RESPIRATORY SYSTEM (CASE 3) LEVEL II GROUP 6

1. What is the etiologic agent of pneumonia in this patient? What are the etiologic agents causing community acquired pneumonia in the different age groups? Describe their morphology, physiology and laboratory identification/diagnosis of each etiologic agent.

Community - acquired pneumonias may be bacterial or viral. Often, the bacterial infection follows an upper respiratory tract viral infection. Bacterial invasion of the lung parenchyma causes the alveoli to be filled with an inflammatory exudate, thus causing

consolidation ("solidification") of the pulmonary tissue. Many variables, such as the specific etiologic agent, the host reaction, and the extent of involvement, determine the

precise form of pneumonia. Predisposing conditions include extremes of age, chronic diseases (congestive heart failure, COPD, and diabetes),

congenital or acquired immune deficiencies, and decreased or absent splenic function (sickle cell disease or post splenectomy, which puts the patient at risk for infection with encapsulated bacteria such as pneumococcus).

Streptococcus Pneumoniae Streptococcus pneumoniae, or pneumococcus, is the most common cause of community-acquired acute pneumonia. Examination of Gram-stained sputum is an important step in the diagnosis of acute pneumonia. The presence of numerous neutrophils containing the typical Gram-positive, lancet-shaped diplococci supports the

diagnosis of pneumococcal pneumonia, but it must be remembered that S. pneumoniae is a part of the endogenous flora in 20% of adults, and therefore false-positive results may be obtained.

Isolation of pneumococci from blood cultures is more specific but less sensitive (in the early phase of illness, only 20% to 30% of patients have positive blood cultures).

Pneumococcal pneumonias respond readily to penicillin treatment, but there are increasing numbers of penicillin-resistant strains of pneumococci, so whenever possible, antibiotic sensitivity should be determined. Pneumococcal vaccines containing capsular polysaccharides from the common serotypes are available for use in patients at high risk.

Haemophilus Influenzae Haemophilus influenzae is a pleomorphic, Gram-negative organism that is a major cause of life-threatening acute lower

respiratory tract infections and meningitis in young children. In adults it is a very common cause of community-acquired acute pneumonia.98 This bacterium is a ubiquitous colonizer

of the pharynx, where it exists in two forms: encapsulated (5%) and unencapsulated (95%). Typically, the encapsulated form dominates the unencapsulated forms by secreting an antibiotic called haemocin that

kills the unencapsulated H. influenzae. Although there are six serotypes of the encapsulated form (types a to f), type b, which has a polyribosephosphate

capsule, used to be the most frequent cause of severe invasive disease. With routine use of H. influenzae conjugate vaccines, the incidence of disease caused by the b serotype has declined

significantly. By contrast, infections with nonencapsulated forms are increasing. Also called nontypable forms, they spread along the

surface of the upper respiratory tract and produce otitis media (infection of the middle ear), sinusitis, and bronchopneumonia.

Pili on the surface of H. influenzae mediate adherence of the organisms to the respiratory epithelium. 100 In addition, H. influenzae secretes a factor that disorganizes ciliary beating and a protease that degrades IgA, the major class of antibody secreted into the airways.

Survival of H. influenzae in the bloodstream correlates with the presence of the capsule, which, like that of pneumococcus, prevents opsonization by complement and phagocytosis by host cells.

Antibodies against the capsule protect the host from H. influenzae infection, hence the capsular polysaccharide b is incorporated in the vaccine for children against H. influenzae.

H. influenzae pneumonia, which may follow a viral respiratory infection, is a pediatric emergency and has a high mortality rate.

Descending laryngotracheobronchitis results in airway obstruction as the smaller bronchi are plugged by dense, fibrin-rich exudate of polymorphonuclear cells, similar to that seen in pneumococcal pneumonias.

Pulmonary consolidation is usually lobular and patchy but may be confluent and involve the entire lung lobe. Before a vaccine became widely available, H. influenzae was a common cause of suppurative meningitis in children up to

5 years of age. H. influenzae also causes an acute, purulent conjunctivitis (pinkeye) in children and, in predisposed older patients, may cause septicemia, endocarditis, pyelonephritis, cholecystitis, and suppurative arthritis.

H. influenzae is the most common bacterial cause of acute exacerbation of COPD.

Moraxella Catarrhalis Moraxella catarrhalis is being increasingly recognized as a cause of bacterial pneumonia, especially in the elderly. It is the second most common bacterial cause of acute exacerbation of COPD. Along with S. pneumoniae and H.

influenzae, M. catarrhalis constitutes one of the three most common causes of otitis media in children.

Staphylococcus Aureus Staphylococcus aureus is an important cause of secondary bacterial pneumonia in children and healthy adults following

viral respiratory illnesses (e.g., measles in children and influenza in both children and adults). Staphylococcal pneumonia is associated with a high incidence of complications, such as lung abscess and empyema. Intravenous drug abusers are at high risk of developing staphylococcal pneumonia in association with endocarditis. It is also an important cause of nosocomial pneumonia, as will be discussed later.

Klebsiella Pneumoniae Klebsiella pneumoniae is the most frequent cause of Gram-negative bacterial pneumonia. It commonly afflicts debilitated

and malnourished people, particularly chronic alcoholics. Thick and gelatinous sputum is characteristic because the organism produces an abundant viscid capsular polysaccharide,

which the patient may have difficulty coughing up.

Pseudomonas Aeruginosa

Although Pseudomonas aeruginosa most commonly causes nosocomial infections, it is mentioned here because of its occurrence in cystic fibrosis patients. It is common in patients who are neutropenic and it has a propensity to invade blood vessels with consequent extrapulmonary spread.

Pseudomonas septicemia is a very fulminant disease.

Legionella Pneumophila Legionella pneumophila is the agent of Legionnaires disease, an eponym for the epidemic and sporadic forms of

pneumonia caused by this organism. Pontiac fever is a related self-limited upper respiratory tract infection caused by L. pneumophila, without pneumonic

symptoms. This organism flourishes in artificial aquatic environments, such as water-cooling towers and within the tubing system of

domestic (potable) water supplies. The mode of transmission is thought to be either inhalation of aerosolized organisms or aspiration of contaminated

drinking water. Legionella pneumonia is common in individuals with some predisposing condition such as cardiac, renal, immunologic, or

hematologic disease. Organ transplant recipients are particularly susceptible. It can be quite severe, frequently requiring hospitalization, and immunosuppressed patients may have fatality rates of up

to 50%. Rapid diagnosis is facilitated by demonstration of Legionella antigens in the urine or by a positive fluorescent antibody

test on sputum samples; culture remains the gold standard of diagnosis.

COMMUNITY-ACQUIRED ATYPICAL (VIRAL AND MYCOPLASMAL) PNEUMONIAS

The term "primary atypical pneumonia" was initially applied to an acute febrile respiratory disease characterized by patchy inflammatory changes in the lungs, largely confined to the alveolar septa and pulmonary interstitium.

The term "atypical" denotes the moderate amount of sputum, no physical findings of consolidation, only moderate elevation of white cell count, and lack of alveolar exudate.

The pneumonitis is caused by a variety of organisms, the most common being Mycoplasma pneumoniae. Mycoplasma infections are particularly common among children and young adults. They occur sporadically or as local epidemics in closed communities (schools, military camps, and prisons). Other etiologic agents are viruses, including influenza virus types A and B, the respiratory syncytial viruses, adenovirus,

rhinoviruses, rubeola, and varicella viruses; Chlamydia pneumoniae; and Coxiella burnetti (Q fever). In some cases, the cause cannot be determined. Any one of these agents can cause merely an upper respiratory tract

infection, recognized as the common cold, or a more severe lower respiratory tract infection. The circumstances that favor such extension of the infection are often mysterious but include malnutrition, alcoholism,

and underlying debilitating illnesses. The common pathogenetic mechanism is attachment of the organisms to the upper respiratory tract epithelium followed

by necrosis of the cells and an inflammatory response. When the process extends to the alveoli, there is usually interstitial inflammation, but there may also be some

outpouring of fluid into alveolar spaces, so that on chest films the changes may mimic bacterial pneumonia. Damage to and denudation of the respiratory epithelium inhibit mucociliary clearance and predispose to secondary

bacterial infections.

Morphology All causal agents produce essentially similar morphologic patterns. The pneumonic involvement may be quite patchy or may involve whole lobes bilaterally or unilaterally. The affected areas are red-blue, congested, and subcrepitant. The pleura is smooth, and pleuritis or pleural effusions are infrequent. The histologic pattern depends on the severity of the disease.

