CHEMICAL STRUCTURES OF LEVOFLOXACIN AND OFLOXACIN

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Hannah Carpenter
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Update on Treatment of Typhoid Fever with Fluoroquinolon Prof. dr. R.H.

FQ untuk DT Study terbuka Levo vs Cipro Group I Group II Group III Group IV Monocyclic Bicyclic derivate Tricyclic Tetracyclic derivate

Miloxacin floxacin Verbafloxacin E 7 Ruloxacin eoquinoron DJ 78 S-9 CP 9 Droxacin A-4 Pufloxacin D 9494 A-84 Group II B Group II B

.0) Pyrimidine Fluorinated on-fluorinated on-fluorinated Fluorinated Pipemidic acid7-piperazine 7-pyrolidine thers Acruxacin alidixic

Birfloxacin Piroxacin Enoxacin Tosufloxacin E-499 Difloxacin etc Pinfloxacin Y-0 A-7 A-848 CP 999 Pyridol (.

1 Update on Treatment of Typhoid Fever with Fluoroquinolon Prof. dr. R.H.H. ELWA, DTM&H, SpPD-KPTI DIVISI PEYAKIT TRPIK DA IFEKSI DEPARTEME ILMU PEYAKIT DALAM FKUI / RSUP-CM JAKARTA. Fluorokuinolon (FQ). FQ untuk DT Study terbuka Levo vs Cipro Group I Group II Group III Group IV Monocyclic Bicyclic derivate Tricyclic Tetracyclic derivate derivate derivate R-4478 R-4978 on-fluorinated Fluorinated KE-4 Tionic acid Flumequine MF 9 xolinic acid Abuloxacin Mertofloxacin Miloxacin floxacin Verbafloxacin E 7 Ruloxacin eoquinoron DJ 78 S-9 CP 9 Droxacin A-4 Pufloxacin D 9494 A-84 Group II B Group II B -Membered ring -Membered ring II A - II A II A -.8 apthycline Pyrido (..0) Pyrimidine Fluorinated on-fluorinated on-fluorinated Fluorinated Pipemidic acid7-piperazine 7-pyrolidine thers Acruxacin alidixic acid 7-Pyrolidine Piramidic acid orfloxacin P 74 Y-804 W 48 AT 9 thers Pefloxacin Cinefloxacin 7-Piperacine AT 78 BWY pynil Birfloxacin Piroxacin Enoxacin Tosufloxacin E-499 Difloxacin etc Pinfloxacin Y-0 A-7 A-848 CP 999 Pyridol (.4) Sparfloxacin E 4 etc Piyrazine Lomefloxacin BWY 4 CFC- etc CS 940 BWY 40 etc U 9909E Chemical Classification of the Quinolone Derivates Effect of F group on side-effect profile has not been reported Controls GABA binding, theophylline interaction F R7 Influences phototoxicity and genetic toxicity R C8 4 7 Controls phototoxicity R R Metal binding and chelation controls interaction with antacids, milk, iron; divalent cation H Controls theophylline interaction and genetic toxicity o side effects associated with this position H C- CHEMICAL STRUCTURES F LEVFLXACI AD FLXACI F CH CH H C- H F H H floxacin CH CH

CLASSIFICATI F FLURQUILE MECHAISM F ACTI GE. AME ATIBACT.

enterobacteriaceae predominantly for gram negative bacteria & limited gram positive bacteria Strained supercoiling /

pos,atypical Topoisomerase IV Gen IV Gatifloxacin Moxifloxacin Gemifloxacin rd generation plus anaerobes Replication

Dis, 000; :47-8 Hooper DC Clin Infect Dis 998 ; 7 (suppl I) : S4- Body fluid & tissue Dose (mg) n Time after

Saliva 00 8 0.77 -.70 0.4-.0 Salivary gland 00 - - 8 0.9-.7.7 torrhea 00 Intratympanic cavity mucosa 00 - Maxillary sinus mucosa 00 - <0.

