Fever in the Infant and Toddler 

Updated: Jan 08, 2019
Author: Jane M Gould, MD, FAAP; Chief Editor: Russell W Steele, MD 

Overview

Background

Fever in the infant and toddler is one of the most common problems and greatest challenges faced by those caring for them. This article addresses the most common etiologies of fever in these age groups and the appropriate clinical prediction rules for identifying infants and toddlers at lowest risk for serious bacterial infections. (See also Fever Without a Focus and Emergent Management of Pediatric Patients With Fever.)

Neonates

Neonates (≤28 d) with fever may have few clues on history and physical examination to guide therapy; however, 3% have a serious bacterial infection. Obtaining the pertinent medical history from the mother regarding the pregnancy, delivery, and early neonatal life of the febrile neonate is essential. Typically, infections that occur in the first 7 days of life are secondary to vertical transmission, and those infections occurring after the first 7 days are usually community acquired or hospital acquired.

Definitive identification of a serious bacterial infection requires laboratory investigation; a full sepsis evaluation; and a positive result in blood culture, cerebrospinal fluid (CSF), and/or urine. Bacterial meningitis is more common in the first month of life than at any other time. An estimated 5-10% of neonates with early onset group B streptococcal (GBS) sepsis have concurrent meningitis.[1]

Young Infants

The general approach to fever in a febrile infant aged 28-60 days includes maintaining a high index of suspicion, because these patients often lack clues on physical examination. The prevalence of a serious bacterial infection in an infant younger than 3 months is approximately 6-10%, most often urinary tract infections (UTIs). Interestingly, infants aged 3 months or younger with a confirmed viral infection are at lower risk for a serious bacterial infection when compared with those in whom a viral infection is not identified[2] ; although a UTI is still a significant concurrent infection in infants with bronchiolitis.

Children Aged 3 Months to 3 Years

According to guidelines from the Agency of Health Care Policy and Research published in 2012, in infants younger than 3 months with rectal temperatures 38o C or higher, the prevalence of serious bacterial infection reported in studies conducted in North American emergency departments or primary care practices ranged from 4.1-25.1%.[3]

Historically, children aged 3 months to 3 years with rectal temperatures of 38.5o C or higher had a risk of 2-4% for occult bacteremia.[4] The leading cause of bloodstream infection was Streptococcus pneumoniae, followed by Haemophilus influenzae type b. With the introduction of effective vaccines for these pathogens, the incidence and epidemiology of childhood bacteremia in the immunologically normal host has changed considerably; only 1 in 200 (0.5%) febrile children are now found to be bacteremic.[5, 6]

The incidence of occult bacteremia in this population now ranges from 0.25-0.7%; moreover, 2 of every 3 blood isolates from these children represent an artifact (contamination) and not a true pathogen.[5, 7, 8] S pneumoniae and Escherichia coli are the most common pathogens, accounting for two thirds of cases. In infants with S pneumoniae, many isolates are strains not covered by the currently available heptavalent conjugate vaccine.

Children with pneumococcal bacteremia may present with acute otitis media, pneumonia, symptoms of sinusitis, meningitis, febrile seizures, cellulitis (including orbital or facial cellulitis), or nonspecific febrile illnesses. E coli bacteremia is most common in children younger than 1 year and is usually associated with urinary tract infection (UTI). Staphylococcus aureus accounts for 15% of bloodstream infections and may be associated with skin, soft tissues, or musculoskeletal infections. Salmonella species, Neisseria meningitides, and S pyogenes account for most of the remaining infections.

As with most patients, the approach to the febrile child aged 3 months to 3 years consists of a targeted medical history, a complete physical examination, and the judicious use of the laboratory tests.

 

Presentation

History and Examination of Neonates

A thorough history is essential for all neonates with fever. Associated symptoms may be system specific (eg, diarrhea, cough) or nonspecific (eg, poor feeding, irritability, lethargy). Seizures have been reported in 20-50% of neonates with meningitis. Exposures to sick contacts in the household or daycare should be ascertained, as well as a recent history of a previous illness, immunization, or antibiotic use while in the birth hospital or since discharge.

Prenatal history

A review of the prenatal history, including maternal history of sexually transmitted infections (human immunodeficiency virus [HIV], hepatitis B and hepatitis C, syphilis, gonorrhea, chlamydia, herpes simplex), maternal group B Streptococcus (GBS) status and prophylaxis, mode of delivery, prolonged rupture of membranes, and history of maternal fever should be noted.

A birth weight of less than 2500 g, rupture of membranes before the onset of labor, septic or traumatic delivery, fetal hypoxia, maternal peripartum infection, and galactosemia are all risk factors for a serious bacterial infection in the neonate. Gestational age should be determined, because premature infants are at increased risk for serious bacterial infections. See the Gestational Age from Estimated Date of Delivery (EDD) calculator.

