INFECTIOUS DISEASES CAUSED BY BACTERIAL PATHOGENS

Bacterial pathogens may be classified by criteria such as Gram stain characteristics (gram-positive or gram-negative), shape (cocci, bacilli, coccobacilli, curved bacilli, spiral bacteria), growth atmosphere (aerobic, anaerobic, microaerophilic, CO₂ supplemented), optimal growth temperature (25, 35, 42°C), growth rate, inhibition on selective agar (e.g., MacConkey), required enrichment (e.g., heme, cysteine), and other factors. Definitive identification and characterization may depend on biochemical, serologic, molecular, or other testing.

Mycobacteria and other acid-fast organisms are discussed in a separate section.

Gram-negative bacilli, nonfastidious: The pathogens in this group grow within 24–48 hours on routine laboratory media, like sheep blood agar (SBA). Inoculation of selective and differential media, like MacConkey (MAC) agar, may facilitate isolation from contaminated specimens. Aerobic gram-negative bacteria (GNBs) may be grouped on the basis of their ability to ferment glucose. Glucose-fermenting pathogenic GNBs include the “enterics,” like Escherichia coli and Salmonella, as well as the Vibrio spp. Glucose nonfermenters (nGNBs) include Pseudomonas aeruginosa and Acinetobacter spp. Gram staining demonstrates avidly staining organisms. These GNBs demonstrate a variety of resistance mechanisms. Standardized susceptibility testing is required to guide treatment for most infections caused by this group of pathogens.

Gram-negative bacilli, fastidious: Organisms in this group are usually capable of growth in vitro but require enriched media or special techniques for isolation.

Gram-negative cocci: Organisms in this group usually grow well and rapidly on routine laboratory media but may require chocolate or other enriched media for isolation. Selective media may be used to improve isolation from specimens likely to be contaminated with endogenous flora. Empirical therapy is usually successful, but susceptibility testing is recommended for patients who fail to respond or in regions with decreased rates of susceptibility to standard treatments. Serologic testing does not play a role in routine diagnosis or management.

Gram-positive bacilli: The gram-positive bacilli (GPB) usually grow within 24–48 hours on routine laboratory media, like SBA. Inoculation of selective and differential media, like Columbia colistin–nalidixic acid (CNA) or phenylethyl alcohol agar (PEA), may facilitate isolation from contaminated specimens.

Gram-positive cocci: Gram-positive cocci (GPCs) cause a wide variety of infections in immunocompromised and immunocompetent hosts. Organisms grow well and rapidly on media routinely inoculated for bacterial infections. Selective media improve detection of carriage from specimens with mixed flora, as for methicillin-resistant Staphylococcus aureus or vancomycin-resistant enterococci (VRE). Standardized susceptibility testing may be required for management of some infections because of unpredictable susceptibility patterns. Molecular methods are playing an increasing role in diagnosis of some infections. Serologic testing does not play a role in diagnosis of acute infection.

Intracellular bacterial pathogens: These organisms are unable to proliferate independently outside of host eukaryotic cells, limiting the use of routine culture for diagnosis; some agents may grow in eukaryotic cell culture, such as used for virus isolation. Infection may be confirmed by direct detection, serologic response, or molecular diagnostic methods.

Spiral bacteria: The spiral bacteria form a large, metabolically diverse group of microorganisms. The organisms in this group do not grow or are difficult to grow, in vitro. In addition, special staining techniques, like silver staining, dark-field, or immunofluorescent microscopy, are needed for direct detection in specimens. Therefore, serologic techniques play a major role in specific diagnosis of these infections. Molecular diagnostic techniques are also emerging as important diagnostic tools.

Cell wall–deficient bacteria: These pathogens lack the rigid outer cell wall that is typical of bacteria. They do not stain by Gram staining but may be visualized by special stains, like acridine orange. Agents are not isolated by routine culture techniques; serologic testing and molecular diagnostic testing are important methods when specific diagnosis is required.

ACINETOBACTER INFECTION

Definition

Acinetobacter baumannii is a nonfastidious, glucose nonfermenting GNB. This species is the second most frequently isolated nGNB in the clinical laboratory, playing an important role in the etiology of nosocomial infections.

Who Should Be Suspected?

Acinetobacter species are able to survive in very diverse environments. Although Acinetobacter species may be isolated as culture contaminants, they are now well established as important primary and nosocomial pathogens. Infections in virtually all organ systems have been described. Major infections include the following:

Wounds: Acinetobacter baumannii emerged as a significant cause of infection in battlefield injuries during the Vietnam conflict and recently in casualties from Afghanistan and Iraq. It is now established as an important cause of wound and burn infections in nonmilitary patients.

Hospital-acquired pneumonia: Acinetobacter baumannii causes a significant minority (approximately 10%) of nosocomial pneumonias, both as isolated infections or epidemic outbreaks.

Meningitis: Acinetobacter baumannii, along with other gram-negative rods (GNRs), is playing an increasing role as a complication of neurosurgery and external CSF drain placement.

Nosocomial bloodstream infection: Acinetobacter baumannii is responsible for up to 2% of nosocomial bloodstream infection, usually in ICU patients. The reported mortality rate is approximately 40%, exceeded only by Pseudomonas aeruginosa and Candida.

UTI: Acinetobacter baumannii is an established, but uncommon, cause of nosocomial UTI, usually in patients with indwelling catheters.

Treatment of A. baumannii infections poses a significant challenge to clinicians because of intrinsic and acquired resistance. Carbapenem antibiotics are usually effective. Isolates often develop resistance to drugs used to treat these infections. Resistance may quickly emerge to the preferred agents used for nosocomial infections. Definitive treatment should be determined by susceptibility testing of the initial isolate; retesting, to detect emerging resistance, is recommended for subsequent isolates recovered during therapy.

ANAPLASMOSIS AND EHRLICHIOSIS

Definition

The agents of ehrlichiosis and anaplasmosis are small, obligate intracellular bacterial pathogens. Infection is transmitted primarily by the bite of ticks. Specific diseases show restricted geographic distribution based on arthropod vector ranges.

Human granulocytotropic anaplasmosis (HGA) is caused by Anaplasma phagocytophilum, transmitted by Ixodes scapularis or Ixodes pacificus (black legged tick). Disease occurs in New England and the North Central and Pacific United States. Like Borrelia burgdorferi, HGA may cause coinfection with other agents transmitted by Ixodes ticks. Deer and the white-footed mouse are the primary reservoir for HGA in the United States.

Human monocytotropic ehrlichiosis (HME) is caused by Ehrlichia chaffeensis and is transmitted by the lone star tick, Amblyomma americanum. Disease is seen in the South and mid-Atlantic, the Central United States, and some areas of New England. The white tail deer is the primary reservoir for HME.

HME and HGA are national notifiable diseases, reportable to the CDC and local departments of public health.

Who Should Be Suspected?

Disease develops 1–2 weeks after the tick bite. Fever is present in most infected patients, but asymptomatic or mild disease is common. Nonspecific symptoms are common, including headache, malaise, myalgias, arthralgias, and nausea and vomiting. Rash occurs in a significant minority of patients with HME but is unusual in HGA. Rash caused by coinfection, like rickettsiosis or Lyme disease, should be considered. Mental status changes or meningeal signs may occur in a minority of patients. Renal and respiratory failures have been described infrequently.

