Streptococcus pneumoniae

Streptococcus pneumoniae ou informalmente Pneumococo uma espcie de bactrias Gram-positivas, pertencentes ao gnero Streptococcus, com forma decocos que so uma das principais causas de pneumonia e meningite em adultos, e causam outras doenas no ser humano. Biologia Como todos os estreptococos, so cocos com cerca de 1 micrmetro, anaerbios facultativos. Agrupam-se sempre aos pares (diplococos) ou em curtas cadeias, e as estirpes patognicas possuem cpsula. Eles so alfa-hemolticos, ou seja em cultura de sangue produzem um halo mucoide esverdeado de destruio parcial deeritrcitos. Os pneumococos so exigentes no meio de cultura, necessitando de vrios nutrientes normalmente fornecidos em cultura de sangue (de vaca ou outro animal). Os pneumococos so sensiveis optoquina ou blis, detergentes fracos, ao contrrio de outros estreptococos, e esta caracterstica til para os distinguir. So bacterias que so transmitidas facilmente de pessoa para pessoa por meio de espirros, objetos infectados, etc, sendo as causadoras da pneumonia. Ao contrrio dos estafilococos, a resistncia penicilina devida no penicilinase mas a protenas que se ligam ao antibitico inibindo a sua ao sem o destruir. Factores de virulncia

Cpsula protege da fagocitose e do reconhecimento pelo sistema imunitrio. Adesinas que permitem a adeso s clulas da faringe e epitlio respiratrio. Pneumolisinas: so protenas secretadas que desestabilizam as membranas da clulas humanas, destruindo-as. Activam o complemento, usando-o contra as clulas do hspede. Protease de IgA: inactiva este tipo de anticorpos presentes nas mucosas. cido teicico: activa o complemento, gastando-o e direccionando-o para o hspede. Produz perxido de hidrognio que causa danos nas clulas. Fosforilcolina: liga-se a recpetores das clulas do hospede, permitindo ao pneumococo entrar nelas e escapar ao sistema imune.

Epidemiologia Esto presentes em 40-70% do tracto respiratrio dos adultos, sem sintomas. Tendem a causar doenas nestes individuos quando eles esto fragilizados, por exemplo podem causar pneumonias em doentes com gripe. O seu reservatrio so os prprios humanos. Doenas causadas O diagnstico por recolha de amostras e cultura, serologia (deteco de anticorpos especficos). O sistema imune produz anticorpos anti-capsulares efectivos, mas demora algum tempo (varivel), podendo os danos j ser srios nessa altura. A imunidade a uma

estirpe no confere proteco contra outras. A pneumonia e a meningite so as manifestaes mais frequentes, e ambas so perigosas.

Pneumonia: pneumonia lobar e broncopneumonia. Febres altas (39-41 C), com tosse e expectorao amarela purulenta. Ocorre frequentemente aps doena respiratria viral (e.g. gripe), que destroi os clios do epitlio respiratrio permitindo bactria instalar-se e multiplicar-se sem ser expulsa pela aco mecnica dos clios. A mortalidade de 5%. Meningite: infeco das meninges do crebro que uma emergncia potencialmente fatal. O pneumococo a principal causa de meningite em adultos. Inicio sbito de dores de cabea, vmitos, sensibilidade luz. O tratamento com antibiticos tem de ser instituido pouco depois do inicio dos sintomas ou a morte torna-se inevitvel. Septicmia: invaso e multiplicao no sangue. Mortalidade muito elevada. Normalmente ocorre aps multiplicao num rgo especfico sem limitao efectiva. Sinusite Otite media Osteomielite lcera corneal Artrite sptica Endocardite Abcessos cerebrais Celulite

Diagnstico Laboratorial Cultura com presena de Alfa Hemlise, Catalase Negativo, Antibiograma com identificao de sensibilidade Optoquina, Bilesolubilidade Positiva. Tratamento A penicilina ou ampicilina ainda so a primeira escolha apesar do aumento das cepas resistentes. Caso exista resistncia, usamse macroldeos, cloranfenicol, vancomicina, SMZ/TMP ou cefalosporinas. Existem vacinas contendo derivados imunognicos (estimuladores do sistema imunitrio) da cpsula do pneumococo. Protegem contra doenas causadas por pneumococos em 85% dos casos. No protege contra todas as cepas, apenas 23 (existem muitas mais). Histria No sculo XIX foi demonstrado que coelhos imunizados com pneumococos mortos eram protegidos contra pneumococos vivos. O soro sanguineo de coelhos j infectados mas que tinham recuperado tambm conferia proteco. Foi uma das primeiras demonstraes das possibilidades da imunizao. A vacina foi demonstrada no incio do sculo XX em mineiros da frica do Sul, numa experincia desumana que usou negros como cobaias.

Na dcada de 1920 foi demonstrado que eram formados anticorpos contra os polissacardeos da cpsula, conferindo imunizao, e que eram esses mesmos anticorpos presentes no soro de coelhos j infectados que protegiam, durante algum tempo, os coelhos no imunes. A vacina foi usada eficazmente numa epidemia em 1936. Na dcada de 1940 o DNA foi pela primeira vez identificado enquanto repositrio da informao gentica em experincias com pneumococos encapsulados e no encapsulados. Os encapsulados mortos, juntamente com no-encapsulados vivos (incapazes de causar doena), geravam encapsulados vivos que matavam coelhos, o que se provou ser devido absoro pelos no-encapsulados vivos de DNAproveniente dos encapsulados mortos.

Infeces pneumoccicas
As infeces pneumoccicas so infeces causadas pela bactria grampositiva Streptococcus pneumoniae. Os pneumococos costumam habitar no segmento superior das vias respiratrias dos humanos, e so hspedes naturais, particularmente durante o Inverno e o comeo da Primavera. Apesar da sua localizao, os pneumococos s causam pneumonia em certas ocasies. Dado que a pneumonia pneumoccica (Ver seco 4, captulo 41) raramente se transmite de pessoa a pessoa, quem tiver a doena no precisa de evitar o contacto com os outros. Os pneumococos tambm podem causar infeces no crebro, no ouvido e noutros rgos. Quem corre especialmente um risco de desenvolver uma pneumonia pneumoccica so aqueles que padecem de doenas crnicas e cujo sistema imunitrio deficiente (por exemplo, os que sofrem da doena de Hodgkin, linfoma, mieloma mltiplo, desnutrio ou drepanocitose). Como os anticorpos produzidos no bao ajudam normalmente a evitar a infeco pneumoccica, os indivduos a quem foi extirpado o bao ou cujo bao no funciona esto muito expostos s referidas infeces. A pneumonia pneumoccica pode surgir depois de uma bronquite crnica ou se um vrus respiratrio comum, sobretudo o vrus da gripe, lesar o revestimento das vias respiratrias. Existe uma vacina pneumoccica altamente eficaz a partir dos 2 anos de idade. A referida vacina protege contra as variedades mais comuns de pneumococos e reduz as possibilidades de surgir pneumonia pneumoccica e bacteriemia em aproximadamente 80 %, enquanto as possibilidades de se morrer por este motivo se reduzem em 40 %. Essa vacina recomendada aos indivduos de idade avanada e queles que sofrem de uma doena pulmonar ou cardaca crnica, de diabetes, da doena de Hodgkin, de infeco por vrus da imunodeficincia humana ou da perturbaes do metabolismo. Tambm pode ser de grande ajuda nas crianas com drepanocitose e para aqueles indivduos cujo bao foi extirpado ou no funciona adequadamente. A penicilina o tratamento de primeira escolha para a maioria das doenas pneumoccicas. Administra-se por via oral nas infeces do ouvido e seios e por via endovenosa nas infeces mais graves.

Background
Streptococcus pneumoniae is a gram-positive, catalase-negative cocci that has remained an extremely important human bacterial pathogen since its initial recognition in the late 1800s. The term pneumococcus gained widespread use by the late 1880s, when it was recognized as the most common cause of bacterial lobar pneumonia. Worldwide, S pneumoniae remains the most common cause of communityacquired pneumonia (CAP), bacterial meningitis, bacteremia, and otitis media. S pneumoniae infection is also an important cause of sinusitis, septic arthritis, osteomyelitis, peritonitis, and endocarditis and an infrequent cause of other less-common diseases. An image depicting pneumococcal pneumonia can be seen below.

Lobar consolidation with pneumococcal pneumonia. Posteroanterior film. Courtesy of R. Duperval, MD. Pneumococcal vaccination, particularly routine childhood pneumococcal conjugate vaccine (introduced in the United States in 2000), has led to decreased rates of invasive pneumococcal infections (>90%) caused by pneumococcal serotypes covered by the vaccine, as well as overall decreased rates of invasive disease (45% overall; 77% in children < 5 y). In addition, herd immunity has led to decreased rates of disease in older children and adults. [1, 2,
3]

Many subsequent studies have shown increased rates of invasive and noninvasive disease caused by serotypes not covered by the vaccine, including serotypes 15, 19A, and 33F. Serotype 19A has received the most attention, not only because of increased disease rates associated with this serotype but also because of its increased association with drug resistance. Increased rates of

invasive disease with such serotypes have caused the overall rates of invasive disease to remain somewhat steady since 2002, although still greatly reduced from rates prior to introduction of the conjugate vaccine.[1, 4, 5, 6, 7, 8, 9, 10, 3] Data from 2006-2007 revealed that only 2% of invasive pneumococcal disease in children younger than 5 years in the United States was caused by serotypes contained in pneumococcal conjugate vaccine 7 (PCV7), while an additional 6 serotypes accounted for almost two thirds of invasive disease in this age group.[11]Development of a vaccine containing additional serotypes continued, and pneumococcal conjugate vaccine 13 (PCV13) was approved by the FDA February 24, 2010.[12] Despite an overall decreased incidence of otitis media caused by serotypes not covered by vaccination since the introduction of the conjugate pneumococcal vaccine, an increase in rates of disease caused by serotypes not covered by the vaccine has occurred, as well as an increase in rates of diseases caused by vaccine-covered serotypes in incompletely immunized children. The incidence of otitis media caused by serotype 19F has remained steady. Overall health care utilization for otitis media has decreased, as has the incidence of recurrent otitis media in some populations and studies.[2, 13, 14, 15]

Pathophysiology
Adherence and invasion
S pneumoniae is an example of a typical extracellular bacterial pathogen. Pathogenicity requires adherence to host cells, along with the ability to replicate and to escape clearance and/or phagocytosis. The organism must then gain access to areas where it can manifest infection, either via direct extension or lymphatic or hematogenous spread. The rates of pneumococcal colonization in healthy children and adults provide information about the success of adherence and replication of the pneumococcus. After colonization, organisms may gain access to areas of the upper and/or lower respiratory tracts (sinuses, bronchi, eustachian tubes) by direct extension. Under normal conditions in a healthy host, anatomic and ciliary clearance mechanisms prevent clinical infection. However, clearance may be inhibited by chronic (smoking, allergies, bronchitis) or acute (viral infection, allergies) factors, which can lead to infection. Alternatively, pneumococci may reach normally sterile areas, such as the blood, peritoneum, cerebrospinal fluid, or joint fluid, by hematogenous spread after mucosal invasion. In the absence of previously acquired serotype-specific antibodies (see below), clinically apparent infection is likely to occur.

