July 29, 2015
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Ceftin

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Ceftin




CLINICAL PHARMACOLOGY

Mechanism Of Action

CEFTIN is an antibacterial drug [see Microbiology].

Pharmacokinetics

Absorption

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. Serum pharmacokinetic parameters for cefuroxime following administration of CEFTIN tablets to adults are shown in Table 8.

Table 8: Pharmacokinetics of Cefuroxime Administered in the Postprandial State as CEFTIN Tablets to Adultsa

Doseb (Cefuroxime Equivalent) Peak Plasma Concentration (mcg/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) AUC (mcg•h/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
a Mean values of 12 healthy adult volunteers.
b Drug administered immediately after a meal.

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

All pharmacokinetic and clinical effectiveness and safety trials in pediatric subjects 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 subjects.

Lack of Bioequivalence: Oral suspension was not bioequivalent to tablets when tested in healthy adults. The tablet and 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 were established in separate clinical trials.

Distribution

Cefuroxime is distributed throughout the extracellular fluids. Approximately 50% of serum cefuroxime is bound to protein.

Metabolism

The axetil moiety is metabolized to acetaldehyde and acetic acid.

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 pediatric subjects have not been studied. Until further data are available, the renal elimination of cefuroxime axetil established in adults should not be extrapolated to pediatric subjects.

Specific Populations

Renal Impairment: In a trial of 28 adults with normal renal function or severe renal impairment (creatinine clearance < 30 mL/min), the elimination half-life was prolonged in relation to severity of renal impairment. Prolongation of the dosage interval is recommended in adult patients with creatinine clearance < 30 mL/min [see DOSAGE AND ADMINISTRATION].

Pediatric Patients: Serum pharmacokinetic parameters for cefuroxime in pediatric subjects administered CEFTIN for oral suspension are shown in Table 9.

Table 9: Pharmacokinetics of Cefuroxime Administered in the Postprandial State as CEFTIN for Oral Suspension to Pediatric Subjectsa

Doseb (Cefuroxime Equivalent) n Peak Plasma Concentration (mcg/mL) Time of Peak Plasma Concentration (h) Mean Elimination Half-life (h) AUC (mcg•h/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
a Mean age = 23 months.
b Drug administered with milk or milk products.

Geriatric Patients: In a trial of 20 elderly subjects (mean age = 83.9 years) having a mean creatinine clearance of 34.9 mL/min, the mean serum elimination half-life was prolonged to 3.5 hours; however, despite the lower elimination of cefuroxime in geriatric patients, dosage adjustment based on age is not necessary [see Use in Specific Populations].

Drug Interactions

Concomitant administration of probenecid with cefuroxime axetil tablets increases the cefuroxime area under the serum concentration versus time curve and maximum serum concentration by 50% and 21%, respectively.

Microbiology

Mechanism of Action

Cefuroxime axetil is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Cefuroxime axetil has activity in the presence of some β-lactamases, both penicillinases and cephalosporinases, of gram-negative and gram-positive bacteria.

Mechanism of Resistance

Resistance to cefuroxime axetil is primarily through hydrolysis by β-lactamase, alteration of penicillin-binding proteins (PBPs), decreased permeability, and the presence of bacterial efflux pumps.

Susceptibility to cefuroxime axetil will vary with geography and time; local susceptibility data should be consulted, if available. Beta-lactamase-negative, ampicillin-resistant (BLNAR) isolates of H. influenzae should be considered resistant to cefuroxime axetil.

Cefuroxime axetil has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see INDICATIONS AND USAGE]:

Gram-positive Bacteria

Staphylococcus aureus (methicillin-susceptible isolates only)
Streptococcus pneumoniae

Streptococcus pyogenes

Gram-negative Bacteria

Escherichia colia
Klebsiella pneumoniaea

Haemophilus influenzae

Haemophilus parainfluenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

a Most extended spectrum β -lactamase (ESBL)-producing and carbapenemase-producing isolates are resistant to cefuroxime axetil.

