Sepsis in the Newborn

Rajiv Aggarwal, Nupur Sarkar, Ashok K Deorari, Vinod K Paul Division of Neonatology, Department of Pediatrics All India Institute of Medical Sciences Ansari Nagar, New Delhi 110029

Address for correspondence: Dr Ashok K Deorari Additional Professor Department of Pediatrics All India Institute of Medical Sciences Ansari Nagar, New Delhi 110029 Email: ashokdeorari_56@hotmail.com

Abstract Systemic infection in the newborn is the commonest cause of neonatal mortality. Data from National Neonatal Perinatal Database 2000 suggests that Klebsiella pneumoniae and Staphylococcus aureus are the commonest causes of neonatal sepsis in India. Two forms of clinical presentations have been identified. Early onset sepsis, probably related to perinatal risk factors, usually presents with respiratory distress and pneumonia within 72 hours of age. Late onset sepsis, related to hospital acquired infections, usually presents with septicemia and pneumonia after 72 hours of age. Clinical features of sepsis are nonspecific in neonates and a high index of suspicion is required for the timely diagnosis of sepsis. Although blood culture is the gold standard for the diagnosis of sepsis, reports are available after 48-72 hours. A practical septic screen for the diagnosis of sepsis has been described and some suggestions for antibiotic use have been included in the protocol.

Sepsis in the Newborn 1. Introduction Sepsis is the commonest cause of neonatal mortality and is probably responsible for 3050% of the total neonatal deaths each year in developing countries1,2. It is estimated that 20% of all neonates develop sepsis and approximately 1% die of sepsis related causes2. Sepsis related mortality is largely preventable with rational antimicrobial therapy with aggressive supportive care.

2. Indian data According to recent data from National Neonatal Perinatal Database (NNPD) 2000, the incidence of neonatal sepsis has been reported to be 38 per 1000 intramural live births in tertiary care institutions3. Septicemia was the commonest clinical category with an incidence of 24 per 1000 live births. Meningitis was diagnosed in 0.5 per 1000 live births. Neonatal sepsis was one of the common causes of neonatal mortality contributing to 23% of all neonatal deaths3. Klebsiella pneumoniae was the most frequently isolated pathogen (31.2%), followed by Staphylococcus aureus (17.5%) among the intramural live births. Among extramural babies admitted for neonatal problems, Klebsiella pneumoniae was the commonest organism (36.4%), followed by Staphylococcus aureus (14.3%) and Pseudomonas (13.2%).

3. Definition Neonatal sepsis is a clinical syndrome of bacteremia characterized by systemic signs and symptoms of infection in the first month of life. Neonatal sepsis encompasses systemic

infections of the newborn including septicemia, meningitis, pneumonia, arthritis, osteomyelitis and urinary tract infection of the newborn.

4. Classification of neonatal sepsis Neonatal sepsis can be divided into two main classes depending on the onset of symptoms related to sepsis4. Early onset sepsis: Early onset sepsis usually presents within the first 72 hours of life. In severe cases, the neonate may be symptomatic in utero (fetal tachycardia, poor beat to beat variability) or within a few hours after birth. The source of infection is generally the maternal genital tract. Clinically, neonates usually present with respiratory distress and pneumonia. Presence of some perinatal risk factors has been associated with an increased risk of early onset sepsis. Recommendations from developed countries suggest that presence of 2 risk factors should be considered an indication for starting antibiotics. However the main organism is group B streptococci (GBS) which is not a problem in our neonatal intensive care units. Hence, their recommendations may not be applicable to our setting. Since definitive data for our setting is lacking, an empirical approach has been recommended. Presence of the following high-risk factors has been associated with an increased risk of early onset sepsis4,5: 1. Low birth weight (<2500 grams) or preterm baby 2. Febrile illness in the mother within 2 weeks prior to delivery. 3. Foul smelling and/ or meconium stained liquor amnii. 4. Prolonged rupture of membranes >24 hours. 5. More than 3 vaginal examinations during labor

