Spectraceph, 200 mg 14 pcs

Pharmacological action – antibacterial.

Pharmacodynamics

The mechanism of action. Cefditorena pivaxil is a semi-synthetic beta-lactam antibiotic, is a prodrug of cefditorena (third generation cephalosporin). The mechanism of action of the drug is associated with inhibition of bacterial wall synthesis due to its affinity to penicillin-binding proteins.

Pharmacokinetic/pharmacodynamic characteristics. When the drug is administered at a dose of 200 mg 2 times daily, its plasma concentration exceeds the minimum suppressive concentration against 90% of microorganisms (MPK90) for Moraxella catarrhalis, Haemophilus influenzae, Haemophilus parainfluenzae, Streptococcus pyogenes and penicillin-sensitive strains of Streptococcus pneumoniae for at least 50% of the dosing interval. Administration of cefditorin at a dose of 400 mg twice daily maintains its concentration above the minimum suppressive concentration (MSC) for 51% of the dosing interval, which exceeds the minimum suppressive concentration against 50% of microorganisms (MSC50) for penicillin-resistant Streptococcus pneumoniae.

The mechanisms of resistance. Cefditorin as a third-generation cephalosporin has common resistance mechanisms for this group of antibiotics. Resistance of gram-positive microorganisms may be associated with a change in the penicillin-binding protein of Streptococcus pneumoniae and Streptococcus viridans, or the appearance of an additional penicillin-binding protein (PBP2a) in Staphylococcus spp. Cefditorin is resistant to most of the most common chromosomal and plasmid beta-lactamases of Gram-negative bacteria. At the same time, like other cephalosporins, cefditorin is hydrolyzed by broad-spectrum plasmid-mediated beta-lactamases. In addition, the production of chromosomal beta-lactamase in mutant strains of Enterobacter spp., Citrobacter spp., Morganella spp. and Serratia spp.

The mechanism of action of cefditorin is similar to other cephalosporin antibiotics and differs from the mechanism of action of other groups of antibiotics. In general, no cross-resistance between cefditorene and other groups of antibiotics has been noted. However, in rare cases, certain mechanisms of action (e.g., 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 antibiotic groups. This accounts for a certain level of resistance to all antibiotics.

The MPC. The recommended MAC values for cefditorin to classify microorganisms with high, intermediate sensitivity and resistance are: sensitive ≤0.5 µg/mL, intermediate sensitivity, >0.5 and < 2 µg/mL, resistant ≥2 µg/mL.

Sensitivity. Table 1 below outlines the sensitivity spectrum of most microorganisms for approved indications. The prevalence of acquired resistance may vary by geographic area as well as in individual pathogens. For this reason, it is desirable to obtain information on the sensitivity of microorganisms in a particular region, especially when treating severe infections. In cases where pathogen resistance is questionable, the assistance of a specialist may be sought to evaluate the appropriateness of prescribing ceftiditorin in a particular clinical setting.

Table 1

Sensitivity spectrum for most microorganisms for approved indications

1Clinical efficacy has been shown for sensitive pathogens for approved indications.

2Some strains with high penicillin resistance may have reduced sensitivity to ceftiditorin. Strains resistant to cefotaxime and ceftriaxone should not be considered sensitive to ceftiditorin. 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 ceftiditorin despite their apparent susceptibility in vitro.

Pharmacokinetics

Intake. After oral administration of cefditoren pivoxil, it is absorbed in the gastrointestinal tract and is hydrolyzed to cefditoren under the action of esterases. Oral administration of 200 mg of the drug after a meal is accompanied by reaching a maximum concentration (Cmax) of 2.6 mcg/ml in about 2.5 hours, while 400 mg of the drug leads to reaching Cmax of 4.1 mcg/ml after the same period. The absolute bioavailability of ceftiditorin after oral administration compared to intravenous administration is approximately 15-20%.

