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Bacteremia

Last Updated: June 23, 2004 Rate this Article

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Synonyms and related keywords: bacteriemia, fever, fever without a source, FWS, occultbacteremia, bloodstream infection, serious bacterial infection, SBI

Author:Brian J Holland, MD, Staff Physician, Department of Pediatrics, Tripler Army MedicalCenter

Coauthor(s): Denise Demers, MD, FAAP, Assistant Professor of Pediatrics, UniformedServices 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 AlphaEditor(s): Itzhak Brook, MD, MSc, Professor, Department of Pediatrics, GeorgetownUniversity School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor,University of Nebraska Medical Center College of Pharmacy; Mark R Schleiss, MD, AssociateProfessor, Department of Pediatrics, Division of Infectious Diseases, University of Cincinnatiand Children's Hospital Research Foundation; Robert W Tolan, Jr, MD, Chief of PediatricInfectious Diseases, St. Peter's University Hospital and Capital Health System, ClinicalAssociate Professor of Pediatrics, Drexel University College of Medicine; and Russell Steele,MD, Professor and Vice Chairman, Department of Pediatrics, Head, Division of InfectiousDiseases, 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 underlyingillness 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 havean 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 organdysfunction. Septic shock occurs in children who do not respond to adequate volumeresuscitation or require vasopressors or inotropes. Bacteria may be present in the bloodstream ofchildren with focal infections, sepsis, severe sepsis, or septic shock; however, those topics arebeyond 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 infectionother than fever (Harper, 1993). First described in the 1960s in young febrile children withunsuspected pneumococcal infection, bacteremia is defined as the presence of bacteria in thebloodstream of a previously healthy child with a fever; the child does not clinically appear to beill and has no apparent focus of infection (Lorin, 1993; Swindell, 1993). A recent review definesoccult bacteremia as bacteremia identified in a patient without clinical evidence of sepsis (shockor purpura) or a toxic appearance, without underlying significant chronic medical conditions,
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without clear foci of infection on examination (other than acute otitis media), and who isdischarged 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 thefirst 2 years of life (McCarthy, 1998). Fever also prompts a large number of visits to the pediatricclinic and emergency department. Approximately 8-25% of doctor's visits by children youngerthan 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 andBass, 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 toillness or stress (McCarthy, 1998). Approximately 1% of infants younger than 2 months presentwith fever, and fever is twice as common in infants aged 1-2 months as it is in newborns youngerthan 1 month (McCarthy, 1998).

Of all pediatric patients presenting for evaluation of fever, 20% have fever for which the sourceof infection is undetermined after a history and physical examination (Baraff, 2000). Of allinfants and young children who present to the hospital for any reason, 1.6% are nontoxicappearing, 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. Thepresumed mechanism begins with bacterial colonization of the respiratory passages; bacteria mayegress 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 possiblesequelae of septicemia include shock, disseminated intravascular coagulation, multiple organfailure, and death (Harper, 1993; Bass, 1993).

Fever is often the only presenting sign in patients with occult bacteremia; it is defined asincreased temperature caused by resetting the thermoregulatory center in the hypothalamus byaction of cytokines (McCarthy, 1998). The cytokines may be produced in response to viral orbacterial pathogens or by immune complexes. An increased temperature does not alwaysrepresent a fever. Hyperthermia may also be due to increased heat production as occurs inexercise 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 whethercytokines are produced to mount a fever response. The risk of life-threatening bacterial disease isgreatest in young infants when their immune system is least mature; they have poorimmunoglobulin G (IgG) antibody response to encapsulated bacteria and decreased opsoninactivity, macrophage function, and neutrophil activity (Baker, 1999; Jaskiewicz, 1993).


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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-riskcriteria based on a combination of these, and past medical history. These studies are partof 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 bynumerous investigators (see Physical). A child who is toxic or lethargic is generallydescribed as making poor eye contact, having poor interactions with parents and theenvironment, and showing signs on global assessment of poor perfusion, hypoventilationor hyperventilation, or cyanosis (Baraff and Bass, 1993).

In children younger than 3 months, the risk of bacteremia is 1.2-2% in infants who arenot toxic and 10-11% in infants who are toxic (Baraff and Bass, 1993; Baraff, 1992). Inchildren aged 3-36 months who are toxic, the risk of bacteremia or serious bacterialinfection 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 relationshipbetween temperature and risk of occult bacteremia. Most studies define fever as atemperature 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 predictoccult bacteremia, they include only children who have FWS, which is defined as anacute febrile illness in which the etiology is not apparent after a careful history andphysical 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 FWSwas 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 theconjugateHaemophilus influenzae type b (Hib) vaccine, the risk of occult bacteremia was1.5-2.3% 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 pneumococcalvaccine is 90% effective in preventing invasive disease caused by Streptococcuspneumoniae. Widespread use is likely to significantly decrease the overall risk of occultbacteremia (Baraff, 2000; Black, 2001; Kaplan, 2002).

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

Mortality/Morbidity: The natural history, morbidity, and mortality of occult bacteremia aloneare not clearly understood. In prospective studies of occult bacteremia, although many childrenwere observed untreated initially, all were administered antibiotics once blood cultures becamepositive (Kuppermann, 1999). Occult bacteremia results in morbidity and mortality due to focalinfections that arise following the initial bloodstream infection. Most episodes of occult
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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 untreatedbacteremia had an 18-21% risk of developing persistent bacteremia and a 2-15% risk ofdeveloping 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 thedeveloped world, recent reviews, analyses, and studies have focused on invasive S pneumoniaedisease. Children with occult pneumococcal bacteremia have a 6-17% risk of persistentbacteremia, 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, pneumococcalmeningitis 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 theprevalence of meningococcal bacteremia is much lower than that of pneumococcal disease (seeCauses), the morbidity and mortality is much greater. Children with meningococcal bacteremiahave 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 rateof 4% (Harper, 1993; Kuppermann, 1999; Baraff, 2000).When untreated, Salmonella bacteremia carries a 50% risk of persistent bacteremia. It can causemeningitis, sepsis, and death in infants younger than 3 months or in persons who are debilitatedor immunocompromised (Kuppermann, 1999). However, in previously healthy young childrenaged 3-36 months, the risk of meningitis or serious bacterial infection following Salmonellabacteremia 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 nochange with age in risk of occult bacteremia (Bass, 1993), while other analyses have found thatvariations 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 to2 years are at increased risk (Swindell, 1993; Kuppermann, 1999; Lee, 1998), and a peak in theincidence of pneumococcal meningitis occurs in infants aged 3-5 months. Meningococcalbacteremia 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 ofSalmonella bacteremia is greatest in infants younger than 1 year, especially in those younger than2 months (Kuppermann, 1999).A seasonal variation exists in febrile children presenting for evaluation. The peak is from late fallto early spring in children of all ages, likely because of respiratory and gastrointestinal viralinfections. Another peak occurs during the summer in infants younger than 3 months, likelybecause of enteroviral infections and thermoregulation during hot weather (McCarthy, 1998).However, seasonal variation in bacteremia is not specifically addressed by most studies.
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History: Many studies have been performed to determine if elements of the past medical historyand history of the acute illness may help in deciding whether a given febrile child is at high riskfor bacterial infection.The significance of history varies on the basis of age. In neonates younger than 1 month with afever, elements of the past medical history are not useful in determining whether the bacterialinfection is serious (Kadish, 2000). The history of the acute febrile illness is also not useful

