Cefepime

Cefepime belongs to the pharmacological class of Fourth-generation cephalosporin antibiotics.

Cefepime has been approved to relieve symptoms and also for the treatment and maintenance of Bloodstream infection, Cystic fibrosis, Diabetic foot infection, Intra-abdominal infection, Intracranial abscess and spinal epidural abscess, Meningitis, Neutropenic enterocolitis, Neutropenic fever, Osteomyelitis and/or discitis, Peritonitis, Pneumonia, Prosthetic joint infection, Sepsis and septic shock, Septic arthritis, Skin and soft tissue infections, Urinary tract infection

Cefepime has a low plasma protein binding of approximately 20% and is eliminated primarily by the kidneys through glomerular filtration and tubular secretion. The elimination half-life of cefepime is approximately 2 hours in patients with normal renal function. However, the half-life can be prolonged in patients with impaired renal function, and dosage adjustments are recommended in such cases. Cefepime has a volume of distribution of approximately 18 liters, indicating that it is widely distributed throughout the body. Cefepime is administered intravenously and achieves peak plasma concentrations within 1 hour. Its onset of action is rapid, with bactericidal activity observed within 30 minutes of administration. The duration of action is approximately 8 hours, allowing for once or twice-daily dosing in most infections.

The common side effects involved in using Cefepime are Diarrhea, Nausea, Vomiting, Abdominal pain, Headache, Dizziness, Rash, Itching, Elevated liver enzymes

Cefepime is available in the form of Cefepime is available in the form of Intramuscular and Intravenous Solutions

Cefepime is approved in Germany, Japan, Malaysia, India, U.K., U.S, and China.

Cefepime belongs to the pharmacological class of Fourth-generation cephalosporin antibiotics.

Cefepime is a type of cephalosporin antibiotic that acts as a bactericidal agent in a similar way to other beta-lactam antibiotics. This drug interferes with the synthesis of bacterial cell walls by binding and inhibiting penicillin-binding proteins (PBPs), which are crucial enzymes involved in the final stages of peptidoglycan layer formation. Consequently, susceptible microorganisms undergo lysis and die. Cefepime exhibits a broad range of activity in vitro, affecting both Gram-positive and Gram-negative bacteria. This drug specifically targets PBP-3 and PBP-1 in Pseudomonas aeruginosa and Escherichia coli, respectively, as well as PBP-2 in Enterobacter cloacae and E. coli.

Cefepime has been approved to relieve symptoms and also for the treatment and maintenance of Bloodstream infection, Cystic fibrosis, Diabetic foot infection, Intra-abdominal infection, Intracranial abscess and spinal epidural abscess, Meningitis, Neutropenic enterocolitis, Neutropenic fever, Osteomyelitis and/or discitis, Peritonitis, Pneumonia, Prosthetic joint infection, Sepsis and septic shock, Septic arthritis, Skin and soft tissue infections, Urinary tract infection

The maximum plasma concentration (Cmax) of cefepime after intravenous (IV) administration occurs approximately 1 hour after the infusion is completed. The time to reach maximum concentration (Tmax) is also around 1 hour.

The onset of action of cefepime varies depending on the indication for which it is used. In general, it is a rapidly acting antibiotic, and its onset of action is typically within 1-2 hours.

The duration of action of cefepime also varies depending on the indication and severity of the infection being treated. The half-life of cefepime in adults is approximately 2 hours, but it may be longer in patients with impaired renal function. In general, the recommended dosing schedule for cefepime is every 8-12 hours, depending on the indication and patient factors.

Cefepime is found to be available in the form of Intramuscular and Intravenous Solutions.

Cefepime can be used in the following treatment:

• Bloodstream infection
• Cystic fibrosis
• Diabetic foot infection
• Intra-abdominal infection
• Intracranial abscess and spinal epidural abscess
• Meningitis
• Neutropenic enterocolitis
• Neutropenic fever
• Osteomyelitis and/or discitis
• Peritonitis
• Pneumonia
• Prosthetic joint infection
• Sepsis and septic shock
• Septic arthritis
• Skin and soft tissue infections
• Urinary tract infection

Cefepime can help to relieve symptoms and also for the treatment and maintenance of Bloodstream infection, Cystic fibrosis, Diabetic foot infection, Intra-abdominal infection, Intracranial abscess and spinal epidural abscess, Meningitis, Neutropenic enterocolitis, Neutropenic fever, Osteomyelitis and/or discitis, Peritonitis, Pneumonia, Prosthetic joint infection, Sepsis and septic shock, Septic arthritis, Skin and soft tissue infections, Urinary tract infection.

