Clinical Microbiology.

 

 

The most important aspects of diagnostic bacteriology are (1) the collection of an adequate amount of the con correct specimen, and (2) communication between the physician and the microbiologist outlining the clinical diagnosis and suggesting an) unusual organisms that could be the causative agent of the disease in question Provided with a specimen and the clinical evaluation of the disease it is the job of the microbiologist to isolate the etiologic agent of the disease supply a profile of antibiotic susceptibilities to the physician and identify the organism is quickly as possible. However, even after the isolation and identification of organisms present in a laboratory specimen it is not always possible to determine whether such organisms are the etiologic agents of the disease in question or merely contaminants from the normal flora. As shown in Table 1, many organisms that can be present without causing disease or symptoms of any kind also can produce serious infections under special conditions.

Table 1

Bacteria Frequently Present as Normal Flora Occasionally Causing Overt Disease

 

 

 

 

It is not always clear why an organism sometimes causes disease and sometimes does not. It is known that organisms of the genera Fusobacterium and Bacteroides rarely cause disease when confined to their normal habitat in the large intestine but cause severe abscesses when introduced into wounds In this chapter little is said in regard to this question beyond acknowledging its existence Rather, this section is designed to furnish a brief outline of the steps involved in the isolation and identification of the organisms causing bacterial infections

 

Collection and Culturing of Specimens

The collection of an adequate specimen is useless if the time between collection and culturing allows the disease-producing organism to die or to be overgrown by normal flora that may contaminate or normally be present in the specimen (Table 2). It is of utmost importance that specimens be transported quickly to the diagnostic laboratory, where they can be processed promptly to ensure he best possible chance of growth, isolation and identification of the disease-producing organism In some situations, it is recommended that the growth medium be inoculated immediately after obtaining the specimen from the patient, and that the, inoculated medium then be taken to the laboratory to be incubated and the bacteria identified In other cases, material can be protected in a buffered transport medium and then transported to the laboratory to be grown In all cases, quick processing of specimens aids in providing the fastest and most reliable identification of the disease producing organism

 

Table 2

Growth Characteristics of Bacteria Frequently Isolated From Blood on Some Commonly Used Agar Media

Organisms	Selective Enterococcus Agar	Staphylococcus 110 Agar	Mannitol, Salt	Mitis-Salivarius Agar	Chocolate Agar	Thayer-Martin
Enterococci	Translucent to whitish colonies surrounded by dark brown to black zones	Mostly inhibited	Mostly inhibited	Blue black, shiny center, clear periphery	White to gray
Listeria	Pinpoint colonies with reddish to black brown zones	Inhibited	Inhibited	Inhibited	Gray
Neisseria sp.					Opaque, grayish white	Mosdy inhibited
N. gonorrhoeae					Opaque, grayish white	Gray
N. meningitidis					Opaque, grayish white	Gray
Staphylococcus	Small white gray colonies	White, orange to yellow	Colonies with yellow zones (mannitol fermenters); colonies with red or purple zones (mannitol not fermented	Mostly inhibited	White to gray	White to gray, mostly inhibited
Streptococci	Tiny colonies	Mostly inhibited	Mostly inhibited	Small blue colonies		White to gray
b Hemolytic	Tiny colonies
S. salivarius				Blue gumdrop colonies
S. mitis				Small blue colonies

 

 

 

Etiology of different human infections

 

 

 

 

 

 

BLOOD

Microbemia

Etiology

Gram-negative enteric bacilli, Staphylococcus aureus, and Streptococcus pneumoniae are the most common pathogens in the United States. Of these, the most likely agent of a given case of microbemia depends on host characteristics (age, granulocyte count, associated conditions, prior antimicrobial therapy) and epidemiologic setting (community vs. hospital-acquired, travel, animal exposure, etc.).

Pathogenesis

Microbes generally enter the circulatory system via the lymphatics from areas of localized infection or from diseased skin and mucous membranes colonized by members of the normal bacterial flora.

Clinical Manifestations

Microbemias may be asymptomatic, symptomatic, transient, continuous, or intermittent. Microbemias due to small numbers of relatively nonpathogenic microorganisms are usually asymptomatic. Larger inocula or more pathogenic organisms may produce systemic signs and symptoms: fever, chills, rigors, sweating, malaise, sleepiness, and fatigue.

Microbiologic Diagnosis

Techniques used in diagnosis include cultures of localized sites of infection, multiple blood cultures, and (rarely) blood serology.

Prevention and Treatment

Prevention in hospitals consists of hand-washing by personnel in contact with patients and avoidance of unnecessary urinary and intravenous catheterization. After samples are taken for culturing, treatment with intravenous broad-spectrum antimicrobial agents is usually begun, based on an estimate of the most likely organisms and their usual antimicrobial susceptibility patterns. This empirical therapy is modified if necessary when the pathogen and its susceptibility pattern are identified.

Septic Shock

Etiology

Gram-negative enteric bacilli are the most common causes of septic shock, but the syndrome may be produced by a wide range of microorganisms.

Pathogenesis

Vascular injury from the microbes and release of inflammatory mediators cause local circulatory failure and multiorgan failure.

Clinical Manifestations

Manifestations of septic shock are widespread; they include hypotension, hypoxia, respiratory failure, lactic acidosis, renal failure, disseminated intravascular coagulation, and bleeding.

Microbiologic Diagnosis

Diagnosis is made by culturing local infections thought to be the source of microbemia and by culturing the blood.

Prevention and Treatment

Preventive measures are the same as for microbemia. Treatment consists of high-dose intravenous broad-spectrum antimicrobial agents, intravenous fluids, supplemental oxygen therapy, mechanical ventilation, hemodialysis, and transfusions of blood products and clotting factors, as needed.

Infective Endocarditis

Etiology

Staphylococcus aureus, viridans streptococci, and enterococci are the most common causes of endocarditis.

Pathogenesis

Microbes that enter the blood lodge on heart valves. Previously damaged heart valves are more susceptible. Bacterial colonies become covered with fibrin and platelets, which protect the organisms from phagocytes and complement. Clots may dislodge as infected emboli.

Clinical Manifestations

Infective endocarditis may affect native or abnormal cardiac valves, prosthetic valves, and, secondarily, other intravascular sites. Manifestations include fever, malaise, fatigue, weight loss, skin petechiae, embolic infarction of vital organs, and valve dysfunction with congestive failure. Metastatic infection in acute endocarditis is caused by virulent organisms.

Microbiologic Diagnosis

Infective endocarditis is diagnosed through blood cultures.

Prevention and Treatment

Antimicrobial prophylaxis is administered to patients with defective heart valves who are undergoing dental and other procedures known to produce bacteremia. Therapy consists of prolonged intravenous treatment with bactericidal antibiotics to eradicate bacteria within the protective clot. Surgical replacement of infected valves may be required to cure prosthetic valve infections.

Introduction

The circulatory system, consisting of the blood, blood vessels, and the heart, is normally free of microbial organisms. Isolation of bacteria or fungi from the blood of ill patients usually signifies serious and uncontrolled infection that may result in death. The presence of bacteria (bacteremia) and fungi (fungemia) in the blood occurs in more than 250,000 individuals per year in the United States and causes at least 50,000 deaths annually. Because rapid isolation, identification, and performance of antimicrobial susceptibility tests may lead to initiation of lifesaving measures, the culturing of blood to detect microbemia is one of the most important clinical microbiology laboratory procedures. Bacteremia may be prevented in some instances by the early recognition of localized infection and initiation of appropriate treatment with antimicrobial agents and surgical drainage of abscesses.

 

Clinical Syndromes

Microbemia

Asymptomatic Microbemia

Microbes enter the circulatory system via lymphatic drainage from localized sites of infection or mucosal surfaces that are subject to trauma and are colonized with members of the normal bacterial flora. Organisms may also be introduced directly into the bloodstream by infected intravenous needles or catheters or contaminated intravenous infusions. A number of disseminated viral infections are also spread through the body via the bloodstream. Viremias are discussed in Chapter 45. Small numbers of organisms or nonvirulent microbes are removed from the circulation by fixed macrophages in the liver, spleen, and lymph nodes. The phagocytes are assisted by circulating antibodies and complement factors present in serum. Under certain conditions, antibodies and complement factors may kill Gram-negative bacteria by lysis of the cell wall. Also, they may promote phagocytosis by coating bacteria (opsonization) with antibody and complement factors that have receptor sites for neutrophils and macrophages.

When defense mechanisms effectively remove small numbers of organisms, clinical signs or symptoms of microbemia may not occur (asymptomatic microbemia). Asymptomatic bacteremias caused by members of the endogenous bacterial flora have been observed in normal individuals after vigorous chewing, dental cleaning or tooth extraction, insertion of urinary bladder catheters, colon surgery, and other manipulative procedures. Asymptomatic bacteremias may occur if localized infections are subjected to trauma or surgery.

Most asymptomatic bacteremias are of no consequence; however, occasionally, virulent organisms that cause a localized infection (such as a Staphylococcus aureus skin boil) may produce infection at a distant site (e.g., bone infection) by means of asymptomatic bacteremia. Similarly, artificial or damaged heart valves may be colonized by viridans streptococci during asymptomatic bacteremia induced by dental manipulation. Infection of the heart valve (infective endocarditis) is fatal if not treated. Therefore, individuals with known valvular heart disease who undergo dental work or other procedures that produce asymptomatic bacteremias are given antibiotics to prevent colonization of the heart.

Symptomatic Microbemia

When a sufficient number of organisms are introduced into the bloodstream, an individual will develop fever, chills, shivering (rigors), and sweating (diaphoresis). Patients with symptomatic microbemias usually look and feel ill. As macrophages and polymorphonuclear leukocytes phagocytose microbes, they synthesize and release interleukin-1 into the circulation. This small protein acts on the temperature-regulatory center in the brain and sets the body thermostat at a higher level. The thermoregulatory center acts to decrease heat loss by reducing peripheral blood flow to the skin (pale appearance) and increases heat production by muscular activity (shivering), resulting in a rise in body temperature. When either a high body temperature level is attained or the microbemia terminates, the central nervous system thermostat becomes reset at a lower level and acts to reduce body temperature by increased peripheral blood flow to the skin (flushed appearance) and by sweating.

Symptomatic microbemias are most commonly caused by the organisms listed in Figure 94-1. In recent years, the incidence of Gram-positive coccal bacteremias resulting from intravascular access infections in debilitated patients with serious underlying conditions has increased steadily, but Gram-negative bacillary infection still predominates. Hospitalized patients frequently have had surgery, severe trauma, or neoplasms that predispose to complicated local infections; also, these individuals’ host defenses have been compromised by malnutrition, age, or corticosteroid or cancer chemotherapy. Granulocytopenia due to leukemia, cancer, or cancer chemotherapy is a frequent predisposing cause of microbemia and a reason for poor response to antimicrobial therapy. Gram-negative bacteremia is frequently due to pulmonary infections in intubated patients receiving ventilator therapy or to urinary tract infections caused by indwelling urinary catheters. Table 94-1 lists a number of conditions predisposing to symptomatic microbemia and the organisms most commonly associated with those conditions. Organisms other than those listed in Table 94-1 may produce microbemia in severely compromised hosts. Skin contaminants, such as Staphylococcus epidermidis and diphtheroid species, may cause significant microbemias (indicated by isolation from multiple blood cultures). Bacteremias of this type are associated with intravenous catheters or prosthetic heart valves.

Figure 94-1

Common causes of symptomatic microbemia.

Table 94-1

Conditions Predisposing to Symptomatic Microbemia.

Transient microbemias are self:limited and often due to manipulation of infected tissues, such as incision and drainage of an abscess; early phases of localized infection, such as pneumococcal bacteremia in pneumococcal pneumonias; or bacteremias associated with trauma to mucosal surfaces colonized by the normal host flora. When multiple blood cultures are positive over a period of 12 hours or more, a continuous microbemia is present. The presence of continuous microbemia suggests a severe spreading infection that has overwhelmed host defenses. A continuous microbemia may originate from an intravascular site of infection in which organisms are shed directly into the bloodstream (e.g., infective endocarditis or an infected intravascular catheter), or from an early phase of a specific infection characterized by a continuous microbemia (e.g., typhoid fever).

Microbemias may persist despite treatment with antimicrobial agents to which the organisms are susceptible. Therefore, repeated blood cultures should be performed in patients who do not appear to respond to sustained antimicrobial treatment. During the first 3 days of treatment, positive blood cultures often are associated with inadequate antimicrobial dosage. Microbemias that persist longer than 3 days may be caused by organisms resistant to multiple antimicrobial agents, by undrained abscesses, or by intravascular foci of infection. When positive blood cultures with the same organism are separated by negative cultures, an intermittent microbemia is present.

Septic Shock

Septic shock occurs in approximately 40 percent of patients with Gram-negative bacillary bacteremia and 5 percent of patients with Gram-positive bacteremia. The septic shock syndrome consists of a fall in systemic arterial blood pressure with resultant decreased effective blood flow to vital organs. Septic shock patients frequently develop renal and pulmonary insufficiency and coma as part of a generalized metabolic failure caused by inadequate blood flow. Survival depends on rapid institution of broad-spectrum antimicrobial therapy, intravenous fluids, and other supportive measures. Elderly patients and those with severe underlying surgical or medical diseases are less likely to survive. Mortality from Gram-negative septic shock ranges from 40 to 70 percent. Septic shock may also occur with rickettsial, viral, and fungal infections .

Septic shock due to Gram-negative bacillary bacteremias constitutes the most common serious infectious disease problem in hospitalized patients. The high frequency of septic shock in Gram-negative bacillary infeHtion is attributed to the toxic effect on the circulatory system of lipopolysaccharides (endotoxin) found in the cell wall of Gram-negative organisms (Fig. 94-2). Endotoxin within the circulatory system has multiple and complex effects oeutrophils, platelets, complement, clotting factors, and inflammatory mediators in the blood. The symptoms of bacteremia and septic shock are reproduced when purified cell wall endotoxin is injected into the circulation.

Figure 94-2

Pathogenesis of septic shock.

Infective Endocarditis

Heart valve infections generally are classified as acute endocarditis, subacute endocarditis, and prosthetic valve endocarditis. If they are untreated, these infections are fatal. With treatment, mortality averages 30 percent; it is higher in acute and prosthetic valve infections.

Acute endocarditis usually occurs when heart valves are colonized by virulent bacteria in the course of microbemia (Fig. 94-3). The most common cause of acute endocarditis is Staphylococcus aureus; other less common causes are Streptococcus pneumoniae, Neisseria gonorrhoeae, Streptococcus pyogenes, and Enterococcus faecalis. Patients with acute endocarditis usually have fever, marked prostration, and signs of infection at other sites. Infected heart valves may be destroyed rapidly, leading to heart failure from valve leaflet perforation and acute valvular insufficiency. Infected pieces of fibrin and platelet vegetations on the valves may break loose into the circulation and lodge at distant sites, producing damage to target organs. Metastatic infection due to emboli may involve arterial walls (mycotic aneurysm) or produce abscesses.

Figure 94-3

Infective endocarditis: metastatic infections due to emboli.

Patients with subacute endocarditis usually have underlying valvular heart disease and are infected by less virulent organisms such as viridans streptococci, enterococci, nonenterococcal group D streptococci, microaerophilic streptococci, and Haemophilus species. Frequently, the source and onset of infection are not clear, and patients consult physicians with complaints of fever, weight loss, or symptoms related to embolic phenomenon and congestive heart failure.

Prosthetic valvular endocarditis may present either acute or subacute in onset, and the infecting organisms differ, depending on whether endocarditis develops within 2 months of surgery or later (Table 94-1). Whereas infections oonprosthetic valves usually are eradicated by antimicrobial therapy alone, prosthetic valve infections frequently require surgical removal of the infected valve before the infection is eliminated. Antimicrobial therapy of endocarditis is prolonged and should be guided by susceptibility studies. Fungal endocarditis is rare, but Candida infections occur in those with prosthetic valves and in drug addicts. Aspergillus endocarditis may occur after cardiac valve surgery.

Blood Cultures

Because several commercial blood culture systems are used by clinical microbiology laboratories, blood culture specimens may be processed differently by different laboratories. Most clinical laboratories will give a preliminary report of a negative culture if no growth is detected after 4 days of incubation. A final negative report is made if there is no growth after 7 days of incubation.

Clinicians should know when it is necessary for the laboratory to use special or nonroutine blood culture techniques to detect microorganisms. Failure to tell the clinical laboratory about the need for special culture conditions may result in false-negative blood culture reports.

If the patient has received antimicrobial agents before the blood specimen was obtained, the clinical laboratory can add penicillinase to remove β-lactam antibiotics, use an antimicrobial removal device or special resin bottle to remove or inactivate the antimicrobial agent, or prolong blood incubation for 2 weeks to improve the chances of obtaining a positive culture. If infective endocarditis is suspected, the blood culture bottles should be incubated for 2 weeks to allow growth of slow-growing or fastidious microorganisms. When fungemia is suspected, special media and techniques are used to grow fungi. When Mycobacterium avium-intracellulare bacteremia is suspected in patients with human immunodeficiency virus (HIV) infection, the laboratory must be alerted to use special mycobacterium culture bottles and media. Special culture techniques or media are required for the isolation of brucellae, Listeria monocytogenes, leptospires, Francisella tularensis, and Mycoplasma hominis.

If a central venous catheter infection is suspected, blood should be drawn both from the line and from a peripheral vein, and the results of quantitative cultures compared. If the catheter blood culture has a 10-fold greater count than the peripheral blood culture or has more than 100 CFU/ml, the catheter is probably infected. Semi-quantitative culture of peripheral intravenous catheters may also help establish whether they are the portal of entry for bacteremia. When the results of blood cultures do not fit with the clinical condition of an infected patient, the clinician should review the situation with the clinical microbiology laboratory director or an infectious diseases specialist.

 

 

Bacteremia — bacteria in the blood —frequently is accompanied by the onset of chills and fever, an increase in pulse rate, and a drop in blood pressure Even in infections in which bacteremia is a major aspect of the disease, the organisms in the bloodstream are not always constantly present in sufficient numbers to be grown from a single blood specimen Patients with such infections may have to provide several blood specimens before the causative agent can be isolated When an intermittent bacteremia is suspected, it is routine to obtain three 10 to 20 -ml blood samples over a 24 hour period to maximise chances for isolation of the organism

Collection of a Blood Specimen

In taking a blood specimen for culture, one should be aware that although blood is normally sterile, the skin that must be penetrated is not sterile Routinely, the skin should be cleansed first with 70% to 95% alcohol to remove dirt, lipids, and fatty acids The site then should be scrubbed with a circular, concentric motion (working out from the starting point) using a sterile gauze pad soaked in an iodophor. The iodine should be allowed to remain on the skin for at least 1 minute before it is removed by wiping with a sterile gauze pad soaked with 70% to 95%alcohol It must be emphasised, however, that all this will be useless if the person drawing the blood palpates the vein after the cleaning process, thereby contaminating the very site that had been cleaned

After cleansing the penetration site, the blood can be withdrawn using either a sterile needle and syringe or a commercially available, evacuated blood collection tube

Media Inoculated With Blood Specimens

Blood always should be inoculated into the appropriate medium at the bedside partially evacuated, commercially available, blood culture bottles, which contain 30 to 100 ml of a rich, liquid medium such as brain-heart infusion or trypticase soy broth is routinely used.

If possible, 10 to 20 ml of blood should be taken from the patient and inoculated into an approximately10 told excess of the blood culture medium when possible, two such bottles should be inoculated. One is vented to permit the growth of aerobic bacteria (by inserting a sterile, cotton plugged needle through the rubber stopper until the bottle has filled with air), and the other is not vented to allow the growth of anaerobic organisms. Special media for aerobic and anaerobic culture are available Some commercially available bottles are provided with a venipuncture set, which allows the blood to be injected into the medium.

Identification of Blood Isolates

Blood cultures are incubated at 36°C and observed daily for at least 1 week for evidence of turgidity or hemolysis. Gram’s stains, streak plates, and antibiotic susceptibility tests should be carried out as quickly as possible after the observation of visible growth in the original broth culture. In the absence of- obvious growth in 1 or 2 days, blind subcultures on chocolate blood agar plates may speed the appearance of obligately aerobic organisms. Commercially available penicillinase can be added to blood cultures from patients who have received penicillin therapy. Penicillinase preparations should be checked for sterility to eliminate them as a potential source of contamination. Resins incorporated in special blood culture media can neutralise a broad spectrum of antibiotics.

Once a Gram’s stain has rendered some information concerning the type of organism involved, special supplementary or differential media should be inoculated. MacConkey or eosin-methylene blue plates should be streaked if gram negative rods are present, and prereduced media should be inoculated if obligate anaerobes such as Bacteroides or Fusobacterium are suspected. Table 36 2 lists a few of the more common organisms that could be isolated from blood, with their colonial appearances on certain specialised media.

The finding of organisms that constitute the normal flora or are frequent inhabitants of the skin (eg, diphtheroids, Staphylococcus epidermidis. Bacillus sp.) usually is viewed with suspicion, unless the frequency of isolation or the clinical setting indicates they did not arrive as contamination during the collection of the blood

 

RESPIRATORY TRACT AND MOUTH

 

Because of the myriad normal resident flora in the upper respiratory tract, the isolation of lower respiratory tract infectious agents can be difficult and contusing. This is complicated further by the occasional presence of small numbers of potential pathogens such as pneumococci, meningococci,  streptococci,  Staphylococcus  aureus, Haemophilus influenzae, or enteric organisms that      are indigenous to the upper respiratory tract.

