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Cephalosporin (1) -lactum antibiotics containing 7-aminocephalosporanic acid nucleus

Classification:Based on antibacterial activity

1stgeneration- good activity against gram

positive & relatively modest activity againstgram negative

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Cephalosporin (2)

2ndgeneration- increased activity against gramnegative

3rdgeneration- increased spectrum of activityagainst gram negative, but less active againstgram positive than 1stgeneration

4thgeneration- extended spectrum of activityagainst gram positive & negative

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Cephalosporin (3)

Generation Example Spectrum

FirstCephalexin

Cephalothin

Mostly gram positive

Few gram negative

Second CefuroximeCefaclor

Covers most gram negative

Third

Cefotaxime*

Ceftriaxone

Cefpodoxime proxetil*

Increased spectrum for gram

negative

Less active against gram

positive

FourthCefepime

CefpiromeExtended spectrum of activity

*Most active a ainst ram ositive or anisms in the rou

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Cefpodoxime proxetil

CONH

OCH3

C

H H

NH2N

N

S

CH2OCH

3

COOCHOCOOCH(CH3)2

O

SN

CH3

Methoxymethyl group improves theantibacterials activity against gram+ve

bacteria and increases the GI stability.

Methoxymino group

protects against

hydrolysis

by beta lactamases

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Cefpodoxime proxetil

3rdgeneration, extended spectrum, semi-synthetic, oral cephalosporins

Prodrug- active metabolite is cefpodoxime

Active against wide spectrum of gram positive &gram negative organisms

Stable against many -lactamases producingorganisms

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Mechanism of Action

Inhibition of bacterial cell wall synthesis

Binds to PBPs & inhibits transpeptidationreaction involved in final step in synthesis of

bacterial cell wall

Also binds to the inhibitor of murein hydrolase

which causes lysis of bacterial cell

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Spectrum of Activity (1)

Aerobic Gram-Positive microorganisms:

Staphylococcus aureus (including penicillinaseproducing & excluding MRSA)

Staphylococcus saphrophyticus

Streptococcus pneumoniae (excluding penicillin-

resistant)

Streptococcus pyogenes

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Spectrum of Activity (2)

Aerobic Gram-Negative microorganisms:

Escherichia coli

Klebsiella pneumoniae

Hemophilus influezae (including -lactamaseproducing)

Proteus mirabilis

Moraxella (Branhamella) catarrhalis

Neisseria gonorrhoeae ( including penicillinaseproducing)

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Comparison of antibacterial activity of

cefpodoxime

Organisms Cefpodoxime(MIC90mcg/mL)

Cefixime(MIC90 mcg/mL)

Cefaclor(MIC90 mcg/mL)

Gram Positive Organisms

Staph. aureus 2 32 8

Strep. pyogenes 0.02 0.13 0.25

Strep. pneumoniae 0.02 0.13 0.25

Strep. agalactae >0.12 0.28 32

Gram Negative Organisms

H. influenzae 0.25 0.25 16

M. catarrhalis 0.125 0.06 1

K. pneumoniae 0.125 0.5 8

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Pharmacokinetics

Rapidly absorbed from GIT & de-esterified to itsactive metabolite, cefpodoxime

Bioavailability 50%

Cmax= 1.4 mcg/mL (100 mg)2.3 mcg/mL (200 mg)

3.9 mcg/mL (400 mg)

T1/2 = 2.09 to 2.84

Plasma Protein Binding = 21-29%

Food enhances absorption

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Pharmacokinetics

Distribution:

Skin-blister fluid:

200 mg BD for 5 days-mean maximum concentration 1.6 mcg/mL

Tonsil tissue:100 mg single dose-0.24 mcg/mL at 4 hrs & 0.09 mcg/mL at 7 hrs

(exceed MIC90for S. pyogenes)

Lung tissue:

200 mg single oral dose- 0.63 mcg/mL at 3 hrs; 0.52 mcg/mL at 6 hrs &0.19 at 12 hrs (exceed MIC90for S. pneumoniae & H. influenzae)

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Pharmacokinetics

Metabolism:

Minimal metabolism of cefpodoxime

Most drug excreted in urine as intact (29-33%) & metabolites

Renal Failure:

Elimination reduced in sever renal impairment (Creatinine clearance

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Indications (1)

Treatment of infections caused by susceptiblestrains of microorganisms

Acute otitis media

Pharyngitis & Tonsillitis

Community-acquired pneumonia

Acute bacterial exacerbation of chronicbronchitis (AECB)

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Indications (2)

Acute, uncomplicated urethral & cervical gonorrhea

Acute, uncomplicated ano-rectal infections in women

Uncomplicated skin & skin structure infections (SSTIs)

Acute maxillary sinusitis

Uncomplicated urinary tract infections

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Contraindications

Patients with known allergy tocefpodoxime or cephalosporin group

Warnings:

