4/16/2013 1 Pathophysiology and Diagnosis of Pathophysiology and Diagnosis of Thyphoid Fever Thyphoid Fever Iskandar Zulkarnain Division of Tropical Medicine and Infectious Diseases Departement of Internal Medicine Faculty of Medicine, University of Indonesia Dr. Cipto Mangunkusumo General Hospital Jakarta Typhoid Fever Typhoid Fever l Typhoid fever is an acute systemic infection caused by Salmonella enterica serotype typhi or paratyphi, characterized by constitutional and gastrointestinal symptoms Epidemiologic Distribution of Typhoid Fever
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Iskandar Zulkarnain - · PDF filePathophysiology and Diagnosis of ... Typhoid Fever lTyphoid fever is an acute systemic infection caused by Salmonella enterica serotype typhi or paratyphi,
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4/16/2013
1
Pathophysiology and Diagnosis of Pathophysiology and Diagnosis of Thyphoid FeverThyphoid Fever
Iskandar Zulkarnain
Division of Tropical Medicine and Infectious DiseasesDepartement of Internal Medicine
Faculty of Medicine, University of IndonesiaDr. Cipto Mangunkusumo General Hospital
Jakarta
Typhoid FeverTyphoid Fever
l Typhoid fever is an acute systemic infection caused by Salmonella entericaserotype typhi or paratyphi, characterized by constitutional and gastrointestinal symptoms
l Similar but often less severe disease is caused by Salmonella serotype paratyphi A & B.
l Contains 3 important antigens:1. O antigen: a lipopolysaccharide part of the cell wall. It is an
important pathogenic factor and is common for typhi and paratyphi species (group-specific)
2. H or flagellar antigen: strain specific; important in diagnosis
3. Polysaccharide capsule Vi: present in about 90% of all freshly isolated S. typhi and has a protective effect against the bactericidal action of the serum of infected patients.
S. typhiS. typhi
TransmissionTransmission
l Reservoir is chronic carriers: Organisms may live for months or years in the Gall Bladders of carriers and are passed intermittently in stool and less frequently in urine.
l Infection occurs by fecal-oral route. Common sources are infected water supply and polluted vegetables and food. Direct contact and insects as flies play a minor role.
l Occurrence of clinical disease depends on the amount of infecting organism.
Clinical features: symptomsClinical features: symptomsl Second week
Patient is more ill, prostrated with continuous high fever. Abdominal symptoms are more severe with jaundice in some cases. Others may have delerium or stupor.
l Third week Cure or Complications ?Untreated, patients may improve gradually or toxaemia increases and pass into coma (typhoid state). This is rare now and the course is modified by the early use of antibiotics.
0 5 7 14
Fever pattern in Typhoid Fever
High feverHeadacheAbdominal discomfortDiarrhea or constipationRelative bradicardia
Female 31 yo, fever since 2 weeks agoHb 9.3 L 1600 Ht 28 Tr 107.000Diff -/1/4/62/31/2 ESR 60 CRP 68Widal ty O 1/160 H >1/640 ty B H 1/160Treatment : Ceftriaxone 3g/dayGall culture - PCR S typhi +
l Culture: is essential for diagnosis. – Blood culture is positive in >70% in the first week and rate
of positivity declines thereafter. – Bone marrow aspirate culture gives the highest yield all
through the disease and should be performed in presence of a negative blood culture.
– Urine culture is positive in 10% temporarily in the first week. – Stool culture is positive in 30% in the 2nd and 3rd weeks but
is difficult and unreliable due to presence of other Salmonellae in stool.
Laboratory Diagnosis: Widal testAgglutination test that detects antibodies against S. typhi and paratyphi
in the patient’s serum. Involves reaction against 5 antigens : O antigen and H antigens of typhi
and paratyphi A, B & C; O antibodies appear on days 6-8 and H antibodies on days 10-12.
The role of Widal test in diagnosis of typhoid vever is complicated by:1. False negative results in up to 30% of culture-proven cases of typhoid
fever2. False positive results: S. typhi shares O and H antigens with other
Salmonella serotypes and has cross-reacting epitopes with other Enterobacteriacae
3. Results should be interpreted with care in accordance with appropriate local cut-off values for the determination of positivity which depends on endemicity of infection and application of vaccination.
l Definite- Positive gall culture or PCR Salmonella typhi - Widal serology agglutinin O titer > 1/640 or H titer >1/1280 - Increased of O titer twice or more
l ProbableWidal serology agglutinin O titer 1/320 or H titer 1/640.
