Version May 2024
INTRODUCTION — Streptococcus pneumoniae (pneumococcus) is the most commonly identified bacterial cause of community-acquired pneumonia (CAP). Mortality associated with pneumococcal pneumonia in hospitalized patients is high, ranging from 12 to 30 percent. Risk for severe infection, complications, and mortality are highest among older patients with chronic illnesses, particularly when complications, such as bacteremia are present.
This topic reviews pneumococcal pneumonia that requires hospitalization as distinguished from other forms of CAP. An overview of CAP, its diagnosis, and treatment are discussed separately. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults" and "Treatment of community-acquired pneumonia in adults in the outpatient setting".)
EPIDEMIOLOGY
Prevalence — Pneumococcus has historically been the most common cause of pneumonia, by far [1], and remains the most common bacterial cause of community-acquired pneumonia (CAP) leading to hospitalization of adults today. In the United States, 5 to 15 percent of CAP cases have been attributed to pneumococcus [2-4]. However, more recent quantitative molecular [5] and bacteriologic data [6] indicate that this is an underestimate and suggest that 20 to 25 percent of cases may be due to pneumococcus [5,6]. This percentage is higher in Europe [7-10] and is even higher in developing countries [11].
In the preantibiotic era, all pneumonia was community acquired, and S. pneumoniae was responsible for more than 90 percent of cases [1]. The median age at onset of infection was in the upper 30s, contrasted to data at the end of the twentieth century showing a median age of 70 [12]. Even as other causative organisms of CAP were demonstrated (eg, influenza, Mycoplasma, other respiratory viruses, Haemophilus, Moraxella, and Chlamydia spp), pneumococcus continued to be the major cause of pneumonia in adults through the 1960s. Studies since then have shown a declining proportion of pneumonia to be due to this organism [7].
Factors that have contributed to the decline in S. pneumoniae as a cause of CAP in the United States include the widespread acceptance of pneumococcal vaccines by older adults, a substantial reduction in cigarette smoking by adults (these two factors likely distinguish the United States from Europe), and the universal use of pneumococcal conjugate vaccines in children. The impact of pneumococcal vaccination on the incidence of pneumonia is discussed in greater detail separately. (See "Pneumococcal vaccination in adults" and "Pneumococcal vaccination in children".)
The true prevalence of pneumococcus as a cause of CAP may be higher than the studies above suggest. Most studies of CAP have failed to identify a causative organism in over 50 percent of cases and it is likely that pneumococcus is responsible for some proportion of these cases [13]. The principal reason for failing to recognize S. pneumoniae as a cause of pneumonia is methodologic. Blood cultures are positive in no more than 20 to 25 percent of pneumococcal pneumonia [1,13], and the urine antigen test in nonbacteremic disease has only moderate sensitivity (see 'Diagnosis' below); thus, the diagnosis of pneumococcal pneumonia rests, in many cases, on sputum Gram stain and culture.
Many patients with pneumonia are unable to provide a valid sputum sample (rather than "spit" or saliva) at admission and, after 18 to 24 hours of antibiotic treatment, the yield of sputum Gram stain and culture declines greatly [14]. Prospective studies of pneumococcal pneumonia [15,16] have found approximately equal numbers of bacteremic and nonbacteremic cases, suggesting that there are two additional cases of nonbacteremic pneumococcal pneumonia for every one that is recognized. In one study evaluating hospitalized patients who were able provide a purulent sputum at hospital admission (or soon after), a microbiologic diagnosis was made in 95 percent of cases [6]. S pneumoniae accounted for approximately 25 percent.
Risk factors — Approximately 90 percent of patients have one or more underlying condition(s) that probably contributes to susceptibility of developing the infection [12]. These conditions include:
●Extremes of age − Pneumococcal pneumonia occurs most frequently in infants and toddlers and in older adults, although the success of protein-conjugate pneumococcal vaccine has greatly reduced the incidence of pneumococcal disease in the former age group.
It is suggested that the global burden of pneumococcal disease will increase as life expectancy increases [17]. The effect of older age is multifactorial, including (but not limited to) increased likelihood of unrecognized aspiration and/or decreased clearance of aspirated nasopharyngeal bacteria, decreased cytokine production and/or decreased responsiveness to interleukin 1 and tumor necrosis factor-alpha, and suboptimal nutritional status [18].
●Crowded living conditions − The incidence of pneumococcal pneumonia has been shown to be greatly increased in South African miners [19] and newly recruited military troops [20] who have in common crowded living conditions and physical and emotional stress. Very close contact at work, for example, in shipyards, has been implicated [21]. Outbreaks of pneumococcal pneumonia have also been described in shelters [22], jails [23], and nursing homes and long-term care facilities [24,25] where similar conditions may prevail.
●Race/ethnicity − Pneumococcal pneumonia occurs more frequently in Black Americans and Native Americans than in the White American population [26-28]. While it is difficult to distinguish environmental and other contributing factors from genetic determinants, susceptibility in these groups may involve genetic determinants.
●Viral infection − Influenza infection greatly predisposes to secondary pneumococcal pneumonia [29], and infection by other viruses probably does, as well, as evidenced by the prevalence of viral and pneumococcal coinfection [2,3,5,6]. The principal explanation is damaged clearance of bacteria that have bypassed usual (but not constant) protection of a closed glottis. Other explanations include increased expression of genes that govern growth and metabolism of pneumococci during coinfection with influenza virus [30] and the ability of pneumococci to carry viral particles on its surface during aerosol transmission [31].
