ACP medicine, 3rd Edition

Infectious Disease

Infections Due to Haemophilus, Moraxella, Legionella, Bordetella, and Pseudomonas

Shawn J. Skerrett MD1

Associate Professor of Medicine

1University of Washington School of Medicine

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

March 2006

Haemophilus, Moraxella, Legionella, Bordetella, and Pseudomonas are gram-negative bacteria that are important respiratory pathogens. All can also cause other types of infections. Vaccines have markedly reduced the incidence of disease from Haemophilus and Bordetella, but these organisms remain sources of morbidity and potentially life-threatening infection.

Haemophilus influenzae Infections

In 1892, the German bacteriologist Richard Pfeiffer made the sensational claim that he had identified the etiologic agent of influenza.1 He had repeatedly observed a bacillus in purulent sputum obtained from influenza victims and found that this organism could be cultured on media supplemented with blood. Pfeiffer's blood-loving bacillus was named Haemophilus influenzae.1 Although the causative link with influenza proved false, H. influenzae was subsequently recognized as the leading cause of meningitis in young children and an important agent of respiratory infections.

  1. influenzaeoccurs in encapsulated and unencapsulated forms.2Encapsulated strains express one of six antigenically distinct capsular polysaccharides, designated a through f. The type b strain was responsible for most invasive Haemophilus infections before the widespread use of conjugate vaccines began in the 1980s. The other capsular groups are rarely implicated as pathogens. Unencapsulated strains do not react with antisera directed at the polysaccharide antigens and thus are nontypeable. These strains are common commensals but can cause mucosal and invasive infections.

EPIDEMIOLOGY

  1. influenzaeis strictly a human parasite: no nonhuman host is known, and H. influenzaeis not found free in nature. Essentially all persons are colonized by one or more strains of Haemophilus by 1 year of age.2 The primary reservoir for H. influenzae is the human upper respiratory tract, although the organism can also be carried on the conjunctivae and in the genital tract. Population studies have found that 40% to 80% of persons harbor unencapsulated strains of H. influenzae in the nasopharynx.2,3 Type b strains were recovered from nasopharyngeal swabs of 2% to 4% of children before the widespread use of the conjugate vaccines, but now such strains are found in less than 1% of children in vaccinated populations. The specific strains colonizing a person's pharynx change over time, and multiple strains can be found concurrently.2,3 Colonization of the normally sterile tracheobronchial tree with nontypeable strains of H. influenzae occurs commonly in people with chronic airway disease, such as cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease (COPD), and in asymptomatic smokers.2,4 In very young infants, nasopharyngeal colonization with H. influenzae is associated with an increased risk of otitis media.2 Persistent colonization of the lower respiratory tract with H. influenzae is associated with increased airway inflammation5and may contribute to the progression of COPD.4
  2. influenzaecan be transmitted from person to person, leading to secondary cases of infection in households, day care centers, and institutions.2The risk of invasive H. influenzae infection is age related. The incidence is highest in children younger than 5 years, with a second peak late in life.6 The distribution and burden of invasive H. influenzae infection have been dramatically altered by the use of conjugate vaccines directed against the type b capsular polysaccharide.7 In unvaccinated populations, the incidence of infection peaks between 6 and 18 months of age, but in vaccinated populations, the risk is highest in the first 6 months of life, before the primary immunization series is completed. In the prevaccine era, there were approximately 20,000 cases a year of invasive H. influenzae infection in children younger than 5 years in the United States. Meningitis accounted for 60% of these cases, and 95% of the infections were caused by type b strains.7 Currently, fewer than 400 cases of invasive H. influenzae infection in children younger than 5 years are reported to the Centers for Disease Control and Prevention (CDC) each year, and the minority of these are type b infections.6 Conjugate vaccine usage has also reduced the overall incidence of invasive H. influenzae infection in older children and adults, although an increase in non-serotype b infections has been observed.8 Most cases of invasive H. influenzae in the United States now occur in adults, with pneumonia being the most common type of infection.6 Certain population groups remain at increased risk, including Native Americans, Alaskan Natives, and African Americans.7 An increased risk of invasive H. influenzae type b infection is also observed in association with complement deficiencies, hypogammaglobulinemia, and splenic dysfunction. The incidence of H. influenzae pneumonia is increased in the settings of recent influenza, HIV infection, alcoholism, advanced age, and underlying COPD.

PATHOGENESIS AND IMMUNITY

All Haemophilus organisms are small, pleomorphic, nonmotile, gram-negative coccobacilli. They are facultative anaerobes with fastidious nutritional requirements. Aerobic growth of H. influenzae requires X and V factors, both of which are contained in red blood cells. X factor (hematin) is not a single nutrient but, rather, refers to several diffusable pigments that supply protoporphyrins. V factor is nicotinamide adenine dinucleotide, a coenzyme that is released by lysis of red cells. All species of Haemophilus grow well on chocolate agar, which contains red cells that have been disrupted by heating.

Unencapsulated strains of H. influenzae selectively colonize and locally invade the respiratory tract. H. influenzae binds to airway mucins but evades mechanical clearance by inhibiting ciliary beat frequency and damaging ciliated epithelium. The ciliotoxic properties of H. influenzaehave been attributed to the lipid A, peptidoglycan, and lipoprotein components of the bacterial cell wall. Most strains of H. influenzae also produce a protease that cleaves both serum and secretory IgA, thus inactivating a major component of mucosal host defense.2,3 H. influenzae attaches to respiratory epithelial cells with the aid of several adhesins, including pili, high-molecular-weight hemagglutinins, and other surface proteins.3 H. influenzae preferentially binds to nonciliated cells and to epithelium damaged by recent viral infection or exposure to toxins such as cigarette smoke.2,3 H. influenzae not only can attach to the surface of respiratory epithelium but can enter and survive in epithelial cells and mucosal macrophages and penetrate intercellular junctions to invade the submucosal interstitium.2,4

  1. influenzaetype b is less efficient at colonization than unencapsulated strains, but it has a much greater capacity to invade and survive within the bloodstream.

The magnitude and duration of bacteremia is a critical determinant in the development of H. influenzae meningitis, which results mainly from hematogenous seeding rather than direct spread from contiguous infection.2 The type b capsule facilitates invasion by shielding the organism from complement- and antibody-mediated phagocytosis.2 The lipo-oligosaccharide in the H. influenzae outer membrane is another important factor in the pathophysiology of invasive H. influenzae infection: its lipid A component has typical endotoxin activity and contributes to local and systemic inflammatory manifestations of infection, including septic shock.3

Antibodies constitute the principal defense against H. influenzae type b. These antibodies are directed against the bacteria's capsule, which is composed of repeating units of polyribosyl ribitol phosphate (PRP). Anticapsular antibodies facilitate ingestion of H. influenzae by phagocytes and mediate the complement-dependent bactericidal activity of immune serum. Antibodies specific for the PRP component of H. influenzae appear by 4 years of age and coincide with the age-related decline in susceptibility to invasive disease.2 Host resistance to nontypeable strains of H. influenzae is less well understood but also involves humoral immunity.2,3,4

CLINICAL SYNDROMES

In the prevaccine era, H. influenzae type b was responsible for nearly all invasive H. influenzae infections in young children and approximately 50% of invasive infections in adults.9,10,11 Meningitis accounted for more than half of the childhood cases of invasive H. influenzae type b infection, followed by pneumonia, epiglottitis, primary bacteremia, cellulitis, and musculoskeletal infections.12 In adults, pneumonia has been the most common manifestation of invasive H. influenzae infection, followed by primary bacteremia, epiglottitis, meningitis, obstetric infections, and septic arthritis.9,10,11 Widespread use of conjugate vaccines has dramatically reduced the overall incidence of invasive type b infections, but infections caused by nontypeable H. influenzae remain important in both children and adults. Unencapsulated strains of H. influenzae are principally associated with otitis media, sinusitis, bronchitis, and pneumonia but can also infect other sites.

Meningitis

  1. influenzaetype b is the leading cause of meningitis in children younger than 5 years in unvaccinated populations but has become rare in immunized communities.7,12In adults, H. influenzae (predominantly type b) accounts for approximately 4% of cases of community-acquired and nosocomial meningitis.9,13,14 Adult cases often are associated with contiguous infection of the paranasal sinuses, mastoids, or middle ear or with antecedent head trauma.13,14,15 Childhood cases, in contrast, result from bacteremic seeding and often follow an upper respiratory infection.

The clinical manifestations of H. influenzae meningitis in both children and adults are typical of acute bacterial meningitis.9,15 Most patients present with fever, headache, and lethargy. The cerebrospinal fluid is usually cloudy, with a neutrophilic pleocytosis, increased protein concentration, and reduced glucose levels. The diagnosis is made by detecting H. influenzae in blood or CSF (see below). The clinical course may be fulminant, leading to death within 24 hours. The overall mortality of H. influenzae meningitis in young children is approximately 5%, but 20% to 30% of survivors suffer residual neurologic sequelae. Morbidity is reduced in children treated with dexamethasone.16 The mortality in adult cases is 10% to 30%.

Epiglottitis

Epiglottitis is a life-threatening infection that is most prevalent in children 2 to 7 years of age but also occurs in older children and adults.H. influenzae type b is the most common cause of epiglottitis in all age groups, and the incidence of epiglottitis has declined since the availability of conjugate vaccines.2,17

The usual presenting symptoms of epiglottitis are sore throat, odynophagia, dyspnea, and fever; respiratory symptoms are more common in children than adults.17 The onset of epiglottitis is often abrupt, and the progression can be very rapid. On examination, patients are anxious and may assume an airway-protective posture, sitting erect with the neck extended and the chin protruding forward. Drooling and a muffled voice are useful clues. Stridor, tachypnea, and use of accessory muscles to breathe are common findings in children. The diagnosis can be confirmed by laryngoscopy, with visualization of the cherry-red swollen epiglottis in children or the diffuse supraglottic edema more typical of adult cases. Laryngoscopy must be undertaken with care because the procedure may precipitate acute airway obstruction. A lateral neck x-ray also can be diagnostic, but the supine position should be avoided and patients with suspected epiglottitis should not travel to the radiology suite unless accompanied by a physician prepared to secure an airway. Blood cultures are positive in many cases.

An artificial airway (endotracheal intubation or tracheostomy) should be established emergently in all children with epiglottitis and in adults with evidence of airway compromise. All patients with epiglottitis should be admitted to the hospital for observation and treatment with parenteral antibiotics. Death can result from acute airway obstruction or from septic shock. The mortality is less than 5%.