because nonspecific symptoms such as feeding intolerance, temperature instability, mildrespiratory 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 thosepatients with negative blood cultures (mean 25 h) (Bass, 1993). However, this differenceis not statistically significant, and screening for bacteremia based on duration of feverless than 2 days would include 80% of patients with bacteremia and 74% of those withoutbacteremia (Kuppermann, 1999). Overall, duration of fever is inadequate to clinicallydistinguish 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 localepidemiology involving an outbreak of meningococcus, along with history of contactwith someone with known meningococcal disease, can raise clinical suspicion and helpconfirm 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 youngchildren are at increased risk for bacterial infection, including occult bacteremia.

o 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 60days or younger (Jaskiewicz, 1993; Baraff, 1992). These criteria include thefollowing:

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

o 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 (38C [100.4F], 3-36 moand 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)
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History of underlying medical condition: A recent longitudinal study of invasive

pneumococcal infections found that a history of an underlying medical condition was asignificant risk factor for increased mortality. Children with invasive pneumococcalinfections and an underlying medical condition had a mortality rate of 3.4%, whereaspreviously healthy children with invasive pneumococcal infections had a mortality rate of0.84% (Kaplan, 2002).

History of other reason for increased temperature: The history may also indicate possibleexplanations for increased temperature other than fever in response to an acute infection,such as recent vaccinations, overbundling, or environmental exposure to heat in a younginfant (Baraff and Bass, 1993). A thorough evaluation for illness or infection should beperformed in all febrile children before determining that increased temperature is causedby any extrinsic factor.

Diarrhea, Salmonella: A history of gastroenteritis should increase the clinical suspicion

forSalmonella bacteremia. Salmonella is an uncommon cause of gastroenteritis, but mostpatients who develop Salmonella bacteremia have gastroenteritis, and 6.5% of childrenyounger 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 notexcluded from studies of occult bacteremia. Results suggest that the risk of bacteremia infebrile 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 havebeen associated with an increased risk of pneumococcal bacteremia include day careattendance (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 aremore 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 patienttruly has an FWS. Toxic or lethargic children and patients with focal infection and sepsis aretreated appropriately, and children with nonfocal physical examination findings are furtherevaluated for occult bacteremia (Baraff and Bass, 1993; Baker, 1999; Dirnberger, 1996).

General appearance

o The initial aspect of the physical examination, assessment of general appearance,

has been formally defined by a number of investigators in an attempt to assessthe utility in determining the presence of bacterial disease. The Yale ObservationScale (YOS)/Acute Illness Observation Scale (AIOS) has been widely used. It isused 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).

o Rigorous studies by a number of authors have found that the use of clinical

scores, observation scores, social smile, and general appearance has not beenclinically useful in distinguishing occult bacteremia, especially in young infants


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(Harper, 1993; Bass, 1993; Baker, 1999; Strait, 1999; Bass, 1996). Generalappearance using observation scores had a sensitivity of 74% and specificity of75% 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 youngerthan 2 months (Baker, 1999). General appearance had 5.2% sensitivity fordetecting occult bacteremia, and social smile was 45% sensitive and 51% specific

for bacteremia (Kuppermann, 1999; Bass, 1996).o A recent cost-effectiveness analysis suggests that clinical judgment of general

appearance (YOS


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shown a variation in risk at given temperatures based on age; this has led to thefever cutoffs listed above.

Table 1. Age, Fever, and Bacterial Infection*

Age Temperature Rate of bacterial infection

Neonates 40C 18%

Infants aged 1-2 mo 38-38.9C 3%39-39.9C 5%>40C 26%

*Bonadio, 1993

Table 2. Children Aged 3-36 Months - Fever and Occult Bacteremia*

Temperature Occult Pneumococcal Bacteremia, % Positive BloodCulture, % Positive Blood Culture, % Occult Pneumococcal

Bacteremia, %

41C 9.3 9.2 12 10-10.4

*Kuppermann, 1999; Harper, 1993; Swindell, 1993; Baraff, 2000; Baraff, 1997

o 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 orclinical appearance after defervescence exists. Both groups experience the same decreasein 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 infectionsshould be treated appropriately and does not require evaluation for occult bacteremia(Baraff and Bass, 1993).