Laboratory Findings

Culture: not available for routine diagnostic testing.

Direct examination of peripheral blood or buffy coat smear stained by routine hematologic methods: Examination may demonstrate organism-filled vacuoles (morulae) in the cytoplasm of infected cells. Inclusions in granulocytes may be seen in 20–80% of patients with confirmed HGA but in a minority (1–20%) of monocytes in patients with HME. The diagnosis of HGA or HME is not ruled out by a negative smear examination. Disease should be confirmed by specific serology or other definitive test. When HME or HGA is suspected, manual differential examination should be specifically ordered. Automated methods are unlikely to detect abnormalities or trigger manual examinations.

Immunochemical staining: Immunohistochemical staining may be useful in severe or fatal cases, or for patients with early antimicrobial therapy, which may delay the immune response. Specific staining may be used on affected tissues, like bone marrow, or postmortem tissues, including the spleen, liver, lung, kidney, heart, or brain.

NAAT: Molecular diagnostic tests have been developed for diagnosis of HME, HGA, and related organisms. PCR may be positive in serum or CSF in acute stage, but moderate sensitivity (60–85%) may limit the utility of these tests; infection is not ruled out by a negative result.

Serology: Specific antibody response may provide an accurate diagnosis; IFA is the serologic method of choice. Patients are usually negative for specific IgG and IgM in the first week of disease. Therefore, testing paired acute serum sample and another collected 2–3 weeks later is recommended.

A probable case designation may be achieved in patients with a compatible illness in whom a single serum specimen, collected in early acute infection, shows an IFA titer that exceeds a cutoff established by the laboratory that is performing the test. Diagnosis is established by demonstration of a fourfold increase (or decrease) in IFA titer of specific IgG (A. phagocytophilum, E. chaffeensis, or other Ehrlichia species) in paired serum specimens. IgM testing has not been shown to be superior to paired IgG studies.

Core laboratory: Leukopenia (with left shift of PMNs), thrombocytopenia, and elevation of serum aminotransferases are commonly seen but are nonspecific findings in patients with HME and HGA.

CSF findings: Pleocytosis and protein elevation are commonly seen in patients with neurologic complications of HME; CSF is usually normal in HGA patients with neurologic complications.

ANTHRAX (BACILLUS ANTHRACIS)

Definition

Anthrax is caused by infection with Bacillus anthracis, a large, spore-forming grampositive rod (GPR). Naturally occurring anthrax is a zoonotic disease associated with grazing animals in regions without effective vaccination programs; humans may be infected as secondary hosts, usually through contact with spores. In the United States, sporadic infection has been associated with contact with animal products imported from regions with endemic infection.

Anthrax has been recognized as a potential agent of bioterrorism or biologic warfare because of the ability to “weaponize” the organism and the severity of disease caused by airborne spores.

Anthrax is a national notifiable infectious disease. Reporting to public health departments is mandated for all suspected or confirmed cases of B. anthracis infection.

Who Should Be Suspected?

There are three major anthrax syndromes, cutaneous, alimentary tract, and inhalational, depending on the route of transmission. Other organ systems may be infected by spread from a primary site of infection. The diagnosis of anthrax requires a high index of suspicion. Early recognition and antibiotic treatment are critical for successful management of patients with GI, pulmonary, or other invasive infections.

Laboratory Findings

Cultures: Specimens may include vesicular fluid, swab, or tissue from below the leading edge of cutaneous lesions, lower respiratory secretions/sputum, feces, or CSF, or specimens from other infected sites. Blood cultures should be submitted for all patients with suspected anthrax.

Gram stain: Shows large GPBs; may form short chains. Capsules may be apparent. Spores may be seen in subcultures.

BARTONELLOSIS

Definition

Bartonellosis refers to a range of syndromes caused by infection with Bartonella species, fastidious GNBs. The bacteria may be isolated from a wide range of animals, which serve as the likely reservoir for human infection.

Who Should Be Suspected?

Bartonella henselae infection most commonly manifests as cat scratch disease (CSD). CSD is most commonly manifested by self-limited lymphadenopathy, but a number of organ systems may be involved. Bartonella henselae should be strongly suspected on the basis of typical clinical presentation after exposure to cats, especially if flea infested.

Almost all patients with CSD present with a cutaneous lesion at the site of inoculation and regional lymphadenopathy. Skin lesions appear within 3–10 days after inoculation and may show vesicular, erythematous, and papular phases. Lesions are minimally symptomatic and resolve after several weeks, healing without scarring. Primary lesions may occur on the mucous membranes or conjunctiva. Tender solitary lymphadenopathy, typically with overlying erythema, develops in the 2nd or 3rd week after infection but may be delayed up to several months. In uncomplicated cases, lymphadenopathy usually resolves within 1–4 months.

Bartonella quintana was associated with trench fever during World War I. Trench fever is transmitted by the body louse; patients present with fever, malaise, sweats and chills, conjunctivitis, retro-orbital pain, back and neck pain, and anterior tibial pain. In recent years, B. quintana has emerged as a cause of “urban trench fever” in indigent populations with bacteremia and endocarditis, peliosis, and bacillary angiomatosis, primarily in patients with AIDS. Suspect infection in patients with culture-negative endocarditis, vascular proliferative lesions (bacillary angiomatosis [BA]), and cystic lesions of the liver or other internal organs (peliosis).

Laboratory Findings

Direct examination and histopathology: Histopathologic examination may provide strong support for diagnosis of bartonellosis. Demonstration of typical granulomas and typical organisms (Warthin-Starry stain) strongly supports the diagnosis of CSD. Histologic appearance of excised lymph node, skin lesions, and so on may be characteristic but are nonspecific. In BA, there is H&E staining of vascular proliferation. Lesions show eosinophilic debris; Warthin-Starry staining reveals masses of small bacteria.

Molecular diagnosis: Sensitive and specific molecular diagnostic assays have been described. PCR and related methods are playing an increasing role in the diagnosis of infections caused by Bartonella species, when available. There are no FDA-approved methods, however.

Culture: Isolation of Bartonella in culture provides a definitive diagnosis, but special culture techniques and prolonged incubation are required. Cultures are often negative in infected patients. In addition, most clinical laboratories cannot perform the testing required for specific identification, so isolates must be sent to a reference laboratory for further characterization. The lysis centrifugation method is recommended for blood cultures to detect Bartonella bloodstream infections.

Serology: The sensitivity and specificity of serologic assays are not high, limiting their utility for the diagnosis of bartonellosis. There may be cross-reactions with other Bartonella species and other, unrelated organisms. The prevalence of seropositivity in general populations may be significant, suggesting that asymptomatic Bartonella infection is common. In CSD, B. henselae IFA IgG titer of ≥1:256 is consistent with recent infection, supporting a diagnosis of CSD. Titers ≥1:64 to 128 are suggestive but should be repeated after 2 weeks to confirm diagnosis; titers <1:64 indicate that recent infection is unlikely. A positive reaction for B. henselae IgM strongly supports recent infection, but IgM production is typically brief.

