2. Intrapartum risk factors include: prolonged rupture of membranes (> 12 to 18 hours), vaginal GBS colonization, chorioamnionitis, uterine tenderness, purulent amniotic fluid, foul-smelling amniotic fluid, maternal fever greater than 38 ° C/101 ° F, prolonged or difficult labor, premature labor, maternal UTI, invasive intrapartum procedures (i.e., internal fetal monitoring), elevated maternal heart rate (> 100 beats per minute [bpm]), and elevated fetal heart rate (> 180 bpm).

B. Neonatal.

C. Environmental.

B. Specific manifestations of sepsis by systems:

2. Neurologic: lethargy, jitteriness, irritability, seizures, hypotonia or hypertonia, bulging fontanelles, high-pitched or abnormal cry.

3. Respiratory distress (most common clinical sign): tachypnea, grunting, nasal flaring, retractions, cyanosis, apnea, respiratory acidosis, respiratory insufficiency, and radiologic evidence of pneumonia or pleural effusion.

4. Cardiovascular: tachycardia or bradycardia; arrhythmias; hypotension or hypertension; cold, clammy, or mottled skin; decreased peripheral perfusion or vasoconstriction; poor peripheral pulses; delayed capillary refill (> 3 seconds); cardiomegaly; and poor cardiac function.

5. Gastrointestinal: poor feeding, vomiting, diarrhea, abdominal distention, feeding intolerance, hypoactive bowel sounds, and radiologic evidence of ileus, portal venous gas, pneumatosis, or free air.

6. Integumentary: rash, pustules or vesicles, jaundice, pallor, and petechiae.

7. Internal organ: hepatomegaly and splenomegaly.

8. Metabolic: hyperglycemia, hypoglycemia, or glucose instability, and metabolic acidosis.

b. Increased work of breathing, tachypnea, retractions, apnea, progressing to respiratory insufficiency and failure.

c. Persistent pulmonary hypertension with resulting decreased oxygenation.

d. Poor perfusion with pallor, mottling, delayed capillary refill (> 3 seconds), weak pulses, cool extremities, wide pulse pressures.

e. Hypotension, decreased urinary output, organ dysfunction, ileus.

f. Metabolic acidosis and other electrolyte disorders.

g. Coagulopathy, oozing or bleeding, may progress to disseminated intravascular coagulation.

h. Edema from capillary leak.

i. Myocardial dysfunction, arrhythmias, impending cardiac arrest.

ANC=WBCs×%Immatureneutrophils+%Matureneutrophils×0.01.

(2) Not a consistent correlation with presence of serious infection. Low immature band counts may be due to depleted bone marrow reserves producing misleading low I/T ratios.

b. Thrombocytopenia (< 100,000/mm³): possible association with bacterial sepsis or viral infection, but usual onset does not occur until 1 to 3 days after infection onset (late indicator). May also occur with maternal HELLP syndrome (hemolysis, elevated liver function test results, and low platelet count), pregnancy-induced hypertension, and intrauterine growth restriction, as well as some syndromes such as trisomies 13, 18, and 21, Turner’s syndrome, and hemolytic disease.

b. Bacterial growth is evident within 48 hours for most cultures. Culture results are followed at 24-hour intervals, with a final report at 5 to 7 days.

b. Polymorphonuclear leukocytes are often present in newborns.

c. Elevated protein concentration occurs in newborns and is higher in premature and VLBW than term infants. By the third month of life, protein levels reach the normal values for older infants in term babies (< 40 mg/dL), but may take longer in premature infants.

(2) Repeat the CSF tap every 24 to 36 hours until culture is sterile.

(3) Duration of antibiotic therapy is based on when the first negative culture is documented.

(4) There is a direct correlation between adverse neonatal outcomes and persistence of bacteria in the CSF.

C. Urine culture.

D. Repeat studies.

2. Persistent bacteremia may be caused by resistance to antibiotics, incorrect administration of antibiotics, an occult site of infection that may require surgical intervention (e.g., abscess), or presence of invasive devices left in place during treatment for bacteremia.

2. Tachycardia, defined as a mean heart rate greater than 2 standard deviations above normal for age in the absence of external stimulus, painful stimulus, or chronic medications. Otherwise, persistent unexplained elevation over a half-hour to 4-hour time frame.

