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Cephalosporins
Indications
Cephalosporins are β-lactam antimicrobials used to manage various infections caused by both gram-positive and gram-negative bacteria. Cephalosporins are categorized into 5 generations based on their spectrum of coverage against gram-positive and gram-negative bacteria and their temporal discovery. The 5 generations of cephalosporins demonstrate efficacy in treating skin and soft tissue infections, pneumonia, meningitis, and other infections. First-generation cephalosporins have coverage against most gram-positive cocci and some gram-negative bacteria, including Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. Second-generation cephalosporins have coverage against Haemophilus influenzae, Moraxella catarrhalis, and Bacteroides spp. Third-generation cephalosporins have less coverage against most gram-positive organisms but have increased coverage against Enterobacteriaceae, Neisseria spp, and H influenzae. Fourth-generation cephalosporins have similar coverage as third-generation cephalosporins but with additional coverage against gram-negative bacteria with antimicrobial resistance, such as β-lactamase. Fifth-generation cephalosporins have coverage against methicillin-resistant staphylococci and penicillin-resistant pneumococci.
First-generation cephalosporins include cefazolin, cephalothin, cephapirin, cephradine, cefadroxil, and cephalexin. First-generation cephalosporins have active coverage against most gram-positive cocci, such as staphylococci spp and streptococci spp, while having minimal coverage against gram-negative bacteria. Gram-negative bacteria that are more susceptible to first-generation cephalosporins include P mirabilis, E coli, and K pneumoniae. Oral first-generation cephalosporins are commonly prescribed against uncomplicated skin and soft tissue infections such as cellulitis and abscesses due to staphylococci spp or streptococci spp. Additionally, clinicians can use them for bone, respiratory tract, genitourinary tract, biliary tract, bloodstream infection, otitis media, and surgical prophylaxis. Cefazolin is the cephalosporin of choice for surgical prophylaxis. One off-label use is first-generation cephalosporins for endocarditis prophylaxis for those susceptible and undergoing a dental or respiratory procedure.[1][2][3]
Second-generation cephalosporins divide into 2 subgroups—the second-generation and the cephamycin subgroup. Some of the second-generation subgroups include cefuroxime and cefprozil. The cephamycin subgroup includes cefmetazole, cefotetan, and cefoxitin. Within the first subgroup, cefuroxime has increased coverage against H influenzae. Indications for cefuroxime also include Lyme disease in pregnant women and children. The cephamycin subgroup has increased coverage against Bacteroides species. Second-generation cephalosporins have less activity against gram-positive cocci than first-generation cephalosporins but have improved activity against gram-negative bacilli. They are often prescribed to treat respiratory infections such as bronchiolitis or pneumonia. Other indications for second-generation cephalosporins are similar to first-generation indications (bone, respiratory tract, genitourinary tract, biliary tract, bloodstream infection, otitis media, and surgical prophylaxis). In addition to the gram-negative bacteria covered by first-generation cephalosporins, second-generation cephalosporins also have coverage against H influenzae, Enterobacter aerogenes, Neisseria spp, and Serratia marcescens.[4]
Third-generation cephalosporins include cefotaxime, ceftazidime, cefdinir, ceftriaxone, cefpodoxime, cefoperazone, and cefixime. This generation has extended gram-negative bacteria coverage, often used to treat gram-negative infections resistant to the first- and second-generation or other β-lactam antimicrobials. When given intravenously (IV), third-generation can penetrate the blood-brain barrier and cover bacteria in the cerebral spinal fluid, especially ceftriaxone and cefotaxime. Ceftriaxone can be prescribed to treat meningitis caused by H influenzae, Neisseria meningitidis, or Streptococcus pneumoniae. Ceftriaxone is also used to treat gonorrhea and disseminated Lyme disease. Ceftazidime, very importantly, has Pseudomonas aeruginosa coverage.[5]
Fourth-generation cephalosporin includes cefepime. Cefepime is a broad-spectrum antimicrobial that can penetrate the cerebral spinal fluid. Cefepime has an additional quaternary ammonium group, allowing it to better penetrate the outer membrane of gram-negative bacteria. Similar to the activity of cefotaxime and ceftriaxone, cefepime can cover S pneumoniae and methicillin-sensitive Staphylococcus aureus (MSSA). Similar to ceftazidime, cefepime, very importantly, can cover for P aeruginosa. In addition to the gram-negative bacteria that third-generation covers (Neisseria spp, H influenzae, and Enterobacteriaceae), cefepime can provide coverage against β-lactamase-producing gram-negative bacilli. Although effective against gram-positive and gram-negative bacteria, cefepime is reserved for severe systemic infection in patients with multi-resistance organisms.[6]
Fifth-generation cephalosporins include ceftaroline and ceftobiprole. Ceftaroline is also a broad-spectrum antimicrobial and thus can cover susceptible gram-positive and gram-negative organisms. However, what makes it unique from the rest of the cephalosporins is coverage against methicillin-resistant S aureus (MRSA). Ceftaroline can also cover Listeria monocytogenes and Enterococcus faecalis. However, ceftaroline does not cover P aeruginosa.[7] Ceftobiprole (pending approval from the US Food and Drug Administration, FDA) has activity against MRSA, E faecalis, and penicillin-resistant S pneumoniae.[8][9][10]
FDA-Approved Indications
Cefiderocol is a novel siderophore cephalosporin that exhibits remarkable antibacterial activity. This drug was approved by the US Food and Drug Administration (FDA) in November 2019 to treat complicated urinary tract infections and ventilator-associated pneumonia caused by highly resistant gram-negative bacteria. The approval is specifically for cases caused by susceptible gram-negative microorganisms, such as K pneumonia, E coli, P aeruginosa, P mirabilis, and Acinetobacter baumannii.