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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 beincreased if a petechial rash is found (Baraff and Bass, 1993; Baraff, 2000). However, arecent prospective cohort of children with fever and petechiae found a 1.6% risk forbacteremia or sepsis and a 0.5% risk of meningococcal infection. The children withserious bacterial infection in this study had additional findings from the history and

physical examination that suggest a bacterial cause for petechiae. These findings includeill 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 moststudies of occult bacteremia, these children were included for evaluation. The results ofthese studies show that the risk of bacteremia is the same in children with acute otitismedia 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

o 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 soundshave 94-99% specificity for pneumonia (Bachur, 1999). Febrile children whohave none of these findings rarely have pneumonia. Recent studies suggest thatpulse oximetry may be a more reliable predictor of pulmonary infections thanrespiratory rate in infants and young children; a recent guideline recommendsthat patients with oxygen saturation less than 95% be evaluated for pneumonia bymeans of chest radiography (Baraff, 2000).

o

Evaluation for occult bacteremia is still warranted in febrile children with clinicalor radiographic pneumonia. Mild respiratory distress may indicate a seriousbacterial infection in a very young infant, and studies of occult bacteremia foundthat patients with pneumonia have the same prevalence of bacteremia as patientswithout 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 otherrecognizable viral infections are generally accepted as a fever source. Children withvaricella, croup, gingivostomatitis, herpangina, and bronchiolitis have less than 1%chance of bacteremia (Kuppermann, 1999). A retrospective study of children with theserecognizable viral syndromes found a risk of 0.2% for true pathogens and 1.4% for

contaminants (Greenes, 1999). Group A streptococcal bacteremia occurs sporadically inchildren with varicella, but these children usually are toxic or have focal findings(Kuppermann, 1999). Physical examination findings consistent with these viral infectionsgenerally remove children from studies of bacteremia; these children should be treatedfor viral infection without further evaluation for occult bacteremia (Harper, 1993;Kuppermann, 1999; Greenes, 1999).


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Causes: Causes of occult bacteremia vary depending on the age of the infant or child. The mostcommon causes of infection for very young infants are acquired from the mother duringchildbirth. 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 orHigher*Age Organism Positive Blood Cultures

Neonates


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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, 1998Also, E coli, S aureus, Streptococcus pyogenes, group B Streptococcus, Moraxella species,Kingella species, Yersinia species, andEnterobacterspeciesThe 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 occultbacteremia (Alpern, 2001). A recent multicenter surveillance found that 82-94% ofS pneumoniaeinvasive disease was caused by isolates that are contained in the 7-valent conjugatepneumococcal vaccine, which is the only pneumococcal vaccine that the Food and DrugAdministration (FDA) has approved for infants and young children at the time of this writing(Kaplan, 2002).A list of strains ofS pneumoniae and the percentage of pneumococcal bacteremia caused by eachstrain is as follows (all except S pneumoniae 6 are 98% covered by the 7-valent conjugatepneumococcal 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 syndromeAutoimmune disorder Poor thermoregulation, environmental problemsTumorAcute subdural hematomaFocal bacterial infection Quick Find

Lab Studies:

White blood cell count

o The WBC count has been the most widely studied laboratory parameter in occult

bacteremia. The risk of occult bacteremia and occult pneumococcal bacteremiahas been consistently found to increase with an increased WBC count
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(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 usedslightly different inclusion and exclusion criteria, age ranges, and fever cutoffs. Aconsistent trend has been that children aged 3-36 months with FWS and a WBCcount higher than 15 are at increased risk for occult bacteremia (Kuppermann,

1999; Baraff and Bass, 1993; Baraff, 2000; Baraff, 1993; Bass, 1993; Baraff,1997).

o 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 WBCcounts 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%o Receiving operator characteristic (ROC) curves for WBC count were superior to

nearly all other laboratory studies, although a recent analysis found that thescreening characteristics of WBC counts were not significant when adjusted forother variables such as absolute neutrophil count (ANC), temperature, age, andYOS (Lee, 1998; Strait, 1999; Kuppermann, 1999).

Table 5. WBC Count as a Screen for Occult Bacteremia*

WBC Count Sensitivity, % Specificity, % PPV, % NPV,

%

15 80 69 6 99.3

>15 (post-Hib) 86 77 5.1

>15 48 79 5.5 98.3

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

o Infants younger than 3 months are considered separately in most studies of

bacteremia. Guidelines established by groups in Rochester, Boston, andPhiladelphia were published inPediatrics in 1993. All of these guidelines aimedat defining populations of infants who are at low risk for bacterial infection. Eachof 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 1993Pediatrics guideline - 5,000-15,000

Absolute neutrophil count


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o 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 ANCas a screen for bacteremia (Baraff and Bass, 1993), more recent studies andguidelines suggest that ANC higher than 7-10 has favorable screeningcharacteristics.

o ROC curves for ANC are equal to the WBC count, and a recent analysis foundthat the screening characteristics of ANC remained significant when adjusting forother 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 pneumococcalbacteremia 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 Sensitivity Specificity PPV NPV

10,000 76% 78% 8% 99.2%

>7200 82% 74% 7.5% 99.4%*Kuppermann, 1999; Strait, 1999

Band count

o 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 foroccult bacteremia generally tends to increase with increasing ABC; however, nowell-defined cutoff exists, ROC curve characteristics are poor compared withthose of ANC and WBC count, and any changes in ABC are not significant whenadjusting for other variables.

o Elevated band counts have also been found in 21-29% of patients with culture-

proven viral infections (Wack, 1994). The ABC may be the most importantcomponent of the CBC for meningococcal bacteremia, but the low overallprevalence 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%

o Bandemia (band >15%) is related to cases of viral infections as follows (Wack,

1994):

Influenza A and B - 29% Enterovirus - 23%
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Respiratory syncytial virus - 22% Rotavirus - 22%

o In most studies of bacteremia, infants younger than 3 months are considered

separately. Groups in Rochester, Boston, and Philadelphia have establishedguidelines aimed at defining populations of infants who are at low risk forbacterial 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 bandcriteria 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 1993Pediatrics - Less than 1000 ABC

Erythrocyte sedimentation rate and C-reactive protein

o A number of studies have evaluated erythrocyte sedimentation rate (ESR) and C-

reactive protein (CRP) as markers for bacterial infection. Most studies wereconducted before widespread use of the conjugate Hib vaccine and includedhospitalized patients and patients with focal infections. These studies found thatESR 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 ofthis information, ESR and CRP are not currently recommended as screening testsfor occult bacteremia (Kuppermann, 1999; Baraff and Bass, 1993).

o 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) andpneumonia in addition to occult bacteremia. The studies found overall rates ofserious bacterial infections that were higher than other published data. However,the results suggest that CRP may be a better screening tool than ANC or WBCcount for detecting occult bacterial infections. The prospect of a rapid effectivescreening 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 theselevels 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-6as a test for occult bacteremia had a sensitivity of 88%, a specificity of 70%, a PPV of7.0%, and an NPV of 99.6% (Strait, 1999). These cytokines still have not beenthoroughly investigated; they have marginal clinical utility, unknown cost-effectiveness,and are not recommended as routine screening laboratory studies for occultbacteremia (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 articleshave examined PCT as a marker for bacterial infection in the setting of sepsis or focalinfections. A few small studies have also looked at PCT as a marker of bacterial infectionin FWS and UTI (Lacour, 2001; Gervaix, 2001). Early data suggest that PCT may be


