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Management and outcome of sepsis in term and late preterm infants

Management and outcome of sepsis in term and late preterm infants
Author:
Morven S Edwards, MD
Section Editors:
Sheldon L Kaplan, MD
Joseph A Garcia-Prats, MD
Deputy Editor:
Carrie Armsby, MD, MPH
Literature review current through: Mar 2022. | This topic last updated: Apr 30, 2021.

INTRODUCTION — Sepsis is an important cause of morbidity and mortality among newborn infants. Although the incidence of sepsis in term and late preterm infants is low, the potential for serious adverse outcomes, including death, is of such great consequence that caregivers should have a low threshold for evaluation and treatment for possible sepsis in neonates. The approach discussed below is generally consistent with guidelines published by the American Academy of Pediatrics and the Centers for Disease Control and Prevention [1,2].

The treatment and outcome of sepsis in term and late preterm infants will be reviewed here. The epidemiology, clinical features, diagnosis, and evaluation of sepsis in term and late preterm infants; neonatal sepsis in preterm infants; management of well-appearing infants at risk for group B streptococcal (GBS) infection; and evaluation of febrile or ill-appearing newborns are discussed separately:

(See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants".)

(See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation".)

(See "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation".)

(See "Management of neonates at risk for early-onset group B streptococcal infection".)

(See "Group B streptococcal infection in neonates and young infants".)

(See "The febrile infant (29 to 90 days of age): Management".)

(See "Approach to the ill-appearing infant (younger than 90 days of age)".)

TERMINOLOGY — The following terms will be used throughout this discussion on neonatal sepsis:

Neonatal sepsis is a clinical syndrome in an infant 28 days of life or younger manifested by systemic signs of infection and isolation of a bacterial pathogen from the bloodstream. A consensus definition for neonatal sepsis is lacking [3]. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Diagnosis'.)

Term infants are those born at a gestational age of 37 weeks or greater.

Late preterm infants (also called near-term infants) are those born from 34 through 36 completed weeks of gestation [4]. (See "Late preterm infants".)

Preterm infants are those born at less than 34 weeks of gestation [4].

Neonatal sepsis is classified according to the infant's age at the onset of symptoms:

Early-onset sepsis is defined as the onset of symptoms before seven days of age, although some experts limit the definition to infections occurring within the first 72 hours of life [5].

Late-onset sepsis is defined as the onset of symptoms at ≥7 days of age [5]. Similarly to early-onset sepsis, there is variability in its definition, ranging from an onset at >72 hours of life to ≥7 days of age [5,6].

SUPPORTIVE CARE — Symptomatic infants should be treated in a care setting with full cardiopulmonary monitoring and support because the clinical course of these infants can deteriorate rapidly. Although there are no data demonstrating the importance of supportive care measures in neonates with sepsis, it is generally accepted that the following supportive measures are critical components of management:

Maintaining adequate oxygenation and perfusion (see "Respiratory support, oxygen delivery, and oxygen monitoring in the newborn")

Prevention of hypoglycemia and metabolic acidosis (see "Management and outcome of neonatal hypoglycemia")

Maintenance of normal fluid and electrolyte status (see "Fluid and electrolyte therapy in newborns")

Severely ill patients may require ventilatory, volume, and/or vasopressor support to maintain adequate oxygenation and perfusion. (See "Overview of mechanical ventilation in neonates" and "Neonatal shock: Etiology, clinical manifestations, and evaluation".)

ONGOING DIAGNOSTIC EVALUATION

Other diagnostic considerations — In infants with suspected sepsis, additional testing for other conditions may be warranted based on clinical signs and symptoms. Signs and symptoms of neonatal sepsis are often nonspecific, as summarized in the table (table 1). It may be difficult to differentiate neonatal sepsis from other diseases; however, given the morbidity and mortality of neonatal sepsis, empiric antibiotic therapy should be provided (after cultures are obtained) to infants with suspected sepsis, pending definitive culture-based diagnosis. Alternative diagnoses should be entertained when an infant with suspected sepsis has negative cultures. The differential diagnosis is summarized in the table (table 1) and discussed in greater detail separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Differential diagnosis'.)

