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Gram-Positive Pneumonias
Symposium on Infectious Lung Diseases
Gram-Positive Pneumonias Carmelita U. Tuazon, M.D. *
Pneumonias caused by gram-positive cocci (e.g., Streptococcus pneumoniae, Staphylococcus aureus and group A beta-hemolytic streptococci) account for most bacterial community-acquired pneumonias. With recent advances in medical technology and increasing number of immunocompromised patients S. aureus has also become a significant cause of nosocomial infections, including pneumonia. Bacillus species other than B. anthracis are being recognized as pathogens with increased frequency among drug abusers and other patients with impaired host defense mechanisms. The purpose of this article is to review the clinical features and microbiologic aspects of the different gram-positive pneumonias. Newer diagnostic techniques and a proper approach to management of these pneumonias are discussed. Recent developments in the treatment and prevention including emergence of antibiotic resistant strains and status of various vaccines are presented.
PNEUMOCOCCAL PNEUMONIA In the pre-antibiotic era 95 per cent of pneu,monias in hospitalized patients was attributed to the pneumococcus, and the mortality rate was nearly 30 per cent. Since the introduction of effective antibiotics this figure has decreased to 10 per cent; however, there has been no significant reduction in the number of pneumococcal infections. More recently, newer diagnostic techniques and the reintroduction of vaccination are attempts to control the disease.
The Organism Streptococcus pneumoniae (pneumococcus) is a gram-positive, lancet-shaped diplococcus. Since they can occur in clumps and form chains of varying lengths, the name Diplococcus has been abandoned. Pneumococci grow aerobically, but have the properties of facultative anaerobes. On blood agar plates the organisms give an alpha-hemolytic reaction, and thus need to be differentiated from the viridans streptococci. The two biochemical tests used routinely in most laboratories for identification are the bile solubility test and the optochin
"AsSOCiate Professor of Medicine, Director, Division of Infectious Diseases, George Washington University Medical Center, Washington, D. C. Supported in part by a special research grant from Wyeth Laboratories
Medical Clinics of North America-Vol. 64, No. 3, May 1980
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(ethyl hydrocupreine) disk sensitivity. Colonies appear smooth, glistening, and flat on blood agar, but one may suspect the type III serotype if colonies appear large and mucoid. Inulin was thought to be quite specific for Streptococcus pneumoniae but other viridans species such as S. mitior and S. sanguis ferment this sugar, and not all strains of S. pneumoniae ferment inulin. 82 On gram stain of clinical specimens (pus, sputum or body fluids) it may sometime be difficult to differentiate pneumococci from other gram-positive cocci. A helpful procedure is to demonstrate the capsule of the pneumococcus by using type-specific anti-serum that allows the capsule to swell. This is known as the quellung reaction. The major anti genic component of the pneumococcus is the capsular polysaccharide. The virulence of the organism is related to the amount of this capsular material. Serotyping the pneumococcus is based on the capsular polysaccharide, and over 80 serotypes capable of causing human infections have been identified. The vaccine available is directed toward the more common serotypes.
Epidemiology and Pathogenesis The true incidence of pneumococcal pneumonia is difficult to ascertain, and has been estimated at a rate of 1 to 2 cases per 1000 per year. 4.40 The age distribution for pneumococcal pneumonia is similar to that of many other infectious diseases. The incidence is greatest in infants and young children under 5 years and in the elderly. This is in part related to the lower capacity of the very young and the old to mount an effective immune response. Other susceptible groups include those with underlying diseases such as chronic heart or lung disorders, diabetes mellitus, or chronic alcoholism with cirrhosis.1 5 Likewise, splenectomized patients or those with impaired immunoglobulin production (multiple myeloma) or defective opsonic factors (sickle c.ell disease) are predisposed to pneumococcal infections. 55 The pneumococcus is carried in the upper respiratory tract of 5 to 70 per cent of normal people depending on the population studied. 33,49 Of the factors which predispose to spread of pneumococcus, crowding has been shown to enhance transmission. 17.67 Recent studies have further documented that spread of the pneumococcus occurs in association with upper respiratory tract infections, and simultaneous transmission of the pneumococcus and the rhinovirus has been demonstrated. 46 Pneumococcal pneumonia shows a seasonal distribution similar to other respiratory tract infections. It often appears during the coldest months of the year, presumably because of increased crowding of people into closed environments. It also, of course, occurs sporadically since pneumococcal pneumonia is essentially a disease of carriers. The normal human host is highly resistant to the induction of pneumonia by the pneumococcus and only develops it when host defense mechanisms are impaired. The infecting organism is usually one that resides in the upper airway and subsequently gains entry to the alveoli. Any impairment of the cough reflex or mucociliary action predisposes to invasion. Following entry of micro-organisms into the lower respiratory tract and alveolar spaces there is an outpouring of edema fluid and accumulation of polymorphonuclear leukocytes. Infection spreads peripherally and organisms multiply in the edema fluid. The infection
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may next extend to the pleura by direct invasion, to the lymphatics with involvement of the hilar lymph nodes or from the lymphatics to the blood. Hematogenous spread with metastatic lesions in various organs (meninges, pericardium, heart valves, joint or bone) may then occur.
Clinical Features A preceding upper respiratory tract infection is usual before the classic attack of pneumococcal pneumonia. The incubation period is usually 1 to 3 days. About 80 per cent of patients would present with a single shaking chill. Temperature may be as high as 106°F. Nausea and vomiting may also be seen, and generalized systemic symptoms of malaise, myalgias, and weakness are common. Cough, productive of purulent sputum which has been characterized as greenish, bloody, or rusty, is frequent. Pleuritic chest pain is also common. In the elderly or debilitated patient, illness may present more insidiously and major manifestations are mental obtundation, congestive heart failure, or marked prostration. In this group fever may not be present or only slight elevation of temperature may be noted. On physical examination, the patient usually appears toxic, dyspneic and febrile. Chest findings usually reveal consolidation with decreased breath sounds, dullness, and egophony. A pleural friction rub is frequently heard. In patients with lower lobe pneumonia, abdominal pain, distention, and paralytic ileus may be seen. With prompt institution of antimicrobial therapy, uncomplicated pneumococcal pneumonia usually responds within the first 24 hours. One often notes an abrupt decrease in temperature, improved breathing, and decreased chest pain. Supportive therapy is equally important as antimicrobial therapy. Good hydration and adequate pulmonary toilet should be ensured. If, after several days of adequate antimicrobial and supportive therapy, the patient continues to have high fever and appears ill, one should look carefully for complications such as empyema, pericarditis, endobronchial obstruction, abscess formation, superinfection, or metastatic seeding, resulting in meningitis, endocarditis, or arthritis. Bacteremia occurs in approximately 25 to 30 per cent of patients, depending on the serotypes. Mortality is high in patients with bacteremia and more so in patients with splenic dysfunction and disseminated intravascular coagulation. 11.12 Other poor prognostic factors are leukopenia, infection with serotype Ill, multilobar involvement, old age, and chronic alcoholism. 6
Laboratory and Roentgenographic Manifestations The laboratory findings of pneumococcal pneumonia are nonspecific. Leukocytosis of over 20,000 per cu mm is typical with predominantly neutrophils and early band forms. Leukopenia may develop in extremely ill patients. Liver function abnormalities such as bilirubinemia are often seen in bacteremic patients. 82 Hypoxemia is usually mild but may occasionally be profound. Chest x-ray shows homogenous consolidation of lung parenchyma. Seldom is complete lobar consolidation seen.41 Disease is usually confined to one lobe, but sometimes develops simultaneously in two or more lobes, and the prognosis is less favorable in these patients. 6 Cavitation is rare except with infection caused by serotype III organisms. We recently cared for a 61 year old alcoholic man
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with chronic lung disease with type III pneumococcal pneumonia. Initial chest x-ray showed right upper lobe consolidation (Fig. 1, above), and after a few days cavitation and abscess formation were noted (Fig. 1, below). Rarely, massive pulmonary gangrene, similar to that which occurs in Friedlander's pneumonia, may be seen with pneumococcal pneumonia. 31 Resolution of the infiltrate may take as long as seven weeks. 30,101 A recent study54 examined the radiographic characteristics of resolving pneumococcal pneumonia and found 34 to 37 per cent of patients had persistent consolidation at 1 month which eventually resolved by 8 to 10 weeks. 54 Residual pleural disease persisted for over 4 months before clearing completely. Repeat radiographic examination is therefore appropriate only after an interval of at least 6 weeks. In the management of organizing pneumonic infiltrates it is important to consider carcinoma as a cause of delayed resolution. 59 Pleurisy is quite common in pneumococcal pneumonia21 but pleural effusions were previously considered to be unusual. 82 In a recent study, however, parapneumonic effusions were detected in 57 per cent of cases of pneumococcal pneumonia. 91 Effusions were correlated significantly with the duration of symptoms before admission, bacteremia and prolonged fever after therapy.
Diagnosis Initial antimicrobial therapy for patients with pneumococcal pneumonia is usually based on a presumptive diagnosis from clinical and laboratory data, One should obtain smears and cultures of blood, sputum, urine, and other (pleural, cerebrospinal) fluids, depending on the clinical presentation, The importance of absence or presence of pneumococci in expectorated sputum has been controversial. 8,92 We find that a gram stain of the sputum is very useful in making a presumptive diagnosis since results are available within minutes. Cultures, however, may not be helpful because of stringent growth requirements of the organism especially if the sputum is not cultured immediately. Recent work suggests that the sputum gram stain is a valuable tool in the initial evaluation of patient with community-acquired pneumonia.29.34.80 Moreover one should not overlook the usefulness of the quellung reaction for sputum smears which show gram-positive cocci of uncertain identity. In certain groups of patients (myeloma, sickle cell disease, functional asplenia and splenectomized) with overwhelming bacteremia organisms may be seen on peripheral blood smears. 44.79 Definitive diagnosis requires isolation of S. pneumoniae from pleural fluid, blood, lung, or transtracheal aspirates since up to 50 per cent of normal persons carry S. pneumoniae in their upper airways, and thus may give false-positive sputum culture results. More recently, a rapid and simple diagnostic method has been utilized in the detection of antigen in the sputum. The counter immunoelectrophoresis technique detects pneumococcal antigen in patients with pneumococcal pneumonia in as many as 75 per cent of cases. 63.68 In addition, antigen has been detected in serum or urine in patients with pneumococcal pneumonia and is usually associated with bacteremia, infections with low numbered serotypes or more severe and protracted illnesses. 25 Any body fluid can be checked for presence of antigen with the use of counter immunoelectrophoresis.
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Figure 1. Pneumococcal pneuRlonia. The initial chest film (abave) shows TIght upper lobe consolidation. Mter a few days, cavitation and abscess formation were noted (below).
