1

Update on Treatment of Typhoid Fever with Fluoroquinolon

Prof. Prof. ddr. R.H.H. NELWAN, r. R.H.H. NELWAN, DTM&H, DTM&H, SpPDSpPD--KPTIKPTIDIVISI PENYAKIT TROPIK DAN INFEKSI

DEPARTEMEN ILMU PENYAKIT DALAM FKUI / RSUPN-CM

JAKARTA

1. Fluorokuinolon (FQ)2. FQ untuk DT§ Study terbuka§ Levo vs Cipro

Group I Group II Group III Group IVMonocyclic

derivateRO-145478

Bicyclic derivate Tricyclic derivate

Tetracyclic derivate

RO-149678KE-5246

MF 961MertofloxacinVerbafloxacinNeoquinoronCP 91121Pufloxacin

FluorinatedNon-FluorinatedTionic acidOxolinic acidMiloxacinEN 272DJ 6783Droxacin

FlumequineAbuloxacinOfloxacinRuloxacinS-25932OA-241DN 9494A-62824Levofloxacin

Group II B5-Membered ring

Group II B3-Membered ring

II A - 11.8 Napthycline

II A – 2Pyrido (2.3.0)Pyrimidine

II A - 3

Non-Fluorinated Fluorinated

Nalidixic acid

7-PiperacineEnoxacinA-57132

7-PyrolidineAT 3296AT 3786TosufloxacinA-85485BWY 4336BWY 41602U 91909E

OthersBWY 40062E-3499CP 99219CFC-222

Pipemidic acidPiramidic acid

Pyridol (2.34)Piyrazine

Non-FluorinatedFluorinated

AcruxacinWN 36438Piroxacin

OthersY-28024BirfloxacinY-20611 etc

7-pynilPinfloxacinE 3624etc

7-pyrolidinePO 117546Cinefloxacinetc

7-piperazineNorfloxacinPefloxacinDifloxacinSparfloxacinLomefloxacinCS 940etc

Chemical Classification of the Quinolone Derivates

Controls GABA binding,

theophylline interaction

Influences phototoxicity and genetic toxicity

Metal binding and chelation – controls interaction with antacids, milk, iron; divalent cation

OORR55 OO

OOHH

NN11CC88 RR22

RR11

RR77

FF

RR22

FF

RR11

RR77

5566 44

33

2277

Effect of F group on side-effect profile has not

been reported

Controls phototoxicity

Controls theophylline interaction and genetic toxicity

No side effects associated with

this position

CHEMICAL STRUCTURES OF LEVOFLOXACIN AND OFLOXACIN

COOHCOOHCOOHCOOHOO

FF

NN

OO

FF

NN

CHCH33

NNHH

OO

CHCH33

NN

OO

HH33CC--NN

Levofloxacin Ofloxacin

HH33CC--NN HH

HH

2

CLASSIFICATION OF FLUOROQUINOLONE

ClinClin Inf. Inf. DisDis, 2000; 31:47, 2000; 31:47-- 8282

GEN.GEN. NAMENAME ANTIBACT. ACTIVITYANTIBACT. ACTIVITY

Gen IGen I NalidixicNalidixic acidacid predominantly for predominantly for enterobacteriaceaeenterobacteriaceae

Gen IIGen II CiprofloxacinCiprofloxacin predominantly for grampredominantly for gramPefloxacinPefloxacin negative bacteria & limitednegative bacteria & limitedOfloxacinOfloxacin gram positive bacteriagram positive bacteria

Gen IIIGen III LevofloxacinLevofloxacin ‘‘Broad spectrum’ activeBroad spectrum’ activeSparfloxacinSparfloxacin gram gram negneg & & pos,atypicalpos,atypical

Gen IVGen IV GatifloxacinGatifloxacin 33rdrd generation plusgeneration plusMoxifloxacinMoxifloxacin anaerobesanaerobesGemifloxacinGemifloxacin

MECHANISM OF ACTION

Double helix DNADouble helix DNA

Strained supercoiling / overwindingStrained supercoiling / overwinding

DNA gyraseDNA gyrase

Negative supercoil double helix DNANegative supercoil double helix DNA

Topoisomerase IVTopoisomerase IV

Replication transcriptionReplication transcription

DeathDeath

Hooper DC Hooper DC ClinClin Infect Infect DisDis 1998 ; 27 (1998 ; 27 (supplsuppl I) : S54I) : S54--6363

Half-life (h)

Body fluid & tissue Dose (mg) n

Time after administratio

n (h)

Concentrations (ug/ml or g)

Sputum 100 2 2.2 - 3.1

Sputum 200 2 3.0 - 3.4

Saliva 100 8 0.77 - 1.70

Salivary gland 100 1 - 3 2 - 8

Otorrhea 100 3 2

Intratympanic cavity mucosa 100 3 1 - 2

Maxillary sinus mucosa 100 2 2 - 6

Ethmoidal sinus mucosa 100 1 1

Frontal sinus cystic tissue 100 1 1

Palatine tonsil 100 24 2 - 6

Parotid gland 100 4 2 - 5

Submandibular gland 100 3 2 - 8

MIC90 against main causative pathogens (ug/ml)

