Pediatric Sepsis 

Updated: Dec 14, 2018
Author: Shankar Santhanam, MD; Chief Editor: Russell W Steele, MD 

Overview

Practice Essentials

Pediatric sepsis is generally considered to comprise a spectrum of disorders that result from infection by bacteria, viruses, fungi, or parasites or the toxic products of these microorganisms. Early recognition and intervention clearly improve outcome for infants and children with conditions that lead to sepsis.

The spectrum of sepsis ranges from microbial invasion of the bloodstream or intoxication with early signs of circulatory compromise—including tachycardia, tachypnea, peripheral vasodilation, and fever (or hypothermia)—to full-blown circulatory collapse with multiple organ dysfunction syndrome (MODS) and death (see the image below).

Pathogenesis of sepsis and multiple organ dysfunct Pathogenesis of sepsis and multiple organ dysfunction syndrome (MODS).

Signs and symptoms

Obtain a complete history as part of the evaluation for possible sepsis. Symptoms that may be noted include the following:

  • Fever (most common presenting symptom of children with systemic inflammatory response syndrome [SIRS])

  • Racing heart

  • Rapid or labored breathing

  • Cool extremities

  • Color changes

The following should be inquired into:

  • Exposures to infectious illnesses and other sources of insult

  • Activity level

  • Mental status (relative to age)

  • Urine output

  • Immunizations

  • Drug allergies

Perform a complete physical examination. Findings reflective of sepsis may include the following:

  • Subtle changes in vital signs (often the first indicators of impending SIRS)

  • Hypotension, mental status changes, and anuria (late signs)

  • Hypothermia (often more ominous than fever)

  • Localizing signs of infection

See Presentation for more detail.

Diagnosis

Laboratory studies that may be helpful include the following:

  • Complete blood count (CBC)

  • Measures of clotting function and coagulation parameters.

  • Electrolyte levels

  • Renal and liver function tests

  • Etiology-specific serologies

  • Urinalysis

  • Tests for inflammatory markers and acute-phase reactants

  • Culture of blood, urine, cerebrospinal fluid (CSF), or other tissues

Other studies that may be considered, depending on the clinical context, are as follows:

  • Chest radiography

  • Computed tomography (CT)

  • Magnetic resonance imaging [MRI)

  • Echocardiography.

  • Lumbar puncture for CSF evaluation

See Workup for more detail.

Management

The initial focus of treatment is on stabilization and correction of metabolic, circulatory, and respiratory abnormalities, which may include the following:

  • Aggressive fluid resuscitation and support of cardiac output

  • Ventilatory support with supplemental oxygen therapy

  • Maintenance of adequate hemoglobin concentration

  • Correction of physiologic and metabolic derangements

  • Monitoring of urine output and other end-organ functioning

Antimicrobial agents should be given as soon as possible, according to the most likely pathogens. The following therapies are commonly employed:

  • Newborns and infants in the first 6-8 weeks of life: Ampicillin and gentamicin, ampicillin and cefotaxime, or ampicillin and ceftriaxone

  • Older infants and children with sepsis of unclear etiology: A third-generation cephalosporin plus vancomycin. Add clindamycin if S aureus or GABHS are possible etiologies.

  • Patients who have indwelling catheters or those who are at high risk for methicillin-resistant Staphylococcus aureus (MRSA) infection: As above, with the addition of vancomycin

  • Patients who have fever and neutropenia: Broad-spectrum coverage with an emphasis on Gram-negative rods

Surgical intervention (eg, abscess drainage or venous access) is occasionally required.

Adjunctive therapies may be considered, including the following:

  • Inhaled nitric oxide

  • Extracorporeal membrane oxygenation

  • Corticosteroids

  • Pentoxifylline

  • Intravenous immunoglobulin (IVIg)

  • Terlipressin

  • Bovine lactoferrin

Generally, these patients should not be fed until gut hypoxia and hypoperfusion have been excluded. Once feeding can safely begin, immune-enhancing nutrition may reduce mortality.

See Treatment and Medication for more detail.

Background

Pediatric sepsis, like sepsis in adults, is generally considered to comprise a spectrum of disorders that result from infection by bacteria, viruses, fungi, or parasites or the toxic products of these microorganisms. (See also Neonatal Sepsis.) The terms bacteremia, viremia, fungemia, and parasitemia refer to bloodstream invasions (BSIs) that may be associated with fever but have no other signs or symptoms of circulatory compromise or end-organ malperfusion or dysfunction.