Pneumonia

  1. influenzaeis the second or third most common cause of community-acquired pneumonia in adults, identified in 1% to 12% of hospitalized cases.18Most of the isolates in these cases are nontypeable strains.19 In contrast, community-acquired H. influenzae pneumonia in children is caused mainly by type b and now is rare in vaccinated populations.12

In adults, the risk factors for H. influenzae pneumonia include COPD, advanced age, alcoholism, and HIV infection.9,19,20 H. influenzae has also been identified as an important cause of nosocomial pneumonia in the first 5 days of hospitalization, before the indigenous flora of the upper respiratory tract have been replaced.21

  1. influenzaepneumonia presents as a typical acute pneumonia, with fever, cough productive of purulent sputum, chest pain, and dyspnea.9,19Crackles and diminished breath sounds usually are evident on lung auscultation. The chest x-ray may reveal a bronchopneumonic pattern or focal consolidation, often multilobar. Pleural effusions are common. The diagnosis of H. influenzae pneumonia is made most often from the sputum Gram stain and culture, although the organism is frequently missed on sputum smears.18 Blood cultures are positive in 20% to 30% of cases. Complications of H. influenzae pneumonia include empyema, purulent pericarditis, and metastatic infection. The reported mortality of H. influenzae pneumonia is 5% to 20%, but it is higher in patients with bacteremia or suppurative complications.

Tracheobronchitis

  1. influenzaecan cause tracheobronchitis in patients with underlying COPD and, more rarely, in immunocompromised patients.4,19The airways of patients with chronic lung disease are often colonized with nontypeable strains of H. influenzae, and the acquisition of new strains is associated with acute exacerbations of chronic bronchitis.4,22 The clinical presentation is characterized by an increase in cough, purulent sputum production, and dyspnea. Fever and leukocytosis may also be present, but the chest film is clear. The sputum Gram stain shows abundant leukocytes, with a predominance of gram-negative coccobacilli.

Otitis Media and Sinusitis

Nontypeable strains of H. influenzae are isolated from 15% to 30% of purulent middle-ear effusions in both children and adults.23 H. influenzae is now the leading cause of persistent otitis media in children immunized with the pneumococcal conjugate vaccine.24

As with all cases of otitis media, infants typically present with fever and irritability and older children and adults complain primarily of ear pain. The clinical diagnosis is made by otoscopy. A bacteriologic diagnosis requires tympanocentesis, but this procedure is warranted only for evaluation of treatment failures. Nontypeable strains of H. influenzae can also be isolated from maxillary aspirates in approximately 25% of children and adults with acute sinusitis.25 In addition to experiencing common cold symptoms such as rhinorrhea and cough, patients with sinusitis often have unilateral pain, purulent nasal discharge, and reduced transillumination. Confirmatory sinus x-rays and diagnostic aspiration are usually unnecessary.25 Empirical management includes topical or systemic decongestants, or both, and antibiotics that are effective against S. pneumoniae, H. influenzae, and Moraxella (Branhamella) catarrhalis.

Extrapulmonary Infections

Cellulitis

  1. influenzaetype b is an important cause of cellulitis in unvaccinated children younger than 5 years and is rarely implicated in skin infections of older persons.9,12,26The face is the most common site in young children. A raised, warm, tender area of erythema on the cheek or periorbital area is typical, sometimes with a distinctive bluish hue. Underlying sinusitis is common with periorbital and orbital infection. Blood cultures are often positive.

Bone and joint infections

In the prevaccine era, H. influenzae type b caused approximately 10% of cases of septic arthritis and hematogenous osteomyelitis in infants and young children, but this is now uncommon.27 Most cases of H. influenzae septic arthritis in children are monoarticular, involving large weight-bearing joints. A respiratory source of infection is usually evident. The diagnosis is established by arthrocentesis.

Rare cases of H. influenzae pyarthrosis have been described in adults.9,28 About half of these cases are polyarticular, and most are in patients with alcoholism, immunodeficiency, joint disease, or trauma. Extra-articular sites of infection are apparent in 50% of patients. As in children, most adult cases of H. influenzae septic arthritis are caused by type b strains and accompanied by bacteremia.

Conjunctivitis

Nontypeable strains of H. influenzae have long been appreciated as common causes of purulent conjunctivitis. These infections are contagious, and outbreaks can occur, particularly in day care centers.2 H. influenzae conjunctivitis is easily diagnosed from stains and cultures of conjunctival swabs.

Robert Koch was the first to identify small gram-negative rods in conjunctival exudates collected in Egypt in 1883.1 This organism was successfully cultured 3 years later by John Weeks, an American ophthalmologist. The Koch-Weeks bacillus, formerly named Haemophilus aegyptius, is now known to be a variant of H. influenzae. A particularly virulent strain of this organism has been responsible for outbreaks and sporadic cases of Brazilian purpuric fever in young children. This is a fulminant illness in which resolution of an episode of purulent conjunctivitis is followed by high fever, vomiting, abdominal pain, petechiae, purpura, peripheral necrosis, and vascular collapse.2

Bacteremia

  1. influenzaeb bacteremia without localizing infection can occur in children younger than 5 years and in older persons with defective humoral immunity.9,12These patients can deteriorate rapidly, and in rare cases, the bacteremia resembles meningococcemia with purpura fulminans or the Waterhouse-Friderichsen syndrome.26 Nontypeable strains of H. influenzae have also been implicated in neonatal and puerperal sepsis.9,10,26

Other infections

  1. influenzaeis a rare cause of genitourinary infections, including salpingitis, endometritis, chorioamnionitis, epididymitis, and prostatitis.10,26Other rare manifestations of H. influenzae infection include appendicitis, chlolecystitis, peritonitis, and endocarditis.9,26

MICROBIOLOGIC DIAGNOSIS

The diagnosis of invasive H. influenzae infection is generally made from positive cultures of blood, CSF, joint fluid, or other normally sterile sites. CSF and joint fluid Gram stains reveal bacteria in 70% to 80% of cases of meningitis and septic arthritis, respectively. However, the morphology of the organisms is often misleading: plump gram-negative rods, filamentous organisms, gram-negative diplococci, and underdecolorized gram-positive cocci have been described.9,15,26 Similarly, sputum Gram stains of patients with tracheobronchitis or pneumonia usually show abundant leukocytes and the characteristic gram-negative coccobacilli, but misinterpretations are common.18 The small gram-negative rods can be overlooked in the pink background on the slide or misinterpreted as gram-positive cocci if the specimen is poorly decolorized.

Type b capsular antigen can be detected by latex agglutination or enzyme-linked immunosorbent assay (ELISA) in CSF, serum, or concentrated urine in up to 90% of invasive infections. Antigen detection is particularly attractive in patients who have already received antibiotic therapy at the time of presentation, but the results rarely influence outcome, because cultures or Gram stains are diagnostic in nearly all antigen-positive cases.29

ANTIBIOTIC TREATMENT

The initial antibiotic of choice for meningitis and other invasive H. influenzae infections is a third-generation cephalosporin such as ceftriaxone or cefotaxime. These agents are highly active against all isolates of H. influenzae, penetrate the CSF, and eradicate nasopharyngeal carriage of H. influenzae type b. The pediatric dose of ceftriaxone is 50 mg/kg every 12 hours and that for cefotaxime is 50 mg/kg every 6 hours. For adults, the maximum dose of ceftriaxone is 2 g every 12 hours, and that for cefotaxime is 2 g every 6 hours. The preferred alternative treatment for H. influenzae meningitis is chloramphenicol (75 to 100 mg/kg/day in six divided doses). Children with H. influenzae meningitis also should receive dexamethasone (0.6 mg/kg/day in four divided doses). Other antibiotics that are highly active against nearly all strains of H. influenzae include carbapenems, aztreonam, β-lactam/β-lactamase inhibitor combinations, fluoroquinolones, azith romycin, and tetracycline30,31 [see Table 1]. Ampicillin is highly effective against sensitive strains, but 35% to 40% of North American isolates of H. influenzae are resistant to ampicillin. Most ampicillin resistance is mediated by β-lactamase production, but conventional susceptibility testing is recommended for invasive isolates to detect all resistant strains. Intravenous antibiotic therapy is recommended for meningitis and endocarditis and for the initial treatment of other invasive infections. Less severe H. influenzae infections can be managed with oral antibiotics. Most H. influenzae infections can be cured with 7 to 10 days of therapy, but treatment should continue for 3 to 6 weeks in cases of osteomyelitis or endocarditis.

Table 1 Antibiotics Effective against Haemophilus influenzae and Moraxella catarrhalis30,31

Antibiotic

H. influenzae
Susceptible (%)

M. catarrhalis
Susceptible (%)

Ceftriaxone

100

100

Cefpodoxime

100

99

Cefdinir

98

100

Cefuroxime

98–99

99

Ampicillin

68–72

< 10

Amoxicillin-clavulanate

> 99

> 99

Fluoroquinolones

> 99

100

Azithromycin

> 99

100

Clarithromycin

60–90

100

Telithromycin

98

100

Tetracycline

> 98

> 99

Chloramphenicol

> 99

100

Trimethoprim-sulfamethoxazole

79–82

> 97

PREVENTION

Immunization

The introduction of conjugate vaccines in the late 1980s has resulted in a greater than 97% reduction in the incidence of invasive H. influenzae type b infections in children younger than 5 years.7,12 Currently, four conjugate vaccines are licensed in the United States.32 All are composed of the PRP component of the H. influenzae type b capsule in covalent linkage with a carrier protein and elicit protective antibodies directed at PRP. Conjugate vaccines have succeeded the polysaccharide vaccines introduced in the 1970s; those earlier polysaccharide vaccines did not contain a carrier protein and were less effective.12

The vaccines are given in a primary series starting at 2 months of age, with the schedule depending on the product. A booster dose is given at 12 to 15 months of age. Immunocompromised children may require additional boosters.32 Local reactions are experienced by about 25% of persons, but systemic reactions are rare. Adults at high risk for invasive H. influenzae infection as a result of sickle cell disease, splenectomy, immunoglobulin or complement deficiency, B cell malignancy, or HIV infection should be considered for vaccination, but specific guidelines have not been developed.

Secondary Prevention

Chemoprophylaxis with rifampin (20 mg/kg/day; maximum, 600 mg a day for 4 days) is more than 95% effective in eliminating nasopharyngeal carriage of H. influenzae and is recommended to prevent secondary cases of invasive infection in children at risk. Rifampin prophylaxis should be administered to all adults and children in households with at least one member (other than the index case) who is younger than 4 years and is unimmunized or incompletely immunized.32 Treatment should also be given to all contacts in households with at least one member younger than 1 year who has completed the primary series but has not yet received a booster dose. Chemoprophylaxis of children and supervisory adults in child care and nursery school settings is recommended if at least two cases of invasive disease have occurred in the attendees within 60 days and if incompletely immunized children are in attendance. Finally, rifampin should be given to victims of invasive disease unless they were treated with ceftriaxone or cefotaxime, which eradicate the carrier state.

