GBS WHY ARE WE TALKING ABOUT AN OLD PROBLEM? Dr. Chelsea Elwood - - PowerPoint PPT Presentation

GBS WHY ARE WE TALKING ABOUT AN OLD PROBLEM?

Julianne van Schalkwyk MD MSc FRCSC Department Head, Obstetrics and Gynecology, BCWH Clinical Associate Professor OBGYN and Reproductive Infectious Diseases Specialist Deborah Money, MD, FRCSC Executive Vice-Dean and Reproductive Infectious Diseases Specialist Faculty of Medicine The University of British Columbia

• Dr. Chelsea Elwood

Reproductive Infectious Diseases Fellow Department of Obstetrics and Gynecology University of British Columbia Chelsea.elwood@cw.bc.ca

• DR. VANESSA PAQUETTE
• DR. JOCELYN SRIGLEY
• DR. NANCY KENT

Disclosures and Collaborators

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OUTLINE

• What is Early Onset GBS
• What are approaches for screening
• What are treatment options
• Preterm GBS and PPROM

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OUTCOME INTERVENTION SCREENING/INDICATION

Intrapartum Antibiotic Prophylaxis Risk Factors

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WHERE DOES THIS BUG COME FROM? MATERNAL GBS COLONIZATION

• Streptococcus agalactiae
• Gram positive cocci
• part of normal vaginal microbiome (reservoir is rectum)
• Colonization can be transient, chronic or intermittent
• GBS bacteriuria
• heavy maternal colonization (assoc. with neonatal disease)
• Vaginal colonization in early pregnancy does not predict colonization at delivery

10-30% of women are colonized at delivery

• (BCWH = 30%)

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MATERNAL GBS COLONIZATION

Preterm labour and PPROM assoc. with heavy colonization with GBS

• (AJOG 1996;174:1354) OR 1.5 [1.1-1.9]
• GBS bacteriuria - 2-4% of pregnancies
• - assoc. with including risk of neonatal disease and maternal urinary disease
• (Scand. J. I.D. 1986;18:525)

Post partum morbidity endometritis and wound infections (18%)

• (JID, 1999;179:1410)

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EARLY ONSET NEONATAL GBS DISEASE

• Occurs at < 7 days of age
• 5-20% neonatal mortality
• 74% Bacteremia/sepsis
• 12% pneumonia
• 14% meningitis
• 25% of the cases occur in preterm infants (<37 wks)
• tend to a higher mortality rate

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NEONATAL GBS DISEASE

Incidence of GBS neonatal disease prior to intrapartum antibiotic prophylaxis:

• 2-3/1,000 in US in pre-antibiotic era
• At BCWH 2.4/1,000 (1987-1992 )

Incidence post antibiotic prophylaxis

• U.S. - 70% reduction in post-antibiotic era (1999)
• 0.5/1,000 live births
• B.C. - 0.1-0.7/1,000

1-2.4% of these infants develop early onset disease

• (in the absence of prophylaxis)

case fatality was 50% in the 1970’s - now ~15%

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OUTCOME INTERVENTION SCREENING/INDICATION

Intrapartum Antibiotic Prophylaxis Risk Factors

• 1981-1988 all public antenatal patients were screened 32

weeks' gestation

• 30,197 livebirths screened public patients and 26 915

unscreened private patients

• ZERO cases early onset neonatal GBS infections in infants of

treated asymptomatic carrier mothers.

• 27 infections and 8 deaths in unscreened patients

1997 – SOGC Guidelines 1997 American Academy of Pediatrics

Why was there a positive neonatal blood culture for GBS? Can we do better?

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EARLY ONSET GBS AT BCWH

Reviewed All cases of positive neonatal blood cultures and CSF cultures from 2008-2016 (October) Restricted to +Blood Cultures within 7 days of delivery

• 15 Cases
• 13 Cases had charts here adequate for full review

Term Preterm GBS positiv e GBS unknown GBS negative Received Intrapartum Prophylaxis Pen Allergy Eligible to Receive Neonatal demise 7 6 7 4 2 1 10 1

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WITHIN COHORT

2 cases of maternal screen GBS (-) with neonatal GBS disease 2 cases of known GBS (+), treat based on risk factors 4 PPROM 2 cases of precipitous deliveries 1 lethal anomaly

• Was NOT the GBS related demise
• 1. Screening and

treatment of GBS positive patients?

• 2. What about

intrapartum prophylaxis?

• 3. Screening and

treatment of PTL and/or PPROM?

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OUTCOME INTERVENTION SCREENING/INDICATION

Intrapartum Antibiotic Prophylaxis Risk Factors

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HOW AND WHO DO WE SCREEN?

