Cefixime and Clavulanic Acid: A combination of third generation cephalosporin (Cefixime) and ß-lactamase inhibitor (Clavulanic acid) used for the treatment of various types of infections.

MECHANISM OF ACTION^1-2:

Cefixime is a semisynthetic, third generation cephalosporin antibiotic, effective against a wide spectrum of sensitive Gram positive, Gram negative and anaerobic bacterial pathogens including beta-lactamase producing strains. It has high affinity for penicillin binding proteins with varying site of activity. It acts by inhibition of bacterial cell-wall synthesis. The elimination half-life is about 3 hours, with little variation over the usual therapeutic dosage range.

Clavulanic acid is a naturally derived beta lactamase inhibitor produced by Streptomyces clavuligerus. Clavulanic acid is an irreversible inhibitor of intracellular and extracellular β-lactamases, demonstrating concentration-dependent and competitive inhibition.

Rationale for combination: Although Clavulanic acid does have some degree of bacterial activity, its principal role is as a beta-lactamase inhibitor. Beta-lactam antibiotics, such as the penicillins and cephalosporins, act by disrupting the development of bacterial cells walls thus causing the disintegration of the bacteria. However, some bacteria acquire the genes to produce enzymes which inactivate this mode of action - so called beta-lactamases - drastically reducing the efficacy of this class of antibiotics.

Clavulanic acid has a similar structure to the beta-lactam antibiotics but binds irreversibly to the beta-lactamase enzymes. Used in combination with the beta-lactam antibiotics, it has become one of the most prescribed antibiotics prolonging the effective life of antibiotics.

Cefixime is found to be ineffective against bacteria which produces ESBL (Extended-Spectrum Beta-Lactamases) enzyme and resistance is seen in such types of bacteria. The combination of cefixime and clavulanic acid (ß-lactamase inhibitor) provides a solution for treatment of bacterial infections caused by beta lactam resistant pathogens.

INDICATIONS^1-2:

Cefixime-Clav should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. Cefixime-Clav is indicated for the treatment of:

Uncomplicated Urinary Tract Infections caused by Escherichia coli and Proteus mirabilis.

Otitis Media caused by Haemophilus influenzae (beta-lactamase positive and negative strains), Moraxella (Branhamella) catarrhalis, (most of which are beta-lactamase positive) and S. pyogenes*.

Pharyngitis and Tonsillitis, caused by S. pyogenes.

Acute Bronchitis and Acute Exacerbations of Chronic Bronchitis, caused by Streptococcus pneumoniae and Haemophilus influenzae (beta-lactamase positive and negative strains).

Uncomplicated gonorrhea (cervical/urethral), caused by Neisseria gonorrhoeae (penicillinase-and non-penicillinase- producing strains).


DOSAGE^1-4:

Adults and Children over 10 Years: One tablet twice daily. The usual course of treatment is 7 days. This may be continued for up to 14 days if required.

MICROBIOLOGY^1-2:

As with other cephlalosporins, bactericidal action of Cefixime results from inhibition of cell wall synthesis. Cefixine is highly stable in the presence of beta-lactamse enzymes. As a result, many organism resistant to penicillin and some cephalosporins due to the presence of betalactamses, may be susceptable to cefixime. Cefixime has been shown to be active against most strians of the following organism both in vitro and in clinical infections.

Gram-positive Organisms
Streptococcus pneumoniae
Streptococcus pyogenes

Gram-negative microorganisms
Haemophilus influenzae
Moraxella (Branhamella) catarrhalis (most of which are beta-lactamase positive),
Escherichia coli,
Proteus mirabilis,
Neisseria gonorrhoeae (including penicillinase and nonpencillinase producing strains).

Cefixime has been shown to be active in vitro against most strains of the following organism; however, clinical efficacy has not been established.

Gram Positive Organism
Streptococcus agalactiae

Gram-negative Organism
Haemophilus parainfluenzae (beta-lactamse positive and negative strains),
Proteus vulgaris
Klebsiella pneumoniae
Klebsiella oxytoca
Pasteurella multocida,
Providencia species,
Salmonella species
Shigella species
Citrobacter amalonaticus
Citrobacter diversus
Serratia marcescens

Note: Psedomanas species, strains of group D Streptococci (including Enterococci, Listeria monocytogenes, most strains of Staphylococci (includung methicillin- resistant strains) and most strains of Enterobacter are resistant to Cefixime. In addition, most strains of Bacteroides fragilis and Clostridia are resistant to cefixime.