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effective in differentiating infection from inflammation and that it may be fairly specificin distinguishing bacterial versus viral infection early in the clinical course of infection.Although prolactin is currently used mostly in research laboratories, rapid tests have beendeveloped 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 betweenvacuoles or toxic granulations and bacterial infection were performed in the era beforethe conjugate Hib vaccine. In one study, which included patients with focal disease,vacuoles and toxic granulations were found to have greater sensitivity and PPV thanWBC counts (Harper, 1993; Kuppermann, 1999). Another study found that vacuolizationcorrelated with fever and leukocytosis but not with bacterial disease (Kuppermann,1999). These WBC microscopic changes are generally not recommended as a screen foroccult bacteremia.

Latex agglutination: Latex agglutination is sensitive for the detection of occult H

influenzae bacteremia, but widespread use of the conjugate Hib vaccine has essentiallyeliminated Hib as a cause of occult bacteremia (see Causes). Latex agglutination is notsensitive 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 recommendedfor 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 aspecificity of 55% (Isaacman, 1998). Two recent reviews concluded that the overall lowlevel of clinical accuracy seems insufficient to justify its use in screening for occultbacteremia. Use of PCR in the evaluation of occult meningococcal bacteremia has notbeen studied. In studies of known meningococcal disease, PCR is sensitive and specificand 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 thisfocal infection and do not require further evaluation for occult bacteremia. Ofchildren evaluated for FWS, approximately 7% of males younger than 6 monthsand 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 1month recommend a laboratory evaluation for UTI, and most guidelines alsorecommend urine studies in girls younger than 1-2 years and boys younger than 6months (Baraff and Bass, 1993).

o 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 asfewer than 5-10 WBCs per high-powered field (HPF), no bacteria, and negativenitrite 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 positiveurine culture were not detected by the screening urinalysis (Baraff, 1993).


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o Recent studies using enhanced urinalysis (cell count by hemocytometer and urine

Gram stain) and Gram stain of urine sediment showed 99-100% sensitivity and100% NPV for UTI (Baraff, 1993; Herr, 2001). Improvement in sensitivity ofurine studies has great potential for improving detection of systemic bacterialinfection (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 inpneumococcal bacteremia. A WBC count is not a useful screening test becausemost infants and children with Salmonella bacteremia have a WBC count lessthan 15,000, and only one half of patients have a left shift of the WBCdifferential (Kuppermann, 1999). Most patients who develop Salmonellabacteremia have gastroenteritis, and 6.5% of children younger than 1 year whohave Salmonella gastroenteritis become bacteremic (Kuppermann, 1999).Because of this association, stool cultures are recommended for children withdiarrhea (Baraff and Bass, 1993; Baraff, 1993).

o 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 ofpatients with Salmonella bacteremia were improperly identified as being at lowrisk by these guidelines, and current guidelines recommend a screening stoolevaluation in young infants with diarrhea. Patients with fewer than 5 WBCs perHPF 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 themorbidity and mortality associated with meningococcemia is very high (seeCauses and Morbidity/Mortality). Laboratory findings in meningococcalbacteremia 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 countless than 5. Overall, WBC counts and ANCs have not proved consistently usefulin 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 withmeningococcal bacteremia have a band count greater than 10%, and a

retrospective review of FWS found that the band count was the only laboratoryvalue that was significantly higher in patients with meningococcal bacteremiathan in those without bacteremia (Kuppermann, 1999; Kuppermann and Malley,1999). However, the clinical utility of an elevated band count is limited becauseof the low overall prevalence of meningococcal bacteremia. The PPV of a bandcount 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
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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 fullsepsis evaluation, including CSF and empiric treatment with parenteralantibiotics (Baraff and Bass, 1993).

o 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 CSFlaboratory tests and a CSF culture; the guidelines published inPediatrics in 1993recommend that a CSF evaluation be performed in certain situations (see MedicalCare). Negative screening test results were defined as fewer than 8-10 WBCs perHPF, no bacteria, and normal glucose and protein levels (Baraff and Bass, 1993;Baker, 1999; Jaskiewicz, 1993; Baraff, 1992). Children with laboratory valuessuggesting meningitis should be treated for this focal infection. Evaluation andtreatment 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 occultbacteremia. Blood cultures that are positive for single isolates of knownpathogenic bacteria (see Causes) are generally considered to be true positiveresults; cultures that grow multiple isolates or nonpathogenic bacteria areconsidered contaminated. How fast the culture becomes positive is also useful indistinguishing pathogens from contaminants; true pathogens generally growfaster than contaminants, with most pathogens turning positive in less than 24hours (Kuppermann, 1999; Baraff, 2000). The routine mean detection time forseveral pathogens are as follows (Kuppermann, 1999):

S pneumoniae - 11-15 hours Salmonella species - 9-12 hours N meningitidis - 12-23 hours

o Whether the quantity of colonies grown is useful in detecting occult bacteremia

or in predicting prognosis is unclear. Occult pneumococcal bacteremia may yieldfewer than 10 colony-forming units (CFU)/mL, which is lower than in focaldisease. The yield in meningococcal infection varies widely, but one study foundthat patients with yields higher than 700 CFU/mL were at increased risk formeningitis (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 noother source of infection. Specific findings on physical examination include grunting,flaring, retracting, rhonchi, wheezing, rales, and focal decreased breath sounds. Thesefindings are 94-99% specific for pneumonia (Bachur, 1999). Obtain a chest radiograph aspart of the evaluation of children with any of these findings; evaluation for pneumonia infebrile children without any of these findings is of very low yield (Baraff, 2000; Baraff,1993).
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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 guidelinerecommends that chest radiography be used to evaluate for pneumonia if the patient'soxygen 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 normalphysical examination findings and WBC counts higher than 20,000 had chestradiographic findings consistent with pneumonia. This guideline recommends that a chestradiograph be obtained in febrile infants and children with signs and symptoms ofpneumonia and in febrile infants and children without signs and symptoms of pneumoniawho 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 ratefor blood cultures is improved with larger volumes of blood and a shorter time betweenthe 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 andincubation 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 MedicalCare). 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 maypossibly 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 andMedical Care). Although UTIs are a separatesubject and not fully addressed here, urine collection should be performed using a steriletechnique to limit contamination. Suprapubic bladder aspiration and in-and-out bladdercatheterization 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 isreasonable and widely accepted. Studies have shown that ibuprofen 10 mg/kg/dose every 8 hoursor 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?
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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 inabilityto 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 forbacterial 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, andRochester 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 1-2 months 1-2 months 0-3 months 1-3 months

