Ketolide Telithromycin - Paul Ehrlich Gesellschaft

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Ketolide Telithromycin - Paul Ehrlich Gesellschaft

19. Jahrestagung der

Paul-Ehrlich-Gesellschaft

für Chemotherapie e.V.

23.-25. September 2004

Bonn

Symposium

! Neues aus der Industrie

Surveillance: PROTEKT

Telithromycin: Safety

Levofloxacin: Clinical Development

Katrin Roscher, Priv.-Doz. Dr. W. Dieter Paar

Klinische Entwicklung Praxis & Klinik, Sanofi Aventis Deutschland


Prospektive Resistant Organism Tracking

and Epidemiology for the Ketolide Telithromycin

Felmingham D. J Antimirob Chemother 2002; 50 (S1): 1-7

Design

! Longitudinal, global, multicentre, surveillance study

Objectives

! to examine the in vitro susceptibility to telithromycin

compared with other antibacterials

! to document the prevalence of resistance phenotypes

and genotypes and the activity of a range of antimicrobial

agents including telithromycin against such strains

Participants

! initially 1999-2000 69 centers from 25 countries

! US based study component (PROTEKT-US) since 2000

Funded by Aventis, Data management by Micron Research Ltd, UK


Prospektive Resistant Organism Tracking

and Epidemiology for the Ketolide Telithromycin

PROTEKT Worldwide:

Enrolling Study Centres in 2001-2002

115 Centres in 33 Countries

Canada(9)

USA(6)

Mexico(4)

Germany(12)

NL(1)

Belgium(2)

UK (2)

Ireland(2)

France(4)

Switzerland(2)

Spain(10)

Portugal(2)

Italy(5)

Sweden(1)

Poland(1)

Russia(1)

Austria(3)

Hungary(1)

Turkey(2)

Sth Korea(2)

Japan(12)

China(2)

Taiwan(3)

Hong-Kong(1)

Other

South America(5)

Brazil(5)

Argentina(3) South Africa(10) Australia(2)

PROTEKT study HMR 3647A/ v001 - 2001/2002.


Prospektive Resistant Organism Tracking

and Epidemiology for the Ketolide Telithromycin

Reinert RR et al. Chemotherapy 2004; 50: 143-151

Aachen, Berlin, Cologne, Cottbus, Frankfurt am Main, Leipzig, Lübeck


Prospektive Resistant Organism Tracking

and Epidemiology for the Ketolide Telithromycin

Reinert RR et al. Chemotherapy 2004; 50: 143-151


Prospektive Resistant Organism Tracking

and Epidemiology for the Ketolide Telithromycin

Reinert RR et al.

Chemotherapy

2004; 50: 143-151


Prospektive Resistant Organism Tracking

and Epidemiology for the Ketolide Telithromycin

Reinert RR et al. Chemotherapy 2004; 50: 143-151


Prospektive Resistant Organism Tracking

and Epidemiology for the Ketolide Telithromycin

Reinert RR et al. Chemotherapy 2004; 50: 143-151

Conclusions

! Penicillin resistance in Germany remains low

! Macrolide resistance is rising

! Continued surveillance necessary to guide

optimal empirical therapy

! New antimicrobials, like telithromycin, need to be

developed with improved potency against target

pathogens and low propensity for the

development of resistance


Prospektive Resistant Organism Tracking

and Epidemiology for the Ketolide Telithromycin

Rybak MJ. Ann Pharmacother 2004; 38: S8-13

206 sites in 44 states

16.727 respiratory isolates

About 60% S. pneumoniae


Prospektive Resistant Organism Tracking

and Epidemiology for the Ketolide Telithromycin

Rybak MJ.

Ann Pharmacother

2004; 38: S8-13


Prospektive Resistant Organism Tracking

and Epidemiology for the Ketolide Telithromycin

Rybak MJ. Ann Pharmacother 2004; 38: S8-13


Prospektive Resistant Organism Tracking

and Epidemiology for the Ketolide Telithromycin

Rybak MJ. Ann Pharmacother 2004; 38: S8-13


Prospektive Resistant Organism Tracking

and Epidemiology for the Ketolide Telithromycin

Rybak MJ. Ann Pharmacother 2004; 38: S8-13

Conclusions

! prevalence of antimicrobial-resistant respiratory

pathogens continues to rise

! ß-lactam- and macrolide isolates of S. pneumoniae

are increasing

! fluoroquinolone resistance is emerging in the US

! new pharmacologic strategies designed to combat

this growing pattern of resistance, such as

ketolides, are coming in the forefront of clinical care


Post Marketing Authorization Survey

of Telithromycin

Lorenz J, Roscher K. accepted 44nd ICAAC, Washington DC, 2004

Design

! multicentre, open, non-comparative, in the period 2001 - 2003

Objectives

! evaluation of safety, efficacy and short course treatment in

daily practice

! all approved indications in a total of 34.929 patients:

