Neonatal bacterial sepsis: Management, prevention, and outcome

INTRODUCTION — 

Bacterial sepsis is an important cause of morbidity and mortality among newborn infants. Preterm and very low birth weight neonates are at higher risk for sepsis than those born at or near term. Management of sepsis in neonates requires antibiotics and supportive care (eg, maintaining adequate oxygenation and perfusion). Empiric antibiotics are narrowed to organism-specific antibiotic therapy once the organism and antimicrobial susceptibilities are known. Prevention and timely treatment of sepsis are important. Delays in initiating appropriate antibiotic therapy are associated with increased risk of morbidity and mortality.

This topic will review the management, prevention, and prognosis of bacterial sepsis in preterm and term neonates, including neonates who remain hospitalized after birth and those who are admitted from the community within the first 28 days of life. The epidemiology, clinical features, and diagnosis of bacterial sepsis in neonates are discussed separately. (See "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at <35 weeks of gestation" and "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates ≥35 weeks gestation".)

Other related topics are also discussed separately:

●Initial management of well-appearing newborns at risk for early-onset sepsis – (See "Approach to risk assessment and initial management of newborns with risk factors for early-onset sepsis".)

●Prevention and management of group B streptococcal (GBS) infection in neonates and young infants – (See "Prevention of early-onset group B streptococcal disease in neonates" and "Group B streptococcal (GBS) infection in neonates and young infants".)

●Outpatient evaluation and management of febrile neonates – (See "The febrile neonate (28 days of age or younger): Outpatient evaluation" and "The febrile neonate (28 days of age or younger): Initial management".)

●Evaluation of ill-appearing young infants – (See "Approach to the ill-appearing infant (younger than 90 days of age)".)

TERMINOLOGY — 

The following terms will be used throughout this topic:

●Preterm and term neonates – In general, preterm and term neonates are defined as follows:

•Preterm neonates are born at <34 weeks of gestation. (See "Preterm birth: Definitions of prematurity, epidemiology, and risk factors for infant mortality".)

•Late preterm (also called near-term) neonates are born between 34 and 36 completed weeks of gestation. (See "Late preterm infants".)

•Term neonates are born at ≥37 weeks of gestation. Gestational age (GA) can be derived from a calculator (calculator 1).

When discussing neonatal sepsis, we use the term preterm neonates to refer to those who are born at <35 weeks of gestation. This is consistent with the age threshold used to guide the approach endorsed in the American Academy of Pediatrics (AAP) guidelines on neonatal sepsis [1].

●Very low birth weight (VLBW) neonates – VLBW neonates are those with birth weights <1500 grams.

●Neonatal sepsis – In neonates (infants 28 days of age or younger), bacterial sepsis is defined as the isolation of a pathogenic bacterial organism from blood or cerebrospinal fluid culture. This is in contrast to the definition of sepsis in other populations, which refers to a dysregulated host response and organ dysfunction in the setting of infection but does not require bacteremia. (See "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at <35 weeks of gestation", section on 'Establishing the diagnosis' and "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates ≥35 weeks gestation", section on 'Diagnosis'.)

Sepsis is classified according to the neonate's age at the onset of symptoms:

•Early-onset sepsis (EOS) – This is defined as sepsis that occurs within the first 72 hours after birth, although some experts use <48 hours or extend the definition to infections occurring within the first seven days after birth [1-5].

•Late-onset sepsis (LOS) – This is defined as sepsis that occurs at ≥72 hours after birth. Similar to early-onset sepsis, there is variability in its definition, ranging from onset at ≥48 or 72 hours of life to ≥7 days of age [4].

Preterm and term neonates with EOS and preterm neonates with LOS typically present with symptoms during their birth hospitalization. Term neonates with LOS typically present to the outpatient setting or emergency department unless comorbid conditions have prolonged the birth hospitalization. The approach to the evaluation and initial management of febrile neonates in the outpatient setting is discussed separately. (See "The febrile neonate (28 days of age or younger): Outpatient evaluation" and "The febrile neonate (28 days of age or younger): Initial management".)

●Healthcare-associated infections – These are defined as infections (eg, late-onset sepsis) acquired in the hospital while receiving treatment for other conditions [6].

Definitions of early- and late-onset infections for infection control surveillance and reporting may vary. For example, the CDC National Healthcare Safety Network defines early-onset infections as those occurring on or before three days after birth (day of birth is day zero) [7]. These are considered "present on admission" and are not eligible for central line-associated bloodstream infection or hospital-acquired infection reporting. However, group B Streptococcus infection is considered "present on admission" if it occurs at <7 days of age.

GENERAL AND SUPPORTIVE MANAGEMENT

Site of care — Symptomatic neonates with suspected or proven bacterial sepsis should be treated in a care setting with full cardiopulmonary monitoring and support because their clinical condition can deteriorate rapidly. In general, these neonates are cared for in the neonatal intensive care unit (NICU). Infants who are hemodynamically stable and do not require significant respiratory support may be managed in an intermediate care unit or general ward setting.

Supportive care — Supportive care is initially focused on ensuring adequate oxygenation and peripheral perfusion. This includes respiratory support with supplemental oxygen and/or noninvasive support (eg, continuous positive airway pressure [CPAP]), as needed, and hemodynamic support with intravenous (IV) fluids. In severely ill neonates, invasive mechanical ventilation and vasopressors may be needed. For example, patients with fulminant sepsis (ie, severe sepsis or septic shock that is likely to result in death within 48 hours) require resuscitative intervention. (See "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn" and "Overview of mechanical ventilation in neonates" and "Neonatal shock: Management".)

In addition, for all neonates, electrolyte and metabolic (eg, hypoglycemia) abnormalities should be monitored and corrected. (See "Fluid and electrolyte therapy in newborns" and "Management and outcome of neonatal hypoglycemia".)

For preterm neonates, a thermoneutral environment should be maintained. (See "Overview of short-term complications in preterm infants", section on 'Prevention of hypothermia'.)

Source control — When possible, sources of infection and/or microbial contamination should be eliminated because localized foci of infection may not respond to antibiotics alone. In particular, catheters that may be the foci of bacterial infection should be removed as early as possible. Delayed removal (>48 hours after diagnosis of sepsis) or failure to remove catheters has been associated with an increased risk of complications (eg, end-organ damage and thrombocytopenia) and persistent bacteremia [8-11]. This is especially important for preterm neonates, who are at increased risk for healthcare-associated (ie, nosocomial) infections due to the need for supportive devices (eg, central venous catheters) or other interventions. (See "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at <35 weeks of gestation", section on 'Risk factors associated with interventions'.)

In some cases, additional interventions may be warranted to remove a localized focus of infection (eg, cutaneous abscess, intestinal perforation or enterocolitis), as discussed separately. (See "Skin and soft tissue infections in neonates: Evaluation and management" and "Spontaneous intestinal perforation of the newborn" and "Neonatal necrotizing enterocolitis: Management and prognosis".)

