Ceftin (Cefuroxime Axetil) - Description and Clinical Pharmacology

CLINICAL PHARMACOLOGY

Absorption and Metabolism

After oral administration, cefuroxime axetil is absorbed from the gastrointestinal tract and rapidly hydrolyzed by nonspecific esterases in the intestinal mucosa and blood to cefuroxime. Cefuroxime is subsequently distributed throughout the extracellular fluids. The axetil moiety is metabolized to acetaldehyde and acetic acid.

Pharmacokinetics

Approximately 50% of serum cefuroxime is bound to protein. Serum pharmacokinetic parameters for CEFTIN Tablets and CEFTIN for Oral Suspension are shown in Tables 1 and 2.

Table 1. Postprandial Pharmacokinetics of Cefuroxime Administered as CEFTIN Tablets to Adults*

Dose† (Cefuroxime Equivalent)	Peak Plasma Concentration (mcg/mL)	Time of Peak Plasma Concentration (hr)	Mean Elimination Half-Life (hr)	AUC (mcg-hr mL)
125 mg	2.1	2.2	1.2	6.7
250 mg	4.1	2.5	1.2	12.9
500 mg	7.0	3.0	1.2	27.4
1,000 mg	13.6	2.5	1.3	50.0
*Mean values of 12 healthy adult volunteers.
†Drug administered immediately after a meal.

Table 2. Postprandial Pharmacokinetics of Cefuroxime Administered as CEFTIN for Oral Suspension to Pediatric Patients*

Dose† (Cefuroxime Equivalent)	n	Peak Plasma Concentration (mcg/mL)	Time of Peak Plasma Concentration (hr)	Mean Elimination Half-Life (hr)	AUC (mcg-hr mL)
10 mg/kg	8	3.3	3.6	1.4	12.4
15 mg/kg	12	5.1	2.7	1.9	22.5
20 mg/kg	8	7.0	3.1	1.9	32.8
*Mean age = 23 months.
†Drug administered with milk or milk products.

Comparative Pharmacokinetic Properties

A 250 mg/5 mL-dose of CEFTIN Suspension is bioequivalent to 2 times 125 mg/5 mL-dose of CEFTIN Suspension when administered with food (see Table 3). CEFTIN for Oral Suspension was not bioequivalent to CEFTIN Tablets when tested in healthy adults. The tablet and powder for oral suspension formulations are NOT substitutable on a milligram-per-milligram basis. The area under the curve for the suspension averaged 91% of that for the tablet, and the peak plasma concentration for the suspension averaged 71% of the peak plasma concentration of the tablets. Therefore, the safety and effectiveness of both the tablet and oral suspension formulations had to be established in separate clinical trials.

Table 3. Pharmacokinetics of Cefuroxime Administered as 250 mg/5 mL or 2 x 125 mg/5 mL CEFTIN for Oral Suspension to Adults* With Food

Dose (Cefuroxime Equivalent)	Peak Plasma Concentration (mcg/mL)	Time of Peak Plasma Concentration (hr)	Mean Elimination Half-Life (hr)	AUC (mcg-hr mL)
250 mg/5 mL	2.23	3	1.40	8.92
2 x 125 mg/5 mL	2.37	3	1.44	9.75
*Mean values of 18 healthy adult volunteers.

Food Effect on Pharmacokinetics

Absorption of the tablet is greater when taken after food (absolute bioavailability of CEFTIN Tablets increases from 37% to 52%). Despite this difference in absorption, the clinical and bacteriologic responses of patients were independent of food intake at the time of tablet administration in 2 studies where this was assessed.

All pharmacokinetic and clinical effectiveness and safety studies in pediatric patients using the suspension formulation were conducted in the fed state. No data are available on the absorption kinetics of the suspension formulation when administered to fasted pediatric patients.

Renal Excretion

Cefuroxime is excreted unchanged in the urine; in adults, approximately 50% of the administered dose is recovered in the urine within 12 hours. The pharmacokinetics of cefuroxime in the urine of pediatric patients have not been studied at this time. Until further data are available, the renal pharmacokinetic properties of cefuroxime axetil established in adults should not be extrapolated to pediatric patients.

