73: Postdelivery Antibiotics

Two infants are born within the last hour. One infant's mother had premature rupture of membranes (PROM) but no antibiotics. The other infant's mother was pretreated with antibiotics for a positive group B Streptococcus (GBS) culture taken at 36 weeks. Should a sepsis workup be done, and should antibiotics be started in either of these newborns?

Early-onset sepsis (EOS) occurs within the first 3 days of life and is vertically transmitted (ascending organisms from the birth canal) and can occur from ruptured membranes, inhaling or swallowing infected amniotic fluid, or an amniotic fluid leak before or during labor. Sepsis in the first 3 days of life is a leading cause of morbidity and mortality among preterm infants. The incidence of sepsis is 1–10 in 1000 live births and 1 in 250 live premature births, with GBS being the most common pathogen followed by Escherichia coli. Black preterm infants have the highest incidence and case fatality. Since the institution of Centers for Disease Control and Prevention (CDC) guidelines, the incidence of early-onset GBS has decreased by 80%. Late-onset sepsis is discussed in Chapter 130, and infections of premature infants with prolonged hospital stays may require a different workup and antibiotic choice. This on-call problem focuses on postdelivery antibiotics for early-onset or suspected sepsis. The American Academy of Pediatrics (AAP) has a practical evidence-based approach to managing infants with suspected and culture-proven early-onset sepsis.

1. Are there any major risk factors for early-onset sepsis? Major risk factors are preterm birth, low birthweight (risk factor most associated with early-onset sepsis), rupture of membranes (ROM) >18 hours, maternal colonization with GBS (if inadequate intrapartum therapy), or maternal chorioamnionitis (defined as maternal fever ≥38.0°C [≥100.4°F] and a minimum of 2 of the following: maternal white blood cell [WBC] count >15,000 mm³, maternal tachycardia [>100 beats/min], fetal tachycardia [>160 beats/min], uterine tenderness, foul odor of the amniotic fluid).

2. Are there any other maternal risk factors for sepsis in the infant? Other risk factors include African race, maternal malnutrition, recently acquired sexually transmitted disease/sexually transmitted infection (STD/STI), maternal age <20 years, low socioeconomic status, and asymptomatic maternal bacteriuria. Maternal history of a previous infant with GBS infection also increases the risk of sepsis.

3. Are there other intrapartum risk factors for sepsis in the infant? These include maternal infection, any untreated or incompletely treated infection of the mother, and maternal fever without identifiable cause. The use of fetal scalp electrodes in the intrapartum period increases the risk of infection in the infant. Meconium-stained amniotic fluid and traumatic delivery are also risk factors.

4. Are there any other neonatal risk factors involved? Other risk factors include male sex, low Apgar scores, severe depression at birth with intubation and resuscitation, perinatal asphyxia, twin birth, and presence of the metabolic disorder galactosemia (increased risk of gram-negative sepsis).

5. How long before delivery did the membranes rupture? ROM that occurs >18 hours before birth is associated with an increased incidence of infection in the neonate.

6. Was the infant monitored during labor? Fetal tachycardia (>160 beats/min), especially sustained, and decelerations (usually late) can be associated with neonatal infection. Prolonged duration of intrauterine monitoring is a risk factor for early-onset group B streptococcal disease.

7. Did the mother have a cerclage for cervical incompetence? Cerclage increases the risk of infection in the infant. Preterm PROM occurs in 38% of women with cerclage in place. Retention of cerclage for more than 24 hours after PROM was found to prolong pregnancy for more than 48 hours, but also to increase maternal chorioamnionitis and neonatal mortality from sepsis.

8. Are signs of sepsis present in the infant? Signs of sepsis are nonspecific and can include apnea and bradycardia, temperature instability (hypothermia or hyperthermia), feeding intolerance, tachypnea, jaundice, cyanosis, poor peripheral perfusion, hypoglycemia, lethargy, poor sucking reflex, increased gastric aspirates, and irritability. Other signs include tachycardia, shock, vomiting, seizures, abnormal rash, abdominal distention, and hepatomegaly. Neonatal sepsis is associated with systolic and diastolic myocardial dysfunction. Bacteremia can also occur without clinical signs.