6. Prolonged and difficult delivery with instrumentation 7. Perinatal asphyxia (Apgar score <4 at 1 minute or age) or difficult resuscitation Neonates with presence of foul smelling liquor or three of the above mentioned risk factors should be considered to have early onset sepsis and treated with antibiotics. Presence of 2 risk factors should be investigated with a septic screen and treated accordingly. 3.b. Late onset sepsis: Late onset sepsis usually presents after 72 hours of age. The source of infection is either nosocomial or community-acquired and neonates usually present with septicemia, pneumonia or meningitis6,7. Various factors that predispose to an increased risk of nosocomial sepsis include NICU admissions, low birth weight, prematurity, invasive procedures, parenteral fluid therapy, ventilation and use of stock solutions. Factors that may increase risk of community-acquired late onset sepsis include poor hygiene, poor cord care, bottle-feeding and prelacteal feeds. Breast-feeding, on the other hand, prevents infection in neonates.

4. Clinical features 4.a. Non-specific features of sepsis: The earliest signs of sepsis are often subtle and nonspecific and need a high index of suspicion for early diagnosis. Babies with sepsis may present with one or more of the following symptoms and signs (a) Hypothermia or fever (former is more common in low birth weight babies) (b) Lethargy, poor cry, refusal to suck (c) Poor perfusion, prolonged capillary refill time (d) Hypotonia, absent neonatal reflexes (e) Bradycardia; tachycardia (f) Respiratory distress, apnea and gasping respiration (g) Hypoglycemia, hyperglycemia (h)Metabolic acidosis

4.b. Specific features related to various systems. Central nervous system (CNS): Bulging anterior fontanelle, blank look, high-pitched cry, excess irritability, not arousable, comatose, seizures, neck retraction. Presence of these features should raise a clinical suspicion of meningitis Cardiac: Hypotension, poor perfusion, shock Gastrointestinal: Feed intolerance, vomiting, diarrhea, abdominal distension, paralytic ileus, necrotizing enterocolitis (NEC). Hepatic: Hepatomegaly, direct hyperbilirubinemia (especially with UTI) Renal: Acute renal failure Hematological: Bleeding, petechiae, purpura, Skin changes: Multiple pustules, abscess, sclerema, mottling, umbilical redness and discharge.

5. Investigations It is important that the supportive and antimicrobial therapy of a neonate with sepsis is instituted quickly8. Hence minimum and rapid investigations should be undertaken. 5.a. Blood culture: It is the gold standard for the diagnosis of septicemia and should be done in all cases of suspected sepsis prior to starting antibiotics. A positive blood culture and sensitivity of the isolate is the best guide to antimicrobial therapy. Therefore the procedure for collecting a blood culture should be strictly followed to avoid contamination. The staff involved should wear sterile gloves prior to the procedure and prepare a patch of skin approx. 5-cm in diameter over the proposed veni-puncture site. This area should be cleansed thoroughly with alcohol followed by povidone-iodine,