Other Haemophilus Infections

There are now 15 recognized species of the genus Haemophilus. H. parainfluenzae, H. aphrophilus, and H. paraphrophilus can be found among the flora of the oral cavity and upper respiratory tract. These organisms are primarily commensals, but in rare cases, they cause endocarditis and respiratory tract infection. Endocarditis caused by Haemophilus species usually develops on a diseased valve, is typically subacute in onset, and is often complicated by major systemic emboli. Combination antibiotic therapy is generally curative, but valve replacement is frequently necessary. Non-influenzae species of Haemophilus have antimicrobial susceptibilities that are similar to H. influenzae, but they are less likely to be ampicillin resistant.33

Moraxella (Branhamella) catarrhalis Infections

  1. catarrhaliswas first described by the German microbiologist Seifert in 1882. Originally called Micrococcus catarrhalis, the organism was renamed Neisseria catarrhalisin 1920, then assigned to the new genus Branhamella in 1970, and subsequently reclassified as Moraxella (Branhamella) catarrhalis. Although recognized as a cause of tracheobronchitis and pneumonia by early investigators, M. catarrhalis was dismissed as a harmless commensal for much of the 20th century, until regaining stature as a potential pathogen over the past 25 years.34

EPIDEMIOLOGY

The distribution of M. catarrhalis is limited to the human respiratory tract, except for occasional isolates from the conjunctiva and genital tract. Nearly 80% of children harbor M. catarrhalis in the nasopharynx by 2 years of age, but colonization declines with age. Fewer than 6% of healthy adults carry M. catarrhalis, although the organism can be isolated from the sputum of 5% to 32% of patients with chronic bronchitis or bronchiectasis. 4,35,36 Colonization is a dynamic process, with individual strains persisting for only a few months. Carriage ofM. catarrhalis also exhibits seasonal variation, with colonization and infection being more prevalent in the winter months.36

  1. catarrhalisis the third most common cause of otitis media, sinusitis, and acute exacerbations of chronic bronchitis, after H. influenzaeand S. pneumoniae.25,35The majority of lower respiratory tract infections attributed to M. catarrhalis in adults occur in patients with underlying COPD.35

PATHOGENESIS

  1. catarrhalisis a nonmotile, gram-negative diplococcus that is morphologically indistinguishable from Neisseriaspecies. M. catarrhalisgrows well aerobically on blood agar and chocolate agar. The characteristic convex, opaque colonies can be pushed across the agar surface in the manner of a hockey puck. Other species of Moraxella are predominantly gram-negative coccobacilli that can be found among the normal flora of humans and other mammals, but they rarely cause disease.

The virulence of M. catarrhalis is related to its capacity to colonize the respiratory mucosa. M. catarrhalis expresses a number of potential adhesins, but the mechanisms underlying the respiratory tropism of this organism are poorly understood.4,35 Similarly, the factors that influence the transition from asymptomatic colonization to infection have not been deciphered. In the case of otitis media and sinusitis, it is likely that nasopharyngeal bacteria will gain access to adjacent spaces after mucosal injury. The expression of particular virulence factors also may be important in pathogenesis. For example, strains of M. catarrhalis isolated from symptomatic persons are more likely to exhibit resistance to the bactericidal activity of serum complement than strains harbored by asymptomatic carriers. Recovery from M. catarrhalisinfection is accompanied by strain-specific antibody responses,35,36 but the key elements of host defense against this organism are unknown.

CLINICAL SYNDROMES

Tracheobronchitis

Acute exacerbations of chronic bronchitis are the most common manifestations of M. catarrhalis infection in adults.4,33,34 As with exacerbations caused by other organisms, dyspnea and cough productive of purulent sputum are the cardinal symptoms; fever also may be present. M. catarrhalis can be implicated by the predominance of gram-negative diplococci on Gram stains of purulent sputum, with isolation of M. catarrhalis in culture. In approximately 30% of cases involving M. catarrhalis, additional pathogens are present in the sputum.

Pneumonia

Most cases of pneumonia caused by M. catarrhalis occur in the elderly, particularly those with underlying COPD.35 The clinical features are those of a mild, acute pneumonia: fever, cough productive of purulent sputum, dyspnea, and chest pain are the common symptoms. Focal evidence of consolidation may be evident on physical examination. The chest x-ray usually reveals patchy alveolar or interstitial opacities that are often multilobar. Pleural effusions are uncommon. The diagnosis is usually made from the sputum Gram stain and culture. Bacteremia, empyema, and other suppurative complications are rare.

Otitis Media and Sinusitis

  1. catarrhaliscan be isolated from middle-ear effusions in 15% to 20% of cases of acute otitis media in children, usually in pure culture.35Polymerase chain reaction detects M. catarrhalisDNA in an even higher proportion of middle-ear exudates. Similarly, maxillary aspirates yield M. catarrhalis in about 20% of children with acute sinusitis.25,35 However, less than 10% of episodes of acute sinusitis in adults can be attributed to M. catarrhalis.25

Other Infection

Nosocomial outbreaks of M. catarrhalis infection, predominantly involving the respiratory tract and occurring mainly in patients with underlying cardiopulmonary disease, have been reported in children and adults.35 The mode of transmission has not been clear. M. catarrhalis has also been reported as a rare cause of invasive infections, including meningitis, endocarditis, septic arthritis, and bacteremia.35 Underlying lung disease and neutropenia have been identified as risk factors for M. catarrhalis bacteremia, but invasive infections originating in the upper respiratory tract have occurred in previously healthy individuals. M. catarrhalis can also cause conjunctivitis and rare urogenital infections.35

ANTIBIOTIC TREATMENT

More than 90% of clinical isolates of M. catarrhalis produce β-lactamases that render ampicillin and amoxicillin ineffective.30,31 Penicillin-β-lactamase-inhibitor combinations, second- and third-generation cephalosporins, fluoroquinolones, macrolides, and tetra cyclines are active against nearly all strains of M. catarrhalis [see Table 1].

Legionellosis

In the summer of 1976, a mysterious outbreak of pneumonia occurred among participants in the American Legion's bicentennial convention in Philadelphia, killing 34 of the 221 people afflicted.37 The disorder became known as Legionnaires disease. Its cause remained obscure until Joseph McDade and his colleagues at the CDC isolated a novel bacterium from the spleens of guinea pigs that had been injected with lung tissue harvested from victims of the epidemic.38 The new agent was named Legionella pneumophila. Studies with stored sera identified this organism as the cause of Pontiac fever—so named after an outbreak of a nonpneumonic, influenzalike illness that occurred in Pontiac, Michigan, in 1968—as well as other cases of epidemic and sporadic respiratory disease dating back to 1943.39 L. pneumophila was the first of several previously unknown agents to emerge as important human pathogens in the late 20th century. In the years since the Philadelphia outbreak of legionellosis, many other Legionella species have been identified and implicated in a growing spectrum of human disease.

The family Legionellaceae now includes more than 40 species of the genus Legionella, with over 60 distinct serotypes.40 Almost all of these organisms have been isolated from the environment, and approximately half of them have been associated with human disease. L. pneumophila remains the most important human pathogen in this family, accounting for more than 80% of legionellosis cases diagnosed in the United States.40,41 Other species of Legionella produce a similar spectrum of disease and may be underappreciated as causes of human infection.40

EPIDEMIOLOGY

The Legionellaceae are widely distributed in freshwater habitats throughout the world.39,40 They thrive in warm water enriched with iron, often in biofilms with other organisms that supply essential nutrients, such as blue-green algae or macrophytes. Legionellae can also replicate in free-living protozoa, and amebae may be their natural hosts. Man-made aquatic environments that often harbor legionellae include hot-water systems, cooling towers, air conditioners, industrial coolants, whirlpool baths, and humidifiers. The factors that promote the growth of legionellae in water tanks and potable water supplies include a temperature between 30° and 60° C, stagnation, decayed or rusted pipes and fixtures, and infrequent or ineffective decontamination. Water systems harboring legionellae can be disinfected by superheating (> 70° C) and flushing, hyperchlorination, or metallic ionization.40,41

Legionellosis is acquired mainly by the inhalation of aero solized bacteria from an environmental source,39,40,41 typically a man-made device. Examples of proven disseminators include showerheads, water faucets, cooling towers, evaporative condensers, respiratory therapy equipment, produce misters, whirl pool baths, and decorative fountains. Only a few cases of legion ellosis have been linked to natural aquatic sources such as hot springs. Potting soil also has been identified as a source of infection. Transient contamination of the oropharynx followed by microaspiration may occur occasionally, particularly in patients with nasogastric tubes; stable colonization of the upper respiratory tract by legionellae has not been described. Wounds can be infected by direct inoculation with contaminated water, and oral ingestion has been postulated as a potential source of rare intestinal infections. There is no evidence for person-to-person transmission.

The epidemiologic patterns of legionellosis include common-source epidemics, sporadic cases, and endemic disease in institutions with contaminated water supplies. The infection is more common in the summer months, when seasonal conditions promote the growth of legionellae in the environment, and the use of air conditioners and other cooling devices facilitates the dissemination of airborne bacteria.

Legionella species have been reported to cause from 1% to 15% of community-acquired pneumonias leading to hospitalization,18 but they consistently rank among the leading causes of severe community-acquired pneumonia leading to respiratory failure.42 In hospitals with contaminated water supplies, legionellae are important agents of nosocomial pneumonias.

The risk factors for Legionella pneumonia include cigarette smoking; alcoholism; recent travel; chronic lung, heart, or kidney disease; diabetes mellitus; cancer; and the use of immunosuppressive medications (especially corticosteroids).41 Transplant recipients are at particularly high risk and have been the sentinel victims in several nosocomial outbreaks. Legionella infections are uncommon but unusually severe in HIV-infected patients.