Ongoing diagnostic evaluation — In neonates with suspected sepsis, ongoing diagnostic evaluation, including additional testing for other conditions, may be warranted. Signs of neonatal sepsis (eg, cardiorespiratory symptoms, temperature instability (table 1)) are often nonspecific; thus, it can be difficult to differentiate sepsis from other diagnoses based on the presentation alone. The differential diagnosis of sepsis is summarized in the table (table 2).

The clinical features, diagnostic evaluation, and differential diagnosis of sepsis are discussed in greater detail separately. (See "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at <35 weeks of gestation" and "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates ≥35 weeks gestation".)

INITIAL EMPIRIC ANTIBIOTIC THERAPY — 

Neonates with clinical concern for sepsis because of birth circumstances or clinical features (table 1) require prompt diagnostic evaluation and initiation of parenteral empiric antibiotic therapy because of the risk of death and severe morbidity [1,2,12].

The initial choice of antimicrobials for suspected sepsis depends on the neonate's age at the onset of symptoms (ie, early-onset, [age <72 hours] versus late-onset [age ≥72 hours] sepsis). Other important considerations include the likely pathogens (table 3), the presence of an apparent source of infection (eg, skin, joint, or bone involvement) (table 4), and antimicrobial susceptibility patterns of organisms in a particular nursery or neonatal intensive care unit (NICU). (See 'Early-onset sepsis' below and 'Late-onset sepsis' below.)

The approach discussed in the following sections is generally consistent with guidelines published by the American Academy of Pediatrics and the Centers for Disease Control and Prevention [1,2,13]. (See 'Society guideline links' below.)

Risk stratification and clinical evaluation for sepsis vary by gestational age and are discussed in more detail separately. (See "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at <35 weeks of gestation" and "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates ≥35 weeks gestation".)

Early-onset sepsis — The choice of empiric antibiotic therapy for early-onset sepsis (EOS; age <72 hours) is based on coverage for likely pathogens and local antimicrobial susceptibility patterns.

●Preferred empiric regimen – For empiric therapy of suspected EOS in most preterm and term neonates, we suggest ampicillin plus gentamicin (table 4). Amikacin is used instead of gentamicin in centers with a high prevalence of gentamicin resistance among gram-negative isolates.

In neonates with signs of critical illness due to suspected sepsis and potential for resistant infection, we suggest a modified regimen to provide broader-spectrum antibiotic coverage with ampicillin plus a third- or fourth-generation cephalosporin (eg, cefotaxime [if available], ceftazidime, or cefepime).

This includes neonates who are:

•Born at any gestational age who require vasopressor support

•Born at ≥35 weeks of gestation who require continuous positive airway pressure (CPAP) support or mechanical ventilation

•Born at <35 weeks of gestation who require mechanical ventilation and have been exposed to extended periods of antepartum antibiotic therapy due to preterm rupture of membranes

Rarely, the pregnant parent is known to be colonized or infected with an antibiotic-resistant pathogen (eg, methicillin-resistant S. aureus or extended beta-lactamase producing gram-negative organism). In this situation, empiric antibiotic therapy for the newborn should include antimicrobial agents that would be effective against the pathogen isolated from the pregnant parent as well as other common pathogens that cause neonatal sepsis. (See 'Staphylococcus species' below and 'Other gram-negative bacilli' below.)

For neonates with suspected meningitis, empiric therapy is further modified based on cerebrospinal fluid (CSF) studies, as discussed separately. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empiric therapy'.)

When a cephalosporin is warranted, we use cephalosporins other than ceftriaxone because of the risk of adverse events. In neonates, ceftriaxone may increase the risk of acute bilirubin neurotoxicity, and adverse cardiopulmonary events when given concomitantly with intravenous (IV) calcium (including parenteral nutrition) [14-16].

Antibiotic dosing and monitoring are discussed separately. (See 'Antibiotic dosing and monitoring' below.)

●Rationale and supporting evidence – Ampicillin plus an aminoglycoside is our preferred regimen because it is active against the most common pathogens that cause EOS in neonates, including group B Streptococcus (GBS) and most isolates of Escherichia coli, as well as less common pathogens such as Listeria and Enterococcus (table 3) [1,2,17]. In the available studies, the majority of isolates from culture-proven EOS were susceptible to ampicillin, gentamicin, or both [18-22]. In addition, ampicillin and aminoglycosides are synergistic in treating infections caused by GBS and Listeria monocytogenes.

Ampicillin plus a third- or fourth-generation cephalosporin is also active against most common pathogens. However, for most neonates, it does not offer major advantages over the combination of ampicillin and an aminoglycoside [23,24]. For example, in a large cohort study, treatment with ampicillin plus gentamicin was associated with lower mortality compared with ampicillin plus cefotaxime (1.9 versus 4.2 percent, respectively) [23]. Cephalosporins are not active against L. monocytogenes.

In addition, routine use of a third- or fourth-generation cephalosporin to treat neonatal sepsis is generally discouraged as part of antimicrobial stewardship efforts because of the emergence of cephalosporin-resistant organisms (especially Enterobacter, Klebsiella, and Serratia species). Risk factors associated with colonization with antibiotic-resistant bacteria include very low birth weight (birth weight <1500 g) and exposure to third-generation cephalosporins [25-27].

However, we favor broader-spectrum empiric antibiotic coverage with cephalosporins for neonates with signs of severe infection, who may be at higher risk for worse outcomes without appropriate antibiotic therapy, and for those who may have an increased risk of resistance. Cephalosporins also have excellent penetration in the cerebrospinal fluid. Antibiotic therapy should also be adjusted based on local antibiotic susceptibility patterns.

Late-onset sepsis — The choice of empiric antibiotic therapy for late-onset sepsis (LOS; age ≥72 hours) depends on whether the neonate is admitted from the community or has been hospitalized since birth. Another consideration for antibiotic selection is whether there is an apparent focal source of infection (eg, meningitis, pneumonia, or other infection). (See 'Coverage for focal sources/specific infections' below.)

Admitted from the community

●Preferred empiric regimen – For empiric therapy of suspected LOS in preterm and term neonates without signs of severe infection who are admitted from the community, we suggest ampicillin plus gentamicin (table 4) [4]. Amikacin is used instead of gentamicin in centers with a high prevalence of gentamicin resistance among gram-negative isolates. A reasonable alternative is ampicillin plus a third- or fourth-generation cephalosporin (eg, cefotaxime [if available], ceftazidime, or cefepime) [4].

For neonates with signs of severe infection (eg, hemodynamic or respiratory instability), we use vancomycin plus either cefepime or ceftazidime (or, if there is no concern for Pseudomonas and it is available, cefotaxime) to provide broader-spectrum antibiotic coverage for methicillin-resistant Staphylococcus aureus (MRSA) and gram-negative bacteria.

Alternative empiric regimens or additional antimicrobial agents may be warranted when there is suspicion for a focal source of infection (including meningitis or herpes simplex virus [HSV] infection), as discussed below. (See 'Coverage for focal sources/specific infections' below.)

For febrile neonates ≥22 days of age who are otherwise well-appearing and for whom there is low suspicion of sepsis, other regimens may be appropriate. (See "The febrile neonate (28 days of age or younger): Initial management", section on 'Neonates 22 to 28 days old'.)