●Alcohol use disorder − For more than a century, alcohol use disorder has been highly associated with susceptibility to pneumococcal pneumonia [1,27,32]. The reasons for this increased susceptibility are complex and differ for acute versus chronic alcohol abuse [32]. Multiple elements of host defenses are impaired in alcohol abuse including decreased cough and epiglottis reflex, defects in mucociliary clearance, suppression of cytokine and chemokine responses, and numerous aspects of neutrophil function (adhesion, migration to site of infection, and killing of pneumococci). With chronic alcohol use disorder, malnutrition and liver disease play further contributory roles.
●Cigarette smoking − Nasopharyngeal colonization is increased in cigarette smokers and even in children of parents who smoke [33]. Pneumococcal pneumonia (specifically, invasive pneumococcal disease, most of which is due to pneumonia) is highly associated with cigarette smoking (odds ratio [OR] 4.1, 95% CI 2.4-7.3) and with passive smoke exposure (OR 2.5, 95% CI 1.2-5.1) [34]. A dose-response relationship was demonstrable for number of cigarettes smoked per day, packs per year of smoking, and time since quitting. Presumably, damaged pulmonary clearance is largely responsible, but other lifestyle factors also play a role.
●COPD and other pulmonary disorders − Patients with chronic obstructive pulmonary disease (COPD) have increased rates of hospitalization due to pneumococcal pneumonia [35]. There are conflicting data regarding the risk among patients with asthma [36].
●Splenectomy – Patients who have undergone surgical splenectomy or autosplenectomy (eg, as a result of sickle cell disease) are at increased risk of overwhelming pneumococcal infection unless they have antibody to the infecting serotype because the spleen plays a principal role in removing unopsonized bacteria from the bloodstream. (See "Clinical features, evaluation, and management of fever in patients with impaired splenic function", section on 'Streptococcus pneumoniae (pneumococcus)'.)
●Immunocompromise − The principal host defense against pneumococcal pneumonia is antibody to pneumococcal capsular polysaccharide, thus, any condition that reduces the antibody response to new antigens is highly likely to predispose to pneumococcal pneumonia. Historically, in addition to congenital or acquired agammaglobulinemia, multiple myeloma and lymphoma were the best recognized examples of this association [37,38]. HIV infection was subsequently recognized as a major predisposing condition; early in the AIDS era, the nearly 200-fold increase in age-adjusted invasive pneumococcal disease in San Francisco was due to the dramatically increased numbers of HIV-infected patients in that population [39,40]. An association with systemic lupus erythematosus has been documented [41]. The incidence of pneumococcal pneumonia has been shown to be increased in malignancy [42], hemodialysis [42], transplantation [43-45] and, in particular, hematopoietic cell transplantation complicated by chronic graft-versus-host disease [42,46]. The incidence of pneumococcal pneumonia is greatly increased by a variety of mechanisms, only one of which is the well-recognized autosplenectomy that results from poor flexibility of sickle cells to pass through splenic capillaries [47].
●Other conditions − Opioid use [48] and welding [49] are independent risk factors for pneumococcal disease.
PATHOGENESIS
●Human to human transmission – S. pneumoniae is an exclusively human pathogen and is spread from person to person by aerosol inhalation or close contact.
●Nasopharyngeal colonization – Colonization of the nasopharynx results when pneumococcal surface proteins (eg, pneumococcal surface protein A, choline binding protein C) [50,51] react with ligands on human mucosal epithelial cells [52]. At any given time, 25 to 50 percent of children and 5 to 10 percent of adults are colonized with pneumococcus in the nasopharynx. Several serotypes may be carried at the same time. Children carry a larger number of organisms (the "bacterial burden" is much greater), and family studies have shown that children generally serve as the major source for the spread of pneumococci to adults [53]. Once colonized, healthy adults continue to carry pneumococci for 4 to 12 weeks; carriage persists longer in immunocompromised persons.
Colonization of the nasopharynx by pneumococcus is not a passive process. Bacterial antigen is taken up by dendritic cells and, within 10 to 14 days, antibody to capsular polysaccharide is detected in serum [54]. This antibody is highly protective, and if pneumococcal disease occurs at a later time, it generally follows acquisition of a new serotype [55].
●Aspiration leading to pneumonia – Pneumonia develops when nasopharyngeal secretions containing pneumococci are carried into the lungs (ie, aspiration) and are not cleared rapidly and effectively. Aspiration is successfully prevented during waking hours by the glottis but regularly occurs during sleep, being especially prevalent in older and more frail adults [56]. Normal clearance mechanisms will greatly reduce the likelihood of disease, but may be overcome by aspiration of a sufficiently large bacterial inoculum [57]. Clearance mechanisms may be damaged by a broad range of factors including suppression of cough by alcohol or drugs and by any chronic inflammatory condition affecting the airways, such as cigarette smoking, viral respiratory infections, etc, which produce mucus and/or damage ciliary clearance.
Within the alveolus, pneumococci encounter antimicrobial peptides and shed the polysaccharide capsule [58]. This reveals pili and surface proteins that can bind to host epithelial cell carbohydrates and receptors. As pneumococci multiply in the alveoli and spread through the pores of Cohn or via tertiary bronchioles, pneumonia progresses. To disseminate to other organs, bacteria enter alveolar type II cells by binding to the receptor for platelet-activating factor (PAF) and cross into capillaries [59]. This attachment occurs through bacterial display of surface-localized phosphorylcholine, a chemical constituent shared between the bacteria and the human chemokine PAF. The host innate defense element C-reactive protein binds to phosphorylcholine blocking bacterial entry and facilitating phagocytosis.
