Definition Neonatal septicemia is defined as generalized

systemic infection of the newborn,associated with pure growth of bacteria from one or more sites.

It is one of the most important causes of mortality and morbidity in newborn.

Among the low birth weight & pre term babies,neonatal septicemia is the most important cause of mortality,especially in developing countries including India.

According to NNPD-2,the incidence ranges from 0.1 to 4.5 percent with an overall mortality rate varying from 22-30%.

With an estimated 25 million births occuring in India and approximately 2% incidence of sepsis,the figure for neonatal sepsis in India would be 5,00,000 babies every year with about one-third,i.e.170,000 babies succumbing to the disease.

When pathogenic bacteria gain access into the blood stream, they may cause overwhelming infection

without much localization (septicemia), may get predominantly localized to the lung

(pneumonia),the meninges (meningitis).

Importance.

Neonatal sepsis is the single most important cause of neonatal deaths in the community, accounting for over half of them.

If diagnosed early and treated aggressively with antibiotics and good supportive care, it is possible to save most cases of neonatal sepsis.

Classification.

Neonatal sepsis can be classified into two sub-types depending upon whether the onset of symptoms is before 72 hours of life (early onset) or later (late onset).

Early onset sepsis

Early onset sepsis (EOS) often presents as a fulminant, multi-system illness within 72 hours of delivery and is mainly due to bacteria acquired before and during delivery

Early onset sepsis manifests frequently as pneumonia and less commonly as septicemia or meningitis.

The associated factors for early-onset sepsis include low birth weight, prolonged rupture of membranes > 24 hours, foul smelling liquor, multiple per vaginum examinations, maternal fever, difficult or prolonged labour,and aspiration of meconium.

Risk factors for neonatal sepsis.Maternal factors:

Fever,Urinary tract infection,diarrhea,Prolonged rupture of the membrane>24hrs,Foul smelling amniotic fluid,Maternal amnionitis,Maternal genital tract infection,& genital

colonization,Socio economic factors:poor socio economic

status,poor nutrition and hygiene.

Neonatal factors:Preterm and low birth weight,Perinatal asphyxia,Vigorous resuscitation,Invasive procedures,Congenital

malformations,e.g.meningomyelocele,Male child.

Risk factors.Prolonged rupture of membranes(PROM):the

risk is reported to be 1% percent compared to a baseline incidence of 0.1 to 0.5 percent.

Chorioamnionitis:increases the risk of sepsis by 2 to 3 times.

If PROM is associated with chorioamnionitis ,the risk of sepsis increases by four fold.

Prematurity & low birth weight:pre term babies are deficient in immunoglobulin concentration,complement function & phagocytic activity.

They have 3 to 10 times higher risk of developing sepsis than term infants.

Chorioamnionitis may coexist & may trigger for preterm labor.

Association of chorioamnionitis is and low birth weight increases the risk of sepsis to 16 percent compared to association with normal weight babies.

Perinatal asphyxia:asphyxia is associated with depressed immune function.in addition,several interventional procedures increase the risk of infection.

Presence of low apgar score (6 or less at 5 minutes)along with prolonged rupture of membranes has shown to increase the risk of infection by 4% & 27%.

Male gender:boys have 2 to 6 times higher risk of development of neonatal sepsis.

Other factors:maternal fever,G.U.T.infection,poor socio economic condition & feeding artificial milk.

Late onset sepsis.Late-onset septicemia is caused by the

organisms thriving in the external environment of the home or the hospital.

late onset sepsis (LOS) can present as either a fulminant or a smoldering infection.

The infection is often transmitted through the hands of the care-providers.

The onset of symptoms is usually delayed beyond 72 hours after birth and the presentation is that of septicemia, pneumonia or meningitis.

The associated factors of late-onset sepsis include: low birth weight, lack of breastfeeding, superficial infections (pyoderma, umbilical

sepsis), aspiration of feeds, disruption of skin integrity with needle pricks

and use of intravenous fluids.

These factors enhance the chances of entry of organisms into the blood stream of the neonates whose immune defences are poor as compared to older children and adults.

National neonatology forum of India defines neonatal sepsis as follows;Proven sepsis:the baby presents with clinical picture

of sepsis & isolation of pathogens from blood,csf.,urine or other body fluids or autopsy evidence of sepsis.

Probable sepsis:newborn with clinical picture suggestive of sepsis with one or more of the following criteria Existence of predisposing factors,e.g.maternal fever foul

smelling liquor or prolonged rupture of the membrane (>12 hours) or gastric polymorphs more than 6/high power field.

Positive sepsis screen(2 of the 4 parameters to be present). Total leukocytes count<5,000/mm3,immature to total

neutrophil count ratio>0.2,c-reactive protein positive & micro ESR > 15 mm/1st hour or >age in days + 3.

Radiological evidence of pneumonia.

Sepsis syndrome:when septicemia is associated with altered organ perfusion(hypoxia,increased blood lactate,oliguria & altered mental state)it is termed as sepsis syndrome.

