Your activity: 4 p.v.

Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia

Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia
Author:
Daniel J Sexton, MD
Section Editor:
Thomas M File, Jr, MD
Deputy Editor:
Milana Bogorodskaya, MD
Literature review current through: Dec 2022. | This topic last updated: Jan 24, 2022.

INTRODUCTION — Invasive pneumococcal disease is defined as an infection confirmed by the isolation of Streptococcus pneumoniae from a normally sterile site (eg, blood, cerebrospinal fluid, and pleural, joint, or peritoneal fluid but not sputum). S. pneumoniae (the pneumococcus) is an important and well-known cause of bacteremia in both immunocompetent and immunosuppressed patients. Pneumococcal bacteremia can occur as a result of pneumococcal pneumonia or in its absence. When bacteremia is present, secondary complications, such as arthritis, meningitis, and/or endocarditis, may occur.

This topic review will focus on the epidemiology, clinical manifestations, diagnosis, and treatment of pneumococcal bacteremia and selected aspects of other forms of invasive pneumococcal infections, such as meningitis, endocarditis, peritonitis, and various focal infections. The clinical features, epidemiology, and treatment of pneumococcal pneumonia and meningitis as well as vaccination against S. pneumoniae and the microbiology and pathogenesis of S. pneumoniae are discussed separately. (See "Pneumococcal pneumonia in patients requiring hospitalization" and "Pneumococcal vaccination in adults" and "Microbiology and pathogenesis of Streptococcus pneumoniae".)

EPIDEMIOLOGY — The incidence of invasive pneumococcal disease in any population is affected by geographic location, time of year, serotype prevalence, age, comorbidities, and vaccination status. The highest incidence of invasive pneumococcal disease occurs in adults ≥65 years of age, in children <2 years of age, and in those with certain underlying conditions, such as HIV infection. According to the United States Active Bacterial Core surveillance (ABCs) database of the Emerging Infections Program Network, in 2010 the incidence of invasive pneumococcal disease in individuals ≥65 years of age was 36.4 cases per 100,000 population and, in infants <1 year, the incidence was 34.2 cases per 100,000 population, compared with 3.8 cases per 100,000 population in individuals between 18 and 34 years of age (table 1) [1]. However, some subgroups have markedly higher risks. For example, in adults aged 18 to 64 years of age with a hematologic malignancy, the incidence was 186 per 100,000 population and, for individuals with HIV infection, the incidence was 173 per 100,000 population in 2010 [2]. The epidemiology of pneumococcal pneumonia and pneumococcal meningitis are discussed separately. (See "Pneumococcal pneumonia in patients requiring hospitalization" and "Pneumococcal pneumonia in children" and "Epidemiology of bacterial meningitis in adults".)

Impact of childhood vaccination — The overall incidence of invasive pneumococcal disease in the United States declined following the introduction and widespread use of the 7-valent pneumococcal conjugate vaccine (PCV7) in children, beginning in 2000 [3-9]. This reduction was due to declines in the incidence of invasive pneumococcal disease in the vaccinated population (children) and in adults presumably due to indirect effects on pneumococcal transmission via herd immunity. However, simultaneous increases in the proportion of cases of pneumococcal infections and nasopharyngeal colonization due to pneumococcal serotypes not included in the PCV7 vaccine (so-called replacement strains) were observed [4-7].

Following the introduction of PCV7, reductions in pneumococcal meningitis and hospitalizations for all-cause pneumonia were observed in both children and adults [10,11]. In a population-based study in one county in Minnesota, reductions in case-fatality and mortality rates were also observed [12]. The largest reductions in case-fatality rates were observed in adults ≥65 years of age and in patients with invasive pneumonia. Declines in invasive pneumococcal disease have also been reported in Europe. As an example, there was a substantial decline in pneumococcal meningitis among adults in the Netherlands following the introduction of pneumococcal conjugate vaccination in children [13]. However, the timing and extent of these changes vary in different countries because of differences in immunization policies and herd immunity.

A 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in the United States in 2010 and replaced PCV7 for universal use in infants and children. United States Centers for Disease Control and Prevention (CDC) surveillance after the introduction of PCV13 indicates a reduction in invasive pneumococcal disease (IPD) caused by the serotypes included in PCV13. Compared with the incidence expected among children younger than five years if PCV7 alone had been continued, incidence of IPD overall declined by 64 percent and IPD caused by PCV13 minus PCV7 serotypes declined by 93 percent [14]. Among adults, incidence of IPD overall declined by 12 to 32 percent and IPD caused by PCV13 minus PCV7 type IPD declined by 58 to 72 percent, depending on age. CDC population-based surveillance from 10 areas of the United States indicates little change in the incidence of IPD caused by nonvaccine serotypes among children younger than five years following the introduction of PCV13 [15]. However, a 26 percent increase in IPD caused by nonvaccine serotypes among adults ages 50 to 64 suggests serotype replacement. (See "Impact of universal infant immunization with pneumococcal conjugate vaccines in the United States" and "Pneumococcal vaccination in children", section on 'Efficacy and effectiveness'.)

Drug-resistant disease — Most surveillance data have shown a decline in the proportion of pneumococcal isolates from patients with invasive infections that are nonsusceptible to penicillin and other antibiotics after PCV7 was added to the routine childhood immunization schedule. As an example, data from Active Bacterial Core surveillance areas in the United States indicate that rates of penicillin-nonsusceptible invasive pneumococcal disease among children younger than five years declined by 64 percent between 1998 to 1999 and 2007 to 2008 (ie, before and after the introduction of PCV7, respectively, but before replacement of PCV7 with PCV13 in 2010); similarly, rates of penicillin-nonsusceptible invasive pneumococcal disease among adults ≥65 years of age declined by 45 percent between these two time periods, suggesting a herd effect [16]. (See "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics", section on 'Definitions and prevalence of resistance'.)

During 2007 to 2008, the six serotypes in PCV13 but not in PCV7 (table 2) (almost exclusively serotype 19A) accounted for 97 percent of penicillin-nonsusceptible IPD among children younger than five years, suggesting potential for further decline in rates of penicillin-nonsusceptible IPD with the routine use of PCV13. Surveillance from eight children's hospitals in the United States found a decline in the proportion of isolates nonsusceptible to penicillin and ceftriaxone after the introduction of PCV13 [17]. In a later study, rates of antibiotic-nonsusceptible IPD caused by serotypes included in PCV13 but not PCV7 decreased between 2009 and 2013 from 4.4 to 1.4 cases per 100,000 in adults aged ≥65 years [18]. This issue is discussed in greater detail separately. (See "Impact of universal infant immunization with pneumococcal conjugate vaccines in the United States", section on 'Antibiotic resistance'.)