General laboratory: ESR and CRP are usually increased in bartonellosis. WBC count is usually normal but may be slightly elevated ≤13,000/μL; eosinophils may be increased. Other laboratory findings are related to specific organ involvement.

BORDETELLA PERTUSSIS

See Chapter 13, Respiratory, Metabolic, and Acid–Base Disorders.

BOTULISM (CLOSTRIDIUM BOTULINUM)

Definition

Botulism describes a toxin-mediated paralytic disease caused by heat-labile toxins of Clostridium botulinum. Botulism toxins bind to the synaptic vesicles of cholinergic nerves, preventing release of acetylcholine into the neurosynaptic cleft. Botulism intoxication results in acute, symmetrical, flaccid paralysis. Patients usually present with impairment of cranial nerves and muscles of the head and neck. Symptoms progress to symmetrical paralysis of the musculature of the trunk, progressing to the extremities. Respiratory paralysis is usually the most life-threatening manifestation of botulism.

Several distinct botulism syndromes have been described. Foodborne botulism usually presents in adults after ingestion of preformed toxin in C. botulinum– contaminated food. Infant botulism, the most commonly encountered form of botulism, results from the ingestion of C. botulinum organisms or spores that proliferate and produce toxin within the infant’s gut. Wound botulism is a rare form of botulism in which toxin is formed in vivo by C. botulinum organisms causing wound infection.

Clinicians must be alert to patients presenting with signs and symptoms compatible with botulism because they may represent an index case of a bioterror incident. Reporting to public health authorities is mandated for suspected or documented botulism.

Laboratory Findings

Culture: In the proper clinical setting, diagnosis may be established by isolation of C. botulinum or botulinum toxin from patient specimens or food. Isolation of C. botulinum by anaerobic culture may be attempted for infected patient specimens or feces. Isolation from food should only be attempted by specialized reference laboratories.

Toxin detection: Typical specimens include any food suspected in an outbreak, serum (15–20 mL in adults; 2–3 mL in infants), gastric contents or vomitus, and feces (as much as possible, up to approximately 50 g). Toxin detection is performed by specialized reference or public health laboratories.

Core laboratory: Routine laboratory tests are usually normal.

BRUCELLA

Definition

Brucella species are fastidious, slowly growing GNRs. Isolates are highly infectious and pose a serious risk of laboratory-acquired infections; clinicians should alert the laboratory when brucellosis is suspected. The CDC has classified Brucella species as potential bioterror agents, and reporting is mandated when Brucella infection is suspected or confirmed.

Who Should Be Suspected?

Brucellosis causes a wide spectrum of clinical disease with acute and chronic forms. In affected patients, fever, chills, night sweats, malaise, headache, and other nonspecific symptoms are common and may mimic other acute or chronic illness or fever of unknown origin (FUO). Bacteremia often occurs and may result in secondary localized infections; suppurative lesions may affect any organ system, including bone and joints, liver, and spleen.

Laboratory Findings

Cultures: Brucella species primarily infect the RE system with secondary spread to other organ systems. Therefore, blood and bone marrow cultures are specimens of choice for diagnosis. Other infected patient samples may also be submitted for culture.

Serology: Acute serum samples should be collected, followed by convalescent samples several weeks later. IgM titers are increased within the first 1–2 weeks of acute infection; there is a transition to IgG production after the 2nd week. Titers fall in response to effective therapy.

BURKHOLDERIA INFECTIONS

Definition

Burkholderia species are nonfastidious, glucose nonfermenting GNBs. Burkholderia pseudomallei and Burkholderia cepacia are the species most commonly associated with human disease. Burkholderia pseudomallei has a fairly restricted, geographically limited incidence; primary infection in the United States is uncommon. Burkholderia cepacia has been isolated from numerous environmental sources.

Burkholderia mallei (a primary pathogen of horses) and B. pseudomallei have been classified by the CDC as potential bioterror agents. Reporting is mandated as soon as B. mallei or B. pseudomallei infection is suspected or confirmed.

Who Should Be Suspected?

Burkholderia pseudomallei causes melioidosis, an infection with a restricted geographic distribution; disease is largely confined to Southeast Asia and northern Australia. Direct contact with or inhalation of contaminated soil or water is the most common mode of transmission. Most infections are asymptomatic or minimally symptomatic with a flu-like syndrome but may present with acute or chronic illness, including pneumonia, skin and soft tissue infections, chronic suppurative infections, and bacteremia.

Burkholderia cepacia has emerged as a significant pathogen, primarily causing disease in patients with CF and chronic granulomatous disease. In patients with CF, respiratory tract colonization may be associated with a rapid decline in pulmonary function and an increased mortality in the year following acquisition.

Laboratory Findings

Culture: Burkholderia pseudomallei or mallei may be isolated by routine bacterial culture but may require additional incubation time. Selective media should be used for isolation of B. cepacia from lower respiratory specimens collected from CF patients.

Susceptibility: Burkholderia cepacia is intrinsically resistant to aminoglycosides but typically susceptible to TMP/SMX.

CAMPYLOBACTER GASTROENTERITIS

Definition

Campylobacter species are microaerophilic, curved GNBs. Campylobacter species cause diarrheal infections globally and are the most common bacterial cause of significant diarrheal illness in most countries. Campylobacter jejuni is the most important human pathogen. In developed countries, asymptomatic infection is uncommon.

Who Should Be Suspected?

Infection is usually acquired by contact with animals, mainly poultry, in which Campylobacter species are common components of endogenous gut flora. Personto-person transmission is uncommon. Most infections resolve within 7 days. Campylobacter GI infection typically results in diarrhea with fever, cramping, and vomiting. Blood may be present in the stools. A nonspecific colitis, with marked fecal leukocytes, is common. Guillain-Barré syndrome has been associated with campylobacteriosis. Disease outside the GI tract is uncommon. Septic arthritis, bacteremia, proctocolitis, meningitis, and other infections have been reported.

Laboratory Findings

Culture: The special culture procedures required for isolation of Campylobacter species are included in routine stool culture protocols in clinical microbiology laboratories.

CHLAMYDIA AND CHLAMYDOPHILA INFECTIONS

Definition

Chlamydia and Chlamydophila species are obligate intracellular bacterial pathogens.

Who Should Be Suspected?

The Chlamydiaceae are responsible for a number of distinctive disease syndromes, including

Chlamydia genital tract infection. Chlamydia trachomatis is the most common cause of sexually transmitted bacterial infections in industrialized nations; serovars D through K are responsible for these genital infections. Serovars L1, L2 (including a and b variants), and L3 are responsible for lymphogranuloma venereum (LGV), a systemic STD most commonly encountered in developing countries.

Most sexually transmitted C. trachomatis infections are asymptomatic, contributing to their spread. Common clinical manifestations include urethritis, mucopurulent cervicitis, ascending infections, female genital tract conditions (PID, endometritis, salpingitis, perihepatitis syndrome), male genital tract problems (epididymitis), conjunctivitis (nonscarring), and proctitis. Complications of C. trachomatis genital infection may include scarring of the fallopian tubes, infertility, and ectopic pregnancy. Maternal C. trachomatis infection at the time of delivery may result in neonatal infection, which typically manifests as conjunctivitis or pneumonia. Acute, nonscarring inclusion conjunctivitis occurs in 18–50% of infants of mothers with untreated genital infection.