If untreated,this condition leads to early septic shock with decreased capillary refilling and low blood pressure,which can be reversible with appropriate treatment.

If untreated,this state progresses quickly into refractory shock & leads to multi organ dysfunction.

The common organisms reported by NNPD Survey showed 3.8 percent incidence of neonatal sepsis from pooled hospital data with Klebsiella,Staph.aureus,Esch.coli,Pseudomonas,Enterobacter,Coagulase negative staphylococcus,Acenatobacter and Candida as the predominant organisms.

In the Indian subcontinent, the distinction between EOS and LOS is somewhat blurred (Sundaram V et al).

The clinical presentations of EOS and LOS are different and the risk factors are different, but the organisms causing the EOS and LOS are similar and so are their antibiograms (Zaidi AK et al,NNPD NETWORK).

The early & efficient diagnosis of neonatal bacterial sepsis remains a difficult task since most of the symptoms & signs of sepsis in the neonatal period are of non specific nature.

The spectrum & severity of symptoms required to decide in the evaluation of sepsis is a matter of clnical judgement.

It is estimated that between 11 & 23 non infected newborns are treated in neonatal intensive care nurseries for every one with documented infection.

Clinical features The manifestations of neonatal septicemia are

often vague and therefore demand a high index of suspicion for early diagnosis.

The possibility of sepsis must be considered with any clinical deterioration unless the event is readily explained by other causes.

The most common and characteristic manifestation is An alteration in the established feeding behavior in

late onset sepsis,Respiratory distress in early onset sepsis.

The baby, who had been active and sucking well, gradually or suddenly, becomes lethargic, inactive or unresponsive and refuses to suckle.

Hypothermia is a common manifestation of sepsis, whilst fever is infrequent.

Diarrhea, vomiting and abdominal distension may occur.

Episodes of apneic spells or gasping may be the only manifestation of septicemia.

In sick neonates, the skin may become tight

giving a hide-bound feel (sclerema) and the perfusion becomes poor (capillary refill time of over 3 seconds).

Cyanosis may appear.

The additional features of pneumonia or meningitis may be present depending upon the localization of infection in different systems and organs of the body.

The evidence of pneumonia includes tachypnea, chest retractions, grunting, early cyanosis, apneic spells in addition to inactivity and poor

feeding. Cough is unusual. Findings on auscultation of the chest are non-

specific and non- contributory.

Meningitis is often silent, the clinical picture being dominated by manifestations of associated septicemia. the appearance of excessive or high-pitched

crying, fever, seizures, blank look, neck retraction,bulging anterior fontanel are highly suggestive

of meningitis.

Classification of sick young infants for bacterial infection(WHO).

Convulsion,Fast breathing,Severe chest indrawing, Nasal flaring,Grunting, possible Bulging fontanelle, serious Pus draining from ear, bacterialUmbilical redness extending to skin, infection.Fever or hypothermia,Many or severe skin pustules,Lethargic or unconscious,or less than normal movement.

Red umbilicus or draining pus, local bacteria infection.Skin pustules

Laboratory diagnosis.Sensitivity:if infection is present,how often is

the test result abnormal?

Specificty:if infection is absent,how often is the test result normal?

Positive predictive value:if the test result is abnormal,how often is the infection present?

Negative predictive value:if the test result is normal,how often is infection absent?

Diagnostic tests with maximal(100%)sensitivity & negative predictive value are desirable for diagnosis of neonatal sepsis.

This indicates if infection were present,the result would always be abnormal & if results were normal,infection would always be absent.

A good specificity & positive predictive value is also acceptable.

Diagnostic tests.Definitive,specific Nonspecific,diagnosticBlood culture,Cerebrospinal fluid

examination & culture,Urine culture,Tracheal aspirates,Polymerase chain

reaction,Latex particle

agglutination test.

White blood cell count,C-reactive protein(CRP),Erythrocyte

sedimentation rate,Other acute phase

reactants,Miscellaneous tests.

Definitive,specific diagnostic tests.Isolation of organism from blood or a central

body fluid is the standard & most specific method to confirm the diagnosis of neonatal sepsis.

The main draw back is that,the results are available after 48 to 72 hrs.

Another dilemma often faced by the clinicians is the high percentage of cases(upto 40%)where no bacteria can be isolated from blood even in highly suspected cses of sepsis.

Blood culture.The standard is to collect 1 ml of blood by sterile

venepuncture in a blood culture bottle.Umblical artery catheter is preferred over

umbilical vein catheter for sampling.The blood culture should be incubated for at least

72 hours before being considered negative.In a study conducted by Geme JW et al,13 percent

of positive blood culture did not grow until beyond 72 hours.

The late growing organisms were anaerobes & coagulase negative staphylococci.

Blood culture should not be considered as the final arbiter for the clinical diagnosis of neonatal infections because,It is negative in 20% cases where infection was

proven by immedite post mortem culture and autopsy.

In the mildly symptomatic neonate and at the earliest onset of septicemia,the false negative blood culture rate would be very high.