Lumbar puncture — If not done during the initial evaluation, a lumbar puncture should be performed in infants, whenever possible, with culture-proven or culture-negative clinical sepsis. Clinical signs suggesting meningitis can be lacking, and blood culture may be negative in infants with meningitis. (See "Bacterial meningitis in the neonate: Clinical features and diagnosis".)

ANTIBIOTIC THERAPY

Whom to treat — The decision to start antibiotic therapy is based on assessment of risk factors, clinical evaluation, and laboratory tests. Indications for empiric antibiotic therapy include (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Evaluation and initial management'):

Ill appearance (see "Approach to the ill-appearing infant (younger than 90 days of age)")

Concerning symptoms, including temperature instability or respiratory, cardiocirculatory, or neurologic symptoms (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Clinical manifestations')

Cerebrospinal fluid (CSF) pleocytosis (white blood cell count of >20 to 30 cells/microL) (table 2) (see "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Interpretation of cerebrospinal fluid')

Confirmed or suspected maternal chorioamnionitis (intraamniotic infection) (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Maternal risk factors')

Positive blood, urine, or CSF culture (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Blood culture')

Initial empiric therapy — The initial choice of parenteral antimicrobials for suspected sepsis in term and late preterm neonates is based on the infant's age, likely pathogens, susceptibility patterns of organisms in a particular nursery, and presence of an apparent source of infection (eg, skin, joint, or bone involvement) (table 3).

Early-onset sepsis — Our recommended empiric regimen for suspected early-onset sepsis is ampicillin plus gentamicin. For term and late preterm neonates ≤7 days old, the dose of ampicillin is 100 mg/kg/dose given intravenously (IV) every eight hours [7,8]. Gentamicin dosing is 4 mg/kg/dose IV every 24 hours [6-8]. We generally obtain baseline renal function tests (ie, blood urea nitrogen and creatinine levels) at the initiation of treatment with gentamicin. Serum gentamicin levels should be obtained in infants receiving a full course of antibiotics but are not required if a treatment course of only 48 hours is anticipated and renal function is normal [6,9].

The combination of ampicillin and gentamicin is effective in treating most common pathogens that cause early-onset sepsis, including group B Streptococcus (GBS), Listeria, Enterococcus, and most isolates of Escherichia coli (table 4) [1,10].

In the available studies from the contemporary era, >90 percent of isolates from culture-proven, early-onset neonatal sepsis were susceptible to ampicillin, gentamicin, or both [11-13].

Ampicillin and gentamicin are preferred over ampicillin and a third-generation cephalosporin (eg, cefotaxime or ceftriaxone), based upon the following:

The regimen of ampicillin and a third-generation cephalosporin is not more effective than the combination of ampicillin and gentamicin [14].

The emergence of cephalosporin-resistant gram-negative organisms (eg, Enterobacter cloacae, Klebsiella, and Serratia species) can occur when cephalosporins are used routinely [15].

Ampicillin and gentamicin are synergistic in treating infections caused by GBS and Listeria monocytogenes. Cephalosporins are not active against L. monocytogenes.

In a large cohort study, infants who received ampicillin plus cefotaxime had a 1.5-fold increase in mortality compared with those treated with ampicillin plus gentamicin (4.2 versus 1.9 percent; adjusted odds ratio 1.5, 95% CI 1.4-1.7) [14].

Ceftriaxone is highly bound to albumin and appears to displace bilirubin [16,17]. Although displacement of free bilirubin by ceftriaxone has not been reported, it is advisable to avoid ceftriaxone in neonates at risk for acute bilirubin encephalopathy.

The addition of an expanded-spectrum cephalosporin (eg, cefotaxime [where available], ceftazidime, or cefepime) to the regimen of ampicillin and gentamicin is warranted for infants with suspected meningitis and critically ill neonates with risk factors associated with ampicillin-resistant infections (ie, prolonged rupture of membranes and/or prolonged antenatal maternal ampicillin treatment). If there is concern for meningitis caused by a multidrug-resistant, gram-negative organism, a carbapenem (eg, meropenem) is preferred for empiric therapy [18].