9. Did the mother have epidural analgesia? Studies have shown an increase in maternal intrapartum fever (15–20%) with the use of epidural analgesia. Because of this fever, an increase in sepsis evaluations and antibiotic treatment was found. However, the study did not find that epidurals caused infections or even increased the risk of infections.

10. Was the mother tested for GBS, and did she receive antibiotics if she tested positive? There are now specific guidelines to follow after delivery if the mother was treated for GBS.

11. Did the mother have chorioamnionitis? See definition above. Chorioamnionitis is a major risk factor for sepsis, and its incidence varies inversely with gestational age. Histological chorioamnionitis increases the chance of having markers of infection (increased C-reactive proteins and neutrophilia, bacterial colonization [by gastric lavage and ear swab] and congenital sepsis). Fourteen to twenty-eight percent of mothers who deliver preterm infants at 22 to 28 weeks have signs of chorioamnionitis. Risk factors for chorioamnionitis include spontaneous labor, low parity, multiple digital vaginal examinations, meconium-stained amniotic fluid, presence of genital tract microorganisms, long length of labor and membrane rupture, and internal fetal or uterine monitoring.

1. Culture-proven sepsis. Cultures confirm sepsis diagnosis.

2. Suspected sepsis. An infant has nonspecific signs of sepsis or there is a high likelihood that the infant has sepsis based on clinical signs. Sepsis needs to be “ruled out” in the infant. From 18 to 33% of infants with negative blood cultures have sepsis confirmed at autopsy.

3. Increased risk for sepsis. The infant has risk factors (preterm birth, maternal colonization with GBS, rupture of membranes at >18 hours before birth, mother has signs of an intra-amniotic infection) that can increase the risk of early-onset sepsis.

4. Infant at low risk for sepsis. Newborns without the risk factors noted previously are at low risk of sepsis.

1. Complete maternal, perinatal, and birth history. This should be obtained and reviewed in an attempt to identify risk factors, as noted previously. Maternal history is just as important as the birth history. It is especially important to discuss the diagnosis of chorioamnionitis with the obstetrics (OB) department since it has major implications for the management of the newborn.

2. Physical examination. Observe for signs of sepsis (see above). Clinical observation is important. One study found that affect, peripheral perfusion, and respiratory status were key predictors in sepsis compared with feeding patterns, level of activity, and level of alertness. The maternal clinical examination should be reviewed with the obstetrics and gynecology (OB/GYN) service. Early-onset sepsis can occur in infants who appear healthy at birth.

3. Laboratory studies

   1. Complete blood count (CBC) with differential. A single WBC count is not helpful when compared to serial tests. Timing of the CBC is important; an early CBC is not recommended. CBC at 4–6 to 12 hours is optimal, after the inflammatory response has occurred. The incidence of sepsis is increased only when the WBC count and absolute neutrophil count is low. Some recommend interval likelihood ratios to be used to interpret CBC instead of using normal ranges.

      1. Normal total WBC. The total leukocyte count is a very unreliable indicator of neonatal infection. Normal WBC counts may be seen in as many as 50% of culture-proven sepsis cases. A normal WBC count does not rule out sepsis, but a normal WBC is a better negative predictor of sepsis.

      2. Abnormally low or high WBC count is worrisome. Values <6000 cells/mm³ or >30,000 cells/mm³ in the first 24 hours of life are abnormal. A band neutrophil count >20% is abnormal. Only half of infants with WBC <5000 cells/mm³ or WBC >20,000 cells/mm³ have positive blood cultures (BCs). Septic infants with a WBC count <5000 cells/mm³ are more likely to have bacterial meningitis.

