What are the key indications for cefepime. How does cefepime work against bacterial infections. What is the recommended dosing regimen for cefepime. What are the potential adverse effects of cefepime. How should cefepime be administered in clinical practice.

Understanding Cefepime: A Powerful Fourth-Generation Cephalosporin

Cefepime is a fourth-generation cephalosporin antibiotic belonging to the beta-lactam class. It plays a crucial role in treating various bacterial infections due to its broad-spectrum activity against both gram-positive and gram-negative organisms. As healthcare professionals, it’s essential to understand the nuances of this powerful antibiotic to ensure optimal patient outcomes.

What sets cefepime apart from other cephalosporins?

Cefepime distinguishes itself from earlier generations of cephalosporins through several key features:

• Enhanced stability against beta-lactamases
• Broader gram-negative coverage
• Improved penetration into gram-negative bacterial cell walls
• Maintained activity against certain staphylococcal species

These characteristics make cefepime a valuable option for treating complex infections, particularly in hospitalized patients.

Key Indications for Cefepime Therapy

Healthcare providers should consider cefepime for the following conditions:

• Pneumonia
• Complicated and uncomplicated urinary tract infections
• Skin and soft tissue infections
• Complicated intra-abdominal infections (in combination with metronidazole)
• Empiric treatment for febrile neutropenia

Is cefepime effective against all bacterial strains? While cefepime demonstrates broad-spectrum activity, it’s important to note that certain bacteria, particularly extended-spectrum beta-lactamase (ESBL) producing organisms, may be resistant. However, a subgroup of ESBLs known as Amp-C producers often remains susceptible to cefepime, though careful evaluation of minimum inhibitory concentrations (MICs) and dosing regimens is crucial.

Mechanism of Action: How Cefepime Combats Bacterial Infections

Cefepime’s bactericidal activity relies on its ability to disrupt bacterial cell wall synthesis. The process involves:

1. Covalent binding to enzymes responsible for transpeptidation during peptidoglycan wall synthesis
2. Creation of defects in the bacterial cell wall
3. Induction of autolysis, leading to bacterial death

Why is cefepime more effective against certain gram-negative bacteria? Its zwitterionic structure allows for faster penetration of gram-negative bacterial cell walls, contributing to its enhanced spectrum of activity compared to third-generation cephalosporins.

Pharmacokinetics and Distribution of Cefepime

Understanding the pharmacokinetics of cefepime is crucial for optimal dosing and clinical efficacy:

• Wide distribution throughout body tissues and fluids, including pleural fluid, synovial fluid, bones, cerebrospinal fluid, and breast milk
• Rapid metabolism with less than 10% of the metabolized product undergoing excretion
• Primary excretion through glomerular filtration as an unchanged drug
• Half-life of approximately 2 to 2.3 hours in patients with normal renal function

How does renal function impact cefepime dosing? In patients with renal impairment, the half-life of cefepime is prolonged, necessitating dose adjustments to prevent toxicity while maintaining therapeutic efficacy.

Cefepime Dosage Forms and Administration Guidelines

Cefepime is available in several formulations to accommodate various clinical scenarios:

• Intravenous solution: 1 g / 50 mL and 2 g / 100 mL
• Injection powder for reconstitution: 500 mg, 1 g, and 2 g vials
• Intravenous solution for reconstitution: 1 g cefepime per 50 mL (5% w/v) dextrose USP in water for injection

What is the preferred route of administration for cefepime? Intravenous (IV) administration is most common, typically involving doses of 1 to 2 g every 8 to 12 hours, depending on the infection being treated. Standard infusions occur over 30 minutes, though extended infusion protocols have been studied.

Extended Infusion Protocols: A Potential Optimization Strategy

Some studies have explored the use of extended infusions (4 hours) for cefepime administration. While certain investigations have suggested potential benefits such as lower overall mortality and reduced ICU lengths of stay, it’s important to note that these findings have not been consistently replicated across all studies. The use of extended infusions for febrile neutropenia appears feasible, but further research is needed to establish definitive clinical recommendations.

Dosing Considerations for Special Populations

Proper dosing of cefepime requires careful consideration of patient-specific factors:

Renal Impairment

Patients with reduced renal function require dose adjustments to prevent drug accumulation and potential toxicity. The extent of dose reduction depends on the degree of renal impairment, as measured by creatinine clearance.

Pediatric Patients

Cefepime dosing in children is typically based on body weight, with adjustments made for the severity of infection and specific indications. Close monitoring is essential to ensure both safety and efficacy in this population.

Elderly Patients

While age alone does not necessarily require dose adjustment, elderly patients are more likely to have reduced renal function. Therefore, careful assessment of renal function and appropriate dose modifications are crucial in this population.

How can healthcare providers ensure appropriate cefepime dosing across diverse patient populations? Individualized dosing strategies based on patient characteristics, infection site, and pathogen susceptibility are essential for optimizing treatment outcomes while minimizing the risk of adverse effects.

Potential Adverse Effects and Monitoring Considerations

While cefepime is generally well-tolerated, healthcare providers should be aware of potential adverse effects:

• Gastrointestinal disturbances (nausea, vomiting, diarrhea)
• Hypersensitivity reactions (rash, pruritus, anaphylaxis in rare cases)
• Neurotoxicity (particularly in patients with renal impairment)
• Hematologic effects (eosinophilia, neutropenia)
• Liver enzyme elevations
• Clostridium difficile-associated diarrhea

What specific monitoring is recommended for patients receiving cefepime? Regular assessment of renal function, complete blood counts, and liver function tests is advisable. Additionally, clinicians should remain vigilant for signs of neurotoxicity, particularly in patients with renal impairment or those receiving high doses.

Neurotoxicity: A Serious Concern

Cefepime-induced neurotoxicity can manifest as encephalopathy, seizures, or myoclonus. Risk factors include:

• Renal impairment
• Advanced age
• High doses or prolonged therapy
• Pre-existing neurological conditions

Early recognition and prompt discontinuation or dose adjustment of cefepime are crucial in managing this potentially serious adverse effect.

Drug Interactions and Precautions

While cefepime has a relatively favorable drug interaction profile, healthcare providers should be aware of potential interactions and take appropriate precautions:

Nephrotoxic Agents

Concurrent use of cefepime with other nephrotoxic drugs (e.g., aminoglycosides, vancomycin) may increase the risk of renal toxicity. Close monitoring of renal function is essential when combination therapy is necessary.

Probenecid

Probenecid can inhibit the renal excretion of cefepime, potentially leading to increased serum concentrations. Dose adjustments may be necessary when these drugs are used concomitantly.

Live Vaccines

As with other antibiotics, cefepime may reduce the effectiveness of live bacterial vaccines. Healthcare providers should consider the timing of vaccinations in relation to cefepime therapy.

How can healthcare providers minimize the risk of drug interactions with cefepime? Thorough medication reconciliation, careful consideration of concomitant therapies, and regular monitoring of patient response and potential adverse effects are key strategies for optimizing cefepime use while minimizing interaction risks.

Antimicrobial Stewardship Considerations

As a broad-spectrum antibiotic, cefepime plays a crucial role in antimicrobial stewardship programs. Healthcare providers should consider the following principles when prescribing cefepime:

• Reserve use for appropriate indications and susceptible pathogens
• Obtain cultures and susceptibility testing whenever possible before initiating therapy
• Consider de-escalation to narrower-spectrum agents when culture results become available
• Optimize dosing based on pharmacokinetic and pharmacodynamic principles
• Monitor for emergence of resistance during therapy
• Limit duration of therapy to the shortest effective course

Why is antimicrobial stewardship particularly important for broad-spectrum antibiotics like cefepime? Judicious use of these agents helps preserve their effectiveness, reduce the development of antimicrobial resistance, and minimize potential adverse effects associated with unnecessary antibiotic exposure.

Role of Rapid Diagnostic Tests

Implementing rapid diagnostic tests can enhance antimicrobial stewardship efforts by allowing for more targeted therapy. These tests can help identify pathogens and resistance patterns quickly, enabling clinicians to optimize cefepime use or switch to alternative agents when appropriate.

