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 on the basis of 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 early-onset sepsis include GBS status, the presence of chorioamnionitis, infant prematurity, or prolonged rupture of membranes [3]. For late-onset infection, consider whether the patient has indwelling foreign bodies such as a central venous catheter or endotracheal tube, is dependent on parenteral nutrition, or receives proton-pump inhibitor or histamine-2 blocking therapy.

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, 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 one is in place. Urine cultures are usually not recommended for evaluation of EOS but should be considered for evaluation of 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 (PCR) 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 PCR

Complete blood count (CBC) with differential and C-reactive protein (CRP) are also important lab tests to obtain and are 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]. Elevated immature to total neutrophil (I/T)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 CBC 6 to 12 hours to avoid the normal physiological CBC parameters' changes seen immediately after delivery[16]. 

CRP levels start rising within 6 to 8 hours during an infectious episode in neonates and peak at about 24 hours [17]. Persistently normal CRP levels provide strong evidence against bacterial sepsis. This good correlation can be used to 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. 

Empiric treatment with antibiotics should be started as soon as 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 for the most common pathogens in EOS (GBS, E. coli, and L. monocytogenes) [10]. With LOS, nosocomial coverage should be provided for the hospital-acquired pathogens such as coagulase-negative Staphylococcus, S. aureus, and Pseudomonas species. It is recommended to start these patients 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. Antibiotics stewardship teams play an essential role in preventing the unjustified prolonged use of antibiotics [20]. 

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

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, type of the infection, 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, abscess 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 two crucial principles that should motivate the clinicians to tailor the 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 prior to obtaining cultures, or false-negative tests. Determining adequate antibiotic therapy without any positive cultures can make the determining duration of therapy difficult. Most neonates with highly suspected clinical sepsis with negative culture will receive 7-10 days of antimicrobial therapy [3]. 

Mortality rates are inversely proportional to gestational age, such that preterm or younger neonates have higher mortality rates than do 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.

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 (ELBW) 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.

Pediatricians or neonatologists can adequately manage neonatal sepsis. However, the following subspecialties and ancillary services can provide essential support in complicated cases:

• Pediatric surgery: to manage associated surgical complications ( gastrointestinal perforation, abscess, necrotizing fasciitis, omphalitis, and others)
• Pediatric infectious disease specialist if the infant is not responding to antibiotics, or if there is concern regarding adequate antimicrobial coverage
• Pediatric pharmacists can provide meaningful input and recommendations about monitoring trough levels to avoid toxic antibiotic levels

Educating the neonate's family about the disease process and keeping them updated throughout the treatment process is an integral part of management. Neonatal sepsis is often an unexpected and scary situation for parents and caregivers. Doctors should be mindful of this and ensure that parents be informed of all of the tests that must be performed, the importance of each test, and the results. Any changes in antibiotics or the treatment plan must be communicated to the parents.Upon hospital discharge, caregivers of all infants, including healthy newborns, should be educated to watch for signs of illness or sepsis. These may include fever, jaundice, increased lethargy, a decline in feeding habits, difficulty or increased breathing, and cyanosis of the fingertips and toes. Caregivers should be informed to call their doctors if their neonate experiences any of these symptoms, as they could indicate LOS.

Neonatal sepsis is a significant cause of morbidity and mortality in neonates. Attempts to prevent sepsis's development or progression have been a driving factor for many quality improvement projects in newborn nurseries and NICUs.Managing such infants is complex and requires multidisciplinary care approach ( Clinicians, nurses, pharmacies, lactation consultant, and social worker) supported by medical decisions made during family-based care rounds. Obstetric physicians are important in ensuring that GBS screening and all other prenatal screening for infections are performed and adequately treated before and during delivery. Nursery nurses are also important in preventing and managing neonatal sepsis as they can pick up and detect early signs of sepsis. In-hospital pediatricians are essential in managing the evolving treatment of neonatal sepsis and making adjustments as necessary. They are also important in reaching out to the proper consultants, such as pediatric surgeons and pharmacists. Despite optimal treatment, neonatal sepsis continues to have high mortality rates and poor outcomes. While the mortality rates have started to decline, the recovery for most infants is prolonged, and there is a risk for neurodevelopmental disabilities.