PBP/penicillin-binding proteins

Cefepime chloride binds to proteins that bind penicillin to produce its antibacterial action [2].

Cefepime chloride (80 mg/kg; intraperitoneally) considerably lengthened the half-life and the mice survived [4].

Animal/Disease Models: Male CD-1 mice [4]
Doses: 80 mg/kg
Route of Administration: intraperitoneal (ip) injection
Experimental Results: The half-life of cefepime was Dramatically prolonged in all mice treated with cisplatin 18-22 mg/kg and 26 mg /kg all survived during pretreatment. kg cisplatin Dramatically diminished survival rate, and the half-life of cefepime was not Dramatically longer than 18 mg/kg cisplatin.

Absorption, Distribution and Excretion
Following a single intravenous infusion of 500 mg, 1 g, and 2 g cefepime in nine healthy adult male volunteers, the peak plasma concentrations (Cmax) were 39.1, 81.7, and 163.9 μg/mL, respectively, with corresponding AUCs of 70.8, 148.5, and 284.8 h⋅μg/mL. Conversely, following a single intramuscular injection of 500 mg, 1 g, and 2 g cefepime in the same nine healthy adult male volunteers, the peak plasma concentrations (Cmax) were 13.9, 29.6, and 57.5 μg/mL, respectively, with corresponding AUCs of 60, 137, and 262 h⋅μg/mL, and corresponding time to peak concentrations (Tmax) of 1.4, 1.6, and 1.5 h, respectively. A study in healthy adult male volunteers (n=7) demonstrated that cefepime did not accumulate in the body after 9 days of treatment with clinically relevant doses. The pharmacokinetics of cefepime followed a linear model across a dose range of 250 mg to 2 g. In pediatric patients (n=8) receiving 50 mg/kg intramuscularly, the absolute bioavailability of cefepime was 82.3%. Cefepime is primarily excreted by the kidneys, with the majority excreted unchanged. Approximately 85% of cefepime administered to normal subjects is excreted unchanged in the urine. Less than 1% of N-methylpyrrolidine (NMP) is recovered in the urine, 6.8% is NMP-N-oxide, and 2.5% is the epimer. Because renal excretion plays a crucial role in the clearance of cefepime, dose adjustments are necessary for patients with renal impairment or undergoing hemodialysis. The mean steady-state volume of distribution of cefepime is 18.0 L. In pediatric patients, the mean steady-state volume of distribution was 0.3 L/kg. The total clearance of cefepime was 120 mL/min in healthy volunteers and 3.3 mL/min/kg in pediatric patients. In elderly patients (65 years and older) and those with impaired renal function, the total clearance of cefepime decreased proportionally to creatinine clearance. Less than 1% of cefepime is metabolized in the liver. Cefepime is metabolized to N-methylpyrrolidine (NMP), which is rapidly oxidized to the more stable compound NMP-N-oxide. NMP-N-oxide is the major metabolite of cefepime, while NMP and the 7-epimer of cefepime are minor byproducts. Studies have shown that flavin-containing mixed-function oxygenases mediate the oxidation of NMP to NMP-N-oxide.