0.050.05 0.10.1 0.20.2 0.390.39 1.561.560.780.78 6.256.253.133.13

1.021.02--1.291.293.113.11--4.234.23

1.091.09--1.511.51

0.190.19--0.770.77

0.840.84--1.371.37

0.540.54--1.061.060.190.19--1.371.37

0.040.04--0.850.85

<0.01<0.01--1.211.21

0.840.84

0.780.78--1.061.06

4.104.10

0.0060.006 0.050.05 0.10.1 0.20.2 0.780.780.390.39 1.561.56 3.133.13 6.256.25

H. influenzaeH. influenzaeN. gonorrhoeaeN. gonorrhoeae

E.coliE.coliK. K. pneumoniaepneumoniaeB. catarrhalisB. catarrhalisP. mirabilisP. mirabilis

S. aureusS. aureusS. epidermidisS. epidermidis C. trachomatisC. trachomatis

S. pneumoniaeS. pneumoniaeP. aeruginosaP. aeruginosa

Antibiotic Cyst concentration Serum concentration Cyst : serum ratio

Levofloxacin 4.4 ug/ml 4.6 ug/ml 0.96

Ampicillin 20 ug/ml >50 ug/ml < 0.40

3

†Single 500-mg or 750-mg oral dose.LEVAQUIN Tablet s/Inject ion Prescribing Information, November 2000.

Pharmacokinetic Properties of Levofloxacin

§§ CCmaxmax 5.1 µg/mL5.1 µg/mL§§ TTmaxmax 1.3 h1.3 h§§ tt1/21/2 6.3 h6.3 h§§ AUCAUC 47.9 µg/mL h47.9 µg/mL h§§ Oral BioavailabilityOral Bioavailability 99%99%§§ EliminationElimination RenalRenal

500 500 mg POmg PO500 mg IV500 mg IV

Time (h)Time (h)

88

66

44

22

00

00 66 1212 1616 2424 3030 3636

Plas

ma

Con

cent

ratio

n (

Plas

ma

Con

cent

ratio

n (µµ

g/m

L)g/

mL) SERUM CONCENTRATION

0

0.5

1

1.5

2

1/0/00 1/25/00 2/19/00

Time after administration (h)

Seru

m c

once

ntra

tion

Healt hy adult s* (Ccr ≥ 70 mL/ min;n=5)

Group I : patient s with mild renaldysfunction (Ccr 40-69 mL/min; n=7)

Group II : patients with moderaterenal dysfunct ion (Ccr 20-39mL/min; n=11)Group III : patient s wit h severe renaldysfunction (Ccr < 20 mL/min; n=5)

24 48 72

URINARY EXCRETION

0

50

100

1/ 2/ 00 1/ 25/ 00 2/ 17/ 00 3/ 11/ 00

Time after administration (h)

Cum

ulat

ive ex

cret

ion

rate

Healthy adults* (Ccr ≥ 70 mL/min;n=5)

Group I : patients w ith mild renaldysfunction (Ccr 40-69 mL/min;n=7)

Group II : patients w ith moderaterenal dysfunction (Ccr 20-39mL/min; n=11)

Group III : patients w ith severerenal dysfunction (Ccr < 20mL/min; n=5)

24 48 72

Dose Plasma conc Tissue/Fluid conc Ratio

500 mg 4.1 27.7 (alv. makrofag) 6.8

500 mg 2.93 11.3 (lung) 5.0

500 mg 4.1 10.9 (epithel) 3.0

200 mg 1.73 1.85 (skin) 1.1

100 mg 1.10 1.27 (sputum) 1.1

500 mg mg/L 130 (urine) 37.8

Pathogenesis of Typhoid Fever

Open Study on Efficacy and Safety of Levofloxacin in Treatment of

Uncomplicated Typhoid Fever

RHH Nelwan1, Khie Chen1, Nafrialdi2, and Diana Paramita3

1Divison of Tropical and Infectious Diseases, 2Department of Internal Medicine, Medical university, University of Indonesia/dr. Cipto Mangunkusumo National General Hospital, Jakarta ; 3Department of Internal Medicine, Persahabatan Hospital, Jakarta, Indonesia

4

Subject Characteristic (n=30)

n %Sex- Male- Female

1119

36.763.3

Age- <20- 21-30- 31-40- 41-50- >50

5121012

16.740.033.33.36.7

n %

Fever before tx (mean 6.1 days)- <4 days- 4 days- 5 days- 6 days - 7 days- 8 days- 9 days- 10 days

35634612

1016.72010

13.3203.36.7

Definite Cases Probable Cases

n % n %Clinical EfficacyClinical EfficacyResponseResponse 2121 100100 99 100100FailureFailure 00 00

