• Pyelonephritis.
• Necrotizing fasciitis.
• Lyme disease with CNS involvement and with or without parenchymal involvement.
• Mild to severe intraabdominal infections.
• Encephalitis and meningitis. In general, meningitis caused by Haemophilus influenzae, meningococci, and Enterobacteriaceae can be treated with cefotaxime, ceftriaxone, ceftazidime, or ceftizoxime. Pseudomonas aeruginosa meningitis can be treated with ceftadizime. Pneumococcal meningitis can be treated with cefotaxime, ceftizoxime, or ceftriaxone.
• Febrile neutropenia (ceftazidime).
• Alternative treatment options include syphilis, gonorrhea, acute bacterial rhinosinusitis, endometritis, pharyngitis, uncomplicated cystitis, infectious diarrhea, combat wounds.
• Endoscopic urologic procedures with mucosal trauma, vertebral osteomyelitis, skin and soft tissue infections caused by Nocardia spp., infectious diarrhea caused by Salmonella spp. or Shigella spp., infective endocarditis, and antibiotic locks (once susceptibilities for organisms are known)
• Cefotaxime is the most commonly used third-generation cephalosporin over an aminoglycoside in neonatal early-onset sepsis due to wider therapeutic index, superior cerebrospinal fluid penetration, and lower incidence of nephrotoxicity.[18]

The fourth-generation cephalosporins (e.g., cefepime), while retaining their activity against gram-negative like third-generation, also have improved gram-positive activity. Cefepime is active on many gram-positive and gram-negative strains and is used to treat severe infections such as ICU pneumonia, abdominal infections, sepsis, and meningitidis.[19] The novel fifth-generation cephalosporins such as ceftaroline are active against methicillin-resistant Staphylococcus aureus (MRSA) and various other beta-lactamase-producing organisms such as penicillin-resistant streptococci, and ampicillin-susceptible and beta-lactamase-producing Enterococcus faecalis.[20] On the other hand, ceftaroline is ineffective against Pseudomonas aeruginosa. Ceftolozane/tazobactam and ceftazidime/avibactam are two beta-lactam/beta-lactamase combination antibiotics. They can be useful against multidrug-resistant gram-negative bacteria, including Pseudomonas aeruginosa. Furthermore, ceftazidime/avibactam is also active against carbapenem-resistant Enterobacteriaceae that produce Klebsiella pneumoniae carbapenemases.[21]

Mechanism of Action

Cephalosporins act similarly to beta-lactam antibiotics. They inhibit the synthesis of the bacterial cell wall, in particular of peptidoglycan. Peptidoglycans are the exoskeleton of bacteria that provides structural integrity and shape to the cells and protects them from bursting.[22] These structures 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).[23]

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.[24]

Administration

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 outpatient settings. Except for ceftibuten and cefdinir, all the oral compounds are esters and are hydrolyzed by esterases in the gastrointestinal tract for absorption.[25] 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. The protein binding varies from 17% for ceftazidime to 96% for ceftriaxone. This latter has a high protein binding capacity and the longest-half life among antibiotics in this generation when administered as a once-daily dose.[26] The volume of distribution ranges from 9 L for ceftriaxone to 27 L for cefotaxime.

Cephalosporins have excellent penetration into most body fluids and the extracellular fluid of most tissues, especially in the presence of inflammation (which increases diffusion). It involves therapeutic levels in the blood, urine, bile, lung, peritoneal fluid, and skin blisters. Consequently, ceftazidime is also helpful as an inhalational agent in bronchiectasis, ventilator-associated pneumonia, and post-transplant airway infections.[27] There are also documented accounts of intraventricular administration of third-generation cephalosporins in the brain for meningitis.[28] 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 Food and Drug Administration (FDA) discontinued cefoperazone from the market in the USA.[29]

Concerning metabolism, cefotaxime is metabolized to a biologically active form. This compound, known as desacetylcefotaxime, has good antibacterial properties, penetration into extravascular tissue, and synergy with cefotaxime. Nevertheless, its activity is eight-fold weaker than cefotaxime.[30]

Third-generation cephalosporins are eliminated by the renal or biliary system. In particular, most agents are excreted primarily by the kidneys, while the biliary system eliminates cefoperazone for up 70%. Finally, ceftriaxone has a dual mechanism of excretion with about 40% of secretion in the bile.[7]

In Adults, Dosages (Per Os, PO; Intravenous, IV; Intramuscular, IM)

• Cefpodoxime proxetil PO: 100-400 mg, q12h. 
• Cefditoren pivoxil PO: 200-400 mg, q12h. 
• Ceftibuten PO: 400 mg, q24h. 
• Cefdinir PO: 300-600 mg, q12-24h.
• Cefotaxime IV/IM: 1-2 g, q4-8h.
• Ceftizoxime IV/IM: 1-2 g, q8-12h.
• Ceftriaxone IV/IM: 1-2 g, q12-24h. 
• Cefoperazone IV/IM: 1-2 g, q12h. 
• Ceftazidime IV/IM: 1-2 g, q8h. 

