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Leading Contract Manufacturers of Clavulanic Formulations
 
/ Cefpodoxime + Clavulanic Acid
 
Products / Cefpodoxime + Clavulanic Acid Formulations
 
Combinations of Cefpodoxime + Clavulanic Acid
  • Cefpodoxime 200 mg. & Clavulanic Acid 125 mg. Tablets

  • Cefpodoxime 100 mg. & Clavulanic Acid 62.5 mg. Tablets

  • Cefpodoxime 50 mg. & Clavulanic Acid 31.25 mg. Tablets

  • Cefpodoxime 50 mg. & Clavulanic Acid 31.25 mg. per 5 ml. Dry Syrup
 
Cefpodoxime 200mg + Clavulanic Acid 125 mg: A Combination of Cefpodoxime (third generation oral cephalosporin) and a beta lactamase inhibitor, Clavulanic Acid, used for the treatment of urinary tract infections, pneumonia, bronchitis, gonorrhea, and multiple other infections (see INDICATIONS).
 
EXECUTIVE SUMMARY
Drug Name Cefpodoxime + Clavulanic Acid
Mechanism of Action Cefpodoxime: Inhibition of cell wall synthesis

Clavulanic Acid: Enzyme inhibitor that enhances the antibacterial activity
Indication Multiple Infections (see INDICATIONS)
Form

Tablets (Cefpodoxime/Clavulanic Acid): 200 mg/125 mg

Tablets (Cefpodoxime/Clavulanic Acid): 100 mg/62.5 mg

Dry Syrup (Cefpodoxime/Clavulanic Acid): 100 mg/62.5 mg

Dry Syrup (Cefpodoxime/Clavulanic Acid): 50 mg/32.25 mg

 
CONTENTS
  • Mechanism of Action
  • Indications
  • Dosage
  • Highlights
  • Microbiology
  • Pharmacokinetics
  • Clinical Trial Summary
  • Warnings / Precautions
  • Special Population
  • Adverse Events
  • References
 
MECHANISM OF ACTION1,2:

Cefpodoxime, a third generation semi-synthetic cephalosporin, exhibits activity against several Gram positive as well as Gram negative microorganisms. This compound is also stable in beta lactamase environment. Cefpodoxime exhibits exceptional activity against methicillin susceptible Staphylococci, Streptococcus pneumoniae, Haemophilus influenzae, Nesseria spp, and Moxaxella catarrhalis, which are referred as the most common hospital acquired and community acquired infections.

Clavulanic acid is a natural inhibitor of beta lactamase, which are produced by Streptomyces clavuligerus. It binds to beta lactamase moieties and inactivates them, thus restricting the cefpodoxime destruction. Clavulanic acid has very little antimicrobial activity.

INDICATIONS1,2:

Cefpodoxime-Clav is indicated in the following infections when caused by susceptible organisms
  • Acute bacterial exacerbations of chronic bronchitis
  • Acute community acquired Pneumonia
  • Upper and lower respiratory tract infections
  • Skin and soft tissue infections
  • Urinary tract infections
  • Pharyngitis and/or tonsillitis
  • General gonorrhea (men and women) and rectal gonococcal infections (women)
  • Acute maxillary sinusitis
 
DOSAGE1,2:
 
TABLE 1: Cefpodoxime Dosage Schedule for Adults (Age 12 years and older)
 
Type of Infection Total Daily Dosage Dosage Frequency Duration
Pharyngitis and/or tonsillitis 200 mg 100 mg Q 12 hrs 5 to 10 days
Acute community acquired Pneumonia 400 mg 200 mg Q 12 hrs 14 days
Acute bacterial exacerbations of chronic bronchitis 400 mg 200 mg Q 12 hrs 10 days
Uncomplicated gonorrhea (men and women) and
rectal gonococcal infections (women)
200 mg Single dose  
Skin and skin structure 800 mg 400 mg Q 12 hrs 7 to 14 days
Acute maxillary sinusitis 400 mg 200 mg Q 12 hrs 10 days
Uncomplicated urinary tract infection 200 mg 100 mg Q 12 hrs 7 days
 
TABLE 2: Cefpodoxime Pediatric Dosage Schedule
 
Type of Infection Total Daily Dosage Dosage Frequency Duration
Pharyngitis and/or tonsillitis 200 mg 100 mg Q 12 hrs 5 to 10 days
Acute community acquired Pneumonia 400 mg 200 mg Q 12 hrs 14 days
Acute bacterial exacerbations of chronic bronchitis 400 mg 200 mg Q 12 hrs 10 days
Uncomplicated gonorrhea (men and women) and
rectal gonococcal infections (women)
200 mg Single dose  
Skin and skin structure 800 mg 400 mg Q 12 hrs 7 to 14 days
Uncomplicated urinary tract infection 200 mg 100 mg Q 12 hrs 7 days
Acute maxillary sinusitis 400 mg 200 mg Q 12 hrs 10 days
 
Special population:

Patients with Renal Dysfunction

For patients with severe renal impairment (< 30 mL/min creatinine clearance), the dosing intervals should be increased to Q 24 hours. In patients maintained on hemodialysis, the dose frequency should be 3 times/week after hemodialysis.