Importance of serotype — The risk of invasive disease appears to be closely related to which serotype is present [19-21]. The magnitude of this effect was addressed in a meta-analysis that evaluated isolates from patients with invasive disease and nasal or nasopharyngeal isolates from asymptomatic children in seven different locations [19]. Certain serotypes (eg, serotypes 1, 5, and 7) were up to 60 times more likely to be found in patients with invasive disease than other serotypes (eg, serotypes 3, 6A, and 15) commonly isolated from asymptomatic individuals. In addition, there was a significant inverse correlation between invasive disease and the prevalence of nasopharyngeal carriage; the serotypes most commonly isolated from patients with invasive disease were the serotypes least commonly isolated from asymptomatic carriers and vice versa.

Serotype also may be an important determinant of the severity of pneumococcal meningitis. As an example, in a study of patients with pneumococcal meningitis in Denmark, serotype 1 was associated with a much lower case-fatality rate than serotype 3 (3 versus 23 percent) [20]. (See "Initial therapy and prognosis of bacterial meningitis in adults", section on 'Mortality'.)

The possible role of serotype in nosocomial pneumococcal bacteremia was addressed in a prospective review of 796 hospitalized adults with pneumococcal bacteremia [22]. There was no association between infection with invasive serotypes 1, 5, and 7 and mortality and no difference in disease severity or mortality between infections caused by vaccine and nonvaccine serotypes. On the other hand, mortality was significantly associated with host risk factors, such as age ≥65 years, immunosuppression, and severity of underlying preexisting diseases.

The complexity of the relationship between serotype and the risk of invasive disease was reviewed in an editorial that accompanied the above study [23]:

Invasive and noninvasive clones may exist within invasive serotypes.

Cell wall components and pilus-like structures in some pneumococcal strains are related to the propensity to cause invasive disease.

Capsular polysaccharides, which determine serotype, may impede complement activation and/or phagocytosis and therefore promote tissue invasion and bacteremia; in contrast, other pneumococcal virulence factors may be responsible for outcome after bacteremia has occurred. If this occurs, studies that examine the impact of serotype on outcome of bacteremia in cohorts that already have bacteremia are not likely to find a relationship between serotype and mortality.

Risk factors for infection — The incidence of invasive pneumococcal disease is increased in patients with certain underlying medical conditions or demographic risk factors, including [1,2,24-39]:

Age <2 or ≥65 years (table 1) (see 'Epidemiology' above)

Certain racial/ethnic groups, including people of African descent, Alaskan Natives, and American Indians

Male sex

Chronic cardiovascular disease (eg, heart failure, cardiomyopathy)

Chronic pulmonary disease (eg, chronic obstructive pulmonary disease, emphysema, asthma)

Chronic liver disease (eg, cirrhosis)

Chronic renal failure or nephrotic syndrome

Diabetes mellitus

Alcohol abuse

Smoking

Crack cocaine use

Opioid use

Functional or anatomic asplenia (eg, sickle cell disease, splenectomy)

Immunosuppressive conditions (eg, HIV infection, congenital immunodeficiency, malignancy, B cell defects, multiple myeloma)

Solid organ or hematopoietic cell transplantation

Treatment with alkylating agents, antimetabolites, or systemic glucocorticoids

Cerebrospinal fluid leaks

Cochlear implants (see "Cochlear implant infections")

Inflammatory bowel disease

The risk of invasive pneumococcal disease seems to be associated with the presence of viral respiratory illnesses, such as influenza [40-42]. This association may be related to enhanced expression of receptors for pneumococcal attachment on virally activated respiratory epithelial cells [40]. A temporal association between invasive pneumococcal disease and exposure to common respiratory viruses during winter months was observed in a prospective study of 4147 invasive pneumococcal disease episodes [43]. The weekly frequency of invasive pneumococcal disease correlated directly with the weekly frequency of isolation of respiratory syncytial virus (RSV) and influenza.

In general, pneumococcal vaccination is recommended for all of the patients in the high-risk groups listed above. Specific recommendations for vaccination can be found separately. (See "Pneumococcal vaccination in adults" and "Pneumococcal vaccination in children", section on 'Immunization of high-risk children and adolescents'.)

HIV infection — The presence of HIV infection substantially increases the risk of invasive pneumococcal infection, particularly among those patients with a low CD4 count <200 cells/mm3 [44,45]. Antiretroviral treatment reduces this risk but, despite such treatment, the incidence of invasive pneumococcal infections remains higher in HIV-infected patients than in the general population [46,47]. A retrospective case-control study of a large cohort of HIV-infected patients living in France showed that a higher Charlson Comorbidity Index, a CD4 count less than 200 cells/mcL, and an HIV viral load >400 copies/mL were all associated with a higher risk of invasive pneumococcal disease [45]. The efficacy and use of pneumococcal vaccines in HIV-infected individuals is discussed separately (see "Pneumococcal immunization in adults with HIV"). Some of the unique features of pneumococcal pneumonia in patients with AIDS are that there is a high rate of recurrence usually with a different serotype within six months (8 to 25 percent), thus emphasizing the need for vaccination [48,49], that response to penicillin is good [50], and that prophylactic trimethoprim-sulfamethoxazole predicts antibiotic resistance [51].

CLINICAL MANIFESTATIONS — The clinical manifestations of invasive pneumococcal infection depend upon the primary site of infection and the presence or absence of bacteremia. Pneumococcal meningitis is the most frequent and severe suppurative complication associated with pneumococcal bacteremia. Even with appropriate antimicrobial treatment, pneumococcal meningitis has a mortality rate of 20 to 30 percent [52-54]. (See "Initial therapy and prognosis of bacterial meningitis in adults", section on 'Mortality'.)