●Robust inflammatory response – The inflammatory response to pneumococcal replication in the alveoli is intense. Pneumolysin, a pore-forming toxin with the capacity to kill host cells contributes substantially to alveolar damage [60]. Bacterial components, especially peptidoglycan, activate innate Toll-like receptors that trigger strong signaling to induce cytokine production [61,62]. Bronchoalveolar lavage fluid in pneumonia contains high amounts of tumor necrosis factor, interleukins 1 and 6, and nitric oxide, reflective of strong recruitment of leukocytes to the infected focus [63]. Alveoli fill with plasma, white blood cells, and bacteria producing the inflammatory exudate that is seen as opacities on chest radiograph and that causes ventilation-perfusion defects. There is little permanent tissue destruction or necrosis during this process, however, perhaps explaining why patients recover fully from these lesions, although, infrequently, cavitation or necrotizing pneumonia occurs [64,65].
●Potential invasive infection – Invasive pneumococcal infection is defined by the detection of pneumococci in normally sterile body sites. Bacteremia, by definition an invasive infection, is detected by results of blood culture (image 1 and image 2). Other organs can become infected leading to complications such as meningitis, arthritis, myocarditis, and endocarditis. (See "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia in adults".)
CLINICAL MANIFESTATIONS
Pneumococcal pneumonia
Symptoms — The "classic" syndrome associated with pneumococcal pneumonia is acute onset fever, chills, cough, pleuritic chest pain, and rusty-colored sputum [1]. This description is derived from reports in the preantibiotic era when pneumococcal pneumonia more often affected young adults who likely had robust immune responses to infection. This syndrome is now seen less frequently. Currently, the median age of patients with pneumococcal pneumonia is around 65 to 70 years. The onset is more insidious, often preceded by symptoms consistent with a viral illness for several days with a distinct deterioration when the bacterial infection sets in. Once symptoms of pneumonia appear, infection progresses fairly rapidly such that most patients who require hospitalization present within the next three days [15,66,67].
Based on studies, cough, shortness of breath, and subjective fever and/or chills are present in more than 80 percent of adults with pneumococcal pneumonia [12,15,66-70]. Sputum production is variably present, more frequently in middle-aged men, especially those with chronic lung disease. Sputum is bloody (often described as rusty rather than frankly bloody because of the admixture of inflammatory exudate and red cells in the alveoli) in 15 percent of patients. About one-quarter of patients have chest pain and a similar number have confusion. Importantly, all these symptoms except for confusion tend to be less prominent in older adult patients (the persons in whom pneumococcal pneumonia is most common) [67]. Some older patients may just "look ill," become confused, or "not be themselves." The less prominent manifestations of pneumococcal pneumonia in older adults probably reflects generation of lesser amounts of inflammatory cytokines and/or lower responsiveness to those that are produced. Diarrhea or vomiting, observed in some patients, result from the action of circulating cytokines on the gut.
Physical examination — On physical examination, patients with pneumococcal pneumonia are generally ill-appearing [15]. Tachypnea and tachycardia are common. Because of perfusion/ventilation mismatch, up to one-half have abnormally low partial pressure of oxygen. Somewhat surprisingly to most clinicians, fever, if defined as body temperature exceeding 99.4°F, is seen in fewer than 50 percent of cases, although the absence of fever, tachypnea, and tachycardia renders the diagnosis of pneumonia very unlikely [71].
Abnormal physical findings, including rales, increased fremitus, and/or dullness to percussion over the affected lung, may be found in the majority of cases. However, careful study of patients with community-acquired pneumonia (CAP) has shown that these, and other physical findings, are not consistently documented and that there may be substantial intraobserver difference in eliciting them [71-73].
Laboratory findings — In 10 to 30 percent of patients with bacteremic pneumococcal pneumonia, the admitting blood hemoglobin is <10 g/dL. The white blood cell (WBC) count usually exceeds 10,000, and early (band) forms are seen in about 20 percent of cases. In one study, 10 percent of patients with pneumococcal pneumonia had WBC counts <6000 and 8 percent had WBC counts >25,000; 56 percent of patients with low WBC counts were bacteremic, and the mortality in these two groups was fivefold and threefold greater, respectively, than in all those with WBC counts between 6000 and 25,000 [73]. Bilirubin and liver enzymes may be mildly elevated; the pathogenesis of these abnormalities is multifactorial with hypoxia, cytokine release, involvement of the right lower lobe, and breakdown of red blood cells in the alveoli all playing a role. Albumin is low in more than 50 percent of patients. In some of these, malnutrition may have been a contributing cause, but in the great majority the low albumin has developed acutely as a result of the pneumonia [16].
Chest imaging — Abnormal findings in pneumococcal pneumonia range from "increased markings" or "possible atelectasis" to infiltration or lobar consolidation with air bronchograms. In some cases, abnormalities are only seen on computed tomography (CT) scan, which are increasingly ordered routinely in emergency departments. Ultrasound is increasingly being used to diagnose pneumonia, but often by physicians who lack appropriate training to correctly obtain and interpret them.
Dense consolidation of a segment or lobe is associated with bacteremia and more severe disease [74]. Necrotizing changes or frank abscesses are uncommon. In a study of 351 patients with pneumococcal pneumonia, necrotizing changes were not reported in any original chest radiograph readings and in 6 of 136 (4.4 percent) of initial CT readings [65]. Even upon rereading, only 8 of 351 (2.3 percent) chest radiographs and 15 of 136 (11 percent) chest CTs showed necrotizing changes. Frank lung abscess is rarely reported [75].