Future Directions and Research Opportunities

As the landscape of bacterial infections and antimicrobial resistance continues to evolve, ongoing research into cefepime and its clinical applications remains crucial. Some areas of active investigation include:

• Optimizing dosing strategies, including extended and continuous infusion protocols
• Exploring combination therapies to combat multidrug-resistant organisms
• Developing novel formulations or delivery methods to enhance efficacy or reduce toxicity
• Investigating the role of therapeutic drug monitoring in optimizing cefepime use
• Assessing the impact of cefepime on the gut microbiome and long-term health outcomes

How might advances in personalized medicine impact cefepime therapy in the future? As our understanding of individual patient factors, pathogen characteristics, and host-pathogen interactions improves, we may see more tailored approaches to cefepime dosing and administration, potentially leading to improved clinical outcomes and reduced adverse effects.

Emerging Technologies in Antibiotic Development

While cefepime remains a valuable antibiotic, research into new antimicrobial agents and alternative approaches to combat bacterial infections continues. Some promising areas include:

• Development of novel beta-lactam/beta-lactamase inhibitor combinations
• Exploration of bacteriophage therapy
• Investigation of antimicrobial peptides and immunomodulatory strategies
• Advancements in nanotechnology-based drug delivery systems

These emerging technologies may complement or enhance the use of cefepime in future clinical practice.

In conclusion, cefepime remains a crucial tool in the management of serious bacterial infections. By understanding its mechanisms of action, optimal dosing strategies, potential adverse effects, and role in antimicrobial stewardship, healthcare providers can maximize the benefits of this powerful antibiotic while minimizing risks. As research continues to advance our understanding of cefepime and related antimicrobial therapies, we can look forward to more refined and effective approaches to combating bacterial infections in the future.

Cefepime – StatPearls – NCBI Bookshelf

Continuing Education Activity

Cefepime is a cephalosporin in the beta-lactam class of antibiotics used to manage and treat gram-negative and gram-positive bacterial infections. This activity outlines the indications, mechanism of action, and contraindications for cefepime as a valuable agent in managing bacterial infections for hospitalized patients. This activity will highlight the mechanism of action, adverse effects, and other essential factors such as dosing and monitoring appropriate for all interprofessional team members when treating patients with cefepime.

Objectives:

• Describe the mechanism of action of cefepime.

• Review the chemical structures of cefepime vs. penicillin to explain why IgE mediated cross-reactivity reaction is unlikely.

• Summarize the possible toxic effects that cefepime.

• Outline interprofessional team approaches for improving care coordination for the safe use of cefepime that will reduce morbidity and improve patient safety.

Access free multiple choice questions on this topic.

Indications

Cefepime hydrochloride is a fourth-generation cephalosporin that belongs to a class of antibiotics known as beta-lactams. It is indicated to treat gram-positive and gram-negative bacterial infections that are susceptible to its activity. These include:[1][2]

• Pneumonia

• Complicated and uncomplicated urinary tract infections

• Skin and soft tissue infections

• Complicated intra-abdominal infections (with metronidazole)

• Empiric treatment for neutropenic fever

Selections of bacteria susceptible to cefepime are as follows: Streptococcus pneumoniae, Klebsiella pneumoniae, Enterobacter group, Haemophilus influenza, Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Streptococcus pyogenes, methicillin-susceptible Staphylococcus aureus, Streptococci viridans species, Bacteroides fragilis. 

An ever-growing number of bacteria are becoming resistant to the activity of beta-lactam, known as extended-spectrum beta-lactamase (ESBL) producing organisms. Many ESBL organisms are resistant to cefepime. However, there is a sub-group of ESBLs known as Amp-C producers that are susceptible. Although these organisms may be susceptible to cefepime, the minimum inhibitory concentration (MIC) and the dosing regimen must be carefully evaluated before treatment to ensure effective coverage.[3][4][5]

Mechanism of Action

Cefepime has a similar mechanism of action to other beta-lactams. Cefepime inhibits bacterial cell wall synthesis by covalently binding enzymes responsible for the final step in transpeptidation during peptidoglycan wall synthesis. This binding causes defects in the cell wall leading to autolysis and subsequent death of the organism. 

Cefepime has increased gram-negative coverage and is more stable against beta-lactamases when compared to third-generation cephalosporins due to a few mechanisms. One such mechanism is that penicillin-binding enzymes have a lower affinity for cefepime. Another is the chemical structure differs from older generations with a substitution of a side chain, lending it more activity against staphylococcal species. Cefepime is also a zwitterion giving it an advantage for faster cell wall penetration of gram-negative bacteria, which is why it has broader gram-negative coverage than the third-generation.

Cefepime, like most cephalosporins, is widely distributed throughout body tissue and fluids, including pleural fluid, synovial fluid, bones, cerebral spinal fluid, and breast milk. Cefepime rapidly metabolizes with less than 10% of the metabolized product undergoing excretion. The remaining compound gets excreted through glomerular filtration as an unchanged drug. The half-life is about 2 to 2.3 hours and is longer in patients with renal failure.[1][6]

Administration

Dosage Forms

• Intravenous solution as cefepime hydrochloride: 1 g / 50 mL (50 mL), 2 g / 100 mL (100 mL)

• Injection powder for reconstitution as cefepime hydrochloride: 500 mg (each vial), 1 g (each vial), 2 (each vial)

• Intravenous, Solution for reconstitution, as cefepime hydrochloride: 1 gm cefepime per 50 ml ( 5% w/v ) dextrose USP in water for injection

Dosing

Cefepime is not well absorbed by the gastrointestinal tract and must be administered intravenously (IV) or intramuscularly (IM). The most common method is by IV — typical administration is 1 to 2 g every 8 to 12 hours depending on the infection treated. Infusions are usually administered over 30 minutes. Studies have looked at extended infusions of 4 hours, showing lower overall mortality and reduced intensive care unit (ICU) lengths of stay compared with the standard 30-minute rate; however, other studies have failed to confirm these findings. Extended infusion rates for febrile neutropenia have been studied and appear feasible for treatment. 

Table

Urinary Tract Infections: Mild / Moderate, Uncomplicated / Complicated Urinary Tract Infections: Severe, Uncomplicated / Complicated

Specific Patient Population

Pediatric Patients: Pediatric administration is usually 50 mg/kg (up to a 40 kg child) every 8 to 12 hours. 

Hepatic Impairment: No adjustment in dosing is necessary for hepatic impairment.

Renal Impairment: The dose requires adjustment for patients with renal dysfunction, defined as a creatinine clearance less than or equal to 60 mL/min. Either daily dose is reduced, or dose is given at extended intervals for these patients.[7][8][9]

Pregnancy/Breastfeeding Implications: Cefepime is listed as pregnancy category B medicine, and it gets excreted in breast milk. Caution is necessary with cefepime in pregnant or breastfeeding women and should only be used if absolutely needed.[1]

Adverse Effects

Cefepime is usually well tolerated by both adults and pediatric patients. The most common adverse effects in adults are diarrhea and rash. The most common adverse effects in the pediatric population are fevers, diarrhea, and rash.

There are multitudes of other less common adverse effects listed according to the system affected:

• Neurological: headache, fever, and neurotoxicity

• Gastrointestinal: nausea, vomiting, abdominal pain, hepatic injury, colitis including pseudomembranous colitis, oral candidiasis

• Genitourinary: vaginitis, renal injury

• Dermatological: local site injection irritation, pruritus, urticaria, Stevens-Johnson syndrome, and erythema multiforme 

• Hematological: positive Coombs test without hemolysis, pancytopenia, and anaplastic anemia

Adverse effects typically reverse upon removal of the medication.

Neurotoxicity is a serious, life-threatening adverse effect that deserves special mention. Symptoms can present as altered mental status, encephalopathy, seizures, myoclonus, hallucinations, coma, and stroke-like symptoms. The onset of symptoms is typically four days after starting cefepime. Risk factors include renal failure (creatinine less than or equal to 60 mL/min), the aging adult, critically ill patients in ICU, strokes, Alzheimer disease, brain malignancy, seizure history, and a compromised blood-brain barrier (BBB). The theorized mechanism is that cefepime can cross the BBB and antagonize gamma-aminobutyric acid receptors.[10][11]

Treatment consists of stopping the drug, seizure management with benzodiazepines, or renal replacement therapy in severe refractory cases. It is important to monitor and adjust dosing with renal dysfunction; however, reports exist of neurotoxicity in patients with normal kidney function.[12][13][14]

Drug Interactions: Significant drug interaction exists when using cefepime. Concurrent use of cefepime with other aminoglycoside antibiotics increases the risk of cytotoxicity and nephrotoxicity. Concurrent use of cephalosporins (cefepime) and potent diuretics (e.g., furosemide) can result in nephrotoxicity. Monitor renal function when these medicines are administered to the patient.