Nursery course

The neonate’s nursery course should be noted, including the age at which the patient went home from the nursery, whether or not a male neonate has been circumcised, and the use of peripartum or antepartum antibiotics. Any underlying diseases or conditions, as well as the use of medications that may increase the risk of infection, should be ascertained. Diet (ie, quantity and description of milk consumed; breast milk vs formula; and, if pertinent, the method the caregiver uses for preparing and storing the formula) and sleep histories should be obtained, because decreased oral intake or an acute change in sleep patterns may be clues to an invasive infection.

Household contacts

Any ill contacts in the household should also be noted. Exposure to any animals inside the home of the caregiver or outside the home (eg, in daycare facility) should be determined. The vaccination status of household members should be determined. A history of maternal fetal loss or death due to an infectious disease in a previous infant increases the suspicion of congenital anomalies and primary immunodeficiencies.

Identifying who is in the neonate’s household, who is the primary caregiver, contact with recent immigrants, and exposure to homelessness and poverty all impact the care the neonate receives.

Review of systems and physical examination

A thorough review of systems must be obtained to identify any other symptoms associated with the fever. A complete physical examination including vital signs (temperature 38°C = 100.4°F), pulse oximetry, and growth parameters with percentiles is necessary. General appearance should be noted for activity level, color, tone, and irritability. Signs of localized infection should be identified via a thorough examination of the skin, mucous membrane, ear, and extremities.

The presence of an umbilical stump after age 4 weeks should be noted, because it is a potential clue to leukocyte adhesion deficiency, and the lack of a circumcision in males should be noted, because it increases the risk for a urinary tract infection (UTI). In addition to fever, the most common clinical features of a UTI in a neonate include failure to thrive, jaundice (typically secondary to conjugated hyperbilirubinemia from cholestasis), and vomiting. Irritability, inconsolability, poor perfusion, poor tone, decreased activity, and lethargy can be signs of a serious infection in this age group.

Most neonates with bacterial meningitis have a full fontanelle with normal neck flexion at the time of presentation. Remember that neonates younger than 28 days with significant bacterial infections can appear to be at low risk when analyzing history, physical examination findings, and laboratory values; thus, a high index of suspicion must be maintained.

History and Examination of Young Infants

As is the case in neonates, a febrile infant aged 28-60 days may have symptoms that are nonspecific (eg, poor feeding, irritability, lethargy) or specific symptoms (eg, diarrhea, cough). History of exposure to sick contacts in the household or daycare should be obtained, as well as a recent history of a previous illness, immunization, and recent antibiotic use.

Past medical history and household contacts

The past medical history needed is essentially the same as in neonates. A prenatal, perinatal, and neonatal history should be obtained. Underlying diseases or conditions and the use of medications that may increase the risk of infection should be ascertained. In addition, as with neonates, diet and sleep histories should be obtained, because decreased oral intake or an acute change in sleep patterns may be clues to an invasive infection.

Exposure to any animals inside the home of the caregiver or outside the home such as in the daycare facility should be determined. A travel history of all household contacts should be obtained. The vaccination status of household members should also be determined.

As with neonates: (1) a family history of a previous death in a young infant from an infectious disease increases the suspicion of congenital anomalies and primary immunodeficiencies, and (2) identifying who lives in the household, who is the primary caregiver, exposure to any recent immigrants, and exposure to homelessness and poverty helps establish risk for infection and how to manage the patient.

Review of systems and physical examination

A thorough review of systems must be obtained to identify any other symptoms associated with the fever. A complete physical examination including vital signs (temperature 38°C = 100.4°F), pulse oximetry, and growth parameters with percentiles is necessary. A heart rate of more than 160 beats per minute in infants and a respiratory rate of more than 60 beats per minute are associated with an increased mortality risk and often signal the development of septic shock.

As with a neonate, general appearance should be noted for activity level, color, tone, and irritability. Irritability, inconsolability, poor perfusion, poor tone, decreased activity, and lethargy can be signs of a serious infection. Likewise, signs of localized infection should be identified via a thorough examination of the skin, mucous membranes, ear, and extremities. Lack of a circumcision in males should be noted.

Unfortunately, bacterial meningitis is often associated with minimal signs and symptoms in this age group, and a bulging fontanelle is a late sign. Nuchal rigidity is only present in 27% of infants younger than 6 months.

History and Examination of Children Aged 3 Months to 3 Years

The medical history should focus on factors that would predispose the infant or toddler to serious bacterial infection.