Cefepime is approved for use in the following clinical indications:

• Bloodstream infection
• Cystic fibrosis
• Diabetic foot infection
• Intra-abdominal infection
• Intracranial abscess and spinal epidural abscess
• Meningitis
• Neutropenic enterocolitis
• Neutropenic fever
• Osteomyelitis and/or discitis
• Peritonitis
• Pneumonia
• Prosthetic joint infection
• Sepsis and septic shock
• Septic arthritis
• Skin and soft tissue infections
• Urinary tract infection

Bloodstream infection: IV: 1 to 2 g every 8 to 12 hours.

Cystic fibrosis, acute pulmonary exacerbation: IV: 50 mg/kg/dose every 8 hours; maximum dose: 2,000 mg/dose.

Diabetic foot infection, moderate to severe: IV: 2 g every 8 hours.

Intra-abdominal infection, health care–associated or high-risk community-acquired infection: IV: 2 g for every 8 hours in combination with metronidazole.

Intracranial abscess and spinal epidural abscess: IV: 2 g every 8 hours.

Meningitis, bacterial: IV: 2 g every 8 hours.

Neutropenic enterocolitis: IV: 2 g every 8 hours.

Neutropenic fever, high-risk cancer patients: IV: 2 g every 8 hours.

Osteomyelitis and/or discitis: IV: 2 g every 8 hours.

Peritonitis, treatment: Intraperitoneal: Intermittent: 15 mg/kg/dose every 24 hours into the long dwell; Continuous: Loading dose: 500 mg per liter of dialysate; maintenance dose: 125 mg per liter.

Pneumonia: IV: 2 g every 8 hours.

Prosthetic joint infection, pathogen-specific therapy for gram-negative bacilli: IV: 2 g every 8 hours in combination with an aminoglycoside.

Sepsis and septic shock: IV: 2 g every 8 hours.

Septic arthritis: IV: 2 g every 8 hours.

Skin and soft tissue infections, moderate to severe: IV: 2 g every 8 hours.

Urinary tract infection, complicated: IM, IV: 1 g every 12 hours for mild to moderate infection; IV: 2 g every 12 hours for severe infection.

• Injection: 500 mg, 1 g, and 2 g single-dose vials or pre-filled syringes
• Powder for injection: 1 g and 2 g vials

Intramuscular and Intravenous Solutions.

• Dosage Adjustments in Kidney Patients:

In patients with creatinine clearance less than or equal to 60 mL/min, adjust the dose of Cefepime (cefepime hydrochloride) to compensate for the slower rate of renal elimination. High and prolonged serum cefepime concentrations might occur from usual dosages in patients with renal impairment, so the cefepime dosage should be reduced when administered to such patients. The continued dosage should be determined by the degree of renal impairment, severity of infection, and susceptibility of the causative organisms.

• Dosage Adjustments in Pediatric Patients:

Cystic fibrosis is a chronic respiratory disease that can lead to acute pulmonary exacerbations. Infants, children, and adolescents may receive IV treatment with a maximum dose of 2,000 mg/dose every 8 hours for 50 mg/kg/dose. More resistant pseudomonal isolates may require a higher frequency of treatment. Some experts prefer extended or continuous infusion methods for optimizing antipseudomonal beta-lactam exposure.

For endocarditis with prosthetic valves, treatment within one year of replacement in children and adolescents involves a combination of vancomycin, rifampin, and gentamicin for the first two weeks. The recommended IV dosage is 50 mg/kg/dose every 8 to 12 hours, with a maximum dose of 2,000 mg/dose, for 6 weeks.

