Intrapartum antibiotic prophylaxis failure and group-B streptococcus early-onset disease

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Intrapartum antibiotic prophylaxis failure and group-B

streptococcus early-onset disease

Journal: The Journal of Maternal-Fetal & Neonatal Medicine

Manuscript ID: DJMF-2010-0475.R2

Manuscript Type: Original Paper

Date Submitted by the Author:

20-Dec-2010

Complete List of Authors: Berardi, Alberto; Azienda Ospedaliero-Universitaria Policlinico, Scienze Ostetriche, Ginecologiche e Pediatriche Lugli, Licia; Azienda Ospedaliero-Universitaria Policlinico, Scienze Ostetriche, Ginecologiche e Pediatriche Rossi, Cecilia; Azienda Ospedaliero-Universitaria Policlinico, Scienze Ostetriche, Ginecologiche e Pediatriche China, Mariachiara; Azienda Ospedaliero-Universitaria Policlinico, Scienze Ostetriche, Ginecologiche e Pediatriche Chiossi, Claudio; Ospedale Civile, Unità Operativa di Pediatria Gambini, Lucia; Unità Operativa di Terapia Intensiva Neonatale, Azienda Ospedaliero-Universitaria, Parma, Italy Guidi, Battista; Ospedale Civile, Unità Operativa di Pediatria Pedna, Maria; Laboratorio di Microbiologia, Area Vasta Romagna, Pieve Sistina Piepoli, Marina; Ospedale G da Saliceto, Unità Operativa di Pediatria, Simoni, Angela; Ospedale B Ramazzini, Unità Operativa di Pediatria Ferrari, Fabrizio; Azienda Ospedaliero-Universitaria Policlinico, Scienze Ostetriche, Ginecologiche e Pediatriche

Keywords: Group B Streptococcus, Prophylaxis, Sepsis, Infant

URL: http://mc.manuscriptcentral.com/djmf Email: [email protected]

The Journal of Maternal-Fetal & Neonatal Medicine

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Intrapartum antibiotic prophylaxis failure and group-B streptococcus early-onset disease

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Abstract

Objectives: To determine factors influencing intrapartum antibiotic prophylaxis (IAP) failure in the

prevention of group B streptococcus (GBS) early-onset disease (EOD)

Methods: GBS EOD case is defined as isolation of GBS from a normally sterile body site (e.g.,

blood or cerebrospinal fluid) in infants aged ≤7 days. During a consecutive 93 month period, GBS

EOD cases and care data were reviewed.

Results: Seventy-nine GBS EOD cases were registered; 67 infants were born to women who

received no i.v. antibiotics during labor. The 12 EOD cases exposed to IAP were more likely to be

associated with emergency caesarean section (P=0.0015), maternal obstetric risk factors (ORFs)

(P=0.0061), particularly intrapartum fever (P=0.0002), and to present with signs of illness at birth

(P=0.0015). Correct dosages, agents and timing were registered in 3 cases only; of which 2 were

associated with intrapartum fever.

Conclusions: ORFs, emergency caesarean section and signs of illness at birth are significantly

associated with GBS EOD in infants exposed to IAP. This study also suggests that recommended

IAP agents, dosages and timing are infrequently associated with EOD. Strict protocol adherence is

recommended in all cases.

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Introduction

Group B streptococcus (GBS) is a major cause of severe bacterial infection in neonates [1].

Infection presenting within the first week of life (early-onset disease or EOD) is predominantly

caused by exposure to maternal GBS during childbirth. The risk of EOD increases for infants born

to GBS colonized mothers, with one or more obstetrical risk factors (ORFs: preterm birth, GBS

bacteriuria identified during the current pregnancy, previous infant with GBS infection, membrane

rupture ≥8 hours prior to delivery, maternal temperature ≥38° C during labour) [1,2].

EOD is mostly preventable through the administration of antibiotics during labour (intrapartum

antibiotic prophylaxis or IAP). The Centre for Disease Control and Prevention (CDC) guidelines

recommend maternal screening in late pregnancy (35-37 weeks of gestation) and the administration

of IAP to GBS screened culture-positive women, to women with GBS bacteriuria during current

pregnancy ant to women with a previous GBS infected infant [1].

As a result of prevention efforts, EOD rates have decreased over the past 15 years, but cases

continue to occur [3]. There is therefore a need to assess if further opportunities for preventing EOD

exist.