IN-VITRO AND IN-VIVO SUMMARY / CLINICAL TRIAL SUMMARY^1-4:

Acute Otitis Media:

Cefixime is used in adults or children for the treatment of acute otitis media (AOM) caused by Haemophilus influenzae (including β-lactamase-producing strains), Moraxella catarrhalis (including β-lactamase-producing strains), Streptococcus pyogenes (group A β-hemolytic streptococci), or S. pneumoniae.

In clinical studies in children 6 months to 16 years of age with AOM, a 10-day regimen of oral cefixime produced a favorable clinical response (e.g., clinical cure or improvement with absence of fever, irritability, otalgia, and tympanic membrane erythema with or without middle ear effusion) in 83–100% and a presumptive bacteriologic cure in 60–97% of patients. At 2–4 weeks after cefixime therapy, a clinical cure was still evident in 71–77% of children with H. influenzae infections, 84–100% of those with M. catarrhalis infections, and 69–82% of those with S. pneumoniae infections; persistent effusions were present in 15% of patients and 17% were considered to be treatment failures. In studies in children with AOM, oral cefixime (8 mg/kg once daily or 4 mg/kg twice daily) was as effective as oral amoxicillin (20 or 40 mg/kg daily given in 3 equally divided doses), oral amoxicillin and clavulanate potassium (40 mg of amoxicillin per kg daily in 3 equally divided doses), oral cefpodoxime proxetil (10 mg/kg once daily), or oral cefaclor (40 mg/kg daily given in 3 equally divided doses) for the treatment of infections caused by susceptible β-lactamase-producing M. catarrhalis or H. influenzae. Both the once- and twice-daily cefixime regimens appear to be equally effective in the treatment of AOM caused by susceptible organisms.

Pharyngitis and Tonsillitis:

Results of open-label, randomized studies in pediatric patients with S. pyogenes pharyngitis and tonsillitis indicate that a 10-day regimen of oral cefixime is more effective than a 10-day regimen of oral penicillin V and that a 5-day regimen of oral cefixime is at least as effective as the 10-day penicillin V regimen. The bacteriologic eradication rate was 94% in those who received a 10-day regimen of oral cefixime, 82.6% in those who received a 5-day regimen of oral cefixime, and 77–88% in those who received a 10-day regimen of oral penicillin V. Once-daily dosing with cefixime is as effective as twice-daily dosing in the treatment of pharyngitis and tonsillitis.

In another open, controlled, randomized multicenter study5, 160 children suffering from pharyngitis and/or tonsillitis were treated with either 8 mg cefixime/kg body weight once daily for 5 days or 20,000 I.U. penicillin V/kg body weight t.i.d. for 10 days. One hundred fifty-one children were evaluable for clinical efficacy. In the cefixime group, 65 (86.7%) children were cured, seven (9.3%) were significantly improved, one (1.3%) relapsed and in two (2.7%) therapy failed. Of the patients treated with penicillin V, 69 (90.8%) were cured, five (6.6%) improved, one (1.3%) relapsed and in one (1.3%) therapy failed. Elimination of initial pathogens occurred in 57 (82.6%) patients treated with cefixime and in 60 (88.2%) treated with penicillin V. At 3 to 4 weeks after the end of treatment, six relapses were seen in the cefixime group and eight in the penicillin V group. Mild-to-moderate adverse events that were possibly related to the medication were seen in four children treated with cefixime and in five treated with penicillin V.

Cefixime for pharyngeal gonorrhoea⁴:

A study of the efficacy of treatment of pharyngeal gonorrhoea with a single oral dose of 400 mg of cefixime was undertaken; 83% of patients also received a single oral dose of azithromycin to treat possible concurrent anogenital chlamydial infection. Of the 54 patients studied, only one of 45 patients who attended for at least one test of cure had a positive culture seven days after treatment; the possibility of reinfection could not have been excluded. Two tests of cure were obtained from 18 patients. Cefixime, therefore, seems to be effective in the treatment of pharyngeal gonorrhoea.

PHARMACOKINETICS^1,2:

CEFIXIME:

Approximately 30–50% of a single dose of cefixime is absorbed following oral administration. in-vivo studies indicate that the drug is absorbed from the upper and middle part of the small intestine and probably transported across the intestinal membrane by a dipeptide carrier system.

Presence of food in the GI tract decreases the rate of absorption of cefixime but generally does not affect the extent of absorption of the drug. The time to peak concentrations is increased approximately 0.8 hours by administration with food. GI absorption of cefixime is not affected by concomitant administration of antacids.