Trachoma: Trachoma refers to chronic C. trachomatis conjunctivitis, usually caused by serovars A, B1, B2, and C. Infection leads to corneal scarring and, in late stages, blindness.

Chlamydophila pulmonary infections (Chlamydophila pneumoniae and Chlamydophila psittaci): C. pneumoniae is most commonly associated with lower and upper respiratory tract infections (e.g., pneumonia, bronchitis, sinusitis). This pathogen has been implicated in a significant minority (approximately 15%) of community-acquired cases of pneumonia.

Chlamydophila psittaci infection causes psittacosis. Birds are the natural reservoir for this organism; infectious forms may remain viable in the environment for extended periods. Human infection is easily transmitted by inhalation of infectious organisms directly shed from birds or from organisms in their environment. Patients usually present with nonspecific symptoms in acute infection, including flu-like illness: fever, severe headache, hepatomegaly, splenomegaly, and GI symptoms. Chronic pneumonitis may develop.

Laboratory Findings

Molecular diagnostic testing: NAATs are considered the gold standard for the diagnosis of genital C. trachomatis infections. FDA-approved kits are available for endocervical, urine, urethral specimens, and liquid-based Pap test specimens. The sensitivities reported for NAATs range from approximately 90 to 97%; the specificities are >99%. NAATs have been described for detection of C. pneumoniae and C. psittaci, but FDA-approved kits are not available, and their performance has not been clearly defined.

Culture: Isolation of C. trachomatis in culture remains an important technique for diagnosis of nongenital infections and is considered the standard for evidence in medicolegal cases, such as rape and child abuse. For optimal isolation, it is critical to collect samples that contain the host cells infected by chlamydia and to transport in conditions that will maintain the viability of the organisms. For detection of genital infections, the sensitivity of tissue culture is approximately 65–85%, with specificity near 100%.

Direct detection: DFA staining kits are available for direct detection of C. trachomatis from genital specimens. Slides require examination by an experienced laboratorian, and slides must be carefully evaluated to ensure adequate specimen collection (i.e., the presence of columnar epithelial cells). Under optimal conditions, the sensitivity of DFA is approximately 60–80% with specificity >98%. Typical intracytoplasmic inclusions in epithelial cells of Giemsa-stained smears from conjunctival scrapings are found in 50% of patients with C. trachomatis conjunctivitis.

EIA detection: A number of EIA kits for the diagnosis of C. trachomatis genital infection are commercially available. Sensitivities of approximately 60% are reported for cervical infections. Reported specificity is high, but false-positive reactions are possible for tests based on detection of C. trachomatis lipopolysaccharide.

Serology: Serologic testing is not helpful for the diagnosis of acute genital infection caused by C. trachomatis. Serology may be useful to document diagnosis of psittacosis, LGV, and respiratory tract infections.

Complement fixation (CF) assays target response to LPS common to all members of the Chlamydiaceae, so positive results must be interpreted in the context of disease. CF testing is most useful for LGV, where titers ≥256 are considered diagnostic.

Microimmunofluorescence (MIF) assays are useful for the diagnosis of neonatal pulmonary infection because they allow specific detection of IgM and IgG. An IgM titer of ≥32 supports the diagnosis. In LGV, an IgG titer of ≥128 provides strong support for diagnosis. Chlamydophila pneumoniae infection may be documented by a fourfold increase in titer between acute and convalescent specimens, an IgM titer ≥16 or an IgG titer ≥512.

EIA assays, based on synthetic peptides, have been developed to simplify the technically demanding MIF procedure. In general, results have compared favorably to results of MIF testing.

CLOSTRIDIAL INFECTIONS: GENERAL

Clostridium species are anaerobic, spore-forming gram-positive bacilli. The formation of spores results in efficient survival of clostridia in the environment; the spores serve as the source of infections of exogenous origin (e.g., Clostridium difficile colitis, Clostridium perfringens food poisoning). Clostridia may also cause infections of endogenous origin (e.g., myonecrosis). Clostridium species produce some of the most potent toxins, which are responsible for some clostridial diseases (e.g., tetanus). Botulinum toxin is considered to have significant potential for use as a bioterror agent.

Clostridia grow well and rapidly on media for anaerobic culture, but selective media may be needed for contaminated specimens. The interpretation of cultures positive for Clostridium species is usually straightforward, but because of the ubiquitous distribution of clostridia in the environment, positive cultures must be interpreted in the context of the clinical presentation. Standardized susceptibility testing is available using specialized techniques, but many laboratories do not offer the testing in-house.

CLOSTRIDIAL GAS GANGRENE, CELLULITIS, AND PUERPERAL SEPSIS

Definition

These syndromes may be caused by a number of clostridial species of endogenous or exogenous origin. Most cases of clostridial gangrene are caused by C. perfringens, Clostridium novyi, and Clostridium septicum.

Who Should Be Suspected?

Patients present with rapidly progressive tissue necrosis, tissue liquefaction, and gas formation. Gas formation in tissue is not specific for clostridial infections and may be formed by other bacterial pathogens. Clostridial myonecrosis should be considered a medical emergency, and rapid and effective communication with clinical personnel, especially surgeons, is critical.

Laboratory Findings

Direct detection: Gram stain typically shows massive tissue necrosis, a lack of PMNs, and the presence of typical organisms (usually large “box-car” GPBs; the absence of spores on Gram stain is common and does not rule out clostridial infection; other bacterial morphotypes may be seen in mixed infections).

Culture: Blood cultures may be positive.

Core laboratory: WBC count is increased (15,000–40,000/μL). Platelets are decreased in 50% of patients. Protein and casts are often present in urine. Renal insufficiency may progress to uremia. Laboratory findings typical for underlying diseases (e.g., DM) or complications of clostridial infection are seen. In postabortion sepsis, sudden severe hemolytic anemia is common with conditions such as hypoglobulinemia, hemoglobinuria, increased serum bilirubin, spherocytosis, and increased osmotic and mechanical fragility.

CLOSTRIDIUM DIFFICILE INFECTION (CDI) AND ASSOCIATED (PSEUDOMEMBRANOUS) COLITIS

Definition

Clostridium difficile is a major cause of antibiotic-associated diarrhea and colitis. It is the most important cause of pseudomembranous colitis. CDI is usually acquired nosocomially.

Who Should Be Suspected?

Several factors are associated with increased risk for C. difficile disease, including recent or current antimicrobial (or antineoplastic) therapy, age (>65 years), suppression of gastric acid production, and debilitating underlying medical conditions.

Laboratory Findings

Culture: Specific laboratory diagnosis is based on the growth of C. difficile from stool culture or by detection of C. difficile–specific antigen, toxins, or DNA. Testing should be performed only on liquid stool specimens; asymptomatic carriage may be seen. Formed stool should be rejected if submitted for testing. Isolation of toxigenic C. difficile, using selective anaerobic culture, is considered the “gold standard” for diagnosis. Toxin production by isolates must be documented and may be confirmed by PCR, antigen, or cytotoxicity assays. The complexity and turnaround time required for toxigenic culture assays have limited their use for routine testing.

