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Bacteremia
Last Updated: June 23, 2004 Rate this Article Email to a Colleague Synonyms and related keywords: bacteriemia, fever, fever without a source, FWS, occult bacteremia, bloodstream infection, serious bacterial infection, SBI Author: Brian J Holland, MD, Staff Physician, Department of Pediatrics, Tripler Army Medical Center Coauthor(s): Denise Demers, MD, FAAP, Assistant Professor of Pediatrics, Uniformed Services University of the Health Sciences; Chief, Division of Pediatric Infectious Diseases, Department of Pediatrics, Tripler Army Medical Center Brian J Holland, MD, is a member of the following medical societies: Alpha Omega Alpha Editor(s): Itzhak Brook, MD, MSc, Professor, Department of Pediatrics, Georgetown University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Mark R Schleiss, MD, Associate Professor, Department of Pediatrics, Division of Infectious Diseases, University of Cincinnati and Children's Hospital Research Foundation; Robert W Tolan, Jr, MD, Chief of Pediatric Infectious Diseases, St. Peter's University Hospital and Capital Health System, Clinical Associate Professor of Pediatrics, Drexel University College of Medicine; and Russell Steele, MD, Professor and Vice Chairman, Department of Pediatrics, Head, Division of Infectious Diseases, Louisiana State University Health Sciences Center Background: Bacteremia is the presence of viable bacteria in the circulating blood (Spraycar, 1995). Transient bacteremia may occur following dental work or other iatrogenic manipulations, but it is generally clinically benign and self-resolved in children who do not have underlying illness or turbulent cardiac blood flow. Bacteremia may also occur in children with focal infections or in children who have sepsis (ie, clinical evidence of a systemic response to infection other than fever). Children with sepsis have an increased heart rate or respiratory rate, with or without an increase or decrease in temperature. Children with sepsis syndrome or severe sepsis have hypotension, hypoperfusion, or organ dysfunction. Septic shock occurs in children who do not respond to adequate volume resuscitation or require vasopressors or inotropes. Bacteria may be present in the bloodstream of children with focal infections, sepsis, severe sepsis, or septic shock; however, those topics are beyond the scope of this article and are addressed in separate eMedicine articles. The focus of this article is occult bacteremia. Patients with occult bacteremia do not have clinical evidence of a systemic response to infection other than fever (Harper, 1993). First described in the 1960s in young febrile children with unsuspected pneumococcal infection, bacteremia is defined as the presence of bacteria in the bloodstream of a previously healthy child with a fever; the child does not clinically appear to be ill and has no apparent focus of infection (Lorin, 1993; Swindell, 1993). A recent review defines occult bacteremia as bacteremia identified in a patient without clinical evidence of sepsis (shock or purpura) or a toxic appearance, without underlying significant chronic medical conditions,

without clear foci of infection on examination (other than acute otitis media), and who is discharged to home after outpatient evaluation (Kuppermann, 1999). Often, the only manifestation of occult bacteremia is fever or a minor infection (eg, otitis media, upper respiratory infection) (Harper, 1993). Therefore, in a busy clinic or emergency department, distinguishing infants and young children with occult bacteremia from the accompanying waiting room throng is challenging. Fever is very common in pediatric patients. Infants and young children average 4-6 fevers in the first 2 years of life (McCarthy, 1998). Fever also prompts a large number of visits to the pediatric clinic and emergency department. Approximately 8-25% of doctor's visits by children younger than 3 years are for fever (Harper, 1993; McCarthy, 1998; Baraff and Bass, 1993; Baraff, 2000); 65% of children visit a physician for acute febrile illness before they are aged 3 years (Baraff and Bass, 1993; Baraff, 1993). Fever is less common in infants younger than 3 months than in those aged 3 months to 3 years. Young infants may not mount a fever response and may also be hypothermic in response to illness or stress (McCarthy, 1998). Approximately 1% of infants younger than 2 months present with fever, and fever is twice as common in infants aged 1-2 months as it is in newborns younger than 1 month (McCarthy, 1998). Of all pediatric patients presenting for evaluation of fever, 20% have fever for which the source of infection is undetermined after a history and physical examination (Baraff, 2000). Of all infants and young children who present to the hospital for any reason, 1.6% are nontoxic appearing, previously healthy, older than 3 months, and have a fever without a source (FWS) (Baraff, 2000). Pathophysiology: Much of the pathophysiology of occult bacteremia is not fully understood. The presumed mechanism begins with bacterial colonization of the respiratory passages; bacteria may egress into the bloodstream of some children because of host- and organism-specific factors. Once viable bacteria have gained access to the bloodstream, they may be cleared spontaneously, they may establish a focal infection, or the infection may progress to septicemia; the possible sequelae of septicemia include shock, disseminated intravascular coagulation, multiple organ failure, and death (Harper, 1993; Bass, 1993). Fever is often the only presenting sign in patients with occult bacteremia; it is defined as increased temperature caused by resetting the thermoregulatory center in the hypothalamus by action of cytokines (McCarthy, 1998). The cytokines may be produced in response to viral or bacterial pathogens or by immune complexes. An increased temperature does not always represent a fever. Hyperthermia may also be due to increased heat production as occurs in exercise or decreased heat loss as occurs in overbundling, neither of which involves resetting of the hypothalamic thermostat. A child's immune system helps determine which bacteria gain initial access to the bloodstream, whether bacteremia resolves spontaneously or progresses to serious bacterial illness, and whether cytokines are produced to mount a fever response. The risk of life-threatening bacterial disease is greatest in young infants when their immune system is least mature; they have poor immunoglobulin G (IgG) antibody response to encapsulated bacteria and decreased opsonin activity, macrophage function, and neutrophil activity (Baker, 1999; Jaskiewicz, 1993).

Frequency:

In the US: The risk of bacteremia has been studied by categorizing infants and young children based on age, appearance, temperature, laboratory criteria, a number of low-risk criteria based on a combination of these, and past medical history. These studies are part of an ongoing attempt to decide which children require evaluation and treatment and which children can be safely observed without intervention. Toxic and lethargic are terms that have been loosely and specifically defined by numerous investigators (see Physical). A child who is toxic or lethargic is generally described as making poor eye contact, having poor interactions with parents and the environment, and showing signs on global assessment of poor perfusion, hypoventilation or hyperventilation, or cyanosis (Baraff and Bass, 1993). In children younger than 3 months, the risk of bacteremia is 1.2-2% in infants who are not toxic and 10-11% in infants who are toxic (Baraff and Bass, 1993; Baraff, 1992). In children aged 3-36 months who are toxic, the risk of bacteremia or serious bacterial infection ranges from 10-90%, depending on criteria (Baraff and Bass, 1993; Baraff, 1993). The bacteremia literature defines a fever by studies designed to determine the relationship between temperature and risk of occult bacteremia. Most studies define fever as a temperature of at least 38C (100.4F) in infants younger than 3 months and at least 39C (102.2F) in children aged 3-36 months. Because these studies were designed to predict occult bacteremia, they include only children who have FWS, which is defined as an acute febrile illness in which the etiology is not apparent after a careful history and physical examination (Baraff, 1993). A number of studies published in the early 1990s found that 2-15% of febrile infants younger than 3 months were bacteremic (Baker, 1999; Kadish, 2000; Jaskiewicz, 1993; Baskin, 1993), and the risk of occult bacteremia in children aged 3-36 months with FWS was 2.5-11% (Harper, 1993; Baraff and Bass, 1993; Baraff, 2000; Baraff and Oslund, 1993; Jones, 1993). According to more recent studies performed after introduction of the conjugate Haemophilus influenzae type b (Hib) vaccine, the risk of occult bacteremia was 1.5-2.3% in children aged 3-36 months with FWS (Alpern, 2001; Lee, 1998; Lee, 2001). Clinical trials and postlicensure studies suggest that the 7-valent conjugate pneumococcal vaccine is 90% effective in preventing invasive disease caused by Streptococcus pneumoniae. Widespread use is likely to significantly decrease the overall risk of occult bacteremia (Baraff, 2000; Black, 2001; Kaplan, 2002).

Internationally: According to the World Health Organization, at least 6 million children die each year of pneumococcal infections (eg, pneumonia, meningitis, bacteremia); most of these fatalities occur in developing countries (Giebink, 2001).

Mortality/Morbidity: The natural history, morbidity, and mortality of occult bacteremia alone are not clearly understood. In prospective studies of occult bacteremia, although many children were observed untreated initially, all were administered antibiotics once blood cultures became positive (Kuppermann, 1999). Occult bacteremia results in morbidity and mortality due to focal infections that arise following the initial bloodstream infection. Most episodes of occult

bacteremia resolve spontaneously, and serious sequelae are increasingly uncommon. However, serious bacterial infections occur, including pneumonia, septic arthritis, osteomyelitis, cellulitis, meningitis, and sepsis, and death can result (Kuppermann, 1999; Kramer, 1997). In studies performed before the introduction of the Hib conjugate vaccine, children with untreated bacteremia had an 18-21% risk of developing persistent bacteremia and a 2-15% risk of developing important focal infections such as meningitis (Harper, 1993; Baraff and Bass, 1993; Baraff, 1993; Harper, 1995). Because widespread use of the Hib vaccine has virtually eliminated invasive Hib disease in the developed world, recent reviews, analyses, and studies have focused on invasive S pneumoniae disease. Children with occult pneumococcal bacteremia have a 6-17% risk of persistent bacteremia, a 2-5.8% risk of meningitis, and a 6-10% risk of other focal complications (Harper, 1993; Kuppermann, 1999; Baraff and Bass, 1993; Bauchner, 1997; Baraff, 1993; Lee, 2001). Of all focal infections that develop as a result of pneumococcal bacteremia, pneumococcal meningitis carries the highest risk for significant morbidity and mortality, including a 25-30% risk of neurologic sequelae such as deafness, mental retardation, seizures, and paralysis (Kuppermann, 1999; Baraff, 2000). The mortality rate of pneumococcal meningitis is 6.3-15%, and the overall mortality rate of pneumococcal bacteremia is 0.8% (Kuppermann, 1999, Baraff, 2000; Kaplan, 2002). Neisseria meningitidis also causes bacteremia in infants and young children. Although the prevalence of meningococcal bacteremia is much lower than that of pneumococcal disease (see Causes), the morbidity and mortality is much greater. Children with meningococcal bacteremia have a 42-50% risk of meningitis; a 50% risk of serious bacterial infection such as septic shock, pneumonia, and neurologic changes; a 3% risk of extremity necrosis; and an overall mortality rate of 4% (Harper, 1993; Kuppermann, 1999; Baraff, 2000). When untreated, Salmonella bacteremia carries a 50% risk of persistent bacteremia. It can cause meningitis, sepsis, and death in infants younger than 3 months or in persons who are debilitated or immunocompromised (Kuppermann, 1999). However, in previously healthy young children aged 3-36 months, the risk of meningitis or serious bacterial infection following Salmonella bacteremia is low (Harper, 1993). Race: Studies of the prevalence of bacteremia in children in diverse settings have identified no racial, geographic, or socioeconomic predisposition (Harper, 1993; Swindell, 1993; Bass, 1993; Fleisher, 1994). However, antibiotic resistance patterns vary in different geographic regions, which may impact the treatment of children with bacteremia. Sex: No known sex-based difference in the prevalence or course of bacteremia exists (Bass, 1993). Age: Studies of occult bacteremia focus on children younger than 3 years. Some studies show no change with age in risk of occult bacteremia (Bass, 1993), while other analyses have found that variations in risk based on age are dependent on the infecting organism. Pneumococcal bacteremia is observed in children of all ages; however, children aged 6 months to 2 years are at increased risk (Swindell, 1993; Kuppermann, 1999; Lee, 1998), and a peak in the incidence of pneumococcal meningitis occurs in infants aged 3-5 months. Meningococcal bacteremia occurs most frequently in infants aged 3-12 months; the highest risk of meningococcal meningitis is in infants aged 3-5 months (Kuppermann, 1999; Bass, 1993). The risk of Salmonella bacteremia is greatest in infants younger than 1 year, especially in those younger than 2 months (Kuppermann, 1999). A seasonal variation exists in febrile children presenting for evaluation. The peak is from late fall to early spring in children of all ages, likely because of respiratory and gastrointestinal viral infections. Another peak occurs during the summer in infants younger than 3 months, likely because of enteroviral infections and thermoregulation during hot weather (McCarthy, 1998). However, seasonal variation in bacteremia is not specifically addressed by most studies.

