3 The Disease - USA GBS emerged as an important pathogen in the 1970s Leading cause of sepsis in neonates Incidence: 0.4-4/1000. (Belgium= 2/1000) Motality > 14% Belgium: –240 cases/year –48 deads/ year L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
4 Comparison with other Killers in Childhood. Meningococcal Invasive Disease –Incidence 2.3/100.000 children –Dead 0.2/100.000 children Road Accidents –Incidence 2.5 deads/ 100.000 children GBS invasive disease –Incidence 220/ 100.000 newborns –Deads 33/100.000 newborns Neonatal GBS is an underestimated Public Health Problem.
5 Invasive GBS Disease Incidence by Age Group and Race MMWR Vol. 41 (No. SS-6) 1992
6 GBS Disease in Infants A Schuchat. Clin Micro Rev 1998;11:497-513. L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
7 Early-Onset Neonatal GBS Disease A Schuchat. Clin Micro Rev 1998;11:497-513. L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
8 Clinical Manifestations of Group B Streptococcus Infection
9 Early-Onset Infection < 6 days of life 85% :within 24 hours of birth case:fatality ratio 5-10% low 5 min Apgar, shock, neutropenia, pleural effusion, apnea, delay treatment, low birth weight, prematurity
11 5-10%, especially serotype III strains clinical presentation ~ bacteremia most common sign = Convulsions THUS: CSF !! persistent seizures, (semi)coma = poor prognosis Early-Onset Infection meningitis
12 35 - 55% acute respiratory signs: grunting, tachypnea, apnea often at birth, most < 24h low Apgar (<5 at 1min) X-ray abnormalities: –> 50% HMD –30% infiltrates –occasionally absent (~ persistent fetal circulation) Early-Onset Infection pneumonia
13 Profound progressive hypoxemia that is usually out of proportion to the radiographic evidence of pulmonary disease Early-Onset Infection persistent fetal circulation
14 Early-Onset Infection pneumonia
18 7 days - 12 weeks postnatal age case:fatality ratio 2-6% serotype III strains “clusters” in NICU (~ early onset) manifestations: –meningitis –bacteremia without focus –focal: osteomyelitis, septic arthritis, cellulitis, adenitis Late-Onset Infection
20 low incidence, high morbidity disease EOS = Pneumonia PFC hypoxia death LOS = Meningitis GBS Disease Big Disease with a Little Name
21 Maternal to Infant Transmission GBS colonized mother Non-colonized newborn Colonized newborn Asymptomatic Early-onset sepsis, pneumonia, meningitis 50% 98%2% L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen Risk Factors
22 GBS strain virulence Genital inoculum GBS bacteriuria Delivery <37 weeks’ gestation Premature rupture of membranes Rupture of membranes >18 hours Low levels of CPS-specific IgG Complement component deficiency Immature WBC function Early-Onset Infection risk factors
23 GBS Maternal Colonization GBS Carriers –10% - 30% of women (Belgium= 13-25%) –higher in African Americans and nonsmokers –clinical signs not predictive (Asymptomatic) –dynamic condition When to culture? –culture at delivery -- too late –prenatal cultures predict delivery status L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
24 Risk Factors for Early-Onset GBS Disease Obstetric: prolonged rupture of membranes, preterm, intrapartum fever GBS bacteriuria Previous infant with GBS disease Demographic (African American race, young age) Immunologic (low antibody to GBS capsular polysaccharide) L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
25 Prevention with Antibiotics WHEN are antibiotics most effective? –Antenatal –Postnatal –Intrapartum WHO should receive antibiotics ? –GBS carriers –OB risk factors –GBS carriers with OB risk factors L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
26 Prevention Strategies: 1992 American College of Ob & Gyn (ACOG) –no prenatal screening –prophylaxis for women with OB risk factors American Academy of Pediatrics (AAP) –universal prenatal screening –prophylaxis for carriers with OB risk factors EITHER approach expected to prevent 60-75% of early-onset disease L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
27 Early-Onset GBS Disease 1991 vs 1993 Active surveillance data Lab audits conducted for both years
28 Barriers to Effective GBS Disease Prevention 63% of clinicians collected prenatal cultures for GBS BUT: 91% used suboptimal sites (not vag/rectal) few clinicians knew what media their labs used <10% of 200 labs surveyed were using optimal media (selective broth) Jafari et al., Pediatr Infect Dis J 1995;14:662-7. Whitney et al., OB GYN 1997;89:28-32.
