Pneumococci and Streptococci: testing and clinical implications of susceptibility changes

(1)

Pneumococci

& streptococci

_{& streptococci}

Testing and clinical implications

of susceptibility changes

Pierrette

Melin

Medical

Medical microbiologymicrobiology University

University HospitalHospital of

(2)

Key questions

_What

_is

_the

_clinical

_importance

_of

streptococci

?

_What

_are

_their

_resistances

_to

antimicrobial

agents ?

_What

_are

_the

_clinical

_implications

for

(3)

STREPTOCOCCUS PNEUMONIAE

_Lower

_respiratory

_tract

infections,

pneumonia

_the_the _single_single_most_most _important_important

bacterial

bacterial pathogenpathogen

_Otitis

_media

_{Main cause in}_{Main cause in}_children_children

_Hearing_Hearing _impairment_impairment _if_if

reccurrence

_Meningitis

_Life_Life_-_-_threatening_threatening (children₍children, , elderlyelderly))

_Neurologic_Neurologic _sequelae_sequelae

(4)

The

challenging

_challenging

pathogens

_pathogens

In

hospital

S.aureus

_S.aureus

(MRSA, _(MRSA, GISA, VRSA)

GISA, VRSA)

Enterococci

_Enterococci

(GRE)_(GRE)

Enterobacteriaceae

_{Enterobacteriaceae}

(ESBL,

(ESBL, carbapenemasecarbapenemase, , FQ) FQ) _MDR_MDR_-_-

P.aeruginosa

_P.aeruginosa

_MDR_MDR_-_-

Acinobacter

_Acinobacter

baumanii

In

community

_MDR

-

_-

_S

.pneumoniae

_.pneumoniae

_CA_CA_-_-_MRSA_MRSA

Salmonella

_Salmonella

(ESBL,_(ESBL, FQ)FQ)

Campylobacter

_{Campylobacter}

(FQ, _(FQ, macrolides)

macrolides)

_Helicobacter_Helicobacter _pylori_pylori

(5)

STREPTOCOCCUS PNEUMONIAE

_Emergence

_of

_{antimicrobial}

_resistance

_Treatment

_failures

_Increased

_morbidity

_/

_mortality

_Increased

_duration

_of

_diseases

_Costs

Key role for laboratory :

To recognize

(6)

Global

antibiotic

_antibiotic

resistance

_resistance

in

S.pneumoniae

_S.pneumoniae

Invasive

Invasive isolatesisolates non-non-S to S to penicillinpenicillin in 2002 -in 2002

-Non

Non

-

S to

penicillin

(7)

Global

antibiotic

_antibiotic

resistance

_resistance

in

S.pneumoniae

_S.pneumoniae

Invasive

Invasive isolatesisolates nonnon--S to S to erythromycinerythromycin in 2002 in 2002 -- EARSSEARSS

Non

-

S to

erythromycin

(8)

Antibiotic

resistance

_resistance

(%) in

_{(%) in}

S.pneumoniae

(

Blood

/CSF)

EARSS 1999

-

2002

0 10 20 30 40 Pen R Pen IR/Blood Pen IR/CSF Macrolides IR % Slovenia Austria Hungary Croatia Italy

(9)

S.pneumoniae

:

Mechanisms

of

_of

resistance

_resistance

_Resistance

_to

_Penicillin

_Modification_Modification_of_of _Penicillin_Penicillin _Binding_Binding _Proteins_Proteins

Qualitative & quantitative _{Qualitative & quantitative}alterationalteration ofof thethe targetstargets

Transformation and_{Transformation}and/or /or stepwisestepwise chromosomallychromosomally mediated

mediated mutations; mutations; genesgenes < oral < oral streptococcistreptococci

Decreased_Decreased susceptibilitysusceptibility to to allall ββββββββ--lactamslactams

Ceph_Ceph. III . III andand amoxicillinamoxicillin lessless affectedaffected

_Clonal_Clonal_spread_spread _{AND local}_{AND local}_emergence_emergence

(10)