Pneumococcal endocarditis and other suppurative complications of pneumococcal infections, such as pneumococcal arthritis, ileitis, and pericarditis, were much more common in the preantibiotic era (prior to the early 1940s). This is illustrated by the findings of a review of pneumococcal peritonitis in children hospitalized between 1925 and 1970. Fifty of 56 cases of pneumococcal peritonitis identified in children occurred between 1925 and 1970; only six cases were identified from 1955 to 1970 [55].

Pneumococcal endocarditis — In 1881, Osler described the clinical triad of pneumococcal endocarditis, meningitis, and pneumonia. This triad, also called Austrian's syndrome, was thought to be more prevalent in alcoholic patients [56]. In the antibiotic era, 1 to 25 percent of patients with pneumococcal endocarditis have been reported to have the triad [57,58]. However, S. pneumoniae has been responsible for less than 3 percent of all cases of native valve endocarditis since the discovery of penicillin in the early 1940s.

Other notable clinical features of patients with pneumococcal endocarditis include the following:

Infection of the aortic valve is common [57,58].

Infection may occur on valves that were presumed to be morphologically and functionally normal prior to onset of the infection.

Onset of infection and the clinical evolution of infection may be acute.

A more detailed discussion of pneumococcal endocarditis is presented separately. (See "Antimicrobial therapy of left-sided native valve endocarditis", section on 'Streptococcus pneumoniae'.)

Other manifestations — Other manifestations of invasive pneumococcal disease, including abdominal infections (eg, peritonitis, appendicitis, terminal ileitis), have been primarily described in case reports or small case series [59-61]. These infections may occur with or without concurrent or recently detected bacteremia [59]. S. pneumoniae may cause suppurative abdominal complications, such as peritonitis and ileitis, particularly in patients with nephrotic syndrome.

Purulent pericarditis, septic arthritis, osteomyelitis, and epidural and brain abscess due to S. pneumoniae are rarely recognized in modern practice [62-66]. Pneumococcal tenosynovitis, chorioamnionitis, and abscesses involving the psoas, liver, pancreas, spleen, and kidney are even less common [66]. Despite their rarity, case reports of sporadic cases underscore an important clinical point: S. pneumoniae can cause suppurative infections in almost any site. Furthermore, these localized infections can follow an episode of pneumococcal bacteremia or occur simultaneously with pneumococcal bacteremia. In the former instance, these uncommon focal infections may be erroneously presumed to have arisen de novo.

DIAGNOSIS AND LABORATORY FEATURES — General laboratory findings in patients with invasive pneumococcal infections and bacteremia are nonspecific: typically, there is a leukocytosis (white blood cell [WBC] >12,000/mL), and anemia is common [67]. Poor prognostic factors in patients with extrameningeal invasive pneumococcal disease include coma, respiratory failure, shock, elevated liver function tests (alanine aminotransferase [ALT] >100 international units/L), or leukopenia (WBC <4000/mL). These prognostic factors have a particularly strong correlation with mortality in children with invasive pneumococcal infections [68].

Blood cultures — Definitive diagnosis of pneumococcal bacteremia or invasive pneumococcal infection requires the culture of S. pneumoniae from the blood or another normally sterile site. S. pneumoniae is rarely if ever a skin contaminant. Thus, when S. pneumoniae is recovered from blood cultures, it is considered to be a pathogen. (See "Detection of bacteremia: Blood cultures and other diagnostic tests".)

Antigen tests — The pneumococcal antigen test is a rapid immunochromatographic membrane assay that detects the presence of C polysaccharide cell wall antigen common to all serotypes of S. pneumoniae. The test is approved for the diagnosis of invasive pneumococcal disease using urine samples and, since most patients with pneumococcal meningitis are also bacteremic, it can also be used for the diagnosis of pneumococcal meningitis (by testing cerebrospinal fluid [CSF] or urine). The utility of this antigen test in blood culture samples is being evaluated, as illustrated by the following studies:

In a study of pneumococcal antigen testing of blood culture broth from cultures that were flagged as positive by BactT/ALERT system testing but failed to grow pneumococci by culture, antigen testing improved the yield during one surveillance period, with 43 of 182 samples (24 percent) yielding a positive result; however, during a later surveillance period, antigen testing was positive in only 7 of 221 samples (3.2 percent) [69]. When antigen testing was performed on uninoculated broth, weak positive results were observed.

In another study, 43 of 43 (100 percent) blood culture samples that grew S. pneumoniae had positive pneumococcal antigen tests [70]. In addition, 3 of 12 blood cultures that grew S. mitis had false-positive results on pneumococcal antigen testing, which is consistent with other studies that have reported false-positive results in patients with bacteremia caused by viridans group streptococci, particularly members of the S. mitis group.

Further study of the utility of pneumococcal antigen testing on blood culture samples is necessary. Such testing may be useful for the early detection of pneumococcal bacteremia when a Gram stain is positive and cultures are negative. However, false-positive results may occur in some patients with S. viridans (especially S. mitis) bacteremia. Furthermore, weak positive results should be interpreted with caution.

The use of pneumococcal antigen tests for the diagnosis of pneumococcal pneumonia and meningitis is discussed in greater detail separately. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults", section on 'Urine pneumococcal antigen testing' and "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Rapid tests'.)

TREATMENT — All isolates of S. pneumoniae were uniformly sensitive to penicillin until outbreaks of antibiotic-resistant pneumococci occurred in South Africa in the late 1970s [71,72]. (See "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics".)

Since then, pneumococci have developed resistance to several classes of antibiotics, including:

Beta-lactams

Macrolides and lincosamides

Tetracyclines

Trimethoprim-sulfamethoxazole

Glycopeptides (eg, vancomycin)

Fluoroquinolones

A detailed discussion of pneumococcal resistance to these antibiotic classes is presented separately. (See "Resistance of Streptococcus pneumoniae to the macrolides, azalides, lincosamides, and ketolides" and "Resistance of Streptococcus pneumoniae to the fluoroquinolones, doxycycline, and trimethoprim-sulfamethoxazole" and "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics".)

Impact of resistance on outcome — There is a continuing debate as to whether infection with pneumococcal strains that are resistant to beta-lactam antibiotics affects outcome when infection occurs in extrameningeal sites.

In a large prospective study of 1255 children with extrameningeal invasive pneumococcal infection, the proportion of susceptible and resistant strains were similar in the 19 children who died compared with those who survived their pneumococcal infection [73]. In a retrospective study also involving children, clinical outcome of extrameningeal penicillin-resistant pneumococcal infection was more closely related to the clinical condition at the time of presentation than to the level of antimicrobial resistance of the infecting strain [74].

