Streptococcus Pneumoniae: Epidemiology, Risk ...

Streptococcus pneumoniae: Epidemiology and Risk Factors

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Streptococcus Pneumoniae: Epidemiology, Risk Factors, and Clinical Features Åke Örtqvist, M.D., Ph.D., F.C.C.P.; Jonas Hedlund, M.D., Ph.D.; Mats Kalin, M.D., Ph.D. Semin Respir Crit Care Med. 2005;26(6):563-574. ©2005 Thieme Medical Publishers Posted 01/20/2006

Abstract Streptococcus pneumoniae is the most common cause of both pneumonia overall and fatal pneumonia. Antibiotic resistance has developed worldwide and is most frequent in pneumococcal serotypes that are most prevalent in children (types/groups 6, 14, 19, and 23). The incidence of pneumococcal disease is the highest in children < 2 years of age and in adults > 65 years of age. Other important risk factors are chronic heart and lung disease, cigarette smoking, and asplenia. A 23-valent capsular polysaccharide vaccine and a heptavalent proteinpolysaccharide conjugate vaccine are currently available. The latter is specially designed for pediatric use because small children respond poorly to polysaccharide antigens. Both vaccines are efficacious in prevention of invasive pneumococcal disease. The clinical presentation of pneumococcal pneumonia is variable, and neither clinical features nor laboratory or radiographic findings can reliably predict the etiology of pneumonia. Blood culture is the most important tool for establishing a definitive diagnosis, but Gram's stains and sputum culture are also of value in skilled hands. A recently developed urinary antigen test may provide a rapid diagnosis of pneumococcal pneumonia in adults. Penicillin (penicillin G/amoxicillin) remains the drug of choice for strains that are fully sensitive or have a moderately decreased susceptibility to penicillin, whereas cefotaxime and ceftriaxone are the first-line alternatives in cases with higher levels of resistance.

Incidence Of Pneumococcal Disease Streptococcus pneumoniae is one of the most important human pathogens, and pneumococcal disease is endemic all over the world. For more than a century S. pneumoniae has been known as the most common cause of acute otitis media, sinusitis, and pneumonia and one of the most important causes of bacterial meningitis.[1,2] In developing countries pneumonia is a serious disease in children and it is estimated that more than a million children below the age of 5 each year die from pneumococcal pneumonia.[3] In the United States the pneumococcus each year probably accounts for 3000 cases of meningitis, 500,000 cases of pneumonia, and 7,000,000 cases of otitis media.[2] The incidence of pneumococcal pneumonia has probably not decreased significantly during the previous century,[1] but the case fatality rate has decreased dramatically with the advent of antibiotics. There has also been a shift toward the disease becoming severe in mostly the elderly and those with underlying diseases. The total yearly incidence of pneumonia in Western populations is around 1% and S. pneumoniae is probably responsible for almost half of the cases of community-acquired pneumonia (CAP).[4-9] Thus almost five in 1000 persons each year contract pneumococcal pneumonia, with the incidence being several times higher in the very young and the elderly.[6,10-12] The major cause of pneumococcal bacteremia is pneumonia. The total annual incidence of pneumococcal bacteremia in North America and Europe is at least 10 to 20 per 100,000 individuals, but a more correct figure may well be more than 40 per 100,000.[2,12] The risk of invasive pneumococcal disease has been found to be more than 20-fold greater in small children if they are attending day care centers.[13,14] Moreover, it

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is higher still in certain populations such as Alaskan natives.[15] In recent years a substantial increase in the incidence of pneumococcal bacteremia has been noted in several countries, including the United States, Sweden, Norway, and Denmark.[16-19] The incidence of pneumococcal disease is highest during the winter months.[4,20] One reason for this may be that viral respiratory infections predisposing to pneumococcal disease are more common during winter.[21,22] Outbreaks of pneumococcal disease may occur if a new strain is introduced in a closed setting, such as schools, military camps, nursing homes, or jails.[1,12,23,24]

Molecular Epidemiology, Pathogenesis, and Carriage All wild strains of S. pneumoniae are provided with a polysaccharide capsule. To date, 90 distinct capsular types have been described.[25] Types that are antigenically related to each other are included in groups (labeled, e.g., 9A, 9L, 9N, and 9V), whereas types without close antigenic relationship to other types are given numbers only (e.g., types 1, 2, 3, 4, 5). The capsular polysaccharides are composed of repeating units of oligosaccharides and for most of them the chemical structure is known.[26] Molecular analysis of the genes responsible for the synthesis of some of the capsular substances has shown that they are arranged in cassettes comprising all the genetic material necessary for capsule synthesis.[27] Being naturally transformable, pneumococci may exchange genetic material between different strains. By such processes capsule specificity, in a cassette type-recombination event, can be exchanged in vitro as well as in vivo.[27-29] Capsule transformation was described as early as 1928[1] and is, according to recent evidence, a rather common event in nature.[29-31] In three recent studies comprising 5000 to 10,000 strains from patients with invasive disease in several different countries a total of 64 to 77 different types were identified.[11,32,33] Thus only a few serotypes were not found, but the prevalence of most types was very low. In a fourth study, comprising a total of 13,616 worldwide pneumococcal isolates[34] (Fig. 1) the 10 most prevalent types together made up 61.7% and the 30 most prevalent types 91.5%, so the 60 least common types together accounted for only 8.5%. In children the number of commonly isolated strains is even more limited. Types/groups 6, 14, 18, 19, and 23 are clearly more prevalent in small children, whereas in adults the type distribution pattern is much more scattered.[11,25,32,35,36] The reason for the dominance of serotypes 6, 14, 18, 19, and 23 in children, with their immature immune system, is that these serotypes are less immunogenic than other types.[37]

Figure 1. Type distribution among 13,616 pneumococcal strains isolated from patients with invasive infections in several countries worldwide.

In the beginning of the 20th century types 1 and 2 accounted for up to 65% of the cases of lobar pneumonia in the