History: Many studies have been performed to determine if elements of the past medical history and history of the acute illness may help in deciding whether a given febrile child is at high risk for bacterial infection. The significance of history varies on the basis of age. In neonates younger than 1 month with a fever, elements of the past medical history are not useful in determining whether the bacterial infection is serious (Kadish, 2000). The history of the acute febrile illness is also not useful because nonspecific symptoms such as feeding intolerance, temperature instability, mild respiratory distress, or irritability may indicate a serious bacterial infection in a very young infant (Jaskiewicz, 1993). Duration of fever: The duration of fever at presentation has been noted to be shorter in patients whose blood cultures eventually became positive (mean 18 h) than in those patients with negative blood cultures (mean 25 h) (Bass, 1993). However, this difference is not statistically significant, and screening for bacteremia based on duration of fever less than 2 days would include 80% of patients with bacteremia and 74% of those without bacteremia (Kuppermann, 1999). Overall, duration of fever is inadequate to clinically distinguish occult bacteremia (Strait, 1999). History that indicates specific illness: Although meningococcal infections are very uncommon causes of bacteremia (see Causes), patients with meningococcemia are at high risk for morbidity and mortality (see Morbidity/Mortality). Knowledge of local epidemiology involving an outbreak of meningococcus, along with history of contact with someone with known meningococcal disease, can raise clinical suspicion and help confirm an important diagnosis (Kuppermann, 1999). History that indicates risk for occult bacteremia: Numerous studies have attempted to establish elements of the history that can help distinguish which febrile infants and young children are at increased risk for bacterial infection, including occult bacteremia.
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The Rochester criteria are formal elements of the history that have been widely accepted as indicating a decreased risk for occult bacteremia in infants aged 60 days or younger (Jaskiewicz, 1993; Baraff, 1992). These criteria include the following: Was previously healthy Had a term of at least 37 weeks' gestation Did not receive perinatal antibiotics Was not hospitalized longer than the mother following delivery Did not receive treatment for unexplained hyperbilirubinemia Has no history of current antibiotic use Has no previous hospitalizations Has no chronic or underlying illness Elements of the history that indicate an increased risk for occult bacteremia in infants and children after the neonatal period include the following (Harper, 1993; Baraff and Bass, 1993; Baker, 1999; Dirnberger, 1996): Age, which determines the cutoff used to define fever Febrile temperature (<3 mo and temperature >38C [100.4F], 3-36 mo and temperature >39-39.5C [102.2-103.1F]) History of current antibiotic use Previous hospitalizations Chronic or underlying illness Immunodeficiency (eg, hypogammaglobulinemia, sickle cell anemia, HIV, malnutrition, asplenia)

History of underlying medical condition: A recent longitudinal study of invasive pneumococcal infections found that a history of an underlying medical condition was a significant risk factor for increased mortality. Children with invasive pneumococcal infections and an underlying medical condition had a mortality rate of 3.4%, whereas previously healthy children with invasive pneumococcal infections had a mortality rate of 0.84% (Kaplan, 2002). History of other reason for increased temperature: The history may also indicate possible explanations for increased temperature other than fever in response to an acute infection, such as recent vaccinations, overbundling, or environmental exposure to heat in a young infant (Baraff and Bass, 1993). A thorough evaluation for illness or infection should be performed in all febrile children before determining that increased temperature is caused by any extrinsic factor. Diarrhea, Salmonella: A history of gastroenteritis should increase the clinical suspicion for Salmonella bacteremia. Salmonella is an uncommon cause of gastroenteritis, but most patients who develop Salmonella bacteremia have gastroenteritis, and 6.5% of children younger than 1 year with Salmonella gastroenteritis become bacteremic (Kuppermann, 1999). Epidemiology: Although a history of family members or frequent contacts with obvious viral syndromes such as upper respiratory infections may suggest a viral syndrome (Baraff and Bass, 1993), children with common cold symptoms were generally not excluded from studies of occult bacteremia. Results suggest that the risk of bacteremia in febrile children is the same whether common cold symptoms are present (Kuppermann, 1999). Risk factors for invasive pneumococcal disease: Recent studies have begun to evaluate the relationship between history and pneumococcal disease. Elements of history that have been associated with an increased risk of pneumococcal bacteremia include day care attendance (Kuppermann, 1999; Baraff, 2000; Levine, 1999), lack of breastfeeding (Baraff, 2000; Levine, 1999), and underlying illness such as sickle cell disease and AIDS (Baraff, 2000; Levine, 1999). Although the overall rate of infection is not affected by recent antibiotic use, children who were treated with antibiotics in the last 30 days are more likely to be infected with S pneumoniae that is resistant to penicillin (Levine, 1999).

Physical: Evaluation of a febrile infant or young child begins by establishing whether the patient truly has an FWS. Toxic or lethargic children and patients with focal infection and sepsis are treated appropriately, and children with nonfocal physical examination findings are further evaluated for occult bacteremia (Baraff and Bass, 1993; Baker, 1999; Dirnberger, 1996). General appearance
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The initial aspect of the physical examination, assessment of general appearance, has been formally defined by a number of investigators in an attempt to assess the utility in determining the presence of bacterial disease. The Yale Observation Scale (YOS)/Acute Illness Observation Scale (AIOS) has been widely used. It is used to assess an infant's quality of cry, reaction to parents, state variation, color/perfusion, hydration, and response to social cues in the environment (Swindell, 1993; Jaskiewicz, 1993). Other authors have looked at irritability, consolability, and social smile (Bass, 1993; Bass, 1996). Rigorous studies by a number of authors have found that the use of clinical scores, observation scores, social smile, and general appearance has not been clinically useful in distinguishing occult bacteremia, especially in young infants

(Harper, 1993; Bass, 1993; Baker, 1999; Strait, 1999; Bass, 1996). General appearance using observation scores had a sensitivity of 74% and specificity of 75% in detecting serious illness in older children (Baraff and Bass, 1993; Baraff, 1993); it had a sensitivity of 33% in detecting bacterial disease in infants younger than 2 months (Baker, 1999). General appearance had 5.2% sensitivity for detecting occult bacteremia, and social smile was 45% sensitive and 51% specific for bacteremia (Kuppermann, 1999; Bass, 1996). A recent cost-effectiveness analysis suggests that clinical judgment of general appearance (YOS <6 equals low-risk), with an estimated sensitivity of 28% and specificity of 82%, may be a useful screening criterion because the overall prevalence of occult pneumococcal bacteremia falls with widespread use of the conjugate pneumococcal vaccine (Lee, 2001).

Vital signs
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Temperature, pulse, respiratory rate, and blood pressure can be very useful in raising clinical suspicion for sepsis or pneumonia and for establishing the risk for occult bacteremia. Temperature is addressed separately below. Recent studies also suggest that pulse oximetry should be used routinely as a fifth vital sign (Baraff, 2000). In studies of occult bacteremia, children were not excluded on the basis of specific vital sign parameters; in very young infants, no significant pulse, respiratory rate, or blood pressure differences may exist between patients with and without serious bacterial infection (Kadish, 2000). However, tachycardia, tachypnea, or hypotension in a febrile or hypothermic infant are signs of sepsis and warrant a complete evaluation (Harper, 1993).

Fever defined
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Studies in the bacteremia literature were designed to determine the relationship between temperature and risk of occult bacteremia. Most studies define fever as a temperature of at least 38C (100.4F) in infants younger than 3 months and a temperature of at least 39C (102.2F) in children aged 3-36 months. Hypothermia may be the presenting sign of bacterial infection in young infants. One guideline defined hypothermia as a temperature less than 36C (96.8F) (Baraff and Bass, 1993). Although the proper method to be used when measuring temperature is continuously debated, a rectal temperature taken with a glass mercury thermometer remains the standard (McCarthy, 1998). Tactile fever has been found to correlate poorly with the presence of actual fever documented by a healthcare professional using rectal or oral thermometry (Bonadio, 1993); thus, parental reports that a child had a fever because they feel warm should not be used as part of the evaluation of febrile infants and children. Home measurement of fever using a thermometer reading has generally been accepted as true and accurate.

Febrile temperature o The upper extreme of the febrile temperature alone is inadequate to distinguish occult bacteremia; however, the risk of bacteremia has consistently been found to increase with increases in temperature (Lee, 1998; Strait, 1999). Studies have

shown a variation in risk at given temperatures based on age; this has led to the fever cutoffs listed above. Table 1. Age, Fever, and Bacterial Infection* Age Neonates <1 mo Temperature 38-38.9C 39-39.9C >40C Infants aged 1-2 mo 38-38.9C 39-39.9C >40C *Bonadio, 1993 Table 2. Children Aged 3-36 Months - Fever and Occult Bacteremia* Temperature Culture, % Bacteremia, % <39C 39-39.4C 39.5-39.7C 39.8-39.9C 40-40.2C 40.3-40.5C 40.5-40.9C >41C Occult Pneumococcal Bacteremia, % Positive Blood Culture, % Occult Very low 1.2 2.5 2.5 3.2 3.2 4.4 9.3 1.6 1.6 2.8 2.8 3.7 3.7 3.8 9.2 1 5 5 5 5 5 12 12 Positive Blood Pneumococcal 10-10.4 10-10.4 10-10.4 10-10.4 Rate of bacterial infection 5% 7.5% 18% 3% 5% 26%

*Kuppermann, 1999; Harper, 1993; Swindell, 1993; Baraff, 2000; Baraff, 1997
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Children who are aged 2-3 years and have a temperature lower than 39.5C have less than 1% risk of occult pneumococcal bacteremia (Kuppermann, 1999).

Response to antipyretics: Patients with bacterial and viral sources of infection respond similarly to antipyretics; no significant difference in either temperature decrease or clinical appearance after defervescence exists. Both groups experience the same decrease in temperature as a result of antipyretic therapy (Harper, 1993; Kuppermann, 1999; Bonadio, 1993). Focal infection on physical examination: Thoroughly examine the patient for signs of skin, soft tissue, bone, or joint infection. A patient with any of these focal infections should be treated appropriately and does not require evaluation for occult bacteremia (Baraff and Bass, 1993).

Petechiae: A febrile child with petechial rash on physical examination has a 2-8% risk of serious bacterial infection. The clinical suspicion for meningococcemia should be increased if a petechial rash is found (Baraff and Bass, 1993; Baraff, 2000). However, a recent prospective cohort of children with fever and petechiae found a 1.6% risk for bacteremia or sepsis and a 0.5% risk of meningococcal infection. The children with serious bacterial infection in this study had additional findings from the history and physical examination that suggest a bacterial cause for petechiae. These findings include ill appearance, purpura, petechiae below the nipple line, and no mechanical explanation (eg, cough, vomiting, tourniquet) for petechiae (Mandl, 1997). Acute otitis media or upper respiratory infection: An evaluation for bacteremia is still warranted in children with acute otitis media or upper respiratory infection. In most studies of occult bacteremia, these children were included for evaluation. The results of these studies show that the risk of bacteremia is the same in children with acute otitis media or upper respiratory infection as in children without these findings (Harper, 1993; Kuppermann, 1999; Baraff and Bass, 1993; Lee, 1998; Kramer, 1997; Harper, 1995). Pneumonia
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Consider the diagnosis of pneumonia in febrile children who have no other source of infection. Specific physical examination findings such as grunting, flaring, retracting, rhonchi, wheezing, rales, and focal decreased breath sounds have 94-99% specificity for pneumonia (Bachur, 1999). Febrile children who have none of these findings rarely have pneumonia. Recent studies suggest that pulse oximetry may be a more reliable predictor of pulmonary infections than respiratory rate in infants and young children; a recent guideline recommends that patients with oxygen saturation less than 95% be evaluated for pneumonia by means of chest radiography (Baraff, 2000). Evaluation for occult bacteremia is still warranted in febrile children with clinical or radiographic pneumonia. Mild respiratory distress may indicate a serious bacterial infection in a very young infant, and studies of occult bacteremia found that patients with pneumonia have the same prevalence of bacteremia as patients without focus of infection (Jaskiewicz, 1993; Kuppermann, 1999; Kramer, 1997).