What is the current gold standard test What are the different screening approaches

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HOW IS SCREENING DONE?

Vaginal Rectal Swab

• Current screening method mean PPV 69%, mean NPV 94%
• With population prevalence 30% may be as high as PPV 90%/NPV95%

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WHAT MAY COME….

PCR based techniques

• Sensitivities 90.7% and specificity 97.6%
• Advantages
• rapid,
• higher sensitivity and specificity
• Disadvantage
• Does not provide antimicrobial sensitivities (Pen allergic),
• false negative rate related to ROM,
• ?cost?

Potential role in women with PPROM?

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OUTCOME INTERVENTION SCREENING/INDICATION

Intrapartum Antibiotic Prophylaxis Risk Factors

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WHAT ARE APPROACHES FOR SCREENING AND TREATMENT?

Universal

• Screen at 35-37 weeks by

vag/rectal swab in enriched broth culture

• >37w provide intrapartum IV

antibiotics at time of ROM and/or at onset of labour:

– All women with + screen (and induce if ROM) – Any women with previous GBS affected infant – Any woman with GBS bacteriuria

“Risk based”

• Treat

– If unknown status and > 18 hrs ruptured – If unknown status and < 37 weeks – Any women with previous GBS affected infant – Any woman with GBS bacteriuria

• ZERO cases early onset

neonatal GBS infections in infants of treated asymptomatic carrier mothers.

• 27 infections and 8 deaths in

unscreened patients

• Incidence of GBS neonatal disease prior to

intrapartum antibiotic prophylaxis:

– At BCWH 2.4/1,000 (1987-1992 )

• Incidence post antibiotic prophylaxis

– B.C. - 0.1-0.7/1,000

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WHAT ABOUT TAKING TREATING BASED ON RISK FACTORS?

RCOG 2017

• Does not recommend universal screening

Lower population prevalence 0.5/1000

• matches the prevalence after initiation of screening and treatment in US and Canada

Theoretical Risks of antibiotic use Significant screening burden costs in the UK for which infrastructure is not available

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UNIVERSAL SCREENING VS RISK FACTOR BASED TESTING

Retrospective Cohort Study of 612, 915 live birth 1998-1999

• Subset of 5144 live births
• Stratified them for missed antibiotic opportunities
• Compared Risk factor vs Universal Screening and Treatment

RR 0.48 for early onset GBS disease No head to head trial comparing the two

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Retrospective Cohort Study 1997-2002 single center in Sweden Universal Screening and treatment with one risk factor

• Incidence was 1/1000
• Reduced 0.5/1000
• At BCWH 2.4/1,000
• Post Universal Screening and treatment B.C. - 0.1-

0.7/1,000

WHAT IS THE EVIDENCE?

Ontario College of Midwifery

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Offer universal screening between 35-37w with culture including women with planned CS Provide IV antibiotics onset of labour or ROM

• Positive swab
• Previously infected infant
• GBS bacteriuria regardless of CFU
• <37 weeks requires 48h of GBS prophylaxis IV unless testing has been done within 5

weeks

• Term PROM offer IOL
• If GBS status is unknown treat based on risk factors

CURRENT RECOMMENDATION

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OUTCOME INTERVENTION SCREENING/INDICATION

Intrapartum Antibiotic Prophylaxis Risk Factors

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EARLY ONSET GBS AT BCWH

Reviewed All cases of positive neonatal blood cultures and CSF cultures from 2008-2016 (October) Restricted to +Blood Cultures within 7 days of delivery

• 15 Cases
• 13 Cases had charts here adequate for full review

Term Preterm GBS positiv e GBS unknown GBS negative Received Intrapartum Prophylaxis Pen Allergy Eligible to Receive Neonatal demise 7 6 7 4 2 1 10 1

WHAT IS APPROPRIATE ANTIBIOTIC THERAPY?

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ANTIBIOTIC PHARMACOKINETICS

Am J Obstet Gynecol 1966; 96: 938–42. Int J Clin Pharmacol Ther 2006; 44(2): 57-63

Ancef Clinda Vancomycin

Penicillin G: narrowest, most active agent in vitro

• T ½: 30 minutes
• Q4h interval of administration, do not delay re-dosing
• Elimination: renal
• Placental transfer: complete
• Present in fetal serum and amniotic fluid within 5 minutes, reaching concentrations

in fetal serum similar to maternal serum within 60 minutes (above the MIC for GBS) Ampicillin:

• T ½: 60 minutes
• Elimination: renal
• Placental transfer: complete
• Present in fetal serum and amniotic fluid within 5 minutes, reaching concentrations

in the fetal serum similar to maternal serum within 60 minutes (above the MIC for GBS)

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ANTIBIOTIC PHARMACODYNAMICS: WHY 4 HOURS?