followed again by alcohol. Application of povidone-iodine should be done in concentric circles moving outward from the centre. The skin should be allowed to dry for at least 1 minute before the sample is collected. A one-ml sample of blood should be adequate for a blood culture bottle containing 5-10 ml of culture media. Blood cultures should be collected from a fresh veni-puncture site because samples collected from indwelling lines and catheters are likely to be contaminated. All blood cultures should be observed for at least 72 hours before they are reported as sterile. It is now possible to detect bacterial growth within 12-24 hours by using improved bacteriological techniques such as BACTEC and BACT/ALERT blood culture systems. These advanced techniques can detect bacteria at a concentration of 1-2 colony-forming unit (cfu) per ml. 5.b. Septic screen9,10: All newborns suspected to have neonatal sepsis should have a septic screen to corroborate the diagnosis of sepsis. However, if there is a strong clinical suspicion of sepsis, the decision to start antibiotics need not be conditional to a sepsis screen. Presence of any factor in neonates at risk of early onset sepsis should have a septic screen to decide antibiotic therapy. The various components of the septic screen include total leukocyte count, absolute neutrophil count, immature to total neutrophil ratio, micro-erythrocyte sedimentation rate and C reactive protein. (Table 1). The absolute neutrophil count varies considerably in the immediate neonatal period and normal reference ranges are available in Manroes charts11. The lower limit for normal total neutrophil counts in the newborn begins at 1800/cmm, rises to 7200/cmm at 12 hours of age and then declines and persists at 1800/cmm after 72 hours of age. The ratio of immature to total neutrophils (I/T ratio) is 0.16 at birth and declines to a peak value of 0.12 after 72 hours of age. Presence of

two abnormal parameters in a screen is associated with a sensitivity of 93-100%, specificity of 83%, positive and negative predictive values of 27% and 100% respectively in detecting sepsis. Hence, if two parameters are abnormal, it should be considered as a positive septic screen and it is reasonable to start antibiotic therapy. If a septic screen is negative in the presence of strong clinical suspicion, it should be repeated within 12 hours. If the screen is still negative, sepsis can be excluded with reasonable certainity. For early onset sepsis, documentation of polymorphs in the neonatal gastric aspirate at birth serves as a marker of chorioamnionitis and it may be taken as one parameter of sepsis screen. 5.c. Lumbar puncture (LP) Since clinical features of sepsis and meningitis are non-specific in neonates, it is likely that meningitis may be present without specific symptomatology along with sepsis. The incidence of meningitis in neonatal sepsis has varied from 0.3-3% in various studies and 0.5% according to the NNPD 2000 data3-6. However the morbidity involved with a delayed or a missed diagnosis of meningitis probably justifies the extra precaution of performing lumbar punctures in patients suspected of neonatal sepsis. In situations of early onset sepsis, a lumbar puncture is indicated in the presence of either a positive blood culture or presence of clinical picture of septicemia. It is probably not indicated if antibiotics have been started solely due to the presence of risk factors only. In situations of late onset sepsis, a lumbar puncture should be done in all infants with signs and symptoms prior to starting antibiotics. The lumbar puncture should be postponed in a critically sick and hemodynamically unstable baby. However it should be considered

after the clinical condition stabilizes. The cerebrospinal fluid characteristics are unique in the newborn period and normal values have been given in Table 212. 5.d. Radiology: A chest x-ray should be considered in the presence of respiratory distress or apnea. An abdominal x-ray is indicated in the presence of abdominal signs and/ or suspicion of necrotizing enterocolitis (NEC). An ultrasound head and CT scan should be done in all patients diagnosed to have meningitis. 5.e. Urine culture: In early onset sepsis, urine cultures have a low yield and are not indicated. Although a suprapubic bladder puncture sample or bladder catheterization sample has been recommended in all cases of late onset sepsis, the procedure is painful and the yield is very poor. We do not recommend a routine urine culture in babies with sepsis. However, patients at risk for fungal sepsis and very low birth weight babies with poor weight gain should have a urine examination to exclude urinary infection. Urinary tract infection may be diagnosed in presence of one of the following: (a) >10 WBC/mm3 in a 10 ml centrifuged sample (b) >104 organisms /ml in urine obtained by catheterization and (c) Any organism in urine obtained by suprapubic aspiration

6. Management 6.a. Supportive: Attention should be given to basic supportive care in a sick child. The infant should be nursed in a thermo-neutral environment taking care to avoid hypothermia/ hyperthermia. Oxygen saturation should be maintained in the normal range and ventilation should be initiated as required. The infant should be regularly monitored for hypoglycemia/ hyperglycemia. Colloids and inotropes should be used for maintaining normal tissue perfusion and blood pressure. Enteral feeds should be avoided till the baby

is hemodynamically stable. Packed cells and fresh frozen plasma should be used appropriately for the management of anemia and bleeding diathesis