Sepsis is a problem that presents a management challenge to those who care for infants and children; however, early recognition and intervention clearly improves the outcome for infants and children with infections or intoxications that lead to sepsis.

Most infants and children with sepsis require monitoring and treatment in an intensive care setting. Initial focus should be on stabilization and correction of metabolic, circulatory, and respiratory derangements. Appropriate antimicrobial therapy should be started as soon as possible after evaluation occurs. Ongoing reevaluation is essential.

Critical care expertise is essential for moderate-to-severe cases. Consultation with an infectious diseases specialist may be necessary. Other consultations should be obtained in accordance with the specific clinical circumstances.

A report on sepsis by the CDC that included a retrospective review of 246 adult and 79 pediatric patients (31 infants younger than 1 year and 48 children between 1 and 17 years of age) with severe sepsis or septic shock found that nearly 80% of patients develop infections leading to sepsis outside a hospital. The study also found that 7 in 10 sepsis patients had seen a healthcare provider in the month preceding sepsis admission or had chronic diseases requiring frequent medical care.[1, 2]

Pathophysiology

The spectrum of sepsis ranges from microbial invasion of the bloodstream or intoxication with early signs of circulatory compromise—including tachycardia, tachypnea, peripheral vasodilation, and fever (or hypothermia)—to full-blown circulatory collapse with multiple organ dysfunction syndrome (MODS) and death (see the image below).

Pathogenesis of sepsis and multiple organ dysfunct Pathogenesis of sepsis and multiple organ dysfunction syndrome (MODS).

All these manifestations are part of what is more appropriately termed the systemic inflammatory response syndrome (SIRS), which may be caused by noninfectious or infectious conditions. SIRS results from an insult (infectious, traumatic, chemical, malignant, autoimmune, or idiopathic) and the host response to the insult. The outcome depends on the intricate interplay of upregulating and downregulating cytokines and inflammatory cells and the direct effects of the insult itself. Sepsis is SIRS developing in conjunction with infection.

Experts have come together to develop a consensus on definitions of sepsis, SIRS, severe sepsis, and septic shock that are appropriate for the pediatric population.[3] Age-related variables have been applied to the definition of SIRS and sepsis. The definition of SIRS now requires either fever or white blood cell (WBC) abnormality.

The earliest, mildest manifestation of SIRS is typified by the triad of hyperthermia (or hypothermia), tachypnea, and tachycardia. If SIRS is identified and reversed early, the subsequent inflammatory cascade can often be avoided or mitigated. However, in some situations, further damage occurs because the insult or the resultant host immune response is too great. This damage can result in increased cardiac output, peripheral vasodilation, increased tissue oxygen consumption, and a hypermetabolic state (ie, warm shock).

If SIRS is not identified and reversed early, cardiac output may fall, peripheral vascular resistance may increase, and shunting of blood may ensue (ie, cold shock). This results in tissue hypoxia, end-organ dysfunction, metabolic acidosis, end-organ injury or failure, and death.

Etiology

Bacterial causes

Myriad bacteria, viruses, fungi, and parasites can cause sepsis. Among the bacterial causes of sepsis, the following age-related patterns are observed.[4]

In patients with early-onset neonatal sepsis, Streptococcus agalactiae, Escherichia coli, Haemophilus influenzae, and Listeria monocytogenes are the most frequent organisms encountered.

In patients with late-onset neonatal sepsis, coagulase-negative Staphylococcus,[5] Staphylococcus aureus, E coli, Klebsiella species, Pseudomonas aeruginosa, Enterobacter species, Candida species, S agalactiae, Serratia species, Acinetobacter species, and various anaerobes are some of the most commonly involved organisms.

In most infants worldwide, the most frequent causes of bacterial sepsis are H influenzae type b (Hib), Streptococcus pneumoniae, Neisseria meningitidis, and Salmonella species. In the United States and the developed world, E coli, S aureus, S pneumoniae, and Nmeningitidis predominate because conjugate Hib vaccination has essentially eliminated disease caused by Hib and conjugate pneumococcal vaccination has significantly decreased the incidence of that infection.[6] In regions where malaria occurs, Plasmodium falciparum is a frequent cause of SIRS in infancy.

