Current Diagnosis & Treatment in Infectious Diseases

Section V - Bacterial Infections

56. Haemophilus, Bordetella, & Branhamella Species

Joseph W. St. Geme III MD

HAEMOPHILUS INFLUENZAE & OTHER HAEMOPHILUS SPECIES

Essentials of Diagnosis

  • Haemophilus influenzaeis generally acquired via the aerosol route or by direct contact with respiratory secretions.
  • The most common associated syndromes include otitis media, sinusitis, conjunctivitis, bronchitis, pneumonia, and, to a lesser extent, meningitis, epiglottitis, arthritis, and cellulitis.
  • Gram stain shows pleomorphic gram-negative coccobacilli.
  • In cases of meningitis, epiglottitis, arthritis, and cellulitis, organisms are typically recovered from blood, and type-b polysaccharide capsular material may be detected in the urine.
  • Organisms and type-b polysaccharide capsule may also be present in other appropriate sterile body fluids, such as cerebrospinal fluid (CSF) in meningitis and joint fluid in arthritis.

General Considerations

  1. Epidemiology.Before 1990, strains of Haemophilus influenzaetype b were found in the upper respiratory tract of 3–5% of children and a small percentage of adults. Colonization rates with type-b strains are even lower now, reflecting routine immunization of infants against H influenzae type b. Non–type-b encapsulated H influenzae are present in the nasopharynx of < 2% of individuals, whereas nonencapsulated (nontypable [see below]) strains colonize the respiratory tract of 40–80% of children and adults.

Historically, H influenzae type b was the leading cause of bacterial meningitis and epiglottitis in children < 5 years old and a major cause of septic arthritis, pneumonia, pericarditis, and facial cellulitis in this same age group. In the United States, ~ 1 in 200 children experienced invasive (bacteremic) disease with this organism before the age of 5 years, with a peak incidence of disease at 6–7 months of age. Invasive disease was more frequent in boys, children of African descent, Alaskan Eskimos, Apache and Navajo Indians, child care center attendees, and children living in overcrowded conditions. Other factors predisposing to invasive disease included sickle cell disease, asplenia, human immunodeficiency virus (HIV) infection, certain immunodeficiency syndromes, and malignancies. The introduction of efficacious vaccines and their routine use in infants, beginning in 1991, resulted in a marked decrease in the incidence of H influenzae type-b infections, which now are quite rare. The Immunization Practices Advisory Committee of the Centers for Disease Control and Prevention and the Committee on Infectious Diseases of the American Academy of Pediatrics currently recommend administration of a licensed conjugate vaccine to all children starting at 2 months of age. Invasive disease in this country now occurs primarily in undervaccinated children.

Nonencapsulated strains of H influenzae are a common cause of localized respiratory tract disease in both children and adults. In children, these organisms are the most common cause of purulent conjunctivitis, the second most common cause of otitis media (after Streptococcus pneumoniae), and a frequent cause of sinusitis. Among children in developing countries, they are a frequent cause of pneumonia and an important source of mortality. In adults they are especially common as a cause of community-acquired pneumonia and exacerbations of underlying lung disease and also account for ~ 30% of cases of otitis media and sinusitis. Beyond producing localized disease, nontypable H influenzae is an occasional cause of serious systemic disease, such as sepsis, meningitis, and pyogenic arthritis, particularly in neonates and individuals with compromised immunity.

In the mid-1980s, H influenzae biogroup aegyptius was recognized as the etiology of Brazilian purpuric fever (BPF), a septicemic illness occurring in young children and associated with a case fatality rate of ~ 60%. In most cases, disease is preceded by purulent conjunctivitis. Both epidemics and sporadic cases have been reported, primarily in the neighboring Brazilian states of Sao Paulo and Parana and in the more distant state of Mato Grosso. Almost all cases of BPF occurring in Brazil have been caused by the same bacterial clone, referred to as the BPF clone.

Disease resulting from non–type-b encapsulated H influenzae occurs on occasion and is most common in patients living in underdeveloped countries. For example, among children in Papua, New Guinea, ~ 25% of H influenzae isolates associated with acute lower respiratory tract infection and roughly 15% of H influenzae isolates recovered from CSF are non–type-b encapsulated strains. In the United States, as the incidence of invasive disease from H influenzae type b has declined, serotype f strains have grown in importance as an etiology of H influenzae sepsis, meningitis, and pneumonia.

H ducreyi is the causative agent of chancroid, a sexually transmitted disease characterized by genital ulceration and inguinal lymphadenitis. Chancroid is a common cause of genital ulcers in developing countries. In contrast, it is relatively uncommon in the United States. Nevertheless, a number of large outbreaks have been identified in the United States since 1981. After a peak of 5000 cases in 1988 and a gradual decline since then, 243 cases of chancroid were reported in 1997 in the United States. These outbreaks have generally resulted from prostitution and its relationship to illicit drug use. Most cases have involved heterosexual transmission, and affected individuals have been primarily black or Hispanic. There is recent evidence that chancroid, like other forms of genital ulcer disease, is an important cofactor in the transmission of HIV. In addition, as many as 10% of patients with chancroid may be coinfected with Treponema pallidum or herpes simplex virus.

Haemophilus spp. other than H influenzae and H ducreyi are members of the normal flora in the upper respiratory tract and occasionally the genital area. These organisms have been reported in association with a number of local and systemic infections. Together, H parainfluenzae, H aphrophilus, and H paraphrophilus account for ~ 5% of cases of infective endocarditis.

  1. Microbiology.H influenzaeis a nonmotile, non–spore-forming, gram-negative bacterium. Microscopic examination reveals pleomorphic coccobacilli with an average size of 1 × 0.3 µm. H influenzae is capable of growing both aerobically and anaerobically. It requires supplements known as factors X and V under aerobic conditions and factor X alone in an anaerobic environment. These factors have not been precisely identified. Factor X can be supplied by heat-stable, iron-containing pigments, including hemin and hemoglobin, whereas factor V can be supplied by nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADP), or nicotinamide nucleoside. Factor V is pres-ent in red blood cells but must be released to support growth. Consequently, growth media such as Fildes, which contains erythrocytes that have been disrupted by peptic digestion, and chocolate agar, which contains 1% hemoglobin, are required for optimal growth. Incubation in the presence of 5–10% carbon dioxide facilitates primary isolation of some strains.

Isolates of H influenzae are classified by their polysaccharide capsule, with six known capsular types (serotypes a–f). In addition, strains can be nonencapsulated; these strains are defined by their failure to react with typing antisera against capsular serotypes a–f and are referred to as nontypable. Based on the results of biochemical reactions that determine the production of indole and the presence of ornithine decarboxylase and urease, isolates can be separated into eight different subgroups called biotypes. Most type-b isolates are biotype I, whereas nontypable strains are usually biotype II or III. Clinical isolates that are biotypes IV through VIII are relatively uncommon and are almost always nontypable. In recent years, the use of multilocus enzyme electrophoresis has demonstrated that the population structure of H influenzae is clonal and that most nontypable strains are not recent capsule-deficient variants of extant encapsulated clones. Nontypable strains are genetically distinct and are more heterogeneous than encapsulated H influenzae.

H influenzae biogroup aegyptius represents a distinct subgroup of H influenzae biotype III with a predilection for causing purulent conjunctivitis. Historically, this organism was referred to as H aegyptius and was considered distinct from H influenzae. However, no single phenotypic characteristic consistently distinguishes one organism from the other. Moreover, DNA hybridization studies indicate that these two organisms belong to the same species. To account for the fact that these organisms cannot be phylogenetically separated but appear to differ clinically, the name H influenzae biogroup aegyptius has been used instead of H aegyptius.

