Spectracef
Cefditoren pivoxil is a semisynthetic beta-lactam antibiotic, a prodrug of cefditoren (a third generation cephalosporin). The mechanism of action of the drug is associated with inhibition of bacterial wall synthesis due to its affinity for penicillin-binding proteins.
When the drug is prescribed at a dose of 200 mg 2 times a day, its plasma concentration exceeds the minimum inhibitory concentration for 90% of microorganisms (MIC90) for Moraxella catarrhalis, Haemophilus influenzae, Haemophilus parainfluenzae, Streptococcus pyogenes and penicillin-sensitive strains of Streptococcus pneumoniae for at least 50% of the time of the dosing interval. The administration of cefditoren at a dose of 400 mg 2 times a day ensures that its concentration is maintained above the MIC for 51% of the time of the dosing interval, which exceeds the MIC for 50% of microorganisms (MIC50) for Streptococcus pneumoniae, resistant to penicillin.
Mechanisms of resistance
Cefditoren, as a third generation cephalosporin, has common resistance mechanisms for this group of antibiotics. Resistance of gram-positive microorganisms may be associated with changes in the penicillin-binding protein of Streptococcus pneumoniae and Streptococcus viridans, or the appearance of an additional penicillin-binding protein (PBP2a) in Staphylococcus spp. Cefditoren is resistant to most of the most common chromosomal and plasmid beta-lactamases of gram-negative bacteria. However, like other cephalosporins, cefditoren is hydrolyzed by broad-spectrum beta-lactamases mediated by plasmids. In addition, the cause of resistance may be the production of chromosomal beta-lactamase in mutant strains of Enterobacter spp., Citrobacter spp., Morganella spp. and Serratia spp. The mechanism of action of cefditoren is similar to other cephalosporin antibiotics and differs from the mechanism of action of other groups of antibiotics. In general, no cross-resistance was observed between cefditoren and other groups of antibiotics. However, in rare cases, some mechanisms of action (for example, related to the impermeability of the inner membrane or the presence of a mechanism for active removal of the antibiotic from the cell) may be similar for all groups of antibiotics. This causes a certain level of resistance to all antibiotics.
Minimum inhibitory concentration (MIC)
Recommended MIC values for cefditoren, allowing to classify microorganisms with high, intermediate sensitivity and resistance: sensitive - ≤0.5 µg/ml, with intermediate sensitivity - > 0.5 µg/ml and < 2 µg/ml, resistant - ≥2 µg/ml.
Sensitivity
The table below provides information on the sensitivity spectrum of most microorganisms for approved indications.
The prevalence of acquired resistance may vary depending on the geographical area and also among individual pathogens. For this reason, it is desirable to obtain information about the susceptibility of microorganisms in a particular region, especially when treating a severe infection. In cases where the resistance of pathogens is in doubt, you can seek help from a specialist who will assess the advisability of prescribing cefditoren in a specific clinical case.
Typically susceptible species (less than 10% resistance, European data):
Aerobic gram-positive microorganisms:
Streptococci groups C and G, methicillin-sensitive strains of Staphylococcus aureus1, Streptococcus agalactiae, Streptococcus pneumoniae1,2 Streptococcus pyogenes1.
Aerobic gram-negative microorganisms:
Haemophilus influenzae1, Moraxella catarrhalis1.
Anaerobic microorganisms:
Clostridium perfringes, Peptostreptococcus spp.
Microorganisms with initial resistance to cefditoren
Aerobic gram-positive microorganisms:
Enterococcus spp., methicillin-resistant strains of Staphylococcus aureus.
Aerobic gram-negative microorganisms:
Acinetobacter baumanii Pseudomonas aeruginosa.
Anaerobic microorganisms:
group Bacteroides fragilis, Clostridium difficile.
Other:
Chlamydia spp., Mycoplasma spp., Legionella spp.
1—clinical efficacy has been demonstrated for sensitive pathogens for approved indications.
2 - some strains with high resistance to penicillin may have reduced sensitivity to cefditoren. Strains resistant to cefotaxime and ceftriaxone should not be considered susceptible to cefditoren.
Gram-negative microorganisms that contain chromosomal beta-lactamases, such as Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii, Serratia marcescens, should be considered resistant to cefditoren, despite their apparent susceptibility in vitro.
Spectracef tablets p.p.o. 200 mg No. 20
Action
Cefditoren pivoxil is a semisynthetic beta-lactam antibiotic, a prodrug of cefditoren (a third-generation cephalosporin).
The mechanism of action of the drug is associated with inhibition of bacterial wall synthesis due to its affinity for penicillin-binding proteins. Pharmacokinetic/pharmacodynamic features
When the drug is prescribed at a dose of 200 mg 2 times a day, its plasma concentration exceeds the MIC for 90% of microorganisms (MIC90) for Moraxella catarrhalis, Haemophilus influenzae, Haemophilus parainfluenzae, Streptococcus pyogenes and penicillin-sensitive strains of Streptococcus pneumoniae for at least 50% of the time from the dosing interval.
The administration of cefditoren at a dose of 400 mg 2 times a day ensures that its concentration is maintained above the MIC for 51% of the time of the dosing interval, which exceeds the MIC for 50% of microorganisms (MIC50) for Streptococcus pneumoniae, resistant to penicillin.