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United States and Europe, and types 1, 2, and 3 together for up to 75% of the bacteremic cases.[1,4,25,38] Also type 5 was common. Today types 2 and 5 are almost never isolated in Western countries and type 1 most often in low frequencies only. Instead other types have become increasingly more prevalent (Fig. 1). Interestingly the type distribution pattern in developing countries is often similar to that seen in the United States and Europe in the beginning of the 20th century, with a few types predominating, particularly types 1 and 5. Types 1, 2, 3, and 5, in comparison with other types, are more immunogenic, have been less often isolated from carriers, and seem to have a more pronounced tendency to spread epidemically.[38] It may be speculated that in living conditions with poverty and crowding, exposure to active cases of pneumococcal disease may be more prevalent, whereas in Western countries small children that are asymptomatic carriers may be the predominant source from which spread of pneumococci occurs. Remarkable differences in the distribution of prevalent types may also exist between different geographical areas and there may be substantial changes over time within a specific area.[11,25,36] For example, type 3 remained one of the most prevalent types from the beginning of the 20th century until a few decades ago, when it was found to decrease in frequency in many countries.[17-19,33,36] Instead, type 14 has become much more prevalent. In Sweden, a fourfold increase in the total number of invasive infections was noted around the decade from 1987 to 1997,[18] which was in 1987-92 paralleled by a threefold increase in type 14 isolates and in 1992-97 by a 10-fold increase in type 1 isolates.[39] These increases of type 14 and 1, respectively, were due to expansion and spread of two particular clones of pneumococci. Also, in the United States, clonal spread of type 1 has been demonstrated.[40] These findings may be of interest because the type distribution pattern and its changes are of crucial importance in achieving protection efficacy with different vaccines. It has been known for a century that the polysaccharide capsule is crucial for virulence.[1,38,41] The binding of typespecific anticapsular antibodies to the capsule changes the structure of the cellular surface so that phagocytosis is facilitated. A functioning antibody response is crucial for an effective defense against pneumococcal infections, and only type-specific antibodies directed against the capsular polysaccharide have been shown to be protective against pneumococcal disease.[38,42] The most common host-parasite interrelationship is asymptomatic nasopharyngeal carriage.[43,44] Carriage is especially frequent (≥ 50%) in small children, particularly those attending day care centers and other crowded settings.[44,45] A particular pneumococcal strain may be carried in the nasopharynx for a few days to several months.

Antibiotic Resistance Antibiotic resistance has developed primarily in pneumococcal strains belonging to the serotypes that are most prevalent in children, types 6, 14, 19, and 23. The probable reason is the common use of antibiotic therapy in small children and hence a frequent exposure of strains of these serotypes to antimicrobial drugs, providing a selective advantage to resistant mutants.[46] Pneumococci with reduced susceptibility to penicillin can today be found in most parts of the world but with greatly variable prevalence. Comparison of penicillin binding protein (PBP) genes from such strains from different parts of the world demonstrates a great variation, indicating that such genes have probably arisen in many different places during the last few decades.[30] In contrast, pneumococci with higher levels of penicillin resistance display much more limited variation in the PBP genes, and much of the increase in antibiotic resistance has been caused by the expansion of a very limited number of pneumococcal clones and variants of these clones.[30,44,47] A few clones have been particularly successful and have spread between countries and continents, notably those with the original capsular types 23F, 9V, and 6B. Most remarkably, a multiresistant type 23F clone has been prevalent in Spain for ~20 years and has successively given rise to a very significant part of the β-lactam resistance in S. pneumoniae worldwide. Strains that by genetic examination belong to one of the welldescribed pandemic clones may also be found expressing a new capsular type after natural transformation of the capsular encoding genes. Thus the originally Spanish 23F clone is today commonly found with capsular types 19A, 19F, and 14 in different countries.[29,31] Types 3 and 9N have also been detected with this clone.[31]

Immune Response As T cell-independent antigens, the capsular polysaccharides are poorly immunogenic in infants and small children and elicit an antibody response that is not boostered upon new contact with the antigen.[38] To improve the immunogenicity for vaccination purposes, pneumococcal polysaccharides have been coupled to suitable carrier proteins to convert them into protein antigens. With such conjugates an antibody response can also be elicited in children a few months of age.[37] An immunogenic memory and a booster effect upon revaccination are obtained as well as a reduction of carriage. The main problem with the pneumococcal conjugate vaccines is that it is possible to include only a limited number of types, at present a maximum of seven to 11 of the known 90 serotypes. The coverage is therefore restricted and there is a risk that widespread use of conjugate vaccine may lead to a change in


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serotype prevalence by exerting a selective pressure.[48] A change of type specificity may also take place in prevalent clones by recombination.[29,31]

Risk Factors Age and gender are important risk factors for pneumococcal pneumonia. The incidence of pneumococcal disease is up to 50 times higher in children < 2 years of age and in adults > 65 years of age, than in adolescents.[49] A male:female ratio of ~1.5-2:1 is seen in most,[6,11,49,50] but not all,[19,51,52] studies of pneumococcal disease. This predominance of males may be due to the fact that underlying conditions such as smoking and alcoholism have been more common among males. An increased risk of pneumococcal disease is also associated with defects in the nonspecific or specific defense mechanisms against colonization, aspiration, or invasion of S. pneumoniae. Examples of such defects are decreased cough reflex, poor ciliary function, and immune deficiencies such as a- or hypogammaglobulinemia, complement defects, leukopenia, or asplenia. Accordingly, these defects are mirrored by the predisposing conditions found in observational clinical studies of pneumococcal disease ( Table 1 ).[6,49,52-55] That many of these risk factors are of importance has been confirmed in two case-control studies. Lipsky et al[56] demonstrated that dementia, seizure disorders, current cigarette smoking, congestive heart failure, cerebrovascular disease, institutionalization, and chronic obstructive pulmonary disease (COPD) were statistically independent risk factors for pneumococcal pneumonia in male patients admitted to hospital. A higher risk was seen by increasing age and in patients who had been previously hospitalized for any reason. Nuorti et al[57] showed that smoking, both active and passive, was the single most important risk factor for invasive pneumococcal disease in immunocompetent adults 18 to 64 years of age. Other factors that were significantly associated with pneumococcal disease were male sex, black race, low level of education, chronic illnesses, and living with children under the age of 6 years who were in day care. Asplenia, functional or anatomical, is associated with the highest risk, with an overall incidence of invasive pneumococcal disease of ~500 per 100,000 per year.[58] In asplenia, the risk for pneumococcal infection is higher in patients with sickle-cell disease, thalassemia major, or malignant disease, than in those where splenectomy was necessary because of trauma.[1,5,58,59] Similarly, alcoholism has been associated with a high risk for pneumonia and for development of severe pneumococcal disease.[6,49,52,60-62] The alcoholic patient has an increased risk for aspiration, and in addition ethanol may lead to a decreased neutrophil mobilization and lowered bactericidal efficacy. [61]

S. pneumoniae is the most commonly identified bacterial pathogen causing pneumonia in patients with human immunodeficiency virus (HIV) infection, and this patient group has 10 to 100 times higher risk for pneumococcal pneumonia and bacteremia than non-HIV infected persons.[63-65] However, the case-fatality rate of invasive pneumococcal disease in HIV infected persons, compared with non-HIV infected, does not seem to be higher, which may in part be due to the fact that the former are most often young, do not have other underlying diseases, and receive prompt attention by medical care.[63,64,66] Other respiratory tract infections, especially influenza[21,67] but also Mycoplasma pneumoniae and Chlamydophila pneumoniae, may predispose for a pneumococcal pneumonia.

Prevention of Pneumococcal Disease Influenza Vaccination In the elderly influenza vaccination is an important measure to reduce the risk for all-cause pneumonia, which may be decreased by ~50%.[68,69] Pneumococcal pneumonia incidence is likewise reduced. In a study from Stockholm, influenza vaccination was found to have a 58% protective efficacy against invasive pneumococcal disease in the elderly, but the number of included patients was too small to obtain a statistical significance (OR 0.42, 95% CI 0.151.21, p < .1).[70] Pneumococcal Vaccination There are currently two pneumococcal vaccines available. A 23-valent (containing 23 serotypes) capsular polysaccharide vaccine, representing ~90% of all serotypes that cause invasive pneumococcal disease, has been available for more than 15 years. More recently a heptavalent protein-polysaccharide conjugate vaccine, specially designed for pediatric use, has been licensed in many countries.