H ducreyi also has fastidious growth requirements, including a need for factor X, thus resulting in placement in the genus Haemophilus. However, recent studies of DNA homology and ribosomal RNA gene sequences indicate major differences between H ducreyi and other Haemophilus species.

A variety of other Haemophilus species have occasionally been implicated in human disease, including H parainfluenzae, H aphrophilus, H paraphrophilus, H haemolyticus, H parahaemolyticus, and H segnis. Like H influenzae and H ducreyi, these species are small, pleomorphic, gram-negative coccobacilli. Growth requirements include factor X, factor V, or both (Table 56-1). For some species, growth requires incubation in the presence of carbon dioxide.

  1. Pathogenesis.H influenzaeis transmitted by airborne droplets or by direct contact with respiratory tract secretions. Colonization with a particular strain can persist for weeks to months, and most individuals remain asymptomatic throughout this period. A variety of bacterial factors appear to influence the process of respiratory tract colonization. The lipid A component of H influenzae lipopolysaccharide (also called lipo-oligosaccharide) and possibly low-molecular-weight glycopeptides cause ciliostasis and thereby interfere with mucociliary clearance. In addition, both pilus and nonpilus adherence factors facilitate direct bacterial binding to respiratory epithelium. Like several other mucosal pathogens, H influenzae produces an immunoglobulin A1 (IgA1) protease, an enzyme that cleaves human IgA1 and likely facilitates evasion of the local immune response. Bacterial antigenic variation may also promote evasion of local immunity.

Table 56-1. Differential characteristics of Haemophilus species associated with human disease.

 

Growth Factor Requirement

Organism

X

V

Hemolysis

Catalase

CO2 Dependence

H influenzae

+

+

-

+

-

H parainfluenzae1

-

+

-

±

-

H aphrophilus

+

-

-

-

+

H paraphrophilus1

-

+

-

±

+

H haemolyticus

+

+

+

+

-

H parahaemolyticus

-

+

+

+

-

H segnis1

-

+

-

±

-

H ducreyi

+

-

+

-

+

1Differentiation of H parainfluenzaeH paraphrophilus, and H segnis is facilitated by assessment of lactose and mannose fermentation. H paraphrophilus ferments both lactose and mannose, H parainfluenzae ferments mannose alone, and H segnis ferments neither

In certain circumstances, colonization is followed by contiguous spread within the respiratory tract, resulting in local disease in the middle ear, sinuses, conjunctiva, or lungs. Anatomic factors, deficiencies in local immune function, viral respiratory infection, exposure to cigarette smoke, and allergies predispose to localized respiratory tract disease. On occasion, bacteria penetrate the nasopharyngeal epithelial barrier and enter the bloodstream. The determinants of this event remain poorly defined but may include bacterial lipo-oligosaccharide. In most cases, bacteremia probably is transient. However, in nonimmune hosts, intravascular bacteria, especially those that express the type-b capsule, are sometimes able to survive, replicate, and disseminate to distant sites. In the absence of specific antibody, the type-b polysaccharide capsule promotes resistance to serum bactericidal activity and to phagocytosis.

The pathogenesis of disease caused by H ducreyi begins with intradermal inoculation, generally during sexual intercourse. Although the mechanisms of virulence remain poorly defined, several putative virulence factors have recently been identified and characterized. Most isolates express fine flexible pili, which by analogy with other pathogens may be important in initiating infection. More recent data indicate that H ducreyi lipo-oligosaccharide is important for adherence to keratinocytes and is capable of causing ulcers in rabbits and mice. In addition, H ducreyi elaborates at least two toxins, including a cell-associated cytotoxin that kills cultured human foreskin fibroblasts and a secreted toxin that kills epithelial cells (cytolethal distending toxin). Both toxins presumably contribute to the pathology associated with chancroid. H ducreyi also expresses a protein that confers resistance to serum killing.

CLINICAL SYNDROMES

H influenzae was first isolated during the 1892 influenza pandemic and was originally believed to be the causative agent of influenza. Although subsequent studies revealed the fallacy of this idea, H influenzae has proved to be a common cause of localized respiratory tract and systemic disease, including meningitis, epiglottitis, pneumonia, pyogenic arthritis, cellulitis, otitis media, and sinusitis, among others (Box 56-1).

  1. MENINGITIS

Meningitis is the most common and serious form of invasive H influenzae type-b disease. In the mid-1980s, before the introduction of effective vaccines, ~ 10,000–12,000 cases of H influenzae type-b meningitis occurred in the United States each year, and 95% of cases involved children < 5 years old. Nowadays, there are < 200 cases/year, with most episodes occurring after 5 years of age.

Clinical Findings

  1. Signs and Symptoms.Symptoms usually include fever, irritability, lethargy, and vomiting. Antecedent symptoms of an upper respiratory infection are common. Occasionally, the course is fulminant, with rapid neurologic deterioration leading to respiratory arrest. Shock is present in 20% of cases of meningitis and can be associated with coagulopathy and purpura.
  1. Laboratory Findings.Bacteria can almost always be recovered from CSF. In roughly 70% of patients with H influenzaemeningitis, Gram stain of the CSF is positive for gram-negative coccobacilli. In cases of culture-proven meningitis, capsular antigen can be detected ~ 90% of the time in CSF and even more frequently in concentrated urine. False-positive reactions are uncommon, but occasionally occur owing to cross-reactivity with E coli, S pneumoniae, Staphylococcus spp., or Neisseria meningitidis.
  2. Complications.Complications of H influenzaetype-b meningitis include subdural effusion or empyema, ischemic or hemorrhagic cortical infarction, cerebritis, ventriculitis, intracerebral abscess, and hydrocephalus. The overall mortality rate is ~ 5%. Among survivors, between 5% and 10% have permanent sensorineural hearing loss, and ~ 30% have some other significant handicap. Tests for more subtle neurologic deficits reveal sequelae in up to one-half of survivors. Meningitis caused by nontypable H influenzae is usually associated with sinusitis, otitis media, or an anatomic communication between the upper respiratory tract and the central nervous system, and results from direct extension from the contiguous focus of infection.

BOX 56-1 Clinical Manifestations of H influenzae Disease1

Disease

Signs and Symptoms

Meningitis

· Irritability

· Lethargy

· Photophobia

· Stiff neck

Epiglottitis

· Sore throat

· Dysphagia

· Dyspnea

· Drooling

Pyogenic Arthritis

· Joint pain

· Swelling

· Decreased range of motion

Cellulitis

· Skin erythema (sometimes with violaceous hue)

· Warmth

· Tenderness

Otitis Media

· Ear pain

· Bulging tympanic membrane with distorted landmarks and decreased mobility

Sinusitis

· Nasal discharge

· Fever

· Cough

· Headache

· Facial tenderness

Pneumonia

· Cough

· Tachypnea

· Crackles on auscultation

Exacerbation of Lung Disease

· Increased dyspnea

· Sputum production

· Sputum purulence

1For all H influenzae diseases, fever is a prominent sign.

  1. EPIGLOTTITIS

Epiglottitis is a life-threatening infection involving cellulitis of the epiglottis and the aryepiglottic folds. Complete obliteration of the vallecular and pyriform sinuses is typical, and acute airway obstruction can occur.