The same pathogens that cause sepsis in infancy also cause it in childhood, although the presence of encapsulated organisms generally becomes less frequent as a child’s immune response to polysaccharide antigens improves with age.

Risk factors

Underlying conditions predispose to infection with particular pathogens, such as the following:

  • AIDS predisposes to sepsis from various usual and unusual pathogens, particularly pneumococcus

  • Children with hemoglobin SS disease have a 400-fold increased risk of sepsis due to pneumococcus and Salmonella, among other pathogens

  • Congenital heart disease is a risk factor for endocarditis and sepsis, and genitourinary anomalies often increase the risk of urosepsis

  • Infants and children with significant burns are at risk for sepsis caused by skin flora and nosocomial gram-negative pathogens in particular

  • Splenic dysfunction or absence, as well as complement, immunoglobulin, and properdin deficiency, predispose to sepsis due to encapsulated organisms

  • Infants and children with hematologic and solid-organ malignancies (before or during treatment) are at increased risk for sepsis from a considerable variety of organisms

  • Neonates, infants, and children who are hospitalized (particularly in the intensive care unit [ICU]) are at increased risk for SIRS

  • Those with indwelling devices or prosthetic material and other breaches in barrier protective function are also at increased risk for SIRS

In a retrospective cohort study of 3967 infants in the neonatal intensive care unit who underwent placement of 4797 peripherally inserted central catheters (PICCs), Milstone et al found that the risk of central-line-associated bloodstream infection (CLABSI) increased steadily in the initial 2 weeks following catheter insertion and remained high thereafter. After adjustment for independent predictors of CLABSI, the risk was higher in infants with a catheter dwell time of more than 2 weeks than in infants with a shorter dwell time.[7, 8]

Epidemiology

SIRS remains an infrequent but significant cause of death among infants and children in the United States. The incidence of sepsis is somewhat higher in the developing world than it is in the United States. However, reports are fewer, and precise figures are unavailable.

The risk of sepsis is inversely related to age. Neonates are at the highest risk, with bacterial sepsis occurring in 1-10 per 1000 live births in the United States. No sex predilection for sepsis is known, except for urosepsis, which is more common in females and uncircumcised males. No particular racial predilection is noted for sepsis, except that invasive bacterial infections are more common in Eskimos, American Indians, and individuals with hemoglobin SS disease.

A review of 20-year trends in maternal/neonatal care, complications, and mortality among extremely preterm infants born at Neonatal Research Network centers reported that despite no improvement from 1993 to 2004, rates of late-onset sepsis declined between 2005 and 2012 for infants of each gestational age.[9]

McMullan et al conducted a study to describe the epidemiology of Staphylococcus aureus bacteremia in children and adolescents younger than 18 years from Australia and New Zealand. The study found that of the 1073 children with SAB who had complete outcome data available, the median age was 57 months, and that the annual incidence for Australian children was 8.3 per 100 000 population and was higher in indigenous children. The study also found that seven- and 30-day mortality rates were 2.6% and 4.7%, respectively and risk factors for mortality were age younger than 1 year; Māori or Pacific ethnicity; endocarditis, pneumonia, or sepsis; and receiving no treatment or treatment with vancomycin.[10]

Prognosis

Mortality from pediatric sepsis ranges from 9% to 35%. Different insults are associated with different outcomes. Host immune status is important in determining outcome. Aggressive fluid resuscitation early in the course of SIRS results in decreased mortality (except, possibly, in resource-limited, developing countries).[11, 12]

Almost half of neonatal deaths are caused by sepsis, although advances in diagnosis and treatment have caused this rate to decrease substantially, especially in preterm infants. Again, mortality tends to decrease as age increases in the pediatric population.

Patient Education

Parents of newborns should understand that any fever in the first few months of life necessitates immediate evaluation. The importance of fever as a marker of possible serious infection, rather than a concerning symptom itself, should be emphasized.

Front-line providers must recognize the importance of aggressive resuscitation for the patient with early signs of SIRS.

Vaccination is the key to preventing many of these infections. Travelers should be warned of the possibility of serious infections during travel.

For patient education information, see the Infections Center, as well as Sepsis.