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Treatment and Prevention Penicillin G remains the drug of choice for patients with pneumococcal infections. The antibiotic dosage varies depending on the severity of the infection. Uncomplicated pneumonia responds to low dose penicillin, 600,000 to 1.2 million units per day, in divided doses. We prefer to treat hospitalized patients with intravenous penicillin 400,000 to 600,000 units given every 4 hours for the first 24 to 48 hours or until signs of clinical toxicity abate. A recent study has shown that there was no difference in clinical response between those patients treated with low versus high dose penicillin, the latter defined as over 5 million units. 16 If complications are present (emypema or abscesses) 6 to 12 million units in divided doses should be given. If evidence of metastatic seeding is present, such as meningitis, endocarditis, or arthritis, as much as 24 million units per day may be necessary. For patients allergic to penicillin with uncomplicated pneumococcal pneumonia, cephalothin or erythromycin may be given, and for meningitis, chloramphenicol is the alternative drug. Tetracycline is not a good alternative drug for pneumonia because of the high incidence of resistant strains. 45 Clindamycin also is not advised because of its relatively high minimum bactericidal concentration. Although it is rare in the United States, penicillin-resistant pneumococci have been reported recently in clinically significant pulmonary and nonpulmonary infections.20.75.76 Initial reports of resistant pneumocci came from South Africa where an extensive epidemiologic study was carried out. The multiple resistant strains were usually sensitive to rifampin, fusidic acid, novobiocin, vancomycin, and bacitracin. 53 The clinical significance of these resistant strains is not readily apparent with infections like pneumonia because of the high levels of antibiotics achievable with regular dosages. In severe infections (e. g., meningitis) one should be aware of the potential for resistance because of the relatively low levels of penicillin achieved in the cerebrospinal fluid. There has been a revival of interest in use of pneumococcal polysaccharide vaccine. Although mortality from pneumococcal infections has decreased, the incidence of pneumococcal disease has not changed. When studies were. done on bacteremic infections as well as community acquired pneumococcal pneumonias, it became apparent that certain serotypes predominate.3.5.6.19.72 Based on these studies, a polyvalent pneumococcal polysaccharide vaccine has been developed. It has been proven to be immunogenic in normal adults, and in one study was 82 per cent effective in preventing type-specific bacteremic pneumonia in young adult men. 5 There are 14 different capsular polysaccharides in the currently available vaccine. Usually, 0.5 ml is administered intramuscularly or subcutaneously. Booster injections are usually given every 3 years. Susceptible patients, as mentioned earlier, should receive the vaccine, but in addition it should be considered in outbreaks caused by multiple antibioticresistant strains of pneumococci. The vaccine is contraindicated in patients less than 2 years old, pregnant women, and those with febrile illnesses. One should be aware that certain groups of patients have impaired antibody responses to pneumococcal polysaccharide vaccines, including those treated for Hodgkin's disease,70.86 bone marrow transplant patients, lOO and patients with sickle cell disease. 1
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STREPTOCOCCAL PNEUMONIA In the adult, streptococcal pneumonia occurs primarily in epidemic outbreaks in military populations. 9 ,102 In the preantibiotic era, 5 per cent of cases of acute pneumonia were caused by group A beta-hemolytic streptococci and, like S. aureus pneumonia, was associated with a high mortality. 57 Streptococcal pneumonia is rarely seen nowadays, although cases do appear after respiratory infection l8 and may complicate measles and childhood exanthema. 58
The Organism Group A streptococci (Strep. pyogenes) are gram-positive cocci which may be found in pairs but more commonly occur as chains in clinical specimens. They are catalase negative, aerobic but also are facultative anaerobes. On blood agar plates, they appear as white to gray colonies 1 to 2 mm in diameter surrounded by zones of complete hemolysis or beta hemolysis. Bacitracin disc sensitivity is used for routine identification, but is by no means specific, since other streptococci may be bacitracin sensitive. 36 Final identification is made with use of specific antisera. Group A streptococci are important human pathogens since they account for the majority of cases of severe pharyngitis and also because of the classic nonsuppurative complications related to such infections, rheumatic fever, and acute glomerulonephritis. Like S. aureus, pathogenicity is also related to enzyme and toxin productions. M antigen, one of several antigenic substances contained in the cell wall of this organism, is the antigen of major virulence.
Epidemiology and Pathogenesis The incidence of streptococcal pneumonia appears to increase from age 5 to 6 to young adulthood. Like pneumococcal and staphylococcal pneumonia, it occurs most frequently during the winter. The organism enters the lungs by inhalation and/or aspiration and under the influence of gravity passes to the most dependent portions. Thus, disease is almost invariably localized to the lower lobes. It is unusual for pneumonia to occur as a result of seeding to the lung from a bacteremic focus. Two forms of streptococcal pneumonia have been described in autopsy series. 18 The most common form is interstitial bronchopneumonia. Pathologic changes include thickening of the bronchiolar walls, necrosis of the mucosal lining, purulent engorgement of the lymphatics, and microabscesses with rupture through the pleura. This pattern was the one described in the cases reported by Kevy and Lowe. 58 The second type is much less common and is a lobar pneumonia with consolidation and large areas of necrosis similar to those of pneumococcal pneumonia.
Clinical Features High fever (usually greater than 39°C), cough, and pleuritic chest pain are the most common presenting symptoms of streptococcal pneumonia. 9 ,18,57 The patient usually appears quite ill and physical findings are compatible with bronchopneumonia. In one series, the clinical picture was thought to resemble Reyes' syndrome because of fever, chills, confusion, lethargy, meningeal signs, and
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abdominal signs and symptoms. 71 As many as 30 to 65 per cent of patients have an associated streptococcal pharyngitis. 9.71 Empyema has been described in 66 to 86 per cent of adult cases57.102 and in 100 per cent of pediatric cases. Rapid accumulation of fluid can occur within hours,71.108 similar to staphylococcal pneumonia. The effusion initially is serous, then serosanguinous, and rapidly becomes fibrinopurulent. The consistency of fluid can present drainage problems and may require pleural stripping or frequent chest tube replacement. 71 Amount of drainage averages 100 to 150 ml per day. In some series, profuse drainage up to 3,000 ml per day can occur, and if the course is prolonged, hypoproteinemia may develop. In addition to empyema, other major pulmonary complications include atelectasis, pneumothorax, bronchopleural fistula, pneumatoceles, and persistent atelectasis. These complications have been reported in 1 to 10 per cent of cases. 57.102 Extrapulmonary complications include anemia which probably results from serosanguineous drainage and intravascular hemolysis. Thrombocytopenia, either separately or as part of purpura fulminans, may be seen as a complication of streptococcal bacteremia.21.27.58 Biopsy proven acute glomerulonephritis has been reported as well. 65 Acute rheumatic fever however has never been reported as a complication of streptococcal pneumonia. Purulent pericarditis occurs in less than 10 per cent of cases9.18.58.93 and inappropriate secretion of antidiuretic hormone has also been noted. 71 Resolution is slow, especially if the disease is complicated with empyema. Chest pain can linger for 8 to 10 days.
Laboratory and Roentgen Manifestations The white blood count is usually less than 20,000 per cu mm except in those patients with empyema in whom counts of greater than 20,000 per cu mm are usually seen. 9.57 Anemia is a common finding. 9.71 The chest roentgenogram frequently shows an interstitial pattern usually involving both lower lobes. Pleural effusion is a frequent finding and empyema has been described in over 50 per cent of cases. Diagnosis The diagnosis is confirmed when group A beta-hemolytic streptococcus is cultured either from the sputum, pleural fluid, or blood. Gram-stain of sputum and pleural fluid specimens might give one a clue as to the presence of the streptococcal organism, but is by no means a definitive way of making a diagnosis. Positive blood cultures are found in 2 to 12 per cent of cases. 9 . 57 In very severe cases the yield is higher, 55 per cent in one series58 and as high as 100 per cent in another.71 These patients often have purpura fulminans and the majority die. An elevated antistreptolysin titer in a convalescent patient is good supportive evidence. Treatment and Prevention Penicillin is the antibiotic of choice for streptococcal infections. For patients who are allergic to penicillin, cephalothin or erythromycin are good alternative drugs. Dosage varies according to severity of the disease. For uncomplicated streptococcal pneumonia, dosages similar to those for pneumococcal pneumonia
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may be given, but higher doses are used in those with effusions or empyema. In the setting in which a bacteriologic diagnosis is not promptly available, one should initially consider using a penicillinase-resistant penicillin because differentiation between streptococcal and staphylococcal pneumonia on the basis of clinical features or gram stain smears may be difficult. Surgical management includes early and vigorous chest drainage to prevent late pulmonary complications .. Much work has been done on the development of streptococcal vaccines, and it appears that the prospect of immunization against streptococcal infections is optimistic. 89 Prophylaxis at the present time consist oflow-dose penicillin orally or intramuscular benzathine penicillin for patients with rheumatic fever. In epidemic outbreaks of streptococcal pneumonia, prophylactic antibiotics should be considered.
STAPHYLOCOCCAL PNEUMONIA Staphylococcal pneumonia is an unusual infection which seldom occurs as a primary disease. In adults, for instance, it classically follows a preceding influenza infection. Although staphylococcal pneumonia comprises only 3 to 10 per cent of all pneumonias,47 it is nevertheless an important infection to consider because mortality is high. In the preantibiotic era, 80 to 90 per cent of patients died. 22 With the initial introduction of antibiotics such as sulfonarnides, mortality dropped to 30 per cent. 38 However, no further decrease in mortality was seen with the advent of the penicillinase-resistant penicillins. 66 ,85 This most likely reflects the typically poor response of patients whose host defense mechanisms are impaired. 47,61,73
Microbiology Staphylococcus aureus is a gram-positive coccus belonging to the family Micrococciae, On gram stain, organisms are usually in clusters, but can occur singly or in pairs, On blood agar plates, colonies.appear golden yellow, hence the name "aureus." Tests that differentiate S. aureus from the less pathogenic species S. epidermidis and S. saprophyticus are the coagulase and mannitol fermentation tests. More than 95 per cent of pathogenic staphylococci produce coagulase. In addition, S. aureus has ribitol teichoic acid in its cell wall while S. epidermidis contains glycerol teichoic acid. Antibody to teichoic acid has been utilized recently in the diagnosis of serious staphylococcal infections. 74,99,100 In epidemic situations phage typing is very useful for epidemiologic investigations.
Epidemiology S. aureus is a normal component of the human microflora. Approximately 20 to 40 per cent of normal adults carry the organism in their nares. 88 Certain groups, however, have markedly increased carriage rates, probably reflecting underlying diseases, immune status, health practices, or regular needle use. Examples include drug abusers, diabetics, and patients in chronic renal failure receiving hemodialysis. 6o ,97,98 The incidence of staphylococcal infections in general has increased, presumably because the organism has taken full advantage of the ecologic changes brought about by antibiotics, modem technologic pro-
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cedures, and chemotherapeutic agents, and prolonged survival of patients with impaired host defenses. 73 •88
Pathogenesis Two types of staphylococcal pneumonia are recognized, depending on the mode of acquisition. Primary pneumonia arises from the upper respiratory tract usually in the setti~g of a post-viral infection. Secondary or bacteremic staphylococcal pneumonia results from blood-borne dissemination to the lung. When staphylococci are present in the upper respiratory tract they may be aspirated into the lung, causing primary pneumonia. Viral infections such as influenza appear to predispose adult patients to staphylococcal pneumonia by destroying the ciliated surface epithelium, thus leaving the bronchial surface vulnerable to secondary bacterial infection.22.69.77 Patients who develop aspiration pneumonia while hospitalized also appear to be at risk of acquiring S. aureus pneumonia. 73.88 Among the pediatric age group, infants under the age of 6 months account for the majority of cases. This may be related to a higher frequency of colonization of the respiratory tract of newborns particularly during nursery epidemics. 87 Cystic fibrosis patients are also predisposed to S. aureus pneumonia. 88 The bacteremic form of staphylococcal pneumonia occurs after hematogenous dissemination. Patients most susceptible are those with chronic illnesses, those receiving immunosuppressive therapy and drug abusers with tricuspid valve endocarditis. 73.94 The clinicopathologic findings in influenzal-staphylococcal pneumonia can probably be attributed to the potent activity of staphylococcal exotoxins. An extracellular necrotizing toxin aids in breaking through bronchial and arterial walls, hyaluronidase aids rapid bacterial spreading, coagulase enzymes favor the formation of thromboses, and leukocidin destroys resisting leukocytes. 83 The primary lesion of influenzal-staphylococcal pneumonia is a suppurative and ulcerative bronchiolitis with necrosis of bronchiolar wall. 69 As bronchiolar wall becomes necrotic, extension into adjacent tissues occurs easily with seeding-into the alveolar capillaries. Bronchial artery thrombosis can occur which may lead to septic infarction and abscess formation. If peribronchial abscesses communicate with the airway, entry of air into the abscess pocket occurs and the characteristic pneumatocele is formed. 69 In cases of bacteremic staphylococcal pneumonias from endocarditis septic emboli cause pulmonary infarcts with subsequent pneumonitil; and abscess formation.