Predominant is the interstitial nature of the inflammatory reaction, virtually localized within the walls of the alveoli. The alveolar septa are widened and edematous and usually have a mononuclear inflammatory infiltrate of lymphocytes,

histiocytes, and occasionally plasma cells. In acute cases, neutrophils may also be present. The alveoli may be free from exudate, but in many patients, there is intra-alveolar proteinaceous material, a cellular

exudate, and characteristically pink hyaline membranes lining the alveolar walls, similar to those seen in hyaline membrane disease of infants.

These changes reflect alveolar damage similar to that seen diffusely in ARDS. Eradication of the infection is followed by reconstitution of the normal architecture of the lung.

Superimposed bacterial infection modifies the histologic picture by causing ulcerative bronchitis and bronchiolitis and may yield the anatomic changes that were described in the section on bacterial pneumonia.

Some viruses, such as herpes simplex, varicella, and adenovirus, may be associated with necrosis of bronchial and alveolar epithelium and acute inflammation.

Epithelial giant cells with intranuclear or intracytoplasmic inclusions may be present in cytomegalic inclusion disease. Other viruses produce cytopathic changes.

Clinical Course The clinical course is extremely varied. Many cases masquerade as severe upper respiratory tract infections or as chest

colds. Even patients with well-developed atypical pneumonia have few localizing symptoms. Cough may well be absent, and the major manifestations may consist only of fever, headache, muscle aches, and pains in

the legs. The edema and exudation are both strategically located to cause mismatching of ventilation and blood flow and thus

evoke symptoms out of proportion to the scanty physical findings. The ordinary sporadic form of the disease is usually mild with a low mortality rate, below 1%. Interstitial pneumonia, however, may assume epidemic proportions with intensified severity and greater mortality, as

documented in the devestating influenzal pandemics of 1915 and 1918 and the many smaller epidemics since then. Secondary bacterial infection by staphylococci or streptococci is common in such circumstances

Influenza Infections The genome of influenza virus is composed of eight helices of single-stranded RNA, each encoding a single gene and

each bound by a nucleoprotein that determines the type of influenza virus (A, B, or C). The spherical surface of influenza virus is a lipid bilayer (envelope) containing the viral hemagglutinin and

neuraminidase, which determine the subtype of the virus (H1 to H3; N1 or N2). Host antibodies to the hemagglutinin and neuraminidase prevent and ameliorate, respectively, future infection with the influenza virus.

Two mechanisms account for the clearance of primary influenza virus infection: cytotoxic T cells kill virus-infected cells, and an intracellular anti-influenza protein (called Mx1) is induced in macrophages by the cytokines interferon-α and interferon-β.101

Morphology o Viral upper respiratory infections are marked by mucosal hyperemia and swelling with a predominantly

lymphomonocytic and plasmacytic infiltration of the submucosa accompanied by overproduction of mucus secretions.

o The swollen mucosa and viscid exudate may plug the nasal channels, sinuses, or the Eustachian tubes and lead to suppurative secondary bacterial infection.

o Virus-induced tonsillitis with enlargement of the lymphoid tissue within Waldeyer ring is frequent in children, although lymphoid hyperplasia is not usually associated with suppuration or abscess formation, such as is encountered with streptococci or staphylococci.

In laryngotracheobronchitis and bronchiolitis, there are vocal cord swelling and abundant mucous exudation. Impairment of bronchociliary function invites bacterial superinfection with more marked suppuration.

Plugging of small airways may give rise to focal lung atelectasis. In the more severe bronchiolar involvement, widespread plugging of secondary and terminal airways by cell debris, fibrin, and inflammatory exudate may, when prolonged, cause organization and fibrosis, resulting in obliterative bronchiolitis and permanent lung damage.

Viral pneumonias, like bacterial pneumonias, take a variety of anatomic forms as described above. Soource: Robins and Cotran Patho

2. What are the etiologic agent of acute acquired viral pneumonia in the different age groups?

Table 22-1 Viruses Associated with Pneumonia in Children(source: Kendig’s Respiratory Diseases in Children)

Viruses Age Group

Infants Preschool School Age

Respiratory syncytial +++ ++ +

Parainfluenza type 3 ++ + +

Parainfluenza type 1 ++ ++ +

Influenza A + ++ ++

Influenza B + + ++

Parainfluenza type 2 + + +

Adenovirus + + +

Measles + + +

Cytomegalovirus + + +

Picornavirus + + +

3. what is the pathophysiology of pneumonia?

Pathophysiology

Pneumonia results from the proliferation of microbial pathogens at the alveolar level and the host's response to those pathogens.

Microorganisms gain access to the lower respiratory tract in several ways. The most common is by aspiration from the oropharynx. Small-volume aspiration occurs frequently during sleep (especially in the elderly) and in patients with decreased levels of

consciousness. Many pathogens are inhaled as contaminated droplets. Rarely, pneumonia occurs via hematogenous spread (e.g., from tricuspid endocarditis) or by contiguous extension from

an infected pleural or mediastinal space. Mechanical factors are critically important in host defense.

The hairs and turbinates of the nares catch larger inhaled particles before they reach the lower respiratory tract, and the branching architecture of the tracheobronchial tree traps particles on the airway lining, where mucociliary clearance and local antibacterial factors either clear or kill the potential pathogen.

The gag reflex and the cough mechanism offer critical protection from aspiration. In addition, the normal flora adhering to mucosal cells of the oropharynx, whose components are remarkably constant,

prevents pathogenic bacteria from binding and thereby decreases the risk of pneumonia caused by these more virulent bacteria.

When these barriers are overcome or when the microorganisms are small enough to be inhaled to the alveolar level, resident alveolar macrophages are extremely efficient at clearing and killing pathogens.

Macrophages are assisted by local proteins (e.g., surfactant proteins A and D) that have intrinsic opsonizing properties or antibacterial or antiviral activity.

Once engulfed, the pathogens even if they are not killed by macrophages are eliminated via either the mucociliary elevator or the lymphatics and no longer represent an infectious challenge.

Only when the capacity of the alveolar macrophages to ingest or kill the microorganisms is exceeded does clinical pneumonia become manifest.

In that situation, the alveolar macrophages initiate the inflammatory response to bolster lower respiratory tract defenses. The host inflammatory response, rather than the proliferation of microorganisms, triggers the clinical syndrome of

pneumonia. The release of inflammatory mediators, such as interleukin (IL) 1 and tumor necrosis factor (TNF), results in fever.

Chemokines, such as IL-8 and granulocyte colony-stimulating factor, stimulate the release of neutrophils and their attraction to the lung, producing both peripheral leukocytosis and increased purulent secretions.

Inflammatory mediators released by macrophages and the newly recruited neutrophils create an alveolar capillary leak equivalent to that seen in the acute respiratory distress syndrome (ARDS), although in pneumonia this leak is localized (at least initially).

Even erythrocytes can cross the alveolar-capillary membrane, with consequent hemoptysis. The capillary leak results in a radiographic infiltrate and rales detectable on auscultation, and hypoxemia results from

alveolar filling. Moreover, some bacterial pathogens appear to interfere with the hypoxic vasoconstriction that would normally occur

with fluid-filled alveoli, and this interference can result in severe hypoxemia. Increased respiratory drive in the systemic inflammatory response syndrome (SIRS) leads to respiratory alkalosis.

Decreased compliance due to capillary leak, hypoxemia, increased respiratory drive, increased secretions, and occasionally infection-related bronchospasm all lead to dyspnea.

If severe enough, the changes in lung mechanics secondary to reductions in lung volume and compliance and the intrapulmonary shunting of blood may cause the patient's death.

(Harrison's Principles of Internal Medicine 17th Edition)

4. What are the pathologic changes/findings in pneumonia. How are they correlated with chest x-ray findings? (Robbin’s Pathology 7th )

(BACTERIAL) PNEUMONIASMorphology.

Bacterial pneumonia has two gross patterns of anatomic distribution: lobular bronchopneumonia and lobar pneumonia. Patchy consolidation of the lung is the dominant characteristic of bronchopneumonia. Lobar pneumonia is an acute bacterial infection resulting in fibrinosuppurative consolidation of a large portion of a lobe

or of an entire lobe. These anatomic but still classic categorizations are often difficult to apply in the individual case because patterns overlap. The patchy involvement may become confluent, producing virtually total lobar consolidation; in contrast, effective

antibiotic therapy for any form of pneumonia may limit involvement to a subtotal consolidation. Moreover, the same organisms may produce bronchopneumonia in one patient, whereas in the more vulnerable

individual, a full-blown lobar involvement develops.

Most important from the clinical standpoint are identification of the causative agent and determination of the extent of disease.