Contraindications

Cefepime is contraindicated in patients with prior hypersensitivity reactions to the drug in the past.

Cephalosporins have a long history of being contraindicated in patients with severe hypersensitivity reactions to penicillin. Early testing of cephalosporins (up until the 1980s) came from the Penicillium mold of penicillin. The thinking is that these early cephalosporins were contaminated with penicillin and accounted for cross-reactivity allergic response. Thus, avoiding cephalosporins in patients with penicillin allergies likely developed from these early studies.[15][16]

Cephalosporins are similar to penicillins with the beta-lactam ring but differ by the various side chains. The similarities of these side chains to the penicillin structure account for the IgE mediated cross-reactivity and not the beta-lactam ring, as previously thought. The newer the generation of cephalosporins have, the greater difference in the side chain structures. A severe IgE mediated hypersensitivity reaction to cefepime in a penicillin-allergic patient is rare. It is worth mentioning that the delayed T-cell hypersensitivity reactions can still occur because T-cells can recognize the entire beta-lactam ring and the side chains.[17][18]

Caution is advisable with use in patients with compromised renal function (creatinine clearance less than or equal to 60 mL/min) as roughly 85% of the drug is excreted through the urine unchanged. Caution is necessary with cefepime in pregnant or breastfeeding women and should only be used if the benefits outweigh the risks.[1]

Monitoring

It is essential to monitor every patient for signs of a hypersensitivity reaction, especially if they have reacted to other beta-lactams in the past. In addition, since cefepime is often used empirically for broad-spectrum coverage, the culture sensitivities should have close monitoring to deescalate treatment to a narrow-spectrum antibiotic. 

Renal function should be monitored with blood urea nitrogen and serum creatinine, especially when administering to the aging adult or patients with pre-existing kidney dysfunction. In addition, it is essential to monitor for signs of neurological changes, particularly in the elderly, patients with renal dysfunction, and patients with febrile neutropenia. 

The effectiveness of cefepime can vary drastically with critically ill patients treated in the intensive care unit. Drug monitoring is suggested if the patient’s creatinine clearance is less than or equal to 50 mL/min or if the minimum inhibitory concentration (MIC) for the given pathogen is greater or equal to 4 mg/L. If treating outside of these parameters, then dose adjustment is indicated.[19][20][21]

Toxicity

In the event of a suspected overdose, the clinician should discontinue the drug or adjust the dose. Determining if the symptoms result from an actual cefepime overdose or preexisting comorbidities may be difficult. If suspicion is high or symptoms do not subside after dose adjusting or discontinuing, blood and/or cerebral spinal fluid levels should be obtained to evaluate if the toxicity stems from elevated cefepime levels. Dialysis may be necessary in severe cases.

Enhancing Healthcare Team Outcomes

Cefepime is a common antibiotic prescribed in the hospital setting. It is often prescribed empirically to septic patients before a pathogen is known, as it covers a broad spectrum of gram-positive and gram-negative bacteria. Therefore, all members of the health care team must monitor each patient for immediate hypersensitivity reactions after initial administration. 

Clinicians need to bear in mind that the drug’s pharmacokinetics can undergo alteration in patients with sepsis, renal dysfunction, or the older person leading to undesired peaks and troughs and potentially serious adverse effects. For example, if a patient exhibits a change in mental status or develops neurological signs such as seizure activity, the offending agent might be cefepime, and discontinuation or dose adjustment may be necessary. These changes are more likely to occur in patients with sepsis or renal dysfunction and the aging adult. However, cefepime can be overlooked as a possible source as it is a common medication given that is usually well tolerated.

The clinician will decide to treat the patient with cefepime, but a consult with a pharmacist, particularly one with board certification in infectious disease, might be in order. Pharmacists can review the antibiogram and verify dosing and duration. Nursing can counsel the patient on taking the medication, answering any questions, monitoring patient compliance and therapeutic effectiveness, and reporting any concerns to the prescriber. Cefepime therapy requires the collaborative effort of an interprofessional healthcare team to include physicians, specialty-trained nurses, pharmacists, and potentially infectious disease specialists, all working together to achieve optimal patient outcomes. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

References

1.

Chapman TM, Perry CM. Cefepime: a review of its use in the management of hospitalized patients with pneumonia. Am J Respir Med. 2003;2(1):75-107. [PubMed: 14720024]

2.

Rivera CG, Narayanan PP, Patel R, Estes LL. Impact of Cefepime Susceptible-Dose-Dependent MIC for Enterobacteriaceae on Reporting and Prescribing. Antimicrob Agents Chemother. 2016 Jun;60(6):3854-5. [PMC free article: PMC4879407] [PubMed: 27067319]

3.

Nguyen HM, Shier KL, Graber CJ. Determining a clinical framework for use of cefepime and β-lactam/β-lactamase inhibitors in the treatment of infections caused by extended-spectrum-β-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother. 2014 Apr;69(4):871-80. [PubMed: 24265230]

4.

Patel HB, Lusk KA, Cota JM. The Role of Cefepime in the Treatment of Extended-Spectrum Beta-Lactamase Infections. J Pharm Pract. 2019 Aug;32(4):458-463. [PubMed: 29166830]

5.

Walker KJ, Lee YR, Klar AR. Clinical Outcomes of Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae Infections with Susceptibilities among Levofloxacin, Cefepime, and Carbapenems. Can J Infect Dis Med Microbiol. 2018;2018:3747521. [PMC free article: PMC5833881] [PubMed: 29670677]

6.

Kessler RE. Cefepime microbiologic profile and update. Pediatr Infect Dis J. 2001 Mar;20(3):331-6. [PubMed: 11303846]

7.

Bauer KA, West JE, O’Brien JM, Goff DA. Extended-infusion cefepime reduces mortality in patients with Pseudomonas aeruginosa infections. Antimicrob Agents Chemother. 2013 Jul;57(7):2907-12. [PMC free article: PMC3697364] [PubMed: 23571547]

8.

Wrenn RH, Cluck D, Kennedy L, Ohl C, Williamson JC. Extended infusion compared to standard infusion cefepime as empiric treatment of febrile neutropenia. J Oncol Pharm Pract. 2018 Apr;24(3):170-175. [PubMed: 28077047]

9.

Zhu LL, Zhou Q. Optimal infusion rate in antimicrobial therapy explosion of evidence in the last five years. Infect Drug Resist. 2018;11:1105-1117. [PMC free article: PMC6089111] [PubMed: 30127628]

10.

Payne LE, Gagnon DJ, Riker RR, Seder DB, Glisic EK, Morris JG, Fraser GL. Cefepime-induced neurotoxicity: a systematic review. Crit Care. 2017 Nov 14;21(1):276. [PMC free article: PMC5686900] [PubMed: 29137682]

11.

Deshayes S, Coquerel A, Verdon R. Neurological Adverse Effects Attributable to β-Lactam Antibiotics: A Literature Review. Drug Saf. 2017 Dec;40(12):1171-1198. [PubMed: 28755095]

12.

Huwyler T, Lenggenhager L, Abbas M, Ing Lorenzini K, Hughes S, Huttner B, Karmime A, Uçkay I, von Dach E, Lescuyer P, Harbarth S, Huttner A. Cefepime plasma concentrations and clinical toxicity: a retrospective cohort study. Clin Microbiol Infect. 2017 Jul;23(7):454-459. [PubMed: 28111294]

13.

Isitan C, Ferree A, Hohler AD. Cefepime induced neurotoxicity: A case series and review of the literature. eNeurologicalSci. 2017 Sep;8:40-43. [PMC free article: PMC5730896] [PubMed: 29260037]

14.

Appa AA, Jain R, Rakita RM, Hakimian S, Pottinger PS. Characterizing Cefepime Neurotoxicity: A Systematic Review. Open Forum Infect Dis. 2017 Fall;4(4):ofx170. [PMC free article: PMC5639733] [PubMed: 29071284]

15.

Vorobeichik L, Weber EA, Tarshis J. Misconceptions Surrounding Penicillin Allergy: Implications for Anesthesiologists. Anesth Analg. 2018 Sep;127(3):642-649. [PubMed: 29757781]

16.