Complications
Pleural effusion and empyema — Approximately one-third of patients with pneumococcal pneumonia have a pleural effusion that is detectable by special studies, but only a fraction of these have enough fluid to do a pleurocentesis [76]. When sufficient fluid is present in a patient with pneumococcal pneumonia, pleurocentesis should be performed. (See "Epidemiology, clinical presentation, and diagnostic evaluation of parapneumonic effusion and empyema in adults".)
Empyema (frankly purulent pleural fluid) has always been the most common serious pulmonary complication of pneumococcal pneumonia, occurring in approximately 5 percent of cases. Whether organisms reach the pleural space from local extension or from bacteremic spread has not been established. In either scenario, the presence of empyema alters management, mandating prompt drainage and prolonged antibiotic treatment. (See "Management and prognosis of parapneumonic pleural effusion and empyema in adults".)
Bacteremia — Bacteremia complicates pneumococcal pneumonia in approximately 25 percent of cases [1,13]. The onset of illness also tends to be more acute, fever and pulse rates are higher, and there is a higher likelihood of sepsis. Multilobar infiltrates and pleural effusions are more common as are, expectedly, complications such as septic arthritis or meningitis.
Bacteremic disease is more common in younger patients (often in their mid-50s) than nonbacteremic disease (often in their mid to upper 60s). Patients with alcohol use disorder are more likely, and those with chronic obstructive pulmonary disease are less likely, to have bacteremia when they have pneumococcal pneumonia. Bacteremic pneumonia tends to be more acute in onset with a shorter time from onset of symptoms to admission. In-hospital mortality is about 12 to 15 percent and 90-day mortality is about 25 to 30 percent in bacteremic patients, in each case about twice as high as for nonbacteremic patients [15,16,70].
Other infectious complications — Other life-threatening complications of pneumococcal pneumonia result from bacteremia, and include meningitis, endocarditis, pericarditis, myocarditis, septic arthritis, and peritonitis. (See "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia in adults".)
Cardiac events and other noninfectious complications — Observational data shows a strong association with acute cardiac events and pneumococcal pneumonia. Short-term cardiac complications occur in one-third of patients, with myocardial infarction reported in 7 percent of cases, new onset of a major cardiac arrhythmia (atrial fibrillation in most) in 5 percent, and new onset or worsening congestive heart failure in 8 percent of cases [15,77-79]. Compared with CAP patients without acute cardiac events, CAP patients with acute cardiac events have longer time to clinical stability, increased rates of clinical failure, and increased 30- and 90-day mortality [80,81]. Mortality in patients with a cardiac event is far greater than for those who do not have such an event. Increased risk for a cardiac event extends to at least a year following pneumonia.
Subsequent studies have shown this association in patients with all-cause CAP [80], other bacterial infections [82], and, to a lesser extent, influenza [83]. The general explanations have been that: (1) inflammation elsewhere in the body increases inflammation in a vulnerable plaque, leading to rupture and acute obstruction of a coronary artery, or (2) increased physiologic stress with increased demand for oxygen, possibly together with decreased oxygen supply due to ventilation/perfusion mismatch cause acute ischemia [84]. An additional mechanism has been documented specifically for pneumococcal infection by the finding of microcolonies of pneumococci in cardiac muscle in animals that have been infected with S. pneumoniae or in humans who have died from pneumococcal infection [85]. These foci of bacteria lead to focal death of cardiomyocytes, permanent scarring, and subsequent heart failure or arrhythmias.
Pneumococcal pneumonia has also been associated with new-onset stroke [86,87].
Long-term outcome — An increased risk for mortality persists for up to 10 years after pneumococcal infection, and risk is greater throughout this time in proportion to the severity of infection [88]. This phenomenon is likely due to epigenetic changes that result from the acute infection [89].
DIAGNOSIS
Approach to diagnosis — For most hospitalized patients with community-acquired pneumonia (CAP), we obtain blood cultures, sputum Gram stain and culture, and a urine pneumococcal antigen test. The results of these tests help direct therapy, identify complications, and inform prognosis (table 1). (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)
While the definitive diagnosis of pneumococcal pneumonia requires culture of pneumococcus from a normally sterile site (eg, blood or pleural fluid), the detection of pneumococcus in sputum culture and/or a positive urine pneumococcal antigen test in a patient who presents with pneumonia is generally sufficient to make a presumptive diagnosis and direct therapy. The detection of gram-positive cocci singly and in pairs in a high-quality sputum specimen obtained from a patient with CAP who has not received antibiotics for more than 18 hours is also highly suggestive of pneumococcal pneumonia [14,90].
Microbiologic testing
Sputum Gram stain and culture — The sensitivity and specificity of sputum Gram stain and culture are dependent upon the quality of the sputum sample obtained and, if antibiotics have been begun, the duration. Although the value of sputum Gram stain and culture for the diagnosis of bacterial CAP has been debated [91,92], there are diagnostic and therapeutic benefits of establishing a microbiologic diagnosis. A meta-analysis of 24 studies indicated Gram stain of a good-quality sputum sample was highly specific to diagnose pneumococcal disease (sensitivity of 0.69 and specificity of 0.91) [93]. (See "Sputum cultures for the evaluation of bacterial pneumonia".)