The epidemiologic features of pneumonic and nonpneumonic legionellosis differ in several respects.39,43 During epidemics, the attack rate ofLegionella pneumonia varies from 0.2% to 7%, whereas nonpneumonic legionellosis afflicts over 65% of the people exposed. The incubation period of Legionnaires disease varies from 2 to 12 days, but Pontiac fever usually strikes within 48 hours of exposure. One or more risk factors can be identified in most victims of Legionella pneumonia. In contrast, nonpneumonic legionellosis readily affects the normal host. Common sources have resulted in cases of both Legionnaires disease and Pontiac fever, suggesting that bacterial inoculum and host factors are important in determining the clinical course of infection. It is possible that Pontiac fever results primarily from the inhalation of bacterial endotoxin.43

PATHOGENESIS AND PATHOLOGY

The Legionellaceae are small, pleomorphic, flagellated gram-negative bacilli that often appear coccobacillary in tissue.39,40 They are enveloped by a laminated outer membrane with a unique lipid structure that differs from the lipopolysaccharide of other gram-negative bacteria. Legionellae are facultative intracellular parasites: they can replicate independently or in other cells. They are strictly aerobic but grow best in a reduced-oxygen environment. Buffered charcoal-yeast extract agar supplemented with L-cysteine, ferric iron, and α-ketoglutarate is the most suitable artificial medium.

After inhalation into the lungs, L. pneumophila enters alveolar macrophages via coiling or conventional phagocytosis and replicates in a specialized vacuole.40,44 The formation of this protected intracellular compartment is directed by the dot (defective organelle trafficking) and icm (intracellular multiplication) genes of L. pneumophila. These genes encode for a type IV secretion system that modifies the endocytic pathway of the host cell and delays fusion of the phagosome with lysosomes. As nutrients become scarce, the production of cytotoxins by the stressed bacteria leads to rupture of the macrophage, and the cycle begins anew. The secretion of proteases by L. pneumophila contributes to tissue injury.44 Spreading infection leads to the recruitment of blood-borne phagocytes, but L. pneumophila is relatively resistant to killing by neutrophils and multiplies within monocytes. Humor al immunity appears to play little role in host defense against this infection, because L. pneumophila is resistant to the lytic effects of antibody and complement, and opsonization by specific antibody promotes uptake of the organism by phagocytic cells without stimulating bacterial killing. Ultimately, the infection is probably contained by suppression of intracellular re plication by interferon-gamma-mediated activation of macro phages and the destruction of infected cells by cytotoxic lymphocytes.45

Impairments in specific host defenses underlie the increased risk of legionellosis in certain groups. For example, the alveolar macrophages of smokers are greater in number and more susceptible to parasitism by L. pneumophila than the macrophages of nonsmokers.46 Smokers' macrophages exhibit greater expression of the CD11b/CD18 integrin complex that mediates uptake of L. pneumophila, and they also contain more iron, an essential bacterial nutrient, than the alveolar macrophages of nonsmokers. Toll-like receptors (TLRs) stimulate the immune response to Legionella, and single-nucleotide polymorphisms that affect the functions of TLR4 and TLR5 have been associated with susceptibility to Legionnaires disease.47,48 Conditions associated with impaired cellular immunity, such as T cell malignancies, HIV infection, and the use of immunosuppressive medications, result in deficient macrophage activation and failure to contain intracellular infection.

Pathologically, pneumonic legionellosis is characterized by confluent multilobular or lobar consolidation, with no predilection for particular segments.49 Involvement is bilateral in approximately half the cases. Small pleural effusions are common, but empyema is unusual. The most common histologic pattern is an acute fibrinopurulent alveolitis, with little or no involvement of the conducting airways. There is a dense intra-alveolar infiltrate of macrophages and polymorphonuclear leukocytes, accompanied by an abundant fibrinous exudate and proteinaceous debris. The alveolar septae are congested, and there may be a minor vasculitic component. The bacteria are found in the alveolar exudate and are located mainly within macrophages.

A second histologic pattern of Legionnaires disease is diffuse alveolar damage. This is characterized by an intra-alveolar, fibrinoserous exudate with hyaline membrane formation and evidence of epithelial injury. Few organisms can be identified in this setting, but bacterial invasion of the interstitium may be observed. These features may coexist with the fibrinopurulent pattern and are predominantly found in immunocompromised patients. Fibrosis may occur with resolution of the infection. Bronchi olitis obliterans organizing pneumonia is an unusual complication.

CLINICAL SYNDROMES

Two distinct clinical syndromes of legionellosis have been recognized: the pneumonic form known as Legionnaires disease, and the nonpneumonic, self-limited syndrome called Pontiac fever. The spectrum of infection also includes asymptomatic sero conversion and rare focal infections of extrapulmonary organs.

Legionnaires Disease

The classic picture of Legionnaires disease is that of a chronically ill, middle-aged smoker with rapidly progressive pneumonia associated with nonpurulent sputum, diarrhea, confusion, hyponatremia, and abnormal liver function tests. The clinical features of Legionnaires disease are protean, however, so the disorder cannot reliably be distinguished from other pneumonias on clinical grounds alone39,50,51 [see Table 2].

Table 2 Manifestations of Legionnaires Disease80

Manifestations

Percentage of Cases

Symptoms and signs

 

   Fever

67–100

   Chills

42–77

   Cough

65–92

   Sputum production

41–75

   Hemoptysis

0–41

   Chest pain

14–52

   Dyspnea

14–59

   Headache

17–56

   Myalgias

20–43

   Altered mental status

21–43

   Diarrhea

21–47

   Nausea, vomiting

9–37

   Abdominal pain

5–20

Laboratory abnormalities

 

  Leukocytosis

53–78

   Hyponatremia

17–55

   Elevated liver enzymes

14–88

   Hypophosphatemia

25–51

   Azotemia

15–60

   Proteinuria

25–56

   Hematuria

0–50

Legionnaires disease typically begins with a brief prodrome of profound weakness, malaise, myalgias, and headache. High fever and shaking chills accompany the development of a cough that is productive in approximately half the cases. Sputum is generally nonpurulent. Chest pain is common, and progressive dyspnea is the rule. Watery diarrhea, nausea, and vomiting are often reported.

Physical examination usually reveals a distressed, tachypneic patient. High fever is a hallmark of legionellosis, and temperatures exceeding 39° C (102.2° F) are found in most patients, even those who are immunosuppressed.50 Relative bradycardia (a heart rate less than 100 beats a minute despite a temperature of 40° C [104° F] or higher) may be present. Evidence of consolidation is typically evident on lung auscultation. An encephalopathy ranging from mild confusion to obtundation is common, and focal neurologic deficits have been described.

Routine laboratory tests also typically show an array of abnormalities39,50,51 [see Table 2]. The complete blood count typically demonstrates leukocytosis with a left shift, although a white blood cell count above 15,000/mm3 is unusual. Hyponatremia and abnormal liver enzymes are reported in approximately half the cases. Hypophosphatemia, azotemia, an elevated creatine kinase level, and an increased serum amylase level may also be found. Urinalysis often reveals proteinuria, hematuria, or both.

The chest x-ray in Legionella pneumonia may demonstrate poorly marginated, rounded nodules; patchy alveolar infiltrates; or consolidation in a segmental or lobar distribution.50,52 The infiltrates are unilobar at presentation in most cases, but radiologic progression to multilobar disease is common. Small pleural effusions are frequently evident, but empyema is unusual. Cavitation is an uncommon finding that is most often seen in immunocompromised patients.

Extrapulmonary manifestations of Legionnaires disease can be striking and may reflect the effects of bacterial toxins, host-derived mediators, or metastatic infection.41 Neurologic deficits are usually metabolic in origin, but focal bacterial encephalitis has been described. The pathogenesis of the watery diarrhea that often accompanies Legionella pneumonia is obscure, but intestinal abscesses and peritonitis have been reported. Acute renal failure may complicate legionellosis, as a result of acute tubular necrosis, rhabdomyolysis, or glomerulonephritis. Pyelo nephritis is rare. Overt dissemination of Legionella infection from the lungs to other organs occurs most commonly in immunocompromised persons.

Unusual sites of Legionella infection include the skin (cellulitis and wound infection), the heart (myocarditis, pericarditis, and prosthetic valve endocarditis), and the abdomen (pancreatitis, colitis, and appendicitis).41 Infections at these sites have been reported in the absence of pneumonia. In some instances, the infection appears to have resulted from direct inoculation of tissue or a prosthetic device with contaminated water. Other cases may result from bacteremic seeding from the lungs.

Pontiac Fever

The most common nonpneumonic form of legionellosis is Pontiac fever.39 This syndrome is characterized by a prodrome of malaise, diffuse myalgias, and headache, followed hours later by fever and chills. A mild, nonproductive cough and sore throat may develop, but respiratory tract symptoms are not prominent. Nausea, vomiting, and diarrhea are common, as are neurologic disturbances such as dizziness, neck pain or stiffness, confusion, irritability, nightmares, and ataxia. The physical examination is unremarkable except for the presence of fever, and laboratory tests reveal only leukocytosis. The chest film is clear. The diagnosis is primarily made serologically and supported by the isolation of Legionella from an environmental source. Evidence of infection can be detected by PCR or, in some cases, urinary antigen testing. The acute illness resolves spontaneously in 2 to 5 days, but full recovery may take weeks.

MICROBIOLOGIC DIAGNOSIS

The diagnosis of legionellosis requires the isolation of the organism in culture, detection of microbial antigens or nucleic acids in body fluids, or demonstration of serologic evidence of infection [see Table 3]. However, an early clue to the diagnosis of Legionnaires disease can be obtained from nonspecific stains of sputum, bronchoalveolar lavage fluid, or lung tissue.18 Although legionellae are poorly seen on routine Gram stain, visualization of these small, pleomorphic gram-negative bacilli is improved if basic fuchsin is used as the counterstain in place of safranin O. The intracellular organisms can also be seen on Gimenez, Dieterle, or Wright-Giemsa stains. L. micdadei is unique among the Legionellaceae in appearing acid fast in clinical specimens.

Table 3 Diagnostic Tests for Legionellosis18,53

Test

Specimen

Sensitivity (%)

Specificity (%)

Comment

Culture

Sputum, BALF

11–80

100

All species; requires selective media

Direct fluorescent antibody

Sputum, BALF

22–75

> 90

Legionella pneumophilaonly

Urinary antigen

Urine

48–90

> 95

L. pneumophila serogroup 1 only

Serology

 

   Fourfold change*

Blood

60–80

> 90

L. pneumophila only

   Single titer

 

10–27

> 85

 

PCR

Sputum, BALF, serum, urine

10–100

> 95

All species; not widely available

*Between acute and convalescent samples.
BALF—bronchoalveolar lavage fluid PCR—polymerase chain reaction

Culture of sputum, bronchoalveolar lavage fluid, or lung tissue is the preferred means of confirming the diagnosis.18,41 Specialized media are required for the isolation of Legionella (see above), so cultures for these pathogens must be specifically requested of the laboratory. AllLegionella species can be isolated after 3 to 5 days of incubation, and the recovery of organisms from any body fluid or tissue is diagnostic of infection. Sputum submitted from patients with suspected legionellosis should not be discarded even if epithelial cell contamination occurs, because poor-quality specimens may still yield the organism. Experienced microbiology laboratories can recover legionellae from pretreatment sputum in most cases of legionellosis, but not all laboratories are skilled in this regard, and many patients do not produce sputum.

