Pneumococcus:Antibiotic Resistance

in the Region

Çiğdem Bal KayacanIstanbul University

Istanbul Faculty of MedicineDepartment of Microbiology & Clinical Microbiology

Drug Resistance in S.pneumoniae

penicillin macrolide

trim/sulfa quinolone

tetracycline

PenicillinNon-Susceptible

S.pneumoniae (PNSP)

• Penicillin Intermediate (PISP)MIC = 0.12-1 μg/mL

• Penicillin Resistant (PRSP)MIC ≥2 μg/mL

• By changes in PBPs 2B, 2X and 1A

• Rates HIGHER in pediatric patients & respiratory infections

MACROLIDE Resistance in S.pneumoniae

• Macrolide resistance ratehigh in many countries

• Pneumococcal strainsresistant to both penicillinand erythromycinincreasing faster thanstrains singly resistant toeither

• Significant increase in MDR-S.pneumoniae since 1990s

McCormick AW et al. Nat Med 2003; 9:424File Jr. Clin Microbiol Infect 2006; 12(Suppl

3):31

M-type (Efflux)low level resistance tomacrolides (14-, 15-)

MIC = 1-32 μg/mL

MLSB-typehigh level resistance tomacrolides,

lincosamides, streptogramin B

MIC ≥ 64 μg/mL

PenicillinNon-SusceptibleS.pneumoniae

the ALEXANDER PROJECT

WORLDWIDE

13,9

14,7

16

12,7

17,1

15,9

0

10

20

30

40

EUROPE LATINAMERICA

NORTHAMERICA

PRSP

PISP

28,6 28,733

PNSP

SENTRY1999-2003

EUROPE

3,9

25,8

29,7

0

5

10

15

20

25

30

PRSPPISPPNSP

1996-97national

multicenter

respiratory isolates

TURKEY

PNSP

TURKEY: PNSP in National Studies

PISP PRSPStudy Period

29,7 29

39,5

34,232,2

39

17,8

0

5

10

15

20

25

30

35

40

1996-1997

Gür

1999-2002

Altun

1999-2003

PROTEKT

2002-2003

e-BASKETT

2004-2005

SOAR

2001-2004

Yalçın ARMed

PNSPPISPPRSP

Multicenter Studies;Last 10 Years

respiratory invasive

TURKEY

PNSP

36,940,9

5

27,6

5

20,5

51,9

62,6

8

25,7

0

10

20

30

40

50

60

70

PNSP Erythro DUAL Trim/Sulfa Tetra

19972005

OVERALL• PRSP 2.4% PISP 30%• Significant increase in the mean MIC’s of PENICILLIN

Gür D, Güçiz Doğan B. (P754) ECCMID 2006

9 year period1406 isolates

Pediatric Isolates

PNSP:Overall

in Turkey

27,3

2,3

27,8

3,4

32,7

7,4

0

5

10

15

20

25

30

35

40

45

1990-1995 1995-2000 2000-2004

PRSPPISP

40,1

31,229,6

TURKEY

TURKEY

0

10

20

30

40

50

60

70

GREECE ISRAEL RUSSIA S.ARABIA TURKEY

PNSPPISPPRSP

PROTEKT 2002-2003REGION

PNSP

respiratory

isolates

European Antimicrobial ResistanceSurveillance System (EARSS)

Highest levels of antibiotic resistance

within theMediterranean

countries

www.earss.rivm.nl

2006Austria ItalyBelgium LatviaBulgaria LithuaniaCroatia LuxembourgCyprus Malta Czech Republic NetherlandsDenmark NorwayEstonia PolandFinland PortugalFrance RomaniaGermany SloveniaGreece SpainHungary SwedenIceland Turkey*Ireland United KingdomIsrael

7

29

6

7

31

13

5

0

10

20

30

40

BULG

ARIA

ISRA

EL

CYPR

US

TURK

EY

PRSP

PISP

EARSS 2006

7

3538

18 REGION

PNSP

invasive isolates

EARSS: PNSP 2006

invasive

isolates

RO

BU

ISR

CYP

CHANGE in CLSI BREAKPOINTSfor Spn & Penicillin

• PRSP: MICPenicillin ≥ 2 μg/mL• PNSP: MICPenicillin > 0.06 μg/mL

• Same for oral Pen V• Lowered for parenteral for meningitis:

PNSP=PRSP ≥ 0.12 μg/mL (No Low Level)• Highered for parenteral for non-meningitis:

PNSP ≥ 4 μg/mLPRSP ≥ 8 μg/mL

2007

2008

ErythromycinErythromycinResistanceResistance

in S.in S.pneumoniaepneumoniae

the ALEXANDER PROJECT

penicillin resistance

erythromycin resistance

PROTEKT

2001-2004

PROTEKT-global

Erythromycin MICsare increasing !