Specimen Collection From the Respiratory Tract

The microbiologist must be certain that lower respiratory tract specimens represent sputum that has been brought up by a deep cough. However, it may not be possible to obtain a good sputum sample from a young child, a debilitated older person, or someone who is comatose. In such situations, other procedures must be carried out to obtain a specimen from the lower respiratory tract. One technique is transtracheal aspiration, which, as shown diagrammatically in Figure, uses a needle and tube inserted into the trachea. This technique also overcomes the problem of contamination from the oropharynx. On some occasions, sterile saline solution is injected through the tube before aspiration.

Organisms causing upper respiratory tract infections that may cause lesions in the throat should be obtained with a cotton swab and streaked on a suitable medium as soon as possible or used for direct antigen detection. Nasopharyngeal cultures usually are obtained with a cotton swab on a bent wire, which can be passed through either the nose or the mouth, carefully bypassing the tongue and oropharynx. Nasopharyngeal cultures are especially important for detecting carrier states for meningococci, Corynebacterium diphtheriae, group A – b-hemolytic streptococci, and H influenzae. The last organism also can cause an acute epiglottitis, but initial treatment for that infection is based on clinical evaluation and must be initiated before laboratory isolation would be possible.

 

 

 

FIGURE. Transtracheal aspiration A pillow should be placed beneath the neck to permit maximum extension or the neck. After cleansing the skin, a 14 gauge needle is inserted into the trachea, and a polyethylene tube is passed through the needle into the lung 1 he needle is withdrawn, and the tube is connected to a syringe containing 3 ml to 4 ml of physiologic saline. The saline is injected into the lung and immediately with drawn for culture.

 

Media Inoculated With Respiratory Tract Specimens

All throat swabs should be kept moist until delivered to the laboratory. Special media arc used for the isolation of specific pathogens, and the laboratory should be in-formed by the clinician what range of pathogens is possible. For instance, sheep blood-agar plates are sufficient for the isolation of b-hemolytic streptococci, but S aureus, Streptococcus pneumoniae and Neisseria meningitidis grow better on chocolate blood agar in the presence of excess CO; A suspected C diphtheriae would be inoculated additionally on a Loeffler’s coagulated-serum slant and a potassium tellurite-agar plate. To isolate and identify Bordetella pertussis from a suspected case of whooping cough, special medium would be inoculated from a swab. A swab containing a possible H influenzae would be streaked on a chocolate-blood agar plate. Thick sputum that is to be cultured for Mycobacterium tuberculosis usually is thinned by digestion in 4% NaOH and a mucolytic agent at 37°C for 1 hour, followed by high-speed centrifugation (2000 times gravity for 30 minutes). Other digestion procedures also have been reported. These procedures result in a concentration of the tubercle bacilli and the destruction of most contaminating organisms. It should be recognized that these digestion procedures also destroy the tubercle bacilli, and the time and temperature should not be extended beyond the recommended limits. After centrifugation, sediment material can be used to inoculate media, such as Lowenstein-Jensen medium (Table 3).

Table 3

ORGANISMS  COMMONLY ISOLATED FROM RESPIRATORY TRACT SAMPLES AND SPECIALISED PROCEDURES USED FOR THEIR IDENTIFICATION

 

Identification of Respiratory Tract Isolates

The appearance of the colony on sheep blood agar and the use of the Gram’s stain are the most powerful tools available for a presumptive identification of a potential pathogen. If tuberculosis is suspected, acid-fast stains should be made on the centrifuged sediment obtained from the sputum digestion procedure described earlier.

Many other specialised procedures are available, and the choice depends on information received from the clinician and on the appearance of the initial isolates. Fluorescein-labelled antibody or latex particles with attached antibody directed against group A streptococcus provides rapid identification of these organisms. Table 3 lists some common isolates from the respiratory tract with a few of the special procedures that aid in their identification.

Chapter 93Infections of the Respiratory System

 

 

(http://www.ncbi.nlm.nih.gov/books/n/mmed/A4986/)

 

Etiology: Most upper respiratory infections are of viral etiology. Epiglottitis and laryngotracheitis are exceptions with severe cases likely caused by Haemophilus influenzae type b. Bacterial pharyngitis is often caused by Streptococcus pyogenes

Pathogenesis: Organisms gain entry to the respiratory tract by inhalation of droplets and invade the mucosa. Epithelial destruction may ensue, along with redness, edema, hemorrhage and sometimes an exudate.

Clinical Manifestations: Initial symptoms of a cold are runny, stuffy nose and sneezing, usually without fever. Other upper respiratory infections may have fever. Children with epiglottitis may have difficulty in breathing, muffled speech, drooling and stridor. Children with serious laryngotracheitis (croup) may also have tachypnea, stridor and cyanosis.

Microbiologic Diagnosis: Common colds can usually be recognized clinically. Bacterial and viral cultures of throat swab specimens are used for pharyngitis, epiglottitis and laryngotracheitis. Blood cultures are also obtained in cases of epiglottitis.

Prevention and Treatment: Viral infections are treated symptomatically. Streptococcal pharyngitis and epiglottitis caused by H influenzae are treated with antibacterials. Haemophilus influenzae type b vaccine is commercially available and is now a basic component of childhood immunization program.

Lower Respiratory Infections: Bronchitis, Bronchiolitis and Pneumonia

Etiology: Causative agents of lower respiratory infections are viral or bacterial. Viruses cause most cases of bronchitis and bronchiolitis. In community-acquired pneumonias, the most common bacterial agent is Streptococcus pneumoniae. Atypical pneumonias are cause by such agents as Mycoplasma pneumoniae, Chlamydia spp, Legionella, Coxiella burnetti and viruses. Nosocomial pneumonias and pneumonias in immunosuppressed patients have protean etiology with gram-negative organisms and staphylococci as predominant organisms.

Pathogenesis: Organisms enter the distal airway by inhalation, aspiration or by hematogenous seeding. The pathogen multiplies in or on the epithelium, causing inflammation, increased mucus secretion, and impaired mucociliary function; other lung functions may also be affected. In severe bronchiolitis, inflammation and necrosis of the epithelium may block small airways leading to airway obstruction.

Clinical Manifestations: Symptoms include cough, fever, chest pain, tachypnea and sputum production. Patients with pneumonia may also exhibit non-respiratory symptoms such as confusion, headache, myalgia, abdominal pain, nausea, vomiting and diarrhea.

Microbiologic Diagnosis: Sputum specimens are cultured for bacteria, fungi and viruses. Culture of nasal washings is usually sufficient in infants with bronchiolitis. Fluorescent staining technic can be used for legionellosis. Blood cultures and/or serologic methods are used for viruses, rickettsiae, fungi and many bacteria. Enzyme-linked immunoassay methods can be used for detections of microbial antigens as well as antibodies. Detection of nucleotide fragments specific for the microbial antigen in question by DNA probe or polymerase chain reaction can offer a rapid diagnosis.

Prevention and Treatment: Symptomatic treatment is used for most viral infections. Bacterial pneumonias are treated with antibacterials. A polysaccharide vaccine against 23 serotypes of Streptococcus pneumoniae is recommended for individuals at high risk.

Upper Respiratory Infections

Infections of the respiratory tract are grouped according to their symptomatology and anatomic involvement. Acute upper respiratory infections (URI) include the common cold, pharyngitis, epiglottitis, and laryngotracheitis (Fig. 93-1). These infections are usually benign, transitory and self-limited, altho ugh epiglottitis and laryngotracheitis can be serious diseases in children and young infants. Etiologic agents associated with URI include viruses, bacteria, mycoplasma and. Respiratory infections are more common in the fall and winter when school starts and indoor crowding facilitates transmission.

Figure 93-1

Upper and lower respiratory tract infections.

Common Cold

Etiology

Common colds are the most prevalent entity of all respiratory infections and are the leading cause of patient visits to the physician, as well as work and school absenteeism. Most colds are caused by viruses. Rhinoviruses with more than 100 serotypes are the most common pathogens, causing at least 25% of colds in adults. Coronaviruses may be responsible for more than 10% of cases. Parainfluenza viruses, respiratory syncytial virus, adenoviruses and influenza viruses have all been linked to the common cold syndrome. All of these organisms show seasonal variations in incidence. The cause of 30% to 40% of cold syndromes has not been determined.

Pathogenesis

The viruses appear to act through direct invasion of epithelial cells of the respiratory mucosa (Fig. 93-2), but whether there is actual destruction and sloughing of these cells or loss of ciliary activity depends on the specific organism involved. There is an increase in both leukocyte infiltration and nasal secretions, including large amounts of protein and immunoglobulin, suggesting that cytokines and immune mechanisms may be responsible for some of the manifestations of the common cold (Fig. 93-3).

Figure 93-2

Pathogenesis of viral and bacterial mucosal respiratory infections.

Figure 93-3

Pathogenesis of upper respiratory tract infections.

Clinical Manifestations

After an incubation period of 48–72 hours, classic symptoms of nasal discharge and obstruction, sneezing, sore throat and cough occur in both adults and children. Myalgia and headache may also be present. Fever is rare. The duration of symptoms and of viral shedding varies with the pathogen and the age of the patient. Complications are usually rare, but sinusitis and otitis media may follow.

Microbiologic Diagnosis

The diagnosis of a common cold is usually based on the symptoms (lack of fever combined with symptoms of localization to the nasopharynx). Unlike allergic rhinitis, eosinophils are absent iasal secretions. Although it is possible to isolate the viruses for definitive diagnosis, that is rarely warranted.

Prevention and Treatment

Treatment of the uncomplicated common cold is generally symptomatic. Decongestants, antipyretics, fluids and bed rest usually suffice. Restriction of activities to avoid infecting others, along with good hand washing, are the best measures to prevent spread of the disease. No vaccine is commercially available for cold prophylaxis.

Sinusitis

Sinusitis is an acute inflammatory condition of one or more of the paranasal sinuses. Infection plays an important role in this affliction. Sinusitis often results from infections of other sites of the respiratory tract since the paranasal sinuses are contiguous to, and communicate with, the upper respiratory tract.

Etiology

Acute sinusitis most often follows a common cold which is usually of viral etiology. Vasomotor and allergic rhinitis may also be antecedent to the development of sinusitis. Obstruction of the sinusal ostia due to deviation of the nasal septum, presence of foreign bodies, polyps or tumors can predispose to sinusitis. Infection of the maxillary sinuses may follow dental extractions or an extension of infection from the roots of the upper teeth. The most common bacterial agents responsible for acute sinusitis are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Other organisms including Staphylococcus aureus, Streptococcus pyogenes, gram-negative organisms and anaerobes have also been recovered. Chronic sinusitis is commonly a mixed infection of aerobic and anaerobic organisms.

Pathogenesis

Infections caused by viruses or bacteria impair the ciliary activity of the epithelial lining of the sinuses and increased mucous secretions. This leads to obstruction of the paranasal sinusal ostia which impedes drainage. With bacterial multiplication in the sinus cavities, the mucus is converted to mucopurulent exudates. The pus further irritates the mucosal lining causing more edema, epithelial destruction and ostial obstruction. When acute sinusitis is not resolved and becomes chronic, mucosal thickening results and the development of mucoceles and polyps may ensue.

Clinical Manifestations

The maxillary and ethmoid sinuses are most commonly involved in sinusitis. The frontal sinuses are less often involved and the sphenoid sinuses are rarely affected. Pain, sensation of pressure and tenderness over the affected sinus are present. Malaise and low grade fever may also occur. Physical examination usually is not remarkable with no more than an edematous and hyperemic nasal mucosa.

In uncomplicated chronic sinusitis, a purulent nasal discharge is the most constant finding. There may not be pain nor tenderness over the sinus areas. Thickening of the sinus mucosa and a fluid level are usually seen in x-ray films or magnetic resonance imaging.

Microbiologic Diagnosis

For acute sinusitis, the diagnosis is made from clinical findings. A bacterial culture of the nasal discharge can be taken but is not very helpful as the recovered organisms are generally contaminated by the resident flora from the nasal passage. In chronic sinusitis, a careful dental examination, with sinus x-rays may be required. An antral puncture to obtain sinusal specimens for bacterial culture is needed to establish a specific microbiologic diagnosis.

Prevention and Treatment

Symptomatic treatment with analgesics and moist heat over the affected sinus pain and a decongestant to promote sinus drainage may suffice. For antimicrobial therapy, a beta-lactamase resistant antibiotic such as amoxicillin-clavulanate or a cephalosporin may be used. For chronic sinusitis, when conservative treatment does not lead to a cure, irrigation of the affected sinus may be necessary. Culture from an antral puncture of the maxillary sinus can be performed to identify the causative organism for selecting antimicrobial therapy. Specific preventive procedures are not available. Proper care of infectious and/or allergic rhinitis, surgical correction to relieve or avoid obstruction of the sinusal ostia are important. Root abscesses of the upper teeth should receive proper dental care to avoid secondary infection of the maxillary sinuses.

Otitis

Infections of the ears are common events encountered in medical practice, particularly in young children. Otitis externa is an infection involving the external auditory canal while otitis media denotes inflammation of the middle ear.

Etiology

For otitis externa, the skin flora such as Staphylococcus epidermidis, Staphylococcus aureus, diphtheroids and occasionally an anaerobic organism, Propionibacterium acnes are major etiologic agents. In a moist and warm environment, a diffuse acute otitis externa (Swimmer’s ear) may be caused by Pseudomonas aeruginosa, along with other skin flora. Malignant otitis externa is a severe necrotizing infection usually caused by Pseudomonas aeruginosa.

For otitis media, the commonest causative bacteria are Streptococcus pneumoniae, Hemophilus influenzae and beta-lactamase producing Moraxella catarrhalis. Respiratory viruses may play a role in otitis media but this remains uncertain. Mycoplasma pneumoniae has been reported to cause hemorrhagic bullous myringitis in an experimental study among nonimmune human volunteers inoculated with M pneumoniae. However, iatural cases of M pneumoniae infection, clinical bullous myringitis or otitis media is uncommon.

Pathogenesis

The narrow and tortuous auditory canal is lined by a protective surface epithelium. Factors that may disrupt the natural protective mechanisms, such as high temperature and humidity, trauma, allergy, tissue maceration, removal of cerumen and an alkaline pH environment, favor the development of otitis externa. Prolonged immersion in a swimming pool coupled with frequent ear cleansing increases the risk of otitis externa.

Acute otitis media commonly follows an upper respiratory infection extending from the nasopharynx via the eustachian tube to the middle ear. Vigorous nose blowing during a common cold, sudden changes of air pressure, and perforation of the tympanic membrane also favor the development of otitis media. The presence of purulent exudate in the middle ear may lead to a spread of infection to the inner ear and mastoids or even meninges

Clinical Manifestations

Otitis externa

Furuncles of the external ear, similar to those in skin infection, can cause severe pain and a sense of fullness in the ear canal. When the furuncle drains, purulent otorrhea may be present. In generalized otitis externa, itching, pain and tenderness of the ear lobe on traction are present. Loss of hearing may be due to obstruction of the ear canal by swelling and the presence of purulent debris.

Malignant otitis externa tends to occur in elderly diabetic patients. It is characterized by severe persistent earache, foul smelling purulent discharge and the presence of granulation tissue in the auditory canal. The infection may spread and lead to osteomyelitis of the temporal bone or externally to involve the pinna with osteochondritis.

Otitis media

Acute otitis media occurs most commonly in young children. The initial complaint usually is persistent severe earache (crying in the infant) accompanied by fever, and, and vomiting. Otologic examination reveals a bulging, erythematous tympanic membrane with loss of light reflex and landmarks. If perforation of the tympanic membrane occurs, serosanguinous or purulent discharge may be present. In the event of an obstruction of the eustachian tube, accumulation of a usually sterile effusion in the middle ear results in serous otitis media. Chronic otitis media frequently presents a permanent perforation of the tympanic membrane. A central perforation of the pars tensa is more benign. On the other hand, an attic perforation of the pars placcida and marginal perforation of the pars tensa are more dangerous and often associated with a cholesteatoma.

Diagnosis

The diagnosis of both otitis externa and otitis media can be made from history, clinical symptomatology and physical examinations. Inspection of the tympanic membrane is an indispensable skill for physicians and health care workers. All discharge, ear wax and debris must be removed and to perform an adequate otoscopy. In the majority of patients, routine cultures are not necessary, as a number of good bacteriologic studies have shown consistently the same microbial pathogens mentioned in the section of etiology. If the patient is immunocompromised or is toxic and not responding to initial antimicrobial therapy tympanocentesis (needle aspiration) to obtain middle ear effusion for microbiologic culture is indicated.

Prevention and Treatment

Otitis externa

Topical therapy is usually sufficient and systemic antimicrobials are seldom needed unless there are signs of spreading cellulitis and the patient appears toxic. A combination of topical antibiotics such as neomycin sulfate, polymyxin B sulfate and corticosteroids used as eardrops, is a preferred therapy. In some cases, acidification of the ear canal by applying a 2% solution of acetic acid topically may also be effective. If a furuncle is present in the external canal, the physician should allow it to drain spontaneously.

Otitis media

Amoxicillin is an effective and preferred antibiotic for treatment of acute otitis media. Since beta-lactamase producing H influenzae and M catarrhalis can be a problem in some communities, amoxicillin-clavulanate is used by many physicians. Oral preparations of trimethoprim/sulfamethoxazole, second and third generation cephalosporins, tetracyclines and macrolides can also be used. When there is a large effusion, tympanocentesis may hasten the resolution process by decreasing the sterile effusion. Patients with chronic otitis media and frequent recurrences of middle ear infections may be benefitted by chemoprophylaxis with once daily oral amoxicillin or trimethoprim/sulfamethoxazole during the winter and spring months. In those patients with persistent effusion of the middle ear, surgical interventions with myringotomy, adenoidectomy and the placement of tympanotomy tubes has been helpful.

Use of polyvalent pneumococcal vaccines has been evaluated for the prevention of otitis media in children. However, children under two years of age do not respond satisfactorily to polysaccharide antigens; further, no significant reduction in the number of middle ear infections was demonstrable. Newer vaccines composed of pneumococcal capsular polysaccharides conjugated to proteins may increase the immunogenicity and are currently under clinical investigation for efficacy and safety.

Pharyngitis

Etiology

Pharyngitis is an inflammation of the pharynx involving lymphoid tissues of the posterior pharynx and lateral pharyngeal bands. The etiology can be bacterial, viral and fungal infections as well as noninfectious etiologies such as smoking. Most cases are due to viral infections and accompany a common cold or influenza. Type A coxsackieviruses can cause a severe ulcerative pharyngitis in children (herpangina), and adenovirus and herpes simplex virus, although less common, also can cause severe pharyngitis. Pharyngitis is a common symptom of Epstein-Barr virus and cytomegalovirus infections.

Group A beta-hemolytic streptococcus or Streptococcus pyogenes is the most important bacterial agent associated with acute pharyngitis and tonsillitis. Corynebacterium diphtheriae causes occasional cases of acute pharyngitis, as do mixed anaerobic infections (Vincent’s angina), Corynebacterium haemolyticum, Neisseria gonorrhoeae, and Chlamydia trachomatis. Outbreaks of Chlamydia pneumoniae (TWAR agent) causing pharyngitis or pneumonitis have occurred in military recruits. Mycoplasma pneumoniae and Mycoplasma hominis have been associated with acute pharyngitis. Candida albicans, which causes oral candidiasis or thrush, can involve the pharynx, leading to inflammation and pain.

Pathogenesis

As with common cold, viral pathogens in pharyngitis appear to invade the mucosal cells of the nasopharynx and oral cavity, resulting in edema and hyperemia of the mucous membranes and tonsils (Fig 93-2). Bacteria attach to and, in the case of group A beta-hemolytic streptococci, invade the mucosa of the upper respiratory tract. Many clinical manifestations of infection appear to be due to the immune reaction to products of the bacterial cell. In diphtheria, a potent bacterial exotoxin causes local inflammation and cell necrosis.

Clinical Manifestations

Pharyngitis usually presents with a red, sore, or “scratchy” throat. An inflammatory exudate or membranes may cover the tonsils and tonsillar pillars. Vesicles or ulcers may also be seen on the pharyngeal walls. Depending on the pathogen, fever and systemic manifestations such as malaise, myalgia, or headache may be present. Anterior cervical lymphadenopathy is common in bacterial pharyngitis and difficulty in swallowing may be present.

Microbiologic Diagnosis

The goal in the diagnosis of pharyngitis is to identify cases that are due to group A beta-hemolytic streptococci, as well as the more unusual and potentially serious infections. The various forms of pharyngitis cannot be distinguished on clinical grounds. Routine throat cultures for bacteria are inoculated onto sheep blood and chocolate agar plates. Thayer-Martin medium is used if N gonorrhoeae is suspected. Viral cultures are not routinely obtained for most cases of pharyngitis. Serologic studies may be used to confirm the diagnosis of pharyngitis due to viral, mycoplasmal or chlamydial pathogens. Rapid diagnostic tests with fluorescent antibody or latex agglutination to identify group A streptococci from pharyngeal swabs are available. Gene probe and polymerase chain reaction can be used to detect unusual organisms such as M pneumoniae, chlamydia or viruses but these procedures are not routine diagnostic methods.

Prevention and Treatment

Symptomatic treatment is recommended for viral pharyngitis. The exception is herpes simplex virus infection, which can be treated with acyclovir if clinically warranted or if diagnosed in immunocompromised patients. The specific antibacterial agents will depend on the causative organism, but penicillin G is the therapy of choice for streptococcal pharyngitis. Mycoplasma and chlamydial infections respond to erythromycin, tetracyclines and the new macrolides.

Epiglottitis and Laryngotracheitis

Etiology

Inflammation of the upper airway is classified as epiglottitis or laryngotracheitis (croup) on the basis of the location, clinical manifestations, and pathogens of the infection. Haemophilus influenzae type b is the most common cause of epiglottitis, particularly in children age 2 to 5 years. Epiglottitis is less common in adults. Some cases of epiglottitis in adults may be of viral origin. Most cases of laryngotracheitis are due to viruses. More serious bacterial infections have been associated with H influenzae type b, group A beta-hemolytic streptococcus and C diphtheriae. Parainfluenza viruses are most common but respiratory syncytial virus, adenoviruses, influenza viruses, enteroviruses and Mycoplasma pneumoniae have been implicated.

