Rational Usage of Antibiotics in Typhoid

Fever

SUDIRMAN KATU

Division of Tropical Medicine and Infectious DiseasesDepartement of Internal Medicine

Medical Faculty of Hasanuddin Univesity 2013

A worldwide problem1

Associated with increased morbidity, mortality, and hospital costs1

Occurs in both hospitals and the community2

Antibiotic Resistance

1: R. A. Kulkarni et al. Indian J Surg. 2005: Volume 67(6): 308-315.2 Ben-David D, Rubenstein E. Curr Opin Infect Dis 2002;15:151-156.

“ Policy & Advocacy of IDSA; July 2004 “BAD BUGS, NO DRUGS

As Antibiotic Discovery Stagnates … A Public Health Crisis Brews

Current Problems of Bacterial Resistance

Consideration When Choosingan Antibacterial Agent

Microbiology Mechanism of action Antibacterial spectrum Bacterial mapping

DrugPK

Absorption Distribution Metabolism Excretion Optimal dosing regimen

Concentrationat infection site

Pathogen MIC

PD Time vs. concentration dependent killing Bactericidal vs. bacteriostatic activity Tissue penetration Persistence of antibacterial effect

Outcome Clinical efficacy Bacterial eradication Compliance with dosing regimen Tolerability Rate of resolution Prevention of resistance

(Scaglione, 2002)

Klasifikasi & Mekanisme Kerja AM

Dinding kuman Penisilin, Sefalosporin, Monobaktam, Karbapenem, Glikopeptida, Fosfomisin, Oxasolidine

Inhibisi biosintesis protein Aminoglikosida, Linkosamida, Makrolid, Tetrasiklin/Tygecyclin Kloramfenikol, As. Fusidik

As.folat antagonis Sulfa-Trimethoprim, Kotrimoksasol

Inhibisi b-laktam As.klavulanat, Sulbaktam, Tasobaktam

Sintesis As nukleat Rifampisin, As. Fusidik, Quinolon.

Membran sitoplasma Aminoglikosida, Polimiksin B, Kolistin, Amfoterisin B

Rational Antimicrobial Therapy

Drug

Patient

Micro-organism

Microbiologist

Clinician/Farmakologis

Factors in Choices of Antibiotics:Drug Interactions

Drug interaction Plasma: Competitition for protein binding sites

Receptor sites:Drugs may compete

at binding site

Liver:Induction of liver enzymes -

modified excretion

Kidney:Effect on passive

readsorbtion & active secretion

Bowel: Other drug or food modifies absorbtion

IV fluids:incompatible

drug mixtures

Examples of Antibiotics-Drugs Interactions

IV fluids Many Many - Do not mix IV fluids

Site Antimicrobial Interacting drug/effects

GI tract TetracyclinesQuinolones

Absorbtion by food Absorbtion reduced by iron

Protein bindingChloramphenicolCo-trimoxazole

Warfarin (antiocoagulant), Sulpho-ureas effects

Liver enzymeinduction

Rifampicin Oral contraceptive, warfarin, antidiabetics, cyclosporin, etc, metabolism , i.e., effect

Kidney Amino-glycosides

Loop diuretics (frusemide) ototoxicity

Antibiotic Usage in Clinical Practice

Empirical therapyDefinite therapy

ProphylaxisPre-emptive

1. Immunocompetence2. Immunodeficiency / immunocompromized :

Imunocompromise Primer :Immunocompromized Secunder :

• Neutropenia• Neoplasm • Cytotoxic agent• Diabetes• Drugs user, Alcoholic• Elderly, neonatal, pregnancy and purpureum• Dialysis, implants/ prostheses

Who is the Host ?

