β-lactam
Bacterial cell wall synthesis (Penicillin-binding proteins, PBPs) [4].

With a MIC90 value of 0.25 μg/mL, cefixime exhibits strong antibacterial activity against clinical isolates of Salmonella typhi. It also exhibits antibacterial activity against strains that are resistant to amoxicillin (HY-B0467A) and produce β-lactamase.

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The Minimum Inhibitory Concentration (MIC) of cefixime against the extended-spectrum cephalosporin-susceptible (ESC^s) Neisseria gonorrhoeae strain FA1090 was determined to be 0.0075 μg/ml using the agar dilution method, as recommended by the CDC [4].
The Minimum Inhibitory Concentration (MIC) of cefixime against the multidrug-resistant, extended-spectrum cephalosporin-resistant (ESC^r) Neisseria gonorrhoeae strain H041 was determined to be 8 μg/ml using the agar dilution method, performed in triplicate [4].

Mice challenged with FA1090 (ESC-susceptible strain) have lower bacterial burdens when cefixime (0.75–60 mg/kg) is administered orally[4]. Cefixime (50 or 150 mg/kg, oral gavage) alters the composition and diversity of the C57BL/6J mice's gut microbiota, resulting in a decrease in the microbial community's diversity and a shift toward a predominate Firmicutes phylum[5].

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In a murine genital tract infection model, a single oral dose of 12 mg/kg cefixime was 100% effective in clearing infection with the susceptible N. gonorrhoeae strain FA1090 (MIC 0.0075 μg/ml) within 48 hours. This dose corresponded to a predicted therapeutic time (the time that the free drug concentration remains above the MIC, fT_MIC) of 36.8 hours [4].
Single oral doses of cefixime up to 120 mg/kg were ineffective against the resistant strain H041 (MIC 8 μg/ml), as predicted by PK data. Fractionated dosing regimens (120 mg/kg given as 40 mg/kg TID, and 60 mg/kg BID) also did not result in free plasma levels above the MIC for H041 and failed to clear infection in a majority of mice [4].
To attempt efficacy against H041, higher doses of cefixime were tested. Dosing regimens of 300 mg/kg (QD, BID, TID) showed a significant difference in bacterial clearance compared to placebo, but did not clear the infection in a majority of mice by 48 hours. The most effective regimen, 300 mg/kg administered TID (every 8 hours), cleared infection in 50% of mice, with a predicted therapeutic time of 27 hours. This was comparable to the gentamicin control but did not achieve complete clearance, unlike the 36.8-hour fT_MIC target established for the susceptible strain [4].

Antimicrobial Susceptibility Testing (Etest): The MIC of cefixime for N. gonorrhoeae strain F89 was determined using the Etest method, performed according to the manufacturer's instructions, to assess its susceptibility level [2].
Transformation Experiments to Determine Resistance Mechanism: To confirm that the novel penA-CI allele was responsible for high-level cefixime resistance, the full-length penA-CI allele from strain F89 was amplified and used to transform a set of recipient N. gonorrhoeae strains with varying genetic backgrounds. The resulting transformants were sequence-verified for the presence of the allele. Subsequently, the MICs of cefixime for the parent strains and their transformants were measured using the Etest method. The fold-change in MIC was calculated to demonstrate the causal role of the penA-CI allele in conferring resistance [2].

Pharmacokinetic (PK) Study Protocol:** Uninfected, estradiol-treated female BALB/c mice were administered a single oral dose of cefixime at concentrations ranging from 0.19 to 120 mg/kg. Venous blood samples were collected from the retro-orbital sinus at 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-dose. Blood was collected from each mouse at two time points (n=4 mice/time point). Samples were processed to K₃EDTA plasma and stored at ≤ -70°C until analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine cefixime concentrations [4].
* **In Vivo Efficacy Study Protocol (Susceptible Strain):** Female BALB/c mice were implanted with a 17β-estradiol pellet and treated with antibiotics to promote gonococcal infection. Mice were then inoculated vaginally with *N. gonorrhoeae* strain FA1090. On day 0 post-inoculation, a single dose of cefixime (0.19, 0.75, 3, 12, or 60 mg/kg) was administered by oral gavage. Cefixime was prepared in sterile endotoxin-free PBS (pH 6.0) with 0.1M NaHCO₃ (1:10). Infection was monitored for 8 days post-treatment by daily quantitative culture of vaginal swab specimens [4].
* **In Vivo Efficacy Study Protocol (Resistant Strain):** Using the same mouse model, mice were inoculated with the resistant strain H041. Cefixime was administered by oral gavage in various fractionated dosing regimens over 24 hours to attempt to achieve therapeutic times above the elevated MIC (8 μg/ml). Regimens tested included single doses (QD) of 120 mg/kg and 300 mg/kg, two doses (BID, every 12 hours) of 60 mg/kg and 150 mg/kg, and three doses (TID, every 8 hours) of 40 mg/kg and 100 mg/kg. Gentamicin (i.p., 48 mg/kg, 5 doses, QD) was used as a positive control. Infection was monitored for 8 days post-treatment by daily quantitative culture of vaginal swab specimens [4].