Pathogenesis

A viral upper respiratory infection may precede infection with H influenzae in episodes of epiglottitis. However, once H influenzae type b infection starts, rapidly progressive erythema and swelling of the epiglottis ensue, and bacteremia is usually present. Viral infection of laryngotracheitis commonly begins in the nasopharynx and eventually moves into the larynx and trachea. Inflammation and edema involve the epithelium, mucosa and submucosa of the subglottis which can lead to airway obstruction.

Clinical Manifestations

The syndrome of epiglottitis begins with the acute onset of fever, sore throat, hoarseness, drooling, dysphagia and progresses within a few hours to severe respiratory distress and prostration. The clinical course can be fulminant and fatal. The pharynx may be inflamed, but the diagnostic finding is a “cherry-red” epiglottis.

A history of preceding cold-like symptoms is typical of laryngotracheitis, with rhinorrhea, fever, sore throat and a mild cough. Tachypnea, a deep barking cough and inspiratory stridor eventually develop. Children with bacterial tracheitis appear more ill than adults and are at greater risk of developing airway obstruction.

Haemophilus influenzae type b is isolated from the blood or epiglottis in the majority of patients with epiglottis; therefore a blood culture should always be performed. Sputum cultures or cultures from pharyngeal swabs may be used to isolate pathogens in patients with laryngotracheitis. Serologic studies to detect a rise in antibody titers to various viruses are helpful for retrospective diagnosis. Newer, rapid diagnostic techniques, using immunofluorescent-antibody staining to detect virus in sputum, pharyngeal swabs, or nasal washings, have been successfully used. Enzyme-linked immunosorbent assay (ELISA), DNA probe and polymerase chain reaction procedures for detection of viral antibody or antigens are now available for rapid diagnosis.

Prevention and Treatment

Epiglottitis is a medical emergency, especially in children. All children with this diagnosis should be observed carefully and be intubated to maintain an open airway as soon as the first sign of respiratory distress is detected. Antibacterial therapy should be directed at H influenzae. Patients with croup are usually successfully managed with close observation and supportive care, such as fluid, humidified air, and racemic epinephrine. For prevention, Haemophilus influenzae type b conjugated vaccine is recommended for all pediatric patients, as is immunization against diphtheria.

Lower Respiratory Infections

Infections of the lower respiratory tract include bronchitis, bronchiolitis and pneumonia (Fig 93-1). These syndromes, especially pneumonia, can be severe or fatal. Although viruses, mycoplasma, rickettsiae and fungi can all cause lower respiratory tract infections, bacteria are the dominant pathogens; accounting for a much higher percentage of lower than of upper respiratory tract infections.

Bronchitis and Bronchiolitis

Etiology

Bronchitis and bronchiolitis involve inflammation of the bronchial tree. Bronchitis is usually preceded by an upper respiratory tract infection or forms part of a clinical syndrome in diseases such as influenza, rubeola, rubella, pertussis, scarlet fever and typhoid fever. Chronic bronchitis with a persistent cough and sputum production appears to be caused by a combination of environmental factors, such as smoking, and bacterial infection with pathogens such as H influenzae and S pneumoniae. Bronchiolitis is a viral respiratory disease of infants and is caused primarily by respiratory syncytial virus. Other viruses, including parainfluenza viruses, influenza viruses and adenoviruses (as well as occasionally M pneumoniae) are also known to cause bronchiolitis.

Pathogenesis

When the bronchial tree is infected, the mucosa becomes hyperemic and edematous and produces copious bronchial secretions. The damage to the mucosa can range from simple loss of mucociliary function to actual destruction of the respiratory epithelium, depending on the organisms(s) involved. Patients with chronic bronchitis have an increase in the number of mucus-producing cells in their airways, as well as inflammation and loss of bronchial epithelium, Infants with bronchiolitis initially have inflammation and sometimes necrosis of the respiratory epithelium, with eventual sloughing. Bronchial and bronchiolar walls are thickened. Exudate made up of necrotic material and respiratory secretions and the narrowing of the bronchial lumen lead to airway obstruction. Areas of air trapping and atelectasis develop and may eventually contribute to respiratory failure.

Clinical Manifestations

Symptoms of an upper respiratory tract infection with a cough is the typical initial presentation in acute bronchitis. Mucopurulent sputum may be present, and moderate temperature elevations occur. Typical findings in chronic bronchitis are an incessant cough and production of large amounts of sputum, particularly in the morning. Development of respiratory infections can lead to acute exacerbations of symptoms with possibly severe respiratory distress.

Coryza and cough usually precede the onset of bronchiolitis. Fever is common. A deepening cough, increased respiratory rate, and restlessness follow. Retractions of the chest wall, nasal flaring, and grunting are prominent findings. Wheezing or an actual lack of breath sounds may be noted. Respiratory failure and death may result.

Microbiologic Diagnosis

Bacteriologic examination and culture of purulent respiratory secretions should always be performed for cases of acute bronchitis not associated with a common cold. Patients with chronic bronchitis should have their sputum cultured for bacteria initially and during exacerbations. Aspirations of nasopharyngeal secretions or swabs are sufficient to obtain specimens for viral culture in infants with bronchiolitis. Serologic tests demonstrating a rise in antibody titer to specific viruses can also be performed. Rapid diagnostic tests for antibody or viral antigens may be performed oasopharyngeal secretions by using fluorescent-antibody staining, ELISA or DNA probe procedures.

Prevention and Treatment

With only a few exceptions, viral infections are treated with supportive measures. Respiratory syncytial virus infections in infants may be treated with ribavirin. Amantadine and rimantadine are available for chemoprophylaxis or treatment of influenza type A viruses. Selected groups of patients with chronic bronchitis may receive benefit from use of corticosteroids, bronchodilators, or prophylactic antibiotics.

Pneumonia

Pneumonia is an inflammation of the lung parenchyma (Fig 93-4). Consolidation of the lung tissue may be identified by physical examination and chest x-ray. From an anatomical point of view, lobar pneumonia denotes an alveolar process involving an entire lobe of the lung while bronchopneumonia describes an alveolar process occurring in a distribution that is patchy without filling an entire lobe. Numerous factors, including environmental contaminants and autoimmune diseases, as well as infection, may cause pneumonia. The various infectious agents that cause pneumonia are categorized in many ways for purposes of laboratory testing, epidemiologic study and choice of therapy. Pneumonias occurring in usually healthy persons not confined to an institution are classified as community-acquired pneumonias. Infections arise while a patient is hospitalized or living in an institution such as a nursing home are called hospital-acquired or nosocomial pneumonias. Etiologic pathogens associated with community-acquired and hospital-acquired pneumonias are somewhat different. However, many organisms can cause both types of infections.

Figure 93-4

Pathogenesis of bacterial pneumonias.

Etiology

Bacterial pneumonias

Streptococcus pneumoniae is the most common agent of community-acquired acute bacterial pneumonia. More than 80 serotypes, as determined by capsular polysaccharides, are known, but 23 serotypes account for over 90% of all pneumococcal pneumonias in the United States. Pneumonias caused by other streptococci are uncommon. Streptococcus pyogenes pneumonia is often associated with a hemorrhagic pneumonitis and empyema. Community-acquired pneumonias caused by Staphylococcus aureus are also uncommon and usually occur after influenza or from staphylococcal bacteremia. Infections due to Haemophilus influenzae (usually nontypable) and Klebsiella pneumoniae are more common among patients over 50 years old who have chronic obstructive lung disease or alcoholism.

The most common agents of nosocomial pneumonias are aerobic gram-negative bacilli that rarely cause pneumonia in healthy individuals. Pseudomonas aeruginosa, Escherichia coli, Enterobacter, Proteus, and Klebsiella species are often identified. Less common agents causing pneumonias include Francisella tularensis, the agent of tularemia; Yersinia pestis, the agent of plague; and Neisseria meningitidis, which usually causes meningitis but can be associated with pneumonia, especially among military recruits. Xanthomonas pseudomallei causes melioidosis, a chronic pneumonia in Southeast Asia.

Mycobacterium tuberculosis can cause pneumonia. Although the incidence of tuberculosis is low in industrialized countries, M tuberculosis infections still continue to be a significant public health problem in the United States, particularly among immigrants from developing countries, intravenous drug abusers, patients infected with human immunodeficiency virus (HIV), and the institutionalized elderly. Atypical Mycobacterium species can cause lung disease indistinguishable from tuberculosis.

Aspiration pneumonias

Aspiration pneumonia from anaerobic organisms usually occurs in patients with periodontal disease or depressed consciousness. The bacteria involved are usually part the oral flora and cultures generally show a mixed bacterial growth. Actinomyces, Bacteroides, Peptostreptococcus, Veilonella, Propionibacterium, Eubacterium, and Fusobacterium spp are often isolated.

Atypical pneumonias

Atypical pneumonias are those that are not typical bacterial lobar pneumonias. Mycoplasma pneumoniae produces pneumonia most commonly in young people between 5 and 19 years of age. Outbreaks have been reported among military recruits and college students.

Legionella species, including L pneumophila, can cause a wide range of clinical manifestations. The 1976 outbreak in Philadelphia was manifested as a typical serious pneumonia in affected individuals, with a mortality of 17% (see Ch. 40). These organisms can survive in water and cause pneumonia by inhalation from aerosolized tap water, respiratory devices, air conditioners and showers. They also have been reported to cause nosocomial pneumonias.

Chlamydia spp noted to cause pneumonitis are C trachomatis, C psittaci and C pneumoniae. Chlamydia trachomatis causes pneumonia ieonates and young infants. C psittaci is a known cause for occupational pneumonitis in bird handlers such as turkey farmers. Chlamydia pneumoniae has been associated with outbreaks of pneumonia in military recruits and on college campuses.

Coxiella burnetii the rickettsia responsible for Q fever, is acquired by inhalation of aerosols from infected animal placentas and feces. Pneumonitis is one of the major manifestations of this systemic infection.

Viral pneumonias are rare in healthy civilian adults. An exception is the viral pneumonia caused by influenza viruses, which can have a high mortality in the elderly and in patients with underlying disease. A serious complication following influenza virus infection is a secondary bacterial pneumonia, particularly staphylococcal pneumonia. Respiratory syncytial virus can cause serious pneumonia among infants as well as outbreaks among institutionalized adults. Adenoviruses may also cause pneumonia, serotypes 1,2,3,7 and 7a have been associated with a severe, fatal pneumonia in infants. Although varicella-zoster virus pneumonitis is rare in children, it is not uncommon in individuals over 19 years old. Morality can be as high as 10% to 30%. Measles pneumonia may occur in adults.

Other pneumonias and immunosuppression

Cytomegalovirus is well known for causing congenital infections ieonates, as well as the mononucleosis-like illness seen in adults. However, among its manifestations in immunocompromised individuals is a severe and often fatal pneumonitis. Herpes simplex virus also causes a pneumonia in this population. Giant-cell pneumonia is a serious complication of measles and has been found in children with immunodeficiency disorders or underlying cancers who receive live attenuated measles vaccine. Actinomyces and Nocardia spp can cause pneumonitis, particularly in immunocompromised hosts.

Among the fungi, Cryptococcus neoformans and Sporothrix schenckii are found worldwide, whereas Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum and Paracoccidioides brasiliensis have specific geographic distributions. All can cause pneumonias, which are usually chronic and possible clinically inapparent iormal hosts, but are manifested as more serious diseases in immunocompromised patients. Other fungi, such as Aspergillus and Candida spp, occasionally are responsible for pneumonias in severely ill or immunosuppressed patients and neonates.

Pneumocystis carinii produces a life-threatening pneumonia among patients immunosuppressed by acquired immune deficiency syndrome (AIDS), hematologic cancers, or medical therapy. It is the most common cause of pneumonia among patients with AIDS when the CD4 cell counts drop below 200/mm³.

Pathogenesis and Clinical Manifestations

Infectious agents gain access to the lower respiratory tract by the inhalation of aerosolized material, by aspiration of upper airway flora, or by hematogenous seeding. Pneumonia occurs when lung defense mechanisms are diminished or overwhelmed. The major symptoms or pneumonia are cough, chest pain, fever, shortness of breath and sputum production. Patients are tachycardic. Headache, confusion, abdominal pain, nausea, vomiting and diarrhea may be present, depending on the age of the patient and the organisms involved.

Microbiologic Diagnosis

Etiologic diagnosis of pneumonia on clinical grounds alone is almost impossible. Sputum should be examined for a predominant organism in any patient suspected to have a bacterial pneumonia; blood and pleural fluid (if present) should be cultured. A sputum specimen with fewer than 10 while cells per high-power field under a microscope is considered to be contaminated with oral secretions and is unsatisfactory for diagnosis. Acid-fast stains and cultures are used to identify Mycobacterium and Nocardia spp. Most fungal pneumonias are diagnosed on the basis of culture of sputum or lung tissue. Viral infection may be diagnosed by demonstration of antigen in secretions or cultures or by an antibody response. Serologic studies can be used to identify viruses, M pneumoniae, C. burnetii, Chlamydia species, Legionella, Francisella, and Yersinia. A rise in serum cold agglutinins may be associated with M pneumoniae infection, but the test is positive in only about 60% of patients with this pathogen.

Rapid diagnostic tests, as described in previous sections, are available to identify respiratory viruses: the fluorescent-antibody test is used for Legionella. A sputum quellung test can specify S pneumoniae by serotype. Enzyme-linked immunoassay, DNA probe and polymerase chain reaction methods are available for many agents causing respiratory infections.

Some organisms that may colonize the respiratory tract are considered to be pathogens only when they are shown to be invading the parenchyma. Diagnosis of pneumonia due to cytomegalovirus, herpes simplex virus, Aspergillus spp. or Candida spp require specimens obtained by transbronchial or open-lung biopsy. Pneumocystis carinii can be found by silver stain of expectorated sputum. However, if the sputum is negative, deeper specimens from the lower respiratory tract obtained by bronchoscopy or by lung biopsy are needed for confirmatory diagnosis.

Prevention and Treatment

Until the organism causing the infection is identified, decisions on therapy are based upon clinical history, including history of exposure, age, underlying disease and previous therapies, past pneumonias, geographic location, severity of illness, clinical symptoms, and sputum examination. Once a diagnosis is made, therapy is directed at the specific organism responsible.

The pneumococcal vaccine should be given to patients at high risk for developing pneumococcal infections, including asplenic patients, the elderly and any patients immunocompromised through disease or medical therapy. Yearly influenza vaccinations should also be provided for these particular groups. An enteric-coated vaccine prepared from certain serotypes of adenoviruses is available, but is only used in military recruits. In AIDS patients, trimethoprim/sulfamethoxazole, aerosolized pentamidine or other antimicrobials can be given for prophylaxis of Pneumocystis carinii infections.

 

Microbiology of the Nervous System

 

http://www.ncbi.nlm.nih.gov/books/n/mmed/A5132/

General Concepts

The anatomy of the brain and meninges determines the special character of central nervous system (CNS) infections. Epidural abscesses remain localized, whereas subdural abscesses spread over a hemisphere. Subarachnoid space infections spread widely over the brain and spinal cord. The blood-brain barrier formed by the tight junctions between cells of the cerebral capillaries, choroid plexus, and arachnoid largely prevents macromolecules from entering the brain parenchyma. As a result, immunoglobulins and immune-competent cells are scarce in the brain except at foci of inflammation. The space between cells in the brain parenchyma is too small to permit passage even of a virus. However, tetanus toxin and some viruses travel through the CNS by axoplasmic flow.

Meningitis

Etiology

Major bacterial causes are Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis. Major viral causes are enteroviruses, mumps virus and lymphocytic choriomeningitis virus.

Pathogenesis

Most agents invade from blood. Bacteria grow rapidly in cerebrospinal fluid; viruses infect meningeal and ependymal cells.

Clinical Manifestations

Headache, fever and stiff neck are the symptoms of meningitis. Untreated bacterial meningitis is usually fatal; viral meningitis is benign. Cerebrospinal fluid findings are critical in differential diagnosis.

Treatment

Antibiotics are used to treat bacterial and fungal meningitis. Viral meningitis is treated symptomatically.

Brain Abscess

Etiology

Brain abscesses often exhibit a mixed flora of aerobic and anaerobic bacteria. Fungi are uncommon.

Pathogenesis

Abscesses begin when bacteria seed sites of necrosis, caused usually by infarction.

Clinical Manifestations

Headache, focal signs and seizures indicate a brain abscess. There are also characteristic computed tomography (CT) and magnetic resonance image (MRI) findings.

Treatment

Treatment consists of surgical drainage and appropriate antibiotics.

Encephalitis

Etiology

Many viruses cause mild meningoencephalitis; herpes simplex viruses and arboviruses are the major causes of potentially fatal disease.

Pathogenesis

Herpes simplex virus causes acute diffuse encephalitis ieonates. Herpes simplex type 1 causes focal temporal and frontal encephalitis in children and adults probably owing to invasion along olfactory or sensory nerves in the immune host. Arboviruses invade from the blood and cause diffuse predominantly neuronal infection. Rabies invades along peripheral nerves.

Clinical Manifestations

Encephalitis causes headache, fever, CNS depression, seizures, and mononuclear cells in cerebrospinal fluid. Focal temporal lobe signs occur in herpes simplex virus encephalitis.

Treatment

Acyclovir is used to treat herpes simplex encephalitis. Some arboviruses can be prevented by mosquito control or vaccines.

Slow and Chronic CNS Infections

Spirochetes

Untreated syphilis and Lyme disease can cause varied later CNS disease.

Retroviruses

Human immunodeficiency virus can cause acute and progressive CNS disease. HTLV-I causes chronic spastic paraparesis in a small number of infected persons.

Conventional Viruses

Persistent measles and rubella virus infections can cause subacute encephalitis with dementia. JC virus, a papovavirus, can cause progressive demyelinating disease in immunodeficient patients.

Unconventional Agents

Kuru and Creutzfeldt-Jakob disease are chronic noninflammatory, degenerative diseases of the brain that are caused by unconventional agents called prions.

Parasites

Parasites may cause acute meningitis or encephalitis, chronic encephalopathy, and cerebral granulomas. Neurocysticercosis is the most common parasitic neurologic disease.

Introduction

Infections of the nervous system are rare but life-threatening complications of systemic infections. The central nervous system (CNS) presents a special milieu for bacterial, fungal, viral and parasitic infections: the brain and spinal cord are protected by bone and meningeal coverings that compartmentalize infection; they are divided by barriers from the systemic circulation; they lack an intrinsic immune system; and they have a unique compact structure.

Gross Anatomy

The brain is protected by the bony calvaria, and the outer meningeal covering, the dura, is tightly bound to the bone. Epidural infections usually arise from bone infection (osteomyelitis) and remain localized (Fig. 96-1). At the foramen magnum the dura becomes free, forming a true epidural space around the spinal cord. The dura and arachnoid are not adherent to each other. Consequently, when bacteria penetrate the dura into the subdural space, infection can spread rapidly over a cerebral hemisphere. However, subdural empyema is usually confined to one hemisphere by the dural reflexions along the falx and tentorium. The subarachnoid space is a true space, containing cerebrospinal fluid (CSF) that flows from the ventricles to the basilar cisterns over the convexities of the hemispheres and through the spinal subarachnoid space. The CSF contains little antibody or complement and few phagocytic cells. Therefore, bacteria that enter this space undergo an initial phase of logarithmic growth, accounting for the often explosive onset of acute bacterial meningitis.

Figure 96-1

Anatomy and site of infection of the brain and spinal cord. (Modified from Butler IJ, Johnson RT: Central nervous system infections. Pediatr Clin N Am 21:650, 1974, with permission.)

Blood-Brain Barrier

Dyes such as trypan blue injected into the systemic circulation stain virtually all tissues, with the exception of the brain and spinal cord. This blood-brain barrier, which excludes most macromolecules and microorganisms, is due to the cellular configuration of the cerebral capillaries, the choroid plexus, and arachnoid cells (Fig. 96-2). This barrier excludes not only most microbes, but most immunocompetent cells and antibodies. Therefore, although the barrier deters invasion of infectious agents, it hampers their clearance once it is penetrated.

Figure 96-2

Blood-brain barrier. Tight junctions envelop the CNS between capillary endothelial cells, choroid plexus epithelial cells, and arachnoid cells. The cerebral capillaries (A) lack fenestrations, have (more…)

Immune System

Antibodies found in the normal CNS are derived from the serum. Levels of IgG and IgA in the CSF are approximately 0.2 to 0.4 percent of the serum levels. Since diffusion of macromolecules across the barrier is largely size dependent, IgM is present at even lower levels. There is also no lymphatic system in the usual sense, and few, if any, phagocytic cells. Complement is also largely excluded.

When trauma or inflammation disrupts the blood-brain barrier, antibody molecules passively leak into the CNS along with other serum proteins. When an inflammatory reaction has been mounted against an infection, B cells from the peripheral circulation can move into the perivascular spaces of the CNS and generate immunoglobulins intrathecally.

Polymorphonuclear cells are the dominant inflammatory cells in acute bacterial infections of the CNS; they are attracted by chemotactic factors mediated primarily by components of complement activated by antibody-antigen reactions. Mononuclear cells are the dominant inflammatory cells in viral infections and in subacute infections such as tuberculosis and fungal infections. In viral infections, specifically sensitized T-cells cross the blood-brain barrier into the CNS first, and lymphokines released by these cells probably recruit the entry of B cells and macrophages.

Cellular Structure

There is no brain-CSF barrier. The ependymal cells have no tight junctions, so the CSF in the ventricles and extracellular fluid in the brain are in direct contact. However, the cellular gap betweeeural cells measures only about 10 to 15 nm, less than the diameter of even the smallest virus, and thus free movement of inflammatory cells or microorganisms within the extracellular space of the brain and spinal cord is restricted.