History of present illness

Documentation of the child’s temperature and how it was measured is essential. A rectal temperature of more than 38.5o C (101o F) is abnormal in this age group. In addition to identifying when the fever started and how long it has lasted, a detailed search should be made for other symptoms, including but not limited to diarrhea, vomiting, rhinorrhea, cough, rash, and changes in weight or feeding habits.

Past medical history

Every effort should be made to identify previous infectious episodes and risk factors for serious bacterial infections. Underlying chronic diseases, previous surgery, history of urinary tract infections (UTIs), and incomplete immunization to Streptococcus pneumoniae or Haemophilus influenzae type b must be specifically delineated. In children younger than 9 months, neonatal and perinatal history is also important.

Family history

Episodes of recurrent infections among siblings and first cousins or a history of maternal fetal loss raises suspicion of primary immunodeficiencies. Parental human immunodeficiency (HIV) status is essential information. A history of chronic infections (eg, hepatitis B, hepatitis C, tuberculosis) in the immediate or extended family is also important to obtain. The presence of acute illness in the family, such as croup or respiratory infection, is also important information.

Social history and household contacts

Animal, insect, and sylvan exposure; exposure to contaminated potable water and sewage; recent travel (particularly international travel); and attendance at daycare provide epidemiologic and environmental clues to the etiology of fever. Exposure to sick individuals outside of the household is also critical information.

Review of systems and physical examination

A detailed review of systems helps to identify other symptoms associated with fever. Important associations include rash, conjunctivitis, ear pain or drainage, lymphadenopathy, respiratory symptoms, changes in appetite, weight loss, diarrhea, vomiting, changes in frequency of voiding, pain with voiding, failure to bear weight, pain on passive motion of an extremity, and overt neurologic symptoms.

A careful and thorough physical examination is essential in the evaluation of the febrile child. Vital signs, including length and weight with percentiles, should be part of the evaluation. The child’s general state of nutrition, level of activity, and level of arousal should be noted.

Physical examination findings that suggest serious bacterial infections in febrile children (aged 3-36 mo) include ill appearance, fever, vomiting, tachypnea with retractions, and delayed capillary refill. These findings are associated with bacterial infection in more than 39.5% of febrile children aged 24-36 months and in more than 39% of children aged 3-24 months.

Close examination of the skin, lymphatics, eyes, ears, nose, and throat is necessary, because many febrile infants have viral infections with associated rashes or associated respiratory symptoms. Inspection and auscultation of the chest should be included in all evaluations. The abdomen should be inspected for signs of distention. Auscultation may reveal signs of ileus or hyperactivity. The extremities should be evaluated for capillary refill; range of motion, signs of infection, and local tenderness should be evaluated. Neurologic and developmental examinations appropriate for age should be performed.

 

DDx

Diagnostic Considerations

Clinicians must maintain a high index of suspicion for serious bacterial and/or viral infections in febrile infants and toddlers. The diagnostic approach consists of a targeted medical history, a complete physical examination, and the judicious use of the laboratory tests.

Differential Diagnoses

 

Workup

Approach Considerations

Diagnostic studies in infants and toddlers with fever are based on their age groups. Febrile neonates (< 28d) and young infants (28-60d) may require a full sepsis workup. Young infants are generally assessed for urinary tract and respiratory infections as well as their risk for serious bacterial infections. Febrile children aged 3 months to 3 years are evaluated based on epidemiologic and focal findings revealed during the history taking and physical examination as well as whether or not these children are at low risk for serious bacterial infections.

Diagnostic Studies in Neonates

A full sepsis evaluation is often recommended in febrile neonates and young infants. This includes a complete blood cell (CBC) count, blood culture, urinalysis, urine culture, and cerebrospinal fluid (CSF) analysis and culture. These patients should be hospitalized with intravenous antibiotics pending results of these cultures.

A study by Cruz et al analyzed the accuracy of individual complete blood cell count parameters to identify febrile infants with invasive bacterial infections. The study included 4313 infants, 1340 (31%) were aged 0 to 28 days, of which ninety-seven (2.2%) had an invasive bacterial infection. The study reported low sensitivities for common CBC parameter thresholds. WBC less than 5000/µL, was detected 10% of the time, white blood cell count ≥15 000/µL, 27%; absolute neutrophil count ≥10 000/µL, 18%; and platelets < 100 x103 /µL, 7%.[9]

CSF studies

A lumbar puncture for CSF examination is recommended in all neonates younger than 28 days if empiric antibiotics are to be given or if the neonate had a seizure. CSF should be assessed for WBC count and differential, glucose level, protein level, Gram stain, and routine culture. CSF should be assayed for herpes simplex virus (HSV) using polymerase chain reaction (PCR) in all neonates in the first 28 days of life who appear ill, who have mucocutaneous lesions, or who have had a seizure.

Enterovirus PCR analysis should be performed on the CSF during the summer enteroviral season.

