Late-Onset Sepsis in Premature Infants: A Global Perspective

Arun K. Pramanik, MD Professor of Pediatrics

LSU Health, Shreveport, LA,

USA

Disclosures

None

Objectives • What is ‘Late-Onset’ Sepsis (LOS)?

• Its Incidence, Epidemiology and etiology (organism)?

• Starting and stopping antibiotics; which ones?

• What are the preventive strategies for LOS?

• Is breast milk feeding always safe?

Definition of Late-Onset Sepsis

• Clinical signs of Sepsis along with positive blood culture

from two sites (CDC, 2008).

• Hospital (NICU), or

Community acquired Sepsis after 7th postnatal day (CDC), or 2-3 days.

Causes of death in the NICU

Jack Jacob et al. Pediatrics 2015;135:e59-e65

EP/ELBW

14% NE

C 10% SIP

1.1% Lung hypoplasia, 10%

RDS, 8%

BPD 3% Pulmonary hemorrhage 2%

Airleak 0.6%

IVH/ICH,

9%

Sepsis ≤7 days, 5%

Sepsis >7 days, 7%

Lethal anomaly, 8%

Genetic syndrome, 5%

HIE, 6%

Major heart defects, 3% Shock/anemia %

Renal failure % CDH %

Pulmonary hypertension %

Other %

Epidemiology of Late Onset Sepsis (LOS) • Incidence of LOS is inversely associated with gestational age and birthweight :

<28 weeks …………… 36%

29-32 weeks …………. 30%

33-36 weeks …………. 18%

37-39 weeks …………. 5-16%

• Risk Factors: - Prematurity

- Invasive interventions: intravascular catheters, ET tube ventilation

- prolonged antibiotic use, intravenous nutrition (hospitalizations)

- delayed enteral feeding

- surgery, transfusion of blood products

- cardio-respiratory failure

Incidence of Late Onset Sepsis(LOS) by birth weight

References Birth weight (G) No. of neonates LOS No. (%)

Boghossian et al, USA 400-500 223 146 (66)

(J. Pediatrics, 2013) 501-750 2680 1372 (51)

751-1000 4090 1309 (33)

Vergnano et al, England 1000-1499 1110 113 (10)

1500-2500

2945 66 (2)

>2500 5340

88 (2)

Causative organisms for Late Onset Sepsis

• Gram positive organisms: - Coagulase negative 53-75%

- Coagulase positive: S. aureus (MSSA, MRSA)

• Gram negative bacilli: - E. Coli

- Klebsiella sp.

- Enterococcus

- Pseudomonas

• Fungal infections: - Candida albicans, C. parasillosis

Major Causative pathogens of neonatal late-onset sepsis and their incidence by geographical areas.

Dong Y, Speer C. Arch Dis Child Fetal Neonatal Ed 2015. F257-63.

Common pathogens of neonatal sepsis in developed countries Early-onset Sepsis Late-onset Sepsis

Pathogen

Frequency (%)

Pathogen

Frequency (%)

Group B Streptococcus

43–58

Coagulase negative Staph.

39–54

E. coli

18–29

Staph. aureus

6–18

Other gram negative bacteria

7–8

E. Coli 5–13

Staph. aureus

2–7

Candida albicans

6–8

Coagulase -ve Staph.

1–5

Klebsiella sp.

4–9

L. monocytogenes

0.5–6

Enterococcus sp.

6–8

Pseudomonas aureginosa

3–5

Other Candida sp.

3–4

Common pathogens of neonatal sepsis in developing countries Pathogen

Early

Frequency (%)

Onset

Pathogen

Late

Frequency (%)

Onset

Klebsiella sp.

14–21

*Klebsiella sp. 16–28

S. aureus

13–26

S. aureus 8–22

E. coli 8–18 E . coli 5–16

Group B Streptococcus

2–8

Coagulase-negative

Staphylococcus

8–28

S. pneumonia

2–5

*Pseudomonas sp. 3–10

Salmonella sp.