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Vaccination of Adults. In adults, immunogenicity studies have not yet shown that the conjugate vaccine is consistently superior to the polysaccharide vaccine.[71] No efficacy studies have been published with the conjugate vaccine in adults. The protective efficacy of the polysaccharide vaccine in adults has been evaluated in seven meta-analyses or systematic reviews.[72-78] These studies have clearly shown that in young healthy adults the vaccine prevents against bacteremic pneumococcal pneumonia (70-80% effective), but also against presumptive pneumococcal pneumonia and against death in pneumonia overall. However, it must be noted that this finding is mostly based on studies performed in South African gold miners during the 1970s.[79,80] In the elderly, two randomized, controlled studies have indicated a protective efficacy of 60 to 80% against invasive pneumococcal disease.[81,82] Although these findings were not statistically significant due to the low number of patients with invasive disease, they did corroborate the results of several case-control or cohort studies.[35,83,84] The two most recent meta-analyses,[73,76] which included both randomized and nonrandomized studies, confirmed that the pneumococcal polysaccharide vaccine is ~50 to 60% effective in prevention of invasive pneumococcal disease in the elderly. There is no evidence from randomized studies of high quality or from systematic reviews that the polysaccharide vaccine prevents against all pneumonia, and the results from cohort studies have varied. In one study of elderly persons with COPD pneumococcal vaccination was associated with a 43% reduction of hospitalization for pneumonia,[85] whereas another study in a general elderly population indicated that vaccinated persons had a slightly higher risk (14%, 95% CI 2-28%) for hospitalization for pneumonia.[84] Finally, a 3-year prospective cohort study of all elderly (n = 260,000) in Stockholm indicated that pneumococcal vaccination was associated with a 10 to 20% lower risk for hospitalization for pneumonia.[70,86] Although there is little available data, the polysaccharide vaccine seems to have poor efficacy in most immunocompromised patients, with the exception of patients with splenectomy.[35] In HIV infected patients, conflicting but mostly negative results have been obtained.[87,88] Vaccination of Children. A recent meta-analysis has demonstrated that pneumococcal conjugate vaccines prevent against vaccine-type invasive pneumococcal disease (> 90% efficacious) and also against x-ray verified pneumonia in children < 2 years of age.[89] The meta-analysis on prevention against pneumonia was based on three studies, one with the heptavalent conjugate vaccine and two with a nine-valent conjugate vaccine that is not yet licensed. [22,48,90] The pooled vaccine efficacy of the three studies was 22% (95% CI 11-31%) for radiologically proven pneumonia. Population-based data recently demonstrated a substantial decline in invasive pneumococcal disease in the United States after the introduction of general immunization of small children with a seven-valent conjugate vaccine.[91] Interestingly a certain decline was also notable in unvaccinated adults, probably reflecting a decreased circulation of vaccine-type pneumococci in the community.

Symptoms and Signs The classic description of the clinical features of pneumococcal pneumonia is sudden onset of chills and pleuritic chest pain followed by fever and then cough productive of rusty sputum.[4] However, the clinical presentation varies greatly. Respiratory tract symptoms may be absent, especially among patients with bacteremic disease.[52] Lack of fever is not uncommon and indicates a poor prognosis.[92,93] Gastrointestinal symptoms such as nausea, vomiting, or diarrhea are present in 15 to 20% of patients with pneumococcal pneumonia[12] and may sometimes dominate the clinical presentation. The elderly can present a diagnostic challenge because they more frequently present with nonspecific or absent symptoms and signs.[94] Many elderly patients have no fever[8] but instead present with confusion, and pneumonia will only be suspected when focal physical abnormalities and an elevated respiratory rate [95] are identified. These nonspecific clinical features were well known to Sir William Osler, who observed that "In old age pneumonia may be latent, coming out without a chill; the cough and expectoration are slight, the physical signs ill-defined and changeable."[96] There are a few differences in the presentation of bacteremic and nonbacteremic pneumococcal pneumonia. Patients with bacteremic pneumococcal pneumonia more frequently have chills and gastrointestinal symptoms but less often myalgia and respiratory symptoms, including sputum production, compared with patients with nonbacteremic pneumococcal pneumonia.[52,97] Elevated blood urea nitrogen and serum creatinine levels are also more common among bacteremic patients.[97]


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Bacteremic Pneumococcal Pneumonia It has been estimated that 20 to 25% of cases of pneumococcal pneumonia are associated with bacteremia.[4,98] Before the antibiotic era the mortality rate for patients with pneumococcal bacteremia was nearly 80%.[99] After introduction of antibiotic therapy the mortality has been dramatically reduced. However, even with effective antibiotic treatment the mortality for patients with pneumococcal bacteremia has remained high, around 20 to 30%,[53,100] although studies conducted during the last 3 decades have shown somewhat lower mortality.[51,92,93] The casefatality rate in bacteremic pneumococcal disease has also been shown to differ up to fourfold (5-20%) between different countries, which may in part be explained by differences of disease severity and underlying conditions in the studied populations.[51,101] Nonbacteremic Pneumococcal Pneumonia A major problem in describing the clinical features of pneumococcal pneumonia is to establish the etiology as S. pneumoniae in cases of pneumonia.[12] Pharyngeal carriage of S. pneumoniae is common among preschool children [43] and among patients with COPD.[102] In healthy adults carriage rates of 3 to 18% have been reported.[43,103,104] Therefore, if accepted criteria are strictly followed, isolation of S. pneumoniae from sputum can only be considered a probable cause of a pneumonia, whereas a definite etiology is established by the recovery of the pathogen from an uncontaminated specimen.[105] On the other hand, there is also a problem of underdiagnosis because only around 10 to 20% of cases of CAP are found to be caused by S. pneumoniae in studies where the diagnosis is based solely on blood and sputum culture.[8,106] The percentage of cases of CAP due to S. pneumoniae thus depends upon the diagnostic techniques used, the assiduousness with which specimens are collected, and the rapidity with which they are transported to the microbiology laboratory.[97]