In upto 50% of cases with congenital bacterial pneumonia proved by tracheal aspirate culture ,blood culture is negative.

In a prospective observational study from India, 101 cases of suspected neonatal sepsis were used to compare the manual method of blood culture with an automated BacT/Alert system for detection of neonatal septicemia.

The mean times to positivity with the manual and BacT/Alert 3D systems were 53.1 h and 14.3 h, respectively (p <0.001)(Hasana AS,et al)

With conventional methods the detection rate is 89.1% by day 2 and 99.5% by day 4.

Cerebro-spinal fluid (CSF) examination.In an unstable neonate, the LP can be

deferred, until stabilization is achieved. The cellular and biochemical abnormalities in

the CSF of older patients with bacterial meningitis persist for up to 3 days.

Gram positive bacteria clear in 36 hours of appropriate therapy whereas gram negative bacteria may take up to 5 days.

Apart from culture and gram stain, 4 parameters are commonly evaluated: total WBC count (per micro L), percentage neutrophil count, glucose protein.

Traditionally, the following cut-offs have been used: 30 cells, more than 60% of polymorphs, glucose less than 50% of blood glucose, protein more than 150 mg/dL in term babies and

180 mg/dL in preterm babies. These cut-offs are no longer acceptable as they are

based on old normative data, and represent an over-simplified approach based on single cut-off points derived from 2 standard deviation values.

Preterm infants: Treat if CSF WBC count ≥10 OR glucose <24 OR protein >170.

Do not treat if “CSF WBC count <10 AND glucose ≥25 AND protein <170”.

For in-between results, clinical judgment will have to be used, keeping in mind clinical features (seizures, degree of altered sensorium, fullness of fontanelles) and prematurity (the lower the gestation, lower should be the threshold for diagnosis).

Term infants: Treat if CSF WBC count >8 OR glucose <20 OR protein >120.

There is no safe cut-off at which one can recommend “do not treat”. Clinical judgment as above would have to be used.(The WHO Young Infant Study Group, Ahmed AS et al, Smith PB et al, Garges HP et al)

In a neonate with meningitis not showing clinical recovery after institution of antibiotics, LP should be repeated after 48 hours.

If the LP is traumatic, the CSF should be sent for gram stain and culture.

The concentration of glucose is not significantly altered by a traumatic lumbar puncture.

Therefore a low CSF glucose in the setting of a traumatic LP is abnormal.

Ideally, the WBC cell count must be performed within 30 minutes of drawing the sample.

It must be noted that CSF WBC and glucose rapidly fall with time, giving spurious results(Rajesh NT,et al).

Tracheal aspirate.Useful in first 12 hours of life.

A positive tracheal culture may be found in 44% cases with pneumonia were blood culture was sterile.

There is a positive co-relation of tracheal aspirate gram stain for bacteria with clinical or pathological pneumonia and has a 47% predictive accuracy in bacteremic infants.

Latex particle agglutination tests:a relatively simple test to perform but is not very sensitive.

The standard kits for group B streptococcus,pneumococcus and meningococcus are available & hence cannot be used routinely.

Polymerase chain reaction:a definitive advancement,but the prohibitive cost & difficult technique precludes its use in the routine evaluation of neonatal sepsis.

Nonspecific diagnostic septic screening tests. These tests indicate infection without

identifying the infecting micro organisms.Because of the severity of the disease,it is

essential for these indirect tests not to miss any case(have 100% sensitivity),

To rule out convincingly sepsis when it is not present(have a high negative value).

White blood cell count.A total leukocyte count<5000/mm3,

Total neutrophil count<1750/mm3,

An immature to total neutrophil count ratio(I/T)of >0.2 are suggestive of sepsis.

It has been well documented that the CBC depends upon the infant’s age,on whether the sample is arterial or venous,and on whether the infant is crying vigorously.

This means that for a given infant,a test value is not a static value;there is considerable intraindividual variability.

In addition,maternal hypertension,perinatal asphyxia & intra ventricular h’age may cause neutropenia.

Non specific stresses such as asphyxia,maternal fever or stressful labor can elevate the I/T ratio.

The presence of neutrophil vacuolization or toxic granulation are also good indicators of neonatal sepsis.

C-reactive protein.CRP is a rapidly responsive acute phase

reactant,synthesizd by the liver within 6-8 hrs of stimulus of inflammatory process.

A positive CRP latex agglutination test corresponds to plasma CRP concentration of 0.8 to 1.0 mg/dl.

A single value of negative CRP done at the outset may not be of much significance.

Therefore,n suspected cases,a repeat CRP test is done 12 hours later is more significant.

If the test is negative negative-it almost excludes sepsis.

Normalization of CRP is a helpful tool in determining the response to antimicrobial therapy and duration of treatment.

Failure to mount a CRP response is a poor prognostic sign.

Erythrocyte sedimentation rate.Micro ESR is an inexpensive & easy bedside

screenig test for neonatal sepsis.

Normal values increase with postnatal age & are equal to the day of life plus 3mm/hour upto a maximum of 15 mm/hour.