Antibiotic dosing and monitoring are also discussed separately. (See 'Antibiotic dosing and monitoring' below.)

●Rationale and supporting evidence – The combination of ampicillin plus an aminoglycoside or ampicillin plus a third- or fourth-generation cephalosporin (eg, cefotaxime [if available], ceftazidime, or cefepime) is effective in treating the most common pathogens that cause LOS in neonates, including GBS and most isolates of Escherichia coli, as well as less common pathogens such as Listeria and Enterococcus (table 3) [18,28]. The available limited clinical trial data comparing different antibiotic regimens for LOS have not demonstrated any convincing superiority of one regimen over others [29,30]. However, broader-spectrum antibiotics such as vancomycin (ie, instead of ampicillin) or cephalosporins (ie, instead of aminoglycosides) are warranted for neonates with signs of severe infection or those with an apparent focal source of infection to provide adequate antimicrobial coverage for MRSA and other pathogens. Antibiotic therapy should also be adjusted based on local antibiotic susceptibility patterns.

Hospitalized since birth

●Preferred empiric regimen – For empiric therapy of suspected LOS in preterm and term neonates without signs of severe infection who are hospitalized since birth, we suggest a penicillinase-resistant penicillin such as oxacillin or nafcillin plus gentamicin (table 4). Amikacin is used instead of gentamicin in centers with a high prevalence of gentamicin resistance among gram-negative isolates.

We replace oxacillin or nafcillin with vancomycin for neonates with known colonization with MRSA and use cefepime or ceftazidime instead of an aminoglycoside for those with known colonization with Pseudomonas. For those with signs of severe infection (eg, hemodynamic or respiratory instability), we use vancomycin plus either cefepime or ceftazidime (or, if there is no concern for Pseudomonas and it is available, cefotaxime).

Alternative empiric regimens or additional antimicrobial agents may be warranted when there is suspicion for a focal source of infection (including meningitis or HSV infection), as discussed below. (See 'Coverage for focal sources/specific infections' below.)

Antibiotic dosing and monitoring are discussed separately. (See 'Antibiotic dosing and monitoring' below.)

●Rationale and supporting evidence – The available limited clinical trial data comparing different antibiotic regimens for LOS have not demonstrated any convincing superiority of one regimen over others [29,30]. Oxacillin (or nafcillin) plus an aminoglycoside is our preferred regimen as it covers GBS, Escherichia coli, and staphylococci, which are common causes of LOS in neonates who have been hospitalized since birth (table 3) [18,28]. Oxacillin and nafcillin are superior to vancomycin for the treatment of methicillin-susceptible S. aureus (MSSA) [31], and thus are preferred unless there are specific reasons to cover MRSA. Routine coverage for other pathogens is less important. For example, although the regimen is not active against Listeria, that pathogen is an uncommon source of LOS in neonates [28]. Antibiotic therapy should be adjusted based on local antibiotic susceptibility patterns.

Broader coverage with vancomycin (ie, instead of oxacillin, nafcillin) or cephalosporins (ie, instead of aminoglycosides) is warranted for neonates who are known to be colonized with antimicrobial-resistant organisms such as MRSA, those with signs of severe infection and/or in whom a focal source of infection is suspected [32-34]. Several studies have highlighted the importance of coverage for staphylococci. In a retrospective study of 3339 neonates with S. aureus infection in 348 neonatal intensive care units, inadequate empiric antibiotic therapy (defined as not including ≥1 antibiotic with antistaphylococcal activity on day 1 of therapy) was associated with increased 30-day mortality (odds ratio 2.03, 95% CI 1.08-3.82) among infants with infection due to MRSA but not among those with MSSA infection [35].

Although many coagulase-negative staphylococci (CoNS) are resistant to oxacillin, they usually do not cause severe disease, even in preterm neonates; thus, empiric coverage is not necessary. In a retrospective study, among neonates with LOS due to CoNS, vancomycin started on day one of therapy decreased the median duration of bacteremia by one day but did not decrease 30-day mortality compared with delayed vancomycin therapy started after blood culture results [36].

Coverage for focal sources/specific infections — For neonates with LOS and a suspected focal source of infection, the empiric antibiotic regimen is modified as follows (table 4):

●Meningitis – Neonates in whom the lumbar puncture suggests meningitis (eg, CSF pleocytosis), and neonates with suspected meningitis based on clinical symptoms who were unable to undergo a lumbar puncture at initial sepsis evaluation, are treated with ampicillin or vancomycin plus a third- or fourth-generation cephalosporin (eg, cefotaxime [if available], ceftazidime, or cefepime). The choice of ampicillin or vancomycin depends on whether there is concern for infection or known colonization with MRSA, as discussed separately. (See 'Admitted from the community' above and 'Hospitalized since birth' above.)

Treatment with a cephalosporin broadens empiric coverage for gram-negative organisms and provides optimal activity in the CSF against pneumococci. If there is suspicion for meningitis caused by a multidrug-resistant, gram-negative organism, a carbapenem (eg, meropenem) is the preferred agent for empiric therapy [37]. (See 'Other gram-negative bacilli' below.)

We use cephalosporins other than ceftriaxone because it is associated with adverse events in neonates (eg, acute bilirubin neurotoxicity, adverse cardiopulmonary events when given concomitantly with IV calcium, including parenteral nutrition) [14-16].

Empiric treatment of bacterial meningitis in neonates is discussed in more detail separately. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empiric therapy'.)

●Pneumonia – Similarly to empiric treatment for sepsis, empiric regimens for the treatment of neonates with a suspected pulmonary infection are based on the neonate's age at the onset of symptoms (ie, early- or late-onset) and the clinical setting (for late-onset). Empiric antibiotic therapy for neonatal pneumonia is discussed in detail separately. (See "Neonatal pneumonia", section on 'Initial empiric therapy'.)

●Skin, soft tissue, bone, and joint infections – If there is a suspicion for infection involving the skin (eg, cellulitis), umbilicus (eg, omphalitis), soft tissues (eg, mastitis), or invasive infections (eg, bone, or joints) treatment with oxacillin, nafcillin, or vancomycin plus an aminoglycoside (eg, gentamicin) or a third- or fourth-generation cephalosporin (eg, ceftazidime, cefepime, or cefotaxime) should be initiated to provide adequate coverage for S. aureus [38]. This is discussed separately.

•(See "Skin and soft tissue infections in neonates: Evaluation and management", section on 'Antimicrobial therapy'.)

•(See "Staphylococcus aureus in children: Overview of treatment of invasive infections", section on 'Treatment of neonates'.)

•(See "Mastitis and breast abscess in infants younger than two months", section on 'Antimicrobial therapy'.)

●Catheter-related infection – For neonates with suspected intravascular catheter-related infection, antimicrobial treatment is the same as for neonates who are hospitalized since birth and depends on the risk for infection with MRSA. (See 'Hospitalized since birth' above and "Intravascular non-hemodialysis catheter-related infection: Treatment", section on 'Empiric antibiotic therapy'.)