Clinical Findings

  1. Signs and Symptoms.Symptoms are often sudden in onset and usually include high fever, sore throat, and dyspnea, with rapid progression to dysphagia, pooling of secretions, and drooling. In children < 2 years old, fever may be low grade, dysphagia and drooling may be minimal, and a croup-like cough may be present. Regardless of age, the patient is usually restless and anxious and adopts a sitting position with the neck extended and the chin protruding to reduce airway obstruction. Abrupt deterioration can occur within a few hours, resulting in death unless an artificial airway is established.
  2. Laboratory Findings.Cultures of the epiglottis usually are positive but should be obtained only after establishment of an artificial airway.
  3. Imaging.Direct laryngoscopy at the time of controlled placement of an endotracheal tube reveals a red and swollen epiglottis and swollen aryepiglottic folds. On lateral neck radiograph, the swollen epiglottis produces the “thumb sign.”
  4. PNEUMONIA

Clinical Findings

  1. Signs and Symptoms.Generally, H influenzae pneumonia is more insidious in onset than is pneumonia caused by Staphylococcus aureus or Streptococcus pneumoniae. Productive cough, fever, pleuritic chest pain, and dyspnea dominate the clinical presentation.
  1. Imaging.Pneumonia caused by H influenzaeis usually associated with a consolidative pulmonary infiltrate. In 50% of cases caused by H influenzae type b, there is evidence of pleural involvement on initial chest radiograph, and up to 90% of these patients have pleural fluid recoverable by thoracentesis.
  2. Complications.An important complication is contiguous spread to the pericardium, resulting in purulent pericarditis, which is manifest by severe dyspnea (grunting in infants), tachycardia, and cardiac failure. Although patients with H influenzaetype-b pneumonia often have persistent pleural reaction with secondary restrictive lung function at the time of hospital discharge, long-term abnormalities are rare.
  3. PYOGENIC ARTHRITIS

In the pre-Haemophilus vaccine era, H influenzae type b was the most common cause of pyogenic arthritis in children < 2 years of age.

Clinical Findings

In most cases a single large, weight-bearing joint (hip, knee, or ankle) is involved, and in 10–20% of patients, contiguous osteomyelitis develops. Response to systemic antibiotics in combination with prompt drainage of the joint is dramatic, but long-term follow-up is important because residual joint dysfunction can occur. On occasion, culture-negative arthritis develops during treatment of H influenzae type-b meningitis, presumably as a result of immune complex deposition in the joint. In 75% of patients with reactive arthritis, signs of joint inflammation begin after a week or more of therapy.

  1. CELLULITIS

Cellulitis is the result of metastatic spread of blood-borne H influenzae type b.

Clinical Findings

  1. Signs and Symptoms.Typically, the patient presents with fever and a warm, tender area of erythema or violaceous discoloration on the cheek or in the periorbital area. Cheek (buccal) cellulitis invariably occurs in children < 1 year of age. The age of the child, the location of the cellulitis, and the occasional distinctive violaceous color should suggest the etiology.
  2. Laboratory Findings.Aspirate cultures, either from the center of the lesion or the leading edge, usually yield the organism.
  3. Complications.Related to the fact that bacteremia is generally present, ~ 10% of children develop another focus of infection, for example, meningitis. H influenzaeis not associated with cellulitis that occurs as a complication of trauma to the skin.
  4. OTITIS MEDIA

Among H influenzae isolates from patients with acute otitis media, > 90% are nontypable. Based on studies reported from the United States and Scandinavia, the peak age-specific incidence of H influenzae acute otitis media is between 6 and 15 months.

Clinical Findings

Characteristic manifestations include ear pain, fever, irritability, sleep disturbance, and otorrhea. On examination, the tympanic membrane is usually red or yellow and bulging with distorted landmarks. Pneumatic otoscopy reveals decreased mobility, indicative of middle ear fluid.

In addition to producing acute otitis media, nontypable H influenzae is the most common bacterial etiology of otitis media with effusion, which is typically asymptomatic and is characterized by a minimally discolored and often retracted tympanic membrane. Nontypable H influenzae is also associated with dual infection of the conjunctiva and the middle ear, referred to as the “conjunctivitis-otitis syndrome.”

  1. SINUSITIS

H influenzae accounts for ~ 30% of all cases of acute sinusitis. The majority of patients with sinusitis have nasal discharge or cough that persists without improvement for > 10 days. Other patients present acutely with high fever and purulent nasal discharge. Physical examination often reveals tenderness over the involved paranasal sinuses.

  1. EXACERBATIONS OF UNDERLYING LUNG DISEASE

Because sputum frequently is contaminated by pharyngeal bacterial flora, the interpretation of H influenzae growth from sputum cultures is difficult. Nevertheless, there is reasonable evidence that H influenzae plays a role in exacerbations of chronic bronchitis, bronchiectasis, and cystic fibrosis. Most isolates in these patients are nontypable. The clinical presentation is characterized by increases in dyspnea, sputum production, and sputum purulence, sometimes associated with fever.

  1. NEONATAL SEPSIS

During the past 2 decades, nontypable H influenzae has become recognized as a cause of early onset neonatal sepsis similar to that caused by group B streptococcus. Disease occurs primarily in premature neonates and is associated with a mortality rate of nearly 50%.

Clinical Findings

  1. Signs and Symptoms.Most infants develop symptoms within the first few hours of life, with pneumonia and respiratory distress dominating the clinical presentation. Meningitis occurs infrequently.
  2. Laboratory Findings.H influenzaeusually can be cultured from the genitourinary tract of mothers of infected infants, often in association with maternal postpartum endometritis. At least one study indicates that a large percentage of these isolates are biotype IV, a subgroup of nontypable H influenzaefound uncommonly at other sites of infection. Genotypic analysis of these biotype IV strains suggests that they represent a distinct Haemophilus species.
  3. BRAZILIAN PURPURIC FEVER

Clinical Findings

  1. Signs and Symptoms.Brazilian purpuric fever is characterized by high fever, abdominal pain, and vomiting. In most patients, purpura and vascular collapse develop within 12 h of fever onset. Patients range in age between 3 months and 10 years, and ~ 90% have a recent history of conjunctivitis, which in most cases begins 1–2 weeks before the onset of fever.
  2. Laboratory Findings.Aside from blood cultures, laboratory studies are nonspecific. Leukocyte counts are often elevated, with a preponderance of neutrophils and band forms, and thrombocytopenia and prolonged coagulation times are also seen.
  3. CHANCROID

Clinical Findings

  1. Signs and Symptoms.Chancroid usually begins with a papule on the genitalia that develops after an incubation period of 4–7 days. The papule is typically surrounded by erythema and evolves over 2–3 days to a pustule, which spontaneously ruptures to form a sharply circumscribed ulcer. The ulcer is characterized by tenderness and a tendency to bleed. The surrounding skin generally lacks evidence of inflammation. Roughly 50% of patients develop inflamed inguinal lymph nodes, which often become fluctuant and rupture spontaneously. On occasion, chancroid presents with multiple ulcers that coalesce. In addition, ulcers can appear and then resolve spontaneously, with the development of suppurative inguinal adenitis 1–3 weeks later.

Table 56-2. Clues to the laboratory diagnosis of H influenzae, B pertussis, and B catarrhalis disease.

 

H influenzae

B pertussis

B catarrhalis

Morphology

Pleomorphic, gram-negative coccobacilli

Small, gram-negative coccobacilli or rods

Kidney-shaped, gram-negative diplococci

Cultivation

Fildes or chocolate agar

Regan-Lowe, Bordet-Gengou, or others

Blood or chocolate agar

Other diagnostics

Assay for type-b antigen in sterile body fluids

Direct immunofluorescence or polymerase chain reaction assay

None

Serology

Available, generally not useful

Moderately useful

Not available

  1. Laboratory Findings.Gram stain of material obtained by swabbing a lesion can show gram-negative bacteria in a “school of fish” configuration.

Diagnosis

Consideration of the diagnosis of meningitis, epiglottitis, pneumonia, pyogenic arthritis, or cellulitis is usually prompted by the history and physical examination (Table 56-2). In most cases of invasive H influenzae type-b disease, blood cultures are positive. H influenzae is often cultivated from samples of pleural fluid, joint fluid, or pericardial fluid in affected patients.