Culture-proven EOD is rare in infants exposed to IAP [4]. We compared all consecutive culture-

proven EOD cases over a period of 93 months in infants; they were classified according to the

administration or lack thereof of IAP. Individual patient demographic, clinical and infection

information were further analysed in infants who were exposed to IAP, in order to identify why

prophylaxis fails.

Methods

A prospective, population-based study has been ongoing in Emilia-Romagna since 2003 (a

northern region of Italy, population of 4,500,000). The GBS active surveillance network involves

regional neonatal and pediatric departments, and microbiologic laboratories [5].

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Standardized forms are used to collect both, maternal (antenatal colonization, gestational age,

ethnicity, mode of delivery, hours since membrane rupture, antibiotic administration) and neonatal

data (Apgar scores, sex, birth weight, health status, laboratory evaluation).

A GBS case is defined as the isolation of GBS from a normally sterile body site (e.g., blood or

cerebrospinal fluid) in infants aged ≤90 days. Bacteraemia is a GBS positive blood culture in infants

without any signs of illness. Proven sepsis is the growth of GBS from blood culture associated with

clinical symptoms consistent with sepsis [6]. A detailed description of most EOD cases has recently

been reported by the GBS active surveillance network [5].

Antenatal maternal GBS recto-vaginal screening is performed between 35-37 weeks of gestation.

CDC guidelines recommend penicillin (or ampicillin) as the first line agents for prophylaxis [1].

Ampicillin is routinely administered in Italy, as penicillin is not produced in this country. We

recommend a standard dose of ampicillin (2 g intravenously plus 1 g intravenously every 4 hours

until delivery) during active labor. Prophylaxis is considered adequate, according to the CDC

guidelines, if penicillin (or ampicillin) is administered at least 4 hours prior to delivery.

Alternative agents, recommended for penicillin-allergic women, include cefazolin for women

without a consistent risk of anaphylaxis [1], as cases of resistance to group B streptococcus have

not been reported in literature to date, and its activity is most similar to that of penicillin.

In cases of anaphylaxis risk, GBS isolates testing of susceptibility should be performed prior to the

administration of erythromycin or clindamycin [1].

Wider spectrum antibiotics are recommended for women with intrapartum fever or

chorioamnionitis.

A full diagnostic evaluation for infants exhibiting signs of sepsis, and a limited diagnostic

evaluation (blood count and blood culture) for healthy appearing newborns who did not receive

adequate IAP (administration <4 hours prior to delivery) are recommended as standard clinical

practice [5].

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Statistical analysis was performed according to the χ2 test and Mann-Whitney U test when

appropriate. A p value <0.05 was used as a threshold for statistical significance and 0.10<p<0.05 as

an indication of a trend. Data are presented as mean ± SD with ranges.

Results

Between 1st January 2003 to 31 August 2010, 307,148 live births were recorded, from which 79

EOD cases were registered (incidence rate of 0.26 per 1,000 live births).

Twenty-five mothers (31.6%) delivered by emergency caesarean section, whereas no cases of

EOD with planned caesarean section were identified. Maternal ORFs were found in 34 (43.0%) of

cases.

Clinical signs of illness were observed in 83.5% (66) of patients, whereas 16.5% (13) were

asymptomatic (bacteraemia). Mean gestational age was 37.1 weeks ± 4.6 (range 23-42), mean birth

weight was 2,936.8 gr ± 884.8.

Of the 79 EOD cases, 15.2% (12) were exposed to IAP and the remaining 85.8% (67) were not

(Table I). Characteristics of infants with and without IAP exposure are compared in Table 1.

Infants exposed to IAP

A significantly higher proportion of newborns exposed to IAP were delivered by emergency

caesarean section (p=0.0015), had identified ORFs (p=0.0061), particularly intra-partum fever

(p=0.0002), and presented with symptoms (p=0.0015) immediately (p=0.0031), compared with

EOD infected patients who had no exposure to IAP. The 12 individual patient characteristics,

management of IAP administration and EOD diagnosis are outlined in Table II.

Maternal ORFs were documented in 83.3% (≥2 ORFs were documented in 7 cases). Preterm

delivery was noted in 33.3%.

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All cases of non protocol specified agent (azythromycin) administration (case 1-3) occurred in the

same maternity unit.

Inadequate protocol specified agents were administered in 3 cases (<4 hours prior to delivery;

cases 4-6), GBS isolates were resistant in 2 cases (cases 7, 11), and narrow spectrum antibiotics

were administered in 2 cases (cases 11-12).