These findings are at variance with other studies in which treatment of extrameningeal penicillin-resistant pneumococcal infections with beta-lactam antibiotics was associated with an increased likelihood of a fatal outcome [75,76]. The difference between the findings in these studies may have been due to differences in the populations studied. Specifically, one of the two studies that reported an association between the presence of antimicrobial resistance and mortality was conducted in a population with a high prevalence of HIV infection [75] and both studies included adults [75,76]. Furthermore, one of the studies found an association between older age and mortality [76].

The impact of concordant (eg, receipt of an antibiotic with in vitro activity against S. pneumoniae) versus discordant (antibiotic inactive in vitro) therapy on mortality was also assessed at 14 days in a subset of 360 of 844 hospitalized adults with pneumococcal bacteremia receiving monotherapy [77]. Surprisingly, discordant therapy with penicillins, cefotaxime, and ceftriaxone (but not cefuroxime) did not result in a higher mortality rate. In contrast, discordant therapy with cefuroxime was associated with a significantly higher mortality (36 compared with 6 percent with concordant cefuroxime treatment). The authors hypothesized that inadequate duration of time above the minimum inhibitory concentration (MIC) for cefuroxime serum concentration was responsible for the worse outcome in these patients. The statistical evaluation was underpowered to evaluate the impact of monotherapy with a fluoroquinolone or macrolide on the outcome of invasive pneumococcal disease.

Suppurative complications such as meningitis, empyema, endocarditis, lung abscess, or pericarditis do not occur more frequently in patients infected with strains of penicillin-resistant S. pneumoniae compared with those infected with penicillin-susceptible strains [77].

Risk factors for antibiotic nonsusceptibility — Risk factors for penicillin nonsusceptibility were examined in a prospective international observational study of 844 patients with pneumococcal bacteremia [77]. Two risk factors were found to be statistically significant using multivariate statistical methods:

The presence of an underlying immunosuppressive condition (HIV infection, splenectomy, hematological malignancy, autoimmune disorder, or transplant or chemotherapy within the preceding four weeks)

Prior receipt of antibiotics (defined as use of antibiotics for ≥1 day in the past three months)

Another important issue is the impact of community-wide antibiotic use on the prevalence of antibiotic nonsusceptibility. In one study, the relationship between outpatient antibiotic prescribing and nonsusceptibility among isolates causing invasive pneumococcal disease was evaluated using data from seven of the United States Active Bacterial Core surveillance sites between 1996 and 2003 [78]. Outpatient antibiotic prescription data for penicillins, cephalosporins, macrolides, and trimethoprim-sulfamethoxazole were reviewed. Sites with high rates of antibiotic prescribing had a higher proportion of nonsusceptibility among invasive pneumococcal disease isolates to each of the antibiotic classes evaluated. Cephalosporin and macrolide prescribing were associated with penicillin and multidrug nonsusceptibility and invasive serotype 19A infections; serotype 19A isolates are frequently multidrug resistant. These data suggest that local prescribing patterns contribute to local resistance patterns.

Approach to management — Debate continues as to whether combination therapy or monotherapy is more appropriate for treatment of known or suspected invasive pneumococcal infection prior to the availability of in vitro susceptibility results. In a retrospective study of 1154 patients with invasive pneumococcal disease, most of whom had bacteremia, the receipt of two antimicrobial agents concurrently was independently associated with decreased 30-day mortality (hazard ratio 0.54, 95% CI 0.34-0.84) [79]. The optimal duration of combination therapy is also unknown.

Until further studies lead to a better understanding of these issues, we, along with most experts, use combination therapy (ie, the use of two antibiotics with different anti-pneumococcal mechanisms of action) for patients with known or suspected invasive pneumococcal infections until susceptibility results are available. This approach is especially important for patients at high risk of resistant organisms. (See 'Risk factors for antibiotic nonsusceptibility' above.)

The choice of an empiric antibiotic regimen chosen for the treatment of suspected or known invasive pneumococcal infections depends upon local patterns of in vitro pneumococcal resistance. In all cases, empiric therapy should be reassessed and then adjusted or simplified if possible after susceptibility results are available. The interpretive breakpoints for S. pneumoniae are presented in the following table (table 3).

The approach to management of pneumococcal pneumonia and bacteremic pneumococcal pneumonia are discussed separately. (See "Pneumococcal pneumonia in patients requiring hospitalization" and "Pneumococcal pneumonia in children".)

Antibiotic therapy

Empiric therapy — Because concurrent meningitis can often not be definitively excluded at the time of presentation and because mortality is notoriously high during the first 72 hours of treatment, for adults, we recommend vancomycin (table 4) be given with ceftriaxone (2 g IV every 12 hours) or cefotaxime (2 g IV every 4 to 6 hours) for the initial empiric treatment of invasive pneumococcal infection. (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults".)

Although a fluoroquinolone may be a reasonable alternative for patients with allergy to beta-lactam antibiotics, we recommend the use of a third-generation cephalosporin and vancomycin in patients who do not have a history of type I (IgE-mediated, anaphylactic) allergy to beta-lactams because of their combined superior central nervous system penetration. Vancomycin with or without moxifloxacin is the best alternative choice in patients with a history of type I allergy to beta-lactam antibiotics who are not candidates for desensitization. (See "Treatment of bacterial meningitis caused by specific pathogens in adults", section on 'Streptococcus pneumoniae'.).

We also give adjunctive dexamethasone to adults with suspected or proven acute pneumococcal meningitis. (See "Dexamethasone to prevent neurologic complications of bacterial meningitis in adults".)

Targeted therapy — Empiric therapy should be altered once the laboratory has ascertained susceptibility of the organism. Vancomycin should be continued if concern for meningitis still exists and high-level penicillin resistance has been documented or if the infecting strain has an MIC >1 mcg/mL to third-generation cephalosporins (table 5). Following the return of in vitro susceptibility testing, it is reasonable to simplify therapy to penicillin if the isolate is susceptible (for patients with meningitis: penicillin MIC ≤0.06 mcg/mL, and for patients without meningitis: penicillin MIC ≤2 mcg/mL). Penicillin G (4 million units IV every four hours) can be used instead of a third-generation cephalosporin, although it is also reasonable to continue therapy with a third-generation cephalosporin given the excellent efficacy, convenient dosing, and affordability of these agents. A detailed discussion of the treatment of pneumococcal meningitis is presented separately. (See "Treatment of bacterial meningitis caused by specific pathogens in adults", section on 'Streptococcus pneumoniae'.)