 

Presentation

History

Obtain a complete history as part of the evaluation of the infant or child with possible sepsis. Fever is the most common presenting symptom of children with systemic inflammatory response syndrome (SIRS). A parental report of measured (not tactile) fever can generally be assumed to be reliable.

Ask the caregiver whether any of the following have been noted: a racing heart, rapid or labored breathing, cool extremities, or color changes. Identify exposures to infectious illnesses and other sources of insult.

Discuss the child’s activity level. Perform an age-appropriate evaluation of mental status. Ask about urine output because it is the most sensitive historical marker of dehydration and potential renal hypoperfusion. Verify immunizations, and confirm drug allergies.

Physical Examination

Perform a complete physical examination of the infant or child with suspected sepsis. Subtle changes in vital signs (eg, minimal tachycardia, widened pulse pressure, minimal tachypnea, minimally delayed capillary refill) may be the first signs of impending SIRS. Hypotension, mental status changes, and anuria are late signs. Hypothermia is often a more ominous sign than fever.

Elicit localizing signs of infection. A petechial or purpuric rash associated with fever is of particular concern. Frequent reassessment during interventions is required.

Because the manifestations of pediatric sepsis are protean, the possible complications are as well. Complications depend on the nature of the triggering insult and the resultant host response.

 

DDx

Diagnostic Considerations

In addition to the conditions in the differential diagnosis, other problems to be considered in the diagnosis of pediatric sepsis include cardiogenic shock, coagulase-negative Staphylococcus, complement deficiency, congenital heart disease, fungal infections, hemophagocytic syndromes, inborn errors of metabolism, infections after solid organ transplantation, macrophage activation syndromes, neoplasms, poisoning, pulmonary embolus, and S agalactiae.

Differential Diagnoses

 

Workup

Laboratory Studies

Blood and urine studies

Obtain a complete blood count (CBC). In the era of pneumococcal occult bacteremia, the likelihood of a positive blood culture result for pneumococci increased as the white blood cell (WBC) count increased. However, an elevated WBC count is no longer predictive of bacteremia when widespread pneumococcal conjugate vaccination is practiced.

Elevated band and other immature counts, toxic granulation, toxic vacuolation, Dohle bodies, and, particularly, low WBC counts are findings of particular concern (although they are quite nonspecific). Hemoconcentration may be present and can be helpful as a gauge of hydration status.

Measures of clotting function and coagulation parameters may be helpful. Disseminated intravascular coagulopathy (DIC), hypercoagulability, and other clotting dysfunctions may be seen in infants and children with systemic inflammatory response syndrome (SIRS).

Electrolyte level tests, renal and liver function tests, and other chemistry tests may have a role. Serum transaminase levels and other measures of liver dysfunction are often elevated in situations such as disseminated viral and anaerobic infections.

Etiology-specific serologies may be helpful, and urinalysis may have a role in clarifying the level of risk of urinary tract infection in infants and children. In addition, non–culture-based molecular modalities and other diagnostic methods are becoming increasingly important.[13]

The use of inflammatory markers and acute-phase reactants (eg, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], interleukin [IL]–1b, IL-6, IL-8, tumor necrosis factor–alpha, leukotriene B4, procalcitonin [PCT]) in the diagnosis and management of pediatric sepsis is evolving.[14, 15]

A study aimed to determine biomarker phenotypes that differentiate children with sepsis who require intensive care from those who do not. The study concluded that in children ages 2-17 years, combining metabolomic and inflammatory protein mediator profiling early after presentation may differentiate children with sepsis requiring care in a pediatric intensive care unit from children with or without sepsis safely cared for outside a pediatric intensive care unit. The authors also add that these results may aid in making triage decisions, particularly in an ED without pediatric expertise.[16]

In a prospective study of 19 newborns with late-onset sepsis and 21 uninfected control subjects, presepsin (P-SEP), a trunked portion of soluble CD14, which is a diagnostic and prognostic marker of sepsis in adults, was found to be an accurate biomarker of late-onset sepsis in premature infants, as well as potentially useful in monitoring treatment response.[17, 18]

Median P-SEP values were higher in newborns with sepsis at study enrollment and over the course of the study (1295 ng/L in the late-onset sepsis group vs 562 ng/L in the control group).[18] The receiver operating characteristic curve of P-SEP values at baseline had an area under the curve of 0.972, suggesting that P-SEP is an accurate diagnostic test for late-onset sepsis. The best cutoff value was 885 ng/L, with 94% sensitivity, 100% specificity, a negative likelihood ratio of 0.05, and a positive likelihood ratio of infinity.