Cytotoxicity assays: These assays are based on detection of the cytotoxic effect of C. difficile toxin B on cultured eukaryotic cells. Testing may be performed on stool filtrate or C. difficile culture supernatant.

Toxin EIA: A number of enzyme immunoassays are commercially available for rapid detection of C. difficile toxin B or both toxins A and B. Because of their simplicity and rapid turnaround time (<1 hour), EIA tests have been widely used for diagnosis of CDI. EIA assays have shown high specificity (>95%), but the sensitivity of different assays is variable, ranging from approximately 60 to 95%, which has limited their use in critically ill patients or infection control investigations.

Antigen detection: Detection of C. difficile–specific glutamate dehydrogenase (GDH) antigen may be used to screen stools for C. difficile. The sensitivity of the GDH assay depends on the reference standard; sensitivities ranging from approximately 70 to >95% have been reported. Toxin must be documented in GDH antigen–positive specimens because nontoxigenic C. difficile strains are detected by this assay.

Molecular diagnostic testing: PCR assays that target the toxin B gene have emerged as clinically important assays for the diagnosis of C. difficile GI infection. Several FDA-approved methods are commercially available. Reported performance of molecular diagnostic assays has shown S/S both in the range approximately 95–99%. The use of real-time PCR assays provides for results within 24 hours.

Combination tests: Some laboratories have combined EIA, GDH antigen, and/ or PCR testing in simultaneous or sequential test algorithms to improve the S/S and cost-effectiveness of these test methods.

CLOSTRIDIUM TETANI INFECTION

Definition

Tetanus describes disease caused by a heat-labile toxin (tetanospasmin) elaborated by Clostridium tetani. Infection typically results from “dirty” traumatic injuries (e.g., deep puncture wounds, crush injuries) contaminated by spores of C. tetani. Toxin diffuses from the site of infection into the circulation, where it gains access to peripheral motor neurons. Toxin is transported through the neurons to the CNS, where it blocks inhibitory signals from the CNS to motor neurons. Tetanospasmin also binds to receptors at the myoneural junctions (different from the receptors for botulinum toxin), inhibiting the release of acetylcholine. Tetanus has been essentially eliminated in populations with an effective vaccination program, but sporadic cases occur in unvaccinated populations.

Who Should Be Suspected?

Patients present with spasm of flexor and extensor muscles. Patients develop pathologic hyperresponsiveness to minor stimuli. Common features include “lock jaw,” risus sardonicus, and back spasms resulting in relentless arching.

Laboratory Findings

Diagnosis is usually made on the basis of typical clinical findings. Culture from an infected site usually has poor sensitivity and is usually noncontributory. Core laboratory findings are usually normal.

DIPHTHERIA

See Chapter 13, Respiratory, Metabolic, and Acid–Base Disorders.

ENTEROCOCCAL INFECTIONS

Definition

Enterococcus species are aerobic GPCs that form pairs and short chains. Enterococcus species are universal components of the endogenous lower GI tract flora in healthy humans; colonization of the urogenital mucosa is common. Enterococci are moderately virulent, but the mechanisms are not clearly understood.

Enterococci may demonstrate intrinsic and acquired resistance to antibiotics, including vancomycin. This characteristic is at least partially responsible for the emergence of enterococci as significant nosocomial pathogens. Enterococcus faecalis and E. faecium are the species most commonly associated with human infection.

Who Should Be Suspected?

Enterococci may cause infection in virtually any organ system; common infections include UTIs, bacteremia, endocarditis, intra-abdominal infections, and wound infections. Hospitalized patients who are rectal carriers of VRE may transmit these pathogens to other patients that may be at high risk for invasive VRE infection.

Laboratory Findings

Culture: Isolates grow in 24–48 hours on media for GPC isolation under standard incubation conditions. Susceptibility testing must be performed for significant clinical isolates.

ESCHERICHIA COLI INFECTION

Definition

Escherichia coli is a nonfastidious, glucose-fermenting GNB. E. coli is the most common clinical isolate in most microbiology laboratories. It is a ubiquitous component of the GI bacterial flora and is the most common cause of community-acquired UTI in normal hosts. Escherichia coli is a major cause of nosocomial infections and infections in immunocompromised patients. Escherichia coli isolates may cause enteritis or gastroenteritis by a number of mechanisms, including toxin production and adherence to mucosal epithelial cells of the colon.

Who Should Be Suspected?

Escherichia coli should be considered in any patient with UTI. Escherichia coli may also be suspected in patients with “traveler’s diarrhea” (abrupt onset, with profuse, watery diarrhea after travel to an endemic area). Enterohemorrhagic E. coli infection may be suspected in patients with diarrhea, especially in patients who develop HUS after diarrheal illness. See the discussion of foodborne causes of diarrhea in Chapter 5, Digestive Diseases.

Escherichia coli is responsible for a wide spectrum of opportunistic and nosocomial infections. It is a major cause of nosocomial pneumonia, bloodstream infection, surgical site infection, and UTI. It is also responsible for a significant proportion of severe neonatal infections, including sepsis and meningitis.

Laboratory Findings

Culture: Recognition of E. coli strains that cause enterohemorrhagic gastroenteritis may be improved by the use of the differential sorbitol–MAC agar. These strains produce Shiga toxin 1 and/or toxin 2, which may be directly detected in stool specimens by antigen testing or NAAT.

Serotyping: In the United States, most isolates are serotype O157:H7. Although there are tests that can be used to identify other types of diarrheagenic E. coli, testing is not widely available. Specific diagnosis is rarely needed for patient management.

FRANCISELLA TULARENSIS INFECTION

Definition

Tularemia is caused by F. tularensis, a fastidious, tiny gram-negative coccobacillus. Naturally acquired tularemia is a zoonotic, tick-transmitted infection. The normal host species include rabbits, rodents, squirrels and other small mammals, and deer. Domestic livestock, especially sheep, are also susceptible to infection. Human infection is transmitted by direct contact with an infected animal or through the bite of an intermediate arthropod vector.

Francisella tularensis is highly infectious and poses a serious risk for laboratoryacquired infections; clinicians should alert the laboratory when tularemia is suspected so that appropriate precautions and culture techniques are used. The CDC has classified F. tularensis as a potential bioterror agent. Possible or confirmed F. tularensis infections must be reported to state departments of health.

Who Should Be Suspected?

Disease usually occurs 2–10 days after exposure, with ulceration at the site of tick bite and painful regional adenopathy. Nonspecific symptoms are common, including fever, chills, headache, sweats, severe conjunctivitis, and regional adenopathy. Approximately 20% of patients present with acute onset of fever and abdominal symptoms, including nonbloody diarrhea, vomiting, pain, and tenderness.

Laboratory Findings

Gram stain: Tiny faintly staining coccobacilli.

Culture: Samples of blood, bone marrow, primary ulcers, lymph node aspirates, or other infected tissue. Cysteine is required for growth.