Capsule
Other than some isolates associated with conjunctivitis outbreaks, essentially all clinical isolates of S pneumoniae are encapsulated. Repeating oligosaccharides that make up the capsule of an individual bacterial isolate are transported to the cell surface, where they bind tightly with the cell-wall polysaccharides. Based on antigenic differences within these capsular polysaccharides, 91 serotypes of S pneumoniae have been identified. The virulence of each organism is determined in part by the makeup and amount of capsule present. In a pneumococcus-naive host (or in the absence of antibody to pneumococcal capsule) host-cell phagocytosis is severely limited because of the inhibition of phagocytosis and the inhibition of the activation of the classic complement pathway. In addition, in vitro and in vivo studies of clinical isolates have shown that pneumococci have the ability to obtain DNA from other pneumococci (or other bacteria) via transformation, allowing them to switch to serotypically distinct capsular types. There are 2 recognized numbering systems based on pneumococcal serotypes. In the American system, the serotypes were numbered in order of discovery, with lower numbers corresponding to serotypes that more frequently cause clinical disease, meaning that they were identified earlier. The Danish numbering system is based on grouping of serotypes with similar antigenicity and is more widely accepted and used worldwide. Today, serotyping provides important epidemiological information, especially with the increasingly widespread use of vaccination, but rarely provides timely clinical information. The Quellung reaction is demonstrated by combining sera of previously immunized animals with capsular antigen. Agglutination causes capsule refractility and the ability to observe the capsule microscopically.

Toxins and other virulence factors

Pneumococcal isolates produce few toxins; however, all serotypes produce pneumolysin, which is an important virulence factor that acts as a cytotoxin and activates the complement system. In addition, pneumolysin causes a release of tumor necrosis factor-alpha and interleukin-1. Other potential virulence factors include cell surface proteins such as surface protein A and surface adhesin A and enzymes such as autolysin, neuraminidase, and hyaluronidase. The contributions of these substances to pneumococcal virulence are being studied extensively, and some are being investigated as potential vaccine constituents.[16]

Complement activation
Much of the clinical severity of pneumococcal disease is due to the activation of the complement pathways and cytokine release, which induce a significant inflammatory response. S pneumoniae cell wall components, along with the pneumococcal capsule, activate the alternative complement pathway; antibodies to the cell wall polysaccharides activate the classic complement pathway. Cell wall proteins, autolysin, and DNA released from bacterial

breakdown all contribute to the production of cytokines, inducing further inflammation.

Epidemiology
Frequency
United States Colonization S pneumoniae remains an important pathogen in large part because of its ability to first colonize the nasopharynx efficiently. Studies performed in the United States prior to universal vaccination recommendations have shown average carriage rates of 40%-50% in healthy children and 20%-30% in healthy adults. Factors such as age, daycare attendance, composition of household, immune status, antibiotic use, and others obviously affect these numbers.[17, 18, 19] With the implementation of childhood vaccination with the heptavalent conjugate vaccine for S pneumoniae, the colonization rates have decreased in children receiving the vaccine and in adults and other children in their household because of the phenomenon of herd immunity. Most individuals who are colonized with S pneumoniae carry only a single serotype at any given time; the duration of colonization varies and depends on specific serotype and host characteristics. Invasive disease is usually related to recent acquisition of a new serotype. However, in most healthy hosts, colonization is not associated with symptoms or disease but allows for the continued presence of S pneumoniae within the population, allowing for prolonged low-level transmission among contacts. S pneumoniae infection is the most common cause of CAP, bacterial meningitis, bacteremia, and otitis media in the United States. There is a clear seasonality, with infections peaking in the fall and winter months.[20]

Noninvasive disease
Pneumococcal colonization allows for spread of organisms into the adjacent paranasal sinuses, middle ear, and/or tracheobronchial tree down to the lower respiratory tract. This spread results in specific clinical syndromes (sinusitis, otitis media, bronchitis, pneumonia) related to the noninvasive spread of the organisms. Worldwide, the most common cause of death due to pneumococcal disease is pneumonia. In adults admitted to the hospital in the United States for pneumonia treatment, S pneumoniae remains the most common organism isolated. Until 2000, 100,000-135,000 patients were hospitalized for pneumonia proven to be caused by S pneumoniae infection in the United States annually. These numbers are likely a gross underestimate, as a definite cause is not determined in most cases of pneumonia treated each year. In addition, the actual rates are also likely decreasing owing to implementation of pneumococcal conjugate vaccination.[21] S pneumoniae infection is an important cause of bacterial co-infection in patients with influenza and can increase the morbidity and mortality in these patients. This has been emphasized recently by the increased number of cases of invasive pneumococcal disease seen in association with increased rates of hospitalizations for influenza during the 2009 H1N1 influenza A pandemic.[22] Postmortem lung specimens from patients who died of H1N1 influenza A from May to August of 2009 were examined for evidence of concomitant bacterial infection. Twenty-nine percent of the specimens showed evidence of bacterial coinfection, with almost half of these being S pneumoniae.[23] S pneumoniae infection is estimated to cause over 6-7 million cases of otitis media annually in the United States. These numbers have likely decreased somewhat with the

advent of universal vaccinations; however, S pneumoniaeinfection remains the most common cause of otitis media.[24, 19]

Invasive disease
Statistics regarding invasive pneumococcal disease in the United States are based on active surveillance using the Centers for Disease Control and Prevention (CDC) Active Bacterial Core Surveillance (ABC) system. Calculations for 2008 estimated 43,000 (14.3 per 100,000 population) cases of invasive disease nationally, with 4,400 (1.5 cases per 100,000 population) deaths. Children younger than 5 years and adults older than 65 years are two identified age groups in whom rates of disease and death are increased. In 2008, rates of pneumococcal invasive disease in these groups were 20 per 100,000 population and 40.8 per 100,000 population, respectively. This compares with rates of 21.8 and 39.2 in 2007 and 23.2 and 43.3 in 2002, respectively. More than half of deaths due to invasive pneumococcal disease occur in adults with specific risk factors (age, immunosuppression) for severe disease. Such risk factors are an indication for vaccination.[25] International Despite the worldwide importance of disease due to S pneumoniae infection, very little information is available on the extent of pneumococcal disease, particularly in developing countries.

Children
In developing countries, pneumococcus remains the most common and important diseasecausing organism in infants. Although exact numbers are difficult to obtain, it is estimated that pneumococcus infection is responsible for more than one million of the 2.6 million annual deaths due to acute respiratory infection in children younger than 5 years. Case fatality rates associated with invasive disease vary widely but can approach 50% and are greatest in patients with meningitis.[24, 26] Estimates of pneumococcal disease in Gambian children show high rates of infection in the first year of life (500 per 100,000 children).[27] Latin American studies also show a particularly high risk in infants younger than 6 months, and children in southern India have higher rates of colonization at younger ages compared with US children, according to US clinical studies. Some particular populations, such as indigenous Australians and minority Israeli persons, also have disproportionately higher rates of disease, similar to the native Alaskan and native Indian populations in the United States, although determining the role of socioeconomic factors in the higher incidence of disease in these populations is difficult.[27] In Europe, children younger than 2 years constitute the population most at risk for pneumococcal infection, with rates decreasing as persons age. The overall incidence of invasive disease is estimated to be somewhat lower in Europe (14 per 100,000 persons in Germany vs 35.8 per 100,000 persons in England vs 45.3 per 100,000 persons in Finland vs 90 per 100,000 persons in Spain vs 235 per 100,000 persons in the United States), although many have postulated that this may be due in part to the more liberal bloodculture collection practices in the American health care system.[27, 24]

Adults
Even fewer data are available on the worldwide incidence of pneumococcal disease in adults. As in the United States, the most common cause of CAP in Europe is S pneumoniae infection, affecting approximately 100 per 100,000 adults each year. Overall rates of febrile bacteremia and meningitis are also similar, (1519 per 100,000 adults and 12 per 100,000 adults, respectively), with the risk for these diseases increased in elderly and infant populations.[28] Because no population-based data on pneumococcal disease in adults in developing countries are available, estimates of disease burden are based on small clinical studies,

vaccine trials, extrapolation from data in developed countries, and studies of persons at high risk for disease. The information gleaned from these sources suggests that the incidence of and mortality rates associated with pneumococcal disease are high, with HIVpositive populations exhibiting particularly high rates of infection. Further studies are greatly needed.[29, 24]

Mortality/Morbidity
Although exact rates are difficult to determine, the World Health Organization (WHO) estimates that, worldwide, 1.6 million deaths were caused by pneumococcal disease in 2005, with 700,000 to 1 million of these occurring in children younger than 5 years.[30] Even in patients in developed countries, invasive pneumococcal disease carries a high mortality ratean average of 10-20% in adults with pneumococcal pneumonia, with much higher rates in those with risk factors for disease.[31, 32]

Race
In the United States, invasive pneumococcal disease is more common in native Alaskans, Navajo and Apache Indians, and African Americans than in other ethnic groups. Some studies have shown this difference persists even when the results are controlled for socioeconomic factors, and the reasons for this discrepancy among certain populations are unclear.[18]

Sex
Most clinical studies of pneumococcal disease show a slight male predilection for disease; the reason for this is unclear.

Age
Children younger than 2 years carry the highest burden of S pneumoniae disease worldwide. In developed countries, the incidence is highest in those aged 6 months to 1 year, while, in developing countries, the disease is particularly common in children younger than 6 months. Adults older than 55-65 years are the next most commonly affected age group worldwide. Immunosuppressed persons of any age are at a higher risk for pneumococcal disease.

