Cefixime
Description
Introduction to Cefixime: Structural and Pharmacological Significance
This compound is a semisynthetic cephalosporin characterized by its β-lactam core and distinct substituents. It inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins (PBPs), critical enzymes in peptidoglycan cross-linking. Its oral bioavailability and resistance to hydrolysis by β-lactamases make it a valuable agent against Gram-positive and Gram-negative pathogens.
| Key Features | Details |
|---|---|
| Core Structure | β-Lactam ring fused to a dihydrothiazine ring (cephem nucleus) |
| Side Chain Modifications | Methoxyimino group at C7, 2-aminothiazole moiety, and ethenyl group at C3 |
| β-Lactamase Resistance | Enhanced stability due to Z-oxime configuration and steric hindrance |
Chemical Identity and IUPAC Nomenclature
This compound’s chemical identity is defined by its complex IUPAC name and molecular structure:
IUPAC Name :
(6R,7R)-7-[[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-[(carboxymethoxy)imino]acetyl]amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid .
Key Identifiers :
- Molecular Formula : $$ \text{C}{16}\text{H}{15}\text{N}5\text{O}7\text{S}_2 $$
- Molecular Weight : 453.45 g/mol
- CAS Number : 79350-37-1
- InChI Key : OKBVVJOGVLARMR-QSWIMTSFSA-N
Synonyms :
Historical Development and Classification as a Third-Generation Cephalosporin
This compound emerged from structural modifications to earlier cephalosporins, driven by the need for β-lactamase stability. Its development aligns with the evolution of third-generation cephalosporins, characterized by:
- Enhanced Gram-Negative Activity : Superior to first- and second-generation agents due to improved penetration into bacterial cells.
- β-Lactamase Resistance : Stability against plasmid-mediated β-lactamases (e.g., TEM, SHV) and chromosomal β-lactamases (e.g., AmpC) .
Key Milestones :
Key Structural Features Governing β-Lactamase Stability
This compound’s structural innovations mitigate β-lactamase-mediated hydrolysis, a critical limitation of earlier cephalosporins:
Z-Oxime Configuration
The methoxyimino group at the C7 position adopts a Z-configuration, which is 20,000-fold more stable than the E-isomer against β-lactamase hydrolysis . This configuration enhances electronic delocalization, reducing vulnerability to enzymatic attack.
2-Aminothiazole Side Chain
The 2-aminothiazole moiety at the C7 side chain introduces steric hindrance and electronic effects that deter β-lactamase binding . This group also participates in hydrogen bonding with bacterial enzymes, further stabilizing the drug-enzyme complex .
Ethynyl Group at C3
The ethenyl (vinyl) group at the C3 position improves membrane permeability in Gram-negative bacteria while maintaining stability against β-lactamases .
Comparative Structural Analysis :
Properties
IUPAC Name |
7-[[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 |
Source
|
|---|---|---|
| Details | Computed by Lexichem TK 2.7.0 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
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) |
Source
|
| Details | Computed by InChI 1.0.6 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
OKBVVJOGVLARMR-UHFFFAOYSA-N |
Source
|
| Details | Computed by InChI 1.0.6 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C=CC1=C(N2C(C(C2=O)NC(=O)C(=NOCC(=O)O)C3=CSC(=N3)N)SC1)C(=O)O |
Source
|
| Details | Computed by OEChem 2.3.0 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C16H15N5O7S2 |
Source
|
| Details | Computed by PubChem 2.1 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID20861014 |
Source
|
| Record name | 7-{2-(2-Amino-1,3-thiazol-4-yl)[(carboxymethoxy)imino]acetamido}-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID20861014 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
453.5 g/mol |
Source
|
| Details | Computed by PubChem 2.1 (PubChem release 2021.05.07) | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
CAS No. |
79350-37-1 |
Source
|
| Record name | 5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2Z)-2-(2-amino-4-thiazolyl)-2-[(carboxymethoxy)imino]acetyl]amino]-3-ethenyl-8-oxo-, (6R,7R) | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.119.331 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
Preparation Methods
Role of 7-AVCA in Cephalosporin Backbone Formation
7-AVCA provides the β-lactam core structure essential for this compound’s antibacterial activity. Its vinyl group at the C3 position enhances stability against β-lactamases compared to earlier cephalosporins. In the coupling reaction with MICE, the primary amine of 7-AVCA undergoes nucleophilic attack on the activated carbonyl of MICE, facilitated by organic bases.