HAEMOPHILUS INFECTIONS

Definition

Haemophilus species are fastidious gram-negative coccobacilli and are responsible for a variety of infectious syndromes. They are common components of the endogenous flora of the mouth and upper respiratory tract. Most of the respiratory species have limited virulence and are able to cause disease only when normal host defenses are compromised. Strains of Haemophilus influenzae may be encapsulated (serotypes a, b, c, d, e, and f). The serotype b capsular material is a virulence factor and is responsible for the ability of H. influenzae type b (Hib) to cause severe, invasive infections. Haemophilus ducreyi causes the STD chancroid.

Who Should Be Suspected?

Most Haemophilus infections present as localized infections of the pararespiratory structures, like sinusitis or otitis media. Acute sinusitis is usually manifested by nasal congestion with purulent discharge, which may be unilateral. See the discussion of sinusitis in Chapter 13. Respiratory, Metabolic, and Acid–Base Disorder.

Haemophilus influenzae may cause an acute lobar pneumonia, but lower respiratory disease is most commonly manifested as bronchitis in patients with underlying lung disease. These patients typically present with nonproductive cough, wheezing, and increasing shortness of breath. In these patients, Haemophilus infection may cause significant deterioration of pulmonary function tests, hypoxemia, and dyspnea. Low-grade fever may be seen.

Epiglottitis, cellulitis of the supraglottic structures, is a life-threatening manifestation of Hib infection. The tissue may be directly seeded by posterior pharyngeal organisms or as a result of bacteremia. There is typically an abrupt onset of fever, malaise, severe sore throat, and dysphagia. Dyspnea, inspiratory stridor, and drooling develop with progression to severe disease, caused by obstruction of the airway by the swelling of the supraglottic tissue. Attempts to collect swab specimens for culture may stimulate acute obstruction, so they are contraindicated prior to securing a protected airway. Lateral x-ray studies of the hypopharyngeal region demonstrate swelling of the epiglottis. Culture of blood commonly yields H. influenzae.

Encapsulated strains, especially type b, may cause meningitis or invasive disease. Culture and analysis of blood and CSF should be submitted to establish the diagnosis. Other localized infections associated with bacteremic disease include septic arthritis, osteomyelitis, and cellulitis. Buccal and periorbital cellulitis have been commonly, but not exclusively, associated with Hib. Buccal cellulitis presents with swelling of the cheek with deep red discoloration. Periorbital cellulitis presents with signs and symptoms of pus accumulation in the orbital tissues and a characteristic purple discoloration of the lids and skin surrounding the affected eye. Haemophilus influenzae may also cause acute conjunctivitis and endophthalmitis. Haemophilus influenzae biogroup aegyptius has been implicated in conjunctivitis and Brazilian purpuric fever, a bacteremia syndrome with fever and hypotension, purpuric rash, vomiting, and abdominal pain.

Haemophilus ducreyi causes chancroid, an ulcerative STI that occurs primarily in tropical regions. Disease is manifested by multiple genital and perineal ulcers. Unlike the chancres of syphilis, the ulcers of chancroid are painful and have ragged borders with minimal induration. Inguinal adenopathy is common and may progress to draining buboes. Like other genital ulcerative diseases, chancroid increases the risk of transmission of HIV infection.

Laboratory Findings

Gram stain: Diagnosis of Haemophilus infection depends primarily of Gram stain and culture of infected specimens. Gram staining shows small, pleomorphic, faintly staining gram-negative rods; some end-to-end pairing or small filamentous forms may be present.

Culture: Haemophilus species are fastidious but are efficiently isolated on chocolate agar and in routine blood culture media. Positive cultures from the upper respiratory tract must be interpreted with caution because Haemophilus species, including encapsulated strains, are common components of the endogenous flora. Specimens for the diagnosis of chancroid are collected from the margin and undermined base of fresh ulcers. Haemophilus ducreyi is difficult to isolate by culture, requiring specialized enriched media that should be inoculated at bedside.

Antigen detection (for detection of Hib from CSF, serum, or urine): Use of antigen detection is not recommended, having been shown to rarely contribute to the clinical management of patients.

HELICOBACTER PYLORI INFECTION

Definition

Helicobacter pylori is a fastidious, curved GNB. Helicobacter pylori infection shows a global distribution.

Most infections are transmitted by the fecal–oral route.

Who Should Be Suspected?

Helicobacter pylori is the cause of most gastric and duodenal ulcers through disruption of the protective mucous layer. This organism is epidemiologically linked to gastric adenocarcinoma and lymphoma.

Laboratory Findings

Helicobacter pylori may be diagnosed by several invasive or noninvasive means:

Histologic examination of gastric mucosa: Organisms stain poorly with H&E but may be demonstrated with Giemsa or silver staining.

Culture of gastric mucosa: Special culture techniques are required for isolation. The organism is microaerophilic and capnophilic and yields growth within 5 days on enriched media.

Urease activity (direct tissue or breath test): Strongly positive.

Specific antigen: A commercially available assay for detection of H. pylori antigen in feces shows a sensitivity of approximately 90% and specificity of approximately 95% for detection of active infection. Helicobacter pylori antigen may be useful for monitoring response to therapy.

Serology: Helicobacter pylori antibody IgG is typically measured. Positive response is predictive of active infection in patient populations where the prevalence of active infection is not high. Antibody levels may remain persistently positive for a period after successful therapy, so serology may have a limited role in early test of cure.

KLEBSIELLA PNEUMONIAE INFECTION

Definition

Klebsiella pneumoniae is a nonfastidious, glucose-fermenting GNB. Klebsiella pneumoniae is widely distributed in nature as well as the normal fecal flora of humans. It is a common isolate in the clinical laboratory, often associated with nosocomial infection or infection of immunocompromised hosts.

Who Should Be Suspected?

Klebsiella pneumoniae is associated with severe pneumonia, especially in alcoholics. The pneumonia results in necrosis and hemorrhage; mucoid, “currant jelly” sputum is classic. Bacteremia is seen in a significant number of cases. Klebsiella pneumoniae is also associated with primary or hospital-acquired UTI, nosocomial bloodstream, ventilator-associated, or other extraintestinal infection. Klebsiella pneumoniae isolates are of particular importance in hospital-acquired infections because of their intrinsic and acquired resistance to antimicrobial agents.

Laboratory Findings

Cultures: Klebsiella pneumoniae isolates often produce mucoid colonies due to production of capsular material.

Susceptibility: All Klebsiella species are intrinsically resistant to ampicillin and ticarcillin. Many hospital isolates have additional resistance through acquisition of plasmids that carry resistance genes. Extended-spectrum beta-lactamases confer resistance to third-generation cephalosporins and most other beta-lactam antibiotics. Klebsiella pneumoniae carbapenemases confer resistance to imipenem, ertapenem, and meropenem in addition to most beta-lactam antibiotics.

LISTERIA INFECTION

Definition

Listeriosis is caused by infection with Listeria monocytogenes, an aerobic, pleomorphic gram-positive bacillus. This organism is widely distributed in nature, and up to 5% of asymptomatic, healthy adults carry L. monocytogenes as a component of their endogenous fecal flora. CNS and placental tissue are predisposed to Listeria infection. Most infections are thought to occur as a result of oral ingestion, followed by invasion across the gut mucosa and systemic spread. Disease may occur in a sporadic or epidemic pattern.