Temperature 38.2C >38C >38C >38C

Appearance AIOS


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Rochester NPV - 98.3-99%

AAP 1993 - 99-99.8%

Application of low-risk criteriaSee Image 1for 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 ofage, temperature, and screening laboratory test results to determine the risk for serious bacterialinfection or occult bacteremia. Low-risk children are generally monitored as outpatients. Childrenwho do not fit low-risk criteria are treated with empiric antibiotics either as inpatients or asoutpatients.A number of studies have compared the effectiveness of oral and parenteral antibiotics inreducing complications of occult bacteremia. Many of these studies were conducted beforewidespread use of the conjugate Hib vaccine (Kuppermann, 1999); parenteral antibiotics weregenerally found to be significantly more effective than oral treatment or no treatment in reducingthe sequelae of occult bacteremia, most importantly meningitis (Baraff and Bass, 1993; Fleisher,1994).Table 8. Occult Bacteremia - Relationship Between Outpatient Antibiotic Use andComplications*

Complication No Antibiotic Therapy PO Antibiotic Therapy IM/IVAntibiotic Therapy

Persistent bacteremia 18-21% 3.8-5% 0-5%

New focal infection 13% 5-6.6% 5-7.7%

Meningitis 9-10% 4.5-8.2% 0.3-1%*Baraff and Bass, 1993; Baraff, 1993; Harper, 1995; Bass, 1993; Fleisher, 1994Recent 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 areequally effective in reducing complications of pneumococcal bacteremia (Kuppermann, 1999;Baraff and Bass, 1993), but a recent meta-analysis found no statistical change in occurrence ofmeningitis between patients with and without treatment with oral antibiotics (Rothrock, 1997).Table 9. Pneumococcal Bacteremia - Relationship Between Outpatient Antibiotic Use andComplications*

Complication No Antibiotic Therapy Any Antibiotic Therapy PO AntibioticTherapy IM/IV Antibiotic Therapy

Persistent bacteremia 7-17% 1-1.5% 2.5%

Focal infection/SBI9.7-10% 3.3-4%

Meningitis 2.7-6% 0.4-1% 0.4-1.5% 0.4-1%
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*Kuppermann, 1999; Baraff and Bass, 1993; Baraff, 1993; Jones, 1993; Lee, 2001; Bauchner,1997; Baraff, 1997; Rothrock, 1997; Baraff, 2000Meningococcal 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 ororal antibiotics in reducing complications. The risk of developing meningitis with no antibiotictherapy 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 canhave serious complications. The risk of serious complications in previously healthy children aged3-36 months with Salmonella bacteremia is small (Harper, 1993; Kuppermann, 1999). Empiricoral antibiotics have not been proven to prevent focal complications or persistence of bacteremiain children with occult nontyphoidal Salmonella bacteremia (Kuppermann, 1999). However,some form of antibiotic treatment, oral or intravenous, is recommended for all children withSalmonella bacteremia and for young infants and immunocompromised children with Salmonellagastroenteritis (Abramson, 2000).

Choice of drug

The choice of empiric antibiotic treatment is based primarily on the likely causes of bacteremiafor a given patient and the likelihood of resistance.In very young infants, bacterial causes are most commonly acquired from the mother duringchildbirth. For neonates younger than 1 month, Streptococcus species and E coli are the mostcommon pathogens. Other gram-positive and gram-negative infections are also observed,including infections withListeria species (see Causes). Treatment with ampicillin and gentamicinis 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-negativecoverage for the most likely pathogens, and ampicillin is effective against Listeria. Third-generation cephalosporins are very useful in older infants and children, but they are not activeagainst Listeria and are not recommended as single-agent therapy in the empiric treatment ofneonates 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 ofbacteremia in infants aged 1-3 months are a combination of organisms (see Causes). Empiricantibiotics used in practice vary in this age group. Some practitioners use ampicillin andgentamicin, 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 inchildren older than 4-6 weeks, and debate exists regarding whether coverage for Listeria isrequired in infants aged 1-3 months at risk for occult bacteremia. All these possible antibioticregimens have excellent coverage against the other childbirth- or community-acquired bacterialpathogens in this age group.Empiric treatment of infants and children aged 3-36 months at risk for occult bacteremia isusually with ceftriaxone. This third-generation cephalosporin has broad-spectrum gram-positiveand 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, andhigh serum concentrations can be sustained for 24 hours with a single dose. Most body tissuesand fluids are penetrated, including the CSF (Bass, 1993).Early studies of empiric coverage with oral antibiotics examined a variety of agents, includingamoxicillin 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 consideredwhen choosing an antibiotic treatment. Studies evaluating adverse effects of ceftriaxone and
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amoxicillin/clavulanic acid have shown that, while amoxicillin/clavulanic acid more commonlycauses diarrhea, the overall rate of adverse effects (eg, diarrhea, vomiting, maculopapularexanthems) is similar at approximately 5% (Bass, 1993; Fleisher, 1994). Regarding compliance,the administration of antibiotic treatment is essentially witnessed when the antibiotic isadministered intramuscularly. However, in a study of compliance with 2 days of amoxicillintaken 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 carecenters are penicillin-resistant (Nilsson, 2001).To understand the role of penicillin-resistant pneumococcus in serious bacterial infection andoccult bacteremia, realize that all pneumococci are not equal, antibiotic resistance patterns are notstatic, and resistance does not necessarily equal virulence. Penicillin resistance varies from mildlyresistant (minimal inhibitory concentration [MIC] 1). The prevalence of penicillin resistance is increasing over time, andno change in mortality seems to be associated with invasive pneumococcal disease due to theincrease in antibiotic-resistant pneumococcus (Kaplan, 2002; Friedland, 1995; Arditi, 1998).Longitudinal studies of invasive pneumococcal disease show that the prevalence ofintermediately penicillin-resistant pneumococcus (MIC 0.1-1) has increased from 5-10% in 1993to 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 ofpneumococcal meningitis in the mid 1990s found 13% intermediately penicillin-resistantpneumococcus (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 alongitudinal 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 ofinvasive disease from intermediately penicillin-resistant (MIC 0.1-1) S pneumoniae in 1993 was5.3-10% and the rate for highly resistant (MIC >1) S pneumoniae was 4%. In 1999, the rate ofinvasive disease from intermediately penicillin-resistant S pneumoniae was 22%, and the rate forhighly 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-resistantpneumococcus may also be resistant to third-generation cephalosporins (Kaplan, 2002). At thattime, less than 1% of pneumonococci were resistant to ceftriaxone (Fleisher, 1994). Since then,ceftriaxone resistance has increased, but it remains significantly less common than penicillinresistance (Kaplan, 2002; Fleisher, 1994; Arditi, 1998).Longitudinal studies of invasive pneumococcal disease show that the prevalence ofintermediately 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-resistantpneumococcus (MIC >1) has increased from 0.5% in 1993 to 2% in 1999 (Kaplan, 2002). Asurvey of pneumococcal meningitis in the mid 1990s found 4.4% intermediately ceftriaxone-resistant 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 (MIC0.1-1) S pneumoniae from 1987-1991 was 0.6%, it was 2.6% in 1993, and it was 9% in 1999. Therisk of invasive disease from highly ceftriaxone-resistant (MIC >1) S pneumoniae was 0.5% in1993 and was 2% in 1999 (Fleisher, 1994; Kaplan, 2002).Morbidity and mortality with resistance