1–5

Enterobacter sp. 4–12

Candida sp. 0.3–3

` Incidence of Late Onset Sepsis: Global Data Country

No. of

Centers

Birth year of

cohort

Number of

neonates

Definition of

onset of LOS

LOS No. (%) Proportion (%)

of CONS

Boghossian, USA 6 2002-2008 15,178 72 h 3797 (25) 53

Lahra, Australia 1 1992-2004 798 48 h 220 (28) 64

Troger, Germany 46 2003-2011 5886 72 h 882 (15) 58

Vergnano, England 12 2006-2008 14,225 48 h 868 (6) 54

Van den Hoogen,

Netherland

1 2003-2006 2278 48 h 318 (14) 78

Shim, Korea 1 1996-2005 1479 96 h 134 (9) 6

Morioka, Japan 5 2006-2008 6894 72 h 42 (0.6) 12

Al-Talar, Far-east 4 2006-2009 36,842 72 h 782 (0.12) 42

Tsai, Taiwan 1 2004-2011 5,010 6 days 713 (14) 40

Hammoud, Kuwait 1 2005-2009 12,987 6 days 949 (7) 36

Leal, Mexico 1 2004-2007 11,790 72 h 78 (0.66) 47

Clinical Signs of Neonatal Sepsis • Respiratory distress (90%), Apnea, ↓ SaO2, bradycardia

• Temperature instability

• Gastrointestinal: vomiting, diarrhea, abdominal distension,

ileus, poor feeding

• Neurologic: lethargy, irritability, tremor, seizure,

hyporeflexia, hypotonia

• Cardiovascular: hypotension, metabolic acidosis, tachycardia

• Hematological: bruising, bleeding

• Skin: pallor, mottling, petechiae, cyanosis.

Manroe et al (1979) J Pediatrics 95(1):89

Change in WBC 1st Days of Life

CRP levels of infants in GA ≤32 weeks) and GA > 32 weeks) at 0, 12, 24, 48, 72, and 96 hours

of septic work-up. Values are least square means. Both groups showed significant changes

over time (p < 0.0001). Response and the change in the response rate over time was similar in

both the groups, p = 0.59 and 0.74. CRP, C-reactive protein; GA, gestational age. Am J Perinatology 2015;32:1281-1286

Preterm infants: C-Reactive Protein (CRP) response

Late-Onset Sepsis and Necrotizing Enterocolitis (NEC)

• Late onset sepsis and NEC may coexist: Hence we must have a high index of suspicion, and

commence immediately with appropriate therapies.

• Breast Feeding: encourage trophic feeds with

expressed Breast Milk.

• H2 antagonists are contraindicated: because its use is associated with NEC.

Choose appropriate antibiotics Empirical antibiotic treatment to cover most organisms:

- Vancomycin (serum trough level: 10 to 15 ug/ml), and Gentamycin;

- Ampicillin (or Flucloxacillin) and Gentamycin (UK);

- If NEC suspected: Add Flagyl or Clindamycin.

Note: 1. Tailor therapy to local pathogens;

2. 14% to 40% organism resistant to Gentamycin and/or 3rd generation Cephalosporin;

3. Practice antibiotic Stewardship.

Hospital infection control and microbiology depts.

Every day

Weekly

Monthly

Never

Other

ANTIBIOGRAM USAGE

20%

43%23%

11%

3%

Risk of missed infection

or delayed treatment

Risk of overtreatment

Antibiotic Stewardship

Overuse of Antibiotics in NICUs Retrospective observational study of 323 antibiotic courses for a

total of 3344 antibiotic days.

35% of neonates received at least one inappropriate dose due to

continuation of antibiotics versus initiation of therapy

(39 versus 4% respectively, p < 0.001).

Vancomycin was most commonly used: 895 antibiotic days,

of which 284 days were considered inappropriate.

Patel et. al. Pediatr Infect Dis J 2009;28: 1047–1051

Decreasing vancomycin utilization in a NICU (LOS)

• Efficacy of education versus audit and feedback

in decreasing vancomycin use?

• Baseline Data collected after:

• educating in late-onset sepsis (LOS) treatment guidelines, versus • prospective audit ➛feedback to physicians

Am Jr. of Infection control. 2015;43:1253-7

• Guidelines: 2 blood cultures → Nafcillin & Gentamycin [Methicillin Resistant Staphylococcus Aureus (MRSA) colonized]: start Vancomycin + Gentamycin.