Who Should Be Suspected?

Listeria is responsible for a small proportion of foodborne infections, and most cases are sporadic, but the case–fatality rate is relatively high. Outbreaks have been caused by a variety of types of food, including delicatessen meats, unpasteurized cheeses, smoked seafood, and processed meat spreads. Ingestion of contaminated food may cause self-limited gastroenteritis in normal hosts, with onset typically several days after exposure. Symptoms include fever, nausea, vomiting, and diarrhea. Flu-like symptoms are common.

Risk factors associated with increased infection risk and severity include immunocompromise, age ≥70 years, alcoholism, glucocorticoid therapy, kidney disease, nonhematologic malignancy, neonatal infection, and pregnancy.

In normal hosts, complete recovery is typical after several days of illness. During pregnancy, listeriosis usually presents with flu-like symptoms and may resolve spontaneously. Severe listeriosis may occur in the third trimester where placental infection and transmission to the fetus or neonate may occur. The signs and symptoms of Listeria sepsis are not distinctive, and diagnostic cultures are critical for specific diagnosis. Patients present with fever and malaise that may progress to shock and sepsis. Symptoms of meningoencephalitis are nonspecific and may include meningeal signs, mental status changes, or focal neurologic defects (e.g., ataxia, cranial nerve abnormalities, and deafness). Direct hematogenous seeding of the brain parenchyma may result in cerebritis or brain abscess, most typically manifested by stroke-like symptoms or focal neurologic defects.

Laboratory Findings

Culture (blood): Most reliable diagnostic test; culture of CSF and other infected tissue is indicated on the basis of clinical presentation. Isolation of Listeria from suspected food samples requires special techniques performed at reference laboratories.

Gram stain: CSF Gram stain is only positive in about one third of patients with meningoencephalitis and lower in localized CNS infections. Listeria may be misidentified as Streptococcus pneumoniae, diphtheroids, or even H. influenzae.

CSF findings: Pleocytosis is typical (100 to 10,000 WBCs/μL). Significant CSF lymphocytosis (>25%) may be seen on CSF WBC differential prior to antibiotic therapy. CSF protein concentration is typically moderately elevated; CSF glucose is reduced in only approximately 40% of patients with CNS infection. CSF findings may lead to misdiagnosis as viral infection, syphilis, Lyme disease, or TB.

Serology: Not usually useful for diagnosis of acute listeriosis.

LYME DISEASE

Definition

Lyme disease is a systemic, chronic borreliosis caused by Borrelia burgdorferi, a fastidious spiral bacterium. Infection is transmitted by the bite of Ixodes ticks. A variety of clinical manifestations are seen. Recurrent clinical disease may be caused by reinfection. Lyme disease is reportable in the Nationally Notifiable Infectious Diseases Surveillance System. Criteria for case definition may be seen on the CDC Web site: (http://www.cdc.gov/ncphi/disss/nndss/casedef/lyme_disease_2008.htm).

Who Should Be Suspected?

Acute disease occurs about 1–4 weeks after tick bite, manifested by nonspecific febrile symptoms that may be confused with a “viral syndrome.” Erythema migrans (EM) is characteristic for Lyme disease and occurs in 60–80% of infected patients. EM typically begins as a red papule with surrounding erythema that expands over days to weeks. The central region commonly clears, resulting in a bull’s-eye appearance. Secondary EM lesions may appear. Other common acute symptoms include fever, headache, and fatigue. Myalgias, arthralgias, and mild meningeal signs may occur. EM is diagnostic for Lyme disease in patients at epidemiologic risk, but its absence does not exclude this diagnosis. Laboratory confirmation is recommended for patients with EM with no known exposure or for patients with nonspecific signs and symptoms of Lyme disease.

Late symptoms are typically manifested by musculoskeletal, cardiovascular, or nervous system signs and symptoms. Chronic, intermittent arthritis affecting one or a few large joints is a common manifestation of late, chronic infection and may occur weeks to years after acute infection. The knee is commonly involved. Progressive arthritis or symmetric polyarthritis is not typical and should prompt consideration or another diagnosis. Nonspecific findings include arthralgias or myalgias.

Laboratory Findings

Culture: Not widely available and usually positive only early during the acute infection.

Serology: Not helpful or necessary at the early, acute stage; tests are only 40–60% sensitive, and diagnosis is not ruled out by a negative test. Testing should be ordered only to support clinical diagnosis, not for screening persons with nonspecific symptoms because of their intrinsic poor sensitivity and specificity. Vaccination produces seropositivity. See Chapter 17, Infectious Disease Assays for details of serologic testing for B. burgdorferi infection.

A negative EIA or IFA result usually excludes Lyme disease, but testing paired acute- and convalescent-phase serum samples may be needed for patients with a high index of suspicion and negative results of initial testing. Patients with disseminated or chronic Lyme disease are usually strongly positive for specific anti-B. burgdorferi IgG.

Specific IgM antibodies usually appear 2–4 weeks after EM and peak after 3–6 weeks of illness. IgM usually declines to undetectable levels after 4–6 months. In some patients, IgM remains elevated for many months or reappears late in illness, indicating continued infection. A negative test within 2 weeks of onset of symptoms does not rule out infection.

Specific IgG titers rise more slowly, usually appearing 4–8 weeks after rash. IgG titers peak after 4–6 months and may remain high for months or years, even with successful antibiotic therapy. A single increased IgG titer may be due to previous infection or vaccination and must be interpreted in the context of clinical symptoms. An IgG titer ≥1:800 usually indicates active infection; a titer of 1:200 to 1:400 is indeterminate. Titers <1:100 are considered negative.

Paired acute and convalescent sera at 4- to 6-week intervals may demonstrate a significant rise in titer, indicating active infection. Testing of paired serum samples may be needed to confirm infection in patients with compatible symptoms, but without a known tick bite or rash, who have been in endemic area.

RF may cause false-positive result for IgM. False-positive IgG in high titers may be caused by antibodies from spirochetal diseases (syphilis, relapsing fever, yaws, pinta); low titers may be found in infectious mononucleosis, hepatitis B, autoimmune diseases (e.g., SLE, RA), periodontal disease, ehrlichiosis, rickettsiosis, other bacteria (e.g., H. pylori). Five percent to fifteen percent of persons in endemic areas may be seropositive without any signs or symptoms of active infection.

Western blot assays: Used to confirm initial serologic testing with EIA or IFA. IgG WB assays may not become positive until after many months of illness; negative WB should be repeated in 2–4 weeks if Lyme disease is strongly suspected.

Molecular tests: PCR plays a limited role in the diagnosis of Lyme disease and is not recommended in seronegative patients. PCR may be positive for CSF in acute lymphocytic meningitis (not encephalomyelitis or other neurologic syndrome) or for synovial fluid of joints with active disease. PCR is not reliable for other types of specimens.

Synovial fluid of affected joints: Shows mild to moderate increased WBCs, typically with granulocyte predominance.