Clinical Features The manifestations of staphylococcal pneumonia vary according to age group and pathogenesis of the infection. Primary staphylococcal pneumonia is most often seen in infants, patients with underlying disease (e.g., cystic fibrosis, chronic lung disease) or in immunosuppressed patients. The clinical presentation is highly variable. Frequently, patients appear more ill than physical findings suggest. In previously healthy adults, if there is a preceding viral illness, chills, high fever, progressive dyspnea, and pleurisy may herald the onset of staphylococcal involvement as illustrated in Case 1.
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CASE 1. A 22 year old white male student presented to the Emergency Room with a 5 day history of increasing fatigue, headache, and shortness of breath. These initial complaints followed by fever, shaking chills, sweats, and a nonproductive cough. Several students in his dormitory had similar symptoms which resolved spontaneously. On the third day of illness, he felt better, only to be awakened a day later with severe leftsided pleuritic Erythromycin, 250 mg four times a day, was prescribed for presumed pneumococcal or mycoplasma pneumonia. However, persistent high fever and increasingly severe chest pain precipitated admission one day later. Examination revealed egophony, decreased breath sounds, and dullness over the left lower chest compatible with consolidation and effusion. Repeat chest x-ray showed a larger infiltrate and an effusion. Thoracentesis revealed cloudy fluid with white blood cell count of 96,000 per cu mm (95 per cent neutrohils), increased protein, and decreased glucose. Culture grew S. aureus. Treatment was begun with intravenous nafcillin, 2 gm every 4 hours, and a chest tube was inserted for drainage of empyema. His course was complicated by loculations of the empyema which required multiple tube reinsertions and finally had decortication. He received a total course of 20 days intravenous nafcillin and another week of oral dicloxacillin.
On occasion staphylococcal pneumonia may present less dramatically in subacute form as illustrated by Case 2. She was afebrile and had no pulmonary symptoms on admission. Diagnosis was made by examination of sputum obtained at bronchoscopy and the evolution of changes on chest x-ray. CASE 2. A 36 year old schoolteacher was admitted in diabetic ketoacidosis which responded rapidly to standard treatment. Previously, she had undergone a left modified radical mastectomy for comedocarcinoma. At the time, multiple nodes were positive for tumor and incidental findings included noncaseating granulomas in the nodes and liver. Cultures for fungi and mycobacteria were negative. Ophthalmologic examination revealed bilateral anterior uveitis. She received cancer chemotherapy, and was also treated for sarcoidosis with prednisone. Isoniazid prophylaxis was also given. Chest x-ray examination on admission revealed nodular density in the left lower lobe (Fig. 2A). Because sputum induction was unsuccessful, bronchoscopy was performed and revealed purulent material in the left lower bronchus which on gram stain showed numerous white blood cells and sheets of gram-positive cocci in clusters. Culture grew S. aureus. Therapy with intravenous nafcillin was begun and later changect to cephalothin when a few Klebsiella were also isolated. Follow up chest films (Fig. 2B and C) showed abscess formation which required drainage via multiple bronchoscopies.
Few cases of subacute staphylococcal pneumonia have been reported. 42 ,62 Although this infection is characterized by mild symptoms of cough, low grade fever, and sputum production, abscesses are usually present on chest roentgenograms,62 Most patients do not have severe underlying diseases. In secondary staphylococcal pneumonia arising hematogenously from a nonpulmonary focus of infection, the onset of clinical disease is often not dramatic, In the setting of drug abuse, a drug addict is typically admitted with fever, chills and weight loss, and in those with the full blown picture, blood-streaked sputum or frank hemoptysis may be present. 73,88,94 Cough is not a prominent symptom and purulent sputum is unusual, Evidence of metastatic infection elsewhere may also be present. Physical findings in patients with staphylococcal pneumonia are variable. A toxic appearance and fever may be the only detectable manifestations. Dullness to percussion is not an early sign, and signs of frank consolidation are rare on admission. Coarse or fine rales may be heard. Pleural effusions and empyema are, however, frequent. In the early reports of staphylococcal pneumonia the description or sputum as friable, purulent material of a dirty salmon-pink color
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A
B Figure 2. Staphylococcal pneumonia. On admission, the chest x-ray CA) reviewed a nodular density in the left lower lobe. Follow-up chest films CB and C) showed abscess formation which required drainage via multiple bronchoscopies.
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c Figure 2 Continued
resembling anchovy sauce or the contents of an overripe furuncle was considered a characteristic feature. 22
Laboratory and Roentgenographic Manifestations The leukocyte count is usually elevated to between 15,000 and 25,000 per cu mm. A leukocyte count greater than 15,000 in an adult with influenza should raise the question of a secondary bacterial pneumonia. Chest x-rays in primary staphylococcal pneumonia may show either a diffuse or a localized non-specific infiltrate. When radiologic examination reveals small areas of cavitation in the lung, pneumatoceles, empyema, or pyopneumothorax, S. aureus should be strongly suspected although none of these changes is pathognomonic. 24 ,50 Pneumatoceles and pyopneumothorax are more common in pediatric age groups. It is important to differentiate pneumatocele from pyopneumothorax because the latter requires surgical drainage. Lung abscess occurs in 25 per cent and empyema in 10 per cent of patients. BB Pneumatoceles are rare in adults. 39 In bacteremic staphylococcal pneumonia initial chest films may be clear or show only single leSion, but two or three days later evidence of multiple small lesions are often seen. They appear as small (0.5 to 1 cm) oval densities at the periphery of the lung and frequently increase in size and may cavitate. In narcotic addicts, septic pulmonary emboli may be the only clinical manifestation of right-Sided endocarditis.
Diagnosis Since bacteremia occurs in less than 20 per cent of cases of primary S. aureus pneumonia, its presence should strongly suggest that respiratory infection is a result of metastatic seeding.
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The most helpful procedure used to diagnose staphylococcal pneumonia is the gram stain examination of sputum, tracheal aspirate, or lung puncture. The presence of numerous polymorphonuclear leukocytes and gram-positive cocci in clusters, often intracellular, provides the best evidence of pneumonia caused by S. aureus. Sputum culture may confirm the diagnosis but may be difficult to interpret without an accompanying sputum gram stain. If a pleural effusion is present as in Case 1, prompt thoracentesis with appropriate smears and cultures is indicated since finding S. aureus in this site confirms the diagnosis. Lung punctures have been advocated by some if sputum or pleural fluid is not available. 32 This procedure should not, however, be routinely used. Bronchoscopy may also be helpful as illustrated by Case 2. Recently a serolOgiC test has been reported useful in diagnosis and therapy of serious staphylococcal infections. 74,99,100 Our experience is very limited in terms of primary staphylococcal pneumonia. Both Cases 1 and 2 did not develop serum teichoic acid antibodies. However, in bacteremic staphylococcal pneumonia, titers would be predictably positive at a significant level. 100
Treatment and Prevention Treatment for S. aureus pneumonia includes adequate antimicrobial therapy
for a prolonged period and careful observation for complications such as empyema or bronchopleural fistula which may require surgical drainage. In most survivors, late sequelae are uncommon and residual, pulmonary damage rarely occurs.107 Despite the use of appropriate antibiotics, the mortality from primary S. aureus pneumonia remains high, ranging from 20 to 30 per cent. Therapy of bacteremic staphylococcal pneumonia usually requires 4 to 6 weeks. Therapeutic guidelines for this group of patients has been reported elsewhere. 100 For primary staphylococcal pneumonia, a 2 week course of systemic antibiotics is usually adequate, but complications such as empyema or abscess may require longer treatment. A penicillinase-resistant penicillin such as nafcillin, oxacillin, or methicillin is appropriate initial therapy. We prefer nafcillin because it seldom causes hemotologic or renal toxicity or hypersensitivity reactions. 56 In patients who are allergic to penicillin, cephalosporins (e.g., cephalothin or cefazolin) may be used. If the organism recovered is methicillin resistant, vancomycin would be the drug of choice. There is no effective vaccine against S. aureus infection, One useful measure to prevent staphylococcal pneumonia is influenza vaccination because of the close association between these two respiratory diseases. Groups who should receive the vaccine include patients with chronic lung disease, cardiac disease, immunosuppressed patients, and those with cystic fibrosis and other high risk patients.
BACILLUS PNEUMONIA Anthrax Bacillus anthracis is the most pathogenic of the bacillus species. It is a gram-positive, spore-forming, and nonmotile rod. The spores which are the infective forms are quite resistant to disinfectants and low heat but can be destroyed by boiling for 10 minutes or exposure to dry heat at 140°C for 3 hours.
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B. anthracis colonies are raised, opaque, and grayish white when cultured on blood agar. The disease caused by B. anthracis, anthrax, is principally an occupational risk for those working with animal hair or its derivatives and thus the term "wool sorters disease."IQ It has been estimated that 75 per cent of all cases in the United States occur in the northeastern states chiefly as the result of industrial exposure. 43 Investigations of the epidemic of inhalation anthrax has led to a better understanding of the pathogenesis and clinical features of the disease. 14.78 There are two forms of the disease: cutaneous anthrax (malignant pustule) and inhalation anthrax which can lead to septicemia. This discussion will be confined to inhalation anthrax. After inhalation of the organisms, spores are ingested as inert particles by alveolar macrophages in the alveoli. 84 The spore bearing macrophages migrate through the alveolar membrane into the lymphatics and are carried to the hilar lymph nodes where multiplication of the bacilli occurs. 7 This process is accompanied by hemorrhage and edema of the lymph nodes and surrounding mediastinal connective tissue. Dissemination occurs through the blood stream to the lungs, causing a hemorrhagic pneumonitis. Seeding may also occur to other sites including the meninges, spleen and gastrointestinal tract. Inhalation anthrax is characterized by two clinical stages: initially patients may present with the insidious onset of mild fever, myalgia, malaise, fatigue, nonproductive cough, and a sensation of precordial oppression. 78 Physical findings are minimal. Fever and rhonchi may be the only objective findings. The second stage of the disease is manifested by the acute onset of dyspnea, respiratory failure, and subsequent cyanosis. The patient usually appears toxic with high fever and profuse diaphoresis. Stridor may result from extrinsic obstruction of the trachea by enlarged mediastinal nodes. Subcutaneous edema of the chest and neck may also be present. Moist crepitant rales and signs of pleural effusion are usually observed. Chest x-ray shows mediastinal widening resulting from node enlargement as well as patchy nonsegmental opacities probably related to hemorrhagic edema. The white blood count is usually normal. A high index of suspicion is essential to make the diagnosis of anthrax. If a person who has had recent contact with infected materials, especially those imported from the Middle East or the Far East, presents with severe dyspnea after a few days of mild febrile illness, one should suspect anthrax. The definitive diagnosis is made by isolation of B. anthracis from sputum, cerebrospinal fluid or blood. Gram stains of these specimens should be done in order to establish a presumptive diagnosis before culture results are available. The chest x-ray, as mentioned above, may be very suggestive if the epidemiologic setting is appropriate. Penicillin is the treatment of choice. High doses should be given (20 million units) and streptomycin may be added to achieve synergy. After appropriate cultures have been obtained, therapy should be started promptly. In penicillinallergic patients, erythromycin, chloramphenicol, or tetracycline may be used as alternatives.