Overall, 7 mothers were treated with alternative agents to ampicillin. Erythromycin or

clindamycin were administered in 3 cases, but no susceptibility testing was performed prior to

administration. Timing and agents administered prior to delivery are illustrated in the Table II.

Four newborns had no signs of illness (bacteraemia). According to protocol, these infants were

culture tested because of maternal ORF identification and/or inadequate antibiotics administration.

Two newborns (case 4, 7) were mechanically ventilated and 3 (cases 4,8-9) received

cathecolamine support.

Brain lesions were documented at hospital discharge in one case (case 9). One infant, born

severely preterm with inadequate IAP administration (case 4), died 8 days after birth caused by

acute respiratory failure.

Discussion

GBS prevention has been adopted extensively and the rate of EOD incidence have decreased to

0.26 per 1,000 live birth. In this population (>300.000 live births), only 15.2% of infants with EOD

were exposed to IAP.

Interestingly, most of them had identified maternal ORFs. Compared with EOD cases without

IAP administration, cases exposed to IAP were more likely to be associated with maternal

intrapartum fever, to be delivered by emergency caesarean section and to present clinical signs of

illness at birth. These are possibly characteristics of an advanced infection in utero.

In this region, nearly 90% of women treated with IAP receive ampicillin during labor; the

remaining 10% receive alternative agents.

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Interestingly, most EOD cases exposed to IAP identified in this study were treated with

alternative agents to ampicillin. Resistant to these alternative agents by GBS is suspected, and

highlighted in this study was the question of the effectiveness of clindamycin and erythromycin.

Cefazolin, the recommended agent for women at risk of anaphylaxis, was only associated with 1

case of EOD, compared with 2 cases of clindamycin or erythromycin which were not tested for

susceptibility.

We do not know which was the actual risk of anaphylaxis for these penicillin-allergic mothers.

However, the choice of agent was guided mainly by the concern of adverse reactions. Having no

susceptibility testing, such agents were administered despite possible ineffectiveness.

Resistance of erythromycin and clindamycin to GBS isolates is increasingly reported in USA [7-

9]. Nevertheless, susceptibility testing to macrolides is rarely performed (<1% of colonized women

who are allergic to penicillin) and clindamycin is administered to 70% of women allergic to

penicillin [10].

In our case series, all non protocol specified agents were administered in the same maternity unit,

which was contacted and no further cases were registered.

Moreover, a protocol defined agent (ampicillin) was adequately administered in 3 mothers

according to correct dosages and timing. Strictly speaking, these cases only can be considered

failures of prophylaxis. Intrapartum fever (suspected chorioamnionitis) was observed in 2 cases and

all 3 newborns had severe disease at birth. Fetal acquisition of infection prior to initiation of IAP

was hypothesized. However, according to our local protocol and CDC guidelines, cases of

suspected chorioamnionitis should be treated with wider spectrum antibiotics rather than ampicillin

alone.

A limitation of this study is that we didn’t consider clinical sepsis (clinical course suggesting

sepsis with sterile blood culture). Sepsis may have been more common than this data shows, as

antibiotics may inhibit GBS growth in cultures.

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Further, we documented the presence of histological chorioamnionitis in 2 preterm newborns.

Those patients were possibly already infected in uterus and prophylaxis should not be expected to

be effective, as infants needed treatment rather than IAP. However, information on the presence of

histological chorioamnionitis was very scanty, as only recently it has been routinely obtained.

Therefore we could not assess the exact proportion of infants with an underlying chorioamnionitis.

In conclusion, this study has an epidemiological relevance, as it reflects the data and GBS cases

of a large area. Correct dosages, agents and timing were infrequently associated with EOD. These

results highlight how valid is prophylaxis and the need of doing it well. Further, we emphasize the

importance of susceptibility testing before erythromycin or clindamycin administration and

continued clinical education regarding strict protocol adherence in all cases of GBS infection risk.

Acknowledgments

We thank dr. Johanna Chester, who kindly revised the manuscript and gave valuable suggestions

Declaration of Interest statement

The authors report no declarations of interest

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References:

1. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A: Prevention of perinatal group B

streptococcal disease. Revised guidelines from CDC. MMWR Recomm Rep. 2002;

51(RR-11):1-22 .

2. Benitz WE, Gould JB, Druzin ML: Risk factors for early-onset group B streptococcal

sepsis: estimation of odds ratios by critical literature review. Pediatrics 1999;103:e77.