S.pneumoniae

:

Mechanisms

of

_of

resistance

_resistance

_Resistance

_{to Macrolides}

_Alteration_Alteration _of_of _ribosomal_ribosomal_methylase_methylase ₍₍

erm

_erm

_B_B _gene_gene₎₎

Constitutive or inducible_{Constitutive or}inducible (D test)(D test)

MLS_MLS_B_B phenotypephenotype

_ATP_ATP_-_-_dependant_dependant _efflux_efflux_pump_pump ₍₍

mef

_mef

_E_E _gene_gene₎₎

_Resistance

_to

_{fluoroquinolones}

_Chromosomal_Chromosomal _mutations_mutations_of_of _gene_gene _encoding_encoding _for_for

Topoisomerase_{Topoisomerase} IV (IV (parparC, C, parparE)E)

DNA _DNAgyrasegyrase ((gyrgyrAA, , gyrgyrBB))

(11)

Susceptibility

/

_/

Resistance

_Resistance

testing

methods

_methods

_Disk

_diffusion

_Penicillin

_{: NOT}

_reliable

_!!

_Oxa

_screen

NCCLS 1_{NCCLS 1} µµµµµµµµg diskg disk (S >= 20 mm)(S >= 20 mm)

SFM 5 _{SFM 5}µµµµµµµµg g diskdisk (S >= 26 mm) (S >= 26 mm)

_No_No_{dicrimination}_{dicrimination} _between_between _I_I_and_and _R_R_isolates_isolates

_False_False _R_R_and_and _a_a_few_few _false_false _S_S

Need

(12)

S.pneumoniae

:

SIR

and

_and

penicillin

_penicillin

_S

_{Susceptibility}_{Susceptibility} ₍₍_MIC_MIC _{<= 0.064 mg/L)}_{<= 0.064 mg/L)}_correlates_correlates

with

with clinicalclinical outcomeoutcome withwith standard dosagesstandard dosages

_I

_Intermediate_Intermediate _{susceptibility}_{susceptibility} ₍₍_MIC_MIC _{<= 0.12}_{<= 0.12}_-_- ₁₁

mg/L)

mg/L) requiresrequires a a highhigh penicillinpenicillin dose for dose for clinicalclinical outcome

outcome

_R

_Resistance_Resistance ₍₍_MIC_MIC _{>= 2 mg/L)}_{>= 2 mg/L)}_necessitates_necessitates

alternative

(13)

Susceptibility

/

_/

Resistance

_Resistance

testing

methods

_methods

_{MICs in routine}

_Automated_Automated _{microdilution}_{microdilution} _system_system

Vitek_Vitek 2 (BioM2 (BioMéérieuxrieux))

Risk_Risk ofof underestimationunderestimation ofof RR

_Etest_Etest

The_The easiesteasiest andand affordableaffordable

Detects_Detects subtlesubtle decreasesdecreases in Sin S

Validated_Validated, , «« referencereference methodmethod »»

(14)

S.pneumoniae

AST

algorithm

Res

Respiratory

MIC/

MIC/EtestEtest

Pen Pen G G Amoxicillin Amoxicillin Cefotaxime Cefotaxime** Disc Disc Erythro Erythro ( (ClindaClinda.).) SXT SXT New FQ New FQ MIC/

MIC/EtestEtest

Pen Pen G G Cefotaxime Cefotaxime** Meropenem Meropenem Vancomycin Vancomycin New FQ if non New FQ if non--CSFCSF Disc Disc Oxacillin Oxacillin 11µµµµµµµµgg « « S >= 20 mmS >= 20 mm »» Erythro Erythro ( (ClindaClinda.).) SXT SXT New FQ New FQ or or

Blood

or

sterile

site

If If < 20 < 20

(15)

Streptococcus

(16)

Streptococcus

pyogenes

_Pharyngitis_Pharyngitis _and_and _asymptomatic_asymptomatic _carriage_carriage (1-₍₁-70%)70%)