Other Bacillus Species Members of the genus bacillus with the exception of Bacillus anthracis are often not cosidered to be significant pathogens when recovered from clinical
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materials.105 Recently, serious bacillus infections have been reported in immunosuppressed patients as well as drug abusers.26.51.96 Such infections include both primary pneumonia and that cased by metastatic seeding from distant sites or endocarditis. A review of reported cases of Bacillus pneumonias reveal that almost all the patients with pulmonary involvement, either in the form of pneumonia, pseudotumor, or pleuritis, have had some underlying disease such as leukemia or lymphoma. The most common species isolated in chest infections has been B. cereus followed by B. sphaericus. In addition to primary pneumonia, B. cereus and B. subtilis have been recovered from blood cultures of drug abusers with right-sided endocarditis.28.81.lo3 As part of this syndrome, pneumonitis resulting from septic emboli to the lungs may occur.28 The source of the organism is probably the contaminated heroin and/or colonized injection paraphernalia. 95 The pathogenicity of B. cereus has been attributed to the production of an extracellular toxin which produces massive thrombi in pulmonary vessels. 13 In contrast to B. anthracis which is uniformly sensitive, B. cereus is consistently resistant to penicillin and the cephalosporins. 25a They are usually sensitive to aminoglycosides, chloramphenicol, erythromycin, and clindamycin. 96 Therapy should be guided by antibiotic sensitivity testing. ACKNOWLEDGMENT
The author is grateful to Henry Murray, M.D., for his valuable suggestions and critical review of this manuscript, and to Ms. Santa Bost for her secretarial skill.
REFERENCES 1. 1\honkhai, V. I.. Landesman. S. H .. Fiklig, S. M., et al.: Failure of pneumococcal vaccine in children with sickle-cell disease. New Engl. J, Med., 301 :26-27, 1979. 2. Ahronheim, G. A, Reich, B., and Marks, M. I.: Penicillin-insensitive pneumococci. Amer. J, Dis. Child., 133:187-191, 1979. 3. Austlian, R.: Pneumococcal vaccines. J,AM.A., 231 :345-346, 1975. 4. Austrtan, R.: Random gleanings from a life with the pneumococcus. J, Infect. Dis., 131 :474-483, 1975. 5. Austrtan, R.: Douglas, R. G., Schiffman, G., et al.: Prevention of pneumococcal pneumonia by vaccination. Trans. Assoc. Amer. Phys., 89: 184, 1976. 6. Austrtan, R., and Gold, J,: Pneumococcal bacteremia with especial reference to bacteremic pneumococcal pneumonia. Ann. Intern. Med., 60:759-775, 1964. 7. Bames, J, M.: The development of anthrax following the administration of spores by inhalation. Blit. J Exper. Path., 28:385, 1947. 8. Barrett-Conner, E.: The nonvalue of the sputum culture in the diagnosis of pneumococcal pneumonia. Amer. Rev. Resp. Dis., 103:845-848, 1971. 9. Basiliere, J, L., Bistrong, H. W., and Spence, W. F.: Streptococcal pneumonia. Recent outbreaks in military recruit populations. Amer. J, Med., 44:580-589, 1968. 10. Bell, J, H.: On woolsorter's disease. Lancet, 1:871, 1880. 11. Bisno, A L.: Hyposplenism and overwhelming pneumococcal infection: A reappraisal. Amer. J, Med., 262: 101-107, 1971. 12. Bisno, A L., and Freeman, J, C.: The syndrome of asplenia pneumococcal sepsis and disseminated intravascular coagulation. Ann. Intern. Med., 72:389-393, 1970. 13. Bonventre, P. F., and Eckert, N. J,: The biologic activities of Bacillus anthracis and Bacillus cereus culture filtrates. Amer. J Path., 43:201-211, 1963. 14. Brachman, P. S., Plotkin, S. A., Bumford, F. H., et al.: An epidemic of inhalation anthrax: The first in the twentieth century. Amer. J Hyg., 72:6-23, 1960. 15. Brayton, R. G., Stokes, P. E., Schwartz, M. S., et al.: Effect of alcohol and various diseases on leukocyte mobilization, phagocytosis and intracellular bacterial killing. New Engl. J, Med., 282:123-128, 1970.
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16. Brewin, A., Arango, L., Hadley, K, et al.: High dose penicillin therapy and pneumococcal pneumonia. JAM.A, 230:409-413, 1974. 17. Brimblecombe, F. S. W., Cruickshank, R., Masters, P., et al.: Family studies ofrespiratory infections. Brit. Med. J, 1: 119-128, 1958. 18. Burmeister, R. W., and Overholt, E. L.: Pneumonia caused by hemolytic streptococcus. Arch. Intern. Med., 111 :367-375, 1963. 19. Calder, M. A., McHardy, V. U., and Schonell, M. E.: Importance of pneumococcal typing in pneumonia. Lancet, 1:5-7, 1970. 20. Cates, K L., Gerrard, J M., Giebink, G. S., et al.: A penicillin-resistant pneumococcus. J Pediatr., 93:624-628, 1978. 21. Chartard, J A.: An analytical study of acute lobar pneumonia. lohns Hopkins Hosp. Rep., 15:55-80, 1910. 22. Chickering, H. T., and Park, J H.: Staphylococcus aureus pneumonia. JAM.A., 72:617-626, 1919. 23. Clark, G. M., and Robinson, J S.: Group A beta hemolytic streptococcal septicemia. Complications and management. Med. J Aust., 1:324-327, 1971. 24. Clemens, H. H., and Weens, H. S.: Staphylococcic pneumonia in infants: Occurrence of pneumopyothorax. J Pediatr., 20:281-296, 1942. 25. Coonrod, J D., and Drennan, D. P.: Pneumococcal pneumonia: Capsular polysaccharide antigenemia and antibody responses. Ann. Intern. Med., 84:254-260, 1976. 25a. Coonrod, J D., Leadley, P. J, and Eickhoff, T. C.: Antibiotic susceptibility of Bacillus species. J Infect. Dis., 123:102--105, 1971. 26. Coonrod, J D., Leadley, P. J, and Eickhoff, T. C.: Bacillus cereus pneumonia and bacteremia. Amer. Rev. Resp. Dis., 103:711-714, 1971. 27. Corigan, J J: Thrombocytopenia: A sign of septicemia. J Pediatr., 85:219-221, 1974. 28. Craig, C. P., Lee, W. S., and Ho, M. S.: Bacillus cereus endocarditis in an addict. Ann. Intern. Med., 80:41~19, 1974. 29. Danner, P. K, MacFarland, D. R., and Felson, B.: Massive pulmonary gangrene. Amer. J Roentgen., 103:548--554, 1968. 30. Davidson, M., Tempest, B., and Palmer, D. L.: Bacteriologic diagnosis of acute pneumonia. Comparison of sputum, transtracheal aspirates and lung aspirates. JAM.A., 235:158--163, 1976. 31. Davies, D. T., Hodgson, H. G., and Whitley, L. E. H.: A study of pneumococcal pneumonia. Lancet, 1:791-796, 1935. 32. Disney, M. E., Wolff, G., and Wood, B. S. B.: Staphylococcal pneumonia in infants. Lancet, 1 :767-771, 1956. 33. Dowling, J N., Sheehe, P. R., and Feldman, H. A: Pharyngeal pneumococcal acquisitions in "normal" families: A longitudinal study. J Infect. Dis., 124:9-17, 1971. 34. Drew, W. L.: Value of the sputum culture in diagnosis of pneumococci pneumonia. J Clin. Microbiol., 6:62--65, 1977. 35. Farrar, W. E.: Serious infections due to "nonpathogenic" organisms of the genus Bacillus. Amer. J Med., 34:134-141, 1961. 36. Feingold, D. S., Stagg, N. L., and Kunz, L. J: Extra respiratory streptococcal infections. Importance of the various serologic groups. New Engl. J Med., 275:356--361, 1966. 37. Feldman, S., and Pearson, T.: Fatal Bacillus cereus pneunionia and sepsis in a child with cancer. Clin. Pediatr., 13:649-655, 1974. 38. Finland, M., Peterson, O. L., and Strauss, E.: Staphylococcic pneumonia occurring during an epidemic of influenza. Arch. Intern. Med., 70: 183--205, 1942. 39. Fisher, A M., Trever, R. W., Curtin, J A, et al.: Staphylococcal pneumonia. A review of21 cases in adults. New Engl. J Med., 258:919-928, 1958. 40. Foy, H. M., Wentworth, B., and Kenny, G. E.: Pneumococcal isolations from patients with pneumonia and central subjects in a prepaid medical group. Amer. Rev. Resp. Dis., 111 :595-603, 1975. 41. Fraser, R. G., and Wortzman, G.: Acute pneumococcal lobar pneumonia: The significance of nonsegmental distribution. J Canad. Assoc. Radiol., 10:37-46, 1959. 42. Gallis, H. A.: Subacute staphylococcal pneumonia in a renal transplant patient. Amer. Rev. Resp. Dis., 112:109-112, 1975. 43. Gold, H.: Anthrax. Arch. Intern. Med., 96:387-396, 1955. 44. Gopal, V., and Bisno, A. L.: Fulminant pneumococcal infections in "normal" asplenic hosts. Arch. Intern. Med., 137:1526--1530, 1977. 45. Gopalakrishna, K V., and Lerner, P. I.: Tetracycline-resistant pneumococci. Amer. Rev. Resp. Dis., 108:1007-1010, 1973. 46. Gwaltney, J. M., Sande, M. A, Austrian, R., et al.: Spread of Streptococcus pneumoniae in families. n. Relation of transfer of S. pneumoniae to incidence of colds and serum antibody. J Infect. Dis., 132:62--68, 1975. 47. Hausmann, W., and Karlish,A.J: Staphylococcal pneumonia in adults. Brit. Med.J, 11:845-847, 1956. 48. Heineman, H. S.: Quellung test for pneumonia. New Engl. J Med., 288:1027, 1973.
