Role of CipValTM in Typhoid

Typhoid fever

• Typhoid Fever is caused by salmonella typhi. [1]

– Characterized by: fever, headache, myalgia,

bradycardia, constipation (diarrhoea & vomiting).
[2]

– Spread by contaminated food & water. [3]

• Associated with significant mortality rate, estimated

22 million cases of enteric fever with 200,000 deaths
in 2002. [4]

• With improvements in food handling & water/sewage

treatment, enteric fever has become rare in
developed nations. [4]

1. Davidson’s Principle & Practice of Medicine – 18thEdition Pg:123

2. Davidson’s Principle & Practice of Medicine – 18thEdition Pg:124
3. Harrison’s Principle of Internal Medicine – 17th Edition Pg:959
4. Harrison’s Principle of Internal Medicine – 17th Edition Pg:957
 Typhoid fever

• Prompt administration of appropriate antibiotic

therapy prevents complications of enteric fever &
reduces case fatality rate of <1%. [1]

1. Harrison’s Principle of Internal Medicine – 17th Edition Pg:958

 Distribution and Incidence
• Incidence is highest in south-central & south-east Asia, medium
in the rest of Asia, Africa, Latin America & Oceania & low in
other parts of the world. [1]

• In endemic regions, enteric fever is more common in urban than

in rural areas & among young children & adolescents.[1]

• The mortality of untreated typhoid can be as high as 30%

whereas with appropriate anti-microbial therapy it is <1%. [2]

• It is estimated that there is one case of paratyphoid fever for

every four cases of typhoid fever, but incidence of infection
associated with S.paratyphi A appears to be increasing. [1]

1. Harrison’s Principle of Internal Medicine – 17th Edition Pg:957

2. J. Med Microbiol, Vol. 44 Pg: 317-319, 1996 The Pathological Of Great Britain & Ireland.
 Method of Transmission

• Ingestion of contaminated food, milk or water. [1]

• Infected shellfish are occasionally responsible for an

outbreak. [1]

• The bacilli may live in the gallbladder of carriers for

months or years after clinical recovery & pass
intermittently in the stool & less commonly in the
urine. [1]

1. Davidson’s Principle & Practice of Medicine – 18thEdition Pg:123

 Patterns of disease in Community

• In Developed Countries:
• It is a rare imported infection in developed
countries. [1]

• In Developing Countries;
• A major problem because safe water supply,
environmental sanitation & food hygiene are not
optimal. [1]
• Because of difficulties in preventing typhoid by
public health measures or immunisation in
developing countries great reliance is placed on
anti-microbial chemotherapy. [1]

1. J. Med Microbiol, Vol. 44 Pg: 317-319, 1996 The Pathological Of Great Britain & Ireland.
 Pathology in the Intestine

• Four classic pathologic stages: [1]

 Phase 1: hyperplasia of lymphoid follicles [1]

 Phase 2: necrosis of lymphoid follicles during 2nd

week. [1]
 Phase 3: ulceration in the long axis of bowel. [1]

 Phase 4: healing from the 4th week onwards. [1]

1. Journal, Indian Academy of Clinical Medicine Vol. 2, No. 1 & 2. January-June 2001
 Pathogenesis
S. typhi [1]
S.Typhi Incubation period
(7-14 days)

Primary bacteremia Secondary bacteremia

Small Intestine

7-10 days 7-10 days 7-10 days 7-10 days

Mesenteric Fever
Lymph Nodes

Liver
Spleen
Blood Gall bladder Onset of Antibodies
Kidney
Bone M symptoms appear

1. Taken from PDA, Ref # 5, Zulfiqar Bhutta A.et al. “Typhoid fever during childhood in South Asia: A review” JCPSP 2002,
Vol.12 (6): 372-380.
 Clinical Manifestations
• First week: [1]
Fever, headache, myalgia, bradycardia, constipation(diarrhoea
& vomiting). [1]

• End of first week: [1]

Rose spots on trunk, spleenomegaly, cough, abdominal
distention, diarrhoea. [1]

• End of second week: [1]

Delirium, complications, then coma & death (if untreated). [2]

1. Davidson’s Principle & Practice of Medicine – 18thEdition Pg:124

 Symptoms on Admission [1]

• Fever 99% • Cough 30%

• Weakness 99% • Vomiting 18%
• Anorexia 55% • Myalgias 20%
• Headache 80% • Arthralgias 2-4%
• Dizziness 80% • Coated tongue 51-56%
• Abdominal pain 30-40% • Spleenomegaly 5-6%
• Nausea 18-24% • Abdominal 4-5%
• Chills 35-45% tenderness
• Diarrhea 22%-28% • Melana 12%
• Constipation 13-16% • Epistaxis 10%
• Sweating 20-25% • Malaise 10%

1. Harrison’s Principle of Internal Medicine – 17th Edition Pg:958

 Complications and unusual manifestations
• Development of severe disease which occurs in 10-
15% of patients depends on host factors such as;
immunosupression, antacid therapy, previous exposure
& vaccination. [1]

• Gastrointestinal bleeding (10-20%) [1]

• Intestinal perforation (1-3%) most commonly occurs in

3rd & 4th week of illness & results from hyperplasia,
ulceration & necrosis of ileocecal peyer’s patches at the
initial site of salmonella infiltration. [1]