In febrile neutropenia, empiric therapy may involve IV treatment with a maximum dose of 2,000 mg/dose every 8 hours for 50 mg/kg/dose in infants, children, and adolescents. Duration of therapy is dependent on the patient's febrile neutropenia risk-status, with high-risk patients being able to discontinue empiric antibiotics if negative blood cultures are confirmed at 48 hours, afebrile for at least 24 hours, and evidence of marrow recovery. Low-risk patients may discontinue empiric antibiotics after 72 hours if the blood culture is negative and have been afebrile for 24 hours.

Intra-abdominal infections, complicated in infants, children, and adolescents may receive IV treatment with a maximum dose of 2,000 mg/dose every 12 hours for 50 mg/kg/dose in combination with metronidazole. The recommended duration of therapy is 4 to 7 days, provided the source is controlled, according to IDSA guidelines.

For meningitis including health care-associated ventriculitis/meningitis, infants, children, and adolescents may receive IV treatment with a maximum dose of 2,000 mg/dose every 8 hours for 50 mg/kg/dose. Treatment duration should be individualized based on patient characteristics and response. The recommended minimum duration for gram-negative bacilli is 10 to 14 days, although some experts recommend at least 21 days and at least 14 days after the first negative cerebrospinal fluid culture.

In peritonitis (peritoneal dialysis), infants, children, and adolescents may receive intraperitoneal intermittent or continuous treatment. For intermittent treatment, the recommended dose is 15 mg/kg/dose every 24 hours into the long dwell. For continuous treatment, the loading dose is 500 mg per liter of dialysate, and the maintenance dose is 125 mg per liter.

For pneumonia, moderate to severe, infants ≥2 months, children, and adolescents may receive IV treatment with a maximum dose of 2,000 mg/dose every 8 hours for 50 mg/kg/dose for 10 days if due to P. aeruginosa. If not due to P. aeruginosa, the recommended IV dosage is 50 mg/kg/dose every 12 hours for 10 days.

For uncomplicated skin and skin structure infections, infants ≥2 months, children, and adolescents may receive IV treatment with a maximum dose of 2,000 mg/dose every 12 hours for 50 mg/kg/dose for 10 days.

For complicated and uncomplicated urinary tract infections in infants ≥2 months and children, the recommended IV dosage is 50 mg/kg/dose every 12 hours for 10 days, with a maximum dose of 1,000 mg/dose.

There are no specific dietary restrictions related to the use of Cefepime.

Cefepime may be contraindicated under the following conditions:

• In patients with known hypersensitivity to Cefepime, cephalosporins, penicillin, or any component of the formulation.

The physician should closely monitor the patients and keep pharmacovigilance as follows:

Prior to administering Cefepime for Injection, it is crucial to investigate if the patient has had any immediate hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other drugs. If the patient is sensitive to penicillin, caution must be exercised due to the possibility of cross-hypersensitivity among beta-lactam antibiotics, which has been observed in about 10% of patients with a history of penicillin allergy. In case of an allergic reaction to Cefepime, discontinue the drug immediately.

Postmarketing surveillance has revealed serious adverse reactions associated with the use of cefepime, such as encephalopathy, myoclonus, seizures, and nonconvulsive status epilepticus. Most cases were observed in patients with renal impairment who did not receive the appropriate dosage adjustment. Some cases of neurotoxicity also occurred in patients who received a dosage adjustment suitable for their level of renal impairment. In most cases, symptoms of neurotoxicity were reversible and resolved after discontinuation of cefepime or hemodialysis. In the event of neurotoxicity associated with cefepime therapy, healthcare professionals should consider discontinuing cefepime or adjusting the dosage appropriately for patients with renal impairment.

The use of nearly all antibacterial agents, including cefepime, has been linked to the development of Clostridium difficile associated diarrhea (CDAD). Clostridium difficile associated diarrhea can range in severity from mild diarrhea to fatal colitis. The administration of antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile. Clostridium difficile associated diarrhea should be considered in all patients who develop diarrhea following antibiotic use. Healthcare professionals should obtain a careful medical history as Clostridium difficile associated diarrhea can occur over 2 months after the administration of antibacterial agents. If Clostridium difficile associated diarrhea is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.