●Intestinal source – If the infection is thought to arise from the gastrointestinal tract, treatment with ampicillin plus an aminoglycoside and clindamycin or metronidazole is warranted to include coverage for anaerobic bacteria. An alternative option is piperacillin-tazobactam with or without an aminoglycoside. (See "Neonatal necrotizing enterocolitis: Management and prognosis", section on 'Choice and duration of antibiotic regimen'.)

●Potential viral infection – Treatment may also be necessary for viral infections such as:

•Herpes simplex virus – (See "Neonatal herpes simplex virus (HSV) infection: Management and prevention", section on 'Indications'.)

•Influenza – (See "Seasonal influenza in children: Management", section on 'Indications and preferred regimens'.)

•Cytomegalovirus – Treatment is generally reserved for documented infection, which should especially be considered in preterm neonates with early- or late-onset sepsis. (See "Overview of cytomegalovirus (CMV) infections in children", section on 'Diagnosis'.)

Antibiotic dosing and monitoring — Dosing regimens may vary by institution. Additional monitoring may be warranted for neonates receiving aminoglycosides and vancomycin, as discussed below.

●Ampicillin – In neonates ≥35 weeks of gestation, our suggested dosing for ampicillin is generally based on weight and postnatal age [4,39-41]. For neonates <35 weeks of gestation, our suggested dosing for ampicillin and gentamicin is dependent on weight, GA, and postnatal age [39,41,42].

In neonates with possible meningitis, higher than usual doses for ampicillin are used. Once meningitis is excluded based on CSF parameters, the dose of ampicillin is reduced. (See 'Early-onset sepsis' above and 'Coverage for focal sources/specific infections' above.)

●Aminoglycosides – In neonates ≥35 weeks of gestation, our suggested dosing for aminoglycosides (eg, gentamicin and amikacin) is generally based on weight and postnatal age [4,39-41]. For neonates <35 weeks of gestation, our suggested dosing for gentamicin is dependent on weight, GA, and postnatal age [39,41,42].

At the initiation of aminoglycoside therapy, we generally obtain baseline kidney function tests (ie, blood urea nitrogen [BUN] and creatinine levels). Serum gentamicin or amikacin levels are not required if a treatment course of ≤48 hours is anticipated and kidney function is normal; however, levels should be obtained in neonates receiving a full course of gentamicin or amikacin therapy [40,43].

●Vancomycin – Weight-based vancomycin dosing regimens for preterm and term neonates vary somewhat between institutions. At our institutions, initial vancomycin dosing in preterm neonates (GA <35 weeks) is based on weight and postnatal age [41]. Two other common approaches include dosing according to serum creatinine (Scr) and dosing according to postmenstrual age (PMA) [39,44].

For neonates receiving ongoing vancomycin therapy, trough levels should be monitored and the dose adjusted as needed to maintain the desired therapeutic target (typically 8 to 12 mcg/mL for bloodstream infection and 15 to 20 mcg/mL for meningitis) [41].

Continuous infusion dosing regimens have also been described, but additional data are needed before this method can be employed routinely. Continuous infusion may be associated with earlier attainment of target concentrations and lower total daily dose compared with intermittent dosing [45,46]; however, it is unclear whether this results in more rapid clearance of infection compared with standard dosing. Most studies on continuous vancomycin infusion have focused on MRSA infections. The importance of achieving a particular vancomycin exposure for the successful treatment of coagulase-negative staphylococci infections is not well established.

Vancomycin dosing based on the AUC (ie, area under the serum concentration versus time curve) for infants with serious staphylococcal infections is an evolving area of pharmacokinetic research. The AAP provides parameters for serum creatinine and AUC-guided vancomycin dosing and monitoring [47].

DIRECTED ANTIBIOTIC THERAPY

Positive blood cultures — In neonates with positive blood cultures (ie, culture-proven sepsis), empiric antibiotic therapy is tailored based on the isolated pathogen and its antimicrobial susceptibility pattern [48,49]. If not done during the initial evaluation, cerebrospinal fluid (CSF) studies should be obtained whenever possible to evaluate for bacterial meningitis. The diagnostic evaluation of neonatal sepsis is discussed in more detail separately. (See "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at <35 weeks of gestation", section on 'Establishing the diagnosis' and "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates ≥35 weeks gestation", section on 'Diagnosis'.)

Pathogen-specific therapy — Once a pathogen has been isolated on culture, the antibiotic regimen should be tailored to the narrowest spectrum antibiotic that targets the isolated pathogen. We use the following parenteral antimicrobial regimens for the most common causative organisms of neonatal sepsis (table 4):

Group B Streptococcus (GBS) — Penicillin is the drug of choice for the treatment of isolated GBS infection (table 5). Ampicillin is an alternative option. The treatment of GBS infection in neonates is discussed in more detail separately. (See "Group B streptococcal (GBS) infection in neonates and young infants", section on 'Definitive therapy'.)

Escherichia coli — Antibiotic therapy for infection caused by E. Coli is determined by the susceptibility pattern of the isolate:

●Ampicillin-sensitive E. coli – For neonates with ampicillin-susceptible E. coli infection in whom meningitis has been excluded (ie, negative CSF cultures) and repeat blood cultures are negative, the empiric regimen may be transitioned to ampicillin monotherapy [37].

●Ampicillin-resistant E. coli – For neonates with ampicillin-resistant E. coli, antibiotic selection depends on the susceptibility pattern. We use cefazolin, cefotaxime (if available), ceftazidime, or cefepime and choose the agent with the narrowest spectrum that is active against the isolate.

If the organism is not susceptible to these antibiotics, we use meropenem. Piperacillin-tazobactam is an alternative option if E. coli is susceptible and meningitis has been excluded based on CSF studies.

Antimicrobial resistance is a growing issue in many locations. For example, in studies from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network, approximately 80 percent of early-onset Escherichia coli infections were resistant to ampicillin [20-22,25,26].

The treatment of neonatal meningitis due to E. coli is discussed in more detail separately. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Escherichia coli and other gram-negative organisms'.)

Other gram-negative bacilli — Antibiotic therapy for infections caused by other gram-negative bacilli (eg, Klebsiella, Proteus, Serratia, Salmonella, Shigella) is based on the susceptibility pattern of the isolate. If the organism is susceptible, a third-generation cephalosporin (eg, ceftazidime or, if available, cefotaxime) can be used. Ceftazidime, cefepime, and piperacillin-tazobactam monotherapy can be used for susceptible Pseudomonas. However, many of these species may have drug resistance due to the production of beta-lactamase enzymes.

Increased antibiotic resistance in such organisms is due to the production of two beta-lactamase enzymes [48,50-52] (see "Extended-spectrum beta-lactamases"):

●AmpC beta-lactamases – Chromosomally encoded or plasmid-derived AmpC beta-lactamases can be produced by certain Enterobacter, Klebsiella, and Citrobacter species. These organisms are resistant to penicillins and first-, second- and (often) third-generation cephalosporins.