The type-b capsular polysaccharide is secreted during bacterial growth, and detection of capsular antigen in serum, CSF, urine, and other normally sterile body fluids can help establish the diagnosis. Antigen detection techniques are most valuable in patients who have received prior antibiotic therapy and have sterile cultures. In addition, they may be useful in confirming a diagnosis before bacterial growth is appreciated in the clinical laboratory, thus allowing for earlier chemoprophylaxis of contacts (see below). Of note, H influenzae type-b conjugate vaccines can produce positive reactions in urine and CSF for days to weeks after vaccination.

Because H influenzae is a common commensal organism in the upper respiratory tract, establishing H influenzae as an etiology of localized respiratory tract disease is challenging. Procedures such as tympanocentesis, sinus aspiration, tracheal or lung aspiration, bronchoscopy, and bronchoalveolar lavage can provide a definitive diagnosis, but generally are reserved for patients with persistent or recurrent infection or an underlying immunodeficiency. Several studies have examined the predictive value of surface cultures of the nose, throat, or nasopharynx in patients with acute or chronic sinusitis. Although the organisms isolated from direct aspiration of infected sinuses are generally recovered from surface cultures, they are not consistently the predominant organisms. As a result, surface cultures are of minimal value in establishing an etiologic diagnosis; nevertheless, they may be useful to exclude a particular cause.

In patients with chancroid, an accurate diagnosis relies on cultivation of H ducreyi from the lesion. Selective and supplemental media are necessary for isolation. Although a variety of media have been used, the highest rates of recovery from clinical samples have been obtained with chocolate agar containing Isovitale X and 3 µg/mL of vancomycin; GC agar base containing 1–2% hemoglobin, 5% fetal bovine serum, and 3 µg/mL of vancomycin; and Mueller-Hinton agar supplemented with horse blood, Isovitale X, and vancomycin. For optimal recovery, cultures are incubated at 33°C in a humid CO2-enriched environment. Colonies are of pinpoint size at 24 h and increase to 1–2 mm in diameter at 48 h.

In blood culture, Haemophilus species other than H influenzae and H ducreyi have a tendency to grow in small colonies along the sides of the bottle or in the red blood cell mass, leaving the broth clear. As a result, recovery of these organisms from the blood of patients with endocarditis is enhanced by routine subculture of blood cultures to chocolate agar, use of a biphasic system, or use of a system that detects growth radiometrically.

BOX 56-2 Treatment of H influenzae Systemic Disease

 

Medication

Children

Adults

First Choice

· Cefotaxime or

· Ceftriaxone

· 150–200 mg/kg/d divided every 8 h

· 50–100 mg/kg/d divided every 12 h

· 1–2 g every 4–8 h

· 2 g every 12 h

Second Choice

· Ampicillin, if susceptible, or

· Chloramphenicol if susceptible

· 200–400 mg/kg/d divided every 6 h

· 75–100 mg/kg/d divided every 6 h (ad- justed according to serum levels)

· 200–400 mg/kg/d divided every 6 h

· 50–100 mg/kg/d divided every 6 h (adjusted according to serum levels)

Adjunctive Therapy (for Meningitis)

· Dexamethasone

· 0.6 mg/kg/d divided every 6 h for 4 d or

· 0.8 mg/kg/d divided every 12 h for 2 d

· 0.6 mg/kg/d divided every 6 h for 4 d or

· 0.8 mg/kg/d divided every 12 h for 2 d

Treatment

Empiric therapy for invasive disease caused by H influenzae generally includes either a third-generation cephalosporin, such as cefotaxime or ceftriaxone, or the combination of ampicillin and chloramphenicol (Box 56-2). In the United States, ~ 30% of H influenzae isolates are resistant to ampicillin, and thus ampicillin should never be used alone as empiric therapy. Ampicillin resistance usually is related to plasmid-mediated production of β-lactamase, but occasionally is caused by decreased affinity of certain penicillin-binding proteins. To distinguish one form of resistance from the other, both disk susceptibility testing and a β-lactamase assay should be performed. Chloramphenicol is bactericidal for H influenzae and reliably penetrates into the CSF. Although resistance to chloramphenicol has been reported, it remains rare in the United States, especially among invasive isolates.

In recent years, the third-generation cephalosporins have become the treatment of choice for H influenzae meningitis. Both cefotaxime and ceftriaxone have potent activity against H influenzae (including ampicillin-resistant isolates) and achieve high levels in the CSF. For patients with uncomplicated meningitis, therapy for 7–10 days is adequate. For patients who fail to respond promptly or develop complications, therapy for > 10 days may be necessary. Based on empiric experience, most experts recommend that other invasive infections caused by H influenzae also be treated with an appropriate parenteral antibiotic for 7–10 days.

Among patients with invasive H influenzae disease, antibiotic therapy represents only one component of management. In patients with meningitis, optimal ventilation and judicious fluid administration are important. In addition, dexamethasone should be administered with the first dose or before initiation of antibiotic therapy, whenever possible (without delaying institution of treatment). Dexamethasone serves to diminish production of tumor necrosis factor and other cytokines that contribute to development of cerebral edema and neurologic sequelae. Patients with epiglottitis require placement of an artificial airway, and children with pneumonia often require treatment with supplemental oxygen. When pleural empyema, purulent pericarditis, or pyogenic arthritis is present, prompt drainage is essential to good outcome.

Otitis media, sinusitis, pneumonia, and exacerbations of underlying lung disease are often treated effectively with oral amoxicillin, but amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, an oral second- or third-generation cephalosporin, erythromycin-sulfisoxazole, azithromycin, and clarithromycin are acceptable alternatives (Box 56-3). Historically, treatment of otitis media and sinusitis was continued for 7–14 days, but recent evidence suggests that shorter courses of therapy are equally efficacious. Treatment for 7–10 days is usually adequate for pneumonia and bronchitis.

Several antibiotic regimens are effective in the treatment of chancroid. These include ceftriaxone, 250 mg IM as a single dose, azithromycin, 1 g orally as a single dose, and erythromycin, 500 mg orally four times daily for 7 days. Alternative regimens that have not been evaluated as thoroughly include ciprofloxacin, 500 mg orally twice daily for 3 days, and amoxicillin-clavulanate, 500 mg-125 mg, orally three times daily for 7 days. If therapy is successful, ulcers begin to improve within 3 days and usually resolve after 7 days of treatment. Clinical isolates often have plasmid-mediated resistance to ampicillin, chloramphenicol, tetracyclines, and sulfonamide and may be resistant to other antibiotics as well. Thus, when patients do not respond to treatment promptly, susceptibility testing should be performed. Short courses of therapy may be ineffective in patients with HIV infection.

BOX 56-3 Treatment of H influenzae Localized Respiratory Tract Disease

 

Medication

Children

Adults

First Choice

· Amoxicillin, if susceptible

· 40 mg/kg/d divided into 3 equal doses

· 500 mg three times daily

Second Choice

· Amoxicillin plus clavulanate (Augmentin)

· 40 mg/kg/d divided into 2 or 3 equal doses (amoxicillin component)

· 500 mg three times daily1(amoxicillin component)

· Trimethoprim- sulfamethoxazole (TMP-SMX)

· 8–12 mg TMP/40–60 mg SMX/kg/d divided into 2 equal doses

· 160 mg TMP/800 mg SMX twice daily

· Oral second and third-generation cephalosporins

· Depends on particular agent

· Depends on particular agent

· Erythromycin- sulfisoxazole

· 40 mg/kg/d divided into 3–4 equal doses (erythromycin component)

· 500 mg four times daily (erythromycin component)

· Azithromycin

· 10 mg/kg loading dose, then 5 mg/kg per day

· 500 mg loading dose, then 250 mg per day

· Clarithromycin

· 15 mg/kg/d divided into 2 equal doses

· 500 mg twice daily

1 Both twice daily and three times daily formulations are available.

Traditionally, uncomplicated infections from other Haemophilus species have been treated with ampicillin. Haemophilus endocarditis has been treated with high-dose ampicillin, often in combination with an aminoglycoside. However, resistance to ampicillin, usually related to β-lactamase production, is being recognized with increasing frequency. Consequently, a second- or third-generation cephalosporin (eg, ceftriaxone) should be used until antibiotic susceptibility results are available (see Box 56-2).