In lobar pneumonia, four stages of the inflammatory response have classically been described: congestion, red hepatization, gray hepatization, and resolution.

Present-day effective antibiotic therapy frequently slows or halts the progression. In the first stage of congestion, the lung is heavy, boggy, and red.

It is characterized by vascular engorgement, intra-alveolar fluid with few neutrophils, and often the presence of numerous bacteria.

The stage of red hepatization that follows is characterized by massive confluent exudation with red cells (congestion), neutrophils, and fibrin filling the alveolar spaces.

On gross examination, the lobe now appears distinctly red, firm, and airless, with a liver-like consistency, hence the term hepatization.

The stage of gray hepatization follows with progressive disintegration of red cells and the persistence of a fibrinosuppurative exudate, giving the gross appearance of a grayish brown, dry surface.

In the final stage of resolution, the consolidated exudate within the alveolar spaces undergoes progressive enzymatic digestion to produce a granular, semifluid, debris that is resorbed, ingested by macrophages, coughed up, or organized by fibroblasts growing into it.

Pleural fibrinous reaction to the underlying inflammation, often present in the early stages if the consolidation extends to the surface (pleuritis), may similarly resolve.

More often, it undergoes organization, leaving fibrous thickening or permanent adhesions. Foci of bronchopneumonia are consolidated areas of acute suppurative inflammation. The consolidation may be patchy through one lobe but is more often multilobar and frequently bilateral and basal

because of the tendency of secretions to gravitate into the lower lobes. Well-developed lesions are usually 3 to 4 cm in diameter, slightly elevated, dry, granular, gray-red to yellow, and poorly delimited at their margins.

Histologically, the reaction usually elicits a suppurative, neutrophil-rich exudate that fills the bronchi, bronchioles, and adjacent alveolar spaces.

Complications of pneumonia include 1. tissue destruction and necrosis, causing abscess formation (particularly common with type 3 pneumococci or Klebsiella infections); 2. spread of infection to the pleural cavity, causing the intrapleural fibrinosuppurative reaction known as empyema;3. organization of the exudate, which may convert a portion of the lung into solid tissue; and 4. bacteremic dissemination to the heart valves, pericardium, brain, kidneys, spleen, or joints, causing metastatic abscesses, endocarditis, meningitis, or suppurative arthritis.

ATYPICAL (VIRAL AND MYCOPLASMAL) PNEUMONIASMorphology.

All causal agents produce essentially similar morphologic patterns. The pneumonic involvement may be quite patchy or may involve whole lobes bilaterally or unilaterally. The affected areas are red-blue, congested, and subcrepitant. The pleura is smooth, and pleuritis or pleural effusions are

infrequent. The histologic pattern depends on the severity of the disease. Predominant is the interstitial nature of the inflammatory reaction, virtually localized within the walls of the alveoli. The alveolar septa are widened and edematous and usually have a mononuclear inflammatory infiltrate of lymphocytes,

histiocytes, and occasionally plasma cells. In acute cases, neutrophils may also be present. The alveoli may be free from exudate, but in many patients, there is intra-alveolar proteinaceous material, a cellular

exudate, and characteristically pink hyaline membranes lining the alveolar walls, similar to those seen in hyaline membrane disease of infants.

These changes reflect alveolar damage similar to that seen diffusely in ARDS . Eradication of the infection is followed by reconstitution of the normal architecture of the lung.

Superimposed bacterial infection modifies the histologic picture by causing ulcerative bronchitis and bronchiolitis and may yield the anatomic changes that were described in the section on bacterial pneumonia.

Some viruses, such as herpes simplex, varicella, and adenovirus, may be associated with necrosis of bronchial and alveolar epithelium and acute inflammation.

Epithelial giant cells with intranuclear or intracytoplasmic inclusions may be present in cytomegalic inclusion disease.

CHRONIC PNEUMONIAMorphology.

In the lungs of otherwise healthy adults, Histoplasma infections produce epithelioid cell granulomas, which usually undergo coagulative necrosis and coalesce to produce large areas of consolidation but may also liquefy to form cavities. With spontaneous or drug control of the infection, these lesions undergo fibrosis and concentric calcification (tree-bark appearance).

Histologic differentiation from tuberculosis, sarcoidosis, and coccidioidomycosis requires identification of the 3- to 5-μm thin-walled yeast forms (stained with methenamine silver) that may persist in tissues for years.

In chronic histoplasmosis, gray-white granulomas are usually present in the apices of the lungs with retraction and thickening of the pleura and in the hilar nodes.

Further progression involves more and more of the lung parenchyma, with cavity formation less frequent than in tuberculosis.

In fulminant disseminated histoplasmosis, which occurs in immunosuppressed individuals, epithelioid cell granulomas are not formed; instead, there are focal accumulations of mononuclear phagocytes filled with fungal yeasts throughout the tissues and organs of the body.

The presence of macrophages stuffed with organisms resembles that found in severe cases of visceral leishmaniasis.

(Harrison’s 16th edition)

PATHOLOGY The pathology of pneumonia manifests as four general patterns: lobar pneumonia, bronchopneumonia, interstitial

pneumonia, and miliary pneumonia.

Lobar Pneumonia

Lobar pneumonia classically involves an entire lung lobe relatively homogeneously, although in some patients a small portion of the lobe may be unaffected or at an earlier stage of involvement.

Four stages of lobar pneumonia may exist simultaneously in the same lung, as the tendency of the progression to be synchronous is not absolute.

The first stage —congestiono occurs during the first 24 h and is characterized grossly by redness and a doughy consistency and

microscopically by vascular congestion and alveolar edema. o At this stage, many bacteria are present and are swept by the rapid expansion of edema fluid throughout the

lobe via the pores of Kohn. o Only a few neutrophils are seen at this stage.

The second stage o termed red hepatization because of the color of the lung and the similarity of its airless, noncrepitant firmness

to the consistency of liver—is characterized microscopically by the presence of many erythrocytes, neutrophils, desquamated epithelial cells, and fibrin in the alveolar spaces.

In the third stage —gray hepatizationo the lung is dry, friable, and gray-brown to yellow as a consequence of a persistent fibrinopurulent exudate, a

progressive disintegration of red blood cells, and the variable presence of hemosiderin. o The exudate contains macrophages as well as neutrophils, but bacteria are seldom visible.o The second and third stages last for 2 to 3 days each, with a 2- to 6-day duration of maximal consolidation.

The final stage —resolutiono is characterized by enzymatic digestion of the alveolar exudate; resorption, phagocytosis, or coughing up of

the residual debris; and restoration of the pulmonary architecture.o Fibrinous inflammation may extend to and across the pleural space, causing a rub heard by auscultation, and

may lead to resolution or to organization and pleural adhesions.

Bronchopneumonia Bronchopneumonia, a patchy consolidation involving one or several lobes, usually involves the dependent lower and

posterior portions of the lung—a pattern attributable to the distribution of aspirated oropharyngeal contents by gravity. The consolidated areas are usually poorly demarcated, although in some cases there is an abrupt delimitation of the

pneumonia at interlobular septa. The neutrophilic exudate is centered in bronchi and bronchioles, with centrifugal spread to the adjacent alveoli and

diminishing cellular exudate; often there is only edema in the periphery of the lesion.

Interstitial Pneumonia Interstitial pneumonia is defined by histopathologic identification of an inflammatory process predominantly involving

the interstitium, including the alveolar walls and the connective tissue around the bronchovascular tree. The inflammation may be patchy or diffuse. The alveolar septa contain an infiltration of lymphocytes, macrophages, and plasma cells. The alveoli do not contain a significant exudate, but protein-rich hyaline membranes similar to those found in adult

respiratory distress syndrome (ARDS)may line the alveolar spaces. Some viruses with tropism for epithelial cells of the airways and alveoli may cause necrosis of the epithelium. In some instances, there may be a significant inflammatory exudate, with extensive degradation of inflammatory cells. Bacterial superinfection of viral pneumonia can also produce a mixed pattern of interstitial and alveolar airspace

inflammation.

Miliary Pneumonia The original description of miliary pneumonia was based on the resemblance of the diffusely distributed 2- to 3-mm

lesions of hematogenous tuberculosis to millet seeds. The current concept of miliary pneumonia is based on its numerous discrete lesions resulting from the spread of the

pathogen to the lungs via the bloodstream. The varying degrees of immunocompromise in miliary tuberculosis, histoplasmosis, and coccidioidomycosis manifest as

variations in the tissue reaction (from granulomas with caseous necrosis to foci of necrosis); the fibrinous exudate; and the weak, poorly formed cellular reaction.