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Pharmacokinetic (PK) Study Protocol: Uninfected, estradiol-treated female BALB/c mice were administered a single oral dose of cefixime at concentrations ranging from 0.19 to 120 mg/kg. Venous blood samples were collected from the retro-orbital sinus at 0.08, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-dose. Blood was collected from each mouse at two time points (n=4 mice/time point). Samples were processed to K₃EDTA plasma and stored at ≤ -70°C until analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine cefixime concentrations [4].
In Vivo Efficacy Study Protocol (Susceptible Strain): Female BALB/c mice were implanted with a 17β-estradiol pellet and treated with antibiotics to promote gonococcal infection. Mice were then inoculated vaginally with N. gonorrhoeae strain FA1090. On day 0 post-inoculation, a single dose of cefixime (0.19, 0.75, 3, 12, or 60 mg/kg) was administered by oral gavage. Cefixime was prepared in sterile endotoxin-free PBS (pH 6.0) with 0.1M NaHCO₃ (1:10). Infection was monitored for 8 days post-treatment by daily quantitative culture of vaginal swab specimens [4].
In Vivo Efficacy Study Protocol (Resistant Strain): Using the same mouse model, mice were inoculated with the resistant strain H041. Cefixime was administered by oral gavage in various fractionated dosing regimens over 24 hours to attempt to achieve therapeutic times above the elevated MIC (8 μg/ml). Regimens tested included single doses (QD) of 120 mg/kg and 300 mg/kg, two doses (BID, every 12 hours) of 60 mg/kg and 150 mg/kg, and three doses (TID, every 8 hours) of 40 mg/kg and 100 mg/kg. Gentamicin (i.p., 48 mg/kg, 5 doses, QD) was used as a positive control. Infection was monitored for 8 days post-treatment by daily quantitative culture of vaginal swab specimens [4].

Absorption, Distribution and Excretion
Oral cefixime, whether taken on an empty stomach or with food, has an absorption rate of approximately 40%-50%. However, when taken with food, the time to peak concentration is prolonged by about 0.8 hours. In healthy male volunteers, a single oral dose of 200 mg cefixime tablets resulted in a peak plasma concentration (Cmax) of 3.25 mg/L and a time to peak concentration (Tmax) of 4 hours. In healthy volunteers, an oral dose of 200 mg cefixime solution resulted in a peak plasma concentration (Cmax) of 3.22 μg/mL; while doses of 200 mg and 400 mg cefixime capsules resulted in peak plasma concentrations (Cmax) of 2.92 μg/mL and 4.84 μg/mL, respectively. Following administration of cefixime via 200 mg intravenous injection, 200 mg oral solution, 200 mg capsules, and 400 mg capsules, the mean area under the curve (AUC) was 47.0 μg·h/mL, 26.0 μg·h/mL, 23.6 μg·h/mL, and 39.4 μg·h/mL, respectively. Approximately 50% of absorbed cefixime is excreted unchanged in the urine within 24 hours. The mean volume of distribution of orally administered cefixime is 0.1 L/kg body weight. In children aged 6 to 13 years with urinary tract infections, the mean apparent total clearance of cefixime suspension administered orally at a dose of 8 mg/kg was 4.74 ml/min/kg. Metabolites/Metabolites: There is currently no evidence that cefixime is metabolized in the body.

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Biological Half-Life
The average serum half-life of cefixime in healthy subjects is 3 to 4 hours, regardless of dosage form. In some healthy volunteers, the half-life can reach 9 hours. In patients with severe renal impairment (creatinine clearance of 5 to 20 mL/min), the average half-life of cefixime is prolonged to 11.5 hours.

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Following a single oral dose in mice, plasma cefixime levels showed a clear dose-response over a 24-hour period [4].
The free (microbiologically active) plasma concentrations were calculated by adjusting measured total plasma concentrations for protein binding, which was reported as 72.5% bound in mouse plasma [4].
For the N. gonorrhoeae strain FA1090 (MIC 0.0075 μg/ml), a single 12 mg/kg oral dose, which was 100% efficacious in mice, corresponded to a predicted therapeutic time (fT_MIC) of 36.8 hours [4].
Against the resistant strain H041 (MIC 8 μg/ml), a single 120 mg/kg dose of cefixime was predicted to result in free plasma levels that do not exceed the MIC. The therapeutic time for this dose was estimated to be 13 hours. Fractionated dosing with 120 mg/kg (40 mg/kg TID) was predicted to yield a therapeutic time of 20 hours, and 300 mg/kg fractionated as 100 mg/kg TID was predicted to yield a therapeutic time of 27 hours [4].