Am J Obstet Gynecol 2007; 197(6): 583.e1 Obstet Gynecol 1998; 91:112–4

Data for improved neonatal outcome when IV antibiotics administered at least 4 hours prior to delivery Nadir of GBS colonization occurs approximately 3 hours after administration of IV penicillin G

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WHAT ARE THE RISKS?

Anaphylaxis

• 1:10000 to 1:25 000
• fetus cannot have an anaphylactic reaction to Pen
• Maternal IgE does not cross the placenta

Cross reactivity

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PENICILLIN CROSS SENSITIVITY WITH CEPHALOSPORINS

Ann Allergy Asthma Immunol 2014; 112: 404 -412 Expert Opinion on Drug Safety 2012; 11(3): 381-399

Two areas of potential sensitivity:

• Beta lactam core
• R group side chains

Penicillins can have side chains that are the same as some cephalosporins Reported cross sensitivity ranges from < 2% up to 18% (usually quoted as 10% in manufacturers labelling)

• This data has multiple limitations and includes patients who were not confirmed allergic

to penicillin via skin testing

• Limiting the data to patients with a confirmed allergy to penicillin after 1980 (when

cephalosporins were no longer manufactured with traces of penicillin), the cross sensitivity rate is reported as 2% or less

Expert Opinion on Drug Safety 2012; 11(3): 381-399

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PENICILLIN CROSS SENSITIVITY WITH CEPHALOSPORINS

CDC MMWR 2010; 59: RR-10

Non severe penicillin reaction – use cefazolin Severe penicillin allergy (hypotension, urticaria, angioedema, wheezing, anaphylaxis) – use clindamycin ONLY IF PROVEN SENSITIVE Severe penicillin allergy, clindamycin resistant or sensitivity unknown – use vancomycin

Bottom line: Cross reactivity is likely lower than previously reported If patient reported reaction to penicillin is not likely Anaphylactic (IgE mediated), give cephalosporin

WHAT IS APPROPRIATE ANTIBIOTIC THERAPY?

CLINDAMYCIN AND ERYTHROMYCIN

Erm 43% resistance rate Clindamycin 37% resistance rate

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REQUESTING SENSITIVITIES

Lab BCWH hold specimens for 5 days

• If you forget to request sensitivities then call and they can do them

Urine positive for GBS

• Don’t forget Pen Allergic

ARE YOU CHANGING MY MICROBIOME?

• Evaluated 50 infants

– 25 exposed, 25 unexposed – 3 day stool samples – No difference in aerobic flora, slight decrease in anaerobic flora – No increase in B lactam resistant bacteria

• No single variable including

intrapartum antibiotic prophylaxis altered the infant

• ral, skin or gut microbiome

• Used targeted sequencing
• nly
• No long term follow up
• Studied 9 patients!!
• All patients were <32w GA

experiencing PTB!

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WHAT ARE THE OTHER THEORETICAL RISKS

Antimicrobial Resistance- ?Clinical significance?

• Neonatal sepsis, unless proven to be GBS will not be treated with Penicillin
• GBS is universally susceptible to penicillin
• Highly likely that any microbial resistance is maternal colonization and predates

intrapartum prophylaxis

• Decreases in the incidence of early-onset GBS sepsis have not been accompanied by

increases in incidence of early-onset sepsis caused by other pathogens

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PHARMACOKINETICS: WHY NOT ORAL ANTIBIOTICS?

Erythromycin: (increasing resistance to GBS – no longer recommended even in IV form)

• Time to peak concentration = 3 hours
• Bioavailability: < 50%

Vancomycin:

• Not orally absorbed (only clinical utility =

C diff infections) Overall, delayed time to achieve maximal maternal serum concentrations and lower concentrations achievable in fetal serum and amniotic fluid

• Amoxicillin:

– Time to peak concentration = 2 hours – Bioavailability: 75 – 90%

• Cephalexin:

– Time to peak concentration = 1 hour – Bioavailability: 90%

• Clindamycin:

– Time to peak concentration = 1 hour – Bioavailability: 90%

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PHARMACODYNAMICS: WHY NOT ORAL ANTIBIOTICS?