Miliary herpesvirus, cytomegalovirus, or varicella-zoster virus infection in severely immunocompromised patients results in numerous acute necrotizing hemorrhagic lesions.

CHEST RADIOGRAPHY Chest radiography is often the initial diagnostic study performed to evaluate patients with respiratory symptoms, but it

can also provide the initial evidence of disease in patients who are free of symptoms. Perhaps the most common example of the latter situation is the finding of one or more nodules or masses when the

radiograph is performed for a reason other than evaluation of respiratory symptoms. A number of diagnostic possibilities are often suggested by the radiographic pattern. A localized region of opacification

involving the pulmonary parenchyma can be described as a nodule (usually >3 cm in diameter), a mass (usually >3 cm in diameter), or an infiltrate.

Diffuse disease with increased opacification is usually characterized as having an alveolar, an interstitial, or a nodular pattern. In contrast, increased radiolucency can be localized, as seen with a cyst or bulla, or generalized, as occurs with emphysema.

The chest radiograph is also particularly useful for the detection of pleural disease, especially if manifested by the presence of air or liquid in the pleural space.

An abnormal appearance of the hila and/or the mediastinum can suggest a mass or enlargement of lymph nodes.

INTEGRATION OF THE PRESENTING CLINICAL PATTERN AND DIAGNOSTIC STUDIES Patients with respiratory symptoms but a normal chest radiograph most commonly have diseases affecting the airways,

such as asthma or chronic obstructive pulmonary disease. However, the latter diagnosis is also commonly associated with radiographic abnormalities, such as diaphragmatic

flattening and attenuation of vascular markings. Other disorders of the respiratory system for which the chest radiograph is normal include disorders of the respiratory

pump (either the chest wall or the neuromuscular apparatus controlling the chest wall) or pulmonary circulation and occasionally interstitial lung disease.

Chest examination and pulmonary function tests are generally helpful in sorting out these diagnostic possibilities. Obstructive diseases associated with a normal or relatively normal chest radiograph are often characterized by findings

on physical examination and pulmonary function testing that are typical for these conditions. Similarly, diseases of the respiratory pump or interstitial diseases may also be suggested by findings on physical

examination or by particular patterns of restrictive disease seen on pulmonary function testing. When respiratory symptoms are accompanied by radiographic abnormalities, diseases of the pulmonary parenchyma or

the pleura are usually present. Either diffuse or localized parenchymal lung disease is generally visualized well on the radiograph, and both air and liquid

in the pleural space (pneumothorax and pleural effusion, respectively) are usually readily detected by radiography. Radiographic findings in the absence of respiratory symptoms often indicate localized disease affecting the airways or the

pulmonary parenchyma. One or more nodules or masses can suggest intrathoracic malignancy, but they can also be the manifestation of a current

or previous infectious process. Patients with diffuse parenchymal lung disease on radiographic examination may be free of symptoms, as is sometimes

the case with pulmonary sarcoidosis.

DIAGNOSIS The usual standard for the diagnosis of pneumonia is chest radiography, which, however, is not 100% sensitive. High-resolution computed tomography (CT)occasionally detects pulmonary opacities in patients with symptoms and signs

suggestive of pneumonia in whom chest radiographs are reported as not showing pneumonia. CT is also more likely than chest radiography to show bilateral involvement. If pneumonia is strongly suspected on clinical

grounds and no opacity is seen on the initial chest radiograph, it is useful to repeat the radiograph in 24 to 48 h or to perform CT.

It is important to remember that an opacity visible on chest radiograph may not be due to pneumonia; many other disease processes can result in opacities.

Furthermore, there is variability among radiologists in the interpretation of chest radiographs; most commonly, subsegmental lower-lobe opacities in patients with suboptimal chest radiographs may be reported as atelectasis by one radiologist and as pneumonia by another.

Occasionally, an etiologic diagnosis is suggested by the findings on chest radiography. For example, a cavitating upper-lobe lesion raises the likelihood of tuberculosis, and pneumatoceles suggest S. aureus

pneumonia. An air-fluid level suggests a pulmonary abscess, which is often polymicrobial. In the immunocompromised host, a crescent (meniscus)sign suggests aspergillosis. In most instances, however, no

etiologic inference can be made from radiographic findings. Concomitant diseases (such as congestive heart failure or pulmonary fibrosis) may make both the clinical and the

radiologic diagnosis of pneumonia difficult. However, serial clinical and radiographic observations usually allow the clinician to determine whether there are two

diseases or just one and to identify which one is causing the clinical and radiographic findings.

5. What are the clinical manifestations of pneumonia and correlate these with the pathologic findings?

CLINICAL MANIFESTATIONS Pneumonia can range in severity from mild to fulminant and fatal, with serious disease developing even in previously

healthy persons. The onset may be sudden and dramatic or insidious.

Fever, cough (nonproductive or productive of purulent or rust-colored sputum), pleuritic chest pain, chills or rigors, and shortness of breath are typical—albeit nonspecific—manifestations of pneumonia.

Symptoms reported with some frequency include headache, nausea, vomiting, diarrhea, myalgia, arthralgia, and/or fatigue.

Falls and new-onset or worsening confusion may be important manifestations in an elderly person. The physical signs associated with pneumonia are tachypnea, dullness to percussion, increased tactile and vocal fremitus,

egophony, whispering pectoriloquy, crackles, and pleural friction rub. In two studies, patients with a respiratory rate of >25/min had a pneumonia likelihood ratio of 1.5 to 3.4.

In another study, patients with a heart rate of </=100/min, a temperature of </=37.8°C, and a respiratory rate of </=20/min were five times less likely to have pneumonia than patients who had all of these abnormal parameters.

A diagnosis of pneumonia based on physical examination has a sensitivity of 47 to 69% and a specificity of 58 to 75%; thus a clinical diagnosis of pneumonia should be confirmed by chest radiography.

For patients who have pneumonia clinically diagnosed in an office setting, the physician must decide whether or not to obtain a chest radiograph. Even if the clinical assessment suggests mild disease, all patients with pneumonia who have an oral temperature of >38.5°C or who have pleuritic chest pain should have a chest radiograph.

Pulmonary embolus is always a consideration with pleuritic chest pain, and further investigations are warranted if the chest radiograph is normal in this setting.

If pneumonia is extensive in a patient with this degree of fever, further evaluation and perhaps hospitalization are necessary.

The single most useful clinical sign of the severity of pneumonia is a respiratory rate of >30/min in a person without underlying lung disease.

Of the several measures of pneumonia severity, the simplest is the British Thoracic Society rule, which relies on three clinical findings and one laboratory finding.

If none of these features is present, the mortality rate is 2.4%; with one feature, the mortality rate is 8%; with two, 23%; with three, 33%; and with all four, 83%.

6. What is the drug of choice for pneumonia in this patient? What are the drugs of choice for the pneumonias in the different age groups?

6.1 Classify the drug as to its therapeutic group of family.6.2 Give the pharmacodynamic properties of each drug.6.3 Give the pharmacokinetic properties of each drug.6.4 Give the toxicology of each drug.

Drug of choice in different age groups.

Treatment of suspected bacterial pneumonia is based on the presumptive cause and the clinical appearance of the child. For mildly ill children who do not require hospitalization , amoxicillin is recommended. In communities with a

high percentage of penicillin-resistant pneumococci, high doses of amoxicillin (80–90?mg/kg/24?hr) should be prescribed. Therapeutic alternatives include cefuroxime axetil or amoxicillin/clavulanate.

For school-aged children and in those in whom infection with M. pneumoniae is suggested, a macrolide antibiotic such as azithromycin is an appropriate therapeutic choice.

The empirical treatment of suspected bacterial pneumonia in a hospitalized child requires an approach based on the clinical manifestations at the time of presentation. Parenteral cefuroxime (75–150?mg/kg/24?hr) is the mainstay of therapy when bacterial pneumonia is suggested. If features suggest staphylococcal pneumonia (e.g., pneumatoceles, empyema), initial therapy should also include vancomycin or clindamycin.

If viral pneumonia is suggested, it is reasonable to withhold antibiotic therapy. However, this option should be reserved for those patients who are mildly ill, have clinical evidence suggesting viral infection, and are in no respiratory distress. Up to 30% of patients with known viral infection may have co-existing bacterial pathogens; therefore, if the decision is made to withhold antibiotic therapy based on presumptive diagnosis of a viral

infection, deterioration in clinical status should signal the possibility of superimposed bacterial infection and antibiotic therapy should be initiated.