Late-onset sepsis — The choice of empiric therapy for late-onset sepsis depends upon whether the infant is admitted from the community and thus is at lower risk for infection caused by a multidrug-resistant pathogen or is hospitalized since birth and thus at a higher risk.

Admitted from the community — Neonates admitted from the community are at lower risk for infection caused by a multidrug-resistant pathogen than are infants who remain hospitalized since birth. The combination of ampicillin plus gentamicin or ampicillin plus an expanded-spectrum cephalosporin (eg, cefotaxime [if available], ceftazidime, or cefepime) are regimens for empiric treatment of sepsis without an apparent focus of infection in this setting (table 3) [5]. The preferred regimen is generally ampicillin plus gentamicin; however, local antibiotic resistance patterns must be considered.

For term and late preterm neonates >7 days old, the dose of ampicillin is 75 mg/kg/dose IV every six hours [7,8]. Gentamicin dosing is 5 mg/kg/dose IV every 24 hours [6-8]. We generally obtain baseline renal function tests (ie, blood urea nitrogen and creatinine levels) at the initiation of treatment with gentamicin. Serum gentamicin levels should be obtained in infants receiving a full course of antibiotics but are not required if a treatment course of only 48 hours is anticipated and renal function is normal [6,9].

In a national surveillance study (2006 to 2008), 96 percent of isolates from late-onset bacteremia were susceptible to the combination of amoxicillin and gentamicin [11].

The addition of an expanded-spectrum cephalosporin (eg, cefotaxime [where available], ceftazidime, or cefepime) to an ampicillin and gentamicin regimen is warranted for neonates with suspected meningitis. If there is concern for gram-negative meningitis caused by a multidrug-resistant organism, a carbapenem (eg, meropenem) is the preferred agent for empiric therapy [18]. (See 'Special circumstances' below.)

Hospitalized since birth — Infants who continue to be hospitalized since birth are at higher risk for multidrug-resistant organisms, and, therefore, vancomycin is substituted for ampicillin (table 3). The initial IV loading dose of vancomycin is 20 mg/kg; subsequent dosing depends on serum creatinine (Scr) [8]:

Scr <0.7 mg/dL – 15 mg/kg/dose IV every 12 hours

Scr 0.7 to 0.9 mg/dL – 20 mg/kg/dose IV every 24 hours

Scr 1 to 1.2 mg/dL – 15 mg/kg/dose IV every 24 hours

Scr 1.3 to 1.6 mg/dL – 10 mg/kg/dose IV every 24 hours

Scr >1.6 mg/dL – 15 mg/kg/dose IV every 48 hours

Alternative neonatal dosing recommendations for vancomycin based on weight and gestational age are available (refer to Lexicomp pediatric drug information) [7]. Continuous infusion dosing regimens have also been described, but further clinical trials 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 [19,20]; 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 methicillin-resistant S. aureus (MRSA) infections. The importance of achieving a particular vancomycin exposure for successful treatment of coagulase-negative staphylococci infections is not well established.

Special circumstances — Alternative regimens based upon specific clinical circumstances include the following (table 3):

Suspected meningitis – In neonates with late-onset sepsis in whom the lumbar puncture suggests meningitis (eg, CSF pleocytosis), an expanded-spectrum cephalosporin (eg, cefotaxime [where available], ceftazidime, or cefepime) should be included in the regimen. Adding an expanded-spectrum cephalosporin to the regimen of ampicillin and gentamicin broadens empiric coverage for gram-negative organisms and provides optimal activity in the CSF against pneumococci. If there is concern for meningitis caused by a multidrug-resistant, gram-negative organism, a carbapenem (eg, meropenem) is the preferred agent for empiric therapy [18]. Treatment of bacterial meningitis in neonates is discussed in detail separately. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empiric therapy'.)

Suspected pneumonia – Empiric regimens for the treatment of infants with a pulmonary focus of infection include ampicillin and gentamicin, ampicillin and an extended-spectrum cephalosporin, vancomycin and an extended-spectrum cephalosporin, or vancomycin and gentamicin. Treatment of pneumonia in neonates is discussed in detail separately. (See "Neonatal pneumonia", section on 'Management'.)

