Infections due to Streptococcus pneumoniae
The aim of this report is to analyse the impact of Streptococcus pneumoniae, with regards to financial and social cost, as well as the range of diseases that it can cause, including pneumonia, both nosocomial and community-acquired and otitis media, especially in children. Another important aim of this report is to look at possible Streptococcus pneumoniae treatments, including antibiotics and prophylactic treatments in vaccines. Streptococcus pneumoniae is a worldwide common cause of mortality and morbidity, and the most common cause of bacterial community-acquired pneumonia. In Australia, during the period of 2004 to 2012 cases of hospitalisations due to infections by Streptococcus pneumoniae had an average case fatality rate of 6.1%. Streptococcus pneumoniae typically colonises the nasopharynx of newborns within the first few weeks to months of life, resulting in approximately 80% of children under five, having at least one episode of otitis media and a large proportion having recurring infections, resulting in three or more. Vaccinations for Streptococcus pneumoniae are critical due to increasing drug resistance and are limited by the ever-increasing number of serotypes of the bacteria.
Streptococcus pneumoniae (S. pneumoniae) is a critical cause of community-acquired infections among individuals with underlying host defence irregularities, elderly and children. It is the main bacterial pathogen causing respiratory tract infections, and through invasion, mechanisms can cause other infectious syndromes, including sepsis, peritonitis and meningitis. S. pneumoniae (pneumococcus) was responsible for 495 reported cases of invasive pneumococcal disease, between April 1st and June 30th in 2017. S. pneumoniae can cause invasive disease, which is nationally notifiable in Australia, and non-invasive disease, which is not notifiable (Pennington, 2017)
Streptococci are facultatively anaerobic, gram-positive, catalase-negative bacteria which forms ovoid or spherical cells less than 2 µm in diameter. The polysaccharide capsule that covers the cell wall, characterising gram-positive bacteria, is the principal protective and antiphagocytic structure, preventing leucocyte access to the cell wall components. These capsules are useful for identifying and serotyping, with 9 serotypes of S. pneumoniae currently discovered. Serotyping is typically unhelpful in providing clinical information. Thus it is primarily used for epidemiological purposes. Thus, for the clinical purposes, streptococci are divided into species based on biochemical profile, colony size, the haemolytic pattern on blood agar and Lancefield group antigen. S. pneumoniae are non-beta-haemolytic streptococci that are bile esculin-negative, bile soluble and optochin-positive. In a liquid, it replicates in chains, and on blood agar, it forms alpha-haemolytic colonies with a depression in the centre of the colony, that form alpha-haemolysin, that breaks haemoglobin down into a green pigment (J. Weber and A. Rutala, 2003).
Significance in terms of incidence and impact on the community with respect to cost and patient wellbeing
S. pneumoniae is the most common cause of bacterial community-acquired pneumonia worldwide, and though exact numbers are difficult to determine, in 2005 an estimated 1.6 million deaths were due to clinical syndromes of S. pneumoniae, with between 700,000 and 1 million of those deaths in children less than 5 years. S. pneumoniae infections carry a high mortality rate, even in developed countries especially in patients who are positive for certain risk factors, including age, especially children younger than 2, and adults older than 55, and immunosuppression, such as in HIV (Prado and Perloff, 2017).
In Australia, significant morbidity and mortality have been attributed to S. pneumoniae, especially in the elderly and young children. In 2011-2012 pneumonia hospitalisation, attributable to S. pneumoniae, among adults older than 65 years was 274 per 100,000 population. The hospitalisations correspond to an average of 2235 deaths from the period of 2004 to 2012, an average fatality rate of 6.1%. An average of 455 pneumococcal pneumonia per 100,000 population visits to GP, from 2008 to 2013, account for the largest portion of healthcare encounters. The estimated annual cost of pneumococcal pneumonia treatment was approximately A$1,604,189 for GP visits and A$55,722,136 for hospitalisations. A significant difficulty in accurate collection of pneumococcal disease data in Australia is that only IPD is notifiable, and IPD likely only represents a small percentage of pneumococcal disease, with non-invasive, non-notifiable forms of the disease likely to occur more frequently (Earle and Williams, 2016).
