Neonatal Sepsis

Etiology

EOS is generally caused by the transmission of pathogens from the female genitourinary system to the newborn or the fetus. These pathogens can ascend the vagina, the cervix, and the uterus and can also infect the amniotic fluid. Neonates can also become infected in utero or during delivery as they pass through the vaginal canal. Typical bacterial pathogens for EOS include group B streptococcus (GBS), Escherichia coli, coagulase-negative Staphylococcus, Haemophilus influenza, and Listeria monocytogenes. Maternal factors that increase the risk of neonatal sepsis include chorioamnionitis, GBS colonization, delivery before 37 weeks, and prolonged rupture of membranes greater than 18 hours [3].

LOS usually occurs via transmitting pathogens from the surrounding environment after delivery, such as contact from healthcare workers or caregivers. A percentage of LOS may also be caused by a late manifestation of vertically transmitted infection. Infants requiring intravascular catheter insertion or other invasive procedures that disrupt the mucosa are at increased risk for developing LOS. Preterm neonates are at higher risk for sepsis/infection than term neonates. The increased susceptibility for infections seen in preterm neonates is mainly due to : 

• Deficient immune system, mainly due to decreased IgG antibodies and incompetent opsonization and complement activation
• Comprised innate immune system, caused primarily by the immature epithelial barrier
• The increased need for invasive devices (vascular access, endotracheal tube, feeding tubes, and urinary tract catheters) due to associated severe illnesses

Coagulase-negative staphylococcal species, especially Staphylococcus epidermis, are the leading cause, responsible for over 50% of LOS cases in industrialized countries. However, many other bacterial and viral pathogens can be associated with LOS [3]. 

Epidemiology

The epidemiology of neonatal sepsis has been changing with time [4]. The incidence of EOS has decreased since the 1990s due to the introduction of universal screening of GBS in pregnant women and intrapartum antibiotic prophylaxis[5]. However, rates of LOS have remained relatively the same. Escherichia coli now accounts for more cases of EOS  [6]. The incidence of EOS with positive blood cultures in the United States is estimated to be 0.77 to 1 per 1,000 live births [7][8]. Due to the nonspecific neonatal presentation for sepsis and the high risk of mortality and morbidity without treatment, many asymptomatic neonates undergo a sepsis workup if risk factors are present and/or clinically indicated. Although approximately 7% to 13% of all neonates are treated for sepsis, only 3% to 8% have positive cultures [3]. Maternal administration of antibiotics and the low blood volume obtained for blood culture could explain the low rate of positive blood cultures. The incidence of sepsis is significantly higher in premature infants, as well as those with very low birth weight (<1000 grams). African American infants have an increased risk of GBS and LOS, likely secondary to the higher rate of GBS carrier rates in African American females. Males have a higher risk of sepsis and meningitis, especially with gram-negative enteric bacilli [3]. 

Pathophysiology

The immature immune system is the major contributing factor to increased neonatal susceptibility to sepsis. The immature function of polymorphonuclear neutrophils, macrophages, and T lymphocytes makes these cells incapable of carrying out a complete inflammatory response in neonates. Furthermore, neonates have limited immunoglobulins at birth and cannot generate a quantitative and/or qualitative adequate mounting response against infectious agents. The insufficient time that premature has in the uterus decreases the transfer of immune globulins to the fetus. This deficiency in immunoglobulins puts premature infants at much higher risk for sepsis when compared to term infants [9]. 

History and Physical

Signs and symptoms of neonatal sepsis can range from nonspecific or vague symptoms to hemodynamic collapse. Early symptoms may include irritability, lethargy, or poor feeding. Others may quickly develop respiratory distress, fever, hypothermia, or hypotension with poor perfusion and shock. Sometimes, the diagnosis may only be suspected based on laboratory findings, which may reveal hyperglycemia or hypoglycemia, acidosis, or hyperbilirubinemia. A high index of suspicion is, therefore, necessary for timely diagnosis. Therefore, physicians must be aware of any factors that may increase an infant’s risk of developing sepsis. Prematurity and very low birth weights are also important risk factors to consider. Maternal factors that put neonates at risk of EOS include GBS status, the presence of chorioamnionitis, infant prematurity, or prolonged rupture of membranes [3]. Consider whether the patient has indwelling foreign bodies such as a central venous catheter or endotracheal tube for late-onset infection, depends on parenteral nutrition, or receives proton-pump inhibitor or histamine-2 blocking therapy.

Evaluation

Neonates with bacteremia can be asymptomatic and have a normal physical examination. Thus, laboratory testing plays an important role in diagnosis. In a neonate with suspected sepsis, a blood culture should be immediately drawn. It is recommended to draw at least 1 ml of blood as low-level bacteremia may not be detected with smaller aliquotes [10]. Cultures should also be drawn from the catheter site if 1 is in place. Urine cultures are usually not recommended for evaluating EOS but should be considered for evaluating LOS [11]. Lumbar puncture with cerebrospinal fluid (CSF) analysis and culture should be evaluated in any infant with positive blood culture or if the neonate has a clinical presentation that suggests central nervous system involvement. Lumbar puncture should be repeated within 48 hours of therapy to confirm sterility of the CSF. New technology using polymerase chain reaction is currently being studied as a diagnostic tool to identify sepsis and the causative organism faster than blood cultures [12]