0 Antibiotic Cyst concentration Serum concentration Cyst : serum ratio Ethmoidal sinus mucosa 00 Frontal sinus cystic

2 CLASSIFICATI F FLURQUILE MECHAISM F ACTI GE. AME ATIBACT. ACTIVITY Double helix DA Half-life (h) Gen I Gen II alidixic acid Pefloxacin floxacin predominantly for enterobacteriaceae predominantly for gram negative bacteria & limited gram positive bacteria Strained supercoiling / overwinding egative supercoil DA gyrase double helix DA Gen III Sparfloxacin Broad spectrum active gram neg & pos,atypical Topoisomerase IV Gen IV Gatifloxacin Moxifloxacin Gemifloxacin rd generation plus anaerobes Replication Death transcription Clin Inf. Dis, 000; :47-8 Hooper DC Clin Infect Dis 998 ; 7 (suppl I) : S4- Body fluid & tissue Dose (mg) n Time after administratio n (h) Concentrations (ug/ml or g) Sputum Sputum Saliva Salivary gland torrhea 00 Intratympanic cavity mucosa 00 - Maxillary sinus mucosa 00 - < Antibiotic Cyst concentration Serum concentration Cyst : serum ratio Ethmoidal sinus mucosa 00 Frontal sinus cystic tissue 00 Palatine tonsil Parotid gland Submandibular gland 00-8 MIC90 against main causative pathogens (ug/ml) H. influenzae. gonorrhoeae E.coli K. pneumoniae B. catarrhalis P. mirabilis S. pneumoniae S. aureus P. aeruginosa S. epidermidis C. trachomatis 4.4 ug/ml 4. ug/ml 0.9 Ampicillin 0 ug/ml >0 ug/ml < 0.40

Pharmacokinetic Properties of Plasma Concentration (µg/ml) 8 4 0 C max. µg/ml T max. h t /. h AUC 47.

4 0 Time (h) Serum concentration SERUM CCETRATI. 0. 0 /0/00 //00 4 /9/00 48 7 Time after administration (h) Healthy adults* (Ccr 70 ml/ min; n=) Group I : patient s with mild renal dysfunction (Ccr

3 Pharmacokinetic Properties of Plasma Concentration (µg/ml) C max. µg/ml T max. h t /. h AUC 47.9 µg/ml h ral Bioavailability 99% Elimination Renal 00 mg P 00 mg IV Time (h) Serum concentration SERUM CCETRATI /0/00 //00 4 /9/ Time after administration (h) Healthy adults* (Ccr 70 ml/ min; n=) Group I : patient s with mild renal dysfunction (Ccr 40-9 ml/min; n=7) Group II : patients with moderate renal dysfunct ion (Ccr 0-9 ml/min; n=) Group III : patient s wit h severe renal dysfunction (Ccr < 0 ml/min; n=) Cumulative excretion rate URIARY EXCRETI Time after administration (h) / / 00 / / 00 / 7/ 00 / / 00 Healthy adults* (Ccr 70 ml/min; n=) Group I : patients w ith mild renal dysfunction (Ccr 40-9 ml/min; n=7) Group II : patients w ith moderate renal dysfunction (Ccr 0-9 ml/min; n=) Group III : patients w ith severe renal dysfunction (Ccr < 0 ml/min; n=) Single 00-mg or 70-mg oral dose. LEVAQUI Tablet s/injection Prescribing Information, ovember 000. Pathogenesis of Typhoid Fever Dose Plasma conc Tissue/Fluid conc Ratio 00 mg (alv. makrofag).8 00 mg.9. (lung).0 00 mg (epithel).0 00 mg.7.8 (skin). 00 mg.0.7 (sputum). 00 mg mg/l 0 (urine) 7.8 pen Study on Efficacy and Safety of in Treatment of Uncomplicated Typhoid Fever RHH elwan, Khie Chen, afrialdi, and Diana Paramita Divison of Tropical and Infectious Diseases, Department of Internal Medicine, Medical university, University of Indonesia/dr. Cipto Mangunkusumo ational General Hospital, Jakarta ; Department of Internal Medicine, Persahabatan Hospital, Jakarta, Indonesia

Sex - Male - Female Age - <0 - -0 - -40-4-0 - >0 Subject Characteristic (n=0) n % 9 0.7..7 40.

days) - <4 days - 4 days - days - days - 7 days - 8 days - 9 days - 0

7 0 0. 0..7 Clinical Efficacy Definite Cases Probable Cases n % n % Response 00 9 00 Failure

4. A Single Blind Comparative Randomized Multi Centre Study for Efficacy and Safety of vs In

al Comparison of Defervescence from Several Typhoid Studies Typhoid Fever : Levo vs Cipro

Dosage Duration Fever Clearance () 00 BID days,0 days floxacin() 00 mg D 7 days,40 days

