eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Bacteremia

Author: Nicholas John Bennett, MBBCh, PhD, Staff Physician, Department of Pediatrics, State University of New York Upstate Medical University
Coauthor(s): Joseph Domachowske, MD, Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York-Upstate Medical University; Brian J Holland, MD, Consulting Staff, Department of Pediatrics, US Army Hospital, Wuerzburg, Germany
Contributor Information and Disclosures

Updated: Jun 26, 2008

Introduction

Background

Bacteremia is the presence of viable bacteria in the circulating blood.¹ This may or may not have any clinical significance because harmless, transient bacteremia may occur following dental work or other minor medical procedures; however, this bacteremia is generally clinically benign and self-resolving in children who do not have an underlying illness or immune deficiency or a turbulent cardiac blood flow. The concern with occult bacteremia is that it could progress to a more severe local or systemic infection if left untreated. Most episodes of occult bacteremia spontaneously resolve, and serious sequelae are increasingly uncommon. However, serious bacterial infections occur, including pneumonia, septic arthritis, osteomyelitis, cellulitis, meningitis, and sepsis, possibly resulting in death.^2,3

Patients with occult bacteremia do not have clinical evidence other than fever (a systemic response to infection).⁴ 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 febrile child who was previously healthy; the child does not clinically appear to be ill and has no apparent focus of infection.^5,6 Occult bacteremia has been defined as bacteremia not associated with clinical evidence of sepsis (shock or purpura) or toxic appearance, underlying significant chronic medical conditions, or clear foci of infection (other than acute otitis media) upon examination in a patient who is discharged and sent home after an outpatient evaluation.²

Often, the only manifestation of occult bacteremia is fever or a minor infection (eg, otitis media, upper respiratory tract infection).⁴ Therefore, in a busy clinic or emergency department, infants and young children with occult bacteremia are difficult to distinguish from others in the waiting-room.

Fever is common in pediatric patients. Children average 4-6 fevers by age 2 years.⁷ Fever also prompts many visits to the pediatric clinic and emergency department. Approximately 8-25% of doctor's visits by children younger than 3 years are for fever;^4,7,8,9 65% of children younger than 3 years visit a physician for acute febrile illness.^8,10

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.⁷ 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.⁷

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.⁹ Of all infants and young children who present to the hospital for any reason, 1.6% appear nontoxic, were previously healthy, are older than 3 months, and have a fever without a source (FWS).⁹

Bacteremia may also occur in children with focal infections or in children who have sepsis (ie, clinical evidence other than fever of a systemic response to infection). Children with sepsis generally appear ill, have an increased heart rate or respiratory rate and may have a change in temperature (typically fever, although hypothermia is often seen in very young infants and newborns). Severe sepsis results in hypotension, hypoperfusion, or organ dysfunction. Septic shock occurs in children who do not respond to adequate volume resuscitation or require vasopressors or inotropes. Although bacteria may be present in the bloodstream of children with focal infections, sepsis, severe sepsis, or septic shock, the focus of this article is occult bacteremia.

Pathophysiology

Much of the pathophysiology of occult bacteremia is not fully understood. The presumed mechanism begins with bacterial colonization of the respiratory passages or other mucosal surface; bacteria may egress into the bloodstream of some children because of host-specific and organism-specific factors. Once viable bacteria have gained access to the bloodstream, they may be spontaneously cleared, 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.^4,11

Often, fever is the only presenting sign in patients with occult bacteremia and is defined as increased temperature caused by resetting the thermoregulatory center in the hypothalamus by action of cytokines.⁷ 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 spontaneously resolves 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.^12,13

Clearly, some children are more susceptible to bacterial infection, which may initially be uncomplicated bacteremia but could rapidly lead to more serious complications. Immunosuppression due to neoplastic disease or its treatment or defects in antibody responses or neutrophil responses predispose certain children to invasive infection. Bacteremia should be considered, with a low threshold for evaluation and treatment, in patients with impaired immunity or invasive medical devices such as indwelling central venous lines.

The pathogens implicated in occult bacteremia change in response to vaccination against the common pathogenic strains. These changes govern the choices for empiric therapy of suspected bacteremia.

Frequency

United States

The risk of bacteremia has been studied by categorizing infants and young children based on age, appearance, temperature, laboratory criteria, numerous low-risk criteria based on a combination of these factors, 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.

