β-lactam
Cefditoren Pivoxil targets bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs), thereby inhibiting the final transpeptidation step of peptidoglycan synthesis. This leads to cell lysis and death. The compound is stable to many beta-lactamases of clinical importance, making it effective against beta-lactamase-producing strains. Cefditoren has a broad spectrum of activity against both Gram-positive organisms (e.g., Streptococcus pneumoniae, Streptococcus pyogenes) and Gram-negative organisms (e.g., Haemophilus influenzae, Moraxella catarrhalis). It exhibits potent activity against penicillin-resistant S. pneumoniae (PRSP) with an MIC80 of 0.20 µg/mL, which is 15.7-fold more potent than cefdinir and 3.9-fold more potent than cefpodoxime.

Cefditoren has MIC50/MIC90 results for Moraxella catarrhalis and Haemophilus influenzae of 0.12/0.5 and < or = 0.008/0.015 mg/mL, respectively. Cefditoren (MIC(90), 0.5 mg/mL) is 4- to 128-fold more active than comparison beta-lactams against the pneumoococci and was the most potent beta-lactam (including penicillin) versus beta-haemolytic streptococci. Cefditoren (MIC(90) in mg/mL/% susceptible) activity against all tested H. influenzae (0.03/100) and M. catarrhalis (0.06-0.5/100) is comparable to Cefixime and significantly greater than cefaclor. Cefditoren pharmacokinetics demonstrate a T(1/2) of 1.5-2 hours and C(max) values of 2.8 and 4.6 mg/mL, respectively with 200 or 400 mg doses of Cefditoren pivoxil. Cefditoren possesses a broad-spectrum of cidal antibacterial activity against both Gram-positive and Gram-negative species with stability to many beta-lactamases of clinical importance. Cefditoren is also effective against methicillin-susceptible strains of Staphylococcus aureus. Cefditoren has compared favorably against other orally administered antibiotics used against the most commonly isolated respiratory tract pathogens. Cefditoren up-regulates the expression levels of Mrp2, Bcrp and Oat2, and down-regulate P-gp and Oct1 mRNA expression.

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Cefditoren Pivoxil (Cefditoren pivoxyl) (CAS#: 117467-28-4) (as its active form cefditoren) was evaluated in vitro against 1249 recent clinical isolates.
Against Moraxella catarrhalis (250 strains, 89.6% β-lactamase producers): cefditoren showed MIC50/MIC90 of 0.12/0.5 μg/mL. All M. catarrhalis strains were susceptible to erythromycin, rifampin, tetracycline, and trimethoprim/sulfamethoxazole. [1]
Against Haemophilus influenzae (499 strains, including 173 β-lactamase-positive): cefditoren showed uniformly high activity with MIC90 of 0.015 μg/mL regardless of β-lactamase production. For β-lactamase-negative strains, MIC range ≤0.008-0.12 μg/mL, MIC50 ≤0.008 μg/mL, MIC90 0.015 μg/mL; for β-lactamase-positive strains, MIC range ≤0.008-0.06 μg/mL, MIC50 ≤0.008 μg/mL, MIC90 0.015 μg/mL. [1]
Against Streptococcus pneumoniae (500 strains, 32.8% non-susceptible to penicillin): cefditoren showed decreased activity with increasing penicillin MIC. For penicillin-susceptible strains (n=336): MIC range ≤0.008-0.12 μg/mL, MIC50 ≤0.008 μg/mL, MIC90 0.015 μg/mL. For penicillin-intermediate strains (n=108): MIC range 0.015-2 μg/mL, MIC50 0.12 μg/mL, MIC90 0.5 μg/mL. For penicillin-resistant strains (n=56): MIC range 0.25-4 μg/mL, MIC50 0.5 μg/mL, MIC90 2 μg/mL. Cefditoren was at least twofold more active against penicillin-intermediate and -resistant S. pneumoniae (MIC90s 0.5 and 2 μg/mL, respectively) compared to other tested β-lactams including amoxicillin/clavulanic acid. The highest recorded MIC for cefditoren against penicillin-resistant S. pneumoniae was 4 μg/mL. The rank order of activity against all tested S. pneumoniae: rifampin (100% susceptible) > cefditoren (99.4% at ≤2 μg/mL) > ofloxacin (97.2%) > cefditoren (95.6% at ≤0.5 μg/mL) > clindamycin (94.8%) > erythromycin (82%) > amoxicillin/clavulanic acid (80.4%) > trimethoprim/sulfamethoxazole (77.4%) > cefuroxime (74.8%). [1]
In vitro studies have demonstrated that Cefditoren Pivoxil possesses broad-spectrum antibacterial activity. It exhibits potent activity against Streptococcus pneumoniae with an MIC50 of 0.25-0.5 mg/L. Against penicillin-resistant S. pneumoniae (PRSP), the MIC80 is 0.20 µg/mL, which is 15.7-fold lower than cefdinir and 3.9-fold lower than cefpodoxime. Against BLNAR H. influenzae, the MIC90 is 0.25 µg/mL. Cefditoren also shows activity against a range of Gram-positive cocci and Gram-negative rods. The compound's bactericidal activity has been confirmed in time-kill studies and other in vitro assays. Its stability to beta-lactamases contributes to its broad-spectrum activity.

