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Group B Streptococcus Infection

Chiara Poggi, MD, PhDNeonatal Intensive Care Unit,

Department of Maternal and Child Health,Careggi University Hospital, Florence

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Conflict of Interest Statement

Nothing to disclose in relationship with this presentation/this course


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Burden of disease-US

Jordan, Pediatr Infect Dis J 2008

EOS 0.3/1000 LBs


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Burden of disease-EU/US

Edmond, Lancet 2012

GBS-disease


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Burden of disease

Trijbels-Smeulders, Pediatr Infect Dis J 2004

EU/GBS disease

GBS-EOSn. cases/1000 LBs

Edmond, Lancet 2012

•Under-reporting•Under-estimation

(early death)


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Burden of disease

Stoll, Pediatrics 2011

395586 LBs (2006-2009)

16 centers NRN

611 newborns EOS and/or EOM


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Spectrum of GBS diseaseEARLY ONSET LATE ONSET

Age at onset (mean) <7d (1 hr) 7d-3mo (28 d)

Clinical features at onset

Respiratory distressHyporeactivityAbnormal skin colour

FeverAbnormal skin colorDifficult feedingHyporeactivityIrritability

Localization Sepsis (most common)Pneumonia (30%)Meningitis (15%)

Sepsis (40-50%)Meningitis (30-40%)Osteoarthritis (5-10%)

Risk factors Positive maternal VRSGBS bacteriuriaPrematurityIntrapartum feverPROM> 18 hrsPrevious affected child

Positive maternal VRSBlack racePrematurity

Transmissione route Vertical VerticalBreastfeedingHands of personel

Prematurity Frequent Frequent

Common serotypes I, III, V III (90%), Ia, V

Mortality 5-18% 2-6%

Sequelae 10-30% 25-50%

Melin, Vaccine 2013Edmond, Lancet 2012


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EOS-Pathogenesis

10-35% colonization 40-60% colonization at birth- through birth canal- PROM

1-2% EOS

Berardi, Pediatr Infect Dis J 2014

Bacterial virulence factors Host susceptibility-genetic factors?

Di Renzo, J maternal Fetal Neonatal Med 2014


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ACTION

WHO

POLICY

Preventive strategies

By intrapartum administration of systemic antibiotics(IAP, Intrapartum Antibiotic Prophylaxis)

GOAL

TO REDUCE/ELIMINATE GBS TRANSMISSION FROM THE MOTHER TO THE NEWBORN

ALL GBS-COLONIZED PREGNANT WOMEN

PREGNANT WOMEN WITH SPECIFIC RISK FACTORS

UNIVERSAL SCREENING STRATEGY

RISK-BASED STRATEGY

Di Renzo, J Maternal Fetal Neonatal Med 2014

OR


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IAP-Efficacy

• 4 Trials (1986-2002)• 852 women with known colonization• 3 Trials: IAP vs. no treatment

IAP reduced:GBS-EOS RR 0.17 (95% CI 0.04-0.74)

IAP did not reduce:- Mortality from GBS infections;- Mortality from other infections;- All cause mortality.

Conclusion. There is lack of evidence from well designed and conducted trials to recommend

IAP to reduce neonatal EOGBSD.Olhsson, Cochrane Database of Systematic Reviews 2014, CD007467.


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Preventive strategies

RISK-BASED STRATEGY

UNIVERSAL SCREENING STRATEGY


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Risk-based strategyhttps://www.nice.org.uk/guidance/cg62

2008

2012

http://legacy.screening.nhs.uk/groupbstreptococcusESCMID Online Lecture Library

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Risk-based strategy: rationale

Edmond, Lancet 2012

• Low incidence of GBS-EOS (lower than US before universalscreening introduction);

• Likely GBS-EOS occurrence isnot going to decrease furtherwith universal screening;

• No significant differences vs. universal screening regions.

GBS-EOS/1000 LBs

NSC 2010


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Risk-based strategy - RCOG

https://www.rcog.org.uk/en/guidelines-research-services/audit-quality-improvement/gbs-audit/

[accidental]ESCMID Online Lecture Library

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Risk-based strategy: safety issues?

https://www.gov.uk/government/publications/health-protection-report-volume-10-2016

GBS-EOS in England, Wales and Northern Ireland (cases/1000 LBs)

Steer, Semin Fetal Neonatal Med 2011

+ 24%


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Risk-based strategy: safety issues?