Pichichero ME, Zagursky R. Penicillin and cephalosporin allergy. Ann Allergy Asthma Immunol. 2014 May;112(5):404-12. [PubMed: 24767695]

17.

Mine Y, Nishida M, Goto S, Kuwahara S. Cefazolin, a new semisynthetic cephalosporin antibiotic. IV. Antigenicity of cefazolin and its cross reactivity with benzylpenicillin, ampicillin and cephaloridine. J Antibiot (Tokyo). 1970 Apr;23(4):195-203. [PubMed: 5429508]

18.

Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010 Oct;105(4):259-273. [PubMed: 20934625]

19.

Durand-Maugard C, Lemaire-Hurtel AS, Gras-Champel V, Hary L, Maizel J, Prud’homme-Bernardy A, Andréjak C, Andréjak M. Blood and CSF monitoring of cefepime-induced neurotoxicity: nine case reports. J Antimicrob Chemother. 2012 May;67(5):1297-9. [PubMed: 22298349]

20.

Lamoth F, Buclin T, Pascual A, Vora S, Bolay S, Decosterd LA, Calandra T, Marchetti O. High cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients with mild impairment of renal function. Antimicrob Agents Chemother. 2010 Oct;54(10):4360-7. [PMC free article: PMC2944571] [PubMed: 20625153]

21.

Chapuis TM, Giannoni E, Majcherczyk PA, Chioléro R, Schaller MD, Berger MM, Bolay S, Décosterd LA, Bugnon D, Moreillon P. Prospective monitoring of cefepime in intensive care unit adult patients. Crit Care. 2010;14(2):R51. [PMC free article: PMC2887166] [PubMed: 20359352]

22.

Endimiani A, Perez F, Bonomo RA. Cefepime: a reappraisal in an era of increasing antimicrobial resistance. Expert Rev Anti Infect Ther. 2008 Dec;6(6):805-24. [PMC free article: PMC2633657] [PubMed: 19053894]

Disclosure: Audrey O’Connor declares no relevant financial relationships with ineligible companies.

Disclosure: Michael Lopez declares no relevant financial relationships with ineligible companies.

Disclosure: Ambika Eranki declares no relevant financial relationships with ineligible companies.

Cefepime – StatPearls – NCBI Bookshelf

Continuing Education Activity

Cefepime is a cephalosporin in the beta-lactam class of antibiotics used to manage and treat gram-negative and gram-positive bacterial infections. This activity outlines the indications, mechanism of action, and contraindications for cefepime as a valuable agent in managing bacterial infections for hospitalized patients. This activity will highlight the mechanism of action, adverse effects, and other essential factors such as dosing and monitoring appropriate for all interprofessional team members when treating patients with cefepime.

Objectives:

• Describe the mechanism of action of cefepime.

• Review the chemical structures of cefepime vs. penicillin to explain why IgE mediated cross-reactivity reaction is unlikely.

• Summarize the possible toxic effects that cefepime.

• Outline interprofessional team approaches for improving care coordination for the safe use of cefepime that will reduce morbidity and improve patient safety.

Access free multiple choice questions on this topic.

Indications

Cefepime hydrochloride is a fourth-generation cephalosporin that belongs to a class of antibiotics known as beta-lactams. It is indicated to treat gram-positive and gram-negative bacterial infections that are susceptible to its activity. These include:[1][2]

• Pneumonia

• Complicated and uncomplicated urinary tract infections

• Skin and soft tissue infections

• Complicated intra-abdominal infections (with metronidazole)

• Empiric treatment for neutropenic fever

Selections of bacteria susceptible to cefepime are as follows: Streptococcus pneumoniae, Klebsiella pneumoniae, Enterobacter group, Haemophilus influenza, Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Streptococcus pyogenes, methicillin-susceptible Staphylococcus aureus, Streptococci viridans species, Bacteroides fragilis. 

An ever-growing number of bacteria are becoming resistant to the activity of beta-lactam, known as extended-spectrum beta-lactamase (ESBL) producing organisms. Many ESBL organisms are resistant to cefepime. However, there is a sub-group of ESBLs known as Amp-C producers that are susceptible. Although these organisms may be susceptible to cefepime, the minimum inhibitory concentration (MIC) and the dosing regimen must be carefully evaluated before treatment to ensure effective coverage.[3][4][5]

Mechanism of Action

Cefepime has a similar mechanism of action to other beta-lactams. Cefepime inhibits bacterial cell wall synthesis by covalently binding enzymes responsible for the final step in transpeptidation during peptidoglycan wall synthesis. This binding causes defects in the cell wall leading to autolysis and subsequent death of the organism. 

Cefepime has increased gram-negative coverage and is more stable against beta-lactamases when compared to third-generation cephalosporins due to a few mechanisms. One such mechanism is that penicillin-binding enzymes have a lower affinity for cefepime. Another is the chemical structure differs from older generations with a substitution of a side chain, lending it more activity against staphylococcal species. Cefepime is also a zwitterion giving it an advantage for faster cell wall penetration of gram-negative bacteria, which is why it has broader gram-negative coverage than the third-generation.

Cefepime, like most cephalosporins, is widely distributed throughout body tissue and fluids, including pleural fluid, synovial fluid, bones, cerebral spinal fluid, and breast milk. Cefepime rapidly metabolizes with less than 10% of the metabolized product undergoing excretion. The remaining compound gets excreted through glomerular filtration as an unchanged drug. The half-life is about 2 to 2.3 hours and is longer in patients with renal failure.[1][6]

Administration

Dosage Forms

• Intravenous solution as cefepime hydrochloride: 1 g / 50 mL (50 mL), 2 g / 100 mL (100 mL)

• Injection powder for reconstitution as cefepime hydrochloride: 500 mg (each vial), 1 g (each vial), 2 (each vial)

• Intravenous, Solution for reconstitution, as cefepime hydrochloride: 1 gm cefepime per 50 ml ( 5% w/v ) dextrose USP in water for injection

Dosing

Cefepime is not well absorbed by the gastrointestinal tract and must be administered intravenously (IV) or intramuscularly (IM). The most common method is by IV — typical administration is 1 to 2 g every 8 to 12 hours depending on the infection treated. Infusions are usually administered over 30 minutes. Studies have looked at extended infusions of 4 hours, showing lower overall mortality and reduced intensive care unit (ICU) lengths of stay compared with the standard 30-minute rate; however, other studies have failed to confirm these findings. Extended infusion rates for febrile neutropenia have been studied and appear feasible for treatment. 

Table

Urinary Tract Infections: Mild / Moderate, Uncomplicated / Complicated Urinary Tract Infections: Severe, Uncomplicated / Complicated

Specific Patient Population

Pediatric Patients: Pediatric administration is usually 50 mg/kg (up to a 40 kg child) every 8 to 12 hours. 

Hepatic Impairment: No adjustment in dosing is necessary for hepatic impairment.

Renal Impairment: The dose requires adjustment for patients with renal dysfunction, defined as a creatinine clearance less than or equal to 60 mL/min. Either daily dose is reduced, or dose is given at extended intervals for these patients.[7][8][9]

Pregnancy/Breastfeeding Implications: Cefepime is listed as pregnancy category B medicine, and it gets excreted in breast milk. Caution is necessary with cefepime in pregnant or breastfeeding women and should only be used if absolutely needed.[1]

Adverse Effects

Cefepime is usually well tolerated by both adults and pediatric patients. The most common adverse effects in adults are diarrhea and rash. The most common adverse effects in the pediatric population are fevers, diarrhea, and rash.

There are multitudes of other less common adverse effects listed according to the system affected:

• Neurological: headache, fever, and neurotoxicity

• Gastrointestinal: nausea, vomiting, abdominal pain, hepatic injury, colitis including pseudomembranous colitis, oral candidiasis

• Genitourinary: vaginitis, renal injury

• Dermatological: local site injection irritation, pruritus, urticaria, Stevens-Johnson syndrome, and erythema multiforme 

• Hematological: positive Coombs test without hemolysis, pancytopenia, and anaplastic anemia

Adverse effects typically reverse upon removal of the medication.