3. Bradycardia with heart rate less than 10th percentile for age in the absence of external vagal stimulus, β-blocker medications, or heart disease. Otherwise, persistent unexplained bradycardia over a half-hour to 4-hour time frame.

4. Mean respiratory rate greater than 2 standard deviations above normal for age, mechanical ventilation related to acute deterioration, not due to neuromuscular disease or general anesthesia.

5. Elevated or depressed leukocyte count for gestation, or greater than 10% immature neutrophils.

6. Proven or suspected sepsis caused by any pathogen, or a clinical syndrome associated with high likelihood of infection. Positive evidence of infection, including derangements in examination, imaging, or laboratory tests, such as WBCs in normally sterile body fluid, perforated viscus, chest x-ray with pneumonia, petechial or purpuric rash, or purpura fulminans.

7. SIRS in the presence of or as a result of proven or suspected infection.

C. Practitioners have the difficult task of deciding to discontinue empirical antibiotics with negative cultures.

b. Treatment for suspected LOS must include coverage for prevalent HAIs such as coagulase-negative staphylococci (CoNS) and Staphylococcus aureus, or organisms with increased incidences specific to the individual nursery.

2. Ampicillin is commonly used in combination with an aminoglycoside such as gentamicin or tobramycin for synergy for initial broad-spectrum treatment of suspected or confirmed bacterial EOS.

3. If meningitis is suspected with EOS, ampicillin and cefotaxime are the antibiotics of choice until a specific organism has been identified.

b. Third-generation cephalosporins may lead to rapid emergence of drug-resistant bacteria when used extensively for presumptive therapy and therefore should be limited to infants with evidence of meningitis or gram-negative sepsis.

4. Vancomycin and an aminoglycoside for synergy are used for initial treatment of suspected bacterial LOS due to penicillin G and ampicillin resistance of the majority of S. aureus organisms.

2. Treat hypovolemia with isotonic crystalloid (normal saline, lactated Ringer’s solution) for acute volume expansion.

3. Transfuse with packed red blood cells (RBCs), platelets, fresh frozen plasma, or cryoprecipitate for anemia, blood loss for disseminated intravascular coagulation.

4. Correct metabolic and electrolyte derangements, provide adequate nutrition, and avoid hypoglycemia due to increased energy demands and to avoid catabolism.

5. Treat hypotension with inotropic agents and consider cortisol.

b. Epinephrine—potent inotropic and chronotropic effects, frequently used in infants nonresponsive to dopamine.

2. Spirochete infections—syphilis.

3. Parasitic infections—congenital malaria, toxoplasmosis.

4. Fungal infection—candidiasis.

5. Other bacterial infections include UTIs, osteomyelitis or septic arthritis, pneumonia, and tuberculosis.

6. Other diagnoses that may present with similar nonspecific findings include neonatal hypoxia, inborn errors of metabolism, cyanotic congenital heart disease, and neonatal respiratory distress.

Following are brief descriptions of common focal sites and pathogens that contribute to the overall septicemia seen in neonates.

4. Gram-negative bacillus is responsible for 3.6% of cases in which neonates present with meningitis. It is the fifth most common cause of meningitis in infants. Gram-negative bacilli seed the CSF secondary to bacteremia, trauma, and surgery. Subsequent meningitis can develop as a result of bacterial multiplication and induction of inflammation in the subarachnoid and ventricular space; this is followed by a progression of inflammation and development of neuronal damage.

(2) Late-onset seizures in approximately 25%.

(3) Cerebral palsy in approximately 20%.

(4) Hearing loss in approximately 10%.

(5) Cortical blindness in less than 10%.

(2) Seizures have been reported as a presenting feature in 20% to 50%. Meningitis resulting from gram-negative pathogens presents with seizures, usually focal rather than generalized, more often than gram-positive pathogens.

(3) Bulging fontanelle is present in approximately 25% of infants, and nuchal rigidity in approximately 15%. Findings of a full, but not bulging, fontanelle and normal neck flexion at the time of initial presentation are more the rule than the exception.

c. Other findings reported are:

(2) Respiratory distress in 33% to 50%.