THE PENICILLINS

Classification of the Penicillins and Summary of Their Pharmacological Properties Penicillin G and its close congener penicillin V are highly active against sensitive strains of gram-positive cocci, but they

are readily hydrolyzed by penicillinase. Thus they are ineffective against most strains of S. aureus. The penicillinase-resistant penicillins [methicillin (discontinued in the United States), nafcillin, oxacillin, cloxacillin (not

currently marketed in the United States), and dicloxacillin] have less potent antimicrobial activity against microorganisms that are sensitive to penicillin G, but they are the agents of first choice for treatment of penicillinase-producing S. aureus and S. epidermidis that are not methicillin-resistant.

Ampicillin, amoxicillin, and others make up a group of penicillins whose antimicrobial activity is extended to include such gram-negative microorganisms as Haemophilus influenzae, E. coli, and Proteus mirabilis. Frequently these drugs are administered with a b-lactamase inhibitor such as clavalanate or salbactam to prevent hydrolysis by broad-spectrum b-lactamases that are found with increasing frequency in clinical isolates of these gram-negative bacteria.

The antimicrobial activity of carbenicillin (discontinued in the United States), its indanyl ester (carbenicillin indanyl), and ticarcillin is extended to include Pseudomonas, Enterobacter, and Proteus spp. These agents are inferior to ampicillin against gram-positive cocci and Listeria monocytogenes and are less active than piperacillin against Pseudomonas.

Mezlocillin, azlocillin (both discontinued in the United States), and piperacillin have excellent antimicrobial activity against Pseudomonas, Klebsiella, and certain other gram-negative microorganisms. Piperacillin retains the activity of ampicillin against gram-positive cocci and L. monocytogenes.

Penicillin G and Penicillin V

Antimicrobial Activity. The antimicrobial spectra of penicillin G (benzylpenicillin) and penicillin V (the phenoxymethyl derivative) are

very similar for aerobic gram-positive microorganisms. However, penicillin G is 5 to 10 times more active against Neisseria spp. that are sensitive to penicillins and against certain anaerobes.

Penicillin G has activity against a variety of species of gram-positive and gram-negative cocci, although many bacteria previously sensitive to the agent are now resistant.

Most streptococci (but not enterococci) are very susceptible to the drug; concentrations of less than 0.01 mg/ml usually are effective.

However, penicillin-resistant viridans streptococci and S. pneumoniae are becoming more common. Many penicillin-resistant pneumococci also are resistant to third-generation cephalosporins.

Absorption Oral Administration of Penicillin G . About one-third of an orally administered dose of penicillin G is absorbed

from the intestinal tract under favorable conditions. Gastric juice at pH 2 rapidly destroys the antibiotic. The decrease in gastric acid production with aging accounts for better absorption of penicillin G from the

gastrointestinal tract of older individuals. Absorption is rapid, and maximal concentrations in blood are attained in 30 to 60 minutes. The peak value is approximately 0.5 unit/ml (0.3 mg/ml) after an oral dose of 400,000 units (about 250 mg) in an

adult. Ingestion of food may interfere with enteric absorption of all penicillins, perhaps by adsorption of the antibiotic onto food particles.

Thus oral penicillin G should be administered at least 30 minutes before a meal or 2 hours after. Despite the convenience of oral administration of penicillin G, this route should be used only in infections in

which clinical experience has proven its efficacy.

Oral Administration of Penicillin V. The virtue of penicillin V in comparison with penicillin G is that it is more stable in an acidic medium and therefore is better absorbed from the gastrointestinal tract.

On an equivalent oral-dose basis, penicillin V (K+ salt; VEETIDS) yields plasma concentrations two to five times greater than those provided by penicillin G.

The peak concentration in the blood of an adult after an oral dose of 500 mg is nearly 3 mg/ml. Once absorbed, penicillin V is distributed in the body and excreted by the kidney in a manner similar to that of

penicillin G. Parenteral Administration of Penicillin G. After intramuscular injection, peak concentrations in plasma are

reached within 15 to 30 minutes. This value declines rapidly because the half-life of penicillin G is 30 minutes. Many means for prolonging the sojourn of the antibiotic in the body and thereby reducing the frequency of

injections have been explored. Probenecid blocks renal tubular secretion of penicillin, but it is used rarely for this purpose. More commonly, repository preparations of penicillin G are employed. The two such compounds currently favored are penicillin G procaine (WYCILLIN, others) and penicillin G

benzathine (BICILLIN L-A, PERMAPEN). Such agents release penicillin G slowly from the area in which they are injected and produce relatively low but

persistent concentrations of antibiotic in the blood. Penicillin G procaine suspension is an aqueous preparation of the crystalline salt that is only 0.4% soluble in

water. Procaine combines with penicillin mole for mole; a dose of 300,000 units thus contains approximately 120 mg

procaine. When large doses of penicillin G procaine are given (e.g., 4.8 million units), procaine may reach toxic

concentrations in the plasma. If the patient is believed to be hypersensitive to procaine, 0.1 ml of 1% solution of procaine should be injected

intradermally as a test. The anesthetic effect of the procaine accounts in part for the fact that injections of penicillin G procaine are

virtually painless. The injection of 300,000 units of penicillin G procaine produces a peak concentration in plasma of about 0.9

mg/ml within 1 to 3 hours; after 24 hours, the concentration is reduced to 0.1 mg/ml, and by 48 hours it has fallen to 0.03 mg/ml.

A larger dose (600,000 units) yields somewhat higher values that are maintained for as long as 4 to 5 days. Penicillin G benzathine suspension is the aqueous suspension of the salt obtained by the combination of 1 mol of

an ammonium base and 2 mol of penicillin G to yield N,N¢-dibenzylethylenediamine dipenicillin G. The salt itself is only 0.02% soluble in water.

The long persistence of penicillin in the blood after a suitable intramuscular dose reduces cost, need for repeated injections, and local trauma.

The local anesthetic effect of penicillin G benzathine is comparable with that of penicillin G procaine. Penicillin G benzathine is absorbed very slowly from intramuscular depots and produces the longest duration of

detectable antibiotic of all the available repository penicillins. For example, in adults, a dose of 1.2 million units given intramuscularly produces a concentration in plasma of

0.09 mg/ml on the first, 0.02 mg/ml on the fourteenth, and 0.002 mg/ml on the thirty-second day after injection. The average duration of demonstrable antimicrobial activity in the plasma is about 26 days.

Excretion. Under normal conditions, penicillin G is eliminated rapidly from the body mainly by the kidney but in small part

in the bile and by other routes. Approximately 60% to 90% of an intramuscular dose of penicillin G in aqueous solution is eliminated in the urine,

largely within the first hour after injection. The remainder is metabolized to penicilloic acid. The half-life for elimination of penicillin G is about 30 minutes in normal adults. Approximately 10% of the drug is eliminated by glomerular filtration and 90% by tubular secretion.

Renal clearance approximates the total renal plasma flow. The maximal tubular secretory capacity for penicillin in the normal adult male is about 3 million units (1.8 g) per hour.

Clearance values are considerably lower in neonates and infants because of incomplete development of renal function; as a result, after doses proportionate to surface area, the persistence of penicillin in the blood is several times as long in premature infants as in children and adults.

The half-life of the antibiotic in children younger than 1 week of age is 3 hours; by 14 days of age it is 1.4 hours. After renal function is fully established in young children, the rate of renal excretion of penicillin G is considerably

more rapid than in adults. Anuria increases the half-life of penicillin G from a normal value of 0.5 hour to about 10 hours. When renal

function is impaired, 7% to 10% of the antibiotic may be inactivated each hour by the liver. Patients with renal shutdown who require high-dose therapy with penicillin can be treated adequately with 3

million units of aqueous penicillin G followed by 1.5 million units every 8 to 12 hours. The dose of the drug must be readjusted during dialysis and the period of progressive recovery of renal function. If, in addition to renal failure, hepatic insufficiency also is present, the half-life will be prolonged even further.

The Penicillinase-Resistant Penicillins The penicillins described in this section are resistant to hydrolysis by staphylococcal penicillinase. Their appropriate use should be restricted to the treatment of infections that are known or suspected to be caused by

staphylococci that elaborate the enzyme¾which now includes the vast majority of strains of this bacterium that are encountered clinically.

These drugs are much less active than is penicillin G against other penicillin-sensitive microorganisms, including non-penicillinase-producing staphylococci.

The role of the penicillinase-resistant penicillins as the agents of choice for most staphylococcal disease is changing with the increasing incidence of isolates of so-called methicillin-resistant microorganisms.

As commonly used, this term denotes resistance of these bacteria to all the penicillinase-resistant penicillins and cephalosporins.