• After 48 hrs.⇾ cultures negative: discontinue antibiotics.

• If clinical improvement- continue Nafcillin and Gentamycin for 7 to 10 d.ays

• If 2/2 blood culture positive for CNS⇾ repeat BCx 2 →Naf. to Vancomycin & D/C Genta..

• If ½ positive CNS⇾ repeat BC, If negative: discontinue antibiotics→ because contaminant.

• If any other organism grows⇾ obtain CSF and treat.

• Suspect NEC: If no pneumatosis ⇾ Ampicillin and Gentamycin; if Pneumatosis⇾ Ampicillin, Gentamycin and Metronidazole.

• Conclusion: Vancomycin utilization and administration >3 days significantly decreased with education and guideline use, but it was not affected by audit and feedback.

Am Jr. of Infection control. 2015;43:1253-7

Decreasing vancomycin utilization in a NICU for LOS (Continued)

Postnatal CMV (pCMV) present as LOS in Premies. • Symptomatic pCMV in preterm infants with CMV positive breast milk exposure.

•Transfusion of CMV negative blood: Elimination of transfusion associated pCMV since 1980s.

• Prospective screening study of 462/539 mother-infant dyads:

- CMV NAT: 882/954 (93%) cellular blood units transfused:

- No case of CMV detection or transfusion related pCMV

•‘ Among infants managed with CMV negative and leukoreduced transfusions,

breast milk transmission is the primary source of postnatal CMV infection.

Yeager et al, J Peds, 1981; Dworskyet al, Pediatrics, 1983; Josephson et al, JAMA Peds, 2014

Estimates of pCMV in Very Preterm Infants 17 studies (two from

North America)

• Infants with birth

weight <1500g (VLBW)

• Born to seropositive

mothers: neonates

were fed breast milk.

• Extrapolated for

43,048 VLBW and <32

weeks infants born in

US in 2008.

Breast

milk

pCMV

infection

pCMV

Symptom pCMV

Sepsis-

like

Fresh

(n=299)

6.5

(3.7–10.9)

3.4

(1.7–5.8) 1.4

(0.7–2.4)

No. of

Infants 2800 1500 600

(% Prevalence (95% Confidence Limits)

Lanzieri et al, Pediatrics, 2013

Does pCMV worsen morbidities of prematurity? Study Design Number

Outcome Difference

Kelly, 2015

Retrospective Propensity

score

303 cases

303 controls

BPD 1.33

(1.2-1.5)

Martins-Cellini,

2016 Cohort

study

24 cases

164controls ROP

stage 2-3

2.5

(1.1-5.9)

Martins-Cellini et al, Clinical Infect Dis. 2016, Kelly et al, JAMA Pediatrics, 2015

Strategies to PREVENT late Onset Sepsis

Infection control and Prevention • Hand Hygiene practices: soap or hand gel before and after patient contact; NO

artificial nails, rings or nail polish; audit of hand hygiene with feedback.

• Environment control: bed space cleaning with audit and feedback, environment cleaning, minimize overcrowding.

• Antibiotic stewardship: Limit empirical therapy to narrowest-spectrum agents that cover likely pathogens in the unit; avoid prolonged and unnecessary antibiotic treatment for suspected or proven infections; surveillance of antibiotic use, with feedback and interventions.

• Multidisciplinary approach: Involve neonatologist, infection control, nurses, unit managers, RTs, environment services and microbiology. To avoid outbreaks: proven benefit of routine prevention, hospital administrators and health department can expedite.

Results and Winner of the Clean Hands Challenge for World Hand Hygiene Day 2018

Highly vulnerable patient population,

with staff dedicated to strategies to protect them.

Controlled environment

Well-defined leadership structure

Practice Improvement in NICU

Neonatal Intensive Care Unit Antibiotic use Interquartile 1.5 times the median AUR (total # of patients exposed to antibiotics/antifungals

CPQCC☞ CCS: Septic workups done in

127 California NICUs (n= 52,061):

Similar burden of proven infection, NEC, surgical

volume, and mortality, yet

40-fold variation (2.4% - 97%) in antibiotic

prescribing practice.