TreatmentTreatmentl Non Pharmacologic : Bed Rest, Nutrition
l Pharmacologic : 1. Symptomatic & Supportive Treatment
2. AntibioticAmpicillin/Amoxicillin 2x750 or 3x500 mgCotrimoxasazole2 x 960 mgChloramphenicol 4 x 500mg / Tiamphenicol 4 x 500 mgCephalosporin : Ceftriaxone 3-4 g/daysFluoroquinolones : Ciprofloxaxin 2 x 500 mg
Clinical Trials of Typhoid FeverClinical Trials of Typhoid Fever
Amoxicillin in Typhoid fever study with twice Amoxicillin in Typhoid fever study with twice daily dosagedaily dosageHendarwanto, Nelwan RHH, Zulkarnain I, et alHendarwanto, Nelwan RHH, Zulkarnain I, et al
Drugs : Amoxicillin loading dose 2250mg then 2x750vs 3x 1000 oral for 14 days
Design : Open randomized controlledSubject : 25 vs 23 uncomplicated typhoid feverResults : Clinical efficacy 100%
Microbiological efficacy 88 vs 91% on day 3rd
100% in day 10th
Devervescens 6.8 vs 7.2 days
CLASSIFICATION OF FLUOROQUINOLONEGEN. NAME ANTIBACT. ACTIVITY
Gen I Nalidixic acid predominantly for enterobacteriaceae
Gen II Ciprofloxacin predominantly for gramPefloxacin negative bacteria & limitedOfloxacin gram positive bacteria
Gen III Levofloxacin ‘Broad spectrum’ activeSparfloxacin gram neg & pos,atypical
Gen IV Gatifloxacin 3rd generation plusMoxifloxacin anaerobesGemifloxacin
Fluoroquinolones for treating typhoid and paratyphoid fever (Cochrane Review)
Thaver D, Zaidi AK, Critchley J, Madni SA, Bhutta ZA
Main results:Compared with chloramphenicol, fluoroquinolones were not statistically
significantly different Compared with co-trimoxazole, we detected no statistically significant
difference Among adults, fluoroquinolones reduced clinical failure compared with
ceftriaxone but showed no difference for microbiological failure or relapse.
We detected no statistically significant difference between fluoroquinolones and cefixime orazithromycin
In trials of hospitalized children, fluoroquinolones were not statistically significantly different from ceftriaxone or cefixime
Authors' conclusions: Many trials were small, and methodological quality varied widely. Although enteric fever most commonly affects children, trials in this group were particularly sparse. Insufficient data in all comparisons preclude any firm conclusions to be made regarding superiority of fluoroquinolones over first-line antibiotics in children and adults.
Open Study of Efficacy and Safety 500 mg Once Daily Open Study of Efficacy and Safety 500 mg Once Daily Levofloxacin in Treatment of Uncomplicated Typhoid Levofloxacin in Treatment of Uncomplicated Typhoid FeverFever
R H H. Nelwan, Khie Chen, Nafrialdi
Division of Tropical Medicine and Infectious Diseases, Department of Internal Medicine, Medical Faculty
University of Indonesia/Dr. Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia.
Primary endpoint: Primary endpoint: efficacy and day of defervesecenceefficacy and day of defervesecenceSecondary endopoint :Secondary endopoint :SafetySafety
Design : Open StudyLocation : Dr. Cipto Mangunkusumo and Affiliated
Hospital in JakartaPeriod : October 2003 – April 2004 Subject : Uncomplicated Typhoid feverLevofloxacin (Daichi) 500 mg od (oral or iv) for 7 days.
Aims
Methods
Diagnostic criteriaDiagnostic criteria
l Definite :Positive gall culture or PCR Salmonella typhi Widal serology agglutinin O titer > 1/640
or H titer >1/1280 Increased of O titer twice or more
l Probable :Widal serology agglutinin O titer 1/320
Definite 20 4 excl other diagnosisProbable 9 AnalyzedClinical 11
Definite (n= 21 ) 70Positive Microbiological Blood Culture 4Positive Salmonella typhi PCR 8Positive S.typhi PCR & Blood Culture 1Widal agglutinin O titer 1/640 1Widal agglutinin H titer 1/1280 1Increasing Widal agglutinin O titer > 2 times 6
Probable (n=9) 30Widal agglutinin O titer 1 /320 7Widal agglutinin H titer 1/640 2
DISTRIBUTION OF SUBJECTS ACCORDING TO DIAGNOSTIC CRITERIA
Diagnostic criteria n %
CLINICAL RESULTS OF TREATMENT
Treatment results Definite cases Probable casesn % n %
Clinical efficacyResponse 21 100 9 100Failure 0 0
Defervescence on:1st day after treatment 4 19.0 1 11.12nd day after treatment 6 28.6 6 66.73rd day after treatment 10 47.6 1 11.14th day after treatment 0 1 11.15th day after treatment 1 4.8 0Mean (days) 2.43 2.22
* probably related **definitely related *** unlikely related
Adverse events n %
Results of Preliminary study of Levofloxacin Results of Preliminary study of Levofloxacin for uncomplicated typhoid feverfor uncomplicated typhoid fever
A preliminary open study of levofloxacin in treatment of uncomplicated typhoid fever showed that this drug was effective and relatively safe. The day of defervescence also quite short (mean 2.4 days).
ConclusionsConclusionsl Typhoid fever is an acute systemic infection caused by
Salmonella enterica serotype typhi or paratyphil Clinical manifestation include local symptoms in GI tract,
systemic manifestation and/or complicationsl Treatment include supportive and antimicrobialsl Antibiotics include :
Amoxicillin, Cotrimoxazole, Chloramphenicol, Ceftriaxone and fluoroquinolones (Cipro, Oflo, Flero,Peflo) are effective.
l Some complications possible include severe toxic, intestinal bleeding and perforation should be anticipated.