Neonatal Sepsis and Recent Challenges

Mohammad Khasswneh, MD

Assistant Professor of Pediatrics

JUST

introduction

• Common– 20% of VLBW has sepsis– In term 0.1%– Inter-institution difference 11-32% (NICHD net work)

• Serious– mortality is 3-5 times more for infant with sepsis in NICU

Classification

• Early onset sepsis (EOS):– bacteria acquired before and during delivery– 5-7/1000 live birth– 1.5% of VLBW infants had EOS (intrapartum antibiotics)

• Late onset sepsis (LOS): – bacteria acquired after delivery (Nosocomial

or community)– 20% of VLBW infants

Who is the septic neonate?

• Positive blood culture with clinical symptoms of infection– Coagulase-negative Staphylococcus (CoNS)

• 2 positive blood cultures • One positive blood culture and elevated CRP

• Clinical sepsis” or “probable sepsis

Adult and PediatricsDefinitions

• Systemic Inflammatory response syndrome (SIRS)

• Sepsis – as SIRS plus infection

• Severe sepsis:– as sepsis associated with organ dysfunction,

hypo perfusion or hypotension, • Septic shock

– sepsis with arterial hypotension despite fluid resuscitation

Blood Culture

–One out of five evaluations for sepsis has positive blood culture

–80% of the time, empiric antibiotics will be given when no organism is isolated from culture

Blood culture

• In a 1999, autopsy study of ELBW infants

• infection was primary cause of death by pathologists in (56 of 111)

• sepsis was not diagnosed prior to death for 61% of these 56 neonates

False negative Blood Culture

• Maternal antibiotics

• Small blood sample• in a prospective study of nearly 300 blood

cultures drawn from critically ill neonates, 55% of culture vials contained less than 0.5 ml of blood

• Bacteria load, timing of sampling

Diagnosis

Clinical Signs according to WHO Integrated Management of

Childhood illness

• Respiratory rate >60 breaths/min

• Retraction, flaring, Grunting

• Crepitation

• Cyanosis

Clinical Sings according to WHO Integrated Management of

Childhood illness

• Temperature >37.7°C (or feels hot) or <35.5°C (or feels cold)

• Convulsions ,Lethargic or unconscious

• Reduced movements and activity)

• Not able to feed (sustain suck)

• Bulging fontanels

Other signs in NICU

• abnormal heart rate characteristics• Reduced digital capillary refill time

• metabolic acidosis

• Increase in weight

Clinical signs of sepsis in VLBW infants NICHD network study

• Apnea in 55%• gastrointestinal problems (46%),• increased need for oxygen or ventilatory

support 36%• lethargy/hypotonia 23%

• Hypotension 5%• The positive predictive value 14 to 20%.

New Diagnostic Methods

• CRP• Interleukin 6,8• IgM• Polymerase chain reaction (PCR)• DNA microarray technology • Immunoassay

CRP

• Best discriminatory value for predicting septicemia

• Expressed by all gestational age

• sensitivity 48 to 63%

Serial CRP

• elevated CRP on day 1 and/or day 2, identify most case of sepsis

– sensitivity (90.2%)

Serial CRP

• When CRP is normal on days 1 and 2 ,neonatal sepsis can be confidently excluded and antibiotic therapy ceased–negative predictive value (97.7%).

CRP

• Sensitivity of serial CRP testing is lower for bacteremia due to gram-positive than to gram-negative bacteria

CRP

• Help in timing of discontinuation of antibiotics when CRP normalize

• Further studies is needed

Polymerase Chain Reaction (PCR)

• PCR: under investigation for bacterial and fungal infection–amplification of 16S rRNA,

–a gene universally present in bacteria but absent in humans

– Results in 9 h of sample acquisition

PCR

–Sensitivity 96%

–Specificity 99.4%

–positive predictive value 88.9%

–negative predictive value 99.8%

Microbiology in Developing Country

• Gram negative organisms – Klebsiella, Escherichia coli, – Pseudomonas, and Salmonella.

• Gram positive less common– Staphylococcus Aureus– Coagulase negative staphylococci (CONS)– Streptococcus pneumoniae, and

Streptococcus pyogenes

Microbiology In Developing Country

• Group B streptococcus (GBS) is rare

• Maternal recto-vaginal Carriage rates for GBS is similar to that in developed country

Meningitisdeveloping country

• 1st week mainly Gram negative.• Older than 1 week:

– Streptococcus pneumonia, 50% of all bacterial meningitis occurring between 7 and 90 days of age

–Fatality rate of 53%.