Defervescence on:Defervescence on:Day 1Day 1 44 1919 11 11.111.1Day 2Day 2 66 28.628.6 66 66.766.7Day 3Day 3 1010 47.647.6 11 11.111.1Day 4Day 4 00 11 11.111.1Day 5Day 5 11 4.84.8 00Mean Mean (days)(days)

2.432.43 2.222.22

Clinical Result of Treatment A Single Blind Comparative Randomized Multi Centre Study

for Efficacy and Safety of Levofloxacin vs Ciprofloxacin

In the Treatment of Typhoid Fever

R.H.H. Nelwan, et.al

Name of Drug Dosage Duration Fever Clearance

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

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

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

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

Levofloxacin 500 mg OD 7 days 2,43 days

Comparison of Defervescencefrom Several Typhoid Studies

Typhoid Fever : Levo vs Cipro

SPECIFIC OBJECTIVE TO DETERMINE

• Clinical efficacy of levofloxacin vs ciprofloxacin

• Bacteriological efficacy of levofloxacin vs ciprofloxacin

• Defervescence time of levofloxacin vs ciprofloxacin

• Safety of levofloxacin vs ciprofloxacin

Typhoid Fever : Levo vs Cipro

Inclusion Criteria

5

Typhoid Fever : Levo vs Cipro

Exclusion Criteria

1. Pregnant or breast feeding female2. Serum creatinin > 1.4 g/dL3. History of adverse reaction or known allergy to

quinolone antibiotics4. Suspected infection or terminal illness with fatal

outcome within 48 hours5. Serious underlying illness, including

immunocompromised and/or neutropenic patients6. History of convulsive disorders7. History of photosensitivity reactions8. Previously been enrolled in this study9. Received and will continuou to receive theophylline

or walfarin preparation10. Severe or complicated typhoid fever that in the

opinion of the Investigator would require more than 7 days of therapy/hospitalization.

Confirmed Typhoid Fever * Confirmed Typhoid Fever * 110110

Probable/clinical Probable/clinical Typhoid FeverTyphoid Fever

102102LevofloxacinLevofloxacin

5454

Total Enrolled: Total Enrolled: 212212 casescases

Distribution of PatientsDistribution of PatientsJune 2006June 2006

CiprofloxacinCiprofloxacin5656

* By m.o. culture, PCR or 4 foldincreased serologic t iters andtiters ≥ 640 for titer O or HSal m o nel l a t h yp i ant ig en

DO DO 11

EvaluableEvaluable5353

DODO11

Other Other 11

Evaluable Evaluable 5454

Levofloxacin (n=53)

Ciprofloxacin (n=54)

M : F Ratio (26 : 27) (25 : 29)Mean AGE (Range) 25.1 (18-53) 26.6 (18-54)Mean Duration of Fever 7.7 days 7.5 daysMean Clinical Score 10.7 point 9.8 point

BaselineNo of patients

Levofloxacin (n=53)

Ciprofloxacin (n=54)

Microbiology Culture 11 14Polymerase Chain Reaction 19 16Serology (Widal Test) 23 24

Diagnosis byNo of patients

*S. Typhi titer O/H >640 or 4 – fold increase**No statistical difference (p>0.05)

Levofloxacin (n=53)

Ciprofloxacin (n=54)

Day 1 1 1Day 2 13 11Day 3 26 12Day 4 9 7Day 5 3 7Day 6 1 4Day >6 0 12Mean 3 5

No of patientsDays

Clinical Efficacy Levo vs Cipro

Levofloxacin (n=53)

Ciprofloxacin (n=54)

Average Defervesence 3 5Fever free at Day 7 100% 77,8%Clinical Relapse 1 1Others (Relapse) 0 1

Clinical EfficacyNo of patients

6

Microbiological Efficacy Levo vs Cipro

Levofloxacin (n=53)

Ciprofloxacin (n=54)

Clearance S. typhi at D7 (Blood)

100% 85.70%

Clearance S. typhi at D7 (Stool) 100% 92.90%

Bacteriological Relapse None 2 casesCarrier at Day 30 None None

Microbiological EfficacyNo of patients

Levofloxacin (n=54)

Ciprofloxacin (n=56)

Nausea (NS) 5 4Vomit (VM) 1 2NS + VM 0 4Epigastric pain 0 2Insomnia 4 2Cephalgia 0 1

No of patientsAdverse Reaction

Comparison of Adverse Reactions Comparison of Unwanted Laboratory Reactions

Levofloxacin (n=54)

Ciprofloxacin (n=56)

Hematologic None NoneRenal None NoneHepatic* 2 6

Laboratory ReactionNo of patients

* More than 3 times increased of initial value

A 7 days oral regimen of Levofloxacin500 mg daily versus twice daily Ciprofloxacin 500 mg for uncomplicated Typhoid fever in Indonesia showed superior fever clearance, superior microbiological result and less adverse reactions for Levofloxacin compared to Ciprofloxacin

Advances in Microbiology, 2013, 3, 122-127