The highly specialized nature of neural cells is important in the pathogenesis of CNS infection. Different subpopulations of neurons have different surface receptors, which have been usurped by viruses to permit entry into cells. Furthermore, both bacterial toxins and viruses can be carried by axoplasmic transport either into the CNS or within the CNS along the long axonal processes to distant but functionally linked neurons. Tetanus toxin, for example, is picked up in vesicles at peripheral axon terminals and is carried to the neuron cell body within the CNS. Viruses, such as rabies, similarly are moved within the axon transport system (Table 96-1).

Table 96-1

Pathways of Spread to the Central Nervous System.

Meningitis

Meningitis is an inflammation of the pia-arachnoid meninges. It can be caused by growth of bacteria, fungi, or parasites within the subarachnoid space or by the growth of bacteria or viruses within the meningeal or ependymal cells. Meningitis is a diffuse infection caused by a variety of different agents (Fig. 96-3).

Figure 96-3

Major causes of acute meningitis (all ages, worldwide). “Other” viruses include herpes simplex virus type 2, arthropod-borne viruses, Epstein-Barr virus, influenza virus, and measles (more…)

Etiology

Approximately 20,000 cases of bacterial meningitis occur in the United States each year. Seventy percent of these are in children younger than 10 years old. Infants are particularly susceptible because of their predisposition to bacterial infection, possible lower integrity of barriers, and immature defense mechanisms. Ieonates younger than 28 days old, meningitis is usually due to enteric bacilli (especially Escherichia coli), group B streptococci, or Listeria. Neonatal meningitis represents fewer than 10 percent of cases of meningitis, but more than 50 percent of meningitis deaths. In the postnatal period, Haemophilus influenzae is the most common cause of bacterial meningitis, but this infection is largely limited to childhood. Significant reductions in some countries are occurring due to use of capsular polysaccharide-protein conjugate vaccines during infancy. Adult bacterial meningitis is predominantly due to Neisseria meningitidis and Streptococcus pneumoniae, except in cases where there had been a penetrating wound to the skull, surgery, or immunosuppression in the host. Neisseria meningitidis causes epidemic disease, all other forms of pyogenic meningitis are sporadic. Tuberculosis and fungi usually cause subacute meningitis. Cryptococcus neoformans often causes meningitis in immunosuppressed patients, but can cause indolent meningitis in immunocompetent individuals. Coccidioides immitis and, rarely, other fungi also cause subacute meningitis.

Viral meningitis occurs more frequently than bacterial meningitis, with over 50,000 cases each year in the United States. The disease is benign and tends to be seasonal. Enteroviruses (echoviruses and coxsackieviruses) cause disease, primarily in the late summer and early fall; mumps virus spreads predominantly in the spring; and lymphocytic choriomeningitis virus is more common in winter, since this virus is acquired from mice, which move indoors during cold weather and increase human exposure.

Pathogenesis

Most bacteria and viruses invade the CNS from the blood (Table 96-1), and the risk of CNS invasion has been shown to be related to the magnitude and duration of the bacteremia or viremia. Particles in the blood, including bacteria or viruses, are normally cleared by the reticuloendothelial system, and speed of removal is proportional to size. The bacteria that maintain a bacteremia (and incidentally cause meningitis) are largely those which elaborate capsid polysaccharides that increase their resistance to phagocytosis. Intracellular bacteria and a variety of viruses elude clearance by growing within blood cells. Enteroviruses and some arthropod-borne viruses (arboviruses) are cleared less effectively from serum because of their small size. Some viruses enter the CNS by infecting endothelial cells or choroid plexus epithelium. Indeed, in mumps virus meningitis, choroid plexus cells containing viral nucleocapsids are frequently found within the CSF.

Clinical Manifestations

The primary clinical manifestations of meningitis are headache, fever, and nuchal rigidity (stiffness of the neck on passive forward flexion due to stretching of the inflamed meninges). Flexion of the neck may also cause reflex flexion of the legs (Brudzinski sign), and meningeal irritation may limit extension of the leg when flexed at the knee (Kernig sign). Meningeal inflammation may also cause some degree of obtundation (reduced consciousness), and seizures are common in children. If bacterial meningitis is not promptly treated, purulent material collects around the base of the brain, which may cause cranial nerve palsies and obstruct the flow of CSF, resulting in hydrocephalus. Vasculitis develops, with infarction of the brain and multifocal neurological deficits. Untreated bacterial meningitis is a uniformly fatal disease. Viral meningitis, on the other hand, is benign and self-limited.

Systemic clinical signs sometimes suggest the agent (e.g., the rash or herpangina of enterovirus infections, the parotitis of mumps, or the multiple petechiae of meningococcemia). Examination of the CSF provides the most important diagnostic information (Table 96-2). Acute bacterial infections evoke a polymorphonuclear cell response in the CSF and profound reductions of CSF sugar content. Bacteria can usually be seen on smears of the CSF and can be cultured if antibiotics have not been given. Subacute tuberculous or fungal meningitis is more difficult to diagnose. The inflammatory response is usually composed of mononuclear cells, and the reduction of CSF sugar evolves slowly. Organisms are difficult to see on direct smears, although cryptococci may be identified by mixing India ink with the CSF to outline the capsule of the organism and differentiate it from mononuclear inflammatory cells. In general, viruses produce a modest mononuclear cell response, and although the CSF protein may be elevated, CSF sugar is normal or only mildly depressed. Viruses, such as enteroviruses and mumps virus, can be grown from the CSF, but this requires special viral cultures. A rapid diagnosis may be achieved by demonstrating antigen of various bacterial and fungal agents or the presence of IgM against specific viral agents.

Table 96-2

CSF Findings in Nervous System Infections.

Treatment

Early diagnosis of bacterial and fungal meningitis and treatment with appropriate antimicrobial agents are crucial. The mortality rate due to untreated disease approaches 100 percent. Even with treatment, the death rate of individuals with acute bacterial meningitis remains approximately 15%; it is as high as 30% for pneumococcal meningitis. Sequelae are frequent in survivors. This mortality and morbidity have remained relatively unchanged since the introduction of antibiotics. Further reduction of death and disability rests primarily on the physician’s early suspicion, diagnosis, and treatment of the disease. Viral meningitis requires only symptomatic treatment since the disease is self-limited; the prime management problem is to rule out nonviral, treatable illnesses that can mimic acute viral meningitis (partially treatable bacterial meningitis, tuberculous or fungal meningitis, syphilis, Lyme disease, etc.).

Infection of the Brain Parenchyma

Abscess

An abscess is a focus of purulent infection and is usually due to bacteria. Brain abscesses develop from either a contiguous focus of infection (such as the ears, the sinuses, or the teeth) or hematogenous spread from a distant focus (such as the lungs or heart, particularly with chronic purulent pulmonary disease, subacute bacterial endocarditis, or cyanotic congenital heart disease). In many cases the source is undetected.

Etiology

Many brain abscesses have a mixed flora of aerobic and anaerobic bacteria. Approximately 60 to 70 percent contain streptococci; and Staphylococcus aureus, enterobacteria and Bacteroides are frequently present. Fungi cause fewer than 10 percent of brain abscesses.

Pathogenesis

Abscesses in the brain parenchyma are thought to result from a bacterial seeding of already devitalized tissue. In experimental animals, direct injection of bacteria into the carotid arteries does not lead to brain abscess, whereas injection of microspheres that occlude small vessels, followed by injection of bacteria does lead to abscess formation. With chronic purulent ear or sinus infection, infection extending along the veins may cause infarction of brain tissue; a bacterial abscess may then evolve. In cyanotic congenital heart disease (right-to-left shunt), emboli cause small infarcts of the brain which are then seeded by bacteria from the blood.

Clinical Manifestations

The primary clinical manifestations of abscess are headache, focal signs, and seizures. The headache may not be severe, however, and the development of signs may be insidious. There may be no fever. If focal signs are present computed tomography (CT) or magnetic resonance imaging (MRI) is performed rather than CSF examination. An abscess is identified by a hypodense area representing pus surrounded by an enhancing area representing the neovascularization and edema around the fibrous abscess wall. The CSF is usually sterile, and bacteriologic diagnosis can only be obtained by culturing an aspirate of the abscess cavity.

Treatment

If a poorly defined area of cerebritis is found, treatment is begun with multiple antibiotics to cover the multiple common organisms. If there is encapsulation, the abscess should be drained to determine specific bacterial flora and prevent catastrophic rupture of the abscess into the ventricles.

In contrast, epidural abscesses usually cause local pain and tenderness. Pressure against a localized area of the brain may lead to focal signs. Spinal epidural and cerebral or spinal subdural abscesses are surgical emergencies. Spinal epidural abscesses have a rapid course, starting with segmental pain along nerve roots, followed by paresthesias of the body below the abscess level, and finally irreversible paraplegia. Subdural abscesses (subdural empyema) spread rapidly over a wider area. Subdural empyema causes septic thrombosis of bridging veins, leading to hemiplegia and seizures (Fig. 96-1).

Encephalitis

Encephalitis is defined as inflammation of the brain. Unlike an abscess, which is a localized area of bacterial or fungal growth, encephalitis is usually due to viruses that produce more widespread intracellular infections.

Etiology

Many viruses, including enteroviruses, mumps, and lymphocytic choriomeningitis viruses, cause mild forms of encephalitis. Life-threatening viral encephalitis is due primarily to herpes simplex viruses and arboviruses. Rabies virus causes uniformly fatal infection, but no more than six cases have occurred in any year since 1979 in the United States.

Pathogenesis

The pathogenesis of encephalitis due to herpes simplex virus, arboviruses, and rabies virus is different for each virus. Herpes simplex viruses, both types 1 and 2 (HSV-1 AND HSV-2), cause encephalitis. Ieonates, the disease is predominantly due to HSV-2 virus, and irrespective of serotype, the acute generalized necrotizing encephalitis is often accompanied by evidence of systemic infection of the liver, adrenals, and other organs. In children and adults, however, encephalitis is caused by HSV-1 virus and is usually localized. This virus, which is acquired in childhood, remains latent within the trigeminal and other ganglia. It may reactivate to cause cold sores. Encephalitis in an immune host results either from the entry of a new virus, possibly across the olfactory mucosa, or from reactivation of latent virus in the trigeminal ganglia, which spread along sensory nerve fibers to the base of the anterior and middle fossa. In either case, infection is localized to the orbital frontal and medial temporal lobes. Because the host is immune, virus presumably spreads from cell to cell over a contiguous localized area, infecting neurons and glial cells.

In contrast, arboviruses (mainly togaviruses, flaviviruses, and bunyaviruses) spread to the brain from the blood. The systemic infection causes few, if any, symptoms. Depending on the virus, between 1 in 20 and 1 in 1000 infections are complicated by CNS infection. The encephalitis is diffuse, but is localized largely to neurons.

Rabies, in contrast, is usually acquired through the bite of a rabid warm-blooded animal. This virus spreads by axonal transport from the inoculated skin or muscle to the corresponding dorsal root ganglion or anterior horn cells and then to populations of neurons throughout the CNS. The early involvement of neurons of the limbic system cause the typical behavioral changes of clinical rabies. Polioviruses also show a selective infection of specific motor neuron populations which explains the asymmetrical flaccid motor paralysis of poliomyelitis.

Clinical Manifestations

Herpes simplex virus-1 encephalitis in the non-neonate typically causes focal signs that may evolve over a period of up to 1 or 2 weeks. In addition to headache and fever, hallucinations and bizarre behavior are common, and these are sometimes confused with psychiatric illness. Focal seizures and hemiparesis are frequent, and aphasia develops if the disease is localized to the dominant temporal lobe.

Arbovirus infections cause a more diffuse and acute disease, with a rapid depression of consciousness, greater frequency of generalized seizures, and multifocal signs. At times, however, this or any other form of encephalitis may localize to the temporal areas, producing signs very similar to those of herpes simplex virus encephalitis.

The CSF examination in acute encephalitis may or may not show an increase in pressure, but usually reveals an inflammatory response of mononuclear cells. Examination early in disease may show no cellular response or a predominance of polymorphonuclear cells. Red blood cells are frequently found in herpes encephalitis because of the necrotizing pathology of the disease, but they are not universally present nor are they specific to the disease. The CSF protein level is usually elevated and the CSF sugar level remains normal. Cultures for herpes simplex virus are usually negative. Polymerase chain reaction tests for herpesvirus sequences are highly sensitive and specific in experienced laboratories. Intrathecal antiherpesvirus antibody may be detected late in the course of the disease, but too late to instigate therapy. In most arbovirus infections, virus-specific IgM is present in spinal fluid, for specific diagnosis at the time of initial presentation.

The electroencephalogram (EEG) is helpful in the diagnosis of herpes simplex virus encephalitis because periodic spikes and slow waves often localize to the infected temporal lobe. In other forms of encephalitis slowing is more diffuse. Computerized tomography in cases of herpes simplex virus encephalitis usually shows an attenuated area in the medial temporal lobes and sometimes a mass effect, but these findings, like the CSF and EEG changes, are not diagnostic. A prompt, definitive diagnosis of HSV-1 encephalitis requires brain biopsy of the area where typical encephalitis with inclusion bodies is seen, and the diagnosis is confirmed by either immunocytochemical staining of herpes simplex virus antigens in brain cells or virus isolation.

Treatment

Rapid diagnosis of herpes simplex virus encephalitis is important because a specific antiviral therapy, acyclovir (acycloguanosine), reduces the mortality from 70 percent without treatment to 25 percent if treatment is initiated prior to the onset of coma. Other forms of viral encephalitis are treated primarily with supportive care, although some arboviral encephalitides, such as Japanese encephalitis, can be prevented by vaccines, and others can be reduced by mosquito control.

Slow and Chronic Infection and Chronic Neurologic Disease

Chronic nervous system infections, such as those that occur with syphilis, persist over many years with the unpredictable appearance of varied neurologic complications. In contrast, slow infections, such as Creutzfeldt-Jakob disease, have more predictable incubation periods with a progressive buildup of infectivity, followed by a disease of predictable course lasting months or years. The slow infections resemble acute infections, with a predictable incubation period and disease course, but extend over months or years. Chronic or slow neurologic diseases due to persistent infection must be differentiated from chronic diseases that represent the static sequelae of acute bacterial meningitis or viral encephalitis; the former are progressive and depend on the ongoing replication of the infectious agent in the nervous system (Table 96-3).

Table 96-3

Slow and Chronic Infections of the Nervous System.

Spirochetes

Syphilis can cause varied neurologic diseases over the lifetime of the untreated patient. During secondary syphilis, 6 weeks to 3 months after primary infection, a benign mild meningitis may accompany the primary CNS invasion that occurs in approximately 25 percent of untreated patients. Later complications include acute meningovascular inflammatory disease leading to stroke (meningovascular syphilis) 3 to 5 years after the primary infection, progressive dementia (general paresis) 8 to 10 years later, or a chronic arachnoiditis involving primarily the posterior roots of the spinal cord (tabes dorsalis) 10 to 20 years after infection. This development of vasculitis, parenchymal involvement and chronic arachnoiditis parallel the complications that occur over weeks during untreated bacterial meningitis. Lyme disease also may be complicated by early and late neurologic involvement. Mild meningitis and facial palsy often accompany the initial rash and systemic symptoms following the tickbite. In 15 percent of untreated patients, subacute or recurrent meningitis, encephalitis, cranial nerve palsies, and peripheral neuropathies develop 1 to 9 months later, and rarely a chronic meningoencephalitis has been described years later.

Retroviruses

Two human retroviruses cause chronic neurological diseases. Human immunodeficiency virus (HIV) infects the CNS soon after systemic infection in most patients. An acute meningitis or acute demyelinating polyneuritis (Guillain-Barré syndrome) occasionally occurs at the time of seroconversion and a recurrent meningitis and motor neuropathies can occur during the long, otherwise asymptomatic seropositive period. Years later at the time of clinical AIDS, dementia, myelopathy and a painful sensory neuropathy are frequent.

In contrast, most persons infected with human T-cell lymphotropic virus type 1 (HTLV-I) suffer no neurologic disease. Less than 1 percent of those infected develop a slowly progressive myelopathy called tropical spastic paraparesis or HTLV-associated myelopathy. This inflammatory disease of the spinal cord usually develops during the fourth or fifth decade of life even though HTLV-1 infection is most frequently acquired from breast feeding during the neonatal period.

In chronic spirochetal and retroviral infections the CSF often has a mild mononuclear cell inflammatory response, mild elevation of protein levels, and elevated IgG in an oligoclonal pattern, suggesting an ongoing infection.

Conventional Viruses

Some conventional viruses occasionally produce chronic disease. This outcome may result from defective replication of the virus or a defect in the host. Following uncomplicated measles, approximately one per million children develop subacute sclerosing panencephalitis (SSPE) 6 to 8 years later. This chronic dementing illness with myoclonic movements is due to a defective measles virus infection in the CNS. Progressive multifocal leukoencephalopathy, in contrast, is due to a ubiquitous papovavirus, JC virus, which infects almost all children without recognized symptoms. In immunodeficient patients, this virus may cause a subacute or chronic demyelinating disease of the brain with multifocal signs, leading to death usually in less than 6 months. Rubella virus has been associated with chronic encephalitis after congenital infection, and, in very rare cases, there has been a relapse of a disease in adolescence resembling SSPE. In these infections the precise location of virus and the virus-host relationship during the long incubation period is not known.

Unconventional Agents

Unconventional agents called prions or spongiform encephalopathy agents are transmissible but have no identified nucleic acid. Kuru, the first of these to be described, has been limited to an isolated population in New Guinea. Creutzfeldt-Jakob disease, however, occurs worldwide. It is a presenile dementia with histopathologic abnormalities limited to the CNS; the brain shows vacuolization of neurons and glia, but no inflammatory response. The disease has a course of rapidly progressive cognitive deficits with myoclonic movements. Death usually occurs in less than 6 months. In experimental infection with these agents, infectivity in the brain and extraneural tissues slowly accumulates during the long incubation period, but no immune response to the agent is found iatural or experimental infection.

Parasites

Parasitic infections such as malaria, amebiasis with free-swimming amoebas and trichinosis can produce acute encephalopathy or meningitis. Others are associated with chronic disease, such as the chronic sleeping sickness of African trypanosomiasis, the chronic cerebral granulomas caused by Schistosoma japonicum, or abscesses caused by Toxoplasma gondii in immunodeficient patients. The commonest parasitic neurologic disease is cysticercosis caused by the larvae form of Taenia solium. The parasitic cysts and resulting basilar arachnoiditis are the most common causes of epilepsy and hydrocephalus in many areas of South America and Asia.

The usual clinical signs of meningitis are headache, fever, vomiting, and a stiff neck; however, many of these signs can be absent, or not evident, in infants. As discussed in earlier chapters of this unit, there are several specific organisms that are frequent causes of meningitis, namely N meningitidis, H influenzae, and S. pneumoniae. In addition, other organisms, such as M tuberculosis and Crypto- coccus neoformans, less frequently cause meningitis. Essentially any organism that gains entrance to the fluid surrounding the brain and spinal cord can grow and casein inflammation of the meanings. Such infections frequently are severe and, unless promptly and adequately treated, can result in the death of the patient in a matter of hours.

Specimen Collection of Cerebrospinal Fluid

Cerebrospinal fluid (CSF) is obtained by a puncture into the lumbar region of the spine. It is of utmost importance that the puncture site be decontaminated in the manner described previously for venipunctures to ensure that no contaminating organisms are mechanically injected into the CSF. The collected specimen should be placed into a sterile screw-cap tube and delivered immediately to the diagnostic laboratory.

Media Inoculated With Cerebrospinal Fluid

A diagnosis of meningitis usually is based on the microbiologic findings in the CSF, chemical determination of teetotal protein and glucose present in the fluid, and its cellular content. Because the total specimen frequently is only 1 to 2 ml., the sample must suffice for the haematology, chemistry, and microbiologic findings. Therefore, after the cell count, the CSF is routinely centrifuged for10 minutes at 1200 times gravity; part of the supernatant is used for the chemical assays, and the sediment is the source for the bacteriologic evaluation.

The sediment from the centrifuged sample is inoculated onto one blood and one chocolate blood-agar plate. Both plates are incubated aerobically under 5% to 10% CO₂  at 35°C, and disks of hematin and NAD are added to allow the growth of H influenzae. Another method of providing these required factors is to make a single streak of S aureus across the plate. The staphylococci release these factors by lysis of the red blood cells in the agar, and H influenzae will be found growing only as satellite colonies adjacent to the growth of the staphylo-cocci. The chocolate-agar plate is incubated under an atmosphere of 10% CO^. Both nutrient broth and a special broth for the growth of anaerobes should be inoculated with the CSF sediment. All cultures should be inspected daily and, in the event of growth; broth media should be subcultured onto an appropriate agar medium.

Identification of Isolates from Cerebrospinal Fluid

Because meningitis frequently presents an emergency situation, it is imperative that a tentative diagnosis is made as soon as possible. It is mandatory that the sediment from the centrifuged CSF be subjected to Gram’s stain and examined microscopically. Because the number of organisms often is small, it is recommended that at least30 minutes be spent for such an examination. If organisms are seen, additional procedures sometimes can be used to substantiate immediately a tentative identification. The most common of these are to carry out a coagglutination reaction using latex beads with known specific antiserum or to stain with specific, fluorescence-labelled antiserum. Capsular antigens of certain streptococci, N meningitidis, and H influenzae can be present even in the absence of bacteria on the Gram’s smear, and using latex bead agglutination procedures may speed up the diagnosis of meningitis. Spinal fluid from a possible case of tuberculosis meningitis should be stained for acid fast organisms, and a possible infection by C. neoformans can be diagnosed tentatively using wet mounts of spinal fluid sediment mixed with India ink or nigrosin to demonstrate the large capsules surrounding the yeast cells. A latex bead test for cryptococci also is available.