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49. Hendley, J 0., Sande, M. A., Stewart, P. M., et al.: Spread of Streptococcus pneumoniae in families. I. Carriage rates and distribution of types. J. Infect. Dis., 132:55--61, 1975. 50. Highman, J H.: Staphylococcal pneumonia and empyema in childhood. Amer. J. Roentgen., 106:103-108,1969. 51. Ihde, D. C., and Armstrong, D.: Clinical spectrum of infection due to Bacillus species. Amer. J. Med., 55:839--845, 1973. 52. Isaacson, P., Jacobs, P. H., Mackenzie, A. M. R., et al.: Pseudotumor of the lung caused by infection with Bacillus sphaericus. J Clin. Path., 29:806-811, 1976. 53. Jacobs, M. R., Koornhof, H. J., Robins-Browne, R. M., et al.: Emergence of multiply resistant pneumococci. New Engl. J Med., 299:735--740, 1978. 54. Jay, S. J., Johanson, W. G., and Pierce, A. K.: The radiographic resolution of Streptococcus pneumoniae pneumonia. New Engl. J Med., 293:798-801, 1975. 55. Johnston, R. B., Newman, S. L., and Struth, A. G.: An abnormality of the alternative pathway of complement activation in sickle cell disease. New Engl. J Med., 288:803-808, 1973. 56. Kancir, L. M., Tuazon, C. U., Cardella, T. A, et al.: A comparison of adverse reactions to methicillin and nafcillin during the treatment of serious infections due to Staphylococcus aureus. Arch. Intern. Med., 138:909--911, 1978. 57. Keefer, C. S., Rantz, L. A, and Rammelkamp, C. H.: Hemolytic streptococcal pneumonia and empyema: A study of 55 cases with special reference to treatment. Ann. Intern. Med., 14:1533-1550, 1941. 58. Kevy, S. V., and Lowe, B. A: Streptococcal pneumonia and empyema in childhood. New Engl. J Med., 264:738-743, 1961. 59. Kirby, W. M., Waddington, W. S., and Francis, B. F.: Differentiation of right upper lobe pneumonia from bronchogenic carcinoma. New Engl. J Med., 256:828-833, 1957. 60. Kirmani, N., Tuazon, C. U., Murray, H. W., et al.: Staphylococcus aureus carriage rate among patients on chronic hemodialysis. Arch. Intern. Med., 138:1657-1659, 1978. 61. K1ein, J 0., and Finland, M.: The new penicillins. New Engl. J Med., 269:1074-1082, 1963. 62. Kuperman, A. S., and Fernandez, R. B.: Subacute staphylococcal pneumonia. Amer. Rev. Resp. Dis., 101 :95--100, 1970. 63. Leach, R. P., and Coonrod, J. D.: Detection of pneumococcal antigens in the sputum in pneumococcal pneumonia. Amer. Rev. Resp. Dis., 116:847-851, 1977. 64. Left', A, Jacobs, R., Gooding, J V., et al.: Bacillus cereus pneumonia: Survival in a patient with cavitary disease treated with gentamicin. Amer. Rev. Resp. Dis., 115:151-154, 1977. 65. Levinson, D. A., and Litivach, K. D.: Glomerulonephritis follOwing streptococcal pneumonia. Chest, 61 :397-400, 1972. 66. Martin, C. M., Kunin, C. M., Gottlieb, L. S., et al.: Asian influenza A in Boston 1957-1958. n. Severe staphylococcal pneumonia complicating influenza. Arch. Intern. Med., 103:532-542, 1959. 67. Masters, P. L., Brumfitt, W., Mendez, R. L., et al.: Bacterial flora of the upper respiratory tract in Paddington families. Brit. Med. J, 1 :120~1205, 1958. 68. Miller, J, Sande, M. A., Gwaltney, J. M., et al.: Diagnosis of pneumococcal pneumonia by antigen detection in sputum. J Clin. Microbiol., 7:459-462, 1978. 69. Miller, W. R., and Jay, A R.: Staphylococcal pneumonia in influenza. Arch. Intern. Med., 109:276-286, 1962. 70. Minor, D. R., Schiffman, G., and McIntosh, L. S.: Response of patients with Hodgkin's disease to pneumococcal vaccine. Ann. Intern. Med., 90:887-892, 1979. 71. Molteni, R. A: Group A B-hemolytic streptococcal pneumonia. Amer. J Dis. Child., 131:1366-1371, 1977. 72. Mufson, M. A., Kruss, D. H., Wasil, R. E., et al.: Capsular types and outcome of bacteremic pneumococcal disease in the antibiotic era. Arch. Intern. Med., 134:505--510, 1974. 73. Musher, D. M., and McKenzie, S. 0.: Infections due to Staphylococcus aureus. Medicine, 56:383-409, 1977. 74. Nagel, J C., Tuazon, C. U., Cardella, T. A, et al.: Teichoic acid serologic diagnosis of staphylococcal infection: Use of gel diffusion and counterimmunoelectrophoretic methods. Ann. Intern. Med., 82:13-17, 1975. 75. Paredes, A., Taber, L. H., Vow, M. D., et al.: Prolonged pneumococcal meningitis due to an organism with increased resistance to penicillin. Pediatrics, 58:378-381. 76. Perlino, C. A, and Burleigh, P.: Penicillin insensitive pneumococci: Isolation from patients with pneumonia. South. Med. J, 72:2~22, 1979. 77. Petersdorf, R. G., Fusco, J ]., Harter, D. H., et al.: Pulmonary infection complicating Asian infuenza. Arch. Intern. Med., 1031:262-272, 1959. 78. Plotkin, S. A., Brachman, P. S., Utell, M., et al.: An epidemic of inhalation anthrax, the first in the twentieth century. I. Clinical features. Amer. J Med., 29:992-1001, 1960. 79. Posner, M. R., Berk, S. L., and Rice, P. A: Pneumococcal bacteremia diagnosed by peripheral blood smear in multiple myeloma. Arch. Intern. Med., 138:172~1721, 1978. 80. Rein, M. F., Gwaltney, J M., Jr., O'Brien, W. M., et al.: Accuracy of gram's stain in identifying pneumococci in sputum. JAM.A., 239:2671-2673, 1978.
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81. Reller, L. B.: Endocarditis caused by Bacillus subtilis. Amer. J Clin. Path., 60:714-718, 1973. 82. Roberts, R. B.: Streptococcus pneumoniae. In Mandell, G. L., Douglas, R. G., and Bennett, J E., eds.: Principles and Practice of Infectious Diseases. New York, John Wiley and Sons, 1979, pp. 1589-1604. 83. Rogers, D. E.: Current problems of staphylococcal infection. Ann. Intern. Med., 45:748-781, 1956. 84. Ross, J M.: The pathogenesis of anthrax follOwing the administration of spores by the respiratory route. J Path. Bact., 73:485-494, 1957. 85. Schwartzmann, S. W., Adler, J L., Sullivan, R. J, et al.: Bacterial pneumonia during the Hong Kong influenza epidemic of 1968-1969. Arch. Intern. Med., 127:1037-1041, 1971. 86. Siber, G. R., Weitzman, S. A, Aisenberg, A C., et al.: Impaired antibody response to pneumococcal vaccine after treatment for Hodgkin's disease. New Engl. J Med., 299:442-448, 1978. 87. Slim, M. S., Firzil, S. S., and Melham, R. E.: Staphylococcic pneumonia in infants under the age of six months. Dis. Chest, 48:6-13, 1965. 88. Smith, I.: Staphylococcus aureus. In Mandell, G. L., Douglas, R. G., and Bennett, J E., eds.: Principles and Practice of Infectious Diseases. New York, John Wiley and Sons, 1979, pp. 1530-1551. 89. Stollerman, G. H.: Streptococcal vaccines revisited. J Clin. Lab. Med., 6:872-880, 1980. 90. Stopler, T., Cameuscu, V., and Voiculescu, M.: Bronchopneumonia with lethal-evolution determined by a microorganism of the genus Bacillus (B. cereus). Rumanian Med. Rev., 2:7-9, 1965. 91. Taryle, D. A, Potts, D. E., and Sahn, S. A.: The incidence and clinical correlates of parapneumonic effusions in pneumococcal pneumonia. Chest, 74: 170-173, 1978. 92. Tempest, B., Morgan, R., Davidson, M., et al.: The value of respiratory tract bacteriology in pneumococcal pneumonia among Navajo Indians. Amer. Rev. Resp. Dis., 109:577-578, 1974. 93. Thomas, D. F.: Management of streptococcal empyema Ann. Thorac. Surg., 2:658-664, 1966. 94. Tuazon, C. U., Cardella, T. A, Sheagren, J N.: Staphylococcal endocarditis in drug users: Clinical and microbiologic aspects. Arch. Intern. Med., 135: 1555-1561, 1975. 95. Tuazon, C. U., Hill, R., and Sheagren, J N.: The microbiologic study of street heroin and injection paraphernalia. J Infect. Dis., 129:327-329, 1974. 96. Tuazon, C. U., Murray, H. W., Levy, C., et al.: Serious infections from Bacillus species. JA.M.A., 241: 1132-1140, 1979. 97. Tuazon, C. U., Perez, A., Kishaba, T., et al.: Staphylococcus aureus among insulin-injecting diabetic patients. An increased carrier rate. JA.M.A, 231: 1272, 1975. 98. Tuazon, C. U., and Sheagren, J N.: Increased rate of carriage of Staphylococcus aureus among narcotic addicts. J Infect. Dis., 129:725-727, 1974. 99. Tuazon, C. U., and Sheagren, J N.: Teichoic acid antibodies in the diagnosis of serious staphylococcal infections. Ann. Intern. Med., 84:543-546, 1976. 100. Tuazon, C. U., Sheagren, J N., Choa, M. S., et al.: Staphylococcus aureus bacteremia: Relationship between teichoic acid antibody formation and the development of metastatic abscesses. J Infect. Dis., 137:57-62, 1978. 101. Van Metre, T. E., Jr.: Pneumococcal pneumonia treated with antibiotics. New Engl. J Med., 251: 1048-1052, 1954. 102. Welch, C. C.: B hemolytic streptococcal pneumonia: Report of an outbreak in a military population. Amer. J Med. Sci., 242: 157-165, 1961. 103. Weller, P. F., Nicholson, A, and Braslow, N.: The spectrum of Bacillus bacteremias in heroin addicts. Arch. Intern. Med., 139:293-294, 1979. 104. Wilson, G. S., and Miles, A.: Principles of Bacteriology and Immunity. Baltimore, Williams & Wilkins Co., 6th ed., 1975, pp. 1079-1108. 105. Winston, D. J" Schiffman, G., Wang, D. C., et al.: Pneumococcal infections after human bone marrow transplantation. Ann. Intern. Med., 91 :835-841, 1979. 106. Wise, M. B., Beaudry, P. H., and Bates, D. V.: Long term follow-up of staphylococcal pneumonia. Pediatrics, 38:398-401, 1966. 107. Zitem, F. M., Jr.: Large pleural effusions with streptococcal pneumonias. J Can. Assoc. Radio!., 20: 185-188, 1969. Division of Infectious Diseases George Washington University Medical Center Washington, D.C. 20037
Gram-Positive Pneumonias Carmelita U. Tuazon, M.D. *
Pneumonias caused by gram-positive cocci (e.g., Streptococcus pneumoniae, Staphylococcus aureus and group A beta-hemolytic streptococci) account for most bacterial community-acquired pneumonias. With recent advances in medical technology and increasing number of immunocompromised patients S. aureus has also become a significant cause of nosocomial infections, including pneumonia. Bacillus species other than B. anthracis are being recognized as pathogens with increased frequency among drug abusers and other patients with impaired host defense mechanisms. The purpose of this article is to review the clinical features and microbiologic aspects of the different gram-positive pneumonias. Newer diagnostic techniques and a proper approach to management of these pneumonias are discussed. Recent developments in the treatment and prevention including emergence of antibiotic resistant strains and status of various vaccines are presented.
PNEUMOCOCCAL PNEUMONIA In the pre-antibiotic era 95 per cent of pneu,monias in hospitalized patients was attributed to the pneumococcus, and the mortality rate was nearly 30 per cent. Since the introduction of effective antibiotics this figure has decreased to 10 per cent; however, there has been no significant reduction in the number of pneumococcal infections. More recently, newer diagnostic techniques and the reintroduction of vaccination are attempts to control the disease.
The Organism Streptococcus pneumoniae (pneumococcus) is a gram-positive, lancet-shaped diplococcus. Since they can occur in clumps and form chains of varying lengths, the name Diplococcus has been abandoned. Pneumococci grow aerobically, but have the properties of facultative anaerobes. On blood agar plates the organisms give an alpha-hemolytic reaction, and thus need to be differentiated from the viridans streptococci. The two biochemical tests used routinely in most laboratories for identification are the bile solubility test and the optochin
"AsSOCiate Professor of Medicine, Director, Division of Infectious Diseases, George Washington University Medical Center, Washington, D. C. Supported in part by a special research grant from Wyeth Laboratories
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(ethyl hydrocupreine) disk sensitivity. Colonies appear smooth, glistening, and flat on blood agar, but one may suspect the type III serotype if colonies appear large and mucoid. Inulin was thought to be quite specific for Streptococcus pneumoniae but other viridans species such as S. mitior and S. sanguis ferment this sugar, and not all strains of S. pneumoniae ferment inulin. 82 On gram stain of clinical specimens (pus, sputum or body fluids) it may sometime be difficult to differentiate pneumococci from other gram-positive cocci. A helpful procedure is to demonstrate the capsule of the pneumococcus by using type-specific anti-serum that allows the capsule to swell. This is known as the quellung reaction. The major anti genic component of the pneumococcus is the capsular polysaccharide. The virulence of the organism is related to the amount of this capsular material. Serotyping the pneumococcus is based on the capsular polysaccharide, and over 80 serotypes capable of causing human infections have been identified. The vaccine available is directed toward the more common serotypes.