In patients with pneumococcal pneumonia, alveoli fill with plasma and white blood cells (WBCs) in response to the presence of pneumococci. When this material is coughed up, it seems only logical that bacteria should be readily detected. However, reported detection rates are variable. This may relate to the quality of the sputum specimens obtained and whether antibiotics were administered prior to obtaining a sputum specimen in available studies. For example, in one study of 105 patients with bacteremic pneumococcal pneumonia, the presence of pneumococci was detected by sputum Gram stain in 31 percent of patients and by culture in 44 percent [14]. However, in 20 percent of those cases, no sputum was submitted to the laboratory; in an additional 15 percent, the sputum sample that was submitted was rejected because it was inadequate. When these cases were removed from the denominator, the sensitivity of Gram stain and culture rose to 57 and 79 percent, respectively. With exclusion of patients who had received antibiotics for >24 hours, sensitivity of Gram stain and culture rose to 63 and 86 percent, respectively; for patients who had received no antibiotics, these values were 80 and 93 percent, respectively [14]. In a recent study that was confined to patients who produced a high-quality sputum sample, microscopic examination yielded results that were consistent with final microbiologic findings in 98 percent of cases in which an etiologic agent (bacterial, viral, or coinfection) was identified [6].
Urine antigen detection — The urine pneumococcal antigen test detects cell wall polysaccharides of S. pneumoniae. The most commonly used assay is the Binax NOW assay. When introduced in 2003, this assay detected about 70 percent of patients with pneumococcal pneumonia [94]. Subsequent studies found similar results, with greater positivity in bacteremic disease and lower positivity in nonbacteremic disease [95]. The specificity of the assay in adults exceeds 98 percent [95]. False positives occur in 10 to 20 percent of healthy young children who have nasopharyngeal colonization [96,97], and the test is not recommended in children.
To augment the sensitivity of the Binax NOW assay, serotype-specific tests that detect capsular polysaccharide were developed [98-100]. However, the tests that are available detect serotypes that are contained in the 13-valent conjugate pneumococcal polysaccharide vaccine; these serotypes have rapidly declined in the population with widespread use of the conjugate vaccine in children. Thus, this assay is unlikely to add value to the existing diagnostic armamentarium.
Blood cultures — Blood cultures are an important part of the diagnostic evaluation and are positive in 20 to 25 percent of cases of pneumococcal pneumonia [1,13]. The presence of bacteremia proves the etiologic diagnosis and helps define the severity of infection, the likelihood of developing complications, and the overall prognosis [15,16,70].
Multiplex panels — Multiplex polymerase chain reaction (PCR) assays, which detect arrays of respiratory bacterial pathogens including S. pneumoniae and several antibiotic-resistance genes, are approved for the diagnosis of pneumonia using bronchoalveolar lavage specimens in the United States [101-103]. Studies evaluating these assays have included patients with CAP and hospital- or ventilator-acquired pneumonia; their usefulness for the diagnosis of pneumococcal pneumonia is uncertain. We have also evaluated a microbial cell-free plasma next-generation sequencing test for pathogen detection in hospitalized patients with pneumonia; in a small sample, the rates of false positives and false negatives (approximately one-third of each) were far too high to make this test reliable [104].
Other tests — A variety of other tests have been used to diagnose pneumococcal pneumonia, including immunoglobulin (Ig)G antibodies to capsular polysaccharides, the autolysin LytA, and pneumolysin [105,106] and several quantitative PCR assays [5,105-109]. None is well validated or routinely used.
TREATMENT
Empiric therapy — Empiric treatment regimens for patients hospitalized with community-acquired pneumonia (CAP) are routinely designed to include an agent that specifically targets pneumococcus, such as ceftriaxone or a respiratory fluoroquinolone [110].
We give intravenous (IV) antibiotics for the initial treatment of hospitalized patients. Shock may develop before oral antibiotic antibiotics are absorbed, and there is always some uncertainty about gastrointestinal absorption of oral antibiotics in severely ill patients. Upon clinical improvement, IV antibiotics can be rapidly transitioned to oral therapy. (See "Overview of community-acquired pneumonia in adults" and "Treatment of community-acquired pneumonia in adults who require hospitalization".)
Directed therapy — Once a diagnosis of pneumococcal pneumonia is made, treatment should be tailored to target pneumococcus. We generally consider culture of pneumococcus from sputum and/or blood or a positive urine pneumococcal antigen to be sufficient to establish the etiologic diagnosis and tailor therapy. For patients whose sputum Gram stain suggests pneumococcal infection (ie, presence of gram-positive cocci singly and in pairs in high-quality sputum sample), we are willing to treat specifically for this organism; other experts prefer to await results of the culture, both to confirm the diagnosis of pneumococcal pneumonia and to exclude the presence of other pathogens before narrowing therapy.
Initial antibiotic selection and approach to management for patients with pneumococcal pneumonia varies based on the severity of illness, presence of complications, concern for drug-resistance, host susceptibilities, and patient allergies. Interpretive breakpoints for selected antibiotics are in this table (table 2).
●Preferred treatment – For most patients with pneumococcal pneumonia (with or without bacteremia) in the United States, we suggest ceftriaxone (1 g IV every 24 hours). Across the United States, 98 percent of pneumococcal isolates are susceptible (minimum inhibitory concentration [MIC] ≤1 mcg/mL) or intermediately susceptible (MIC >1 and ≤2 mcg/mL) to ceftriaxone [111]. At 1 g per day, ceftriaxone will provide a serum level above 2 mcg/mL for a 24-hour period. However, in some regions within the United States (ie, the southeast and Pacific northwest) and, especially, in other regions on the world (eg, Eastern Europe and parts of Asia), ceftriaxone resistance rates are higher. (See "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics".)
