Cefepime


Article Author:
Audrey O'Connor


Article Editor:
Ambika Eranki


Editors In Chief:
Stephen Leslie
Karim Hamawy


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Phillip Hynes
Tehmina Warsi


Updated:
6/26/2019 11:51:01 AM

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: 

  • 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 that are 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-lactams; these are 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.[1][2][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 the 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 unchanged drug. The half-life is about 2 to 2.3 hours and is longer in patients with renal failure.[1][6]

Administration

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 over the course of 30 minutes. There have been studies that looked at extended infusions of 4 hours showing lower overall mortality and reduced intensive care unit (ICU) lengths of stay when 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. 

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

No adjustment in dosing is necessary for hepatic impairment. The dose requires adjustment for patients with renal dysfunction defined as a creatinine clearance less than or equal to 60 mL/min.[7][8][9]

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 by system below.

  • 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 mutiforme 
  • 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 are renal failure (creatinine less than or equal to 60 mL/min), the aging adult, critically ill patients in ICU, strokes, Alzheimer's 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. 

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.[10][11][12][13][14]

Contraindications

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

Cephalosporins have long been reported as contraindicated in patients with severe hypersensitivity reactions to penicillin. Early testing of cephalosporins (up until the 1980s) came from Penicillium mold of penicillin. The thinking is that these early cephalosporins were contaminated with penicillin and accounted for cross-reactivity allergic response. Avoiding cephalosporins with patients who have penicillin allergies likely developed from these early studies. 

Cephalosporins are similar to penicillins with the beta-lactam ring but differ by the various side chains. It is the similarities of these side chains to the penicillin structure that account for the IgE mediated cross-reactivity and not the beta-lactam ring as previously thought. The newer the generation of cephalosporins, the greater the 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 hypersensitive reactions can still occur; this is because T-cells can recognize the entire beta-lactam ring as well as the side chains. 

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. 

Cefepime is listed as category B for pregnancy and gets excreted in breast milk. Caution is necessary with cefepime in women who are pregnant or breastfeeding and should only be used if absolutely needed.[1][15][16][17][18]

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. 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. It is important to monitor for signs of neurological changes particularly in the older person, patients with renal dysfunction, and with febrile neutropenia. 

The effectiveness of cefepime can vary drastically with critically ill patients treated in the ICU. Drug monitoring is suggested if the patient's creatinine clearance is less than or equal to 50 mL/min or if the 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 drug should be discontinued or dose adjusted. Determining if the symptoms are a result of an actual cefepime overdose or from preexisting comorbidities may be difficult. If suspicion is high or if symptoms do not subside after dose adjusting or discontinuing, blood and/or cerebral spinal fluid levels should be obtained to evaluate if the toxicity is stemming 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. It is crucial for all members of the health care team to monitor each patient for immediate hypersensitivity reactions after initial administration. 

Clinicians need to bear in mind that the pharmacokinetics of the drug can undergo alteration in patients with sepsis, renal dysfunction or the older person leading to undesired peaks and troughs and potentially serious adverse effects. If a patient exhibits a change in mental status or develops neurological signs such as seizure activity, the offending agent may be cefepime, and the drug may need to be discontinued, or the dose adjusted. 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.

Cefepime therapy requires the collaborative effort of an interdisciplinary healthcare team, to include physicians, specialty-trained nurses, pharmacists, and potentially infectious disease specialists, all working together to achieve optimal patient outcomes. [Level V]


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Cefepime - Questions

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An 80-year old male presents to the emergency department for ear pain. He was treated with a topical medication that did not work. The pain has been worsening, and now his jaw hurts. He has a past medical history of uncontrolled type 2 diabetes and hypertension. He denies any allergies but was told not to take a certain antibiotic because "it tore my Achilles." The patient recently took up swimming. Examination reveals an inflamed external auditory canal that is painful during tragus tug. Otoscopic examination shows granulation tissue at the inferior portion of the external canal. A contrast-enhanced CT shows bone erosion into the underlying osseous structure of the auditory canal. Vital signs, a complete blood count, and metabolic panel are normal. The sedimentation rate is 90 mm/hr, and C-reactive protein is 12 mg/L. Choose the mechanism of action of the best antibiotic option to treat the most common organism responsible for this infection.



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A 56-year old male with a past medical history of type 2 diabetes, hypertension, and dyslipidemia is admitted to the hospital with worsening shortness of breath, productive cough and fever of 99.8 F (37.6 C). He is diagnosed with pneumonia and started on intravenous cefepime 2 g every 8 hours. Serum studies show: leukocytes 19000/microliter; lactic acid 3.5 mg/dL; blood urea nitrogen (BUN) 14 mg/dL; creatinine 0.8 (Cr) mg/dL; estimated glomerular filtration rate (eGFR) 80 mL/min/1.73 m3. His symptoms slightly worsen as he spiked a temperature of 100.2 F (37.8 C), and now he requires 2L of oxygen by nasal cannula. Repeat blood work show leukocytes of 18000/microliter, lactic acid 2.0 mg/dL, BUN 19 mg/dL, Cr 1.2 mg/dL, eGFR 60 mL/min/1.73 m3. Blood cultures show gram-positive cocci. Vancomycin is added and appropriately dosed by the pharmacy. Which of the following is the most appropriate next step to manage this patient?