Prevention & Control

Antibody to the H influenzae type-b capsule is bactericidal for type-b organisms and confers protection against invasive disease (Box 56-4). Accordingly, the existing vaccines against H influenzae type b contain some derivative of type-b polysaccharide, also called polyribosylribitol phosphate (PRP). To enhance the immunogenicity of these vaccines in young infants, the polysaccharide is conjugated to an immunogenic carrier protein. There are currently four licensed conjugate vaccines, all differing to some extent in the size of the polysaccharide, the chemical linkage between the polysaccharide and the carrier, or the type of protein (see Table 56-3). In addition, these vaccines differ in immunologic characteristics. As a result of differences in immunogenicity, three of the four (HbOC, PRP-T, and PRP-OMP) are licensed for use in infants, and the fourth (PRP-D) is approved only for children ≥ 12 months of age. For HbOC and PRP-T, the primary series of infancy consists of three doses (at 2, 4, and 6 months of age), whereas for PRP-OMP the primary series includes two doses (at 2 and 4 months). In all cases, a booster dose is required between 12 and 15 months of age.

BOX 56-4 Control of H influenzae Infection

Prophylactic Measures

Vaccines are available and effective for type b disease. Chemoprophylaxis:

· Rifampin, 20 mg/kg/d once per day for 4 d; maximum dose 600 mg/d for type b disease

· Amoxicillin, 20 mg/kg/d, OR

· Sulfisoxazole, 50 mg/kg/d for selected patients with recurrent otitis media

Isolation Precautions

· Droplet precautions for first 24 h of treatment for type-b disease

· None for nontypable disease

All four of the conjugate vaccines are well tolerated, with the most common adverse effect being transient redness and swelling at the site of injection. Conjugate vaccines can be administered at the same time as other vaccines, including diphtheria-tetanus–whole-cell pertussis (DTP) or diphtheria-tetanus-acellular pertussis (DTaP), polio, hepatitis B, mumps-measles-rubella (MMR), varicella, pneumococcal vaccines, and meningococcal vaccine, and in some cases have been combined during production with DTP, DTaP, or hepatitis B. Postlicensing studies indicate that the available conjugate vaccines are highly effective against H influenzae type b and have decreased the incidence of invasive H influenzae type-b disease by > 95%; however, these vaccines provide no protection against non–type-b strains.

Table 56-3. Haemophilus influenzae type b conjugate vaccines licensed for use in children.

Vaccine

Trade Name

Polysaccharide

Linkage

Protein carrier

HbOC

HibTITER

Small

None

CRM197 mutant Corynebacterium diphtheriae toxin

PRP-T

ActHIB
OmniHIB

Large

6-Carbon

Tetanus toxoid

PRP-OMP

PedvaxHIB

Medium

Thioether

N meningitidis outer membrane protein complex

PRP-D1

ProHIbiT

Medium

6-Carbon

Diphtheria toxoid

1PRP-D is licensed for children ≥ 12 months old. The other three vaccines are licensed for use in infants.

There are currently no vaccines available for prevention of disease caused by nontypable H influenzae or other Haemophilus species. However, work is underway to identify nontypable H influenzae and H ducreyi antigens that are surface exposed and elicit protective antibody, and several promising candidates exist.

Chemoprophylaxis is another important intervention for preventing invasive disease caused by H influenzae type b. The intent is to eradicate nasopharyngeal colonization and thereby prevent subsequent invasion of the bloodstream in individuals at increased risk for invasive disease. Eradication of colonization will also interrupt transmission to other susceptible hosts. In households with a child < 12 months old, the index case and all members of the household should receive rifampin prophylaxis. The same is true in households with at least one contact < 48 months old who is incompletely immunized against H influenzae type b and in families with a fully immunized but immunocompromised child, regardless of age. When two or more cases of invasive disease occur within a 60-day period among attendees of a child care center and incompletely vaccinated children attend the facility, rifampin is recommended for all attendees and supervisors. Management of a single case at a child care center is controversial and depends on the age and immunization status of attendees and the duration of daily contact between attendees and the index patient. Because most secondary cases in households occur during the first week after hospitalization of the index case, chemoprophylaxis should be initiated as soon as possible.

Chemoprophylaxis is also a consideration in children who have recurrent otitis media caused by nontypable H influenzae (or other typical pathogens). In this situation, chronic prophylaxis with either amoxicillin or sulfisoxazole may be effective in reducing infectious episodes, an effect that must be balanced against the possibility of selecting for resistant organisms. According to a recent report, among patients who develop conjunctivitis caused by the BPF clone of H influenzae biogroup aegyptius, oral rifampin may be effective in preventing BPF.

BORDETELLA SPECIES

Essentials of Diagnosis

  • Key signs and symptoms of whooping cough include sudden attacks of severe, repetitive coughing, the presence of an inspiratory whoop at the end of an episode of coughing, and post-tussive vomiting.
  • Predisposing factors include the lack of adequate immunization with a pertussis vaccine and exposure to an adult with a coughing illness of > 14 days.
  • Bordetella pertussisis acquired by the respiratory route via exposure to aerosol droplets.
  • Definitive diagnosis is established by recovery of organisms from nasopharyngeal mucus or detection of B pertussisantigens by direct immunofluorescent assay of nasopharyngeal secretions.

General Considerations

  1. Epidemiology.Bordetella pertussisis a respiratory pathogen with a tropism for ciliated respiratory epithelial cells and is the usual cause of an acute respiratory infection called pertussis or whooping cough, which was described as far back as 1500. B parapertussis accounts for ~ 5% of cases of pertussis in the United States and typically produces more mild disease. The term pertussis means “intense cough,” reflecting the most striking feature of the illness.

Pertussis is a common disease worldwide, with ~60 million cases and > 500,000 deaths each year. During the prevaccine era in the United States, pertussis was the leading cause of death from a communicable disease among children < 14 years, and in 1945, pertussis caused more deaths in infants in the United States than did diphtheria, polio, measles, and scarlet fever combined. The introduction of a pertussis vaccine in the late 1940s resulted in a more than 100-fold decrease in the incidence of pertussis by 1970. However, in recent years there has been a steady increase in the incidence of disease, with epidemics in a number of states. In 1996, 7796 cases were reported to the Centers for Disease Control and Prevention, representing the highest number since 1967. Of note, it is estimated that only 10% of actual cases are reported.

Pertussis is transmitted person-to-person by the respiratory route and is highly contagious, with attack rates of > 90% in unimmunized populations exposed to aerosol droplets at close range (eg, nonimmune household contacts). Asymptomatic infection has been demonstrated but is considered unlikely to be a major factor in transmission. Adolescents and adults have been recently recognized as a major reservoir for B pertussis and account for nearly 25% of reported cases, usually with mild or atypical symptoms. They are the usual source for infection in infants and children. Patients are most contagious during the first stage of illness, before the onset of paroxysms (see Clinical Findings, below); communicability then diminishes rapidly but may persist for 3 weeks or more after the onset of cough.

