Management of severe streptococcal infectionShiranee SriskandanImperial College London

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

• Managing severe GAS infection: peripartum sepsis▫ Use of clindamycin▫ Use of pooled intravenous immunoglobulin▫ Preventing nosocomial iGAS (12% of iGAS)

Cellulitis Pneumonia Bacteremia Necrotisingfasciitis

Peripartumsepsis

Toxic  shockSTSS

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

“..Sepsis has become the leading cause of Direct  maternal deaths in the UK since Confidential Enquiries  into Maternal Deaths commenced in 1952”

Linked with increase in Group A Streptococcal infections

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Peripartum sepsis: the international context

Ronsmans et al, Lancet. 2006;368(9542):1189‐200

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

The current increase in maternal deaths due to sepsis in the UK

Source: CMACE. Saving Mothers’ Lives: reviewing maternaldeaths to make motherhood safer: 2006–08. The Eighth Report on Confidential Enquiries into Maternal Deaths in the UnitedKingdom. BJOG 2011;118(Suppl. 1):1–203.

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

MicrobiologySevere sepsis/deaths

Group A streptococcus  >50%Staphylococcus aureus 10‐15%Strep pneumoniae 2‐5%Clostridium spp.  2‐5%

E. coli  20‐30%Pseudomonas 2‐10%Klebsiella spp 2‐5%Acinetobacter etc 2‐5%

Endometritis

Gram positiveGroups A, B, D streptococci

Staphylococcus aureus

Gram negativeEscherichia coli, Enterobacteriaceae

Citrobacter, Pseudomonas aeruginosa, Proteus mirabilis

Haemophilus , Gardenerella vaginalis

AnaerobesPeptostreptococcus sp.,Bacteroides

Clostridium spp, Fusobacterium

MiscellaneousChlamydia trachomatisMycoplasma hominis

Ureaplasma urealyticum

Bacteremia

Group B streptococcusGroup A streptococcusE.coli, S. aureus, Listeria

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Excess risk of iGAS in peripartum women• USA Deutscher et al Clin Infect Dis. 2011;53:114‐23 . Postpartum women have specific x20‐fold risk of GAS and GBS bacteremia .

• E&W:  52 cases of severe iGAS in postpartum women in 2009• Overall risk >120 times higher in 28d postpartum period (and >30 times higher if genital infection is excluded) compared to 15‐44y women who had not recently delivered a child.(Lamagni et al, XVIII Lancefield Symposium, 2011, Palermo.)

• Reasons for excess risk unknown▫ Contact with young children▫ Sore throat in self/near family

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Interaction of Group A streptococcus with human immune system

GAS adhesion,Biofilm

Mucosae: GAS resistance toantimicrobial peptides, complement

Host triggers

GAS Regulatory genes de-activated (or mutations arise)

GAS virulence genes de-repressedEg Capsule; SpyCEP (chemokine cleavage)

GAS invasive infection

Hostantibody

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Opsonic antibody against emm1 group A streptococci among 200 pregnant women

Turner et al , 2011, unpublished

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Case• 39 year old primagravid, caucasian

• Presented to local emergency dept• Flu‐like illness, diarrhoea 36h• NVD healthy infant 6d earlier

• Clinical signs of severe sepsis▫ HR 130, RR32, BP 86/50; mottling of skin

• Investigations ▫ Hb 14.5, plt 94, wcc 6.2; CRP 685; PT 15.2, APTT 39.6

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Management• As for severe sepsis (surviving sepsis guidance)• Early goal‐directed therapy; ICU• Antibiotics for community‐acq sepsis of unknown cause (ceftriaxone)

• PT  15.2 – 17 ‐ 18.9• APTT  39.6 ‐ 43.6 ‐51

• Increasing hypoxia • Increasing pain L foot

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Progress on ICU• Severe sepsis ‐DIC, shock• MRI L. foot :  nec. fasciitis• Clindamycin added• Further deterioration• Transferred to 2nd ICU with obstetric and plastic surgery units on site

• Eventual recovery after debridements

0

200

400

600

800

Day0

Day1

Day2

Day3

Day4

Day5

Day7

CRP

Microbiology

HVS (d1)  3+ Group A strepHVS (d2) 2+ Group A strepBlood (d1) No growth? Genital tract as portal of entry

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Foci of peripartum iGAS infection

Focus No.  (%  )

Bacteremia without focus  40 (46)Endometritis 24 (28)Peritonitis  7 (8)Septic abortion  6 (7)Cellulitis 3 (3)Septic arthritis  3 (3)Necrotizing fasciitis  3 (3)Strept toxic shock  3 (3)Chorioamnionitis 3 (3)Pneumonia  1 (1)Abscesses  0 (0)Others* 3 (3)*Meningitis, thrombophlebitis, and septic emboli.

