cefexta (cefdinir) an extended spectrum antibiotic

Cefexta An Extended Spectrum Antibiotic

Rezaur Rahman SiddiquiSenior Product Manager

UniMed UniHealth Pharmaceutical Ltd

Otitis is one of the most frequent diseases in early childhood and one of the reasons for first prescription of antibiotics.

Streptococcus pneumoniae (SP) is the most frequent pathogen identified and increasing resistance may influence antibiotic treatment.

Key Concept in Otitis Media

Ref: Textbook of Infectious Disease 2017, P 236

Key Concept in Otitis Media

Ref: Drugs 2004; 64 (13): 1433-1464

S. pneumoniae 25–50% of cases, H. influenzae (incidence 15–35%) M. catarrhalis (3–20%).

β-lactamase producing M. catarrhalis strains have become more prevalent during the last 30 years such that currently >90% of strains worldwide are β-lactamase producers.

Recommended Therapy Textbook of Infectious Diseases 2017, 4th ED

Structure of Cefdinir

Unique Structure offers

Why Cefexta ?

Ref: Principles and Practice of INFECTIOUS DISEASES, 2015, C 21

Including TEM 1 by H. InfluenzaeBRO-1, BRO-2 by M. Catterhallis (Chormosomal)

Why Cefexta ?

Why Cefexta ?

in vitro potency of cefdinir against these pathogens and supports clinical consideration of this agent as an alternative to parenteral cephems in infections where adequate tissue and body fluid concentrations can be safely achieved.

Why Cefexta ?

Why Cefexta ?

American Academy of Pediatrics recommended in Otitis Media as first-line therapyin children with penicillinallergyIn addition to acute otitis media, cefdinir is currentlyapproved bythefor the treatment of pharyngitis or tonsillitis in children and adults, as wellas uncomplicated skin and skin structure infections. It is also approved foruse in community acquired pneumonia, acute exacerbations of chronicbronchitis, and acute maxillarysinusitis in adolescents and adults.

Why Cefexta ?

CLINICAL EFFICACY in OTITIS MEDIA vs AM/C


Cefdinir given either once daily or twice-daily is a safe and effective treatment for pediatric patients with acute suppurative otitis media.

Conclusion: For children with nonrefractory AOM, based only on clinical endpoints, 5 days of therapy with cefdinir 14 mg/kg divided or 300mg twice daily was comparable overall with 10 days of therapy with low dose amoxicillin/clavulanate 45/6.4 mg/kg divided twice daily.

(Pediatr Infect Dis J 2004;23: 834–838)


CLINICAL EFFICACY in OTITIS MEDIA

cefdinir resulted in an overall successful clinical response at end of treatment of 83%. Thisregimen was efficacious against penicillin-susceptible S. pneumoniae


Conclusions. A 5-day regimen of cefdinir was effective in the eradication of the common causative pathogens of nonrefractory AOM, including intermediate penicillin-resistant S. pneumoniae and beta-lactamase-producing organisms. Cefdinir should be considered a suitable second line antibiotic for AOM.


Journal of Clinical Therapeutics

CLINICAL EFFICACY in Other Indications

The total daily dose for all infections is 600 mg.

Once daily dosing for 10 days is as effective as BID dosing.

Once daily dosing has not been studied in pneumonia or skin infections.

Cefexta Capsules may be taken without regard to meals.

Dosage and administration:

PharmacologyMechanism of ActionThird-generation cephalosporin; inhibits mucopeptide synthesis in bacterial cell wall; typically bactericidal, depending on organism susceptibility, dose, and serum or tissue concentrations

AbsorptionBioavailability: 16-21% (capsule); 25% (suspension)Peak plasma time: 2-4 hrPlasma protein: 60-70%

DistributionDistributed into blister fluid, middle-ear fluid, tonsils, sinus tissue, bronchial mucosa, epithelial lining fluidVd: 0.29-1.05 L/kg (6 months-12 years); 0.06-0.64 L/kg (adults)

MetabolismNot appreciably metabolized

EliminationHalf-life: 100 min, Excretion: Urine (7-25% as unchanged drug)