30 Consensus Guidelines Key Issues –predictive value of prenatal cultures –culture methods –disease in the asymptomatic carrier –risk stratification of women –cost-effectiveness
31 GBS Screening WHEN ? L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
32 Predictive Value of Antenatal Cultures by Interval to Delivery N=826; 26.5% GBS carriers Yancey et al., OB GYN 1996;88:811-5. > L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
33 Sensitivity and Specificity of Late Antenatal Cultures > N=826 Yancey et al., OB GYN 1996;88:811-5. L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
34 GBS screening WHERE ? L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
35 GBS Carriage by Culture Site * P <0.05 both vs. vaginal only L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
36 Specimen technique Lower vagina + Rectum (through anal sphincter) –One swab –Without speculum –Out patient setting or patient herself Transport –non-nutritive medium (Amies, Stuart’s without charcoal) –Store at room t° or in fridge (max. 48h)
37 GBS culture HOW ? L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
38 GBS Carriage by Culture Method * P <0.05 selective broth vs. blood agar L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
39 What is ‘Selective Broth Medium’? 1. Incubatie overnight on 35-37°C: –Todd-Hewitt broth supplemented with: nalidixic acid (15 mg/L) and colistin (10 mg/L) –Appropriate media are commercially available (e.g. LIM broth [BD]) 2. Subculture 18-24h: –Granada medium agar (Biomedics, Spain or distr. by International Medical) (anaerobically or glass coverslip) L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
40 Granada medium Orange colonies
41 Is Intrapartum Screening an Alternative?
42 Intrapartum screening Sensitivity should be > 85% (= culture) Rapid Covenient for laboratory –24h a day –7 days a week Alternatives
43 Intrapartum GBS Screening- Alternatives GBS antigen test. –Sensitivity to low (65%) –Positive= heavy colonization. –Negative = Unknown colonization. Real time PCR. –Sensitivity 97%, –Specificity 96.9% –45 min. Maximum –Not available on 24h basis –Not available in every Lab. At Present No Good Alternative
44 Communication To laboratory; –Clearly request “GBS screening” –Expected site of delivery –Expected time of delivery To Clinician; –address of expected delivery (Fax?) –Physician’s office. –Report only QUALITATIVE (Positive or Negative)
45 GBS screening WHO ? L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
46 CDC’s Prevention Recommendations 1996 PICK EITHER APPROACH: Screening-based approach 35-37 wk culture, offer IAP to preterm and to GBS carriers Risk-based approach IAP to preterm, ROM > 18 h, or intrapartum fever (T > 38 C) L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
47 Prevention Strategy Using Risk-Based Approach Any of the following: Delivery < 37 wks gestation* ROM > 18 hrs Intrapartum temp > 38C (100.4 F) Previous infant w/GBS disease GBS bacteriuria this pregnancy Give intrapartum penicillin No intrapartum antibiotics YES NO * For ROM w/out labor at <37 wks, collect GBS culture and EITHER: treat until cultures complete and negative or begin treatment once positive culture results available
48 Criticisms of Earlier Strategies AAP Strategy –predictive value of cultures at 26-28 wks –GBS carriers without OB risk factors –pressure to respond to positive culture result ACOG Strategy –>25% of all GBS cases unprevented –screening preference of some mothers –no evidence in clinical trials
49 Obstetric Risk Factors Among Women with GBS Infants * obstetric risk factors * no obstetric risk factors n = 245 * premature 18 hr, temp > 100.4 F (38 C) Rosenstein N. OB GYN 1997;90:901-6.
51 Advantages of the Risk-Based Strategy Logistically easier Potentially less expensive Particularly applicable to settings with low prenatal care L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
52 Cases and Deliveries by Prenatal Colonization and Risk Factors Boyer & Gotoff, Antibiot Chemother 1985.
53 Prevention Strategy Using Screening-Based Approach Risk factors: Previous infant w/GBS disease GBS bacteriuria this pregnancy Delivery < 37 wks gestation Collect rectal & vaginal swab at 35-37 wks No intrapartum prophylaxis needed Risk factors: Intrapartum fever > 38C ROM > 18 hrs Give intrapartum penicillin Offer intrapartum penicillin Give intrapartum penicillin YES NO GBS- GBS+ YES Not done, incomplete, or results unknown L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
54 Advantages of the Screening-Based Strategy Optimizes prenatal screening –fewer false negatives –less pressure on physicians to treat Antibiotics to all GBS carriers –antibiotics start earlier before development of risk factors –adequate time for antibiotic effectiveness L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
55 Comparison of Prevention Strategies * fever, ROM > 12 hr, gestation < 37 wks Rouse et al., OB GYN 1994;83:483-94.
56 Potential Impact of Each Strategy Early-onset GBS disease by Year, Area A Screening-Based Approach Risk-Based Approach Rosenstein N, et al., OB GYN 1997;90:901-6.