AmpC beta-lactamase-producing organisms can be effectively treated with fourth-generation cephalosporins (eg, cefepime) if they are susceptible [53,54], or with carbapenems if they are not susceptible to cefepime. These organisms can develop induced resistance when treated with second- or third-generation cephalosporins. Thus, these antimicrobials should not be used to treat infections caused by AmpC beta-lactamase-producing organisms, even when they appear to be susceptible to them.

●Extended-spectrum beta-lactamases – Plasmid-mediated extended-spectrum beta-lactamases (ESBLs) can be present in a variety of gram-negative organisms, primarily E. coli and Klebsiella species. ESBL-producing organisms can be resistant to penicillins, cephalosporins, monobactams, and aminoglycosides.

Carbapenems (eg, meropenem and imipenem) are often needed for ESBL-producing organisms [55,56]. Some ESBL-producing organisms can be effectively treated with cefepime or piperacillin-tazobactam. Meropenem is the preferred carbapenem in neonates, as the safety profiles of other carbapenems have not been established in these patients [39]. Carbapenem-resistant organisms are also an emerging issue. These multi-drug-resistant infections should be managed in consultation with an infectious diseases expert.

The treatment of neonatal meningitis due to gram-negative pathogens is discussed in more detail separately. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Escherichia coli and other gram-negative organisms'.)

Staphylococcus species — Antibiotic therapy for infection caused by staphylococci is determined by the sensitivity of the isolate to specific antibiotic agents:

●S. aureus – Antibiotic selection for S. aureus depends on the susceptibility of the isolate:

•Methicillin-sensitive S. aureus (MSSA) – MSSA infection is treated with oxacillin or nafcillin. Cefazolin is an alternative option.

•Methicillin-resistant S. aureus (MRSA) – MRSA infection is treated with vancomycin.

Many institutions utilize rapid testing to identify S. aureus and determine methicillin susceptibility once gram-positive cocci grow on culture, so that tailored therapy can be used promptly. Otherwise, while susceptibility testing is pending, practice varies. Some experts use vancomycin plus oxacillin or nafcillin while susceptibilities are pending; others use oxacillin or nafcillin and reserve empiric vancomycin therapy only for those with toxicity (in addition to oxacillin or nafcillin) or a history of MRSA colonization.

Treatment of S. aureus in neonates is discussed in more detail elsewhere. (See "Skin and soft tissue infections in neonates: Evaluation and management".)

●Coagulase-negative staphylococci (CoNS) – CoNS infections are treated with vancomycin. CoNS is often resistant to methicillin.

While CoNS is commonly isolated in culture in preterm neonates, it may or may not reflect true infection. Considerations for additional evaluation and treatment of culture-positive CoNS infection are discussed in more detail separately. (See "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at <35 weeks of gestation", section on 'CoNS isolated'.)

Listeria monocytogenes — Combination therapy with ampicillin and gentamicin is the preferred treatment for L. monocytogenes. Cephalosporins are not active against L. monocytogenes. The treatment of L. monocytogenes infection is discussed in more detail separately. (See "Treatment and prevention of Listeria monocytogenes infection", section on 'Antibiotic therapy'.)

Duration of therapy — In most cases, symptomatic neonates with culture-proven sepsis improve clinically within 24 to 48 hours. We treat neonates with uncomplicated bacteremia in whom meningitis has been ruled out (eg, GBS infection or gram-negative bacteremia with negative repeat cultures) for a duration of 7 to 10 days [57-59]. Randomized trials evaluating the duration of antibiotic therapy for neonatal sepsis are limited; small trials suggest that shorter durations of therapy (ie, 7 or 10 versus 14 days) are safe and effective in neonates with uncomplicated infection [58-60]. A longer duration of antimicrobial therapy may be necessary for infections with certain organisms (eg, Pseudomonas or S. aureus bacteremia) [61]. A longer duration of therapy is also necessary for those with meningitis or other focal infections (eg, septic arthritis), as discussed separately. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Duration' and "Bacterial arthritis in infants and children: Treatment and outcome", section on 'Total duration'.)

Assessing response to therapy — In neonates with bacteremia, a repeat blood culture should be obtained after 24 to 48 hours of therapy to evaluate for treatment response. Failure to sterilize the bloodstream suggests that either the chosen antimicrobial(s) are not active against the infecting pathogen or that there is an unrecognized focus of infection. In these neonates, additional evaluation for alternative sources of infection and consultation with a pediatric infectious disease specialist is warranted.

Negative (sterile) blood cultures — For neonates with negative (sterile) blood cultures, the decision to continue or stop antibiotic therapy is individualized based on the neonate's clinical status and the judgment of the attending neonatologist.

Clinically unwell — Neonates with ongoing signs of clinical instability despite negative (sterile) blood cultures should be evaluated for other possible explanations (eg, viral or fungal infection, noninfectious condition (table 2)) for their clinical findings. If not done during the initial evaluation, cerebrospinal fluid (CSF) studies should be obtained whenever possible to rule out bacterial meningitis. Evaluation for alternative causes is discussed in more detail separately. (See "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates born at <35 weeks of gestation", section on 'Testing for alternative diagnoses' and "Neonatal bacterial sepsis: Clinical features and diagnosis in neonates ≥35 weeks gestation", section on 'The dilemma of "culture-negative sepsis"'.)

The decision to continue antibiotic therapy is made based on clinical judgment. Some clinicians may choose to continue antibiotic therapy. In this case, the empiric antibiotic regimen is altered after 24 to 48 hours of treatment depending on whether meningitis has been excluded:

●Meningitis excluded – For neonates with negative blood cultures in whom meningitis has been excluded (ie, no CSF pleocytosis, negative CSF Gram stain and culture, negative CSF molecular testing [if performed]), the ampicillin dosing regimen can be reduced [41]. If an alternative diagnosis is not identified, it is reasonable to discontinue antibiotics after five days [62].

●Meningitis not excluded – If meningitis has not been excluded (eg, CSF findings indicate meningitis or a lumbar puncture has not been performed), ampicillin is continued at a higher dose [41], and a longer duration of antibiotic therapy is necessary. This is discussed separately. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Duration'.)

Clinically improved or well-appearing — In neonates with clinically improved or resolved symptoms and negative blood cultures at 24 to 48 hours, empiric antibiotic therapy should be discontinued unless there is evidence of a site-specific infection [2,63]. Sepsis is unlikely in well-appearing neonates whose blood culture is sterile at 36 to 48 hours. Discontinuation of unnecessary antibiotics is an important component of antibiotic stewardship, as discussed below. (See 'Prevention of healthcare-associated infections' below.)

Prophylactic antifungal therapy for ELBW neonates — Extremely low birth weight (ELBW; BW <1000 grams) neonates who receive antibiotic therapy are also treated with prophylactic antifungal therapy as they are at high risk for developing invasive Candida infections. Indications for antifungal prophylaxis may vary by institution depending on local microbial patterns and other factors (eg, duration or type of antibiotic therapy, specific BW or disease state). Prophylactic antifungal therapy is discussed in more detail separately. (See "Candida infections in neonates: Treatment and prevention", section on 'Targeted prophylaxis'.)