Following oral administration of a single 200 or 400mg dose of cefixime as capsules, tablets, or oral suspension, the time to peak serum concentrations averages 3.1–4.4 hours (range: 2–6 hours). In one study in healthy, fasting adults, time to peak serum concentrations of cefixime was dose dependent and averaged 2.7, 3.4, 3.9, and 4.3 hours following a single 50, 100, 200, and 400mg oral dose, respectively. Following oral administration of a single 200 or 400mg tablet of cefixime, peak serum concentrations average 2 mcg/mL (range: 1–4 mcg/mL) or 3.7 mcg/mL (range: 1.3–7.7 mcg/mL); serum concentrations average 1.5 or 2.7 mcg/mL, respectively, 6 hours after the dose and average 0.4 or 0.6 mcg/mL, respectively, 12 hours after the dose.

Peak serum concentrations of cefixime are approximately 15–50% higher when the drug is administered as an oral suspension rather than as tablets. When 200 or 400mg doses of cefixime are administered as an oral suspension, peak serum concentrations average 3–3.4 mcg/mL (range: 1–4.78 mcg/mL) and 4.6 mcg/mL (range: 1.9–7.7 mcg/mL), respectively. In the dosage range of 100–400 mg, the areas under the concentration-time curves (AUCs) are approximately 10–25% higher with the oral suspension than with the tablets.

Studies in healthy adults using cefixime doses of 100 mg to 2 g given as capsules or an oral solution or suspension indicate that peak serum concentrations and AUCs increase with increasing dose but are not directly dose proportional; there is some evidence that decreased GI absorption occurs with increasing dose. Studies in children using cefixime doses of 4 to 8mg/kg also indicate that serum concentrations of cefixime are not directly dose proportional.

There is no evidence that cefixime accumulates in serum or urine of patients with normal renal function following multiple doses of the drug given once or twice daily. In one study in healthy adults receiving 400 mg once daily or 200 mg twice daily as cefixime capsules, peak serum concentrations and AUCs determined after 8 and 14–15 days of therapy were similar to those reported on the first day of therapy.

Although the difference was not considered clinically important, one study in geriatric patients older than 64 years of age receiving 400mg doses of cefixime once daily for 5 days indicated that peak serum concentrations of cefixime were 20–26% higher and AUCs were approximately 40–42% higher in these geriatric adults than in healthy adults 18–35 years of age.

ADVERSE EVENTS^5-6

The most frequent side effects seen with Cefixime-Clav are diarrhoea and stool changes. Events like nausea/vomiting, transient elevation in liver transaminases, alkaline phosphatase and jaundice can also occur.

Thrombocytosis, thrombocytopenia, leucopenia, hypereosinophilia, neutropenia and agranulocytosis may also occur.

Other adverse events that may occur are abdominal pain, abdominal cramps, flatulence, indigestion, headache, vaginitis, vulvar itch, rash, hives, itch, dysuria, chills, chest pain, shortness of breath, mouth ulcers, swollen tongue, sleepiness, thirst, anorexia.

WARNINGS / PRECAUTIONS^1,5,6

• Before therapy with Cefixime-Clav is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cephalosporins, penicillins or other drugs.
• Cefixime as with other broad-spectrum antibiotics should be prescribed with caution in individuals with a history of colitis.
• Increases in prothrombin times may occur and therefore care should be taken in patients receiving anticoagulant therapy.
• No adequate and well-controlled studies in pregnant women have been reported so Cefixime-Clav should therefore not be used in pregnancy or in nursing mothers unless considered essential by the physician.

DRUG INTERACTIONS^1-2

Carbamazepine: Elevated carbamazepine levels have been reported when cefixime is administered concomitantly.

Warfarin and Anticoagulants: Increased prothrombin time, with or without clinical bleeding, has been reported when cefixime is administered concomitantly.

Oral Contraceptives: Cefixime may interfere with the effectiveness of birth control pills.

Glucose Test: A false positive reaction for glucose in the urine may occur with Benedict's or Fehling's solutions or with copper sulphate test tablets.

Coombs test: A false positive direct Coombs test has been reported during treatment with cephalosporin antibiotics.

REFERENCES:

1. Prescribing information for Cefixime (www.drugs.com)
2. Prescribing information for Clavulanic acid
3. Adam, D.; Hostalek, U. and Tröster K. 5-day Cefixime therapy for bacterial pharyngitis and/or
   tonsillitis: Comparison with 10-day Penicillin V therapy, Infection, (1995), 23, S83-S86.
4. McMillan, A. and Young, H. The treatment of pharyngeal gonorrhoea with a single oral dose of Cefixime, International Journal of STD and AIDS, (2007), 18, 253-254.
5. Mayorga C, Torres M, Blanca M. Cephalosporin allergy. N Engl J Med 2002; 236:380–381
6. Norrby S. Side effects of cephalosporins. Drug 1987; 34(Suppl 2):105–120.