Predicting the Etiology of Cap from Clinical Features Pneumococcal etiology has been shown to be more likely in the presence of some clinical features, such as cardiovascular comorbidity, an acute onset, and pleuritic chest pain, and less likely if patients have had a cough or flulike symptoms or had received an antibiotic before admission.[107] However, in the management of a patient the presenting clinical features cannot reliably predict the etiology of CAP.[8,108] General Laboratory Findings On admission to hospital a marked polymorphonuclear leukocytosis is usually present,[109] but a substantial portion of patients may have normal white blood cell (WBC) counts.[52,110] Leukopenia is found in 5 to 10% of patients and indicates a poor prognosis.[93] Also a normal leukocyte count seems to be associated with higher mortality compared with leukocytosis.[55] C-reactive protein (CRP) levels are usually markedly elevated, commonly around 150 to 300 mg/L, and are significantly higher than those of patients with pneumonia caused by atypical agents.[111] An elevated bilirubin level is seen frequently in the course of pneumococcal infection and is probably due to multiple factors such as hypoxia, hemolysis, and hepatic inflammation.[93,109] Radiographic Findings In most cases, and in almost all cases of pneumococcal bacteremia, pulmonary infiltrates are alveolar in nature, most often involving one or more segments within a single lobe.[52,110] Lobar consolidation or an air bronchogram is present only in a minority of cases but is more frequent in patients with bacteremia.[55,110] Pleural effusion is a common finding, whereas a complicating empyema is seen rarely.[55,93,110,112] Although pleural effusions and multilobe involvement are more common, especially in bacteremic disease, the radiographic pattern is not unique and cannot reliably be used in the differential diagnosis between pneumococcal pneumonia and CAP caused by other pathogens.[113]

Microbiological Diagnosis A definite pneumococcal etiology can be established by the recovery of the organism from uncontaminated specimens (blood or pleural fluid) or by specimens obtained with invasive methods (transtracheal, bronchoscopic, or transthoracic aspirates with quantitative cultures). Blood culture is the most important tool, although the sensitivity is low, around 15%. Culture of pleural fluid may lead to a definite diagnosis in a few additional cases. Invasive


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methods should be considered in severely ill patients and in patients who do not respond to empirical antimicrobial chemotherapy. Percutaneous lung needle aspiration is almost 100% specific and very sensitive[9,114] and transtracheal aspiration generally gives accurate results.[115] These techniques, however, are of limited value, considering the risk for complications, such as bleeding and pneumothorax.[116] Among invasive methods, fiberoptic bronchoscopy, using a protected brush or bronchoalveolar lavage, is probably the most feasible way to reach a microbiological diagnosis. The method is safe, highly specific, and has a good sensitivity in previously untreated patients.[117] The usefulness of microscopic examination of Gram-stained sputum specimens and sputum culture for diagnosis of pneumonia is controversial.[118,119] However, experienced clinicians consider properly performed and interpreted Gram stains and cultures of appropriately obtained sputum specimens as useful.[120,121] A recent study by Musher et al[122] showed that microscopic examination of sputum samples obtained before antibiotics were administered, and performance of culture within 24 hours, yielded the correct diagnosis in > 80% of patients with pneumococcal pneumonia. For patients who have been on antibiotics before admission the value of sputum cultures is dubious. [118,122] In these cases, immunological methods, such as coagglutination, latex agglutination, counterimmunoelectrophoresis, or enzyme immunoassays, for the detection of soluble pneumococcal antigen in sputum may be of value.[5,123,124] Capsular polysaccharide antigens can also be detected in urine. A new commercially available urine antigen test for S. pneumoniae (Binax NOW Streptococcus pneumoniae Antigen Test, Binax, Inc., Scarborough, ME) has shown significantly greater sensitivity rates (50-80%) than routine blood or sputum cultures, and a specificity around 90% in studies of CAP in adults.[125,126] In children, however, the test lacks specificity and is not likely to be useful for distinguishing cases of pneumococcal pneumonia from those who are merely colonized with S. pneumoniae.[127] Lastly, growth of S. pneumoniae in nasopharyngeal cultures is suggestive of pneumococcal etiology in adult patients with pneumonia.[128] Although the test has low sensitivity (~30%), it is easy to obtain and provides a presumptive diagnosis when all other tests are negative.

Complications In the preantibiotic era suppurative complications of pneumococcal infections occurred frequently.[4,99] In a study of 1586 cases of pneumococcal pneumonia[99] 12% had a suppurative complication. Empyema was most common at 7% followed by pulmonary abscess (2.7%), endocarditis (1%), and meningitis (1.2%). With effective antibiotic treatment suppurative complications have become rare. In a recent study of 158 patients with pneumococcal pneumonia the suppurative complication rate was 3.8%; 1.9% of the patients had empyema, 0.6% had endocarditis, and none had meningitis.[97] Other, even more rare, manifestations of pneumococcal infection include pericarditis, peritonitis, septic arthritis, brain abscess, pancreatic and liver abscesses, aortitis, tubo-ovarian abscesses and necrotizing fasciitis.[97,109,129]

Treatment Penicillin has been used as the standard drug for treating pneumococcal infections for more than half a century. The treatment of choice in uncomplicated pneumococcal pneumonia has been oral penicillin V (3-4 g/d in three to four divided doses) or penicillin G (1-3 g every 6-8 hours IV) for more severe disease. However, the rapid emergence of antibiotic resistance to pneumococci during the last 2 decades has made the treatment of pneumococcal pneumonia more complicated. Penicillin remains the drug of choice for fully sensitive strains with minimum inhibitory concentration (MIC) < 0.1 µg/L. Also strains with moderately decreased susceptibility (MIC 0.1-1.0 µg/L) can be effectively treated with penicillin G, provided that the dose and dosing intervals are adequate.[105,130] Resistance to penicillin may be clinically important for strains with MIC ≥ 2 µg/L, and especially for strains with high-level resistance (i.e., MIC > 2 µg/L).[105] However, it should be noted that, so far, no bacteriological failure has been documented in patients treated with penicillin G for pneumococcal pneumonia. The majority of strains with reduced susceptibility to penicillin are more susceptible to certain third-generation cephalosporins, such as cefotaxime or ceftriaxone, but there is always some cross-resistance within the β-lactam group, and resistance to these drugs is increasing.[105,131,132] For oral treatment of pneumococcal pneumonia amoxicillin has pharmacokinetic advantages such as better absorption, longer half-life, and lower protein binding as compared with penicillin V.[105,109,132] In addition, in strains with decreased susceptibility the MICs of amoxicillin are also usually somewhat lower than that of penicillinV. Oral cephalosporins, on the other hand, are less active than penicillins. Among β-lactam-resistant strains, resistance to other antibiotic classes, such as tetracyclines, cotrimoxazole,


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chloramphenicol, macrolides, and clindamycin is more prevalent than among fully susceptible strains.[109] Levofloxacin, moxifloxacin, and other fluoroquinolones with enhanced activity against S. pneumoniae are active against most pneumococci, including penicillin-resistant strains,[105] but extensive use of quinolones is associated with emergence of resistance,[133,134] and clinical and bacteriological failures due to resistance to levofloxacin have been reported.[135] The choice of alternatives to penicillin/amoxicillin for treatment of patients who are allergic to penicillin or who are infected with pneumococci with high-level resistance depends on the type of allergy and on the results of the in vitro susceptibility tests. In critically ill patients, cefotaxime or ceftriaxone is most often the primary alternative if there is no indication of a type 1 allergy to penicillin.[105] Other alternative drugs include the carbapenems, newer quinolones, clindamycin, telithromycin, linezolid, and vancomycin. Based on some recent studies, treatment guidelines today often recommend the use of β-lactam/macrolide combinations as empirical therapy for patients with severe pneumonia.[105,106,136,137] Data from retrospective studies[138,139] and one observational prospective study[140] of patients with severe pneumococcal bacteremia have suggested that combination therapy may be associated with reduced mortality, as compared with β-lactam monotherapy, irrespective of the level of resistance to penicillins. However, these findings have yet to be confirmed by randomized, double-blind, prospective studies.