Urine and stool studies

Because the incidence of urinary tract infections (UTIs) is high in this age group, a urine specimen should be obtained for urinalysis and urine culture. A negative urine dipstick or urinalysis finding alone does not exclude the diagnosis of a UTI; only a negative urine culture finding can exclude this diagnosis.[10] A urine culture should be obtained via either a suprapubic aspiration or urethral catheterization, because bag urine specimens are frequently contaminated.

A study by Tzimenatos et al that included an analysis of data from 4147 febrile infants ≤60 days old reported that for the 289 infants with a UTI and colony counts ≥50 000 CFUs/mL, a positive urinalysis regardless of bacteremia showed sensitivities of 0.94; 1.00 with bacteremia; and 0.94 without bacteremia. Specificity in all groups was 0.91.[26]

A stool culture is recommended when blood, mucus, or both are present in the stool; when diarrhea is present; and when more than 5 white blood cells (WBCs) per high-power field (HPF) are noted on methylene blue stain of fresh stool.

Pulmonary studies

A chest radiograph should be considered for neonates with signs of respiratory illness such as cough, coryza, tachypnea, rales, rhonchi, retractions, grunting, nasal flaring, or wheezing. During respiratory viral season, an attempt should be made to identify a respiratory viral etiology using direct fluorescent antigen (DFA) detection or PCR and viral culture on nasal wash specimens.

Diagnostic Studies in Young Infants

In infants older than 28 days, low risk criteria are well defined. The reference range white blood cell (WBC) count is 5,000-15,000 cells/μL. The band count should be less than 1500 cells/μL. However, the WBC count alone has poor sensitivity and specificity for identifying young infants with bacteremia and meningitis; thus, the decision to perform a sepsis workup should not be based on the WBC count alone.

Urine and stool studies

Because the incidence of urinary tract infections (UTIs) is still high in this age group, obtain a urine specimen for urinalysis and urine culture. In one study, only 20% of febrile infants with the diagnosis of pyelonephritis had pyuria. A urine culture should be obtained by either a suprapubic aspiration or urethral catheterization, because bag urine specimens are frequently contaminated. 

A stool culture is recommended when blood, mucus, or both are present in the stool, when diarrhea is present, and when more than 5 WBCs per high-power field (HPF) are noted on methylene blue stain of fresh stool.

Pulmonary studies

Chest radiography should be considered for infants with signs of respiratory illness, such as cough, coryza, tachypnea, rales, rhonchi, retractions, grunting, nasal flaring, or wheezing. During respiratory viral season, an attempt should be made to identify a respiratory viral etiology using direct fluorescent antigen (DFA) detection or polymerase chain reaction (PCR) and viral culture on nasal wash specimens.

Criteria for low risk of occult bacteremia

Although some experts consider a lumbar puncture optional in well-appearing infants with low-grade fever who are older than 28 days, a diagnosis of meningitis carries a significant risk of morbidity and mortality, and acceptable risk must be determined for each individual patient.

Various criteria have been developed in an attempt to identify the infant older than 28 days at low risk for a serious bacterial infection. The incidence of a serious bacterial infection in infants categorized as low risk after a full evaluation is small (0.5% in studies that included a lumbar puncture and 1.1% in studies without a lumbar puncture).

These studies have led to the development of the Rochester, Boston, and Philadelphia protocols, all of which were conducted in urban emergency departments. The Rochester and Boston criteria exclude patients with ear infections from low-risk groups, and the Philadelphia criteria considers low-risk infants those with an "unremarkable physical examination."

However, subsequent studies have shown that, when these criteria are applied to the neonatal population (age, 1-28 d), an increased number of infants with serious bacterial illnesses are misidentified as low risk when compared with infants aged 1-3 months. Neonates should be considered high risk and a complete sepsis evaluation should be performed. All febrile neonates should be hospitalized and should receive empiric antibiotic therapy.

The following criteria have not been universally adopted by community practitioners. The importance of reliable follow-up cannot be overstressed if the decision is made not to perform invasive studies in a febrile, well-appearing infant; no guidelines for the minimal evaluation of a febrile, well-appearing infant are recognized. If empiric antibiotics are given, a lumbar puncture should always be performed.