ESR is less sensitive but more specific than CRP or I/T rato.

Other acute phase reactantsHaptoglobin & orosomucoid are acute phase

reactants that have been evaluated for diagnostic aids for neonatal sepsis,are of limited utility because of their slower response to infection.

A low plasma fibronectin concentration is suggestive of neonatal sepsis,

It is also depressed by RDS & perinatal asphyxia,thus limiting its use.

Miscellaneous tests.Elastase-alpha-1-proteinase inhibitor

complex:raises rapidly,100% sensitive but not highly specific.

C3D,Endotoxin,Direct visualization of bacteria in

neutrophils stained by acridine orange,NBT reduction by neutrophils,Gastric aspirate of polymorph count &

culture:has limited value,indicative of high risk because of exposure to chorioamnionitis.

Newer diagnostic modalities.Procalcitonin:a pro-peptide,released into the

blood 3-6 hrs after endotoxin injection & increses upto 24 hours.

Very high serum procalcitonin levels are present in neonates with proven or clinically diagnosed bacterial infection;early decrease of these concentrations reflects appropriate antibiotic therapy.

Compared with CRP,proclcitonin has the advantage that it increases more rapidly.

A recent meta analysis showed that procalcitonin showed better accuracy than the CRP test for LOS.

Cytokines and receptors. Interleukin-6(IL-6),Interleukin-1 receptor antagonist(IL-1ra)The level of these two markers increases two days

before clinical diagnosis of sepsis.IL-6 although a very early marker,the level

becomes normal later even if infection continues.The simultaneous determination of CRP can

obviate this problem because the rise in plasma CRP levels occurs 12 to 48 hours after the onset of infection,at a time when IL-6 level would have fallen.

Specific leukocyte surface antigens. CD11b-promising marker for diagnosing

early onset sepsis.CD64-late onset sepsis.Preterm express CD 64 to the same degree as

those from term infants,children & adults.G-CSF;a higher level has been found to be

associated with a sensitivity of 95 percent for prediction of sepsis & a specificity of 73 percent if the level is >200pg/ml.

The best combination for newer markers for sepsis would be estimation of IL-6,IL-1ra:1-2 days before the onset of

symptoms,IL-6,IL-1ra,IL-8,CD 11b,G-CSF,TNF,CRP &

hematological indices on day 1,CRP on the following days to monitor response

to treatment.CD 64 is probably one of the most useful

infection markers for diagnosis of late onset nosocomial sepsis.

However,none of the current diagnostic markers are sensitive and specific enough to influence the judgement to withhold antimicrobial treatment independent of the clinical findings.

Approach to a neonate with suspected EOS.There is no rationale for performing a “sepsis

screen” (i.e. CRP,hematological parameters, micro ESR) in suspected EOS.

The negative predictive value (NPV) of various sepsis screen parameters is too low to confidently rule out EOS (Benitz WE et al, Mahale R et al,).

Procalcitonin and IL-6 are more promising than the standard screen for the diagnosis of EOS, but they are currently not easily available on the bedside and are not considered standards of care.

Neonates who turn symptomatic within 72 hours must be clinically assessed for probability of sepsis.

Twenty percent of symptomatic neonates in

India suspected to have EOS are blood culture positive (Mahale R et al).

The following neonates need not be immediately started on antibiotics but their clinical course must be carefully monitored:

Those who are born without any of the known risk factors of sepsis preterm, premature rupture of membranes (pPROM), prolonged rupture of membranes (PROM) >18 hrs, spontaneous preterm onset of labor (SPTOL), clinical chorioamnionitis, foul smelling liquor, unclean vaginal examinations, maternal fever,

maternal urinary or other systemic infections, frequent (>3) per vaginal examinations in labor, perinatal asphyxia, and maternal recto-vaginal group B

Streptococcus carriage],

AND Chest X ray is not suggestive of pneumonia, Have alternative reasons to explain the

symptoms.

Those symptomatic neonates with any of the known risk factors or who have a chest X-ray suggestive of pneumonia or do not have any alternate explanation for the signs, must be immediately started on antibiotics after drawing a blood culture.

Lumbar puncture (LP) for CSF examination must be performed in all symptomatic neonates, with the exception of premature neonates presenting with respiratory distress at birth with no risk factors for sepsis (Eldadah M et al, Weiss MG et al,)

The decision for performing LP should not be based on sepsis screen results or blood culture results.

Approach to a neonate with suspected LOS.Neonates who become symptomatic after 72

hours must be evaluated for LOS.

30% neonates clinically suspected to have LOS in an NICU setting have positive blood culture (Singh SA et al).

A single episode or transient presence of one of the above signs may not warrant any action. The more persistent the sign the more likely it is associated with LOS (Kudawla M et al,).

Based on clinical assessment the neonate must be categorized into those with low probability of sepsis or high probability of sepsis.

The rule of thumb is “low probability” represents situations where the clinician would be willing to withhold antibiotics if the sepsis screen is negative.

Those assessed to have a low probability of sepsis (eg. single episode of apnea or vomiting, but otherwise well)should undergo a sepsis screen.