Recognizable viral infections: Although symptoms of upper respiratory infection should not be accepted as an explanation of fever in an infant and young child, a number of other recognizable viral infections are generally accepted as a fever source. Children with varicella, croup, gingivostomatitis, herpangina, and bronchiolitis have less than 1% chance of bacteremia (Kuppermann, 1999). A retrospective study of children with these recognizable viral syndromes found a risk of 0.2% for true pathogens and 1.4% for contaminants (Greenes, 1999). Group A streptococcal bacteremia occurs sporadically in children with varicella, but these children usually are toxic or have focal findings (Kuppermann, 1999). Physical examination findings consistent with these viral infections generally remove children from studies of bacteremia; these children should be treated for viral infection without further evaluation for occult bacteremia (Harper, 1993; Kuppermann, 1999; Greenes, 1999).

Causes: Causes of occult bacteremia vary depending on the age of the infant or child. The most common causes of infection for very young infants are acquired from the mother during childbirth. As a patient's age increases, a gradual shift toward community-acquired causes occurs. Table 3. Causes of Occult Bacteremia in Neonates and Infants with a Temperature of 38C or Higher* Age Organism Positive Blood Cultures Neonates <1 month Group B Streptococcus 73% Escherichia coli S pneumoniae Staphylococcus aureus Enterococcus species Enterobacter cloacae Infants aged 1-2 months Group B Streptococcus E coli Salmonella species S pneumoniae H influenzae type b S aureus 8% 3% 3% 3% 3% 31% 20% 16% 10% 6% 4%

E cloacae 4% *Kadish, 2000; Baskin, 1993; Baker, 1999; Jaskiewicz, 1993; Baraff, 1992 Also, Listeria species, Klebsiella species, group A Streptococcus, Staphylococcus epidermis, Streptococcus viridans, and N meningitidis Older infants and children are at risk for bacteremia from colonization of the nasopharynx or community-acquired organisms. Hib conjugate vaccine has decreased the incidence of invasive Hib disease by 90% or more in industrialized countries (Baraff, 2000). Also, with the disappearance of Hib as a cause of occult bacteremia in children, the relative incidence of S pneumoniae has increased in some medical centers to more than 90% (Bass, 1994). Table 4. Causes of Occult Bacteremia and Changes Over Time in Children Aged 3-36 Months with FWS* Organism 1975-1993 1993 1990 to Present 1993-1996 S pneumoniae H influenzae type b N meningitidis 83-86% 5-13% 1-3% 93% 2% 89% 0% 92% 0%

Salmonella species 1-7% *Harper, 1993; Kuppermann, 1999; Baraff and Bass, 1993; Bass, 1993; Baraff and Oslund, 1993; Alpern, 2001; Fleisher, 1994; Baraff, 1993; Harper, 1995; Lee, 1998 Also, E coli, S aureus, Streptococcus pyogenes, group B Streptococcus, Moraxella species, Kingella species, Yersinia species, and Enterobacter species The prevalence of occult bacteremia caused by pneumococcus is anticipated to decrease greatly in the near future because of the introduction of the 7-valent conjugate pneumococcal vaccine, which was designed to cover 98% of the strains of S pneumoniae responsible for occult bacteremia (Alpern, 2001). A recent multicenter surveillance found that 82-94% of S pneumoniae invasive disease was caused by isolates that are contained in the 7-valent conjugate pneumococcal vaccine, which is the only pneumococcal vaccine that the Food and Drug Administration (FDA) has approved for infants and young children at the time of this writing (Kaplan, 2002). A list of strains of S pneumoniae and the percentage of pneumococcal bacteremia caused by each strain is as follows (all except S pneumoniae 6 are 98% covered by the 7-valent conjugate pneumococcal vaccine): S pneumoniae 14 - 42%

S pneumoniae 23F - 15% S pneumoniae 6B - 13% S pneumoniae 4 - 9% S pneumoniae 18C - 8% S pneumoniae 19F - 6% S pneumoniae 9V - 6% S pneumoniae 6 - 2%

Other Problems to be Considered: Viremia, viral Autoimmune Poor thermoregulation, Tumor Acute subdural Focal bacterial infection Quick Find Lab Studies: White blood cell count
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environmental

syndrome disorder problems hematoma

The WBC count has been the most widely studied laboratory parameter in occult bacteremia. The risk of occult bacteremia and occult pneumococcal bacteremia has been consistently found to increase with an increased WBC count

(Kuppermann, 1999; Baraff and Bass, 1993; Baraff, 2000; Baraff, 1993; Bass, 1993; Baraff, 1997). Randomized control trials, retrospective reviews, prospective cohorts, and meta-analyses have been conducted. Many have used slightly different inclusion and exclusion criteria, age ranges, and fever cutoffs. A consistent trend has been that children aged 3-36 months with FWS and a WBC count higher than 15 are at increased risk for occult bacteremia (Kuppermann, 1999; Baraff and Bass, 1993; Baraff, 2000; Baraff, 1993; Bass, 1993; Baraff, 1997).
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Although the vast majority of young febrile children with increased WBC counts do not have underlying bacterial infections as a cause for fever, a cutoff of WBC counts higher than 15 has favorable screening test characteristics, as follows (Kuppermann, 1999; Lee, 1998; Strait, 1999): Sensitivity 50-80% Specificity 70-80% Positive predictive value (PPV) 5-6% Negative predictive value (NPV) approximately 99% Receiving operator characteristic (ROC) curves for WBC count were superior to nearly all other laboratory studies, although a recent analysis found that the screening characteristics of WBC counts were not significant when adjusted for other variables such as absolute neutrophil count (ANC), temperature, age, and YOS (Lee, 1998; Strait, 1999; Kuppermann, 1999). Table 5. WBC Count as a Screen for Occult Bacteremia* WBC Count % 15 80 Sensitivity, % Specificity, % PPV, % 69 86 79 6 77 5.5 99.3 5.1 98.3 NPV,

>15 (post-Hib) >15 48

*Kuppermann, 1999; Lee, 1998; Strait, 1999

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Infants younger than 3 months are considered separately in most studies of bacteremia. Guidelines established by groups in Rochester, Boston, and Philadelphia were published in Pediatrics in 1993. All of these guidelines aimed at defining populations of infants who are at low risk for bacterial infection. Each of these guidelines uses WBC criteria as part of the low-risk criteria. Low-risk WBC criteria according to these guidelines are as follows: Boston guideline - Less than 20,000 Philadelphia guideline - Less than 15,000 Rochester guideline - 5,000-15,000 1993 Pediatrics guideline - 5,000-15,000

Absolute neutrophil count

The ANC has also been evaluated as a screen for occult bacteremia; the risk of occult bacteremia increases with increase in ANC (Kuppermann, 1999). Although guidelines before the conjugate Hib vaccine did not recommend ANC as a screen for bacteremia (Baraff and Bass, 1993), more recent studies and guidelines suggest that ANC higher than 7-10 has favorable screening characteristics. ROC curves for ANC are equal to the WBC count, and a recent analysis found that the screening characteristics of ANC remained significant when adjusting for other variables such as WBC count, temperature, age, and YOS (Kuppermann, 1999). An ANC higher than 7,000-10,000 has a 76-82% sensitivity, a 74-78% specificity, a 7-8% PPV, and a 99% NPV for occult bacteremia (Kuppermann, 1999; Strait, 1999). The ANC is related to cases of occult pneumococcal bacteremia as follows (Kuppermann, 1999): Less than 5,000 - 0% 5,000-9,000 - 1.4% 10,000-14,900 - 5.8% Greater than 15,000 - 12.2% Table 6. ANC as a Screen for Occult Bacteremia* ANC 10,000 Sensitivity 76% Specificity 78% PPV 8% 7.5% NPV 99.2% 99.4%

>7200 82% 74% *Kuppermann, 1999; Strait, 1999 Band count

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The absolute band count (ABC) has been found to have poor test characteristics as a screen for occult bacteremia and is not recommended as a screening test (Kuppermann, 1999; Baraff and Bass, 1993). In febrile children, the risk for occult bacteremia generally tends to increase with increasing ABC; however, no well-defined cutoff exists, ROC curve characteristics are poor compared with those of ANC and WBC count, and any changes in ABC are not significant when adjusting for other variables. Elevated band counts have also been found in 21-29% of patients with cultureproven viral infections (Wack, 1994). The ABC may be the most important component of the CBC for meningococcal bacteremia, but the low overall prevalence limits its clinical utility (see N meningitidis). The ABC (X 103/mm3) is related to cases of occult pneumococcal bacteremia as follows (Kuppermann, 1999): Less than 0.5 - 1.5% 0.5-0.99 - 1.7% 1-1.5 - 1.7% 1.5-1.9 - 5.2% Greater than 2 - 6.3% Bandemia (band >15%) is related to cases of viral infections as follows (Wack, 1994): Influenza A and B - 29% Enterovirus - 23%

Respiratory syncytial virus - 22% Rotavirus - 22% In most studies of bacteremia, infants younger than 3 months are considered separately. Groups in Rochester, Boston, and Philadelphia have established guidelines aimed at defining populations of infants who are at low risk for bacterial infection. These guidelines were published in Pediatrics in 1993. Most of these guidelines use band count as part of the low-risk criteria. Low-risk band criteria according to these guidelines are as follows: Boston guideline - None Philadelphia guideline - Less than 0.2 band-neutrophil ratio Rochester guideline - Less than 1500 ABC 1993 Pediatrics - Less than 1000 ABC

Erythrocyte sedimentation rate and C-reactive protein

o

A number of studies have evaluated erythrocyte sedimentation rate (ESR) and Creactive protein (CRP) as markers for bacterial infection. Most studies were conducted before widespread use of the conjugate Hib vaccine and included hospitalized patients and patients with focal infections. These studies found that ESR and CRP had better sensitivity than the WBC count and similar specificity. A recent review found that the ESR and CRP did not predict occult bacteremia, and the WBC count and ANC were more sensitive and specific. On the basis of this information, ESR and CRP are not currently recommended as screening tests for occult bacteremia (Kuppermann, 1999; Baraff and Bass, 1993). A few recent prospective studies have focused specifically on CRP as a screening test for occult bacteremia in children with FWS (Pulliam, 2001; Lacour, 2001). These studies were relatively small and included urinary tract infection (UTI) and pneumonia in addition to occult bacteremia. The studies found overall rates of serious bacterial infections that were higher than other published data. However, the results suggest that CRP may be a better screening tool than ANC or WBC count for detecting occult bacterial infections. The prospect of a rapid effective screening tool that can be obtained from a capillary blood sample is intriguing.