Neurotoxicity is a serious, life-threatening adverse effect that deserves special mention. Symptoms can present as altered mental status, encephalopathy, seizures, myoclonus, hallucinations, coma, and stroke-like symptoms. The onset of symptoms is typically four days after starting cefepime. Risk factors include renal failure (creatinine less than or equal to 60 mL/min), the aging adult, critically ill patients in ICU, strokes, Alzheimer disease, brain malignancy, seizure history, and a compromised blood-brain barrier (BBB). The theorized mechanism is that cefepime can cross the BBB and antagonize gamma-aminobutyric acid receptors.[10][11]

Treatment consists of stopping the drug, seizure management with benzodiazepines, or renal replacement therapy in severe refractory cases. It is important to monitor and adjust dosing with renal dysfunction; however, reports exist of neurotoxicity in patients with normal kidney function.[12][13][14]

Drug Interactions: Significant drug interaction exists when using cefepime. Concurrent use of cefepime with other aminoglycoside antibiotics increases the risk of cytotoxicity and nephrotoxicity. Concurrent use of cephalosporins (cefepime) and potent diuretics (e.g., furosemide) can result in nephrotoxicity. Monitor renal function when these medicines are administered to the patient.

Contraindications

Cefepime is contraindicated in patients with prior hypersensitivity reactions to the drug in the past.

Cephalosporins have a long history of being contraindicated in patients with severe hypersensitivity reactions to penicillin. Early testing of cephalosporins (up until the 1980s) came from the Penicillium mold of penicillin. The thinking is that these early cephalosporins were contaminated with penicillin and accounted for cross-reactivity allergic response. Thus, avoiding cephalosporins in patients with penicillin allergies likely developed from these early studies.[15][16]

Cephalosporins are similar to penicillins with the beta-lactam ring but differ by the various side chains. The similarities of these side chains to the penicillin structure account for the IgE mediated cross-reactivity and not the beta-lactam ring, as previously thought. The newer the generation of cephalosporins have, the greater difference in the side chain structures. A severe IgE mediated hypersensitivity reaction to cefepime in a penicillin-allergic patient is rare. It is worth mentioning that the delayed T-cell hypersensitivity reactions can still occur because T-cells can recognize the entire beta-lactam ring and the side chains.[17][18]

Caution is advisable with use in patients with compromised renal function (creatinine clearance less than or equal to 60 mL/min) as roughly 85% of the drug is excreted through the urine unchanged. Caution is necessary with cefepime in pregnant or breastfeeding women and should only be used if the benefits outweigh the risks.[1]

Monitoring

It is essential to monitor every patient for signs of a hypersensitivity reaction, especially if they have reacted to other beta-lactams in the past. In addition, since cefepime is often used empirically for broad-spectrum coverage, the culture sensitivities should have close monitoring to deescalate treatment to a narrow-spectrum antibiotic. 

Renal function should be monitored with blood urea nitrogen and serum creatinine, especially when administering to the aging adult or patients with pre-existing kidney dysfunction. In addition, it is essential to monitor for signs of neurological changes, particularly in the elderly, patients with renal dysfunction, and patients with febrile neutropenia. 

The effectiveness of cefepime can vary drastically with critically ill patients treated in the intensive care unit. Drug monitoring is suggested if the patient’s creatinine clearance is less than or equal to 50 mL/min or if the minimum inhibitory concentration (MIC) for the given pathogen is greater or equal to 4 mg/L. If treating outside of these parameters, then dose adjustment is indicated.[19][20][21]

Toxicity

In the event of a suspected overdose, the clinician should discontinue the drug or adjust the dose. Determining if the symptoms result from an actual cefepime overdose or preexisting comorbidities may be difficult. If suspicion is high or symptoms do not subside after dose adjusting or discontinuing, blood and/or cerebral spinal fluid levels should be obtained to evaluate if the toxicity stems from elevated cefepime levels. Dialysis may be necessary in severe cases.

Enhancing Healthcare Team Outcomes

Cefepime is a common antibiotic prescribed in the hospital setting. It is often prescribed empirically to septic patients before a pathogen is known, as it covers a broad spectrum of gram-positive and gram-negative bacteria. Therefore, all members of the health care team must monitor each patient for immediate hypersensitivity reactions after initial administration. 

Clinicians need to bear in mind that the drug’s pharmacokinetics can undergo alteration in patients with sepsis, renal dysfunction, or the older person leading to undesired peaks and troughs and potentially serious adverse effects. For example, if a patient exhibits a change in mental status or develops neurological signs such as seizure activity, the offending agent might be cefepime, and discontinuation or dose adjustment may be necessary. These changes are more likely to occur in patients with sepsis or renal dysfunction and the aging adult. However, cefepime can be overlooked as a possible source as it is a common medication given that is usually well tolerated.

The clinician will decide to treat the patient with cefepime, but a consult with a pharmacist, particularly one with board certification in infectious disease, might be in order. Pharmacists can review the antibiogram and verify dosing and duration. Nursing can counsel the patient on taking the medication, answering any questions, monitoring patient compliance and therapeutic effectiveness, and reporting any concerns to the prescriber. Cefepime therapy requires the collaborative effort of an interprofessional healthcare team to include physicians, specialty-trained nurses, pharmacists, and potentially infectious disease specialists, all working together to achieve optimal patient outcomes. [Level 5]

Review Questions

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• Comment on this article.

References

1.

Chapman TM, Perry CM. Cefepime: a review of its use in the management of hospitalized patients with pneumonia. Am J Respir Med. 2003;2(1):75-107. [PubMed: 14720024]

2.

Rivera CG, Narayanan PP, Patel R, Estes LL. Impact of Cefepime Susceptible-Dose-Dependent MIC for Enterobacteriaceae on Reporting and Prescribing. Antimicrob Agents Chemother. 2016 Jun;60(6):3854-5. [PMC free article: PMC4879407] [PubMed: 27067319]

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Nguyen HM, Shier KL, Graber CJ. Determining a clinical framework for use of cefepime and β-lactam/β-lactamase inhibitors in the treatment of infections caused by extended-spectrum-β-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother. 2014 Apr;69(4):871-80. [PubMed: 24265230]

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Patel HB, Lusk KA, Cota JM. The Role of Cefepime in the Treatment of Extended-Spectrum Beta-Lactamase Infections. J Pharm Pract. 2019 Aug;32(4):458-463. [PubMed: 29166830]

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Walker KJ, Lee YR, Klar AR. Clinical Outcomes of Extended-Spectrum Beta-Lactamase-Producing Enterobacteriaceae Infections with Susceptibilities among Levofloxacin, Cefepime, and Carbapenems. Can J Infect Dis Med Microbiol. 2018;2018:3747521. [PMC free article: PMC5833881] [PubMed: 29670677]

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Kessler RE. Cefepime microbiologic profile and update. Pediatr Infect Dis J. 2001 Mar;20(3):331-6. [PubMed: 11303846]

7.

Bauer KA, West JE, O’Brien JM, Goff DA. Extended-infusion cefepime reduces mortality in patients with Pseudomonas aeruginosa infections. Antimicrob Agents Chemother. 2013 Jul;57(7):2907-12. [PMC free article: PMC3697364] [PubMed: 23571547]

8.

Wrenn RH, Cluck D, Kennedy L, Ohl C, Williamson JC. Extended infusion compared to standard infusion cefepime as empiric treatment of febrile neutropenia. J Oncol Pharm Pract. 2018 Apr;24(3):170-175. [PubMed: 28077047]

9.

Zhu LL, Zhou Q. Optimal infusion rate in antimicrobial therapy explosion of evidence in the last five years. Infect Drug Resist. 2018;11:1105-1117. [PMC free article: PMC6089111] [PubMed: 30127628]

10.

Payne LE, Gagnon DJ, Riker RR, Seder DB, Glisic EK, Morris JG, Fraser GL. Cefepime-induced neurotoxicity: a systematic review. Crit Care. 2017 Nov 14;21(1):276. [PMC free article: PMC5686900] [PubMed: 29137682]

11.

Deshayes S, Coquerel A, Verdon R. Neurological Adverse Effects Attributable to β-Lactam Antibiotics: A Literature Review. Drug Saf. 2017 Dec;40(12):1171-1198. [PubMed: 28755095]

12.

Huwyler T, Lenggenhager L, Abbas M, Ing Lorenzini K, Hughes S, Huttner B, Karmime A, Uçkay I, von Dach E, Lescuyer P, Harbarth S, Huttner A. Cefepime plasma concentrations and clinical toxicity: a retrospective cohort study. Clin Microbiol Infect. 2017 Jul;23(7):454-459. [PubMed: 28111294]

13.