Factors Involved in Optimal Initial Antibiotic Therapy

Optimal

Therapy

Pathogen

coverage

Correct dose

Timely initiatio

n

Correct route

Increased survival

Impact of the appropriateness of antibiotics therapy on mortality of Gram-negative

bacteremia84

42

10

28

85

67

29

49

0

30

60

90

Rapidly fatal Ultimately fatal Nonfatal total

Mortality with appropiate Abs

Mortality without appropiateAbs

P<0.001

P<0.001

P<0.001

NS

Bochud PY. Intensive Care Med 2001;27:s33-8

Antimicrobial Treatment based on Microbiological Culture Results

Microbiological culture results

Colonization Pathogen

No treat Sensitive Resistant

Treat with Antibiotics Optimized

Recommended Combination PKPD

Antibiotics

Control of Antibiotic UsageAvoid antibiotic homogeneityPromote appropriate use of multiple drug classApply formulary control and restrict of specific agent or drug class that resistant Consider antibiotic cycling, rotation or mixed use of antibiotic classesDevelop and promote antibiotic guidelines and protocol based on local data

Antibiotic PolicyClassification of antibiotics

Class A : Not restricted Class B : Not restricted, under

supervision Class C : Restricted

ImplementationEvaluation and surveillanceAuditing

Classification of Antibiotics Class A Class B Class C

Aminoglicoside PenicillinCephalosporin gen.I,IIChloramphenicolFucidic acidLincosamideMacrolideNitroimidazolFluoroquinolone gen.I,IITetracylineTMP-SMXFosfomicin Polypeptide

Cephalosporine gen IIIFluoroquinolone gen III-IVSulperazoneErtapenemAztreonamVancomycin

TeicoplaninLinezolideCefepimeCefpiromeCeftazidimePip-TazoCarbapenemTygecicline

Implementation of Antimicrobial Policy in Hospital

Community Hospital

Outpatient Class A Class A

Inpatient

Class B

Class B/C

Class C

Class C

WARD

Mild Moderate Severe

ICU

Evaluation category of Antibiotics Usage by Gyssens

I. Correct UsageII. Incorrect due to:

a) Incorrect dose b) Incorrect interval c) Incorrect routeIII. Incorrect due to:

a) duration too long b) duration too shortIV. Incorrect due to: Alternative drug that is

a) more effective b) less toxic c) cheaper d) more specificV. No IndicationVI. Medical record is insufficient to be

evaluated

Evaluation and SurveillanceSurveillance of every inpatient ward, intensive care ward, and surgery room periodically, e.g. monthly surveillance in internal medicine wardReport of surveillance periodically, e.g. report of surveillance in internal medicine ward every 6 months

AuditingPeriodically done by antibiotic team (multi department), commissioned by management of hospitalAudit of medical records, copy of prescriptions Percentage of compliance to antibiotic guideline Reward and punishment

ANTIBIOTICS FOR TYPHOID FEVER(KONSENSUS PETRI 2010)

AB DOSE FREK

ROUTE

DURATION SE

MILD SEVEREKLORAMFENICOL

• 50-100 mg/kgBB/hr

• 30 mg/kg BB /hr (fever -)

4 O/IM/IV Fever & 7 days fever (-)

Fever & 7 days fever (-)

Bone marrow deppression

THIAMFENICOL

50 – 100 mg/kgBB/hr

4 O Fever & 7 days fever (-)

Tidak direkomendasikan

-

AMPISILLIN & AMO

Chloramphenicol The recommended dose is 50 - 75 mg divided into four doses

per kg per day for 14 days , or for at least 5 to 7 days after defervescence.

Oral administration gives slightly greater bioavailability than IM or IV route.

Chloramphenicol has been for decades the drug of choice for typhoid fever and is still used in many endemic areas

The disadvantages of its use include a relatively high rate of relapse (57%), long treatment courses (14 days) and the frequent development of a carrier state in adults.

Treatment

TreatmentFluoroquinolones Optimal for the treatment of typhoid fever Relatively inexpensive, well tolerated and more rapidly and

reliably effective than the former first-line drugs, viz. chloramphenicol, ampicillin, amoxicillin and trimethoprim-sulfamethoxazole. Microbial resistance is increasing against these agents especially in India and Southeast Asia.