There is no specific alcohol warning associated with the use of Cefepime in the package insert. However, it is generally recommended to avoid consuming alcohol while taking antibiotics as it may increase the risk of side effects and decrease the effectiveness of the medication.

Cefepime is excreted in human breast milk in very low concentrations (0.5 mcg/mL). Therefore, caution should be exercised when cefepime is administered to a nursing woman. Healthcare professionals should weigh the potential benefits of cefepime treatment against the potential risks to the nursing infant.

Pregnancy Category B

Cefepime is a commonly used antibiotic that has been tested for teratogenic effects during pregnancy. Animal studies have shown that cefepime was not teratogenic or embryonical when administered during the period of organogenesis to rats at doses up to 1000 mg/kg/day, mice at doses up to 1200 mg/kg, or rabbits at a dose level of 100 mg/kg. However, there are no adequate and well-controlled studies of cefepime use in pregnant women. Therefore, cefepime should be used during pregnancy only if clearly needed and under the supervision of a healthcare professional.

There are no specific food warnings related to the use of cefepime according to USFDA. However, cefepime should be administered with caution in patients with a history of gastrointestinal disease, particularly colitis, as colitis has been reported to occur in patients receiving cephalosporins. It is recommended to avoid the concomitant use of cefepime with drugs that may cause gastrointestinal irritation or bleeding. Patients should also be advised to take cefepime with food to reduce the risk of gastrointestinal adverse effects.

The adverse reactions related to Cefepime can be categorized as follows:

Common:

• Diarrhea
• Nausea and vomiting
• Headache
• Rash
• Pain, inflammation, or phlebitis at the injection site
• Elevation of liver enzymes

Less Common:

• Abdominal pain
• Dizziness
• Itching or hives
• Fever or chills
• Joint pain
• Fatigue
• Anxiety or confusion
• Anemia
• Thrombocytopenia
• Increased risk of bleeding
• Changes in taste

Rare:

• Seizures or convulsions
• Encephalopathy or confusion
• Nephrotoxicity or kidney damage
• Hemolytic anemia
• Stevens-Johnson syndrome or toxic epidermal necrolysis
• Agranulocytosis
• Superinfection
• Clostridioides difficile-associated diarrhea

The clinically relevant drug interactions of Cefepime is briefly summarized here:

If high doses of aminoglycosides are administered with Cefixime, renal function should be carefully monitored due to the increased potential for nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Concomitant administration of other cephalosporins along with potent diuretics such as furosemide has been reported to cause nephrotoxicity.

The following are the side effects involving Cefepime:

• Diarrhea
• Nausea and vomiting
• Headache
• Dizziness
• Rash
• Itching
• Swelling, redness, or pain at the injection site
• Fever
• Abdominal pain
• Decreased appetite
• Insomnia
• Confusion or hallucinations
• Seizures (especially in patients with kidney problems)
• Difficulty breathing or wheezing
• Fast or irregular heartbeat
• Jaundice (yellowing of the skin or eyes)
• Kidney problems (including decreased urine output or blood in the urine)

Pregnancy:

Pregnancy Category B

Cefepime is a commonly used antibiotic that has been tested for teratogenic effects during pregnancy. Animal studies have shown that cefepime wasn't teratogenic or embryocidal when administered during the period of organogenesis to rats at doses up to 1000 mg/kg/day, mice at doses up to 1200 mg/kg, or rabbits at a dose level of 100 mg/kg. However, there was found to beare no adequate and well-controlled studies of cefepime use in pregnant women. Therefore, cefepime should be used during pregnancy only if clearly needed and under the supervision of a healthcare professional.

Breastfeeding:

Cefepime is excreted in human breast milk in very low concentrations (0.5 mcg/mL). Therefore, caution should be exercised when cefepime is administered to a nursing woman. Healthcare professionals should weigh the potential benefits of cefepime treatment against the potential risks to the nursing infant.

Pediatric use:

Cefepime has been proven safe and effective in treating uncomplicated and complicated urinary tract infections, pneumonia, uncomplicated skin and skin structure infections, and as empiric therapy for febrile neutropenic patients in patients aged 2 months to 16 years. The use of cefepime in these age groups is supported by adequate and well-controlled studies in adults, along with pharmacokinetic and safety data from pediatric trials. However, the safety and effectiveness of cefepime in pediatric patients under 2 months of age has not been established, and there is insufficient clinical data to support its use in treating serious infections caused by Haemophilus influenzae type b in the pediatric population.