History
After successful colonization, S pneumoniae can cause a wide variety of clinical symptoms. By direct extension from the nasopharynx, S pneumoniae infection can spread and then manifest as otitis media, sinusitis, tracheobronchitis, bronchitis, and pneumonia. By invasion and hematogenous spread, S pneumoniaeinfection can cause primary bacteremia, meningitis, osteomyelitis, pericarditis, endocarditis, myositis, septic arthritis, and peritonitis. Factors that should prompt consideration of pneumococcal disease in patients with the above conditions include the following:

High-risk age groups

Children younger than 5 years, particularly aged 2 years or younger are at an increased risk of disease. In addition, absence of breastfeeding, exposure to cigarette smoke, daycare attendance, and lack of immunization with the pneumococcal conjugate vaccine further increase the risk of disease. Adults older than 55-65 years are also at an increased risk of disease.

Immunodeficiencies
Conditions that cause immune deficits, including HIV infection, malignancy, diabetes mellitus, functional or actual absence of the spleen, humoral immunity defects, complement deficiencies, and neutrophil dysfunction, are associated with an increased risk of disease.

Conditions associated with decreased pulmonary clearance functions

These include asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), viral infections, and active/passive cigarette smoke exposure.

Presentation in the late fall to early spring

Pneumococcal infections peak in late fall to early spring in the Northern Hemisphere.

Physical
Clinical signs and symptoms and physical examination findings alone do not distinguish S pneumoniae disease from that caused by other pathogens.

Diseases Due to Direct Extension

Conjunctivitis
Bacterial conjunctivitis is more likely to be bilateral and purulent than viral conjunctivitis. S pneumoniae is found in up to one third of patients with bacterial conjunctivitis; the rate of isolates that are not susceptible to penicillin is increasing.

Otitis media
S pneumoniae is the most commonly isolated bacterial pathogen from children and adults with otitis media. Several early studies suggested or showed that S pneumoniae otitis media is usually accompanied by fever and pain and that the fever is higher than in otitis media caused by other common bacterial pathogens.[18] Pneumococcal disease is less likely to resolve spontaneously. Eustachian tube congestion caused by a preceding viral infection is common.

Increasing antibiotic resistance has led to decreased effectiveness of the antibiotics that were once used most commonly to treat otitis media. S pneumoniae infection is the most common cause of mastoiditis, a complication of otitis media that was more common in the pre-antibiotic era; this complication is now more commonly associated with untreated or improperly treated cases of otitis media.

Sinusitis
As in otitis media, S pneumoniae is the most commonly isolated bacterial organism from patients with acute sinusitis. Acute sinusitis manifestations may vary depending on the age of the patient and the developmental status of individual sinuses. In children younger than 5 years, infection is usually limited to the ethmoid and maxillary sinuses. Acute sinusitis is usually preceded by a viral infection, leading to sinus mucosal swelling and ostia obstruction. This is followed by the development of a purulent discharge and cough. Malodorous breath and worsening cough at night due to postnasal drip are often noted.

Acute exacerbations of chronic bronchitis (AECB)

Acute exacerbations of chronic bronchitis manifest as a change from baseline chronic symptoms. Symptoms include shortness of breath, increased production and/or purulence of sputum, increased sputum tenacity, and cough. An estimated 80% of cases of acute exacerbations of chronic bronchitis are caused by infection, with about one half of those caused by aerobic bacteria, of which S pneumoniae is the most commonly isolated organism. Symptoms such as sore throat, cold symptoms, and dyspnea may indicate a viral cause.[33]

Pneumonia
Classic pneumococcal pneumonia often develops in older children and adults. It may be preceded by a viral illness that is followed by an acute onset of high feveroften with rigors, productive cough, pleural pain, dyspnea, tachypnea, tachycardia, sweats, malaise, and fatigue. Patients typically appear ill and may have an anxious appearance. On careful physical examination, rales can be heard in most patients. About half of all patients exhibit dullness to percussion, and splinting due to pain may be seen. Signs of effusion/empyema may be found on examination and include dullness to percussion at the bases. Diaphragmatic motion that is decreased from that expected in light of the patient's tachypnea. In children (particularly school-aged and younger children), the potential manifestations of pneumonia are broad and often nonspecific. These may include nonspecific mild respiratory symptoms, with or without a cough on initial presentation; tachypnea, dyspnea, and splinting: high fever; abdominal pain; abdominal distention; anorexia; emesis (often suggesting a primary gastrointestinal disease); meningeal signs due to meningeal irritation with right upper lobe pneumonias; or chest pain due to pleural irritation. In elderly patients with pneumococcal pneumonia, tachypnea may be the primary presenting sign. Temperature elevations may be mild or absent. S pneumoniae is a common cause of bacterial CAP in HIV patients. The most common complication of pneumococcal pneumonia is pleural effusion. Although up to 40% of patients with pneumococcal pneumonia may have pleural effusion, only an

estimated 10% of these patients have enough fluid to aspirate, with only 2% of these patients meeting criteria for true empyema. S pneumoniaeinfection, along with Staphylococcusaureus infection, remains one of the most common causes of pediatric empyema.[18, 19, 34]

Invasive Disease
Meningitis
As a cause of meningitis, S pneumoniae usually invades the meninges via the bloodstream. Recent studies have shown that this is most likely due to pneumococcal adherence to up-regulated platelet-activating factor on vascular endothelial meningeal surfaces. S pneumoniae can also directly invade the meninges after basilar skull fractures or other trauma that compromises the dura and is the most common cause of recurrent bacterial meningitis in these patients. In countries with routine-vaccination policies, S pneumoniae infection is the most common cause of sporadic bacterial meningitis in both children and adults. Most patients with pneumococcal meningitis present non-acutely after hours to days of developing signs and symptoms. Presenting signs and symptoms may be nonspecific and include fever, irritability, emesis, lethargy, anorexia, and malaise. Neurologic signs and symptoms are usually prominent and may include mental-status changes, delirium, lethargy, nuchal rigidity with positive Brudzinski and Kernig signs, cranial nerve palsies, and other focal neurological deficits. A bulging fontanelle and poor feeding may be seen infants. Elderly patients may present with more indolent signs, including increasing lethargy, nonresponsiveness, or coma. Twenty to 25% of patients with pneumococcal meningitis experience seizures. Bacteremia may be found when blood cultures are obtained. Prolonged or secondary fevers are not uncommon but do not usually affect outcomes. Complications of pneumococcal meningitis include hearing loss, seizures, learning disabilities, mental difficulties, and cranial nerve palsies. In a study from Denmark, 240 patients who survived pneumococcal meningitis were examined using audiometry.[35] More than half (54%) had a hearing deficit, and 39% of those patients were not suspected of hearing loss at discharge from the hospital. Of the 240 patients, 7% had profound unilateral hearing loss, and another 7% had bilateral profound hearing loss. Significant risk factors for hearing loss included advanced age, the presence of comorbidity, and severity of meningitis. Audiometry should be performed on all patients who survive pneumococcal meningitis. Pneumococcal meningitis carries a greater risk of death and significant neurological disabilities than does meningitis of other common bacterial causes (eg, Haemophilus influenzae type B [Hib] and Neisseria meningitidis).[18, 19, 34]

Bacteremia
Bacteremia is the most common manifestation of invasive pneumococcal disease. Most cases are primary bacteremia and are found in children younger than 2 years. It is estimated that S pneumoniae infection has been the cause of 90% of occult bacteremia (bacteremia without a source) cases in these children since the widespread use of the Hib

vaccine. The incidence of occult bacteremia has decreased since the institution of routine pneumococcal immunization in infants.[36, 37] In adult patients, pneumococcal bacteremia is much more likely to be associated with another focal infection such as pneumonia, meningitis. Signs, symptoms, and physical examination findings are usually nonspecific in patients with occult bacteremia due to pneumococcal infection. In most patients, fever develops within 24 hours of positive culture findings. Higher temperatures are more often associated with the development of occult bacteremia. A peripheral WBC count greater than 15,000 cells/L is associated with the presence of occult bacteremia. Bacteremia is less likely in patients with fever and signs or symptoms of focal infection (eg, otitis media). Most cases of occult bacteremia spontaneously resolve. Complications develop in an estimated 10% of patients with occult bacteremia and include meningitis, osteomyelitis, pneumonia, soft tissue and joint infections, and sepsis. Patients with higher WBC counts and fever, those who have not undergone prior antibiotic therapy, and children younger than 20 months are at a higher risk for persistent bacteremia or the development of focal infection.[19, 18]

Joint and bone infections

S pneumoniae infection is an uncommon cause of osteomyelitis and septic arthritis, causing approximately 4% and 20% of cases in children, respectively. Septic arthritis: Pneumococcal septic arthritis usually manifests as painful, swollen, and hot joints. The ankles and knees are most commonly involved, and one or more joints may be affected. Blood or synovial cultures usually grow S pneumoniae. Up to half of patients with pneumococcal septic arthritis have concomitant osteomyelitis. Osteomyelitis: The femur and humerus are most often involved in cases of pneumococcal osteomyelitis in children; the vertebral bones are often involved in adult patients. Up to 20% of patients with pneumococcal osteomyelitis develop long-term sequelae, similar to rates of osteomyelitis sequelae caused by other organisms. One clinical study performed by the Pediatric Multicenter Pneumococcal Surveillance Study Group (PMPSSG) showed that more than 40% of patients with joint and bone pneumococcal infections had associated bacteremia.[38] Patients with prostheses or rheumatic fever are at increased risk for joint disease.

Soft tissue infections

Although uncommon, S pneumoniae infection can be a cause of mild-to-serious soft tissue infections, including cellulitis, myositis, periorbital cellulitis, and abscess, particularly in some compromised hosts (eg, those with SLE). Most patients have WBC counts greater than 15,000 cells/L and elevated temperatures. Physical findings are related to the site of infection and usually include redness, warmth, and tenderness of the involved area. Movement may be limited by pain and/or swelling. The incidence of soft tissue infections is increased in persons with HIV infection or underlying connective tissue disease; however, most affected individuals are otherwise healthy and respond well to antibiotic therapy.[18]

Peritonitis
Overall, primary peritonitis (peritonitis caused by the spread of organisms via blood or lymph to the peritoneal cavity) is rare, accounting for less than 20% of peritonitis cases.

S pneumoniae is the most commonly isolated organism in patients with primary peritonitis. Primary peritonitis in children is usually associated with underlying conditions such as nephrotic syndrome or other immunocompromising diseases. In adults, primary peritonitis is usually associated with cirrhosis. Females with severe pelvic inflammatory disease due to S pneumoniae infection may develop peritonitis. In such cases, organisms may gain access to the peritoneum via the fallopian tubes from the female genital tract. This is the only invasive disease caused by S pneumoniae infection that is more common in females. Other persons at risk for peritonitis include persons with gastrointestinal injury, ulcers, or malignancy. Presenting symptoms of peritonitis include abdominal pain, anorexia, emesis, diarrhea, and fever; children with right lower quadrant abdominal pain are often initially investigated for appendicitis.

