Cefditoren

Cefditoren is a cephalosporin with antibacterial activity against gram-positive and gram-negative pathogens. The bactericidal activity of cefditoren results from the inhibition of cell wall synthesis via affinity for penicillin-binding proteins (PBPs).

Cefditoren is stable in the presence of a variety of β-lactamases, including penicillinases and some cephalosporinases. Cefditoren has been shown to be active against most strains of the following bacteria, both in vitro and in clinical infections.

Aerobic Gram-Positive Microorganisms:

Staphylococcus aureus (methicillin-susceptible strains, including β-lactamase-producing strains)
Note: Cefditoren is inactive against methicillin-resistant Staphylococcus aureus
Streptococcus pneumoniae (penicillin-susceptible strains only)
Streptococcus pyogenes

Aerobic Gram-Negative Microorganisms:

Haemophilus influenzae (including β-lactamase-producing strains)
Haemophilus parainfluenzae (including β-lactamase-producing strains)
Moraxella catarrhalis (including β-lactamase-producing strains)

The following in vitro data are available, but their clinical significance is unknown. Cefditoren exhibits in vitro minimum inhibitory concentrations (MICs) of ≤0.125 µg/mL against most (≥90%) strains of the following bacteria; however, the safety and effectiveness of cefditoren in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.

Aerobic Gram-Positive Microorganisms:

Streptococcus agalactiae
Streptococcus Groups C and G
Streptococcus, viridans group (penicillin-susceptible and -intermediate strains)

Absorption

Oral Bioavailability

Following oral administration, cefditoren pivoxil is absorbed from the gastrointestinal tract and hydrolyzed to cefditoren by esterases. Maximal plasma concentrations (C_max) of cefditoren under fasting conditions average 1.8 ± 0.6 µg/mL following a single 200 mg dose and occur 1.5 to 3 hours following dosing.

Less than dose-proportional increases in C_max and area under the concentration-time curve (AUC) were observed at doses of 400 mg and above. Cefditoren does not accumulate in plasma following twice daily administration to subjects with normal renal function. Under fasting conditions, the estimated absolute bioavailability of cefditoren pivoxil is approximately 14%. The absolute bioavailability of cefditoren pivoxil administered with a low fat meal (693 cal, 14 g fat, 122 g carb, 23 g protein) is 16.1 ± 3.0%.

Food Effect

Administration of cefditoren pivoxil following a high fat meal (858 cal, 64 g fat, 43 g carb, 31 g protein) resulted in a 70% increase in mean AUC and a 50% increase in mean C_max compared to administration of cefditoren pivoxil in the fasted state. After a high fat meal, the C_max averaged 3.1 ± 1.0 µg/mL following a single 200 mg dose of cefditoren pivoxil and 4.4 ± 0.9 µg/mL following a 400 mg dose. Cefditoren AUC and C_max values from studies conducted with a moderate fat meal (648 cal, 27 g fat, 73 g carb, 29 g protein) are similar to those obtained following a high fat meal.

Distribution

The mean volume of distribution at steady state (V_ss) of cefditoren is 9.3 ± 1.6 L. Binding of cefditoren to plasma proteins averages 88% from in vitro determinations, and is concentration-independent at cefditoren concentrations ranging from 0.05 to10 µg/mL. Cefditoren is primarily bound to human serum albumin and its binding is decreased when serum albumin concentrations are reduced. Binding to α-1-acid glycoprotein ranges from 3.3 to 8.1%. Penetration into red blood cells is negligible.

Skin blister fluid

Maximal concentrations of cefditoren in suction-induced blister fluid were observed 4 to 6 hours following administration of a 400 mg dose of cefditoren pivoxil with a mean of 1.1 ± 0.42 µg/mL. Mean blister fluid AUC values were 56 ± 15% of corresponding plasma concentrations.

Tonsil tissue

In fasted patients undergoing elective tonsillectomy, the mean concentration of cefditoren in tonsil tissue 2 to 4 hours following administration of a 200 mg dose of cefditoren pivoxil was 0.18 ± 0.07 µg/g. Mean tonsil tissue concentrations of cefditoren were 12 ± 3% of the corresponding serum concentrations.

Cerebrospinal Fluid (CSF)

Data on the penetration of cefditoren into human cerebrospinal fluid are not available.

Metabolism and Excretion

Cefditoren is eliminated from the plasma, with a mean terminal elimination half-life (t_1/2) of 1.6 ± 0.4 hours in young healthy adults. Cefditoren is not appreciably metabolized. After absorption, cefditoren is mainly eliminated by excretion into the urine, with a renal clearance of approximately 4-5 L/h. Studies with the renal tubular transport blocking agent probenecid indicate that tubular secretion, along with glomerular filtration is involved in the renal elimination of cefditoren. Cefditoren renal clearance is reduced in patients with renal insufficiency. (See Special Populations, Renal Insufficiency and Hemodialysis.)