In Pediatric

• Cefpodoxime proxetil PO:10 mg/kg/d, q12h.
• Cefditoren pivoxil PO: Not recommended.
• Ceftibuten PO: 9 mg/kg/d, q24h.
• Cefdinir PO: 7-14 mg/kg/d, q12-24h.
• Cefotaxime IV/IM: 100-150 mg/kg/d, q4-6h.
• Ceftizoxime IV/IM: 100-200 mg/kg/d, q6-8h.
• Ceftriaxone IV/IM: 50-100 mg/kg/d, q12-24h.
• Cefoperazone IV/IM: 100-150 mg/kg/d, q8-12h.
• Ceftazidime IV/IM: 75-150 mg/kg/d, q8h.

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 cephalosporins 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.[31] Again, moxalactam, another third-generation cephalosporin, was discontinued from the market for causing fatal bleeding in patients.[32] Probably, compared with the other cephalosporins, cefotaxime is less likely to provoke coagulopathies and pseudocholelithiasis.[33]

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.[34]

Hypersensitivity reactions have been noted, though severe allergic reactions are uncommon. The incidence of cephalosporin allergy is approximately 1–3% of the general population.[35] Immune-mediated hemolytic anemias and thrombocytopenias are possible, where cephalosporins act as a hapten and can potentially elicit antibody reactions.[36] Patients with hypersensitivity to cephalosporins may result in an anaphylactic reaction and are managed with antihistamines, corticosteroids, epinephrine, or vasopressors.

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 various 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 ceftriaxone-induced encephalopathy featuring limb weakness or numbness, memory impairment, and behavioral problems has been reported.[37] 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.[38]

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.[39] Cephalosporins are one of the leading causes of perioperative anaphylaxis and severe cutaneous adverse reactions.[40] Other more common but less severe adverse effects include stomach discomfort, nausea or vomiting, diarrhea, fungal infection, rash or itching, and injection site reactions.

Contraindications

Cephalosporins are contraindicated in patients with a known allergy to the cephalosporin group of antibiotics. Nevertheless, an allergy to a cephalosporin in one class may not induce any cross-reactivity to another agent within the same or different class/generation.[41] Moreover, cephalosporins share molecular similarities with penicillins and could lead to allergic reactions in 10% of patients with known allergies to penicillins. Nevertheless, the cross-reactivity between penicillins and cephalosporins is still debated and remains an open issue.[42] 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.[43] Ceftriaxone can precipitate in the lungs and kidneys of infants less than 28 days old by reacting to calcium-containing solutions, and this could be life-threatening. Hence, in infants less than 28 days old, ceftriaxone is contraindicated if they are expected to receive any calcium-containing products.[44]

Although not contraindicated, considerable attention is necessary while using cephalosporins and warfarin, as this combination correlates with an increased risk of bleeding.[45] As a precautionary measure, patients should avoid alcohol consumption while on third-generation agents to avert disulfiram-like reactions.

Use in pregnancy and lactating mothers: Because third-generation cephalosporins are pregnancy category B medications under the prior FDA rating system, they are not contraindicated in pregnancy. Compared with cephalosporins of the first and second generations, the third-generation drugs have significantly lower oral bioavailability, and all members of this group are believed compatible with breastfeeding. [46] Cefixime was undetectable in milk after a 100 mg oral dose. Ceftibuten is poorly absorbed with meals, but small to moderate amounts may penetrate milk. After parenteral administration of ceftazidime 1-2 g, concentrations in milk peaked at 5 hours, with an approximate milk penetration of 4.4%.[47] Of the parenteral third-generation cephalosporins, ceftazidime, ceftriaxone, and cefotaxime have been approved by the American Academy of Pediatrics for use in breastfeeding mothers.[46]