Sepsis screen.The purpose of the sepsis screen is to rule

out sepsis rather than to rule in sepsis. Traditionally, the sepsis screen consists of 4

items: C-reactive protein (CRP), absolute neutrophil count (ANC), immature to total neutrophil ratio (ITR) and micro-erythrocyte sedimentation rate (μ-

ESR).

CRP: Quantitative CRP assayed by nephelometry is superior to CRP by ELISA and semiquantitative CRP by a latex agglutination kit. Cut-off value for quantitative assay is 10 mg/L.

ANC: It must be read off Manroe’s charts or Mouzinho’s chart, depending on whether it is a term baby or a preterm baby respectively(Kudawla M, Mouzinho A,et al).

ITR: Value above 27% in term babies is considered positive.18 For preterms, it is considered to be 20%. ITR is defined as Immature neutrophils (band forms, metamyelocytes, myelocytes) (Mature + immature neutrophils).

μ-ESR:Value (in mm in first hour) of more than 3+ age in days in the first week of life or more than 10 thereafter is considered positive.

Two systematic reviews on sepsis screens reached the same conclusions- that there is no ideal test or combination of tests which achieves an LR+ ≥10 or LR- ≤0.1, which are the benchmarks of an excellent test (Schelonka RL et al, Da Silva O et al, Fowlie PW et al).

Among the various tests, quantitative CRP is the best, followed by qualitative CRP and immature to total neutrophil ratio.

If all the parameters of the sepsis screen are negative in a neonate assessed to have low probability of LOS, antibiotics may not be started and the neonate must be monitored clinically.

The screen must be repeated after 12-24 hours. Two consecutive completely negative screens are suggestive of no sepsis.

The practice of designating the screen positive if ≥2 parameters are positive finds its origin in these studies.Autho

rYear

Test Sensi

Specifi

LR+

LR-

Philip et al,

1980

Any 2 + ve of: ITR>0.2,WCC<5000, CRP >8 mg/l, ESR>15 mm/1st hr, Haptoglobulin>25 mg/dl

93 88 7.8

0.08

Gerdes et al,

1987

Any 2 + ve of: WCC<5000/mm3, ITR >0.2, and CRP> 1 mg/dL

100

83 5.9

0

Since we now realize that CRP is the key parameter in the sepsis screen, a pragmatic approach would be that if the quantitative CRP alone is positive or any two parameters of the sepsis screen are positive, a blood culture must be drawn and empirical antibiotics must be started.

A CSF examination must be performed. Meningitis occurs in 3.4% cases of suspected

LOS and 25% cases of culture positive LOS (Fielkow S et al,Kumar et al,).

Neonates assessed to have a high clinical probability of sepsis (for which the clinician is convinced that antibiotics must be started) may not be subjected to a sepsis screen, because a negative screen would not alter the decision to start antibiotics.

A CSF examination must be performed. In recent years, procalcitonin has attracted

interest.Head-to-head comparisons with CRP have shown

that procalcitonin is superior.(Malik A et al, Philip AG et al, Gerdes JS et al,)

Urinary tract infections (UTI) in neonates.The signs of UTI in neonates are nonspecific and

varied. The common clinical signs in cases of UTI in

neonates are – failure to thrive (50%), fever (39%), vomiting (37%), diarrhoea (25%), cyanosis(23%), jaundice (18%) and irritability & lethargy (17%).

The yield of a routine urine culture is very less ( DiGeronimo RJ. Tamim MM et al, Lin DS et al.).

Urine culture must always be performed on a sample obtained by a supra-pubic puncture or by a fresh bladder catheter.

In neonates, use of ultrasound guidance simplifies supra-pubic aspiration and improves the diagnostic yield of obtaining a urine specimen from 60% to almost 97%(Buys H,et al).

Sepsis screen.A practical positive "sepsis screen" takes into

account two or more positive tests as given below:

1. Leukopenia (TLC <5000/cmm) 2. Neutropenia (ANC <1800/cmm) 3. Immature neutrophil to total neutrophil

(I/T) ratio (> 0.2) 4. Micro ESR (> 15mm 1st hour) 5. CRP +ve

Diagnosis Direct method:

Isolation of microorganisms from blood, CSF, urine, pleural fluid or pus is diagnostic.

Indirect method:There are a variety of tests which are helpful

for screening of neonates with sepsis. The most useful and widely used is the white

blood cell count and differential count. An absolute neutrophil count of < 1800 per

cmm is an indicator of infection.

Neutropenia is more predictive of neonatal sepsis than neutrophilia

But it may be present inmaternal hypertension, birth asphyxia and periventricular hemorrhage.

Immature neutrophils (Band cells + myelocytes + metamyelocytes) to total neutrophils ratio (l/T) > 0.20 means that immature neutrophils are over 20 percent of the total neutrophils because bone marrow pushes even the premature cells into circulation, to fight infection.

Platelet count of less than 100,000 per cmm, Toxic granules on peripheral smear, Gastric aspirate smears showing more than 5

leucocytes per high power field are also useful indirect evidences of infection.