Combination therapy should normally not exceed three to four days; monotherapy can usually be used after antimicrobial susceptibility results are available.

When using monotherapy to treat invasive pneumococcal disease, we select one of the following agents in adults:

Ceftriaxone (1 to 2 g IV every 24 hours) or cefotaxime (1 to 2 g IV every 6 to 8 hours). For central nervous system infections, ceftriaxone (2 g IV every 12 hours) or cefotaxime (2 g IV every 4 to 6 hours) should be used.  

Vancomycin (table 4) adjusted for renal function.

We are not aware of data supporting the use of a fluoroquinolone as monotherapy for invasive pneumococcal infections, although on theoretical grounds such therapy should work.

If a fluid collection is identified, it should be drained if possible. Follow-up blood cultures should be obtained after the initiation of therapy, particularly if the patient does not appear to respond to therapy. If blood cultures remain persistently positive despite appropriate therapy, further evaluation for the possibility of endocarditis (with echocardiography) is warranted. Similarly, evaluation for concurrent endocarditis is warranted if signs of valvular dysfunction are present and if sustained bacteremia is documented. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)

Duration of therapy — There have been no controlled trials on the optimal duration of antibiotics for the treatment of invasive pneumococcal infection. Several factors should be considered when planning a treatment course:

Location of primary infection

Immune status of the host

The presence or absence of suppurative complications

The response of the patient to therapy

In general, uncomplicated bacteremia should be treated with a 10- to 14-day course of appropriate antibiotics, assuming the patient has a good therapeutic response. We recommend initiation with intravenous therapy pending in vitro susceptibility results. Completion of therapy with an oral antibiotic is acceptable if the susceptibility pattern allows. The course of therapy will need to be adjusted if the patient has concurrent invasive pneumococcal infection (eg, endocarditis, septic arthritis, brain abscess) or fails to respond to therapy.

The management of pneumococcal meningitis is discussed separately. (See "Treatment of bacterial meningitis caused by specific pathogens in adults", section on 'Streptococcus pneumoniae'.)

Evaluation for risk factors — There is debate as to whether evaluation for risk factors of recurrent pneumococcal infection is warranted following the identification of the first attack of invasive pneumococcal disease. Our practice is to recommend an HIV test in all sexually active patients with invasive pneumococcal infections. In addition, we recommend screening tests for the presence of multiple myeloma in older adult patients with invasive pneumococcal infections and coexisting or preexisting anemia. An evaluation for sickle cell disease is recommended in younger patients with invasive pneumococcal infection and genetic risk factors for sickle cell disease (eg, people of African descent).

PROGNOSIS — Overall mortality rates for patients with pneumococcal bacteremia have consistently ranged from 15 to 20 percent in the antibiotic era. Risk of death in patients with pneumococcal bacteremia is highest during the first 72 hours after bacteremia is identified. In the prospective international observational study described above, the overall mortality rate of pneumococcal bacteremia was 17 percent [77]. Approximately two-thirds of deaths occurred within the first three days following admission to the hospital. Similar outcomes were reported in a cohort of 1875 Belgian patients ages 50 years and older. Sixteen percent of patients died during their hospitalization and an additional 2 percent died within one month of discharge [80].

Risk factors significantly associated with death in representative studies of patients with pneumococcal bacteremia included [22,77,81,82]:

Age ≥65 years

Severity of illness

Presence of an underlying disease or risk factor associated with immunosuppression (especially HIV infection)

In 2010 in the United States, the mortality for individuals ≥65 years of age was 5.61 deaths per 100,000 population, compared with 0.26 deaths per 100,000 population among individuals between 18 and 34 years of age [1].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Community-acquired pneumonia in adults" and "Society guideline links: Bacterial meningitis in adults" and "Society guideline links: Bacterial meningitis in infants and children" and "Society guideline links: Pneumococcal vaccination in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Sepsis in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definition Invasive pneumococcal disease is defined as an infection confirmed by the isolation of Streptococcus pneumoniae from a normally sterile site (eg, blood or cerebrospinal fluid but not sputum). S. pneumoniae (the pneumococcus) is an important and well-known cause of bacteremia in both immunocompetent and immunosuppressed patients. Pneumococcal bacteremia can occur as a result of pneumococcal pneumonia or in its absence. When bacteremia is present, secondary complications, such as arthritis, meningitis, and/or endocarditis, may occur. (See 'Introduction' above.)

Impact of childhood vaccination The incidence of invasive pneumococcal disease in any population is affected by geographic location, time of year, serotype prevalence, age, comorbidities, and vaccination status. The overall incidence of invasive pneumococcal disease in the United States declined following the introduction and widespread use of the pneumococcal conjugate vaccine in children, beginning in 2000. Routine vaccination in young children caused significant declines in the incidence of invasive pneumococcal disease in children <5 years (the age group targeted for vaccination), older children, and adults. However, an increase in disease caused by pneumococcal serotypes not included in the vaccine (eg, replacement disease) has also been observed. After the replacement of the 7-valent pneumococcal conjugate vaccine (PCV7) with a 13-valent pneumococcal conjugate vaccine (PCV13) for universal administration in children in the United States in 2010, there has been a reduction in invasive pneumococcal disease caused by the serotypes included in PCV13. (See 'Impact of childhood vaccination' above.)

Risk factors for infection The incidence of invasive pneumococcal disease is increased in patients with certain underlying medical conditions or demographic risk factors, including age <2 or ≥65 years (table 1); certain racial/ethnic groups (people of African descent, Alaskan Natives, and American Indians); chronic cardiovascular, pulmonary, liver, or renal disease; diabetes mellitus; alcohol abuse; smoking; or immunosuppressive conditions. (See 'Risk factors for infection' above.)