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Antibiotic resistance is increasing in pneumococcal disease, but resistance is not necessarilydirectly correlated with virulence. Several studies have attempted to establish whether infectionwith antibiotic-resistant pneumococci relates to increased morbidity or mortality.In 2 longitudinal studies of invasive pneumococcal disease and pneumococcal meningitis, nodifference was observed in clinical presentation, hospital course, morbidity, or mortality amongpatients 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 treatedempirically with oral or parenteral antibiotics at the discretion of the attending physician. Nosignificant difference was observed between penicillin-resistant and penicillin-sensitive infectionsin terms of duration of illness or rate of improvement. Among all the resistant and sensitivepneumococcal infections, the only treatment failure was due to an abscess caused by a penicillin-sensitive 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 whenchoosing antibiotic treatment.Table 10. Penicillin Resistance Defined*

Resistance Penicillin Concentration, mcg/mL

Mild 1*Friedland, 1995Penicillin 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 oftreatment, no antibiotic is clearly the choice for initial empiric treatment of febrile children aged3-36 months at risk for occult bacteremia. On one hand, the available evidence regarding theeffectiveness of oral antibiotics in preventing pneumococcal meningitis is equivocal. On the otherhand, evidence suggests that morbidity and mortality are not affected by antibiotic resistance andthat 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 andclinics 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 ofbacteremia, namely meningitis. Costs of treatment and cost savings in preventing hospitalization,morbidity, and mortality have also been addressed to assess whether screening and empirictreatment are cost-effective strategies.Screening febrile infants younger than 3 months by means of history, physical examination, andlaboratory 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 thatoutpatient treatment based on these low-risk criteria costs $3100 less per patient than inpatienttreatment (Baker, 1993).


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Screening febrile infants and children aged 3-36 months based on age, degree of fever, andlaboratory 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 forstatistics 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 orANCs 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 thesecutoff values may still miss 25% of children with occult bacteremia because of the large numbersof 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 usedto assess the effectiveness of screening criteria. Two papers have analyzed the NNT to preventmeningitis for different laboratory screening criteria in febrile children aged 3-36 months withtemperatures greater than 39C. One used a WBC count greater than 15,000 and found an NNTof 500 to prevent 1 case of meningitis, and the other used an ANC greater than 10,000 and foundan NNT of 240 (Kuppermann, 1999; Lee, 1998).A recent formal estimate of cost-effectiveness compares the cost of screening and treatment offebrile children using a number of different criteria (Lee, 2001). This analysis also estimates thecost of complications associated with treatment and hospitalization and estimates the costs

incurred while treating patients with sequelae from untreated infections. This analysis uses anestimate of 1.5% for the rate of occult bacteremia in febrile young children, which is consistentwith other current estimates (Alpern, 2001; Lee, 1998). At this rate of bacteremia, empiric testingand treatment were found to be the most cost-effective approaches for treatment of the febrilechild; the cost is $72,000 per life-year saved. This strategy also compares favorably to othermedical treatments that are considered cost-effective.Many authors, including the authors of this article, anticipate that the rate of occult bacteremiawill decrease markedly following widespread use of the 7-valent conjugate pneumococcalvaccine (Baraff, 2000; Giebink, 2001; Lee, 2001). Using an estimate of 0.5% for the predictedrate of occult bacteremia, the authors have also calculated the cost-effectiveness of severalapproaches to treat febrile children. At this rate of bacteremia, the cost of empiric testing andtreatment of febrile children increases markedly from $72,000 to more than $300,000 per life-

year saved.The sensitivity and specificity of clinical judgment in predicting occult bacteremia and seriousbacterial infections has varied greatly in previous studies, with a general consensus that clinicaljudgment 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 studiesperformed on children aged 3-36 months. At a decreased predicted rate of occult bacteremia of0.5%, treatment of febrile children based on clinical judgment was found to be considerably morecost-effective than other approaches; the cost is $38,000 per life-year saved.Table 11. Cost-Effectiveness Analysis*

Intervention Cost Per Life-Year Saved

TPA for acute myocardial infarction $32,678

Medical treatment for hypertension $20,000

CABG for myocardial infarction $ 7,000

Empiric testing and treatment in febrile children when rate of OB is 1.5% $72,300


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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 is0.5% $38,000

*Lee, 2001Tissue plasminogen activator Coronary artery bypass graftingOccult bacteremiaIf the rate of bacteremia declines to 0.5%, this analysis concluded that clinicians shouldreevaluate their approach in the highly febrile child and eliminate strategies that use empirictesting and treatment (Lee, 2001).