The presence of food in the gastrointestinal tract accelerates absorption of ceftiditoren pivoxil that leads to increase of Cmax and area under the pharmacokinetic curve “concentration – time” (AUC) by 50 and 70% compared to values on an empty stomach, respectively.

Binding to plasma proteins and distribution. Binding of ceftiditorin to plasma proteins is 88%. Pharmacokinetic parameters did not differ after multiple and single drug administration; this indicates the absence of cumulation. The volume of distribution of ceftiditorin at equilibrium concentration does not differ significantly from this indicator calculated after single administration; it practically does not depend on the administered dose and always remains within 40-65 l.

After a single injection of 400 mg of the drug penetration into the mucous membrane and bronchial secretion was 60 and 20% of the blood plasma concentration, respectively. The results of administration of a similar dose to healthy volunteers and subsequent evaluation of penetration of the antibiotic into interstitial fluid showed that after 8 and 12 hours the concentration of ceftiditorin in interstitial fluid reached 40 and 56% of the plasma area under the pharmacokinetic curve, respectively.

Metabolism/excretion. Regardless of the dose and duration of treatment, up to 18% of the administered dose of ceftiditorin is excreted unchanged by the kidneys. Half-life of the drug from plasma is about 1.0-1.5 hours. Total clearance with correction for bioavailability is about 25-30 l/h, renal clearance is about 80-90 ml/min. Studies of labeled ceftiditorin in healthy volunteers have shown that unabsorbed part of the drug is excreted through the intestine, and most of the cefditorin is converted into inactive metabolites – P7 and M-ON. During hydrolysis of pivoxil cefditoren, pivalate is formed, which is excreted by the kidneys as pivaloylcarnitine conjugate.

Particular patient groups

Paul. The pharmacokinetics of cefditorin pivoxil have no significant differences in humans according to gender.

Elderly patients. When administered with the same doses, cefditorin concentrations are slightly higher in elderly patients (aged over 65 years) compared to the middle-aged adult population; Cmax and AUC values are about 26% and 33% higher in these patients, respectively. Except in cases of severe renal and/or hepatic impairment, elderly patients do not require dose adjustment.

Renal dysfunction. After repeated administration of cefditorin pivoxil at a dose of 400 mg, AUC values in healthy volunteers and patients with kidney damage of various degrees of severity.

The observed changes in pharmacokinetic parameters of ceftiditorin in patients with mild renal impairment are not considered to be clinically significant. In patients with moderate to severe renal impairment the AUC is approximately 3 times higher compared to healthy volunteers. The currently available data do not allow recommending any doses of the drug to patients on hemodialysis.

Liver dysfunction. The effect of mild to moderate hepatic dysfunction on the pharmacokinetics of ceftiditorin pivoxil after its administration at a dose of 400 mg includes a slight increase in the main pharmacokinetic parameters without statistically significant differences. In addition, there was a slight increase in the amount of the drug excreted by the kidneys compared to healthy volunteers. Similar data in patients with severe hepatic impairment have not been obtained to date.

Indications

Active ingredient

Composition

How to take, the dosage

Ingestion. Tablets should be swallowed whole with plenty of water, preferably after a meal.

The recommended dose depends on the severity of the infection, the patient’s baseline condition, and the potential pathogens.

Adults and children over 12 years of age

Acute tonsillopharyngitis, acute maxillary sinusitis and uncomplicated skin and subcutaneous fatty tissue infections – 200 mg every 12 hours for 10 days.

Exacerbation of chronic bronchitis – 200 mg every 12 hours for 5 days.

In community-acquired pneumonia – 200 mg every 12 hours for 14 days. In severe cases – 400 mg every 12 hours for 14 days.

Patient special groups

Elderly age. No dose adjustment is required in elderly patients, except in cases of severe hepatic and/or renal dysfunction.