Geriatric use:

Regarding geriatric use, cefepime has been studied in more than 6400 adults, of whom 35% were 65 years or older and 16% were 75 years or older. When administered at the usual recommended adult dose, geriatric patients had similar clinical efficacy and safety as non-geriatric adult patients. However, serious adverse events have been reported in geriatric patients with renal insufficiency who were given unadjusted doses of cefepime, including life-threatening or fatal cases of encephalopathy, myoclonus, and seizures. Healthcare professionals should take care in selecting doses and monitoring renal function, especially in elderly patients who are more likely to have decreased renal function.

Physicians should be knowledgeable and vigilant about the treatment and identification of over dosage of Cefepime.

Over dosage of cefepime can cause neurological symptoms such as encephalopathy (disturbance in brain function), seizures, and myoclonus (muscle spasms). Treatment for over dosage of cefepime includes discontinuing the drug and providing supportive care, such as maintaining airway and vital signs, and administering anticonvulsants if necessary. Hemodialysis may be considered in patients with significant renal impairment to remove cefepime from the bloodstream.

In terms of regular treatment, cefepime is approved for the treatment of various infections, including urinary tract infections, lower respiratory tract infections, skin and skin structure infections, intra-abdominal infections, and febrile neutropenia. The recommended dosage and duration of treatment depend on the type and severity of the infection, as well as the patient's age, weight, and renal function.

Pharmacodynamics

Cefepime is an antibiotic belonging to the fourth-generation cephalosporin class, with activity against both Gram-negative and Gram-positive bacteria. It is effective against Enterobacter spp., Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus (methicillin-susceptible isolates only), Streptococcus pneumoniae, Streptococcus pyogenes, and Viridans group streptococci. Compared to third-generation cephalosporins, cefepime has a broader Gram-negative coverage and is not significantly hydrolyzed by beta-lactamases. It is also a poor inducer of type 1 beta-lactamases, making it a good alternative for bacteria resistant to third-generation cephalosporins. Studies in animal models have shown that the time that the unbound plasma concentration of cefepime exceeds the minimum inhibitory concentration (MIC) of infecting organisms is correlated with treatment efficacy. Cefepime has been suggested to be able to cross the inflamed blood-brain barrier and inhibit γ-aminobutyric acid (GABA), which may explain the neurotoxic effects observed in some patients treated with the drug.

Pharmacokinetics

• Absorption:

In a study of healthy adult male volunteers (n=9), different doses of cefepime administered intravenously and intramuscularly resulted in varying Cmax and AUC values. The Cmax values ranged from 13.9 to 163.9 μg/mL and the AUC values ranged from 60 to 284.8 h⋅μg/mL. Additionally, an absolute bioavailability of 82.3% was observed in pediatric patients (n=8) who received an intramuscular dose of 50 mg/kg.

• Volume of Distribution:

The average steady-state volume of distribution of cefepime is found to be 18.0 L, while in pediatric patients, the average steady-state volume of distribution is found to be 0.3 L/kg.

• Metabolism:

Cefepime is minimally metabolized in the liver, with less than 1% of the drug being metabolized. The primary metabolite of cefepime is N-methylpyrrolidine (NMP), which undergoes rapid oxidation to form NMP-N-oxide, the predominant metabolite. NMP and the 7-epimer of cefepime are minor byproducts. Flavin-containing mixed-function oxygenase mediates the oxidation of NMP to NMP-N-oxide.

• Route of Elimination:

Cefepime is mainly eliminated unchanged by the kidneys, with approximately 85% of the administered dose excreted in urine. Less than 1% of the administered dose is recovered from urine as N-methylpyrrolidine (NMP), 6.8% as NMP-N-oxide, and 2.5% as an epimer. Renal excretion is important in eliminating cefepime, and dosage adjustments are necessary in patients with renal dysfunction or those undergoing hemodialysis.

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