Culture of blood, urine, and CSF

Whenever possible, obtain a blood culture before starting antibiotics. The yield is clearly correlated to the volume of blood sampled. Culture of bone marrow may have a higher yield for certain pathogens (eg, Histoplasma capsulatum).

Obtain a urine culture unless, in an older child, a genitourinary source of infection can be reliably excluded.

Obtain a cerebrospinal fluid (CSF) culture before initiating antibiotic therapy if the child’s condition is stable but clinical evaluation cannot exclude central nervous system (CNS) infection. Many pathogens can be recovered from CSF cultures several hours after a dose of antibiotics; thus, a child whose condition is unstable should receive antibiotics and be stabilized before lumbar puncture. Once the child’s condition is stable, identification of CSF pleocytosis is helpful, even if prolonged antibiotic therapy may have rendered culture results negative.

Culture of skin lesions, eye drainage, throat, vagina, rectum, cellulitic areas, nasal secretions, sputum, tracheal aspirates, and stool may be helpful in the appropriate clinical context.

Viral cultures may have a role in certain contexts, although many viral infections are diagnosed via molecular methods or serologically.

Other Studies and Procedures

Obtain a chest radiograph; pneumonia, pleural effusions, adenopathy, and other conditions may be revealed. Pursue other imaging modalities (eg, computed tomography [CT] or magnetic resonance imaging [MRI]) as the clinical context dictates. Echocardiography may be indicated in certain clinical settings.

Lumbar puncture may be indicated for CSF evaluation. Sampling of other fluids or biopsy of various organs or tissues may be necessary.

Other Tests

A study by Balamuth et al reported that an electronic sepsis alert to detect severe sepsis had 86.2% sensitivity (95% confidence interval [CI] 82.0% to 89.5%), 99.1% specificity (95% CI 99.0% to 99.2%), 25.4% positive predictive value (95% CI 22.8% to 28.0%), and 100% negative predictive value (95% CI 99.9% to 100%). A positive electronic sepsis alert was defined as elevated pulse rate or hypotension, concern for infection, and either abnormal capillary refill, abnormal mental status, or high-risk condition.[19]

Scott et al reported that lactate levels greater than 36 mg/dL were associated with mortality in children suspected of sepsis but the test had low sensitivity at 20%.[20]

 

Treatment

Approach Considerations

In treating pediatric sepsis, the initial focus should be on stabilization and correction of metabolic, circulatory, and respiratory derangements.[21] Cardiac output may have to be assessed repeatedly. It may be necessary to use multiple peripheral intravenous (IV), intraosseous, or central venous access devices. Frequent sampling of arterial blood is often required. Ongoing reevaluation is essential.

Antimicrobial agents should be given as soon as possible, according to the most likely pathogens. Surgical intervention (eg, draining an abscess, venous access, appendectomy) is occasionally required. Adjunctive therapies may be needed.

Generally, pediatric patients with sepsis should not be fed until gut hypoxia and hypoperfusion have been excluded. Once feeding can safely begin, immune-enhancing nutrition may reduce mortality. Some studies suggest that arginine, omega-3 fatty acids, and messenger RNA (mRNA) may be beneficial.

Initial Resuscitation and Stabilization

Rapid restoration of circulation, tissue perfusion, and oxygen delivery via aggressive volume replacement therapy is the single most important intervention in the acute management of septic shock.[22] Accordingly, fluid resuscitation with crystalloid or colloid parenteral solutions should be initiated immediately.[23] If circulatory derangements do not resolve with 3 IV fluid boluses of 20 mL/kg, vasopressor support should follow.

One study analyzed the outcome of African children who received bolus fluid resuscitation for shock and life-threatening infections and suggested that this practice could be associated with increased mortality in some settings.[11] The study subjects received boluses of 20-40 mL of 5% albumin solution or 0.9% saline solution in quantities of 20-40 mL/kg body weight; the control group received no bolus.

