Resistance and Strategies for Streptococcus pneumoniae Vanhoof, R. - - PowerPoint PPT Presentation

Resistance and Strategies for Streptococcus pneumoniae

Vanhoof, R.

Unit of Antibiotic Research Institute Pasteur Brussels

UCL, Brussels, 07/04/2005

Host MICROBE DEFENCE PATHOGENICITY ANTI- BIOTIC TOXICITY K I N E T I C S RESISTANCE ACTIVITY

ANTIBIOTIC

+

MICROBE ANTIBIOTIC RESISTANCE PROBLEM

Streptococcus pneumoniae is one of the most important pathogens exhibiting both a high degree

• f morbidity

and a considerable rate of mortality.

Penicillin G has been considered as the drug of choice in the treatment

• f

pneumococcal infections, though its clinical utility has been hampered by the appearance

• f

penicillin-insusceptible isolates.

In 1967, the first penicillin-insusceptible S. pneumoniae was reported from Australia. In Belgium, the first isolates with reduced susceptibility to penicillin were reported in 1980 by Vanhoof et al. In Belgium, steadily increase of reduced susceptibility to penicillin since 1994- 1995.

Follow-up of Antibiotic Resistance in S. pneumoniae

• National Reference Centre,

University Hospital Gasthuisberg.

• The Belgian SPN Study Group.
• Institute Pasteur Brussels.
• 15 participating Centres
• National Reference Centre

Factors impacting Resistance in

• S. Pneumoniae

Usage and clones Geography Population density (urban/rural) Specimen source Vaccine use Travel Social/cultural behaviour Climate Hospitalisation, day care, LCF Age, gender ……..

• S. Pneumoniae: epidemiology of resistance

Resistance Rates

Evolution of Penicillin Resistance in Belgium following the Belgian SP-Study Group (Vanhoof et al)

12,5 12,3 16,1 21 15 14,7 5 10 15 20 25 %R

1995 1997 1999 2001 2003 2004

Evolution of Penicillin Resistance in Belgium following the National Reference Centre

%R

2 4 7,6 7,1 9,5 10 14,2 16,5 17,6 15 15,1 13 2 4 6 8 10 12 14 16 18 %R 1 2 3 4 5 6 7 8 9 10 11 12

1985 1993 1994 1995 1996 1997 1998 2003 2001 2000 1999 2002

Comparison of the Evolution of Penicillin Resistance in Belgium

5 10 15 20 25 %R Reeks1 Reeks2

Ref.C. SP gr. 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

RESULTS Resistance rates

6,2 6,2 5,7 6,6 6,8 9,3 10,8 10,2 6,6 8,4 8,3 6,4

5 10 15 20 25 % 1995 1997 1999 2001 2003 2004

Evolution of Pen-insusceptibility

R I

Resistance rates (%): β-lactams Antibiotic 1995 1997 1999 2001 2003 2004 PEN 12.5 12.3 16.1 21.0 15.0 14.7 AMX/C 1.0 1.6 2.6 1.2 CRX 9.1 9.9 15.1 16.9 13.6 12.7 CTX 6.2 7.6 12.7 7.3 4.9 6.2

Evolution of MIC Distributions: Penicillin

10 20 30 40 50 60 70 , 2 , 8 , 3 , 1 2 , 5 2 8 % 1995 1997 1999 2001 2003 2004

Resistance rates (%): Fluoroquinolones Antibiotic 1995 1997 1999 2001 2003 2004 CIP NT NT 15.6 11.2 13.8 9.0 LEV NT NT 2.0 2.5 3.3 2.8 MOX NT NT NT NT 0.6 0.2 OFL NT NT NT NT 13.5 9.0

Resistance rates (%): MLS + TET Antibiotic 1995 1997 1999 2001 2003 2004 ERY 21.6 31.4 36.1 30.3 26.1 24.7 TEL NT NT NT NT 0.8 0.2 TET 27.3 31.1 22.9 38.5 32.3 22.1

5 10 15 20 25 30 35 40 %R 1995 1997 1999 2001 2003 2004

Evolution of ERY Resistance

SPN REF 5 10 15 20 25 30 35 40 %R 1995 1997 1999 2001 2003 2004

Evolution of TET Resistance

SPN REF

Distribution of the susceptibility Phenotypes

0% 20% 40% 60% 80% 100% 1995* 1997* 1999 2001 2003 2004

Evolution of Phenotypes

S 4AB 3AB 2AB 1AB

• S. Pneumoniae: epidemiology of resistance

Resistance and sampling site

MEF: 1.63 more likely than blood to be Pen-NS MEF: 1.43 more likely than CSF to be Pen-NS

Multivariate logistic regression analysis of Belgian Data (Reference Centre) by R. Mera (USA).