Skin, soft tissue, bone, and joint infections – If there is a focus of infection involving the skin, soft tissues, bone, or joints (in which case, S. aureus is a likely pathogen), vancomycin should be substituted for ampicillin [21]. In a toxic-appearing infant, nafcillin should also be added.

Catheter-related infection – If intravascular catheter-related infection is a concern, treatment should be initiated with vancomycin and gentamicin to provide empiric coverage for coagulase-negative staphylococci, S. aureus, and gram-negative bacteria.

Suspected intestinal source – If infection is thought to arise from the gastrointestinal tract (eg, anaerobic bacteria), clindamycin or another suitable agent, such as metronidazole, should be added to the therapeutic regimen to improve coverage for these pathogens.

Culture-proven sepsis — In neonates with culture-proven sepsis, the usual course of therapy is 10 days [9,22]. Longer treatment courses may be warranted if a specific focus of infection is identified (eg, meningitis, osteomyelitis, or septic arthritis). Antimicrobial therapy should be altered based upon the susceptibility profile of the pathogen isolated.

Pathogen-specific therapy — For the most common causative organisms of neonatal sepsis, antimicrobial therapy is as follows (table 3):

Group B Streptococcus — The drug of choice for GBS is penicillin. Thus, when GBS is identified and resolution of bacteremia is documented by a repeat blood culture and, in infants with meningitis, the CSF is sterile, we recommend discontinuing gentamicin and continuing therapy with penicillin G alone (table 5). (See "Group B streptococcal infection in neonates and young infants", section on 'Definitive therapy'.)

Escherichia coli — In patients with ampicillin-sensitive E. coli sepsis who have improved clinically and in whom meningitis has been excluded, ampicillin monotherapy is administered for a 10-day course.

For patients with ampicillin-resistant E. coli, the choice of definitive therapy is based upon the susceptibility profile. An expanded-spectrum cephalosporin (eg, cefotaxime [where available], ceftazidime, or cefepime) is often employed if the isolate is susceptible.

Other gram-negative bacilli — Antimicrobial treatment of infections caused by Klebsiella, Proteus, Enterobacter, Serratia, Pseudomonas, Salmonella, or Shigella should be selected based upon the susceptibility profile of the organism. Single-agent therapy is sufficient in most cases.

Infections caused by multidrug-resistant, gram-negative bacilli, including those caused by extended-spectrum beta-lactamase-producing organisms or those with hyperproduction of beta-lactamases, should be treated with meropenem.

Listeria monocytogenes — The combination of ampicillin and gentamicin is used for initial therapy. Treatment with both agents is more effective than ampicillin alone in vitro and in animal models of Listeria infection. Cephalosporins are not active against L. monocytogenes. Duration of therapy usually is 10 days. (See "Treatment and prevention of Listeria monocytogenes infection", section on 'Antibiotic therapy'.)

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

S. aureusVancomycin or, in a toxic-appearing infant, vancomycin plus nafcillin, should be employed for S. aureus infection until the susceptibility profile is available. The regimen then should be adjusted according to the susceptibility profile:

Methicillin-susceptible S. aureus (MSSA) – Treatment of MSSA infection should be completed with nafcillin. Cefazolin is an alternative for treatment of most MSSA infections outside of the central nervous system and not involving endocarditis. (See "Staphylococcus aureus bacteremia in children: Management and outcome".)

MRSA – Treatment should be completed with vancomycin. (See "Staphylococcus aureus in children: Overview of treatment of invasive infections", section on 'Treatment of neonates'.)

Coagulase-negative staphylococci – Coagulase-negative staphylococcal infections require treatment with vancomycin.

Probable but unproven sepsis — In infants with a negative blood culture but a clinical status that remains concerning for a systemic infection (eg, ongoing temperature instability; ongoing respiratory, cardiocirculatory, or neurologic symptoms not explained by other conditions; or laboratory abnormalities suggestive of sepsis), antibiotic therapy can be extended for as long as a total of 5 to 10 days.

