PBP/penicillin-binding proteins

Cefepime is a semisynthetic, broad-spectrum, fourth-generation cephalosporin with antibacterial activity. Cefepime binds to and inactivates penicillin-binding proteins (PBPs) located on the inner membrane of the bacterial cell wall. PBPs are enzymes involved in the terminal stages of assembling the bacterial cell wall and in reshaping the cell wall during growth and division. Inactivation of PBPs interferes with the cross-linkage of peptidoglycan chains necessary for bacterial cell wall strength and rigidity. This results in the weakening of the bacterial cell wall and causes cell lysis.
Cefepime is a bactericidal cephalosporin with a mode of action similar to other beta-lactam antibiotics. Cefepime disrupts bacterial cell walls by binding and inhibiting transpeptidases known as penicillin-binding proteins (PBPs), which are enzymes involved in the final stages of peptidoglycan layer synthesis. This results in the lysis and death of susceptible microorganisms. Cefepime has a broad spectrum of _in vitro_ activity that includes both Gram-positive and Gram-negative bacteria. Cefepime has affinity for PBP-3 and PBP-1 in _Escherichia coli_ and _Pseudomonas aeruginosa_, as well as PBP-2 in _E. coli_ and _Enterobacter cloacae_.
Cefepime is a fourth-generation cephalosporin antibiotic. It is active against Gram-negative bacteria such as _Enterobacter_ spp., _Escherichia coli_, _Klebsiella pneumoniae_, _Proteus mirabilis_ and _Pseudomonas aeruginosa_, and Gram-positive bacteria such as _Staphylococcus aureus_ (methicillin-susceptible isolates only), _Streptococcus pneumoniae_, _Streptococcus pyogenes_ and Viridans group streptococci. Compared to third-generation cephalosporins, cefepime has an extended Gram-negative coverage. Whereas other cephalosporins are degraded by plasmid- and chromosome-mediated beta-lactamases, cefepime is stable and not significantly hydrolyzed by these enzymes. Cefepime is also a poor inducer of type 1 beta-lactamases and, therefore, a good alternative against bacteria resistant to third-generation cephalosporins. In animal models of infection, the time that the unbound plasma concentration of cefepime exceeds the minimum inhibitory concentration (MIC) of infecting organisms has been shown to correlate with treatment efficacy. It has been suggested that cefepime can cross the inflamed blood-brain barrier. This, along with its ability to inhibit γ-aminobutyric acid (GABA), could lead to the neurotoxic effects observed in some of the patients treated with cefepime.

Cefepime is indicated for the treatment of pneumonia caused by susceptible bacteria, and for empiric therapy for febrile neutropenic patients. Cefepime is also indicated for the treatment of uncomplicated and complicated urinary tract infections (cUTI) including pyelonephritis, uncomplicated skin and skin structure infections, and complicated intra-abdominal infections (used in combination with [metronidazole]) in adults caused by susceptible bacteria. Cefepime is also used in combination with [enmetazobactam] to treat cUTI.
CEFEPIME is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 1996 and has 8 approved and 12 investigational indications.
A fourth-generation cephalosporin antibacterial agent that is used in the treatment of infections, including those of the abdomen, urinary tract, respiratory tract, and skin. It is effective against PSEUDOMONAS AERUGINOSA and may also be used in the empiric treatment of FEBRILE NEUTROPENIA.

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]. Human serum paraoxonase-1 (hPON1): in vitro inhibition effects of moxifloxacin hydrochloride, levofloxacin hemihidrate, cefepime hydrochloride, cefotaxime sodium and ceftizoxime sodium. J Enzyme Inhib Med Chem. 2015;30(4):622-8.

Cefepime hydrochloride is a semi-synthetic, β-lactamase-resistant fourth-generation cephalosporin antibiotic derived from Fusarium fungi, possessing broad-spectrum bactericidal activity. Administered parenterally, cefepime binds to and inactivates penicillin-binding protein (PBP) located on the inner membrane of bacterial cell walls, thereby inhibiting bacterial cell wall synthesis. PBP inactivation interferes with peptidoglycan chain cross-linking, which is crucial for maintaining the strength and rigidity of bacterial cell walls, ultimately leading to decreased cell wall stability and cell lysis. Compared to third-generation cephalosporins, this drug is more effective against a variety of Gram-positive pathogens.
A fourth-generation cephalosporin antibacterial drug used to treat a variety of infections, including those of the abdomen, urinary tract, respiratory tract, and skin. It is effective against Pseudomonas aeruginosa and can also be used for empirical treatment of febrile neutropenia.
See also: Cefepime hydrochloride (note moved to).

C19H25N6O5S2+.CL-.HCL

553.48294

552.078

C, 41.23; H, 4.74; Cl, 12.81; N, 15.18; O, 14.45; S, 11.59

107648-80-6

103296-32-8 (E);88040-23-7;123171-59-5 (HCI hydrate);88040-23-7; 107648-78-2 (sulfate);

5491294

Typically exists as solid at room temperature

150ºC (dec.)

1.192

4

11

7

34

874

2

C[N+]1(CC2=C(N3C([C@@H](NC(/C(/C4=CSC(N4)=N)=N\OC)=O)[C@H]3SC2)=O)C([O-])=O)CCCC1.Cl.Cl

XQQAUWFZBOTKFQ-MHRNPJSASA-N

InChI=1S/C19H24N6O5S2.2ClH/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);2*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;hydrochloride

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.)