In vivo studies have shown that Cefditoren Pivoxil displays activity in several infectious models in mice, including burn, abscess, and pulmonary infection models. PK/PD models confirm bactericidal attainment for MICs ≤0.5 mg/L. The compound's efficacy has been demonstrated in animal models of respiratory tract infections and other bacterial infections. Due to its low water solubility, Cefditoren Pivoxil is typically administered to animals as a suspension. The compound's in vivo efficacy correlates with its in vitro potency and pharmacokinetic properties. Clinical studies have confirmed its efficacy in treating mild to moderate infections in adults and adolescents.

Non-cellular antimicrobial susceptibility assays for Cefditoren Pivoxil typically involve determining the minimum inhibitory concentration (MIC) using broth microdilution or agar dilution methods according to Clinical and Laboratory Standards Institute (CLSI) guidelines. The compound is tested against a panel of bacterial strains, including quality control strains, at various concentrations. The MIC is defined as the lowest concentration that inhibits visible bacterial growth after overnight incubation. MIC50 and MIC90 values are calculated from the distribution of MICs for a population of isolates. These assays are essential for characterizing the antimicrobial spectrum and potency of Cefditoren Pivoxil. Beta-lactamase stability can be assessed by comparing MICs in the presence and absence of beta-lactamase inhibitors.

In vitro cell-based assays for Cefditoren Pivoxil are not typically performed, as the compound's antibacterial activity is assessed in cell-free or bacterial culture systems rather than in mammalian cell-based assays. However, cytotoxicity assays may be performed in mammalian cell lines to assess the compound's safety profile. These assays typically involve culturing cells in appropriate media and treating them with Cefditoren Pivoxil at various concentrations. Cell viability is assessed using MTT, CCK-8, or similar assays. The compound's selectivity for bacterial cells over mammalian cells is a key aspect of its safety profile. Due to its low water solubility, Cefditoren Pivoxil is typically dissolved in DMSO for in vitro studies.

In vivo animal studies for Cefditoren Pivoxil typically involve mouse models of bacterial infection, including burn wound infection, abscess, and pulmonary infection models. Mice are infected with bacterial strains (e.g., S. pneumoniae, H. influenzae) and treated with Cefditoren Pivoxil at various doses, typically administered orally as a suspension due to its low water solubility. The compound's efficacy is assessed by measuring survival rates, bacterial burden in tissues (e.g., lungs, blood), and histopathological changes. Dose-response studies are conducted to determine the ED50 and efficacy. PK/PD studies are performed to correlate pharmacokinetic parameters with antibacterial efficacy. Body weight and general health parameters are monitored throughout the study.

Pharmacokinetic studies of Cefditoren Pivoxil have shown that it is a prodrug that is hydrolyzed to the active form cefditoren after oral administration. The compound's low water solubility necessitates formulation as a suspension for oral administration. Cefditoren is absorbed from the gastrointestinal tract and distributed to tissues, achieving concentrations that exceed the MIC for susceptible organisms. The compound is eliminated primarily by renal excretion. PK/PD models have confirmed bactericidal attainment for MICs ≤0.5 mg/L. However, detailed PK parameters such as half-life, Cmax, AUC, and bioavailability are available in the clinical literature and regulatory documents. Cefditoren Pivoxil is approved for clinical use in various countries.

Toxicological data for Cefditoren Pivoxil have been evaluated in preclinical studies and clinical trials. The compound's safety profile has been characterized in standard toxicology studies, including acute and chronic toxicity, genotoxicity, and reproductive toxicity assessments. Mutagenicity studies, including the reverse mutation assay in bacteria, have been conducted. Cefditoren Pivoxil is generally well-tolerated at therapeutic doses, with adverse effects typical of cephalosporin antibiotics (e.g., gastrointestinal disturbances, hypersensitivity reactions). However, specific toxicological findings are detailed in the product labeling and regulatory documents. Cefditoren Pivoxil is approved for clinical use and is available by prescription.