The range of diseases associated with S. pneumoniae infection
Due to the ability to cause disease via haematogenous spread by vascular invasion along with direct extension into the anatomic structures surrounding the nasopharynx S. pneumoniae can manifest as many different clinical symptoms. Diseases associated with haematogenous spread via vascular invasion include meningitis, bacteraemia, joint and bone infections such as osteomyelitis and septic arthritis, soft tissue infection including myositis, periorbital cellulitis and abscesses, peritonitis and cardiac infections such as endocarditis (Prado and Perloff, 2017).
Meningitis is usually caused by pneumococcal invasion of the meninges via the bloodstream, and through multiple possible mechanism and factors acting together, allow the blood-brain barrier (BBB) to be crossed, and allow infection of the central nervous system. Pneumococcal adherence to platelet-activating factor receptors is important in allowing the organism to cross the BBB by meningeal vascular endothelial cell transcytosis. Another mechanism of invasion involves trauma that compromises the dura, such as basilar skull fracture, allow S. pneumoniae to directly invade the meninges. Pneumococcal meningitis typically presents with nonspecific symptoms, including irritability, malaise, lethargy, vomiting, fever and anorexia, along with neurological signs which are often obvious, including delirium, focal neurological deficits, positive Kernig and Brudzinski signs and other mental status changes (Prado and Perloff, 2017).
Bacteraemia is the most frequent indicator of IPD, with most cases found in children under two as to primary bacteraemia, with an estimated 90% of occult bacteraemia caused by S. pneumonia. Whereas in adults, pneumococcal bacteraemia is typically associated with the infection focus being elsewhere, such as pneumonia or meningitis. Occult bacteraemia typically presents with nonspecific symptoms, including the development of a fever (Prado and Perloff, 2017).
S. pneumoniae infection is an uncommon cause of joint and bone infections, responsible for approximately 4% of osteomyelitis cases and 20% of septic arthritis cases in children. The ankles and knees are the most common, with one or more affected joints. In children with pneumococcal osteomyelitis, the humerus and femur are the most commonly affected bones, whereas in adults it is typically the vertebral bones (Prado and Perloff, 2017).
Soft tissue infections are uncommon, though pneumococcal infection can be responsible for some moderate to severe soft tissue infections, especially in immunocompromised hosts, such as in cases of Systemic Lupus Erythematosus or HIV (Prado and Perloff, 2017).
Primary peritonitis, caused by spread of bacteria to the peritoneal cavity via lymph or blood, is rare, making up less than 20% of cases of peritonitis, though pneumococcus is the organism most commonly isolated in those cases. In adults this is usually associated with cirrhosis, and in children it is associated with immunocompromising diseases, nephrotic syndrome or other underlying conditions. In females, S. pneumoniae can cause severe inflammatory disease, and gain access to the peritoneum via the fallopian tubes from the genital tract. Gastrointestinal injury, ulcers or other malignancies increase the risk for peritonitis (Prado and Perloff, 2017).
Diseases associated with direct anatomic structural extension include conjunctivitis, otitis media (especially in children), sinusitis, acute exacerbations of chronic bronchitis (AECB) and pneumonia. Conjunctivitis due to bacterial pathogens is more likely to be purulent and bilateral than when due to viral pathogens. S. pneumoniae is isolated in approximately 33% of patients with bacterial conjunctivitis, and the rates of non-penicillin susceptible isolates is increasing (Prado and Perloff, 2017).
S. pneumoniae is the most common isolate in patients with acute sinusitis. Symptoms can be dependent on age and sinus developmental status. This acute sinusitis is usually preceded by a viral infection resulting in mucosal oedema and obstruction of the ostia, succeeded by cough and purulent nasal discharge. A postnasal drip is common, and results in a chronic productive cough, especially at night, and halitosis (Prado and Perloff, 2017).
