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KEFPOD- O

Gastrointestinal tract

Digestive System
Functions:

It is involved in
Ingestion Digestion Absorption Excretion of the food

Common worldwide bacterial disease An acute illness associated with

fever that is most often caused


by the Salmonella typhi bacteria

Transmitted by the ingestion of


contaminated food or water

Typhoid
Typhoid (Enteric fever) remains endemic in many areas of the developing world

Causes over 26 million infections and over 2,00,000 deaths annually


Incidence is highest in south-central Asia and South East Asia (over 100/100 000 cases/year), with the highest burden of disease in children aged 2-15 years

Thaver D. BMJ 2009;338:b1865

Typhoid
Causes:
Caused by several species of Salmonella: S. typhi, S. paratyphi The proximate cause in most cases is water or food contamination by a human carrier

Incubation period - 1 to 2 wks Duration of the illness - 4 to 6 wks The patient experiences
poor appetite abdominal pain headaches generalized aches and pains; fever, often up to 104 F;

Typhoid Symptoms

lethargy (usually only if untreated);

Typhoid Symptoms
Some people with typhoid fever develop a rash called "rose spots," which are small red spots on the abdomen and chest.

Diagnosis
A complete blood count (CBC) will show a high number of white blood cells. A blood culture during the first week of the fever can show S. typhi bacteria.

Widal test : "O" agglutinin antibody titer 1:80 and "H" 1:160 or "O" 4
times higher supports a diagnosis of typhoid fever Other tests that can help diagnose this condition include:
ELISA urine test to look for the bacteria that cause Typhoid fever
Fluorescent antibody study to look for substances that are specific to Typhoid bacteria Platelet count (platelet count will be low) Stool culture

Complication
Intestinal hemorrhage

Intestinal perforation
Encephalitis

Metastatic abscesses
Cholecystitis Endocarditis

Antibiotics and supportive care (IV fluids) Prior to the use of antibiotics, the fatality rate was 20% With antibiotics and supportive care, mortality has been reduced to 1%-2% With appropriate antibiotic therapy, there is usually improvement within 1-2 days and recovery within 7-10 days

Antibiotics are the mainstay of the therapy in the management of Typhoid

Chloramphenicol Ampicillin Trimethoprim-sulfamethoxazole Fluroquinolones like ciprofloxacin, ofloxacin Third generation cephalosporins like ceftriaxone (injectable)

Treatment
Chloramphenicol was the original drug of choice for many years. Advantages:
Low cost, wide availability

Disadvantage:
Not reduces the relapse rate

No effect on carrier state


Not useful for treating MDR s typhi. Rare serious side effects

Fluoroquinolones (ciprofloxacin, ofloxacin, enoxacin, and pefloxacin) are a large family of anti-infective drugs synthesized around the quinolone core and that possess a broad antibacterial spectrum (Congeni 2002). Fluoroquinolones effectively penetrate macrophages and achieve high concentrations in bile (Miller 2000).

Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever) (Review) 10 Copyright 2008 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd.

Third generation cephalosporins ( both oral and injectable) achieve good concentration in bile and are effective in the management of typhoid

Antibiotics like fluroquinolones and third

generation cephalosporins the mainstay


of the therapy in the management of Typhoid

MDR strains of S. Typhi, carrying resistance to all

conventional first-line antibiotics (chloramphenicol, cotrimoxazole, and ampicillin or amoxicillin), have become highly prevalent in several areas of the world since 1989 In the Indian subcontinent and China, the frequency of these MDR strains ranged from 50% to 80% of all S. Typhi

isolates and reached 100% during outbreaks (Lee 2000)

Fluoroquinolones for treating typhoid and paratyphoid fever (enteric fever) (Review) 10 Copyright 2008 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd.

There is decreased susceptibility to drugs (Chloramphenicol, Ampicillin, Chloramphenicol, Cotrimoxazole & Ciprofloxacin) with consequent therapeutic failure

To complicate further, it is often necessary to commence


treatment before the results of diagnosis or laboratory sensitivity tests for resistance are available

Threlfall EJ. EID 2008;14[5]:860-1

Incidence of multi-drug resistant [MDR] salmonella typhi is as high as 92%


Krishnan P. IJPM 2009;52[4]:505-8

Similarly ciprofloxacin resistant enteric fever has evolved due to their rampant use
Capoor MR. JMM 2007;56:1490-4

Ciprofloxacin resistant Typhoid isolates ..rising incidence in Developed countries


Incidence of resistance to ciprofloxacin in isolates of S. typhi [UK, 2006]

Major concern..Antibacterial Resistance

Threlfall EJ. EID 2008;14[5]:860-1

Ciprofloxacin resistant Typhoid isolates rising incidence confirmed in India

Characterized by rising MIC levels [>0.25 mcg/ml]

MIC [mcg/ml]