3. Jordan HT, Farley MM, Craig A, Mohle-Boetani J, Harrison LH, Petit S, Lynfield R,

Thomas A, Zansky S, Gershman K, Albanese BA, Schaffner W, Schrag SJ; Active

Bacterial Core Surveillance (ABCs)/Emerging Infections Program Network, CDC.

Revisiting the need for vaccine prevention of late-onset neonatal group B streptococcal

disease: a multistate, population-based analysis. Pediatr Infect Dis J. 2008;27:1057-64

4. Illuzzi JL, Bracken MB: Duration of intrapartum prophylaxis for neonatal group B

streptococcal disease: a systematic review. Obstet Gynecol. 2006;108:1254-65.

5. Berardi A, Lugli L, Baronciani D, Rossi C, Ciccia M, Creti R, Gambini L,Mariani S,

Papa I, Tridapalli E, Vagnarelli F, Ferrari F: Group B Streptococcus early-onset disease in

Emilia-romagna: review after introduction of a screening-based approach. Pediatr Infect

Dis J. 2010;29:115-21.

6. Gerdes JS. Clinicopathologic approach to the diagnosis of neonatal sepsis. Clin Perinatol.

1991;18:361-81.

7. Phares CR, Lynfield R, Farley MM, Mohle-Boetani J, Harrison LH, Petit S, Craig AS,

Schaffner W, Zansky SM, Gershman K, Stefonek KR, Albanese BA, Zell ER, Schuchat A,

Schrag SJ; Active Bacterial Core surveillance/Emerging Infections Program Network.

Epidemiology of invasive group B streptococcal disease in the United States, 1999-2005.

JAMA. 2008;299:2056-65.

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8. Castor ML, Whitney CG, Como-Sabetti K, Facklam RR, Ferrieri P, Bartkus JM, Juni

BA, Cieslak PR, Farley MM, Dumas NB, Schrag SJ, Lynfield R. Antibiotic resistance

patterns in invasive group B streptococcal isolates. Infect Dis Obstet Gynecol.

2008;2008:727505.

9. Blaschke AJ, Pulver LS, Korgenski EK, Savitz LA, Daly JA, Byington CL.

Clindamycin-resistant group B Streptococcus and failure of intrapartum prophylaxis to

prevent early-onset disease. J Pediatr. 2010;156:501-3.

10. Van Dyke MK, Phares CR, Lynfield R, Thomas AR, Arnold KE, Craig AS, Mohle-

Boetani J, Gershman K, Schaffner W, Petit S, Zansky SM, Morin CA, Spina NL, Wymore

K, Harrison LH, Shutt KA, Bareta J, Bulens SN, Zell ER, Schuchat A, Schrag SJ.

Evaluation of universal antenatal screening for group B streptococcus. N Engl J Med. 2009

18;360:2626-36

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Table I: Characteristics, clinical findings and outcome of infants with EOD, according to IAP

exposure

Infants without

IAP exposure

Infants with IAP

exposure

P

value

Patients, n 67 12

Emergency caesarean section, n (%) 16 (23.9) 9 (75.0) 0.0015

Mean birth weight, g, ± SD (range)

2,952.6 ± 889.3

(580-4700)

2848.8 ± 892.3

(745-3775)

NS

Mean gestational age, wks ± SD (range) 37.1 ±4.5 (23-42) 36.75 ± 5 (24-42) NS

Preterm delivery, n (%) 16 (23.4) 4 (33.3) NS

Identified maternal ORFs, n (%) 24 (35.8) 10 (83.3) 0.0061

Maternal intrapartum fever 2 (0.03) 5 (41.7) 0.0002

Mean Apgar score, 5th min., ± SD (range) 9.0 ± 1.7 (2-10) 8.5 ± 1.6 (5-10) NS

Bacteraemia, n (%) 9 (13.4) 4 (33.3) NS

Sepsis, n (%) 56 (83.6)* 8 (66.7) NS

Meningitis, n (%) 7 (10.4)* 0 NS

Signs of illness at birth, n (%) 8 of 59 pts (13.6) 8 of 8 pts (100) 0.0015

Mean age at symptom presentation, hrs ± SD

(range) ¥

10.4 ± 16.4 (0-72) 0 ± 0 0.0031

Catecholamine support, n (%) 10 (14.9) 3 (25.0) NS

Mechanical ventilation, n (%) 13 (19.4) 3 (25.0) NS

Documented brain lesions at discharge, n (%) 6 (9.0) 1 (8.3) NS

In hospital mortality, n (%) 5 (7.5) 1 (8.3) NS

NS; Not statistically significant

* 4 patients were infected with both, sepsis and meningitis

¥ 13 infants without any sign of illness were excluded from calculation

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Table II: Table II: Cases exposed to intrapartum antibiotics: doses, timing and agents administered

prior to delivery

Case Birth

weight,

gr (GA,

wks)