Microbiology in Developed Country

• EOS – GBS and E coli – Recently decrease in Gram positive organisms (GBS)

and increase in Gram negative organisms

• LOS:– Coagulase Negative Staph (CON),– GBS– Staph Aureus.

New trends

• incidence of GBS sepsis decreased from 5.9 to 1.7 per 1,000

• the incidence of sepsis from E. coli increased from 3.2 to 6.8 per 1,000 between 1991-1993 and 1998-2000

Case Fatality

• EOS: more severe and case fatality rate is higher( all-causes mortality was 37%)

• LOS: less sever (CoNS) 18%.

Mortality Per Organisms percentages/ LBW infants

• Gram-negative 257cases (36%)– E coli 53 cases (34%)– Klebsiella 62 cases (22%)– Pseudomonas 43 cases (74%)– Enterobacter 41 cases (26%)– Serratia 39 cases (35%)

• fungal 151cases (31%)

Mortality Rate by Organisms in low birth weight infants

• Gram-positive 905 case 101 deaths (11.2%)– CoNS . 606 cases (9.1%)– S aureus 99 cases (17.2%)– GBS 32 cases (21.9%)– All other streptococci 65 cases (10.8%)

Sepsis Risk Factors

• Prematurity

• Birth weight– Term 0.1%– 1,000 -1,500 g 10%– <1,000 g 35%– <750 g. 50%

• Delay enteral feeding and Prolonged TPN

Frequent Blood Drawing??

Group B streptococcus (GBS)

• Maternal colonization 15 to 40%

• 50% of infants acquire surface colonization at delivery

• 1% of colonized full-term infants develop EONS

GBS

• In 1996, GBS guidelines

• Incidence declined from 5.9-1.7 per 1,000 in 1992 and 1999 respectively

• Emergence of penicillin resistance among GBS (Japan)

GBS Guideline

• the incidence of infections with gram-negative bacteria increased

• antibiotic resistance among gram-negative pathogens has increased

Coagulase-Negative Staphylococci

• commonest cause of nosocomial bacteremia

– ventriculoperitoneal shunt infection

–Endocarditis with umbilical lines

• S. epidermidis, S. haemolyticus, S. hominis, S. saprophyticus,

Coagulase-Negative Staphylococci

• Sepsis with CoNS is often indolent

• nonspecific symptoms

Coagulase-negative staphylococci

• a positive blood culture for CoNS may represent either contamination – 26 cases, in only 16 cases were cultures

from two sites positive, and the other 10 cases were considered to represent contamination

Coagulase-negative staphylococci

• Studies have shown that initial therapy of suspected LONS with nafcillin or oxacillin and an aminoglycoside,rather than vancomycin did not change outcome (decrease resistance)

Staphylococcus aureus

• Less commonly seen• S. aureus strains remained

sensitive to extended-spectrum penicillins (oxacillin or nafcillin)

Gram Negative bacteria

• Klebsiella pneumoniae in our area

• E. coli in united states

• Increase in incidence

• Multiresistance

• Invasion of CNS, Citrobacter koseri

Gram Negative

• P. aeruginosa – conjunctivitis – systemic disease high mortality

• Haemophilus influenzae. – Non typeable– Fulminant, simulating RDS. – Mortality 90%

Antibiotics Resistance

• Induced by antibiotic pressure (over use)

• Broad-spectrum cephalosporin induce chromosomal ESBLs in gram-negative bacilli

Antibiotics Resistance

• Ampicillin and Amikacin for empiric treatment of EONS

• Oxacillin and amikacin for empiric treatment of LONS reduce colonization with resistant gram-negative bacilli from 32 to 11%

Practical points

• LP should be done in evaluation of sepsis even with negative blood culture

• Urine culture is not part of work up for EOS

• Vesicoureteral reflux was present in 14% of VLBW infants with UTI.

Conclusions

• Gram negative organism is becoming more common worldwide

• GBS is not common in our area• Multi-resistance organism mandate

different approaches for N. sepsis treatment

Conclusions

• CRP can help in early discontinuation of antibiotics

• New Diagnostic Technology will play role in both – Early diagnosis and treatment– Restrict antibiotics over use