(3) Apnea in 10% to 30%.

(4) Diarrhea in 20%.

7. Diagnostic features that are characteristic of neonatal bacterial meningitis include:

(2) Neonates in whom a traumatic lumbar puncture occurred should be treated for presumed sepsis and meningitis, pending results of CSF culture.

b. Increased white blood cell counts in CSF of greater than 1000 WBCs/mcl with predominately neutrophils.

c. Decreased CSF glucose of less than 30 mg/dL in term and less than 20 mg/dL in preterm infants.

d. Elevated CSF protein of greater than 100 mg/dL in term and greater than 150 mg/dL in preterm infants.

e. Neuroimaging is indicated to assist in defining the potential complications of neonatal meningitis. It is suggested that a neuroimaging study be done 48 to 72 hours before the anticipated end of therapy.

(2) Computed tomography or magnetic resonance imaging can demonstrate the degree of cerebral edema, obstruction of CSF flow, infarction, abscess, and subdural fluid collections.

8. Antibiotic therapy. Prompt initiation is crucial for optimal outcome, and antibiotics may be administered before results of CSF specimen are obtained.

b. When meningitis resulting from a gram-negative organism is strongly suspected or CSF Gram stain reveals gram-negative bacilli, the empirical regimen of ampicillin and an aminoglycoside should be expanded to include cefotaxime for CSF penetration.

c. Antibiotic choice in the neonate who presents with LOS bacterial meningitis depends on the preliminary CSF findings.

(2) Once the causative pathogen and susceptibility pattern are known, the antimicrobial therapy should be altered accordingly.

d. GBS is uniformly susceptible to penicillin and ampicillin, and a combination of either with an aminoglycoside is recommended. The aminoglycoside is to improve synergy.

e. Gram-negative enteric bacteria: E. coli—ampicillin is the antimicrobial of choice.

f. Ampicillin-resistant E. coli and other gram-negative organisms usually are treated with cefotaxime in combination with gentamicin.

g. Coagulase-negative staphylococci—vancomycin is the antibiotic of choice.

9. Management.

b. Gram-positive bacteria usually clear from the CSF within 24 to 48 hours after initiation of appropriate therapy. Gram-negative pathogens may persist for several days in severe cases.

c. Failure to respond to clinically and bacteriologically appropriate antimicrobial therapy can lead to significant neurologic sequelae such as hydrocephalus, multicystic encephalomalacia, porencephaly, and cerebral cortical and/or white matter atrophy.

d. Infants with suspected bacterial meningitis need to be in the NICU setting and monitored for signs of increased intracranial pressure, such as bradycardia, hypertension, respiratory distress, bulging fontanelle, accelerated head growth, separation of the cranial sutures, hemiparesis, and focal seizures and/or new-onset seizures.

(2) Evaluation and management with infectious disease experts to ensure adequate duration of antimicrobial therapy.

e. Long-term follow-up for survivors of neonatal meningitis includes monitoring of hearing, visual acuity, and development status.

b. Intrauterine aspiration of contaminated amniotic fluid.

c. Aspiration of infected amniotic fluid during or after birth. The neonate can aspirate vaginal organisms that are colonizing the maternal genital area, leading to respiratory colonization.

2. Late-onset pneumonia usually occurs after 3 days of life, and generally arises from colonized organisms present in the hospitalized newborn. Horizontal transmission, or nosocomial infection, is acquired from infected caregivers, family members, or contaminated equipment. Microorganisms can invade through injured tracheal or bronchial mucosa or through the bloodstream.

3. The pathologic changes vary with the type of organism, either bacterial or viral.

b. Viruses typically cause an interstitial pneumonia. The extensive inflammation occasionally occurs with hyaline membrane formation, followed by varying degrees of interstitial fibrosis and scarring.

c. In the United States, GBS is the most common early-onset pathogen. Injury from GBS in the lungs increases the permeability that contributes to the development of alveolar edema and hemorrhage and possibly the mechanism that is responsible for bloodstream extension.

b. E. coli, Serratia marcescens, Enterobacter cloacae, S. pneumoniae, and P. aeruginosa may cause pneumatoceles.

c. Citrobacter diversus is frequently associated with brain abscess and can also cause lung abscess.

d. Chlamydia trachomatis has a long incubation period and typically is associated with pneumonia occurring between 2 and 4 weeks of age. Occurs where untreated sexually transmitted disease is present.