      3. Neutropenia can be a good marker for sepsis because it occurs only in sepsis, asphyxia, inborn errors of metabolism (IEMs), hemolytic disease, and pregnancy-induced maternal hypertension. The neutropenia ranges depend on gestational age (WBC count increases with gestational age), type of delivery (vaginal births have higher WBC counts than cesarean section without labor), type of sample (arterial samples give lower WBC counts than venous samples), and altitude (WBC counts are higher at higher altitudes). Results from Manroe (Table 73–1) are for late preterm and term infants at low altitudes <500 ft. Results from Schmutz et al are for preterm to term infants at higher altitudes, ∽4800 ft.

         1. Total neutrophil count is more sensitive than the total leukocyte count but too often is normal in cases of infection. It peaks in 12 hours, and it has a poor sensitivity and poor predictive accuracy for early-onset sepsis. See Tables 73–1 and 73–2 for Manroe data. For high altitude (Schmutz data), the lower and upper limits of normal for neutrophils at birth are

            • (a) <28 weeks' gestation. 500–8000/mm³.

            • (b) 28–36 weeks' gestation. 1000–10,500/mm³.

            • (c) >36 weeks' gestation. 3500–18,000/mm³.

            Peak values are seen 6–8 hours after birth. The lower and upper limits of normal at that time are

            • (a) <28 weeks' gestation. 1500–41,000/mm³.

            • (b) 28–36 weeks' gestation. 3500–25,000/mm³.

            • (c) >36 weeks' gestation. 7500–28,500/mm³.

         2. Total immature neutrophil count has poor sensitivity but better positive predictive value. See Table 73–1.

         3. Ratio of immature to total neutrophils (I:T) has the highest sensitivity for early-onset neonatal sepsis. The greatest value relies in its negative predictive value; the likelihood of infection is minimal if the I:T ratio is normal. In the majority of healthy preterm infants at <32 weeks (96%), the I:T ratio is <0.22. The total neutrophil count can be calculated, and normal reference ranges can be found in Tables 73–1 and 73–2.

   2. Peripheral blood cultures are the gold standard for diagnosis of sepsis. Small specimen volumes decrease the sensitivity (minimum of 1 mL per single bottle, aerobic culture only recommended). Antibiotic removal device bottles should be used if the mother has received any antibiotics. Acceptable ways to obtain blood culture in a neonate: peripheral vein, arterial puncture, newly placed intravenous catheter, umbilical artery catheter (UAC) immediately after placement. Umbilical venous catheter (UVC) at delivery is also acceptable if the cord is adequately prepared.

   3. Urine culture is no longer recommended in infants <72 hours of age in an early-onset sepsis workup. More appropriately done for late-onset sepsis workup.

   4. Gastric aspirates. Gram stain is of limited value and not recommended. WBCs in the gastric aspirate represent maternal response and do not correlate with sepsis in the neonate.

   5. Body surface cultures (axilla, external ear canal, umbilical stump, groin) are not recommended.

   6. Lumbar puncture (LP) for cerebrospinal fluid (CSF) examination is controversial. The AAP recommends that a LP be done with positive blood culture, if the infant deteriorates or does not respond on antibiotic therapy, and in infants whose lab data or clinical course suggests bacterial sepsis. Approximately 13% of infants with early-onset sepsis will also have meningitis. Infants with bacteremia have a risk of meningitis of 23%. Blood cultures can be negative in 38% of infants with meningitis. Infants with respiratory distress syndrome (RDS) and high-risk, healthy-appearing infants are at low risk of meningitis.

   7. Tracheal aspirate. May be of benefit for Gram stain and culture if performed immediately after endotracheal tube placement. Some advocate this only if pneumonia is suspected or volume of secretions increases, or in overwhelming newborn EOS. Tracheal aspirates done after several days of intubation are of no value.