Pertussis is endemic, with superimposed periodic outbreaks that usually occur every 3–4 years. The majority of cases are diagnosed between July and October. Approximately 35% of reported cases occur in infants < 6 months, and ~ 60% occur in children < 5 years. Infants born prematurely are at increased risk for severe pertussis, with higher frequencies of hospitalization and death. The incubation period ranges between 6 and 20 days and is usually 7–10 days.

  1. Microbiology.B pertussisis a small, gram-negative organism that grows as coccobacilli or short rods ranging in size from 0.2 × 0.5 µm to 0.5 × 2.0 µm. It is a fastidious obligate aerobe with an optimum growth temperature of 35–37°C. Some evidence suggests that growth is impaired in an environment containing 5 to 10% CO2. A number of substances, including fatty acids, heavy metal ions, sulfides, and peroxides, inhibit growth. Media for primary isolation include Bordet-Gengou, modified Stainer-Scholte, Jones-Kendrick charcoal, and Regan-Lowe charcoal-horse blood agar, which contain substances such as starch, charcoal, ion-exchange resins, or a high percentage of blood to inactivate the inhibitory substances.

 

Other Bordetella species associated with human disease include B parapertussis, B bronchiseptica, B hinzii, and B holmesii (Table 56-4). B pertussis and B parapertussis are obligate human pathogens, whereas B bronchiseptica causes disease predominantly in animals. B hinzii and B holmesii have been recently recognized as rare causes of bacteremia in immunocompromised patients and infect avian or canine hosts as well. All Bordetella species possess DNA with a high mole percent of guanine plus cytosine (66 to 70%). Interestingly, based on DNA hybridization and multilocus enzyme electrophoresis studies, B pertussis, B parapertussis, and B bronchiseptica are not sufficiently diverse to be classified as separate species. Nevertheless, they are associated with distinct clinical syndromes and continue to be considered individual species.

  1. Pathogenesis.B pertussisproduces a number of molecules that have been implicated in the pathogenesis of disease, including filamentous hemagglutinin (FHA), fimbriae (types 2 and 3), pertactin, pertussis toxin, adenylate cyclase toxin, dermonecrotic toxin, tracheal cytotoxin, and lipo-oligosaccharide. Among these factors, all but tracheal cytotoxin and lipo-oligosaccharide are activated by a regulatory locus referred to as the Bordetella virulence gene (Bvg) system. The roles for these factors can be considered in the context of the sequence of events involved in the pathogenesis of disease, namely entry into the host and attachment to a target tissue, persistence in the respiratory tract, and production of local damage. B pertussis does not invade beyond the respiratory mucosa. Thus systemic manifestations presumably result from dissemination of bacterial components, such as pertussis toxin.

FHA, types 2 and 3 fimbriae, pertactin, and pertussis toxin facilitate attachment to respiratory epithelium. Tracheal cytotoxin is derived from the bacterial cell wall and causes ciliostasis and sloughing of ciliated cells, thus allowing the organism to overcome mucociliary clearance. Adenylate cyclase toxin, a pore-forming cytotoxin that belongs to the RTX family, inhibits phagocyte functions, including chemotaxis, phagocytosis, oxidative burst, and bactericidal activity, and presumably enables the organism to evade local immunity. Pertussis toxin also impairs phagocyte functions, including neutrophil chemotaxis and phagocytosis. Tracheal cytotoxin, adenylate cyclase toxin, dermonecrotic toxin, and lipo-oligosaccharide may contribute to local damage to the respiratory mucosa.

Table 56-4. Differential characteristics of Bordetella species associated with human disease.

Organism

Motility

Oxidase

Urease

Utilizes Citrate

Reduces Nitrate

B pertussis

-

+

-

-

-

B parapertussis

-

-

+

+

-

B bronchiseptica

+

+

+

+

+

B hinzii1

+

+

-

+

-

B holmesii1

-

-

-

-

-

1B hinzii and B holmesii have been identified as causes of disease only infrequently.

CLINICAL SYNDROME

Classical pertussis occurs in three clinical stages: catarrhal, paroxysmal, and convalescent (Box 56-5).

Clinical Findings

  1. Signs and Symptoms.The catarrhal stage is characterized by nonspecific upper respiratory symptoms, including rhinorrhea, mild cough, and low-grade fever. During this stage, which typically lasts 1–2 weeks, the disease is highly communicable. The paroxysmal stage is marked by sudden attacks or paroxysms of severe, repetitive coughing, often culminating with the characteristic whoop and frequently followed by vomiting. A marked lymphocytosis usually accompanies this stage of the disease, with lymphocyte counts sometimes exceeding 50,000/mm3and usually representing 70% or more of total circulating leukocytes. The paroxysmal stage typically lasts 1–4 weeks and can be associated with a variety of complications, including secondary bacterial infections such as pneumonia and otitis media, toxic central nervous system manifestations such as seizures and encephalopathy, and effects of increased intrathoracic and intra-abdominal pressure such as pneumothorax, hernia, and rectal prolapse. The beginning of the convalescent (recovery) stage is marked by a reduction in frequency and intensity of coughing spells. After clinical pertussis, immunity to disease is lifelong.

Although most cases of pertussis follow a characteristic course, exceptions exist. In infants < 3 months, the catarrhal stage is usually no longer than a few days, and the paroxysmal and convalescent stages are extremely protracted, with coughing spells that continue throughout the first year of life. In infants < 6 months, apnea is a common manifestation, and the whoop is often absent. Paradoxically, in infants, cough and whoop may become louder and more classic during convalescence, reflecting growth in body mass and increased strength. In immunized children, all three stages are shortened, and in adults, only a protracted cough may be present. Post-tussive vomiting is common in pertussis at all ages and is a major clue to the diagnosis in adolescents and adults. With subsequent respiratory illnesses over the next several months, paroxysmal coughing may recur, though not because of recurrence of active Bordetella infection.

  1. Laboratory Findings.During the catarrhal stage, organisms are most readily isolated from cultures of the posterior nasopharynx. During the paroxysmal stage, it is increasingly difficult to recover the organism from the respiratory tract.
  2. Imaging.The chest radiograph is mildly abnormal in the majority of hospitalized infants, showing perihilar infiltrates or interstitial edema and patchy atelectasis. Pneumothorax, pneumomediastinum, and soft tissue air are sometimes seen.
  3. Complications.Surveillance data on pertussis in the United States from 1980 to 1989 demonstrated that the clinical course in infants was complicated by pneumonia in 21.7% of cases, by seizures in 3.0% of cases, and by encephalopathy in 0.9% of cases. The mortality rate was 1.3% in infants < 1 month and 0.3% in infants 2–11 months of age. Considering all individuals with pertussis, pneumonia develops in ~ 10%, seizures in ~ 2%, and encephalopathy in 0.5% to 1%.

BOX 56-5 Clinical Manifestations of B pertussis Disease (Whooping Cough)

Catarrhal Stage

· Low-grade fever

· Rhinorrhea

· Mild cough

Paroxysmal Stage

· Paroxysms of severe, repetitive coughing, often with whoop and vomiting

Convalescent Stage

· Decreasing intensity and frequency of cough

Diagnosis

The traditional approach for diagnosing pertussis involves culturing B pertussis or B parapertussis from nasopharyngeal mucus (see Table 56-2). Mucus should be collected by aspiration or by swabbing the nasopharynx with a dacron or calcium alginate swab. After plating on an appropriate medium, B pertussis is usually detected in 3–5 days, and B parapertussis is visible in 2–4 days. Regan-Lowe agar or a related charcoal-horse blood agar containing 40 µg/mL cephalexin is the preferred medium for primary isolation.

