The approach to neonatal bacterial infections

Irja Lutsar

University of Tartu

Estonia

Budapest, 18. april 2015

Bacterial infections in neonate

• Mostly neonatal sepsis– < 1500 g of all hospitalised babies

• EOS – 1,5% - 2%• LOS – 21% - 25%

– In patients with risk factors• EOS – 4,9%• LOS – 26%

• Other infections– Meningitis – 3% of all infections– Osteomyelitis – 1.5% of all infections– Endocarditis – 5-12/100,000 newborns

Early Human Development 88S2; 2012: S69–S74Acta Paediatr. 2010; 99: 665-72

Origin of sepsis in neonates

neonatal infection

Mucosalcolonisation

Skincolonisation

Cathetercolonisation

motherHospital

environment

Molecular types of CoNS

S. epidermidis S. haemolyticus

– gut and blood isolates of different molecular type

– gut and blood isolates of similar molecular type

MLVA – multilocus variable number of tandem repeats analysis

MLST – multilocus sequence typing

PFGE – pulsed-field gel electrophoresis

CoNS from gutand blood

genotypicallysimilar in 13 of

22 neonates

Pediatr Infect Dis J. 2013; 32: 389-93

CoNS from gutand blood

genotypicallysimilar in 13 of 22

neonates

Definitions• Early onset sepsis – aquired from mother (maternal

microflora)– <48 h after birth– <72h after birth– <7 days after birth– Risk factors: pregnancy and delivery

• Late onset sepsis – nosocomial infection– Sepsis occurring > 48 h after birth– Risk factors as in other nosocomial infections

• Poor condition of the baby (low birth weight, repeated antibiotics)• poor hospital infection control measures• Indwelling catheters• Invasive procedures

Etiology of EOS US ~ 400,000 births

BW <1500g (n = 142)

E.coli

GBS

Other

BW >2500g (n = 196)

E.coli

GBS

Other

Pediatrics 2011; 127: 817-26

The Lancet Infectious Diseases 2014; 11: 1083 – 1089Dashed line – introduction of prevention programme

Incidence of GBS and E. coli invasive disease in the Netherlands in patients >3 mo

Risk factors for EOS

Risk factor

Invasive GBS infection in a previous baby

Maternal GBS colonisation, bacteriuria or infection in the current pregnancy

Prelabour rupture of membranes

Preterm birth following spontaneous labour (before 37 weeks’ gestation)

Suspected or confirmed rupture of membranes for more than 18 hours in a preterm birthIntrapartum fever higher than 38°C, or confirmed or suspected chorioamnionitis

Parenteral antibiotic treatment given to the woman for confirmed or suspected invasive bacterial infection (such as septicaemia) at any time during labour, or in the 24-hour periods before and after the birth [This does not refer to intrapartum antibiotic prophylaxis]Suspected or confirmed infection in another baby in the case of a multiple pregnancy

Causative pathogens of LOS

G-positive

G-negative

Candida

Other

CoNS -28%S.aureus – 15%Enterococcus – 7%

Enterobacteriaceae – 20%Pseudomonas – 2%

Early Human Development 88S2 (2012) S69–S74

Risk factors of LOS

• Low GA

• High SNAP score

• Presence of CVC and/or CAC > 4days

• TPN >7 days

• Ventilator use (CR-BSI)

Am J Perinatol. 2014 Dec 8

Age at LOS onset in NeoMero pilot

Eur J Pediatr. 2014; 173: 997-1004

AAP: Evaluation of asymptomatic infants

<37 weeks’ gestation with risk factors for

sepsis

AAP: Evaluation of asymptomatic infants ≥37

weeks’ gestation with risk factors for sepsis

(no chorioamnionitis)

Our own experience – babies with risk

factors of EOS

• On admission - Test (blood culture) and treat patients withrisk factors– Asymptomatic babies

• VLBW/Late preterm and term baby – penicillin + gentamicin• ELBW – ampicillin + gentamicin

– Symptomatic baby• Cefotaxime + gentamicin

• On Day 3– Asymptomatic and blood culture negative – stop AB treatment– Clinical/laboratory symptoms and blood culture negative – cont.

AB for 2-3 days– Clinical/laboratory symptoms worsening but culture negative –

change to 3rd generation cephalosporins– Culture positive – treat according to antibiogram

Laboratory testing of patients with

suspected sepsis

• CRP– >10 xx in ELBW– >15-20 xx in other neonates

• WBC - <4000 or >20, 000• IL-6 – good correlation with CRP• I/T ratio• Blood culture• Cultures from non-sterile sites• LP in patients with sepsis• PCR + blood culture

The number of neonatal blood cultures obtained

and proportion positive

(St. George’s Hospital, Jan 2001-Dec 2010)

*All organisms except; diphtheroids, Bacillus, Propionibacterium, coagulase-negative staphylococci, viridans group streptococci, Aerococcus, Micrococcus