57 GBS chemoprophylaxis WHEN to Start ? L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
58 Timing of Intrapartum Ampicillin and Transmission of GBS De Cueto et al., OB GYN 1998;91:112-4.
59 GBS chemoprophylaxis What to Start ? L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
60 Antimicrobial Resistance in Belgium. -lactams (Pen, Amp, Cephalo-I) : –Today 100 % Sensitive! Erythromycine & Clindamycine –Belgium : 10 à 20 % in 2001 –88 % type MLS (20 % inducable) P. Melin (ULG)
61 Intrapartum Prophylaxis Penicillin G –5 million units IV load, then 2.5 million units IV every 4h until delivery Ampicillin –2 g IV load, then 1g IV every 4h until delivery –acceptable alternative, but broader spectrum may select for resistant organisms
62 Penicillin “allergic” –History = 12% –Proven peni-allergy is only 1-2% Alternative drugs: –No anaphylaxic history: cephalosporins 1st. Gen. (cephazolin) Loading: 2g, then 1g IV Q8h –Clindamycin (Dalacin) 900 mg Q8h –Vancomycin (Vancocin) in Clinda-R organisms? Intrapartum Prophylaxis Efficacy of these drugs NOT proven !
63 CDC’s Recommendations for Prenatal GBS Cultures Optimize cultures: Site: vagina and rectum –single swab or two swabs –through anal sphincter Timing: 35 to 37 weeks Collection: NOT by speculum –self collection an option Processing: selective broth medium L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
64 Impact of Prevention?
65 Incidence of GBS Disease and Hospital Prevention Policy Rate of Early-Onset Group B Streptococcal Disease By Surveillance Site in 1996 Percent of Hospitals with a Group B Streptococcal Prevention Policy in 1996
66 Early-Onset GBS Disease by Year and Location Active Surveillance (190,000 births/year) MMWR 1997;46 (No. 21):473-77.
67 What we Think is NOT What we Do !
68 Flemish Obstetricians’ profile in 1999 - A Survey. L.Mahieu et al, 2000, J Obst Gyn;5:460-4
69 Survey - Objective –Flemish obstetricians’ attitude regarding the prevention of perinatal GBS. –To determine the physician characteristics that predict divergent opinions from the screening based approach
71 Results Demografic Characteristics Surveys returned by 310 (53%) of 582 Age: 40 (25-79) years Gender: 62% male No. of deliveries: 153 (10-500) / year Hospital: 18% university, 64% non- academic, 18% rural Obstetrical interests: 61% Group practice: 56%
72 Results Feed back Total = 310/582 (53%)
73 Never (4.2%): –No consensus –Does not influence AB prophylaxis Always (44%): –Indication for AB therapy –Negative experience –Routine If “risk factor” (52%): –PPROM –previous child GBS+ Results Screening - Who?
74 Results Screening - When and where? Sensitivity 88 % Affected by: –vagina + rectum –transport medium –growth medium
75 Results Screening - Where?
76 Results Screening - When?
77 Results Prophylaxis - When?
78 Results Prophylaxis - What?
79 Independent Demographic Predictors of Compliance to CDC Guidelines (*) (*) Ordinal logistic regression
80 9.86 9.64 8.22 7.63 9.09 Independent Demographic Predictors of Compliance to CDC Guidelines (*)
81 Independent Demographic Predictors of Compliance to CDC Guidelines (*)
82 Independent Demographic Predictors of Compliance to CDC Guidelines (*) (*) Ordinal logistic regression
83 Minority (44%) believe in routine prenatal GBS screening. 1/3 screen at cervix. 3/4 use broadspectrum AB (ampi, +/- clavulanic acid). Compliance to guidelines is influenced by: –province (E- & W-Flanders) –High age of Obstetrician Conclusions Priorities for Improvement?