The organism is rarely found after the fourth week of illness, and culture is less likely to be positive in immunized individuals and in those who have received antibiotics. Examination of nasopharyngeal secretions by direct immunofluorescent assay is considered an alternative approach to diagnosis. However, direct immunofluorescent assay has low sensitivity and variable specificity and requires experienced personnel for interpretation. Polymerase chain reaction has been used on an investigational basis and is more rapid than culture but is variably sensitive.

B pertussis infections stimulate a heterogeneous antibody response that differs among individuals, depending on age, previous exposure to the organism, and immunization status, and thus no single serologic test is diagnostic. Nevertheless, in experienced research laboratories, the serologic diagnosis of pertussis has excellent sensitivity and specificity when acute serum is collected early in the illness and paired acute and convalescent sera are tested for antibodies to a number of antigens.

Absolute lymphocytosis is often present in patients with classic pertussis but represents a nonspecific finding, especially in infants. The degree of lymphocytosis usually parallels the severity of the patient's cough. The lymphocytes include both T cells and B cells and are normal small cells rather than large atypical lymphocytes. Adults and partially immunized children have less marked increases in lymphocyte count.

Because laboratory confirmation of pertussis can be difficult, clinicians often need to make the diagnosis on the basis of characteristic manifestations, including a prolonged paroxysmal cough, an inspiratory whoop, post-tussive emesis, and lymphocytosis. For sporadic cases, cough of > 14 days duration in combination with either paroxysms, whoop, or post-tussive vomiting has a sensitivity of 81% and a specificity of 58% for culture confirmation. In a study of university students, 25% of subjects with a coughing illness for 7 or more days had pertussis.

Treatment

Infants < 6 months and other patients with potentially severe disease often require hospitalization for supportive care to manage coughing paroxysms, apnea, cyanosis, feeding difficulties, and other complications. Antibiotic therapy initiated during the catarrhal stage promotes more rapid clinical improvement (Box 56-6). However, after the onset of paroxysms, antimicrobial agents usually have little discernible effect on the course of illness. Nevertheless, they are recommended to limit the spread of the organism to others. The drug of choice is erythromycin. Currently, the recommended duration of therapy is 14 days, although recent evidence suggests that a 7-day course is also efficacious. Azithromycin and clarithromycin are alternatives based on clinical studies demonstrating the ability of these drugs to eradicate the organism.

Trimethoprim/sulfamethoxazole is another possible alternative, but its efficacy is unproven. In in vitro studies, B pertussis is also susceptible to fluoroquinolones and to a lesser extent ampicillin and rifampin. B parapertussis is less susceptible in vitro to all agents except erythromycin.

BOX 56-6 Treatment of B pertussis Disease

First Choice

· Erythromycin, 40–50 mg/kg/d orally divided into four equal doses for 14 d (but see text); maximum dose: 2 g/d

Second Choice

· Azithromycin, 10 mg/kg/d once per day for 5 days; maximum dose 500 mg/d; or clarithromycin, 10 mg/kg/d divided into 2 equal doses for 7 d; maximum dose, 1 g/d

· Trimethoprim-sulfamethoxazole (TMP-SMX), 8 mg TMP, 40 mg SMX/kg/d orally divided into two doses

Among patients with pertussis who are treated with erythromycin, nasopharyngeal cultures almost always become negative within 5 days after initiating therapy. In order to prevent secondary transmission effectively, antibiotic treatment also should be prescribed for all household and other close contacts, including those who have been immunized against B pertussis, since vaccine-induced immunity is not absolute and may not prevent infection. Individuals exposed to a patient with pertussis should be closely monitored for respiratory symptoms over the ensuing 2–3 weeks.

Corticosteroids, albuterol, and pertussis-specific immunoglobulin may be effective in reducing paroxysms of coughing but require further evaluation before they can be recommended.

Prevention & Control

Universal immunization with pertussis vaccine is critical for control of pertussis (Box 56-7). Whole-cell and acellular pertussis vaccines in combination with diphtheria and tetanus toxoids (DTP and DTaP, respectively) are available in the United States and should be administered to all children < 7 years. The primary series includes doses at 2, 4, 6, and 15–18 months of age, followed by a booster at 4–6 years of age. Whole-cell vaccines are prepared from a suspension of inactivated B pertussis cells, whereas acellular vaccines contain one or more antigens derived from B pertussis and lack endotoxin. These antigens include pertussis toxin, filamentous hemagglutinin, fimbriae type 2, fimbriae type 3, and pertactin. All acellular vaccines contain pertussis toxin, in an inactivated form.

Based on household studies of children in the United States exposed to pertussis, the efficacy of whole-cell vaccines for children who received at least three doses is estimated to be 50 to 90%, depending on the case definition. Protection is greatest against culture-confirmed, more severe cases. Vaccine-induced immunity persists for at least 3 years and then diminishes. Although whole-cell vaccines have been highly effective in reducing the burden of disease and deaths due to B pertussis, they are associated with a number of troublesome adverse effects, including redness, induration, and tenderness at the injection site, low-grade fever, drowsiness, irritability, and anorexia. Less common serious adverse reactions include seizures, hypotonic-hyporesponsive episodes, fever > 40°C, and persistent, severe, inconsolable crying lasting 3 or more hours. Encephalopathy, other neurologic conditions, and sudden infant death syndrome have been attributed to vaccination with whole-cell pertussis vaccines, but evidence for a causal association is lacking.

Acellular pertussis vaccines were first demonstrated to be efficacious in studies in Japan involving children 2 years of age and older, and in 1991, two different formulations were licensed in the United States for use as the fourth and fifth (booster) doses in the routine series. More recent studies in Europe compared acellular and whole-cell vaccines in infants and found them to be associated with similar levels of protective efficacy. Concentrations of serum antibody to PT, FHA, fimbriae, and pertactin were at least as high after immunization with the acellular vaccines as they were after vaccination with a whole-cell vaccine. Furthermore, adverse reactions were significantly less frequent among recipients of the acellular vaccines. With this information in mind, five acellular vaccines are now approved in the United States for use during infancy, and licensure of additional products is anticipated. Given their efficacy and safety profile, acellular vaccines are preferred over whole cell vaccines in the United States.

BOX 56-7 Control of B pertussis Infection

Prophylactic
Measures

· Vaccines are available and effective

· Chemoprophylaxis for contacts: erythromycin or alternative (same as treatment dose)

Isolation
Precautions

Droplet precautions for first 5 d of treatment

Once a case of pertussis has been diagnosed, all contacts should be identified. Close contacts < 7 years who have received fewer than four doses of pertussis vaccine (DTP or DTaP) should have pertussis immunization initiated or continued. As mentioned above, contacts should also receive chemoprophylaxis with erythromycin or a suitable alternative.

For the hospitalized patient, droplet precautions are recommended for 5 days after initiation of effective therapy. Similarly, outpatients should be excluded from day care or school until 5 days of treatment are completed. If antibiotic therapy is not administered, precautions should be continued until 3 weeks after the onset of paroxysms.

BRANHAMELLA CATARRHALIS

Essentials of Diagnosis

  • Branhamella catarrhalisis presumed to be acquired by direct contact with contaminated respiratory tract secretions or by droplet spread.
  • The most common infections include otitis media, sinusitis, and, to a lesser extent, exacerbations of underlying lung disease.
  • Gram stain of infected fluid shows gram-negative diplococci. Culture of infected fluids when indicated is also useful.

