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The clinical manifestations of pneumococcal disease depend on the site of infection and the duration of illness. Clinical syndromes are classified as noninvasive (e.g., otitis media) or invasive (e.g., bacteremic pneumonia, meningitis) according to whether a normally sterile site is infected. The pathogenesis of noninvasive illness involves contiguous spread from the nasopharynx or skin; invasive disease involves infection of a normally sterile body fluid or follows bacteremia. Regardless of the mechanism, all pneumococcal infections result from nasopharyngeal acquisition of the organism.
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Pneumonia is the most common serious pneumococcal syndrome and is considered invasive when associated with a positive blood culture. Whether to categorize nonbacteremic pneumococcal pneumonia as invasive or noninvasive remains debatable.
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Pneumococcal pneumonia can present as a mild community-acquired infection at one extreme and as a life-threatening disease requiring intubation and intensive support at the other.
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Presenting Manifestations
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The presentation of pneumococcal pneumonia does not reliably distinguish it from pneumonia of other etiologies. In a subset of cases, pneumococcal pneumonia is recognized at the outset as associated with a viral upper respiratory infection and is characterized by the abrupt onset of cough and dyspnea accompanied by fever, shaking chills, and myalgias. The cough evolves from nonpurulent to productive of sputum that is purulent and sometimes tinged with blood. Patients may describe stabbing pleuritic chest pain and significant dyspnea indicating involvement of the parietal pleura. Among the elderly, the presenting clinical symptoms may be less specific, with confusion or malaise but without fever or cough. In such cases, a high index of suspicion is required because failure to treat pneumococcal pneumonia promptly in an elderly patient is likely to result in rapid evolution of the infection, with increased severity, morbidity, and risk of death.
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Findings on PHYSICAL Examination
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The clinical signs associated with pneumococcal pneumonia among adults include tachypnea (defined as >30 breaths/min) and tachycardia, hypotension in severe cases, and fever in most cases (although not in all elderly patients). Respiratory signs are varied, including dullness to percussion in areas of the chest with significant consolidation, crackles on auscultation, reduced expansion of the chest in some cases as a result of splinting to reduce pain, bronchial breathing in a minority of cases, pleural rub in occasional cases, and cyanosis in cases with significant hypoxemia. Among infants with severe pneumonia, chest wall indrawing and nasal flaring are common. Nonrespiratory findings can include upper abdominal pain if the diaphragmatic pleura is involved as well as mental status changes, particularly confusion in elderly patients.
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Differential Diagnosis
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The differential diagnosis of pneumococcal pneumonia includes cardiac conditions such as myocardial infarction and heart failure with atypical pulmonary edema; pulmonary conditions such as atelectasis; and pneumonia caused by viral pathogens, mycoplasmas, Haemophilus influenzae, Klebsiella pneumoniae, Staphylococcus aureus, Legionella, or (in HIV-infected and otherwise immunocompromised hosts) Pneumocystis. In cases with abdominal symptoms, the differential diagnosis includes cholecystitis, appendicitis, perforated peptic ulcer disease, and subphrenic abscesses. The challenge in cases with abdominal symptoms is to remember to include pneumococcal pneumonia—a nonabdominal process—in the differential diagnosis.
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Some authorities advocate treating uncomplicated, nonsevere, community-acquired pneumonia without determining the microbiologic etiology, given that this information is unlikely to alter clinical management. However, efforts to identify the cause of pneumonia are important when the disease is more severe and when the diagnosis of pneumonia is not clearly established. The gold standard for etiologic diagnosis of pneumococcal pneumonia is pathologic examination of lung tissue. In lieu of that procedure, evidence of an infiltrate on chest radiography warrants a diagnosis of pneumonia. However, cases of pneumonia without radiographic evidence do occur. An infiltrate can be absent either early in the course of the illness or with dehydration; upon rehydration, an infiltrate usually appears. The radiographic appearance of pneumococcal pneumonia is varied; it classically consists of lobar or segmental consolidation (Fig. 141-6) but in some cases is patchy. More than one lobe is involved in ~30% of cases. Consolidation may be associated with a small pleural effusion or empyema in complicated cases. In children, “round pneumonia,” a distinctly spherical consolidation on chest radiography, is associated with a pneumococcal etiology. Round pneumonia is uncommon in adults. S. pneumoniae is not the only cause of such lesions; other causes, especially cancer, should be considered.