6. Risks: Patients who require assisted ventilation are at highest risk for late-onset pneumonia.

7. Clinical manifestations:

b. Some infants develop pulmonary hypertension.

c. Ventilatory-dependent infants may have increased oxygen and ventilator requirements or purulent tracheal secretions.

8. Diagnosis: Because signs of pneumonia are nonspecific, any newborn infant with sudden onset of respiratory distress or other signs of illness should be evaluated for pneumonia and/or sepsis.

b. If viral or other nonbacterial infection is suspected, specific studies should be obtained, including PCR.

c. Gram stain and culture of tracheal aspirates may identify the causative organism.

d. Chest x-ray examination.

(b) Pleural effusions occur in up to 67% of infants with pneumonia, but are rarely found in RDS. However, pleural effusions can also be seen in infants with transient tachypnea of the newborn, congenital heart disease, and hydrops fetalis.

9. Therapy: The choice of empirical regimens is based upon whether the infection is early- or late-onset.

(2) Gram-negative bacilli can rapidly develop resistance to cephalosporins.

b. For late-onset pneumonia, antibiotic choice depends on the prevalence sensitivity of bacteria in both the community and the hospital. The choice for term infants is vancomycin plus gentamicin.

c. The usual treatment course for uncomplicated pneumonia is 10 to 14 days.

C. Urinary tract infections. UTIs in newborns frequently are associated with bacteremia and may result in long-term complications. Newborns with UTI should be evaluated for associated systemic infection and anatomic or functional abnormalities of the urinary tract.

2. E. coli is the most common organism found, accounting for 80% of cases responsible for UTIs.

b. Most common gram-positive organisms were Staphylococcus and Enterococcus species, but they occur less frequently than do gram-negative pathogens.

3. Most UTIs in newborns represent upper tract infection (pyelonephritis). Pathogenesis includes either hematogenous spread secondary to bacteremia or ascending infections, especially in infants with urinary tract abnormalities. Approximately 30% to 50% of term newborns with a UTI have urinary tract abnormalities, of which vesicoureteric reflux is the most common. Other lesions found in infants with UTI include obstructive abnormalities such as posterior urethral valves, malformations such as ectopic ureter, and renal conditions such as polycystic diseases.

4. Clinical manifestations: General signs are often nonspecific and may include temperature instability, poor weight gain, poor feeding, cyanosis, abdominal distention, hyperglycemia, hematuria, and proteinuria. Localized signs consist of a weak urinary stream and/or bladder distention.

5. Diagnosis: A urine specimen should be obtained by sterile catheterization.

b. Because of the associated risk of bacteremia, blood cultures should be obtained.

6. Therapy: antimicrobial agents. Treatment with parenteral IV broad-spectrum antibiotics as soon as cultures of urine, blood, and CSF (if indicated) have been obtained.

7. Management: Repeat urine culture should be sterile within 36 to 48 hours after initiation of antimicrobial therapy.

2. GBS infection in neonates is classified by age at onset into early-onset GBS, occurring within 24 hours of birth up to day 7 of life; late-onset GBS, which has a broader range from 7 to 89 days; and late, late-onset GBS, which occurs in infants older than 3 months of age.

3. Risk factors include:

b. Premature rupture of membranes.

c. Rupture of membranes ≥ 18 hours before delivery.

d. Clinical signs of chorioamnionitis, maternal temperature ≥ 100.4 ° F or (38 ° C) during labor.

e. Maternal GBS bacteriuria during the current pregnancy.

f. Prior delivery of an infant with GBS disease.

g. Heavy maternal colonization inoculum (> 10⁵ colony-forming units/mL) vaginally.

b. Pneumonia.

c. Meningitis.

b. Penicillin remains the preferred agent, with ampicillin an acceptable alternative.

