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Management of severe streptococcal infectionShiranee SriskandanImperial College London
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• 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
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“..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
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Peripartum sepsis: the international context
Ronsmans et al, Lancet. 2006;368(9542):1189‐200
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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.
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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
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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
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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
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Opsonic antibody against emm1 group A streptococci among 200 pregnant women
Turner et al , 2011, unpublished
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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
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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
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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
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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)
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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?
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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
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Medical Obstetric Early Warning Charts
Who should use them?
Community?A&E depts
Must be linked to clear action plans when patients trigger
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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
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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
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• 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
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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
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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
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But may be problematic elsewhere
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60
70
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% 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
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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)
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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
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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
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Control
IVIG
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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
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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
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What is the protective mechanism of IVIG?
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No IVIG AdsorbedIVIG
ControlIVIG
Growth of G
AS in who
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bloo
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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
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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
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No IVIG AdsorbedIVIG
ControlIVIG
CFU/m
Lbloo
d
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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
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IVIG enhances clearance of GAS in HLA‐transgenic mouse model
Control GAS‐infected IVIG‐treated GAS‐infected
Mouse 1
Mouse 2
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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
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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
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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
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IVIG use in infectious diseases in UK
Immunoglobulin database, 2010, Dept Health
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Slide withheld at request of author
Online Lecture Library
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Slide withheld at request of author
Online Lecture Library
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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
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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
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Single case
Outbreak
Colonised HCW
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• 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
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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
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