An evaluation of a patient’s inflammatory response also aids in the diagnosis of a meningeal infection. In general, polymorphonuclear leukocytes predominate in the CSF in acute bacterial infections, whereas meningitis resulting from fungi, Leptospira, or M. tuberculosis is characterized by the presence of lymphocytes.

 

WOUNDS AND ABSCESSESBone, Joint, and Necrotizing Soft Tissue Infections(http://www.ncbi.nlm.nih.gov/books/n/mmed/A5381/)

 

General Concepts

Necrotizing Soft Tissue Infections

Etiology

Anaerobic microorganisms such as Bacteroides species, Peptostreptococcus species, and Clostridium species are largely responsible for these infections. Mixed infections by aerobic and facultative anaerobic organisms are common.

Pathogenesis

Susceptible persons have experienced trauma or surgery and frequently have diabetes and/or vascular insufficiency. Organisms gain entry via direct inoculation. Local hypoxia and decreased oxygen-reduction potentials favor anaerobic growth.

Clinical Manifestations

This signs of disease include production of tissue gas, a putrid discharge, tissue necrosis, fever, (occasionally) systemic toxicity, and absence of classic signs of inflammation.

Microbiologic Diagnosis

These infections are usually diagnosed by clinical presentation. Aerobic and anaerobic wound cultures help identify the major pathogens.

Prevention and Treatment

Immediate surgical debridement of all necrotic tissue is vital. High-dose parenteral antibiotic therapy should be started immediately. Hyperbaric oxygen therapy may be indicated.

Joint Infections

Etiology

Neisseria gonorrhoeae and S taphylococcus aureus are responsible for most cases of bacterial arthritis.

Pathogenesis

Joint infections are usually a result of hematogenous spread, but may also arise from traumatic inoculation or by extension from an adjacent focus of infection. Proteolytic enzymes of polymorphonuclear leukocytes, bacterial toxins, and pressure from joint swelling all contribute to the damage of articular surfaces.

Clinical Manifestations

Joint swelling. pain, warmth (inflammation), decreased range of motion, and fever are the classic symptoms. Disseminated gonococcal infections may also cause migratory polyarthritis, dermatitis, and tenosynovitis.

Microbiologic Diagnosis

Aspiration and culture of synovial fluid usually provides the definite diagnosis.

Prevention and Treatment

Gonococcal arthritis may be prevented by techniques used to decrease the risk for sexually transmitted disease. The treatment for all septic arthritides is administration of parenteral antibiotics. Some cases may require aspiration and/or surgical debridement.

Bone Infections

Etiology

Staphylococcus aureus is the most commonly isolated pathogen. Polymicrobic infections are frequent in contiguous-focus osteomyelitis.

Pathogenesis

Organisms may reach the bones by hematogenous spread, by direct extension from a contiguous focus of infection, or as a result of trauma. A cycle of increased pressure from infection, inflammation, local ischemia, and bone necrosis may establish itself and lead to a chronic infection.

Clinical Manifestations

Hematogenous osteomyelitis classically presents with high fever and pain around the involved bone. Sinus tracts with purulent drainage are evidence of chronic osteomyelitis.

Microbiologic Diagnosis

Bone biopsy and/or debridement cultures are mandatory with rare exceptions. Sinus tract cultures are unreliable.

Prevention and Treatment

Treatment consists of surgical debridement and long-term, culture-directed antimicrobial therapy. Hematogenous osteomyelitis in children may be treated with antibiotics alone.

Introduction

Necrotizing infections of the soft tissues are characterized by extensive tissue necrosis and production of tissue gas. These infections may extend through tissue planes and are not well contained by the usual inflammatory mechanisms. They may develop and progress with dramatic speed, and extensive surgery and systemic antibiotic therapy are required to eradicate them.

Arthritis or inflammation of a joint space may be caused by a wide variety of infectious or noninfectious processes. Non-infectious arthritis is the more common type of arthritis and is usually secondary to degenerative, rheumatoid, or posttraumatic changes within the joint. Infectious arthritis, although less common, is often accompanied by a striking polymorphonuclear inflammatory response and can cause severe destruction of the articular cartilage if not properly diagnosed and treated.

Bone infections are called osteomyelitis (from osteo [bone], plus myelitis [inflammation of the marrow]). Hematogenous osteomyelitis and contiguous-focus osteomyelitis are the two major types of bone infections. Both types can progress to a chronic bone infection characterized by large areas of dead bone.

Bone, joint, and soft tissues, with the exception of the skin, are normally sterile areas. Bacteria may reach these sites by either hematogenous spread or spread from an exogenous or endogenous contiguous focus of infection (Fig. 100-1). Host defenses are important in containing necrotizing soft tissue infections. A systemically or locally compromised host (Table 100-1) is more likely to develop these types of infections and to be unable to contain them.

Figure 100-1

Bacterial spread to bone, joints, and soft tissue.

Table 100-1

Systematic and Local Factors That Adversely Affect the Host Response.

Necrotizing Soft Tissue Infections

An exact classification of necrotizing subcutaneous, fascial, and muscle infections is difficult because the distinctions between many of the clinical entities are blurred. Clinical classification is as follows: (1) crepitant anaerobic cellulitis, (2) necrotizing fasciitis, (3) nonclostridial myonecrosis, (4) clostridial myonecrosis, (5) fungal necrotizing cellulitis, and (6) miscellaneous necrotizing infections in the immunocompromised host. These types of infections usually occur in traumatic or surgical wounds or around foreign bodies and in patients who are medically compromised by diabetes mellitus, vascular insufficiency, or both. In the traumatically, surgically, or medically compromised patient, local tissue conditions, hypoxia, and decreased oxidation-reduction potential (E_h) promote the growth of anaerobes. Most necrotizing soft tissue infections have an endogenous anaerobic component. Since anaerobes are the predominant members of the microflora on most mucous membranes, there are many potential pathogens. Hypoxic conditions also allow proliferation of facultative aerobic organisms, since polymorphonuclear leukocytes function poorly under decreased oxygen tensions. The growth of aerobic organisms further lowers the E_h, more fastidious anaerobes become established, and the disease process rapidly accelerates.

Discernible quantities of tissue gas are present in most of these infections. Carbon dioxide and water are the natural end products of aerobic metabolism. Carbon dioxide rapidly dissolves in aqueous media and rarely accumulates in tissues. Incomplete oxidation of energy sources by anaerobic and facultative aerobic bacteria can result in the production of gases that are less water soluble and therefore accumulate in tissues. Hydrogen is presumably the major tissue gas in mixed aerobic-anaerobic soft tissue infections. Its presence indicates rapid bacterial multiplication at a low E_h.

Clinically, the hallmarks of mixed aerobic-anaerobic soft tissue infections are tissue necrosis, a putrid discharge, gas production, the tendency to burrow through soft tissue and fascial planes, and the absence of classic signs of tissue inflammation. Table 100-2 shows the differentiation between the common bacterial necrotizing soft tissue infections.

Table 100-2

Differentiation of the Common Necrotizing Bacterial Soft Tissue Infection.

Crepitant Anaerobic Cellulitis

Nonclostridial and clostridial cellulitides have a similar clinical picture and are discussed together under the term, crepitant anaerobic cellulitis. Crepitant anaerobic cellulitis appears as a necrotic soft tissue infection with abundant connective tissue gas. The condition usually occurs after local trauma in patients with vascular insufficiency of the lower extremities. Multiple aerobic and anaerobic organisms have been isolated, including Bacteroides species, Peptostreptococcus species, Clostridium species, and members of the family Enterobacteriaceae. Crepitant anaerobic cellulitis can be differentiated from more serious soft tissue infections by the abundance of soft tissue gas, lack of marked systemic toxicity, gradual onset, less severe pain, and absence of muscle involvement.

Necrotizing Fasciitis

Necrotizing fasciitis is a relatively rare infection with a high mortality (40 percent). The infection was originally called hemolytic streptococcal gangrene by Meleney in 1924. Although his clinical description was accurate, better culture techniques have demonstrated that organisms other than Streptococcus pyogenes more commonly cause these infections. Clinical manifestations include extensive dissection and necrosis of the superficial and often the deep fascia. The infection undermines adjacent tissue and leads to marked systemic toxicity. Thrombosis of subcutaneous blood vessels leads to necrosis of the overlying skin. Initial local pain is replaced by numbness or analgesia as the infection involves the cutaneous nerves. Most cases of fasciitis follow surgery or minor trauma. The highest incidence is seen in patients with small vessel diseases such as diabetes mellitus. When careful bacteriologic techniques are used, anaerobes, particularly Peptostreptococcus, Bacteroides, and Fusobacterium species, are found in 50 to 60 percent of cases. Aerobic organisms, especially Streptococcus pyogenes, Staphylococcus aureus, and members of the Enterobacteriaceae have also been isolated. Most infections are mixed aerobic-anaerobic infections, but a type of necrotizing fasciitis caused solely by Streptococcus pyogenes has been reported and is referred to by the lay press as “flesh eating bacteria.”

Nonclostridial Myonecrosis

Nonclostridial myonecrosis, called synergistic necrotizing cellulitis by Stone and Martin, is a particularly aggressive soft tissue infection. It is similar to clostridial myonecrosis in that there is widespread involvement of soft tissue with necrosis of muscle tissue and fascia. The prominent involvement of muscle tissue differentiates this infection from necrotizing fasciitis. Subcutaneous tissue and skin are secondarily involved. Clinically, there is exquisite local tenderness, with minimal skin changes, and drainage of foul-smelling “dish-water” pus from small skin surface ulcers. Severe systemic toxicity is found in most patients. Nonclostridial myonecrosis occurs most frequently in the perineal area, as a result of an extension of a perirectal abscess, and in the lower extremities of patients with vascular insufficiency. Multiple organisms have been isolated, including Peptostreptococcus and Bacteroides species and members of the Enterobacteriaceae. Mortality approaches 75 percent.

Clostridial Myonecrosis

Clostridial myonecrosis, or gas gangrene, is a clostridial infection primarily of muscle tissue. Clostridium perfringens is isolated in 90 percent of these infections. Other clostridial species frequently isolated are C novyi (4 percent), C septicum (2 percent), C histolyticum, C fallax, and C bifermentans. Classically, clostridial myonecrosis has an acute presentation and a fulminant clinical course. The infection usually occurs in areas of major trauma or surgery or as a complication of thermal burns. However, it also has been reported following minor trauma, including intravenous administration of drugs, intramuscular injections of epinephrine, insect bites, and nail punctures. Moreover, it may occur in the absence of recent trauma by activation of dormant clostridial spores in old scar tissue. Finally, clostridial myonecrosis may occur in the absence of trauma, by bacteremic spread of the organism from a gastrointestinal or genitourinary site. Clostridium septicum is the major cause of spontaneous, nontraumatic gas gangrene and is often associated with a lesion in the colon such as an adenocarcinoma.

Clostridial myonecrosis is diagnosed mainly on a clinical basis. The infection may be so rapidly progressive that any delay in recognition or treatment may be fatal. The onset is sudden, often within 4 to 6 hours after an injury. Sudden, severe pain in the area of infection is an early clinical finding. Early in the course of infection, the skin overlying the wound appears shiny and tense and then becomes dusky. Within hours, the skin color may progress from dusky to a bronze discoloration, which can advance at a rate of 1 inch per hour. Vesicles or hemorrhagic bullae appear near the wound. A thin, brownish, often copious fluid exudes from the wound. Bubbles occasionally appear in the drainage. This exudate has often been described as having a sweet “mousy” odor. Swelling and edema in the area of infection is pronounced. Within hours the skin overlying the lesion can rupture and the muscle herniate. At surgery, the infected muscle is dark red to black, is noncontractile, and does not bleed when cut. Crepitus, although not prominent, is sometimes detected. Radiographs may show tissue gas outlining fascial planes and muscle bundles.

The rapid tissue necrosis in clostridial myonecrosis is caused by the clostridial toxins. Clostridial species are capable of producing multiple toxins, each with its own mode of action. Clostridium perfringens produces at least 12 different extracellular toxins. The most common of these, a lecithinase called alpha toxin, is hemolytic, histotoxic, and necrotizing. Other toxins act as collagenases, proteinases, deoxyribonucleases (DNases), fibrinolysins, and hyaluronidases. The systemic toxic reaction cannot be fully explained by a single circulating exotoxin. The “toxic factor” may be produced by interaction of the clostridial toxins with infected tissue. The mortality from clostridial myonecrosis ranges from 15 to 30 percent.

Fungal Necrotizing Cellulitis

Phycomyces and Aspergillus species may cause a gangrenous cellulitis in compromised hosts. The hallmark of these infections is the invasion of blood vessels by hyphae, followed by thrombosis and subsequent necrosis extending to all soft tissue compartments. Spores from these fungi are ubiquitous.

The Phycomyces species are characterized by broad-based nonseptate hyphae. Rhizopus, Mucor, and Absidia are the major pathogenic genera within the family Mucoraceae. Serious rhinocerebral, pulmonary, or disseminated infections have been found in patients with diabetes, lymphoma, or leukemia. Phycomycotic gangrenous cellulitis usually occurs in patients with severe burns or diabetes. The characteristic dermal lesion is a black, anesthetic ulcer or an area of necrosis with a purple edematous margin. There is no gas or exudate, and the infection may progress rapidly.

Aspergillus species are characterized histologically by branching septate hyphae. These fungi can cause serious pulmonary or disseminated infections in compromised hosts. Aspergillus gangrenous cellulitis may be primary or from a disseminated infection. The dermal lesion is an indurated plaque that leads to a necrotic ulcer. Gas and exudate are not present.

Infections of Skin and Nails

http://www.ncbi.nlm.nih.gov/books/n/mmed/A5257/

 

General Concepts

Etiology

Skin diseases can be caused by viruses, bacteria, fungi, or parasites. The most common bacterial skin pathogens are Staphylococcus aureus and group A β-hemolytic streptococci. Herpes simplex is the most common viral skin disease. Of the dermatophytic fungi, Trichophyton rubrum is the most prevalent cause of skin and nail infections.

Pathogenesis

Primary Infections: Primary skin infections have a characteristic clinical picture and disease course, are caused by a single pathogen, and usually affect normal skin. Impetigo, folliculitis, and boils are common types. The most common primary skin pathogens are S aureus, β-hemolytic streptococci, and coryneform bacteria. These organisms usually enter through a break in the skin such as an insect bite. Many systemic infections involve skin symptoms caused either by the pathogen or by toxins; examples are measles, varicella, gonococcemia, and staphylococcal scalded skin syndrome. Dermatophytic fungi have a strong affinity for keratin and therefore invade keratinized tissue of the nails, hair, and skin.

Secondary Infections: Secondary infections occur in skin that is already diseased. Because of the underlying disease, the clinical picture and course of these infections vary. Intertrigo and toe web infection are examples.

Clinical Manifestations

Most skin infections cause erythema, edema, and other signs of inflammation. Focal accumulations of pus (furuncles) or fluid (vesicles, bullae) may form. Alternatively, lesions may be scaling with no obvious inflammation. Nail infections cause discoloration of the nail and thickening of the nail plate.

Microbiologic Diagnosis

Clinical examination and staining and/or culturing of a specimen of pus or exudate are often adequate for diagnosis. Ultraviolet light (Wood’s lamp) is helpful in diagnosing erythrasma and some toe web and fungal infections. Microscopic examination of a KOH preparation of skin scales, nail scrapings, or loose hair is useful for fungal infections. For viral infections, stained smears of vesicle fluid are examined under the microscope for typical cytopathology.

Prevention and Treatment

Cleansing and degerming the skin with a soap or detergent containing an antimicrobial agent may be useful. Drying agents, such as aluminum chloride, and keratinolytic agents, such as topical salicylate, are also helpful. Topical antimicrobial agents can be used for some infections, but systemic therapy may be necessary for patients with extensive disease.

Introduction

Skin diseases are caused by viruses, rickettsiae, bacteria, fungi, and parasites. This chapter focuses on the common bacterial diseases of skin. Viral infections are also described, but of the cutaneous fungal diseases, only nail infections are included. The other fungal diseases are described in the Mycology section.

Skin Infections

Skin infections may be either primary or secondary (Fig. 98-1). Primary infections have characteristic morphologies and courses, are initiated by single organisms, and usually occur iormal skin. They are most frequently caused by Staphylococcus aureus, Streptococcus pyogenes, and coryneform bacteria. Impetigo, folliculitis, boils, and erythrasma are common examples. Systemic infections may also have skin manifestations. Secondary infections originate in diseased skin as a superimposed condition. Intertrigo and toe web infections are examples of secondary infections.

Figure 98-1

Spread of infections to skin.

Clinical manifestations vary from disease to disease. Most skin diseases involve erythema, edema, and other signs of inflammation. Focal accumulations of pus (furuncles) or fluid (vesicles and bullae) may form, but lesions may also be scaling without obvious inflammation.

Methods for Laboratory Diagnosis

Specimen Collection

Bacteria

Specimens are collected with a blade or by swabbing the involved areas of the skin. When pustules or vesicles are present, the roof or crust is removed with a sterile surgical blade. The pus or exudate is spread as thinly as possible on a clear glass slide for Gram staining.

For actinomycetes, pus is collected from closed lesions by aspirations with a sterile needle and syringe. Material is collected from draining sinuses by holding a sterile test tube at the edge of the lesion and allowing the pus and granules to run into the tube. Granules are aggregates of inflammatory cells, debris, proteinaceous material and delicate branching filaments. Pus and other exudates are examined microscopically for the presence of granules.

Viruses

Vesicles are cleaned with 70 percent alcohol followed by sterile saline. Viruses are obtained by unroofing a vesicle with a needle or a scalpel blade. The fluid is collected with a swab or with a tuberculin syringe with a 26- to 27-gauge needle. The fluid obtained from fresh vesicles may contain enough viruses for culture. Direct smears are prepared by scraping cells from the base of the lesions. The cells are smeared on a slide, fixed, and stained with Giemsa or Wright stain or with specific antibodies conjugated to fluorescein or peroxidase.

Fungi

Cutaneous samples are obtained by scraping skin scales or infected nails into a sterile Petri dish or a clean envelope. For suppurative lesions of deep skin and subcutaneous tissues, aspiration with a sterile needle and syringe is recommended. Direct mounts are made by mixing a small portion of the sample in two or three drops of physiologic saline or KOH on a microscopic slide. A glass coverslip is placed over the preparation before microscopic examination.

Cultures

Most pathogenic skin bacteria grow on artificial media, and selection of the medium is important. For general use, blood agar plates (preferably 5 percent defibrinated sheep blood) are recommended. In many situations, a selective medium combined with a general-purpose medium is recommended. For example, Staphylococcus aureus may overgrow Streptococcus pyogenes in blood agar medium when both organisms are present. When crystal violet (1 μg/ml) is added to blood agar, S pyogenes is selected over S aureus. Cultures for meningococci, gonocci, and brucellae must be incubated in a CO₂ atmosphere. If tuberculosis or fungal infection is suspected, specimens are collected on appropriate media and incubated aerobically. Viruses are cultured on tissue cultures selected for the virus that may be contained in the specimen.

Bacterial Skin Infections

The classification of bacterial skin infections (pyodermas) is an attempt to integrate various clinical entities in an organized manner. An arbitrary but useful classification for primary and secondary bacterial infections is presented in Table 98-1. The list is not complete and includes only the more common skin diseases.

Table 98-1

Classification of Selected Bacterial Skin Infections.

Primary Infections

Impetigo

Three forms of impetigo are recognized on the basis of clinical, bacteriologic, and histologic findings. The lesions of common or superficial impetigo may contain group A β-hemolytic streptococci, S aureus, or both, and controversy exists about which of these organisms is the primary pathogen. The lesions have a thick, adherent, recurrent, dirty yellow crust with an erythematous margin. This form of impetigo is the most common skin infection in children. Impetigo in infants is highly contagious and requires prompt treatment.

The lesions in bullous (staphylococcal) impetigo, which are always caused by S aureus, are superficial, thin-walled, and bullous. When a lesion ruptures, a thin, transparent, varnish-like crust appears which can be distinguished from the stuck-on crust of common impetigo. This distinctive appearance of bullous impetigo results from the local action of the epidermolytic toxin (exfoliation). The lesions most often are found in groups in a single reglon.

Ecthyma is a deeper form of impetigo. Lesions usually occur on the legs and other areas of the body that are generally covered, and they often occur as a complication of debility and infestation. The ulcers have a punched-out appearance when the crust or purulent materials are removed. The lesions heal slowly and leave scars.

Cellulitis and Erysipelas

Streptococcus pyogenes is the most common agent of cellulitis, a diffuse inflammation of loose connective tissue, particularly subcutaneous tissue. The pathogen generally invades through a breach in the skin surface, and infection is fostered by the presence of tissue edema. Cellulitis may arise iormal skin. However, the lesion of cellulitis is erythematous, edematous, brawny, and tender, with borders that are poorly defined.

No absolute distinction can be made between streptococcal cellulitis and erysipelas. Clinically, erysipelas is more superficial, with a sharp margin as opposed to the undefined border of cellulitis. Lesions usually occur on the cheeks.

Staphylococcal Scalded Skin Syndrome

Staphylococcal scalded skin syndrome (SSSS), also called Lyell’s disease or toxic epidermal necrolysis, starts as a localized lesion, followed by widespread erythema and exfoliation of the skin. This disorder is caused by phage group II staphylococci which elaborate an epidermolytic toxin. The disease is more common in infants than in adults.

Folliculitis

Folliculitis can be divided into two major categories on the basis of histologic location: superficial and deep.