Cefiderocol demonstrates notable effectiveness against gram-negative bacteria with multidrug resistance, especially those resistant to carbapenems. Literature review suggests cefiderocol as a promising therapeutic option for addressing challenging infections caused by strains resistant to carbapenems.[11][12] Importantly, cefiderocol is the only recently approved β-lactam agent exhibiting in vitro activity against carbapenem-resistant A baumannii (CRAB) isolates. According to the Infectious Diseases Society of America guidelines, cefiderocol should be reserved for cases of CRAB infections that remain unresponsive to other antibiotics or when intolerance to alternative agents prohibits their use.[13]
Mechanism of Action
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Mechanism of Action
Bacteria synthesize a cell wall strengthened by cross-linking peptidoglycan units via penicillin-binding proteins (PBP, peptidoglycan transpeptidase). Initially derived from the fungus Cephalosporium sp., cephalosporins are a large group of bactericidal antimicrobials that work via their β-lactam rings. The β-lactam rings bind to the penicillin-binding protein and inhibit its normal activity. Unable to synthesize a cell wall, the bacteria die. The inability to synthesize a cell wall eventually leads to bacterial cell death.
S aureus, susceptible to cephalosporins, can develop resistance by changing the structure of the penicillin-binding proteins. S aureus does this by having a gene that encodes a modified penicillin-binding protein; this prevents the cephalosporin's β-lactam rings from inactivating the protein. The bacterium that develops this resistance mechanism is MRSA. As mentioned above, out of the five generations of cephalosporin, only the fifth generation of ceftaroline has coverage against MRSA. Another crucial resistance mechanism is producing the enzyme β-lactamase, which cleaves the β-lactam ring, preventing it from attaching to the penicillin-binding proteins, eg, peptidoglycan transpeptidase. β-lactamase inhibitors can be co-formulated with cephalosporins to increase their spectrum of activity, eg, ceftazidime/avibactam and ceftolozane/tazobactam.
Similar to cefepime and ceftazidime, it features a pyrrolidine group at the C3 position for stability and a carboxy-propanoxyamino group at C7 to aid in outer membrane transport. Iron transporters recognize this, enabling efficient penetration to the periplasm, where it strongly binds to PBP-3. Termed the "Trojan horse," this strategy effectively addresses porin loss resistance. Cefiderocol's structural attributes also ensure stability against β-lactamases, including minor carbapenemases.
Cefiderocol is a siderophore cephalosporin with a distinctive structure and mechanism that enhances its potent antibacterial properties. Including a chlorocatechol residue sets it apart from its counterparts, categorizing it as a siderophore. This attribute makes it recognizable by iron transporters and facilitates efficient penetration to the periplasm, where it binds strongly to penicillin-binding proteins. This strategy is called the "trojan horse," which effectively addresses porin loss resistance. Cefiderocol's properties also ensure stability against β-lactamases, including minor carbapenemases.[12][14]
Pharmacokinetics
Absorption: Cephalexin, cephradine, cefaclor, cefixime, cefadroxil, cefprozil, cefpodoxime, ceftibuten, cefuroxime demonstrate effective absorption following oral administration.