After 36 to 48 hours, the empiric regimen is altered based upon whether meningitis has been excluded:

If meningitis has been excluded, the ampicillin dosing regimen can be reduced to 100 mg/kg/dose IV every 12 hours in infants <7 days old or 50 mg/kg/dose IV every six hours in infants ≥7 days old [7].

If a lumbar puncture has not been performed, ampicillin should be continued at a meningitic dose.

Management of infants with CSF pleocytosis and/or positive CSF culture is discussed separately. (See "Bacterial meningitis in the neonate: Treatment and outcome".)

Alternative diagnoses should also be entertained when an infant with suspected sepsis has negative cultures (table 1). Antibiotics should be discontinued when another diagnosis is established. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Differential diagnosis'.)

Infection unlikely — Empiric antibiotics are initiated in many infants with maternal risk factors, abnormal laboratory values, and/or mild to moderate symptoms that subsequently resolve. Sepsis is unlikely in these infants if they remain well and the blood culture is sterile at 36 to 48 hours. Empiric antibiotic therapy should be discontinued after 36 to 48 hours in these neonates unless there is evidence of site-specific infection [1,23].

Response to therapy — In most cases, symptomatic infants with proven sepsis improve clinically within 24 to 48 hours.

In infants with bacteremia, a repeat blood culture should be obtained after 24 to 48 hours of therapy to document sterility. Failure to sterilize the bloodstream suggests that the antimicrobial(s) chosen are not active against the infecting pathogen or that there is an unrecognized focus of infection. Consultation with a pediatric infectious disease specialist may be warranted.

ADJUNCTIVE THERAPIES — The following adjunctive immunotherapeutic interventions have been studied in neonatal sepsis but should not be routinely administered, because they have not been shown to conclusively improve outcomes [24-26]:

Intravenous immune globulin (IVIG) infusions [27,28]

Granulocyte transfusions [29]

Granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) [30,31]

Pentoxifylline [32]

Most of the studies investigating these therapies involved preterm neonates. These data are discussed in greater detail separately. (See "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Adjunct therapy to antibiotics'.)

PREVENTION — The primary intervention to prevent neonatal sepsis is the use of intrapartum antibiotic prophylaxis (IAP) in mothers with group B streptococcal (GBS) colonization and other risk factors. 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 infection in neonates and young infants", section on 'Epidemiology'.)

Comprehensive prevention of neonatal sepsis will require a multi-interventional program including effective maternal vaccination, reduction in preterm delivery, and limited exposure of term infants to potential pathogens. (See "Vaccines for the prevention of group B streptococcal disease".)

Probiotics and lactoferrin have been investigated as potential preventative interventions in preterm neonates [33,34]; however, neither approach has been conclusively proven to reduce the risk of sepsis and these interventions are not routinely used in clinical practice. These data are discussed in greater detail separately. (See "Treatment and prevention of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Potential prophylactic therapy'.)

OUTCOME — Overall mortality in term and late preterm infants with neonatal sepsis is approximately 2 to 3 percent [14,35]. Mortality estimates vary depending on the gestational age of the infant (lower gestational age is associated with higher mortality), pathogen (E. coli is associated with higher mortality than group B Streptococcus [GBS]), and sepsis definition (lower mortality rates tend to be reported if infants with culture-negative clinical sepsis are included compared with cases of culture-proven sepsis only).

Mortality rates for GBS sepsis in term infants after the introduction of IAP and routine use of empirical antibiotic therapy range from 2 to 3 percent for early-onset disease and 1 to 2 percent for late-onset disease. The risk of mortality is higher in infants with birth weight <2500 g, absolute neutrophil count <1500 cells/microL, hypotension, apnea, and pleural effusion [36]. (See "Group B streptococcal infection in neonates and young infants", section on 'Outcome'.)

The risk of mortality is particularly high in neonates with early-onset sepsis caused by E. coli. Estimated mortality rates for term neonates with E. coli sepsis are 6 to 10 percent [10,37,38].

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 women 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 5th to 6th 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 10th to 12th 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

Although the incidence of sepsis in term and late preterm infants is low, the potential for serious adverse outcomes, including death, is of such great consequence that care providers should have a low threshold for evaluation and treatment for possible sepsis. (See 'Introduction' above.)