4 Sex - Male - Female Age - < >0 Subject Characteristic (n=0) n % Fever before tx (mean. days) - <4 days - 4 days - days - days - 7 days - 8 days - 9 days - 0 days n % Clinical Efficacy Definite Cases Probable Cases n % n % Response Failure 0 0 Defervescence on: Day 4 9. Day 8..7 Day Day 4 0. Day Mean (days) Clinical Result of Treatment.4. A Single Blind Comparative Randomized Multi Centre Study for Efficacy and Safety of vs In the Treatment of Typhoid Fever R.H.H. elwan, et.al Comparison of Defervescence from Several Typhoid Studies Typhoid Fever : Levo vs Cipro SPECIFIC BJECTIVE T DETERMIE Typhoid Fever : Levo vs Cipro Inclusion Criteria ame of Drug Dosage Duration Fever Clearance () 00 BID days,0 days floxacin() 00 mg D 7 days,40 days Pefloxacin(7) 400 mg D 7 days,0 days Clinical efficacy of levofloxacin vs ciprofloxacin Bacteriological efficacy of levofloxacin vs ciprofloxacin Defervescence time of levofloxacin vs ciprofloxacin Safety of levofloxacin vs ciprofloxacin Fleroxacin(8) 400 mg D days,4 days 00 mg D 7 days,4 days 4

Typhoid Fever : Levo vs Cipro Exclusion Criteria. Pregnant or breast feeding female. Serum creatinin >.4 g/dl.

Suspected infection or terminal illness with fatal outcome within 48 hours.

History of photosensitivity reactions 8. Previously been enrolled in this study 9.

Severe or complicated typhoid fever that in the opinion of the Investigator would require more than 7 days of

Confirmed Typhoid Fever * 0 4 D Evaluable Distribution of Patients June 00 Total Enrolled: cases D ther Evaluable 4

H Sal m o nel l a t h ypi ant ig en Baseline M : F Ratio ( : 7) ( : 9) Mean AGE (Range). (8-).

5 Typhoid Fever : Levo vs Cipro Exclusion Criteria. Pregnant or breast feeding female. Serum creatinin >.4 g/dl. History of adverse reaction or known allergy to quinolone antibiotics 4. Suspected infection or terminal illness with fatal outcome within 48 hours. Serious underlying illness, including immunocompromised and/or neutropenic patients. 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 0. Severe or complicated typhoid fever that in the opinion of the Investigator would require more than 7 days of therapy/hospitalization. Confirmed Typhoid Fever * 0 4 D Evaluable Distribution of Patients June 00 Total Enrolled: cases D ther Evaluable 4 Probable/clinical Typhoid Fever 0 * By m.o. culture, PCR or 4 fold increased serologic titers and titers 40 for titer or H Sal m o nel l a t h ypi ant ig en Baseline M : F Ratio ( : 7) ( : 9) Mean AGE (Range). (8-). (8-4) Mean Duration of Fever 7.7 days 7. days Mean Clinical Score 0.7 point 9.8 point Diagnosis by Microbiology Culture 4 Polymerase Chain Reaction 9 Serology (Widal Test) 4 *S. Typhi titer /H >40 or 4 fold increase **o statistical difference (p>0.0) Days Day Day Day Day Day 7 Day 4 Day > 0 Mean Clinical Efficacy Levo vs Cipro Clinical Efficacy Average Defervesence Fever free at Day 7 00% 77,8% Clinical Relapse thers (Relapse) 0

6 Microbiological Efficacy Levo vs Cipro Microbiological Efficacy Clearance S. typhi at D7 (Blood) 00% 8.70% Clearance S. typhi at D7 (Stool) 00% 9.90% Bacteriological Relapse one cases Carrier at Day 0 one one Comparison of Adverse Reactions Adverse Reaction (n=) ausea (S) 4 Vomit (VM) S + VM 0 4 Epigastric pain 0 Insomnia 4 Cephalgia 0 Comparison of Unwanted Laboratory Reactions Laboratory Reaction (n=) Hematologic one one Renal one one Hepatic* * More than times increased of initial value A 7 days oral regimen of 00 mg daily versus twice daily 00 mg for uncomplicated Typhoid fever in Indonesia showed superior fever clearance, superior microbiological result and less adverse reactions for compared to Advances in Microbiology, 0,, -7

OPEN STUDY ON EFFICACY AND SAFETY OF LEVOFLOXACIN IN TREATMENT OF UNCOMPLICATED TYPHOID FEVER

OPEN STUDY ON EFFICACY AND SAFETY OF LEVOFLOXACIN IN TREATMENT OF UNCOMPLICATED TYPHOID FEVER RHH Nelwan 1, Khie Chen 1, Nafrialdi 2 and Diana Paramita 3 1 Division of Tropical Medicine and Infectious