MICE as the Side Chain Precursor
MICE introduces the (Z)-methoxyimino group, which confers resistance to enzymatic degradation. The thiobenzothiazole moiety acts as a leaving group during the coupling step, with reaction kinetics heavily dependent on solvent polarity and temperature. Optimal conditions reported include tetrahydrofuran (THF)-water mixtures at 0–4°C, achieving 85–90% conversion rates.
Detailed Preparation Methods
Triethanolamine-Catalyzed Coupling (Nguyen et al., 2025)
This method replaces traditional triethylamine with triethanolamine to enhance reaction efficiency:
- Activation : MICE (1.2 eq) is dissolved in THF/water (4:1 v/v) at 0°C.
- Coupling : 7-AVCA (1.0 eq) and triethanolamine (1.5 eq) are added dropwise over 30 minutes.
- Quenching : The mixture is stirred at 0–4°C for 1.5 hours, then acidified to pH 2.2–2.4 with HCl.
- Isolation : Crude this compound is purified via recrystallization from acetone/water.
Outcomes :
High-Purity Trihydrate Synthesis (US8008478B2)
This patented method addresses color and solubility issues in final products:
- Hydrolysis : this compound methyl ester (1.0 eq) is treated with 2M NaOH at 60–70°C for 4 hours.
- Acidification : Filtrate is adjusted to pH 2.2–2.4 with HCl at 64–68°C to precipitate this compound trihydrate.
- Crystallization : Seeding with this compound trihydrate (0.1% w/w) induces controlled crystal growth.
Key Parameters :
| Parameter | Value |
|---|---|
| Temperature | 64–68°C |
| Purity | 99.76% (HPLC) |
| Solubility | 12.4 mg/mL (pH 7.0) |
This process eliminates DMF, reducing residual solvent levels below 50 ppm.
Phase Transfer Catalysis (US7705142B2)
A biphasic system improves yield and reduces by-products:
- Reaction Setup : this compound ester (1.0 eq) in ethyl acetate + aqueous NaHCO₃ (pH 8.5–9.0).
- Catalysis : Tetrabutylammonium bromide (0.1 eq) accelerates hydrolysis at 25–30°C.
- Workup : Organic layer is separated, and product crystallizes upon acidification.
Performance Metrics :
Comparative Analysis of Industrial Methods
Table 1: Comparison of this compound Synthesis Methods
Insights :
- The trihydrate method achieves the highest purity but requires extended crystallization times.
- Phase transfer catalysis offers a balance between yield and operational simplicity.
Recent Advances and Innovations
Solvent-Free Mechanochemical Synthesis
Emerging techniques use ball milling to couple 7-AVCA and MICE without solvents, achieving 60% yield in 30 minutes. This approach reduces waste and complies with green chemistry principles.
Enzymatic Hydrolysis of Esters
Immobilized lipases (e.g., Candida antarctica Lipase B) selectively hydrolyze this compound methyl ester at pH 7.0, eliminating the need for strong acids/bases. Pilot-scale trials show 92% conversion efficiency.
Chemical Reactions Analysis
Types of Reactions: Cefixime undergoes several types of chemical reactions, including:
Oxidation: this compound can be oxidized to form sulfoxides and sulfones.
Reduction: Reduction reactions can convert this compound to its corresponding amine derivatives.
Substitution: Nucleophilic substitution reactions can modify the side chains of this compound.
Common Reagents and Conditions:
Oxidation: Hydrogen peroxide or peracids are commonly used oxidizing agents.
Reduction: Sodium borohydride or catalytic hydrogenation are typical reducing conditions.
Substitution: Nucleophiles such as amines or thiols are used under basic conditions.
Major Products:
Oxidation: Sulfoxides and sulfones.
Reduction: Amine derivatives.
Substitution: Modified cephalosporin derivatives
Scientific Research Applications
Pharmacological Applications
Cefixime is primarily indicated for the treatment of:
- Uncomplicated Urinary Tract Infections : Effective against pathogens such as Escherichia coli and Proteus mirabilis.
- Otitis Media : Used for infections caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pyogenes.
- Pharyngitis and Tonsillitis : Particularly effective against Streptococcus pyogenes.
- Acute Exacerbations of Chronic Bronchitis : Treats infections caused by Streptococcus pneumoniae and Haemophilus influenzae.
- Uncomplicated Gonorrhea : Effective against both penicillinase and non-penicillinase producing strains of Neisseria gonorrhoeae .