Isitan C, Ferree A, Hohler AD. Cefepime induced neurotoxicity: A case series and review of the literature. eNeurologicalSci. 2017 Sep;8:40-43. [PMC free article: PMC5730896] [PubMed: 29260037]

14.

Appa AA, Jain R, Rakita RM, Hakimian S, Pottinger PS. Characterizing Cefepime Neurotoxicity: A Systematic Review. Open Forum Infect Dis. 2017 Fall;4(4):ofx170. [PMC free article: PMC5639733] [PubMed: 29071284]

15.

Vorobeichik L, Weber EA, Tarshis J. Misconceptions Surrounding Penicillin Allergy: Implications for Anesthesiologists. Anesth Analg. 2018 Sep;127(3):642-649. [PubMed: 29757781]

16.

Pichichero ME, Zagursky R. Penicillin and cephalosporin allergy. Ann Allergy Asthma Immunol. 2014 May;112(5):404-12. [PubMed: 24767695]

17.

Mine Y, Nishida M, Goto S, Kuwahara S. Cefazolin, a new semisynthetic cephalosporin antibiotic. IV. Antigenicity of cefazolin and its cross reactivity with benzylpenicillin, ampicillin and cephaloridine. J Antibiot (Tokyo). 1970 Apr;23(4):195-203. [PubMed: 5429508]

18.

Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010 Oct;105(4):259-273. [PubMed: 20934625]

19.

Durand-Maugard C, Lemaire-Hurtel AS, Gras-Champel V, Hary L, Maizel J, Prud’homme-Bernardy A, Andréjak C, Andréjak M. Blood and CSF monitoring of cefepime-induced neurotoxicity: nine case reports. J Antimicrob Chemother. 2012 May;67(5):1297-9. [PubMed: 22298349]

20.

Lamoth F, Buclin T, Pascual A, Vora S, Bolay S, Decosterd LA, Calandra T, Marchetti O. High cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients with mild impairment of renal function. Antimicrob Agents Chemother. 2010 Oct;54(10):4360-7. [PMC free article: PMC2944571] [PubMed: 20625153]

21.

Chapuis TM, Giannoni E, Majcherczyk PA, Chioléro R, Schaller MD, Berger MM, Bolay S, Décosterd LA, Bugnon D, Moreillon P. Prospective monitoring of cefepime in intensive care unit adult patients. Crit Care. 2010;14(2):R51. [PMC free article: PMC2887166] [PubMed: 20359352]

22.

Endimiani A, Perez F, Bonomo RA. Cefepime: a reappraisal in an era of increasing antimicrobial resistance. Expert Rev Anti Infect Ther. 2008 Dec;6(6):805-24. [PMC free article: PMC2633657] [PubMed: 19053894]

Disclosure: Audrey O’Connor declares no relevant financial relationships with ineligible companies.

Disclosure: Michael Lopez declares no relevant financial relationships with ineligible companies.

Disclosure: Ambika Eranki declares no relevant financial relationships with ineligible companies.

Cefepime powder for solution for injection 1 g Lekhim-Kharkov

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• Pharmacological properties
• Readings
• Contraindications
• Interaction with other medicinal products and other forms of interaction
• Dosage and Administration
• Overdose
• Adverse reactions
• Expiry date
• Storage conditions
• Diagnosis
• Recommended alternatives
• Trade names

Composition:

active ingredient: cefepime;

1 vial contains cefepime (as cefepime hydrochloride) 1.0 g;

excipient: L-arginine.

Dosage form

Powder for solution for injection.

Basic physical and chemical properties: white to light yellow powder.

Pharmacotherapeutic group

Antimicrobial agents for systemic use. β-lactam antibiotics. Fourth generation cephalosporins. ATX code J01D E01.

Pharmacological properties

Pharmacodynamics.

Cefepime inhibits the synthesis of bacterial cell wall enzymes and has a wide spectrum of activity against various Gram-positive and Gram-negative bacteria. Cefepime is highly resistant to hydrolysis by most b-lactamases, has little affinity for b-lactamases encoded by chromosomal genes, and rapidly penetrates Gram-negative bacterial cells.

Spectrum of antibacterial activity.

The following types of microorganisms are sensitive to cefepime:

Gram-positive aerobes: Staphylococcus , methicillin resistant , Streptococcus , Streptococcus pneumonia ;

Gram-negative aerobes: Acinetobacter baumannii , Branhamella catarrhalis , Citrobacter freundii , Citrobacter koseri , Enterobacter , Escherichia coli , Haemophilus influenza , Klebsiella , Morganella morganii , Neisseria , Proteus mirabilis , Proteus vulgaris , Providencia , Salmonella , Serratia , Shigella ;

anaerobes: Clostridium perfringens , Fusobacterium , Peptostreptococcus , Prevotella.

Moderately sensitive to cefepime ( in vitro ) the following types of microorganisms:

Pseudomonas aeruginosa (gram-negative aerobes).

The following types of microorganisms are resistant to cefepim:

Gram-negative aerobes: Burkholderia cepacia , Stenotrophomonas maltophilia ;

anaerobes: Bacteroides fragilis , Clostridium difficile.

* The frequency of resistance to methicillin is approximately 30-50% of all staphylococci and in most cases is characteristic of hospitals.

Pharmacokinetics.

The pharmacokinetics of cefepime is linear over the dose range of 250 mg – 2 g (intravenously) and 500 mg – 2 g (intramuscularly) and is unchanged during the entire period of therapy.

After intramuscular administration, absorption is rapid and complete.

Distribution. Mean plasma concentrations of cefepime after a single 30-minute intravenous infusion of 250 mg, 500 mg, 1 g, 2 g or after a single intramuscular injection of 500 mg, 1 g, 2 g in men are shown in Table 1.

Plasma concentrations of cefepime blood (µg/ml)

intravenous (IV) and intramuscular (IM) administration

Table 1

0.5 hours 1 hour 2 hours 4 hours 8 hours 12 hours 1 g i.v. 78.7 44.5 24.3 10.5 2.4 0.6 1 g i.m. 14.8 25.9 26.3 16.0 4.5 1.4

The distribution of cefepime in tissues does not change in the dose range of 250–2000 mg. The mean volume of distribution at steady state is 18 liters. The average half-life is 2 hours. Accumulation of the drug was not observed in patients taking the drug at a dose of 2 g intravenously every 8 hours for 9days. Binding to blood proteins is below 19% and does not depend on the concentration of cefepime in the blood plasma. The half-life is longer in patients with renal insufficiency.

Metabolism. Cefepime is not metabolized. Approximately 7% of the dose taken is converted to N-methylpyrrolidine, which is rapidly converted to N-methylpyrrolidine oxide and excreted in the urine.

Removal . The average total clearance is 120 ml / min. The average total renal clearance of cefepime is 110 ml / min, its elimination occurs mainly by glomerular filtration. 85% of the administered dose is excreted unchanged in the urine. After intravenous administration of 500 mg of cefepime, its concentration in blood plasma is below the level of quantitative determination after 12 hours, in urine – after 16 hours. The average concentration in the urine 12-16 hours after administration is 17.8 μg / ml. After intravenous administration of 1 g or 2 g of cefepime, the average concentration in the urine in the time interval of 12-24 hours is 26.5 and 28.8 μg / ml, respectively. After 24 hours, the plasma concentration of cefepime is below the level of quantitation.

In patients with impaired liver function, after a single administration of 1 g of cefepime, its pharmacokinetics did not change. Therefore, there is no need to change the dosing regimen.

The distribution of cefepime in elderly patients has only been studied in patients with normal renal function. In the treatment of this group of patients, there is no need to change the dosing regimen.

The pharmacokinetics of cefepime in children over 2 months of age do not differ from those in adults.

In patients with impaired renal function of varying degrees, the half-life of the drug is significantly increased. There is a linear correlation between total clearance and creatinine clearance in patients with impaired renal function. The half-life of cefepime in dialysis patients is 13-17 hours.

Clinical characteristics

Indications

Infections susceptible to cefepime.

Adults:

• septicemia;
• intra-abdominal infections, including peritonitis and biliary tract infections;
• skin and subcutaneous tissue infections;

• gynecological infections;
• respiratory tract infections, including pneumonia, bronchitis;
• prevention of postoperative complications in intra-abdominal surgery;
• empirical therapy of patients with neutropenic fever.

Children:

• pneumonia;
• urinary tract infections, including pyelonephritis;
• skin and subcutaneous tissue infections;
• septicemia;
• empirical therapy of patients with neutropenic fever;
• bacterial meningitis.