Antigen detection provides an opportunity for more rapid diagnosis.18,53 The direct fluorescent antibody (DFA) test can identify organisms in sputum, bronchoalveolar lavage fluid, or lung tissue, even after a few days of antibiotic therapy. However, the interpretation of DFA preparations requires considerable expertise, and the sensitivity of this test is limited to specific antigens. The most commonly used monoclonal antibody preparation detects only L. pneumophila serogroups 1 through 12, and commercially available pooled antisera are limited to a few species. Urinary antigen detection is currently the most helpful test for rapid diagnosis of legionellosis. Antigens appear in the urine within 3 days of the onset of illness and may persist for months, although most patients stop excreting antigen within 6 weeks. The sensitivity of this test is higher in cases of severe pneumonia than in cases of milder disease.54 The major limitation of urinary antigen testing is that currently available tests reliably detect only L. pneumophila serogroup 1.

DNA amplification techniques are very promising for the rapid diagnosis of legionellosis.18,53 Preliminary experience suggests that PCR can detect any species of Legionella in sputum, throat swabs, and bronchoalveolar lavage fluid with high sensitivity and specificity. LegionellaDNA has also been detected in the urine and blood of patients with legionellosis. These tests hold great promise but require additional evaluation and refinement to establish their role in clinical practice.

Serologic evidence of infection can be obtained by indirect immunofluorescence, microagglutination, or ELISA.18 A fourfold increase in titer between acute and convalescent samples is very specific for infection with L. pneumophila serogroup 1, but tests for other serogroups and species are more subject to cross-reactivity and have not been standardized. Approximately half of patients with Legionnaires disease will seroconvert within 4 weeks from the onset of illness, and 75% will do so within 9 weeks. A small number of patients take as long as 14 weeks to demonstrate an antibody response, and no serologic response will be detected in up to 25% of cases. The major limitation of seroconversion is the delay in diagnostic information. A single titer of 1:256 or higher suggests acute infection with L. pneumophila but is found in less than 30% of patients during the acute phase of illness.

TREATMENT AND PROGNOSIS

There are no controlled trials to guide the treatment of legionellosis, but retrospective observations, anecdotal experience, animal studies, and in vitro testing support the efficacy of fluoroquinolones, macrolides, tetracyclines, and rifampin in the treatment of Legionnaires disease [see Table 4].41,42,55 Fluoroquinolones may be preferred in immunocompromised patients because they are bactericidal (in contrast to macrolides and tetracyclines), exhibit the most activity in experimental models, and may induce a more rapid clinical response than macrolides.55,56 All of the fluoroquinolones appear to be effective, but ciprofloxacin is less active than other agents in this class. Azith romycin is the most active macrolide against Legionella. Both azithromycin and clarithromycin are more effective and better tolerated than erythromycin. Rifampin is highly active against Legionella, and anecdotal evidence supports its use in combination with erythromycin in severely ill or immunocompromised patients. Of the tetracyclines, doxycycline and minocycline are the most active agents, but these drugs appear to be less effective than fluoroquinolones or macrolides. Trimethoprim-sulfamethoxazole also may be effective, but clinical experience is limited. All of these agents share the ability to penetrate the intracellular environment of macro phages, where legionellae replicate. β-Lactam antibiotics and amino glycosides generally are ineffective in legionellosis.

Table 4 Treatment of Legionellosis

Antibiotic Class

Drug

Dosage

Comment

Fluoroquinolones

Levofloxacin

500 mg p.o. or I.V. q. 24 hr for 10 days

May be preferred in immunocompromised patients because the agents are bactericidal

Gatifloxacin

400 mg p.o. or I.V. q. 24 hr for 10 days

Moxifloxacin

400 mg p.o. q. 24 hr for 10 days

Ofloxacin

400 mg p.o. or I.V. q. 24 hr for 10 days

Macrolides

Azithromycin

500 mg p.o. or I.V. q. 24 hr for 5–10 days

Most active of its class against Legionella

Clarithromycin

500 mg p.o. or I.V. q. 24 hr for 10 days

Erythromycin

500 mg p.o. or 1 g I.V. q. 6 hr for 10–14 days

Less well tolerated than other macrolides

Tetracyclines

Doxycycline

100 mg p.o. or I.V. q. 12 hr for 10–14 days

May be less effective than fluoroquinolones or macrolides

The optimum duration of therapy is unknown. Immunocompromised persons and patients with unusually severe disease may warrant treatment for 2 to 3 weeks, but experience with newer macrolides and fluoroquinolones suggests that shorter courses are adequate.41,55

The prognosis of Legionella pneumonia is influenced by the status of host defenses and the timely initiation of effective antibiotic treatment.41,42 With appropriate treatment, the mortality of Legionnaires disease varies from approximately 5% in healthy persons to 25% in immunocompromised patients.

Pertussis (Whooping Cough)

Whooping cough was first described in 16th-century France.57 The name pertussis was coined by the English physician Thomas Sydenham in 1679, in reference to the intensive cough that is the hallmark of this disease. Bordetella pertussis, the causative agent, was first isolated by Bordet and Gengou in 1906. Other members of the genus that are associated with human disease include B. parapertussis and B. bronchiseptica.58 B. parapertussis lacks pertussis toxin but causes a mild form of whooping cough. B. bronchiseptica is a zoonotic pathogen that can cause human respiratory illness; in immunocompromised patients, manifestations of disease may be severe.58

EPIDEMIOLOGY

  1. pertussisis exclusively a human pathogen: no carrier state, animal host, or natural reservoir is known. The infection is transmitted from person to person by aerosol droplets and is very contagious, spreading quickly among close contacts. Pertussis is endemic year-round, with the peak incidence in summer and fall.58Epidemics occur at intervals of 2 to 5 years.58 The attack rate is highest in infants younger than 1 year and is higher in females than males.58 In the prevaccine era, pertussis was the leading cause of death in children younger than 14 years in the United States. The introduction of the killed whole cell vaccine in the 1940s led to a marked reduction in the prevalence of pertussis, which fell steadily until reaching its nadir in 1981. Since 1982, there has been a resurgence of reported cases of pertussis in the United States. During this time, the incidence in children younger than 5 years has remained relatively constant, but an increasing proportion of cases has been recognized in adolescents and young adults.58 More than 60% of the 11,647 cases of pertussis reported to the CDC in 2003 occurred in persons older than 10 years.6 Most early childhood cases of pertussis now occur in children who either are too young to have received vaccine or have been inadequately vaccinated.6,58,59 Cases in adolescents and adults probably reflect the waning of immunity 5 to 10 years after vaccination. It is likely that pertussis is markedly underreported in older children and adults, because the characteristic whooping cough is usually absent in these age groups. Mildly ill or asymptomatic adults with unrecognized pertussis serve as important reservoirs for the infection of more susceptible children.

Although effective vaccines have dramatically reduced the importance of pertussis in developed countries, the disease remains a leading cause of morbidity and mortality in unvaccinated populations. An estimated 50 million cases of pertussis occur worldwide each year, leading to 300,000 deaths.60,61

PATHOGENESIS

Bordetellae are small, aerobic, gram-negative coccobacilli. They have fastidious growth requirements (see below). Pertussis is primarily a disease of the conducting airways, characterized histologically by generalized inflammation of the bronchi and bronchioles with a mucopurulent luminal exudate.57 The bacilli grow on the surface of ciliated epithelium, where they thrive through the expression of surface components and secreted toxins that suppress mechanical and cellular host defenses [see Table 5].

Table 5 Virulence Factors of Bordetella pertussis60

Virulence Factor

Effects

Filamentous hemagglutinin

Attachment to ciliated epithelium; uptake by leukocytes via complement receptor 3

Agglutinogens, fimbriae

Attachment to epithelium

Lipopolysaccharide

Endotoxin activity

Tracheal cytotoxin

Ciliostasis, epithelial injury

Adenylate cyclase toxin

Induces increased cyclic adenosine monophosphate; impairs leukocyte function

Dermonecrotic toxin

Vascular smooth muscle contraction, ischemic necrosis

Pertussis toxin

Inhibits G protein–coupled signaling; lymphocytosis, hyperinsulinemia, encephalopathy

Type III secretion system

Delivers proteins into cytoplasm of target cells

Pertussis toxin is the most intriguing factor produced by B. pertussis. This heterodimeric protein catalyzes adenosine diphosphate (ADP)-ribosylation of guanine nucleotide-binding (G) proteins, thereby inhibiting signal transduction through G-coupled transmembrane receptors.58,60 How this action is linked to the pathophysiology of pertussis is not well understood. Pertussis toxin causes lymphocytosis, hyperinsulinemia, and possibly encephalopathy, but its role in the respiratory manifestations of whooping cough remains enigmatic.58,60Antibodies directed against pertussis toxin are protective against disease, yet B. parapertussis, which does not produce the toxin, can cause a similar (albeit milder) respiratory illness.

Relatively little is known of the essential elements of host defense against pertussis, but cellular and humoral immunity are both involved.58,60 Protective maternal antibodies are not transferred across the placenta, contributing to the susceptibility of infants. The resolution of whooping cough is accompanied by the disappearance of B. pertussis from the airway epithelium.

CLINICAL MANIFESTATIONS

Classic pertussis is a three-stage illness lasting 4 to 8 weeks.57,58,60 After an incubation period of 6 to 20 days, the clinical manifestations begin with the catarrhal stage. This phase lasts 1 to 2 weeks and resembles the common cold, with rhinorrhea, conjunctivitis, lacrimation, low-grade fever, and mild nonproductive cough. The distinctive paroxysmal stage follows for 2 to 4 weeks and is characterized by violent spasms of coughing. In a typical episode, a single expiration is punctuated by five to 20 explosive coughs in rapid succession, followed by a gasping, forceful inhalation through a narrowed glottis that produces the characteristic whoop. Paroxysms often are accompanied by cyanosis and followed by emesis. Infants have less pronounced whoops but may become apneic during coughing fits. The violent coughing can result in epistaxis, conjunctival hemorrhage, petechiae, rib fractures, pneumothorax, incontinence, hernias, and rectal prolapse. Paroxysms occur 10 to 30 times a day, often begin without warning, and can be triggered by activities such as eating, drinking, sneezing, yawning, or exposure to airborne irritants. The paroxysms are exhausting, and patients avoid oral intake, leading to dehydration and weight loss.

