Management of resistant Typhoid fever : Management of resistant Typhoid fever ANUPAM MAITY
What is Enteric / Typhoid fever ??? : What is Enteric / Typhoid fever ??? It’s a systemic disease characterized by :
Fever and
Abdominal pain
and
Caused by :
S. Typhi
S. Paratyphi
Drugs Commonly used previously ( former 1st line drugs) : : Drugs Commonly used previously ( former 1st line drugs) : Chloramphenicol
Ampicillin
Amoxicillin
Co-trimoxazole
Resistance patterns : : Resistance patterns :
Typhoid epidemiology : Typhoid epidemiology
Prevalence of Drug resistance pattern of S.Typhi in India : : Prevalence of Drug resistance pattern of S.Typhi in India :
New emergent resistance pattern: : New emergent resistance pattern: In few parts of asia, mainly in South-East part, even in Northern India 3rd. Generation cephalosporin resistance has been noted.
Causes of resistance : : Causes of resistance : Inadequate duration of treatment.
Over the counter drug availability.
Prolonged carrier state, due to inadequate treatment.
Mechanism of resistance : : Mechanism of resistance : MDR is mediated by plasmid acquired from Escherichia coli or other gm (-)ve organism.
Chloramphenicol resistance by getting acetyl transferase-I which deactivate it byacetylation.
Quinolone resistance is frequently mediated by single point mutations in the quinolone-resistance–determining region of the gyrA gene (at drug binding site ).
Nalidixic acid resistant: MIC of fluoroquinolones for these strains was 10 times that for fully susceptible strains.
Management : : Management : INVESTIGATION FOR DRUG SENSITIVITY: Blood / Bone marrow /Stool should be cultured & put for antibiotic sensitivity.
OTHER INVESTIGATIONS :
Complete haemogram
S / U / Cr
Electrolytes
ECG
St. X ray abdomen
Serology etc.
Management Proper : : Management Proper : GENERAL MANAGEMENT :
Hydration ( oral / parenteral )
Antipyretics
Maintenance of Nutrition
90 % of patients can be managed in home with oral medications, reliable care, close medical monitoring for complications or failure to respond to therapy.
Hospital admission criteria : : Hospital admission criteria : Persistent vomiting.
Severe diarrhoea.
Abdominal distension.
─ For intravenous therapy.
Antibiotic therapy : : Antibiotic therapy : Select antibiotic by :
Efficacy.
Availability.
Cost ( in the perspective of 3rd world country).
Local resistance pattern.
Antibiotic therapy for Resistant typhoid fever: : Antibiotic therapy for Resistant typhoid fever:
Fluoroquinolones : : Fluoroquinolones : Excellent tissue penetration.
Kills S.typhi in intra cellular stationary stage in monocyte & macrophage.
Achieve higher active drug level in gall bladder than other drugs.
Rapid therapeutic response by clearance of fever & symptoms in 3 – 5 days.
Very low post-treatment carriage rate.
no evidence of the superiority of any particular fluoroquinolone
Fluoroquinolones : : Fluoroquinolones : Nalidixic acid & Norfloxacin should not be used as fluroquinolones as they have inadequate oral bioavailability .
DOSE SCHEDULE :
3rd. Generation cephalosporin : : 3rd. Generation cephalosporin : In place of Ceftriaxone , Cefotaxime can be used.
DOSE SCHEDULE :
AZITHROMYCIN : : AZITHROMYCIN : 1 gm /day or 1gm on 1st. Day followed by 500 mg/day for 6 days .
It should be taken in empty stomach.
Peak serum level after 500 mg oral Azithromycin is 0.4 μ/ml. but MIC of Azithromycin for 4 – 32 μg/ml. however its effective for enteric fever.
Why such paradox ?? : Why such paradox ?? Azithromycin gets 50 – 100 times more concentrated intracellularly than serum level.
But though S. Typhi is prototypically intracellular infection, only 2/3 rd remain intracellularly.
So, there is a chance of inefficacy for free living subpopulation of organism & chance of emergent resistance.
So, higher dose 1gm/day is preferable.
Treatment in pregnancy / lactation : : Treatment in pregnancy / lactation : Β- lactums are considered safest.
No data indicates Azithromycin is unsafe but alternative should be used if available.
Fluoroquinolones are not recommended.
Few important points : : Few important points : Efficacy of combination therapy is under trial.
Interestingly, combination of Ofloxacin + Azithromycin was found to be less efficacious than Azithromycin alone for Rx of NARST. (Parry CM, Ho VA, Phunong et al. 2007)
Never use Fluoroquinolones with Azithromycin as they can cause QT prolongation.
So, what should be the empirical therapy in India ?? : So, what should be the empirical therapy in India ?? Oral :
Cefixime or,
Azithromycin
I.V. :
Ceftriaxone
Typhoid meningitis : : Typhoid meningitis : Suspect , when CSF is normal but neck rigidity is present on the back ground of enteric fever.
Rx :
DEXAMETHASONE : 3 mg/kg by slow I.V. over 30 min. then 1mg/kg. 6 hrly. for 7 doses.
Mortality can be reduced by 80 – 90 %.
What lies ahead ??????? : What lies ahead ??????? Current available drugs ( 3rd gen cephalosporin, Azithromycin) are of limited in long run regarding there sensitivity / efficacy.
It may not be long before we are unwilling taken back to the pre antibiotic era, when S.Typhi took tool on mankind virtually unchallanged.
One HOPE !!!!!! : One HOPE !!!!!! RESENT ANTIBIOTIC RESISTANCE PATTERN
Older drugs are gradually become sensitive again………………….
Slide 26 : THANK YOU !!!!!!!