7. Other less common (2% to 3%) but well-described late-onset GBS focal infections are:

b. Osteoarthritis.

b. There is a revised colony count threshold for laboratories to report GBS in the urine of pregnant women.

c. There are revised algorithms for GBS screening and use of IAP for women with threatened preterm delivery, including one algorithm for preterm labor and one for preterm premature rupture of membranes.

d. Recommendations for IAP agents are presented in an algorithm format in an effort to promote use of the most appropriate antibiotic for penicillin-allergic women.

e. A minor change has been made to penicillin dosing to facilitate implementation in facilities with different prepackaged penicillin products.

f. The neonatal management algorithm’s scope was expanded to apply to all newborns.

g. It provides management recommendations that depend upon clinical appearance of the neonate and other risk factors such as maternal chorioamnionitis, adequacy of IAP if indicated for the mother, gestational age, and duration of membrane rupture.

h. Changes were made to the algorithm to reduce unnecessary evaluations in well-appearing newborns at relatively low risk for early-onset GBS disease.

b. Mucosal lesions appear as white plaques on oral mucosa.

c. Diaper dermatitis presents with intense erythema and satellite lesions.

4. Congenital candidiasis presents with widespread erythematous maculopapular rash, and preterm infants may present with pneumonia.

5. Disseminated candidiasis may involve any organ or anatomic site and may present with acute respiratory deterioration, acidosis, feeding intolerance, hypotension, skin abscesses, temperature instability, and/or erythematous rash.

b. Invasive disease is treated by prompt removal of infected invasive catheters, and IV amphotericin B remains the drug of first choice for neonates.

(2) Echinocandins are reserved for drug-resistant species and should be used with caution as safety and dosing have not been established in neonates.

(3) Most Candida species are susceptible to amphotericin B, though lipid preparations of amphotericin B may not penetrate into the kidney parenchyma.

b. R—Rubella virus and Respiratory syncytial virus

c. C—Cytomegalovirus

d. H—Herpes simplex virus and Hepatitis B virus

e. E—Enteroviruses

f. S—Syphilis (Treponema pallidum)

g. C—Chickenpox (varicella-zoster virus)

h. L—Lyme disease (Borrelia burgdorferi)

i. A—Acquired immunodeficiency syndrome/human immunodeficiency virus

j. P—Parvovirus B19

B. ToRCHES CLAP organisms.

(b) Severe and often fatal in high-risk populations, including premature infants, infants with chronic lung disease or congenital heart disease, or immunocompromised infants.

(3) Symptoms may be nonspecific and include poor feeding, lethargy, apnea, and irritability. Symptoms of bronchiolitis may include cough, wheezing, tachypnea, rales, rhonchi, increased work of breathing (retractions, nasal flaring, and use of accessory muscles), pneumonia, cyanosis, and pulmonary infiltrates.

(4) Diagnosis is most commonly made by rapid viral antigen detection isolated from nasopharyngeal aspirate. Molecular testing using reverse transcriptase PCR assays is now commercially available and detects RSV at significantly higher rates than antigen or viral culture, but will detect viral RNA for weeks after the infectious period.

(5) Treatment of infants with RSV is primarily supportive care and includes oxygen, clearing airway secretions as indicated, hydration, and isolation. High-risk infants may progress to assisted ventilation because of hypoxemia and hypercapnia.

(ii) Severe liver dysfunction, abnormal CSF findings, seizures, profound sepsis, septic shock, high morbidity and mortality.

(b) Localized CNS disease (30% of cases), may have skin involvement.

(c) Localized skin, eyes, and mouth (SEM) disease (45% of cases); 80% of SEM cases have skin lesions; remainder are localized to eyes and oral mucosal lesions only.

(4) Diagnosis: Positive culture result with specimen obtained from vesicular fluid, blood, or CSF results in a diagnosis. The diagnostic yield of CSF culture for neonates with CNS disease is less than 50%. The PCR test has a much higher yield in CSF and should be performed if available. Other rapid identification tests include direct fluorescent antibody staining of vesicle scrapings and enzyme immunoassay antigen detection in vesicles or body fluids.

(b) Skin swabs of vesicles.

(c) Blood and CSF for HSV culture and HSV PCR, serum alanine aminotransferase (ALT)

(5) Treatment of choice is acyclovir intravenously for 10 days for asymptomatic infants born to mothers with suspected or proven primary infection with active lesions at delivery, 14 days for SEM infection, or 21 days minimum for disseminated infection or CNS infections.