Rochester criteria

The Rochester criteria are used to assess febrile (temperature > 38°C) infants aged 28-60 days.[11] The risk for occult bacteremia in well-appearing febrile infants is 7-9%; if all Rochester criteria are present, the risk is less than 1%. Infants at high risk were hospitalized with empiric antibiotics, and infants at low risk were discharged with follow-up in 24 hours.[11]

The Rochester low-risk criteria for occult bacteremia include the following[11] :

  • Infant must appear generally well

  • Infant has been previously healthy: Born at term (≥ 37 weeks' gestation), no perinatal antimicrobial therapy, no treatment for unexplained hyperbilirubinemia, no previous antimicrobial therapy, no previous hospitalization, no chronic or underlying illness, not hospitalized longer than the mother

  • Infant has no evidence of skin, soft-tissue, bone, joint, or ear infection

  • Infant has the following laboratory values: WBC count of 5,000-15,000 cells/μL, absolute band count of 1,500 bands/μL or less, less than 10 WBCs/HPF on microscopic examination of the urine, less than 5 WBCs/HPF on microscopic examination of stool in an infant with diarrhea

Boston criteria

The Boston criteria are used to assess febrile (temperature > 38°C) infants aged 28-89 days.[12] Infants who met these criteria were managed as outpatients with 50 mg/kg ceftriaxone intramuscularly at the time of discharge. The scheduled follow-up visit was in 24 hours; 5.4% of patients had a serious bacterial infection at follow-up.

The Boston low-risk criteria for occult bacteremia are as follows[12] :

  • No immunizations or antimicrobials within the preceding 48 hours

  • No evidence of dehydration or ear, soft-tissue, or bone infection

  • Well appearing

  • Caretaker available by telephone

  • Infant has the following laboratory values: WBC count less than 20,000 cells/μL, CSF with WBC count less than 10 cells/μL,[13] urinalysis with less than 10 WBCs/HPF on microscopic examination, no infiltrate on chest radiograph (if one was obtained)

Philadelphia criteria

The Philadelphia criteria were used to assess febrile infants aged 29-60 days with fever (> 38.2°C). All high-risk patients were hospitalized and treated with empiric antibiotics. Low-risk patients were not treated with antibiotics, with follow-up in 24 hours. Sensitivity for identifying patients with a serious bacterial infection was 98%, specificity was 42%, positive predictive value was 14%, and the negative predictive value was 99.7%.

The Philadelphia low-risk criteria for occult bacteremia included the following:

  • Well appearing

  • WBC count of less than 15,000 cells/μL

  • Band-neutrophil ratio of less than 0.2

  • Urinalysis reveals less than 10 WBC/HPF on microscopic examination and a negative urine Gram stain result

  • CSF has less than 8 WBCs/μL and a negative CSF Gram stain finding

  • Chest radiograph does not have an infiltrate (if a radiograph was obtained)

  • Stool has no blood and few or no WBCs on the smear

Diagnostic Studies in Children Aged 3 Months to 3 Years

The laboratory evaluation of children aged 3 months to 3 years consists of 2 parts.

The first part is dictated by epidemiologic and focal findings uncovered by the history and physical examination. Children with severe cough and respiratory distress should undergo chest radiography as part of their evaluation; children with limp or evidence of focal infection should undergo appropriate imaging studies.

The second part of the evaluation is designed to identify patients at low risk for serious bacterial infections. Children who appear clinically ill, have a history of vomiting, have chest wall retractions with tachypnea, or have delayed capillary refill times are at increased risk for bacterial infection. Increasing fever also increases the risk of bacterial infection. Children aged 3-24 months with fever exceeding 39o C and children aged 24-36 months with fever exceeding 39.5o C have a higher risk of bacteremia than children with lower temperatures.[14]

Urine studies

Occult urinary tract infection (UTI) is the most common cause of unexplained fever and bacteremia in females and uncircumcised males in this age group; thus, all of such children should undergo a urine culture. This is the only routine laboratory study recommended by most experts. Circumcised males should have a urinalysis and if abnormal, culture of the urine.

Catheterized, unspun urine samples with more than 10 WBCs per high-power field (HPF) or bacteria found in any of 10 oil immersion fields of a Gram-stained sample is highly suggestive of infection. The presence of leukocyte esterase or nitrites by dipstick of unspun samples also suggests infection. Febrile children with suspicious urinalysis findings require cultures of both urine and blood. Urine cultures that yield more than 50,000 colony-forming units/mL are diagnostic of infection.[15]

Laboratory low-risk criteria for occult bacteremia

White blood cell (WBC) counts, absolute neutrophil counts (ANC) (see the Absolute Neutrophil Count calculator), serum C-reactive protein (CRP) concentration, and serum procalcitonin concentration are additional metrics that help to distinguish further children at low risk for serious bacterial infection.

Total WBC counts below 15,000 cells/μL, ANCs below 10,000 neutrophils/μL, CRP concentrations less than 40 mg/L, and serum procalcitonin levels less than 0.5 ng/mL identify children at low risk for serious bacterial infection.[6, 16, 17, 18]

Laboratory findings suggestive of serious bacterial infections include the following:

  • Urinalysis (unspun): More than 10 WBCs/HPF, bacteria in any of 10 HPFs, or positive leukocyte esterase and nitrite findings

  • WBC count: More than 15,000 cells/μL

  • ANC: More than 10,000 neutrophils/μL

  • CRP level: More than 40 mg/L

  • Procalcitonin level: More than 0.5 ng/mL

 

Treatment

Approach Considerations

The clinical management of infants and toddlers with fever is based on their age groups.