Community acquired and nosocomial pneumonia due to S. pneumoniae
Colonisation of the nasopharynx and oropharynx in healthy individuals usually precedes S. pneumoniae infection, which occurs after inhalation of the colonies, infecting the lower respiratory tract. However, infection will not typically occur unless it is a particularly virulent strain, many infectious cells were inhaled, or the patient has predisposing risk factors. The virulence factors of S. pneumoniae include the polysaccharide capsule, which prevents complement C3b from binding to the cell’s surface interfering with phagocytosis, along with bacterial proteins, such as IgA1 protease interfering with mucosal surface host defences, and neuraminidase preventing epithelial cell attachment, as well as pili allowing bacterial adherence to cellular surfaces and inflammation in the host. Drug-resistant and penicillin-resistant strains of S. pneumoniae are becoming more common, penicillin resistance due to penicillin-binding protein alteration, affecting only the binding penicillin, but not other beta-lactams, and drug-resistance due to genetic mutations that can block binding, or ensure active efflux from the cell of the drug (Dion and Ashurst, 2017).
Patients may present with a variety of symptoms, the most common including shortness of breath, sharp chest pain, increased production of sputum and a fever. These symptoms are neither sensitive nor specific for pneumonia. Diagnosis of the causative organism of pneumonia is not aided by routine laboratory investigations. Chest radiography is the standard of pneumonia diagnosis, and lobar pneumonia has been classically taught as S. pneumoniae being the causative organism. New literature, however, suggests that radiography is not reliable in determination of the causative organism, and they are not 100% sensitive in pneumonia diagnosis. Computer tomography is more sensitive and accurate than standard radiography, but due to high cost and radiation exposure is used limitedly. Diagnosis can be obtained through blood cultures, sputum analysis and urinary antigens, though routine blood culture collection has been recommended against by the American College of Emergency Physicians. Sputum cultures have low sensitivity and specificity in detection of the causative organism, though should be obtained in cases where drug-resistant organisms are suspected. Urinary antigens exist to detect S. pneumoniae with a sensitivity of 80 % and specificity of 97%, although this may be less useful in children, due to many already carrying the organism (Dion and Ashurst, 2017).
Effective treatment of pneumococcal pneumoniae involves supportive care, with mechanical ventilation if required, and antibiotic therapy, varying on disease severity. Low-risk community-acquired pneumonia (CAP) is typically treated with macrolides only, while respiratory fluoroquinolones are used to treat patients at higher risk. Hospital non-ICU inpatients are often treated with respiratory fluoroquinolone only, or with macrolides and a beta-lactam. ICU patients however are treated with beta-lactams plus either a respiratory fluoroquinolone or a macrolide (Dion and Ashurst, 2017).
Otitis media in children due to S. pneumoniae
Otitis media is a group of various middle ear affecting inflammatory disorders and is the responsible for the most paediatric emergency department visits worldwide. Approximately four in five of all children have had otitis media at least once, and a large percentage have a recurrent infection, leading to at least three episodes. This is due to S. pneumoniae beginning to colonise nasopharynx mucosal surfaces within weeks to months of life, so that children are commonly colonised successively by many individual serotypes. Otitis media presents as subtypes with acute or chronic elements broadly classified by symptoms, tympanic membrane visual appearance or perforation, middle ear fluid presence and presence of active inflammation. Acute otitis media (AOM) is characterised by sudden symptom onset, pain, inflammation and pus-filled fluid behind the tympanic membrane. AOM typically affects children less than two years old. Otitis media with effusion (OME) in contrast typically affects children between the ages of three and seven, and is a chronic inflammatory condition, that is not typically associated with acute inflammation, but still presents with non-purulent fluid behind the tympanic membrane, and is associated with hearing impairment, that can lead to developmental and cognitive problems over time (Bergenfelz and Hakansson, 2017).