In this study, the 48-hour mortalities were 10.6% (111 of 1050 children) in the albumin-bolus group, 10.5% (110 of 1047 children) in the saline-bolus group, and 7.3% (76 of 1044 children) in the control group; the 4-week mortalities were 12.2%, 12.0%, and 8.7%, respectively.[11] The results suggest that fluid bolus treatment significantly increases the 48-hour mortality in children with severe febrile illness and impaired perfusion who reside in resource-limited settings.

Ventilatory support with supplemental oxygen therapy, aggressive fluid resuscitation and support of cardiac output, maintenance of adequate hemoglobin concentration, correction of physiologic and metabolic derangements, and monitoring of urine output and other end-organ functioning are often vital.

Patients with pediatric sepsis whose circulatory, metabolic, and respiratory derangements are not rapidly corrected should be cared for in an intensive care setting. Transfer should be arranged if the appropriate specialists and intensive care settings are not locally available.

Empiric Antimicrobial Therapy

Empiric antimicrobial therapy for pediatric sepsis of unclear etiology should be based on the pathogens most frequently encountered in each age group. For example, newborns and infants in the first 6-8 weeks of life should generally receive ampicillin and gentamicin, ampicillin and cefotaxime, or ampicillin and ceftriaxone. Older infants and children most often receive a third-generation cephalosporin, vancomycin, plus clindamycin.

Patients who have indwelling catheters or those who are at high risk for methicillin-resistant S aureus (MRSA) infection may require vancomycin as well. Patients who have fever and neutropenia should receive broad-spectrum coverage with an emphasis on gram-negative rods.

Antimicrobial agents that are used less frequently include caspofungin, micafungin, fluconazole, foscarnet, ganciclovir, valganciclovir, cidofovir, liposomal amphotericin B, itraconazole, and voriconazole. Posaconazole is also used and is approved by the US Food and Drug Administration (FDA) for use in children aged 13 years or older and for prophylaxis of invasive Aspergillus and Candida infections in adult patients who are at high risk as a consequence of severe immunosuppression.

Risk stratification

In a retrospective case-control study of 350 newborns with early-onset sepsis (EOS) and 1063 matched controls, Escobar et al found that the use of a risk-stratification system incorporating maternal risk and infants' clinical condition in the first hours of birth could reduce the use of antibiotics for as many as a quarter million newborns annually.[24, 25] The maternal risk factors considered were as follows:

  • Highest maternal antepartum temperature

  • Gestational age

  • Length of time that amniotic membranes were ruptured

  • Carriage of group B Streptococcus

  • Type of intrapartum antibiotic therapy administered

Application of the risk-stratification scheme to the study sample indicated that 4.1% of all live births (60.8% of the EOS cases) should have received systemic antibiotics, pending negative culture results; 11.1% of all live births (23.4% of the EOS cases) warranted more rigorous observation and evaluation with a blood culture; and 84.8% of live births (15.7% of the EOS cases) were low-risk and required only continued observation.[25]

A study reported that antimicrobial utilization and prescription practices in a neonatal intensive care unit decreased the use of ampicillin significantly by 22.5 days of antibiotic therapy per 1,000 patient days. The study also reported an average reduction of 2.65 late-onset sepsis evaluations per year per provider.[26]

A study by Evans et al reported that 1-hour completion of a mandated New York State pediatric sepsis treatment bundle that includes blood cultures, broad-spectrum antibiotics, and a 20-mL/kg intravenous fluid bolus was associated with lower risk-adjusted in-hospital mortality.[27]

Adjunctive Therapies

Adjunctive therapies such as inhaled nitric oxide, extracorporeal membrane oxygenation,[28] corticosteroids (eg, dexamethasone or methylprednisolone), pentoxifylline, and various other mediators of the inflammatory response may be needed. For suspected toxic shock syndrome due to S aureus or GABHS, IVIG is recommended.

In cases of refractory shock, additional adjunctive therapies (eg, terlipressin) have shown potential benefit in initial trials.[29] Further clinical studies are required, but the risks of the drug may be outweighed by its benefits in certain circumstances.

Bovine lactoferrin supplementation (alone or in combination with the probiotic Lactobacillus rhamnosus GG) for very low birth weight neonates reduces the incidence of a first episode of late-onset sepsis.[30, 31, 32] Similarly, pentoxifylline adjunctive therapy may reduce mortality from late-onset sepsis.[33] Studies of other such interventions are under way.