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 axetil of 1 mcg/mL. However, the efficacy of cefuroxime axetil in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria

Staphylococcus epidermidis (methicillin-susceptible isolates only)
Staphylococcus saprophyticus
(methicillin-susceptible isolates only)
Streptococcus agalactiae

Gram-negative Bacteria

Morganella morganii
Proteus inconstans

Proteus mirabilis

Providencia rettgeri

Anaerobic Bacteria

Peptococcus niger

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility tests for antimicrobial drug products used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution Techniques: Quantitative methods are used to determine antimicrobial MICs. These MICs provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth or agar).1,2 The MIC values should be interpreted according to criteria provided in Table 10.2,3

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.4 This procedure uses paper disks impregnated with 30 mcg cefuroxime axetil to test the susceptibility of microorganisms to cefuroxime axetil. The disk diffusion interpretive criteria are provided in Table 10.3

Table 10: Susceptibility Test Interpretive Criteria for Cefuroxime Axetil

Pathogen Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion Zone Diameters (mm)
(S) Susceptible (I) Intermediate (R) Resistant (S) Susceptible (I) Intermediate (R) Resistant
Enterobacteriaceaea ≤ 4 8 - 16 ≥ 32 ≥ 23 15 - 22 ≤ 14
Haemophilus spp.a,b ≤ 4 8 ≥ 16 ≥ 20 17 - 19 ≤ 16
Moraxella catarrhalisa ≤ 4 8 ≥ 16 - - -
Streptococcus pneumoniae ≤ 1 2 ≥ 4 - - -
a For Enterobacteriaceae, Haemophilus spp., and Moraxella catarrhalis, susceptibility interpretive criteria are based on a dose of 500 mg every 12 hours in patients with normal renal function.
b Haemophilus spp. includes only isolates of H. influenzae and H. parainfluenzae.

Susceptibility of staphylococci to cefuroxime may be deduced from testing only penicillin and either cefoxitin or oxacillin.

Susceptibility of Streptococcus pyogenes may be deduced from testing penicillin.3

A report of “Susceptible” indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of “Intermediate” indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. 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 the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test.1,2,4 The QC ranges for MIC and disk diffusion testing using the 30-mcg disk are provided in Table 11.3

Table 11: Acceptable Quality Control (QC) Ranges for Cefuroxime Axetil

QC Strain Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion Zone Diameters (mm)
Escherichia coli ATCC 25922 2 to 8 20 to 26
Staphylococcus aureus ATCC 25923 - 27 to 35
Staphylococcus aureus ATCC 29213 0.5 to 2 -
Streptococcus pneumoniae ATCC 49619 0.25 to 1 -
Haemophilus influenzae ATCC 49766 0.25 to 1 28 to 36
Neisseria gonorrhoeae ATCC 49226 0.25 to 1 33 to 41
ATCC = American Type Culture Collection.

Clinical Studies

Acute Bacterial Maxillary Sinusitis

One adequate and well-controlled trial was performed in subjects with acute bacterial maxillary sinusitis. In this trial, each subject had a maxillary sinus aspirate collected by sinus puncture before treatment was initiated for presumptive acute bacterial sinusitis. All subjects had radiographic and clinical evidence of acute maxillary sinusitis. In the trial, the clinical effectiveness of CEFTIN in treating acute maxillary sinusitis was comparable to an oral antimicrobial agent containing a specific β-lactamase inhibitor. However, microbiology data demonstrated CEFTIN to be effective in treating acute bacterial maxillary sinusitis due only to Streptococcus pneumoniae or non-β-lactamase-producing Haemophilus influenzae. Insufficient numbers of β-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis isolates were obtained in this trial to adequately evaluate the effectiveness of CEFTIN in treating acute bacterial maxillary sinusitis due to these 2 organisms.

This trial randomized 317 adult subjects, 132 subjects in the United States and 185 subjects in South America. Table 12 shows the results of the intent-to-treat analysis.

Table 12: Clinical Effectiveness of CEFTIN Tablets in the Treatment of Acute Bacterial Maxillary Sinusitis

  US Subjectsa South American Subjectsb
CEFTIN 250 mg Twice Daily
(n = 49)
Controlc
(n = 43)
CEFTIN 250 mg Twice Daily
(n = 49)
Controlc
(n = 43)
Clinical success (cure + improvement) 65% 53% 77% 74%
Clinical cure 53% 44% 72% 64%
Clinical improvement 12% 9% 5% 10%
a 95% confidence interval around the success difference [-0.08, +0.32].
b 95% confidence interval around the success difference [-0.10, +0.16].
c Control was an antibacterial drug containing a β-lactamase inhibitor.