   8. Baseline serum glucose.

   9. Arterial blood gas. To rule out metabolic acidosis.

   10. Platelet count and coagulation studies to rule out thrombocytopenia and disseminated intravascular coagulation (DIC). A decreased platelet count is usually a late sign of sepsis. A low platelet count is a nonspecific and insensitive test for sepsis.

   11. Erythrocyte sedimentation rates (ESRs). Increased with infection but have a very limited value in diagnosing or monitoring infection. A low value does not exclude the diagnosis of sepsis.

   12. Acute phase reactants (C-reactive protein [CRP] and procalcitonin [PCT]). Used to identify infants with sepsis. CRP is a quantitative test. An increasing CRP is worrisome and is elevated in 50–90% of infants with sepsis. CRP increases at 6–8 hours and peaks at 24 hours. If CRPs remain normal, sepsis is unlikely. The main interest in CRP is its negative predictive value if repeated over 1–3 days. No recommendations exist on using an elevated CRP to help determine duration of antibiotic therapy. Serum procalcitonin levels are elevated in sepsis and may be helpful as a marker for sepsis. It can also be elevated in RDS, asphyxia, intracranial hemorrhage, pneumothorax, and resuscitation. It has better sensitivity but is less specific than CRP. Serial PCT levels may be helpful in deciding duration of antibiotic therapy. The following is a list of predicted CRP and PCT levels with lower and upper limits in parentheses in term and preterm infants.

       1. CRP (term) in mg/dL. Birth: 0.1 (0.01–0.65); 21 hours: 1.5 (0.2–10.0); 56–70 hours: 1.9 (0.3–13); 96 hours: 1.4 (0.2–9).

       2. CRP (preterm) in mg/dL. Birth: 0.1 (0.01–0.64); 27–36 hours: 1.7 (0.3–11); 90 hours: 0.7 (0.1–4.7).

       3. Procalcitonin (term) in mcg/L. Birth: 0.08 (0.01–0.55); 24 hours: 2.9 (0.4–18.7); 80 hours: 0.3 (0.04–1.8).

       4. Procalcitonin (preterm) in mcg/L. Birth: 0.07 (0.01–0.56); 21–22 hours: 6.5 (0.9–48.4); 5 days: 0.10 (0.01–0.8).

   13. Laboratory tests that could be helpful in screening for sepsis but are not routinely used. Lack of availability, lack of confirmatory studies, and wide variations in results.

       1. Cytokines. Interleukins (IL-1, IL-6, IL-8), soluble IL-2 receptor, and soluble tumor necrosis factor alpha (TNF-α) receptor have been identified; IL-6 has been studied the most. Interleukins 6 and 8 are early sensitive markers of infection. IL-6 is higher in infants with polycythemia.

       2. Neutrophil surface antigens. CD11b is a marker for early-onset sepsis.

       3. Urinary neutrophil gelatinase–associated lipocalin (NGAL). A promising biomarker for sepsis in neonates, it is elevated in sepsis, ischemia, hypoxia, and drug toxicity.

       4. Multiple markers. Using serial and multiple investigational markers showed the best reliability for predicting sepsis.

       5. Septic scoring systems. Usually include a battery of multiple laboratory tests (and sometimes clinical indicators of sepsis) where each test is given a number based on the result and the total score assesses the risk of sepsis. Institutions have devised their own septic scoring systems. Studies of scoring systems (using a combination of the laboratory tests mentioned previously) have shown that they all have limited value in screening for sepsis unless the score is high, with a negative panel being a better predictor than a positive panel. They may be helpful in deciding which healthy high-risk infants do not need antibiotics or whether antibiotics can be stopped.

4. Imaging and other studies

   1. Chest x-ray. With signs of respiratory infection, obtain a chest radiograph to rule out pneumonia.

   2. Echocardiography and Doppler imaging. To assess myocardial function. Infants with sepsis have systolic and diastolic myocardial dysfunction.