Cytokines: Interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor- (TNF) all increase in the serum and cerebrospinal fluid in gram-negative and gram-positive sepsis; the levels increase with the severity of illness. A recent review found that these levels also increase in bacteremia; sensitivity and PPV are similar to WBC count (Kuppermann, 1999). A recent prospective case control study found that IL-6 and TNF were not significantly different between study groups; however, IL-6 had screening test characteristics and ROC curve characteristics similar to a WBC count and ANC. IL-6 as a test for occult bacteremia had a sensitivity of 88%, a specificity of 70%, a PPV of 7.0%, and an NPV of 99.6% (Strait, 1999). These cytokines still have not been thoroughly investigated; they have marginal clinical utility, unknown cost-effectiveness, and are not recommended as routine screening laboratory studies for occult bacteremia (Kuppermann, 1999). Procalcitonin (PCT): PCT is a prohormone of calcitonin that increases rapidly in the serum following exposure to bacterial endotoxin in studies. A number of recent articles have examined PCT as a marker for bacterial infection in the setting of sepsis or focal infections. A few small studies have also looked at PCT as a marker of bacterial infection in FWS and UTI (Lacour, 2001; Gervaix, 2001). Early data suggest that PCT may be

effective in differentiating infection from inflammation and that it may be fairly specific in distinguishing bacterial versus viral infection early in the clinical course of infection. Although prolactin is currently used mostly in research laboratories, rapid tests have been developed and may become widespread as evaluation of clinical utility continues (Gendrel, 2000). WBC vacuoles, toxic granulations: Microscopic changes in WBC morphology have also been associated with infection. A few studies evaluating the relationship between vacuoles or toxic granulations and bacterial infection were performed in the era before the conjugate Hib vaccine. In one study, which included patients with focal disease, vacuoles and toxic granulations were found to have greater sensitivity and PPV than WBC counts (Harper, 1993; Kuppermann, 1999). Another study found that vacuolization correlated with fever and leukocytosis but not with bacterial disease (Kuppermann, 1999). These WBC microscopic changes are generally not recommended as a screen for occult bacteremia. Latex agglutination: Latex agglutination is sensitive for the detection of occult H influenzae bacteremia, but widespread use of the conjugate Hib vaccine has essentially eliminated Hib as a cause of occult bacteremia (see Causes). Latex agglutination is not sensitive or specific enough to be useful in pneumococcal disease, and the utility of latex agglutination for meningococcal bacteremia is low because of inaccuracy of tests (Harper, 1993; Kuppermann, 1999). Currently, latex agglutination is not recommended for the evaluation of occult bacteremia. Serum polymerase chain reaction (PCR): Recently, PCR has been studied for evaluation of occult pneumococcal bacteremia and was found to have a sensitivity of 57% and a specificity of 55% (Isaacman, 1998). Two recent reviews concluded that the overall low level of clinical accuracy seems insufficient to justify its use in screening for occult bacteremia. Use of PCR in the evaluation of occult meningococcal bacteremia has not been studied. In studies of known meningococcal disease, PCR is sensitive and specific and may potentially be useful in detecting meningococcal bacteremia (Kuppermann, 1999; Avner, 2002). Urinalysis
o

Evaluation of children with FWS often requires laboratory analysis to evaluate for UTI. Children with test results suggesting a UTI are generally treated for this focal infection and do not require further evaluation for occult bacteremia. Of children evaluated for FWS, approximately 7% of males younger than 6 months and approximately 8% of females younger than 1 year have a UTI (Baraff, 1993). All the published guidelines for evaluation of FWS in infants younger than 1 month recommend a laboratory evaluation for UTI, and most guidelines also recommend urine studies in girls younger than 1-2 years and boys younger than 6 months (Baraff and Bass, 1993). Although UTI is a separate topic and is not fully addressed here, traditional guidelines for urine studies in infants and children with FWS include urinalysis, microscopy, and urine culture. A negative screening test result is defined as fewer than 5-10 WBCs per high-powered field (HPF), no bacteria, and negative nitrite and leukocyte esterase (Baraff and Bass, 1993; Baker, 1999; Jaskiewicz, 1993; Baraff, 1992; Bachur, 2001). Application of these guidelines revealed that, in infants and children, approximately 20% of UTIs established by a positive urine culture were not detected by the screening urinalysis (Baraff, 1993).

Recent studies using enhanced urinalysis (cell count by hemocytometer and urine Gram stain) and Gram stain of urine sediment showed 99-100% sensitivity and 100% NPV for UTI (Baraff, 1993; Herr, 2001). Improvement in sensitivity of urine studies has great potential for improving detection of systemic bacterial infection (SBI) in young febrile infants at the time of initial evaluation (Bachur, 2001).

Salmonella and stool studies

o

Salmonella bacteremia accounts for a small portion of occult bacteremia (see Causes), and the clinical and laboratory findings are different than in pneumococcal bacteremia. A WBC count is not a useful screening test because most infants and children with Salmonella bacteremia have a WBC count less than 15,000, and only one half of patients have a left shift of the WBC differential (Kuppermann, 1999). Most patients who develop Salmonella bacteremia have gastroenteritis, and 6.5% of children younger than 1 year who have Salmonella gastroenteritis become bacteremic (Kuppermann, 1999). Because of this association, stool cultures are recommended for children with diarrhea (Baraff and Bass, 1993; Baraff, 1993). The initial clinical application of low-risk criteria for infants younger than 3 months with FWS did not include a stool evaluation. However, a number of patients with Salmonella bacteremia were improperly identified as being at low risk by these guidelines, and current guidelines recommend a screening stool evaluation in young infants with diarrhea. Patients with fewer than 5 WBCs per HPF are considered at low risk for bacterial infection (Baraff and Bass, 1993; Jaskiewicz, 1993; Baraff, 1992).

N meningitidis o Meningococcus is also an uncommon cause of occult bacteremia, but the morbidity and mortality associated with meningococcemia is very high (see Causes and Morbidity/Mortality). Laboratory findings in meningococcal bacteremia are also different than in pneumococcal bacteremia. o Although the risk of pneumococcal bacteremia is directly related to increasing WBC counts, 6% of children with meningococcal bacteremia have a WBC count less than 5. Overall, WBC counts and ANCs have not proved consistently useful in determining the risk of meningococcal infection (Kuppermann, 1999; Kuppermann and Malley, 1999). o The band count may be the most important component of the CBC for meningococcus (Kuppermann, 1999). Approximately 60% of patients with meningococcal bacteremia have a band count greater than 10%, and a retrospective review of FWS found that the band count was the only laboratory value that was significantly higher in patients with meningococcal bacteremia than in those without bacteremia (Kuppermann, 1999; Kuppermann and Malley, 1999). However, the clinical utility of an elevated band count is limited because of the low overall prevalence of meningococcal bacteremia. The PPV of a band count greater than 10% is 0.06. o The use of PCR in the evaluation of occult meningococcal bacteremia has not been studied. In studies of known meningococcal disease, PCR is sensitive and

specific and may potentially be useful in detecting meningococcal bacteremia (Kuppermann, 1999). Cerebrospinal fluid analysis
o

Infants and children with FWS may require a laboratory analysis to evaluate for meningitis. Febrile infants and children of any age who are toxic require a full sepsis evaluation, including CSF and empiric treatment with parenteral antibiotics (Baraff and Bass, 1993). Guidelines by groups in Rochester, Boston, and Philadelphia for the treatment of infants who have FWS and are younger than 3 months all include screening CSF laboratory tests and a CSF culture; the guidelines published in Pediatrics in 1993 recommend that a CSF evaluation be performed in certain situations (see Medical Care). Negative screening test results were defined as fewer than 8-10 WBCs per HPF, no bacteria, and normal glucose and protein levels (Baraff and Bass, 1993; Baker, 1999; Jaskiewicz, 1993; Baraff, 1992). Children with laboratory values suggesting meningitis should be treated for this focal infection. Evaluation and treatment for meningitis is a separate topic and is not fully addressed here.

Blood culture
o

A positive blood culture is the criterion standard used to define bacteremia. Blood cultures should be obtained in infants and young children at risk for occult bacteremia. Blood cultures that are positive for single isolates of known pathogenic bacteria (see Causes) are generally considered to be true positive results; cultures that grow multiple isolates or nonpathogenic bacteria are considered contaminated. How fast the culture becomes positive is also useful in distinguishing pathogens from contaminants; true pathogens generally grow faster than contaminants, with most pathogens turning positive in less than 24 hours (Kuppermann, 1999; Baraff, 2000). The routine mean detection time for several pathogens are as follows (Kuppermann, 1999): S pneumoniae - 11-15 hours Salmonella species - 9-12 hours N meningitidis - 12-23 hours Whether the quantity of colonies grown is useful in detecting occult bacteremia or in predicting prognosis is unclear. Occult pneumococcal bacteremia may yield fewer than 10 colony-forming units (CFU)/mL, which is lower than in focal disease. The yield in meningococcal infection varies widely, but one study found that patients with yields higher than 700 CFU/mL were at increased risk for meningitis (Kuppermann, 1999).

Imaging Studies: The only imaging study routinely used in infants and children with FWS is chest radiography to evaluate for pneumonia. Consider pneumonia in febrile children with no other source of infection. Specific findings on physical examination include grunting, flaring, retracting, rhonchi, wheezing, rales, and focal decreased breath sounds. These findings are 94-99% specific for pneumonia (Bachur, 1999). Obtain a chest radiograph as part of the evaluation of children with any of these findings; evaluation for pneumonia in febrile children without any of these findings is of very low yield (Baraff, 2000; Baraff, 1993).

Recent studies suggest that pulse oximetry may be a more reliable predictor of pulmonary infections than respiratory rate in infants and young children. A recent guideline recommends that chest radiography be used to evaluate for pneumonia if the patient's oxygen saturation is less than 95% (Baraff, 2000). A recent study found that a subset of febrile children who did not have physical examination findings suggestive of pneumonia were at increased risk for occult pneumonia. Approximately 20% of febrile children younger than 5 years who had normal physical examination findings and WBC counts higher than 20,000 had chest radiographic findings consistent with pneumonia. This guideline recommends that a chest radiograph be obtained in febrile infants and children with signs and symptoms of pneumonia and in febrile infants and children without signs and symptoms of pneumonia who have WBC counts higher than 20,000 (Bachur, 1999).

Procedures: Blood: Venipuncture is performed to obtain blood for a CBC and blood cultures. This should be performed using a sterile technique to limit contamination. The recovery rate for blood cultures is improved with larger volumes of blood and a shorter time between the blood draw and incubation in the laboratory (Kuppermann, 1999). The recovery rate is 83% with a large (ie, 6 mL) volume of blood and is 60% with a small (ie, 2 mL) volume of blood. The recovery rate is 95% after 2 hours between blood draw and incubation and is 70% after 3 hours between blood draw and incubation.

Lumbar puncture (LP): An LP is performed to obtain CSF for cell count, glucose and protein levels, microscopy, and Gram stain and culture (see Lab Studies and Medical Care). This should be performed a using sterile technique to limit contamination. Although it remains a subject of debate, children with bacteremia who have an LP may possibly have an increased risk of meningitis (Baraff, 2000). Urine specimen: Urine collection is performed for urinalysis, microscopy, Gram stain, cell count, and culture (see Lab Studies and Medical Care). Although UTIs are a separate subject and not fully addressed here, urine collection should be performed using a sterile technique to limit contamination. Suprapubic bladder aspiration and in-and-out bladder catheterization are best in young infants and children.

Medical Care: Antipyretics Most infants and young children who are evaluated for occult bacteremia present with a fever. Some debate exists regarding the benefits of treatment of fever with antipyretics. However, while the child is evaluated to determine a source of the fever, fever reduction with medication is reasonable and widely accepted. Studies have shown that ibuprofen 10 mg/kg/dose every 8 hours or acetaminophen 10-15 mg/kg/dose every 4-6 hours are both effective and well tolerated (Walson, 1992). Infants younger than 3 months Low-risk criteria: Who should be treated?