Type of Infection Dosage Duration

AECB

300mg BID or 600mg OD

5-10 daysPharyngitis/Tonsillitis

Acute Bacterial Otitis Media

Acute Maxillary Sinusitis 10 daysCommunity Acquired Pneumonia

300mg BID 10 daysUncomplicated Skin and Skin Structure Infection

Age 13 to older


Type of Infection Dosage Duration

Pharyngitis/Tonsillitis

7mg/kg BID or 14mg/kg OD

5-10 daysAcute Bacterial Otitis Media

Acute Maxillary Sinusitis 10 daysCommunity Acquired Pneumonia

7mg/kg BID 10 daysUncomplicated Skin and Skin Structure Infection

Age 6months to 12 years


Drug interaction

Side EffectsDiarrheaVaginal MoniliasisNausea and Vomiting HeadacheRash etc

Dosing Modifications

• Renal impairment• CrCl <30 mL/min : Not to exceed 300 mg/day

or 7 mg/kg PO

• Hepatic impairment• No dosage adjustment necessaryCefdininr does not undergo appreciable metabolism in the liver and hepatic insufficiency is not expected to alter its pharmacokinetic profile.

Role of Clavulanic Acid &

Hepatotoxicity

• Isolated from Streptomyces clavuligerus in 1970s

• Not effective by itself as an antibiotic

• It is a β-lactamase inhibitor or an irreversible ‘suicide’ inhibitor or called suicidal drug

• It has a high affinity for the class A β-lactamases. Inclcudes TEM and SHV enzymes, is found frequently in members of the – Enterobacteriaceae, – Haemophilus influenzae and Neisseria

gonorrhoeae. – Klebsiella pneumoniae, Proteus mirabilis, Proteus

vulgaris, Bacteroides fragilis and Moraxella catarrhalis

Clavulanic Acid

Journal of Antimicrobial Chemotherapy (2003) 52, 18–23

• Alteration of the penicillin binding protein

• Production of Beta-lactamase enzyme

• Reduced drug accumulation: by Efflux

• Alteration of metabolic pathway:

Mechanism of antibiotic resistance

NOT all bacteria are able to produce Beta Lactamase to became resistance

Clavulanic Acid

So why should I take this combination?

Chronic liver injury induced by drugs: a systematic review

Most common drugs associated with drug-induced liver injury, antibiotics • Amoxicillin-clavulanic acid, • Trimethoprim-sulfamethoxazole,• Azithromycin) are most likely to cause

chronic injury. Liver Int. 2015 Nov 8.

FACTS

http://www.ncbi.nlm.nih.gov/pubmed/26346512

Comedications alter drug-induced liver injury reporting frequency: Data mining in the WHO VigiBase™

• They examined the effect of these drug-drug interactions on liver safety reports of four drugs highly associated with hepatotoxicity. In the WHO VigiBase™, liver event reports were examined for

• acetaminophen, • isoniazid, • valproic acid, and • amoxicillin/clavulanic acid.

Regul Toxicol Pharmacol. 2015 Aug;72

FACTS

http://www.ncbi.nlm.nih.gov/pubmed/25988394

• associated with jaundice and can be severe and prolonged (with jaundice lasting 4 to 24 weeks)

http://livertox.nih.gov/AmoxicillinClavulanate.htm

Amoxicillin/clavulanate is the most common cause of drug induced acute liver injury both in the USA and Europe

• The liver injury appears to be due to the clavulanate rather than amoxicillin, as re-exposure to amoxicillin alone has not been associated with recurrence, whereas re-exposure to the combination is usually followed by a more rapid onset of a more severe hepatic injury, which can include prolonged cholestasis and development of cirrhosis.


• cause -unknown• probably immunoallergic in origin.

• Other beta lactamase inhibitors (tazobactam and subactam) have not been reported to cause a similar hepatic injury, although it has been reported with other penicillins when combined with clavulanate (ticarcillin/clavulanate)


• Contraindication• History of jaundice/hepatic impairment due to

amoxicillin/clavulanic acid

https://www.medicines.org.uk/emc/medicine/19190

FACTS

CLAVUNALIC ACID

DRUG induced Hepatotoxicity

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cefexta (cefdinir) an extended spectrum antibiotic

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