The most superficial form of skin infection is staphylococcal folliculitis, manifested by minute erythematous follicular pustules without involvement of the surrounding skin. The scalp and extremities are favorite sites. Gram-negative folliculitis occurs mainly as a superinfection in acne vulgaris patients receiving long-term, systemic antibiotic therapy. These pustules are often clustered around the nose. The agent is found in the nostril and the pustules. Propionibacterium acnes folliculitis has been misdiagnosed as staphylococcal folliculitis. The primary lesion is a white to yellow follicular pustule, flat or domed. Gram stain of pus reveals numerous intracellular and extracellular Gram-positive pleomorphic rods. The lesions are more common in men than in women. The process may start at the age when acne usually appears, yet most cases occur years later.

In deep folliculitis, infection extends deeply into the follicle, and the resulting perifolliculitis causes a more marked inflammatory response than that seen in superficial folliculitis. In sycosis barbae (barber’s itch), the primary lesion is a follicular pustule pierced by a hair. Bearded men may be more prone to this infection than shaven men.

A furuncle (boil) is a staphylococcal infection of a follicle with involvement of subcutaneous tissue. The preferred sites of furuncles are the hairy parts or areas that are exposed to friction and macerations. A carbuncle is a confluence of boils, a large indurated painful lesion with multiple draining sites.

Erysipeloid

Erysipeloid, a benign infection that occurs most often in fishermen and meat handlers, is characterized by redness of the skin (usually on a finger or the back of a hand), which persists for several days. The infection is caused by Erysipelothrix rhusiopathiae.

Pitted Keratolysis

Pitted keratolysis is a superficial infection of the plantar surface, producing a punched-out appearance. The pits may coalesce into irregularly shaped areas of superficial erosion. The pits are produced by a lytic process that spreads peripherally. The areas most often infected are the heels, the ball of the foot, the volar pads, and the toes. Humidity and high temperature are frequent aggravating factors. Gram-positive coryneform bacteria have been isolated from the lesions.

Erythrasma

Erythrasma is a chronic, superficial infection of the pubis, toe web, groin, axilla, and inframammary folds. Most lesions are asymptomatic, but some are mildly symptomatic with burning and itching. The patches are irregular, dry and scaly; initially pink and later turning brown. The widespread, generalized form is more common in warmer climates. Corynebacterium minutissimum is the agent. Because of its small size, the organism is difficult to observe in KOH preparations of infected scales; however, it is readily demonstrable by Gram staining of the stratum corneum. Coral red fluorescence of the infected scales under Wood’s light is diagnostic.

Trichomycosis

Trichomycosis involves the hair in the axillary and pubic regions and is characterized by development of nodules of varying consistency and color. The condition is generally asymptomatic and not contagious. Underlying skin is normal. Infected hairs obtained for microscopic examination are placed on a slide in a drop of 10 percent KOH under a coverslip. The nodules on the hairs are composed of short bacillary forms. Three types of coryneforms are associated with trichomycosis; one resembles C minutissimum, one is lipolytic, and the third is C tenuis.

Secondary Infections

Intertrigo

Intertrigo is most commonly seen in chubby infants or obese adults. In the skin fold, heat, moisture, and rubbing produce erythema, maceration, or even erosions. Overgrowth of resident or transient flora may produce this problem.

Acute Infectious Eczematoid Dermatitis

Acute infectious eczematoid dermatitis arises from a primary lesion such as a boil or a draining ear or nose, which are sources of infectious exudate. A hallmark of this disease is a streak of dermatitis along the path of flow of the discharge material. Coagulase-positive staphylococci are the organisms most frequently isolated.

Pseudofolliculitis of the Beard

Pseudofolliculitis of the beard, a common disorder, occurs most often in the beard area of black people who shave. The characteristic lesions are usually erythematous papules or, less commonly, pustules containing buried hairs. This occurs when a strongly curved hair emerging from curved hair follicles reenters the skin to produce an ingrown hair. Gram-positive microorganisms that belong to the resident flora are associated with this disorder—a clear illustration of the opportunism of nonpathogenic bacteria when the host defense is impaired.

Toe Web Infection

The disease commonly referred to as athlete’s foot has traditionally been regarded as strictly a fungal infection. This assumption has been revised, however, because fungi often cannot be recovered from the lesions throughout the disease course. Researchers now believe that the dermatophytes, the first invaders, cause skin damage that allows bacterial overgrowth, which promotes maceration and hyperkeratosis. The fungi, through the production of antibiotics, then create an environment that favors the growth of certain coryneform bacteria and Brevibacterium. Proteolytic enzymes, which are produced by some of these bacteria, may aggravate the condition. If the feet become superhydrated, resident Gram-negative rods become the predominant flora, and the toe webs incur further damage. The fungi are then eliminated either by the action of antifungal substances of bacterial origin or by their own inability to compete for nutrients with the vigorously growing bacteria.

Other Bacterial Skin Diseases

Skin Tuberculosis (Localized Form)

Localized skin tuberculosis may follow inoculation of Mycobacterium tuberculosis into a wound in individuals with no previous immunologic experience with the disease. The course starts as an inflammatory nodule (chancre) and is accompanied by regional lymphangitis and lymphadenitis. The course of the disease depends on the patient’s resistance and the effectiveness of treatment. In an immune or partially immune host, two major groups of skin lesions are distinguished: tuberculosis verrucosa and lupus vulgaris.

Mycobacterium marinum Skin Disease

Many cases of M marinum skin disease occur in children and adolescents who have a history of using swimming pools or cleaning fish tanks. Often, there is a history of trauma, but even in the absence of trauma the lesions appear frequently on the sites most exposed to injury. The usually solitary lesions are tuberculoid granulomata that rarely show acid-fast organisms. The skin tuberculin test is positive.

Mycobacterium ulcerans Skin Disease

Lesions in M ulcerans skin disease occur most often on the arms or legs and occasionally elsewhere, but not on the palms or soles. Most patients have a single, painless cutaneous ulcer with characteristic undermined edges. Geographic association of the disease with swamps and watercourses has been reported. In some tropical areas, chronic ulcers caused by this organism are common.

In scrofuloderma, tuberculosis of lymph nodes or bones is extended into the skin, resulting in the development of ulcers.

A disseminated form of the disease occurs when bacteria are spread through the bloodstream in patients who have fulminating tuberculosis of the skin. When hypersensitivity to tubercle bacilli is present, hematogenously disseminated antigen produces uninfected tuberculous skin lesions such as lichen scrofilloslls.

Actinomycetoma

There are several agents of actinomycetoma. About half of the cases are due to actinomycetes (actinomycetoma); the rest are due to fungi (eumycetoma). The most common causes of mycetoma in the United States are Pseudallescheria (Petriel lidium) boydii (a fungus) and Actinomyces israelii (a bacterium). Regardless of the organism involved, the clinical picture is the same. Causative organisms are introduced into the skin by trauma. The disease is characterized by cutaneous swelling that slowly enlarges and becomes softer. Tunnel-like sinus tracts form in the deeper tissues, producing swelling and distortion, usually of the foot. The draining material contains granules of various sizes and colors, depending on the agent.

Actinomycosis

Actinomyces israelii usually is the agent of human actinomycosis; Arachnia propionica (Actinomyces propinicus) is the second most common cause. The characteristic appearance of the lesion is a hard, red, slowly developing swelling. The hard masses soften and eventually drain, forming chronic sinus tracts with little tendency to heal. The sinus tracts discharge purulent material containing “sulfur” granules. In about 50 percent of cases, the initial lesion is cervicofacial, involving the tissues of the face, neck, tongue, and mandible. About 20 percent of cases show thoracic actinomycosis, which may result from direct extension of the disease from the neck or from the abdomen or as a primary infection from oral aspiration of the organism. In abdominal actinomycosis, the primary lesion is in the cecum, the appendix, or the pelvic organs.

Treatment of the Pyodermas

General Considerations

Debriding superficial pyoderma and then repeatedly cleansing the exposed lesions with topical antiseptics such as chlorhexidine removes the source of infection and minimizes its spread to adjacent skin sites or to other patients. Many secondary superficial skin infections, such as the web infections, will clear with simple twice-daily cleansing. For foot infections, the patient should wear open shoes or sandals, which permit air circulation. Aluminum chloride, a drying agent, inhibits overgrowth of opportunistic bacteria in foot, perineal, and axillary areas. Keratinolytic agents (e.g., topical salicylates) remove hyperkeratotic lesions that harbor pathogens, improving the exposure of the infected skin surface to other topical treatments.

Topical Treatment

Topical antibiotics contain a combination of neomycin, bacitracin, and polymyxin. Some newer preparations contain mupirocin, gramicidin, or erythromycin, and others combine these antibiotics with steroids. For an informed, cooperative patient suffering only minimal disease, topical antibiotics are often preferred to oral antibiotics because of the adverse reactions associated with systemic therapy.

Systemic Therapy

Systemic treatment with antibiotics is mandatory for extensive pyoderma. Systemic antibiotics can be administered orally or parenterally. Oral therapy is sufficient for most extensive dermal infections, but the parenteral route is preferred for severe infections.

A wide range of antibiotics for systemic therapy of pyoderma is available (Table 98-2). The choice of a specific antibiotic should be based on two factors: isolation and identification of the pathogen, and the depth and extent of infection. In this costconscious world one must also relate efficacy to consumer cost. Many less expensive antibiotics are just as effective against a given pathogen as the most expensive drugs with wider spectra.

Table 98-2

Acceptable Antibacterial Agents for Treatment of Bacterial Skin Infections.

Viral Skin Diseases

Viral skin diseases can produce both localized and generalized skin infections (Table 98-3). Viruses from several major groups cause skin lesions.

Table 98-3

Viruses Associated with Skin Infections.

Herpes Simplex Virus

Herpes simplex virus infection is probably the most common viral skin disease (see Ch. 68). Almost the entire adult population has had herpes simplex at one time or another. Herpes simplex virus, a DNA virus, is the agent. There are two types of herpes simplex virus. Type 1 is usually associated with nongenital lesions, whereas type 2 is recovered from genital lesions. The incidence of type 1 genital infections in young patients has recently increased.

Poxviruses

The viruses that cause smallpox, vaccinia, and cowpox are closely related; all are large DNA viruses (see Ch. 69). The smallpox virus is now extinct. Cowpox virus causes an infection of cattle that is acquired by handling infected animals. Vaccinia viruses are vaccine strains developed in the laboratory and adapted to grow in the skin of humans, rabbits, and calves. Several clinical manifestations may occur in individuals who were vaccinated against smallpox with vaccinia virus. The main problem with vaccinia virus arose when it became desirable to vaccinate a person already suffering from eczema or other skin diseases. Vaccination may produce eczema vaccinatum. Molluscum contagiosum also is caused by a poxvirus and is characterized by numerous small, pink nodules, most often on the face, genitalia, or the rectal area. Lesions also occur on the back, arms, buttocks, and inner thighs. The disease is generally harmless and self-limiting.

Papillomaviruses

Human papillomaviruses cause warts (see Ch. 66). Verruca vulgaris occurs commonly on hands and fingers as single or multiple lesions. These warts are generally painless, firm, dry, and rough. They may remain stable or regress spontaneously. Verruca plantaris (plantar wart) is a clinical variety of verruca vulgaris that occurs on the sole of the foot.

During standing, walking, and running, these warts push into the skin and may be painful. Genital warts appear as large lesions of red, soft masses that may coalesce. Verruca plana juvenilis (also known as juvenile flat warts) occurs most commonly in children. The lesions are in groups and may appear on the face, neck, back of the hands, and arms. These warts may also occur in adults.

Treatment

Because of the limited number of effective antiviral agents, prevention is important. Oral and intravenous acyclovir is effective for treatment of primary herpesvirus infection and for recurrent genital herpes and herpes zoster in immunosuppressed persons.

Fungal Skin Diseases

Several genera of fungi are responsible for diseases of the skin. This group of fungi, known collectively as dermatophytes, is discussed in the chapters on mycology. Some nondermatophytes, including yeasts, can also cause skin infections.

Nail

The nail consists of four epidermal components: the matrix, proximal nailfold, nailbed, and hyponychium (Fig. 98-2). The matrix is close to the bony phalanx. The horny end product of the matrix is the nail plate, which migrates distally over the nailbed. The distal portion of the matrix, the lunula, is visible as a white, crescent-shaped structure. The proximal nailfold is a modified extension of the epidermis of the dorsum of the finger, which forms a fold over the matrix; its horny end product is the cuticle. The nailbed is an epidermal structure that begins at the distal margin of the lunula and terminates in the hyponychium, which is the extension of the volar epidermis under the nail plate. It ends adjacent to the nailbed.

Figure 98-2

Longitudinal section (diagrammatic sketch) of fingernail.

Fungal Infections of the Nails

Onychomycoses are infections of the nails by fungi. Universally recognized agents of these diseases are species of Trichophyton, Microsporum (rarely), and Epidermophyton (Table 98-4). These dermatophytes are commonly called ringworm fungi. Nondermatophytic fungi also occasionally cause onychomycoses, but usually cause only toenail problems; they rarely affect the fingernails.

Table 98-4

Fungi Associated with Onychomycosis.

Conventionally, onychomycosis is classified into four types:

1.

Distal subungual onychomycosis primarily involves the distal nailbed and hyponychium, with secondary involvement of the underside of the nail plate. Trichophyton rubrum is one of the organisms that cause this clinical type.

2.

White superficial onychomycosis involves the toenail plate on the surface of the nail. It is caused by T mentagrophytes and by species of Cephalosporium, Aspergillus, and Fusarium.

3.

Proximal subungual onychomycosis is an invasion of the nail plate from the proximal nailfold producing a specific nail condition. It is caused by T rubrum and T megninii. This is a rare type of onychomycosis, but in patients with AIDS proximal white subungual onychomycosis is common.

4.

Candida onychomycosis involves all of the nail plate. It is caused by C albicans and is seen in patients who have chronic cutaneous candidiasis, a syndrome associated with cellular and humoral immune abnormalities.

Treatment of Nail Diseases

Onychomycosis

Superficial types of onychomycosis may be successfully treated. Mechanical scraping of the chalky white material on the nail plate and application of topical antifungal agents such as miconazole, ciclopirox olamine, or clotrimazole are recommended. Newer therapeutic nail lacquers are being tested in the United States. Distal subungual and proximal subungual onychomycosis infections are much more difficult to treat. Oral griseofulvin may be required to bring about clearing of the fingernail. For toenails with extensive involvement, oral itraconazole, fluconazole and terbinafine are effective. No oral or topical medication is effective in eliminating nondermatophyte mold infection of the nails.

Bacterial Nail Infections

Pseudomonas aeruginosa is associated with greeail syndrome, which is essentially a greenish discoloration of the nail plate. Attempts to culture Pseudomonas from the deep section of the nail have not been successful; however, P aeruginosa has been isolated on cultures of specimens from the paronychia (inflammatory lesion around the margin of a nail). Whether there is true invasion of the nail plate by the bacteria or just diffusion of the pigment into the nail plate is not certain. Black paronychia is associated with Proteus species. Staphylococci and streptococci may be found as secondary invaders.

Joint Infections

Infectious arthritis may arise either from hematogenous spread or by direct extension from an adjacent bone or soft tissue infection. The infection is usually a localized suppurative process. Although any joint can become infected, the knee is most commonly involved (53 percent), followed by the hip (20 percent), shoulder (11 percent), wrist (9 percent), ankle (8 percent), and elbow (7 percent). The infection is monarticular almost 90 percent of the time. However, a bacterial polyarthritis may be seen.

In the normal host, polymorphonuclear leukocytes respond rapidly to the infection and release proteolytic enzymes, which can cause extensive destruction of the articular cartilage within 3 days. The joint may also be damaged directly by the release of bacterial toxins and lysosomal enzymes. Furthermore, an effusion is almost always present and is confined within the joint capsule; this increases intra-articular pressure and interferes with blood supply and nutrition. These complications may occur with almost any type of septic arthritis, but are most common iongonococcal bacterial infections. Children are especially vulnerable since extension to the epiphyseal growth plate may stunt bone growth.

Several conditions are known to predispose joints to the development of septic arthritis. Corticosteroid therapy, rheumatoid arthritis, and degenerative joint disease are the most common underlying factors. Total joint arthroplasties are susceptible to hematogenous infections. Patients with diabetes mellitus, leukemia, cancer, cirrhosis, chronic granulomatous diseases, or hypogammaglobulinemia or those undergoing cytotoxic chemotherapy or practicing substance abuse also have an increased incidence of infectious arthritis.

Gonococcal Arthritis

The most common cause of bacterial arthritis in healthy young adults in North America is Neisseria gonorrhoeae. Gonococcal arthritis typically follows primary infection of a mucosal site and is thought to spread hematogenously to the joint. Females are affected four times as often as males, and about one-half of all affected females are either pregnant or menstruating. This association supports the theory that endocrine factors play a role in gonococcal arthritis, although the exact mechanism has not been elucidated. Strains of N gonorrhoeae that cause disseminated gonococcal infections differ phenotypically from those that cause simple mucosal infections and are thought to be more virulent.

The disease may manifest itself as part of a disseminated gonococcal infection or as a monarticular joint infection. The presenting symptoms in disseminated gonococcal infections may be mixed, with migratory polyarthralgias, fever, chills, dermatitis, and tenosynovitis. Most of these patients have asymptomatic genital, anal, or pharyngeal gonococcal infections. Skin lesions, when present, begin as small erythematous papules but usually progress to vesicular or pustular stages. Tenosynovitis is characterized by pain, swelling, and periarticular redness. Patients with monarticular disease often have a history of polyarthralgias, and some authorities believe that this represents a continuum from disseminated gonococcal infection.

Nongonococcal Arthritis

Nongonococcal bacterial arthritis is a serious infection with significant sequelae. Mortality as high as 12 percent has been reported, and up to 75 percent of survivors suffer some type of functional loss in the involved joint. Classically, patients present with fever and pain, swelling, warmth, and decreased range of motion in the involved joint. The joint effusion should be aspirated and cultured to determine the exact etiologic agent. There are variations among age groups, but the most common cause of nongonococcal bacterial arthritis is Staphylococcus aureus. In adults, all Gram-negative bacilli together account for about 20 percent of cases. It is generally accepted that Gram-negative infections are the most virulent, with Pseudomonas aeruginosa and Escherichia coli being the most common. Intravenous drug abusers have a significant incidence of infection with Gram-negative organisms. Streptococcal species engender a small but significant proportion of infections (10 to 15 percent). About 10 percent of patients with nongonococcal arthritis have polymicrobial infections. In addition, there are frequent microbiologic associations with concomitant disease states. For example, bacterial arthritis following infectious diarrhea may be caused by Shigella, Salmonella, Campylobacter, or Yersinia species. Streptobacillus moniliformis may cause a migrating polyarthritis; however, this is rare. In children, Haemophilus influenzae is a cause of septic arthritis.

Diagnosis of Bacterial Arthritis

Several laboratory tests are used to diagnose infectious arthritis. The definitive test involves culturing the fluid from the involved joint after aspiration or incision and drainage. Gram stains are often unreliable, although they may provide initial clues. Synovial fluid analysis usually reveals a turbid fluid with leukocyte counts greater than 100,000/mm³ in 30 to 50 percent of cases. In bacterial arthritis, the level of polymorphonuclear leukocytes often approaches 90 percent. Low joint fluid glucose levels and high lactate levels are indicative of septic arthritis, but are nonspecific. Peripheral blood leukocyte counts are usually elevated in children, but are often withiormal limits in adults. Finally, radiography may show joint space widening and soft tissue swelling in infections more than 2 weeks old.

Granulomatous Arthritis

Infectious arthritis may be caused by mycobacteria and certain fungi. This disease may be very insidious and may progress for several months before infection is even considered. These organisms usually produce a chronic monarticular arthritis with a granulomatous inflammatory response. Mycobacterium tuberculosis infections of the musculoskeletal system are the most common extrapulmonary manifestation of tuberculosis and result from hematogenous dissemination. Atypical mycobacteria, especially M fortuitum, M chelonae, and M marinum, may cause septic arthritis by inoculation or extension from a contiguous focus of infection. The most common cause of fungal arthritis is Sporothrix schenckii. This infection usually follows traumatic inoculation, but may also result from pulmonary dissemination. Because of its relative rarity and indolent course, the diagnosis is often missed or delayed. Coccidiomycosis, histoplasmosis, and blastomycosis may all affect the joint. In addition, Cryptococcus, Aspergillus, and Candida species may cause infectious arthritis in the immunocompromised host. Diagnosis of all the granulomatous arthritides usually involves a higher index of suspicion and appropriate fungal or mycobacterial cultures.

Bone Infections

On the basis of clinical and pathologic considerations, osteomyelitis may be classified as either hematogenous or secondary to a contiguous focus of infection. Contiguous-focus osteomyelitis can be further subdivided into bone infection with relatively normal vascularity and bone infection with generalized vascular insufficiency. Either major type of osteomyelitis may progress to a chronic bone infection.

Hematogenous Osteomyelitis

Hematogenous osteomyelitis occurs mainly in infants and children but has recently been found with increasing frequency in the adult population. In infants and children the metaphysis of long bones (tibia, femur) is most frequently involved. The anatomy in the metaphyseal region of long bones seems to explain this clinical finding. Nonanastomosing capillary ends of the nutrient artery make sharp loops under the growth plate and enter a system of large venous sinusoids where the blood flow becomes slow and turbulent. Any obstruction of the capillary ends leads to an area of avascular necrosis. Minor trauma probably predisposes the infant or child to infection by producing a small hematoma and subsequent bone necrosis, both of which can be infected by a transient bacteremia. The infection produces a local cellulitis, which results in increased bone pressure, decreased pH, and a breakdown of leukocytes. All of these factors contribute to necrosis of bone. The infection may proceed laterally through the haversian and Volkmann canal system, perforate the cortex, and lift the periosteum. It may also extend into the intramedullary canal. Extension leads to further vascular compromise and bone necrosis. In infants, capillaries penetrate the growth plate. Therefore, the infection may also spread to the epiphysis and into the joint space. In children over 1 year old, the growth plate is no longer penetrated by capillaries, and the epiphysis and joint space are protected from infection. In adults, the growth plate has been resorbed and joint extension of a metaphyseal infection can recur. However, in adults, the diaphysis of the long bones and the lumbar and thoracic vertebral bodies of the axial skeleton are most frequently involved. Adults with axial skeleton osteomyelitis often have a history of preceding urinary tract infection or intravenous drug abuse.