Hydrolysis of cefditoren pivoxil to its active component, cefditoren, results in the formation of pivalate. Following multiple doses of cefditoren pivoxil, greater than 70% of the pivalate is absorbed. Pivalate is mainly eliminated (>99%) through renal excretion, nearly exclusively as pivaloylcarnitine. Following a 200 mg BID regimen for 10 days, the mean decrease in plasma concentrations of total carnitine was 18.1 ± 7.2 nmole/mL, representing a 39% decrease in plasma carnitine concentrations. Following a 400 mg BID regimen for 14 days, the mean decrease in plasma concentrations of carnitine was 33.3 ± 9.7 nmole/mL, representing a 63% decrease in plasma carnitine concentrations. Plasma concentrations of carnitine returned to the normal control range within 7 to 10 days after discontinuation of cefditoren pivoxil.

Special Populations

Geriatric

The effect of age on the pharmacokinetics of cefditoren was evaluated in 48 male and female subjects aged 25 to 75 years given 400 mg cefditoren pivoxil BID for 7 days. Physiological changes related to increasing age increased the extent of cefditoren exposure in plasma, as evidenced by a 26% higher C_max and a 33% higher AUC for subjects aged ≥65 years compared with younger subjects. The rate of elimination of cefditoren from plasma was lower in subjects aged ≥65 years, with t_1/2 values 16-26% longer than for younger subjects. Renal clearance of cefditoren in subjects aged ≥65 years was 20-24% lower than in younger subjects. These changes could be attributed to age-related changes in creatinine clearance. No dose adjustments are necessary for elderly patients with normal (for their age) renal function.

0.115 Gender

The effect of gender on the pharmacokinetics of cefditoren was evaluated in 24 male and 24 female subjects given 400 mg cefditoren pivoxil BID for 7 days. The extent of exposure in plasma was greater in females than in males, as evidenced by a 14% higher C_max and a 16% higher AUC for females compared to males. Renal clearance of cefditoren in females was 13% lower than in males. These differences could be attributed to gender-related differences in lean body mass. No dose adjustments are necessary for gender.

Renal Insufficiency

Cefditoren pharmacokinetics were investigated in 24 adult subjects with varying degrees of renal function following administration of cefditoren pivoxil 400 mg BID for 7 days. Decreased creatinine clearance (CL_cr) was associated with an increase in the fraction of unbound cefditoren in plasma and a decrease in the cefditoren elimination rate, resulting in greater systemic exposure in subjects with renal impairment. The unbound C_max and AUC were similar in subjects with mild renal impairment (CL_cr: 50-80 mL/min/1.73 m²) compared to subjects with normal renal function (CL_cr: >80 mL/min/1.73 m²). Moderate (CL_cr: 30-49 mL/min/1.73 m²) or severe (CL_cr: <30 mL/min/1.73 m²) renal impairment increased the extent of exposure in plasma, as evidenced by mean unbound C_max values 90% and 114% higher and AUC values 232% and 324% higher than that for subjects with normal renal function. The rate of elimination from plasma was lower in subjects with moderate or severe renal impairment, with respective mean t_1/2 values of 2.7 and 4.7 hours. No dose adjustment is necessary for patients with mild renal impairment (CL_cr: 50-80 mL/min/1.73 m²). It is recommended that not more than 200 mg BID be administered to patients with moderate renal impairment (CL_cr: 30-49 mL/min/1.73 m²) and 200 mg QD be administered to patients with severe renal impairment (CL_cr: <30 mL/min/1.73 m²).

Hemodialysis

Cefditoren pharmacokinetics investigated in six adult subjects with end-stage renal disease (ESRD) undergoing hemodialysis given a single 400 mg dose of cefditoren pivoxil were highly variable. The mean t_1/2 was 4.7 hours and ranged from 1.5 to 15 hours. Hemodialysis (4 hours duration) removed approximately 30% of cefditoren from systemic circulation but did not change the apparent terminal elimination half-life. The appropriate dose for ESRD patients has not been determined.

Hepatic Disease

Cefditoren pharmacokinetics were evaluated in six adult subjects with mild hepatic impairment (Child-Pugh Class A) and six with moderate hepatic impairment (Child-Pugh Class B). Following administration of cefditoren pivoxil 400 mg BID for 7 days in these subjects, mean C_max and AUC values were slightly (<15%) greater than those observed in normal subjects. No dose adjustments are necessary for patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). The pharmacokinetics of cefditoren in subjects with severe hepatic impairment (Child-Pugh Class C) have not been studied.