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Blood drawn from patients with suspected pneumococcal pneumonia can be used for supportive or definitive diagnostic tests. Blood cultures are positive for pneumococci in a minority (<30%) of cases of pneumococcal pneumonia, as evidenced especially by vaccine clinical trials, which provide an independent method to reveal the contribution of the pneumococcus to pneumonia cases. Nonspecific findings include an elevated polymorphonuclear leukocyte count (>15,000/μL in most cases and upward of 40,000/μL in some), leukopenia in <10% of cases (a poor prognostic sign associated with a fatal outcome), and elevated values in liver function tests (e.g., both conjugated and unconjugated hyperbilirubinemia). Anemia, low serum albumin levels, hyponatremia, and elevated serum creatinine levels are all found in ~20–30% of patients.
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Urinary pneumococcal antigen assays have facilitated etiologic diagnosis, but the application of the results is confounded by the fact that nasopharyngeal colonization with the pneumococcus, in the absence of disease, also results in a positive test. In adults, therefore, a positive pneumococcal urinary antigen test has a high predictive value for etiologic attribution of pneumonia because the prevalence of pneumococcal nasopharyngeal colonization is relatively low. In communities, particularly those in low-income countries, where colonization rates among adults are high, urine antigen assays may be less useful. The same issue holds for children, in whom a positive urinary antigen test is usually uninformative for etiologic attribution of their pneumonia illness because colonization rates are generally high. A recent advance is the development of quantitative serotype-specific urinary antigen detection assays; their application for adults and children holds promise, especially in detecting serotypes that are rarely identified in asymptomatic carriage (e.g., serotype 1), even among children.
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Most cases of pneumococcal pneumonia in adults are diagnosed by Gram’s staining and culture of sputum. The utility of a sputum specimen is directly related to its quality and the patient’s antibiotic treatment status.
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Empyema is the most common focal complication of pneumococcal pneumonia, occurring in <5% of cases. When fluid in the pleural space is accompanied by fever and leukocytosis (even low-grade) after 4–5 days of appropriate antibiotic treatment for pneumococcal pneumonia, empyema should be considered. Parapneumonic effusions are more common than empyema, representing a self-limited inflammatory response to pneumonia. Pleural fluid with frank pus, bacteria (detected by microscopic examination), or a pH of ≤7.1 indicates empyema and demands aggressive and complete drainage, usually through chest tube insertion.
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Pneumococcal meningitis usually presents as a pyogenic condition that is clinically indistinguishable from meningitis of other bacterial etiologies. Meningitis can be the primary presenting pneumococcal syndrome or a complication of other conditions such as skull fracture, otitis media, bacteremia, or mastoiditis. Now that H. influenzae type b vaccine is routinely used in children, S. pneumoniae and Neisseria meningitidis are the most common bacterial causes of meningitis in both adults and children. Pyogenic meningitis, including that due to S. pneumoniae, is associated clinically with findings that include severe, generalized, gradual-onset headache, fever, and nausea as well as specific CNS manifestations such as stiff neck, photophobia, seizures, and confusion. Clinical signs include a toxic appearance, altered consciousness, bradycardia, and hypertension indicative of increased intracranial pressure. A small proportion of adult patients have Kernig’s or Brudzinski’s sign or cranial nerve palsies (particularly of the third and sixth cranial nerves).
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A definitive diagnosis of pneumococcal meningitis rests on the examination of CSF for (1) evidence of turbidity (visual inspection); (2) elevated protein level, elevated white blood cell count, and reduced glucose concentration (quantitative measurement); and (3) specific identification of the etiologic agent (culture, Gram’s staining, antigen testing, or polymerase chain reaction [PCR]). A blood culture positive for S. pneumoniae in conjunction with clinical manifestations of meningitis also is considered confirmatory. As discussed in the section on pneumonia, among adults, detection of pneumococcal antigen in urine is considered highly specific because of the low prevalence of nasopharyngeal colonization in this age group.
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The mortality rate for pneumococcal meningitis is ~20%. In addition, up to 50% of survivors experience acute or chronic complications, including deafness, hydrocephalus, and mental retardation in children and diffuse brain swelling, subarachnoid bleeding, hydrocephalus, cerebrovascular complications, and hearing loss in adults.
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Other Invasive Syndromes
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S. pneumoniae can cause other invasive syndromes involving virtually any body site. These syndromes include primary bacteremia without other sites of infection (bacteremia without a source; occult bacteremia), osteomyelitis, septic arthritis, endocarditis, pericarditis, and peritonitis. The essential diagnostic approach is collection of fluid from the site of infection by sterile technique and examination by Gram’s staining, culture, and—when relevant—capsular antigen assay or PCR. Hemolytic-uremic syndrome can complicate invasive pneumococcal disease.