Cardiac infections
In the antibiotic era, pneumococcal cardiac infections are rare. Endocarditis: Involvement of native aortic and mitral valves are most common; infection can lead to valve destruction, heart failure, and embolization. Presenting signs and symptoms are typical of those seen in other causes of endocarditis and include fever, new or changing murmurs, muscle and/or joint pains, sweating, fatigue, anorexia, and skin findings. In alcoholics, may be part of the triad of endocarditis, pneumonia, and meningitis. Pericarditis: Prior to the widespread use of antibiotics, S pneumoniae infection was the most common cause of purulent pericarditis in children; now, infection in childhood is extremely rare, and nearly all cases of pneumococcal pericarditis occur in adults. Symptoms, signs, and examination findings may include chest and/or pleuritic pain; radiating pain to the neck, abdomen, shoulder, or back; orthopnea; dry cough; extremity swelling; anxiety; fatigue; fever; pericardial rub; and muffled heart sounds.

Causes
S pneumoniae is an encapsulated, gram-positive, catalase-negative cocci that grows as a facultative anaerobe. These organisms often appear on Gram stain as lancet-shaped diplococci that grow in chains (see image below). On blood and chocolate agar plates, a green zone (alpha-hemolysis; due to the breakdown of hemoglobin by pneumolysin) surrounds the colonies. Other identifying properties include sensitivity to optochin (which distinguishes it from other alpha-hemolytic streptococci) and bile solubility.

Sputum Gram stain from a patient with a pneumococcal pneumonia. Note the numerous polymorphonuclear neutrophils and gram-positive, lancet-shaped diplococci. Courtesy of C. Sinave, MD, personal collection.

Predisposing conditions to pneumococcal infection are broad and often overlap; they include the following:

Exposure

o o o o o o o o o o o o

Cigarette smoke Alcohol Glucocorticosteroids Cold Stress Prior respiratory infections (including influenza) Daycare attendance Homeless shelters Military training Prisons Malnutrition Lack of exposure to breastmilk Defects in clearance of pneumococci from the blood o Congenital asplenia o Splenectomy o Decreased splenic function due to autosplenectomy due to sickle cell disease Defects in clearance from sinopulmonary tissue or inflammatory conditions o Asthma o COPD o Cigarette smoking o Influenza and other respiratory viral infections Defective antibody formation o Primary Congenital agammaglobulinemia Common variable hypogammaglobulinemia Selective immunoglobulin G (IgG) subclass deficiency o Secondary Lymphoma Chronic lymphocytic leukemia Multiple myeloma HIV infection Defective complement (primary or secondary): Absent or decreased amounts of C1, C2, C3, or C4 Abnormalities in polymorphonuclear leukocytes o Decreased levels associated with cyclic neutropenia, drug-induced neutropenia, or aplastic anemia o Decreased function caused by conditions such as alcoholism, cirrhosis, diabetes mellitus, renal insufficiency, and steroid therapy Other o Age (children < 2 y and elderly persons) o Fatigue o Chronic disease o Hospitalization[19]

Laboratory Studies
If a pneumococcal infection is suspected or considered, Gram stain and culture of appropriate specimens should be obtained, when possible. Potential specimen sites may include one or more of the following:

Blood Cerebrospinal fluid (CSF) Sputum Pleural fluid or lung aspirate Joint fluid Bone Other abscess or tissue specimens Specimens should be obtained prior to the initiation of antibiotic therapy and inoculated directly into blood-culture bottles, when possible. Antibiotic susceptibilities should be obtained routinely on all cultures with growth of S pneumoniae. Other laboratory values that may be helpful in diagnosis and treatment include a complete blood cell (CBC) count and differential, erythrocyte sedimentation rate (ESR), and Creactive protein (CRP). In children (who do not produce sputum and in adults with a nonproductive cough, the diagnosis may be made by urine antigen testing for S pneumoniae. As with urinary antigen testing for Legionella, antigenuria may not be present early in infection but persists after clinical resolution of infection.

Noninvasive Infections
Conjunctivitis, otitis media, sinusitis
Laboratory work is not usually obtained in patients with conjunctivitis, otitis media, or sinusitis unless they have unusually high fevers or have an extremely ill appearance. If specimens are obtained, they should be sent for Gram stain and culture and susceptibility. In these cases, isolation of S pneumoniae should be considered a strong indication for pathogenicity and treatment.[39]

Pneumonia
Many patients with pneumonia are treated presumptively. Antibiotics used in these cases should include those that cover S pneumoniae. In severe, unusual, or complicated cases or those that require hospitalization, an attempt to obtain sputum cultures should be made.[40] An acceptable sputum sample is indicated by the presence of few epithelial cells and many polymorphonuclear neutrophils (a ratio of 1:10-20).The presence of many gram-positive cocci in pairs and chains on Gram stain provides good evidence for pneumococcus. When large effusions/empyema is present, attempts should be made to obtain pleural fluid for Gram stain and culture. Blood cultures should be obtained in hospitalized patients with pneumonia; in pneumococcal pneumonia, blood cultures are positive in an estimated 10% of children and up to 25% of adults. Most patients with pneumococcal pneumonia have significant leukocytosis (>12,000 cells/L), and up to one fourth have a hemoglobin level of 10 mg/dL or less. Howell-Jolly bodies in the peripheral smear indicate splenic dysfunction. Neutrophil levels, CRP levels, and ESR are often elevated.

A small study by Casado Flores et al evaluated a rapid immunochromatographic test for detection of the pneumococcal antigen, C polysaccharide antigen, in children with pleural effusion.[41] The positive predictive value was 96%, and the sensitivity and specificity were high. In this study, the immunochromatographic test made identification of the pneumococcal origin of effusion easy.

Invasive Infections
In most patients with invasive pneumococcal infections, the WBC count is elevated (>12,000 cells/L) and there is a predominance of neutrophils. However, the WBC count may be normal, especially early in the disease process. An abnormally low WBC count may indicate severe disease and a poor prognosis. The ESR and CRP level are typically elevated in patients with invasive pneumococcal disease. The development of polymerase chain reaction (PCR) assays for S pneumoniaewith sufficient sensitivity and specificity is being widely investigated. Successful commercial assays may prove to be clinically useful.

Meningitis
CSF findings are typical of those found in bacterial meningitis and usually include the following:

Elevated opening pressure Elevated WBC count (1000-5000 cells/L) and elevated neutrophil level (>80%) Elevated protein level (>100 mg/dL) Decreased glucose level (< 40 mg/dL; < 50% of simultaneous blood glucose) Highly elevated lactic acid levels (>6 mmol/L) Most patients with pneumococcal meningitis who do not receive antibiotics in the 4-6 hours prior to lumbar puncture will have positive results on Gram stain and culture. Rapid antigen tests (latex agglutination or enzyme immunosorbent assays) can be performed on CSF (as well as sputum and urine) but rarely provide information beyond what is obtained with Gram stain and culture. CSF obtained from patients pretreated with antibiotics may be an exception. Blood culture results are positive in up to 90% of patients.

Bacteremia
The WBC count may be elevated and blood cultures are positive for growth of S pneumoniae.

Other invasive infections

The WBC count, neutrophil level, CRP level, and ESR are often elevated in patients with bone, joint, soft tissue, cardiac, and other invasive infections. Specimens of appropriate material may yield positive Gram stain findings and/or culture growth. Blood cultures are frequently positive and should be obtained when possible. In females with peritonitis, vaginal swab cultures should be obtained in addition to blood and peritoneal cultures.

Culture and Susceptibility

Antimicrobial susceptibility testing should be performed on all isolates of S pneumoniae, regardless of the isolation site, because of the increasing prevalence of intermediately susceptible and resistant isolates. All isolates should be tested for susceptibility to penicillin and cefotaxime or ceftriaxone. In addition, CSF isolates should be tested for susceptibility to vancomycin and meropenem. CSF isolates that are found to be nonsusceptible to penicillin should be tested for susceptibility to rifampin. Microbiological laboratories should follow established guidelines regarding inoculum size and media (Mueller-Hinton agar with sheep, horse, or lysed horse red blood cells). Isolates from patients with invasive disease should undergo testing with quantitative minimal inhibitory concentration (MIC) techniques (broth microdilution, antibiotic gradient strips). The Clinical and Laboratory Institute (CLSI) (2010) has defined S pneumoniaesusceptibility as follows[42, 43] :

Penicillin (nonmeningeal infections) Penicillin (non-CNS/CNS infections) o Susceptible (non-CNS/CNS): MIC is less than or equal to 2/0.06 g/mL, respectively. o Intermediate (non-CNS/CNS): MIC is 4/CNS isolates treated with intravenous penicillin are considered either susceptible or resistant. o Resistant (non-CNS/CNS): MIC is greater than or equal to 8/0.12 g/mL, respectively. Cefotaxime or ceftriaxone o Susceptible (non-CNS/CNS): MIC is less than or equal to 1/0.5 g/mL, respectively. o Intermediate (non-CNS/CNS): MIC is 2/1 g/mL, respectively. o Resistant (non-CNS/CNS): MIC is greater than or equal to 4/2 g/mL, respectively. Strains with intermediate or resistant susceptibility patterns should be considered nonsusceptible and alternate therapy used.

Imaging Studies
Chest radiography
Chest radiography should be performed in most patients with evidence of invasive pneumococcal infection and in those with pneumococcal pneumonia. The typical chest radiography finding in adolescents and adults with pneumococcal pneumonia is lobar consolidation. Infants and young children with pneumococcal pneumonia more often have a pattern of scattered parenchymal consolidation and bronchopneumonia. Other chest radiography findings may include air bronchograms, pleural effusions/empyema, pneumatoceles, and, rarely, abscesses. Cavitation is not a feature of S pneumoniae pneumonia and, if present, should prompt investigation for other pathogens.

Lobar consolidation with pneumococcal pneumonia. Posteroanterior

film. Courtesy of R. Duperval, MD.

Lobar consolidation with pneumococcal

pneumonia. Lateral film. Courtesy of R. Duperval, MD. by Streptococcus pneumoniae. Anteroposterior film. Courtesy of R. Duperval, MD.

Empyema caused

Ultrasonography/CT scanning
Chest ultrasonography or chest CT scanning may be obtained to provide information on the presence and/or extent of pleural effusion/empyema and parenchymal disease. Sinus CT scanning may provide information about the presence and extent of sinus disease. Positive findings include opacification and/or air-fluid levels. Facial CT scanning should be obtained in patients with periorbital or orbital cellulitis to look for evidence of soft tissue swelling, bony involvement, cranial nerve impingement, or proptosis.