Table 1. Common Predisposing Factors for Pneumococcal Disease

z z z z z z z

Age, < 2 years or > 65 years Male sex Institutionalization Living with children under the age of 6 years who are in day care Cigarette smoking Alcoholism Chronic heart and lung disease z z

z z

Liver cirrhosis Neurological disease z z z z

z

Congestive heart failure Chronic obstructive pulmonary disease

Cerebrovascular disease Dementia Seizure disorders Decreased cough reflex

Immune deficiencies z z z z z

Hypo-, or a-gammaglobulinemia or secondary immunoglobulin deficiency Complement defects, especially C3 Leukopenia Functional or anatomical asplenia Human immunodeficiency virus (HIV) infection

References 1. Austrian R. Some observations on the pneumococcus and on the current status of pneumococcal disease and its prevention. Rev Infect Dis 1981;3(suppl 3):S1-17


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2. Austrian R. The pneumococcus at the millennium: not down, not out. J Infect Dis 1999;179(suppl 2):S338S341 3. Monto AS. Acute respiratory infection in children of developing countries: challenge of the 1990s. Rev Infect Dis 1989;11:498-505 4. Heffron R. Pneumonia: with special reference to pneumococcus lobar pneumonia. A Commonwealth Fund book. Cambridge, MA: The Commonwealth Fund; 1939, reprinted by Harvard University Press 1979 5. Kalin M, Lindberg AA. Diagnosis of pneumococcal pneumonia: a comparison between microscopic examination of expectorate, antigen detection and cultural procedures. Scand J Infect Dis 1983;15:247-255 6. Burman LA, Norrby R, Trollfors B. Invasive pneumococcal infections: incidence, predisposing factors, and prognosis. Rev Infect Dis 1985;7:133-142 7. Örtqvist A, Hedlund J, Grillner L, et al. Aetiology, outcome and prognostic factors in community-acquired pneumonia requiring hospitalization. Eur Respir J 1990;3:1105-1113 8. Fang GD, Fine M, Orloff J, et al. New and emerging etiologies for community-acquired pneumonia with implications for therapy: a prospective multicenter study of 359 cases. Medicine (Baltimore) 1990;69:307316 9. Ruiz-Gonzalez A, Falguera M, Nogues A, Rubio-Caballero M. Is Streptococcus pneumoniae the leading cause of pneumonia of unknown etiology? A microbiologic study of lung aspirates in consecutive patients with community-acquired pneumonia. Am J Med 1999;106:385-390 10. Jokinen C, Heiskanen L, Juvonen H, et al. Incidence of community-acquired pneumonia in the population of four municipalities in eastern Finland. Am J Epidemiol 1993;137:977-988 11. Scott JA, Hall AJ, Dagan R, et al. Serogroup-specific epidemiology of Streptococcus pneumoniae: associations with age, sex, and geography in 7000 episodes of invasive disease. Clin Infect Dis 1996;22:973-981 12. Marrie TJ. Pneumococcal pneumonia: epidemiology and clinical features. Semin Respir Infect 1999;14:227236 13. Gessner BD, Ussery XT, Parkinson AJ, Breiman RF. Risk factors for invasive disease caused by Streptococcus pneumoniae among Alaska native children younger than two years of age. Pediatr Infect Dis J 1995;14:123-128 14. Takala AK, Jero J, Kela E, Ronnberg PR, Koskenniemi E, Eskola J. Risk factors for primary invasive pneumococcal disease among children in Finland. JAMA 1995;273:859-864 15. Davidson M, Schraer CD, Parkinson AJ, et al. Invasive pneumococcal disease in an Alaska native population, 1980 through 1986. JAMA 1989;261:715-718 16. Breiman RF, Spika JS, Navarro VJ, Darden PM, Darby CP. Pneumococcal bacteremia in Charleston County, South Carolina: a decade later. Arch Intern Med 1990;150:1401-1405 17. Magnus T, Andersen BM. Serotypes and resistance patterns of Streptococcus pneumoniae causing systemic disease in northern Norway. Eur J Clin Microbiol Infect Dis 1995;14:229-234 18. Hedlund J, Svenson SB, Kalin M, et al. Incidence, capsular types, and antibiotic susceptibility of invasive Streptococcus pneumoniae in Sweden. Clin Infect Dis 1995;21:948-953 19. Nielsen SV, Henrichsen J. Incidence of invasive pneumococcal disease and distribution of capsular types of pneumococci in Denmark, 1989-94. Epidemiol Infect 1996;117:411-416 20. Mufson MA, Stanek RJ. Epidemiology of invasive Streptococcus pneumoniae infections and vaccine implications among children in a West Virginia community, 1978-2003. Pediatr Infect Dis J 2004;23:779-781 21. O'Brien KL, Walters MI, Sellman J, et al. Severe pneumococcal pneumonia in previously healthy children: the role of preceding influenza infection. Clin Infect Dis 2000;30:784-789 22. Madhi SA, Klugman KP. A role for Streptococcus pneumoniae in virus-associated pneumonia. Nat Med 2004;10:811-813 23. Hodges RG, MacLeod CM. Epidemic pneumococcal pneumonia V: final consideration of the factors underlying the epidemic. Am J Hyg 1946;44:237-243 24. Musher DM, Groover JE, Reichler MR, et al. Emergence of antibody to capsular polysaccharides of Streptococcus pneumoniae during outbreaks of pneumonia: association with nasopharyngeal colonization. Clin Infect Dis 1997;24:441-446 25. Kalin M. Pneumococcal serotypes and their clinical relevance. Thorax 1998;53:159-162 26. van Dam JE, Fleer A, Snippe H. Immunogenicity and immunochemistry of Streptococcus pneumoniae capsular polysaccharides. Antonie Van Leeuwenhoek 1990;58:1-47 27. Dillard JP, Vandersea MW, Yother J. Characterization of the cassette containing genes for type 3 capsular polysaccharide biosynthesis in Streptococcus pneumoniae. J Exp Med 1995;181:973-983 28. Garcia E, Arrecubieta C, Munoz R, Mollerach M, Lopez R. A functional analysis of the Streptococcus pneumoniae genes involved in the synthesis of type 1 and type 3 capsular polysaccharides. Microb Drug Resist 1997;3:73-88 29. Coffey TJ, Enright MC, Daniels M, et al. Recombinational exchanges at the capsular polysaccharide biosynthetic locus lead to frequent serotype changes among natural isolates of Streptococcus pneumoniae. Mol Microbiol 1998;27:73-83