Impact of MEF isolates on Resistance rates (1)

Penicillin Resistance Rates

5 10 15 20 25 30 35 40 1995 1997 1999 2001 2003 %R Total Non-Inv MEF

Impact of MEF isolates on Resistance rates (2)

Erythromycin Resistance Rates

10 20 30 40 50 60 1995 1997 1999 2001 2003 %R Total Non-Inv MEF

RESULTS Resistance rates (%) in MEF and Non Invasive isolates Antibiotic MEF isolates Non Inv.

Penicillin 26.6 15.4 0.01>P>0.001 Amoxicillin 1.1 1.0 NS Cefotaxime 1.1 3.2 NS Imipenem 3.2 3.0 NS Ciprofloxacin 9.3 14.1 NS Erythromycin 44.7 27.7 P<0.001 Tetracycline 36.2 29.8 NS

20 40 60 80 100 % 0-5 6-15 16-39 40-59 60+ age

Age distribution in MEF isolates

• S. Pneumoniae: epidemiology of resistance

Geographic differences

Region Total Adult Pediatric France 50 43 62

Nord-Pas de Calais

48 35 68

Champagne-Ardennes

43 38 55

Lorraine

44 43 45

Alsace

45 42 52 Penicillin insusceptibility (%) in France (2003) 1995 1997 1999 2001 2003 2004 France 38.0 40.5 44.0 55.0 50.0 NA

P.Chahwakilian, personal communication

RESULTS Resistance rates: geographic distribution

5 10 15 20 25 30 35 40 % PEN CIP ERY TET Resistance

Geographic distribution of resistance

North South Bruss

CIP: Bruss < South (0.05>P>0.02)*

35.7% 6.5% 44.8% 11.7%

MIC Distributions: β-lactams

5 10 15 20 25 30 35 40 , 2 , 4 , 8 , 1 5 , 3 , 6 , 1 2 , 2 5 , 5 1 2 4 % 2004 04HAIN

Penicillin

5 10 15 20 25 30 35 40 45 , 2 , 4 , 8 , 1 5 , 3 , 6 , 1 2 , 2 5 , 5 1 2 4 % 2004 04HAIN

Amoxicillin

5 10 15 20 25 30 35 0,002 0,008 0,03 0,12 0,5 2 8 32 % 2004 04HAIN

Cefuroxime

RESULTS Resistance rates (%): β-lactams

14,7 1,2 12,7 11,8 32,5 1,9 23,4 22,1 5 10 15 20 25 30 35 PEN**** AMX CRX*** CRXa*** % 2004 04HAIN

RESULTS Resistance rates (%):MLS +Tetra

24,7 22,1 39,6 31,8 5 10 15 20 25 30 35 40 45 ERY**** TET*** % 2004 04HAIN

Distribution of the susceptibility Phenotypes

Resistance Phenotypes

S 41% 1 AB 24% 2 AB 16% 3 AB 18% 4 AB 1%

Resistance Phenotypes

S 49% 1 AB 25% 2 AB 15% 3 AB 9% 4 AB 2%

04HAIN

National

• S. Pneumoniae: epidemiology of resistance

Resistance Mechanisms

Fluoroquinolone Resistance

FQ Resistance Mechanisms in 71 S.pneumoniae isolates (1999-2003) Type of Mechanisme % gyrA 5.6 parC 16.9 gyrA+parC 14.1 Wt and PmrA+ 60.6 Wt and Pmr- 2.8

MIC distributions and type of mutation in S.pneumoniae isolates

0,25 0,5 1 2 4 8 16 32 MIC gyrA+parC gyrA parC wt

• S. Pneumoniae: epidemiology of resistance

Resistance Mechanisms

MLS Resistance

MLS-TET Resistance Mechanisms

85,2 7,7 1,6 56,2 89,7 6 3,5 10 20 30 40 50 60 70 80 90 100 ermB mefA erm+mef tet % SPgr REF

MLS-TET Resistance Mechanisms in S.pneumoniae isolates

CONCLUSIONS

CONCLUSION (1) SUVEILLANCE OF THE RESISTANCE EPIDEMIOLOGY (resistance rates, population distributions,... SUVEILLANCE OF THE RESISTANCE EPIDEMIOLOGY (resistance rates, population distributions,... STUDY OF FACTORS WITH IMPACT ON RESISTANCE DEVELOPMENT (clinical, geographic, demographic,…) STUDY OF FACTORS WITH IMPACT ON RESISTANCE DEVELOPMENT (clinical, geographic, demographic,…) STUDY OF RESISTANCE MECHANISMS (importance of efflux, ….) STUDY OF RESISTANCE MECHANISMS (importance of efflux, ….)