6.b. Antimicrobial therapy: There cannot be single recommendations for the antibiotic regimen for neonatal sepsis in all settings. The choice of antibiotics depends on the prevailing flora responsible for sepsis in the given unit and their antimicrobial sensitivity. This write up does not aim to provide a universal recommendation for all settings but lays down broad guidelines for the providers to make a rational choice of antibiotic combination. Decision to start antibiotics is based upon clinical features and/ or a positive septic screen. However duration of antibiotic therapy is dependent upon the presence of a positive blood culture and meningitis (see table 3). Indications for starting antibiotics: The indications for starting antibiotics in neonates at risk of early onset sepsis include the following: (a) presence of three risk factors for early onset sepsis (b) presence of foul smelling liquor (c) presence of 2 antenatal risk factor(s) with a positive septic screen and (d) strong clinical suspicion of sepsis. The indications for starting antibiotics in late onset sepsis include (a) positive septic screen and/ or (b) strong clinical suspicion of sepsis. Prophylactic antibiotics: We do not recommend the use of prophylactic antibiotics for single exchange transfusions. An exchange transfusion conducted under strict asepsis (single use catheter, sterile gloves, removal of catheter after the procedure) does not increase the risk of sepsis and does not merit antibiotics. However a messy exchange or 3 exchange transfusions should be treated with prophylactic antibiotics. In our unit, ventilated neonates are treated with prophylactic antibiotics for 5-7 days.

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Choice of antibiotics: Empirical antibiotic therapy should be unit specific and determined by the prevalent spectrum of etiological agents and their antibiotic sensitivity pattern. Antibiotics once started should be modified according to the culture sensitivity reports. Guidelines for empirical antibiotic therapy have been provided in Table 4. The empirical choice of antibiotics is dependent upon the probable source of origin of infection. For infections that are likely to be community-acquired and where resistant strains are unlikely; a combination of ampicillin or penicillin with gentamicin may be a good choice for first line therapy. Chloramphenicol may be added to treat meningitis acquired from the community. For infections that are acquired during hospital stay, resistant pathogens are likely and a combination of ampicillin or cloxacillin with gentamicin or amikacin may be instituted. Cefotaxime or Ceftriaxone should be added for treatment of meningitis where resistant strains are likely. In nurseries where this combination is ineffective due to the presence of multiple resistant strains of klebsiella and other gram-negative bacilli, a combination of a third generation cephalosporin (cefotaxime or ceftizoxime) with amikacin may be appropriate Reserve antibiotics Third generation cephalosporins including cefotaxime, ceftriaxone and ceftazidime have excellent antimicrobial activity against gram negative organisms (including klebsiella) and have very good CSF penetration. Ceftazidime is particularly effective against pseudomonas infections. These antibiotics are an excellent choice for the treatment of nosocomial infections and meningitis. Newer antibiotics like aztreonam and imepenem are also now available in the market. Aztreonam has excellent activity against gram-negative organisms and imepenem is effective against most bacterial pathogens except methicillin resistant Staphylococcus aureus (MRSA) and Enterococcus.

