Update on Treatment of Typhoid

Fever with Fluoroquinolon

Prof. dr. R.H.H. NELWAN, DTM&H, SpPD-KPTI

DIVISI 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 IV
Monocyclic Bicyclic derivate Tricyclic Tetracyclic
derivate derivate derivate
RO-145478 RO-149678
Non-Fluorinated Fluorinated KE-5246
Tionic acid Flumequine MF 961
Oxolinic acid Abuloxacin Mertofloxacin
Miloxacin Ofloxacin Verbafloxacin
EN 272 Ruloxacin Neoquinoron
DJ 6783 S-25932 CP 91121
Droxacin OA-241 Pufloxacin
DN 9494
A-62824
Levofloxacin

Group II B Group II B
3-Membered ring 5-Membered ring

II A - 1 II A – 2 II A - 3
1.8 Napthycline Pyrido (2.3.0)
Pyrimidine Fluorinated Non-Fluorinated
Non-Fluorinated Fluorinated
Pipemidic acid 7-piperazine 7-pyrolidine Others Acruxacin
Nalidixic acid 7-Pyrolidine Piramidic acid Norfloxacin PO 117546 Y-28024 WN 36438
AT 3296 Others
Pefloxacin Cinefloxacin 7-pynil Birfloxacin Piroxacin
BWY 40062
7-Piperacine AT 3786 E-3499
Difloxacin etc Pinfloxacin Y-20611
Enoxacin Tosufloxacin Pyridol (2.34) Sparfloxacin etc
CP 99219 E 3624
A-57132 A-85485 Piyrazine Lomefloxacin
CFC-222 etc
BWY 4336 CS 940
BWY 41602 etc
U 91909E Chemical Classification of the Quinolone Derivates
 Influences phototoxicity Metal binding and
and genetic toxicity chelation – controls
Effect of F group
interaction with
on side-effect
antacids, milk, iron;
profile has not
divalent cation
been reported
R5 O O
F 6
5
4
3 OH

R7 7 C8 N1 2
R2 No side effects
associated with
Controls R1 this position
Controls GABA phototoxicity
binding,
theophylline Controls theophylline
interaction interaction and
genetic toxicity
 CHEMICAL STRUCTURES OF
LEVOFLOXACIN AND OFLOXACIN

O
O
F COOH F COOH

N N N N
H3C-N
H3C-N H H
O
O
CH3 H CH3

Levofloxacin Ofloxacin
 CLASSIFICATION OF FLUOROQUINOLONE
GEN. NAME ANTIBACT. ACTIVITY

Gen I Nalidixic acid predominantly for

enterobacteriaceae

Gen II Ciprofloxacin predominantly for gram

Pefloxacin negative bacteria & limited
Ofloxacin gram positive bacteria

Gen III Levofloxacin ‘Broad spectrum’ active

Sparfloxacin gram neg & pos,atypical

Gen IV Gatifloxacin 3rd generation plus

Moxifloxacin anaerobes
Gemifloxacin
Clin Inf. Dis, 2000; 31:47- 82
 MECHANISM OF ACTION
Double helix DNA

Strained supercoiling / overwinding

DNA gyrase

Negative supercoil double helix DNA

Topoisomerase IV

Replication transcription

Death

Hooper DC Clin Infect Dis 1998 ; 27 (suppl I) : S54-63

Half-life (h)
 Concentrations (ug/ml or g)
Time after
Dose
Body fluid & tissue n administratio 0.05 0.1 0.2 0.39 0.78 1.56 3.13 6.25
(mg)
n (h)

Sputum 100 2 2.2 - 3.1 1.02-1.29

Sputum 200 2 3.0 - 3.4 3.11-4.23

Saliva 100 8 0.77 - 1.70 0.54-1.06

Salivary gland 100 1-3 2-8 0.19-1.37

Otorrhea 100 3 2 <0.01-1.21

Intratympanic cavity mucosa 100 3 1-2 0.04-0.85

0.78-1.06
Maxillary sinus mucosa 100 2 2-6

Ethmoidal sinus mucosa 100 1 1 0.84

Frontal sinus cystic tissue 100 1 1 1.09-1.51

4.10
Palatine tonsil 100 24 2-6
Parotid gland 100 4 2-5 0.19-0.77
Submandibular gland 100 3 2-8 0.84-1.37
0.006 0.05 0.1 0.2 0.39 0.78 1.56 3.13 6.25
MIC90 against main causative
pathogens (ug/ml)
H. influenzae E.coli S. pneumoniae
N. gonorrhoeae K. pneumoniae S. aureus P. aeruginosa
B. catarrhalis S. epidermidis C. trachomatis
P. mirabilis
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

 Pharmacokinetic Properties of Levofloxacin
8

Plasma Concentration (µg/mL)

500 mg PO
6 500 mg IV

0 6 12 16 24 30 36
Time (h)
 Cmax 5.1 µg/mL
 Tmax 1.3 h
 t1/2 6.3 h
 AUC 47.9 µg/mL h
 Oral Bioavailability 99%
 Elimination Renal

†Single
500-mg or 750-mg oral dose.
LEVAQUIN Tablets/Injection Prescribing Information, November 2000.
 SERUM CONCENTRATION
2 Healthy adults* (Ccr ≥ 70 mL/min;
n=5)
Serum concentration