ORFs Antibiotic

(doses)

Administration,

complete hrs

before delivery

Loading

dose

Diagnosis Protocol

violation

1 2730

(36)

P Azythromycin (1) § 1 500 mg Bacteraemia NPSA

2 3650

(40)

F Azythromycin (1) § 4 500 mg Bacteraemia NPSA

3 3775

(40)

B Azythromycin (1) § 3 500 mg Bacteraemia NPSA

4 745

(24)

P, B Ampicillin (1) 2 2 gr, Sepsis,

Pneumonia

/

5 1900

(32)

P,

ROM

Cefazolin (1) 0 ¥ 2 gr Sepsis /

6 2140

(33)

P, B,

ROM

Ampicillin (1) 3 2 gr Bacteraemia /

7 2710

(38)

/ Clindamycin (1) §§ 3 900 mg Sepsis,

EA

/

8 2920

(39)

F,

ROM

Ampicillin (2) 5 2 gr Sepsis,

Pneumonia

/

9

3210

(40)

/ Ampicillin (1) 4 2 gr Sepsis,

Intrapartum

asphyxia

/

10 3270

(42)

F Ampicillin (2) 8 2 gr Sepsis /

11 3215

(40)

F,

ROM

Erythromycin (2) §§ 10 600 mg Sepsis NSA

12 3730

(40)

F Erythromycin (1) 2 600 mg Sepsis NSA

GA= gestational age. Wks = weeks. ORFs= obstetrical risk factors. P= prematurity. ROM= prolonged membrane

rupture (> 18 hours). B= bacteriuria. F= Intrapartum fever. IVH= intraventricular haemorrhage. NPSA=Non protocol

specified agent. OA= oral administration. EA= esophageal atresia. NSA=narrow spectrum antibiotics.

§ GBS sensitivity to azythromycin undetermined

¥ 20 minutes

§§ GBS resistant

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Intrapartum antibiotic prophylaxis failure and group-B streptococcus early-onset disease

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Abstract

Objectives: To determine factors influencing intrapartum antibiotic prophylaxis (IAP) failure in the

prevention of group B streptococcus (GBS) early-onset disease (EOD)

Methods: GBS EOD case is defined as isolation of GBS from a normally sterile body site (e.g.,

blood or cerebrospinal fluid) in infants aged ≤7 days. During a consecutive 93 month period, GBS

EOD cases and care data were reviewed.

Results: Seventy-nine GBS EOD cases were registered; 67 infants were born to women who

received no i.v. antibiotics during labor. The 12 EOD cases exposed to IAP were more likely to be

associated with emergency caesarean section (P=0.0015), maternal obstetric risk factors (ORFs)

(P=0.0061), particularly intrapartum fever (P=0.0002), and to present with signs of illness at birth

(P=0.0015). Correct dosages, agents and timing were registered in 3 cases only; of which 2 were

associated with intrapartum fever.

Conclusions: ORFs, emergency caesarean section and signs of illness at birth are significantly

associated with GBS EOD in infants exposed to IAP. This study also suggests that recommended

IAP agents, dosages and timing are infrequently associated with EOD. Strict protocol adherence is

recommended in all cases.

Comment [MSOffice1]: Added to

text

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Introduction

Group B streptococcus (GBS) is a major cause of severe bacterial infection in neonates [1].

Infection presenting within the first week of life (early-onset disease or EOD) is predominantly

caused by exposure to maternal GBS during childbirth. The risk of EOD increases for infants born

to GBS colonized mothers, with one or more obstetrical risk factors (ORFs: preterm birth, GBS

bacteriuria identified during the current pregnancy, previous infant with GBS infection, membrane

rupture ≥8 hours prior to delivery, maternal temperature ≥38° C during labour) [1,2].

EOD is mostly preventable through the administration of antibiotics during labour (intrapartum

antibiotic prophylaxis or IAP). The Centre for Disease Control and Prevention (CDC) guidelines

recommend maternal screening in late pregnancy (35-37 weeks of gestation) and the administration

of IAP to GBS screened culture-positive women, to women with GBS bacteriuria during current

pregnancy ant to women with a previous GBS infected infant [1].