1/31/2006


Page 10 of 14

30. Hermans PW, Sluijter M, Dejsirilert S, et al. Molecular epidemiology of drug-resistant pneumococci: toward an international approach. Microb Drug Resist 1997;3:243-251 31. Nesin M, Ramirez M, Tomasz A. Capsular transformation of a multidrug-resistant Streptococcus pneumoniae in vivo. J Infect Dis 1998;177:707-713 32. Nielsen SV, Henrichsen J. Capsular types of Streptococcus pneumoniae isolated from blood and CSF during 1982-1987. Clin Infect Dis 1992;15:794-798 33. Verhaegen J, Glupczynski Y, Verbist L, et al. Capsular types and antibiotic susceptibility of pneumococci isolated from patients in Belgium with serious infections, 1980-1993. Clin Infect Dis 1995;20:1339-1345 34. Robbins JB, Austrian R, Lee CJ, et al. Considerations for formulating the second-generation pneumococcal capsular polysaccharide vaccine with emphasis on the cross-reactive types within groups. J Infect Dis 1983;148:1136-1159 35. Butler JC, Breiman RF, Campbell JF, Lipman HB, Broome CV, Facklam RR. Pneumococcal polysaccharide vaccine efficacy: an evaluation of current recommendations. JAMA 1993;270:1826-1831 36. Butler JC, Breiman RF, Lipman HB, Hofmann J, Facklam RR. Serotype distribution of Streptococcus pneumoniae infections among preschool children in the United States, 1978-1994: implications for development of a conjugate vaccine. J Infect Dis 1995;171:885-889 37. Peltola H, Booy R, Schmitt HJ. What can children gain from pneumococcal conjugate vaccines?. Eur J Pediatr 2004;163:509-516 38. Bruyn GA, Zegers BJ, van Furth R. Mechanisms of host defense against infection with Streptococcus pneumoniae. Clin Infect Dis 1992;14:251-262 39. Henriques Normark B, Kalin M, Örtqvist A, et al. Dynamics of penicillin-susceptible clones in invasive pneumococcal disease. J Infect Dis 2001;184:861-869 40. Gonzalez BE, Hulten KG, Kaplan SL, Mason EO Jr. Clonality of Streptococcus pneumoniae serotype 1 isolates from pediatric patients in the United States. J Clin Microbiol 2004;42:2810-2812 41. Watson DA, Musher DM, Verhoef J. Pneumococcal virulence factors and host immune responses to them. Eur J Clin Microbiol Infect Dis 1995;14:479-490 42. Musher DM, Groover JE, Rowland JM, et al. Antibody to capsular polysaccharides of Streptococcus pneumoniae: prevalence, persistence, and response to revaccination. Clin Infect Dis 1993;17:66-73 43. Hendley JO, Sande MA, Stewart PM, Gwaltney JM Jr. Spread of Streptococcus pneumoniae in families, I: Carriage rates and distribution of types. J Infect Dis 1975;132:55-61 44. Pons JL, Mandement MN, Martin E, et al. Clonal and temporal patterns of nasopharyngeal penicillinsusceptible and penicillin-resistant Streptococcus pneumoniae strains in children attending a day care center. J Clin Microbiol 1996;34:3218-3222 45. Ekdahl K, Ahlinder I, Hansson HB, et al. Duration of nasopharyngeal carriage of penicillin-resistant Streptococcus pneumoniae: experiences from the South Swedish Pneumococcal Intervention Project. Clin Infect Dis 1997;25:1113-1117 46. Klugman KP, Friedland IR. Antibiotic-resistant pneumococci in pediatric disease. Microb Drug Resist 1995;1:5-8 47. Tomasz A, Corso A, Severina EP, et al. Molecular epidemiologic characterization of penicillin-resistant Streptococcus pneumoniae invasive pediatric isolates recovered in six Latin-American countries: an overview. PAHO/Rockefeller University Workshop. Pan American Health Organization. Microb Drug Resist 1998;4:195-207 48. Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med 2003;349:1341-1348 49. Davidson M, Parkinson AJ, Bulkow LR, Fitzgerald MA, Peters HV, Parks DJ. The epidemiology of invasive pneumococcal disease in Alaska, 1986-1990: ethnic differences and opportunities for prevention. J Infect Dis 1994;170:368-376 50. Sankilampi U, Herva E, Haikala R, Liimatainen O, Renkonen OV, Leinonen M. Epidemiology of invasive Streptococcus pneumoniae infections in adults in Finland. Epidemiol Infect 1997;118:7-15 51. Kalin M, Örtqvist A, Almela M, et al. Prospective study of prognostic factors in community-acquired bacteremic pneumococcal disease in 5 countries. J Infect Dis 2000;182:840-847 52. Örtqvist A, Grepe A, Julander I, Kalin M. Bacteremic pneumococcal pneumonia in Sweden: clinical course and outcome and comparison with non-bacteremic pneumococcal and mycoplasmal pneumonias. Scand J Infect Dis 1988;20:163-171 53. Austrian R, Gold J. Pneumococcal bacteremia with especial reference to bacteremic pneumococcal pneumonia. Ann Intern Med 1964;60:759-776 54. Gransden WR, Eykyn SJ, Phillips I. Pneumococcal bacteraemia: 325 episodes diagnosed at St Thomas's Hospital. Br Med J (Clin Res Ed) 1985;290:505-508 55. Watanakunakorn C, Bailey TA. Adult bacteremic pneumococcal pneumonia in a community teaching hospital, 1992-1996: a detailed analysis of 108 cases. Arch Intern Med 1997;157:1965-1971 56. Lipsky BA, Boyko EJ, Inui TS, Koepsell TD. Risk-factors for acquiring pneumococcal infections. Arch Intern Med 1986;146:2179-2185