Physical examination during the spasmodic stage often is unremarkable. Eyelid edema may be present, and auscultation of the chest may reveal coarse rales and rhonchi. Fever is unusual in the absence of complications. The blood count at this time is characterized by marked lymphocytosis: the total WBC count often exceeds 30,000/mm3, of which more than 60% are lymphocytes. Hypoglycemia is occasionally observed. Chest radiographs are usually normal but may demonstrate hyperinflation, atelectasis, or perihilar infiltrates.57,62 Complications that can develop during the paroxysmal phase include pneumonia, otitis media, seizures, and encephalopathy. Pneumonia, caused either byB. pertussis or by a secondary invader, develops in 10% to 15% of young children and is responsible for most deaths.59 The convalescent third stage of pertussis, during which the frequency and severity of the cough gradually diminish, usually lasts 1 to 3 weeks but may extend for months.

Adults and adolescents with partial immunity have a less severe illness and typically present with a persistent cough of several weeks' duration. The cough is paroxysmal and often productive of purulent or nonpurulent sputum, but whoops are unusual. As in children, violent coughing in adults with pertussis may result in posttussive vomiting, syncope, urinary incontinence, and rib fractures. About half of adult patients report a preceding catarrhal illness. Lymphocytosis is usually absent. Numerous recent studies suggest that 10% to 32% of adolescents and adults with cough lasting longer than 1 to 2 weeks have serologic evidence of pertussis.58,63 Annual serologic screening programs have found that undiagnosed pertussis is common in adolescents and adults.

A presumptive diagnosis of pertussis can be made in susceptible children with the characteristic whooping cough and lymphocytosis. However, the typical whoop is not uniformly present, and similar illnesses can be caused by B. parapertussis, respiratory viruses (particularly adenovirus, parainfluenza, and respiratory syncytial virus), Mycoplasma pneumoniae, and Chlamydia pneumoniae.58

MICROBIOLOGIC DIAGNOSIS

Microbiologic confirmation of pertussis is best made during the catarrhal or early paroxysmal stages, when B. pertussis can be detected in the nasopharynx by culture, immunofluorescence, or PCR.58,60,64 Cultures of nasopharyngeal aspirates have higher yields than those of nasopharyngeal swabs; if the latter are used, calcium alginate and Dacron are the preferred materials. Throat specimens are unsatisfactory because the oropharynx lacks the ciliated epithelium to which B. pertussis adheres. The nasopharyngeal sample should be directly streaked on suitably enriched media, such as charcoal-blood agar or Bordet-Gengou agar. If a delay in plating is anticipated, a charcoal-containing transport medium (e.g., Regan-Lowe) should be used.64 Typical colonies of tiny gram-negative bacilli appear after 3 to 7 days of culture, and identification can be confirmed by agglutination or immunofluorescence. Culture yield is reduced by antibiotic therapy or prior immunization and falls with the duration of illness. Cultures are usually negative during the paroxysmal phase and in adults with persistent cough.

  1. pertussiscan also be detected in respiratory secretions by DFA staining in 30% to 65% of cases during the catarrhal stage.58,60,64Polyclonal antibody preparations have been plagued by variable sensitivity and poor specificity, but a monoclonal reagent has been found to be more satisfactory.64Nonetheless, immunofluorescence is mainly used as a screening test for outbreak investigation.

PCR testing of nasopharyngeal specimens has been found to be more sensitive than culture or immunofluorescence for the diagnosis of pertussis, with specificity greater than 85%.58,60,64 This very promising technique has become increasingly available, but the methods and reagents for the diagnosis of pertussis by PCR have not yet been standardized.

Detection of serum antibody responses to B. pertussis by ELISA remains an important if imperfect diagnostic tool. Serologic tests are most useful for the diagnosis of pertussis in unvaccinated children, in whom the sensitivity of paired specimens or a single elevated titer more than 5 weeks after the onset of symptoms is 50% to 90%.58,64 Multiple antigens are often used in antibody assays to enhance sensitivity, but pertussis toxin is the only antigen unique to B. pertussis.58,64 The interpretation of serologic results in vaccinated persons is more difficult. The meaning of a single elevated antibody titer should be defined in relation to age-matched, population-specific controls.63,64Paired specimens have limited utility because the anamnestic response to infection is usually so rapid that no significant rise in antibody concentrations occurs between acute and convalescent sera.63,64

TREATMENT

Antibiotic therapy with erythromycin speeds elimination of B. pertussis from the nasopharynx and reduces transmission of infection.58,60Antibiotic treatment may also ameliorate the severity of disease, even if it is started in the paroxysmal phase, but this is less clear. The estolate form of erythromycin, 40 mg/kg/day (maximum, 2 g/day) divided in two to four doses, is preferred and should be administered for 7 to 14 days.65 There is limited evidence that the newer macrolides, clarithromycin (15 to 20 mg/kg/day in two divided doses, to a maximum dosage of 1 g/day for 7 days) and azithromycin dihydrate (15 to 20 mg/kg/day in one dose, to a maximum dosage of 600 mg/day for 5 days), are also effective.65 Alternative agents that speed elimination of B. pertussis include trimethoprim-sulfamethoxazole, tetracycline, and chloramphenicol.60 Fluoroquinolones are active against B. pertussis in vitro, but their efficacy in the treatment of pertussis has not been demonstrated.

The value of antibiotic therapy in adults with persistent cough and suspected pertussis is unknown.

Infants with pertussis should be hospitalized for monitoring, airway suctioning, oxygen supplementation, hydration, and nutritional support. Treatment of severe cases with pertussis immune globulin has shown promise in animal studies and human trials.66 Systemic corticosteroids may be helpful in infants with life-threatening disease.60 Inhaled corticosteroids and bronchodilators are of uncertain value in ameliorating symptoms.

PREVENTION

Pertussis can be prevented by quarantine of infected individuals, prophylactic antibiotic treatment of exposed infants, and vaccination. Patients with active pertussis in the catarrhal and early paroxysmal stages should be isolated for 5 to 7 days after starting antibiotics. Prophylactic treatment of household contacts with a full course of erythromycin can reduce the spread of disease and is recommended for young children who have not completed primary immunization. In neonates, however, erythromycin prophylaxis is associated with an increased risk of hypertrophic pyloric stenosis.67

Immunization with inactivated whole-cell vaccine was introduced in 1948, and acellular vaccines composed of inactivated pertussis toxin and one or more additional components were licensed in 1991. Current recommendations call for primary immunization with an acellular vaccine, which is combined with diphtheria and tetanus toxoids (DTaP), at ages 2, 4, and 6 months, with boosters at 15 to 18 months and at 4 to 6 years.68 Pertussis vaccines provide approximately 80% protection from clinical pertussis, and immunized persons who become ill after exposure experience less severe disease.58,68 Protection declines with time.58 Historically, boosters have not been given to older children and adults because of the unacceptable toxicity of the whole-cell vaccine; reactions to whole-cell pertussis vaccine (DTP) in children include local pain and swelling, fever, anorexia, irritability, vomiting, hypotonic hyporesponsiveness, seizures, and anaphylaxis. All of these reactions are much less common with the acellular vaccines.58,68 The acellular vaccine is immunogenic and well tolerated by adolescents and adults.69,70 The routine use of vaccine in adolescents and adults, who constitute the major reservoir for per tussis, has the potential to reduce the overall burden of pertussis and the transmission of the disease to children; however, recommendations for boosters in these age groups have not been established.

Pseudomonas aeruginosa Infections

  1. aeruginosais an important opportunistic pathogen, with a prominent role in cystic fibrosis. The organism was first isolated from a surgical wound in 1882 by the French pharmacist Carle Gessard.71The species designations in both the original name for the organism, Bacillus pyocyaneus, and its modern name, P. aeruginosa, refer to the blue-green pigments produced by these bacteria, which may serve as clinical markers for infection.72 More than a dozen species of Pseudomonas are now recognized, but only P. aeruginosa is an important human pathogen.

EPIDEMIOLOGY

  1. aeruginosais widely distributed in nature, particularly in water, soil, and vegetation. Nutritional versatility, suppression of competitors, and resistance to antibiotics contribute to the diverse habitat of this organism.72P. aeruginosa is not part of the normal flora of most humans, but it can be cultured from the stool, throat, nose, or moist areas of the skin of up to 20% of healthy persons.71,72
  2. aeruginosais mainly an opportunistic and nosocomial pathogen. It has a marked predilection for colonizing damaged epithelium, such as burned skin, bronchiectatic airways, and sites of indwelling appliances such as tracheostomy tubes, endotracheal tubes, urinary catheters, intravascular devices, peritoneal dialysis catheters, and body piercings.71,73Patients with cystic fibrosis are especially prone to airway colonization. The risk of colonization at any site increases with exposure to broad-spectrum antibiotics and duration of hospitalization.72Colonization is an important antecedent to invasive infection, particularly in neutropenic patients.71,72 Additional risk factors for invasive disease include cytotoxic chemotherapy, treatment with corticosteroids, and HIV infection.71,74 Persons with diabetes mellitus are at risk for invasive external otitis.

Outbreaks of P. aeruginosa infection can result from common-source exposures. Community outbreaks of folliculitis have been associated with swimming pools, whirlpool baths, and hot tubs. Ocular infections have resulted from contaminated cosmetics and contact lens solution.71 In hospitals, epidemics of P. aeruginosa infection have been linked to contaminated sinks, mops, cleaning solutions, therapy pools, respiratory therapy equipment, endoscopic devices, flowers, vegetables, and water pitchers.71

PATHOGENESIS

  1. aeruginosais a motile gram-negative bacillus that is typically thin and either straight or slightly curved. It does not ferment sugars and grows strictly aerobically. P. aeruginosahas simple nutritional requirements and tolerates a wide range of environmental conditions. It grows well on most laboratory media and emits a sweet, grapelike odor. Most strains produce one or more diffusable pigments, including pyocyanin, pyoverdin, pyorubin, and pyomelanin.71
  2. aeruginosais a formidable pathogen that is well equipped by an exceptionally large genome to colonize and invade epithelial surfaces, undermine host defenses, and induce systemic toxicity. P. aeruginosaattaches to tracheobronchial mucus and replicates in a biofilm on the mucosal surface, using quorum sensing to coordinate environmental adaptation and virulence factor production.74,75 Although P. aeruginosaadheres poorly to normal epithelium, it readily attaches to damaged epithelial cells via pili and other adhesins.74,75 The persistence of some strains of P. aeruginosa on epithelial surfaces is aided by the abundant secretion of tenacious mucopolysaccharide, which facilitates adherence to host cells, inhibits ciliary activity, and blocks ingestion by phagocytes. The virulence of P. aeruginosa is further aided by a type III secretion system that permits injection of exotoxins S, T, U, and Y directly into host cells, thus promoting cytotoxicity and inflammation.74,75 Invasion across epithelial surfaces by P. aeruginosa is made possible by proteolytic enzymes that damage epithelial cells, loosen tight junctions, and digest extracellular matrix.74,75 These enzymes also interfere with host defenses by cleaving immunoglobulins, complement, and cytokines. Secreted toxins such as exotoxin A, leukocidin, hemolysins, and pyocyan in cause additional tissue damage, hemolysis, and cytotoxicity to macro phages, neutrophils, and lymphocytes. Vascular injury by exotoxin A can result in local or distant hemorrhagic necrosis. Damage to epithelial and endothelial barriers permits the entry of bacteria, bacterial products, and endogenous proinflammatory mediators into the systemic circulation, leading to systemic toxicity and shock.