! CAP 5.640

! AECB 9.957

! T/P 8.337

! AS 12.860


Post Marketing Authorization Survey

of Telithromycin

98

97,5

97

96,5

96

95,5

95

96,8

97,3

Satisfaction with Treatment

97,1

97,6

97,1

97,6

97,1

AS PT AECB CAP

Patient's assessment

Physician's assessment

97,3

500

450

400

350

300

250

200

150

100

50

0

Incidence of Adverse drug

reactions (n=24.356)

492

2.02% 334

1,37%

94

0,39%

52

0,21%

Total

Gastroint. Disorders

Nervous syst. Disorders

Eye disorders

ADRs. of special interest:

Cardiac disorders: 10 pat. (5 Tachycadia;

3 Palpitations; 2 Cardiovascular disorders

Hepatic disorders: 1 pat. (Biliary colic)

Lorenz J, Roscher K. presented at ICC 2003, Durban, final results accepted for ICAAC 2004, Washington


Treatment of Respiratory Tract Infections:

Comparison of Telithromycin (TEL) and

Azithromycin (AZI)

Guggenbichler JP, Juhl G. ERS Annual Meeting, Glasgow 2004

Design

Objectives

! multicentre, open, comparative, randomized, 227 pts.

! to evaluate outcome, reinfection rates, effects on local flora


Summary of Product characteristics (SMPC)

FDA Approval 2004


Levofloxacin Compared with Imipenem/Cilastatin Followed by

Ciprofloxacin in Adult Patients With Nosocomial Pneumonia:

A Multicenter, Prospective, Randomized, Open Label Study

! Adults with signs and symptoms of HAP

! Hospitalized > 72 hours

! Clinical and laboratory markers of infection

! radiographic evidence of acute pulmonary

infiltrate

Levofloxacin 750 mg QD

iv than orally 7 to 15 days

N = 220

N = 438

Imipenem/Cilastatin 500 – 1 g

Every 6 – 8 hours

Oral Ciprofloxacin 750 mg

7 to 15 days

N = 218

West M et al. Clin Ther 2003, 25: 485-506


Levofloxacin Compared with Imipenem/Cilastatin Followed by

Ciprofloxacin in Adult Patients With Nosocomial Pneumonia:

A Multicenter, Prospective, Randomized, Open Label Study

Clinical

Success rate

(%)

100

90

80

70

60

50

40

30

20

10

0

Levo 750

Comparator

Microbiol

Clinical

ITT

West M et al. Clin Ther 2003, 25: 485-506


Substantial “off label” use of Levofloxacin in Germany in HAP

Findings from two recent German PMS in CAP

CAP (n=986) HAP (n=131)

Results combined Analysis CAP

0,68%

2,30% 1,45%

2,34%

Results combined Analysis HAP

0,78%

10,16%

26,20%

cured

69,38%

improved

unchanged

worsened

26,56%

60,16%

not

assessable

Höffken G, Roscher K. Manuscript in preparation

Welte T, Nowicki J. Manuscript in preparation

-44-


HAP Study: HR 355/3035

Levofloxacin 750mg od vs Piperacillin/

Tazobactam 4g/500mg tid in patients with mild to

moderate HAP

Design ! multicentre, multinational, open, comparative

randomized

Objectives

! evaluation of clinical and microbiological efficacy

and safety

! Inclusion criteria: hospitalised patients with signs of a

nosocomial pneumonia (onset > 72 hrs)

Levofloxacin 750 mg QD

iv than orally

10 to 14 days

N = 420

+ aminoglykoside for positive

P. aeruginosa-culture

Piperacillin/ Tazobactam

4g/500mg tid iv

10 to 14 days


HAP Study: HR 355/3035

Levofloxacin 750mg od vs Piperacillin/ Tazobactam

4g/500mg tid in patients with mild to moderate HAP

! Statistical Assumptions

! non-inferiority testing for cure rates

! Delta 15% in order to be comparable with the West study

! 80% power

! assumed cure rate of 70%

! assuming that 70% of enrolled patients will be

evaluable per protocol

! additional analysis for PK/PD data in selected sites in

Germany


Summary

“Neues aus der Industrie”

! lessons from PROTEKT

! rising macrolide resistance

! need for continued surveillance

! excellent suceptibility rates for telithromycin

! excellent safety and efficacy of telithromycin in the

German

35.000 pts. Post Approval Survey

! favourable influence of telithromycin on microflora

! FDA approval for levofloxacin for the treatment of HAP

! high efficacy of levofloxacin in the “off label” treatment of

HAP

! EU registration trial is ongoing


19. Jahrestagung der

Paul-Ehrlich-Gesellschaft

Für Chemotherapie e.V.

23.-25. September 2004

Bonn

Backup


Prospektive Resistant Organism Tracking

and Epidemiology for the Ketolide Telithromycin

Rybak MJ. Ann Pharmacother 2004; 38: S8-13

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