USA (Chuang et al. Clin Infect Dis. 2002;35:665‐70)

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Recognition of peripartum GAS sepsisSIGNS

• Pyrexia OR Hypothermia• Tachycardia• Tachypnoea (RR>20)• Diarrhoea• Pain (variable degree‐ opiate req.)• (Vaginal discharge/abnormal lochia)

TESTS

• Leucopenia• Raised CRP

• Raised lactate/low pH• Thrombocytopenia

• Coagulopathy

THINK of possibilityNot all postpartum sepsis is genital tractMay present to any team Any other focus?

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Empiric management of peripartum infection• Antibiotics as early as possible (<1h) i.v. full dose▫ MODERATE Co‐amoxiclav (plus metronidazole)▫ OR  Cefuroxime (plus metronidazole)▫ OR if ESBL risk   Carbapenem

▫ SEVERE: Piperacillin/Tazobactam/gent or CarbapenemCLINDAMYCIN, IVIG if group A strep likely (cover MRSA if screening +ve)

• Cultures beforehand (blood), also HVS, throat, urine• Refine antibiotics once culture results known• Source control, repeat imaging if swinging pyrexia• Supportive care – fluids (cvp, catheter), oxygen, ICU‐ Rpt physiology and bloods

• Infection control‐ side room (nb iGAS is notifiable in UK)

RCOG guidelines 2012

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Medical Obstetric Early Warning Charts

Who should use them?

Community?A&E depts

Must be linked to clear action plans when patients trigger

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Rationale for use of clindamycin: in vitro action on GAS virulence factors 

• Inhibition of GAS exotoxinexpression by clindamycin>ampicillin

none ½ MIC

No antibiotic 

¼ MIC clindamycin

½ MIC clindamycin

J Antimic Chemother 1997;40:275‐77

• Enhancement of neutrophilkilling of GAS through inhibition of GAS capsule synthesis

Gemmell CG et al, J Clin Invest 1981; 67: 1249‐1256

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Adapted from: Stevens DL, J. Infect Dis.1993 Jun;167(6):1401‐5.

Rationale for use of clindamycin: in vivo models of iGAS SSTI

1     2     3    4     5     6    7     8     9   10   11   12   13  14  Time (days)

100

80

60

40

20

Survival %

Clindamycin

Erythromycin

Penicillin

Untreated 

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

• Retrospective review of 56 children with iGAS SSTI. Determined failure after 24h of treatment

Zimbelman H, et al. Pediatr Infect Dis J. 1999;18(12):1096‐100.

Rationale for use of clindamycin: retrospective clinical study of iGAS SSTI

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

The potential for problems with clindamycinGenotype Phenotype In English For ID physicians

mefA M Macrolide efflux pump

Resistance to macrolides only

ermA Inducible mlsB Altered target(ribosomal methylation)

Resistance to macrolides and inducible resistance to lincosamides(clindamycin)

ermB Inducible or constitutive mlsB

Altered target(ribosomal methylation)

Constitutive resistance to bothmacrolides and lincosamides

23s ribosomal RNA mutations

23s ribosomal RNA mutations

Constitutive resistance to bothmacrolides and lincosamides

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Macrolide and lincosamide resistance UK...

2010: England, Wales, N. IrelandHealth Protection Report Vol. 5 No. 46 – 18 November 2011 

Sensitive

Ery R ('M')

Ery + Clinda R(mlsB)

Group A Strep2010: London 8%

Group A Strep 4% clinda R

Sensitive

Ery R ('M')

Ery + Clinda R (mlsB)

Group G Strep 10% clinda R

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

But may be problematic elsewhere

0

10

20

30

40

50

60

70

80

90

100

% MLSB

% M% of a

ll GAS

 isolates

Extracted from individual published studies 2008‐2011Specific Emm types associated with emergence of MLSB phenotype eg emm12 and 22 in China 

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Intravenous Immunoglobulin (IVIG)• Purified IgG from pooled donors• Screened for HIV, HBV and HCV▫ Concerns about risks of Prion disease transmission‐supply

• >97% monomeric IgG• Products vary between manufacturers▫ Variety of (rare) adverse side effects▫ IgA and IgM content (Pentaglobin 12% IgM)

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Mechanisms of IVIG action

• Specific antibodies▫ Bacterial cell wall and secreted proteins

• Anti‐inflammatory antibodies▫ Anti‐Fas▫ Anti‐complement

• Monomeric IgG high specificity to FcγRI▫ pro inflammatory/ phagocyte activation

• Immune complexes bind with low affinity to other FcγR▫ Includes activation‐limiting FcγRIIB

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Rationale for use of IVIG in severe iGAS: 1. in vitro opsonic activity across multiple serotypes in whole blood and neutrophil killing assays  

0

50

100

150

200

250

300

350

M1 M1 M1 M1 M2 M3 M3 M3 M12 M22 M28 M28 M58 M75 M75 M78 M81 M89

CFU

Mul

tiplic

atio

n fa

ctor

Control

IVIG

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Rationale for IVIG. 2. in vitro neutralisation of GAS superantigens

Antigen presenting

cell

T cell

Toxic shockIL2TNF

SuperantigenegSPEA, SPEC, SMEZ

Schrage B et al. Clin Infect Dis. 2006;43:743-746

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

In GAS‐infected superantigen‐sensitive HLA‐transgenic mice, polyclonal IVIG can reduce systemic inflammation and bacterial load in spleen and blood

J Antimicrob Chemother 2006;58:117‐24

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

What is the protective mechanism of IVIG?