The striking association of P. aeruginosa with cystic fibrosis (CF) is an area of special interest.76 Most patients with CF are initially colonized with an environmental, nonmucoid strain of P. aeruginosa. These bacteria eventually undergo a phenotypic shift in the CF airway to express an unusual lipopolysaccharide structure and hypersecrete mucoid exopolysaccharide (alginate).76 The factors controlling these adaptations and the mechanisms underlying the persistence of P. aeruginosa in the CF airway remain incompletely understood. P. aeruginosa binds somewhat more avidly to CF epithelium than to normal epithelial cells.75,76 However, the uptake of P. aeruginosa by epithelial cells is defective in CF. The cystic fibrosis transmembrane conductance regulator (CFTR) may serve as a receptor for the internalization of surface bacteria, and shedding of these infected cells may be a normal defense mechanism against P. aeruginosa that is defective in CF.75,76 Also, human β defensin 1, an antibacterial peptide secreted by airway epithelial cells, is inactive in the high salt concentrations that some investigators have found in CF airways.75,76 Chronic inflammation precipitated by P. aeruginosa infection contributes to the airway injury and progressive loss of pulmonary function that characterize CF.

CLINICAL SYNDROMES

Pneumonia

Nosocomial pneumonia

  1. aeruginosais one of the most common causes of hospital-acquired pneumonia and is implicated in approximately 25% of cases complicating mechanical ventilation.21,77Risks for nosocomial P. aeruginosa pneumonia include prolonged hospitalization, mechanical ventilation for 7 days or longer, and exposure to broad-spectrum antibiotics.77 Tracheal colonization with P. aeruginosa usually precedes infection.

The clinical features of ventilator-associated pneumonia are nonspecific: fever, purulent tracheal secretions, leukocytosis, and new or changing infiltrates on chest films.21,77 The radiographic abnormalities are multifocal and bilateral in most cases of P. aeruginosa pneumonia and are more severe than those observed with other nosocomial pathogens.21 Cavitation is evident on plain films or chest tomography in about 25% of cases.78

The diagnosis of hospital-acquired pneumonia in critically ill patients is challenging because tracheal colonization with potential pathogens cannot be distinguished easily from infection on clinical grounds.21,77 The diagnosis of P. aeruginosa pneumonia, particularly in intubated patients, is most accurately made from quantitative cultures of bronchoscopic specimens. Yields of colony-forming units (CFU) of 1,000/ml from a protected specimen brush or 10,000/ml from a bronchoalveolar lavage are indicative of infection. Blood cultures are positive in less than 10% of cases.

Hospital-acquired pneumonia caused by P. aeruginosa is associated with a worse outcome than infections caused by other pathogens. In well-documented cases of P. aeruginosa ventilator-associated pneumonia, the reported crude mortality ranges from 45% to 85% and the attributable mortality is about 40%.77,79 In fatal cases, death usually results from septic shock or multiple-organ failure.77 Relapses are relatively common after successful treatment.77,79

Community-acquired pneumonia

  1. aeruginosais a rare cause of community-acquired pneumonia but is disproportionately represented among the most severe cases.80,81Most patients with P. aeruginosapneumonia have underlying conditions that place them at particular risk for colonization of the lower airways with P. aeruginosa (e.g., cystic fibrosis, bronchiectasis, or tracheostomy); have important defects in host defenses caused by malignancy, aplastic anemia, cytotoxic chemotherapy, or advanced HIV infection; or have been recently hospitalized.80,81 The few cases ofP. aeruginosa pneumonia that have been reported in healthy persons have occurred predominantly in smokers.80

Community-acquired P. aeruginosa pneumonia is typically acute in onset and rapidly progressive.72,80 Fever, cough, chest pain, and progressive dyspnea are the usual symptoms. The cough is generally productive of purulent sputum that may be streaked with blood. On examination, patients are apprehensive, often confused, and acutely ill, with fever, tachypnea, tachycardia, hypotension, and cyanosis. The chest x-ray typically reveals multifocal, nodular alveolar infiltrates, often bilateral. Small areas of parenchymal cavitation may be evident, but large effusions and empyema are unusual. Routine laboratory findings are nonspecific and may include leukocytosis or leukopenia, elevated transaminase levels, and azotemia. Sputum Gram stains demonstrate gram-negative bacilli in nearly all cases, and sputum cultures grow P. aeruginosa in more than 80% of cases.72,80 Blood cultures often are positive. The clinical course is usually rapidly progressive despite therapy, with most patients experiencing respiratory failure. Mortality exceeds 25%.80,81

Pneumonia in HIV disease

  1. aeruginosainfections of the lower respiratory tract are unusually common in patients with advanced HIV disease, and the incidence may be increasing.74,82These infections occur in the setting of very low CD4+ T cell counts (median, < 25 cells/mm3). Additional risk factors in some cases include neutropenia, recent antibiotic therapy, and treatment with corticosteroids. Most infections are community acquired. The clinical course can be fulminant, but a subacute presentation also has been described, characterized by productive cough, fever, and dyspnea for days to weeks. The radiographic features are similar to those of other cases of community-acquired P. aeruginosa pneumonia. P. aeruginosa is readily identified in purulent sputum in the majority of cases; blood cultures are positive in 10% to 30% of cases.

Most patients with P. aeruginosa pneumonia complicating HIV infection respond to antibiotic treatment, but relapses are common.

Cystic Fibrosis

More than 80% of patients with CF develop chronic airway infection with mucoid strains of P. aeruginosa. This infection is associated with chronic airway inflammation, progressive loss of pulmonary function, and eventual death from respiratory failure.74,76 Intensive and prolonged treatment of initial infection with aerosolized tobramycin or colistin may delay chronic infection and preserve pulmonary function.76 Once chronic infection with mucoid P. aeruginosa is established, it is virtually impossible to eradicate.

Patients with CF experience pulmonary exacerbations that are associated with an increased density of P. aeruginosa in sputum. These episodes are characterized symptomatically by increased coughing, more purulent or bloody sputum, chest congestion, and dyspnea. Physical signs include tachypnea, use of accessory muscles for breathing, fever, and weight loss. A decline in airflow is evident on pulmonary function testing, and the chest x-ray may demonstrate new or changing infiltrates.76

Treatment of pulmonary exacerbations in CF includes chest physiotherapy, bronchodilators, mucolytics, and combination antibiotic therapy guided by in vitro susceptibility testing of sputum isolates.76 Intermittent maintenance therapy with inhaled tobramycin (300 mg twice daily during alternate months) can suppress P. aeruginosa, improve airflow, and reduce the need for hospitalization.83 Macrolides such as azithromycin also may improve lung function in CF patients colonized with P. aeruginosa, by mechanisms that are unclear.84

Bacteremia

  1. aeruginosabacteremia occurs predominantly in hospitalized patients with severe underlying disease.74,85,86,87The most common sources of infection are the lower respiratory tract, the urinary tract, and the skin; intravascular catheters are implicated in 7% to 16% of cases. No primary source of infection can be identified in up to 50% of episodes. The overall mortality of P. aeruginosa bacteremia is approximately 20%. An increased risk of death is observed in patients with pneumonia, severe sepsis, fatal underlying disease, and delayed administration of effective antibiotic therapy.

Endocarditis

  1. aeruginosais a rare cause of infective endocarditis. The majority of reported cases have occurred in injection drug users.74,88Occasional episodes have complicated cardiac surgery or involved seeding of a prosthetic device. Most cases have been localized to the right side of the heart and have developed on normal valves.

Patients with right-sided infection often present with a prolonged febrile illness and may complain of cough or chest pain associated with radiographic evidence of septic pulmonary emboli.88 Patients with aortic or mitral valve involvement follow a more acute clinical course that may include evidence of congestive heart failure, myocardial abscess, or systemic embolization.88 The diagnosis of P. aeruginosaendocarditis is made from blood cultures, cardiac auscultation, and echocardiography.

Most right-sided infections can be cured by 6 weeks of high-dose parenteral treatment with an extended-spectrum penicillin and an aminoglycoside. Left-sided infections usually require valve replacement surgery in conjunction with medical therapy.74,88,89 The overall survival in left-sided infections is approximately 50%.

Urinary Tract Infections

  1. aeruginosais a common cause of urinary tract infection in hospitals and chronic care facilities. These infections usually follow instrumentation, surgery, or catheterization of the urinary tract, often in patients recently treated with antibiotics.72,74Symptomatic infections can be treated with single-agent antibiotic therapy. Catheter-associated infections are unlikely to be eradicated unless the catheter is removed.

Ear Infections

Swimmer's ear

  1. aeruginosais commonly isolated from cases of acute diffuse external otitis (swimmer's ear), which is associated with freshwater swimming in warm, humid climates.74This condition is characterized by an inflamed, draining, pruritic, and sometimes painful external auditory canal. Local cleansing followed by topical treatment with an otic solution containing 2% acetic acid or an antibiotic in combination with cortico steroids speeds recovery. Recurrences are common.

Malignant (necrotizing) otitis externa

  1. aeruginosais the pathogen in nearly all cases of malignant external otitis, a chronic, invasive infection of the external auditory canal that predominantly afflicts elderly persons with diabetes mellitus.74,90Rarely, cases have been reported in AIDS patients and immunocompromised children. The infection spreads to the temporal bone and mastoid, often involving the adjacent cranial nerves as they exit the skull. Severe otalgia is the presenting symptom, and most patients have purulent otorrhea with an intact tympanic membrane. Facial nerve paresis is evident in 30% to 40% of cases; other cranial neuropathies are less common. Fever and other systemic signs of infection are usually absent. The erythrocyte sedimentation rate (ESR) is nearly always markedly elevated. Technetium-99m bone scanning is very sensitive but not specific for this condition. CT and magnetic resonance imaging are useful for defining the extent of disease, with MRI being more sensitive for delineating the soft tissue component.74,90 The diagnosis can be made from the clinical presentation, imaging studies, and cultures of diseased bone or granulation tissue in the external canal.