Conclusion: Because antibiotic stewardship

principles dictate that antibiotic use should

correlate with burden of infection,

some NICUS overuse antibiotics

Schulman et al, Pediatrics 135:826, 2015

Mechanisms of feeding strategies to prevent LOS Probiotics ・↑ intestinal mucosal barrier: prevent bacterial translocation

・Competitive exclusion of potential pathogen

・Produce bacteriocins that kill pathogens

・↑ IgA mucosal responses

・modulates host immune reactions to microbial products

・enteral nutrition gut maturation

Early enteral

trophic feeding

・Prevent atrophy of GI mucosa

・establishes healthy gut microflora

・ Decreases use of parenteral nutrition

・Increases gut mucosal immunity

Lactoferrin ・Antimicrobial effect by iron chelation

・Immunomodulation by cytokine production

・↑ growth of probiotic bacteria

・↑ growth and differentiation of enterocytes

・↓ formation of reactive oxygen species

Summary • Late-onset Sepsis in premature neonates causes significant burden of disease.

• Morbidity and mortality: inversely proportionate to gestation and birth weight:

Prolongs hospital stay and cost.

• Nosocomial transmission in NICU due to poor techniques, or is acquired from community (via visitors or staff, e. g. RSV, other viral, MRSA).

• Preventive strategies are very effective:

- hand washing, bundle care (WHO), removal of catheters, tubes, changing

IV tubing, prophylactic fluconazole in <1 kg, trophic feeding (EBM), avoid

H2 blockers, avoid overcrowding, staff and visitors screened for infections.

• QI projects to asses effects of intervention.

• Consider CMV via breast milk, and other viruses as cause of LOS.

27 weeks, 890 gm, born via CS to a 23 yrs. primigravida. Apgar scores 3 and 5 at 1 and 5 minutes.

• Age: 4 days, trophic feeds started with expressed breast milk, PIN continued, FIO2: 0.25 (NC).

• Age: 23 days, was receiving 6 ml breast milk via gavage q.3.h. At 1 a.m. (24 days), nurse

reported 3 ml of digested milk which was replaced and feedings continued.

• Age 24 days: abdominal distension, erythema, hypotension and renal failure.

Diagnosis: Septic shock, NEC & DIC: Labs: X ray abdomen: ‘persistent loop’ sign. ↑ bands.

Management: Gavage feeds discontinued, Vancomycin, gentamycin, Clindamycin, HFOV,

blood products (RBC, platelet and FFP), multiple inotropes, and Penrose drains placed in

NICU. Anuria, ↑creatinine, hyperkalemia and anasarca→ Gentamycin D/Cd, vancomycin

trough q.24.h, furosemide & Bumex drip. Persistent thrombocytopenia→ platelet transfusions x 5.

• Age 33days: developed polyuria, decreasing edema and normal creatinine; low platelets ++.

• Cultures: blood: sterile, peritoneal fluid: S. Epidermidis- total antibiotics x 3 weeks.

• Age 40 days: shock, abdominal distension recurred, respiratory failure, DIC→ Died.

Questions: 1. What is your final diagnosis? 2. How would you have managed it?

• Born at level 2 NICU to 29 year primigravida (poor diabetes control treated with

insulin and diet→ CS. IDM, birth weight 3960 grams, GA 37 weeks.

• Diagnosis: IDM, TTN, hypoglycemia. Discharged home at 6 days.

• Age 10 days: Pediatrician covering saw baby in ER for poor feeding, lethargy,

suspected Sepsis→ admitted and placed on Vancomycin and Gentamycin.

Worsened→ transferred to our PICU→ unresponsive to HFOV→ ECMO.

• Age 15 days: I was consulted for hypotension and bleeding (? attributed to

excessive heparin)! Several echocardiograms showed no cardiac anomaly.

• Age 16 days: Status worsened, anasarca despite maximum support (inotropes,

broad-spectrum antibiotics, blood, diuretics). Bleeding +++, Died at 18 days.

Questions: 1. What is your diagnosis ? 2. How would you have managed this patient?

Questions ?? • “Learn from yesterday, live today. Hope for tomorrow. The important thing is NOT to stop questioning”.

Albert Einstein • “The Art and Science of asking questions is the source of all knowledge”.

Thomas Berger