Diagn Microbiol Infect Dis.1998 Aug;31(4):573-8;Diagn Microbiol Infect Dis.2000 Jun;37(2):99-105;Drugs Exp Clin Res.1994;20(4):127-47.

Cefditoren pivoxil is a prodrug of cefotiam, with the molecular formula neopentyloxymethyl ester. It is both a prodrug and an antibacterial drug. It is a neopentyloxymethyl ester belonging to the 1,3-thiazole, oxime, and cephalosporin classes. Its function is related to that of cefotiam. Cefdextrin pivoxil is a semi-synthetic, broad-spectrum, β-lactamase-resistant third-generation cephalosporin antibiotic with bactericidal activity. Cefdextrin pivoxil is a prodrug that is rapidly hydrolyzed by intestinal esterases during absorption to cefotiam, an active aminothiazole cephalosporin, which has microbial activity. Cefdextrin inactivates penicillin-binding protein (PBP), thereby interfering with peptidoglycan synthesis and inhibiting bacterial cell wall synthesis. Another consequence of β-lactam antibiotic exposure is the loss of lipoteichoic acid from the cell wall. Lipotechiic acid inhibits the activity of cell wall hydrolases, and its absence from the cell wall triggers uncontrolled autolysis, making bacterial cells susceptible to osmotic shocks. This leads to decreased cell wall stability and ultimately cell lysis.
See also: Ceftriaxone (contains the active ingredient).

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Cefditoren Pivoxil (Cefditoren pivoxyl) (CAS#: 117467-28-4) is a new orally administered cephalosporin (formerly ME-1206). It is a methoxyiminocophem of the third-generation cephalosporin class. When formulated as a pivotal ester, it allows acceptable bioavailability for oral use. Its greatest therapeutic potential appears to be its activity against penicillin-resistant Streptococcus pneumoniae, with MIC90 of 0.5-1 μg/mL reported previously, and it has been proven to be bactericidal. Most cefditoren minimum bacterial concentration values were equal to the measured MIC. [1]
Cefditoren Pivoxil (Cefditoren pivoxyl) is a third-generation oral cephalosporin antibiotic with broad-spectrum activity against Gram-positive and Gram-negative bacteria. It has the CAS number 117467-28-4. The compound is a prodrug that is hydrolyzed to the active form cefditoren after oral administration. It is stable to many beta-lactamases and exhibits potent activity against penicillin-resistant S. pneumoniae (MIC80 0.20 µg/mL). Cefditoren Pivoxil is approved for the treatment of mild to moderate infections, including respiratory tract infections, skin infections, and pharyngitis. It is available by prescription in various countries.

C25H28N6O7S3

620.72

620.118

C, 48.38; H, 4.55; N, 13.54; O, 18.04; S, 15.50

117467-28-4

Cefditoren sodium;104146-53-4;Cefditoren-13C,d3

6437877

Light yellow to yellow solid powder

1.6±0.1 g/cm3

207-209ºC

1.710

2.74

2

14

12

41

1160

2

S1C([H])([H])C(/C(/[H])=C(/[H])\C2=C(C([H])([H])[H])N=C([H])S2)=C(C(=O)OC([H])([H])OC(C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])=O)N2C([C@]([H])([C@@]12[H])N([H])C(/C(/C1=C([H])SC(N([H])[H])=N1)=N\OC([H])([H])[H])=O)=O

AFZFFLVORLEPPO-UVYJNCLZSA-N

InChI=1S/C25H28N6O7S3/c1-12-15(41-10-27-12)7-6-13-8-39-21-17(29-19(32)16(30-36-5)14-9-40-24(26)28-14)20(33)31(21)18(13)22(34)37-11-38-23(35)25(2,3)4/h6-7,9-10,17,21H,8,11H2,1-5H3,(H2,26,28)(H,29,32)/b7-6-,30-16-/t17-,21-/m1/s1

(pivaloyloxy)methyl(6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(methoxyimino)acetamido)-3-((Z)-2-(4-methylthiazol-5-yl)vinyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

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 : ~100 mg/mL ( ~161.1 mM )

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.03 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 (4.03 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 (4.03 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 (4.03 mM)

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