PREVENTION — 

The prevention of neonatal sepsis requires a multi-intervention program that includes intrapartum antibiotic prophylaxis (IAP) for group B Streptococcus (GBS) colonization, reduction of preterm delivery, and prevention of healthcare-associated infections and infections with antimicrobial-resistant organisms through infection control techniques and antibiotic stewardship.

Intrapartum antibiotic prophylaxis (IAP) — The use of IAP in pregnant individuals with GBS colonization and other risk factors is the primary intervention to prevent neonatal sepsis. Although IAP has resulted in a decrease in the incidence of early-onset GBS invasive neonatal infection, it has not had a similar impact on the rate of late-onset GBS disease. (See "Prevention of early-onset group B streptococcal disease in neonates" and "Group B streptococcal (GBS) infection in neonates and young infants", section on 'Epidemiology'.)

Prevention of healthcare-associated infections — Prevention of neonatal sepsis due to healthcare-associated (ie, nosocomial) infections focuses primarily on infection control measures. This is particularly important for preterm neonates. In addition to IAP, modifiable risk factors for late-onset sepsis include the use of indwelling catheters and other devices (eg, central venous lines, endotracheal tubes, bladder catheters) and pharmacologic agents (eg, gastric-acid blockers, postnatal glucocorticoids). Use of these devices and agents should be reassessed often to determine if they can be safely discontinued.

Specific strategies to reduce nosocomial infections and infections with antimicrobial-resistant organisms in the neonatal intensive care unit (NICU) include [64]:

●Hand hygiene – Hand hygiene remains one of the most effective methods for reducing healthcare-associated infections [65,66]. Appropriate hand hygiene is discussed separately. (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Hand hygiene'.)

●Catheter care – In neonates with central venous lines, strategies to prevent catheter-related bloodstream infections (CRBSIs) include:

•Setting and adhering to institutional guidelines for the insertion and care of indwelling catheters [67,68]. Guidelines should include:

-The use of sterile technique and application of antiseptic agents at the site during line placement.

-Daily monitoring of catheter sites.

-Redressing and cleaning the site on a weekly basis. Tubing used to infuse dextrose and amino acids should be replaced every four to seven days.

•Prompt removal of catheters – Catheters should be removed promptly when they are no longer essential because the risk of infection generally increases with time; however, studies investigating the effect of dwell time on the risk of infection have been contradictory [69,70].

•Use of a closed system for medication delivery [71].

•Promotion of early enteral feeding with human milk, thereby reducing the need for or length of use of central lines and total parenteral nutrition.

We suggest not routinely using antibiotic lock therapy for the prevention of CRBSI in neonates. In a meta-analysis of three studies including 271 infants, antibiotic lock therapy appeared to be effective in preventing CRBSI in neonates [72]. However, studies have not comprehensively assessed the effect of this intervention on the development of drug-resistant organisms.

General strategies for reducing CRBSI's are discussed in more detail elsewhere. (See "Routine care and maintenance of intravenous devices".)

●Avoidance of overcrowding, contact precautions, and cohorting – Other infection control measures include avoidance of overcrowding and use of contact precautions (ie, gown and gloves) when appropriate. In addition, when outbreaks of specific viral or bacterial pathogens occur within a NICU, cohorting patients and assigning dedicated nursing staff to such patients may reduce the spread of these organisms. (See "Nosocomial infections in the intensive care unit: Epidemiology and prevention", section on 'Contact precautions, cohorting, and dedicated staff'.)

●Surveillance for multi-drug-resistant organisms – Surveillance for infections with multidrug-resistant bacteria within the institution as a whole and within specific NICUs is critical for the early identification and control of epidemic outbreaks and endemic increases of resistant bacteria. The prevalence of isolation of multidrug-resistant bacteria (eg, MRSA, ESBL-producing organisms, and vancomycin-resistant enterococcus [VRE]) should be monitored, and these data should be disseminated to the clinical staff in the NICU as they may impact the choice of empiric antibiotic therapy. (See "Nosocomial infections in the intensive care unit: Epidemiology and prevention", section on 'Surveillance'.)

●Antibiotic stewardship – Antibiotic stewardship refers to the judicious use of antibiotic therapy and is aimed at reducing the risk of antibiotic-resistant bacteria and fungal infections [27,73]. This includes:

•Limiting antibiotic therapy to clinical situations in which bacterial infection is likely.

•Discontinuing empiric therapy when a bacterial infection is not identified. Antibiotic stewardship protocols that include early discontinuation of antibiotics when cultures are negative at 36 hours (instead of at 48 hours) have decreased the use of antibiotics without apparent adverse effects [74,75].

•Changing therapy to the narrowest spectrum based on susceptibility testing. Restricting the use of third-generation cephalosporins may decrease the induction of extended-spectrum beta-lactamases (ESBLs). (See 'Other gram-negative bacilli' above.)

General principles and implementation of antimicrobial stewardship programs in the hospital setting are discussed in more detail elsewhere. (See "Antimicrobial stewardship in hospital settings".)

●Implementing protocols and monitoring compliance – Continued quality improvement focused on increasing health care staff awareness and education, establishing common improvement goals, training, environmental care, and setting guidelines for patient care [76]. (See "Nosocomial infections in the intensive care unit: Epidemiology and prevention", section on 'Environmental cleaning'.)

THERAPIES WITH UNCERTAIN BENEFIT

Immunomodulatory therapies — Several adjunctive immunomodulatory therapies have been evaluated for the treatment of neonatal sepsis. None have been shown to conclusively improve outcomes and we suggest not using them. Most of the studies investigating these therapies have involved preterm neonates.

●Intravenous immune globulin (IVIG) – It has been suggested that IVIG may have some benefit in preterm infants <32 weeks of gestation with serious bacterial infection, as most of the fetal transfer of maternal immunoglobulin occurs after 32 weeks of gestation. However, several clinical trials have failed to demonstrate the benefit of IVIG administration in neonates with suspected or confirmed sepsis [77,78].

●Granulocyte transfusions – There are limited data on granulocyte transfusions in neonatal sepsis. In a meta-analysis of four small trials including 79 infants with sepsis and neutropenia, treatment with granulocyte transfusion did not appear to have a meaningful impact on morbidity or mortality [79]. Adverse effects mainly included pulmonary complications and occurred in 4 percent of treated infants.

●Granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) – A meta-analysis of seven small trials including 257 infants in total did not detect a significant reduction in mortality in neonates with sepsis who were treated with G-CSF or GM-CSF [80]. In a follow-up report of the infants enrolled in one of these trials, neurodevelopmental outcomes, general health, and educational outcomes at age five years were similar in patients who received GM-CSF compared with placebo [81].

●Pentoxifylline – Pentoxifylline, a xanthine derivative, inhibits the release of tumor necrosis factor (TNF)-alpha, which is generally associated wⁱth systemic gram-negative infection. Limited data suggest that the addition of pentoxifylline to antibiotic therapy reduces mortality in neonates with sepsis. In a meta-analysis of six trials (416 neonates), pentoxifylline therapy was associated with a decrease in all-cause mortality during hospital stay (10 versus 17 percent; relative risk [RR] 0.57, 95% CI 0.35-0.93) [82]. However, the trials in the meta-analysis were small and most of them had important methodologic limitations (eg, four of the six trials were judged to be at high risk of bias by the study authors). Thus, the certainty of these findings is low. Larger, well-conducted trials are needed to confirm these findings before pentoxifylline can be routinely recommended in the treatment of neonatal sepsis.