Children with pneumococcal infections typically have a temperature greater than 38oC, though this is symptomatic for any infection of S. pneumoniae. Symptoms specific for pneumococcal otitis media include earache, vomiting and other upper respiratory symptoms. The main physical finding in otitis media is a tympanic membrane that has poor mobility and is yellow, bulging or erythematous, with a visible pus-filled fluid behind it (Varman and Chatterjee, 2017).
Diagnosis of any pneumococcal infections include a white blood cell count and differential, bacterial cultures, blood, cerebrospinal fluid, synovial fluid, pleural fluid or in the case of otitis media, a middle ear effusion. Positive cultures can then be gram stained, which is useful in determination of presence of a capsule, gram-positive and negative, and basic morphology such as coccus, diplococci or streptococci, as S. pneumoniae is a gram-positive streptococcus. Finally, antigen tests can be used in bacterial species identification, though these are usually performed on cerebrospinal fluid and urine and may thus be of limited clinical use in cases of otitis media. If the cause of the otitis media appears to be resistant to antibiotics or standard treatments, tympanocentesis, which involves use of a small gauge needle to puncture the tympanic membrane, may be required to aspirate middle ear fluid to be cultured (Varman and Chatterjee, 2017).
Treatment of otitis media involves supportive care and antibiotic treatment, where successful therapy involves attaining antibiotic concentrations higher than pneumococcus’ minimal inhibitory concentration. The initial antibiotic treatment of otitis media is five to ten days of oral standard-dose amoxycillin. If the condition does not improve with standard dosing, then the recommended treatment regimen involves oral high-dose amoxycillin, amoxycillin and clavulanic acid, cefuroxime or intramuscular ceftriaxone. Amoxycillin is a member of the penicillin family, and thus if the patient has a penicillin allergy, replacements include macrolides, such as azithromycin, cefuroxime or cefprozil, if there is not accompanying cephalosporin allergy or clindamycin (Varman and Chatterjee, 2017).
The availability and limitations of current vaccines for the prevention of S. pneumoniae infections
In Australia, pneumococcal vaccine recommendations vary primarily according to age, with 13-valent, 10-valent and 23-valent vaccines being available. Healthy adults are recommended a single dose of the 23-valent polysaccharide vaccine, while adults with increased risk of invasive disease are recommended up to three doses of 23-valent vaccine, and a single dose of 13-valent vaccine. Children up to 18 months are recommended the 13-valent vaccine, while children aged four to five years who are at increased risk of invasive disease are recommended the 23-valent vaccine. All vaccines share 7 S. pneumoniae serotypes, 4, 6B, 9V, 14, 18C, 19F and 23F, with different vaccines containing different additional serotypes (Chiu and McIntyre, 2013). These vaccines can be separated into two groups, conjugate vaccines and polysaccharide vaccines. The antigen in polysaccharide vaccines is purified polysaccharide capsules from the bacteria, while conjugate vaccines contain conjugated nonpneumococcal protein as an additional immunogenic compound, as purified polysaccharide capsules alone provide less immunogenicity in children under 2. The main limitation of S. pneumoniae vaccines is due to their numerous, and still undiscovered serotypes. This has been partially mitigated through the use of serotypes responsible for IPD, first introduced via the 7-valent vaccine, containing serotypes 4, 6B, 9V, 14, 18C, 19F and 23F (Tang, 2015).
In conclusion, S. pneumoniae is a critical disease-causing bacterium, due to its ability to cause invasive pneumococcal diseases such as life-threatening meningitis. The rise of penicillin and drug resistance in this bacterial species is concerning, as it severely complicates treating syndromes such as otitis media, which approximately 80% of children will have at least one episode of. This, therefore, increases the importance of prophylactic treatments, such as vaccinations, and discovery of important serotypes to package in vaccines.
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