Arch Dis Child Fetal Neonatal Ed. 2012 Jul 27

PCR for neonatal sepsis

• Several assays developed– Need for quantitative assay

• Advantages– Positive results in hours

– Good sensitivity - 90% PCR vs 71% culture

• Disadvantages– Complementary to culture not replacement

– Still high number of unidentified cases (60-80%)

– Lower specificity than culture (80%)

Neonatology 2013; 103: 268-73Arch Pediatr 2014; 21: 162-9

Acinetobacter

baumanniiEnterobacter

cloacaeKlebsiella

pneumoniae

PFGE: genetic similarity of Gram negative

mucosal and BSI isolates

Parm Ülle, 2012

Patients with mucosal colonisation had more likely blood-stream infections

27 had Gram negative BSI and 22 of them had mucosal colonisation with phenotypically similar strain

Colo-nised

N with BSI

Colonised prior BSI OR / 95% CI

E. cloacae 76 5 1 0.66 / 0.28-6.15K. pneumoniae 51 6 4 9.57 / 1.45-77.74E. coli 49 3 3 34.55 / 2.03-20474.48Acinetobacter spp 47 7 2 2.01 / 0.26-12.20K. oxytoca 46 3 3 37.41 / 2.20-22188.59Serratia spp 31 1 1 24.34 / 0.81-16921.25Stenotrophomonas 12 1 1 69.52 / 2.18-49681.68Pseudomonas 7 1 1 125.31 / 3.69-92781.90

J Hosp Infect. 2011; 78: 327-32

Value of mucosal cultures in predicting invasive disease in neonates

Mucosal cultures are poor predictors of BSI in NICUs

J Hosp Infect. 2011; 78: 327-32

LP in patients with LOS

CSF in 29 patients with LOSCulture proven meningitis in

site with LP routinely used vs

not routinely used

Commonly recommended AB regimensfor neonatal bacterial infection

• EOS

– Penicillin + gentamicin

– Ampicillin + gentamicin

– 3rd generation cephalosporin +/- gentamicin

• LOS – depending on local AB susceptibility

– Ampicillin + gentamicin

– 3rd generation cephalosporin +/- gentamicin +/-vancomycin

– vancomycin + gentamicin

Recommendations mostly not evidence based

AB regimen for LOS

E.coli Other

Enterobacteriaceae

CoNS - MRSE Enterococci

Amp + genta Combination> monotherapy

Genta monotherapy+++

Genta monotherapy++

Combination> monotherapy

Oxa + genta Gentamonotherapy+++

Genta monotherpay+++

Genta monotherapy ++Combination>Monotherapy?

Not appropriate

cefotaxime +++ +++ - -

Cefotaxime+/-genta

Combination> monotherapy+++

Genta monotherapy++

NA

meropenem ++++ ++++ - ++ (E.faecalis)

Vanco+genta Genta monotherapy+++

Vancomycin monotherapy usually effective. Toxicity!!

Resistance - ++++ - 0%; +++ <10%; ++ 10-50%; + - 50-90%; 0 - >90%

Green – combination = monotherapy; pink – only one component acive; blue- combination > monotherapy

Antibiotic combinations for EOS

GBS E.coli Other G-neg Enterococci

Pen + gent Combination = monotherapy

++++

Genta monotherapy+++

++++

Amp+ gent Combination = monotherapy

++++

Combination>monotherapy

Gentamonotherapy

+++

++++

Cefotaxime ++++ +++ +++ -

Resistance - ++++ - 0%; +++ <10%; ++ 10-50%; + - 50-90%; 0 - >90%

Ampicillin + gentamicin vs penicillin +

gentamicin in empiric treatment of EOS

0,0

5,0

10,0

15,0

composite AB change in 72h death in 7d

%

AMP PEN

25

Outcome measure Treatment difference % (95% CI)

Composite 0.1 (-8.1; 8.3)

AB change 0.05 (-6.3; 6.4)

Death in 7d 2.2 (-4.7; 9.1)

Metsvaht et al. Acta Paediatr. 2010; 99: 665-72

Ampicillin + gentamicin vs penicillin +

gentamicin in empiric treatment of EOSELBW subgroup

0

5

10

15

20

25

30

composite AB change in 72h death in 7d

%

AMP PEN

26

Outcome measure OR (95% CI)

Composite 1.1 (0.4 – 3.1)

AB change 1.5 (0.3 – 9.3)

Death in 7d 0.9 (0.3 – 2.9)

Risk factors of AB treatment failure

at 72 h

Parameter OR (95% CI)

Serum albumin on Day 2-3 (per 1 g/L increase)

0.87 (0.80-0.95)

Need for vasoactive treatment 4.43 (1.55-12.68)

Low platelets on Day 2-3 0.92 (0.86-0.99)

CRP (per 1 mg/L increase) on Day 1 1.02 (1.00-1.03)

Multiple logistic regression

27

Total

First line of ATB (i) N=113

AMPICILLIN 1 (1%)AMPICILLIN\Gentamicin 7 (6%)