   3. Head ultrasound or magnetic resonance imaging (MRI). May be helpful in meningitis.

1. General measures. For the majority of cases, a decision about whether an infant requires a sepsis workup and antibiotics is usually straightforward. These infants either are clinically sick or have a positive history of an increased risk for sepsis with clinical signs, thereby making the antibiotic decision easy. However, if an infant does not have a clear-cut history and clinical presentation, the decision is more difficult. One single test is often not helpful and it is necessary to “repeat, repeat, and repeat” the test. Once the decision is made to treat the infant, treatment usually involves at least 36–48 hours of antibiotics after obtaining cultures. The following guidelines can be used to help make the decision to treat:

   1. CDC recommendations should be followed if possible. The CDC now recommends universal prenatal screening for vaginal and rectal GBS of all pregnant women at 35–37 weeks' gestation. The following are CDC recommendations for the management of all newborns. If antibiotics are given, use broad spectrum for the most common causes of sepsis (IV ampicillin for GBS and coverage for other organisms [E. coli and other gram-negative organisms]). When deciding antibiotics, check local antibiotic resistance patterns. If there are any signs of sepsis during the observation period, the infant should receive a full diagnostic evaluation. GBS prophylaxis is indicated if there are one or more of the following:

      1. Positive GBS vaginal rectal screening in late gestation (optimal at 35–37 weeks' gestation).

      2. GBS status unknown at onset of labor (culture not done, culture incomplete, or unknown results) with one or more intrapartum risk factors, including delivery <37 weeks' gestation, ROM ≥18 hours or intrapartum T ≥100.4°F (38.0°C), intrapartum nucleic acid amplification test (NAAT) positive for GBS.

      3. GBS bacteriuria during any trimester during the current pregnancy (intrapartum antibiotic prophylaxis [IAP] not indicated if culture and sensitivity [C/S] done before onset of labor with intact membranes).

      4. History of a previous infant with invasive GBS disease.

   2. CDC treatment plan for secondary prevention of early-onset GBS among all newborns (term and preterm). See also Figure 130–1.

      1. Any signs of sepsis. Full diagnostic workup (CBC with differential and platelets, blood culture, chest x-ray [CXR] with abnormal respiratory signs, LP if stable enough to tolerate, and sepsis is strongly suspected). Give empiric antibiotics.

      2. Well infant, mother with suspected chorioamnionitis. Consultation with OB department is important to discuss level of clinical assessment of chorioamnionitis. Perform a limited evaluation: Do a blood culture at birth, CBC with differential, platelet count at birth and/or at 6–12 hours of life. Start empiric antibiotics.

      3. Well infant, mother without chorioamnionitis, and GBS prophylaxis not indicated for the mother. Routine clinical care. If signs of sepsis develop, do a full diagnostic evaluation and initiate antibiotics.

      4. Well infant, GBS prophylaxis indicated for mother and she received adequate intrapartum GBS prophylaxis (≥4 hours of IV penicillin, ampicillin, or cefazolin before delivery). Observe for 48 hours or more; no testing necessary. If signs of sepsis develop, do a full diagnostic evaluation and start antibiotics. Infant may go home after 24 hours if ≥37 weeks' gestation and discharge criteria have been met. Well-appearing infants at gestational age (GA) of 35–36 weeks do not routinely require diagnostic evaluations.

      5. Well infant, mother had indication for GBS prophylaxis but did not receive adequate prophylaxis.

         1. Infant ≥37 weeks and ROM <18 hours. Observe infant for 48 hours or more; no testing. Some recommend CBC and differential at 6–12 hours. If signs of sepsis develop, do a full diagnostic evaluation and start antibiotics.

         2. Infant <37 weeks or ROM ≥18 hours. Limited evaluation (blood culture at birth, CBC with differential at birth and/or at 6–12 hours of life) with observation for 48 hours or more. Some experts recommend a CBC and differential at 6–12 hours. If signs of sepsis develop, do a full diagnostic evaluation and start antibiotics.

