July 1, 2016
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Suprax

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Suprax




CLINICAL PHARMACOLOGY

Mechanism Of Action

Cefixime is a semisynthetic cephalosporin antibacterial drug [see Microbiology].

Pharmacokinetics

Suprax chewable tablets are bioequivalent to oral suspension. Suprax tablets and suspension, given orally, are about 40% to 50% absorbed whether administered with or without food; however, time to maximal absorption is increased approximately 0.8 hours when administered with food. A single 200 mg tablet of cefixime produces an average peak serum concentration of approximately 2 mcg/mL (range 1 to 4 mcg/mL); a single 400 mg tablet produces an average peak concentration of approximately 3.7 mcg/mL (range 1.3 to 7.7 mcg/mL). The oral suspension produces average peak concentrations approximately 25% to 50% higher than the tablets, when tested in normal adult volunteers. Two hundred and 400 mg doses of oral suspension produce average peak concentrations of 3 mcg/mL (range 1 to 4.5 mcg/mL) and 4.6 mcg/mL (range 1.9 to 7.7 mcg/mL), respectively, when tested in normal adult volunteers. The area under the time versus concentration curve (AUC) is greater by approximately 10% to 25% with the oral suspension than with the tablet after doses of 100 to 400 mg, when tested in normal adult volunteers. This increased absorption should be taken into consideration if the oral suspension is to be substituted for the tablet. Because of the lack of bioequivalence, tablets should not be substituted for oral suspension in the treatment of otitis media [see DOSAGE AND ADMINISTRATION]. Crossover studies of tablet versus suspension have not been performed in children.

The 400 mg capsule is bioequivalent to the 400 mg tablet under fasting conditions. However, food reduces the absorption following administration of the capsule by approximately 15% based on AUC and 25% based on Cmax.

Peak serum concentrations occur between 2 and 6 hours following oral administration of a single 200 mg tablet, a single 400 mg tablet or 400 mg of cefixime suspension. Peak serum concentrations occur between 2 and 5 hours following a single administration of 200 mg of suspension. Peak serum concentrations occur between 3 and 8 hours following oral administration of a single 400 mg capsule.

Distribution

Serum protein binding is concentration independent with a bound fraction of approximately 65%. In a multiple dose study conducted with a research formulation which is less bioavailable than the tablet or suspension, there was little accumulation of drug in serum or urine after dosing for 14 days. Adequate data on CSF levels of cefixime are not available.

Metabolism and Excretion

There is no evidence of metabolism of cefixime in vivo. Approximately 50% of the absorbed dose is excreted unchanged in the urine in 24 hours. In animal studies, it was noted that cefixime is also excreted in the bile in excess of 10% of the administered dose. The serum half-life of cefixime in healthy subjects is independent of dosage form and averages 3 to 4 hours but may range up to 9 hours in some normal volunteers.

Special Populations

Geriatrics: Average AUCs at steady state in elderly patients are approximately 40% higher than average AUCs in other healthy adults. Differences in the pharmacokinetic parameters between 12 young and 12 elderly subjects who received 400 mg of cefixime once daily for 5 days are summarized as follows:

Pharmacokinetic Parameters (mean ± SD) for Cefixime in Both Young & Elderly Subjects

Pharmacokinetic parameter Young Elderly
Cmax (mg/L) 4.74 ± 1.43 5.68 ± 1.83
Tmax (h)* 3.9 ± 0.3 4.3 ± 0.6
AUC (mg.h/L)* 34.9 ± 12.2 49.5 ± 19.1
T½ (h)* 3.5 ± 0.6 4.2 ± 0.4
Cave (mg/L)* 1.42 ±0.50 1.99 ± 0.75
*Difference between age groups was significant. (p < 0.05)

However, these increases were not clinically significant [see DOSAGE AND ADMINISTRATION].

Renal Impairment: In subjects with moderate impairment of renal function (20 to 40 mL/min creatinine clearance), the average serum half-life of cefixime is prolonged to 6.4 hours. In severe renal impairment (5 to 20 mL/min creatinine clearance), the half-life increased to an average of 11.5 hours. The drug is not cleared significantly from the blood by hemodialysis or peritoneal dialysis. However, a study indicated that with doses of 400 mg, patients undergoing hemodialysis have similar blood profiles as subjects with creatinine clearances of 21 to 60 mL/min.

Microbiology

Mechanism of Action

As with other cephalosporins, the bactericidal action of cefixime results from inhibition of cell wall synthesis. Cefixime is stable in the presence of certain beta-lactamase enzymes. As a result, certain organisms resistant to penicillins and some cephalosporins due to the presence of beta-lactamases may be susceptible to cefixime.

Resistance

Resistance to cefixime in isolates of Haemophilus influenzae and Neisseria gonorrhoeae is most often associated with alterations in penicillin-binding proteins (PBPs). Cefixime may have limited activity against Enterobacteriaceae producing extended spectrum beta-lactamases (ESBLs). Pseudomonas species, Enterococcus species, strains of Group D streptococci, Listeria monocytogenes, most strains of staphylococci (including methicillin-resistant strains), most strains of Enterobacter species, most strains of Bacteroides fragilis, and most strains of Clostridium species are resistant to cefixime.