Bekker, Lancet 2014

Interpretation.The introduction of prevention guidelines for invasive GBS disease in 1999 did not reduce the incidence in neonates. The guidelines should be reassessed and alternative approaches to prevent infant invasive GBS disease should be sought.

p<0.0001

p<0.0001

GBS

E. Coli


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Universal Screening strategy

http://www.cdc.gov/groupbstrep/guidelines/guidelines.html

Pediatrics 2011ESCMID Online Lecture Library

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Vaginal-rectal GBS screening

TIMING

35-37 weeks of gestationNo more than 5 weeks before delivery (NPV 95-98%)

COLLECTION AND PROCESSING

Swab of lower third of vagina and rectumSpecimen cultured with selective enrichment broth (Todd-Hewitt broth+gentamicin/nalidixicacid or colistin/nalidixic acid) subculture GBS identification with CAMP test or latex agglutination with antisera or chromogenic methods

ANTIMICROBIAL SUSCEPTIBILITY TESTING

Clindamycin and erythromycin susceptibility test in penicillin-allergic women

POPULATION

UniversalExceptions: GBS bacteriuria (current pregnancy)

Previous infant with GBS disease

CDC, MMWR 2010


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Candidates for intrapartum antibiotic prophylaxis

1. PREVIOUS INFANT WITH INVASIVE GBS DISEASE (any kind of delivery, any VRS result)

2. GBS BACTERIURIA-CURRENT PREGNANCY(any VRS result, except CS performed before the onset of labor with intact amniotic membranes)

3. POSITIVE GBS VRS-CURRENT PREGNANCY(except CS performed before the onset of labor with intact amniotic membranes)

4. UNKNOWN GBS STATUS AND ANY OF THE FOLLOWING:• GA < 37 weeks at delivery• PROM > 18 hrs• Intrapartum temperature > 38°C (> 100.4°F) • (Intrapartum NAAT positive for GBS)

CDC, MMWR 2010


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IAP: make the right choice

COMPLETE IAP: started at least 4 hrs

before delivery

CDC, MMWR 2010


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© Henri Cartier-BressonCDC, MMWR 2010


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Newborn with signs of sepsis

1. BLOOD CULTURE

2. CBC (+ WBC differential count)

3. CHEST X-RAY

4. LUMBAR PUNCTURE

Further exams: CRP, PCT, PCR, LKFT

AMPICILLIN/PENICILLIN IV100 mg/Kg x 2/25000-100000 IU X 4 at term

GENTAMICIN IV4 mg/Kg x 1 at term

COVER: GBS + E. COLI and other Gram negatives

CDC, MMWR 2010

FULL DIAGNOSTIC EVALUATION


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“To tap or not to tap?”

Polin, Pediatrics 2012

“LOW RISK” POPULATION:

Well appearing newborn with risk factors for EOS;

Newborn with symptoms likely attributable to non infectious diseases (TTN, RDS, IEM…)ESCMID Online Lectu

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“To tap or not to tap?”

NEWBORNS WITH EOS:EOM UP TO 23%

EOM under-estimated because of LP performed during antibiotic treatment

NEWBORN WITH EOM: NEGATIVE BC UP TO 38%

Missed diagnosis if LP not performed

(GBS>E.Coli)

Garges, Pediatrics 2006Stoll, Pediatrics 2011


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INDICATIONS TO LP-EOS

Polin, Pediatrics 2012

1. SUGGESTIVE CLINICAL SIGNS AND LABORATORY TEST at the beginning of sepsis work-up

2. POSITIVE BC

3. NO RESPONSE TO ANTIBIOTICS

For critically ill newborns with respiratory or cardiocirculatory instabilitythe LP must be delayed until a reasonable stabilty is achieved.ESCMID Online Lectu

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Risk-based strategy vs. ScreeningRISK-BASED SCREENING

Similar GBS-EOS rate in countries which adopted risk-based or screening strategy

Inconclusive data on screening efficacy

VRS identifies colonized women BUTcannot predict the occurrence of GBS-EOSOVERTREATMENT of consistent number of women at low risk

Concerns about inappropriate antibiotic useRESISTANCEANAPHYLAXIS

Increasing medicalization of labor/increasing costs

50% of newborns with GBS-EOS born to mother with NEGATIVE VRS False negatives Late colonization

Consistent public health problem

Decreasing EOS rate since CDC guidelines introduction

No emerging GBS RESISTANCE to beta lactams-no SAFETY ISSUES related to IAP

50-80% of newborns with GBS-EOS are born to mothers with NO RISK FACTORS

CDC, MMWR 2010RCOG 2016, NSC 2012


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Risk-based strategy vs. Screening

Shrag, NEJM 2002

Conclusions. Routine screening for group B streptococcus during pregnancy prevents more cases of early-onset disease than the risk-based approach. Recommendations that endorse both strategies as equivalent warrant reconsideration.

Retrospective cohort study 1998-99 Risk based or screening strategy 8 surveillance areas 5144 LBs randomlysampled from 629912 312 GBS-EOSESCMID Online Lectu

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EU Consensus


STRATEGY Universal screening

TIMING Intrapartum

HOW Rapid real time PCR, or other NAAT with high analytical performances (sensitivity>90%; specificity>95%)

If PCR not available: strict adherence to an optimized antenatal 35–37 weeks GBS culture screening

KEY POINTS


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Intrapartum PCRCRUCIAL TEST CHARACTERISTICS

1.Short turnaround time (NOT exceeding 30-45 mins) AND

2.Accuracy with high sensitivity and specificity, not inferior to 90–95% and 95–98% respectively AND

3.Easiness to perform and to interpret by labor and delivery staff with a minimum of skill and training AND

1.Availability at all times 24/7.