A single pathogenic organism is usually responsible for hematogenous osteomyelitis (Table 100-3). Polymicrobic hematogenous osteomyelitis is rare. Staphylococcus aureus is the most frequent organism isolated, but Streptococcus pyogenes and Streptococcus agalactiae are responsible for a significant number of bone infections, especially in infants. Aerobic Gram-negative organisms are responsible for an increasing number of bone infections. Pseudomonas aeruginosa is often isolated from intravenous drug abusers with vertebral osteomyelitis.

Table 100-3

Commonly Isolated Organisms in Osteomyelitis.

Patients with hematogenous osteomyelitis usually have normal soft tissue around the infected bone. If antimicrobial therapy directed at the pathogen is begun prior to extensive bone necrosis, the patient has an excellent chance of cure.

Contiguous-Focus Osteomyelitis

Osteomyelitis Secondary to a Contiguous Infection with No Generalized Vascular Insufficiency

In contiguous-focus osteomyelitis, the organism either is directly inoculated into the bone by trauma or surgery or reaches the bone from adjacent infected soft tissue. Common predisposing conditions include open fractures, surgical reduction and internal fixation of fractures, and wound infections. In contrast to hematogenous osteomyelitis, multiple bacteria are isolated from the infected bone. The bacteriology is diverse (Table 100-3), but S aureus remains the most commonly isolated pathogen. In addition, aerobic Gram-negative bacilli and anaerobic organisms are frequently isolated. Bone necrosis, soft tissue damage, and loss of bone stability are all common, making this form of osteomyelitis difficult to manage.

Osteomyelitis Secondary to a Contiguous Infection with Generalized Vascular Insufficiency

The small bones of the feet (principally the metatarsal bones and phalanges) are commonly involved in osteomyelitis secondary to a contiguous infection in patients with generalized vascular insufficiency. Most commonly, the infection develops as an extension of a local infection, either cellulitis or a trophic skin ulcer. The inadequate tissue perfusion favors the infection by blunting the local inflammatory response. Multiple aerobic and anaerobic bacteria are usually isolated from the infected bone. Although cure is desirable, a more attainable goal of therapy is to suppress the infection and maintain functional integrity of the involved limb. Recurrent or new bone infections occur in many patients. In time, amputation of the infected area is almost always necessary.

Chronic Osteomyelitis

Both hematogenous osteomyelitis and contiguous-focus osteomyelitis can progress to a chronic bone infection. No exact criteria separate acute from chronic osteomyelitis. Clinically, newly recognized bone infections are considered acute, whereas a relapse of the infection represents chronic disease. However, this simplistic classification is clearly inadequate. The hallmark of chronic osteomyelitis is the presence of large areas of dead bone or sequestra. An involucrum (a reactive bony encasement around the sequestrum) and persistent drainage via one or more sinus tracts are usually present. In chronic osteomyelitis, multiple species of bacteria are usually isolated from the necrotic infected bone (Table 100-3), except in cases of chronic hematogenous osteomyelitis, which usually yield a single organism. Unless the necrotic infected bone can be removed, antibiotic therapy is usually unsuccessful. The prognosis for arresting the infection is worse if there is poor soft tissue integrity surrounding the infection, sclerosis of the involved bone, or bone instability.

Diagnosis of Bacterial Osteomyelitis

The bacteriologic diagnosis of bacterial osteomyelitis rests on isolation of the agent from the bone or the blood. In hematogenous osteomyelitis, positive blood cultures often obviate the need for a bone biopsy when there is associated radiographic or radionuclide scan evidence of osteomyelitis. In chronic osteomyelitis, sinus tract cultures are not reliable for predicting which organism(s) will be isolated from the infected bone. Antibiotic treatment of osteomyelitis should not be based on the results of sinus tract cultures. In most instances, bone biopsy cultures are mandatory to guide specific antimicrobial therapy.

Skeletal Tuberculosis

Skeletal tuberculosis is the result of hematogenous spread of the tuberculosis bacillus early in the course of a primary infection. Rarely, skeletal tuberculosis develops as a contiguous infection from an adjacent caseating lymph node. Either the primary bone infection or a reactivated quiescent primary bone infection elicits an inflammatory reaction, followed by the development of granulation tissue. The granulation tissues erodes and destroys the cartilage and cancellous bone. Eventually the infection causes bone demineralization and necrosis. Proteolytic enzymes that can destroy cartilage are not produced in skeletal tuberculosis. Cartilage is destroyed slowly by granulation tissue, and the joint or disc space is preserved for considerable periods. Healing involves deposition of fibrous tissue. Pain is the most frequent clinical complaint.

Any bone may be involved by skeletal tuberculosis, but the infection usually involves one site. In children and adolescents, the metaphyses of the long bones are most frequently infected. In adults, the axial skeleton, followed by the proximal femur, knee, and small bones of the hands and feet, are most often involved. In the axial skeleton, the thoracic vertebral bodies are most frequently infected, followed by the lumbar and cervical vertebral bodies. Vertebral infection usually begins in the anterior portion of a vertebral body adjacent to an intervertebral disc. Adjacent vertebral bodies may become involved, and a paravertebral abscess may develop. Sixty percent of patients with skeletal tuberculosis have evidence of extraosseous tuberculosis.

Tissue for culture and histology is almost always required for the diagnosis of skeletal tuberculosis. Cultures for Mycobacterium tuberculosis are positive in approximately 60 percent of the cases, but 6 weeks may be required for growth and identification of the organism. Histology showing granulomatous tissue compatible with tuberculosis and a positive tuberculin test are sufficient to begin tuberculosis therapy. However, a negative skin test does not rule out skeletal tuberculosis. Therapy for skeletal tuberculosis involves prolonged chemotherapy and in some cases surgical debridement.

Fungal Osteomyelitis

Bone infections may be caused by a variety of fungal organisms, including Coccidioides, Blastomyces, Cryptococcus, and Sporothrix species. The lesion most often appears as a cold abscess overlying an osteomyelitic lesion. Joint space extension may occur in coccidioidomycosis and blastomycosis. Therapy for fungal osteomyelitis involves surgical debridement and antifun

 

 

Pus and exudate from an infected wound or open abscess would be expected to contain the etiologic agent of the infection. However, in open wounds, skin and soil contaminants almost invariably are found that, under appropriate growth conditions could outgrow the true infectious organism, resulting in an erroneous laboratory report.

Collection of Specimens from Wounds and Abscesses

Whenever possible, a sterile syringe and needle should be used to collect specimens from wounds and abscesses. The use of a swab is routinely unsatisfactory because of the limited amount of material collected by this method, making it difficult or impossible to isolate the etiologic agent or agents. It also is important to remember that wounds and abscesses arc commonly infected with obligately anaerobic bacteria, which quickly die on a swab that are exposed to the atmosphere. Therefore, all aspirates should be transported to the laboratory in special tubes containing oxygen-free gas. Such containers, which can be obtained commercially, usually contain a few drops of0.0003% resazurin, an oxidation-reduction indicator that turns pink if air contaminates the bottle. Table 4 lissom of the more common types of infections in which the obligate anaerobes are involved.

Table 4

Infections in which anaerobes are the predominant pathogens

or are commonly present

 

             Burns often are infected with opportunists such as Pseudomonas aeruginosa, enteric organisms, and staphylococci, and yeast, make isolation of the definitive infectious agent extremely difficult. Quantitative cultures may assist in the interpretation of laboratory findings. Specimens of burned tissue and any drainage material should be sent to the laboratory for culture and evaluation.

 

Media Inoculated With Wound and Abscess Specimens

Because the array of organisms that can infect a wound is so great, the choice of inoculation media can be difficult. In general, obligate anaerobes, such as those in the genera Clostridium, Bacteroides, Eubacterium, Fusobacterium, and  Actinomyces, must be considered. Table 5 lists a few of the features that suggest the involvement of one of these anaerobes.

Table 5

Clinical and Bacteriologic Features Suggesting Possible Infection With Anaerobes

 

Numerous specialised media can be used successfully for the growth of the obligate anaerobes. Most contain whole or lysed blood from sheep, complex infusions such as brain-heart infusion or chopped meat, vitamin supplements such as yeast extract and additional vitamin K, and, in broths, a reducing agent such as thioglycollate or cysteine with 0.1% agar added to reduce convection cur-rents.

Because most wound infections or abscesses contain Multiple organisms, the use of liquid media alone is not satisfactory. In fact, if isolated colonies are obtained on agar plates, little is gained by the examination of broth cultures. However, agar plates must be incubated in an anaerobic jar (a jar from which all oxygen has been re-moved) or a similar device.

Because most infections are caused by mixtures of aerobic and anaerobic bacteria, blood-agar plates as well as selective and differential media (eg, eosin-methyleneblue or Mac Conkey) also must be inoculated and then incubated aerobically at 36°C.

Identification of Wound Isolates

The multiplicity of genera that can be found in a wound makes it difficult to list firm rules for their identification. A Gram’s stain of all specimens should be observed first. The results of microscopic examination may provide in-formation that will aid in a decision regarding which media should be inoculated and under what conditions the culture should be incubated. It is no simple affair to differentiate between the true etiologic agents of wounds and abscess infection and the contaminants that “go along for the ride.”

 

 

 Microbiology of the Gastrointestinal Tract

http://www.ncbi.nlm.nih.gov/books/n/mmed/A5096/

General Concepts

Composition and Distribution of the Intestinal Microflora

The intestinal microflora is a complex ecosystem containing over 400 bacterial species. Anaerobes outnumber facultative anaerobes. The flora is sparse in the stomach and upper intestine, but luxuriant in the lower bowel. Bacteria occur both in the lumen and attached to the mucosa, but do not normally penetrate the bowel wall .

Metabolic Activities

Intestinal bacteria are a crucial component of the enterohepatic circulation in which metabolites that are conjugated in the liver and excreted in the bile are deconjugated in the intestine by bacterial enzymes, then absorbed across the mucosa and returned to the liver in the portal circulation. Many drugs and endogenous compounds undergo enterohepatic circulation. Antibiotics that suppress the flora can alter the fecal excretion and hence the blood levels of these compounds. The flora also plays a role in fiber digestion and synthesizes certain vitamins.

The Intestinal Microflora

The intestinal microflora may prevent infection by interfering with pathogens. The flora includes low populations of potentially pathogenic organisms such as Clostridium difficile. Antibiotics that upset the balance of the normal flora can favor both infection by exogenous pathogens and overgrowth by endogenous pathogens. If the bowel wall is breached, enteric bacteria can escape into the peritoneum and cause peritonitis and abscesses.

Bacterial Diarrheas

Enterotoxin-Mediated Diarrheas: Enterotoxigenic bacteria, such as Vibrio cholerae and enterotoxigenic Escherichia coli strains, colonize the upper bowel and cause watery diarrhea by producing an enterotoxin that stimulates mucosal cells to secrete fluid via an increase in intracellular AMP.

Invasive Diarrheas: Invasive bacteria, such as Shigella and Campylobacter, penetrate the intestinal mucosa. A bloody, mucoid diarrheal stool with inflammatory exudate is produced.

Viral Diarrheas

Rotavirus and Calicivirus (formerly Norwalk virus) are major causes of diarrheal disease. Rotavirus diarrhea affects mostly young children; Calicivirus causes disease in all age groups

Parasitic Diarrheas

Some protozoa (especially Entamoeba histolytica and Giardia lamblia) as well as some intestinal helminths can cause diarrheal disease.

Clinical Diagnosis

In general, enterotoxigenic bacteria and viruses affect the upper bowel, causing watery diarrhea and periumbilical pain. The invasive bacteria act primarily in the colon (Shigella and Campylobacter) or lower ileum (Salmonella). The stool in these diseases may contain blood. Colitis is marked by painful straining at stool (tenesmus).

Composition and Distribution of the Microflora

The bacterial inhabitants of the human gastrointestinal tract constitute a complex ecosystem. More than 400 bacterial species have been identified in the feces of a single person. Anaerobic bacteria predominate. The upper gastrointestinal tract (the stomach, duodenum, jejunum, and upper ileum) normally contains a sparse microflora; the bacterial concentrations is less than 10⁴ organisms/ml of intestinal secretions (Fig. 95-1). Most of these organisms are derived from the oropharynx and pass through the gut with each meal. Colonization of the upper intestine by coliform organisms is an abnormal event and is characteristic of certain infectious pathogens such as Vibrio cholerae and enterotoxigenic Escherichia coli. In contrast, the large intestine normally contains a luxuriant microflora with total concentrations of 10¹¹ bacteria/g of stool (Fig. 95-1). Anaerobes such as Bacteroides, anaerobic streptococci, and clostridia outnumber facultative anaerobes such as E coli by a factor of 1,000.

Figure 95-1

Concentration of the bacterial flora in regions of the gastrointestinal tract.

The character of the bacterial flora changes not only along the length of the gastrointestinal tract but also cross-sectionally with regard to the mucosal surface. Bacteria occupy the lumen, overlie the epithelial cells, and adhere to the mucosa. Penetration of bacteria through the mucosal surface is an abnormal event; pathogens such as Shigella, Salmonella, and Campylobacter invade in this way.

The same mechanisms that control the normal flora also protect the bowel from invasion by pathogens. Gastric acid in the stomach kills most organisms that are swallowed. Individuals with reduced or absent gastric acid have a high incidence of bacterial colonization in the upper small bowel and are more susceptible to bacterial diarrheal disease. Bile has antibacterial properties and thus may be another factor in controlling the flora. Forward propulsive motility (peristalsis) is a key element in suppressing the flora of the upper bowel. Finally, the microflora itself, by producing its own antibacterial substances (e.g., bacteriocins and fatty acids), stabilizes the normal populations and prevents implantation of pathogens.

Metabolic Activites of the Microflora

The metabolic capacities of the intestinal bacteria are extremely diverse. Bacterial enzymes can use as substrate virtually any compound in the intestinal lumen, whether taken orally or entering the intestine by secretion through the biliary tract or directly across the mucosa.

The Enterohepatic Circulation

Enzymes produced by intestinal bacteria play a central role in the enterohepatic circulation. Substances that undergo enterohepatic circulation are metabolized in the liver, excreted in the bile, and passed into the intestinal lumen, where they are reabsorbed across the intestinal mucosa and returned to the liver via the portal circulation. The enterohepatic circulation generally involves compounds that are conjugated in the liver to a polar group such as glucuronic acid, sulfate, taurine, glycine, or glutathione. Conjugation increases the solubility of the metabolite in bile, but the conjugated compounds are poorly absorbed by the intestinal mucosa. Enzymes produced by intestinal bacteria—such as ß-glucuronidase, sulfatase, and various glycosidases—deconjugate these compounds, releasing the parent compounds which are readily absorbed across the intestinal wall. Many endogenous compounds undergo enterohepatic circulation, including bilirubin, bile acids, cholesterol, estrogens, and metabolites of vitamin D. In addition, many drugs that are excreted by the liver, including digitalis, diethylstilbestrol, morphine, colchicine, rifampin, and chloramphenicol, enter this pathway.

Antibiotics block the enterohepatic circulation by suppressing the intestinal flora and thereby reducing the levels of deconjugating enzymes. If an antibiotic is given to a patient who is also taking a drug that undergoes enterohepatic circulation, the resulting depression of the enterohepatic circulation will increase the fecal excretion of the drug and thereby lower its plasma level and half life. For example, the blood levels and half life of the estrogen in birth control pills decrease when antibiotics are administered.

The Microflora and Nutrition

Enzymes produced by intestinal bacteria are important in the metabolism of several vitamins. The intestinal microflora synthesizes vitamin K, which is a necessary cofactor in the production of prothrombin and other blood clotting factors. Treatment with antibiotics, particularly in individuals eating a diet low in vitamin K, can result in low plasma prothrombin levels and a tendency to bleed. Intestinal bacteria also synthesize biotin, vitamin B₁₂, folic acid, and thiamine.

The intestinal flora is capable of fermenting indigestible carbohydrates (dietary fiber) to short-chain fatty acids such as acetate, propionate, and butyrate. The major source of such fermentable carbohydrate in the human colon is plant cell wall polysaccharides such as pectins, cellulose, and hemicellulose. The acids produced from these fiber substrates by bacteria can be an important energy source for the host.

Some people are deficient in intestinal lactase, the mucosal enzyme responsible for hydrolyzing the disaccharide lactose in milk. In these individuals, lactose is not adequately digested and absorbed in the intestine. Lactose that reaches the large bowel undergoes vigorous bacterial fermentation. The result can be distention, flatus, and diarrhea.

The Intestinal Microflora and Infection

Protective Activities of the Flora

Like other complex ecosystems, the intestinal microflora is relatively stable over time, maintaining roughly constant numbers and types of bacteria in each area of the bowel. The stability of normal flora both discourages infection by exogenous pathogens and prevents overgrowth of potentially pathogenic members. New organisms that enter the system in contaminated food or water generally are suppressed by the established flora. This suppression is related to production by members of the resident flora of antimicrobial substances such as bacteriocins or short-chain fatty acids, which inhibit the growth of alien microorganisms. Antibiotics that kill off part of the intestinal flora can upset its balance and may open the door to infection or pathologic overgrowth.

The pathogenesis of Salmonella food poisoning illustrates this phenomenon. Normal individuals are quite resistant to Salmonella, and a large oral inoculum is required to initiate infection. If the intestinal flora is suppressed by antibiotics, however, the individual becomes much more susceptible and can be infected by a relatively small inoculum.

Diseases Caused by Overgrowth of Potential Pathogens

The normal intestinal flora includes small populations of organisms that cause disease if they overgrow. For example, overgrowth of Clostridium difficile produces severe inflammation of the colon with diarrhea (pseudomembranous colitis). Administration of antibiotics initiates the process by suppressing the normal flora.

Peritonitis

Bacteria from the intestinal flora are the prime cause of infection in the peritoneal cavity when the normal barriers of the intestinal wall are violated. The intestinal wall can be perforated by trauma (knife wounds, gunshot wounds, blunt trauma), by disease (appendicitis, penetrating intestinal cancers), or by surgical procedures. Once the mucosal barrier is breached, bacteria penetrate through the intestinal wall into the normally sterile peritoneal cavity and its surrounding structures. Poor circulation, reduced oxygen supply, and dead tissue in the vicinity of the perforation promote the formation of an abscess and particularly favor the growth of anaerobic bacteria. Cultures of a peritoneal abscess generally yield several types of bacteria from the intestinal microflora, particularly species of Bacteroides, Clostridium, and Peptostreptococcus and E coli.

Bacterial Diarrheas

Enterotoxin-Mediated Diarrheal Diseases

Several enterotoxin-producing bacteria cause diarrheal diseases (Table 95-1). The diarrheal disease caused by Vibrio cholerae and enterotoxigenic strains of E coli has three main characteristics. First, there is intestinal fluid loss that is related to the action of an enterotoxin on the small bowel epithelial cells. Second, the organism itself does not invade the mucosal surface; rather, it colonizes the upper small bowel, adhering to the epithelial cells and elaborating the enterotoxin. The mucosal architecture remains intact with no evidence of cellular destruction. Bacteremia does not occur. Third, the fecal effluent is watery and often voluminous, so that the diarrhea can result in clinical dehydration. The fluid originates in the upper small bowel. where the enterotoxin is most active.

Table 95-1

Toxin-Producing Bacteria Associated With Diarrheal Disease.

Cholera

The paradigm of the enterotoxigenic diarrheal diseases is cholera (see Ch. 24), in which stool volume can exceed 1 L/h, with daily fecal outputs of 15 to 20 L if the patient is kept hydrated. Cholera is caused by V cholerae, which is usually ingested in contaminated water. Vibrios that survive passage through the stomach colonize the surface of the small intestine, proliferate, and elaborate the enterotoxin. Cholera toxin acts via adenylate cyclase to stimulate secretion of water and electrolytes from the epithelial cells into the lumen of the gut. The duodenum and upper jejunum are more sensitive to the toxin than the ileum is. The colon is relatively insensitive to the toxin and may still absorb water and electrolytes normally. Thus, cholera is an “overflow diarrhea,” in which the large volumes of fluid produced in the upper intestine overwhelm the resorptive capacity of the lower bowel.

Cholera stool is described as resembling rice water—a clear fluid flecked with mucus—and is isotonic with plasma. Microscopy reveals no inflammatory cells in the fecal effluent; all that can be seen are small numbers of shed mucosal cells.

Enterotoxigenic E coli Diarrhea

Certain strains of E coli cause diarrheal disease by elaborating enterotoxins (see Ch. 25). These strains produce two types of enterotoxin. One, called heat-labile toxin, is similar in structure and in its mechanism of action to cholera toxin. The other, called heat-stable toxin, appears to act via guanylate cyclase. Enterotoxigenic E coli strains are the most common cause of travelers’ diarrhea

Other Diarrhea-Causing Toxins

Many strains of Shigella produce an enterotoxin, called Shiga toxin, that causes secretion of fluid from the small intestine (see Ch. 22). Shiga toxin has a destructive, cytotoxic effect on the small-bowel epithelium, causing gross injury to the bowel surface. It does not activate adenylate cyclase. E coli 0157:H7, the organism associated with consumption of undercooked chopped meat, also produces a Shiga-like toxin; it causes bloody diarrhea and colitis. An organism that produces a different type of cytotoxin is Vibrio parahaemolyticus, a bacterium associated with seafood. Food-poisoning strains of Staphylococcus aureus and Clostridium perfringens both produce enterotoxins that are cytotoxic. The staphylococcal enterotoxin also has a direct effect on the vomiting center in the brain.