Numerous investigators have loosely and specifically defined the terms toxic and lethargic (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.⁸

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.^8,14  In children aged 3-36 months who are toxic, the risk of bacteremia or serious bacterial infection ranges from 10-90%, depending on criteria.^8,10

Most studies designed to determine the relationship between temperature and risk of occult bacteremia define fever as a temperature of at least 38°C (100.4°F) in infants younger than 3 months and at least 39°C (102.2°F) in children aged 3-36 months. Because these studies were designed to predict occult bacteremia, they include children who have only FWS, which is defined as an acute febrile illness in which the etiology is not apparent after history is obtained and a careful physical examination is performed.¹⁰

Numerous studies published in the early 1990s found that 2-15% of febrile infants younger than 3 months had bacteremia.^12,15,13,16 These studies also determined that the risk of occult bacteremia in children aged 3-36 months with FWS was 2.5-11%.^4,8,9,17,18 According to studies performed after the 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.^19,20,21

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 has significantly decreased the overall risk of occult bacteremia, especially with regards to vaccine-specific strains of streptococcus.^9,22,23

The appearance of the nonvaccine pneumococcus strain 19A, which has been responsible for some particularly invasive (and drug-resistant) infections, is a concern. This is discussed in more detail below.

International

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.²⁴

Mortality/Morbidity

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.^4,8,10,26

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.^{4,2,8,27,10,21}

Of all focal infections that develop because 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.^25,9 The mortality rate of pneumococcal meningitis is 6.3-15%, and the overall mortality rate of pneumococcal bacteremia is 0.8%.^25,9,23

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 rates are much greater. Children with meningococcal bacteremia have a 42-50% risk of developing meningitis; a 50% risk of developing serious bacterial infection such as septic shock, pneumonia, and neurologic changes; a 3% risk of developing extremity necrosis; and an overall mortality rate of 4%.^4,25,9

When untreated, Salmonella bacteremia carries a 50% risk of persistent bacteremia and can cause meningitis, sepsis, and death in infants younger than 3 months or in persons who are debilitated or immunocompromised.² However, in previously healthy children aged 3-36 months, the risk of meningitis or serious bacterial infection following Salmonella bacteremia is low.⁴

Race

Studies of the prevalence of bacteremia in children in diverse settings have identified no racial, geographic, or socioeconomic predisposition.^4,6,11,28 However, antibiotic resistance patterns vary in different geographic regions, which may affect the treatment of children with bacteremia.

Sex

No sex-based difference in the prevalence or course of bacteremia is known.¹¹

Age

Studies of occult bacteremia focus on children younger than 3 years. Some studies show that age does not affect the risk of developing occult bacteremia,¹¹ whereas other analyses have found that variations in age-based risk depend on the infecting organism.

Pneumococcal bacteremia is observed in children of all ages; however, children aged 6 months to 2 years are at an increased risk.^6,2,20  The prevalence of pneumococcal meningitis peaks 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.^2,11 The risk of Salmonella bacteremia is greatest in infants younger than 1 year, especially in those younger than 2 months.²

A seasonal variation in febrile children presenting for evaluation is recognized. The peak is from late fall to early spring in children of all ages and is likely because of respiratory and GI viral infections. Another peak occurs during the summer in infants younger than 3 months and is likely due to enteroviral infections and thermoregulation during hot weather.⁷ However, most studies do not specifically address seasonal variation associated with bacteremia.

Clinical

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 a high risk for bacterial infection.

The significance of history varies based on 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.¹⁵ 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.¹³

• Duration of fever: The duration of fever at presentation has been noted to be shorter in patients whose blood culture findings eventually became positive for known bacterial pathogens (mean 18 h) than in those patients with blood culture findings negative for known bacterial pathogens (mean 25 h).¹¹ 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.²⁵ Overall, duration of fever is inadequate to clinically identify occult bacteremia.²⁹
• History that indicates specific illness: Although meningococcal infections are uncommon causes of bacteremia (see Causes), patients with meningococcemia are at high risk for morbidity and mortality (see Mortality/Morbidity). Knowledge of local epidemiology involving an outbreak of meningococcus, along with a history of contact with someone with known meningococcal disease, can raise clinical suspicion and help confirm an important diagnosis.²⁵
• 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 an increased risk for bacterial infection, including occult bacteremia.
  • 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.^13,14 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
    • Not currently using antibiotics
    • 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:^4,8,12,30
    • Age, which determines the cutoff used to define fever
    • Febrile temperature (£ 3 mo and temperature >38°C [100.4°F], 3-36 mo and temperature ³ 39-39.5°C [102.2-103.1°F])
    • Current antibiotic use
    • Previous hospitalizations
    • Chronic or underlying illness
    • Immunodeficiency (eg, hypogammaglobulinemia, sickle cell anemia, human immunodeficiency virus [HIV], malnutrition, asplenia)
• History of underlying medical condition: A longitudinal study of invasive pneumococcal infections reported 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%.²³
• 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 involving a young infant.⁸ 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.
• History of gastroenteritis: 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.²
• Epidemiology: Although a history of family members or frequent contacts with obvious viral syndromes such as upper respiratory infections may suggest a viral syndrome,⁸ 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.²
• Risk factors for invasive pneumococcal disease: Studies have evaluated the relationship between history and pneumococcal disease. Elements of history that have been associated with an increased risk of pneumococcal bacteremia include daycare attendance,^2,9,31 lack of breastfeeding,^9,31 and underlying illness such as sickle cell disease or acquired immunodeficiency syndrome (AIDS).^9,31 Although recent antibiotic use does not affect the overall rate of infection, 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.³¹