>

S. typhi resistance to Fluoroquinolones in vitro Study, New Delhi


Indiscriminate use of the existing therapeutic options for enteric fever has resulted in growing incidence of resistance 31 ciprofloxacin resistant isolates were evaluated for sensitivity to advanced Fluoroquinolones & Azithromycin Most of these drugs showed raised MIC levels Advanced fluoroquinolones including Gatifloxacin showed resistance

Capoor MR. JMM 2007;56:1490-4

Rationale for combination in Typhoid fever

Why Combination ?
Due to the increasing incidence of resistance of the pathogens causing typhoid to the currently used therapies , there is a need of Using combination of drugs

The advantage of combination of drugs


Added synergy of the two drugs

Faster cure
Increases success rate Increased pt compliance

Overcome these challenges . By combining two different antibiotics

Ofloxacin + Cefpodoxime Rationale


Typhoid or Enteric fever is an endemic infection in India Fluoroquinolones with their intracellular action and longer half life offer quicker defervescence in such cases Drug of Choice Inadequate or Rampant use of these drugs has resulted in increased incidence of plasmid resistance to DNA gyrase Newer advanced fluoroquinolones too are resistant in such cases

Ofloxacin + Cefpodoxime Rationale


Second-line therapy including Ceftriaxone & Cefotaxime require parenteral administration Combination with Oral Cephalosporin offers complementary site of action taking care of resistant organisms when used in INITIAL LINE settings

Ofloxacin in Typhoid
Clinical efficacy

Studies by Yousuf (1992), Parry(2007) have demonstrated efficacy of Ofloxacin (200 mg or 10 mg/kg twice daily for 7 to 14 days) in uncomplicated Typhoid

9 pts with typhoid fever were given ofloxacin in a daily dosage of 400 mg for 10 days All patients recovered with no relapses No case of Salmonella typhi carriage was recorded. According to our results, ofloxacin could be

considered as one of the alternatives for treating


typhoid fever
J P Stahl etal. Pathologiebiologie (1986) Volume: 34, Issue: 5, Pages: 505-507

3rd generation cephalosporin Reaches therapeutic concentrations in respiratory tract and genitourinary tracts and bile (PI)

Cefpodoxime Proxetil Typhoid


Clinical efficacy

A study from Asian population has reported about


86% efficacy for cefpodoxime in the treatment of

typhoid fever.
In Bangladesh, where typhoid fever is also

endemic, a clinical trial showed cefpodoxime to be


highly efficacious in the treatment of typhoid fever
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 2008, p. 802803

Kefpod O
Composition
Each tablet of Kefpod O contains
Cefpodoxime 200 mg + Ofloxacin 200 mg

Ofloxacin
2nd generation fluroquinolone Bactericidal Acts on DNA Gyrase and topoisomerase IV Broad Spectrum S/E profile of ofloxacin is better than other

fluroquinolones

Ofloxacin
Ofloxacin is widely distributed to body tissues Between 65 % & 80% of an administered oral dose of ofloxacin is excreted unchanged via the kidneys within 48 hrs of dosing Usual dose of ofloxacin : 200-400 mg BD for 5-7

days

Cefpodoxime Proxetil
3rd Generation cephalosporin Bactericidal acts on the organisms by inhibiting bacterial cell wall synthesis Very active against gram positive and gram negative organisms Has excellent tissue penetration including bile and good half life The usual dosing is- 200 mg BD for 7-10 days

Cefpodoxime Proxetil
Expanded spectrum cephalosporins such as

Cefpodoxime Proxetil shows the promising


results in the management of typhoid

Cefpodoxime delivers the desired


characteristics of an antibiotic and may be the

treatment of choice for MDR typhoid fever

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 2008, p. 802803

Kefpod O
Cefpodoxime Proxetil 3rd generation cephalosporin Inhibits cell wall synthesis Ofloxacin 2nd generation Fluroquinolone Inhibits nuclear DNA gyrase for replication Benefits Complementary different site of actions & therefore more useful in tackling resistance

Broad spectrum including gm-ve organisms


Achieve therapeutic concentration in bile

Broad spectrum involving gm ve


Achieve therapeutic concentration in bile

Ideal for Typhoid

Target cell concentration achieved for immediate & sustained efficacy to prevent further resistance

200 mg BD

200 mg BD for Typhoid

Complementary BD dosage

Compatible Pharmacokinetic

Side Effects
Nausea, Vomiting, GI disturbances

Drug Interactions
Antacid, Theophylline, Warfarin

Indication :
Typhoid fever

Dosage:
1 tablet to be taken twice daily after meals for 714 days depending upon the severity of infections

USP OF Combination of Cefpodoxime and Ofloxacin


Synergistic effects of the drugs Faster cure Better success rate Less chances of relapse Less chances of Carrier stage Better patient compliance the patient has to take only one tablet as against 2 separately

USP OF Combination of Cefpodoxime and Ofloxacin


The combination would have good potential and

would be useful addition for the physician in the


treatment of typhoid including MDR Typhoid

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