Treatment algorithms

The approach to febrile patients aged 3-36 months has been dominated in the United States by the1993 Practice Guidelines, published jointly in Pediatrics and Annals of Emergency Medicine(Baraff and Bass, 1993). Considerable debate in the medical literature has followed thepublication of these guidelines, and surveys indicate that considerable variation from theguidelines occurs and a wide variation exists in practice among pediatricians, familypractitioners, and emergency department physicians (Kramer, 1997; Bauchner, 1997; Baraff,1997; Isaacman, 2001; Jones, 1993).As discussed above and in Deterrence/Preventionbelow, a number of changes have occurredsince these guidelines were published. The conjugate Hib vaccine has become the standard ofcare, essentially eliminating Hib as a cause of bacteremia in febrile children (Lee, 1998). The 7-valent conjugate pneumococcal vaccine has received approval, and this is anticipated todramatically decrease the rate of pneumococcal bacteremia and subsequently decrease the overallrate of bacteremia in young children (Baraff, 2000; Giebink, 2001). The prevalence of penicillin-and ceftriaxone-resistant pneumococcus has increased (Baraff and Bass, 1993; Kaplan, 2002;Fleisher, 1994; Nilsson, 2001); however, no concurrent increase in mortality from pneumococcalinfections is reported (Kaplan, 2002; Friedland, 1995; Arditi, 1998).

Researchers are evaluating a possible role for new laboratory tests such as PCR and cytokinelevels (Kuppermann, 1999; Strait, 1999; Isaacman, 1998). They recommend identifying focalinfections using improved methods such as urine Gram stain for UTI screening (Baraff, 1993;Bachur, 2001; Herr, 2001). Underlying medical conditions have been demonstrated to markedlyincrease the risk for mortality from pneumococcal infections (Kaplan, 2002). Retrospectivereviews have not shown that empiric oral antibiotics are effective in preventing pneumococcalmeningitis (Rothrock, 1997).The 1993 Practice Guidelines 7 for febrile infants and young children aged 3-36 monthsrecommended no tests or antibiotics for children with a temperature less than 39C and anontoxic appearance. For children aged 3-36 months with a temperature at least 39C and anontoxic appearance, a blood culture and empiric antibiotics were recommended, either for allchildren (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 antibioticspending culture results. Urine cultures were recommended for males younger than 6 months andfemales younger than 2 years, stool cultures were recommended for children with blood or mucusin the stool or more than 5 WBCs per HPF on stool smear, and chest radiography wasrecommended for children with dyspnea, tachypnea, rales, or decreased breath sounds. Follow-upin 24-48 hours was recommended in children who had cultures drawn.In response to the 1993 Practice Guidelines, Kramer and Shapiro published an alternate approachthat involved less laboratory screening and no empiric antibiotic treatment (Kramer, 1997).
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Febrile children aged 3-36 months were carefully assessed for bacterial foci; children with a toxicappearance were admitted to the hospital for sepsis workup, and focal infections were treatedappropriately. Children who appeared well and had no focus of infection received a urinalysis ifappropriate for age, while all children received no other laboratory tests and no antibiotics andwere followed up in 24 hours to assess for worsening or persistence of signs and symptoms ofinfection.

A 1999 review by Kupperman proposed an approach to the febrile child aged 3-36 months thatwas based on the risk of occult bacteremia during a time after Hib had been eliminated but beforethe introduction of pneumococcal vaccine (Kuppermann, 1999). His algorithm divided childreninto the following 2 groups based on risk: those aged 3 months to 2 years and those aged 2-3years. 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 witha nontoxic appearance and with a temperature less than 39.5C and for children aged 3 months to2 years with a nontoxic appearance and with a temperature less than 39C. For children aged 3months to 2 years with a temperature of at least 39C and a nontoxic appearance and for thoseaged 2-3 years with a temperature of at least 39.5C and a nontoxic appearance, a blood cultureand 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 3-36months with FWS who have received the 7-valent conjugate pneumococcal vaccine, Baraffrecommended that no blood work be performed in these patients irrespective of the degree offever. He also recommended that no blood work be performed for FWS in children with atemperature less than 39.5C. A blood culture and empiric antibiotics is recommended forchildren with an ANC greater than 10,000 or a WBC count greater than 15,000 if the child'stemperature is at least 39.5C and he or she has not received the pneumococcal vaccine. Baraffstated that for children who have received the pneumococcal vaccine, the overall prevalence ofoccult pneumococcal bacteremia should decrease by 90%, making screening of the WBC count orANC impractical.For application of the algorithm approach to febrile infants and young children aged 3-36 monthssee Image 2.

Drug Category: Antibiotic agents -- Empiric antimicrobial therapy must be comprehensive andshould cover all likely pathogens in the context of the clinical setting.Drug Name Amoxicillin (Amoxil, Biomox, Trimox) -- Interferes with synthesis ofcell wall mucopeptides during active multiplication, resulting in bactericidal activity againstsusceptible bacteria.Adult Dose 250-500 mg/dose PO tid; not to exceed 3 g/dPediatric Dose 40-80 mg/kg/d PO divided tid; not to exceed 2-3 g/dContraindications Documented hypersensitivityInteractions 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 candidiasisDrug Name Ampicillin (Marcillin, Omnipen, Polycillin, Principen, Totacillin) --Bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable totake medication PO. Until recently, the HACEK bacteria were uniformly susceptible toampicillin. Recently, however, beta-lactamaseproducing strains of HACEK have beenidentified.Adult Dose 500-3000 mg IV/IM q4-6h; not to exceed 12 g/dPediatric Dose 100-200 mg/kg/d IV/IM divided q6h
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Contraindications Documented hypersensitivityInteractions Probenecid and disulfiram elevate ampicillin levels; allopurinoldecreases ampicillin effects and has additive effects on ampicillin rash; may decrease effects ofPO contraceptivesPregnancy B - Usually safe but benefits must outweigh the risks.Precautions Adjust dose in renal failure; evaluate rash and differentiate from