As recently as 1984, guidelines for treating febrile young infants recommended evaluation, treatment, and hospitalization because of the increased risk of bacterial infection and the inability to clinically distinguish infants at increased risk for serious bacterial infection (Avner, 1993). Since then, a number of studies have evaluated combinations of age, temperature, history, examination findings, and laboratory results to determine which young infants are at low risk for bacterial infection (Baraff and Bass, 1993; Baker, 1993; Baskin, 1992; Dagan, 1985; Bachur, 2001). Following are the low-risk criteria established by groups from Philadelphia, Boston, and Rochester and the 1993 American Academy of Pediatrics (AAP) guideline. Table 7. Low-Risk Criteria for Infants Younger than 3 Months* Criterion Philadelphia Boston Rochester AAP 1993 Age Temperature Appearance 1-2 months 38.2C AIOS <15 1-2 months >38C Well antibiotics 0-3 months >38C Any in the Previously Nonfocal last 1-3 months >38C Well 24 hours healthy

History Immune No No immunizations in the last 48 hours Previously healthy Examination WBC count BNR <0.2 Band <1,000 Band <1,000 Nonfocal <15,000 <20,000 5-15,000

Nonfocal 5-15,000

Nonfocal

Urine assessment <10 Negative for bacteria Leukocyte esterase negative CSF assessment <8 Negative for bacteria

WBCs per HPF <10 WBCs per <10 WBCs per HPF <5 WBCs per HPF WBCs per <10 WBCs per HPF <10-20 WBCs per HPF

HPF HPF

Chest radiography No infiltrate Within normal limits, if obtained Stool culture

Within normal limits, if obtained

<5 WBCs per HPF <5 WBCs per HPF *Baker, 1993; Baskin, 1992; Dagan, 1985; Baraff and Bass, 1993 Acute illness observation score Low-risk criteria: How well do they work? The above guidelines are presented to define a group of febrile young infants who can be treated without antibiotics. Statistically, this translates into a high NPV, ie, a very high proportion of true negative cultures exists in patients deemed to be at low risk. The NPV of various low-risk criteria for serious bacterial infection and occult bacteremia are presented as follows (Baker, 1999; Kadish, 2000; Baker, 1993; Baskin, 1992; Baraff, 1992; Dagan, 1985; Baraff and Bass, 1993): Philadelphia NPV - 95-100% Boston NPV - 95-98%

Rochester NPV - 98.3-99% AAP 1993 - 99-99.8%

Application of low-risk criteria See Image 1 for a treatment approach in febrile infants younger than 3 months Children aged 3-36 months Empiric antibiotics: How well do they work? The first step in the treatment of children with FWS, described above, is to use a combination of age, temperature, and screening laboratory test results to determine the risk for serious bacterial infection or occult bacteremia. Low-risk children are generally monitored as outpatients. Children who do not fit low-risk criteria are treated with empiric antibiotics either as inpatients or as outpatients. A number of studies have compared the effectiveness of oral and parenteral antibiotics in reducing complications of occult bacteremia. Many of these studies were conducted before widespread use of the conjugate Hib vaccine (Kuppermann, 1999); parenteral antibiotics were generally found to be significantly more effective than oral treatment or no treatment in reducing the sequelae of occult bacteremia, most importantly meningitis (Baraff and Bass, 1993; Fleisher, 1994). Table 8. Occult Bacteremia - Relationship Between Outpatient Antibiotic Use and Complications* Complication Antibiotic Therapy No Antibiotic Therapy 3.8-5% 5-6.6% PO Antibiotic Therapy IM/IV 0-5% 5-7.7%

Persistent bacteremia 18-21% New focal infection 13%

Meningitis 9-10% 4.5-8.2% 0.3-1% *Baraff and Bass, 1993; Baraff, 1993; Harper, 1995; Bass, 1993; Fleisher, 1994 Recent studies and analyses have focused on specific causes of occult bacteremia other than Hib, information more applicable to current evaluation, and treatment of febrile children. Several studies and analyses have concluded that oral antibiotics and parenteral antibiotics are equally effective in reducing complications of pneumococcal bacteremia (Kuppermann, 1999; Baraff and Bass, 1993), but a recent meta-analysis found no statistical change in occurrence of meningitis between patients with and without treatment with oral antibiotics (Rothrock, 1997). Table 9. Pneumococcal Bacteremia - Relationship Between Outpatient Antibiotic Use and Complications* Complication Therapy No Antibiotic Therapy IM/IV Antibiotic Therapy 7-17% 3.3-4% 0.4-1% Any Antibiotic Therapy 1-1.5% 0.4-1.5% 2.5% 0.4-1% PO Antibiotic

Persistent bacteremia Focal infection/SBI9.7-10% Meningitis 2.7-6%

*Kuppermann, 1999; Baraff and Bass, 1993; Baraff, 1993; Jones, 1993; Lee, 2001; Bauchner, 1997; Baraff, 1997; Rothrock, 1997; Baraff, 2000 Meningococcal bacteremia is rare but important because of high rates of morbidity and mortality. Studies have found that parenteral antibiotics are significantly more effective than no treatment or oral antibiotics in reducing complications. The risk of developing meningitis with no antibiotic therapy is 50%, the risk is 29% with oral antibiotic therapy, and it is 0% with intramuscular/intravenous antibiotic therapy (Baraff, 2000). In young infants and debilitated or immunocompromised patients, Salmonella bacteremia can have serious complications. The risk of serious complications in previously healthy children aged 3-36 months with Salmonella bacteremia is small (Harper, 1993; Kuppermann, 1999). Empiric oral antibiotics have not been proven to prevent focal complications or persistence of bacteremia in children with occult nontyphoidal Salmonella bacteremia (Kuppermann, 1999). However, some form of antibiotic treatment, oral or intravenous, is recommended for all children with Salmonella bacteremia and for young infants and immunocompromised children with Salmonella gastroenteritis (Abramson, 2000). Choice of drug The choice of empiric antibiotic treatment is based primarily on the likely causes of bacteremia for a given patient and the likelihood of resistance. In very young infants, bacterial causes are most commonly acquired from the mother during childbirth. For neonates younger than 1 month, Streptococcus species and E coli are the most common pathogens. Other gram-positive and gram-negative infections are also observed, including infections with Listeria species (see Causes). Treatment with ampicillin and gentamicin is widely accepted for patients in this age group; ampicillin and cefotaxime may also be used (Baker, 1999; Jones, 1993). This combination has good gram-positive and gram-negative coverage for the most likely pathogens, and ampicillin is effective against Listeria. Thirdgeneration cephalosporins are very useful in older infants and children, but they are not active against Listeria and are not recommended as single-agent therapy in the empiric treatment of neonates younger than 1 month who are at risk for occult bacteremia (Baraff, 1992). A gradual shift toward community-acquired causes occurs as age increases; the causes of bacteremia in infants aged 1-3 months are a combination of organisms (see Causes). Empiric antibiotics used in practice vary in this age group. Some practitioners use ampicillin and gentamicin, some use ampicillin and cefotaxime, and others use ceftriaxone (Baraff and Bass, 1993; Baker, 1999; Jones, 1993). The risk for infection with Listeria is significantly deceased in children older than 4-6 weeks, and debate exists regarding whether coverage for Listeria is required in infants aged 1-3 months at risk for occult bacteremia. All these possible antibiotic regimens have excellent coverage against the other childbirth- or community-acquired bacterial pathogens in this age group. Empiric treatment of infants and children aged 3-36 months at risk for occult bacteremia is usually with ceftriaxone. This third-generation cephalosporin has broad-spectrum gram-positive and gram-negative coverage, is active against all likely community-acquired pathogens in this age group, and is resistant to beta-lactamases produced by some pathogenic organisms (Bass, 1993; Baraff, 1992). Ceftriaxone has the longest half-life of the third-generation cephalosporins, and high serum concentrations can be sustained for 24 hours with a single dose. Most body tissues and fluids are penetrated, including the CSF (Bass, 1993). Early studies of empiric coverage with oral antibiotics examined a variety of agents, including amoxicillin and penicillin. Because of concern for infection with Hib positive for beta-lactamase, later studies focused on amoxicillin/clavulanic acid. Other than antibiotic spectrum coverage, adverse effects and compliance are also considered when choosing an antibiotic treatment. Studies evaluating adverse effects of ceftriaxone and

amoxicillin/clavulanic acid have shown that, while amoxicillin/clavulanic acid more commonly causes diarrhea, the overall rate of adverse effects (eg, diarrhea, vomiting, maculopapular exanthems) is similar at approximately 5% (Bass, 1993; Fleisher, 1994). Regarding compliance, the administration of antibiotic treatment is essentially witnessed when the antibiotic is administered intramuscularly. However, in a study of compliance with 2 days of amoxicillin taken 3 times per day as outpatient treatment, approximately 10% of families reported missing at least one dose (Fleisher, 1994). Antibiotic-resistant pneumococcus The choice of empiric treatment for occult bacteremia is also impacted by antibiotic resistance, most importantly in S pneumoniae infection. Studies in Sweden, Greece, Israel, Portugal, Russia, and Nebraska have shown that 40-50% of cases of S pneumoniae in children attending day care centers are penicillin-resistant (Nilsson, 2001). To understand the role of penicillin-resistant pneumococcus in serious bacterial infection and occult bacteremia, realize that all pneumococci are not equal, antibiotic resistance patterns are not static, and resistance does not necessarily equal virulence. Penicillin resistance varies from mildly resistant (minimal inhibitory concentration [MIC] <0.1), to intermediately resistant (MIC 0.1-1), to highly resistant (MIC >1). The prevalence of penicillin resistance is increasing over time, and no change in mortality seems to be associated with invasive pneumococcal disease due to the increase in antibiotic-resistant pneumococcus (Kaplan, 2002; Friedland, 1995; Arditi, 1998). Longitudinal studies of invasive pneumococcal disease show that the prevalence of intermediately penicillin-resistant pneumococcus (MIC 0.1-1) has increased from 5-10% in 1993 to 22% in 1999, and highly penicillin-resistant pneumococcus (MIC >1) has increased from 4% in 1993 to 15% in 1999 (Baraff and Bass, 1993; Fleisher, 1994; Friedland, 1995). A survey of pneumococcal meningitis in the mid 1990s found 13% intermediately penicillin-resistant pneumococcus (MIC 0.1-1) and 7% highly penicillin-resistant pneumococcus (MIC >1) (Arditi, 1998). Antibiotic pressure likely has a large role in selecting for antibiotic-resistant pneumococci, and a longitudinal study of invasive pneumococcal disease found an increased risk of penicillin resistance in patients who have used antibiotics in the last 30 days (Kaplan, 2002). The rate of invasive disease from intermediately penicillin-resistant (MIC 0.1-1) S pneumoniae in 1993 was 5.3-10% and the rate for highly resistant (MIC >1) S pneumoniae was 4%. In 1999, the rate of invasive disease from intermediately penicillin-resistant S pneumoniae was 22%, and the rate for highly resistant S pneumoniae was 15% (Baraff and Bass, 1993; Kaplan, 2002; Fleisher, 1994). Since the end of the 1980s, researchers have been concerned that penicillin-resistant pneumococcus may also be resistant to third-generation cephalosporins (Kaplan, 2002). At that time, less than 1% of pneumonococci were resistant to ceftriaxone (Fleisher, 1994). Since then, ceftriaxone resistance has increased, but it remains significantly less common than penicillin resistance (Kaplan, 2002; Fleisher, 1994; Arditi, 1998). Longitudinal studies of invasive pneumococcal disease show that the prevalence of intermediately ceftriaxone-resistant pneumococcus (MIC 0.1-1) has increased from 3% in 1993 to 9% in 1999 (Baraff and Bass, 1993; Kaplan, 2002; Fleisher, 1994); highly ceftriaxone-resistant pneumococcus (MIC >1) has increased from 0.5% in 1993 to 2% in 1999 (Kaplan, 2002). A survey of pneumococcal meningitis in the mid 1990s found 4.4% intermediately ceftriaxoneresistant pneumococcus (MIC 0.1-1) and 2.8% highly ceftriaxone-resistant pneumococcus (MIC >1) (Arditi, 1998). The risk of invasive disease from intermediately ceftriaxone-resistant (MIC 0.1-1) S pneumoniae from 1987-1991 was 0.6%, it was 2.6% in 1993, and it was 9% in 1999. The risk of invasive disease from highly ceftriaxone-resistant (MIC >1) S pneumoniae was 0.5% in 1993 and was 2% in 1999 (Fleisher, 1994; Kaplan, 2002). Morbidity and mortality with resistance