Physical

• General appearance
  • Numerous investigators have formally defined the initial aspect of the physical examination, the assessment of general appearance, in an attempt to assess its utility in determining the presence of bacterial disease. The Yale Observation Scale (YOS)/Acute Illness Observation Scale (AIOS) has been widely 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.^6,13 Other authors have examined irritability, consolability, and social smile.^11,32
  • Rigorous studies by numerous authors have found that the use of clinical scores, observation scores, social smile, and general appearance have not been clinically useful in distinguishing occult bacteremia, especially in young infants.^{4,11,12,29,32}  General appearance based on observation scores had a sensitivity of 74% and specificity of 75% in detecting serious illness in older children;^8,10 it had a sensitivity of 33% in detecting bacterial disease in infants younger than 2 months.¹²  General appearance had 5.2% sensitivity for detecting occult bacteremia, and social smile was 45% sensitive and 51% specific for bacteremia.^32,2
  • A cost-effectiveness analysis suggested that clinical judgment of general appearance (YOS <6 is 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.²¹
• Vital signs
  • 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. Studies have also suggested that pulse oximetry should be used routinely as a fifth vital sign.⁹ In younger infants, poor perfusion as judged by a capillary-refill time of less than 2 seconds is a more sensitive measure of cardiovascular status than pulse or blood pressure in the early phase of sepsis.
  • In studies of occult bacteremia, children were not excluded based on specific vital sign parameters; in very young infants, the presence of a serious bacterial infection may not significantly correlate with differences in pulse, respiratory rate, or blood pressure.¹⁵ However, tachycardia, tachypnea, or hypotension in a febrile or hypothermic infant are signs of sepsis and warrant a complete evaluation.⁴
• Fever defined
  • Most studies designed to determine the relationship between temperature and risk of occult bacteremia define fever as a temperature of at least 38°C (100.4°F) in infants younger than 3 months and a temperature of at least 39°C (102.2°F) 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 36°C (96.8°F).⁸
  • Although the proper method to use when measuring temperature is continuously debated, a rectal temperature taken with a glass mercury thermometer remains the criterion standard.⁷ Tactile fever has been found to poorly correlate with the presence of actual fever documented by a healthcare professional using rectal or oral thermometry.³³ Thus, a parent who reports a child as having a fever because the child feels warm should not be used as part of the evaluation of a infant or child. Home measurement of fever based on a thermometer reading has generally been accepted as true and accurate.
• Febrile temperature
  • 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.²⁰ 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 Infection³³

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    Table

    Age	Temperature, Degrees Celsius	Rate of Bacterial Infection, %
    Neonates <1 mo	38-38.9	5
    	39-39.9	7.5
    	>40	18
    Infants aged 1-2 mo	38-38.9	3
    	39-39.9	5
    	>40	26

    Age	Temperature, Degrees Celsius	Rate of Bacterial Infection, %
    Neonates <1 mo	38-38.9	5
    	39-39.9	7.5
    	>40	18
    Infants aged 1-2 mo	38-38.9	3
    	39-39.9	5
    	>40	26

    
    Table 2. Children Aged 3-36 Months - Fever and Occult Bacteremia^2,4,6,9,34

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    Table

    Temperature, Degrees Celsius	Occult Pneumococcal Bacteremia, %	Positive Blood Culture, %	Positive Blood Culture, %	Occult Pneumococcal Bacteremia, %
    £ 39	Very low	1.6	1	…
    39-39.4	1.2	1.6	5	…
    39.5-39.7	2.5	2.8	5	…
    39.8-39.9	2.5	2.8	5	…
    40-40.2	3.2	3.7	5	10-10.4
    40.3-40.5	3.2	3.7	5	10-10.4
    40.5-40.9	4.4	3.8	12	10-10.4
    >41	9.3	9.2	12	10-10.4