Effluxfor

macrolideresistance

PROTEKT

Antibiotic Resistance Surveillance andControl in the Mediterranean Region:

The ARMed Project

Algeria, Cyprus, Egypt, Jordan, Lebanon, Malta, Morocco, Tunisia and TurkeyMA Borg, E Scicluna, M de Kraker , N van de Sande-Bruinsma , E Tiemersma, D Gür, S Ben Redjeb, O Rasslan, Z Elnassar, M Benbachir, D Pieridou Bagatzouni, K Rahal, Z Daoud, H Grundmann, J Monen. Antibiotic resistance in the southeasternMediterranean – preliminary results from the ARMed project. Euro Surveill 2006;11(7):164

invasive isolates

ARMED

2003-2004

Erythromycin Resistance

16 17

31

16

0

10

20

30

BULGARIA ISRAEL CYPRUS TURKEY

EARSS 2006

15

30

7

11

0

5

10

15

20

25

30

35

40

45

PENICILLIN ERYTHROMYCIN

PRSP

PISPEFFLUX

MLSB

GREECE 2002-2003

GRASP STUDY20 countries

mixt isolates

45

18

erythromycinresistance

EARSS 2006

32,2

16,98,5 5,3 1,3

0

10

20

30

PNSP ERY TET CMLAM/CLAV

PRSP 7.6%PISP 24.6%

TURKEY

respiratory isolates

SOAR in AME2004-2005

Penicillin+Erythromycin

DUAL Resistance

in S.pneumoniae

the ALEXANDER PROJECT

of PRSP

erythromycinresistant

13

EARSS 2004

Penicillin+ErythromycinDual Resistance

in S.pneumoniae

DUAL resistance

EARSS 2006

SEROTYPES SEROTYPES & &

RESISTANCERESISTANCE

TURKEY

EARSS 2006

serogroups & resistance

EARSS 2005 - 2006 Report

Serogroup information from 11 countriesHighest resistance in serogroups 6,9,14,19,23,1,33Penicillin resistance in serogroups 14,9,19,6 and 23

Erythromycin resistance in serogroups 1 and 33

7-valent conjugate vaccine covers all serogroups withpenicillin resistance

In contrast to the 23-valent vaccine, it does not cover serogroup 1 and 33 in which erythromycinresistance is common

It can be expected that the introduction of thisvaccine into the official childhood vaccination programsin many European countries will have considerableimpact on control of penicillin resistance in S.pneumoniae

34,7

20,3

14,4

33,5

21,9

3,5

48,3

22,5

25,8

48,3

35,9

23,2

0

10

20

30

40

50

Pediatric Carriage Adult Infection

PNSPPISPPRSPERYDUALCIP

7-valentpneumococcal

conjugate vaccineestimatedto provide

coverage against71.7% of paediatriccarriage isolates & 51.3% of adultclinical isolates

Serotypes19F, 14, 23F

and 6B most prevalent

among carriage andclinical isolates

9V

9V

GREECE

2004-2006

isolates expressing the erm(B)+mef(A) macrolide-resistant genotype increased

NVS 19A VS 19Fyear 1 7.8% 86.7%year 4 45.5% 51.7%

Antimicrobial Resistance amongVaccine Serotypes No Increase

in 3 years

0

10

20

30

40

50

60

70

PRSP

PISP

ERYTH

RO

AMOX/CLAV

COTRIM MDR

2000–2001 2003–2004

bloodnon-blood

Farrell DJ, Klugman KP, Pichichero M. Pediatr Infect Dis J 2007;26:123

0

10

20

30

40

50

60

70

PRSP PIS

P

ERYT

HRO

AMOX

/CLA

V

COTR

IMMDR

2000–2001

2003–2004

Antimicrobial Resistance amongNon-Vaccine Serotypes Increase

in 3 years

PRSP

PISP

ERYTH

RO

AMOX/CLAV

COTRIM MDR

0

5

10

15

20

25

30

35 2000–2001 2003–2004

non-blood

0

5

10

15

20

25

PRSP

PISP

ERYT

HRO

AMOX/

CLAV

COTR

IM MDR

2000–2001 2003–2004

blood

Farrell DJ, Klugman KP, Pichichero M. Pediatr Infect Dis J 2007;26:123

Summary: TURKEY

PNSP= 40%PRSP= 5-10%

Erythromycin= 15-20%Trim/Sulfa > 50%Tetra <10%Amox/Clav <5%Nearly all isolates susceptible torifampicin, quinolones, linezolid, quinupristin-dalfopristin & telithromycin

Summary: REGIONCyprus, Israel, Romania- High rates of PNSP (>35%)Lebanon- Highest rate of PNSP (>65%)Egypt, Jordan, Morocco, Malta, Tunisia, Algeria-PNSP rates lowest (5-15%)

in invasive isolates

Greece, Bulgaria, Israel- macrolide resistance ratessimilar to Turkey’s (16-17%) in invasive & respiratoryisolatesCyprus, Lebanon- macrolide resistance high (> 30%)

Region- Dual Resistance 10-25%, 5-10% in Turkey