Hospital-acquired strains usually are resistant to the aminoglycosides, tetracyclines, erythromycin, and clindamycin as well.

Vancomycin is considered the drug of choice for such infections. Some physicians use a combination of vancomycin and rifampin, especially for life-threatening infections and those

involving foreign bodies. Community-acquired methicillin-resistant strains are less likely to be resistant to other classes of antibiotics with the

exception of macrolide. Methicillin-resistant S. aureus contains an additional high-molecular-weight PBP with a very low affinity for b-lactam

antibiotics. From 40% to 60% of strains of S. epidermidis also are resistant to the penicillinase-resistant penicillins by the same

mechanism. As with methicillin-resistant S. aureus, these strains may appear to be susceptible to cephalosporins on disk-sensitivity

testing, but there usually is a significant population of microbes that is resistant to cephalosporins and that emerges during such therapy.

Vancomycin also is the drug of choice for serious infection caused by methicillin-resistant S. epidermidis; rifampin is given concurrently when a foreign body is involved.

The Isoxazolyl Penicillins: Oxacillin, Cloxacillin, and Dicloxacillin. These three congeneric semisynthetic penicillins are similar pharmacologically and thus conveniently are

considered together. All are relatively stable in an acidic medium and are absorbed adequately after oral administration. All are

markedly resistant to cleavage by penicillinase. These drugs are not substitutes for penicillin G in the treatment of diseases amenable to it, and they are not

active against enterococci or Listeria.

Furthermore, because of variability in intestinal absorption, oral administration is not a substitute for the parenteral route in the treatment of serious staphylococcal infections that require a penicillin unaffected by penicillinase.

Pharmacological Properties . The isoxazolyl penicillins are potent inhibitors of the growth of most penicillinase-producing staphylococci. This is their valid clinical use.

Dicloxacillin is the most active, and many strains of S. aureus are inhibited by concentrations of 0.05 to 0.8 mg/ml.

Comparable values for cloxacillin and oxacillin are 0.1 to 3 and 0.4 to 6 mg/ml, respectively. These differences may have little practical significance, however, because dosages are adjusted accordingly. These agents are, in general, less effective against microorganisms susceptible to penicillin G, and they are not

useful against gram-negative bacteria. These agents are absorbed rapidly but incompletely (30% to 80%) from the gastrointestinal tract. Absorption of the drugs is more efficient when they are taken on an empty stomach; preferably they are

administered 1 hour before or 2 hours after meals to ensure better absorption. Peak concentrations in plasma are attained by 1 hour and approximately 5 to 10 mg/ml after the ingestion of 1 g

oxacillin. Slightly higher concentrations are achieved after the administration of 1 g cloxacillin, whereas the same oral dose of dicloxacillin yields peak plasma concentrations of 15 mg/ml.

There is little evidence that these differences are of clinical significance. All these congeners are bound to plasma albumin to a great extent (approximately 90% to 95%); none is removed from the circulation to a significant degree by hemodialysis.

The isoxazolyl penicillins are excreted rapidly by the kidney. Normally, about one-half of any of these drugs is excreted in the urine in the first 6 hours after a conventional oral dose.

There also is significant hepatic elimination of these agents in the bile. The half-lives for all are between 30 and 60 minutes.

Intervals between doses of oxacillin, cloxacillin, and dicloxacillin do not have to be altered for patients with renal failure.

The above-noted differences in plasma concentrations produced by the isoxazolyl penicillins are related mainly to differences in rate of urinary excretion and degree of resistance to degradation in the liver.

Nafcillin . This semisynthetic penicillin is highly resistant to penicillinase and has proven effective against infections caused

by penicillinase-producing strains of S. aureus. Pharmacological Properties. Nafcillin is slightly more active than oxacillin against penicillin G-resistant S. aureus

(most strains are inhibited by 0.06 to 2 mg/ml). While it is the most active of the penicillinase-resistant penicillins against other microorganisms, it is not as potent as penicillin G.

Nafcillin is variably inactivated in the acidic medium of the gastric contents. Its oral absorption is irregular regardless of whether the drug is taken with meals or on an empty stomach; injectable preparations therefore should be used.

The peak plasma concentration is about 8 mg/ml 60 minutes after a 1-g intramuscular dose. Nafcillin is about 90% bound to plasma protein. Peak concentrations of nafcillin in bile are well above those

found in plasma. Concentrations of the drug in CSF appear to be adequate for therapy of staphylococcal meningitis.

The Aminopenicillins: Ampicillin, Amoxicillin, and Their Congeners These agents have similar antibacterial activity and a spectrum that is broader than the antibiotics heretofore discussed. They all are destroyed by b-lactamase (from both gram-positive and gram-negative bacteria). Antimicrobial Activity . Ampicillin and the related aminopenicillins are bactericidal for both gram-positive and gram-

negative bacteria. The meningococci and L. monocytogenes are sensitive to this class of drugs. Many pneumococcal isolates have varying

levels of resistance to ampicillin.

Penicillin-resistant strains should be considered ampicillin/amoxicillin-resistant. H. influenzae and the viridans group of streptococci exhibit varying degrees of resistance.

Ampicillin . This drug is the prototype of the group. Pharmacological Properties. Ampicillin (PRINCIPEN, others) is stable in acid and is well absorbed after oral

administration. An oral dose of 0.5 g produces peak concentrations in plasma of about 3 mg/ml at 2 hours. Intake of food prior

to ingestion of ampicillin diminishes absorption. Intramuscular injection of 0.5 or 1 g sodium ampicillin yields peak plasma concentrations of about 7 or 10 mg/ml,

respectively, at 1 hour; these decline exponentially, with a half-life of approximately 80 minutes. Severe renal impairment markedly prolongs the persistence of ampicillin in the plasma. Peritoneal dialysis is ineffective in removing the drug from the blood, but hemodialysis removes about 40% of

the body store in about 7 hours. Adjustment of the dose of ampicillin is required in the presence of renal dysfunction. Ampicillin appears in the bile, undergoes enterohepatic circulation, and is excreted in appreciable quantities in

the feces. Amoxicillin.

This drug, a penicillinase-susceptible semisynthetic penicillin, is a close chemical and pharmacological relative of ampicillin.

The drug is stable in acid and is designed for oral use. It is absorbed more rapidly and completely from the gastrointestinal tract than is ampicillin, which is the major difference between the two.

The antimicrobial spectrum of amoxicillin is essentially identical to that of ampicillin, with the important exception that amoxicillin appears to be less effective than ampicillin for shigellosis.

Peak plasma concentrations of amoxicillin (AMOXIL, others) are 2 to 2 1/2 times greater for amoxicillin than for ampicillin after oral administration of the same dose; they are reached at 2 hours and average about 4 mg/ml when 250 mg is administered.

Food does not interfere with absorption. Perhaps because of more complete absorption of this congener, the incidence of diarrhea with amoxicillin is less than that following administration of ampicillin.

The incidence of other adverse effects appears to be similar. While the half-life of amoxicillin is similar to that for ampicillin, effective concentrations of orally administered amoxicillin are detectable in the plasma for twice as long as with ampicillin, again because of the more complete absorption.

About 20% of amoxicillin is protein-bound in plasma, a value similar to that for ampicillin. Most of a dose of the antibiotic is excreted in an active form in the urine. Probenecid delays excretion of the

drug.

Untoward Reactions to Penicillins Hypersensitivity Reactions. Hypersensitivity reactions are by far the most common adverse effects noted with the

penicillins, and these agents probably are the most common cause of drug allergy. Allergic reactions complicate between 0.7% and 4% of all treatment courses. In approximate order of decreasing frequency, manifestations of allergy to penicillins include maculopapular rash,

urticarial rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens-Johnson syndrome, and anaphylaxis.

Other Adverse Reactions. The penicillins have minimal direct toxicity. Apparent toxic effects that have been reported include bone marrow depression, granulocytopenia, and hepatitis. The administration of penicillin G, carbenicillin, piperacillin, or ticarcillin has been associated with a potentially significant

defect of hemostasis that appears to be due to an impairment of platelet aggregation; this may be caused by interference with the binding of aggregating agents to platelet receptors.

When penicillin is injected accidentally into the sciatic nerve, severe pain occurs and dysfunction in the area of distribution of this nerve develops and persists for weeks.

Intrathecal injection of penicillin G may produce arachnoiditis or severe and fatal encephalopathy. Because of this, intrathecal or intraventricular administration of penicillins should be avoided.

The parenteral administration of large doses of penicillin G (>20 million units per day, or less with renal insufficiency) may produce lethargy, confusion, twitching, multifocal myoclonus, or localized or generalized epileptiform seizures.