0

5000

10000

15000

20000

No IVIG AdsorbedIVIG

ControlIVIG

Growth of G

AS in who

le 

bloo

d CFU/m

l

AdsorbedIVIG

ControlIVIG

T cell proliferatio

n cpm

x 10

3

No IVIG AdsorbedIVIG

ControlIVIG

160

120

80

40

0

Removal of M1 GAS cell wall specific Ab from IVIG by adsorption against whole streptococci (or latex beads)

Removal of cell wall antibodies resulted in loss of opsonic action in whole blood assay

Removal of cell wall antibodies had no effect on neutralisation of M1 

GAS superantigens (T cell proliferation assay)

Davies, F, Charnock D, et al, unpublished

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Opsonising activity is not required for anti‐inflammatory effect of IVIG during iGAS in vivo • Despite absence of in vitro opsonising activity, systemic inflammation was reduced by adsorbed IVIG in transgenic mice infected with emm1 GAS

No IVIG AdsorbedIVIG

ControlIVIG

Davies, F, Charnock D, et al, unpublished

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

0

10000

20000

30000

40000

50000

No IVIG AdsorbedIVIG

ControlIVIG

CFU/m

Lbloo

d

0

10000

20000

30000

40000

No IVIG AdsorbedIVIG

ControlIVIG

CFU/g sp

leen

In vivo, IVIG enhances bacterial clearance even without cell wall specific opsonicantibodies

BloodSpleen

IVIG prevents dissemination of GAS by neutralisation ofadditional GAS virulence factors e.g.chemokine‐cleavingprotease SpyCEP

Davies, F, Charnock D, et al, unpublished

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

IVIG enhances clearance of GAS in HLA‐transgenic mouse model

Control GAS‐infected IVIG‐treated GAS‐infected

Mouse 1

Mouse 2

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Clinical trial of IVIG in STSSPrimary and secondary end points assessing efficacy of administration of high‐dose intravenous polyspecific IgG.Trial stopped due to low recruitment.

Darenberg J et al. Clin Infect Dis. 2003;37:333‐340

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Initial Sepsis‐related OrganFailure Assessment (SOFA)scores and changes duringtreatment in polyspecificintravenous IgG (IVIG)– andplacebo‐treated patients.

Darenberg J et al. Clin Infect Dis. 2003;37:333-340

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Immunoglobulin use in UK for iGASDiagnosis n Volume used 

(g)Average dose (g/patient)

Severe invasive group A streptococcal disease 31 4451 144

Necrotising (PVL‐associated) staphylococcal sepsis

20 2673 134

Severe or recurrent Clostridium difficile colitis 67 2297 34

Staphylococcal toxic shock syndrome 11 1388 126

Toxin‐related infection in paediatric intensive care

19 719 38

Sepsis in the intensive care unit not related to specific toxins or Clostridium difficile

3 384 128

Neonatal sepsis (prevention or treatment) 2 10 5

Other (Infectious diseases) 31 4096 132

Total 184 16,018

Immunoglobulin database, 2010, UK Dept Health

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

IVIG use in infectious diseases in UK

Immunoglobulin database, 2010, Dept Health

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Slide withheld at request of author

Online Lecture Library

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Slide withheld at request of author

Online Lecture Library

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Cumulative nu

mbe

r with

 outbreak strain

GAS can spread rapidly‐ preventing transmission requires speed

Exposures limited to single interactions18 days from first isolate to last isolate

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

1935 Recommendations(Dora Colebrook)

•Symptomatic URTI should be kept awayfrom women in the puerperium

•Prophylactic measures‐scrupulous hygieneincl disinfectants and masks

•Investigate every case and exclude thoseaffected (frequent nosocomial spread)

•Advice on perineal hygiene

•Estimated that 576 of 900 deaths per yearwere preventable

The doctor; 5

The midwife, 15

The handywoman, 

3

The husband; 3

The parent ; 3

A child; 8

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Single case

Outbreak

Colonised HCW

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

• Managing severe invasive GAS (peripartum sepsis)▫ If severe sepsis, likely to be GAS‐ prompt action▫ Not always genital tract sepsis▫ Use of clindamycin but beware resistance▫ Consider  pooled intravenous immunoglobulin▫ No RCTs but plausible mode of action▫ Prompt strategies to prevent nosocomial spread

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor

Acknowledgements• Claire Turner• Frances Davies

• Matthew Dryden, Royal Hampshire County Hospital • Matt Holden, WT Sanger Institute• Androulla Efstratiou, HPA• Theresa Lamagni, HPA• Joe Kearney, HPA & Working Party Guideline group

• UK CRC Centre for Infection Prevention and Management, Imperial College London

ESCMID O

nline

Lectu

re Lib

rary

© by au

thor