As a result of prevention efforts, EOD rates have decreased over the past 15 years, but cases

continue to occur [3]. There is therefore a need to assess if further opportunities for preventing EOD

exist.

Culture-proven EOD is rare in infants exposed to IAP [4]. We compared all consecutive culture-

proven EOD cases over a period of 93 months in infants; they were classified according to the

administration or lack thereof of IAP. Individual patient demographic, clinical and infection

information were further analysed in infants who were exposed to IAP, in order to identify why

prophylaxis fails.

Methods

A prospective, population-based study has been ongoing in Emilia-Romagna since 2003 (a

northern region of Italy, population of 4,500,000). The GBS active surveillance network involves

regional neonatal and pediatric departments, and microbiologic laboratories [5].

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Standardized forms are used to collect both, maternal (antenatal colonization, gestational age,

ethnicity, mode of delivery, hours since membrane rupture, antibiotic administration) and neonatal

data (Apgar scores, sex, birth weight, health status, laboratory evaluation).

A GBS case is defined as the isolation of GBS from a normally sterile body site (e.g., blood or

cerebrospinal fluid) in infants aged ≤90 days. Bacteraemia is a GBS positive blood culture in infants

without any signs of illness. Proven sepsis is the growth of GBS from blood culture associated with

clinical symptoms consistent with sepsis [6]. A detailed description of most EOD cases has recently

been reported by the GBS active surveillance network [5].

Antenatal maternal GBS recto-vaginal screening is performed between 35-37 weeks of gestation.

CDC guidelines recommend penicillin (or ampicillin) as the first line agents for prophylaxis [1].

Ampicillin is routinely administered in Italy, as penicillin is not produced in this country. We

recommend a standard dose of ampicillin (2 g intravenously plus 1 g intravenously every 4 hours

until delivery) during active labor. Prophylaxis is considered adequate, according to the CDC

guidelines, if penicillin (or ampicillin) is administered at least 4 hours prior to delivery.

Alternative agents, recommended for penicillin-allergic women, include cefazolin for women

without a consistent risk of anaphylaxis [1], as cases of resistance to group B streptococcus have

not been reported in literature to date, and its activity is most similar to that of penicillin.

In cases of anaphylaxis risk, GBS isolates testing of susceptibility should be performed prior to the

administration of erythromycin or clindamycin [1].

Wider spectrum antibiotics are recommended for women with intrapartum fever or

chorioamnionitis.

A full diagnostic evaluation for infants exhibiting signs of sepsis, and a limited diagnostic

evaluation (blood count and blood culture) for healthy appearing newborns who did not receive

adequate IAP (administration <4 hours prior to delivery) are recommended as standard clinical

practice [5].

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Statistical analysis was performed according to the χ2 test and Mann-Whitney U test when

appropriate. A p value <0.05 was used as a threshold for statistical significance and 0.10<p<0.05 as

an indication of a trend. Data are presented as mean ± SD with ranges.

Results

Between 1st January 2003 to 31 August 2010, 307,148 live births were recorded, from which 79

EOD cases were registered (incidence rate of 0.26 per 1,000 live births).

Twenty-five mothers (31.6%) delivered by emergency caesarean section, whereas no cases of

EOD with planned caesarean section were identified. Maternal ORFs were found in 34 (43.0%) of

cases.

Clinical signs of illness were observed in 83.5% (66) of patients, whereas 16.5% (13) were

asymptomatic (bacteraemia). Mean gestational age was 37.1 weeks ± 4.6 (range 23-42), mean birth

weight was 2,936.8 gr ± 884.8.

Of the 79 EOD cases, 15.2% (12) were exposed to IAP and the remaining 85.8% (67) were not

(Table I). Characteristics of infants with and without IAP exposure are compared in Table 1.

Infants exposed to IAP

A significantly higher proportion of newborns exposed to IAP were delivered by emergency

caesarean section (p=0.0015), had identified ORFs (p=0.0061), particularly intra-partum fever

(p=0.0002), and presented with symptoms (p=0.0015) immediately (p=0.0031), compared with

EOD infected patients who had no exposure to IAP.

Of the EOD cases, 15.2% (12) were exposed to IAP and the remaining 85.8% (67) did not receive

IAP. (Table I).

Characteristics of all infants with EOD.

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Twenty-five mothers delivered by emergency caesarean section. No cases of EOD with planned

caesarean section were identified. Maternal ORFs were found in 43% of cases. Information

regarding histological or clinical chorioamnionitis was mostly unavailable.