Because cefuroxime is renally excreted, the serum half-life is prolonged in patients with reduced renal function. In a study of 20 elderly patients (mean age = 83.9 years) having a mean creatinine clearance of 34.9 mL/min, the mean serum elimination half-life was 3.5 hours. Despite the lower elimination of cefuroxime in geriatric patients, dosage adjustment based on age is not necessary (see PRECAUTIONS: Geriatric Use).

Microbiology

The in vivo bactericidal activity of cefuroxime axetil is due to cefuroxime's binding to essential target proteins and the resultant inhibition of cell-wall synthesis.

Cefuroxime has bactericidal activity against a wide range of common pathogens, including many beta-lactamase–producing isolates. Cefuroxime is stable to many bacterial beta-lactamases, especially plasmid-mediated enzymes that are commonly found in enterobacteriaceae.

Cefuroxime has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Facultative Gram-Positive Microorganisms

Staphylococcus aureus* (including beta­lactamase–producing isolates)

Streptococcus pneumoniae

Streptococcus pyogenes

*NOTE: Methicillin-resistant staphylococci are resistant to cefuroxime.

Facultative Gram-Negative Microorganisms

Escherichia coli

Haemophilus influenzae (including beta­lactamase–producing isolates)

Haemophilus parainfluenzae

Klebsiella pneumoniae

Moraxella catarrhalis (including beta­lactamase–producing isolates)

Neisseria gonorrhoeae (including beta­lactamase–producing isolates)

Spirochetes

Borrelia burgdorferi

The following in vitro data are available, but their clinical significance is unknown.

At least 90 percent of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefuroxime. However, the efficacy of cefuroxime in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Facultative Gram-Positive Microorganisms

Staphylococcus epidermidis

Staphylococcus saprophyticus

Streptococcus agalactiae

NOTE: Most isolates of enterococci, e.g., Enterococcus faecalis (formerly Streptococcus faecalis), are resistant to cefuroxime. Methicillin-resistant staphylococci and Listeria monocytogenes are resistant to cefuroxime.

Facultative Gram-Negative Microorganisms

Morganella morganii

Proteus inconstans

Proteus mirabilis

Providencia rettgeri

NOTE: Some isolates of Morganella morganii, Enterobacter cloacae, and Citrobacter spp. have been shown by in vitro tests to be resistant to cefuroxime and other cephalosporins. Most isolates of Serratia and Proteus vulgaris are resistant to cefuroxime and most other second-generation cephalosporins, and are resistant to first-generation cephalosporins.

Pseudomonas, Campylobacter, Legionella, and Acinetobacter are resistant to cefuroxime and most other second-generation cephalosporins and are resistant to first-generation cephalosporins.

Anaerobic Microorganisms

Peptococcus niger

NOTE: Most isolates of Clostridium difficile and Bacteroides fragilis are resistant to cefuroxime.

Susceptibility Tests

Dilution Techniques

Quantitative methods that are used to determine MICs provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method¹ (broth, agar, or microdilution) or equivalent with cefuroxime powder. The MIC values obtained should be interpreted according to the following criteria:

MIC (mcg/mL)	Interpretation
≤4	(S) Susceptible
8­16	(I) Intermediate
≥32	(R) Resistant

A report of "Susceptible" indicates that the pathogen, if in the blood, is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in blood. A report of "Intermediate" indicates that inhibitory concentrations of the antibiotic may be achieved if high dosage is used or if the infection is confined to tissues or fluids in which high antibiotic concentrations are attained. This category also provides a buffer zone that prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms. Standard cefuroxime powder should give the following MIC values:

Microorganism	MIC (mcg/mL)
Escherichia coli ATCC 25922	2­8
Staphylococcus aureus ATCC 29213	0.5­2

Diffusion Techniques

Quantitative methods that require measurement of zone diameters provide estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure² that has been recommended (for use with disks) to test the susceptibility of microorganisms to cefuroxime uses the 30-mcg cefuroxime disk. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefuroxime.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-mcg cefuroxime disk should be interpreted according to the following criteria:

Zone Diameter (mm)	Interpretation
≥23	(S) Susceptible
15­22	(I) Intermediate
≤14	(R) Resistant

Interpretation should be as stated above for results using dilution techniques.