Neonates and young infants should be hospitalized with intravenous antibiotics pending results of laboratory tests and cultures.

For the most part, management should be individualized based on risk factors, clinical appearance, and clinical judgment. Ill-appearing children with poor capillary refill and children who have clinical signs and symptoms suggestive of meningitis need to be managed in hospital and perhaps in the critical care setting. Children with focal infections such as sinusitis and pneumonia need to be managed with appropriate antimicrobial therapy.

With the widespread use of pneumococcal vaccine in young children, the incidence of occult bacteremia in febrile children aged 3 months to 3 years has fallen from 4.6% to less than 1%.[5, 19] As such, the evaluation has become more extensive to prevent overtreatment. In the absence of focal findings, any child in the target age group who appears ill or has excessive fever, vomiting, or tachypnea with retractions should be evaluated further.

Parents and medical professionals who want to supplement physical measures with medication in order to maximize the time that children spend without fever should use ibuprofen first and weigh the use of paracetamol plus ibuprofen over 24 hours.[20]

Acetaminophen IV is approved by the FDA for use to treat fever for all aged children, including premature neonates, neonates, and infants.

Fever Management in Neonates and Young Infants

All febrile infants aged 28-60 days, after having a sepsis evaluation, should be hospitalized and empirically started on intravenous antibiotics pending culture results (see Workup). The antibiotic spectrum of coverage must include both community-acquired pathogens (eg, Streptococcus pneumoniae, Haemophilusinfluenzae, Moraxella catarrhalis, Neisseria meningitidis, late-onset group B Streptococcus [GBS], Staphylococcus aureus), perinatally acquired organisms (eg, early onset GBS, Escherichia coli, and other gram-negative organisms and Listeria monocytogenes), or hospital-acquired organisms in the neonate or infant who was recently hospitalized (eg, enteric gram-negative organisms, S aureus).

Empiric antibiotics

Ampicillin and gentamicin, or ampicillin and cefotaxime for the neonate, covers GBS, E coli, Listeria, and most S pneumoniae and N meningitides. For infants aged 1-2 months, recommended empiric coverage includes ampicillin, cefotaxime, and vancomycin to provide adequate coverage for community-acquired pathogens. All antibiotic dosages should be adequate to treat meningitis. For infants older than 2 months, vancomycin and cefotaxime are the empiric antibiotic choices. Vancomycin is especially important if the patient has evidence of soft-tissue infection, given the increasing prevalence of methicillin-resistant S aureus (MRSA), or a cerebrospinal fluid (CSF) profile consistent with bacterial meningitis to cover for antibiotic-resistant S pneumoniae.

Well-appearing and relatively well-appearing infants

Relatively well-appearing febrile infants younger than 28 days who are diagnosed with a viral respiratory illness should have a septic workup that includes cultures of blood, urine, and CSF. These infants should receive empiric antibacterial therapy in hospital until culture results are known.

Infants older than 28 days who look well and whose history, physical examination, and laboratory evaluation findings classify them as low risk can be treated as outpatients with ceftriaxone (50 mg/kg in a single intramuscular dose), as long as 24-hour follow-up can be ensured.

Infants older than 28 days who are diagnosed with bronchiolitis or influenza and are relatively well-appearing should undergo a limited laboratory evaluation, including complete blood cell (CBC) count with differential, blood culture, urinalysis, and urine culture. If the CBC count and urinalysis findings are benign, these patients can be initially managed without antibacterial therapy.

Ill-appearing neonates

Acyclovir (60 mg/kg/d divided every 8 h) is recommended for febrile neonates who appear ill, have mucocutaneous vesicles, experience seizures, or have a CSF pleocytosis.[13] In addition, viral cultures and direct fluorescent antigen detection should be performed on skin vesicles and conjunctival, nasopharyngeal, and rectal mucous membranes. CSF should be assessed for herpes simplex virus (HSV) and undergo polymerase chain reaction (PCR) and viral culture.

Fever Management in Children Aged 3 Months to 3 Years

Empiric antimicrobial therapy in non-toxic children aged 3 months to 3 years is not recommended. For those requiring hospitalization, antimicrobial therapy must provide coverage against the suspected pathogens and must achieve high and sustained serum concentrations.[21] In this setting, a single intramuscular (IM) dose of ceftriaxone has been shown to prevent sustained bacteremia in children whose initial blood culture has yielded Streptococcus pneumoniae.