Clinical manifestations The clinical manifestations of invasive pneumococcal disease depend upon the primary site of infection and the presence or absence of bacteremia. Pneumococcal meningitis is the most frequent and severe suppurative complication associated with pneumococcal bacteremia. Pneumococcal endocarditis and other suppurative complications of pneumococcal infections, such as pneumococcal arthritis, ileitis, and pericarditis, were much more common in the preantibiotic era. (See 'Clinical manifestations' above.)

Diagnosis

Blood cultures Definitive diagnosis of pneumococcal bacteremia or invasive pneumococcal infection requires the culture of S. pneumoniae from the blood or another normally sterile site. (See 'Blood cultures' above.)

Antigen tests The pneumococcal urine antigen test is a rapid immunochromatographic membrane assay that detects the presence of C polysaccharide cell wall antigen common to all serotypes of S. pneumoniae. The test is approved for the diagnosis of invasive pneumococcal disease using urine samples and, since most patients with pneumococcal meningitis are also bacteremic, it can also be used for the diagnosis of pneumococcal meningitis (by testing cerebrospinal fluid or urine). (See 'Antigen tests' above.)

Approach to therapy

We use combination therapy (ie, the use of two antibiotics with different anti-pneumococcal mechanisms of action) for patients with known or suspected invasive pneumococcal infections until susceptibility results are available. The choice of an empiric regimen chosen for the treatment of suspected or known invasive pneumococcal infections depends upon local patterns of resistance. (See 'Approach to management' above.)

Because concurrent meningitis can often not be definitively excluded at the time of presentation and because the mortality rate is notoriously high during the first 72 hours of treatment, for adults we recommend vancomycin (table 4) be given with ceftriaxone (2 g IV every 12 hours) or cefotaxime (2 g IV every 4 to 6 hours) for the initial treatment of invasive pneumococcal infection. Combination therapy should normally not exceed three to four days; monotherapy can usually be used after antimicrobial susceptibility results are available. The management of pneumococcal meningitis is discussed separately. (See 'Antibiotic therapy' above and "Treatment of bacterial meningitis caused by specific pathogens in adults", section on 'Streptococcus pneumoniae'.)

Duration In general, uncomplicated bacteremia should be treated with a 10- to 14-day course of appropriate antibiotics, assuming the patient has a good therapeutic response. (See 'Duration of therapy' above.)

Prognosis Overall mortality rates for patients with pneumococcal bacteremia have consistently ranged from 15 to 20 percent in the antibiotic era. The highest mortality rates are observed in individuals ≥65 years of age, in those with severe disease, and in immunocompromised hosts. (See 'Prognosis' above.)

ACKNOWLEDGMENT — We are saddened by the death of John G Bartlett, MD, who passed away in January 2021. UpToDate gratefully acknowledges his tenure as the founding Editor-in-Chief for UpToDate in Infectious Diseases and his dedicated and longstanding involvement with the UpToDate program.