Antibiotic resistance is increasing in pneumococcal disease, but resistance is not necessarily directly correlated with virulence. Several studies have attempted to establish whether infection with antibiotic-resistant pneumococci relates to increased morbidity or mortality. In 2 longitudinal studies of invasive pneumococcal disease and pneumococcal meningitis, no difference was observed in clinical presentation, hospital course, morbidity, or mortality among patients with disease caused by antibiotic-resistant pneumococci compared with those caused by antibiotic-susceptible pneumococci (Kaplan, 2002; Arditi, 1998). A prospective observational study of pneumococcal disease, which did not include meningitis, compared a variety of SBIs, including occult pneumococcal bacteremia. The patients were treated empirically with oral or parenteral antibiotics at the discretion of the attending physician. No significant difference was observed between penicillin-resistant and penicillin-sensitive infections in terms of duration of illness or rate of improvement. Among all the resistant and sensitive pneumococcal infections, the only treatment failure was due to an abscess caused by a penicillinsensitive pneumococcus (Friedland, 1995). Choice of treatment in the context of antibiotic resistance Analyzing the definitions used for mild, intermediate, and high resistance can be helpful when choosing antibiotic treatment. Table 10. Penicillin Resistance Defined* Resistance Mild Intermediate Penicillin Concentration, mcg/mL <0.1 0.1-1

High >1 *Friedland, 1995 Penicillin concentration (not CSF) after 15 mg/kg amoxicillin PO was 6-14 mcg/mL. On the basis of known information concerning antibiotic resistance and effectiveness of treatment, no antibiotic is clearly the choice for initial empiric treatment of febrile children aged 3-36 months at risk for occult bacteremia. On one hand, the available evidence regarding the effectiveness of oral antibiotics in preventing pneumococcal meningitis is equivocal. On the other hand, evidence suggests that morbidity and mortality are not affected by antibiotic resistance and that tissue concentrations sufficient to treat penicillin-resistant infections, other than meningitis, are achieved with oral therapy (Friedland, 1995). Effectiveness and cost-effectiveness Because of the frequency with which children with fever present to emergency departments and clinics for evaluation, the cost of evaluating and treating children with FWS can be considerable. Several authors have examined how well screening works in identifying infants and young children with occult bacteremia and how efficient empiric treatment is in preventing sequelae of bacteremia, namely meningitis. Costs of treatment and cost savings in preventing hospitalization, morbidity, and mortality have also been addressed to assess whether screening and empiric treatment are cost-effective strategies. Screening febrile infants younger than 3 months by means of history, physical examination, and laboratory tests and treating low-risk infants as outpatients has been shown to be cost-effective (Baraff and Bass, 1993). Furthermore, an analysis of the Philadelphia criteria in 1993 found that outpatient treatment based on these low-risk criteria costs $3100 less per patient than inpatient treatment (Baker, 1993).

Screening febrile infants and children aged 3-36 months based on age, degree of fever, and laboratory results has also been found to be a cost-effective and reasonable approach (Kuppermann, 1999; Baraff and Bass, 1993; Baraff, 1993; Lee, 1998). See Lab Studies for statistics associated with different laboratory values used as screening tools for occult bacteremia; most studies determined that ROC curves were most favorable for WBC counts less than 15 or ANCs less than 10, criteria that were used to define low-risk children. Although these values have an NPV of approximately 99% for occult bacteremia, a number of reviews have noted that these cutoff values may still miss 25% of children with occult bacteremia because of the large numbers of febrile children presenting for evaluation (Kuppermann, 1999; Baraff, 1993; Lee, 1998). Determining the number needed to treat (NNT) to prevent a given event is another method used to assess the effectiveness of screening criteria. Two papers have analyzed the NNT to prevent meningitis for different laboratory screening criteria in febrile children aged 3-36 months with temperatures greater than 39C. One used a WBC count greater than 15,000 and found an NNT of 500 to prevent 1 case of meningitis, and the other used an ANC greater than 10,000 and found an NNT of 240 (Kuppermann, 1999; Lee, 1998). A recent formal estimate of cost-effectiveness compares the cost of screening and treatment of febrile children using a number of different criteria (Lee, 2001). This analysis also estimates the cost of complications associated with treatment and hospitalization and estimates the costs incurred while treating patients with sequelae from untreated infections. This analysis uses an estimate of 1.5% for the rate of occult bacteremia in febrile young children, which is consistent with other current estimates (Alpern, 2001; Lee, 1998). At this rate of bacteremia, empiric testing and treatment were found to be the most cost-effective approaches for treatment of the febrile child; the cost is $72,000 per life-year saved. This strategy also compares favorably to other medical treatments that are considered cost-effective. Many authors, including the authors of this article, anticipate that the rate of occult bacteremia will decrease markedly following widespread use of the 7-valent conjugate pneumococcal vaccine (Baraff, 2000; Giebink, 2001; Lee, 2001). Using an estimate of 0.5% for the predicted rate of occult bacteremia, the authors have also calculated the cost-effectiveness of several approaches to treat febrile children. At this rate of bacteremia, the cost of empiric testing and treatment of febrile children increases markedly from $72,000 to more than $300,000 per lifeyear saved. The sensitivity and specificity of clinical judgment in predicting occult bacteremia and serious bacterial infections has varied greatly in previous studies, with a general consensus that clinical judgment is not a reliable indicator of occult bacteremia (Kuppermann, 1999; Baraff and Bass, 1993; Baraff, 1993; Baker, 1999; Bass, 1996). Clinical judgment has been estimated to be 28% sensitive and 82% specific in predicting occult bacteremia, not inconsistent with previous studies performed on children aged 3-36 months. At a decreased predicted rate of occult bacteremia of 0.5%, treatment of febrile children based on clinical judgment was found to be considerably more cost-effective than other approaches; the cost is $38,000 per life-year saved. Table 11. Cost-Effectiveness Analysis* Intervention TPA for acute myocardial infarction Medical treatment for hypertension CABG for myocardial infarction Cost Per Life-Year Saved $32,678 $20,000 $ 7,000 $72,300

Empiric testing and treatment in febrile children when rate of OB is 1.5%

Empiric testing and treatment in febrile children when rate of OB is 0.5%

>$300,000

Treatment based on clinical judgment, sensitivity 28% and specificity 82%, when rate of OB is 0.5% $38,000 *Lee, 2001 Tissue plasminogen activator Coronary artery bypass grafting Occult bacteremia If the rate of bacteremia declines to 0.5%, this analysis concluded that clinicians should reevaluate their approach in the highly febrile child and eliminate strategies that use empiric testing and treatment (Lee, 2001). Treatment algorithms The approach to febrile patients aged 3-36 months has been dominated in the United States by the 1993 Practice Guidelines, published jointly in Pediatrics and Annals of Emergency Medicine (Baraff and Bass, 1993). Considerable debate in the medical literature has followed the publication of these guidelines, and surveys indicate that considerable variation from the guidelines occurs and a wide variation exists in practice among pediatricians, family practitioners, and emergency department physicians (Kramer, 1997; Bauchner, 1997; Baraff, 1997; Isaacman, 2001; Jones, 1993). As discussed above and in Deterrence/Prevention below, a number of changes have occurred since these guidelines were published. The conjugate Hib vaccine has become the standard of care, essentially eliminating Hib as a cause of bacteremia in febrile children (Lee, 1998). The 7valent conjugate pneumococcal vaccine has received approval, and this is anticipated to dramatically decrease the rate of pneumococcal bacteremia and subsequently decrease the overall rate of bacteremia in young children (Baraff, 2000; Giebink, 2001). The prevalence of penicillinand ceftriaxone-resistant pneumococcus has increased (Baraff and Bass, 1993; Kaplan, 2002; Fleisher, 1994; Nilsson, 2001); however, no concurrent increase in mortality from pneumococcal infections is reported (Kaplan, 2002; Friedland, 1995; Arditi, 1998). Researchers are evaluating a possible role for new laboratory tests such as PCR and cytokine levels (Kuppermann, 1999; Strait, 1999; Isaacman, 1998). They recommend identifying focal infections using improved methods such as urine Gram stain for UTI screening (Baraff, 1993; Bachur, 2001; Herr, 2001). Underlying medical conditions have been demonstrated to markedly increase the risk for mortality from pneumococcal infections (Kaplan, 2002). Retrospective reviews have not shown that empiric oral antibiotics are effective in preventing pneumococcal meningitis (Rothrock, 1997). The 1993 Practice Guidelines 7 for febrile infants and young children aged 3-36 months recommended no tests or antibiotics for children with a temperature less than 39C and a nontoxic appearance. For children aged 3-36 months with a temperature at least 39C and a nontoxic appearance, a blood culture and empiric antibiotics were recommended, either for all children (option 1) or for children with a WBC count higher than 15,000 (option 2). All children who appeared toxic were admitted to the hospital for sepsis workup and parenteral antibiotics pending culture results. Urine cultures were recommended for males younger than 6 months and females younger than 2 years, stool cultures were recommended for children with blood or mucus in the stool or more than 5 WBCs per HPF on stool smear, and chest radiography was recommended for children with dyspnea, tachypnea, rales, or decreased breath sounds. Follow-up in 24-48 hours was recommended in children who had cultures drawn. In response to the 1993 Practice Guidelines, Kramer and Shapiro published an alternate approach that involved less laboratory screening and no empiric antibiotic treatment (Kramer, 1997).

Febrile children aged 3-36 months were carefully assessed for bacterial foci; children with a toxic appearance were admitted to the hospital for sepsis workup, and focal infections were treated appropriately. Children who appeared well and had no focus of infection received a urinalysis if appropriate for age, while all children received no other laboratory tests and no antibiotics and were followed up in 24 hours to assess for worsening or persistence of signs and symptoms of infection. A 1999 review by Kupperman proposed an approach to the febrile child aged 3-36 months that was based on the risk of occult bacteremia during a time after Hib had been eliminated but before the introduction of pneumococcal vaccine (Kuppermann, 1999). His algorithm divided children into the following 2 groups based on risk: those aged 3 months to 2 years and those aged 2-3 years. He also recommended laboratory screening with ANC rather than a WBC count. Kupperman recommended no laboratory tests and no antibiotics for children aged 2-3 years with a nontoxic appearance and with a temperature less than 39.5C and for children aged 3 months to 2 years with a nontoxic appearance and with a temperature less than 39C. For children aged 3 months to 2 years with a temperature of at least 39C and a nontoxic appearance and for those aged 2-3 years with a temperature of at least 39.5C and a nontoxic appearance, a blood culture and empiric antibiotics were recommended if the ANC was greater than 10,000. In 2000, Baraff published a review that included immunization status in the decision analysis of FWS (Baraff, 2000). Because of the low overall risk of occult bacteremia in children aged 3-36 months with FWS who have received the 7-valent conjugate pneumococcal vaccine, Baraff recommended that no blood work be performed in these patients irrespective of the degree of fever. He also recommended that no blood work be performed for FWS in children with a temperature less than 39.5C. A blood culture and empiric antibiotics is recommended for children with an ANC greater than 10,000 or a WBC count greater than 15,000 if the child's temperature is at least 39.5C and he or she has not received the pneumococcal vaccine. Baraff stated that for children who have received the pneumococcal vaccine, the overall prevalence of occult pneumococcal bacteremia should decrease by 90%, making screening of the WBC count or ANC impractical. For application of the algorithm approach to febrile infants and young children aged 3-36 months see Image 2.