• Neurologic manifestations occurs in 2-40% of patients

& include meningitis, Guillain Barre syndrome, neutitis &
neuropsychiatric symptoms. [1]
1. Harrison’s Principle of Internal Medicine – 17th Edition Pg:958
 Diagnosis: Isolation of Organisms
 Blood cultures: the yield of blood cultures is quite
variable; sensitivity is high as 90% during 1st week of
infection & decreases to 50% by 3rd week. [1]
 Bone marrow cultures: remains highly sensitive
(90%) despite <5 days of antibiotic therapy. [1]
 Culture of interstitial secretions
Can be positive despite a negative bone marrow
culture.[1]

 Stool cultures: negative in 60-70% of cases during

the 1st week, can become positive during 3rd week of
infection in untreated patients. [1]

1. Harrison’s Principle of Internal Medicine – 17th Edition Pg:958

 Diagnosis: Serological
1) ANTIBODY DETECTION: [1]
 Widal test: A four-fold rise in the titres of H(falgellar) or
O(somatic) agglutinins indicate a strong likelihood of
disease (2 specimen required). [1]
 Dot Enzyme Immunoassay: for rapid retection of salmonella
typhi IgM & IgG antibodies. [1]
2) ANTIGEN DETECTION: [1]
 CIE(Counter Immunoelectrophoresis): detects
S.typhi O antigen. [1]
 Rapid latex agglutinin test. [1]
3) PCR(Polymerase Chain Reaction) OF BLOOD [2]

1. Journal, Indian Academy of Clinical Medicine Vol. 2, No. 1 & 2. January-June 2001
2. Harrison’s Principle of Internal Medicine – 17th Edition Pg:958
 Widal Test
• Widal reaction detects antibodies to the causative
organism. However, it is not a reliable diagnostic test &
should be interpreted with caution, particularly in typhoid
vaccinated patients. [1]

• In salmonella infection, it relies on patients antibodies to

the O=9, 12 LPS antigens, H=d flagellar antigens & Vi
capsular antigens. [2]

• A Vi agglutinin titre of >1/40 has traditionally been

regarded as indicative of recent infection with S.typhi. [2]

1. Davidson’s Principle & Practice of Medicine – 18thEdition Pg:124

2. Journal of Clinical Pathology 2000 53: 851-853
 Dot Enzyme Immunoassay (Typhidot)

• EIA detects specific IgM & IgG antibodies to salmonella

typhi.[1]

• The detection of IgM reveals acute typhoid in the early

phase of infection, while the detection of both IgG & IgM
suggests acute typhoid in the middle phase of infection. [1]

• The test is reported to be 95% sensitive. [1]

• The EIA offers simplicity, speed, specificity(75%), economy,

early diagnosis & high negative & positive predictive values.
[1]

1. Indian J Med Res 123, April 2006, pp 489-492

The Management
 Chloramphenicol, ampicilin & co-trimoxazole are
important therapies but are losing their effect due to
resistance in many areas of the world. [1]

1. Davidson’s Principle & Practice of Medicine – 20thEdition Pg:325

 WHO criteria for the selection of Antimicrobial therapy 1

Following are important criteria for the selection of first-line

antibiotics to be used in developing countries.

• Efficacy
• Availability
• Cost

1.Background document: The diagnosis, treatment and prevention of typhoid fever. World Health Organization 2003
In line of the WHO criteria & GSK’s Value Health
initiative, Cipval TM(ciprofloxacin) provides
ACCESS to high quality ciprofloxacin to a
large number of Typhoid and Infective diarrhea
patients at an affordable price.
 Susceptibility of Ciprofloxacin (Cipval)TM
for Salmonella is 100%1

All Salmonella strains were found to be

sensitive to Ciprofloxacin (Cipval)TM 1

1. Antimicrobial Agents and Chemotherapy, May 2003, p 1727-1731

 Clinical Cure Rate with Ciprofloxacin (Cipval)TM[1]

1.Taken from PDA, Ref #11, Antimicrobial Agents & chemotherapy , May 2003, p 1727-1731.
 Treatment of Choice

The Fluoroquinolones remain the drug of choice i.e.

Ciprofloxacin (Cipval)TM 500mg 12 hourly [1]

Ciprofloxacin dosage for typhoid [2]

500 mg
b.i.d.

7 days
Short duration of therapy

1. Davidson’s Principle & Practice of Medicine – 20thEdition Pg:325

2. Taken from PDA, Ref #10, Harrison’s principles of internal medicine, 17th Edition. 2008, pg 958-959
Pricing

M.R.P
CipvalTM(ciprofloxacin)250 mg (10’s) Rs.130/
Cipval (ciprofloxacin) 500 mg (10’s)
TM Rs.215/
 Cipval TM(ciprofloxacin) offers:

• Broad spectrum coverage.1

• High clinical success rates.2, 3
• Convenient BD dosage.1
• GSK quality with affordability.

1. CIPVAL Data Sheet.

2. Antimicrobial Agents and Chemotherapy, May 2003, p 1727-1731
3. S S W Chan, Acute bacterial gastroenteritis, Emerg. Med. J. 2003;20;335-338
Thank you