_Scarlet_Scarlet _fever_fever

_Erysipelas_Erysipelas

_{Streptococcal}_{Streptococcal} _pyoderma_pyoderma ₍₍_Impetigo_Impetigo _Contagiosa_Contagiosa₎₎

_Lymphangitis_Lymphangitis

_Cellulitis_Cellulitis

_Necrotizing_Necrotizing _fasciitis_fasciitis

Myositis, _Myositis, pneumoniapneumonia

_STSS_STSS

_Puerperal_Puerperal _sepsis_sepsis

_Endocarditis_Endocarditis

_{Postinfectious}_{Postinfectious} _sequelae_sequelae

Rheumatic_Rheumatic fever, fever, poststreptococcalpoststreptococcal glomerulonephritisglomerulonephritis

The

(17)

Streptococcus

pyogenes

_pyogenes

_Therapeutic

_options

_Penicillin

_,

_Alternatives

_may

_include

_Macrolides_Macrolides_and_and _certain_certain_{cephalosporins}_{cephalosporins}_;_;

_Vancomycine_Vancomycine _for_for_pen_pen_-_-_allergic_allergic _patients_patients_with_with

serious

(18)

Streptococcus

pyogenes

_Penicillin

_{GAS remain 100 % Sensitive}_{GAS remain 100 % Sensitive}

₌₌_drug_drug _of_of _choice_choice

_S_S_-_-_testing_testing _not_not _necessary_necessary

_But

_{, reduced efficacy in severe GAS}

infection

_High_High_inoculum_inoculum

_{Decrease in expression of Penicillin Binding}_{Decrease in expression of Penicillin Binding}

Protein (PBP) by GAS in stationary phase

(19)

Streptococcus

pyogenes

_pyogenes

_{In severe infections:}

_Clindamycin

_more

effective

Not affected by _{Not affected by}inoculuminoculum or stationary phaseor stationary phase

Inhibits synthesis of bacterial toxins_{Inhibits synthesis of bacterial toxins}

Facilitates _Facilitatesphagocytosisphagocytosis of GAS by inhibiting synthesis of M of GAS by inhibiting synthesis of M protein

protein

Suppresses PBP Synthesis _{Suppresses PBP Synthesis} degradation_degradation

Longer post_{Longer post}--antibiotic effect/penicillinantibiotic effect/penicillin

_Resistance

_{to Macrolides}

(+/(+/-- 10%)10%)

Alteration_Alteration ofof ribosomal ribosomal methylasemethylase ((ermermBB genegene))

MLS_MLS_B_B phenotypephenotype, constitutive, constitutive

(20)

Streptococcus

agalactiae

_agalactiae

AsymptomaticAsymptomatic colonizationcolonization

NeonatalNeonatal infectionsinfections

•

• EOD & LODEOD & LOD

Infections Infections duringduring pregnancypregnancy

(21)

Risk factors for neonatal EOD

Vaginal Colonization

Obstetrical risks: Obstetrical risks:

Prolonged rupture of membranes, Prolonged rupture of membranes,

Prematurity

Prematurity, , IntrapartumIntrapartum feverfever

GBS GBS bacteriuriabacteriuria

Previous infant with GBS Previous infant with GBS

infection

Immunologic risks: Immunologic risks:

(22)

How could we

prevent neonatal

EOD ?

Intrapartum

Antibio

-

prophylaxis

Gyneco

Gyneco--ObstObst..