…Full traceability…Minimum of mainteinance and set-up


To prevent more cases of GBS-EOS

To reduce unnecessary IAPsAND

CRUCIAL CHARACTERISTICS


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Intrapartum PCR

Hakansson, J Maternal Fetal Neonatal Med 2014

Phase 1 - RANDOMIZED

Phase 2 - NON RANDOMIZED

ConclusionPCR assay, in the hands oflabor ward personnel, canbe useful for selection ofwomen to which IAPshould be offered.

229 women6 delivery units/SWEDEN

GROUP A: admistered IAP if positive/invalid PCR GROUP B: admistered IAP according to a risk-based strategy


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Intrapartum PCR

https://www.nice.org.uk/guidance/mib28

SENS 83-98%; SPEC 95-99%


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LOS and IAP

IAP does not affect LOS incidence;

IAP does not affect LOS incidence even in infants with onset of disease during the 1st month of life;

IAP does not affect the timing of LOS onset (no delay).

Jordan, Pediatr Infect Dis J 2008

1726 GBS LOS; 26% meningitis; Global case fatality ratio 4.3%; 1990-2005.

LOS

<1mo

LOS

EOS

>1moESCMID Online Lecture Library

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Immunization

POTENTIALS Protection against LOS;

Protection against EOS;

Protection against colonization/ GBS eradication in colonized women;

Reduction of preterm birth due to GBS vertical infection;

Reduction of stillbirths due to GBS vertical infection;

Reduction of GBS puerperal sepsis.

Melin, Vaccine 2013Madhi, Vaccine 2013

Heath, Exp Rev Vaccine 2011

RATIONALE LOS occurrence is not affected by IAP;

IAP does not prevent all cases of EOS;

IAP is not readily accessible worldwide;

Concerns about long term effects of IAP/antibiotic resistance

Evidence of placental passage of IgG class anti-capsular and anti-surface proteins Abs (GA > 34 wks)

Low levels of circulating anti-GBS Abs in the newborns are associated to incresead risk of GBS-disease


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Virulence factors

Melin, Vaccine 2013Edmond, Lancet 2012

CPS Complement inhibitionImpaired phagocytic clearance

Lung microvascular endothelial cells damagepneumonia, bloodstream invasion

Chemotaxins inhibition

CPSSurface proteins(C,R,X,Rib,Sip)

Pili Adherence to hostepithelium

Promotion of transepithelial migration

Mixed CPS-glyconjugates vaccine of the most diffused serotypes

mix of pilus proteins


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GBS Serotypes Distribution

III

Ib

Ia

II

V

8718 newborns with GBS EOS or LOS; 36 countries; 1980-2011.

Edmond, Lancet 2012Madhi, Vaccine 2013

5 serotypes accounted for more than 85% of cases in all regions;

Serotypes distribution is similar in all regions;

Serotypes distribution did not change over a 30 yrs period.

3 serotypes conjugated vaccine would prevent 78% of cases;

5 serotypes conjugated vaccine would prevent 85% of cases.


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GBS Serotypes Distribution

Johri, Vaccine 2013

CHINA INDIA BRAZIL

“Importantly, because the few colonization studies available for developing countries show high levels of carriage, we believe that GBS is largely an

unrecognized pathogen in the developing world. Future studies are needed to define the realistic burden of disease so that evidence-based policy and

appropriate public health interventions can be implemented in order to reduce neonatal mortality”


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Vaccine

• Prospective multicenter trial

• 33 mothers delivering newborns with GBS-EOS

• 99 matched colonized controls delivering healthy newborns

RISK REDUCTION: 90% 90% 70%Baker, JID 2014


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Vaccine

Baker, JID 2014

CPS TYPE Ia CPS TYPE III CPS TYPE V

Posterior mode-most likely value75° th percentile


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Vaccine

Madhi, Lancet Infect Dis 2016

Cohort 1 Cohort 2Healthy NON pregnant women

(age 18-40 yrs)N=60

Pregnant women (GA 28-35 wks)

N=320

Cohort 1

Randomization Randomization

Vaccination N=4020 mcg, 2 doses 1 month apart

Placebo N=20

Vaccination0.5 mcg, single dose

Vaccination2.5 mcg, single dose

Vaccination5 mcg, single dose

Placebo

N=80

N=80

N=80

N=80


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VaccineCohort 2 INFANTS

Madhi, Lancet Infect Dis 2016

N=317

Interpretation. The vaccine was well tolerated and induced capsular-specific antibody responses, in non-pregnant and pregnant women. Maternal vaccination led to higher GBS serotype-specific antibody concentrations in infants than did placebo, whit both intervention resulting in similar safety profiles.

Abs concentrations: • 49-79% of maternal levels• Negligible levels for the placebo group

NO SERIOUS ADVERSE EVENTS RELATED TO VACCINATION IN WOMEN/NEWBORNSESCMID Online Lectu

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Vaccine-HIV• 270 pregnant women (90 HIV neg)• 266 infants• Trivalent glycoconjugate vaccine:

single dose at 25-34 wks GA

Heyderman, Lancet Infect Dis 2016


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Heyderman, Lancet Infect Dis 2016

Vaccine-HIV


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Thank you!

[email protected]@aou-careggi.toscana.it


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