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Biological Half-Life
The mean half-life of cefepime was 2 hours after administration to 9 healthy adult male volunteers. In patients requiring hemodialysis, the mean half-life was 13.5 hours; in patients requiring continuous peritoneal dialysis, the mean half-life was 19 hours.
Absorption
After a single intravenous infusion of 500 mg, 1 g, and 2 g of cefepime in 9 healthy adult male volunteers, the corresponding Cmax were 39.1, 81.7, and 163.9 μg/mL, respectively, and the corresponding AUCs were 70.8, 148.5, and 284.8 h⋅μg/mL, respectively. On the other hand, in healthy adult male volunteers, after a single intramuscular injection of 500 mg, 1 g, and 2 g of cefepime, the peak plasma concentrations (Cmax) were 13.9, 29.6, and 57.5 μg/mL, respectively; the areas under the curve (AUC) were 60, 137, and 262 h·μg/mL, respectively; and the times to peak concentration (Tmax) were 1.4, 1.6, and 1.5 h, respectively. A 9-day clinical-related dose study in 7 healthy adult male volunteers showed that cefepime does not accumulate in the body. Cefepime follows a linear pharmacokinetic model within the dose range of 250 mg to 2 g. In pediatric patients (n=8) receiving a 50 mg/kg intramuscular injection, the absolute bioavailability of cefepime was 82.3%.
Elimination Pathway
Cefepime is primarily excreted via the kidneys, with the majority being excreted unchanged. In normal subjects, approximately 85% of cefepime administered is excreted unchanged in the urine. Less than 1% of the administered dose is recovered in the urine as N-methylpyrrolidine (NMP), 6.8% as NMP-N-oxide, and 2.5% as an epimer. Because renal excretion plays a significant role in the clearance of cefepime, dose adjustments are necessary for patients with renal insufficiency or undergoing hemodialysis.
Volume of Distribution
The mean steady-state volume of distribution of cefepime is 18.0 L. In pediatric patients, the mean steady-state volume of distribution is 0.3 L/kg.
Clearance
The total clearance of cefepime is 120 mL/min in healthy volunteers; in pediatric patients, the mean total clearance is 3.3 mL/min/kg. In elderly patients (65 years and older) and patients with impaired renal function, the total clearance of cefepime decreased proportionally to creatinine clearance.
Protein Binding
The serum protein binding rate of cefepime is approximately 20%, independent of serum concentration.
Metabolism/Metabolites
Less than 1% of cefepime is metabolized in the liver. Cefepime is metabolized to N-methylpyrrolidine (NMP), which is then rapidly oxidized to the more stable compound NMP-N-oxide. NMP-N-oxide is the major metabolite of cefepime, while NMP and the 7-epimer of cefepime are minor byproducts. Studies have shown that flavin-containing mixed-function oxygenases mediate the oxidation of NMP to NMP-N-oxide.
Biological Half-Life
The mean half-life in healthy adult male volunteers (n=9) treated with cefepime was 2 hours. The average half-life for patients requiring hemodialysis is 13.5 hours, and the average half-life for patients requiring continuous peritoneal dialysis is 19 hours.

Medication Use During Pregnancy and Lactation ◉ Overview of Medication Use During Lactation
While there is currently no publicly available information regarding the use of cefepime during lactation, its concentration in breast milk appears to be low. Generally, cephalosporins do not cause serious adverse reactions in breastfed infants. There are reports that cephalosporins occasionally disrupt the infant's gut microbiota, leading to diarrhea or thrush, but these effects have not been fully assessed. Cefepime is safe for use by breastfeeding women. The combined use of cefepime and emmetazobactam has not been studied in breastfeeding women, but adverse reactions should be similar to those in breastfeeding women.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

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Protein Binding
The serum protein binding rate of cefepime is approximately 20%, independent of its serum concentration.
Toxicity Overview
If overdose is suspected, clinicians should discontinue the drug or adjust the dose. Determining whether symptoms are caused by cefepime overdose or pre-existing comorbidities can be difficult. If symptoms do not resolve after strong suspicion, dose adjustment, or discontinuation of the drug, blood and cerebrospinal fluid tests should be performed to assess whether toxicity is caused by elevated cefepime levels. Cefepime-induced neurotoxicity (CIN) can cause widespread periodic discharges and triphasic patterns on electroencephalograms. Severe cases may require dialysis.