Patients with Cirrhosis

Cefpodoxime pharmacokinetics in cirrhotic patients (with or without ascites) are similar to those in healthy subjects. Dose adjustment is not necessary in this population.
 
HIGHLIGHTS4:
Cefpodoxime-Clav is a combination of two drugs and is effectoive against multiple infection types.
Clavulanic acid component protects degeneration of cefpodoxime in presence of ß-lactamase enzymes, and increases the antibiotic spectrum.
Clavulanic acid in Cefpodoxime-Clav, prevents the resistance to Cefpodoxime that may increase with continuous usage of the drug
Cefpodoxime-Clav has shown effectiveness against multiple Gram-positive and Gram-negative bacteria
Cefpodoxime is generally well tolerated
 
HIGHLIGHTS4:

Cefpodoxime

Cefpodoxime has shown efficacy against most strains of the following microorganisms, both in vitro and in clinical infections.

Gram-positive Aerobes:

Staphylococcus aureus (including penicillinase-producing strains)
Staphylococcus saprophyticus
Streptococcus pneumoniae (excluding penicillin resistant strains)
Streptococcus pyogenes

NOTE: Cefpodoxime is inactive against methicillin-resistant staphylococci

Aerobic Gram-negative Microorganisms:

Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Haemophilius influenzae (including beta lactamase strains)
Moraxella (Branhmella) catarrhalis
Nesseria gonorrhoeae (including penicillinase-producing strains)

The following in vitro data are available, but their clinical significance is unknown. Cefpodoxime exhibits in vitro minimum inhibitory concentrations (MICs) of ≤ 2.0 mcg/mL against most (≥90%) of isolates of the following microorganisms. However, the safety and efficacy of cefpodoxime in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic Gram-positive Microorganisms:

Streptococcus agalactiae
Streptococcus spp. (Groups C, F, G)

NOTE: Cefpodoxime is inactive against enterococci.

Aerobic Gram-negative Microorganisms:

Citrobacter diversus
Klebsiella oxytoca
Proteus vulgaris
Providencia rettgeri
Haemophilus parainfluenzae

NOTE: Cefpodoxime is inactive against most strains of Pseudomonas and Enterobacter

Anaerobic Gram-positive Microorganisms:

Peptostreptococcus magnus

Clavulanic Acid

Clavulanic acid is a fermentation product of Streptomyces clavuligerus, and a beta-lactam compound with penicillin like structure. It has the capability to inactivate a broad spectrum of betalactamases through blocking their active sites. Clavulanic acid is specifically active against the clinically important plasmid-mediated beta-lactamases.

CLINICAL TRIAL SUMMARY1,6:

Cefpodoxime, a relatively new broad-spectrum third-generation cephalosporin, has very good in vitro activity against Enterobacteriaceae, Hemophilus spp. and Moraxella spp., including β-lactamase producers and many strains resistant to other oral agents. It also has activity against Gram-positive bacteria, especially against streptococci.

Cefpodoxime, which possesses characteristics of the third-generation cephalosporins, has been investigated in large numbers of patients with upper and lower respiratory tract infections, urinary tract infections (UTIs), or skin and soft tissue infections (SSTIs).

The international clinical experience with this drug has confirmed its efficacy in treating pharyngotonsillitis with 97% to 100% success rates in adults, and 92% to 100% in pediatric patients. In lower respiratory tract infections, cefpodoxime has proven efficacious in bronchial infections (84% to 97% success rate), and in bacterial pneumonia (favorable outcome in 81.8% to 100% of cases). In UTIs, SSTIs, and pediatric infections a more limited experience has provided favorable results, with an efficacy rate ranging from 77% to 95% of cases.

MICROBIOLOGY3,9:

Cefpodoxime

Cefpodoxime has shown efficacy against most strains of the following microorganisms, both in vitro and in clinical infections.

PHARMACOKINETICS1,4,7,8:

Cefpodoxime

Bioavailability of cefpodoxime is 50% in fasting subjects and it increases in presence of food. Peak plasma concentration of Cefpodoxime 200 mg single dose is 2.18 mcg/ml.

The Drug is well distributed after oral administration. Cefpodoxime reaches therapeutic concentrations in respiratory tract and genito-urinary tracts and bile. Protein binding of cefpodoxime ranges from 20 to 30 %. The plasma half life of cefpodoxime is about 2 to 3 hours and is prolonged in patients with impaired renal function. Cefpodoxime is excreted unchanged in urine.
 