Monitoring

Antibiotic Resistance

According to the Centers for Disease Control and Prevention (CDC), antibiotic resistance because of overuse, inappropriate prescribing, and extensive agricultural use is one of the biggest public health challenges of our time. [48] The mechanisms of resistance to cephalosporins are manifold. For example, the production of extended-spectrum β-lactamase (ESBL-E) and overexpression of AmpC cephalosporinase (AmpC-E) are the mechanisms used by Enterobacteriaceae. Of note, although these mechanisms are almost exclusively found in the hospital setting, there is evidence of an increased number of EBSL strains in the community.[49] Another significant concern is the emergence of third-generation cephalosporins resistant Enterobacteriaceae in severely ill neonates admitted to neonatal ICUs.[50] 

In addition to ESBL-E and AmpC-E, other mechanisms of antibiotic resistance have been described to third-generation cephalosporins. For instance, PBP3 and PBP5 substitutions could be implicated in the processes of resistance adopted by Haemophilus parainfluenza. [51]

On these premises, third-generation cephalosporins should be avoided as first-line antibiotic therapy in critically ill patients with the hospital or ventilator-acquired pneumonia caused by AmpC-producing strains. [52] Consequently, antimicrobial stewardship programs based on preauthorization, prospective audit, and feedback systems, as well as ad hoc guidelines, are mandatory to induce judicious use of antibiotics. For example, before instituting treatment with cephalosporins, clinicians should obtain appropriate specimens for culture and isolation of the causative organism and determine its susceptibility to antibiotics. Therapy may commence before receiving the results of susceptibility testing. Regarding antimicrobial stewardship, clinicians should be aware that a third-generation cephalosporin can be used only if Streptococcus pneumoniae and Hemophilus influenzae need to be covered.

Empiric cefotaxime should be reserved for neonates with early-onset sepsis with a high likelihood of fulminant renal failure and or Gram-negative meningitis to minimize the risk of colonization with resistant Gram-negative bacilli.[18]

Several strategies are being studied to combat antibiotic resistance. In addition to the possibility of developing new molecules, biotechnology offers an interesting perspective that can help design novel drug delivery methods. In particular, nanoparticles could be favorably adopted as a vehicle for antimicrobials. For example, chitosan is a natural polymer used to load various drugs that can provide prolonged release of ceftriaxone and other antibiotics.[53]  The early identification of third-generation cephalosporins resistant Enterobacterales directly from positive blood cultures is another potential strategy to avoid fruitless and dangerous therapies. In this regard, research is ongoing to develop reliable methods.[54]

Other Issues 

Clinicians who prescribe oral cephalosporins in the outpatient setting are safe. At the same time, parenteral agents like ceftriaxone, which get infused intravenously, are always done under a hospital in-patient setting and are subject to active monitoring. It is crucial to monitor for signs of an anaphylactic reaction and allergic reactions such as itching, swelling, and hives. Coagulation profile should be evaluated in patients with a known risk of bleeding while on third-generation cephalosporins.[32] Furthermore, dosing these antibiotics usually requires adjusting in geriatric populations, individuals with decreased renal function, and hepatic dysfunction. Consequently, renal function and liver enzymes may require careful monitoring. Again, since some drugs such as cefotaxime can potentially cause hematologic changes, including neutropenia, leukopenia, and agranulocytosis, blood cell counts should also be monitored.[55] Finally, although cephalosporins are potentially valuable for penicillin-allergic patients, they require careful observation for any potential adverse reactions.

Toxicity

This cephalosporins group does not have any 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 occur individually, 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 resistant to third-generation cephalosporins are rising. The use of these agents requires caution, avoiding unwarranted prescriptions from clinicians. [56][57][58] 

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 illnesses in other patients in the hospital or the region can invariably lead to a better treatment protocol. For example, when using cefotaxime to treat gonorrhea causing cervicitis or urethritis, treatment for chlamydia should be added as cefotaxime does not have coverage for this organism. Nurse practitioners and PAs can assist in closely monitoring the patients for adverse drug reactions, and immediate withdrawal of the culprit drug can reduce management complexity. Indeed, an interprofessional collaboration that aims to prevent and rapidly recognize cefalosporin-induced toxicity (e.g., neurotoxicity and bleeding) is mandatory, especially in high-risk patients such as the elderly. Pharmacists can assist in verifying dosing and checking for drug-drug interactions and confirming the infecting organism is being appropriately targeted since failure to do so 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 5]

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