These are most apt to occur in the presence of renal insufficiency, localized lesions of the central nervous system (CNS), or hyponatremia.

When the concentration of penicillin G in CSF exceeds 10 mg/ml, significant dysfunction of the CNS is frequent. The injection of 20 million units of penicillin G potassium, which contains 34 mEq of K+, may lead to severe or even fatal hyperkalemia in persons with renal dysfunction.

Injection of penicillin G procaine may result in an immediate reaction, characterized by dizziness, tinnitus, headache, hallucinations, and sometimes seizures.

This is due to the rapid liberation of toxic concentrations of procaine. It has been reported to occur in 1 of 200 patients receiving 4.8 million units of penicillin G procaine to treat venereal disease.

Reactions Unrelated to Hypersensitivity or Toxicity. Regardless of the route by which the drug is administered, but most strikingly when it is given by mouth, penicillin changes the composition of the microflora by eliminating sensitive microorganisms.

This phenomenon is usually of no clinical significance, and the normal microflora are reestablished shortly after therapy is stopped.

In some persons, however, superinfection results from the changes in flora. Pseudomembranous colitis, related to overgrowth and production of a toxin by Clostridium difficile, has followed oral and, less commonly, parenteral administration of penicillins.

THE CEPHALOSPORINS

Mechanism of Action. Cephalosporins and cephamycins inhibit bacterial cell wall synthesis in a manner similar to that of penicillin.

Classification. Although cephalosporins may be classified by their chemical structure, clinical pharmacology, resistance to b-lactamase, or antimicrobial spectrum, the well-accepted system of classification by "generations" is very useful, although admittedly somewhat arbitrary.

Classification by generations is based on general features of antimicrobial activity . The first-generation cephalosporins, epitomized by cephalothin and cefazolin, have good activity against gram-positive

bacteria and relatively modest activity against gram-negative microorganisms. Most gram-positive cocci (with the exception of enterococci, methicillin-resistant S. aureus, and S. epidermidis) are susceptible. Most oral cavity anaerobes are sensitive, but the B. fragilis group is resistant. Activity against Moraxella catarrhalis, E. coli, K. pneumoniae, and P. mirabilis is good.

The second-generation cephalosporins have somewhat increased activity against gram-negative microorganisms but are much less active than the third-generation agents. A subset of second-generation agents (cefoxitin, cefotetan, and cefmetazole) also is active against the B. fragilis group.

Third-generation cephalosporins generally are less active than first-generation agents against gram-positive cocci, but they are much more active against the Enterobacteriaceae, including b-lactamase-producing strains. A subset of third-generation agents (ceftazidime and cefoperazone) also is active against P. aeruginosa but less active than other third-generation agents against gram-positive cocci.

Fourth-generation cephalosporins, such as cefepime, have an extended spectrum of activity compared with the third generation and have increased stability from hydrolysis by plasmid and chromosomally mediated b-lactamases. Fourth-generation agents are particularly useful for the empirical treatment of serious infections in hospitalized patients when gram-positive microorganisms, Enterobacteriaceae, and Pseudomonas all are potential etiologies. It is important to remember that none of the cephalosporins has reliable activity against the following bacteria: penicillin-resistant S. pneumoniae, methicillin-resistant S. aureus, methicillin-resistant S. epidermidis and other coagulase-negative staphylococci, Enterococcus, L. monocytogenes, Legionella pneumophila, L. micdadei, C. difficile, Xanthomonas maltophilia, Campylobacter jejuni, and Acinetobacter spp.

First-Generation Cephalosporins.

Cefazolin is relatively well tolerated after either intramuscular or intravenous administration, and concentrations of the drug in plasma after a 1-g intramuscular injection reach 64 mg/ml. Cefazolin is excreted by glomerular filtration and is bound to plasma proteins to a great extent (about 85%). Cefazolin usually is preferred among the first-generation cephalosporins because it can be administered less frequently owing to its longer half-life.

Cephalexin is available for oral administration, and it has the same antibacterial spectrum as the other first-generation cephalosporins. However, it is somewhat less active against penicillinase-producing staphylococci. Oral therapy with cephalexin results in peak concentrations in plasma of 16 mg/ml after a dose of 0.5 g; this is adequate for the inhibition of many gram-positive and gram-negative pathogens. The drug is not metabolized, and between 70% and 100% is excreted in the urine.

Cephradine is similar in structure to cephalexin, and its activity in vitro is almost identical. Cephradine is not metabolized and, after rapid absorption from the gastrointestinal tract, is excreted unchanged in the urine. Cephradine can be administered orally, intramuscularly, or intravenously. When administered orally, it is difficult to distinguish cephradine from cephalexin; some authorities feel that these two drugs can be used interchangeably. Because cephradine is so well absorbed, the concentrations in plasma are nearly equivalent after oral or intramuscular administration.

Cefadroxil is the para-hydroxy analog of cephalexin. Concentrations of cefadroxil in plasma and urine are at somewhat higher levels than are those of cephalexin. The drug may be administered orally once or twice a day for the treatment of urinary tract infections. Its activity in vitro is similar to that of cephalexin.

Second-Generation Cephalosporins. Second-generation cephalosporins have a broader spectrum than do the first-generation agents and are active

against Enterobacter spp., indole-positive Proteus spp., and Klebsiella spp. Cefoxitin is a cephamycin produced by Streptomyces lactamdurans. It is resistant to some b-lactamases

produced by gram-negative rods. This antibiotic is less active than the first-generation cephalosporins against gram-positive bacteria. Cefoxitin is more active than other first- or second-generation agents (except cefotetan) against anaerobes, especially B. fragilis. After an intramuscular dose of 1 g, concentrations in plasma are about 22 mg/ml. The half-life is approximately 40 minutes. Cefoxitin's special role seems to be for treatment of certain anaerobic and mixed aerobic-anaerobic infections, such as pelvic inflammatory disease and lung abscess.

Cefaclor is used orally. The concentration in plasma after oral administration is about 50% of that achieved after an equivalent oral dose of cephalexin. However, cefaclor is more active against H. influenzae and Moraxella catarrhalis, although some b-lactamase-producing strains of these organisms may be resistant.

Loracarbef is an orally administered carbacephin, similar in activity to cefaclor, that is more stable against some b-lactamases. The serum half-life is 1.1 hours.

Cefuroxime is similar to loracarbef with broader gram-negative activity against some Citrobacter and Enterobacter spp. Unlike cefoxitin, cefmetazole, and cefotetan, cefuroxime lacks activity against B. fragilis. The half-life is 1.7 hours, and the drug can be given every 8 hours. Concentrations in CSF are about 10% of those in plasma, and the drug is effective (but inferior to ceftriaxone) for treatment of meningitis owing to H. influenzae (including strains resistant to ampicillin), N. meningitidis, and S. pneumoniae.Cefuroxime axetil is the 1-acetyloxyethyl ester of cefuroxime. Between 30% and 50% of an oral dose is absorbed, and the drug then is hydrolyzed to cefuroxime; resulting concentrations in plasma are variable.

Cefotetan is a cephamycin, and like cefoxitin, it has good activity against B. fragilis. It also is effective against several other species of Bacteroides, and it is slightly more active than cefoxitin against gram-negative aerobes. After an intramuscular dose of 1 g, peak plasma concentrations of cefotetan average 70 mg/ml. It has a half-life of 3.3 hours. Hypoprothrombinemia and inhibition of vitamin K activation with bleeding have occurred in malnourished patients receiving cefotetan owing to the methyl-tetrazole-thiomethyl (MTT) group at position 3; this is preventable if vitamin K is administered as well.

Cefprozil is an orally administered agent that is more active than first-generation cephalosporins against penicillin-sensitive streptococci, E. coli, P. mirabilis, Klebsiella spp., and Citrobacter spp. It has a serum half-life of 1.2 to 1.4 hours.

Third-Generation Cephalosporins.

Cefotaxime is highly resistant to many (but not the extended-spectrum product) of the bacterial b-lactamases and has good activity against many gram-positive and gram-negative aerobic bacteria.

However, activity against B. fragilis is poor compared with agents such as clindamycin and metronidazole. Cefotaxime has a half-life in plasma of about 1 hour and should be administered every 4 to 8 hours for serious

infections. The drug is metabolized in vivo to desacetylcefotaxime, which is less active against most microorganisms than is

the parent compound. However, the metabolite acts synergistically with the parent compound against certain microbes. Cefotaxime has been used effectively for meningitis caused by H. influenzae, penicillin-sensitive S. pneumoniae,

and N. meningitides. Ceftizoxime has a spectrum of activity in vitro that is very similar to that of cefotaxime, except that it is less

active against S. pneumoniae and more active against B. fragilis. The half-life is somewhat longer, 1.8 hours, and the drug thus can be administered every 8 to 12 hours for serious infections. Ceftizoxime is not metabolized, and 90% is recovered in urine.