Prophylactic agents — Lactoferrin and probiotics have been investigated as potential preventive interventions for late-onset sepsis (LOS) in preterm neonates [83,84]. However, we suggest not routinely using these therapies as neither approach has been conclusively proven to reduce the risk of sepsis.

●Lactoferrin – Lactoferrin is an iron-binding glycoprotein and a component of the mammalian innate response to infection. It is the major whey protein in colostrum, human milk, tears, and saliva.

Based on the available evidence, it remains uncertain if lactoferrin supplementation reduces the risk of LOS in preterm infants. In a meta-analysis of eight trials including a total of 3575 infants, enteral lactoferrin supplementation decreased the rate of culture-proven bacterial LOS compared with placebo (13.9 versus 16.1 percent; relative risk [RR] 0.86, 95% CI 0.74-1.0) [83]. However, the finding was of borderline statistical significance and the absolute effect size was small (absolute risk difference 2.2 percent, 98% CI 0-4.2). In the largest trial including >2200 neonates (<32 weeks of gestation) randomized to receive enteral bovine lactoferrin or placebo (sucrose), the rate of LOS in the lactoferrin group was similar to that in the placebo group (29 versus 31 percent, respectively; relative risk [RR] 0.95, 95% CI 0.86-1.04); mortality rates were also similar (7 versus 6 percent; RR 1.05, 95% CI 0.66-1.68) [85].

●Probiotics – The efficacy and safety of probiotics (defined as live nonpathogenic microbial preparations that colonize the intestine) in preventing LOS and reducing mortality are unproven. Although the pooled data suggest that probiotics may have a beneficial effect in reducing rates of LOS, the absolute effect size is small, and there is uncertainty as to whether they reduce mortality. In addition, rare but serious cases of probiotic-associated sepsis have been reported [86-90], and other uncertainties regarding optimal dosing and strain selection, duration of therapy, and regulatory control of these products remain. Thus, we suggest against the routine use of probiotics for the purpose of preventing LOS.

In a meta-analysis of 37 trials in preterm infants, probiotics were associated with a small but statistically significant reduction in the risk of LOS compared with placebo or no treatment (14 versus 16 percent; RR 0.86, 95% CI 0.78-0.94) [84]. The report did not include pooled estimates for other outcomes. In the largest randomized multicenter trials included in the meta-analysis (the PiPS and ProPrems trials involving >2300 neonates in total), rates of LOS were similar in neonates (<32 weeks of gestation) who received a probiotic compared with placebo (PiPS: 11 versus 12 percent; RR 0.97, 95% CI 0.73-1.29; ProPrems: 13 and 16 percent) [91,92]. In the PiPS trial, the rates of mortality were similar in both groups (8 versus 9 percent; RR 0.93, 95% CI 0·67-1.30).

In a separate meta-analysis, probiotics reduced mortality (5 versus 7 percent; RR 0.72, 95% CI 0.57-0.92), with the effect most pronounced in studies with high proportions of exclusively breastfed neonates [93]. However, the investigators detected significant publication bias in favor of probiotics, which is an important limitation of these data.

In a population-based retrospective study of nearly 19,000 preterm infants who received probiotics, did not decrease the rate of LOS [90]. Probiotic sepsis occurred in 27 (1.4/1000) neonates, with two suspected probiotic-related deaths.

The use of probiotics for the prevention of NEC is discussed in detail separately. (See "Neonatal necrotizing enterocolitis: Prevention", section on 'Probiotics'.)

OUTCOME — 

Gestational age (GA) and type of pathogen are important determinants of morbidity and mortality in neonatal sepsis. Preterm (GA <35 weeks) and very low birth weight (VLBW; <1500 grams) neonates are at particularly increased risk for both short- and long-term complications and mortality from sepsis. However, mortality estimates vary depending on the definition of sepsis. Lower mortality rates are reported in studies including neonates with both culture-positive and culture-negative clinical sepsis compared with studies limited only to neonates with culture-proven sepsis.

●Term and late preterm neonates – In term and late preterm neonates with bacterial sepsis, overall mortality is approximately 2 to 3 percent [5,23]. After the introduction of intrapartum antibiotic prophylaxis and routine use of empirical antibiotic therapy, mortality rates for group B streptococcal (GBS) sepsis in term neonates range from 2 to 3 percent for early-onset sepsis (EOS) and 1 to 2 percent for late-onset sepsis (LOS). Outcomes for infants with GBS infection are discussed in greater detail separately. (See "Group B streptococcal (GBS) infection in neonates and young infants", section on 'Outcome'.)

●Preterm and VLBW neonates – In preterm and VLBW neonates with bacterial sepsis, estimated mortality rates range between 20 to 30 percent for EOS and 15 to 25 percent for LOS [20,28,94,95]. Among extremely preterm neonates (variably defined in these studies as GA <26 to <28 weeks), mortality rates as high as 40 percent for EOS and 30 percent for LOS have been reported [96,97].

In preterm neonates, sepsis increases the risk for patent ductus arteriosus, prolonged mechanical ventilation, bronchopulmonary dysplasia, NEC, and duration of hospital stay [94,95]. In addition, sepsis is a risk factor for long-term neurodevelopmental impairment (NDI), including cognitive or motor delays, cerebral palsy, and/or sensory impairment (ie, vision or hearing loss) [96,98-102]. Sepsis affects neurodevelopment either by direct infection of the central nervous system or indirectly due to the impact of other associated comorbidities. Survivors of neonatal sepsis are also more likely to require home oxygen, tracheostomy, and/or gastrostomy compared with neonates of similar GA without sepsis [28].

Short- and long-term complications due to preterm birth, including risk factors for NDI, are discussed in greater detail separately.

•(See "Overview of short-term complications in preterm infants".)

•(See "Overview of the long-term complications of preterm birth".)

•(See "Long-term neurodevelopmental impairment in infants born preterm: Epidemiology and risk factors".)