CSF analysis may reveal:

• Elevated protein level
• Elevated WBC
• Positive cultures
• Decreased glucose concentration
• Positive polymerase chain reaction

Complete blood count with differential and C-reactive protein is also an important lab test, often collected on a serial basis. These indices are poor at identifying neonatal sepsis but are better used for ruling it out [10]. Neutropenia has better specificity than neutrophilia as a marker of neonatal sepsis [13]. An elevated immature to total neutrophil ratio of more than 0.27 has a very high negative predictive accuracy (99%) but an inadequate positive predictive value (25%), as it may be elevated in up to 50% of uninfected infants [14][15]. These counts may be falsely elevated, especially after birth. It is better to perform complete blood count 6 to 12 hours to avoid the normal physiological complete blood count parameters' changes seen immediately after delivery[16]. 

C-reactive protein levels start rising within 6 to 8 hours during an infectious episode in neonates and peak at about 24 hours [17]. Persistently normal C-reactive protein levels provide strong evidence against bacterial sepsis. This good correlation can support the clinical judgment of stopping antibiotics in an otherwise well-appearing neonate. Other inflammatory markers, including procalcitonin, haptoglobin, and cytokines, can also be obtained to support the diagnosis or evaluate treatment efficacy. Radiography of the chest may be performed to look for any pulmonary findings in a neonate with respiratory symptoms or signs. 

Treatment / Management

Empiric antibiotic treatment should be started when sepsis is clinically suspected, even without confirmatory lab data. In general, antimicrobial resistance patterns of common bacteria in the neonatal intensive care unit should guide antibiotics' initial choice. Typical treatment regimens include intravenous (IV) ampicillin and aminoglycosides to cover the most common pathogens in EOS (GBS, E. coli, and L. monocytogenes) [10]. With LOS, nosocomial coverage should be provided for hospital-acquired pathogens such as coagulase-negative Staphylococcus, S. aureus, and Pseudomonas species. It is recommended that these patients be started on a combination of vancomycin and an aminoglycoside [18]. Aminoglycosides have poor CNS penetration; for that reason, a third-generation cephalosporin should be considered if CNS infection is suspected [19]. However, ceftriaxone should be avoided, as it can lead to hyperbilirubinemia and the serious precipitation of calcium-ceftriaxone crystals. Increasing antibiotic resistance is a concern for neonatal sepsis. Antibiotic stewardship teams play an essential role in preventing the unjustified prolonged use of antibiotics [20]. 

Differential Diagnosis

Given the nonspecific signs of neonatal sepsis, several differentials must be considered, including but not limited to:

• Infection due to other agents (virus, fungal or parasite)
• Congenital heart disease
• Neonatal encephalopathy
• Metabolic disease
• Prematurity and associated complications (respiratory distress syndrome, intraventricular hemorrhage, apnea of prematurity, and others)
• Hypo or hyperthyroidism
• Transient tachypnea of the newborn
• Meconium aspiration
• Hypoglycemia

Treatment Planning

The treatment regimen for neonatal sepsis varies based on various risk factors and conditions. The typical antibiotics used are discussed above. The duration of therapy can vary based on the isolated organisms, the type of infection, and the presence of any neonatal complications. Neonates with positive blood cultures typically respond to treatment within 24 to 48 hours, and repeat cultures and studies are usually negative by 72 hours [3]. Persistent positive blood cultures should alert the clinicians to a seeding focus that should be managed (central venous access, cardiac vegetations, abscesses, or osteomyelitis). Many providers would continue intervenous therapy for 7 to 14 days based on the organism or longer if meningitis was suspected [18]. Increasing the duration of antibiotics may be necessary for some situations. Increasing the incidence of antibiotic resistance necrotizing enterocolitis or death are 2 crucial principles that should motivate clinicians to tailor antimicrobial therapy if clinically indicated[21].

The treatment for suspect EOS with negative cultures is also variable. Cultures can be negative for various reasons, including maternal antibiotic use, initiation of antibiotics before obtaining cultures, or false-negative tests. Determining adequate antibiotic therapy without any positive cultures can make determining the duration of therapy difficult. Most neonates with highly suspected clinical sepsis with negative culture receive 7-10 days of antimicrobial therapy [3]. 

Prognosis

Mortality rates are inversely proportional to gestational age, such that preterm or younger neonates have higher mortality rates than term neonates [22]. E. coli has also been found to be associated with a higher mortality rate when compared with GBS. As noted above, the introduction of GBS intrapartum antibiotic prophylaxis has decreased mortality rates caused by GBS. The treatment of clinically suspected neonates with negative cultures has also significantly decreased mortality rates. Preterm infants with sepsis may develop impaired neurodevelopment. Also, others may have vision impairment. Those infants pretreated with aminoglycosides may also develop ototoxicity and nephrotoxicity.

Complications

Neonatal sepsis remains a significant contributor to morbidity and mortality in neonates. Prematurity and delayed treatment are commonly associated with adverse outcomes. VLBW infants have been found to have a higher risk of chronic lung disease, and extremely low birth weight infants are at a greater risk of neurodevelopmental risks, such as hearing and visual deficits, cerebral palsy, and impaired psychomotor and mental development [23]. On the other hand, the unnecessary overuse of antibiotics can increase the chances of severe candidiasis and multi-drug resistant organisms.