Labo

Pediatrician

Labor

(23)

Intrapartum

antibio

-

prophylaxis

(CDC 2002,

(CDC 2002, BelgianBelgian HC 2003)HC 2003)

_Penicillin

_G

5 millions U, IV initial dose, + 2,5

_{5 millions U, IV initial dose, + 2,5}

millions U IV

every

4

4 hours

hours

until

delivery

_Ampicilline

2 g IV initial dose, + 1 g IV _{2 g IV initial dose, + 1 g IV}every_every 4 h _{4 h}until_until delivery_delivery

Acceptable _Acceptablealternativealternative, but, but extendedextended spectrumspectrum, , maymay select R

(24)

Intrapartum

antibio

-

prophylaxis

In case

of

penicillin

-

allergy

(CDC 2002,

(CDC 2002, BelgianBelgian HC 2003)HC 2003)

Patient at low risk for anaphylaxis

_{Patient at low risk for anaphylaxis}

_Cefazolin_Cefazolin

Patient at high risk for anaphylaxis

_{Patient at high risk for anaphylaxis}

(25)

Therapeutic

options

_options

_Empiric

_Ampicillin_Ampicillin ₊₊_{aminoglycoside}_{aminoglycoside}

_When

_confirmed

_Penicilline_Penicilline ₊₊_{aminoglycoside}_{aminoglycoside} _{(max 3}_{(max 3}_-_-₅₅_days_days₎₎

(26)

GBS

susceptibility

profile

(Belgium)

0% 20% 40% 60% 80% 100%

Pen Ampi Céph.I Ery/Clin Sensible Résistant 15 15 àà 30 %, en30 %, en 50 % 50 % cMLScMLS_B_B 30 % 30 % iMLSiMLS_B_B 20 % M 20 % M

(27)

GBS

Penicillin

susceptibility

and

tolerance

_tolerance

No tolerance was observed : No tolerance was observed : 79.3 % of isolates had an MBC/MIC = 1 79.3 % of isolates had an MBC/MIC = 1 19 % of isolates had an MBC/MIC = 1.5 19 % of isolates had an MBC/MIC = 1.5

1.7 % of isolates had an MBC/MIC = 2 1.7 % of isolates had an MBC/MIC = 2

(28)

Streptococcus

«

_«

viridans

_viridans

»

_»

_Bacteremia

_Endocarditis

(29)

ββββ

-

hemolytic

streptococci

and

streptococcus

«

_«

viridans

_viridans

»

_»

_Tolerance

_to

ββββ

_-

_lactams

_High_High _MBCs_MBCs_despite_despite _low_low _MICs_MICs

_Progressive

_decreases

_{in S to}

_Penicillin

_in

ββββ

-

hemolytic

streptococci

_Pen

_{R in}

_viridans

_group

_Increasing

_macrolide,

_trimeth

_/

_sulfa

_and

_{FQ R}

MICs

needed

for

serious

infections

or

(30)

ββββ

-

hemolytic

streptococci

and

streptococcus

«

_«

viridans

_viridans

»

_»

_Disc_Disc _diffusion_diffusion

Penicillin_Penicillin andand FQ FQ

Only_Only for for ββββββββ--hemolytichemolytic streptococcistreptococci

_{Microdilution}_{Microdilution} _and_and _automated_automated _systems_systems

Growth_Growth supplementsupplement, CO2, , CO2, etcetc

Not_Not adaptedadapted, except, except for GBSfor GBS

_Etest_Etest

Easy, _Easy, affordableaffordable, , convenientconvenient

Media and_Mediaand atmosphereatmosphere adaptedadapted

Detects_Detects subtlesubtle decreasesdecreases in Sin S

(31)

ββββ

-

_-

hemolytic

_hemolytic

and

_and

viridans

_viridans

streptococci

AST

algorithm

Disc Disc Pen Pen G*G* ( (CefotaximeCefotaxime**)**) Erythromycin Erythromycin ( (ClindamycinClindamycin)) (New FQ) (New FQ) MIC/

MIC/EtestEtest

Pen Pen G* G* ( (CefotaximeCefotaxime**)**) Erythromycin Erythromycin Clindamycin Clindamycin Vancomycin Vancomycin (New FQ if non (New FQ if non--CSF)CSF)

Blood

or

sterile

site or

«

critical

»

patient

*

* PenPen S = S = ββ--lactamslactams SS

** ** or or CeftriaxoneCeftriaxone GAS, GBS, GCS & GAS, GBS, GCS & GGS large colonies GGS large colonies