Case Studies
-
This compound in Early Syphilis Treatment
A randomized clinical study reported that this compound successfully treated 87% of participants with early syphilis. The study highlighted its potential as an alternative treatment, especially for high-risk populations, such as individuals with HIV . -
This compound-Induced Hepatotoxicity
A case report documented a 7-month-old infant who developed severe complications, including acute renal failure, after receiving this compound for a urinary tract infection. This case underscores the importance of monitoring adverse effects in pediatric patients . -
Toxic Epidermal Necrolysis
Another rare case involved a 7-year-old boy who experienced toxic epidermal necrolysis after this compound administration. This highlights the need for careful selection of antibiotics in patients with a history of severe cutaneous reactions .
Comparative Effectiveness
A comparative study evaluated this compound against tetracycline for treating acute respiratory tract infections (ARTIs). Results indicated that this compound was more effective than tetracycline, suggesting its continued use as a frontline antibiotic in managing ARTIs .
Safety Profile
This compound is generally well-tolerated, with common side effects including mild gastrointestinal disturbances like diarrhea, nausea, and vomiting. Serious adverse reactions are rare but can occur, necessitating awareness among healthcare providers .
Data Table: Clinical Efficacy Summary
| Study Focus | Population Size | Treatment Success Rate | Adverse Events Reported |
|---|---|---|---|
| Early Syphilis | 15 | 87% | Mild rash |
| Pediatric Hepatotoxicity Case | 1 | N/A | Severe dehydration |
| Toxic Epidermal Necrolysis Case | 1 | N/A | Severe skin reaction |
| Acute Respiratory Infections | Variable | Superior to tetracycline | Mild GI symptoms |
Mechanism of Action
Cefixime is compared with other third-generation cephalosporins such as ceftriaxone, cefotaxime, and ceftazidime:
Ceftriaxone: Similar spectrum of activity but has a longer half-life and is administered intravenously.
Cefotaxime: Similar antibacterial spectrum but is more effective against certain Gram-negative bacteria.
Ceftazidime: Has a broader spectrum of activity against Pseudomonas aeruginosa.
Uniqueness: this compound is unique in its oral bioavailability, making it a convenient option for outpatient treatment. It is also relatively stable in the presence of β-lactamases, which are enzymes produced by bacteria to inactivate β-lactam antibiotics .
Comparison with Similar Compounds
Pharmacokinetic Comparison with Similar Cephalosporins
Cefixime exhibits unique pharmacokinetic properties compared to other cephalosporins:
This compound’s absorption is pH-dependent, favoring acidic environments, whereas cephradine utilizes both neutral and acidic pH transport systems .
Antimicrobial Spectrum and MIC Comparisons
This compound demonstrates superior or comparable minimum inhibitory concentrations (MICs) against common pathogens relative to other antibiotics:
Table 1: MIC Values (μg/mL) Against Key Pathogens
This compound shows potent activity against N. gonorrhoeae, though resistance rates (3.7–11%) are higher than ceftriaxone (2.9–4%) in some regions . It outperforms amoxicillin/clavulanic acid against K. pneumoniae but is less effective against S. aureus than cefpodoxime .
Clinical Efficacy in Key Indications
Lower Respiratory Tract Infections (LRTIs)
- This compound achieved 74/75 clinical cures in non-comparative trials, with efficacy comparable to intravenous cefotaxime when used as step-down therapy .
- In community-acquired pneumonia (CAP), this compound showed 94% clinical success vs.
Urinary Tract Infections (UTIs)
Gonorrhea
- A single 400 mg oral dose of this compound demonstrated equivalent efficacy to 250 mg intramuscular ceftriaxone, but rising resistance limits its use as a first-line agent .
Emerging Resistance and Synergistic Strategies
- Resistance in N. gonorrhoeae: Resistance to this compound (3.7–11%) is higher than ceftriaxone (2.9–4%) due to altered penicillin-binding proteins (PBPs) .
- Synergy with Natural Compounds: Combining this compound with plant polyphenolic extracts reduced bacterial growth synergistically, with 2MIC achieving >90% inhibition .
Comparison with Novel Antibacterial Agents
Biological Activity
Cefixime is a third-generation cephalosporin antibiotic widely used for treating various bacterial infections. Its biological activity is characterized by its mechanism of action, spectrum of activity, pharmacokinetics, and clinical efficacy, particularly against resistant strains. This article will delve into these aspects, supported by data tables and case studies.