Distribution: Certain cephalosporins, such as ceftriaxone, cefotaxime, ceftazidime, and cefepime, can effectively penetrate the blood-brain barrier, making them a valuable treatment option for meningitis.[15][16] Cephalosporins can also cross the placenta and are present in high concentrations in synovial fluid.[17] After systemic administration of third-generation cephalosporins, they can penetrate well into the aqueous humor. Ceftolozane/tazobactam, ceftobiprole, ceftazidime/avibactam and ceftaroline have excellent pulmonary penetration.[18]
Metabolism: Cefotaxime undergoes metabolic conversion to a biologically active compound known as desacetyl-cefotaxime. This metabolite exhibits favorable antibacterial properties, effective penetration into extravascular tissues, and synergy with cefotaxime. Cefoperazone, ceftazidime, and ceftriaxone have significant biliary excretion.[19][20][21]
Excretion: Cephalosporins are primarily excreted via renal pathways, necessitating dosage adjustments in cases of renal insufficiency. Exceptions include cefpiramide and cefoperazone, primarily excreted in bile. Ceftriaxone, conversely, exhibits mixed renal/nonrenal elimination.[22] Like penicillins, probenecid can reduce the renal tubular secretion of the cephalosporins.
Administration
Available Dosage Forms, Strengths, and Adult Dosages
- First-generation: Cefazolin, cephalothin, and cephapirin are administered parenterally. The administration route for cefadroxil and cephalexin is oral. Cephradine administration can be parenteral or oral.
- Second-generation: Cefuroxime can be administered parenterally or orally. Cefprozil is administered orally. Cefmetazole, cefotetan, and cefoxitin are administered parenterally.
- Third-generation: Cefotaxime, ceftazidime, and ceftriaxone administration via the parenteral route. Cefdinir, cefixime, and cefpodoxime are administered orally. A single intramuscular shot of 125 or 250 mg of ceftriaxone effectively treats uncomplicated gonococcal infection or its complications, such as pelvic inflammatory disease or epididymo-orchitis.[23][24][25]
- Fourth-generation: Cefepime is administered parenterally.
- Fifth-generation: Ceftaroline is administered parenterally.
- Cefiderocol: Cefiderocol is administered parenterally.[13]
Specific Patient Populations
Hepatic impairment: Generally, cephalosporins are known for their low propensity for hepatotoxicity, and instances of drug-induced liver injury attributed to these agents are infrequent in the published literature. Notably, an exception exists with ceftriaxone, a third-generation cephalosporin. When administered parenterally, ceftriaxone has been associated with the formation of biliary sludge, with symptoms resembling those of cholecystitis and cholestatic jaundice.[26] Pharmacokinetic investigations conducted in cirrhosis have demonstrated heterogeneous results concerning the half-life of cefotaxime. However, cefotaxime has a broad therapeutic index, suggesting that dosage adjustments may not be necessary for hepatic impairment. In the context of spontaneous bacterial peritonitis therapy, cefotaxime's comprehensive coverage and high ascitic fluid concentrations make it a preferred antibiotic. Empirical antibiotic therapy, cefotaxime, administered every 8 hours, has demonstrated excellent ascitic fluid concentrations and clinical efficacy.[27]
Renal impairment: Many parenterally administered cephalosporins have short half-lives and must be given more frequently in patients with normal renal function. Cefazolin and ceftriaxone do not require frequent dosing due to their longer half-life. Ceftriaxone does not require dose modification in renal failure. However, the recommended daily dosage should not exceed 2 g in renal and hepatic impairment patients.[28] In chronic kidney disease patients, careful dosing of cephalosporins is imperative to mitigate drug accumulation and associated adverse effects. Cefepime, a fourth-generation cephalosporin, necessitates vigilant renal function monitoring and dose adjustment due to its potential neurotoxicity in renal impairment. Conversely, cephalosporins like cefazolin and ceftazidime, excreted renally, present an opportunity for streamlined dosing in hemodialysis. Administering these agents 3 times weekly post-hemodialysis optimizes convenience and adherence. Individualized decisions, guided by patient-specific factors and nephrotoxicity potential guidelines, are essential to ensure therapeutic efficacy while minimizing risks in chronic kidney disease management.[29]
Pregnancy considerations: The guidelines provided by the American College of Obstetricians and Gynecologists (ACOG) for preventing Group B Streptococcal infection recommend the use of first-generation cephalosporins, specifically cefazolin, for women who have a documented penicillin allergy that indicates a lower risk of anaphylaxis or whose allergy severity is uncertain.[30]
Breastfeeding considerations: Cephalosporin antibiotics, including cefadroxil, cefazolin, cefepime, cefiderocol, cefixime, cefotaxime, cefpodoxime, ceftaroline, and ceftazidime, are generally considered acceptable for use in nursing mothers. These medications produce low concentrations in breast milk and are not anticipated to cause adverse effects in breastfed infants.[31][32][33] Occasional reports mention the potential for disruption of the infant's gastrointestinal flora, leading to diarrhea or thrush; overall, cephalosporins are deemed suitable during breastfeeding.[34][35][36]
Pediatric patients: In children with acute bacterial arthritis due to MSSA, the preferred initial intravenous treatment is a β-lactam agent like cefazolin. Cephalexin is the recommended choice for subsequent oral treatment. Ceftaroline is a reasonable alternative to clindamycin in acute bacterial arthritis caused by MRSA.[37]
Older patients: Older patients with renal impairment and central nervous system (CNS) disorders are at risk of neurotoxicity. Cefepime-induced neurotoxicity may present with altered mental status, myoclonus, and seizures.[38]
Adverse Effects
Cephalosporins have low toxicity and are generally safe. The most common adverse reactions from cephalosporins are nausea, vomiting, lack of appetite, and abdominal pain. Important adverse drug reactions are enumerated below.