The micro-ESR may be elevated with sepsis and fall of > 15 mm during first hour indicates infection.

Acute phase reactants are also frequently used in predicting neonatal sepsis.

The most widely used is C-reactive protein (CRP) which has a high degree of sensitivity for neonatal sepsis.

The CRP can be affected by asphyxia, shock, meconium aspirationprolonged rupture of membranes.

There are a variety of other tests which can be used to predict sepsis but it may be difficult to perform them at all places and hence the clinical acumen remains crucial.

Lumbar puncture.If possible, lumbar puncture should be done

in all cases of late onset (>72 hours) and symptomatic early onset sepsis because 10-15 percent of them may have associated meningitis.

At a small hospital, one may only depend on the CSF cells.

The implications of detecting meningitis in the setting of septicemia include: the need for using antibiotics with a high CSF

penetration and provision of antibiotic treatment for at

least 3 weeks, administered parenterally throughout.

TreatmentNo investigation is required as a

prerequisite to start treatment in a clinically obvious case.

Early treatment is crucial.

Institution of prompt treatment is essential for ensuring optimum outcome of neonates with sepsis who often reach the health care facilities late and in a critical condition.

Supportive care and antibiotics are two equally important components of the treatment.

It should be realized that antibiotics take at least 12 to 24 hours to show any effect and it is the supportive care that makes the difference between life and death early in the hospital course.

Supportive careThe purpose of supportive care is to

normalize the temperature, stabilize the cardiopulmonary status, correct hypoglycemia, prevent bleeding tendency.

There is no role of intravenous immunoglobulin therapy in neonatal sepsis.

Antibiotic therapy – empirical, upgradation and modification.There is generally no distinction in the choice

of empirical antibiotics, be it suspected EOS or LOS as the bacterial and sensitivity profile in India seems to be is similar in both situations(Sundaram V et al, Zaidi AK et al, NNPD network.).

Starting empirical antibiotics.As the profile of organisms is similar for EOS

and LOS, the following policies can be used irrespective of whether it is EOS or LOS.

Policy for community acquired sepsis (Paul VK,et al)

Ampicillin + Gentamicin/Amikacin (empirical)If evidence of staphylococcus : Cloxacillin +

Gentamycin/AmikacinIf evidence of meningitis: Add Cefotaxime.

Policy for nosocomial sepsis:It is not possible to suggest a single antibiotic

policy for use in all newborn units. Every newborn unit must have its own antibiotic

policy based on the local sensitivity patterns and the profile of pathogens.

Preferably choose Penicillin plus an Aminoglycoside combination.

Cephalosporins rapidly induce the production of extended spectrum β-lactamases (ESBL), cephalosporinases and fungal colonization.

Antibiotic therapy Antibiotic therapy should cover the common

causative bacteria, namely, Escherichia coli, Staphylococcus aureus and Klebsiella pneumoniae.

A combination of ampicillin and gentamicin is recommended for treatment of sepsis and pneumonia.

In cases of suspected meningitis, cefotaxime should be used along with an aminoglycoside.

In late-onset sepsis to cover nosocomial staphylococcal infection, first line of antibiotics may comprise of cloxacillin 100 mg per kg per day and an aminoglycoside (gentamicin or amikacin).

In nosocomial sepsis, antibiotic sensitivity pattern of organisms responsible for nursery infection should be known and the antibiotic therapy should be started accordingly.

Usually staphylococci and Gram negative bacilli (Pseudomonas, Klebsiella) should be covered using aminoglycoside (gentamicin or amikacin) and a third generation cephalosporin (cefotaxime).

For resistant staphylococcal infection, vancomycin (30 mg per kg per day) should be used.

On confirmation of sensitivity pattern, appropriate antibiotics are used singly or in combination.

In a baby in whom the antibiotics were started on low suspicion, these may be stopped after 3 days, if baby is clinically well and the culture is negative.

However, if a baby appears ill even though the cultures are negative, antibiotic therapy should be continued for 7 to 10 days as bacterial infection can occur with negative cultures.

The duration of antibiotic therapy in sepsis depends upon the pathogen, site of infection and the clinical response of the baby.

7-10 days therapy is required for soft tissue infections or pneumonia.

Deep-seated infections (osteomyelitis) and meningitis may require therapy for 3-6 weeks.

Upgradation of empirical antibiotics.Empirical upgradation must be done if the

expected clinical improvement with the ongoing line of antibiotics does not occur.

At least 48-72 hours period of observation should be allowed before declaring the particular line as having failed.

If any new sign appears and/or the existing signs fail to begin remitting, it would be considered that the expected clinical improvement has not occurred.

Current evidence does not support the use of serial quantitative CRP as a guide for deciding whether or not antibiotics should be upgraded empirically.

In case the neonate is extremely sick or deteriorating very rapidly and the treating team feels that the neonate may not able to survive 48 hours in the absence of appropriate antibiotics, a decision may be taken to bypass the first line of antibiotics and start with the second-line of antibiotics.