TABLE 31: The Pharmacokinetics of Cefpodoxime in Adult Patients
 
Cefpodoxime Plasma Levels (mcg/ml) in Fasted Adults After Cefpodoxime Proxetil Administration (Single Dose)
Dose
(Cefpodoxime equivalents)
Time After Oral Ingestion
1hr 2hr 3hr 4hr 6hr 8hr 12hr
100 mg 0.98 1.4 1.3 1 0.59 0.29 0.08
200 mg 1.5 2.2 2.2 1.8 1.2 0.62 0.18
400 mg 2.2 3.7 3.8 3.3 2.3 1.3 0.38
 
Pharmacokinetics in Elderly Subjects

Elderly subjects did not require dosage adjustments unless they had diminished renal function.

Clavulanic Acid

Clavulanic acid is well absorbed after oral administration. Peak plasma concentration of Clavulanic acid 125 mg single dose is 2.2 mcg/ml. It is distributed completely after oral administration. Protein binding of clavulanic acid is about 30 %.The plasma half life of clavulanic acid is one hour.

About 60 % of clavulanic acid is excreted unchanged in urine. The clavulanic acid component in the drug combination protects cefpodoxime from degradation by ß-lactamase enzymes, and effectively extends the antibiotic spectrum of cefpodoxime to include many bacteria that are normally resistant to cefpodoxime and other ß-lactam antibiotics.

WARNINGS and PRECAUTIONS1,2

Cross hypersensitivity in penicillin sensitive patients, leading to serious acute hypersensitivity reactions may need treatment with epinephrine along with other emergency measures such as intravenous fluids, oxygen, airway management, and intravenous antihistamine, as clinically indicated.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antimicrobial agents, including cefpodoxime tablets, and may range in severity from mild diarrhea to fatal colitis. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted, as clinically indicated.

In patients with transient or persistent reduction in urinary output due to renal insufficiency, the total daily dose of cefpodoxime should be reduced because high and prolonged serum antibiotic concentrations can occur in such individuals following usual doses. Cefpodoxime, like other cephalosporins, should be administered with caution to patients receiving concurrent treatment with potent diuretics.

As with other antibiotics, prolonged use of cefpodoxime may result in overgrowth of non-susceptible organisms. Repeated evaluation of the patient’s condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

SPECIAL POPULATION1,2

Nursing Mothers

Cefpodoxime is excreted in human milk, so a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and efficacy in infants less than 2 months of age have not been established.

Geriatric Use

Dose adjustment in elderly patients with normal renal function is not necessary.

ADVERSE EVENTS1

Cefpodoxime

Incidence greater than 1% include #Diarrhea: 7%; Nausea: 3.3%; Vaginal Fungal Infections:1%; Vulvovaginal Infections:1.3%; Abdominal Pain: 1.2%; and Headache:1%

Number of diarrhea or loose stools were dose related: decreasing from 10.4% of patients receiving 800 mg per day to 5.7% for those receiving 200 mg per day. Of patients with diarrhea, 10% had C. difficile organism or toxin in the stool.

Other adverse events consists of difficulty breathing or swallowing, Hives, Itching, Mild skin rash, Painful mouth or throat sores, Severe skin rash, Sore throat, Unusual bleeding or bruising, Upset stomach, Vaginal infection, Vomiting, and Wheezing.

Clavulanic Acid

Side effects include bloody diarrhea, bloody urine, painful or difficult urination, unusual weakness, easy bleeding and bruising, confusion, dry mouth, increased urination, chills, body aches, fever, sore throat, headache, seizures, chest pain and irregular heartbeat. These side effects are very rare and do not affect a large amount of users. Treatment should not normally exceed 14 days.

ADVERSE EVENTS1

References:
  1. Prescribing information for Cefpodoxime (www.drugs.com)
  2. Prescribing information for Clavulanic acid
  3. B. Brismar, C. Edlund and C. E. Nord.Impact of cefpodoxime proxetil and amoxicillin on the normal oral and intestinal microflora. European Journal of Clinical Microbiology & Infectious Diseases
  4. Letter to the Editor, Susceptibility Testing with Clavulanic Acid: Fixed Concentration versus Fixed Ratio Antimicrobial Agents and Chemotherapy, Nov 1995 p2591-2592
  5. Physicians' Desk Reference, 54th edition 2000 p2488-2492
  6. Eugénie Bergogne-Bérézin, International clinical experience with cefpodoxime proxetil.Current Therapeutic Research Volume 57, Issue 13, 1996, Pages 103-11
  7. M T Borin, G S Hughes, C R Spillers, et al. oral dosing of cefpodoxime proxetil, plasma and skin blister fluid following;Antimicrobial Agents and Chemotherapy, June 1990, p.1094-1099
  8. Martindale 32nd edition p172
  9. Mitchell J. Schwaber,1,{dagger} Patti M. Raney,2 J. Kamile Rasheed,2 James W. Biddle,2 Portia Williams,3 John E. McGowan Jr.,3 and Fred C. Tenover2*; Utility of NCCLS Guidelines for Identifying Extended-Spectrum ß-Lactamases in Non-Escherichia coli and Non-Klebsiella spp. of Enterobacteriaceae;journal Of Clinical Microbiology Jan 2004 Vol. 42p294 -298
 
 
 
 
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