Ceftriaxone has activity in vitro very similar to that of ceftizoxime and cefotaxime. A half-life of about 8 hours is the outstanding feature. Administration of the drug once or twice daily has been effective for patients with meningitis (Del Rio et al., 1983; Brogden and Ward, 1988), whereas dosage once a day has been effective for other infections. About half the drug can be recovered from the urine; the remainder appears to be eliminated by biliary secretion. A single dose of ceftriaxone (125 to 250 mg) is effective in the treatment of urethral, cervical, rectal, or pharyngeal gonorrhea, including disease caused by penicillinase-producing microorganisms.

Cefpodoxime proxetil is an orally administered third-generation agent that is very similar in activity to the fourth-generation agent cefepime (see below) except that it is not more active against Enterobacter or Pseudomonas spp. It has a serum half-life of 2.2 hours.

Cefditoren pivoxil is a prodrug that is hydrolyzed by esterases during absorption to the active drug, cefditoren. Cefditoren has a half-life of approximately 1.6 hours and is eliminated unchanged in the urine. The drug is active against methicillin-susceptible strains of S. aureus, penicillin-susceptible strains of S. pneumoniae, S. pyogenes, H. influenzae, H. parainfluenzae, and Moraxella catarrhali. Cefditoren pivoxil is only indicated for the treatment of mild-to-moderate pharyngitis, tonsillitis, uncomplicated skin and skin structure infections, and acute exacerbations of chronic bronchitis.

Ceftibuten is an orally effective cephalosporin with a half-life of 2.4 hours. It is less active against gram-positive and gram-negative organisms than cefixime, with activity limited to S. pneumonia and S. pyogenes, H. influenzae, and M. catarrhalis. Ceftibuten is only indicated for acute bacterial exacerbations of chronic bronchitis, acute bacterial otitis media, pharyngitis, and tonsillitis.

Cefdinir is effective orally, with a half-life of approximately 1.7 hours; it is eliminated primarily unchanged in the urine. Cefdinir has a spectrum of activity similar to cefixime . It is inactive against Pseudomonas and Enterobacter spp.

Fourth-Generation Cephalosporins. Cefepime is available for use in the United States, but cefpirome is not. Cefepime is stable to hydrolysis by many

of the previously identified plasmid-encoded b-lactamases (called TEM-1, TEM-2, and SHV-1). It is a poor inducer of, and is relatively resistant to, the type I chromosomally encoded and some extended-

spectrum b-lactamases. Thus it is active against many Enterobacteriaceae that are resistant to other cephalosporins via induction of type

I b-lactamases but remains susceptible to many bacteria expressing extended-spectrum plasmid-mediated b-lactamases (such as TEM-3 and TEM-10). Against the fastidious gram-negative bacteria (H. influenzae, N. gonorrhoeae, and N. meningitidis), cefepime has comparable or greater in vitro activity than cefotaxime.

For P. aeruginosa, cefepime has comparable activity to ceftazidime, although it is less active than ceftazidime for other Pseudomonas spp. and X. maltophilia. Cefepime has higher activity than ceftazidime and comparable activity to cefotaxime for streptococci and methicillin-sensitive S. aureus.

It is not active against methicillin-resistant S. aureus, penicillin-resistant pneumococci, enterococci, B. fragilis, L. monocytogenes, Mycobacterium avium complex, or M. tuberculosis.

Cefepime is excreted almost 100% renally, and doses should be adjusted for renal failure. Cefepime has excellent penetration into the CSF in animal models of meningitis. When given at the

recommended dosage for adults of 2 g intravenously every 12 hours, peak serum concentrations in human beings range from 126 to 193 mg/ml.

The serum half-life is 2 hours.

Adverse Reactions. Hypersensitivity reactions to the cephalosporins are the most common side effects, and there is no evidence that

any single cephalosporin is more or less likely to cause such sensitization. The reactions appear to be identical to those caused by the penicillins, perhaps related to the shared b-lactam structure of both groups of antibiotics.

Immediate reactions such as anaphylaxis, bronchospasm, and urticaria are observed. More commonly, maculopapular rash develops, usually after several days of therapy; this may or may not be accompanied by fever and eosinophilia.

The cephalosporins have been implicated as potentially nephrotoxic agents, although they are not nearly as toxic to the kidney as are the aminoglycosides or the polymyxins.

Renal tubular necrosis has followed the administration of cephaloridine in doses greater than 4 g/day; this agent is no longer available in the United States.

Other cephalosporins are much less toxic and, when used by themselves in recommended doses, rarely produce significant renal toxicity.

High doses of cephalothin (no longer available in the United States) have produced acute tubular necrosis in certain instances, and usual doses (8 to 12 g/day) have caused nephrotoxicity in patients with preexisting renal disease.

There is good evidence that the concurrent administration of cephalothin and gentamicin or tobramycin act synergistically to cause nephrotoxicity, especially in patients older than 60 years of age.

Diarrhea can result from the administration of cephalosporins and may be more frequent with cefoperazone, perhaps because of its greater biliary excretion.

Intolerance to alcohol (a disulfiram-like reaction) has been noted with cephalosporins that contain the MTT group, including cefamandole (no longer available in the United States), cefotetan, moxalactam, and cefoperazone.

Serious bleeding related either to hypoprothrombinemia owing to the MTT group, thrombocytopenia, and/or platelet dysfunction has been reported with several b-lactam antibiotics.

7. What are your supportive therapy/therapies?

Treatment of suspected bacterial pneumonia is based on the presumptive cause and the clinical appearance of the child. For mildly ill children who do not require hospitalization, amoxicillin is recommended.

In communities with a high percentage of penicillin-resistant pneumococci, high doses of amoxicillin (80–90?mg/kg/24?hr) should be prescribed.

Therapeutic alternatives include cefuroxime axetil or amoxicillin/clavulanate. For school-aged children and in those in whom infection with M. pneumoniae is suggested, a macrolide antibiotic such as

azithromycin is an appropriate therapeutic choice. The empirical treatment of suspected bacterial pneumonia in a hospitalized child requires an approach based on the

clinical manifestations at the time of presentation. Parenteral cefuroxime (75–150?mg/kg/24?hr) is the mainstay of therapy when bacterial pneumonia is suggested. If features suggest staphylococcal pneumonia (e.g., pneumatoceles, empyema), initial therapy should also include

vancomycin or clindamycin. If viral pneumonia is suggested, it is reasonable to withhold antibiotic therapy. However, this option should be reserved

for those patients who are mildly ill, have clinical evidence suggesting viral infection, and are in no respiratory distress. Up to 30% of patients with known viral infection may have co-existing bacterial pathogens; therefore, if the decision is

made to withhold antibiotic therapy based on presumptive diagnosis of a viral infection, deterioration in clinical status should signal the possibility of superimposed bacterial infection and antibiotic therapy should be initiated.

(Nelson)

1. Assess pneumonia severity. Pay attention to vital signs, including oxygen saturation. Always count the respiratory rate yourself for 1 min.

2. Ensure adequate oxygenation and support of circulation.3. Perform etiologic workup (dictated by pneumonia severity).4. Determine site of treatment: home, hospital (ward or intensive care unit), or long-term-care facility.5. Institute empirical antibiotic therapy.6. Rule out empyema in all patients with a pleural effusion of _1 cm on lateral decubitus chest radiography.7. Never forget tuberculosis and Pneumocystis infection as possible etiologies. Check your hospital policy regarding the

isolation of patients with CAP. In some centers where tuberculosis is common, all patients with CAP are isolated until sputum smears are found to be negative for acid-fast bacilli.

8. Consider pulmonary embolus in all patients with pleuritic chest pain.9. Consider end-of-life decision-making.10. Monitor and treat comorbid illnesses.11. Monitor for achievement of stability of selected physiologic parameters.12. Assess ability to perform activities of daily living.13. Assess mental status.14. Consider preventive measures:

a. Smoking cessation counseling (if appropriate)b. Assessment of pneumococcal and influenza vaccination status, with vaccine administration as necessaryc. Assessment of risk of aspiration and institution of preventive measures

15. Follow up to ensure radiographic clearance of pneumonia. All patients >40 years old and all tobacco smokers should have a follow-up chest radiograph to document pneumonia resolution.

(Harrison’s)