Drug Category: Antibiotic agents -- Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Drug Name Amoxicillin (Amoxil, Biomox, Trimox) -- Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria. Adult Dose 250-500 mg/dose PO tid; not to exceed 3 g/d Pediatric Dose 40-80 mg/kg/d PO divided tid; not to exceed 2-3 g/d Contraindications Documented hypersensitivity Interactions Allopurinol may increase risk of rash Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Adjust dose in renal impairment; may enhance chance of candidiasis Drug Name Ampicillin (Marcillin, Omnipen, Polycillin, Principen, Totacillin) -Bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable to take medication PO. Until recently, the HACEK bacteria were uniformly susceptible to ampicillin. Recently, however, beta-lactamaseproducing strains of HACEK have been identified. Adult Dose 500-3000 mg IV/IM q4-6h; not to exceed 12 g/d Pediatric Dose 100-200 mg/kg/d IV/IM divided q6h

Contraindications Documented hypersensitivity Interactions Probenecid and disulfiram elevate ampicillin levels; allopurinol decreases ampicillin effects and has additive effects on ampicillin rash; may decrease effects of PO contraceptives Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Adjust dose in renal failure; evaluate rash and differentiate from hypersensitivity reaction Drug Name Ceftriaxone (Rocephin) -- Third-generation cephalosporin with broadspectrum gram-negative activity, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin-binding proteins. Adult Dose 1-4 g/d IV/IM divided q12-24d; not to exceed 4 g/d Pediatric Dose 50-100 mg/kg/d IV/IM divided q12-24h; not to exceed 4 g/d Contraindications Documented hypersensitivity Interactions Probenecid may increase ceftriaxone levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); superinfections and promotion of nonsusceptible organisms may occur with prolonged use or repeated therapy; caution in breastfeeding women Drug Name Cefotaxime (Claforan) -- For septicemia and treatment of gynecologic infections caused by susceptible organisms. Arrests bacterial cell wall synthesis, which in turn inhibits bacterial growth. Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms. Adult Dose 1-2 g/dose IV/IM q6-8h; not to exceed 12 g/d Pediatric Dose 100-200 mg/kg/d IV/IM divided q6-8h; not to exceed 12 g/d Contraindications Documented hypersensitivity Interactions Probenecid may increase cefotaxime levels; coadministration with furosemide and aminoglycosides may increase nephrotoxicity Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); superinfections and promotion of nonsusceptible organisms may occur with prolonged use or repeated therapy; has been associated with severe colitis Drug Name Gentamicin (Garamycin, I-Gent, Jenamicin) -- Aminoglycoside antibiotic used for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes. Consider if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms. Dosing regimens are numerous; adjust dose based on CrCl and changes in volume of distribution. May be administered IV/IM. Adult Dose Serious infections and normal renal function: 3 mg/kg/dose IV q8h Loading dose: 1-2.5 mg/kg IV Maintenance dose: 1-1.5 mg/kg IV q8h Extended dosing regimen for life-threatening infections: 5 mg/kg/d IV divided q6-8h Follow each regimen by at least a trough level drawn 0.5 h prior to the fourth dose; may draw a peak level 0.5 h after 30-min infusion Pediatric Dose <5 years: 2.5 mg/kg/dose IV q8h >5 years: 1.5-2.5 mg/kg/dose IV q8h or 6-7.5 mg/kg/d divided q8h; not to exceed 300 mg/d; monitor as in adults Contraindications Documented hypersensitivity

Interactions Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; because aminoglycosides enhance effects of neuromuscular blocking agents, prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possible irreversible hearing loss of varying degrees may occur (monitor regularly) Pregnancy D - Unsafe in pregnancy Precautions Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (patient not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment Drug Name Vancomycin (Vancocin, Vancoled, Lyphocin) -- Potent antibiotic directed against gram-positive organisms and active against Enterococcus species. Useful in the treatment of septicemia and skin structure infections. Indicated for patients who cannot receive or who have not responded to penicillins and cephalosporins or who have infections with resistant staphylococci. For abdominal penetrating injuries, it is combined with an agent active against enteric flora and/or anaerobes. To avoid toxicity, current recommendation is to assay vancomycin trough levels after third dose drawn 0.5 h prior to next dosing. Use creatinine clearance to adjust dose in patients diagnosed with renal impairment. Used in conjunction with gentamicin for prophylaxis in penicillin-allergic patients undergoing gastrointestinal or genitourinary procedures. Adult Dose 500 mg q6-8h IV for 7-10 d; alternatively, 1 g IV q12h for 7-10 d Pediatric Dose <1 month: <1200 g: 15 mg/kg IV qd 1200-2000 g: 10-15 mg/kg IV q12-18h >2000 g: 15-20 mg/kg IV q8-12h >1 month: 40-60 mg/kg/d IV divided tid/qid for 7-10 d Contraindications Documented hypersensitivity Interactions Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; when taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants Pregnancy C - Safety for use during pregnancy has not been established. Precautions Caution in renal failure and neutropenia; red man syndrome is caused by too rapid IV infusion (dose administered over a few min), but rarely happens when dose is administered IV over 2 h; red man syndrome is not an allergic reaction Drug Name Nafcillin (Unipen, Nafcil, Nallpen) -- Initial therapy for suspected penicillin Gresistant streptococcal or staphylococcal infections. Use parenteral therapy initially in severe infections. Change to PO therapy as condition warrants. Because of thrombophlebitis, particularly in children or elderly patients, administer parenterally only for short term (1-2 d); change to PO route as clinically indicated. Adult Dose 250 mg to 1 g PO q4-6h 500 mg to 1 g IV/IM q4-6h Pediatric Dose <1 month: 50-100 mg/kg/d IV divided q6-12h >1 month: 100-200 mg/kg/d IV divided q4-6h; not to exceed 12 g/d 50-100 mg/kg/d PO divided qid Contraindications Documented hypersensitivity Interactions Associated with warfarin resistance when administered concurrently; effects may decrease with bacteriostatic action of tetracycline derivatives Pregnancy B - Usually safe but benefits must outweigh the risks.

Precautions To optimize therapy, determine causative organisms and susceptibility; >10 d of treatment is necessary to eliminate infection and prevent sequelae (eg, endocarditis, rheumatic fever); take cultures after treatment to confirm that infection is eradicated Drug Name Meropenem (Merrem) -- Bactericidal broad-spectrum carbapenem antibiotic that inhibits cell wall synthesis. Effective against most gram-positive and gramnegative bacteria. Has slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared to imipenem. Adult Dose Mild-to-moderate infection: 1 g IV q8h Meningitis: 2 g IV q8h Pediatric Dose <3 months: Not established >3 months: Mild-to-moderate infection: 60 mg/kg/d IV divided q8h Meningitis: 120 mg/kg/d IV divided q8h; not to exceed 6 g/d Contraindications Documented hypersensitivity Interactions Probenecid may inhibit renal excretion of meropenem, increasing meropenem levels Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Pseudomembranous colitis and thrombocytopenia may occur, requiring immediate discontinuation of medication Drug Name Imipenem and cilastatin (Primaxin) -- For treatment of multiple organism infections in which other agents do not have wide spectrum coverage or are contraindicated because of potential for toxicity. Adult Dose Base initial dose on severity of infection and administer in equally divided doses 250-500 mg IV q6h; not to exceed 3-4 g/d 500-750 mg IM q12h or intra-abdominally Pediatric Dose <1 month: 20-40 mg/kg/d IV divided q12h 1-3 months: 100 mg/kg/d IV divided q6h 3 months to 12 years: 60-100 mg/kg/d IV divided q6h; not to exceed 4 g/d >12 years: Administer as in adults Contraindications Documented hypersensitivity Interactions Coadministration with cyclosporine or ganciclovir may increase CNS toxicity (eg, seizures) Pregnancy C - Safety for use during pregnancy has not been established. Precautions Adjust dose in renal insufficiency Drug Name Cefepime (Maxipime) -- Fourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins but has better gram-positive coverage. Adult Dose Mild-to-moderate infection: 1-2 g IV q12h for 5-10 d Severe infection (eg, pseudomonal, neutropenic fever): 2 g IV q8h Pediatric Dose <2 months: Not established 2 months to 16 years (<40 kg): 50 mg/kg IV q8h; not to exceed 2 g >16 years or >40 kg: Administer as in adults Contraindications Documented hypersensitivity Interactions Probenecid may increase effects of cefepime; aminoglycosides increase the nephrotoxic potential of cefepime Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Adjust dose in severe renal insufficiency (high doses may cause CNS toxicity); prolonged use of cefepime may predispose patients to superinfection

Drug Category: Antipyretic agents -- Inhibits central synthesis and release of prostaglandins that mediate the effect of endogenous pyrogens in the hypothalamus; thus, promotes the return of the set-point temperature to normal. Drug Name Ibuprofen (Advil, Excedrin IB, Ibuprin, Motrin) -- One of the few NSAIDs indicated for reduction of fever. Adult Dose 200-400 mg PO q4-6h while symptoms persist; not to exceed 3.2 g/d Pediatric Dose 10 mg/kg PO q8h Contraindications Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding Interactions Coadministration with aspirin increases risk of inducing serious NSAIDrelated side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Pregnancy category D in third trimester; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in coagulation abnormalities or during anticoagulant therapy Drug Name Acetaminophen (Aspirin Free Anacin, Feverall, Tempra, Tylenol) -Reduces fever by acting directly on hypothalamic heat-regulating centers, which increases dissipation of body heat via vasodilation and sweating. Adult Dose 325-650 mg PO q4-6h or 1000 mg tid/qid; not to exceed 4 g/d Pediatric Dose <12 years: 10-15 mg/kg/dose PO q4-6h prn; not to exceed 2.6 g/d >12 years: Administer as in adults; not to exceed 5 doses in 24 h Contraindications Documented hypersensitivity; known G-6-PD deficiency Interactions Rifampin can reduce analgesic effects of acetaminophen; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity Pregnancy B - Usually safe but benefits must outweigh the risks. Precautions Hepatotoxicity possible with long-term use of high doses or acute overdose; severe or recurrent pain or high or continued fever may indicate a serious illness; contained in many OTC products and combined use with these products may result in cumulative doses exceeding recommended maximum dose Further Inpatient Care: Hospitalization
o

Neonates younger than 1 month: Most guidelines recommend hospitalization, with or without antibiotic therapy, for all febrile infants younger than one month pending culture results (Baraff and Bass, 1993; Baker, 1999). Infants aged 1-3 months: Most guidelines recommend hospitalization for infants in this age group who do not meet low-risk criteria, ie, they are ill-appearing, appear toxic, are hypotensive, or were not previously healthy or they have a focal infection, high-risk petechiae, UTI, or WBC count less than 5 or greater than 15. Infants who need supportive care such as oxygen and IV fluids should also be treated as inpatients, as well as those who cannot be treated as outpatients because of caregiver, transportation, communication, or other logistics (Baraff and Bass, 1993; Jaskiewicz, 1993). Outpatients whose blood or CSF cultures are

positive for known bacterial pathogens should be readmitted for IV antibiotic therapy (Baraff and Bass, 1993).
o

Children aged 3-36 months: Infants and young children in this age group should be hospitalized if a concern for sepsis exists because of toxic appearance, unstable vital signs, or high-risk petechiae on examination. They may also be admitted if they cannot be treated as outpatients because of caregiver, transportation, communication, or other logistics (Baraff and Bass, 1993; Jaskiewicz, 1993). Many infants and young children in this age group are initially treated as outpatients. They may need to be admitted if a blood culture is positive for known pathogens, depending on the clinical status of the patient and the specific organism grown (see Further Outpatient Care).