Epidemiology and Pathogenesis The true incidence of pneumococcal pneumonia is difficult to ascertain, and has been estimated at a rate of 1 to 2 cases per 1000 per year. 4.40 The age distribution for pneumococcal pneumonia is similar to that of many other infectious diseases. The incidence is greatest in infants and young children under 5 years and in the elderly. This is in part related to the lower capacity of the very young and the old to mount an effective immune response. Other susceptible groups include those with underlying diseases such as chronic heart or lung disorders, diabetes mellitus, or chronic alcoholism with cirrhosis.1 5 Likewise, splenectomized patients or those with impaired immunoglobulin production (multiple myeloma) or defective opsonic factors (sickle c.ell disease) are predisposed to pneumococcal infections. 55 The pneumococcus is carried in the upper respiratory tract of 5 to 70 per cent of normal people depending on the population studied. 33,49 Of the factors which predispose to spread of pneumococcus, crowding has been shown to enhance transmission. 17.67 Recent studies have further documented that spread of the pneumococcus occurs in association with upper respiratory tract infections, and simultaneous transmission of the pneumococcus and the rhinovirus has been demonstrated. 46 Pneumococcal pneumonia shows a seasonal distribution similar to other respiratory tract infections. It often appears during the coldest months of the year, presumably because of increased crowding of people into closed environments. It also, of course, occurs sporadically since pneumococcal pneumonia is essentially a disease of carriers. The normal human host is highly resistant to the induction of pneumonia by the pneumococcus and only develops it when host defense mechanisms are impaired. The infecting organism is usually one that resides in the upper airway and subsequently gains entry to the alveoli. Any impairment of the cough reflex or mucociliary action predisposes to invasion. Following entry of micro-organisms into the lower respiratory tract and alveolar spaces there is an outpouring of edema fluid and accumulation of polymorphonuclear leukocytes. Infection spreads peripherally and organisms multiply in the edema fluid. The infection
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may next extend to the pleura by direct invasion, to the lymphatics with involvement of the hilar lymph nodes or from the lymphatics to the blood. Hematogenous spread with metastatic lesions in various organs (meninges, pericardium, heart valves, joint or bone) may then occur.
Clinical Features A preceding upper respiratory tract infection is usual before the classic attack of pneumococcal pneumonia. The incubation period is usually 1 to 3 days. About 80 per cent of patients would present with a single shaking chill. Temperature may be as high as 106°F. Nausea and vomiting may also be seen, and generalized systemic symptoms of malaise, myalgias, and weakness are common. Cough, productive of purulent sputum which has been characterized as greenish, bloody, or rusty, is frequent. Pleuritic chest pain is also common. In the elderly or debilitated patient, illness may present more insidiously and major manifestations are mental obtundation, congestive heart failure, or marked prostration. In this group fever may not be present or only slight elevation of temperature may be noted. On physical examination, the patient usually appears toxic, dyspneic and febrile. Chest findings usually reveal consolidation with decreased breath sounds, dullness, and egophony. A pleural friction rub is frequently heard. In patients with lower lobe pneumonia, abdominal pain, distention, and paralytic ileus may be seen. With prompt institution of antimicrobial therapy, uncomplicated pneumococcal pneumonia usually responds within the first 24 hours. One often notes an abrupt decrease in temperature, improved breathing, and decreased chest pain. Supportive therapy is equally important as antimicrobial therapy. Good hydration and adequate pulmonary toilet should be ensured. If, after several days of adequate antimicrobial and supportive therapy, the patient continues to have high fever and appears ill, one should look carefully for complications such as empyema, pericarditis, endobronchial obstruction, abscess formation, superinfection, or metastatic seeding, resulting in meningitis, endocarditis, or arthritis. Bacteremia occurs in approximately 25 to 30 per cent of patients, depending on the serotypes. Mortality is high in patients with bacteremia and more so in patients with splenic dysfunction and disseminated intravascular coagulation. 11.12 Other poor prognostic factors are leukopenia, infection with serotype Ill, multilobar involvement, old age, and chronic alcoholism. 6
Laboratory and Roentgenographic Manifestations The laboratory findings of pneumococcal pneumonia are nonspecific. Leukocytosis of over 20,000 per cu mm is typical with predominantly neutrophils and early band forms. Leukopenia may develop in extremely ill patients. Liver function abnormalities such as bilirubinemia are often seen in bacteremic patients. 82 Hypoxemia is usually mild but may occasionally be profound. Chest x-ray shows homogenous consolidation of lung parenchyma. Seldom is complete lobar consolidation seen.41 Disease is usually confined to one lobe, but sometimes develops simultaneously in two or more lobes, and the prognosis is less favorable in these patients. 6 Cavitation is rare except with infection caused by serotype III organisms. We recently cared for a 61 year old alcoholic man
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with chronic lung disease with type III pneumococcal pneumonia. Initial chest x-ray showed right upper lobe consolidation (Fig. 1, above), and after a few days cavitation and abscess formation were noted (Fig. 1, below). Rarely, massive pulmonary gangrene, similar to that which occurs in Friedlander's pneumonia, may be seen with pneumococcal pneumonia. 31 Resolution of the infiltrate may take as long as seven weeks. 30,101 A recent study54 examined the radiographic characteristics of resolving pneumococcal pneumonia and found 34 to 37 per cent of patients had persistent consolidation at 1 month which eventually resolved by 8 to 10 weeks. 54 Residual pleural disease persisted for over 4 months before clearing completely. Repeat radiographic examination is therefore appropriate only after an interval of at least 6 weeks. In the management of organizing pneumonic infiltrates it is important to consider carcinoma as a cause of delayed resolution. 59 Pleurisy is quite common in pneumococcal pneumonia21 but pleural effusions were previously considered to be unusual. 82 In a recent study, however, parapneumonic effusions were detected in 57 per cent of cases of pneumococcal pneumonia. 91 Effusions were correlated significantly with the duration of symptoms before admission, bacteremia and prolonged fever after therapy.
Diagnosis Initial antimicrobial therapy for patients with pneumococcal pneumonia is usually based on a presumptive diagnosis from clinical and laboratory data, One should obtain smears and cultures of blood, sputum, urine, and other (pleural, cerebrospinal) fluids, depending on the clinical presentation, The importance of absence or presence of pneumococci in expectorated sputum has been controversial. 8,92 We find that a gram stain of the sputum is very useful in making a presumptive diagnosis since results are available within minutes. Cultures, however, may not be helpful because of stringent growth requirements of the organism especially if the sputum is not cultured immediately. Recent work suggests that the sputum gram stain is a valuable tool in the initial evaluation of patient with community-acquired pneumonia.29.34.80 Moreover one should not overlook the usefulness of the quellung reaction for sputum smears which show gram-positive cocci of uncertain identity. In certain groups of patients (myeloma, sickle cell disease, functional asplenia and splenectomized) with overwhelming bacteremia organisms may be seen on peripheral blood smears. 44.79 Definitive diagnosis requires isolation of S. pneumoniae from pleural fluid, blood, lung, or transtracheal aspirates since up to 50 per cent of normal persons carry S. pneumoniae in their upper airways, and thus may give false-positive sputum culture results. More recently, a rapid and simple diagnostic method has been utilized in the detection of antigen in the sputum. The counter immunoelectrophoresis technique detects pneumococcal antigen in patients with pneumococcal pneumonia in as many as 75 per cent of cases. 63.68 In addition, antigen has been detected in serum or urine in patients with pneumococcal pneumonia and is usually associated with bacteremia, infections with low numbered serotypes or more severe and protracted illnesses. 25 Any body fluid can be checked for presence of antigen with the use of counter immunoelectrophoresis.
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Figure 1. Pneumococcal pneuRlonia. The initial chest film (abave) shows TIght upper lobe consolidation. Mter a few days, cavitation and abscess formation were noted (below).
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Treatment and Prevention Penicillin G remains the drug of choice for patients with pneumococcal infections. The antibiotic dosage varies depending on the severity of the infection. Uncomplicated pneumonia responds to low dose penicillin, 600,000 to 1.2 million units per day, in divided doses. We prefer to treat hospitalized patients with intravenous penicillin 400,000 to 600,000 units given every 4 hours for the first 24 to 48 hours or until signs of clinical toxicity abate. A recent study has shown that there was no difference in clinical response between those patients treated with low versus high dose penicillin, the latter defined as over 5 million units. 16 If complications are present (emypema or abscesses) 6 to 12 million units in divided doses should be given. If evidence of metastatic seeding is present, such as meningitis, endocarditis, or arthritis, as much as 24 million units per day may be necessary. For patients allergic to penicillin with uncomplicated pneumococcal pneumonia, cephalothin or erythromycin may be given, and for meningitis, chloramphenicol is the alternative drug. Tetracycline is not a good alternative drug for pneumonia because of the high incidence of resistant strains. 45 Clindamycin also is not advised because of its relatively high minimum bactericidal concentration. Although it is rare in the United States, penicillin-resistant pneumococci have been reported recently in clinically significant pulmonary and nonpulmonary infections.20.75.76 Initial reports of resistant pneumocci came from South Africa where an extensive epidemiologic study was carried out. The multiple resistant strains were usually sensitive to rifampin, fusidic acid, novobiocin, vancomycin, and bacitracin. 53 The clinical significance of these resistant strains is not readily apparent with infections like pneumonia because of the high levels of antibiotics achievable with regular dosages. In severe infections (e. g., meningitis) one should be aware of the potential for resistance because of the relatively low levels of penicillin achieved in the cerebrospinal fluid. There has been a revival of interest in use of pneumococcal polysaccharide vaccine. Although mortality from pneumococcal infections has decreased, the incidence of pneumococcal disease has not changed. When studies were. done on bacteremic infections as well as community acquired pneumococcal pneumonias, it became apparent that certain serotypes predominate.3.5.6.19.72 Based on these studies, a polyvalent pneumococcal polysaccharide vaccine has been developed. It has been proven to be immunogenic in normal adults, and in one study was 82 per cent effective in preventing type-specific bacteremic pneumonia in young adult men. 5 There are 14 different capsular polysaccharides in the currently available vaccine. Usually, 0.5 ml is administered intramuscularly or subcutaneously. Booster injections are usually given every 3 years. Susceptible patients, as mentioned earlier, should receive the vaccine, but in addition it should be considered in outbreaks caused by multiple antibioticresistant strains of pneumococci. The vaccine is contraindicated in patients less than 2 years old, pregnant women, and those with febrile illnesses. One should be aware that certain groups of patients have impaired antibody responses to pneumococcal polysaccharide vaccines, including those treated for Hodgkin's disease,70.86 bone marrow transplant patients, lOO and patients with sickle cell disease. 1
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STREPTOCOCCAL PNEUMONIA In the adult, streptococcal pneumonia occurs primarily in epidemic outbreaks in military populations. 9 ,102 In the preantibiotic era, 5 per cent of cases of acute pneumonia were caused by group A beta-hemolytic streptococci and, like S. aureus pneumonia, was associated with a high mortality. 57 Streptococcal pneumonia is rarely seen nowadays, although cases do appear after respiratory infection l8 and may complicate measles and childhood exanthema. 58
The Organism Group A streptococci (Strep. pyogenes) are gram-positive cocci which may be found in pairs but more commonly occur as chains in clinical specimens. They are catalase negative, aerobic but also are facultative anaerobes. On blood agar plates, they appear as white to gray colonies 1 to 2 mm in diameter surrounded by zones of complete hemolysis or beta hemolysis. Bacitracin disc sensitivity is used for routine identification, but is by no means specific, since other streptococci may be bacitracin sensitive. 36 Final identification is made with use of specific antisera. Group A streptococci are important human pathogens since they account for the majority of cases of severe pharyngitis and also because of the classic nonsuppurative complications related to such infections, rheumatic fever, and acute glomerulonephritis. Like S. aureus, pathogenicity is also related to enzyme and toxin productions. M antigen, one of several antigenic substances contained in the cell wall of this organism, is the antigen of major virulence.
Epidemiology and Pathogenesis The incidence of streptococcal pneumonia appears to increase from age 5 to 6 to young adulthood. Like pneumococcal and staphylococcal pneumonia, it occurs most frequently during the winter. The organism enters the lungs by inhalation and/or aspiration and under the influence of gravity passes to the most dependent portions. Thus, disease is almost invariably localized to the lower lobes. It is unusual for pneumonia to occur as a result of seeding to the lung from a bacteremic focus. Two forms of streptococcal pneumonia have been described in autopsy series. 18 The most common form is interstitial bronchopneumonia. Pathologic changes include thickening of the bronchiolar walls, necrosis of the mucosal lining, purulent engorgement of the lymphatics, and microabscesses with rupture through the pleura. This pattern was the one described in the cases reported by Kevy and Lowe. 58 The second type is much less common and is a lobar pneumonia with consolidation and large areas of necrosis similar to those of pneumococcal pneumonia.