MRI/CT scanning
MRI or CT scanning of affected bones or joints should be obtained to observe for evidence of joint destruction, periosteal elevation, or a mass. An MRI of the brain may be obtained in patients with meningitis to determine the location and extent of involvement.

Other Tests
Echocardiography should be performed in patients in whom endocarditis is suspected.

Procedures

Middle ear fluid aspiration Pleural fluid aspiration Chest tube thoracostomy or catheter placement Video-assisted thoracoscopy (VATS) or pleural decortication Lumbar puncture Joint fluid aspiration and/or wash-out of joint space Bone biopsy Soft tissue/muscle biopsy

Medical Care
Conjunctivitis, otitis media, sinusitis, bronchitis, and tracheobronchitis
Most patients with conjunctivitis, otitis media, sinusitis, bronchitis, and tracheobronchitis due to S pneumoniae infection can be treated on an outpatient basis with appropriate antibiotics. Compliance and follow-up should be ensured. Infants and elderly patients, as well as those with immunodeficiencies, underlying disease, or signs of severe disease, should be treated more aggressively and hospitalized when indicated.

Pneumonia
Presenting signs and symptoms widely vary in patients with pneumococcal pneumonia, from mild illness to febrile pneumonia to respiratory distress requiring ICU-level care. Factors such as age, type of symptoms, duration of symptoms, underlying and/or chronic illness, compliance with treatment, appropriate home care and potential for worsening disease must be considered in determining the need for and level of hospitalization.[44, 45, 46,
47, 48, 49, 50]

Most hospitalized should be treated with parenteral antibiotics in addition to medications for pulmonary symptoms, pain medications, intravenous fluids and/or parenteral or enteral nutrition, oxygen, and additional medications, as indicated on an individual basis.[51, 52, 53, 54,
55]

Meningitis
Patients with S pneumoniae meningitis should be admitted to the hospital and treated with parenteral antibiotics. The use of steroids in adult patients with bacterial meningitis is usually recommended with caution, as they may decrease CSF antibiotic concentration; patients with meningitis treated with steroids should be monitored closely.[56] Steroids can be considered prior to antibiotic therapy in children aged 6 weeks and older with possible pneumococcal meningitis. If used, they should be given before or at the time of the first dose of antibiotics.[2] Intravenous fluids, parenteral/enteral nutrition, and other medications should be used as indicated in appropriate clinical instances.

Bacteremia and sepsis

Patients with pneumococcal bacteremia should be treated with appropriate antibiotics. Children who undergo a workup to rule out sepsis (or serious bacterial illness) but who are not treated initially with antibiotics and whose cultures subsequently growS pneumoniae are often asymptomatic and have negative repeat blood culture findings at follow-up. Repeat blood cultures should always be obtained in patients with S pneumoniaebacteremia. Patients with signs or symptoms of sepsis should be admitted to the hospital and treated aggressively with antibiotics and other medical therapies, as indicated.

Other infections
Patients with cardiac, skin/soft-tissue, bone, and/or joint infections with S pneumoniae should usually be admitted to the hospital for observation, intravenous

antibiotic therapy, and expedition of further workup and evaluation of location and extent of disease.

Surgical Care
Patients with complicated pneumonia may require a chest tube for drainage of pleural fluid; VATS or decortication may be required in more severe cases. In patients with suspected septic arthritis or osteomyelitis, appropriate specimens should be obtained for Gram stain, cell count, histology, and/or culture. Patients with recurrent or chronic otitis media, periorbital or orbital cellulitis, or facial cellulitis may require surgical intervention.

Consultations

An infectious disease specialist should be consulted, when possible, in all cases of meningitis, complicated pneumonia, spontaneous bacterial peritonitis, osteomyelitis, septic arthritis, severe disease, and infection with resistant isolates. A surgeon should be consulted in cases of complicated pneumonia or complicated softtissue infections. An orthopedic specialist should be consulted in cases of septic arthritis or osteomyelitis. A neurosurgeon should be consulted in cases of recurrent meningitis. A pulmonologist should be consulted in cases of complicated pneumonia. Consultation with an otolaryngologist may be needed in cases of recurrent otitis media or complicated sinusitis. An otolaryngologist and/or an ophthalmologist should be consulted in cases of periorbital and/or orbital cellulitis. A cardiologist should be consulted in all cases of endocarditis or pericarditis.

Medication Summary
Antibiotics are the mainstay of treatment in S pneumoniae infections. Until the 1970s, essentially all pneumococcal isolates were sensitive to easily achievable levels of most commonly used antibiotics, including penicillins, macrolides, clindamycin, cephalosporins, rifampin, vancomycin, and trimethoprim-sulfamethoxazole. Beginning in the 1990s, many pneumococcal isolates in the United States showed decreased susceptibility to penicillin and other commonly used antibiotics. Continued increases in these isolates have led to the need for re-establishment of susceptibility standards. As of 2007, isolates of drug-resistant S pneumoniae have become increasingly common worldwide. The CDC, as well as many state health departments, maintain a populationbased surveillance system (the ABC system) that investigates the epidemiology and susceptibility patterns of invasive pneumococcal infections in the United States. In 2008, 24.8% of all isolates obtained showed intermediate or resistant susceptibility patterns to penicillin (down from 25.6% in 2007).[1] The prevalence of resistance varies greatly among countries, states, counties, and within populations in particular cities and may be as high as 30%-40% in some locations.[57, 58] Resistance rates are generally higher in most European countries, as well as in Hong Kong and Thailand.[59, 60] Unlike many common bacterial organisms, the method of resistance of pneumococcus to penicillin and cephalosporins is through alteration in the cell wall penicillin-binding proteins (PBPs). By altering these sites (where the antibiotics bind), the antibiotic affinity is decreased, subsequently decreasing the organism's susceptibility to the antibiotic. This type of resistance can be overcome if the serum or site levels of the antibiotic exceed the minimum inhibitory concentration (MIC) of the organism for 40%-50% of the dosing interval. Penicillin-resistant pneumococci are often also resistant to multiple other classes of antibiotics, including other penicillins, cephalosporins, sulfonamides, trimethoprimsulfamethoxazole (through amino acid changes), macrolides (through methylation or via an efflux pump), quinolones (through decreased permeability, efflux pumps, and alteration of enzymes), and chloramphenicol (through inactivating enzymes). Resistance is obtained as part of a cassette of genetic information, or a transposon, that encodes resistance to multiple antibiotics. Resistance rates of pneumococcal isolates in the United States to trimethoprimsulfamethoxazole, tetracycline, and the macrolides are relatively high. Some isolates (< 10% in the United States) that are resistant to macrolides are also resistant to clindamycin. Vancomycin-resistant pneumococcal isolates have not been reported in the United States. The phenomenon of tolerance (survival but not growth in the presence of a given antibiotic) has been observed, but its clinical relevance is unknown. Any strain with an in vitro MIC greater than 1 g/mL to vancomycin should be immediately reported to the state health department and arrangements made for confirmatory testing at the CDC. In the United States, most pneumococcal isolates remain susceptible to fluoroquinolones. In certain countries and specific populations in whom the use of "respiratory fluoroquinolones" is more prevalent (eg, nursing homes), an increase in resistance has been seen.[18, 19, 34]

Treatment of Specific Infections

Otitis media The guideline produced by the American Academies of Pediatrics and Family Practitioners for the treatment of otitis media recommends first-line treatment of most patients with amoxicillin 80-90 mg/kg/day. Patients who do not improve within 48-72 hours should be re-evaluated and their antibiotics switched to amoxicillin-clavulanate or a second- or third-generation oral cephalosporin,

although highly resistant pneumococci may require treatment with parenteral ceftriaxone in order to achieve adequate serum levels of antibiotics. Sinusitis The typical pathogens that cause sinusitis mimic those of otitis media; therefore, initial therapeutic recommendations are similar. In adult allergic patients and in adults who do not respond to initial therapy, fluoroquinolones provide appropriate coverage. In this clinical situation, this class of antibiotics is not approved for children. Pneumonia Most patients treated for community-acquired pneumonia (CAP) are treated as outpatients, and the etiological agent is rarely identified. Clinical studies have shown that, when etiological agents are sought, S pneumoniae is the predominating agent found when a bacterial organism is obtained. In children with CAP treated as outpatients, amoxicillin or amoxicillin-clavulanate at dosages used for the treatment of otitis media are recommended. In school-aged children (>5 y), the addition of a macrolide for coverage of atypical organisms is advised. In children ill enough to warrant hospitalization, the use of penicillin, ampicillin-sulbactam, or ceftriaxone is usually appropriate, and decisions for therapy should account for local resistance patterns. In critically ill or immunocompromised children in whom pneumococcal pneumonia is suspected or possible, vancomycin and a broad-spectrum cephalosporin should be used until or unless organism susceptibilities are available.[34] The Infectious Disease Society of America (IDSA) guidelines recommend the initial use of a macrolide (or doxycycline) for outpatient therapy of community-acquired pneumonia in previously healthy adults with no specific risk factors for resistant S pneumoniae infection.[61] In adult patients with underlying chronic disease, immunosuppression (including asplenia or that caused by immunosuppressive therapies), recent use of antibiotics (the preceding 3 mo), or other specific risk factors for resistant organisms (eg, residence in an area with high rates of resistant pneumococcus), the IDSA guidelines recommend use of either (1) a respiratory fluoroquinolone (moxifloxacin, levofloxacin) or (2) a beta-lactam antibiotic (high-dose amoxicillin, amoxicillin-clavulanate, or, alternatively, a second- or third-generation cephalosporin) plus a macrolide (or doxycycline). For inpatient treatment of adult pneumonia on a medical ward, treatment recommendations are as above for outpatient treatment of patients with comorbid conditions. For inpatient treatment of adult patients who require ICU care, recommendations are for a beta-lactam antibiotic plus a macrolide or a fluoroquinolone.[62] Meningitis The recommended initial therapy of presumed bacterial meningitis in children is with vancomycin plus ceftriaxone or cefotaxime at meningeal doses. A beta-lactam (penicillin or, more likely, ceftriaxone or cefotaxime [for CSF penetration]) vancomycin (adequate CSF levels). If the isolate is resistant to penicillin cephalosporins, the regimen started initially should be continued despite in vitro resistance) through the completion of therapy, usually 10 days in uncomplicated cases. For the treatment of pneumococcal meningitis in children who are hypersensitive to betalactams, a combination of vancomycin and rifampin should be considered. Monotherapy with vancomycin should not be attempted, as it is difficult to achieve sustained adequate bactericidal concentrations of vancomycin in the CSF. Monotherapy with rifampin should not be attempted due to the concern for development of resistance.