Tailored antibiotic therapy

o

Although this article focuses on the management of bacteremia caused by S pneumoniae, which is the most common isolated organism, occult bacteremia can be caused by rare pathogens, such as Enterobacteriaceae species and S aureus, which are not optimally covered by the most common empiric antibiotics. As microbiologic laboratory data become available, antibiotic coverage may be tailored for improved coverage against specific organisms. Carbapenems, vancomycin, and cefepime should be considered when pathogens that are resistant to other antibiotics are recovered or suspected. While these antibiotics have not been studied or suggested as empiric coverage in patients with fever without a source, they may be very useful when tailoring antibiotic treatment for a given patient. Microbiology, antibiotic coverage, and the clinical situation should be considered together when tailoring antibiotic therapy. A full discussion of focal infections and treatment approaches to rare pathogens is beyond the scope of this article, but two important situations warrant mention. First, vancomycin should be added upon clinical concern for meningitis to cover possible penicillin- and ceftriaxoneresistant gram-positive organisms. Second, any infant or child with occult S aureus bacteremia should have an evaluation for a likely underlying source of infection, such as osteomyelitis or endocarditis, and should be covered with vancomycin or nafcillin.

Further Outpatient Care: Follow-up care: Febrile infants and young children who have a known source for their fever, such as a recognizable viral infection, soft tissue infection, pneumonia, or UTI, should be monitored based on guidelines for those specific infections. Febrile infants and young children who have been evaluated and found to have FWS should be closely observed and reevaluated in 24 hours. This can be conducted as an inpatient (see Further Inpatient Care) or outpatient, with or without blood cultures and antibiotics.

Antibiotic treatment at follow-up: The 1993 AAP guidelines recommend that all children at risk for occult bacteremia be reevaluated in 18-24 hours. For children who remained asymptomatic, continued to have nonfocal examination findings, and had blood cultures that were negative at 24 hours, a second dose of ceftriaxone 50 mg/kg IM is

recommended to cover for a total of 48 hours of negative cultures (Baraff and Bass, 1993).

Monitoring blood cultures: In addition to reevaluating the patient in 24 hours, monitoring blood cultures is important in detecting occult bacteremia and preventing sequelae of subsequent focal infections. A recent review stated that 50% of patients with serious complications from occult bacteremia returned for evaluation and treatment because of a positive blood culture; only 12% returned because of illness (Kuppermann, 1999). For adequate outpatient follow-up and monitoring of blood culture results, the laboratory must be able to contact the physician, the physician must be able to contact the family, and the family must be able to seek care as soon as the blood culture becomes positive. Positive blood cultures: Patients who are evaluated for FWS and are monitored as outpatients with blood cultures must be reevaluated if the blood cultures become positive with a known pathogen. The appropriate treatment depends on the clinical situation and the specific bacteria present.
o

S pneumoniae Infants and young children with occult pneumococcal bacteremia may be treated and monitored as outpatients if they are well-appearing and afebrile on follow-up (Harper, 1993; Kuppermann, 1999; Baraff and Bass, 1993). Treatment recommendations include a second dose of ceftriaxone with the addition of an oral antibiotic when sensitivities are known or empiric addition of an oral antibiotic on day 2 (Harper, 1993; Kuppermann, 1999; Baraff and Bass, 1993). Therapy with ceftriaxone is recommended if concern for penicillin-resistant pneumococcus exists because of recent antibiotic use (Baraff and Bass, 1993). An alternate choice for oral antibiotic coverage may be necessary if the patient is allergic to penicillin. If a patient with pneumococcal bacteremia is febrile or ill-appearing on follow-up, the treatment should include a complete evaluation with lumbar puncture, parenteral antibiotics, and hospitalization pending culture sensitivities. Serious bacterial infection (eg, meningitis) and pneumococcus resistant to third-generation cephalosporins are concerns; thus, hospitalization and close monitoring are recommended, with adjustment of antibiotic coverage as indicated by sensitivities and clinical course (Harper, 1993; Kuppermann, 1999; Baraff and Bass, 1993). Salmonella: Patients with Salmonella bacteremia should be treated with a course of antibiotics and monitored appropriately. Appropriate therapy depends on the clinical situation; patients who are ill-appearing, febrile, younger than 3 months, or immunocompromised should receive a full sepsis evaluation and parenteral antibiotics, whereas immunocompetent afebrile children aged 3-36 months may be treated with a course of oral antibiotics (Kuppermann, 1999; Abramson, 2000). N meningitidis: As many as 50% of children who develop meningococcal disease are evaluated 2-3 days before the diagnosis and are treated on an outpatient basis for FWS (Kuppermann, 1999). Meningococcal disease has a high rate of occult

presentation, and meningococcal bacteremia has a high potential morbidity and mortality rate because of focal complications such as meningitis, shock, and extremity necrosis. Treatment in patients with meningococcal bacteremia, regardless of clinical appearance, should involve a full sepsis evaluation, parenteral antibiotics, and hospitalization (Harper, 1993; Kuppermann, 1999). In/Out Patient Meds: Amoxicillin, ampicillin, ceftriaxone, cefotaxime (see Medication) Transfer: Transfer is not likely unless complications such as sepsis or focal infections are present. Deterrence/Prevention: Secondary prevention: Early identification of outpatients by screening and empiric antibiotic treatment of febrile infants and young children at risk for occult bacteremia is a form of secondary prevention. This approach does not prevent bacteria from entering the bloodstream in the first place, but it does prevent subsequent focal bacterial illness, morbidity, and mortality (Bass, 1993).

Judicious antibiotic use: Approximately 30% of children with invasive pneumococcal infections received antibiotic treatment in the month before the infection, and children who have received antibiotics within the last month are at increased risk for invasive pneumococcal disease with antibiotic-resistant strains (Kaplan, 2002). This suggests that judicious use of antibiotics for upper respiratory infections, bronchitis, acute otitis media, and sinusitis can prevent pneumococcal infections by decreasing the antibiotic pressure that selects for invasive and resistant pneumococcal strains. Recent history - The conjugate Hib vaccine o Widespread use of the conjugate Hib vaccine in the early 1990s is a recent example of the potential effects of vaccines as primary prevention. Before this vaccine, invasive Hib disease accounted for 10% of occult bacteremia in children aged 3-36 months; children with untreated bacteremia had approximately 20% risk for persistent bacteremia and up to 15% risk for important focal infections such as meningitis (Harper, 1993; Baraff and Bass, 1993; Baraff, 1993; Harper, 1995). o Introduction of the vaccine decreased the incidence of invasive Hib disease by 90% shortly after its widespread use (Baraff, 2000; Baraff, 1993). Use of the vaccine has now essentially eliminated Hib as a cause of invasive disease in immunized children (Lee, 1998). This unabashed success story serves not only as an example of prevention in occult bacteremia, but also, the authors hope, as a roadmap for expectations following widespread use of the conjugate 7-valent pneumococcal vaccine. S pneumoniae vaccine
o

The prevalence of occult bacteremia caused by pneumococcus is anticipated to decrease greatly in the near future because of the introduction of the 7-valent conjugate pneumococcal vaccine, which was designed to cover 98% of the strains of S pneumoniae responsible for occult bacteremia (Alpern, 2001). A recent multicenter surveillance found that 82-94% of S pneumoniae invasive

disease is caused by isolates that are contained in the 7-valent conjugate pneumococcal vaccine (see List of strains of S pneumoniae in Causes) (Kaplan, 2002).
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Results of initial efficacy studies of the 7-valent pneumococcal vaccine are encouraging. Published reports of the phase II US trials in 37,000 children found that that the vaccine was 97% effective for vaccine-associated strains in fully vaccinated children and 89% effective overall (Baraff, 2000; Giebink, 2001). A study of the efficacy of this vaccine during the first year of its licensure indicates that 34-58% of children received at least one dose of vaccine and 14-16% of children were fully vaccinated, and a 58-87% reduction in invasive pneumococcal disease occurred (Black, 2001). A number of authors have expressed a concern that reducing nasopharyngeal carriage of the vaccine serotypes may leave an ecologic niche that will be filled by invasive serotypes not included in the vaccine (Baraff, 2000). Early studies in the United States and a study in East Africa using a 5-valent conjugate pneumococcal vaccine reveal evidence of serotype replacement in nasopharyngeal carriage (Baraff, 2000; Obaro, 1996). However, the connection between colonization and virulence is not necessarily a direct one. No evidence indicates that nonvaccine strains in vaccinated children increase the rates of invasive disease (Baraff, 2000; Black, 2001). A concern also exists that use of the 7-valent conjugate pneumococcal vaccine may alter antibiotic resistance patterns. Early studies show that the most common serogroups associated with penicillin resistance are all included in the vaccine (Kaplan, 2002). Although the indications and dosing schedule for the 7-valent conjugate pneumococcal vaccine are a separate topic and not fully addressed here, evidence suggests that the vaccine should be administered to all children younger than 5 years and priority should be given to children with underlying illnesses because of increased risk of morbidity and mortality associated with invasive pneumococcal infections (Kaplan, 2002).

Complications: Complications of bacteremia (see Morbidity/Mortality)

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Occult bacteremia results in morbidity and mortality due to focal infections that arise following the initial bloodstream infection. Most episodes of occult bacteremia resolve spontaneously, and serious sequelae are increasingly uncommon. However, serious bacterial infections occur, including pneumonia, septic arthritis, osteomyelitis, cellulitis, meningitis, and sepsis; death may result (Kuppermann, 1999; Kramer, 1997). Of all focal infections that develop as a result of pneumococcal bacteremia, pneumococcal meningitis carries the highest risk for significant morbidity and mortality, including a 25-30% risk of neurologic sequelae such as deafness, mental retardation, seizures, and paralysis (Kuppermann, 1999; Baraff, 2000).

Complications of hospitalization
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In addition to complications associated with bacteremia and its sequelae, a number of possible complications are associated with evaluation and empiric treatment of infants and young children at risk for occult bacteremia. A study of hospitalized febrile infants younger than 2 months found that complications were common, many complications were preventable, and most infants were hospitalized longer than necessary (DeAngelis, 1983). In this study, 20% of all admissions resulted in at least one complication, and 60% of these complications were believed to be preventable, eg, medications overdose, fluid overload, IV infiltrate, IV skin sloughing, a kidnapped infant, and follow-up for contaminated cultures. Of the infants in this study who were evaluated and found not to have bacterial disease on the basis of negative cultures, 98% were hospitalized longer than 72 hours. The risk of complications should be considered when weighing the risks and benefits of evaluation and empiric treatment of febrile infants and young children at risk for occult bacteremia and its sequelae. As the overall risk of occult bacteremia decreases with widespread use of the conjugate pneumococcal vaccine, this balance between risk and benefit may need to be reevaluated.

Prognosis: Most episodes of occult bacteremia resolve spontaneously, and serious sequelae are increasingly uncommon. However, serious bacterial infections occur, including pneumonia, septic arthritis, osteomyelitis, cellulitis, meningitis, and sepsis; death may result (Kuppermann, 1999; Kramer, 1997).

Evaluation, treatment, and follow-up of febrile infants and young children at risk for occult bacteremia significantly decrease the risk for serious bacterial infections and sequelae.

Patient Education: For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Sepsis (Blood Infection). Medical/Legal Pitfalls: Lawsuits may be directed at physicians who have performed the initial evaluations of young febrile children with occult bacteremia before the development of focal complications or overt signs of disease are well described (Kuppermann, 1999). Appropriate evaluation, screening, treatment, and follow-up care can significantly decrease sequelae. Caption: Picture 1. Bacteremia. Application of low-risk criteria and approach for the febrile infant - A reasonable approach for treating febrile infants who are younger than 3 months and have a temperature greater than 38C.

Picture Type: Image Caption: Picture 2. Bacteremia. Application of algorithms for children aged 3-36 months - A reasonable approach for treating infants and young children who are aged 3-36 months and have a temperature of at least 39.5C.

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