Hypersensitivity reactions: A hypersensitivity reaction to cephalosporin is infrequent and is more common in first and second-generation cephalosporins. Common allergic reactions to cephalosporin include rash, hives, and swelling. The hypersensitivity reaction will rarely result in anaphylaxis. Patients allergic to penicillin might also show a hypersensitive reaction to cephalosporins. This cross-reactivity is more common in first and second-generation cephalosporins because they have R-groups more similar to penicillin G. Third-generation and beyond show minimal cross-reactivity.[39][40]
Drug-induced immune hemolytic anemia: The proposed mechanism of action of drug-induced immune hemolytic anemia (DIIHA) is that the drug binds to the red blood cell membrane; this causes no harm to the red blood cell itself or the patient. However, if the patient starts making IgG antibodies against the drug, the antibody will bind to the red blood cell. The immune system will react with the abnormal red blood cells, resulting in hemolysis. Cefotetan and ceftriaxone are the 2 cephalosporins most likely to cause DIIHA.[41]
Disulfiram-like reactions: Cephalosporins containing a methyl-tetrazole-thiol side chain can inhibit the aldehyde dehydrogenase enzyme, resulting in the accumulation of acetaldehyde. Cefamandole, cefoperazone, and moxalactam are the most common cephalosporins to present with this reaction.[42]
Vitamin K deficiency: Certain cephalosporins can inhibit vitamin K epoxide reductase, preventing the production of the reduced (active) vitamin K. Therefore, a decreased synthesis of coagulation factors may occur, and the patient is predisposed to hypoprothrombinemia.[43]
Pseudomembranous colitis: Pseudomembranous colitis is often associated with clindamycin and ampicillin. Cephalosporin use is also a common cause of pseudomembranous colitis, especially third-generation cephalosporins.[44][45]
Drug-Drug Interactions
Warfarin: Cephalosporins containing an N-methyl-thiotetrazole (NMTT) side chain are predominantly found in cefotetan, cefamandole, cefmetazole, cefoperazone, moxalactam. NMTT-cephalosporins induce hemostatic abnormalities, such as bleeding, prothrombin time prolongation, and hypoprothrombinemia, due to the NMTT's chemical structure interfering with vitamin K metabolism. These cephalosporins can interact with warfarin, potentiating the risk of hypoprothrombinemia and increasing the likelihood of bleeding incidents.[46] Additionally, the literature review suggests that ceftaroline poses a risk of interaction with warfarin, potentially leading to elevated INR levels and an increased bleeding risk. Saum et al focused on ceftriaxone and discovered significant increases in INR values compared to other antibiotics. This suggests caution when using cephalosporins in patients on chronic warfarin therapy.[47][48]
Furosemide: Concurrent use of cephalosporins and furosemide can increase the risk of nephrotoxicity.[49][50]
Aminoglycosides: Reported cases of drug-induced nephrotoxicity consist of cephalosporin and aminoglycosides in combination, but other factors often cloud the evidence. Therefore, the synergistic nephrotoxicity of cephalosporin and aminoglycoside is not completely understood.[45][51] Concurrent use of cefepime with other aminoglycoside antibiotics increases the risk of nephrotoxicity.[52][53]
Contraindications
One of the contraindications of cephalosporins is if patients are allergic to them or have had an anaphylactic reaction to penicillin or other β-lactam antimicrobials. The cross-reactivity is thought to be due to similar side chains, not the β-lactam ring. However, it is important to understand the contraindications according to the latest guidelines. The guidelines provided by the American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma, and Immunology (ACAAI) offer recommendations for managing patients with a history of cephalosporin or penicillin allergies.[54]
- In instances where patients have a history of nonanaphylactic allergy to cephalosporins, the guidelines from AAAAI and ACAAI suggest the performance of direct challenges to cephalosporins with dissimilar side chains. The guidelines do not advocate for skin tests before the direct challenge.