A randomized, double-blind study by Panigrahi et al on the use of an oral synbiotic (Lactobacillus plantarum plus fructooligosaccharide) in 4,556 rural Indian newborns reported a 40% reduction in the combined outcome of death and sepsis in the synbiotic combination group compared to the placebo (5.4% vs 9%, risk ratio, 0.60; 95% confidence interval, 0.48 - 0.74).[34]

Withdrawal of drotrecogin alfa

Drotrecogin alfa, a recombinant human-activated protein C indicated for reduction of mortality in adults with severe sepsis, was approved by the FDA for treatment of sepsis in adults, but enrollment in its phase III clinical trial for use in pediatric patients was halted in March 2005 after it was determined that the drug was unlikely to demonstrate improvement over placebo.

The drug was withdrawn from the worldwide market on October 25, 2011, after the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS)-SHOCK clinical trial failed to demonstrate a statistically significant reduction in 28-day all-cause mortality in patients with severe sepsis and septic shock. Trial results documented a 28-day all-cause mortality of 26.4% in patients treated with activated drotrecogin alfa, compared with 24.2% in the placebo group.[35, 36, 37, 38]

 

Medication

Medication Summary

The goals of pharmacotherapy are to eradicate the infection, reduce morbidity, and prevent complications.

Antibiotics, Other

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Ampicillin and sulbactam (Unasyn)

Ampicillin and sulbactam is a drug combination of a beta-lactamase inhibitor with ampicillin. It interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms. It is an alternative to amoxicillin when the patient is unable to take medication orally. It covers skin, enteric flora, and anaerobes and is not ideal for nosocomial pathogens.

Vancomycin

Vancomycin provides gram-positive coverage and good hospital-acquired MRSA coverage. It is now used more frequently because of the high incidence of MRSA. Vancomycin should be given to all septic patients with indwelling catheters or devices. It is advisable for skin and soft-tissue infections.

Ceftriaxone (Rocephin)

Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity. It has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Ceftriaxone is used for increasing prevalence of penicillinase-producing microorganisms. It inhibits bacterial cell wall synthesis by binding to 1 or more penicillin-binding proteins. Cell wall autolytic enzymes lyse bacteria, while cell wall assembly is arrested.

Gentamicin

Gentamicin is an aminoglycoside that is bactericidal for susceptible gram-negative organisms, such as Escherichia coli and Pseudomonas, Proteus, and Serratia species. It is effective in combination with ampicillin for Group B Streptococcus and Enterococcus. Recent publications recommend gentamicin (in combination with ampicillin) as first-line therapy for suspected sepsis in the newborn.

Cefotaxime (Claforan)

Cefotaxime is a third-generation cephalosporin with excellent in vitro activity against Group B Streptococcus and E coli and other gram-negative enteric bacilli. It attains good concentrations in serum and cerebrospinal fluid (CSF). Concern exists that emergence of drug-resistant gram-negative bacteria may occur at a more rapid rate with cefotaxime than with traditional penicillin and aminoglycoside coverage.

Cefotaxime is ineffective against Listeria and enterococci; use it in combination with ampicillin. Cefotaxime is not considered a first-line agent for neonatal sepsis because of its association with increased mortality.

Antifungals, Systemic

Class Summary

Antifungal agents preferentially bind to the primary fungal cell membrane sterol (ergosterol). Amphotericin B increases the permeability of the cell membrane, which, in turn, causes intracellular components to leak. Azoles interfere with an enzyme in the sterol biosynthesis pathway production of cell membrane ergosterol. Echinocandins block fungal cell wall synthesis by inhibiting 1,3-beta glucan synthase.

Caspofungin (Cancidas)

Caspofungin is the first of a new class of antifungal drugs (glucan synthesis inhibitors). It inhibits the synthesis of beta-(1,3)-D-glucan, an essential component of the fungal cell wall. It is used to treat refractory invasive aspergillosis.

Posaconazole (Noxafil)

Posaconazole is a triazole antifungal agent that possesses structural similarities to itraconazole. It blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption.

Posaconazole is available as an oral suspension (200 mg/5 mL). It is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.