Clinical signs of illness were observed in 83.5% of patients. Mean gestational age was 37.1

weeks ± 4.6 (range 23-42), mean birth weight was 2,936.8 gr ± 884.8. Characteristics of infants

with and without IAP exposure are compared in table 1.

A significantly higher proportion of newborns with EOD exposed to IAP were delivered by

emergency caesarean section (p=0.0015), had identified ORFs (p=0.0061), particularly intra-partum

fever (p=0.0002), and presented with symptoms (p=0.0015) immediately (p=0.0031), compared

with EOD infected patients who had no exposure to IAP.

Characteristics of infants exposed to IAP

The 12 individual patient characteristics, management of IAP administration and EOD diagnosis are

outlined in Table II.

Maternal ORFs were documented in 83.3% (≥2 ORFs were documented in 7 cases). Preterm

delivery was noted in 33.3%. Histological confirm of chorioamnionitis was available in 2 of 4

mothers (case 4 and 6).

All cases of non protocol specified agent (azythromycin) administration (case 1-3) occurred in the

same maternity unit.

Inadequate protocol specified agents were administered in 3 cases (<4 hours prior to delivery;

cases 4-6), GBS isolates were resistant in 2 cases (cases 7, 11), and narrow spectrum antibiotics

were administered in 2 cases (cases 11-12).

Overall, 7 mothers were treated with alternative agents to ampicillin. Erythromycin or

clindamycin were administered in 3 cases, but no susceptibility testing was performed prior to

administration. Timing and agents administered prior to delivery are illustrated in the Table II.

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Four newborns had no signs of illness (bacteraemia). According to protocol, these infants were

culture tested because of maternal ORF identification and/or inadequate antibiotics administration.

Two newborns (case 4, 7) were mechanically ventilated and 3 (cases 4,8-9) received

cathecolamine support.

Brain lesions were documented at hospital discharge in one case (case 9). One infant, born

severely preterm with inadequate IAP administration (case 4), died 8 days after birth caused by

acute respiratory failure.

Discussion

GBS prevention has been adopted extensively and the rate of EOD incidence have decreased to

0.26 per 1,000 live birth. In this population (>300.000 live births), only 15.2% of infants with EOD

were exposed to IAP.

Interestingly, most of them had identified maternal ORFs. Compared with EOD cases without

IAP administration, cases exposed to IAP were more likely to be associated with maternal

intrapartum fever, to be delivered by emergency caesarean section and to present clinical signs of

illness at birth. These are possibly characteristics of an advanced infection in utero.

In this region, nearly 90% of women treated with IAP receive ampicillin during labor; the

remaining 10% receive alternative agents.

Interestingly, most EOD cases exposed to IAP identified in this study were treated with

alternative agents to ampicillin. Resistant to these alternative agents by GBS is suspected, and

highlighted in this study was the question of the effectiveness of clindamycin and erythromycin.

Cefazolin, the recommended agent for women at risk of anaphylaxis, was only associated with 1

case of EOD, compared with 2 cases of clindamycin or erythromycin which were not tested for

susceptibility.

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We do not know which was the actual risk of anaphylaxis for these penicillin-allergic mothers,

However, the choice of agent was guided mainly by the concern of adverse reactions. Having no

susceptibility testing, such agents were administered despite possible ineffectiveness.

Resistance of erythromycin and clindamycin to GBS isolates is increasingly reported in USA [7-

9]. Nevertheless, susceptibility testing to macrolides is rarely performed (<1% of colonized women

who are allergic to penicillin) and clindamycin is administered to 70% of women allergic to

penicillin [10].

In our case series, all non protocol specified agents were administered in the same maternity unit,

which was contacted and no further cases were registered.

Moreover, a protocol defined agent (ampicillin) was adequately administered in 3 mothers

according to correct dosages and timing. Strictly speaking, these cases only can be considered

failures of prophylaxis. Intrapartum fever (suspected chorioamnionitis) was observed in 2 cases and

all 3 newborns had severe disease at birth. Fetal acquisition of infection prior to initiation of IAP

was hypothesized. However, according to our local protocol and CDC guidelines, cases of

suspected chorioamnionitis should be treated with wider spectrum antibiotics rather than ampicillin

alone.

A limitation of this study is that we didn’t consider clinical sepsis (clinical course suggesting

sepsis with sterile blood culture). Sepsis may have been more common than this data shows, as

antibiotics may inhibit GBS growth in cultures.