Am J Obstet Gynecol 1979; 135(8):1062 Int J Gynaecol Obstet 2008 May; 101(2):125-8

Administration of oral antibiotics in GBS positive non labouring women does not reduce GBS colonization significantly

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EARLY ONSET GBS AT BCWH

Reviewed All cases of positive neonatal blood cultures and CSF cultures from 2008-2016 (October) Restricted to +Blood Cultures within 7 days of delivery

• 15 Cases
• 13 Cases had charts here adequate for full review

Term Preterm GBS positiv e GBS unknown GBS negative Received Intrapartum Prophylaxis Pen Allergy Eligible to Receive Neonatal demise 7 6 7 4 2 1 10 1

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PRETERM INFANTS AND PPROM

Preterm infants are at higher risk of GBS disease (5:1000 t0 12:1000) CDC -78% reduction of GBS disease with treatment for infants < 37 weeks (2009) No direct Evidence for specific treatment of PPROM with GBS prophylaxis in RCT

SOGC 2010 CDC 2010

Why was there a positive neonatal blood culture for GBS? Can we do better?

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CONCLUSIONS

Early onset neonatal GBS disease continues to be largely preventable Universal Screening is the standard of care Send sensitivities and unless documented, avoid clindamycin Chorioamnionitis

• GBS on steroids!!
• Not GBS..this is a polymicrobial infection that can lead to neonatal and maternal

sepsis…treat with respect!

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REFERENCES

1. Ontario College of Midwives GBS guideline 2. ACOG committee opinion. Prevention of early-onset group B streptococcal disease in newborns. Number 173--June 1996. Committee on Obstetric Practice. American College of Obstetrics and Gynecologists. Int J Gynaecol Obstet. 1996;54(2):197-205. 3. Ganor-Paz Y, Kailer D, Shechter-Maor G, Regev R, Fejgin MD, Biron-Shental T. Obstetric and neonatal

• utcomes after preterm premature rupture of membranes among women carrying group B streptococcus. Int J

Gynaecol Obstet. 2015;129(1):13-6. 4. Garland SM, Fliegner JR. Group B streptococcus (GBS) and neonatal infections: the case for intrapartum

• chemoprophylaxis. Aust N Z J Obstet Gynaecol. 1991;31(2):119-22.

5. Jaureguy F, Carton M, Panel P, Foucaud P, Butel MJ, Doucet-Populaire F. Effects of intrapartum penicillin prophylaxis on intestinal bacterial colonization in infants. J Clin Microbiol. 2004;42(11):5184-8. 6. Lim DV, Morales WJ, Walsh AF, Kazanis D. Reduction of morbidity and mortality rates for neonatal group B streptococcal disease through early diagnosis and chemoprophylaxis. J Clin Microbiol. 1986;23(3):489-92. 7. Matorras R, Garcia-Perea A, Omenaca F, Diez-Enciso M, Madero R, Usandizaga JA. Intrapartum chemoprophylaxis of early-onset group B streptococcal disease. Eur J Obstet Gynecol Reprod Biol. 1991;40(1):57-62. 8. Renner RM, Renner A, Schmid S, Hoesli I, Nars P, Holzgreve W, et al. Efficacy of a strategy to prevent neonatal early-onset group B streptococcal (GBS) sepsis. J Perinat Med. 2006;34(1):32-8. 9. Schrag SJ, Zell ER, Lynfield R, Roome A, Arnold KE, Craig AS, et al. A population-based comparison of strategies to prevent early-onset group B streptococcal disease in neonates. N Engl J Med. 2002;347(4):233-9. 10. Tuppurainen N, Hallman M. Prevention of neonatal group B streptococcal disease: intrapartum detection and chemoprophylaxis of heavily colonized parturients. Obstet Gynecol. 1989;73(4):583-7. 11. Yancey MK, Schuchat A, Brown LK, Ventura VL, Markenson GR. The accuracy of late antenatal screening cultures in predicting genital group B streptococcal colonization at delivery. Obstet Gynecol. 1996;88(5):811-5.

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MERCER AND ORACLE

Randomized Trials showing increased latency with either

• IV Amp/Ery for 48h followed by PO amoxil/erythro
• Excluded pen allergic women, non-ressuring fetal heart rate, vaginal bleeding, maternal

indication for delivery, cercalge, Antibiotcs <5d and steroids < 7d, fever, those with fever illness requiring treatment or medical complication Mercer : the primary outcome GBS-negative cohort

Mercer

Randomized up to 36h post rupture Sample size was inadequate to comment on specific improvement of

• utcomes when

GBS+ Powered

• nly for the

GBS negative cohort

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ORACLE

Oracle Trial:

• Collaborative ORACLE 1
• Rate of neonatal early onset GBS sepsis is lower
• Universal screening is not recommended, treatment of known GBS+ patients is

recommended

• However treatment of know

No data was collected on GBS status Cannot comment on the protocol for GBS+ patients