●Concern for ceftriaxone resistance – When resistance to ceftriaxone is a concern based on susceptibility testing (MIC >2 mcg/mL) or local epidemiology, we treat with an antibiotic from a class other than beta-lactams. Generally, we use a respiratory fluoroquinolone because susceptibility to fluoroquinolones remains stably high across regions. Depending on the MIC of the isolate, some experts might, instead, increase the dose of ceftriaxone to 1 g IV every 12 hours to overcome resistance.
Ceftaroline (a broad-spectrum IV late-generation cephalosporin) or lefamulin (an oral pleuromutilin antibiotic) could also be used to treat pneumococcal pneumonia caused by a ceftriaxone-resistant isolate; each drug has been shown to be reliably active against pneumococci in vitro [112,113] and effective for the treatment of pneumonia in clinical trials [8,114-116]. Linezolid is an additional option. In vitro, pneumococci are also routinely susceptible to dalbavancin, omadacycline, and eravacycline [117-119].
Interpretive breakpoints for selected antibiotics are in this table (table 2). Pneumococcal resistance patterns and rates of pneumococci to ceftriaxone and other antibiotics vary regionally are discussed in detail separately. (See "Resistance of Streptococcus pneumoniae to beta-lactam antibiotics" and "Resistance of Streptococcus pneumoniae to the fluoroquinolones, doxycycline, and trimethoprim-sulfamethoxazole" and "Resistance of Streptococcus pneumoniae to the macrolides, azalides, and lincosamides".)
●Beta-lactam allergy or intolerance – For patients with pneumococcal pneumonia who cannot tolerate a third-generation cephalosporin due to allergy or other intolerance, we typically treat with a respiratory fluoroquinolone (ie, levofloxacin 750 mg daily or moxifloxacin 400 mg daily). Fluoroquinolones are equally effective as ceftriaxone but may have a higher adverse effect profile [120]. Lefamulin and linezolid are other alternatives. Cross reactivity with meropenem and ceftaroline are thought to be rare, but these have not been extensively studied [121,122]; since other classes of drugs are available, these two drugs might best be avoided.
Respiratory fluoroquinolones are also appropriate alternatives for patients with severe penicillin hypersensitivities (ie, angioedema and/or anaphylaxis, serious delayed reactions). Patients with milder penicillin allergies can be safely treated with ceftriaxone [121] (algorithm 1). (See "Choice of antibiotics in penicillin-allergic hospitalized patients" and "Allergy evaluation for immediate penicillin allergy: Skin test-based diagnostic strategies and cross-reactivity with other beta-lactam antibiotics" and "Penicillin allergy: Delayed hypersensitivity reactions" and "Penicillin allergy: Immediate reactions".)
Complications – Modifications to this approach are needed for complications other than bacteremia.
●When there is concern for parapneumonic effusion or empyema, thoracentesis is required for diagnosis, and the effusion or empyema should be drained promptly. (See "Management and prognosis of parapneumonic pleural effusion and empyema in adults".)
●When there is a concern for concurrent pneumococcal meningitis, the dose of ceftriaxone is 2 g every 12 hours, and vancomycin should be added, as a small number of strains are resistant to ceftriaxone. Treatment can then be continued with one or both drugs depending upon susceptibility of the organism and is discussed elsewhere. (See "Treatment of bacterial meningitis caused by specific pathogens in adults", section on 'Streptococcus pneumoniae'.)
Adjunctive macrolide therapy — For patients with severe pneumococcal pneumonia, some experts add a macrolide (ie, azithromycin) to ceftriaxone for the first few days of therapy. The macrolide is not added for its antibacterial effect, since approximately 20 percent of pneumococci are macrolide-resistant, nor for any synergistic effect [123]. Rather, macrolides suppress production of transcription factors nuclear factor kappa B (NFkB) and activator protein (AP)-1, thereby inhibiting intracellular signaling pathways. These effects reduce generation of inflammatory cytokines, especially interleukin 8. Macrolides also inhibit production of leukotriene (LT)-B4 and expression of adhesion molecules Mac-1 and ICAM-1 [124]. These effects dampen inflammatory responses and may confer survival benefit.
This survival benefit appears to be most pronounced in patients with severe illness and has been detected in several observational studies comparing outcomes in patients treated with beta-lactam monotherapy versus combination therapy with a macrolide [125-128]. In one cohort study evaluating 844 patients with pneumococcal bacteremia (usually due to pneumococcal pneumonia), combination therapy with a beta-lactam and a macrolide was associated with reduced 14-day mortality when compared with beta-lactam monotherapy (23 versus 55 percent) [126].
Adjunctive glucocorticoids — The same basic principle of dampening an excessive immune response underlies the recommendation that adjunctive glucocorticosteroids be used to treat selected patients who are severely ill with CAP and refractory septic shock [110]. This is discussed in detail separately. (See "Treatment of community-acquired pneumonia in adults who require hospitalization" and "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Adjunctive glucocorticoids'.)
Transition to oral therapy — After the patient's condition has stabilized, IV therapy can be transitioned to oral therapy (stepdown therapy). Selection of an oral antibiotic depends on the susceptibility of the isolate.