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Noninvasive Syndromes
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The two major noninvasive syndromes caused by S. pneumoniae are sinusitis and otitis media; the latter is the most common pneumococcal syndrome and most often affects young children. The manifestations of otitis media include the acute onset of severe pain, fever, deafness, and tinnitus, most frequently in the setting of a recent upper respiratory tract infection. Clinical signs include a red, swollen, often bulging tympanic membrane with reduced movement on insufflation or tympanography. Redness of the tympanic membrane is not sufficient for the diagnosis of otitis media.
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Pneumococcal sinusitis is also a complication of upper respiratory tract infections and presents with facial pain, congestion, fever, and—in many cases—persistent nighttime cough. A definitive diagnosis is made by aspiration and culture of sinus material; however, presumptive treatment is most commonly initiated after application of a strict set of clinical diagnostic criteria.
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TREATMENT Pneumococcal Infections
Historically, the activity of penicillin against pneumococci made parenteral penicillin G the drug of choice for disease caused by susceptible organisms, including community-acquired pneumonia. For susceptible strains, penicillin G remains the most commonly used agent, with daily doses ranging from 50,000 U/kg for minor infections to 300,000 U/kg for meningitis. Other parenteral β-lactam drugs, such as ampicillin, cefotaxime, ceftriaxone, and cefuroxime, can be used against penicillin-susceptible strains but offer little advantage over penicillin. Macrolides and cephalosporins are alternatives for penicillin-allergic patients. While agents such as clindamycin, tetracycline, and trimethoprim-sulfamethoxazole exhibit some activity against pneumococci, resistance to these agents is frequently encountered in different parts of the world.
Penicillin-resistant pneumococci were first described in the mid-1960s, at which point tetracycline- and macrolide-resistant strains had already been reported. Multidrug-resistant strains were first described in the 1970s, but it was during the 1990s that pneumococcal drug resistance reached pandemic proportions. The use of antibiotics selects for resistant pneumococci, and strains resistant to β-lactam agents and to multiple drugs are now found all over the world. The emergence of high rates of macrolide and fluoroquinolone resistance also has been described.
The molecular basis of penicillin resistance in S. pneumoniae is the alteration of penicillin-binding protein (PBP) genes by transformation and horizontal transfer of DNA from related streptococcal species. Such alteration of PBPs results in lower affinity for penicillins. Depending on the specific PBP(s) and the number of PBPs altered, the level of resistance ranges from intermediate to high. For many years, penicillin susceptibility breakpoints have been defined by MICs as follows: susceptible, ≤0.06 μg/mL; intermediate, 0.12–1.0 μg/mL; and resistant, ≥2.0 μg/mL. However, in vitro results often were not predictive of the response of a patient to treatment for pneumococcal diseases other than meningitis. Revised recommendations have been based on the penicillin G breakpoints established in 2008 by the Clinical and Laboratory Standards Institute. For IV treatment of meningitis with at least 24 million units per day in 8 divided doses, the susceptibility breakpoint remains ≤0.06 μg/mL, and MICs of ≥0.12 μg/mL indicate resistance. For IV treatment of nonmeningeal infections with 12 million units per day in 6 divided doses, the breakpoints are ≤2 μg/mL for susceptible organisms, 4 μg/mL for intermediate organisms, and ≥8 μg/mL for resistant organisms; a dosage of 18–24 million units per day is recommended for strains with MICs in the intermediate category. The original breakpoints remain the same for oral treatment of nonmeningeal infections with penicillin V.
Although guidelines for antibiotic therapy should be driven in part by local patterns of resistance, guidelines from national organizations in many countries (e.g., the Infectious Diseases Society of America/American Thoracic Society, the British Thoracic Society, and the European Respiratory Society) lay out evidence-based approaches. The following guidelines for the treatment of individual sepsis syndromes are based on those advocated by the American Academy of Pediatrics and published in the 2015 Red Book.