   3. The AAP guidelines recognize the clinical challenges in this area. The concern of overtreatment is validated by recent data showing that prolonged antibiotic treatment >5 days in preterm infants had a higher incidence of NEC, late-onset sepsis, and mortality. They have come up with management plans for neonates with suspected or proven early-onset bacterial sepsis. When reviewing these specific guidelines, remember these key points. If the mother was diagnosed with chorioamnionitis, it is important to talk to the obstetricians and confirm the diagnosis since it has major treatment implications for the infant. Inadequate IAP means the mother received another antibiotic (not penicillin, ampicillin, or cefazolin) or received the correct antibiotic but the duration was <4 hours.

      1. Any critically ill infant. Requires a complete sepsis evaluation and antibiotics (even if there are no risk factors).

      2. Any mature infant without risk factors for infection with mild findings (tachypnea with or without O₂ requirement). Observe for ∽6 hours after birth. With improvement (tachypnea is resolving, O₂ requirement is decreasing), antibiotics are probably not indicated but continued observation is. With worsening clinical state, obtain cultures and start antibiotics empirically.

      3. Healthy-appearing, asymptomatic infant <37 weeks with one risk factor for sepsis. For example, intrapartum antimicrobial prophylaxis indicated but inadequate or PROM ≥18 hours or chorioamnionitis.

         1. Do blood culture at birth, WBC and differential and optional CRP at age 6–12 hours.

         2. Start broad-spectrum antibiotics. Now what?

            • (a) Blood culture positive. Continue antibiotics. Lumbar puncture is indicated in any infant with a positive blood culture or if sepsis is highly suspected (based on clinical signs, response to treatment, or lab results).

            • (b) Blood culture negative, infant well, lab values abnormal. Continue antibiotics in the infant for a total of 72 hours if mother received antibiotics during labor and delivery. If at 72 hours the physical examination is normal, the antibiotics can be discontinued.

            • (c) Blood cultures negative, infant well, lab values normal. Discontinue antibiotics after 48 hours.

      4. Healthy-appearing, asymptomatic infant ≥37 weeks with risk factor of chorioamnionitis.

         1. Blood culture at birth, WBC and differential and optional CRP at age 6–12 hours.

         2. Start broad-spectrum antibiotics. Now what?

            • (a) Blood culture positive. Continue antibiotics. Lumbar puncture is indicated in any infant with a positive blood culture or if sepsis is highly suspected (based on clinical signs, response to treatment, or lab results).

            • (b) Blood culture negative, infant well, lab values abnormal. Continue antibiotics for a total of 48–72 hours in the infant if mother received antibiotics during labor and delivery. Discontinue antibiotics at 48–72 hours if the physical examination remains normal.

            • (c) Blood culture negative, infant well, lab values normal. Discontinue antibiotics and discharge by 48 hours.

      5. Healthy-appearing, asymptomatic infant ≥37 weeks with risk factors for sepsis but not chorioamnionitis. PROM ≥18 hours or intrapartum antimicrobial prophylaxis indicated but inadequate.

         1. Observation without doing any lab tests. Acceptable if observation is every 2–4 hours for a minimum of 24 hours.

         2. Or do lab tests. Do WBC and differential and optional CRP at age 6–12 hours.

         3. No antibiotics necessary, observation. Now what?

            • (a) Lab values abnormal. Do blood culture. If the blood culture is negative and the infant is well then discharge by 48 hours.

            • (b) Lab values normal. Infant well, discharge by 48 hours. Discharge at 24 hours is acceptable only if other discharge criteria are met, access to medical care is readily available, and there is an able person who can fully comply with instructions for home observation.