●For patients with isolates that are susceptible or intermediately resistant to penicillin (penicillin MIC <2 mcg/mL), we transition to amoxicillin 500 mg orally four times daily. This recommendation applies to treating bacteremic or nonbacteremic pneumococcal pneumonia.
●For isolates with higher levels of resistance (penicillin MIC ≥2 mcg/mL), we use a respiratory fluoroquinolone (eg, levofloxacin 750 mg orally daily or moxifloxacin 400 mg orally daily).
If the organism is susceptible to doxycycline, a macrolide, or clindamycin, and one of these drugs has been used for initial therapy with a good response, it can also be continued orally after completion of IV therapy. If adjunctive macrolide therapy was given at the start of therapy, we generally stop the macrolide when the patient is ready to transition to oral therapy.
In general, we do not lengthen the course of IV therapy nor the length of hospitalization for patients with pneumococcal pneumonia if bacteremia is documented. One cohort study evaluating 125 patients with bacteremic pneumococcal pneumonia and >1800 patients with nonbacteremic CAP found no difference in outcomes between the two groups [129]. In another small study evaluating patients with bacteremia pneumococcal pneumonia, no clinical failures occurred when patients were transitioned to oral therapy upon reaching clinical stability [130].
Duration of therapy — The duration of therapy is based on the patient's clinical response to therapy and presence of complications.
●For patients with pneumococcal pneumonia (without bacteremia or other complication), the recommended duration of therapy is five days. Generally, we treat until the patient is clinically stable, afebrile, and showing continued signs of improvement. In the absence of complications, a treatment course longer than seven days is rarely necessary.
●For patients with bacteremic pneumococcal pneumonia who are responding to therapy, we treat for seven days, acknowledging that there are limited data to support this approach.
Pneumococcal pneumonia that is complicated by meningitis or endocarditis require longer courses of therapy. If empyema or septic arthritis is present, source control and longer courses of therapy are also needed. (See "Initial therapy and prognosis of community-acquired bacterial meningitis in adults" and "Management and prognosis of parapneumonic pleural effusion and empyema in adults" and "Invasive pneumococcal (Streptococcus pneumoniae) infections and bacteremia in adults".)
FAILURE TO IMPROVE — If a patient with pneumococcal pneumonia has not responded to appropriate antibiotic therapy after three or four days of treatment, a careful search for a complication should be made. The most likely complication is an empyema, although evaluation should also include a search for other complications. (See 'Complications' above.)
MORTALITY — The mortality rate for pneumococcal pneumonia varies by severity at presentation and host factors and depends greatly on whether one is considering 7-day, 30-day, 90-day, or long-term survival. In patients who are hospitalized for bacteremic pneumococcal pneumonia, in-hospital mortality is about 12 to 15 percent and 90-day mortality is about 25 to 30 percent. In each case, the mortality is approximately 50 percent lower for patients with nonbacteremic pneumococcal pneumonia [15,16,70,126].
A prospective observational study of 638 patients with pneumococcal pneumonia identified the following features of the pneumonia associated with mortality by multivariate analysis [131]:
●Shock – HR 5.8, 95% CI 3.4-9.8
●Need for mechanical ventilation – OR 4.4
Bilateral disease – Hazard ratio (HR) 2.0, 95% CI 1.2-3.2
●Suspected aspiration – HR 2.8, 95% CI 1.6-5.0
●HIV infection – HR 2.1, 95% CI 1.1-3.8
●Renal failure – HR 1.9, 95% CI 1.1-3.1
●Pneumonia severity index – HR for class IV versus classes I to III: 2.6, 95% CI 1.3-5.4; for class V versus I to III: 3.2, 95% CI 1.5-6.9 (see "Morbidity and mortality associated with community-acquired pneumonia in adults", section on 'Pneumonia severity index')
Comorbid conditions are a significant predictor of poor outcome in bacteremic pneumococcal disease. This was illustrated in a multicenter five-country study of 460 such patients (82 percent with pneumonia). Among those who died, about half of deaths were attributable to worsening of a pre-existing condition [132]. Additional factors independently associated with mortality in a second large observational study included:
●Age >65 years – Odds ratio (OR) 2.2
●Residence in a nursing home – OR 2.8
●Presence of chronic lung disease – OR 2.5
●High acute physiology and chronic health – For scores of 9 to 14, OR 7.6; for scores 15 to 17, OR 22; for scores >17, OR 41
Similarly, a study of predictors of mortality among United States veterans with pneumococcal infections identified dialysis during hospitalization, moderate to severe liver disease, Parkinson disease, multiple sclerosis, dementia, and fluid and electrolyte disorders [133].
It is important for practitioners to explain to their patients that the recovery from pneumococcal pneumonia may be slow. In many patients, especially those who are older adults and for reasons that are unknown, it may take weeks to months before they feel as if they have returned to their previous state of health. For those who survive 90 days, mortality when compared with age-matched persons who have not had pneumococcal pneumonia remains excessive for decades [21,88]. In fact, life expectancy may be shortened by 10 years. While pneumonia may simply be a marker for persons at risk of dying, some studies suggest that long-lasting epigenetic changes may be responsible [134], a concept supported by the finding that the detrimental effect on survival is proportional to the severity of the pneumonia.
The risk of overwhelming bacteremia, septic shock, and death is greatly increased in splenectomized patients since, in the absence of anticapsular antibody, the spleen is the principal site for clearance of this bacterium from the bloodstream. (See "Clinical features, evaluation, and management of fever in patients with impaired splenic function".)