MENINGITIS LIKELY OR PROVEN TO BE DUE TO S. PNEUMONIAE As a result of the increased prevalence of resistant pneumococci, first-line therapy for persons ≥1 month of age is a combination of vancomycin (adults, 30–60 mg/kg per day; infants and children, 60 mg/kg per day) and cefotaxime (adults, 8–12 g/d in 4–6 divided doses; children, 225–300 mg/kg per day in 1 dose or 2 divided doses) or ceftriaxone (adults, 4 g/d in 1 dose or 2 divided doses; children, 100 mg/kg per day in 1 dose or 2 divided doses). If children are hypersensitive to β-lactam agents (penicillins and cephalosporins), rifampin (adults, 600 mg/d; children, 20 mg/d in 1 dose or 2 divided doses) can be substituted for cefotaxime or ceftriaxone. A repeat lumbar puncture should be considered after 48 h if the organism is not susceptible to penicillin and information on cephalosporin sensitivity is not yet available, if the patient’s clinical condition does not improve or deteriorates, or if dexamethasone has been administered and may be compromising clinical evaluation. When antibiotic sensitivity data become available, treatment should be modified accordingly. If the isolate is sensitive to penicillin, vancomycin can be discontinued and penicillin can replace the cephalosporin, or cefotaxime or ceftriaxone can be continued alone. If the isolate displays any resistance to penicillin but is susceptible to the cephalosporins, vancomycin can be discontinued and cefotaxime or ceftriaxone continued. If the isolate exhibits any resistance to penicillin and is not susceptible to cefotaxime and ceftriaxone, vancomycin and high-dose cefotaxime or ceftriaxone can be continued; rifampin may be added as well if the isolate is susceptible and the patient’s clinical condition is worsening, if the CSF remains positive for bacteria, or if the MIC of the cephalosporin in question against the infecting strain is high. Some physicians advocate the use of glucocorticoids in children >6 months old, but this recommendation remains controversial and is not universally considered the standard of care. Glucocorticoids significantly reduce rates of mortality, severe hearing loss, and neurologic sequelae in adults and should be administered to those with community-acquired bacterial meningitis. If dexamethasone is given to either adults or children, it should be administered before or in conjunction with the first antibiotic dose.
INVASIVE INFECTIONS (EXCLUDING MENINGITIS) In previously well children with noncritical illness, therapy with a recommended antibiotic should be instigated at the following dosages: penicillin G, 250,000–400,000 units/kg per day (in divided doses 4–6 h apart); cefotaxime, 75–100 mg/d (doses 8 h apart); or ceftriaxone, 50–75 mg/d (doses 12–24 h apart). For critically ill children, including those who have myocarditis or multilobular pneumonia with hypoxia or hypotension, vancomycin may be added if the isolate may possibly be resistant to β-lactam drugs, with its use reviewed once susceptibility data become available. If the organism is resistant to β-lactam agents, therapy should be modified on the basis of clinical response and susceptibility to other antibiotics. Clindamycin or vancomycin can be used as a first-line agent for children with severe β-lactam hypersensitivity, but vancomycin should not be continued if the organism is shown to be sensitive to other non-β-lactam antibiotics.
For outpatient management, amoxicillin (1 g every 8 h) provides effective treatment for virtually all cases of pneumococcal pneumonia. Neither cephalosporins nor quinolones, which are far more expensive, offer advantages over amoxicillin. Levofloxacin (500–750 mg/d as a single dose) and moxifloxacin (400 mg/d as a single dose) also are highly likely to be effective in the United States except in patients who come from closed populations where these drugs are used widely or who have themselves been treated recently with a quinolone. Clindamycin (600–1200 mg/d every 6 h) is effective in 90% of cases and azithromycin (500 mg on day 1 followed by 250–500 mg/d) or clarithromycin (500–750 mg/d as a single dose) in 80% of cases. Treatment failure resulting in bacteremic disease due to macrolide-resistant isolates has been amply documented in patients given azithromycin empirically. As noted above, rates of resistance to all these antibiotics are relatively low in some countries and much higher in others; high-dose amoxicillin remains the best option worldwide.
The optimal duration of treatment for pneumococcal pneumonia is uncertain, but its continuation for at least 5 days once the patient becomes afebrile appears to be a prudent approach. Cases with a second focus of infection (e.g., empyema or septic arthritis) require longer therapy.
ACUTE OTITIS MEDIA Amoxicillin (80–90 mg/kg per day) is recommended for children with acute otitis media except in situations where observation and symptom-based treatment without antibiotics are advocated. These situations include nonsevere illness and an uncertain diagnosis in children 6 months to 2 years of age and nonsevere illness (even if the diagnosis seems certain) in children >2 years of age. Although the optimal duration of therapy has not been conclusively established, a 10-day course is recommended for younger children and for children with severe disease at any age. For children >6 years old who have mild or moderate disease, a course of 5–7 days is considered adequate. Patients whose illness fails to respond should be reassessed at 48–72 h. If acute otitis media is confirmed and antibiotic treatment has not been started, administration of amoxicillin should be commenced. If antibiotic therapy fails, a change is indicated. Failure to respond to second-line antibiotics as well indicates that myringotomy or tympanocentesis may need to be undertaken in order to obtain samples for culture.
The above recommendations can also be followed for the treatment of sinusitis. Detailed information on the further management of these conditions in children has been published by the American Academy of Pediatrics and the American Academy of Family Physicians.