2. Antibiotic therapy

   1. If the decision is to treat:

      1. Obtain cultures of the blood and spinal fluid if indicated. Lumbar puncture is indicated if there is a positive blood culture or sepsis is highly suspected based on clinical signs or lab values, or if infants do not respond to treatment. Any other cultures that seem appropriate should be sent to the laboratory (eg, if there is eye discharge, send a Gram stain and culture). Tracheal aspirate Gram stain and culture if pneumonia is suspected and there is an increase in tracheal secretions. (Note: Tracheal aspirates need to be obtained right after endotracheal tube placement to be of value in early-onset sepsis.)

      2. Ampicillin and gentamicin are the antibiotics most commonly used for empirical initial therapy in a newborn with sepsis. Once a pathogen is identified, use narrow therapy if possible unless synergism is necessary. If GBS is documented, penicillin G or ampicillin is given, but an aminoglycoside is often added for synergism. Recent reviews have documented that in infants (≥32 weeks' gestation), once-a-day gentamicin is superior to multiple doses a day because it achieves higher peak levels and avoids toxic trough levels. Third-generation cephalosporins are an alternative to gentamicin, but recent studies have shown resistance and increased candidiasis with use. Cefotaxime should only be used in infants with gram-negative meningitis. Cefotaxime and an aminoglycoside should be used in infants with gram-negative meningitis until susceptibility testing is back.

      3. If the cultures are positive, treat accordingly. Bacteremia without source: treat for 10 days. Uncomplicated GBS meningitis: treat for 14 days. Gram-negative meningitis: treat for 21 days or 14 days after obtaining a negative culture.

   2. Discontinuing antibiotics is another controversial topic.

      1. See AAP management guidelines above for neonates with suspected or proven early-onset bacterial sepsis.

      2. Other recommendations

         1. If the cultures are negative, the patient is doing well, and the risk of sepsis low. Antibiotics may be stopped after 48 hours (for asymptomatic term infants, negative cultures after 36 hours may be sufficient). A normal I:T ratio and serial negative CRP might help determine whether antibiotics can be stopped because of their high negative predictive value. Use of procalcitonin concentrations may also be helpful in deciding when to stop antibiotics.

         2. If the cultures are negative but the infant had signs of sepsis (clinical sepsis). Some clinicians treat the infant for 7–10 days.

      3. Beyond antibiotic therapy

         1. Immunoglobulin (Ig) therapy (controversial). Endogenous immunoglobulin synthesis begins at 24 weeks of life. Placental transfer of immunoglobulins does not occur until later and postnatal IgG levels decrease after birth. Studies show a reduction in mortality in proven infection but less reduction in suspected infection. In a recent review, intravenous immune globulin administration resulted in a 3% reduction in sepsis but was not found to not have any significant effect on mortality. The data do not support the routine use in sepsis. Some institutions give a single dose in infants with overwhelming sepsis.

         2. Fresh frozen plasma. Its use is only indicated in disseminated intravascular coagulation, and no benefit has been shown in septic infants.

         3. Granulocyte or neutrophil transfusions. Although benefits of granulocyte transfusions have been documented, there are potential serious side effects. Cochrane review states that there is not enough evidence to either support or refute the use in sepsis.

         4. Cytokines. Granulocyte macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) stimulate bone marrow neutrophils. Cochrane review states that there is not enough evidence to support the use of GM-CSF or G-CSF as treatment to reduce mortality or as prophylaxis.

         5. Double volume exchange transfusion. Exchange transfusion with fresh whole blood is beneficial in severe or gram-negative neonatal sepsis, and it may be used as a last resort. Because of significant risks and that evidence from few prospective studies is not strong on the subject, many institutions have not advocated its use.

         6. Pentoxifylline. Current evidence shows that pentoxifylline as an adjunct to antibiotics reduces mortality in neonatal sepsis and duration of hospitalization. The studies have been small, and the results need to be interpreted with caution. More research is needed.

         7. Selenium/melatonin supplementation. More studies are needed before recommendations can be made.

         8. Lactoferrin. Cochrane review states that there is no recommendation to use or refute the use in treatment of neonatal sepsis.