Voriconazole (Vfend)

Voriconazole is a triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis. Case reports describe efficacy in disseminated disease or meningitis refractory to first-line agents.

Itraconazole (Sporanox)

A triazole analogue of ketoconazole, itraconazole is preferred to its parent compound because of enhanced safety and efficacy. It is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP450-dependent synthesis of ergosterol, a vital component of fungal cell membranes. It is used for mild-to-moderate infections that warrant treatment. Despite poor CSF penetration, it is successfully used to treat coccidioidal meningitis.

An intravenous form is available, but long-term usage is not established. Ketoconazole is also available in an oral solution, which provides better, more consistent absorption than the capsule. Take capsules with full meal to improve absorption, but take oral solution on empty stomach, if possible.

Fluconazole (Diflucan)

Fluconazole is a synthetic triazole antifungal (broad-spectrum bistriazole) that selectively inhibits fungal CYP450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol. It is used to treat mild-to-moderate infections or severe or life-threatening infections in patients intolerant of amphotericin B. Metabolic clearance is prolonged in patients with renal dysfunction.

Amphotericin B lipid complex (ABLC, Abelcet)

This agent is amphotericin B in phospholipid complexed form; it is a polyene antifungal with poor oral availability. Amphotericin B is produced by a strain of Streptomyces nodosus; it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.

Amphotericin B, liposomal (AmBisome)

This is a lipid preparation consisting of amphotericin B within unilamellar liposomes. It delivers higher concentrations of the drug, with a theoretical increase in therapeutic potential and decreased nephrotoxicity.

Amphotericin B is a polyene antifungal with poor oral availability. It is produced by a strain of Streptomyces nodosus, and it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.

Amphotericin B colloidal dispersion (Amphotec)

Amphotericin B colloidal dispersion is a lipid preparation consisting of amphotericin B attached to lipid discoid structures. Amphotericin B is a polyene antibiotic with poor oral availability. It is produced by a strain of Streptomyces nodosus, and it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.

Antivirals, Other

Class Summary

These agents inhibit viral replication.

Ganciclovir (Cytovene)

Ganciclovir is a synthetic guanine derivative that is active against cytomegalovirus (CMV). It is an acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpesviruses in vitro and in vivo. Levels of ganciclovir triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly because of preferential phosphorylation of ganciclovir in virus-infected cells. In patients with progression of CMV retinitis while receiving maintenance treatment with either form, the induction regimen should be re-administered.

Foscarnet

Foscarnet is an organic analog of inorganic pyrophosphate that inhibits replication of known herpesviruses, including CMV, HSV-1, and HSV-2. It inhibits viral replication at pyrophosphate-binding sites on virus-specific DNA polymerases. Poor clinical response or persistent viral excretion during therapy may be due to viral resistance. Patients who can tolerate foscarnet well may benefit from early maintenance treatment at 120 mg/kg/d. Individualize dosing to renal function.

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These drugs modify the body's immune response to diverse stimuli.

Methylprednisolone (A-Methapred, Solu-Medrol, Depo-Medrol)

Methylprednisolone is available in intravenous/intramuscular and oral forms. Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity.

Dexamethasone (Baycadron)

This agent is used in various inflammatory diseases. Dexamethasone may decrease inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Hemorheologic Agents

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These drugs modify the body's immune response to diverse stimuli.

Pentoxifylline (Trental)

Pentoxifylline may alter the rheology of red blood cells, consequently reducing blood viscosity. It increases fibrinolysis and red blood cell deformity and inhibits platelet aggregation.

Immune Globulins

Class Summary

Intravenous immunoglobulin is the usual choice. It is derived from human plasma and is composed of all 4 immunoglobulin G (IgG) subclasses.

Intravenous immunoglobulin (IVIG; Carimune Gammagard S/D, Gamunex-C, Octagam)

Intravenous immunoglobulin (IVIG) uses anti-idiotypic antibodies to neutralize circulating myelin antibodies. IVIG down-regulates proinflammatory cytokines, including interferon-gamma. It blocks Fc receptors on macrophages, suppresses inducer T cells and B cells, and augments suppressor T cells. In addition, IVIG blocks the complement cascade, promotes remyelination, and may increase cerebrospinal fluid (CSF) immunoglobulin G (10%).