Patients with impaired renal function. In patients with mild renal impairment no dose adjustment is required. In patients with moderate renal impairment (creatinine clearance – 30-50 ml/min) the recommended dose should not exceed 200 mg 2 times a day. In patients with severe renal failure (creatinine clearance – less than 30 ml/min), the maximum daily dose should not exceed 200 mg. In patients on hemodialysis, the recommended dose has not been established.

Hepatic impairment. No dose adjustment is required in patients with mild to moderate hepatic impairment (Child-Pugh grades A or B). In severe hepatic impairment (Child-Pugh class C) no data are available to recommend a dose.

Interaction

Antacids
Co-administration of ceftiditorin pixil and antacids containing magnesium hydroxide, aluminum, after meals reduces Cmax and AUC of ceftiditorin by 14% and 11%, respectively. Although the clinical significance of this fact is unknown, it is recommended that the period between the administration of antacids and ceftiditorin pixil should be 2 hours.

Probenecid
Co-administration of probenecid and ceftiditorin pivaxil decreases renal excretion of the antibiotic, increasing Cmax by 49%, AUC by 122%, and increasing the half-life of ceftiditorin by 53%.

H2-histamine receptor blockers
Simultaneous intravenous administration of famotidine and cefditorin pivoxil leads to decrease of Cmax and AUC by 27 and 22% respectively. Thus, concomitant use of cefditorene pivaxil and H2-histamine receptor blockers is not recommended.

Special Instructions

Before prescribing Spectraceph, the patient’s history of allergic reactions should be carefully ascertained. If a hypersensitivity reaction develops, treatment should be discontinued and the patient should receive the necessary treatment.

Patients of advanced age. The incidence of adverse reactions in elderly patients does not differ from that in the general population. Nevertheless, caution should be exercised when prescribing Spectraceph because of decreased physiological functions in the elderly; it is recommended to select doses and intervals according to the current state of patients. Thus, delayed excretion of the drug has been observed in patients with impaired renal function, and blood concentrations have been elevated. A tendency to bleeding has also been reported in the elderly due to vitamin K deficiency after the use of cephalosporins.

As with other broad-spectrum antibiotics, treatment with ceftiditorin may lead to an overgrowth of resistant microflora. For this reason, monitoring of patients receiving this medication is recommended, especially for long-term treatment.

In patients with severe renal impairment, periodic monitoring of renal function is recommended.

Prothrombin activity may decrease during treatment with cephalosporins. For this reason in patients from risk group (with renal or hepatic insufficiency or in case of previous anticoagulant treatment) it is necessary to control prothrombin time.

Diarrhea during or after treatment, especially with its severe, persistent character and presence of blood admixture, may indicate pseudomembranous colitis. In mild cases of diarrhea, withdrawal of the drug is sufficient; in severe cases, therapy with antibiotics to which Clostridium difficile shows sensitivity and administration of infusion therapy are indicated.

Like other cephalosporins, cefditorin may lead to false-positive results of the direct Coombs test, detection of glucose in urine by copper recovery test, but not by an enzyme test.

Because of the high risk of false-negative results of the ferricyanide plasma or blood glucose detection test, it is recommended that glucose oxidase or glucose hexokinase methods be used to determine blood or plasma glucose concentrations in patients during treatment with ceftiditorin.

When combining cephalosporins with aminoglycosides and/or loop diuretics, especially in patients with impaired renal function, an increased risk of nephrotoxicity is possible.

Spectracef contains approximately 13.1 mg (for 200 mg tablets) and 26.2 mg (for 400 mg tablets) of sodium per dose, which should be considered when prescribing the drug in patients on a low-sodium diet.

A decrease in serum carnitine has been reported as a consequence of metabolism of pivalic acid (a metabolite of pivaxil group drugs) during administration of pivaxil-containing drugs.

The effect on the ability to drive and/or operate other mechanisms. No effect of cefditorene pivoxil on the ability to drive vehicles and/or other mechanisms has been reported. At the same time, it should be taken into account that administration of Spectraceph may be accompanied by such adverse events as vomiting, headache.