As with standard dilution techniques, diffusion methods require the use of laboratory control microorganisms. The 30-mcg cefuroxime disk provides the following zone diameters in these laboratory test quality control strains:

Microorganism	Zone Diameter (mm)
Escherichia coli ATCC 25922	20­26
Staphylococcus aureus ATCC 25923	27­35

CLINICAL STUDIES

Ceftin Tablets

Acute Bacterial Maxillary Sinusitis

One adequate and well-controlled study was performed in patients with acute bacterial maxillary sinusitis. In this study each patient had a maxillary sinus aspirate collected by sinus puncture before treatment was initiated for presumptive acute bacterial sinusitis. All patients had to have radiographic and clinical evidence of acute maxillary sinusitis. As shown in the following summary of the study, the general clinical effectiveness of CEFTIN Tablets was comparable to an oral antimicrobial agent that contained a specific beta-lactamase inhibitor in treating acute maxillary sinusitis. However, sufficient microbiology data were obtained to demonstrate the effectiveness of CEFTIN Tablets in treating acute bacterial maxillary sinusitis due only to Streptococcus pneumoniae or non-beta-lactamase–producing Haemophilus influenzae. An insufficient number of beta-lactamase–producing Haemophilus influenzae and Moraxella catarrhalis isolates were obtained in this trial to adequately evaluate the effectiveness of CEFTIN Tablets in the treatment of acute bacterial maxillary sinusitis due to these 2 organisms.

This study enrolled 317 adult patients, 132 patients in the United States and 185 patients in South America. Patients were randomized in a 1:1 ratio to cefuroxime axetil 250 mg twice daily or an oral antimicrobial agent that contained a specific beta-lactamase inhibitor. An intent-to-treat analysis of the submitted clinical data yielded the following results:

Table 10. Clinical Effectiveness of CEFTIN Tablets Compared to Beta-Lactamase Inhibitor-Containing Control Drug in the Treatment of Acute Bacterial Maxillary Sinusitis

	US Patients*		South American Patients†
	CEFTIN (n = 49)	Control (n = 43)	CEFTIN (n = 87)	Control (n = 89)
Clinical success (cure + improvement)	65%	53%	77%	74%
Clinical cure	53%	44%	72%	64%
Clinical improvement	12%	9%	5%	10%
* 95% Confidence interval around the success difference [-0.08, +0.32].
† 95% Confidence interval around the success difference [-0.10, +0.16].

In this trial and in a supporting maxillary puncture trial, 15 evaluable patients had non-beta-lactamase–producing Haemophilus influenzae as the identified pathogen. Ten (10) of these 15 patients (67%) had their pathogen (non-beta-lactamase–producing Haemophilus influenzae) eradicated. Eighteen (18) evaluable patients had Streptococcus pneumoniae as the identified pathogen. Fifteen (15) of these 18 patients (83%) had their pathogen (Streptococcus pneumoniae) eradicated.

Safety

The incidence of drug-related gastrointestinal adverse events was statistically significantly higher in the control arm (an oral antimicrobial agent that contained a specific beta-lactamase inhibitor) versus the cefuroxime axetil arm (12% versus 1%, respectively; P <.001), particularly drug-related diarrhea (8% versus 1%, respectively; P  = .001).

Early Lyme Disease

Two adequate and well-controlled studies were performed in patients with early Lyme disease. In these studies all patients had to present with physician-documented erythema migrans, with or without systemic manifestations of infection. Patients were randomized in a 1:1 ratio to a 20-day course of treatment with cefuroxime axetil 500 mg twice daily or doxycycline 100 mg 3 times daily. Patients were assessed at 1 month posttreatment for success in treating early Lyme disease (Part I) and at 1 year posttreatment for success in preventing the progression to the sequelae of late Lyme disease (Part II).

A total of 355 adult patients (181 treated with cefuroxime axetil and 174 treated with doxycycline) were enrolled in the 2 studies. In order to objectively validate the clinical diagnosis of early Lyme disease in these patients, 2 approaches were used: 1) blinded expert reading of photographs, when available, of the pretreatment erythema migrans skin lesion; and 2) serologic confirmation (using enzyme-linked immunosorbent assay [ELISA] and immunoblot assay [“Western” blot]) of the presence of antibodies specific to Borrelia burgdorferi, the etiologic agent of Lyme disease. By these procedures, it was possible to confirm the physician diagnosis of early Lyme disease in 281 (79%) of the 355 study patients. The efficacy data summarized below are specific to this “validated” patient subset, while the safety data summarized below reflect the entire patient population for the 2 studies.