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
While there is currently no information regarding the use of cefixime during lactation, it is generally believed that cephalosporins do not have adverse effects on 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. Cefixime is safe for use by 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
Approximately 65% of cefixime binds to serum proteins, and the serum protein binding rate is independent of drug concentration.

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[1]. In vitro activity of a new broad spectrum, beta-lactamase-stable oral cephalosporin, cefixime. Pediatr Infect Dis J. 1987 Oct;6(10):958-62.

[2]. High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother. 2012 Mar;56(3):1273-80.

[3]. Antibacterial activity of cefixime against Salmonella typhi and applicability of Etest. J Infect Chemother. 1999 Sep;5(3):176-179.

[4]. Pharmacokinetic Data Are Predictive of In Vivo Efficacy for Cefixime and Ceftriaxone against Susceptible and Resistant Neisseria gonorrhoeae Strains in the Gonorrhea Mouse Model. Antimicrob Agents Chemother. 2019 Feb 26;63(3):e01644-18.

[5]. Restoration of cefixime-induced gut microbiota changes by Lactobacillus cocktails and fructooligosaccharides in a mouse model. Microbiol Res. 2017 Jul;200:14-24.

Pharmacodynamics
Cefixime is a broad-spectrum antibiotic, belonging to the class of orally effective third-generation semi-synthetic cephalosporins. Like other cephalosporins, cefixime's antibacterial action derives from the inhibition of cell wall synthesis. Also like other cephalosporins, cefixime remains stable in the presence of certain β-lactamases, meaning that some microorganisms resistant to penicillin and some cephalosporins due to the presence of β-lactamases may be sensitive to cefixime. Use of cefixime may cause hypersensitivity reactions, including anaphylactic/hypersensitivity reactions and Clostridium difficile-associated diarrhea (CDAD); it may also cause a decrease in prothrombin activity. The dosage of cefixime should be adjusted in patients with impaired renal function, as well as those undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD); patients undergoing dialysis should be monitored while taking cefixime.

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Cefixime is an extended-spectrum cephalosporin (ESC) antibiotic. It was previously recommended as an oral monotherapy for uncomplicated gonococcal infections in humans. Due to the emergence of resistant N. gonorrhoeae strains (like H041), oral ESCs, including cefixime, were no longer recommended for use starting in 2012 [4].
The study established a PK/PD relationship in the mouse model, showing that the in vivo efficacy of cefixime against gonorrhea correlates with the duration of time the free drug concentration remains above the MIC (fT_MIC). This mirrors the PK/PD driver for cephalosporins in humans, where an fT_MIC of >20-24 hours is considered optimal for eradicating uncomplicated urogenital gonococcal infections [4].
The inability of even high-dose, fractionated cefixime regimens to achieve 100% clearance of the H041 strain in mice was accurately predicted by the PK data, which showed that the fT_MIC values (max 27h) were below the 36.8-hour target needed for complete efficacy against a susceptible strain in this model [4].

C16H15N5O7S2

453.45

453.041

C, 42.38; H, 3.33; N, 15.44; O, 24.70; S, 14.14

79350-37-1

Cefixime trihydrate;125110-14-7

5362065

Off-white to slightly yellow solid powder.

1.9±0.1 g/cm3

218-225°C

1.811

1

4

12

8

30

861

2

C(C1=C(C=C)CS[C@@H]2[C@@H](C(N12)=O)NC(=O)/C(/C1=CSC(N)=N1)=N\OCC(=O)O)(=O)O

OKBVVJOGVLARMR-VINNURBNSA-N

InChI=1S/C16H15N5O7S2/c1-2-6-4-29-14-10(13(25)21(14)11(6)15(26)27)19-12(24)9(20-28-3-8(22)23)7-5-30-16(17)18-7/h2,5,10,14H,1,3-4H2,(H2,17,18)(H,19,24)(H,22,23)(H,26,27)/b20-9+/t10-,14-/m1/s1

(6R,7R)-7-[[(2E)-2-(2-amino-1,3-thiazol-4-yl)-2-(carboxymethoxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Cefixima; FR17027; Suprax; Trihydrate, Cefixime; FK 027; FK-027; FK027; FR 17027; FR-17027;Cefixim; Cefixoral; Unixime; Cefiximum;

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)

DMSO : 90~100 mg/mL ( 198.47~220.53 mM )
Ethanol : ~1 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.51 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.51 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.51 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (5.51 mM)

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