    Temperature, Degrees Celsius	Occult Pneumococcal Bacteremia, %	Positive Blood Culture, %	Positive Blood Culture, %	Occult Pneumococcal Bacteremia, %
    £ 39	Very low	1.6	1	…
    39-39.4	1.2	1.6	5	…
    39.5-39.7	2.5	2.8	5	…
    39.8-39.9	2.5	2.8	5	…
    40-40.2	3.2	3.7	5	10-10.4
    40.3-40.5	3.2	3.7	5	10-10.4
    40.5-40.9	4.4	3.8	12	10-10.4
    >41	9.3	9.2	12	10-10.4

  • Children aged 2-3 years who have a temperature lower than 39.5°C have less than a 1% risk of occult pneumococcal bacteremia.²
• Response to antipyretics: Patients with bacterial and viral sources of infection respond similarly to antipyretics; no significant difference in temperature decrease or clinical appearance after defervescence is noted. Both groups experience the same decrease in temperature in response to antipyretic therapy.^4,2,33
• Focal infection on physical examination: Thoroughly examine the patient for signs of infection of the skin, soft tissue, bone, or joints. A patient with any of these focal infections should be appropriately treated and does not require evaluation for occult bacteremia.⁸
• Petechiae: A febrile child with a petechial rash upon 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.^8,9  However, a prospective cohort of children with fever and petechiae found a 1.6% risk of bacteremia or sepsis and a 0.5% risk of meningococcal infection.³⁵ 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 application) for petechiae.
• Acute otitis media or upper respiratory tract infection: An evaluation for bacteremia is warranted in children with acute otitis media or upper respiratory tract 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.^{4,2,8,20,3,26}
• Pneumonia
  • 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.²⁷ Febrile children who have none of these findings rarely have pneumonia. Studies suggest that pulse oximetry may be a more reliable predictor of pulmonary infections than respiratory rate in infants and young children; one guideline recommends that patients with oxygen saturation of less than 95% should be evaluated for pneumonia by means of chest radiography.⁹
  • 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 do patients without a focus of infection.^13,2,3
• Recognizable viral infections: Although symptoms of upper respiratory tract infection should not be accepted as an explanation of fever in an infant or young child, numerous other recognizable viral infections are generally accepted as a fever source. Children with varicella, croup, gingivostomatitis, herpangina, or bronchiolitis have less than a 1% chance of concomitant bacteremia.² A retrospective study of children with these recognizable viral syndromes found a risk of 0.2% for true pathogens and a risk of 1.4% for contaminants.³⁶ Group A streptococcal bacteremia sporadically occurs in children with varicella, but these children are usually toxic or have focal findings.² 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.^4,2,36

Causes

Table 3. Causes of Occult Bacteremia in Neonates and Infants with a Temperature of 38°C or Higher^{15,16,12,13,14}

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^* Also, less frequently (<1%), Listeria species, Klebsiella species, group A Streptococcus, Staphylococcus epidermis, Streptococcus viridans, and N meningitidis

Older infants and children are at risk for bacteremia due to colonization of the nasopharynx or community-acquired organisms. Hib conjugate vaccine has decreased the prevalence of invasive Hib disease by 90% or more in industrialized countries.⁹ With the disappearance of Hib as a cause of occult bacteremia in children, the relative frequency of S Pneumoniae increased in some medical centers to more than 90%.³⁷ Since the introduction and widespread use of the pneumococcal vaccines, the rate of vaccine-specific strains has dropped considerably, leading to significant changes in the patterns of causative organisms in more recent studies.

Table 4. Causes of Occult Bacteremia and Changes Over Time in Children Aged 3-36 Months with FWS^{4,2,8,11,17,26,20}

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^* Also, less frequently (<1%), 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 has greatly decreased since 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.¹⁹ A 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.²³ Rates of heptavalent vaccine-serotype invasive pneumococcal infection postlicensure have dropped by 56%-100%, depending on location and age.^38,39,40,41

S pneumoniae types 4, 6B, 9V, 14, 18C, 19F, and 23F are 98% covered by the 7-valent conjugate pneumococcal vaccine. The pattern of serotypes isolated from patients has undergone considerable change since the introduction of the pneumococcal vaccines. In the first few years of use, the number of cases decreased; more recently, the number of reports of nonvaccine strains replacing vaccine strains as causes of invasive pneumococcal infection has increased. In particular, strain 19A is a drug-resistant strain that has been highlighted in several studies, along with serotypes 15 and 33.^42,43,41

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