This compound works by inhibiting bacterial cell wall synthesis. It binds to penicillin-binding proteins (PBPs), which are essential for the final stages of peptidoglycan synthesis in bacterial cell walls. This inhibition leads to cell lysis, especially in rapidly growing bacteria. This compound is notably stable against many beta-lactamases, which are enzymes that confer resistance to other antibiotics:
- Stability Against Beta-Lactamases : this compound shows high resistance to plasmid-mediated penicillinase and chromosomal β-lactamases, except for specific strains like Bacteroides fragilis .
- Affinity for PBPs : It has a strong affinity for PBPs 3 and 1a of Escherichia coli, contributing to its effectiveness against gram-negative bacteria .
Spectrum of Activity
This compound exhibits significant antibacterial activity against a variety of pathogens:
| Pathogen | Activity Level |
|---|---|
| Enterobacteriaceae | Good activity |
| Haemophilus influenzae | Good activity |
| Neisseria gonorrhoeae | Effective even against beta-lactamase producing strains |
| Streptococcus pneumoniae | High activity |
| Staphylococcus aureus | Not susceptible |
| Pseudomonas aeruginosa | Not susceptible |
This compound's effectiveness is comparable to cefotaxime and superior to cefuroxime and amoxicillin in treating infections caused by these organisms .
Pharmacokinetics
This compound's pharmacokinetic profile is critical for its therapeutic efficacy:
- Absorption : Approximately 40%-50% is absorbed after oral administration, with peak serum concentrations reached around 6.7 hours post-dose .
- Half-Life : The mean elimination half-life is approximately 3.8 hours .
- Tissue Penetration : this compound penetrates tissue fluids effectively, achieving concentrations that exceed minimum inhibitory concentrations (MICs) for most urinary pathogens .
Clinical Efficacy
Recent studies have highlighted this compound's potential in treating various infections, including syphilis and urogenital infections.
Case Studies
-
Treatment of Early Syphilis :
- A randomized non-comparative clinical study found that 87% of participants treated with this compound responded successfully at the 3 or 6-month follow-up. In comparison, benzathine penicillin G achieved a response rate of 93% .
- Treatment failures were noted in both groups, emphasizing the need for careful monitoring .
- Urogenital Infections :
Q & A
Q. What experimental design optimizes photocatalytic degradation of this compound using nanocomposites?
- Methodological Answer : Use a Box-Behnken or central composite design to vary parameters (e.g., pH, catalyst dose, irradiation time). Analyze removal efficiency via Minitab or Design-Expert® software, identifying optimal conditions (e.g., 90% degradation at pH 7, 1.5 g/L Polyaniline/SnO₂). Validate with ANOVA (p<0.05) and confirm kinetics using pseudo-first-order models .
Q. How to evaluate clinical failure rates of this compound in gonorrhea treatment using molecular epidemiology?
- Methodological Answer : Retrospectively analyze culture-positive cases (n=291) treated with 400 mg this compound. Define failure as persistent infection (identical PFGE patterns pre/post-treatment) and stratify by MICs (e.g., failure rate: 25% for MIC ≥0.12 µg/mL vs. 1.9% for MIC <0.12 µg/mL). Use logistic regression to calculate relative risk (RR=13.13, 95% CI: 2.88–59.72) .
Q. What statistical approaches compare OFAT vs. DOE in optimizing this compound analytical methods?
- Methodological Answer : Contrast One-Factor-at-a-Time (OFAT) with Design of Experiments (DOE) using metrics like R², prediction error, and resource efficiency. For example, DOE with CCD reduces runs by 40% compared to OFAT while improving sensitivity (e.g., LOD: 0.2 µg/mL vs. 0.5 µg/mL) .
Q. How to model this compound’s corrosion inhibition properties in sustainable material science?
- Methodological Answer : Use electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization in 1M HNO₃. Calculate inhibition efficiency (e.g., 85% at 100 ppm this compound) and validate with DFT simulations to correlate molecular structure (e.g., sulfonic groups) with adsorption on copper surfaces .
Data Contradictions and Resolution
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
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Please be aware that all articles and product information presented on BenchChem are intended solely for informational purposes. The products available for purchase on BenchChem are specifically designed for in-vitro studies, which are conducted outside of living organisms. In-vitro studies, derived from the Latin term "in glass," involve experiments performed in controlled laboratory settings using cells or tissues. It is important to note that these products are not categorized as medicines or drugs, and they have not received approval from the FDA for the prevention, treatment, or cure of any medical condition, ailment, or disease. We must emphasize that any form of bodily introduction of these products into humans or animals is strictly prohibited by law. It is essential to adhere to these guidelines to ensure compliance with legal and ethical standards in research and experimentation.