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The empirical use of the last two antibiotics is best avoided and should be reserved for situations where sensitivity of the isolate justifies its use. Ciprofloxacillin is another antibiotic with excellent activity against gram-negative organisms although it does not have very good CSF penetration. Hence ciprofloxacillin may be used for the treatment of resistant gram-negative bacteremia after excluding meningitis. A combination of piperacillin or ceftazidime with amikacin should be considered if pseudomonas sepsis is suspected. Penicillin resistant Staphylococcus aureus should be treated with cloxacillin, nafcillin or methicillin. Addition of an aminoglycoside is useful in therapy against Staphylococcus. Methicillin resistant Staphylococcus aureus (MRSA) should be treated with a combination of either ciprofloxacillin or vancomycin with amikacin. For sepsis due to Enterococcus, a combination of ampicillin and gentamicin is a good choice for initial therapy. Vancomycin should be used for the treatment of Enterococcus resistant to the first line of therapy. 6.c. Adjunctive therapy Exchange transfusion (ET): Sadana et al13 have evaluated the role of a single double volume exchange transfusion in septic neonates with sclerema and demonstrated a 50% reduction in sepsis related mortality in the treated group. We perform double-volume exchange transfusion with cross-matched fresh whole blood as adjunctive therapy in septic neonates with sclerema. Intravenous Immunoglobulin (IVIG): Non-specific pooled IVIG has not been found to be useful14. Granulocyte-Macrophage colony stimulating factor (GM-CSF): This mode of treatment is still experimental15.

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References 1. Bang AT, Bang RA, Bactule SB, Reddy HM, Deshmukh MD. Effect of homebased neonatal care and management of sepsis on neonatal mortality: field trial in rural India. Lancet 1999;354:1955-61 2. Stoll BJ. The global impact of neonatal infection. Clin Perinatol 1997;24:1-21 3. Report of the National Neonatal Perinatal Database (National Neonatology Forum) 2000. 4. Kaftan H, Kinney JS. Early onset neonatal bacterial infections. Semin Perinatol 1998;22:15-24 5. Belady PH, Farkouh LJ, Gibbs RS. Intra-amniotic infection and premature rupture of membranes. Clin Perinatol 1997;24:43-57 6. Baltimore RS. Neonatal nosocomial infections. Semin Perinatol 1998;22:25-32 7. Wolach B. Neonatal sepsis: pathogenesis and supportive therapy. Semin Perinatol1997;21:28-38 8. Gerdes JS, Polin R. Early diagnosis and treatment of neonatal sepsis. Indian J Pediatr 1998;65:63-78. 9. Polinski C. The value of white blood cell count and differential in the prediction of neonatal sepsis. Neonatal Netw 1996;15:13-23 10. Da Silva O, Ohlsson A, Kenyon C. Accuracy of leukocyte indices and C-reactive protein for diagnosis of neonatal sepsis: a critical review. Pediatr Infect Dis J 1995;14:362-6

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11. Manroe BL, Weinberg AG, Rosenfeld CR, Browne R. The neonatal blood count in health and disease. I.Refernce values for neutrophilic cells. J Pediatr 1979;95:89-98 12. Sarff LD, Platt LH, McCracken GH Jr. Cerebrospinal fluid evaluation in neonates: Comparison of high-risk neonates with and without meningitis. J Pediatr 1976;88:473-7 13. Sadana S, Mathur NB, Thakur A. Exchange transfusion in septic neonates with sclerema: effect on immunoglobulin and complement levels. Indian Pediatr 1997;34:20-5 14. Jenson HB, Pollock HB. The role of intravenous immunoglobulin for the prevention and treatment of neonatal sepsis. Semin Perinatol 1998;22:50-63 15. Goldman S, Ellis R, Dhar V, Cairo MS. Rationale and potential use of cytokines in the prevention and treatment of neonatal sepsis. Clin Perinatol 1998;25:699710

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Table 1. A practical sepsis screen Components Total leukocyte count Absolute neutrophil count Immature/total neutrophil Micro-ESR C reactive protein (CRP) Abnormal value <5000/mm3 As per Manroe chart11 >0.2 > 15 mm in 1st hour >1 mg/dl

Table 2. Normal cerebrospinal fluid examination in neonates15 CSF components Cells/mm3 PMN (%) CSF protein (mg/dl) Glucose (mg/dl) CSF/ blood glucose (%) Normal range 8 (0-30 cells) 60% 90 (20-170) 52 (34-119) 51 (44-248)