Mechanisms of resistance
Cefditoren, as a third generation cephalosporin, has common resistance mechanisms for this group of antibiotics. Resistance of gram-positive microorganisms may be associated with changes in the penicillin-binding protein of Streptococcus pneumoniae and Streptococcus viridans, or the appearance of an additional penicillin-binding protein (PBP2a) in Staphylococcus spp. Cefditoren is resistant to most of the most common chromosomal and plasmid beta-lactamases of gram-negative bacteria. However, like other cephalosporins, cefditoren is hydrolyzed by broad-spectrum beta-lactamases mediated by plasmids. In addition, the cause of resistance may be the production of chromosomal beta-lactamase in mutant strains of Enterobacter spp., Citrobacter spp., Morganella spp. and Serratia spp.
The mechanism of development of resistance to cefditoren is similar to other cephalosporin antibiotics and differs from the mechanism of action of other groups of antibiotics. In general, no cross-resistance was observed between cefditoren and other groups of antibiotics. However, in rare cases, some mechanisms of resistance (for example, related to the impermeability of the inner membrane or the presence of a mechanism for active removal of the antibiotic from the cell) may be similar for other groups of antibiotics. This causes a certain level of resistance to all antibiotics.
IPC. Recommended MIC values for cefditoren, allowing to classify microorganisms with high, intermediate sensitivity and resistance: sensitive - ≤0.5 µg/ml, with intermediate sensitivity - >0.5 µg/ml and <2 µg/ml, resistant - ≥2 µg /ml.
Sensitivity. The data below provides information on the sensitivity spectrum of most microorganisms for approved indications.
The prevalence of acquired resistance may vary depending on the geographical area and also among individual pathogens. For this reason, it is desirable to obtain information about the susceptibility of microorganisms in a particular region, especially when treating a severe infection. In cases where the resistance of pathogens is in doubt, you can seek help from a specialist who will assess the advisability of prescribing cefditoren in a specific clinical case.
Microorganisms with initial resistance to cefditoren:
- aerobic gram-positive microorganisms: Enterococcus spp.
- methicillin-resistant strains of Staphylococcus aureus;
- aerobic gram-negative microorganisms: Acinetobacter baumanii, Pseudomonas aeruginosa
Anaerobic microorganisms:
- group Bacteroides fragilis, Clostridium difficile.
Other: Chlamydia spp. Mycoplasma spp. Legionella spp.
Gram-negative microorganisms that contain chromosomal beta-lactamases, such as Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Morganella morganii, Serratia marcescens, should be considered resistant to cefditoren, despite their apparent susceptibility in vitro.
Pharmacokinetics
Suction. After oral administration of cefditoren pivoxil, it is absorbed into the gastrointestinal tract and, under the action of esterases, is hydrolyzed to cefditoren. Ingestion of 200 mg of the drug after food is accompanied by a Cmax of 2.6 μg/ml after approximately 2.5 hours, while taking 400 mg of the drug leads to a Cmax of 4.1 μg/ml after the same period of time. The absolute bioavailability of cefditoren after oral administration compared to intravenous administration is about 15–20%.
The presence of food in the gastrointestinal tract accelerates the absorption of cefditoren pivoxil, resulting in an increase in Cmax and AUC by 50 and 70% compared to fasting values, respectively.
Plasma protein binding and distribution. The binding of cefditoren to plasma proteins is 88%. After repeated and single doses of the drug, the pharmacokinetic parameters did not differ; this indicates the absence of cumulation. Vd of cefditoren under conditions of equilibrium concentration does not differ significantly from this indicator calculated after a single administration; it is practically independent of the administered dose and always remains within the range of 40–65 liters.
After a single injection of 400 mg of the drug, penetration into the mucous membrane and bronchial secretions was 60 and 20% of the concentration in the blood plasma, respectively. The results of administering a similar dose to healthy volunteers and subsequent assessment of the penetration of the antibiotic into the interstitial fluid showed that after 8 and 12 hours, the concentration of cefditoren in the interstitial fluid reached 40 and 56% of the plasma AUC, respectively.
Metabolism/excretion. Regardless of the dose and duration of treatment, up to 18% of the administered dose of cefditoren is excreted unchanged by the kidneys.
T1/2 of the drug from plasma is about 1–1.5 hours. Total clearance adjusted for bioavailability is about 25–30 l/h, renal clearance is about 80–90 ml/min. Studies of labeled cefditoren in healthy volunteers showed that the unabsorbed portion of the drug is excreted through the intestine, and a larger proportion of cefditoren is converted into inactive metabolites - P7 and M-OH. During the hydrolysis of cefditorene pivoxil, pivalate is formed, which is excreted by the kidneys in the form of pivaloylcarnitine conjugate.
Special patient groups
Floor. The pharmacokinetics of cefditoren pivoxil does not differ significantly in humans depending on gender.
Elderly patients. At the same dose, the concentration of cefditorene in elderly patients (over 65 years of age) is slightly higher compared to the population of middle-aged adults; Cmax and AUC rates in such patients are approximately 26 and 33% higher, respectively. With the exception of cases of severe renal and/or liver failure, no dose adjustment is required in elderly patients.