General Considerations

  1. Epidemiology.B catarrhaliswas previously thought to be a harmless commensal organism, but it is now clear that this organism is an important cause of human disease. B catarrhalis colonizes the nasopharynx of 5 to 10% of adults and ~ 30% of children. Colonization rates may be even higher during the winter months. B catarrhalis accounts for ~ 15% of all cases of otitis media. Evidence that B catarrhalis is a true middle ear pathogen comes from the observation that antibodies specific for this organism develop after otitis media in which a pure culture of B catarrhalis is obtained from middle ear fluid. B catarrhalis also causes sinusitis and can be recovered alone or in combination with other bacteria from direct sinus aspirates of patients with clinical and radiographic evidence of acute bacterial sinusitis.
  2. Microbiology.The taxonomic position of B catarrhalisremains controversial. There are conflicting proposals to classify this organism as a member of the genus Moraxella, subgenus Branhamella, or to leave it as the only species in the genus Branhamella. The genera Branhamella and Moraxella are classified along with the genera Neisseria, Kingella, and Acinetobacter in the family Neisseriaceae. In contrast to Moraxella spp., which are rod-shaped, B catarrhalis appears as gram-negative diplococci with kidney-shaped cells and thus is morphologically indistinguishable from Neisseria. It grows well on blood agar and chocolate agar, forming small, opaque, gray-white colonies, 1–3 mm in diameter, which are circular and firm. Nevertheless, recovery from mucosal surfaces is facilitated by the use of selective media such as Thayer-Martin or TV broth (Mueller-Hinton broth supplemented with trimethoprim and vancomycin). Isolates typically produce cytochrome oxidase, catalase, and DNase. They are unable to ferment maltose, glucose, lactose, or sucrose, thus distinguishing them from N gonorrhoeae and N meningitidis. B catarrhalis lipopolysaccharide molecules lack long O-polysaccharide side chains and are referred to as lipo-oligosaccharide. These organisms are nonencapsulated.
  3. Pathogenesis.The pathogenesis of localized respiratory tract disease due to B catarrhalisbegins with colonization of the upper respiratory tract mucosa. Subsequently, the organism spreads contiguously to produce disease in the middle ear, the sinuses, or the lower respiratory tract. Factors that increase the likelihood of spread to the tracheobronchial tree include smoking, intercurrent viral infection, corticosteroid use, and other forms of immunosuppression. The determinants of colonization remain poorly defined but may include pili, which are present on most isolates, and a nonpilus protein called UspA1. Persistence on the respiratory mucosa may relate to the ability of the organism to resist complement-dependent bactericidal activity, which is mediated by a high-molecular-weight protein referred to as UspA2 (antigenically related to UspA1 and also called HMW-OMP). In animal models of B catarrhalis lower respiratory infection, the organism appears to release a potent chemotactic factor and elicits a striking neutrophil response in the lung.

CLINICAL SYNDROMES

B catarrhalis causes bronchitis and pneumonia in patients with underlying lung disease, especially chronic obstructive pulmonary disease. It is also a rare cause of invasive disease, including meningitis, endocarditis, bacteremia without a focus, septic arthritis, and cellulitis. In addition, it is a recognized cause of acute conjunctivitis and is periodically mistaken as Neisseria gonorrhoeae in newborn infants with conjunctivitis. B catarrhalis occasionally colonizes the genital mucosa and has been reported as a cause of urethritis.

BOX 56-8 Clinical Manifestations of B catarrhalis Disease

Otitis Media

· Ear pain

· Fever

· Bulging tympanic membrane with distorted landmarks and decreased mobility

Sinusitis

· Nasal discharge

· Fever

· Cough

· Headache

· Facial tenderness

Exacerbation of Lung Disease

· Increased dyspnea

· Fever

· Sputum production

· Sputum purulence

 

Clinical Findings

  • Signs and Symptoms.The signs and symptoms of B catarrhalis acute otitis media and sinusitis are indistinguishable from those present when acute otitis media and sinusitis are caused by other pathogens (Box 56-8). However, episodes of B catarrhalis otitis media are more likely to resolve spontaneously than are those caused by Streptococcus pneumoniae or H influenzae. The clinical manifestations of lower respiratory tract infection caused by B catarrhalisalso are similar to those caused by other bacteria. Episodes of bronchitis in patients with chronic obstructive pulmonary disease are characterized by increased cough, purulent sputum, shortness of breath, and sometimes low-grade fever. Pneumonia due to B catarrhalis occurs almost exclusively in elderly persons and in patients with chronic obstructive pulmonary disease and is characterized by fever as high as 39.4°C, cough, purulent sputum, and shortness of breath.
  • Laboratory Findings.Nasopharyngeal and throat cultures are not helpful in establishing a microbiological diagnosis but can be useful in excluding certain organisms.

Diagnosis

Tympanocentesis is necessary to establish the etiology of otitis media, and sinus aspiration is required to confirm the cause of sinusitis (see Table 56-2). However, these procedures are rarely performed. In patients with pneumonia, auscultation sometimes reveals evidence of consolidation, and chest radiograph sometimes shows patchy or lobar infiltrates. Pleural effusion and empyema are uncommon. The most practical approach to establish the diagnosis of B catarrhalis pneumonia or bronchitis is to examine a gram-stained sputum sample, which will show a predominance of intracellular and extracellular gram-negative diplococci.

BOX 56-9 Treatment of B catarrhalis Disease

Medication

Children

Adults

· Amoxicillin plus clavulanate (Augmentin)

· 40 mg/kg/d divided into 3 equal doses1(amoxicillin component)

· 500 mg three times daily (amoxicillin component)

· Trimethoprim- sulfamethoxazole (TMP-SMX)

· 8–12 mg TMP/40–60 mg SMX/kg/d divided into 2 equal doses

· 160 mg TMP/800 mg SMX twice daily

· Oral second and third-generation cephalosporins

· Depends on particular agent

· Depends on particular agent

· Erythromycin sulfisoxazole

· 40 mg/kg/d divided into 3–4 equal doses (erythromycin component)

· 500 mg four times daily (erythromycin component)

· Azithromycin

· 10 mg/kg loading dose, then 5 mg/kg/d

· 500 mg loading dose, then 250 mg/d

· Clarithromycin

· 15 mg/kg/d divided into 2 equal doses

· 500 mg twice daily

1Both twice daily and three times dialy formulations are available.

Treatment

Approximately 80% of isolates produce β-lactamase, and at least three different B catarrhalis β-lactamases have been identified, including BRO-1, BRO-2, and BRO-3. The activity of these β-lactamases can be inhibited by β-lactamase inhibitors such as clavulanate and sulbactam. Most B catarrhalis infections can be treated with oral agents, including Augmentin (amoxicillin plus clavulanate), erythromycin, trimethoprim-sulfamethoxazole, and tetracycline (Box 56-9). B catarrhalis is also uniformly susceptible to ticarcillin, piperacillin, mezlocillin, azlocillin, most second- and third-generation cephalosporins, chloramphenicol, newer macrolides, and aminoglycosides. B catarrhalis is resistant to penicillin, ampicillin, vancomycin, clindamycin, and methicillin. Approximately 1–2% of isolates are resistant in vitro to tetracycline or erythromycin. Isolates producing β-lactamase may be reported by the clinical laboratory as susceptible to penicillin and ampicillin, because of the low activity of the BRO-β-lactamases. However, clinical treatment failures with such organisms suggest they should be considered resistant to these antibiotics. Similarly, cefaclor and possibly other cephalosporins may be inactivated by the BRO-β-lactamases.

Prevention & Control

Currently, there are no measures for prevention and control of B catarrhalis infection. However, a number of laboratories are characterizing B catarrhalis surface antigens, hoping to develop a vaccine effective against this organism.

REFERENCES

Catlin BW: Branhamella catarrhalis: an organism gaining respect as a pathogen. Clin Microbiol Rev 1990; 3:293.

Centers for Disease Control and Prevention: 1998 Guidelines for Treatment of Sexually Transmitted Diseases. MMWR 1998;47:18.

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