1/31/2006


Page 11 of 14

57. Nuorti JP, Butler JC, Farley MM, et al. Cigarette smoking and invasive pneumococcal disease. N Engl J Med 2000;342:681-689 58. Bisharat N, Omari H, Lavi I, Raz R. Risk of infection and death among post-splenectomy patients. J Infect 2001;43:182-186 59. Foss Abrahamsen A, Hoiby EA, Hannisdal E, et al. Systemic pneumococcal disease after staging splenectomy for Hodgkin's disease 1969-1980 without pneumococcal vaccine protection: a follow-up study 1994. Eur J Haematol 1997;58:73-77 60. Brayton RG, Stokes PE, Schwartz MS, Louria DB. Effect of alcohol and various diseases on leukocyte mobilization, phagocytosis and intracellular bacterial killing. N Engl J Med 1970;282:123-128 61. Jareo PW, Preheim LC, Gentry MJ. Ethanol ingestion impairs neutrophil bactericidal mechanisms against Streptococcus pneumoniae. Alcohol Clin Exp Res 1996;20:1646-1652 62. Perlino CA, Rimland D. Alcoholism, leukopenia, and pneumococcal sepsis. Am Rev Respir Dis 1985;132:757-760 63. Janoff EN, O'Brien J, Thompson P, et al. Streptococcus pneumoniae colonization, bacteremia, and immune response among persons with human immunodeficiency virus infection. J Infect Dis 1993;167:49-56 64. Hirschtick RE, Glassroth J, Jordan MC, et al. Bacterial pneumonia in persons infected with the human immunodeficiency virus. Pulmonary Complications of HIV Infection Study Group. N Engl J Med 1995;333:845-851 65. Feldman C, Glatthaar M, Morar R, et al. Bacteremic pneumococcal pneumonia in HIV-seropositive and HIVseronegative adults. Chest 1999;116:107-114 66. Gilks CF, Ojoo SA, Ojoo JC, et al. Invasive pneumococcal disease in a cohort of predominantly HIV-1 infected female sex-workers in Nairobi, Kenya. Lancet 1996;347:718-723 67. Peltola VT, McCullers JA. Respiratory viruses predisposing to bacterial infections: role of neuraminidase. Pediatr Infect Dis J 2004;23(Suppl 1):S87-S97 68. Gross PA, Hermogenes AW, Sacks HS, Lau J, Levandowski RA. The efficacy of influenza vaccine in elderly persons: a meta-analysis and review of the literature. Ann Intern Med 1995;123:518-527 69. Nichol KL, Margolis KL, Wuorenma J, Von Sternberg T. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med 1994;331:778-784 70. Christenson B, Hedlund J, Lundbergh P, Örtqvist A. Additive preventive effect of influenza and pneumococcal vaccines in elderly persons. Eur Respir J 2004;23:363-368 71. Abraham-Van Parijs B. Review of pneumococcal conjugate vaccine in adults: implications on clinical development. Vaccine 2004;22:1362-1371 72. Cornu C, Yzebe D, Leophonte P, Gaillat J, Boissel JP, Cucherat M. Efficacy of pneumococcal polysaccharide vaccine in immunocompetent adults: a meta-analysis of randomized trials. Vaccine 2001;19:4780-4790 73. Dear K, Holden J, Andrews R, Tatham D. Vaccines for preventing pneumococcal infection in adults. Cochrane Database Syst Rev 2003;(4):CD000422 74. Fine MJ, Smith MA, Carson CA, et al. Efficacy of pneumococcal vaccination in adults: a meta-analysis of randomized controlled trials. Arch Intern Med 1994;154:2666-2677 75. Hutchison BG, Oxman AD, Shannon HS, Lloyd S, Altmayer CA, Thomas K. Clinical effectiveness of pneumococcal vaccine: meta-analysis. Can Fam Physician 1999;45:2381-2393 76. Melegaro A, Edmunds WJ. The 23-valent pneumococcal polysaccharide vaccine, I: Efficacy of PPV in the elderly: a comparison of meta-analyses. Eur J Epidemiol 2004;19:353-363 77. Moore RA, Wiffen PJ, Lipsky BA. Are the pneumococcal polysaccharide vaccines effective? Meta-analysis of the prospective trials. BMC Fam Pract 2000;1:1 78. Watson L, Wilson BJ, Waugh N. Pneumococcal polysaccharide vaccine: a systematic review of clinical effectiveness in adults. Vaccine 2002;20:2166-2173 79. Austrian R, Douglas RM, Schiffman G, et al. Prevention of pneumococcal pneumonia by vaccination. Trans Assoc Am Physicians 1976;89:184-194 80. Smit P, Oberholzer D, Hayden-Smith S, Koornhof HJ, Hilleman MR. Protective efficacy of pneumococcal polysaccharide vaccines. JAMA 1977;238:2613-2616 81. Honkanen PO, Keistinen T, Miettinen L, et al. Incremental effectiveness of pneumococcal vaccine on simultaneously administered influenza vaccine in preventing pneumonia and pneumococcal pneumonia among persons aged 65 years or older. Vaccine 1999;17:2493-2500 82. Örtqvist A, Hedlund J, Burman LA, et al. Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Swedish Pneumococcal Vaccination Study Group. Lancet 1998;351:399-403 83. Shapiro ED, Berg AT, Austrian R, et al. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Engl J Med 1991;325:1453-1460 84. Jackson LA, Neuzil KM, Yu OC, et al. Effectiveness of pneumococcal polysaccharide vaccine in older adults. N Engl J Med 2003;348:1747-1755 85. Nichol KL, Baken L, Wuorenma J, Nelson A. The health and economic benefits associated with


1/31/2006


86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115.

Page 12 of 14

pneumococcal vaccination of elderly persons with chronic lung disease. Arch Intern Med 1999;159:24372442 Hedlund J, Christenson B, Lundbergh P, Örtqvist A. Effects of a large-scale intervention with influenza and 23-valent pneumococcal vaccines in elderly people: a 1-year follow-up. Vaccine 2003;21:3906-3911 Breiman RF, Keller DW, Phelan MA, et al. Evaluation of effectiveness of the 23-valent pneumococcal capsular polysaccharide vaccine for HIV-infected patients. Arch Intern Med 2000;160:2633-2638 French N, Nakiyingi J, Carpenter LM, et al. 23-valent pneumococcal polysaccharide vaccine in HIV-1infected Ugandan adults: double-blind, randomised and placebo controlled trial. Lancet 2000;355:2106-2111 Lucero M, Dulalia V, Parreno R, et al. Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and pneumonia with consolidation on x-ray in children under two years of age. Cochrane Database Syst Rev 2004;(4):CD004977 Black SB, Shinefield HR, Ling S, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr Infect Dis J 2002;21:810-815 Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med 2003;348:1737-1746 Marfin AA, Sporrer J, Moore PS, Siefkin AD. Risk factors for adverse outcome in persons with pneumococcal pneumonia. Chest 1995;107:457-462 Torres JM, Cardenas O, Vasquez A, Schlossberg D. Streptococcus pneumoniae bacteremia in a community hospital. Chest 1998;113:387-390 Marrie TJ. Pneumonia in the elderly. Curr Opin Pulm Med 1996;2:192-197 Metlay JP, Schulz R, Li YH, et al. Influence of age on symptoms at presentation in patients with communityacquired pneumonia. Arch Intern Med 1997;157:1453-1459 Berk SL. Bacterial pneumonia in the elderly: the observations of Sir William Osler in retrospect. J Am Geriatr Soc 1984;32:683-685 Brandenburg JA, Marrie TJ, Coley CM, et al. Clinical presentation, processes and outcomes of care for patients with pneumococcal pneumonia. J Gen Intern Med 2000;15:638-646 Mufson MA. Pneumococcal infections. JAMA 1981;246:1942-1948 Tilghman RC, Finland M. Clinical significance of bacteremia in pneumococcic pneumonia. Arch Intern Med 1937;59:602-619 Mufson MA, Kruss DM, Wasil RE, Metzger WI. Capsular types and outcome of bacteremic pneumococcal disease in the antibiotic era. Arch Intern Med 1974;134:505-510 Örtqvist A, Kalin M, Julander I, Mufson MA. Deaths in bacteremic pneumococcal pneumonia: a comparison of two populations—Huntington, WVa, and Stockholm, Sweden. Chest 1993;103:710-716 Murphy TF, Sethi S. Bacterial infection in chronic obstructive pulmonary disease. Am Rev Respir Dis 1992;146:1067-1083 Kalin M. Bacteremic pneumococcal pneumonia: value of culture of nasopharyngeal specimens and examination of washed sputum specimens. Eur J Clin Microbiol 1982;1:394-396 Krantz I, Alestig K, Trollfors B, Zackrisson G. The carrier state in pertussis. Scand J Infect Dis 1986;18:121123 Bartlett JG, Dowell SF, Mandell LA, File TM Jr, Musher DM, Fine MJ. Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America. Clin Infect Dis 2000;31:347-382 BTS Guidelines for the Management of Community Acquired Pneumonia in Adults. Thorax 2001;56(Suppl 4):IV1-64 Bohte R, Hermans J, van den Broek PJ. Early recognition of Streptococcus pneumoniae in patients with community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 1996;15:201-205 Farr BM, Kaiser DL, Harrison BD, Connolly CK. Prediction of microbial aetiology at admission to hospital for pneumonia from the presenting clinical features. British Thoracic Society Pneumonia Research Subcommittee. Thorax 1989;44:1031-1035 Musher DM. Infections caused by Streptococcus pneumoniae: clinical spectrum, pathogenesis, immunity, and treatment. Clin Infect Dis 1992;14:801-807 Ort S, Ryan JL, Barden G, D'Esopo N. Pneumococcal pneumonia in hospitalized patients: clinical and radiological presentations. JAMA 1983;249:214-218 Örtqvist A, Hedlund J, Wretlind B, Carlstrom A, Kalin M. Diagnostic and prognostic value of interleukin-6 and C-reactive protein in community-acquired pneumonia. Scand J Infect Dis 1995;27:457-462 Light RW, Girard WM, Jenkinson SG, George RB. Parapneumonic effusions. Am J Med 1980;69:507-512 Macfarlane JT, Miller AC, Roderick Smith WH, Morris AH, Rose DH. Comparative radiographic features of community acquired Legionnaires' disease, pneumococcal pneumonia, mycoplasma pneumonia, and psittacosis. Thorax 1984;39:28-33 Shann F. Etiology of severe pneumonia in children in developing countries. Pediatr Infect Dis 1986;5:247252 Steinum O, Alestig K, Brorson JE. Culture from epipharynx of little value in bacterial pneumonia. Scand J