Table 3. Duration of antibiotic therapy in neonatal sepsis Diagnosis Duration

Meningitis 21 days Blood culture positive (no meningitis) 14 days Culture negative but definite clinical sepsis 10-14 days Culture negative, clinically probable sepsis screen positive 7-10 days Culture negative, clinically probable sepsis Screen negative 5-7 days

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Table 4. Empirical choice of antibiotics for treatment of neonatal sepsis Clinical situation FIRST LINE Community-acquired or Resistant strains unlikely SECOND LINE Hospital-acquired or Some resistant strains likely THIRD LINE Hospital-acquired sepsis Resistant strains are most likely Septicemia & Pneumonia Ampicillin or Penicillin and Gentamicin Ampicillin or Cloxacillin and Gentamicin or Amikacin Cefotaxime and Amikacin Meningitis Add Chloramphenicol

Add Cefotaxime

Same

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Table 5. Drugs, route of administration and doses of common antibiotics used. Drug Amikacin Ampicillin Meningitis Others Cefotoxime Meningitis Others Ceftazidime Ceftriaxone Chloramphenicol Cloxacillin Meningitis Others Route I/V, I/M I/V I/V, I/M I/V I/M, I/V I/M, I/V I/M, I/V I/V, PO Birth Weight 2000g 0-7 d >7 days 7.5 q12h 100 q12h 25 q12h 50 q6h 50 q12h 50 q12h 50 q24h 25 q24h 7.5 q8h 100 q8h 25 q8h 50 q6h 50 q8h 50 q8h 50 q24h 25 q24h Birth Weight >2000g 0-7 days >7 days 10 q12h 100 q 8h 25 q8h 50 q6h 50 q12h 50 q8h 50 q24h 25 q24h 10 q8h 100 q6h 25 q6h 50 q6h 50 q8h 50 q8h 75 q24h 25 q12h

I/V I/V

50 q12h 25 q12h 2.5 q12h 4 q24 h 2.5 q12h

50 q8h 25 q8h 2.5 q8h 4 q24 hr 2.5 q8h

50 q8h 25 q8h 2.5 q12h 5 q24h 2.5 q12h 75,000 q8h -1,00,000 25,000 q8h 15 q12h

50 q6h 25 q6h 2.5 q8h 5 q24h 2.5 q8h 75,000 q6h -1,00,000 25,000 q6h 15 q8h

Gentamicin Conventional I/V, I/M Single dose I/M Netilmicin Penicillin G Meningitis Others I/V, I/M I/V I/V, I/M

(units/kg/dose) 75,000 q12h 75,000 q8h -100,000 -1,00,000 25,000 q12h 25,000 q8h 15 q12h 15 q8h

Vancomycin I/V All doses are in mg/kg/dose

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Protocol for sepsis 2 antenatal risk factors present or Clinical features suggestive of sepsis Foul smelling liquor or 3 antenatal risk factors

Sepsis screen (if negative, repeat after 12 hours) Blood culture Lumbar puncture, Chest xray (if required) Abdomen xray, urine examination (if required) Septic screen +ve Start antibiotics

Blood culture

- No meningitis - Blood cultures negative - Screen negative - Clinical course not compatible with sepsis

- No meningitis - Blood cultures negative - Screen negative - Clinical course compatible with sepsis

- No meningitis - Blood cultures negative - Screen positive - Clinical course compatible with sepsis

Treat empirically Antibiotics 3 days

Treat empirically Antibiotics 5-7 days

Individualize Antibiotics 7-14 days

-No meningitis -Blood culture positive -Clinical course compatible with sepsis

-Meningitis present -Blood cultures -Clinical course compatible with sepsis

Antibiotics for 14 days

Antibiotics for 21 days

NB. If no response is seen within 48-72 hours of starting treatment, a repeat blood culture should be obtained to determine appropriate choice and duration of antibiotic therapy. A lumbar puncture should be repeated in gram negative meningitis to assess for response to therapy.

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