In vitro, ceftriaxone is also effective against most strains of Escherichia coli, thus supporting the empiric use of this agent until bacterial culture results are known (see Workup). Children at risk for Staphylococcus aureus infections should receive clindamycin as well. Limited data are available regarding the use of alternative agents.

A retrospective study by Shaikh et al that included 482 children younger than 6 years old with a first or second UTI found that renal scarring was associated with a delay in the initiation of antimicrobial therapy. 35 children (7.2%) developed new renal scaring and the median duration of fever before initiation of antibiotic therapy in the group with renal scaring was 72 hours compared to 48 hours in children with no renal scarring.[22, 23]

 

Medication

Medication Summary

Antibiotics are used to treat occult bacterial infection. Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens for the patient's age range and in the clinical setting. Whenever feasible, select antibiotics based upon blood culture sensitivity.

Antimicrobials

Class Summary

Empiric antimicrobial therapy must provide coverage against the suspected pathogens for a given age group, and treatment must achieve high and sustained serum concentrations (see Treatment).

Ampicillin

Ampicillin is a beta-lactam antibiotic that is bactericidal for susceptible organisms, such as group B Streptococcus (GBS), Listeria, non–penicillinase-producing Staphylococcus, some strains of Haemophilus influenzae, and meningococci. Reports have indicated ampicillin (in combination with gentamicin) is the first-line therapy for suspected sepsis in the newborn.

Gentamicin

Gentamicin is an aminoglycoside that is bactericidal for susceptible gram-negative organisms, such as Escherichia coli and Pseudomonas, Proteus, and Serratia species. This agent is effective in combination with ampicillin for group B Streptococcus (GBS) and Enterococcus. Reports have indicated gentamicin (in combination with ampicillin) is the 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 (GBS) and Escherichia coli and other gram-negative enteric bacilli. This agent has good serum and cerebrospinal fluid (CSF) concentrations. However, concern exists about the emergence of drug-resistant gram-negative bacteria at a more rapid rate than with traditional penicillin and aminoglycoside coverage. In addition, cefotaxime is ineffective against Listeria and enterococci; use in combination with ampicillin. In more recent publications, this drug is not a first-line agent for neonatal sepsis because of its association with increased mortality.

Vancomycin (Vancocin)

Vancomycin is a bactericidal agent against most aerobic and anaerobic gram-positive cocci and bacilli; this is especially important in the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is recommended therapy when coagulase-negative staphylococcal sepsis is suspected. Therapy with rifampin and/or gentamicin may be required with endocarditis or cerebrospinal fluid (CSF) shunt infection by coagulase-negative Staphylococcus.

Ceftriaxone (Rocephin)

Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; and higher efficacy against resistant organisms. The bactericidal activity of this drug results from inhibiting cell wall synthesis by binding to one or more penicillin binding proteins; ceftriaxone exerts antimicrobial effect by interfering with the synthesis of peptidoglycan, a major structural component of bacterial cell wall. Bacteria eventually lyse due to the ongoing activity of cell wall autolytic enzymes while cell wall assembly is arrested.

Ceftriaxone is highly stable in the presence of beta-lactamases, both penicillinase and cephalosporinase, of gram-negative and gram-positive bacteria. Approximately 33-67% of the drug dose is excreted unchanged in urine, and the remainder is secreted in bile and ultimately in feces as microbiologically inactive compounds. Ceftriaxone reversibly binds to human plasma proteins, and binding has been reported to decrease from 95% bound at plasma concentrations < 25 mcg/mL to 85% bound at 300 mcg/mL.

Clindamycin (Cleocin)

Clindamycin is a semisynthetic antibiotic produced by the 7(S)-chloro-substitution of the 7(R)-hydroxyl group of the parent compound lincomycin. This agent inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Clindamycin widely distributes in the body without penetration of the central nervous system (CNS); this drug is protein bound and excreted by the liver and kidneys.

Clindamycin is used for treatment of serious skin and soft tissue staphylococcal infections. It is also effective against aerobic and anaerobic streptococci (except enterococci).

Antivirals

Class Summary

Nucleoside analogs are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit HSV polymerase with 30-50 times the potency of human alpha-DNA polymerase.

Acyclovir (Zovirax)

Acyclovir is a prodrug activated by phosphorylation by virus-specific thymidine kinase that inhibits viral replication. The Herpes virus thymidine kinase (TK), but not host cells TK, uses acyclovir as a purine nucleoside, converting it into acyclovir monophosphate, a nucleotide analogue. Guanylate kinase converts the monophosphate form into diphosphate and triphosphate analogues that inhibit viral DNA replication.