●Pathogen – Neonates with gram-negative infections have a higher risk for mortality and morbidity (eg, a longer duration of hospital stay) than those with gram-positive infections [26,103-109]. The risk of mortality is particularly high in neonates with E. coli sepsis. Estimated mortality rates for term neonates with E. coli sepsis are 5 to 10 percent [17,30,110,111]. In a single-center study of 424 VLBW neonates with LOS, infection with a gram-negative or fungal pathogen was independently associated with an increased risk of mortality [103].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sepsis in neonates" and "Society guideline links: Group B streptococcal infection in pregnant people and neonates".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Sepsis in newborn babies (The Basics)")

SUMMARY AND RECOMMENDATIONS

●General and supportive management – Symptomatic neonates with suspected sepsis should be treated in a care setting with full cardiopulmonary monitoring and support because their clinical course can deteriorate rapidly. Sources of infection or contamination (eg, catheters) should be removed promptly. Supportive care includes (see 'General and supportive management' above):

•Maintenance of adequate oxygenation and perfusion (see "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn" and "Neonatal shock: Management")

•Monitoring and correction of electrolyte and metabolic abnormalities (eg, hypoglycemia) (see "Fluid and electrolyte therapy in newborns" and "Management and outcome of neonatal hypoglycemia")

•For preterm neonates, maintenance of a thermoneutral environment (see "Overview of short-term complications in preterm infants", section on 'Prevention of hypothermia')

●Initial empiric antibiotic therapy – Neonates with suspected sepsis due to birth circumstance or clinical features (table 1) require prompt diagnostic evaluation and initiation of parenteral empiric antibiotic therapy because of the risk of death and severe morbidity. Our approach is as follows (table 4) (see 'Initial empiric antibiotic therapy' above):

●Early-onset sepsis (EOS; age <72 hours) – For preterm and term neonates with suspected EOS, the choice of empiric antibiotic therapy depends on the severity of infection and potential for resistant infection. (See 'Early-onset sepsis' above.)

•For most neonates with suspected EOS, we suggest ampicillin plus an aminoglycoside (usually gentamicin or amikacin depending on local susceptibility patterns) rather than other regimens (Grade 2C). Ampicillin and aminoglycosides are effective in treating the pathogens that cause EOS in neonates (eg, group B Streptococcus [GBS], most isolates of Escherichia coli, Listeria (table 3)).

•For neonates with suspected EOS who require vasopressor support; were born at ≥35 weeks of gestation and require CPAP support or mechanical ventilation; or were born at <35 weeks, require mechanical ventilation, and were exposed to extended antepartum antibiotics, we suggest ampicillin plus a third- or fourth-generation cephalosporin (eg, cefotaxime [if available], ceftazidime, or cefepime) (Grade 2C). These patients may have a higher risk of worse outcomes due to severe infection or resistant infection, and cephalosporins provide better coverage for gram-negative pathogens. (See 'Early-onset sepsis' above.)

•Late-onset sepsis (LOS; age ≥72 hours) – The choice of empiric antibiotic therapy for preterm and term neonates with suspected LOS also depends on the severity of infection (eg, hemodynamic or respiratory instability) and whether the neonate was admitted from the community, hospitalized since birth, or has an apparent source of infection. (See 'Late-onset sepsis' above.)

-Admitted from the community (without severe infection) – For neonates with suspected LOS without signs of severe infection or an apparent focus of infection who are admitted from the community, we suggest ampicillin plus an aminoglycoside (usually gentamicin or amikacin depending on local susceptibility patterns) rather than other regimens (Grade 2C). A reasonable alternative is ampicillin plus a third- or fourth-generation cephalosporin (eg, cefotaxime [if available], ceftazidime, or cefepime). These regimens are effective in treating the pathogens that cause LOS in neonates (eg, GBS, most isolates of Escherichia coli, Listeria (table 3)). (See 'Admitted from the community' above.)

Other regimens may be appropriate for febrile neonates ≥22 days of age who are otherwise well-appearing and for whom there is a low suspicion of sepsis, as discussed separately. (See "The febrile neonate (28 days of age or younger): Initial management", section on 'Neonates 22 to 28 days old'.)

-Hospitalized since birth (without severe infection) – For neonates with LOS without signs of severe infection or an apparent focus of infection who continue to be hospitalized since birth, we suggest oxacillin (or nafcillin) plus an aminoglycoside (usually gentamicin or amikacin depending on local susceptibility patterns) rather than other regimens (Grade 2C). Oxacillin and nafcillin are superior to vancomycin for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA). Vancomycin is used instead of oxacillin (or nafcillin) if the neonate is known to be colonized with methicillin-resistant S. aureus (MRSA). Staphylococci are a common cause of sepsis in neonates who are hospitalized since birth (table 3). (See 'Hospitalized since birth' above.)

-Severe infection – For neonates with suspected LOS and signs of severe infection in whom there is no apparent focus of infection, we suggest vancomycin and a third- or fourth-generation cephalosporin (eg, cefepime or ceftazidime or, if there is no concern for Pseudomonas and it is available, cefotaxime) rather than other regimens (Grade 2C). Broader-spectrum antibiotic therapy provides coverage for MRSA and gram-negative organisms. (See 'Admitted from the community' above and 'Hospitalized since birth' above.)

-Focal source of infection – The empiric antibiotic regimen is modified for neonates with LOS due to an apparent focal source of infection, as summarized in the table (table 4) and discussed above. (See 'Coverage for focal sources/specific infections' above.)

•Dosing and monitoring – Parenteral (IV) antibiotic dosing regimens are provided in the table. However, dosing regimens may vary by institution. Additional monitoring may be warranted for neonates receiving aminoglycosides and vancomycin. (See 'Antibiotic dosing and monitoring' above.)

●Directed antibiotic therapy

•Positive blood cultures – In neonates with positive blood cultures (ie, culture-proven sepsis), empiric antibiotic therapy is tailored based on the isolated pathogen and its antimicrobial susceptibility pattern. For neonates with uncomplicated bacteremia, the duration of antibiotic therapy is usually 7 to 10 days. We reserve longer durations of therapy for those with meningitis or certain focal infections (eg, septic arthritis). (See 'Positive blood cultures' above.)

We assess response to antibiotic therapy with repeat blood cultures 24 to 48 hours after initiation of antibiotics. In neonates with ongoing bacteremia, additional evaluation for alternative sources of infection and consultation with a pediatric infectious disease specialist is warranted. (See 'Assessing response to therapy' above.)

•Negative blood cultures – Neonates with ongoing signs of instability despite negative (sterile) blood cultures should be evaluated for alternative causes of their clinical findings (table 2). Some clinicians may choose to continue antibiotic therapy. In this case, the empiric antibiotic regimen is altered after 24 to 48 hours depending on whether meningitis has been excluded. If meningitis or an alternative diagnosis is not identified, it is reasonable to discontinue antibiotics after five days. (See 'Clinically unwell' above.)

For neonates with negative cultures after 24 to 48 hours and without ongoing clinical concerns for sepsis, empiric antibiotic therapy is discontinued because sepsis is unlikely in these neonates. (See 'Clinically improved or well-appearing' above.)

•Prophylactic antifungal therapy for ELBW neonates – Neonates with extremely low birth weight (ELBW; <1000 grams) who receive antibiotic therapy are also treated with prophylactic antifungal therapy. Indications for prophylaxis may vary. Antifungal prophylaxis is discussed separately. (See "Candida infections in neonates: Treatment and prevention", section on 'Targeted prophylaxis'.)

●Prevention – Preventing neonatal sepsis requires a multi-intervention program that includes intrapartum antibiotic prophylaxis (IAP) for GBS colonization, reducing preterm delivery, and preventing healthcare-associated infections with infection control techniques. (See 'Prevention' above.)

●Outcome – Neonatal sepsis is associated with higher morbidity and mortality in premature and VLBW neonates compared with term neonates. Mortality is also higher in neonates with infections due to gram-negative pathogens compared with gram-positive infections. (See 'Outcome' above.)