1/31/2006


Page 13 of 14

Infect Dis 1987;19:309-312 116. Davidson M, Tempest B, Palmer DL. Bacteriologic diagnosis of acute pneumonia: comparison of sputum, transtracheal aspirates, and lung aspirates. JAMA 1976;235:158-163 117. Örtqvist A, Kalin M, Lejdeborn L, Lundberg B. Diagnostic fiberoptic bronchoscopy and protected brush culture in patients with community-acquired pneumonia. Chest 1990;97:576-582 118. Garcia-Vazquez E, Marcos MA, Mensa J, et al. Assessment of the usefulness of sputum culture for diagnosis of community-acquired pneumonia using the PORT predictive scoring system. Arch Intern Med 2004;164:1807-1811 119. Madison JM, Irwin RS. Expectorated sputum for community-acquired pneumonia: a sacred cow. Arch Intern Med 2004;164:1725-1727 120. Musher DM. Gram stain and culture of sputum to diagnose bacterial pneumonia. J Infect Dis 1985;152:1096 121. Marrie TJ. Community-acquired pneumonia. Clin Infect Dis 1994;18:501-513 122. Musher DM, Montoya R, Wanahita A. Diagnostic value of microscopic examination of Gram-stained sputum and sputum cultures in patients with bacteremic pneumococcal pneumonia. Clin Infect Dis 2004;39:165-169 123. Farrington M, Rubenstein D. Antigen detection in pneumococcal pneumonia. J Infect 1991;23:109-116 124. Venkatesan P, Macfarlane JT. Role of pneumococcal antigen in the diagnosis of pneumococcal pneumonia. Thorax 1992;47:329-331 125. Murdoch DR, Laing RT, Mills GD, et al. Evaluation of a rapid immunochromatographic test for detection of Streptococcus pneumoniae antigen in urine samples from adults with community-acquired pneumonia. J Clin Microbiol 2001;39:3495-3498 126. Ishida T, Hashimoto T, Arita M, Tojo Y, Tachibana H, Jinnai M. A 3-year prospective study of a urinary antigen-detection test for Streptococcus pneumoniae in community-acquired pneumonia: utility and clinical impact on the reported etiology. J Infect Chemother 2004;10:359-363 127. Dowell SF, Garman RL, Liu G, Levine OS, Yang YH. Evaluation of Binax NOW, an assay for the detection of pneumococcal antigen in urine samples, performed among pediatric patients. Clin Infect Dis 2001;32:824825 128. Hedlund J, Örtqvist A, Kalin M. Nasopharyngeal culture in the pneumonia diagnosis. Infection 1990;18:283285 129. Taylor SN, Sanders CV. Unusual manifestations of invasive pneumococcal infection. Am J Med 1999;107 (suppl 1A):12S-27S 130. Pallares R, Gudiol F, Linares J, et al. Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci. N Engl J Med 1987;317:18-22 131. Kaplan SL, Mason EO Jr. Management of infections due to antibiotic-resistant Streptococcus pneumoniae. Clin Microbiol Rev 1998;11:628-644 132. Garau J. Clinical perspectives on the management of community-acquired pneumonia. Diagn Microbiol Infect Dis 1996;25:205-211 133. Chen DK, McGeer A, de Azavedo JC, Low DE. Decreased susceptibility of Streptococcus pneumoniae to fluoroquinolones in Canada. Canadian Bacterial Surveillance Network. N Engl J Med 1999;341:233-239 134. Ho PL, Que TL, Tsang DN, Ng TK, Chow KH, Seto WH. Emergence of fluoroquinolone resistance among multiply resistant strains of Streptococcus pneumoniae in Hong Kong. Antimicrob Agents Chemother 1999;43:1310-1313 135. Davidson R, Cavalcanti R, Brunton JL, et al. Resistance to levofloxacin and failure of treatment of pneumococcal pneumonia. N Engl J Med 2002;346:747-750 136. Mandell LA, Marrie TJ, Grossman RF, Chow AW, Hyland RH. Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. The Canadian Community-Acquired Pneumonia Working Group. Clin Infect Dis 2000;31:383-421 137. Niederman MS, Mandell LA, Anzueto A, et al. Guidelines for the management of adults with communityacquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001;163:1730-1754 138. Waterer GW, Somes GW, Wunderink RG. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Arch Intern Med 2001;161:1837-1842 139. Martinez JA, Horcajada JP, Almela M, et al. Addition of a macrolide to a beta-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia. Clin Infect Dis 2003;36:389-395 140. Baddour LM, Yu VL, Klugman KP, et al. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med 2004;170:440-444 Reprint Address Åke Örtqvist, M.D., Department of Communicable Diseases Control and Prevention, Stockholm County, Norrbacka, Karolinska University Hospital, Solna, SE-171 76 Stockholm, Sweden. E-mail: [email protected]


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Åke Örtqvist, M.D., Ph.D., F.C.C.P., Jonas Hedlund, M.D., Ph.D., and Mats Kalin, M.D., Ph.D., Unit of Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden


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