Contraindications

Hypersensitivity to cephalosporin antibiotics or L-arginine, penicillins or other β-lactam antibiotics.

Interaction with other medicinal products and other forms of interaction

There may be cases of increased activity of oral anticoagulants in patients receiving cephalosporins.

When using high doses of aminoglycosides concomitantly with Cefepime, renal function should be closely monitored due to potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity has been reported following concomitant use of other cephalosporins with diuretics such as furosemide.

Cefepime is compatible with the following solvents: water for injection, 0. 9% sodium chloride solution for injection (with or without 5% glucose solution), 5% and 10% glucose solutions for injection, 1/6M sodium lactate solution for injection, solution Ringer’s lactate (with or without 5% glucose solution), lidocaine hydrochloride solution.

As with other cephalosporins, the reconstituted solution may turn yellow-amber, but this does not indicate a loss of activity.

To avoid possible drug interactions with other drugs, the 5% solution of the drug (like most other β-lactam antibiotics) is not administered simultaneously with solutions of metronidazole, vancomycin, gentamicin, tobramycin sulfate and netilmicin sulfate. In the case of the simultaneous appointment of Cefepime with these drugs, each antibiotic is administered separately.

Application features.

If an allergic reaction occurs, the drug should be discontinued.

Serious immediate hypersensitivity reactions may require the use of epinephrine and other forms of intensive care.

Before starting treatment with cefepime, a careful history should be taken to determine if the patient has a hypersensitivity reaction to cefepime or any other cephalosporin, penicillin, or β-lactam antibiotics.

Antibiotics should be used with caution in all patients with any form of allergy, especially to drugs. If in doubt, a doctor must be present at the first injection to take immediate action in the event of an anaphylactic reaction.

Cases of pseudomembranous colitis have been reported with almost all broad-spectrum antibiotics. Therefore, it is important to consider the possibility of developing this pathology in the event of diarrhea during treatment with the drug. Mild forms of colitis may disappear after the use of the drug, moderate or severe conditions may require special treatment.

The occurrence of diarrhea may indicate the presence of pseudomembranous colitis, the diagnosis of which is based on colonoscopy. This phenomenon requires immediate discontinuation of treatment and the initiation of appropriate specific therapy.

Since renal function declines with age, the dose for elderly patients should be adjusted according to the state of renal function in each individual patient.

Patients with normal renal function do not require dose adjustment. It is advisable to monitor renal function while using cefepime with potentially nephrotoxic antibiotics (especially aminoglycosides) and strong diuretics.

Cephalosporins tend to be absorbed onto the surface of red blood cells and react with antibodies directed against the drugs, resulting in a positive Coombs test. In patients treated with cefepime 2 times a day, a positive Coombs test has been described in the absence of signs of hemolysis.

In patients at high risk of developing severe infections (eg, patients with a history of bone marrow transplantation with decreased activity that occurs in the background of malignant hemolytic disease with severe progressive neutropenia), monotherapy may not be sufficient, therefore complex antimicrobial therapy is indicated. therapy.

False-positive results may occur when testing for glucosuria. For this reason, the determination of glucose in the urine during treatment with Cefepime should be carried out by glucose oxidase methods.

As with other antibiotics, the use of Cefepime may lead to colonization with non-susceptible microflora. In the event of the development of superinfections during treatment, appropriate measures must be taken.

Use during pregnancy or lactation.

Pregnancy.

Clinical data on the use of cefepime in women during pregnancy is insufficient. Cefepime should only be given to pregnant women when the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period.

In small concentrations, cefepime passes into breast milk. Therefore, if cefepime is prescribed, breastfeeding should be discontinued.

The ability to influence the reaction rate when driving vehicles or operating other mechanisms.

The effect on the ability to drive a car and use mechanisms has not been studied, however, when using the drug, the possibility of adverse reactions from the nervous system should be taken into account.

Method of administration and doses

Before using the drug, a skin test for tolerance should be done.

The usual adult dosage is 1 g administered intravenously or intramuscularly at intervals of 12 hours. The usual duration of treatment is 7–10 days; in severe infections, longer treatment is possible.

Dosage and route of administration vary depending on the sensitivity of pathogens, the severity of the infection, and the functional state of the patient’s kidneys. Dosing recommendations for Cefepime for adults are shown in Table 2.

Table 2

Mild to moderate urinary tract infections	500 mg – 1 g IV or IM	every 12 hours
Other mild to moderate infections	1 g IV or IM	every 12 hours
Severe infections	2 g i. v.	every 12 hours
Very severe and life-threatening infections	2 g i.v.	every 8 hours

For the prevention of infections during surgical interventions .

60 minutes before surgery, adults are given 2 g intravenously over 30 minutes. At the end, an additional 500 mg of metronidazole is administered intravenously. Metronidazole solutions should not be co-administered with Cefepime. The system for infusion before the introduction of metronidazole must be flushed.

During prolonged (more than 12 hours) surgery, 12 hours after the first dose, it is recommended to repeat the administration of an equal dose of Cefepime, followed by the administration of metronidazole.

Impaired kidney function. Cefepime is excreted by the kidneys by glomerular filtration, therefore, in patients with impaired renal function (creatinine clearance less than 30 ml / min), the dose of Cefepime should be adjusted.

Recommended doses of cefepime for adults

Table 3

Creatinine clearance (ml/min)	Recommended doses
50	Usual dosage appropriate for severity of infection (see previous table), no dose adjustment needed
	2 g every 8 hours	2 g every 12 hours	1 g every 12 hours	500 mg every 12 hours
30-50	Dose adjustment according to creatinine clearance
	2 g every 12 hours	2 g every 24 hours	1 g every 24 hours	500 mg every 24 hours
11-29	2 g every 24 hours	1 g every 24 hours	500 mg every 24 hours	500 mg every 24 hours
≤10	1 g every 24 hours	500 mg every 24 hours	250 mg every 24 hours	250 mg every 24 hours
Hemodialysis *	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours	500 mg every 24 hours

* On the day of dialysis, the injection must be given after the dialysis session.

If only the serum creatinine concentration is known, then the creatinine clearance can be determined using the following formula.

Men:

body weight (kg) x (140 – age)

creatinine clearance (ml/min) = —————————————————.

72 x serum creatinine (mg/dl)

Women:

creatinine clearance (ml/min) = value from above formula x 0.85.

During hemodialysis, approximately 68% of the drug dose is excreted from the body in 3 hours. After completion of each dialysis session, it is necessary to administer a repeated dose equal to the original dose. For continuous ambulatory peritoneal dialysis, the drug can be used at the initial normal recommended doses of 500 mg, 1 g or 2 g, depending on the severity of the infection, with an interval of 48 hours.

Children from 1 to 2 months . Cefepime is prescribed only for health reasons at the rate of 30 mg/kg of body weight every 12 or 8 hours, depending on the severity of the infection. The condition of children weighing up to 40 kg receiving treatment with Cefepime should be constantly monitored.

Children from 2 months . The maximum dose for children should not exceed the recommended dose for adults. The usual recommended dose for children weighing up to 40 kg with complicated or uncomplicated urinary tract infections (including pyelonephritis), uncomplicated skin infections, pneumonia, and in the case of empirical treatment of febrile neutropenia is 50 mg / kg every 12 hours (patients with febrile neutropenia and bacterial meningitis every 8 hours). The usual duration of treatment is 7-10 days, severe infections may require longer treatment. For children weighing 40 kg or more, Cefepime is prescribed in doses prescribed for

adults.

Children with impaired renal function are advised to reduce the dose or increase the interval between injections.

Calculation of creatinine clearance in children:

0.55 x height (cm)

creatinine clearance (ml/min/1. 73 m ² ) = —————————————— —

Serum creatinine (mg/dl)

or

0.52 x height (cm)

creatinine clearance (ml/min/1.73 m ² ) = ————————————————3.6

Serum creatinine (mg/dl)

Cefepime can be administered by deep intramuscular injection (0.5 g and 1 g), slow intravenous injection or infusion (from 3-5 minutes to 30 minutes).

Intravenous administration . Cefepime is dissolved in water for injection or any other compatible solvent at the concentrations shown in Table 4. Solutions for intravenous administration can be administered directly into a vein by slow (3-5 minutes) injection through an intravenous line or directly into a co-infusion solution (time infusion – 30 minutes).