hypersensitivity reactionDrug Name Ceftriaxone (Rocephin) -- Third-generation cephalosporin with broad-spectrum gram-negative activity, lower efficacy against gram-positive organisms, and higherefficacy against resistant organisms. Arrests bacterial growth by binding to one or morepenicillin-binding proteins.Adult Dose 1-4 g/d IV/IM divided q12-24d; not to exceed 4 g/dPediatric Dose 50-100 mg/kg/d IV/IM divided q12-24h; not to exceed 4 g/dContraindications Documented hypersensitivityInteractions Probenecid may increase ceftriaxone levels; coadministration withethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicityPregnancy 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 prolongeduse or repeated therapy; caution in breastfeeding womenDrug Name Cefotaxime (Claforan) -- For septicemia and treatment of gynecologicinfections caused by susceptible organisms. Arrests bacterial cell wall synthesis, which in turninhibits bacterial growth. Third-generation cephalosporin with gram-negative spectrum. Lowerefficacy against gram-positive organisms.Adult Dose 1-2 g/dose IV/IM q6-8h; not to exceed 12 g/dPediatric Dose 100-200 mg/kg/d IV/IM divided q6-8h; not to exceed 12 g/dContraindications Documented hypersensitivityInteractions Probenecid may increase cefotaxime levels; coadministration withfurosemide and aminoglycosides may increase nephrotoxicityPregnancy B - Usually safe but benefits must outweigh the risks.

Precautions Adjust dose in severe renal insufficiency (high doses may cause CNStoxicity); superinfections and promotion of nonsusceptible organisms may occur with prolongeduse or repeated therapy; has been associated with severe colitisDrug Name Gentamicin (Garamycin, I-Gent, Jenamicin) -- Aminoglycosideantibiotic used for gram-negative coverage. Used in combination with both an agent againstgram-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 ofdistribution. May be administered IV/IM.Adult Dose Serious infections and normal renal function: 3 mg/kg/dose IV q8hLoading dose: 1-2.5 mg/kg IV

Maintenance dose: 1-1.5 mg/kg IV q8hExtended dosing regimen for life-threatening infections: 5 mg/kg/d IV divided q6-8hFollow each regimen by at least a trough level drawn 0.5 h prior to the fourth dose; may draw apeak level 0.5 h after 30-min infusionPediatric Dose 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 adultsContraindications Documented hypersensitivity


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Interactions Coadministration with other aminoglycosides, cephalosporins,penicillins, and amphotericin B may increase nephrotoxicity; because aminoglycosides enhanceeffects of neuromuscular blocking agents, prolonged respiratory depression may occur;coadministration with loop diuretics may increase auditory toxicity of aminoglycosides; possibleirreversible hearing loss of varying degrees may occur (monitor regularly)Pregnancy D - Unsafe in pregnancy

Precautions Narrow therapeutic index (not intended for long-term therapy); cautionin renal failure (patient not on dialysis), myasthenia gravis, hypocalcemia, and conditions thatdepress neuromuscular transmission; adjust dose in renal impairmentDrug Name Vancomycin (Vancocin, Vancoled, Lyphocin) -- Potent antibioticdirected against gram-positive organisms and active against Enterococcus species. Useful in thetreatment of septicemia and skin structure infections. Indicated for patients who cannot receiveor who have not responded to penicillins and cephalosporins or who have infections withresistant staphylococci. For abdominal penetrating injuries, it is combined with an agent activeagainst enteric flora and/or anaerobes.To avoid toxicity, current recommendation is to assay vancomycin trough levels after third dosedrawn 0.5 h prior to next dosing. Use creatinine clearance to adjust dose in patients diagnosedwith renal impairment.

Used in conjunction with gentamicin for prophylaxis in penicillin-allergic patients undergoinggastrointestinal or genitourinary procedures.Adult Dose 500 mg q6-8h IV for 7-10 d; alternatively, 1 g IV q12h for 7-10 dPediatric Dose 1 month: 40-60 mg/kg/d IV divided tid/qid for 7-10 dContraindications Documented hypersensitivityInteractions Erythema, histaminelike flushing, and anaphylactic reactions may occurwhen administered with anesthetic agents; when taken concurrently with aminoglycosides, riskof nephrotoxicity may increase above that with aminoglycoside monotherapy; effects in

neuromuscular blockade may be enhanced when coadministered with nondepolarizing musclerelaxantsPregnancy C - Safety for use during pregnancy has not been established.Precautions Caution in renal failure and neutropenia; red man syndrome is caused bytoo rapid IV infusion (dose administered over a few min), but rarely happens when dose isadministered IV over 2 h; red man syndrome is not an allergic reactionDrug Name Nafcillin (Unipen, Nafcil, Nallpen) -- Initial therapy for suspectedpenicillin 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 parenterallyonly 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 q4-6hPediatric Dose 1 month:100-200 mg/kg/d IV divided q4-6h; not to exceed 12 g/d50-100 mg/kg/d PO divided qidContraindications Documented hypersensitivityInteractions Associated with warfarin resistance when administered concurrently;effects may decrease with bacteriostatic action of tetracycline derivativesPregnancy B - Usually safe but benefits must outweigh the risks.


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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 eradicatedDrug Name Meropenem (Merrem) -- Bactericidal broad-spectrum carbapenemantibiotic that inhibits cell wall synthesis. Effective against most gram-positive and gram-negative bacteria.

Has slightly increased activity against gram-negative organisms and slightly decreased activityagainst staphylococci and streptococci compared to imipenem.Adult Dose Mild-to-moderate infection: 1 g IV q8hMeningitis: 2 g IV q8hPediatric Dose 3 months:Mild-to-moderate infection: 60 mg/kg/d IV divided q8hMeningitis: 120 mg/kg/d IV divided q8h; not to exceed 6 g/dContraindications Documented hypersensitivityInteractions Probenecid may inhibit renal excretion of meropenem, increasingmeropenem levelsPregnancy B - Usually safe but benefits must outweigh the risks.

Precautions Pseudomembranous colitis and thrombocytopenia may occur, requiringimmediate discontinuation of medicationDrug Name Imipenem and cilastatin (Primaxin) -- For treatment of multipleorganism infections in which other agents do not have wide spectrum coverage or arecontraindicated because of potential for toxicity.Adult Dose Base initial dose on severity of infection and administer in equallydivided doses250-500 mg IV q6h; not to exceed 3-4 g/d500-750 mg IM q12h or intra-abdominallyPediatric Dose 12 years: Administer as in adultsContraindications Documented hypersensitivityInteractions Coadministration with cyclosporine

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Bacteremia,Sepsis.37