Antibiotic therapy once culture report is available.It must first be assessed whether the positive

blood culture is a contaminant. The following are suggestive of contamination: growth in only one bottle (if two had been sent), growth of a known non-pathogen: eg. aerobic

spore bearers , mixed growth of doubtful significance and onset of growth beyond 96 hours in the absence

of a history of prior exposure of antibiotics in the 72 hours before sending the blood culture.

If the growth is a non-contaminant, the antibiotic sensitivity must be assessed to decide whether antibiotics need to be changed or not.

The following guidelines would allow a rationale use of antibiotics:If the organism is sensitive to an antibiotic with a

narrower spectrum or lower cost, therapy must be changed to such an antibiotic, even if the neonate was improving with the empirical antibiotics and/or the empirical antibiotics are reported sensitive.

If possible, a single sensitive antibiotic must be used, the exception being Pseudomonas for which 2 sensitive antibiotics must be used.

If the empirical antibiotics are reported sensitive, but the neonate has worsened on these antibiotics, it may be a case of in vitro resistance.

Antibiotics may be changed to an alternate sensitive antibiotic with the narrowest spectrum and lowest cost.

If the empirical antibiotics are reported resistant but the neonate has improved clinically, it may or may not be a case of in-vivo sensitivity.

In such cases are careful assessment must be made before deciding on continuing with the empirical antibiotics.

One must not continue with antibiotics with in vitro resistance in case of Pseudomonas, Klebsiella and MRSA; and in cases of CNS infections and deep-seated infections.

If no antibiotic has been reported sensitive, but one or more has been reported ‘moderately sensitive’, therapy must be changed to such antibiotics at the highest permissible dose. Use a combination, in such cases.

Duration of antibiotics.Culture positive sepsis: Give sensitive antibiotics

for total duration of 10-14 days. There is no definitive published literature

regarding the optimum duration of antibiotics for neonatal sepsis.

neonates infected by Staphylococcus aureus require 14 days of antibiotics.

infected by non-Staphylococcus aureus organisms, without meningitis or deep-seated infections, and who become completely asymptomatic by day five, one may consider a shorter duration of antibiotics. (Chowdhary G,et al)

Culture negative sepsis:Asymptomatic neonate at risk of EOS: stop antibioticsSuspected EOS or LOS and the neonate becomes

completely asymptomatic over time: stop antibiotics.Suspected EOS or LOS and the neonate improves but

does not become asymptomatic: repeat a CRP assay (Ehl S et al, Engle WD et al, Saini SS et al)

If CRP + ve: continue antibioticsIf CRP –ve: stop antibiotics

Suspected EOS or LOS and the neonate have not improved or have worsened: upgrade antibiotics as per the empiric antibiotic policy. Simultaneously, alternative explanations for the clinical signs must be actively sought for.

Culture-proven meningitis:Gram stain-proven meningitis or meningitis

suspected on CSF examination:Give total of 21-day course of parenteral

antibiotics that cross uninflamed meninges. Anti-meningitic doses must be used

throughout the course and use only antibiotics with a proven in vitro sensitivity.

Monitoring protocol following diagnosis of meningitis:At least twice weekly head circumference monitoring,Input/Output monitoring, daily weight monitoring (for

SIADH),Daily neurological examination (focal neurological deficits),Hearing screen after 4-8 weeks,Ultrasound head in the first week and at the end of

antibiotic therapy (look for ventricular size, ventricular wall enhancement, midline shift, intraventricular debris). Ventriculitis may require 6 weeks of antibiotics.

CECT head may be required in case of rapidly rising OFC with suspicious USG, focal seizures, focal neurological deficits or infection with Citrobacter koseri and Enterobacter sakazakii.

UTIMay be treated for 7-14 days. This duration

has no evidence to back it.Start empirical treatment with

Cefotaxime/Ceftriaxone plus Amikacin, and modify as per culture report.

Nalidixic acid or nitrofurantoin should not be used to treat UTI since they do not achieve therapeutic concentrations in the renal parenchyma and blood stream.

UTI occurring in the setting of generalized septicemia may not be associated with VUR or malformations. However, an isolated UTI could be associated with these conditions.

Hence, after treatment of isolated UTI, all cases must be started on Amoxycillin 10 mg/kg once a day oral prophylaxis, till such time that a renal ultrasound, MCU and DMSA scan are performed to exclude VUR or malformations.

Proven bone or joint infections:Must be treated for at least 6 weeks. Start empirical treatment with Cloxacillin or

Vancomycin (plus an aminoglycoside for first 1-2 weeks) and modify as per culture report.

Of this, at least 4 weeks must constitute parenterally administered antibiotics. The rest of the course may be enterally administered.

Adjunctive therapies:a) Intravenous immunoglobulins (IVIG):

The currently available evidence does not support the use of IVIG. The currently undergoing International Neonatal Immunotherapy Study is expected to be provide some important and definitive information in this aspect(The INIS Study).

b) Colony stimulating factors: There is currently no evidence to support the use of colony stimulating factors either as a treatment modality or as a prophylaxis therapy.

c) Blood Exchange Transfusion (BET): BET may be performed in a case of deteriorating sepsis with sclerema provided the general condition of the baby allows the procedure .