When administered intravenously, Cefepime is compatible with the following solvents: water for injection, 0.9% sodium chloride solution for injection (with or without 5% glucose solution), 5 and 10% glucose solutions for injection, 1/6M sodium lactate solution for injection, Ringer’s lactate solution (with or without 5% glucose solution).

Intramuscular injection . Cefepime can be dissolved in water for injection, 0.9% sodium chloride solution for injection, 5% glucose solution for injection, bacteriostatic water for injection with paraben or benzyl alcohol, 0.5% or 1% lidocaine hydrochloride solution at the concentrations indicated in table 4.

When using lidocaine as a diluent, a skin test should be done before administration to determine its tolerance.

Table 4

	Volume of solution for dilution (ml)	Approximate volume of solution obtained (ml)	Approximate concentration of cefepime (mg/ml)
IV: 1 g/vial	10	11.4	90
Intramuscular administration: 1 g/bottle	3	4.4	230

As with other drugs used parenterally, prepared solutions of the drug must be checked for the absence of mechanical impurities before administration.

Appropriate microbiological testing is required to identify the causative organism(s) and determine susceptibility to cefepime. However, cefepime can be used as monotherapy even before the identification of the causative organism, as it has a wide spectrum of antibacterial activity against gram-positive and gram-negative microorganisms. In patients at risk of mixed aerobic-anaerobic (including Bacteroides fragilis ) infection, treatment with Cefepime in combination with an anaerobic drug can be started until the pathogen is identified.

Children.

The drug is used for children from 1 month.

Overdose

Symptoms. In cases of significant excess of the recommended doses, especially in patients with impaired renal function, side effects increase. Overdose symptoms include encephalopathy, which is accompanied by hallucinations, impaired consciousness, stupor, coma, myoclonus, epileptoform seizures, neuromuscular agitation.

Treatment . It is necessary to stop the administration of the drug, conduct symptomatic therapy. The use of hemodialysis accelerates the removal of cefepime from the body; peritoneal dialysis is ineffective. Severe allergic reactions of the immediate type require the use of adrenaline and other forms of intensive care.

Adverse reactions

Cefepime is generally well tolerated.

Allergic reactions: rash, pruritus, urticaria, erythema, anaphylactic shock, fever.

From the gastrointestinal tract: diarrhea, nausea, vomiting, constipation, abdominal pain, dyspepsia, stomatitis, colitis (including pseudomembranous).

From the side of the cardiovascular system: chest pain, tachycardia.

From the side of the hematopoietic system: agranulocytosis, hypereosinophilia, neutropenia, thrombopenia, prolongation of prothrombin time and activated partial thromboplastin time, arterial hypotension, vasodilation, decrease in serum phosphate concentration.

From the respiratory system: cough, sore throat, shortness of breath.

From the side of the central nervous system: headache, dizziness, insomnia, paresthesia, anxiety, confusion, convulsions; encephalopathy, which can be manifested by loss of consciousness, hallucinations, stupor, coma; myoclonus.

Infections: candidiasis.

Injection site reactions: intravenous infusion – phlebitis and inflammation, intramuscular injection – pain, inflammation.

Lab abnormal: elevated alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, anemia, eosinophilia, prolongation of prothrombin time or partial thromboplasty time and positive Coombs test without hemolysis, sometimes transient increase in blood urea nitrogen and/or serum creatinine and transient thrombocytopenia. Transient leukopenia and neutropenia have also been observed.

Other: asthenia, excessive sweating, vaginitis, peripheral edema, back pain.

Shelf life

Cefepime, powder for solution for injection, 1.0 g, 2 years.

Water for injection, parenteral solvent, 10 ml ampoule, 4 years.

Storage conditions

Keep out of the reach of children in the original packaging at a temperature not exceeding 25 °C.

Incompatible.

Do not mix in the same container with other medicinal products. Use the solvents indicated in the section “Method of application and doses”.

Packaging

1 g powder in vial; 1 or 5 or 50 vials per pack; 1 bottle and 1 ampoule with a solvent (water for injection, 10 ml per ampoule) in a blister, 1 blister in a pack.

Dispensing category

By prescription.

Manufacturer

Private Joint Stock Company Lekhim-Kharkov.

Manufactured from in bulk packaging by Kwilu Pharmaceutical Co., Ltd., China.

Location of the manufacturer and address of the place of its activity

Ukraine, 61115, Kharkiv region, Kharkov city, Severina Pototsky street, house 36.

Appendicitis	ICD K37
Ingrown toenail	ICD L60.0
Diaphragmatic hernia	ICD K44.9
Other bacterial pneumonias	ICD J15.8
Other specified diseases of appendix	ICD K38.8
Other forms of cholecystitis	ICD K81.8
MN (malignant neoplasm) of the splenic flexure	ICD C18.5
Ileus	ICD K56.7
Intervertebral disc infection (pyogenic)	ICD M46.3
Ischiorectal abscess	ICD K61.3
Bile duct stones without cholangitis or cholecystitis	ICD K80. 5
Unilateral inguinal hernia	ICD K40.9
Acute lymphadenitis of the face, head and neck	ICD L04.0
Acute lymphadenitis of the trunk	ICD L04.1
Acute cholecystitis	ICD K81.0
Premature rupture of membranes, onset of labor within 24 hours	ICD O42.0
Umbilical hernia	ICD K42.9
Delivery by caesarean section	ICD O82.9
Phlegmon of the trunk	ICD L03.3
Chronic appendicitis	ICD K36

Cefepime Powder for Injection 1 g Bottle #1

Powder for Injection Cefepime is indicated for infections susceptible to cefepime.

Adults: septicemia; intra-abdominal infections, including peritonitis and biliary tract infections; infections of the skin and subcutaneous tissue; gynecological infections; respiratory tract infections, including pneumonia, bronchitis; prevention of postoperative complications in intra-abdominal surgery; empirical therapy of patients with neutropenic fever. Children: pneumonia; urinary tract infections, including pyelonephritis; infections of the skin and subcutaneous tissue; septicemia; empirical therapy of patients with neutropenic fever; bacterial meningitis.

Composition

Active ingredient: cefepime;

1 vial contains cefepime (as cefepime hydrochloride) 1.0 g;

Excipient: L-arginine.

Contraindications

Hypersensitivity to cephalosporin antibiotics or L-arginine, penicillins or other β-lactam antibiotics.

Directions for use

A skin tolerability test should be performed before use.

The usual adult dosage is 1 g administered intravenously or intramuscularly at intervals of 12 hours. The usual duration of treatment is 7-10 days; in severe infections, longer treatment is possible.

Peculiarities of use

Pregnant women

Cefepime should be administered to pregnant women only when the expected benefit to the mother outweighs the potential risk to the fetus.

Children

The drug is used for children from 1 month.

Drivers

The effect on the ability to drive a car and use mechanisms has not been studied, however, when using the drug, the possibility of adverse reactions from the nervous system should be taken into account.

Overdose

Symptoms. In cases of a significant excess of the recommended doses, especially in patients with impaired renal function, side effects increase. Overdose symptoms include encephalopathy, which is accompanied by hallucinations, impaired consciousness, stupor, coma, myoclonus, epileptoform seizures, neuromuscular agitation.

Treatment. It is necessary to stop the administration of the drug, conduct symptomatic therapy. The use of hemodialysis accelerates the removal of cefepime from the body; peritoneal dialysis is ineffective. Severe allergic reactions of the immediate type require the use of adrenaline and other forms of intensive care.

Side effects

Cefepime is generally well tolerated.

Allergic reactions: rash, itching, urticaria, erythema, anaphylactic shock, fever. From the gastrointestinal tract: diarrhea, nausea, vomiting, constipation, abdominal pain, dyspepsia, stomatitis, colitis (including pseudomembranous). From the side of the cardiovascular system: chest pain, tachycardia. On the part of the hematopoietic system: agranulocytosis, hypereosinophilia, neutropenia, thrombopenia, prolongation of prothrombin time and activated partial thromboplastin time, arterial hypotension, vasodilation, decreased serum phosphate concentration. From the respiratory system: cough, sore throat, shortness of breath. From the side of the central nervous system: headache, dizziness, insomnia, paresthesia, anxiety, confusion, convulsions; encephalopathy, which can be manifested by loss of consciousness, hallucinations, stupor, coma; myoclonus.