Other potential antibiotics for use in the treatment of pneumococcal meningitis in children include meropenem (meningeal dosed) or chloramphenicol. In patients infected with rifampin-sensitive pneumococcal isolates, the addition of rifampin to vancomycin should be considered after 48 hours when (1) the clinical condition has worsened despite treatment with vancomycin and cefotaxime/ceftriaxone, (2) repeat lumbar puncture shows persistently positive culture results, and/or (3) the isolate displays an MIC to cefotaxime/ceftriaxone of 4 g/mL or greater. The recommendations for treatment of bacterial meningitis in adults are similar to those in children.

Bacteremia: Treatment of bacteremia should be guided by isolate susceptibilities. Other invasive infections: S pneumoniae is not a particularly common cause of other invasive infections, and initial empiric antibiotic coverage may be adequate, although resistant isolates may require a change in antibiotics if pneumococcus is isolated.

Antibiotics
Class Summary
Penicillin and its derivatives are inexpensive effective antibiotics for treating pneumococcal infections when they are used against susceptible isolates. Penicillins can be administered orally or parenterally and work by inhibiting cell wall synthesis. Penicillin G is the parenteral drug of choice for susceptible S pneumoniae infections, and other parenteral beta-lactams do not provide additional or improved coverage (nor do beta-lactamase inhibitor combinations). Typical doses of penicillin provide more than adequate serum and body fluid concentrations for susceptible organisms (usually even with intermediate-susceptible strains), and many studies have shown similar outcomes in patients with penicillin-resistant versus penicillinsusceptible pneumococcal isolates treated with appropriate doses of beta-lactam antibiotics. Levels of CSF penetration are also therapeutic, although, in most cases, vancomycin should be used in addition to a beta-lactam antibiotic until isolate susceptibilities can be determined given the increasing rate of penicillin-resistant strains of S pneumoniae. Cephalosporins, which are also beta-lactam antibiotics, inhibit pneumococcus in the same way as penicillins and are resisted in the same manner (alteration in the cell wall PBPs). First-generation cephalosporins provide similar coverage in the treatment of penicillinsusceptible strains, although many of them have higher MICs. Most strains of pneumococcus that are not susceptible to penicillin also have some resistance to thirdgeneration cephalosporins, although some may still be susceptible, depending on the particular PBPs affected. In most cases, macrolides have activity against penicillin-susceptible strains of S pneumoniae. However, half or more of pneumococcal strains that have intermediate resistance or that are resistant to penicillin are also resistant to macrolides. Most macrolideresistant isolates of S pneumoniae derive their resistance through an efflux pump mechanism, which may be overcome with levels of drug that exceed the MIC for sufficient periods. Macrolides have poor CSF penetration and should not be used to treatment meningitis.[63] Most pneumococcal isolates in the United States remain susceptible to certain fluoroquinolones, including moxifloxacin (most effective), levofloxacin, gatifloxacin, and gemifloxacin. Ciprofloxacin and ofloxacin have limited activity against pneumococcal infections. Fluoroquinolones provide broad-spectrum treatment for CAP and achieve excellent serum drug levels and tissue penetration. Specific populations in whom the use of fluoroquinolones is traditionally increased (eg, residents of nursing homes) have shown increased levels of pneumococcal resistance to fluoroquinolones, and their empiric use in

respiratory infections should also be tempered by the concern for rapid development of resistance to this class by many organisms. Vancomycin is the only glycopeptide antibiotic that has demonstrated effectiveness against pneumococcal infections. To date, no clinical or in vitro evidence of pneumococcal resistance to vancomycin has been reported in the United States, and it is the drug of choice (with a third-generation cephalosporin) in the treatment of pneumococcal meningitis. The increased number of pneumococcal isolates resistant to trimethoprimsulfamethoxazole precludes its use unless susceptibilities are known and beta-lactam use is contraindicated. Clindamycin may also be used to treat nonmeningeal S pneumoniae infections. Penicillin or macrolide resistance may also be associated with clindamycin resistance in individual isolates. Carbapenems are also effective against S pneumoniae but should be reserved for specific cases given their broad coverage and the potential for development of resistance by multiple organisms.
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Cefotaxime (Claforan)
Third-generation cephalosporin with broad gram-negative spectrum, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. Arrests bacterial cell wall synthesis by binding to one or more of the PBPs, in turn inhibiting bacterial growth. Safety profile is more favorable than aminoglycosides. DOC for meningitis (all ages), inpatient treatment of pneumonia, bacteremia, and other invasive infections.
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Penicillin G (Pfizerpen)
DOC for severe infections, including meningitis attributed to susceptible strains ofS pneumoniae. DOC for severe infections, excluding meningitis attributed to strains of S pneumoniae with intermediate susceptibility to penicillin.
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Amoxicillin (Trimox, Amoxil)

Has better absorption than penicillin VK and administration is q8h instead of q6h. For minor infections, some authorities advocate administration q12h. Probably most active of the penicillins for nonpenicillin-susceptible S pneumoniae.
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Ampicillin (Marcillin, Omnipen)

No advantage over penicillin G in the treatment of pneumococcal infections. Bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable to take medication orally.
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Cefazolin (Ancef, Kefzol, Zolicef)

Alternative choice for parenteral treatment of pneumococcal infection outside CNS. Best beta-lactam for IM administration. Poor capacity to cross blood-brain barrier precludes use for treatment of meningitis.
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Ceftriaxone (Rocephin)
May be used to treat pneumococci that have reduced susceptibility to penicillin. Generally not preferred for infections caused by high-level penicillin-resistance pneumococci. For empiric treatment of meningitis, use in conjunction with vancomycin or rifampin.
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Azithromycin (Zithromax)
Approximately 25% of S pneumoniae strains naturally resistant. Generally better tolerated than erythromycin. Because of long half-life, treatment duration is reduced.
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Vancomycin (Vancocin, Lyphocin)

Always active against strains of S pneumoniae. DOC for the treatment of meningitis caused by nonpenicillin-susceptible S pneumoniae. Has suboptimal capability to cross blood-brain barrier and should be administered with cefotaxime or ceftriaxone for the treatment of meningitis. In adults, glucocorticoids may decrease penetration of vancomycin in the CNS; avoid this medication unless specific indications exist. Vancomycin is frequently the preferred drug for the treatment of severe penicillin-resistant pneumococcal infections outside the CNS and for patients with an IgE-type allergy to penicillin. Only IV administration is effective. The maintenance dose can be estimated using the following formula: 150 + 15 times the creatinine clearance in mL/min = mg of vancomycin to be administered daily.
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Clindamycin (Cleocin)
Lincosamide for treatment of serious skin and soft-tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNAdependent protein synthesis to arrest.
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Meropenem (Merrem IV)

A carbapenem antibiotic alternative for patients allergic to penicillin with meningitis or other severe invasive infections (good CSF penetration). Has been used successfully in patients with meningitis caused by penicillin-resistant pneumococci.
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Linezolid (Zyvox)
Prevents formation of functional 70S initiation complex, which is essential for bacterial translation process. Bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci. Used as alternative in patients allergic to vancomycin and for treatment of vancomycin-resistant enterococci.

Antibiotic, Glycylcycline
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Tigecycline (Tygacil)
A glycylcycline antibiotic that is structurally similar to tetracycline antibiotics. Inhibits bacterial protein translation by binding to 30S ribosomal subunit and blocks entry of aminoacyl tRNA molecules in ribosome A site. Indicated for complicated skin and skin structure infections caused by E coli, E faecalis(vancomycin-susceptible isolates only), S aureus (methicillin-susceptible and methicillin-resistant isolates), S agalactiae, S anginosus group (includes S anginosus, S intermedius, and S constellatus), S pyogenes, and B fragilis.

Further Inpatient Care

Pneumonia
Patients with pneumococcal pneumonia who do not respond or respond slower than usual to initial treatment should undergo follow-up chest radiography. Worsening or developing disease may indicate the need for consultation with a pulmonologist, an infectious disease specialist, and/or a surgeon and further intervention. Repeat chest radiography should be performed after therapy is completed to ensure resolution of disease and to document pulmonary findings. Chest radiography findings may remain abnormal for weeks to months, particularly following severe disease or complicated pneumonias. Oral therapy can be initiated when patients are clinically improved and afebrile.

Bacteremia
In hospitalized patients with pneumococcal bacteremia, follow-up blood cultures should be obtained until culture results are negative.

Meningitis
A repeat lumbar puncture should be considered after 48 hours of therapy in the following circumstances:

Patients whose isolates are not susceptible to penicillin based on oxacillin disk or MIC testing in whom results of cefotaxime and/or ceftriaxone susceptibilities are not yet available Patients whose condition has worsened or has not improved Patients who received steroid therapy (which could alter the ability to observe clinical improvement/worsening) Patients with pneumococcal meningitis should receive the entire course of antibiotic therapy parenterally.

Other invasive infections

Purulent pneumococcal pericarditis and endocarditis are serious diseases and should be treated aggressively with appropriate courses of parenteral antibiotics. Blood cultures should be obtained until multiple negative sets are documented. Repeat chest radiography, echocardiography, and other imaging tests may be repeated as recommended to monitor disease resolution. Patients with osteomyelitis and joint infections caused by S pneumoniae infection should be monitored closely for a decrease in pain and inflammatory markers and improved use of the affected limb or joint. Failure to improve should prompt re-evaluation of the area via aspiration, washout, biopsy, or repeat imaging.

Deterrence/Prevention
Behavior modification and risk factors
Cigarette smoking and passive cigarette smoke exposure have been linked to an increased risk for invasive pneumococcal disease in healthy adults; thus, smoking cessation should be encouraged. Optimal nutrition and living conditions may decrease the risk for pneumococcal disease. Breastfeeding should also be encouraged, when possible.

Daycare attendance is associated with acquisition, carriage (of susceptible and drugresistant strains), infection, and outbreaks of pneumococcal disease in proportion to the number of attendees.

Medical therapy
Antimicrobial prophylaxis may be used in selected patients with recurrent otitis media. Daily antimicrobial prophylaxis with penicillin, in addition to routine vaccination, is recommended in children with true anatomical or functional asplenia to prevent pneumococcal disease. Resistant pneumococcal strains and pneumococcal carriage in these patients have increased, and the optimal duration of prophylaxis in these children is uncertain. Patients with hypogammaglobulinemia due to congenital or acquired immune disorders (including patients with HIV/AIDS and recurrent pneumococcal infections) can be treated with monthly intravenous immunoglobulin in an attempt to maintain immunoglobulin levels above 400 mg/dL.