Acyclovir has affinity for viral TK and, once phosphorylated, causes DNA chain termination when acted on by DNA polymerase. This drug inhibits the activity of both Herpes simplex virus type 1 (HSV-1) and HSV-2. Patients experience less pain and faster resolution of cutaneous lesions when acyclovir is used within 48 hours from rash onset. This agent may prevent recurrent outbreaks. Early initiation of therapy is imperative.

Antipyretics

Class Summary

These agents act on the hypothalamus to produce antipyresis.

Ibuprofen (Advil, Motrin, PediaCare Children's Pain Reliever/Fever Reducer IB)

NSAID that is indicated for reduction of fever.

Acetaminophen (Tylenol, Little Fevers Children's Fever/Pain Reliever, Little Fevers Infant Fever/Pain Reliever)

Indicated for reduction of fever. Caution when administering as the various oral liquid products are available in a variety of dosage concentrations. Carefully calculate dosage and volume of dose according to specific product.

Acetaminophen IV (Ofirmev)

Indicated for reduction of fever in children, infants, and neonates, including premature neonates born at ≥32 weeks gestational age.

 

Follow-up

Patient Education

A study estimated the extent to which Canadian expectant parents would seek medical care in a febrile neonate (age 30 days or less). The study also evaluated expectant parents' knowledge of signs and symptoms of fever in a neonate and the actions Canadian expectant parents would take to optimize the health of their child. Despite universal access to high quality health care in Canada, the study highlighted concerning gaps in the knowledge of the care of the febrile infant in one fifth of expectant parents. Physicians and health providers should strive to provide early education to expectant parents about how to recognize signs of fever in the neonate and how best to seek medical care.[24]

 

Questions & Answers

Overview

What are challenges of fever in the infant and toddler?

How is the etiology of fever in neonates identified?

How is the etiology of fever in infants and toddlers identified?

What is the incidence of bacteremia in infants and children with fever?

Presentation

What is the role of neonate nursery course in the evaluation of fever?

What should be the focus of history in the evaluation of fever in neonates?

What is the role of prenatal history in the evaluation of neonates with fever?

What should be the focus of history of household contacts in the evaluation of fever in neonates?

What should be included in the physical exam for the evaluation of fever in neonates?

What should be the focus of history in the evaluation of young infants with fever?

What is the role of past medical history and household contacts in the evaluation of young infants with fever?

What is included in the physical exam of young infants with fever?

What should be the focus of history in the evaluation of fever in older infants and toddlers?

Which symptoms should be noted in the history of older infants and toddlers with fever?

What is the role of past medical history in the evaluation of fever in older infants and toddlers?

What is the role of family history in the evaluation of fever in older infants and toddlers?

What is the role of environmental and household contacts in the evaluation of fever in older infants and toddlers?

What should be included in the physical exam of fever in older infants and toddlers?

DDX

What are the diagnostic considerations for fever in the infant and toddler?

What are the differential diagnoses for Fever in the Infant and Toddler?

Workup

What is the role of lab studies in the evaluation of fever in the infant and toddler?

What is included in a sepsis evaluation for febrile neonates?

What is the role of cerebrospinal fluid (CSF) studies in evaluation of febrile neonates?

What is the role of urine and stool studies in the evaluation of febrile neonates?

What is the role of chest radiography in the evaluation of febrile neonates?

Which lab studies are included in the evaluation of fever in young infants?

What is the role of urine and stool studies in the evaluation of fever in young infants?

What is the role of chest radiography in the evaluation of fever in young infants?

What are the criteria used for determining risk of occult bacteremia in young infants with fever?

What are the Rochester criteria for assessment of fever in the young infants?

What are the Boston criteria for assessment of fever in the young infants?

What are the Philadelphia criteria for assessment of fever in the young infants?

Which lab studies are included in the evaluation of fever in older infants and toddlers?

What is the role of urine studies in the evaluation of fever in older infants and toddlers?

Which criteria are used to assess the risk of occult bacteremia in older infants and toddlers with fever?

Which lab findings suggest a low risk of occult bacteremia in older infants and toddlers with fever?

Treatment

What is the focus of treatment for fever in the infant and toddler?

What is included in the management of fever in neonates and young infants?

What is the role of empiric antibiotics in the treatment of fever in neonates and young infants?

What is included in the management of well-appearing febrile infants?

What is included in the management of ill-appearing febrile neonates?

What is included in the management of fever in older infants and toddlers?

Medications

Which medications are used in the treatment of fever in the infant and toddler?

Which medications in the drug class Antipyretics are used in the treatment of Fever in the Infant and Toddler?

Which medications in the drug class Antivirals are used in the treatment of Fever in the Infant and Toddler?

Which medications in the drug class Antimicrobials are used in the treatment of Fever in the Infant and Toddler?