  1. Centers for Disease Control and Prevention. Active Bacterial Core Surveillance (ABCs) Report Emerging Infections Program Network: Streptococcus pneumoniae, 2010 (ORIG). http://www.cdc.gov/abcs/reports-findings/survreports/spneu10-orig.pdf (Accessed on March 21, 2013).
  2. Centers for Disease Control and Prevention (CDC). Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2012; 61:816.
  3. Talbot TR, Poehling KA, Hartert TV, et al. Reduction in high rates of antibiotic-nonsusceptible invasive pneumococcal disease in tennessee after introduction of the pneumococcal conjugate vaccine. Clin Infect Dis 2004; 39:641.
  4. Centers for Disease Control and Prevention. Active Bacterial Core surveillance (ABCs). http://www.cdc.gov/abcs/index.html (Accessed on February 01, 2012).
  5. Centers for Disease Control and Prevention (CDC). Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease--United States, 1998-2003. MMWR Morb Mortal Wkly Rep 2005; 54:893.
  6. Shah SS, Ratner AJ. Trends in invasive pneumococcal disease-associated hospitalizations. Clin Infect Dis 2006; 42:e1.
  7. Lexau CA, Lynfield R, Danila R, et al. Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine. JAMA 2005; 294:2043.
  8. Albrich WC, Baughman W, Schmotzer B, Farley MM. Changing characteristics of invasive pneumococcal disease in Metropolitan Atlanta, Georgia, after introduction of a 7-valent pneumococcal conjugate vaccine. Clin Infect Dis 2007; 44:1569.
  9. Pingali SC, Warren JL, Mead AM, et al. Association Between Local Pediatric Vaccination Rates and Patterns of Pneumococcal Disease in Adults. J Infect Dis 2016; 213:509.
  10. Hsu HE, Shutt KA, Moore MR, et al. Effect of pneumococcal conjugate vaccine on pneumococcal meningitis. N Engl J Med 2009; 360:244.
  11. Griffin MR, Zhu Y, Moore MR, et al. U.S. hospitalizations for pneumonia after a decade of pneumococcal vaccination. N Engl J Med 2013; 369:155.
  12. Tsigrelis C, Tleyjeh IM, Lahr BD, et al. Decreases in case-fatality and mortality rates for invasive pneumococcal disease in Olmsted County, Minnesota, during 1995-2007: a population-based study. Clin Infect Dis 2008; 47:1367.
  13. Bijlsma MW, Brouwer MC, Kasanmoentalib ES, et al. Community-acquired bacterial meningitis in adults in the Netherlands, 2006-14: a prospective cohort study. Lancet Infect Dis 2016; 16:339.
  14. Miller E, Andrews NJ, Waight PA, et al. Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study. Lancet Infect Dis 2011; 11:760.
  15. Moore MR, Link-Gelles R, Schaffner W, et al. Effect of use of 13-valent pneumococcal conjugate vaccine in children on invasive pneumococcal disease in children and adults in the USA: analysis of multisite, population-based surveillance. Lancet Infect Dis 2015; 15:301.
  16. Hampton LM, Farley MM, Schaffner W, et al. Prevention of antibiotic-nonsusceptible Streptococcus pneumoniae with conjugate vaccines. J Infect Dis 2012; 205:401.
  17. Kaplan SL, Barson WJ, Lin PL, et al. Early trends for invasive pneumococcal infections in children after the introduction of the 13-valent pneumococcal conjugate vaccine. Pediatr Infect Dis J 2013; 32:203.
  18. Tomczyk S, Lynfield R, Schaffner W, et al. Prevention of Antibiotic-Nonsusceptible Invasive Pneumococcal Disease With the 13-Valent Pneumococcal Conjugate Vaccine. Clin Infect Dis 2016; 62:1119.
  19. Brueggemann AB, Peto TE, Crook DW, et al. Temporal and geographic stability of the serogroup-specific invasive disease potential of Streptococcus pneumoniae in children. J Infect Dis 2004; 190:1203.
  20. Østergaard C, Brandt C, Konradsen HB, Samuelsson S. Differences in survival, brain damage, and cerebrospinal fluid cytokine kinetics due to meningitis caused by 3 different Streptococcus pneumoniae serotypes: evaluation in humans and in 2 experimental models. J Infect Dis 2004; 190:1212.
  21. Hausdorff WP, Feikin DR, Klugman KP. Epidemiological differences among pneumococcal serotypes. Lancet Infect Dis 2005; 5:83.
  22. Alanee SR, McGee L, Jackson D, et al. Association of serotypes of Streptococcus pneumoniae with disease severity and outcome in adults: an international study. Clin Infect Dis 2007; 45:46.
  23. Garau J, Calbo E. Capsular types and predicting patient outcomes in pneumococcal bacteremia. Clin Infect Dis 2007; 45:52.
  24. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 1997; 46:1.
  25. Centers for Disease Control and Prevention (CDC). Advisory Committee on Immunization Practices. Pneumococcal vaccination for cochlear implant candidates and recipients: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 2003; 52:739.
  26. Gentile JH, Sparo MD, Mercapide ME, Luna CM. Adult bacteremic pneumococcal pneumonia acquired in the community. A prospective study on 101 patients. Medicina (B Aires) 2003; 63:9.
  27. Laupland KB, Gregson DB, Zygun DA, et al. Severe bloodstream infections: a population-based assessment. Crit Care Med 2004; 32:992.
  28. Talbot TR, Hartert TV, Mitchel E, et al. Asthma as a risk factor for invasive pneumococcal disease. N Engl J Med 2005; 352:2082.
  29. Hargreaves RM, Lea JR, Griffiths H, et al. Immunological factors and risk of infection in plateau phase myeloma. J Clin Pathol 1995; 48:260.
  30. Twomey JJ. Infections complicating multiple myeloma and chronic lymphocytic leukemia. Arch Intern Med 1973; 132:562.
  31. Chi RC, Jackson LA, Neuzil KM. Characteristics and outcomes of older adults with community-acquired pneumococcal bacteremia. J Am Geriatr Soc 2006; 54:115.
  32. Romney MG, Hull MW, Gustafson R, et al. Large community outbreak of Streptococcus pneumoniae serotype 5 invasive infection in an impoverished, urban population. Clin Infect Dis 2008; 47:768.
  33. Nuorti JP, Butler JC, Farley MM, et al. Cigarette smoking and invasive pneumococcal disease. Active Bacterial Core Surveillance Team. N Engl J Med 2000; 342:681.
  34. Lipsky BA, Boyko EJ, Inui TS, Koepsell TD. Risk factors for acquiring pneumococcal infections. Arch Intern Med 1986; 146:2179.
  35. Cruickshank HC, Jefferies JM, Clarke SC. Lifestyle risk factors for invasive pneumococcal disease: a systematic review. BMJ Open 2014; 4:e005224.
  36. Kantsø B, Simonsen J, Hoffmann S, et al. Inflammatory Bowel Disease Patients Are at Increased Risk of Invasive Pneumococcal Disease: A Nationwide Danish Cohort Study 1977-2013. Am J Gastroenterol 2015; 110:1582.
  37. Shigayeva A, Rudnick W, Green K, et al. Invasive Pneumococcal Disease Among Immunocompromised Persons: Implications for Vaccination Programs. Clin Infect Dis 2016; 62:139.
  38. de St Maurice A, Schaffner W, Griffin MR, et al. Persistent Sex Disparities in Invasive Pneumococcal Diseases in the Conjugate Vaccine Era. J Infect Dis 2016; 214:792.
  39. Wiese AD, Griffin MR, Schaffner W, et al. Opioid Analgesic Use and Risk for Invasive Pneumococcal Diseases: A Nested Case-Control Study. Ann Intern Med 2018; 168:396.
  40. Tuomanen EI, Austrian R, Masure HR. Pathogenesis of pneumococcal infection. N Engl J Med 1995; 332:1280.