Further, we documented the presence histological chorioamnionitis in 2 preterm newborns. Those

patients were possibly already infected in uterus and prophylaxis should not be expected to be

effective, as infants needed treatment rather than IAP.

However, information on the presence of chorioamnionitis was very scanty, as only recently it has

benn routinely obtained. Therefore, we could not assess the exact proportion of infants who had an

underlying chorioamnionitis. Formatted: Italian (Italy)

Deleted: but the concern of adverse

reactions was the main reason

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choice; having no susceptibility testing,

such agents were administered despite

possible ineffectiveness. ¶

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In conclusion, this study has an epidemiological relevance, as it reflects the data and GBS cases

of a large area. newborns exposed to IAP were more likely to be delivered by emergency caesarean

section, to have ORFs and to present with signs of illness at birth. Correct dosages, agents and

timing were infrequently associated with EOD. These results further highlight how valid is GBS

prophylaxis and the need of doing it well. Further, we emphasize the importance of susceptibility

testing before erythromycin or clindamycin administration and continued clinical education

regarding strict protocol adherence in all cases of GBS infection risk.

Acknowledgments

We thank dr. Johanna Chester, who kindly revised the manuscript and gave valuable suggestions

Declaration of Interest statement

The authors report no declarations of interest

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References:

1. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A: Prevention of perinatal group B

streptococcal disease. Revised guidelines from CDC. MMWR Recomm Rep. 2002;

51(RR-11):1-22 .

2. Benitz WE, Gould JB, Druzin ML: Risk factors for early-onset group B streptococcal

sepsis: estimation of odds ratios by critical literature review. Pediatrics 1999;103:e77.

3. Jordan HT, Farley MM, Craig A, Mohle-Boetani J, Harrison LH, Petit S, Lynfield R,

Thomas A, Zansky S, Gershman K, Albanese BA, Schaffner W, Schrag SJ; Active

Bacterial Core Surveillance (ABCs)/Emerging Infections Program Network, CDC.

Revisiting the need for vaccine prevention of late-onset neonatal group B streptococcal

disease: a multistate, population-based analysis. Pediatr Infect Dis J. 2008;27:1057-64

4. Illuzzi JL, Bracken MB: Duration of intrapartum prophylaxis for neonatal group B

streptococcal disease: a systematic review. Obstet Gynecol. 2006;108:1254-65.

5. Berardi A, Lugli L, Baronciani D, Rossi C, Ciccia M, Creti R, Gambini L,Mariani S,

Papa I, Tridapalli E, Vagnarelli F, Ferrari F: Group B Streptococcus early-onset disease in

Emilia-romagna: review after introduction of a screening-based approach. Pediatr Infect

Dis J. 2010;29:115-21.

6. Gerdes JS. Clinicopathologic approach to the diagnosis of neonatal sepsis. Clin Perinatol.

1991;18:361-81.

7. Phares CR, Lynfield R, Farley MM, Mohle-Boetani J, Harrison LH, Petit S, Craig AS,

Schaffner W, Zansky SM, Gershman K, Stefonek KR, Albanese BA, Zell ER, Schuchat A,

Schrag SJ; Active Bacterial Core surveillance/Emerging Infections Program Network.

Epidemiology of invasive group B streptococcal disease in the United States, 1999-2005.

JAMA. 2008;299:2056-65.

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8. Castor ML, Whitney CG, Como-Sabetti K, Facklam RR, Ferrieri P, Bartkus JM, Juni

BA, Cieslak PR, Farley MM, Dumas NB, Schrag SJ, Lynfield R. Antibiotic resistance

patterns in invasive group B streptococcal isolates. Infect Dis Obstet Gynecol.

2008;2008:727505.

9. Blaschke AJ, Pulver LS, Korgenski EK, Savitz LA, Daly JA, Byington CL.

Clindamycin-resistant group B Streptococcus and failure of intrapartum prophylaxis to

prevent early-onset disease. J Pediatr. 2010;156:501-3.

10. Van Dyke MK, Phares CR, Lynfield R, Thomas AR, Arnold KE, Craig AS, Mohle-

Boetani J, Gershman K, Schaffner W, Petit S, Zansky SM, Morin CA, Spina NL, Wymore

K, Harrison LH, Shutt KA, Bareta J, Bulens SN, Zell ER, Schuchat A, Schrag SJ.

Evaluation of universal antenatal screening for group B streptococcus. N Engl J Med. 2009

18;360:2626-36

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Intrapartum antibiotic prophylaxis failure and group-B streptococcus early-onset disease

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