Local debridement and antibiotic therapy for 4 to 8 weeks are successful in most cases. An oral fluoroquinolone (e.g., cipro flox acin, 750 mg twice daily) is usually effective. Parenteral therapy with an antipseudomonal β-lactam with or without an aminoglycoside may be required for recalcitrant cases or those caused by resistant strains.74,90 The ESR, serial gallium-67 scans, or both can be used as markers of disease activity and guides to duration of therapy.

Eye Infections

  1. aeruginosais an important cause of keratitis, particularly in contact lens wearers.74This infection develops as a complication of corneal injury, which permits bacterial attachment to the damaged epithelium and subsequent invasion.

The clinical manifestations begin with a small, painful ulcer that spreads with gray discoloration and edema of the cornea, anterior chamber reaction, and mucopurulent exudate. The microbiologic diagnosis can be made by Gram stain and culture of purulent material in the base of the ulcer.

Emergent treatment is with frequent (every 15 to 30 minutes) topical applications of an ophthalmic solution containing high concentrations of an aminoglycoside or fluoroquinolone. P. aeruginosa is also occasionally implicated in posttraumatic endophthalmitis and nosocomial conjunctivitis.

Central Nervous System Infections

Meningitis caused by P. aeruginosa occurs most often as a complication of neurosurgery.74 Rare cases result from P. aeruginosa bacteremia, particularly in debilitated patients with cancer or severe burns.

Fever and depressed consciousness are the cardinal manifestations. The onset often is insidious in postoperative cases. The diagnosis is made from culture and Gram stain of the cerebro spinal fluid.

Ceftazidime is the preferred treatment, often given in combination with an intravenous aminoglycoside. Alternative agents that achieve adequate levels in the cerebrospinal fluid include meropenem, aztreonam, and ciprofloxacin. Intrathecal therapy with aminoglycosides may be required for refractory cases or highly resistant organisms.74

Bone and Joint Infections

  1. aeruginosais associated with a distinctive spectrum of acute and chronic osteochondral infections that result from hematogenous seeding, direct inoculation, or contiguous spread from adjacent tissues.74Hematogenous infections are most commonly seen in injection drug users and typically involve the sternoclavicular joints, symphysis pubis, sacroiliac joints, or cervical vertebrae. Lumbosacral vertebral osteomyelitis may complicate instrumentation of the urinary tract via contamination of the venous plexus shared by the pelvis and the spine. P. aeruginosa is also the most common cause of osteochondritis after puncture wounds of the foot. This syndrome is most often seen in children and results from direct inoculation of bacteria colonizing the moist insoles of their sneakers. Chronic osteomyelitis caused by P. aeruginosa can develop as a complication of orthopedic surgery, sternotomy, or contiguous infection of pressure sores or ischemic skin ulcers.

The cardinal symptom of acute osteochondral P. aeruginosa infection is pain lasting days to weeks. Examination is notable for local tenderness and diminished mobility, frequently with warmth and erythema. Fever and leukocytosis are often present, and the ESR is almost always elevated. The clinical presentation of chronic osteomyelitis is subtler than that of acute infection. Pain, nonunion, and draining ulcers are common, often without systemic manifestations.

Imaging studies are important in the evaluation of P. aeruginosa bone and joint infections.91 Plain x-rays or CT scans can reveal evidence of bony destruction or periosteal reaction but may be negative early in the clinical course. MRI is more sensitive than radiography, particularly for nonosseous changes. Technetium-99m bone scans are invariably positive in osteomyelitis but may be normal when the infection is confined to the joint. Confirmation of P. aeruginosa as the pathogen is made from joint aspiration or bone biopsy. Blood cultures are negative in most cases.

Treatment of P. aeruginosa osteochondral infections usually requires 4 to 6 weeks of antibiotic therapy. An antipseudomonal β-lactam in combination with an aminoglycoside is generally recommended, but single-agent therapy, particularly with a fluoroquinolone, may be effective.74,91 Surgical debridement is necessary when bone necrosis is evident, but most infections confined to a joint can be treated with antibiotics alone. In the case of P. aeruginosa osteochondritis of the foot in children, 1 week of antibiotic therapy after debridement is sufficient for cure. Chronic infections are difficult to eradicate, and suppressive therapy may be required.

Skin Infections

  1. aeruginosacauses a variety of cutaneous infections that can affect normal skin after submersion in contaminated water.

Folliculitis

Outbreaks of folliculitis, or swimmer's itch, have been associated with the use of hot tubs, whirlpools, therapy baths, and swimming pools.74The presenting feature is a diffuse, pruritic eruption that may be follicular, maculopapular, vesicular, or pustular. The rash develops 8 hours to 5 days after exposure and usually involves skin that had been covered by a swimsuit. Mild headache and other complaints may be present, but fever is unusual. P. aeruginosa can be identified from stains and cultures of pustular lesions. Topical drying agents may ease symptoms, but the rash resolves within 7 days without specific therapy.

Hot-foot syndrome

Another waterborne infection is Pseudomonas hot-foot syndrome, which is characterized by the development of tender, warm, erythematous 1- to 2-cm nodules on a background of plantar or palmar erythema.92 These lesions appeared in children 10 to 40 hours after being in a contaminated wading pool and resolved without antibiotic treatment within 7 to 14 days.

Green-nail syndrome

This syndrome results from discoloration of the nail plate by pyocyanin and occurs in persons who frequently submerge their hands. Local cleansing and debridement, including draining of any associated paronychia, are generally successful.74,93

Toe web infection

  1. aeruginosais a frequent cause of toe web infections. These occur most often in tropical climates and may complicate minor trauma or tinea pedis. The affected toe webs are macerated, thickened, and painfully fissured; a purulent exudate is often present. Examination under a Wood lamp can reveal green-white fluorescence from the elaboration of pyoverdin. Toe web infections often can be managed with local measures, but systemic antibiotics may be needed in severe cases.74,93

Burn wound sepsis

In years past, P. aeruginosa was the most common agent of burn wound sepsis, which was the leading cause of death after thermal injury. With the development of effective topical antimicrobials, wound excision, and other advances in burn wound care, burn wound sepsis has become far less common. Fungi are now the dominant pathogens, but P. aeruginosa remains an important consideration. Suspicion of wound sepsis should be aroused by the appearance of dark-brown, black, or violaceous discoloration of the wound. Hemorrhage, purulent drainage, or green pigment also may be present. Blood cultures may be positive, but the diagnosis of invasive infection is made from wound biopsies demonstrating microbial invasion of normal tissue. Treatment of P. aeruginosa infection is with systemic antibiotics, topical mafenide acetate cream, and surgical debridement.94 P. aeruginosa can also cause posttraumatic cellulitis, deep abscesses, necrotizing fasciitis, and other locally invasive pyodermas, particularly in immunocompromised persons.74

Ecthyma gangrenosum

Ecthyma gangrenosum is a distinctive skin infection that results in most cases from P. aeruginosa bacteremia, usually in the setting of neutropenia, cancer, burns, AIDS, or other severely debilitating conditions.74,93 The lesions may be discrete or multiple and begin as painless macules or nodules that may become vesicular or bullous. The lesions undergo central hemorrhagic necrosis and ulceration over a period of 12 to 24 hours, with a surrounding rim of tender erythema. Ecthyma gangrenosum is characterized histologically by bacterial invasion of dermal veins. Blood cultures are usually positive, and P. aeruginosa can be demonstrated in biopsies or scrapings from the base of the ulcer. Treatment requires prompt administration of intravenous antibiotics and management of the underlying condition.

ANTIBIOTIC TREATMENT

The treatment of P. aeruginosa infections is particularly challenging because of the remarkable resistance of this organism to most antibiotics and its propensity to develop further resistance during the course of therapy. The intrinsic antimicrobial insensitivity of P. aeruginosa arises from several complementary mechanisms.74,95 First, a relatively impermeable outer membrane limits the access of antibiotics to their binding sites. Second, an active efflux pump can expel agents that penetrate the outer barrier. Third, expression of a chromosomally encoded β-lactamase is induced on exposure to β-lactam antibiotics. Furthermore, mutations in P. aeruginosa can result in the rapid selection of resistant organisms during the course of treatment. Fourth, P. aeruginosa can acquire plasmids bearing additional resistance genes, such as those encoding for extended-spectrum β-lactamases, carbapenemases, and enzymes that inactivate aminoglycosides.74,95 Finally, the growth of P. aeruginosa in biofilms induces the production of periplasmic glucans that bind and sequester antibiotics.96

Antimicrobial agents that are effective against most strains of P. aeruginosa include β-lactams, fluoroquinolones, and aminoglycosides [see7:XIV Chemotherapy of Infection]. In the United States, the β-lactams showing the greatest activity against P. aeruginosa are meropenem and piperacillin-tazobactam; the most effective fluoroquinolone remains ciprofloxacin, and the most active aminoglycoside is amikacin.97Local resistance patterns vary, however, so it is important to determine the antibiotic susceptibilities of individual strains by in vitro testing. Hospital isolates exhibit greater resistance than outpatient isolates, and organisms cultured in intensive care units are the most resistant. Multidrug-resistant strains are increasing in prevalence; these may be susceptible to antibiotic combinations or polymyxins.74,97

Treatment of suspected P. aeruginosa infection should begin with high doses of an antipseudomonal β-lactam in combination with an aminoglycoside or fluoroquinolone. The use of two agents increases the likelihood of effective initial therapy, which is associated with reduced mortality.85,87 Whether combination therapy should be continued after sensitivities are known is unclear.98 On the one hand, the combination of an aminoglycoside with a β-lactam antibiotic results in synergistic killing of P. aeruginosa and improves outcome in some animal models of infection.80,99 Prospective observational studies have found combination therapy with β-lactams and aminoglycosides to be associated with improved survival in neutropenic or bacteremic patients with P. aeruginosa infections.99,100 On the other hand, aminoglycosides are relatively toxic, and other antibiotic combinations are less predictably synergistic against P. aeruginosa.80 Recent retrospective clinical studies have not identified any survival advantage of dual-drug therapy over treatment with a single effective agent.77,85,86,87 Combination therapy also has not been shown to suppress the emergence of resistant strains. Despite this uncertainty, it may be prudent to use combination therapy whenever possible because of the high mortality and refractory nature of P. aeruginosainfections. An exception is urinary tract infection, which can be treated effectively with a single agent. Most P. aeruginosa infections can be cured with 2 to 3 weeks of antibiotic therapy, but longer courses are required for endocarditis and osteomyelitis.

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Editors: Dale, David C.; Federman, Daniel D.