Supportive care for symptomatic infants is delivered in an intensive care setting to ensure adequate oxygenation, perfusion, and maintenance of normal fluid and electrolyte balance, especially in severely affected patients. (See 'Supportive care' above.)

Indications for empiric antibiotic therapy include any of the following:

Ill appearance (see "Approach to the ill-appearing infant (younger than 90 days of age)")

Concerning symptoms, including temperature instability or respiratory, cardiocirculatory, or neurologic symptoms (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Clinical manifestations')

Cerebrospinal fluid (CSF) pleocytosis (white blood cell count of >20 to 30 cells/microL) (table 2) (see "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Interpretation of cerebrospinal fluid')

Confirmed or suspected maternal chorioamnionitis (intraamniotic infection) (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Maternal risk factors')

Positive blood, urine, or CSF culture (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Blood culture')

Empiric antibiotic therapy for neonates with suspected sepsis should provide broad coverage for the most likely pathogens (group B Streptococcus [GBS] and gram-negative enteric organisms, including Escherichia coli) (table 4). Our suggested approach is as follows (table 3):

For neonates with early-onset sepsis without an apparent focus, we suggest initial empiric therapy with ampicillin and gentamicin rather than other agents (Grade 2C). (See 'Early-onset sepsis' above.)

For neonates with late-onset sepsis without an apparent focus, we suggest the following (see 'Late-onset sepsis' above):

-For neonates admitted from the community, we suggest ampicillin and gentamicin rather than other agents (Grade 2C)

-For infants who continue to be hospitalized from birth, we suggest vancomycin and gentamicin rather than other agents (Grade 2C)

If the clinical findings suggest a focal source of infection, the empiric antibiotic regimen is modified as follows (table 3) (see 'Special circumstances' above):

-If there is concern of late-onset meningitis, an expanded-spectrum cephalosporin (eg, cefotaxime [where available], ceftazidime, or cefepime) is added to the regimen. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empiric therapy'.)

-If there is concern for pneumonia, acceptable empiric regimens include ampicillin and gentamicin, ampicillin and an expanded-spectrum cephalosporin (eg, cefotaxime [where available], ceftazidime, or cefepime), vancomycin and expanded-spectrum cephalosporin, or vancomycin and gentamicin. (See "Neonatal pneumonia", section on 'Management'.)

-If there is a focus of infection involving the skin, soft tissues, bone, or joints, vancomycin is substituted for ampicillin (in toxic-appearing infants, nafcillin is also added).

-If intravascular catheter-related infection is a concern, the empiric regimen consists of vancomycin and gentamicin.

-If an intestinal source for sepsis is suspected, clindamycin or metronidazole is added to the regimen.

Antibiotic therapy is altered based upon isolation of the causative agent and its antimicrobial susceptibility pattern. (See 'Pathogen-specific therapy' above.)

In infants with culture-proven sepsis, the usual course of therapy is 10 days. Longer treatment is warranted if a specific focus of infection is identified (eg, meningitis, osteomyelitis, or septic arthritis). (See 'Culture-proven sepsis' above.)

In well-appearing infants with negative cultures after 36 to 48 hours, empiric antibiotic therapy should be discontinued since sepsis is unlikely in these infants. (See 'Infection unlikely' above.)

Most infants with culture-proven sepsis improve clinically within 24 to 48 hours after appropriate antibiotic treatment is started. The response to antibiotic therapy is assessed by a repeat blood culture 24 to 48 hours after initiation of antibiotic therapy. Failure to sterilize the bloodstream suggests either that the antimicrobial(s) chosen are not active against the infecting pathogen or that there is an unrecognized focus of infection. (See 'Response to therapy' above.)

The mortality of neonatal sepsis in term infants is <5 percent. However, the risk of mortality varies depending on the gestational age of the infant (lower gestational age is associated with higher mortality) and pathogen (E. coli is associated with higher mortality compared with GBS). (See 'Outcome' above.)

The primary intervention to prevent neonatal sepsis is the use of intrapartum antibiotic prophylaxis (IAP) in mothers with GBS colonization and other risk factors. This is discussed separately. (See "Prevention of early-onset group B streptococcal disease in neonates".)

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