In this trial and in a supporting maxillary puncture trial, 15 evaluable subjects had non- β-lactamase-producing Haemophilus influenzae as the identified pathogen. Of these, 67% (10/15) had this pathogen eradicated. Eighteen (18) evaluable subjects had Streptococcus pneumoniae as the identified pathogen. Of these, 83% (15/18) had this pathogen eradicated.

Early Lyme Disease

Two adequate and well-controlled trials were performed in subjects with early Lyme disease. All subjects presented with physician-documented erythema migrans, with or without systemic manifestations of infection. Subjects 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 subjects (181 treated with cefuroxime axetil and 174 treated with doxycycline) were randomized in the 2 trials, with diagnosis of early Lyme disease confirmed in 79% (281/355). The clinical diagnosis of early Lyme disease in these subjects was validated by 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. The efficacy data in Table 14 are specific to this “validated” patient subset, while the safety data below reflect the entire patient population for the 2 trials. Clinical data for evaluable subjects in the “validated” patient subset are shown in Table 13.

Table 13: Clinical Effectiveness of CEFTIN Tablets Compared with Doxycycline in the Treatment of Early Lyme Disease

  Part I (1 Month after 20 Days of Treatment)a Part II (1 Year after 20 Days of Treatment)b
CEFTIN 500 mg Twice Daily
(n = 125)
Doxycycline 100 mg 3 Times Daily
(n = 108)
CEFTIN 500 mg Twice Daily
(n = 105c)
Doxycycline 100 mg 3 Times Daily
(n = 83c)
Satisfactory clinical outcomed 91% 93% 84% 87%
Clinical cure/success 72% 73% 73% 73%
Clinical improvement 19% 19% 10% 13%
a 95% confidence interval around the satisfactory difference for Part I (-0.08, +0.05).
b 95% confidence interval around the satisfactory difference for Part II (-0.13, +0.07).
c n's include subjects assessed as unsatisfactory clinical outcomes (failure + recurrence) in Part I (CEFTIN - 11 [5 failure, 6 recurrence]; doxycycline - 8 [6 failure, 2 recurrence]).
d 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.

While the incidence of drug-related gastrointestinal adverse reactions was similar in the 2 treatment groups (cefuroxime axetil - 13%; doxycycline - 11%), the incidence of drug-related diarrhea was higher in the cefuroxime axetil arm versus the doxycycline arm (11% versus 3%, respectively).

Secondary Bacterial Infections Of Acute Bronchitis

Four randomized, controlled clinical trials were performed comparing 5 days versus 10 days of CEFTIN for the treatment of subjects with secondary bacterial infections of acute bronchitis. These trials enrolled a total of 1,253 subjects (Study 1 n = 360; Study 2 n = 177; Study 3 n = 362; Study 4 n = 354). The protocols for Study 1 and Study 2 were identical and compared CEFTIN 250 mg twice daily for 5 days, CEFTIN 250 mg twice daily for 10 days, and AUGMENTIN® (amoxicillin/clavulanate potassium) 500 mg 3 times daily for 10 days. These 2 trials were conducted simultaneously. Study 3 and Study 4 compared CEFTIN 250 mg twice daily for 5 days, CEFTIN 250 mg twice daily for 10 days, and CECLOR® (cefaclor) 250 mg 3 times daily for 10 days. They were otherwise identical to Study 1 and Study 2 and were conducted over the following 2 years. Subjects 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. Table 14 demonstrates the results of the clinical outcome analysis of the pooled trials Study 1/Study 2 and Study 3/Study 4, respectively.

Table 14: Clinical Effectiveness of CEFTIN Tablets 250 mg Twice Daily in Secondary Bacterial Infections of Acute Bronchitis: Comparison of 5 versus 10 Days’ Treatment Duration

  Study 1 and Study 2a Study 3 and Study 4b
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%
a 95% confidence interval around the success difference [-0.164, +0.029].
b 95% confidence interval around the success difference [-0.061, +0.103].

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

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. 2015. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

2. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing for Infrequently Isolated or Fastidious Bacteria: Approved Guidelines - Second Edition. 2010. CLSI document M45-A2, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement. 2015. CLSI document M100- S25, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

4. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard - Twelfth Edition. 2015. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

Last reviewed on RxList: 7/13/2015
This monograph has been modified to include the generic and brand name in many instances.

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