Group I : patients with mild renal

1.5 dysfunction (Ccr 40-69 mL/min; n=7)

Group II : patients with moderate

renal dysfunction (Ccr 20-39
1 mL/min; n=11)
Group III : patients with severe renal
dysfunction (Ccr < 20 mL/min; n=5)

0.5

0
1/0/00 24
1/25/00 48
2/19/00 72

Time after administration (h)

 URINARY EXCRETION
100 Healthy adults* (Ccr ≥ 70 mL/min;
n=5)
Cumulative excretion

Group I : patients w ith mild renal

dysfunction (Ccr 40-69 mL/min;
n=7)
rate

50 Group II : patients w ith moderate

renal dysfunction (Ccr 20-39
mL/min; n=11)
Group III : patients w ith severe
renal dysfunction (Ccr < 20
mL/min; n=5)
0 1/ 2/ 00 1/ 25/ 00 2/ 17/ 00 3/ 11/ 00
24 48 72
Time after administration (h)
 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
 Subject Characteristic (n=30)

n % n %
Sex
Fever before tx
- Male 11 36.7
(mean 6.1 days)
- Female 19 63.3
- <4 days 3 10
Age - 4 days 5 16.7
- <20 5 16.7 - 5 days 6 20
- 21-30 12 40.0 - 6 days 3 10
- 31-40 10 33.3 - 7 days 4 13.3
- 41-50 1 3.3 - 8 days 6 20
- >50 2 6.7 - 9 days 1 3.3
- 10 days 2 6.7
 Clinical Result of Treatment
Definite Cases Probable Cases
n % n %
Clinical Efficacy
Response 21 100 9 100
Failure 0 0

Defervescence on:
Day 1 4 19 1 11.1
Day 2 6 28.6 6 66.7
Day 3 10 47.6 1 11.1
Day 4 0 1 11.1
Day 5 1 4.8 0
Mean 2.43 2.22
(days)
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

 Comparison of Defervescence
from Several Typhoid Studies

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

 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
 Typhoid Fever : Levo vs Cipro
Exclusion Criteria
1. Pregnant or breast feeding female
2. Serum creatinin > 1.4 g/dL
3. History of adverse reaction or known allergy to
quinolone antibiotics
4. Suspected infection or terminal illness with fatal
outcome within 48 hours
5. Serious underlying illness, including
immunocompromised and/or neutropenic patients
6. History of convulsive disorders
7. History of photosensitivity reactions
8. Previously been enrolled in this study
9. Received and will continuou to receive theophylline
or walfarin preparation
10. Severe or complicated typhoid fever that in the
opinion of the Investigator would require more than 7
days of therapy/hospitalization.
 Distribution of Patients
June 2006

Total Enrolled: 212 cases

Confirmed Typhoid Fever * Probable/clinical

110 Typhoid Fever
102
Levofloxacin Ciprofloxacin * By m.o. culture, PCR or 4 fold
54 56 increased serologic titers and
titers ≥ 640 for titer O or H
S al m o n e ll a t h y pi a n ti g e n

DO Evaluable DO Other Evaluable

1 53 1 1 54
 No of patients
Baseline Levofloxacin Ciprofloxacin
(n=53) (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 days
Mean Clinical Score 10.7 point 9.8 point
 No of patients
Diagnosis by Levofloxacin Ciprofloxacin
(n=53) (n=54)
Microbiology Culture 11 14
Polymerase Chain Reaction 19 16
Serology (Widal Test) 23 24
*S. Typhi titer O/H >640 or 4 – fold increase
**No statistical difference (p>0.05)
 No of patients
Days Levofloxacin Ciprofloxacin
(n=53) (n=54)
Day 1 1 1
Day 2 13 11
Day 3 26 12
Day 4 9 7
Day 5 3 7
Day 6 1 4
Day >6 0 12
Mean 3 5
 Clinical Efficacy Levo vs Cipro

No of patients
Clinical Efficacy Levofloxacin Ciprofloxacin
(n=53) (n=54)
Average Defervesence 3 5
Fever free at Day 7 100% 77,8%
Clinical Relapse 1 1
Others (Relapse) 0 1
 Microbiological Efficacy Levo vs Cipro

No of patients
Microbiological Efficacy Levofloxacin Ciprofloxacin
(n=53) (n=54)
Clearance S. typhi at D7
100% 85.70%
(Blood)
Clearance S. typhi at D7
100% 92.90%
(Stool)
Bacteriological Relapse None 2 cases
Carrier at Day 30 None None
 Comparison of Adverse Reactions

No of patients
Adverse Reaction Levofloxacin Ciprofloxacin
(n=54) (n=56)
Nausea (NS) 5 4
Vomit (VM) 1 2
NS + VM 0 4
Epigastric pain 0 2
Insomnia 4 2
Cephalgia 0 1
 Comparison of Unwanted
Laboratory Reactions

No of patients
Laboratory Reaction Levofloxacin Ciprofloxacin
(n=54) (n=56)
Hematologic None None
Renal None None
Hepatic* 2 6
* More than 3 times increased of initial value
A 7 days oral regimen of Levofloxacin
500 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