Allergy to penicillin group of antibiotics

H/O severe antibacterial associateddiarrhea

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Precautions

Renal insufficiency

Prolonged use

Pregnancy & Lactation: Pregnancy category BUse only if clearly indicated

Paediatric: Safety & efficacy not established in

infants

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Drug Interactions

Antacids: High doses decreases

absorption of cefpodoxime

Probenecid: Decrease renal excretion of

cefpodoxime

Nephrotoxic drugs: Close monitoring of

renal function is advised

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Adverse Reactions

Well tolerated in various clinical trialsusing recommended dosage range (100-400 mg BD)

Most were transient & mild to moderate inseverity in clinical trials

Diarrhea

Nausea & Vomiting

Abdominal pain

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Dosage

Tablets administered with food to enhanceabsorption

Suspension may be given without regard food

Adult & Adolescents (>12 yrs)

100-400 mg BD for 5-14 days

Children (2 months to

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Children (2 months to

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Adult & adolescents (>12 yrs)

Type of InfectionTotal daily

dose

FrequencyDuration

(Days)

Pharyngitis &/or tonsilitis 200 mg 100 mg BD 5-10

Acute CAP 400 mg 200 mg BD 14

AECB 400 mg 200 mg BD 10

Uncomplicated gonorrhea 200 mg Single dose

SSTI 800 mg 400 mg BD 7-14

Acute maxillary sinusitis 400 mg 200 mg BD 5

Ucomplicated UTI 200 mg 100 mg BD 7

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Application of Switch Therapy

Structural similarity to parenteral antibiotic, Ceftriaxone

Hospital-acquired pneumonia

Pneumonia caused by Gram-negative bacilli

Sepsis of unknown origin

Sepsis caused by Gram-negative bacilli

Pyelonephritis

Arthritis caused by Gram-negative bacilli

J of Antimicrobial Chemotherapy1994;33:169-171

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Similar spectrum of activity (Gram positiveas well as gram negative)

Reduces need for IV administration

Early hospital discharge

Reduces cost of therapy

Step-Down therapy for Ceftriaxone

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Clinical Trial

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Cefpodoxime Vs Cefixime in lower

respiratory tract infections

Study design :Prospective, open label, comparative, multicentric

study

Mean age of recruitment :6 months12 years, (10 years) with LRTIs

Drug intervention :Cefpodoxime in 396 patients-5mg/kg

Cefixime in 380 patients,-4 mg/kg

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Comparison of MIC of Cefpodoxime and Cefixime

MIC (mcg/mL ) Cefpodoxime Cefixime

H. influenza 0.06-0.12 0.06

M. catarrhalis 0.12-0.25 0.12

S. pneumoniae 0.03 0.25

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Comparison of clinical out come

Cefpodoxime Cefixime

Clinical out come

Cure 61.3% 43%

Improvement 35.7% 43.8%

Clinical success 97.0% 86.8%

Failure 3.0% 13.2%

Bacterial out come

Eradication 93.4% 82.9%

Failure 6.6% 17.1%

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Comparison of clinical out come

0%

10%

20%

30%

40%

50%

60%

Excellent V.Good Good Fair Poor

Cefpodoxime

cefixime

Physicians global assessment

Ind ian Jou rnal of Pediatr ics ; Volume 71;2004

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0%

10%

20%

30%

40%

50%

60%

Excellent V.Good Good Fair Poor

Cefpodoxime

cefixime

Patients global assessment

Ind ian Jou rnal of Pediatr ics ; Volume 71;2004

Comparison of clinical out come

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Cefpodoxime Vs Ceftriaxone in

Community-acquired bronchopneumonia

Cefpodoxime Ceftriaxone

Dose 200 mg BD oral for10 days 1 gm/day I.M. for 10days

Clinical cure 98% 95%

Bacterialeradication

94.3% 97.4%

Zuck et al, 1990

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Comparison of Cefpodoxime Vs

Amoxicillin/Clavulanate

Study design :Multicentric, randomized, double blind, clinical study

Recruitment for study :229 children with acute Otitis media

Drug intervention:

Cefpodoxime proxetil -10mg/kg BD for 10 days Amoxicillin/clavulanate -40mg/10mg per kg TID for 10

days

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Bacteriological cure rate

Parameters Cefpodoxime Amoxicillin/

clavulanate

Cured 68% 65%

Improved 24% 23%

Failed 8% 13%

Recurrence

rate

24% 25%

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Adverse events

0%

5%

10%

15%

20%

25%

30%

35%

40%

cefpodoxime

Amoxycillin/cla

vulanate

Pediatric pharmacology and therapeutics. J.Pediatr.1992

Clinical efficacy for Cefpodoxime proxetil b.i.d. is

Equivalent to Amoxicillin/Clavulanate t.i.d. in AOM

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Conclusion

Cefpodoxime proxetil is well tolerated

Superior alternative to other third generation

cephalosporins

Expanded spectrum of activity

First line antimicrobial in pediatric patients ofLRTIs