PREVENTION — The most effective means of prevention is pneumococcal vaccination (see "Pneumococcal vaccination in adults"). This severe risk also applies to patients with sickle cell disease.
The risk of developing pneumococcal pneumonia can be reduced by avoiding behaviors that are associated with the disease (eg, excess alcohol ingestion or cigarette smoking) and by controlling conditions (eg, diabetes mellitus) that increase risk.
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: 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 e-mail 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.)
●Beyond the Basics topic (see "Patient education: Pneumonia in adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Background – Streptococcus pneumoniae (pneumococcus) is the most commonly identified bacterial cause of community-acquired pneumonia (CAP), accounting for 10 to 25 percent of cases in the United States and a higher percentage in Europe and developing countries. (See 'Epidemiology' above.)
●Risk factors – Risk factors for acquisition include extremes of age, crowded living conditions, cigarette smoking, alcohol use disorders, and certain races or ethnicities (ie, Black Americans and Native Americans). Antecedent viral infection, particularly with influenza, also predisposes to pneumococcal pneumonia. (See 'Risk factors' above.)
●Transmission – Transmission of pneumococcus occurs from person to person by intimate contact or aerosol. Following transmission, pneumococci colonize the nasopharynx. Colonization is an active process in which bacterial antigen is incorporated by dendritic cells and is processed leading to antibody production. Pneumonia develops if nasopharyngeal secretions are carried into the lungs (called aspiration) and are not cleared rapidly and effectively before antibody has been produced.(See 'Pathogenesis' above.)
●Clinical features – The "classic syndrome" associated with pneumococcal pneumonia is abrupt onset fever, chills, cough, and pleuritic chest pain. This description is derived from the preantibiotic era when pneumococcal pneumonia affected young adults with robust immune responses. Today, older adults are primarily affected, illness onset is more gradual, and respiratory symptoms may be less pronounced. Findings on physical examination and chest imaging are similar to other forms of CAP. (See 'Clinical manifestations' above.)
●Diagnosis – Definitive diagnosis of pneumococcal pneumonia requires culture of pneumococcus from a normally sterile site (eg, blood or pleural fluid). However, detection of pneumococcus in sputum by Gram stain or culture and/or a positive urine pneumococcal antigen test is generally sufficient to make a presumptive diagnosis and direct therapy. (See 'Approach to diagnosis' above.)
●Preferred treatment – For most patients hospitalized with pneumococcal pneumonia (with or without bacteremia), we suggest ceftriaxone (1 g intravenously [IV] every 24 hours) over other beta-lactams (Grade 2C). Ceftriaxone is preferred because of its once-daily dosing and because ceftriaxone achieves drug levels sufficient to treat most pneumococcal isolates in the United States. Modifications to this approach may be needed for patients who cannot tolerate cephalosporins, when there is concern for ceftriaxone resistance (minimum inhibitory concentration [MIC] >2 mcg/mL), or for complications such as meningitis or empyema. (See 'Directed therapy' above.)
●Cephalosporin resistance or intolerance – For patients with pneumococcal pneumonia who cannot tolerate a third-generation cephalosporin or when ceftriaxone resistance is a concern, we typically treat with a respiratory fluoroquinolone (ie, levofloxacin 750 mg daily or moxifloxacin 400 mg daily) (Grade 2C). Susceptibility to fluoroquinolones remains high and is generally stable across regions. Additional options are discussed above. (See 'Directed therapy' above.)
●Adjunctive treatments – To help quell the profound inflammatory response that can occur with pneumococcal pneumonia, some experts add a macrolide (ie, azithromycin) to ceftriaxone in patients for the first few days of therapy (see 'Adjunctive macrolide therapy' above). For similar reasons, in selected patients with severe pneumonia and marked systemic inflammation (eg, septic shock), giving adjunctive glucocorticoids may be reasonable. (See 'Adjunctive glucocorticoids' above.)
●Transition to oral therapy – For all hospitalized patients, we treat initially with IV antibiotic therapy. We transition to an oral antibiotic once the patient is stable, improving, and able to tolerate oral therapy. For penicillin-susceptible strains we transition to amoxicillin; for strains with reduced susceptibility to penicillin (MIC ≥2 mcg/mL), we transition to a respiratory fluoroquinolone (eg, levofloxacin, moxifloxacin). (See 'Transition to oral therapy' above.)
●Duration of therapy – Duration of therapy is usually five days. Our approach is similar for patients with bacteremic pneumonia, although we treat for seven days. (See 'Duration of therapy' above.)
●Complications – Patients who do not improve within a few days of appropriate antibiotic therapy should be evaluated for complications. Empyema is the most common complication, though endocarditis, pericarditis, and septic arthritis also occur. Meningitis can also complicate pneumonia, though this is typically apparent at presentation. (See 'Failure to improve' above and 'Complications' above.)
●Mortality – In-hospital mortality from pneumococcal pneumonia is approximately 7 to 15 percent. Patients with severe infection, chronic illnesses (eg diabetes, heart failure), impaired antibody responses (eg, AIDS, multiple myeloma) or impaired splenic function are at higher risk for poor outcomes. (See 'Mortality' above.)
●Prevention – The most effective means of prevention is pneumococcal vaccination. Risk can also be reduced by avoiding conditions that are associated with the disease (eg, excess alcohol ingestion or cigarette smoking) and by controlling conditions that are associated (eg, diabetes mellitus). (See 'Prevention' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas J Marrie, MD, who contributed to earlier versions of this topic review.
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