Contraindications

hypersensitivity to cefditorene, other cephalosporins, or any other component of the drug;

Severe allergic reactions to penicillins and other beta-lactam antibacterials;

Child-Pugh class C hepatic impairment;

Patients on hemodialysis;

Hypersensitivity reactions to casein protein in a history;

Primary carnitine deficiency;

concomitant use of cefditorin pivaxil and H2-histamine receptor blockers;

children under 12 years of age.

With caution: patients with hypersensitivity to other beta-lactam antibiotics because of the possibility of cross-allergic reactions; patients with individual or familial/hereditary predisposition to develop allergic reactions such as bronchial asthma, rash or urticaria; patients with severe renal dysfunction (see “Pharmacokinetics”); elderly patients (see “Precautions”). “

Particular Precautions

; concomitant use with aminoglycosides and diuretics (furosemide); patients with gastrointestinal pathology, including a history of colitis; patients with difficulty eating (with impaired swallowing) or receiving parenteral nutrition; and patients with poor general health (such patients should be closely monitored because of the risk of potassium deficiency development).

Side effects

The undesired phenomena presented below are listed according to anatomico-physiological classification and frequency of occurrence. The frequency of occurrence is defined as follows: very frequently, ≥1/10; frequently, ≥1/100 and < 1/10; infrequently, ≥1/1000 and < 1/100; rarely, ≥1/10000 and < 1/1000; very rarely, < 1/10000, including individual cases.

Blood and lymphatic system disorders: infrequent – eosinophilia; rare – granulocytopenia, hemolytic anemia, agranulocytosis, hypoprothrombinemia, tendency to bleeding, enlarged lymph nodes.

Vascular side: rarely – shock.

Gastrointestinal tract: frequent – diarrhea; infrequent – softening of stool, dyspepsia, feeling of discomfort in the abdominal area, abdominal pain; rare – pseudomembranous colitis, feeling of abdominal enlargement, nausea, vomiting, stomatitis, glossitis.

General disorders and disorders at the site of administration: rarely – edema, fever.

Hepatic and biliary tract disorders: rarely – jaundice, liver function disorders.

The immune system: rarely – anaphylaxis.

Infectious and parasitic diseases: rarely – candidiasis.

Laboratory and instrumental data: infrequent – increased alanine aminotransferase (ALT) activity, increased aspartate aminotransferase (AST) activity; rare – thrombocytopenia, increased serum creatinine concentration, increased blood urea nitrogen concentration, increased alkaline phosphatase (ALP) activity; frequency unknown – decreased serum carnitine concentration.

Metabolism and nutrition: rarely – anorexia, symptoms due to vitamin K deficiency, symptoms due to vitamin B group deficiency.

Skeletal-muscular system and connective tissue disorders: rarely – arthralgia.

Nervous system disorders: rarely – headache, neuritis, dizziness, numbness.

Renal and urinary tract: rarely – acute renal failure, proteinuria.

Respiratory system, thoracic and mediastinal organs: rarely – interstitial pneumonia, pulmonary eosinophilic infiltrate.

Skin and subcutaneous tissue disorders: infrequent – rash; rare – Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), urticaria, erythema, pruritus.

Overdose

Symptoms: nausea, vomiting, diarrhea.

Treatment: symptomatic therapy.

Pregnancy use

Pregnancy. No clinical data have been obtained on the use of cefditorin pivoxil in pregnant women. And although animal studies have shown no embryotoxic or teratogenic effects of the drug, Spectracef should not be used during pregnancy unless the expected benefit to the mother exceeds the potential risk to the fetus. Cases of hypocarnitinemia have also been reported in both women who received antimicrobials containing pivaxil and in their newborn children.

Lactation period. There are insufficient data on penetration of cefditorin into breast milk. Therefore, when using Spectraceph, breastfeeding should be discontinued.