Antimicrobial Activity

Cefixime has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections [see INDICATIONS AND USAGE.]

Gram-positive Bacteria

Streptococcus pneumoniae
Streptococcus pyogenes

Gram-negative Bacteria

Escherichia coli
Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

Proteus mirabilis

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefixime against isolates of similar genus or organism group. However, the efficacy of cefixime in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive Bacteria

Streptococcus agalactiae

Gram-negative Bacteria

Citrobacter amalonaticus
Citrobacter diversus

Haemophilus parainfluenzae

Klebsiella oxytoca

Klebsiella pneumoniae

Pasteurella multocida

Proteus vulgaris

Providencia
species
Salmonella
species
Serratia marcescens

Shigella
species

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs 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 for treatment.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method1,2 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 3.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2.3 This procedure uses paper disks impregnated with 5 mcg cefixime to test the susceptibility of bacteria to cefixime. The disc diffusion breakpoints are provided in Table 3.

Table 3: Susceptibility Interpretive Criteria for Cefixime

Pathogen Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion Zone Diameter (mm)
S I R S I R
Enterobacteriaceae1 ≤ 1 2 ≥ 4 ≥ 19 16 to 18 ≤ 15
Haemophilus influenzae2,3 ≤ 1 NA NA ≥ 21 NA NA
Neisseria gonorrhoeae3,4 ≤ 0.25 NA NA ≥ 31 NA NA
1Do not test Morganella species by disk diffusion
2Test Haemophilus influenzae using Haemophilus Test Medium (HTM)
3The current absence of resistant isolates precludes defining any results other than “susceptible” Isolates yielding results other than susceptible should be subjected to additional testing.
4Test Neisseria gonorrhoeae using GC agar base and 1% defined growth supplement. Minimum inhibitory concentrations are determined using the agar dilution method.

A report of Susceptible (S) 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 (I) 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 the 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 (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration 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 individuals performing the test.1,2,3 Standard cefixime powder should provide the following range of MIC values noted in Table 4. For the diffusion technique using the 5 mcg disk, the criteria in Table 4 should be achieved.

Table 4: Acceptable Quality Control Ranges for Cefixime

Quality Control Organisms Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion Zone Diameter (mm)
E.coli ATCC 25922 0.25 to 1 23 to 27
H. influenzae ATCC 49247 0.12 to 1 25 to 33
N.gonorrhoeae ATCC 49226 0.004 to 0.03 37 to 45
S. pneumoniae ATCC 49619 NA 16 to 23
S. aureus ATCC 29213 8 to 32 NA
ATCC = American Type Culture Collection

Clinical Studies

Comparative clinical trials of otitis media were conducted in nearly 400 children between the ages of 6 months to 10 years. Streptococcus pneumoniae was isolated from 47% of the patients, Haemophilus influenzae from 34%, Moraxella catarrhalis from 15% and S. pyogenes from 4%.

The overall response rate of Streptococcus pneumoniae to cefixime was approximately 10% lower and that of Haemophilus influenzae or Moraxella catarrhalis approximately 7% higher (12% when beta-lactamase positive isolates of H. influenzae are included) than the response rates of these organisms to the active control drugs.

In these studies, patients were randomized and treated with either cefixime at dose regimens of 4 mg/kg twice a day or 8 mg/kg once a day, or with a comparator. Sixty-nine to 70% of the patients in each group had resolution of signs and symptoms of otitis media when evaluated 2 to 4 weeks post-treatment, but persistent effusion was found in 15% of the patients. When evaluated at the completion of therapy, 17% of patients receiving cefixime and 14% of patients receiving effective comparative drugs (18% including those patients who had Haemophilus influenzae resistant to the control drug and who received the control antibiotic) were considered to be treatment failures. By the 2 to 4 week follow-up, a total of 30%-31% of patients had evidence of either treatment failure or recurrent disease.

Bacteriological Outcome of Otitis Media at Two to Four Weeks Post-Therapy Based on Repeat Middle Ear Fluid Culture or Extrapolation from Clinical Outcome

Organism Cefixime(a) 4 mg/kg BID Cefixime(a) 8 mg/kg QD Control(a) drugs
Streptococcus pneumoniae 48/70 (69%) 18/22 (82%) 82/100 (82%)
Haemophilus influenzae beta-lactamase negative 24/34 (71%) 13/17 (76%) 23/34 (68%)
Haemophilus influenzae beta-lactamase positive 17/22 (77%) 9/12 (75%) 1/1 (b)
Moraxella catarrhalis 26/31 (84%) 5/5 18/24 (75%)
S. pyogenes 5/5 3/3 6/7
All Isolates 120/162 (74%) 48/59 (81%) 130/166 (78%)
a Number eradicated/number isolated.
b An additional 20 beta-lactamase positive isolates of Haemophilus influenzae were isolated, but were excluded from this analysis because they were resistant to the control antibiotic. In nineteen of these, the clinical course could be assessed and a favorable outcome occurred in 10. When these cases are included in the overall bacteriological evaluation of therapy with the control drugs, 140/185 (76%) of pathogens were considered to be eradicated.

REFERENCES

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

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

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

Last reviewed on RxList: 1/25/2016
This monograph has been modified to include the generic and brand name in many instances.

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