CSF findings: Patients with Lyme encephalomyelitis show lymphocytic pleocytosis, slightly increased protein and globulin, and normal glucose. Oligoclonal bands may be demonstrated. Intrathecal antibody production may be demonstrated by higher titer in CSF than in serum. Almost all of these patients will have positive serum serologic tests.

Core laboratory: Findings related to dysfunction of infected organs may be seen. Nonspecific laboratory findings include increase of ESR, lymphopenia, cryoglobulinemia, and increase of hepatic enzymes. Treponemal tests for syphilis may be positive, but nontreponemal tests should be nonreactive.

MYCOPLASMA PNEUMONIAE AND UREAPLASMA UREALYTICUM INFECTIONS

Definition

Mycoplasma and Ureaplasma species are cell wall–deficient organisms. Cells are surrounded by a trilayer cell membrane. They are the smallest free-living human pathogens.

Who Should Be Suspected?

Mycoplasma pneumoniae is a significant cause of community-acquired pneumonia, typically presenting with upper respiratory tract symptoms and tracheobronchitis. Extrapulmonary symptoms are presumably caused by an autoimmune response to primary pulmonary infection. Extrapulmonary manifestations include arthritis, hemolytic anemia, and neurologic diseases (meningoencephalitis, cranial nerve palsy, ascending paralysis, transverse myelitis).

Ureaplasma urealyticum may be detected in the microflora of genital mucosa in healthy adults, but there is evidence to link U. urealyticum to genital tract and neonatal infections. Infections include epididymitis, neonatal infections (pneumonia, bacteremia), nongonococcal urethritis, and orchitis.

Laboratory Findings

Direct detection: Because of the lack of a rigid cell wall, M. pneumoniae and U. urealyticum do not stain with Gram stain. A DNA stain, like acridine orange, may demonstrate organisms in infected tissue.

Culture: Culture of the organism from sputum, nasopharynx, or other infected specimen shows good sensitivity but requires special culture techniques that are not widely available.

Molecular diagnostic testing: An FDA-approved assay is available for M. pneumoniae.

Serology: Serologic assays have been described for both M. pneumoniae and U. urealyticum. EIA methods are most widely used and provide good sensitivity and specificity. Accurate detection may require testing of both acute and convalescent specimens, especially in adults. EIA methods have been adapted for the detection of specific IgM.

IgM increases in the first week, peaks in the 3rd to 5th week, begins to decrease in 4–6 months but may persist ≤1 year; the interpretation of acute infection based on a positive IgM reaction, therefore, must be made with caution. The presence of IgM (>1:64) or a fourfold rise in IgG titer indicates recent infection. IgG peaks approximately 5 weeks after acute infection. IgG is unusual in the first week of infection, so repeat testing of convalescent serum is recommended. IgG titers increase for several years after acute infection.

Core laboratory: Patients may show nonspecific signs of inflammation (mildly elevated WBCs, increased ESR) on routine laboratory testing. Cold agglutinins (agglutination of type O, Rh-negative RBCs at 4°C) may be seen in approximately 50% of patients with M. pneumoniae infection. Cold agglutinins, however, are not specific, and this test is not recommended for diagnosis of M. pneumoniae infection.

NEISSERIA GONORRHOEAE INFECTION

Definition

Neisseria gonorrhoeae isolates are moderately fastidious gram-negative cocci that typically form pairs with characteristic “coffee bean” morphology. Diseases caused by N. gonorrhoeae are almost exclusively transmitted by sexual contact or exposure to infected genital secretions. Neisseria gonorrhoeae is never considered normal flora; isolates are always considered to represent infection.

Who Should Be Suspected?

Gonorrhea is an STD of adults. Infection in neonates may be acquired by exposure to contaminated secretions during childbirth. Infections in other prepubertal children must be investigated as a possible indication of child abuse.

Males with gonorrhea most commonly present with urethritis, manifested by dysuria and urethral discharge. In the absence of specific antimicrobial therapy, spontaneous resolution is common. Complications include “ascending” infection (epididymitis and seminal vesiculitis, regional adenitis, abscess formation, and urethral stricture) and distant infection by contaminated secretions (e.g., conjunctivitis).

Anorectal and pharyngeal gonorrhea may occur in men who have sex with men. Anorectal infections may be asymptomatic but often present with proctitis or rectal pain with purulent discharge and painful defecation. Pharyngeal infection may be asymptomatic but usually occurs as an acute, suppurative pharyngitis with regional adenopathy.

Most women with N. gonorrhoeae infection present with cervical and urethral infection. Symptoms include vaginal and urethral discharge, pelvic pain, and abnormal vaginal bleeding. Adjacent structures, like Bartholin glands, may become infected by local spread. Ascending infection, resulting in pelvic inflammatory disease (PID) (e.g., salpingitis, endometritis, tuboovarian abscess, perihepatitis), occurs in 10–20% of patients. Anorectal infection in women is most commonly acquired by autoinfection by infected vaginal secretions. PID increases the risk of sterility and tubal pregnancy. N. gonorrhoeae infection during pregnancy may result in premature delivery or spontaneous abortion, chorioamnionitis, and transmission of infection (conjunctival or pharyngeal) to the neonate.

Laboratory Findings

Direct detection: Gonorrhea may be diagnosed accurately by Gram stain of urethral secretions from symptomatic males. The detection of typical gram-negative diplococci within PMNs is diagnostic (S/S of approximately 95%). Gram stain examination of endocervical secretions may support a diagnosis of gonorrheal cervical or anorectal infection if many intracellular gram-negative diplococci are seen (sensitivity approximately 50%), but smears must be interpreted with caution because of the presence of nonpathogenic gram-negative organisms in the endogenous flora of these sites.

Culture: The gold standard for diagnosis of nongenital N. gonorrhoeae infections. Swabs of secretions of anal crypts should be submitted for diagnosis of anorectal gonorrhea; rectal swabs (heavily contaminated with feces) should not be submitted. Cultures are required for other types of specimens and for medicolegal specimens (e.g., child abuse, rape).

Molecular diagnosis: Considered the gold standard for diagnosis of N. gonorrhoeae genital infection. Several advantages of nucleic acid testing include the ability to detect nonviable organisms and increased sensitivity, allowing diagnostic testing on urine specimens. Tests with S/S >98% are available, depending on the assay and specimen type.

NEISSERIA MENINGITIDIS INFECTION

Definition

Neisseria meningitidis is a moderately fastidious gram-negative diplococcus with characteristic “coffee bean” morphology. Neisseria meningitidis may be isolated as components of the endogenous respiratory flora of healthy individuals. In meningococcal disease, infection is usually transmitted by the respiratory route. In susceptible patients, bacteremia may occur by passage of organisms across the epithelial barrier. Infection in multiple organ systems is common in meningococcal disease.

Who Should Be Suspected?

Common infectious syndromes include the following:

Meningococcemia: Meningococcemia may result in sustained bacteremia and seeding of various organ systems. Sustained bacteremia is typically associated with fever, malaise, and leukocytosis. Fulminant disease is usually associated by seeding of the CNS and other organs, DIC, adrenal insufficiency, and multiorgan failure. Meningitis should be actively ruled out by clinical and laboratory evaluation in patients in whom meningococcemia is documented.

CNS infection (meningitis and meningoencephalitis):

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