- The guidelines recommend confirming a negative cephalosporin skin test for patients with a history of anaphylaxis to a cephalosporin before administering a parenteral cephalosporin with a nonidentical R1 side chain.
- In cases where patients have a history of anaphylaxis to penicillin, the guidelines suggest administering a structurally dissimilar R1 side chain cephalosporin without necessitating testing or additional precautions. If any uncertainty exists about allergy testing, it is recommended to consult with an immunologist. A detailed explanation is provided in the guidelines.
Ceftriaxone is contraindicated in neonates with hyperbilirubinemia because of reports that ceftriaxone displaces bilirubin from albumin, increasing the free bilirubin concentrations and increasing the risk of jaundice in neonates.[55][56] Ceftriaxone reacts to a calcium-containing solution, and ceftriaxone-calcium crystals can precipitate in the lungs and kidneys of infants less than 28 days old, which could be life-threatening. Therefore, ceftriaxone is also contraindicated in infants under 28 days old if they are expected to receive calcium-containing products.[57]
Monitoring
Monitoring for possible signs of anaphylaxis and allergic reactions such as hives, itching, and swelling is essential. Clinicians and pharmacists should also monitor renal function periodically, which could potentially warrant changing the cephalosporin dose and dosing frequency (except for ceftriaxone).[58] If DIIHA is suspected, monitor complete blood count (CBC), bilirubin, haptoglobin, and LDH.[59] Clinicians should also monitor for possible signs of a disulfiram-like reaction or pseudomembranous colitis.[60][61] Monitor PT/INR for concerns regarding hypoprothrombinemia.[62][63]
Toxicity
Signs and Symptoms of Overdose
After conducting experiments on rabbits to test the effects of high-dosage cephalosporin, it has been discovered that the drug's impact on the mitochondria system of the kidney results in nephrotoxicity.[64] Cefepime overdose can result in seizures and encephalopathy. Studies show it to potentially result from cefepime crossing the blood-brain barrier and displaying concentration-dependent ϒ-aminobutyric acid (GABA) antagonism, which can also occur with toxic doses of penicillin G. Other studies show altered mental status and a triphasic wave discharge on electroencephalogram (EEG). Discontinuation of cefepime demonstrates normalization of mental status.[65][66]
A study analyzed 511 severe adverse drug reaction reports on cephalosporins recorded in the French Pharmacovigilance database from 1987 to 2017. Patients, primarily older men with compromised renal function, experienced various CNS manifestations, including encephalopathy, confusional state, convulsions, and myoclonia. Cefepime and ceftriaxone were the most implicated cephalosporins.[67]
Management of Overdose
Management of neurotoxicity and seizures involves discontinuing the offending cephalosporin, providing supportive care, and initiating anticonvulsant therapy if necessary.[68]
Enhancing Healthcare Team Outcomes
Effective teamwork among healthcare professionals is vital for providing quality patient care. A shared goal, clear roles, and trust between the team members can increase efficiency. Clinicians should accurately diagnose, prescribe, and inform patients of adverse effects. Nurses should be aware of potential adverse drug reactions. Pharmacists can educate patients, provide information on adverse effects, and report potential interactions to clinicians. A recent study showed that pharmacist-led antimicrobial stewardship interventions, specifically focusing on antibiotics, led to lasting improvements such as increased blood culture collections, more frequent de-escalation of agents, and a significant reduction in hospital-acquired infections.[69]
Patients should be advised to promptly communicate any unusual symptoms they may be experiencing to both the clinician and nurse. Through effective interprofessional teamwork, appropriate management of cephalosporin adverse drug reactions can occur, resulting in better patient outcomes. Adopting an interprofessional team-based approach that involves clinicians, infectious disease specialists, pharmacists, and patients is instrumental in achieving the desired therapeutic outcomes of cephalosporins.
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