Analysis of the submitted clinical data for evaluable patients in the “validated” patient subset yielded the following results:

Table 11. Clinical Effectiveness of CEFTIN Tablets Compared to Doxycycline in the Treatment of Early Lyme Disease

	Part I (1 Month Posttreatment)*		Part II (1 Year Posttreatment)†
	CEFTIN	Doxycycline	CEFTIN	Doxycycline
	(n = 125)	(n = 108)	(n = 105‡)	(n = 83‡)
Satisfactory clinical outcome§	91%	93%	84%	87%
Clinical cure/success	72%	73%	73%	73%
Clinical improvement	19%	19%	10%	13%
* 95% confidence interval around the satisfactory difference for Part I (-0.08, +0.05).
† 95% confidence interval around the satisfactory difference for Part II (-0.13, +0.07).
‡ n’s include patients assessed as unsatisfactory clinical outcomes (failure + recurrence) in Part I (CEFTIN - 11 [5 failure, 6 recurrence]; doxycycline - 8 [6 failure, 2 recurrence]).
§ Satisfactory clinical outcome includes cure + improvement (Part I) and success + improvement (Part II).

CEFTIN and doxycycline were effective in prevention of the development of sequelae of late Lyme disease.

Safety

Drug-related adverse events affecting the skin were reported significantly more frequently by patients treated with doxycycline than by patients treated with cefuroxime axetil (12% versus 3%, respectively; P  = .002), primarily reflecting the statistically significantly higher incidence of drug-related photosensitivity reactions in the doxycycline arm versus the cefuroxime axetil arm (9% versus 0%, respectively; P <.001). While the incidence of drug-related gastrointestinal adverse events was similar in the 2 treatment groups (cefuroxime axetil - 13%; doxycycline - 11%), the incidence of drug-related diarrhea was statistically significantly higher in the cefuroxime axetil arm versus the doxycycline arm (11% versus 3%, respectively; P  = .005).

Secondary Bacterial Infections of Acute Bronchitis

Four randomized, controlled clinical studies were performed comparing 5 days versus 10 days of CEFTIN for the treatment of patients with secondary bacterial infections of acute bronchitis. These studies enrolled a total of 1,253 patients (CAE-516 n = 360; CAE-517 n = 177; CAEA4001 n = 362; CAEA4002 n = 354). The protocols for CAE-516 and CAE-517 were identical and compared CEFTIN 250 mg twice daily for 5 days, CEFTIN 250 mg twice daily for 10 days, and AUGMENTIN^® 500 mg 3 times daily for 10 days. These 2 studies were conducted simultaneously. CAEA4001 and CAEA4002 compared CEFTIN 250 mg twice daily for 5 days, CEFTIN 250 mg twice daily for 10 days, and CECLOR^® 250 mg 3 times daily for 10 days. They were otherwise identical to CAE-516 and CAE-517 and were conducted over the following 2 years. Patients were required to have polymorphonuclear cells present on the Gram stain of their screening sputum specimen, but isolation of a bacterial pathogen from the sputum culture was not required for inclusion. The following table demonstrates the results of the clinical outcome analysis of the pooled studies CAE-516/CAE-517 and CAEA4001/CAEA4002, respectively:

Table 12. Clinical Effectiveness of CEFTIN Tablets 250 mg Twice Daily in Secondary Bacterial Infections of Acute Bronchitis: Comparison of 5 Versus 10 Days’ Treatment Duration

	CAE-516 and CAE-517*		CAEA4001 and CAEA4002†
	5 Day (n = 127)	10 Day (n = 139)	5 Day (n = 173)	10 Day (n = 192)
Clinical success (cure + improvement)	80%	87%	84%	82%
Clinical cure	61%	70%	73%	72%
Clinical improvement	19%	17%	11%	10%
* 95% Confidence interval around the success difference [-0.164, +0.029].
† 95% Confidence interval around the success difference [-0.061, +0.103].

The response rates for patients who were both clinically and bacteriologically evaluable were consistent with those reported for the clinically evaluable patients.

Safety

In these clinical trials, 399 patients were treated with CEFTIN for 5 days and 402 patients with CEFTIN for 10 days. No difference in the occurrence of adverse events was observed between the 2 regimens.