Clinical Features High fever (usually greater than 39°C), cough, and pleuritic chest pain are the most common presenting symptoms of streptococcal pneumonia. 9 ,18,57 The patient usually appears quite ill and physical findings are compatible with bronchopneumonia. In one series, the clinical picture was thought to resemble Reyes' syndrome because of fever, chills, confusion, lethargy, meningeal signs, and
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abdominal signs and symptoms. 71 As many as 30 to 65 per cent of patients have an associated streptococcal pharyngitis. 9.71 Empyema has been described in 66 to 86 per cent of adult cases57.102 and in 100 per cent of pediatric cases. Rapid accumulation of fluid can occur within hours,71.108 similar to staphylococcal pneumonia. The effusion initially is serous, then serosanguinous, and rapidly becomes fibrinopurulent. The consistency of fluid can present drainage problems and may require pleural stripping or frequent chest tube replacement. 71 Amount of drainage averages 100 to 150 ml per day. In some series, profuse drainage up to 3,000 ml per day can occur, and if the course is prolonged, hypoproteinemia may develop. In addition to empyema, other major pulmonary complications include atelectasis, pneumothorax, bronchopleural fistula, pneumatoceles, and persistent atelectasis. These complications have been reported in 1 to 10 per cent of cases. 57.102 Extrapulmonary complications include anemia which probably results from serosanguineous drainage and intravascular hemolysis. Thrombocytopenia, either separately or as part of purpura fulminans, may be seen as a complication of streptococcal bacteremia.21.27.58 Biopsy proven acute glomerulonephritis has been reported as well. 65 Acute rheumatic fever however has never been reported as a complication of streptococcal pneumonia. Purulent pericarditis occurs in less than 10 per cent of cases9.18.58.93 and inappropriate secretion of antidiuretic hormone has also been noted. 71 Resolution is slow, especially if the disease is complicated with empyema. Chest pain can linger for 8 to 10 days.
Laboratory and Roentgen Manifestations The white blood count is usually less than 20,000 per cu mm except in those patients with empyema in whom counts of greater than 20,000 per cu mm are usually seen. 9.57 Anemia is a common finding. 9.71 The chest roentgenogram frequently shows an interstitial pattern usually involving both lower lobes. Pleural effusion is a frequent finding and empyema has been described in over 50 per cent of cases. Diagnosis The diagnosis is confirmed when group A beta-hemolytic streptococcus is cultured either from the sputum, pleural fluid, or blood. Gram-stain of sputum and pleural fluid specimens might give one a clue as to the presence of the streptococcal organism, but is by no means a definitive way of making a diagnosis. Positive blood cultures are found in 2 to 12 per cent of cases. 9 . 57 In very severe cases the yield is higher, 55 per cent in one series58 and as high as 100 per cent in another.71 These patients often have purpura fulminans and the majority die. An elevated antistreptolysin titer in a convalescent patient is good supportive evidence. Treatment and Prevention Penicillin is the antibiotic of choice for streptococcal infections. For patients who are allergic to penicillin, cephalothin or erythromycin are good alternative drugs. Dosage varies according to severity of the disease. For uncomplicated streptococcal pneumonia, dosages similar to those for pneumococcal pneumonia
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may be given, but higher doses are used in those with effusions or empyema. In the setting in which a bacteriologic diagnosis is not promptly available, one should initially consider using a penicillinase-resistant penicillin because differentiation between streptococcal and staphylococcal pneumonia on the basis of clinical features or gram stain smears may be difficult. Surgical management includes early and vigorous chest drainage to prevent late pulmonary complications .. Much work has been done on the development of streptococcal vaccines, and it appears that the prospect of immunization against streptococcal infections is optimistic. 89 Prophylaxis at the present time consist oflow-dose penicillin orally or intramuscular benzathine penicillin for patients with rheumatic fever. In epidemic outbreaks of streptococcal pneumonia, prophylactic antibiotics should be considered.
STAPHYLOCOCCAL PNEUMONIA Staphylococcal pneumonia is an unusual infection which seldom occurs as a primary disease. In adults, for instance, it classically follows a preceding influenza infection. Although staphylococcal pneumonia comprises only 3 to 10 per cent of all pneumonias,47 it is nevertheless an important infection to consider because mortality is high. In the preantibiotic era, 80 to 90 per cent of patients died. 22 With the initial introduction of antibiotics such as sulfonarnides, mortality dropped to 30 per cent. 38 However, no further decrease in mortality was seen with the advent of the penicillinase-resistant penicillins. 66 ,85 This most likely reflects the typically poor response of patients whose host defense mechanisms are impaired. 47,61,73
Microbiology Staphylococcus aureus is a gram-positive coccus belonging to the family Micrococciae, On gram stain, organisms are usually in clusters, but can occur singly or in pairs, On blood agar plates, colonies.appear golden yellow, hence the name "aureus." Tests that differentiate S. aureus from the less pathogenic species S. epidermidis and S. saprophyticus are the coagulase and mannitol fermentation tests. More than 95 per cent of pathogenic staphylococci produce coagulase. In addition, S. aureus has ribitol teichoic acid in its cell wall while S. epidermidis contains glycerol teichoic acid. Antibody to teichoic acid has been utilized recently in the diagnosis of serious staphylococcal infections. 74,99,100 In epidemic situations phage typing is very useful for epidemiologic investigations.
Epidemiology S. aureus is a normal component of the human microflora. Approximately 20 to 40 per cent of normal adults carry the organism in their nares. 88 Certain groups, however, have markedly increased carriage rates, probably reflecting underlying diseases, immune status, health practices, or regular needle use. Examples include drug abusers, diabetics, and patients in chronic renal failure receiving hemodialysis. 6o ,97,98 The incidence of staphylococcal infections in general has increased, presumably because the organism has taken full advantage of the ecologic changes brought about by antibiotics, modem technologic pro-
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cedures, and chemotherapeutic agents, and prolonged survival of patients with impaired host defenses. 73 •88
Pathogenesis Two types of staphylococcal pneumonia are recognized, depending on the mode of acquisition. Primary pneumonia arises from the upper respiratory tract usually in the setti~g of a post-viral infection. Secondary or bacteremic staphylococcal pneumonia results from blood-borne dissemination to the lung. When staphylococci are present in the upper respiratory tract they may be aspirated into the lung, causing primary pneumonia. Viral infections such as influenza appear to predispose adult patients to staphylococcal pneumonia by destroying the ciliated surface epithelium, thus leaving the bronchial surface vulnerable to secondary bacterial infection.22.69.77 Patients who develop aspiration pneumonia while hospitalized also appear to be at risk of acquiring S. aureus pneumonia. 73.88 Among the pediatric age group, infants under the age of 6 months account for the majority of cases. This may be related to a higher frequency of colonization of the respiratory tract of newborns particularly during nursery epidemics. 87 Cystic fibrosis patients are also predisposed to S. aureus pneumonia. 88 The bacteremic form of staphylococcal pneumonia occurs after hematogenous dissemination. Patients most susceptible are those with chronic illnesses, those receiving immunosuppressive therapy and drug abusers with tricuspid valve endocarditis. 73.94 The clinicopathologic findings in influenzal-staphylococcal pneumonia can probably be attributed to the potent activity of staphylococcal exotoxins. An extracellular necrotizing toxin aids in breaking through bronchial and arterial walls, hyaluronidase aids rapid bacterial spreading, coagulase enzymes favor the formation of thromboses, and leukocidin destroys resisting leukocytes. 83 The primary lesion of influenzal-staphylococcal pneumonia is a suppurative and ulcerative bronchiolitis with necrosis of bronchiolar wall. 69 As bronchiolar wall becomes necrotic, extension into adjacent tissues occurs easily with seeding-into the alveolar capillaries. Bronchial artery thrombosis can occur which may lead to septic infarction and abscess formation. If peribronchial abscesses communicate with the airway, entry of air into the abscess pocket occurs and the characteristic pneumatocele is formed. 69 In cases of bacteremic staphylococcal pneumonias from endocarditis septic emboli cause pulmonary infarcts with subsequent pneumonitil; and abscess formation.
Clinical Features The manifestations of staphylococcal pneumonia vary according to age group and pathogenesis of the infection. Primary staphylococcal pneumonia is most often seen in infants, patients with underlying disease (e.g., cystic fibrosis, chronic lung disease) or in immunosuppressed patients. The clinical presentation is highly variable. Frequently, patients appear more ill than physical findings suggest. In previously healthy adults, if there is a preceding viral illness, chills, high fever, progressive dyspnea, and pleurisy may herald the onset of staphylococcal involvement as illustrated in Case 1.
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CASE 1. A 22 year old white male student presented to the Emergency Room with a 5 day history of increasing fatigue, headache, and shortness of breath. These initial complaints followed by fever, shaking chills, sweats, and a nonproductive cough. Several students in his dormitory had similar symptoms which resolved spontaneously. On the third day of illness, he felt better, only to be awakened a day later with severe leftsided pleuritic Erythromycin, 250 mg four times a day, was prescribed for presumed pneumococcal or mycoplasma pneumonia. However, persistent high fever and increasingly severe chest pain precipitated admission one day later. Examination revealed egophony, decreased breath sounds, and dullness over the left lower chest compatible with consolidation and effusion. Repeat chest x-ray showed a larger infiltrate and an effusion. Thoracentesis revealed cloudy fluid with white blood cell count of 96,000 per cu mm (95 per cent neutrohils), increased protein, and decreased glucose. Culture grew S. aureus. Treatment was begun with intravenous nafcillin, 2 gm every 4 hours, and a chest tube was inserted for drainage of empyema. His course was complicated by loculations of the empyema which required multiple tube reinsertions and finally had decortication. He received a total course of 20 days intravenous nafcillin and another week of oral dicloxacillin.
On occasion staphylococcal pneumonia may present less dramatically in subacute form as illustrated by Case 2. She was afebrile and had no pulmonary symptoms on admission. Diagnosis was made by examination of sputum obtained at bronchoscopy and the evolution of changes on chest x-ray. CASE 2. A 36 year old schoolteacher was admitted in diabetic ketoacidosis which responded rapidly to standard treatment. Previously, she had undergone a left modified radical mastectomy for comedocarcinoma. At the time, multiple nodes were positive for tumor and incidental findings included noncaseating granulomas in the nodes and liver. Cultures for fungi and mycobacteria were negative. Ophthalmologic examination revealed bilateral anterior uveitis. She received cancer chemotherapy, and was also treated for sarcoidosis with prednisone. Isoniazid prophylaxis was also given. Chest x-ray examination on admission revealed nodular density in the left lower lobe (Fig. 2A). Because sputum induction was unsuccessful, bronchoscopy was performed and revealed purulent material in the left lower bronchus which on gram stain showed numerous white blood cells and sheets of gram-positive cocci in clusters. Culture grew S. aureus. Therapy with intravenous nafcillin was begun and later changect to cephalothin when a few Klebsiella were also isolated. Follow up chest films (Fig. 2B and C) showed abscess formation which required drainage via multiple bronchoscopies.