Immunization
Until February 2010, two pneumococcal vaccines were available for use in the prevention of pneumococcal disease. On February 24, 2010, the FDA approved the use of PCV13 vaccine for use in children aged 2-71 months and its use replaces PCV7.[12, 64, 65, 66, 67, 68, 69, 70] The capsular polysaccharide vaccine was licensed in 1977 and contains capsular antigens from the 23 serotypes of S pneumoniae that cause most of the infections in the United States. After vaccination with the polysaccharide vaccine, persons aged 5 years and older develop type-specific protective antibodies. Bacterial polysaccharide vaccines produce antibodies primarily through T-cellindependent methods. Because these systems are not fully developed in young children, children younger than 2 years have a poor response to these types of vaccines.[55]In some elderly persons and persons of all ages with immunosuppressive conditions, immunogenicity of the polysaccharide vaccine is poor. No anamnestic response occurs with revaccination, and the duration of immunity with the polysaccharide vaccine is unknown. Neither a decrease in pneumococcal carriage rates or protection of unimmunized persons due to herd immunity has been documented after immunization using the polysaccharide vaccine. The Advisory Committee on Immunization Practices (ACIP) recommends that the pneumococcal polysaccharide vaccine (PPSV23) be given to the following groups (children aged 2-6 years should complete the recommended doses of PCV13 before PPSV23 is given)[69] :
o o o o o o o o o o

Persons aged 65 years or older Immunocompetent persons aged 2-64 years with underlying medical conditions, including the following: Chronic heart disease (excluding hypertension) Chronic lung disease (including chronic obstructive pulmonary disease, emphysema, and asthma) Chronic liver disease Cochlear implant CSF leaks Alcoholism Cigarette smoking Persons aged 2-64 years with functional or anatomic asplenia Persons aged 2-64 years who are immunocompromised due to the following: Congenital or acquired immunodeficiencies HIV infection Leukemia

Lymphoma or Hodgkin disease Multiple myeloma Disseminated malignancy Chronic renal failure or nephrotic syndrome Persons receiving corticosteroids or other immunosuppressive therapies Bone marrow or organ-transplant recipients Persons aged 50-64 years living in high-risk environments (eg, Alaskan natives, certain American Indian populations) The duration of protection is probably 5-10 years but may vary widely. Revaccination is recommended in certain populations, including the following:

o o o o o o

Five years after initial immunization in children aged 2 years or older at high risk for pneumococcal infection or in whom antibody titers are highly likely to rapidly decline, including those with functional or anatomic asplenia, sickle cell disease, or immunosuppression. All other children with underlying medical conditions should receive 1 dose of PPSV23. Persons aged 65 years or older who are at high risk for disease or rapid antibody decline, including those with asplenia, HIV, leukemia, lymphoma, Hodgkin disease, multiple myeloma, malignancy, renal disease, or organ/marrow transplant or those on immunosuppressive therapies A study showed that in elderly patients with chronic illness, dual vaccination with pneumococcal polysaccharide vaccine and influenza vaccine led to decreased complications related to respiratory, cardiovascular, and cerebrovascular diseases.[71] A reduction in hospitalizations, coronary and intensive care admissions, and death was also noted in these patients. A 13-valent pneumococcal conjugate vaccine (PVC13) was licensed for use in 2010 and includes antigens from the capsules of 13 pneumococcal serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F). When this vaccine was introduced and replaced PCV7 in 2010, these additional 6 serotypes accounted for the majority of pneumococcal isolates that caused invasive disease since the introduction of PCV7 in 2000.[11] Pneumococcal conjugate vaccines link capsular polysaccharides to a conjugate (diphtheroid) carrier protein. Responses to these antigens are developed using T-cell dependent mechanisms. These antibodies induce immunologic memory, reduce carriage rates of pneumococcal vaccine-serotype isolates, and provide indirect protection to unimmunized persons via herd immunity. Recommendations for universal vaccination in all children aged 59 months and younger in the United States are now in place. PCV13 immunization follows the same recommendations as that for PCV7 and replaces its use. In addition, PCV13 use is recommended in children aged 60-71 months with underlying medical conditions placing them at increased risk of pneumococcal disease and its complications. Health care providers considering vaccination should refer to the ACIP guidelines and the American Academy of Pediatrics policy statement on recommendations for immunization of children against pneumococcal disease, outlined as follows[64] :

A 4-shot series should be given at ages 2, 4, 6, and 12-15 months. Immunization with PCV13 should replace that of PCV7 as soon as it is available. Children who have received one of more doses of PCV7 should have those doses counted, but complete the series with PCV13. Catch-up immunization should be pursued in all children aged 59 months or younger who are incompletely immunized for age using current recommendations by the American Academy of Pediatrics and ACIP. PCV13 replaces the use and previous recommendations for PCV7.[2, 65] Healthy children aged 24-59 months who have an incomplete schedule of immunization with PCV7/PCV13 should receive a single dose of PCV13.

Children aged 24-71 months who are at high risk for pneumococcal disease with an incomplete schedule of fewer than 3 doses should receive 2 doses of conjugate vaccine 2 months apart, followed at least 2 months later by 1 dose of polysaccharide vaccine. Children with an incomplete schedule of 3 doses should receive 1 additional dose. A single supplemental dose of PCV13 is recommended for all children in the following groups who were previously fully immunized with PCV7:

All healthy children aged 14-59 months old All children aged 14-71 months with underlying medical conditions placing them at increased risk of pneumococcal disease A single dose of PCV13 may be administered to children aged 6-18 years (regardless of previous immunization status with PCV7/13/23) who are at increased risk of IPD because of sickle cell disease, asplenia, HIV/immunocompromise, CSF leaks, or cochlear implants.[64] High-risk patients include those with sickle cell disease or hemoglobinopathies, asplenia (congenital or functional), HIV infection, cochlear implants, those of Alaskan Native descent (and of some American Indian populations) who are younger than 2 years, immunocompromising conditions (congenital immune deficiencies), chronic cardiac or pulmonary illness, diabetes mellitus, chronic renal insufficiency (including nephrotic syndrome), diseases requiring immunosuppressive or radiation therapy, and/or CSF leaks.[2] Table 1. Recommended Schedule for Doses of PCV13, Including Catch-up Immunizations in Previously Unimmunized and Partially Immunized Children[2](Open Table in a new window)
Age at Examination (mo) Immunization History Recommended Regimena

2-6

0 doses

3 doses, 2 mo apart; fourth dose at age 12-15 mo

1 dose

2 doses, 2 mo apart; fourth dose at age 12-15 mo

2 doses

1 dose, 2 mo after the most recent dose; fourth dose at age 12-15 mo

7-11

0 doses

2 doses, 2 mo apart; third dose at age 12 mo

1 or 2 doses before age 7 mo

1 dose at age 7-11 mo, with another dose at age 12-15 mo (2 mo later)

12-23

0 doses

2 doses, 2 mo apart

1 dose at < 12 mo

2 doses, 2 mo apart

1 dose at 12 mo

1 dose, 2 mo after the most recent dose

2 or 3 doses at < 12 mo

1 dose, 2 mo after the most recent dose

24-71[66] 1 dose, 2 mo after the most recent doseb

Healthy children

Any incomplete schedule

(24-59mo)

Children at high

Any incomplete schedule of < 3 doses

2 doses, one 2 mo after the most recent dose and another dose 2 mo later

riskc (24-71 mo)

Any incomplete schedule of 3 doses

a

1 dose, 2 mo after the most recent dose

In children immunized before age 12 mo, the minimum interval between doses is 4 weeks. Doses administered at age 12 months or later should be administered at least 8 weeks apart.

Providers should administer a single dose to all healthy children aged 24-59 mo with any incomplete schedule.

Children with sickle cell disease, asplenia, chronic heart or lung disease, diabetes mellitus, CSF leak, cochlear implant, HIV infection, or another immunocompromising condition. PPV23 is also indicated (see below).

Many clinical investigations have shown the positive impact of the pneumococcal conjugate vaccine on invasive and noninvasive disease in children, as well as the reduction in nasopharyngeal carriage of vaccine serotypes.[72, 73] Nasopharyngeal carriage and invasive disease are still present, and previous nonvaccine serotypes in these roles have emerged over the past several years, particularly serotype 19A (now covered by routine vaccination with PCV13).[8, 4, 5]

Complications

Otitis media - Recurrent or chronic otitis media, mastoiditis, brain abscess, meningitis tympanic membrane perforation Sinusitis - Periorbital/orbital cellulitis, meningitis, cavernous sinus thrombosis, osteomyelitis Pneumonia - Pleural effusion/empyema, abscess Meningitis - Hearing loss, seizure disorder, developmental delay, learning difficulties, cranial nerve palsies, other focal neurological deficits, vasculitis, cerebral infarction, hydrocephalus, cerebral palsy Soft tissue/joint/bone infections - Scarring, disproportionate limb length or size, recurrent infection

Prognosis
Pneumococcal conjunctivitis, otitis media, and sinusitis in developed countries where appropriate antibiotics are available usually carry an excellent prognosis; potential complications are listed above (see Complications). The prognosis of pneumococcal pneumonia depends largely on underlying factors, including age, immunosuppression, availability of antibiotics, and extent of lung involvement. Pneumococcal pneumonia does not tend to cause necrotizing disease, and most healthy patients treated appropriately recover without long-term complications. The prognosis of pneumococcal meningitis is also related in part to host factors. Most studies have shown that morbidity rates in otherwise healthy US children with meningitis are usually less than 10%; however, neurological sequelae are common.

Patient Education
All parents should be advised of the recommendations for universal childhood immunization with the pneumococcal conjugate vaccine. Patients with medical conditions that place them at an increased risk for serious or invasive S pneumoniae disease should be educated about their condition, the potential presenting signs and symptoms of pneumococcal infection, and the need to obtain medical care promptly upon any concern for possible infection. These patients should also be educated about the benefits of the pneumococcal polysaccharide vaccine and should be encouraged to receive it.