(b) Acyclovir suppressive therapy for 6 months following acute phase improves neurodevelopmental outcomes and helps to suppress skin recurrences.

(c) For infants with ocular involvement, a topical ophthalmic drug such as 3% vidarabine, 1% trifluridine, or 0.1% iododeoxyuridine is used in addition to parenteral antiviral therapy. An ophthalmology consultation should be obtained.

(b) Mothers with active lesions may wear clean covering gown to provide care, and a surgical mask should be worn for oral/cold sore lesions. Breastfeeding is permissible if there are no breast lesions and other lesions are covered.

b. HBV.

b. Enterovirus infections occur worldwide and are a common cause of neonatal infection, but clear data are unavailable regarding the incidence of symptomatic congenital and neonatal infections. Infections are most prevalent in the summer and fall in temperate climates, but occur all year in tropical settings. The virus is spread by fecal–oral and respiratory routes and from mother to infant in utero and peripartum, and may also be transmitted by breastfeeding. Polio vaccines have virtually eliminated poliomyelitis in the United States, but it remains endemic in parts of the world.

(2) CNS involvement may be asymptomatic but occurs in approximately 40% of symptomatic infants. Symptoms include progressive hydrocephalus, cranial nerve palsies, optic atrophy, seizures, and neurodevelopmental delay.

(3) Periostitis of long bones, with guarding of extremities, or “pseudoparalysis of Parrot” (lack of movement associated with pain from bone lesion).

d. Diagnosis is made by serologic testing of maternal blood with Venereal Disease Research Laboratory (VDRL) or rapid plasma reagin (RPR) test early in pregnancy and at the time of delivery.

(b) Reactive RPR.

(c) Serum IgM level greater than 20 mg/dL.

(d) Confirmation with a positive result on darkfield microscopic examination or direct fluorescent antibody staining of suspicious lesions, body fluids, placenta, or umbilical cord.

(2) Uninfected infants possess maternally acquired antibodies at concentrations similar to those of infected infants. It may be difficult to interpret neonatal laboratory data; therefore, it is important to determine adequacy of maternal treatment, possibility of reexposure, and family compliance with follow-up.

e. Treatment.

(b) May treat with single dose of benzathine penicillin G intramuscularly if mother had adequate treatment.

(3) No treatment necessary if all of the following are true: mother adequately treated with appropriate response in titers (decrease four-fold after therapy; VDRL ≤ 1:2 or RPR ≤ 1:4) and levels remained stable and low, maternal treatment occurred more than 4 weeks prior to delivery, and mother has no evidence of relapse or infection.

f. Isolation procedures: Standard Precautions.

7. C—Chickenpox.

(2) HIV-1 requires reverse transcriptase enzyme to convert RNA to DNA, then becomes integrated in the host cell genome as a provirus.

(3) Suppression of T-helper lymphocytes. This results in B-cell and suppressor T-cell dysfunction, with subsequent defects in cell-mediated immunity and development of opportunistic infections.

(2) Generalized lymphadenopathy, hepatomegaly, and splenomegaly.

(3) Recurrent oral and diaper candidiasis.

(4) Systemic bacterial infections.

(5) Lymphoid interstitial pneumonitis.

(6) Hyperreflexia, hypertonia, floppiness, developmental delay.

(7) Parotitis, hepatitis, nephropathy, and cardiomyopathy.

(8) Recurrent diarrhea.

(9) Opportunistic infections (viral and bacterial).

(10) Unexplained fevers.

(11) Malignancies.

(3) Plasma viral RNA assesses viral load and can aid in monitoring disease progression and therapy efficacy, but is unreliable for diagnosis in the first 2 weeks of life.

(4) Viral culture; expensive and long time for results, not recommended.

(2) Initiate oral ZDU from birth through 6 weeks of life.

(3) An additional one- to two-drug regimen is used for infants born to HIV-infected mothers who did not receive any ARVs prior to onset of labor or for infants proven to be infected while on ZDU prophylaxis. Additional medications include lamivudine, nelfinavir, didanosine, stavudine, nevirapine, or lopinavir–ritonavir, but not all may be paired due to adverse reactions. Standards are still evolving, and collaboration with an HIV treatment center is recommended.