84 Managment of the Neonate at Risk for GBS.
85 The Symptomatic Neonate Full diagnostic evaluation –FBC + differential –CRP –Culture blood –Culture CSF (if indicated) –Endotracheal cultures (ventilated infant) –Surface cultures (nose and/or ear) Start antibiotics: Ampicillin + AG. –10 days for sepsis, 14 days for meningitis, 28 days for ventriculitis, osteomyletis –AG stop after 3-5 days.
86 Asymptomatic Newborn at Risk. Limited evaluation if –Duration of IAP < 4h (< 2 doses) –Optimal IAP but Gestation < 35 weeks Serial measurement at birth, 12h and/or 24h –FBC –CRP –No cultures unless AB treatment is started.
87 Laboratory Indices for EOS. CRP > 1.4 mg/dL or Increase (X 2-4). Leucopenia < 5000/mm³
88 Sample Algorithm for Management of Newborn if Maternal IAP Maternal IAP for GBS? Full diagnostics evaluation Empiric therapy yes Signs/sx of sepsis in newborn? Gestational age Duration of maternal IAP before delivery No evaluation No therapy Observe at least 48 hrs no 35 wks+ >4 hrs or >2 doses < 4 hrs or < 2 doses Limited evaluation Observe at least 48 hrs If sepsis suspected, full diagnostic evaluation and empiric therapy < 35 wks
89 Adjuvant Treatment IV Immunoglobulines? –opsonisation Cytokines? –GM-CSF –G-CSF Surfactant? –SP-A NO
90 Hoge Gezondheidsraad-2003 Ministerie van Volksgezondheid en Leefmilieu Microbilogist: Mellin P. Claeys G. Naessens A. Hubinon C. Gynecologists: De Mol P. Donders G. Temmerman M. Beckstedde I. Foulon W. Van Eldere J. Pediatricians: Mahieu L. Tuerlinckx D Levy J Lepage P. Ministery: DeVleeschouwer G./ Dubois J.
91 Need for Continuous Medical Education and development of Written Guidelines L. Mahieu et al. Obstet. Gynecol. 2000; 20: 460-464
92 Evaluating Prevention Programs Consider developing surveillance for: –Neonatal GBS disease? –Adverse reactions to prophylaxis? –Emergence of resistant perinatal infections? Economic evaluation? Compliance to guidelines? L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
93 Perinatale GBS. Beter voorkomen. Dan genezen ! L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
94 Laboratory Algorithm Inoculate swabs into selective broth –Todd-Hewitt broth with nalidixic acid (15 µg/ml) and EITHER colistin (10 µg/ml) or gentamicin (8 µg/ml) –Commercially: SBM or LIM broth Incubate broth 18-24 h. Subculture to sheep blood agar plate L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
95 Laboratory Algorithm, continued Inspect and ID suggestive organisms –B-hemolytic or nonhemolytic, Gram+, catalase- If GBS not identified after 18-24h on sheep BAP, reincubate and inspect at 48h Various GBS ag detection tests (slide agglutination, genetic probes, fluor. antibodies) may be used for specific identification or CAMP test for presumptive identification
96 Sample Diagnostic Evaluation of Infants Born to Mothers with IAP Full Evaluation –CBC & differential –Blood culture –+/- Chest X-ray –+/- Lumbar puncture Limited Evaluation –CBC & differential –Blood culture L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
97 Evaluating Prevention Programs Consider developing surveillance for: –neonatal GBS disease –adverse reactions to prophylaxis –emergence of resistant perinatal infections L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
98 Preventable 1995 GBS Cases by Each Strategy, by Area Rosenstein N, et al., OB GYN 1997:90:901-6.
100 Key GBS Resources MMWR 1996;45 (No. RR-7):1-24. ACOG Comm Opin 1996;173:1-8. Pediatrics 1997;99:489-96. CDC's GBS Internet page –http://www.cdc.gov/ncidod/dbmd/gbs GBS Association home page –http://www.groupbstrep.org
101 Impact of Prevention Early-Onset GBS Disease by Year and Percent Hospitals with a GBS Policy -- Atlanta, GA ACOG Tech Bulletin AAP Guidelines Provider Practice Survey CDC Draft Guidelines (Dec) Consensus Meeting Consensus Guidelines (May) Hospital Site Visits