The majority of isolates are still sensitive. Attain excellent tissue penetration, kill S. typhi in its intracellular

stationary stage in monocytes/macrophages and achieve higher active drug levels in the gall bladder than other drugs.

Rapid therapeutic response, i.e. clearance of fever and symptoms in 3 to 5 days, and very low rates of post-treatment carriage.

Fluoroquinolones Ofloxacin 400mg BID, ciprofloxacin 750mg BID, Levofoxacin 500mg

BID. Quinolones are contraindicated in children (<17y old) and pregnant women. Resistance to quinolones is emerging.

Cephalosporins Ceftriaxone: 50-75mg/kg/day one or two doses Cefotaxime: 40-80mg/kg/day in 2-3 doses Cefoperazone: 50-100mg/kg/day

Other antibiotics:- Trimethoprim-sulfamethoxazole is still considered by some the drug

of choice.- Azithromycin has been shown effective in uncomplicated cases and

can be used for multiresistant strains.

Treatment

Clinical Trials of Fluoroquinolones in Typhoid fever

Invest Year Medication Treatment number Clinical BacterialIgator duration cases efficacy efficacy

Arnold 1993 FLX 14 35 100 96Nelwan 1993 PEF 7 20 100 100Hien 1994 FLX 7 16 100 100Nelwan 1994 OFL 7 12 100 100Nelwan 1995 CIP 6 31 100 100Duong 1995 FLX 5 41 97.5 94Duong 1995 FLX 3 22 100 100Nelwan 1997 FLX 3 4 100 100

Group beta-lactam non-cephalosphorins– Ampicillin : 4 (50%)– Aztreonam : 4 (75%)

Group cephalosphorins– Cephalothin : 4 (0%)– Cephopherazone : 3 (100%)– Cefotaxime : 4 (75%)– Ceftriaxon : 4 (100%)

Quinolones– Ciprofloxacin : 4 (100%)– Levofloxacin : 4 (100%)

Others antibiotic– Chloramphenicol : 3 (100%)– Cotrimoksazole : 4 (100%)– Azythromycin : tidak ada data

Antimicrobial Sensitivity in Typhoid fever(RSCM/FMUI Januari - Juni 2011

COMPARISON OF DEFERVESCENCE IN TYPHOID FEVER

Name of Drug Dosage Duration Fever Clearance

Ciprofloxacine(5) 500 BID 6 days 3,60 days

Ofloxacine(6) 600 mg OD 7 days 3,40 days

Pefloxacine(7) 400 mg OD 7 days 3,10 days

Fleroxacine(8) 400 mg OD 5 days 3,4 days

Treatment of uncomplicated typhoid

Treatment of severe typhoid

MDRST 1 :– Ciprofloxacin / Levofloxacin – Third generation cephalosporin

MDRST 2 :– Monobactam (Aztreonam) -> India , Korsel– Carbapenem

TREATMENT OF MDRST

John Wine, J Infect Developing Countries 2008Yonsei Med J 50(1):147 - 151, 2009

ConclusionsTypes of antibiotic usage in typhoid fever: definite and prophylaxisRational antibiotic therapy: rapid, appropriate, cost effectiveThe implementation of antibiotic policy to promote: • rational use of antibiotics, • cost-effective therapy, • prevent collateral damage • Prevent of MDRST

Antimicrobial Combination: When we need?

Unknown focus of infectionPolymicrobial infection, eg: abscess caused by multiple aerob and anaerob organismsDecrease resistance rate, eg: Tb treatment Decrease dose related toxicityIncrease antimicrobial potency

Chambers HF. Antimicrobial agents. 2001

Strategy in Managing MDR

Treat pathogen not colonizationBased on local susceptibility dataMonotherapy or combinationOptimalization PK/PDConsidered comorbidities, organ functionPrevent transmission