Gastrointestinal Disease Caused by Invasive Bacteria

Unlike the enterotoxigenic organisms, invasive bacteria exert their main impact on the host by causing gross destruction of the epithelial architecture; histologic findings include mucosal ulceration and an inflammatory reaction in the lamina propria. The principal pathogens in this group are Salmonella, Shigella, Campylobacter, invasive E coli, and Yersinia. The enteric viruses also invade intestinal epithelial cells, but the extent of mucosal destruction is considerably less than that caused by invasive bacterial pathogens.

Salmonella Enteritis

Salmonella species are a common cause of food poisoning. The main site of attack is the lower ileum, where the salmonellae cause mucosal ulceration. They rapidly make their way through the epithelial surface into the lamina propria and enter the lymphatics and bloodstream. At least two virulence factors are associated with intestinal infection: one responsible for mucosal invasion, and the other causing secretion of fluid and electrolytes into the bowel.

Shigella Dysentery

Shigella organisms cause bacillary dysentery, an invasive diarrheal disease of the lower bowel in which the stool contains an inflammatory exudate composed of polymorphonuclear leukocytes. The bacilli invade the epithelium of the colon and cause superficial ulceration. This invasive process depends on the presence of two virulence factors. The first mediates the initial penetration of the mucosal surface by destroying the brush border; the bacteria are subsequently engulfed by invagination of the plasma membrane. The second virulence factor allows the organism to multiply within the mucosal tissue. Mucosal ulceration results, accompanied by an intense inflammatory response in the lamina propria. The infection is usually restricted to the mucosa; lymph node involvement and bacteremia are uncommon.

Fluid Production in Invasive Diarrheal Diseases

The mechanism(s) by which the fluid that causes watery diarrhea is produced in the invasive diarrheal diseases is under debate. Three mechanisms have been proposed. First, Shigella and possibly Salmonella strains apparently produce an enterotoxin that stimulates the mucosa to secrete water and electrolytes. Second, there is evidence that invasive organisms stimulate prostaglandin synthesis at the site of inflammation and that the prostaglandins induce fluid secretion. In experimental animals, fluid secretion can be blocked by prostaglandin inhibitors such as indomethacin and aspirin. Third, some evidence suggests that damage to the colonic epithelium causes diarrhea by prevention of normal resorption of fluid.

Viral Diarrheas

Two viruses—rotavirus (see Ch. 63) and Calicivirus (Norwalk virus) (see Ch. 65)—have been identified as major enteric pathogens in humans. The rotaviruses are a very important cause of infantile diarrhea, which in undeveloped countries can be fatal. Adults may be infected and shed virus, but clinical disease appears almost exclusively in children younger than 2 years. Calicivirus, in contrast, can produce gastroenteritis in all age groups and is a cause of major epidemics. The initial lesion forms in the proximal small bowel. The mucosal architecture is damaged, with shortening of the villi and hyperplasia of the crypts. An inflammatory exudate then appears in the lamina propria.

The mechanisms responsible for fluid secretion in viral diarrheas have not been elucidated. It is known that infection with Calicivirus can produce steatorrhea and xylose malabsorption and causes direct damage to brush border enzymes. The activity of adenylate cyclase in the epithelial cells is not altered in the acute illness.

Parasitic Diarrheas

Several species of protozoa and helminths can cause diarrheal disease. Some of these infections can be acquired in the United States, although exposure to enteric parasites is far more common in tropical and developing countries. Some of the more common causes of parasitic diarrhea are Entamoeba histolytica, Giardia lamblia, Strongyloides stercoralis, and the intestinal flukes.

thophysiology can be used to make a presumptive diagnosis in patients with infectious diarrhea (Table 95-2). Perhaps the most convenient approach is to separate pathogens that involve the small intestine from those that attack the large bowel. Enterotoxigenic bacteria (E coli, V cholerae), viruses, and the parasite Giardia are examples of small-bowel pathogens. These organisms produce watery diarrhea, which may lead to dehydration. Abdominal pain, although often diffuse and poorly defined, is generally periumbilical. Microscopic examination of the stool fails to reveal formed cellular elements such as erythrocytes and leukocytes.

Table 95-2

Clinical Features of Diarrheal Diseases.

The large-bowel pathogens (the major ones being Shigella and Campylobacter) are invasive organisms and cause the clinical syndrome known as dysentery. Involvement of the colon is strongly suggested by the characteristic rectal pain known as tenesmus. Although the fecal effluent may be watery at first, by the second or third day of illness the stool is scanty and often bloody or mucoid. Microscopic examination almost invariably reveals abundant erythrocytes and leukocytes. Proctoscopy shows a diffusely ulcerated, hemorrhagic, and friable colonic mucosa.

Salmonella food poisoning does not fit into this simple scheme, because the disease can display features typical of both small- and large-bowel disease. The organism is invasive for the mucosa of the small intestine, particularly the lower ileum, and can cause voluminous fluid secretion. In additional, septicemia and metastatic spread of the pathogen to other organs sometimes occur.

 

Gastrointestinal illnesses usually are characterized by diarrhoea or the presence of blood, mucus, and, in certain cases, white blood cells in voided stools. Many such disturbances are cases of food poisoning resulting from the ingestion of a preformed toxin. Symptoms of such intoxication rarely last beyond 24 hours, and treatment usually is confined to the intravenous replacement of lost fluids and electrolytes.

A bacteriologic examination of food suspected of causing an illness would be more likely to yield informative data concerning the etiology of intoxication than would an examination of a faecal specimen. For example, a Gram’s stain revealing large numbers of staphylococci, together with a history and the clinical symptoms of staphylococcal food poisoning, would provide strong circumstantial evidence that the gastroenteritis was due to the ingestion of food contaminated with staphylococcal enterotoxin. A similar situation would be seen in food poisoning due to Clostridium perfringens. In both cases, the organisms would be present in large numbers in the contaminated food; however, be-cause the staphylococcal enterotoxin is more stable to heat inactivation than arc the staphylococci themselves, it would not be unusual to see large numbers of staphylococci in a Gram’s stain (of a heated cream soup) an dyet not be able to culture significant numbers of organisms from the suspected food. On the other hand, be-cause the C perfringens enterotoxin is produced only during sporulation, large numbers of viable organisms might be found in a similar situation. It is likely that many cases of gastro-enteritis are of viral origin, and some of these agents arc discussed in Unit Five. With these qualifications as a preface, the laboratory diagnosis of gastrointestinal infections that result from the presence of the etiologic agent in the intestinal contents is discussed.

Specimens from Intestinal Contents

In culturing intestinal contents, the choice of material to be taken from the patient is obvious, although best results are obtained when the faecal specimen is collected during the acute stage of an episode of diarrhoea. If a specimen contains blood or mucus, these should be included in material to be sent to the laboratory. When a sterile swab is used instead of a faecal specimen, the swab must be inserted past the anal sphincter and rotated several times before being withdrawn.

It is a common misconception that the microorganisms found in faeces arc rather hearty and those special precautions to preserve the viability of suspected pathogens are not required. Nothing could be further from the truth! Unless faecal specimens can be taken directly to the laboratory for culturing, they should be refrigerated or placed in a stool preservative containing a buffer that will maintain the pH near neutrality. One such preservative uses about equal parts of sterile glycerol (containing 0.033 M phosphate buffer, pH 7.4) and faeces. A pH indicator also can be included to ensure that a drop in pH does not go unnoticed. Failure to use a preservative will result in the death of many of the enteric pathogens, especially the Shigella and, to a lesser extent, the salmonellae. Faecal specimens of l to 2 g arc adequate for bacteriologic procedures.

 

Media Inoculated With Intestinal Specimens

The major intestinal flora consists of obligately anaerobic gram negative rods, including organisms in the genera Bactericides, Fusobacterium, Eubacterium, and Clostridium. All these can cause serious abscesses but, with the exception of the enterotoxins from C perfringens and Clostridium difficile, none of the obligate anaerobes has been implicated in gastrointestinal disease characterized by diarrhoea. Therefore, unlike the processing of blood or abscess specimens, it is not usual to culture faecal specimens under anaerobic conditions (Table 6).

When species of either Salmonella, or Shigella are the possible pathogens, it is advisable to inoculate an enrichment medium that will selectively permit the growth of these organisms over that of the normal gram-negative flora. Many such media are available, and it is probable that some diagnostic laboratories use various modifications of these media. Two of the more common enrichment media are a tetrathionate and a selenite F medium, both of which are commercially available. After incubation of the inoculated enrichment medium for 12 to 16 hours at 35°C to 37°C, it should be streaked on standard, differential media such as MacConkey or eosin-methylene blue and deoxycholate agar plates. Hektoen enteric or xylose-lysine-deoxycholate plates also can be used. Many other differential and selective media are available that can be used for the isolation of the pathogenic Enterobacteriaceae, and it is likely that diagnostic laboratories vary somewhat in their preference of one medium over another

In cases of suspected cholera, faecal specimens or rectal swabs should be plated directly oonselective media such as taurocholate gelatine agar and outrient agar. In addition, selective agar plates containing thiosultate citrate bile salts or telluride taurocholate gelatine should be heavily streaked Because Vibrio cholerae will grow at a more alkaline pH than most enteric organisms, an enrichment peptone broth, pH 8 5, should be inoculated All enrichment cultures should be streaked oonselective media after 8 to 18 hours of incubation at 35°C

Vibrio parahaemolyticus, a major source of food poisoning acquired from eating undercooked seafood, is a halophytic (salt loving) organism that can be enriched by growth in a medium containing excess NaCl. Thus, the inoculation of a faecal specimen into a 1% peptone broth (pH 7,1) containing 3% NaCI greatly increases the chances of isolation of this organism The enrichment broth then can be streaked on any of several nonselective agar plates (such as described for V. cholerae) for final isolation

In addition to staphylococcal food poisoning resetting from the ingestion of preformed enterotoxin, S. aureus on rare occasions causes an ulcerative enteritis as a consequence of the actual invasion of the bowel wall. In such cases, blood or mucus present in the stool should be plated on a blood agar medium and a selective e medium such as mannitol salt agar.

 

Table 6

Growth Characteristics on Some Commonly Used Agar Media of Bacteria Frequently Isolated From Feces

Organism	Eosin Methylene Blue Agar	MacConkey Agar	Hektoen Enteric Agar	Salmonella- Shigella Agar	Bismuth Sulfite Agar	Xylose-Lysine- Deoxycholate Agar	Selective Enterococcus Agar
Arizona	Translucent, colorless	Uncolored, trans parent; red (LF)	Similar to Salmonella	Black centered, clear periphery	Black; green-brown (LF)	Black-centered red colonies	Inhibited
Citrobacter	Translucent colonies, greenish Metallic sheen(LF)	Uncolored, trans- parent; red(LF)	Usually inhibited; when present, colonies are small and bluish green	Similar to Arizona	Black; green brown	Opaque, yellow	Inhibited
Enterobacter, Serratia	Metallic sheen, similar to E coil but somewhat larger	Red pink	Green centers with yellow to brown periphery	White or cream colored, opaque, mucoid	Raised mucoid colonies, silvery sheen	Opaque, yellow	Inhibited
Escherichia coli (rapid lac tose ferMentens)	Dark center; greenish metallic Sheen	Red or pink; may be surrounded by a zone of precipitated bile	Moderately inhibited; orange to salmon pink	Red to pink; colorless with a pink center	Mostly inhibited; black-brown, greenish surface; no metallic sheen	Opaque, yellow	Inhibited
Klebsiella	Larger than E coil mucoid, Brownish, tend to coalesce, of Ten convex	Pink, mucoid	Yellow centers, periphery orange	Red to pink; colorless with a pink center	Mostly inhibited	Opaque, yellow	Inhibited
Proteus	Translucent, colorless	Uncolored, Transparent	Most strains are ihibited; dark centered, greenish (H2S produceers), similar to Salmonella	Black centered, clear periphery	Green; black (H;S producers); mostly inhibited	Opaque, yellow (P. mirabilis, P. vulgaris), red (P. rettgerri,  P. morgaii)	Small gray colonies (few)
Pseudomonas	Translucent, colorless amber	Uncolored, Trans parent	Most strains are inhibited; colonies are small, flat, and green to brown	Mostly inhibited; transparent colorless colonies	Inhibited	Sometimes red colonies	Inhibited
Salmonella	Translucent, amber colonies; colorless	Uncolored, transparent	Blue to blue green; most colonies have black centers (H2S producers)	Opaque; transparent; uncolored; black centered, clear periphery	S. typhi black with sheen or dotdotted black or greenish gray, other Salmonella are black or green	Black-centered red (ELS producers) red color (no H2S)	Inhibited
Shigella  LF, lactose fermented	Translucent, amber Colonies; colorless	Uncolored, transparent	Blue to blue-green; periphery of colonies lighter than center portion	Opaque, transparent	Mostly inhibited; S. flexneri and S. sonnei are brown, raised and crater-like	Red	Inhibited

Identification of Fecal Isolates

Because of the large numbers of facultative, gram negative rods that make up the normal intestinal flora, the isolation and identification of the morphologically similar Shigella and salmonellae requires the use of selective and differential media as well as considerable experience in working with these organisms Table 36 6 lists a few of the enteric organisms tour some of the media commonly used to culture these organisms

As outlined, numerous kits are available for use in identifying members of the Enterobacteriaceae. One widely used kit, termed the API 20E, consists of a plastic strip containing wells of dehydrated media and appropriate indicators. The wells are inoculated with a suspension of the unknown organisms and, after 24 hours, a numerical value is assigned to each positive reaction. Using the sum of these values, a complete identification can be made from tables that accompany the kit

The identification of staphylococci from a faecal specimen is i moderately easy task it the laboratory has been instructed that the clinical symptoms are compatible with those of a staphylococcal enteritis Large colonies on selective sheep blood agar plates showing Fs hemolysis and grape like clusters of gram positive cocci should be tested additionally for coagulate production and, if specific antiserum is available, for the production of enterotoxin

Intestinal infections by yeast, such as species of Candida, or any of the many parasitic protozoa worms are diagnosed by the direct microscopic examination of a faecal specimen.

 

Microbiology of the Genitourinary System

http://www.ncbi.nlm.nih.gov/books/n/mmed/A5195/

General Concepts

Clinical Presentations

In women, genital infections may cause a vaginal discharge, mucosal ulceration producing local discomfort and pain on intercourse, or pelvic inflammatory disease. Ongoing infection of the upper genital tract leads to infertility, ectopic pregnancies and chronic pelvic pain. In men, genital infection may cause urethral discharge, pain on voiding, and painful scrotal swellings. Genital ulcers are usually painful. Some diseases cause enlarged inguinal lymph nodes.

Etiology

Primary genitourinary infections are usually sexually transmitted; common pathogens include parasites (Trichomonas vaginalis), bacteria (Treponema pallidum, Neisseria gonorrhoeae, Chlamydia trachomatis, Haemophilus ducreyi), and viruses (herpes simplex virus, human papillomavirus, human immunodeficiency virus). Members of the normal flora, such as the fungus Candida albicans, may cause opportunistic infections.

Pathogenesis

Pathogens may enter the genital tract by local invasion or ascending infection. Treponema pallidum, H ducreyi, herpes simplex virus, etc., locally invade the skin and mucous membranes. T pallidum and Human Immunodeficiency Virus disseminate via the bloodstream to distant sites. Other pathogens such as N gonorrhoeae cause ascending infection through the urethra and cervix. Infants born through a genital tract infected with some of these pathogens may become infected.

Microbiologic Diagnosis

The organisms responsible for genital infections are generally fastidious and often difficult to culture. Specimens must be correctly collected and transported. Dark-field examination and serologic studies are necessary to diagnose syphilis; specialized tissue culture or antigen detection techniques are used for C trachomatis, viral culture for herpes simplex virus, and specialized media for culturing N gonorrhoeae and H ducreyi.

Prevention and Treatment

Education to modify sexual behavior and use of condoms are essential. Screening asymptomatic individuals in some populations and case contact tracing are also effective measures. Effective drug therapies exist for all bacterial genital infections and for herpes simplex.

Urinary Tract Infections

Clinical Manifestations

Urinary tract infections in adults may cause painful, frequent urination with a feeling of incomplete emptying of the bladder, perineal pain, fever, chills, and back pain. Most elderly patients are asymptomatic, and in small children, the symptoms are nonspecific.

Etiology

Most urinary infections are caused by bacteria from the intestinal flora. Eschericia coli causes about 70 percent of all infections. Staphylococcus saprophyticus causes about 10 percent of infections in young women. Pseudomonas aeruginosa, Serratia marcescens, Enterococcus faecalis, and Staphylococcus epidermidis are common hospital-acquired pathogens. Yeasts and, in some parts of the world, protozoa are occasional pathogens.

Pathogenesis

Organisms can ascend through the urethra to infect the bladder and renal pelvis. Occasionally, they may interfere with renal function or produce abscesses within renal tissue. Because of the shorter urethra, intercourse can facilitate urinary tract infections in women. Pyuria is almost always present. Hydrolysis of urea by bacteria (e.g., Proteus mirabilis) can cause the formation of struvite stones.

Microbiologic Diagnosis

Presumptive diagnosis can be made by demonstrating pyuria. Quantitative urine culture is essential for diagnosis. Specimens should be refrigerated until cultured to prevent bacterial replication. Properly submitted urine that contains >10⁵ or 10⁸ organisms/ml indicates significant infection. However, with acute cystitis, bacterial counts may be lower. Blood cultures may be positive in patients with pyelonephritis.

Prevention and Treatment

Antimicrobial agents cure most urinary tract infections. Recurrence is common, and may be prevented by prolonged therapy. Prolonged use of a urinary catheter greatly increases the likelihood of a urinary tract infection.

roduction

Genitourinary infections fall into two main categories: (1) primary infections due to sexually transmitted pathogenic microorganisms and (2) infections due to members of the resident flora. Genital infections are uncommon in children and increase dramatically in sexually active adults, in whom sexually transmitted diseases are the second most prevalent group of reportable communicable illness in North America. Sexually transmitted pathogens include parasites (Trichomonas vaginalis), bacteria (Treponema pallidum, Neisseria gonorrhoeae, Chlamydia trachomatis, Haemophilus ducreyi), and viruses (Herpes simplex virus, human papillomavirus, human immunodeficiency virus). Genital infections due to the fungus Candida albicans or to members of the endogenous bacterial flora (Bacteroides fragilis and members of the family Enterobacteriaceae) are not known to be sexually transmitted. Bacterial vaginosis occurs when the balance of vaginal flora is upset.

The urinary tract and urine are normally sterile. Numerous mechanical and biologic processes ensure that microorganisms do not enter the urinary tract. Women are more susceptible to urinary infections because the female urethra is short and because the area around the urethral opening is colonized with potential pathogens (e.g. E coli and E faecalis).

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Urethritis and Epididymitis

Clinical Manifestations

Urethritis (inflammatory disease of the urethra) is characterized by urethral discharge (Table 97-1). The incubation time varies, averaging 3 days for gonococcal urethritis and 7 days for nongonococcal urethritis. The clinical symptoms range from mild to severe. In both men and women, dysuria is common. Discharge and dysuria are seen in 70 percent of patients with gonococcal urethritis, whereas patients with nongonococcal urethritis are more likely to have one or the other of these symptoms but not both. Other symptoms include itching, frequency, urgency, or a feeling of heaviness in the genitals. Polyarthralgia, involving large joints, characteristic rash, and low-grade fever are typically present in patients with disseminated gonococcal infection.

Table 97-1

Gential Infections in Males.

Orchitis and epididymitis are complications of both N gonorrhoeae and C trachomatis infections that present as a painful, swollen mass in the scrotum. Testicular atrophy follows in some patients with orchitis.

Etiology

Neisseria gonorrhoeae and C trachomatis account for most cases of urethritis in men. Chlamydia trachomatis is responsible for 40 to 60 percent of cases of nongonococcal urethritis (Fig. 97-1). The etiology of chlamydia-negative nongonococcal urethritis is uncertain. Ureaplasma urealyticum can cause nongonococcal urethritis; however, the high incidence of this organism in the normal genital flora makes it difficult to interpret its role iongonococcal urethritis. Less common agents isolated from nongonococcal urethritis include herpes simplex virus and Trichomonas vaginalis. Although gonococcal urethritis is a more acute disease than nongonococcal urethritis, overlap in the symptoms mandates laboratory confirmation. Patients often have multiple sexually transmitted pathogens. Approximately 1/3 of heterosexual men infected with Neisseria gonorrhoeae are concurrently infected with Chlamydia trachomatis. If only the gonococci are treated, these patients develop a nongonococcal urethritis called postgonococcal urethritis. Therefore, patients with gonorrhea should also be treated with agents that will effectively eradicate C trachomatis.

Figure 97-1

Major causes of urethritis.

Pathogenesis

Neisseria gonorrhoeae and C trachomatis are transmitted by sexual intercourse (Fig. 97-2). Neisseria gonorrhoeae attaches to mucosal cells via pili and other surface proteins. The organism then is phagocytosed and passes through the mucosal epithelium. Proliferation occurs with subsequent influx of polymorphonuclear neutrophils (PMN), which produce the exudate that is the hallmark of gonorrhea. Neisseria gonorrhoeae spreads to cause disseminated gonococcal infection in approximately 1 to 3 percent of patients with gonorrhea. Disseminated gonococcal infection is more prevalent in women than in men. Up to 80 percent of patients with disseminated gonococcal infection have had an asymptomatic local infection for 7 to 30 days prior to dissemination.