Classification
Higher order taxa

Bacteria; Firmicutes; Bacilli; Lactobacillales; Streptococcaceae

Species

Streptococcus pneumoniae

Description and significance

Electron microscope photomicrograph ofStreptococcus pneumoniae. Source: CDC Public Health Image Library. Public domain. Streptococcus pneumoniae are Gram-positive bacteria in the shape of a slightly pointed cocci. They are usually found in pairs (diplococci), but are also found singly and in short chains. S. pneumoniae are alpha hemolytic (a term describing how the cultured bacteria break down red blood cells for the purpose of classification). Individual bacteria are between 0.5 and 1.25 micrometers in diameter. S. pneumoniae do not form spores and are nonmotile, though they sometimes have pili used for adherence. (5) S. pneumonia are found normally in the upper respiratory tract, including the throat and nasal passages. (2) They are mesophillic, living optimally at temperatures between 30 and 35 degrees Celsius. S. pneumoniae was isolated in 1881 by Louis Pasteur. The species was then known as pneumococcus due to its role in the disease, pneumonia. It was termed Diplococcus pneumonia in 1926 due to its propensity to exist in pairs of cells, and renamed Streptococcus pneumoniae in 1974 because of its formation of chains in liquid. S. pneumoniae played a significant role in the history molecular genetics, being the subject of the experiments that gave birth to the field. In 1928 Frederick Griffith transformed live, harmless S. pneumoniaeinto a deadly strain by combining them with an extract from heat-killed, virulent S. pneumoniae. Further, in 1944, Avery, MacLeod, and McCarthy proved that

genetic material is DNA by showing that the transforming factor in Griffith's experiments was not protein, but DNA. (7)

Genome structure
The genome ofS. pneumoniae D39, the virulent strain used in the revolutionary experiments of Griffiths and McCarthy, consists of a single circular chromosome with about 2 million base pairs. Its GC content is 39.7%, and it codes for 1914 proteins and 73 RNAs. (2) Several surface proteins have been identified that may serve as vaccine candidates. Several different strains of Streptococcus pneumoniae have been identified, possibly accounting for differences in virulence and the presence of antigens. (1) S. pneumoniae has shown a significant increase in antibiotic resistance over the past 20 years. This is likely due to its use of a natural transformation system used for genetic exchange. It can also develop resistance to antibiotics through mutation and natural selection. S. pneumoniae has a relatively fast growth rate and reaches great cell densities in infections environments, conditions which favor natural transformation and natural selection toward antibiotic resistance. (5)

Cell structure and metabolism

Streptococcus pneumoniae is characterized by a polysaccharide capsule that completely encloses the cell, and plays a key role in its virulence. The cell wall of S. pneumoniae is composed of peptidoglycan, with teichoic acid attached to every third N-acetylmuramic acid, and is about 6 layers thick. Lipoteichoic acid is attached to the membrane via a lipid moiety, and both teichoic and lipoteichoic acid contain phosphorylcholine. Two choline residues may exist on each carbohydrate repeat, which is important to S. pneumniae because the choline adheres to choline-binding receptors located on human cells. (5) S. pneumoniae contains more than 500 different surface proteins. A notable group is the family of choline-binding proteins (CBPs). Twelve of these are bound to the choline moiety of the cell wall and assist in attaching various functional elements onto the surface of the cell. Among the CBPs are found important determinants of virulance, including PspA (protective antigen), LytA, B, and C (autolysins), and CbpA (adhesin). (5) S. pneumoniae lacks catalase and ferments glucose to lactic acid, like most other streptococci. However, unlike most other streptococci, it does not display an M protein and it hydrolyzes insulin. (5) S. pneumoniae gets a significant amount of its carbon and nitrogen through extracellular enzyme

systems that allow the metabolism of polysaccharides and hexosamines, as well as cause damage to host tissue and enable colonization. (1) S. pneumoniae has the ability to enzymatically disrupt and disintegrate itself. This enzyme, an autolysin, causes a culture of S. pneumonia to undergo an autolysis, which kills the entire culture during the stationary phase (the phase in which growth slows due to exhaustion of available nutrients and buildup of toxins). With initial growth beginning in optimal conditions, autolysis usually begins within 18-24 hours, with colonies collapsing in the centers. (5)

Ecology
Streptococcus pneumoniae is found in the respiratory tracts of mammals. While it is part of the normal flora of this environment, going unnoticed when present in small densities, it acts as a pathogen toward its host when present in large enough densities. S. pneumoniae shares its mucosal microenvironment with another pathogen, Haemophilus influenzae. In vitro, competition between S. pneumoniae and H. influenzae leads to the former killing off the latter by attacking it with hydrogen peroxide. Tested individually in vivo, both bacteria are able to successfully grow; however, when both are present in the same environment, H. influenza rapidly outcompetes S. pneumoniae. Research shows that the inflammatory response elicited by H. influenza causes the clearing of the other pathogen, S. pneumoniae. (6)

Pathology
Streptococcus pneumoniae is known to cause bacteremia, otitis media, and meningitis in humans, though it is best known for causing pneumonia, a disease of the upper respiratory tract that causes illness and death all over the world. (5) Symptoms of pneumonia include a cough accompanied by greenish or yellow mucous, fever, chills, shortness of breath, and chest pain. The bacteria enter the body most commonly via inhalation of small water droplets. Very young children and the elderly are the most prone to catching pneumonia. The virulence factors of S. pneumoniae include a plysaccharide capsule that prevents phagocytosis by the host's immune cells (5), surface proteins that prevent the activation of complement (part of the immune system that helps clear pathogens from the body), and pili that enable S. pneumoniae to attach to epithelial cells in the upper respiratory tract. (4) The polysaccharide capsule interferes with phagocytosis through its chemical composition, resisting by interfering with binding of complement C3b to the

cell's surface. Encapsulated strains of S. pneumoniaeare found to be 100,000 times more virulent than unencapsulated strains during invasion of mucosal surfaces. (5) Pili are long, thin extracellular organelles that are able to extend outside of the polysaccharide capsule. They are encoded by the rlrA islet (an area of a genome in which rapid mutation takes place) which is present in only some isolated strains of S. pneumoniae. These pili contribute to adherence and virulence, as well as increase the inflammatory response of the host. (4)

Application to Biotechnology
Streptococcus pneumoniae is mainly found in the lab for the purpose of creating a vaccine against it. It is today the most common infections agent leading to hospitalization in the world. There are 90 different capsular types of S. pneumoniae, so a vaccine that is based on polysaccharide alone will not work. The most feasible vaccines against this bacteria work against different highly prevalent subgroups. In 1945, there were 4 targeted subgroups, which rose to 14 in the 1970's, and finally to the current vaccine that targets 23 subgroups. These 23 targeted types represent 85-90% of the virulent types, and the vaccine has an efficiency of around 60%. However, utilization of this vaccine remains very low considering the number of S. pneumoniae infections around the world. (5) Pneumonia caused by S. pneumoniae is most prevalent in poorer countries, increasing the need for an economical and effective vaccine. A potential candidate is the bacterium Lactococcus lactis, which produces the S. pneumoniae surface protein A (PspA). Exposure to this antigen may stimulate antibody production effective against S. pneumoniae, offering an economical alternative to current options. (3)

Current Research
Streptococcus pneumoniae remains actively virulent in today's world with an increasing resistance to antibiotics. The genome sequences for a few different strains have just been mapped, including the capsulated, virulent strain D39 and the unencapsulated, avirulent strain R6. Comparisons of the different strains expose modern mutations and information about regulation, metabolism, and virulence in the bacteria. (2) Due to a continuing increase in S. pneumoniae's antibiotic resistance, the search for a better vaccine is ongoing. Research on the Lactococcus lactis bacteria for use as a vaccine is promising; its production of the pneumococcal surface protein PspA makes it a good candidate for a mucosal vaccine, which could be administered through the nose instead of an injection

(a promising aspect). Studies show that the lactococcal vaccine offers better protection against respiratory infection by S. pneumoniae than injections of similar amounts of recombinant PspA administered by injection. There is considerable potential to develop a vaccine with L. lactis, for use against S. streptococcus and more. (3) Penicillin resistance in S. pneumoniae has an effect on mortality rates of patients hospitalized with pneumonia. Studies show that the mortality rate in patients infected by the penicillin-nonsusceptible S. pneumoniae were around 19.4%, and those infected by the penicillin-susceptible S. pneumoniae had a mortality rate around 15.7%. Penicillin resistance is therefore strongly associated with a increased mortality rate. Additional research is needed to understand the mechanisms of this association. (8)

References
1. Herv, T., et al. "Complete Genome Sequence of a Virulent Isolate of Streptococcus pneumoniae". Science. July 20, 2001. Volume 293. p. 498-506. http://www.sciencemag.org/cgi/content/abstract/293/5529/498 2. Lanie, J., Ng, W., Kazmierczak, K., Andrzejewski, T., Davidsen, T., Wayne, K., Tettelin, H., Glass, J., Winkler, M. "Genome sequence of Avery's virulent serotype 2 strain D39 of Streptococcus pneumoniae and comparison with that of unencapsulated laboratory strain R6". Journal of Bacteriology. 2007. Volume 189. p. 38-51. http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list_u ids=17041037&dopt=Abstract 3. Hanniffy, S., Carter, A., Hitchin, E., and Wells, J. "Mucosal Delivery of a Pneumococcal Vaccine Using Lactococcus lactis Affords Protection against Respiratory Infection". The Journal of Infectious Diseases. 2007. Volume 195. p. 185-193. http://www.journals.uchicago.edu/JID/journal/issues/v195n2/36706/brief/367 06.abstract.html?erFrom=-2043069302250900887Guest 4. Barocchi, M., Ries, J., Zogaj, X., Hemsley, C., Albiger, B., Kanth, A., Dahlberg, S., Fernebro, J., Moschioni, M., Masignani, V., Hultenby, K., Taddei, A., Beiter, K., Wartha, F., von Euler, A., Covacci, A., Holden, D., Normark, S., Rappuoli, R., Henriques-Normark, B. "A pneumococcal pilus influences virulence and host inflammatory responses". Proceedings of the National Academy of Sciences of the United States of America. 2006. Volume 103. p. 2857-62.

http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=pubmed&dopt= Abstract&list_uids=16481624 5. Todar, K. "Streptococcus pneumoniae: Pneumococcal pneumonia". Todar's Online Textbook of Bacteriology. 2003. http://textbookofbacteriology.net/S.pneumoniae.html 6. Lysenko, E., Ratner, A., Nelson, A., Weiser, J. "The role of innate immune responses in the outcome of interspecies competition for colonization of mucosal surfaces". PLoS Pathogens. 2005. Volume 1. p. 1. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedi d=16201010 7. Lederberg, J., Gotschlich, E. "A Path to Discovery: The Career of Maclyn McCarty". PLoS Biology. 2005. Volume 3. p. 341. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1250295 8. Tleyjeh IM, Tlaygeh HM, Hejal R, Montori VM, Baddour LM. "The impact of penicillin resistance on short-term mortality in hospitalized adults with pneumococcal pneumonia: a systematic review and meta-analysis". 2006. Volume 42. p. 788-97. http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_ui ds=16477555&dopt=Abstract Retrieved from "http://microbewiki.kenyon.edu/index.php/Streptococcus_pneumoniae"