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Adverse Reactions
Cefepime is generally well tolerated in adults and children. The most common adverse reactions in adults are diarrhea and rash. The most common adverse reactions in children are fever, diarrhea, and rash. Depending on the affected system, there are many other less common adverse reactions: Nervous system: headache, fever, and neurotoxicity Gastrointestinal system: nausea, vomiting, abdominal pain, liver damage, colitis (including pseudomembranous colitis), oral candidiasis Genitourinary system: vaginitis, kidney damage Skin: local injection site irritation, pruritus, urticaria, Stevens-Johnson syndrome, and erythema multiforme Hematologic system: positive Coombs test without hemolysis, pancytopenia, and aplastic anemia Adverse reactions usually subside after discontinuation of the drug. Neurotoxicity is a serious, life-threatening adverse reaction that warrants special attention. Symptoms may include altered mental status, encephalopathy, seizures, myoclonus, hallucinations, coma, and stroke-like symptoms. Symptoms usually appear 4 days after starting cefepime. Risk factors include renal failure (creatinine ≤60 mL/min), elderly patients, critically ill patients in the ICU, stroke, Alzheimer's disease, brain malignancies, a history of epilepsy, and impaired blood-brain barrier (BBB). The hypothesized mechanism is that cefepime can cross the blood-brain barrier and antagonize γ-aminobutyric acid receptors. Treatment options include discontinuation of the drug, control of seizures with benzodiazepines, or renal replacement therapy in severely refractory cases. The clinical team must monitor renal function and adjust the dosage accordingly; however, neurotoxicity has been reported in patients with normal renal function. Drug Interactions Significant drug interactions exist when using cefepime. Concomitant use of cefepime with aminoglycoside antibiotics increases the risk of cytotoxicity and nephrotoxicity. Concomitant use of cephalosporins (such as cefepime) with potent diuretics (such as furosemide) can lead to nephrotoxicity. Renal function should be monitored when patients are taking these medications. Cefepime can cause false-positive urine glucose tests; a urine glucose test based on the glucose oxidase reaction is recommended. Concurrent administration of cefepime with intravesical BCG vaccination for bladder cancer is not recommended, as this may adversely affect the treatment outcome. Simultaneous administration of cholera and typhoid vaccines is not recommended, as it may reduce vaccine efficacy.

[1]. Efficacy and safety of cefepime: a systematic review and meta-analysis. Lancet Infect Dis. 2007 May;7(5):338-48.

[2]. Barradell LB, Bryson HM. Cefepime. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs. 1994;47(3):471-505.

[3]. Cefepime-induced neurotoxicity: a systematic review. Crit Care. 2017 Nov 14;21(1):276. doi: 10.1186/s13054-017-1856-1.

[4]. The effect of different doses of cisplatin on the pharmacokinetic parameters of cefepime in mice. Lab Anim. 2006 Jul;40(3):296-300.

C19H25CLN6O5S2

517.022000074387

516.101638

107648-79-3

Cefepime;88040-23-7; Cefepime Dihydrochloride Monohydrate;123171-59-5; Cefepime chloride;107648-79-3; 107648-78-2 (sulfate); 103296-32-8 (compound E); 123171-59-5 (2HCl hydrate);107648-80-6 (2HCl)

Typically exists as solid at room temperature

3

11

7

33

874

2

[Cl-].S1CC(=C(C(=O)O)N2C([C@H]([C@@H]12)NC(/C(/C1=CSC(N)=N1)=N\OC)=O)=O)C[N+]1(C)CCCC1

MMRINLZOZVAPDZ-LSGRDSQZSA-N

InChI=1S/C19H24N6O5S2.ClH/c1-25(5-3-4-6-25)7-10-8-31-17-13(16(27)24(17)14(10)18(28)29)22-15(26)12(23-30-2)11-9-32-19(20)21-11;/h9,13,17H,3-8H2,1-2H3,(H3-,20,21,22,26,28,29);1H/b23-12-;/t13-,17-;/m1./s1

(6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid chloride

Cefepime (chloride); 107648-79-3; 1-(((6R,7R)-7-((Z)-2-(2-Aminothiazol-4-yl)-2-(methoxyimino)acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)-1-methylpyrrolidin-1-ium chloride; orb1744769;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)