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A 66-year-old male is brought to the emergency department with a 2-day history of fever, shaking chills, headache, and neck stiffness. He does not use alcohol or drugs and smokes cigarettes occasionally. His only past medical history was a recent cystoscopy with biopsy after having painless hematuria and treated for a urinary tract infection. Microbiological specimens from his urine sample at that time grew gram-negative aerobic rods with a flagellum. He is diaphoretic and appears ill. Physical exam reveals a painful response with knees slightly elevated when attempting passive motion of his neck. Lung sounds are clear, and the abdomen is soft. Temperature is 101.3 F (38.5 C), blood pressure 108/79 mm Hg, heart rate 119 beats/min, respiratory rate 28 breaths/min. Laboratory studies show a leukocyte count 23000/microliter with a left shift, lactic acid 3.2 mg/dL. CT brain was negative for any mass or midline shift. A lumbar puncture was performed, and the results are pending. Blood and urine cultures are collected and pending. Urinalysis is positive for bacteria without squamous cells and large leukocyte esterase. The patient is admitted to a step-down unit and started on intravenous hydration. Which of the following are the best options for initial antimicrobial coverage?



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An 82-year old woman with a past medical history of chronic obstructive pulmonary disease on 3 L oxygen at baseline, congestive heart failure, type 2 diabetes, hypertension, hypothyroidism, and stage-3 chronic kidney disease is hospitalized for urinary tract infection treated with cefepime for the past 3 days. Her home medications are oxygen, metoprolol, lisinopril, insulin, levothyroxine, and atorvastatin. The patient has never used alcohol or drugs and is compliant with her medications. She has never had a stroke or brain injury. Her initial symptoms of altered mental status, leukocytosis and pyuria had resolved, and she was getting ready to be discharged on oral antibiotics as soon as culture sensitivities returned. On the third night, the nurse was called into her room by a family member and found the patient unresponsive with her upper extremities jerking in a non-rhythmic fashion. The symptoms stop after 5 minutes, and that patient was mildly confused. The attending physician was notified, and orders were placed. Arterial blood gas showed paCO2 45 mm Hg, paO2 84 mm Hg, pH 7.43, HCO3 25 mEq/L. A complete blood count, metabolic panel, liver function tests were all unremarkable. Other laboratory studies were thyroid-stimulating hormone 1.9 mU/L, blood glucose 127 mg/dL, lactic acid 2.9 mg/dL. Which of the following is the next best step in this patients care?



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Cefepime - References

References

Clinical Outcomes of Extended-Spectrum Beta-Lactamase-Producing {i}Enterobacteriaceae{/i} Infections with Susceptibilities among Levofloxacin, Cefepime, and Carbapenems., Walker KJ,Lee YR,Klar AR,, The Canadian journal of infectious diseases & medical microbiology = Journal canadien des maladies infectieuses et de la microbiologie medicale, 2018     [PubMed]
The Role of Cefepime in the Treatment of Extended-Spectrum Beta-Lactamase Infections., Patel HB,Lusk KA,Cota JM,, Journal of pharmacy practice, 2017 Jan 1     [PubMed]
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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. The Journal of antimicrobial chemotherapy. 2014 Apr;     [PubMed]
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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. The Journal of antimicrobial chemotherapy. 2012 May;     [PubMed]
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. Antimicrobial agents and chemotherapy. 2010 Oct;     [PubMed]
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. Critical care (London, England). 2010;     [PubMed]
Vorobeichik L,Weber EA,Tarshis J, Misconceptions Surrounding Penicillin Allergy: Implications for Anesthesiologists. Anesthesia and analgesia. 2018 Sep;     [PubMed]
Pichichero ME,Zagursky R, Penicillin and cephalosporin allergy. Annals of allergy, asthma     [PubMed]
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. The Journal of antibiotics. 1970 Apr;     [PubMed]
Drug allergy: an updated practice parameter. Annals of allergy, asthma     [PubMed]
Bauer KA,West JE,O'Brien JM,Goff DA, Extended-infusion cefepime reduces mortality in patients with Pseudomonas aeruginosa infections. Antimicrobial agents and chemotherapy. 2013 Jul;     [PubMed]
Wrenn RH,Cluck D,Kennedy L,Ohl C,Williamson JC, Extended infusion compared to standard infusion cefepime as empiric treatment of febrile neutropenia. Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2018 Apr;     [PubMed]
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