AMPICILLIN\NETILMICIN 1 (1%)Amikacin 2 (2%)Amikacin\Cefotaxime 2 (2%)Amikacin\Colistin 1 (1%)Amikacin\Meropenem 2 (2%)Amikacin\PenicillinG 1 (1%)Amikacin\Teicoplanin 1 (1%)Amikacin\Vancomycin 10 (9%)Amikacin\Vancomycin\Meropenem 1 (1%)AmpicillinSulbactam 1 (1%)AmpicillinSulbactam\NETILMICIN 1 (1%)CEFEPIME 4 (4%)CEFEPIME\Teicoplanin 1 (1%)CEFEPIME\Vancomycin 1 (1%)Cefotaxime 4 (4%)Cefotaxime\Gentamicin 1 (1%)

Cefotaxime\Gentamicin\PenicillinG 2 (2%)Ceftazidime 1 (1%)Ceftazidime\Teicoplanin 2 (2%)Ceftazidime\Vancomycin 8 (7%)Cefuroxime 2 (2%)Cefuroxime\Meropenem\Vancomycin 1 (1%)Colistin 1 (1%)Gentamicin 3 (3%)Gentamicin\Meropenem\Vancomycin 1 (1%)Gentamicin\PIPERACILLINTazobact 2 (2%)Gentamicin\PIPERACILLINTazobact\PenicillinG 1 (1%)

Total

First line of ATB (ii) N=113

Gentamicin\PenicillinG 2 (2%)Gentamicin\Vancomycin 2 (2%)IMIPENEM\Metronidazole\NETILMICIN\Colistin 1 (1%)

Meropenem 10 (9%)

Meropenem\Teicoplanin 1 (1%)Meropenem\Vancomycin 13 (12%)Metronidazole 1 (1%)NETILMICIN\Vancomycin 1 (1%)

PIPERACILLINTazobact\Gentamicin\Meropenem 1 (1%)Teicoplanin 1 (1%)Teicoplanin\CEFEPIME 1 (1%)Vancomycin 9 (8%)Vancomycin\CIPROFLOXACIN 1 (1%)

Vancomycin\NETILMICIN 2 (2%)Vancomycin\PIPERACILLINTazobact 1 (1%)

43 different empiric AB

regimens were used

Eur J Pediatr. 2014; 173: 997-1004

AB regimen for LOS in five

European countries (n = 111)

Eur J Pediatr. 2014; 173: 997-1004

Antibiotics and gut colonisation

Empiric AB regimen and mucosal

colonisation

• Penicillin and ampicillin have similar effect on gut colonisation with Gram-negatives

• Ampicillin promotes colonisation with S. haemolyticus, S. hominis

• Penicillin promotes colonisation with Enterococcus spp, S. aureus

Per subject p= CD p=

K. pneumoniae 0.012

AR Serratia spp 0.012

S. haemolyticus 0.039 S. haemolyticus 0.001

S. hominis 0.009 S. hominis 0.001

Candida spp 0.02

AR Acinetobacter 0.001

Enterococcus spp <0.001 Enterococcus spp 0.001

S. aureus 0.006 S. aureus 0.052

Multifactorial mixed effect model analyses

Ampicillin treatment associated with increased colonisation

Penicillin treatment associated with increased colonisation

Eur J Clin Microbiol Infect Dis. 2010; 29: 807-16

Bacteroides and Bifidobacterium at three

different time points in ELBW neonates

Gut Microbes. 2014; 5: 304-12

Beneficial effects of probiotics in

premature neonates

GA < 37 weeks

BW < 2500g

RR (95% CI)

BW < 1500g

RR (95% CI)

Number of studies 20 17

NEC stage 2-3 0.43 (0.33-0.56) 0.41 (0.31-0.56)

Culture proven sepsis 0.91 (0.80-1.03) 0.92 (0.81-1.04)

Fungal sepsis 5.10 (0.25-103.6) ND

Mortality 0.65 (0.52-0.81) 0.63 (0.5-0.81)

Is there are time to change practice?Is there are time to change practice?

Which probiotic(s) are the most effective?

How about ELBW babies?

Is there an effect on long term outcome?

Cochrane Database Syst Rev. 2014 Apr 10;4

IVIG for prevention and treatment of

neonatal sepsis

Prevention: presence of sepsisTreament of suspected/proveninfection: mortality

IVIG is not effective in treatment or prevention of neonatal sepsis

IVIG should not be used or studied for these indications

Cochrane Database of Systematic Reviews 2 JUL 2013

Conclusions• Despite all efforts neonatal sepsis is still difficult

to manage condition in neonatology

• Most data are based on expert opinion rather than controlled trials

• Clinical and laboratory findings are poor –– risk factor based treatment of EOS is justified but

should be short• Penicillin+ gentamicin – term neonates

• Ampicillin + gentamicin – very preterm neonates

• More data are needed for empiric and targeted treatment of LOS and meningitis