  41. Ampofo K, Bender J, Sheng X, et al. Seasonal invasive pneumococcal disease in children: role of preceding respiratory viral infection. Pediatrics 2008; 122:229.
  42. Burgos J, Larrosa MN, Martinez A, et al. Impact of influenza season and environmental factors on the clinical presentation and outcome of invasive pneumococcal disease. Eur J Clin Microbiol Infect Dis 2015; 34:177.
  43. Talbot TR, Poehling KA, Hartert TV, et al. Seasonality of invasive pneumococcal disease: temporal relation to documented influenza and respiratory syncytial viral circulation. Am J Med 2005; 118:285.
  44. French N, Gordon SB, Mwalukomo T, et al. A trial of a 7-valent pneumococcal conjugate vaccine in HIV-infected adults. N Engl J Med 2010; 362:812.
  45. Munier AL, de Lastours V, Porcher R, et al. Risk factors for invasive pneumococcal disease in HIV-infected adults in France in the highly active antiretroviral therapy era. Int J STD AIDS 2014; 25:1022.
  46. Thornhill J, Sivaramakrishnan A, Orkin C. Pneumococcal vaccination in people living with HIV. Vaccine 2015; 33:3159.
  47. Marcus JL, Baxter R, Leyden WA, et al. Invasive Pneumococcal Disease Among HIV-Infected and HIV-Uninfected Adults in a Large Integrated Healthcare System. AIDS Patient Care STDS 2016; 30:463.
  48. McEllistrem MC, Mendelsohn AB, Pass MA, et al. Recurrent invasive pneumococcal disease in individuals with human immunodeficiency virus infection. J Infect Dis 2002; 185:1364.
  49. Schuchat A, Broome CV, Hightower A, et al. Use of surveillance for invasive pneumococcal disease to estimate the size of the immunosuppressed HIV-infected population. JAMA 1991; 265:3275.
  50. Jacobs MR, Good CE, Bajaksouzian S, Windau AR. Emergence of Streptococcus pneumoniae serotypes 19A, 6C, and 22F and serogroup 15 in Cleveland, Ohio, in relation to introduction of the protein-conjugated pneumococcal vaccine. Clin Infect Dis 2008; 47:1388.
  51. Mwenya DM, Charalambous BM, Phillips PP, et al. Impact of cotrimoxazole on carriage and antibiotic resistance of Streptococcus pneumoniae and Haemophilus influenzae in HIV-infected children in Zambia. Antimicrob Agents Chemother 2010; 54:3756.
  52. Schuchat A, Robinson K, Wenger JD, et al. Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med 1997; 337:970.
  53. Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 1998; 129:862.
  54. Durand ML, Calderwood SB, Weber DJ, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993; 328:21.
  55. Fowler R. Primary peritonitis: changing aspects 1956-1970. Aust Paediatr J 1971; 7:73.
  56. AUSTRIAN R. Pneumococcal endocarditis, meningitis, and rupture of the aortic valve. AMA Arch Intern Med 1957; 99:539.
  57. Gransden WR, Eykyn SJ, Phillips I. Pneumococcal bacteraemia: 325 episodes diagnosed at St Thomas's Hospital. Br Med J (Clin Res Ed) 1985; 290:505.
  58. Aronin SI, Mukherjee SK, West JC, Cooney EL. Review of pneumococcal endocarditis in adults in the penicillin era. Clin Infect Dis 1998; 26:165.
  59. Petti CA, Ignatius Ou SH, Sexton DJ. Acute terminal ileitis associated with pneumococcal bacteremia: case report and review of pneumococcal gastrointestinal diseases. Clin Infect Dis 2002; 34:E50.
  60. Heltberg O, Korner B, Schouenborg P. Six cases of acute appendicitis with secondary peritonitis caused by Streptococcus pneumoniae. Eur J Clin Microbiol 1984; 3:141.
  61. Astagneau P, Goldstein FW, Francoual S, et al. Appendicitis due to both Streptococcus pneumoniae and Haemophilus influenzae. Eur J Clin Microbiol Infect Dis 1992; 11:559.
  62. Ross JJ, Saltzman CL, Carling P, Shapiro DS. Pneumococcal septic arthritis: review of 190 cases. Clin Infect Dis 2003; 36:319.
  63. Ryczak M, Sands M, Brown RB, Sklar JH. Pneumococcal arthritis in a prosthetic knee. A case report and review of the literature. Clin Orthop Relat Res 1987; :224.
  64. Turner DP, Weston VC, Ispahani P. Streptococcus pneumoniae spinal infection in Nottingham, United Kingdom: not a rare event. Clin Infect Dis 1999; 28:873.
  65. Grigoriadis E, Gold WL. Pyogenic brain abscess caused by Streptococcus pneumoniae: case report and review. Clin Infect Dis 1997; 25:1108.
  66. Taylor SN, Sanders CV. Unusual manifestations of invasive pneumococcal infection. Am J Med 1999; 107:12S.
  67. Musher DM, Alexandraki I, Graviss EA, et al. Bacteremic and nonbacteremic pneumococcal pneumonia. A prospective study. Medicine (Baltimore) 2000; 79:210.
  68. Ma JS, Chen PY, Mak SC, et al. Clinical outcome of invasive pneumococcal infection in children: a 10-year retrospective analysis. J Microbiol Immunol Infect 2002; 35:23.
  69. Baggett HC, Rhodes J, Dejsirilert S, et al. Pneumococcal antigen testing of blood culture broth to enhance the detection of Streptococcus pneumoniae bacteremia. Eur J Clin Microbiol Infect Dis 2012; 31:753.
  70. Petti CA, Woods CW, Reller LB. Streptococcus pneumoniae antigen test using positive blood culture bottles as an alternative method to diagnose pneumococcal bacteremia. J Clin Microbiol 2005; 43:2510.
  71. Appelbaum PC, Bhamjee A, Scragg JN, et al. Streptococcus pneumoniae resistant to penicillin and chloramphenicol. Lancet 1977; 2:995.
  72. Jacobs MR, Koornhof HJ, Robins-Browne RM, et al. Emergence of multiply resistant pneumococci. N Engl J Med 1978; 299:735.
  73. Kaplan SL, Mason EO Jr, Barson WJ, et al. Three-year multicenter surveillance of systemic pneumococcal infections in children. Pediatrics 1998; 102:538.
  74. Choi EH, Lee HJ. Clinical outcome of invasive infections by penicillin-resistant Streptococcus pneumoniae in Korean children. Clin Infect Dis 1998; 26:1346.
  75. Turett GS, Blum S, Fazal BA, et al. Penicillin resistance and other predictors of mortality in pneumococcal bacteremia in a population with high human immunodeficiency virus seroprevalence. Clin Infect Dis 1999; 29:321.
  76. Feikin DR, Schuchat A, Kolczak M, et al. Mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997. Am J Public Health 2000; 90:223.
  77. Yu VL, Chiou CC, Feldman C, et al. An international prospective study of pneumococcal bacteremia: correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clin Infect Dis 2003; 37:230.
  78. Hicks LA, Chien YW, Taylor TH Jr, et al. Outpatient antibiotic prescribing and nonsusceptible Streptococcus pneumoniae in the United States, 1996-2003. Clin Infect Dis 2011; 53:631.
  79. Marrie TJ, Tyrrell GJ, Garg S, Vanderkooi OG. Factors predicting mortality in invasive pneumococcal disease in adults in Alberta. Medicine (Baltimore) 2011; 90:171.
  80. Verhaegen J, Flamaing J, De Backer W, et al. Epidemiology and outcome of invasive pneumococcal disease among adults in Belgium, 2009-2011. Euro Surveill 2014; 19:14.
  81. Marrie TJ, Tyrrell GJ, Majumdar SR, Eurich DT. Effect of Age on the Manifestations and Outcomes of Invasive Pneumococcal Disease in Adults. Am J Med 2018; 131:100.e1.
  82. Beatty JA, Majumdar SR, Tyrrell GJ, et al. Prognostic factors associated with mortality and major in-hospital complications in patients with bacteremic pneumococcal pneumonia: Population-based study. Medicine (Baltimore) 2016; 95:e5179.
Topic 3168 Version 32.0

References