Few cases of subacute staphylococcal pneumonia have been reported. 42 ,62 Although this infection is characterized by mild symptoms of cough, low grade fever, and sputum production, abscesses are usually present on chest roentgenograms,62 Most patients do not have severe underlying diseases. In secondary staphylococcal pneumonia arising hematogenously from a nonpulmonary focus of infection, the onset of clinical disease is often not dramatic, In the setting of drug abuse, a drug addict is typically admitted with fever, chills and weight loss, and in those with the full blown picture, blood-streaked sputum or frank hemoptysis may be present. 73,88,94 Cough is not a prominent symptom and purulent sputum is unusual, Evidence of metastatic infection elsewhere may also be present. Physical findings in patients with staphylococcal pneumonia are variable. A toxic appearance and fever may be the only detectable manifestations. Dullness to percussion is not an early sign, and signs of frank consolidation are rare on admission. Coarse or fine rales may be heard. Pleural effusions and empyema are, however, frequent. In the early reports of staphylococcal pneumonia the description or sputum as friable, purulent material of a dirty salmon-pink color
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A
B Figure 2. Staphylococcal pneumonia. On admission, the chest x-ray CA) reviewed a nodular density in the left lower lobe. Follow-up chest films CB and C) showed abscess formation which required drainage via multiple bronchoscopies.
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c Figure 2 Continued
resembling anchovy sauce or the contents of an overripe furuncle was considered a characteristic feature. 22
Laboratory and Roentgenographic Manifestations The leukocyte count is usually elevated to between 15,000 and 25,000 per cu mm. A leukocyte count greater than 15,000 in an adult with influenza should raise the question of a secondary bacterial pneumonia. Chest x-rays in primary staphylococcal pneumonia may show either a diffuse or a localized non-specific infiltrate. When radiologic examination reveals small areas of cavitation in the lung, pneumatoceles, empyema, or pyopneumothorax, S. aureus should be strongly suspected although none of these changes is pathognomonic. 24 ,50 Pneumatoceles and pyopneumothorax are more common in pediatric age groups. It is important to differentiate pneumatocele from pyopneumothorax because the latter requires surgical drainage. Lung abscess occurs in 25 per cent and empyema in 10 per cent of patients. BB Pneumatoceles are rare in adults. 39 In bacteremic staphylococcal pneumonia initial chest films may be clear or show only single leSion, but two or three days later evidence of multiple small lesions are often seen. They appear as small (0.5 to 1 cm) oval densities at the periphery of the lung and frequently increase in size and may cavitate. In narcotic addicts, septic pulmonary emboli may be the only clinical manifestation of right-Sided endocarditis.
Diagnosis Since bacteremia occurs in less than 20 per cent of cases of primary S. aureus pneumonia, its presence should strongly suggest that respiratory infection is a result of metastatic seeding.
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The most helpful procedure used to diagnose staphylococcal pneumonia is the gram stain examination of sputum, tracheal aspirate, or lung puncture. The presence of numerous polymorphonuclear leukocytes and gram-positive cocci in clusters, often intracellular, provides the best evidence of pneumonia caused by S. aureus. Sputum culture may confirm the diagnosis but may be difficult to interpret without an accompanying sputum gram stain. If a pleural effusion is present as in Case 1, prompt thoracentesis with appropriate smears and cultures is indicated since finding S. aureus in this site confirms the diagnosis. Lung punctures have been advocated by some if sputum or pleural fluid is not available. 32 This procedure should not, however, be routinely used. Bronchoscopy may also be helpful as illustrated by Case 2. Recently a serolOgiC test has been reported useful in diagnosis and therapy of serious staphylococcal infections. 74,99,100 Our experience is very limited in terms of primary staphylococcal pneumonia. Both Cases 1 and 2 did not develop serum teichoic acid antibodies. However, in bacteremic staphylococcal pneumonia, titers would be predictably positive at a significant level. 100
Treatment and Prevention Treatment for S. aureus pneumonia includes adequate antimicrobial therapy
for a prolonged period and careful observation for complications such as empyema or bronchopleural fistula which may require surgical drainage. In most survivors, late sequelae are uncommon and residual, pulmonary damage rarely occurs.107 Despite the use of appropriate antibiotics, the mortality from primary S. aureus pneumonia remains high, ranging from 20 to 30 per cent. Therapy of bacteremic staphylococcal pneumonia usually requires 4 to 6 weeks. Therapeutic guidelines for this group of patients has been reported elsewhere. 100 For primary staphylococcal pneumonia, a 2 week course of systemic antibiotics is usually adequate, but complications such as empyema or abscess may require longer treatment. A penicillinase-resistant penicillin such as nafcillin, oxacillin, or methicillin is appropriate initial therapy. We prefer nafcillin because it seldom causes hemotologic or renal toxicity or hypersensitivity reactions. 56 In patients who are allergic to penicillin, cephalosporins (e.g., cephalothin or cefazolin) may be used. If the organism recovered is methicillin resistant, vancomycin would be the drug of choice. There is no effective vaccine against S. aureus infection, One useful measure to prevent staphylococcal pneumonia is influenza vaccination because of the close association between these two respiratory diseases. Groups who should receive the vaccine include patients with chronic lung disease, cardiac disease, immunosuppressed patients, and those with cystic fibrosis and other high risk patients.
BACILLUS PNEUMONIA Anthrax Bacillus anthracis is the most pathogenic of the bacillus species. It is a gram-positive, spore-forming, and nonmotile rod. The spores which are the infective forms are quite resistant to disinfectants and low heat but can be destroyed by boiling for 10 minutes or exposure to dry heat at 140°C for 3 hours.
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B. anthracis colonies are raised, opaque, and grayish white when cultured on blood agar. The disease caused by B. anthracis, anthrax, is principally an occupational risk for those working with animal hair or its derivatives and thus the term "wool sorters disease."IQ It has been estimated that 75 per cent of all cases in the United States occur in the northeastern states chiefly as the result of industrial exposure. 43 Investigations of the epidemic of inhalation anthrax has led to a better understanding of the pathogenesis and clinical features of the disease. 14.78 There are two forms of the disease: cutaneous anthrax (malignant pustule) and inhalation anthrax which can lead to septicemia. This discussion will be confined to inhalation anthrax. After inhalation of the organisms, spores are ingested as inert particles by alveolar macrophages in the alveoli. 84 The spore bearing macrophages migrate through the alveolar membrane into the lymphatics and are carried to the hilar lymph nodes where multiplication of the bacilli occurs. 7 This process is accompanied by hemorrhage and edema of the lymph nodes and surrounding mediastinal connective tissue. Dissemination occurs through the blood stream to the lungs, causing a hemorrhagic pneumonitis. Seeding may also occur to other sites including the meninges, spleen and gastrointestinal tract. Inhalation anthrax is characterized by two clinical stages: initially patients may present with the insidious onset of mild fever, myalgia, malaise, fatigue, nonproductive cough, and a sensation of precordial oppression. 78 Physical findings are minimal. Fever and rhonchi may be the only objective findings. The second stage of the disease is manifested by the acute onset of dyspnea, respiratory failure, and subsequent cyanosis. The patient usually appears toxic with high fever and profuse diaphoresis. Stridor may result from extrinsic obstruction of the trachea by enlarged mediastinal nodes. Subcutaneous edema of the chest and neck may also be present. Moist crepitant rales and signs of pleural effusion are usually observed. Chest x-ray shows mediastinal widening resulting from node enlargement as well as patchy nonsegmental opacities probably related to hemorrhagic edema. The white blood count is usually normal. A high index of suspicion is essential to make the diagnosis of anthrax. If a person who has had recent contact with infected materials, especially those imported from the Middle East or the Far East, presents with severe dyspnea after a few days of mild febrile illness, one should suspect anthrax. The definitive diagnosis is made by isolation of B. anthracis from sputum, cerebrospinal fluid or blood. Gram stains of these specimens should be done in order to establish a presumptive diagnosis before culture results are available. The chest x-ray, as mentioned above, may be very suggestive if the epidemiologic setting is appropriate. Penicillin is the treatment of choice. High doses should be given (20 million units) and streptomycin may be added to achieve synergy. After appropriate cultures have been obtained, therapy should be started promptly. In penicillinallergic patients, erythromycin, chloramphenicol, or tetracycline may be used as alternatives.
Other Bacillus Species Members of the genus bacillus with the exception of Bacillus anthracis are often not cosidered to be significant pathogens when recovered from clinical
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materials.105 Recently, serious bacillus infections have been reported in immunosuppressed patients as well as drug abusers.26.51.96 Such infections include both primary pneumonia and that cased by metastatic seeding from distant sites or endocarditis. A review of reported cases of Bacillus pneumonias reveal that almost all the patients with pulmonary involvement, either in the form of pneumonia, pseudotumor, or pleuritis, have had some underlying disease such as leukemia or lymphoma. The most common species isolated in chest infections has been B. cereus followed by B. sphaericus. In addition to primary pneumonia, B. cereus and B. subtilis have been recovered from blood cultures of drug abusers with right-sided endocarditis.28.81.lo3 As part of this syndrome, pneumonitis resulting from septic emboli to the lungs may occur.28 The source of the organism is probably the contaminated heroin and/or colonized injection paraphernalia. 95 The pathogenicity of B. cereus has been attributed to the production of an extracellular toxin which produces massive thrombi in pulmonary vessels. 13 In contrast to B. anthracis which is uniformly sensitive, B. cereus is consistently resistant to penicillin and the cephalosporins. 25a They are usually sensitive to aminoglycosides, chloramphenicol, erythromycin, and clindamycin. 96 Therapy should be guided by antibiotic sensitivity testing. ACKNOWLEDGMENT
The author is grateful to Henry Murray, M.D., for his valuable suggestions and critical review of this manuscript, and to Ms. Santa Bost for her secretarial skill.
REFERENCES 1. 1\honkhai, V. I.. Landesman. S. H .. Fiklig, S. M., et al.: Failure of pneumococcal vaccine in children with sickle-cell disease. New Engl. J, Med., 301 :26-27, 1979. 2. Ahronheim, G. A, Reich, B., and Marks, M. I.: Penicillin-insensitive pneumococci. Amer. J, Dis. Child., 133:187-191, 1979. 3. Austlian, R.: Pneumococcal vaccines. J,AM.A., 231 :345-346, 1975. 4. Austrtan, R.: Random gleanings from a life with the pneumococcus. J, Infect. Dis., 131 :474-483, 1975. 5. Austrtan, R.: Douglas, R. G., Schiffman, G., et al.: Prevention of pneumococcal pneumonia by vaccination. Trans. Assoc. Amer. Phys., 89: 184, 1976. 6. Austrtan, R., and Gold, J,: Pneumococcal bacteremia with especial reference to bacteremic pneumococcal pneumonia. Ann. Intern. Med., 60:759-775, 1964. 7. Bames, J, M.: The development of anthrax following the administration of spores by inhalation. Blit. J Exper. Path., 28:385, 1947. 8. Barrett-Conner, E.: The nonvalue of the sputum culture in the diagnosis of pneumococcal pneumonia. Amer. Rev. Resp. Dis., 103:845-848, 1971. 9. Basiliere, J, L., Bistrong, H. W., and Spence, W. F.: Streptococcal pneumonia. Recent outbreaks in military recruit populations. Amer. J, Med., 44:580-589, 1968. 10. Bell, J, H.: On woolsorter's disease. Lancet, 1:871, 1880. 11. Bisno, A L.: Hyposplenism and overwhelming pneumococcal infection: A reappraisal. Amer. J, Med., 262: 101-107, 1971. 12. Bisno, A L., and Freeman, J, C.: The syndrome of asplenia pneumococcal sepsis and disseminated intravascular coagulation. Ann. Intern. Med., 72:389-393, 1970. 13. Bonventre, P. F., and Eckert, N. J,: The biologic activities of Bacillus anthracis and Bacillus cereus culture filtrates. Amer. J Path., 43:201-211, 1963. 14. Brachman, P. S., Plotkin, S. A., Bumford, F. H., et al.: An epidemic of inhalation anthrax: The first in the twentieth century. Amer. J Hyg., 72:6-23, 1960. 15. Brayton, R. G., Stokes, P. E., Schwartz, M. S., et al.: Effect of alcohol and various diseases on leukocyte mobilization, phagocytosis and intracellular bacterial killing. New Engl. J, Med., 282:123-128, 1970.
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