Superficial infections Superficial infections can be treated with local

application of antimicrobial agents. Pustules can be punctured with sterile needles

and cleaned with spirit or betadine. Purulent conjunctivitis can be treated with

neosporin or chloramphenicol ophthalmic drops.Oral thrush responds to local application of

clotrimazole or nystatin (200,000 units per ml) and hygienic precautions.

Superficial infections must be adequately managed; if neglected they can lead to sepsis or even an epidemic.

Prevention of infections A good antenatal care goes a long way in

decreasing the incidence, morbidity and mortality from neonatal sepsis.

All mothers should be immunized against tetanus.

All types of infections should be diagnosed early and treated vigorously in pregnant mothers.

Babies should be fed early and exclusively with expressed breast milk (or breastfed) without any prelacteal feeds.

Cord should be kept clean and dry. Unnecessary interventions should be avoided.

Hand washing This is the simplest and the most effective

method for control of infection in the hospital.All persons taking care of the baby should

strictly follow hand washing policies before touching any baby.

The sleeves should be rolled above the elbows. Rings, watches and jewellery should be removed.

Wash hands up to elbows with a thorough scrub for 2 minutes with soap and water taking care to cover all areas including the under surface of well trimmed nails.

Rinse thoroughly with running water. Dry hands with sterile hand towel/paper towel.

Wash hands up to the wrist for 20 seconds in between patients.

Hands should be rewashed after touching contaminated material like one’s face, hair, papers etc.

It is preferable to use bar soaps rather than liquid soaps as the latter tend to harbor organisms after storage.

In emergency situations bactericidal and virucidal solutions like Sterillium can be used to clean hands before touching babies.

Surgical, elbow- operated taps should be used in the hospitals for hand washing.

Prevention of infection in hospital The nursery environment should be clean and

dry with 24 hour water supply and electricity.There should be adequate ventilation and

lighting. The nursery temperature should be

maintained between 30+2°C. Overcrowding should be avoided.

All procedures should be performed after wearing mask and gloves.

Unnecessary invasive interventions such as needle pricks and setting up of intravenous lines should be kept to the barest minimum.

There should be no compromise in the use of disposables. Stock solutions for rinsing should be avoided.

Every baby must have separate thermometer and stethoscope and all barrier nursing measures must be followed.

Strict house-keeping routines for washing, disinfection, cleaning of cots and incubators should be ensured and these policy guidelines should be available in the form of a manual in the nursery.

The use of prophylactic antibiotics for prevention of nosocomial infections is strongly condemned.

They are not only useless but also dangerous because of the potential risk of emergence of resistant strains of bacteria.

Control of outbreak General measures for the control of an

outbreak include detailed epidemiological investigations, increased emphasis on hand washing, review of protocols, procedures and techniques, disinfection and sterilization of nursery assessment of the need for additional

measures.

The nursery may be fumigated using formalin 40% and potassium permanganate (70 gms of KMNO4 with 170 ml of formalin for 1000 cubic feet area).

Alternatively, bacillocid spray for 1-2 hours may be used. Linen and cotton should be washed thoroughly, dried and autoclaved.

Use of disposable items for invasive and non- invasive interventions (catheters, probes, cannulae, chest tubes etc.) though costly, reduces the risk of infection.

Depending upon the pathogen and type of outbreak, culture surveys of susceptible patients, cohorting of infants in nursery and a review of antibiotic policy may be necessary.

Most of the times a scrupulous reinforcement of general control measures may be sufficient to stop the outbreak.

Conclusion In conclusion, manifestations of neonatal

sepsis are non-specific. A high index of suspicion with or without lab

evidences of infection is the key for early diagnosis.

Prompt institution of antibiotic therapy and supportive care will save most of the cases of neonatal sepsis.

Take home messages.In India, both early and late onset sepsis are caused by

similar organisms with similar antibiotic sensitivities.Clinical features of neonatal sepsis are non-specific

and any unexplained clinical deterioration should be investigated for sepsis.

There is no role of performing sepsis screen in early onset neonatal sepsis.

Lumbar puncture (LP) for CSF examination must be performed in all symptomatic neonates being initiated on antibiotics, with the exception of premature neonates presenting with respiratory distress at birth with no risk factors for sepsis.

The traditional cut-offs for interpretation of cerebrospinal fluid values are based on relatively old studies with methodological problems.

A new set of guidelines for interpretation is proposed.

Routine urine culture in all neonates with non-specific symptoms is not recommended.

Every newborn unit must have its own antibiotic policy based on the local sensitivity patterns and the profile of pathogens.

Apart from appropriate antibiotics, the survival of a sick septic newborn often depends upon aggressive supportive care.

There may be a potential role of intravenous immunoglobulins in treatment of neonatal sepsis but larger studies are required.

There is currently no role for the use of colony stimulating factors.

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