Chapter 268. Moraxella Catarrhalis

Moraxella catarrhalis is a gram-negative aerobic diplococcus that belongs to the Neisseraceae family. It has been known as Micrococcus catarrhalis, Niesseria catarrhalis, and Branhamella catarrhalis. It commonly inhabits the upper respiratory tract. For many years, it was considered a nonpathogenic member of the resident flora of the nasopharynx. Over the past 25 to 30 years, it has been recognized as a genuine mucosal pathogen and is now considered an important cause of otitis media and sinusitis in healthy children and adults. It also causes lower respiratory tract infections and exacerbation of bronchitis in adults with chronic lung disease. Occasionally, it can cause a variety of severe infections, including septicemia, pneumonia, and meningitis, especially in the immunocompromised hosts.

Epidemiology

M catarrhalis is a normal inhabitant of the upper respiratory tract. Nasopharyngeal colonization rate is highest during infancy and early childhood and lowest in adulthood. Colonization rates of as high as 36% to 50% in infants and young children,1 and 1% to 3% in adults,2 have been reported. In one study of a large cohort of infants who were followed prospectively from birth to 2 years of age, 66% became colonized with M catarrhalis by 1 year and 77.5% by 2 years of age. In the same group, nasopharyngeal colonization increased from 27% during healthy visits to 63% on visits associated with otitis media.3 Other studies have shown that colonization of children varies with the season and is more common in fall and winter (46%) than in spring and summer (9%).4 Overall, colonization was higher in children with upper respiratory tract infection (36%) than in children without (18%), and was more common in children ages 24 months (32%) than in children older than 24 months (14%). Colonization with M catarrhalis is reported to be more common in asthmatic children than in normal children.

Factors influencing colonization and elimination are not fully understood, but adhesion to mucosal receptors and immune responses are implicated in addition to bacterial colonization dynamics. In general, potential pathogens are more likely to colonize the nasopharynx of children prone to recurrent otitis media, where impaired local immunity and repeated exposure to respiratory pathogens are additional risk factors.5Colonization appears to be an ongoing process with an elimination-colonization turnover of various strains.

The mode of transmission of the organism is presumed to be direct contact with contaminated respiratory tract secretions and/or droplet spread.

Pathophysiology

M catarrhalis is an aerobic gram-negative diplococcus that has a striking resemblance to meningococcus and gonococcus, except that it is unencapsulated. It grows well on blood and chocolate agars, forming small, opaque, gray-white nonhemolytic colonies. Recovery of the organism from the mixed flora of mucosal surfaces can be enhanced by using selective culture media such as modified Thayer-Martin or TV broth (Mueller-Hinton broth supplemented with trimethoprim and vancomycin).

After the nasopharynx is colonized, the organism appears to spread contiguously from its respiratory colonizing position to the infection site and cause mainly otitis media and sinusitis in children and less often pneumonia in adults. There is no pathognomic feature of M catarrhalis otitis media, sinusitis, or pneumonia. Colonization of the tracheobronchial tree may lead to the development of bronchitis or pneumonia in adults with underlying risk factors, such as smoking, intercurrent viral infection, corticosteroid treatment, or immunosuppression.

In children, pneumonia may develop in those with intercurrent viral infection, underlying lung disease, prematurity, or immunoglobulin deficiency. Risk factors for development of bacterial tracheitis and pneumonia in children in an intensive care setting include endotracheal intubation and frequent suctioning.

The predominant bacteria associated with otitis media in children are Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and M catarrhalis. A cohort of 306 infants were followed from birth through 12 months to determine frequency and duration of nasopharyngeal colonization and risk of acute otitis media (AOM) and otitis media with effusion (OME). M catarrhalis was the most common bacterium isolated. Infants colonized at 3 months of age or younger were at increased risk of AOM and OME. Early colonization with M catarrhalis revealed the greatest risk (relative risk [RR] = 1.24), especially for OME (RR = 1.57). A strong relationship was noted between the frequency of colonization and OM (r = 0.37, P < 0.001) for each pathogen.6

Relatively little is known about the virulence traits of M catarrhalis. A small number of studies on the interaction between M catarrhalis receptors and human antigens have been undertaken. In one study, the CD outer membrane protein (OMP) of M catarrhalis specifically attached to the mucin molecules from the nasopharynx and middle ear, but not to mucin from the saliva and tracheobronchial mucin.7

Such interaction represents the first step in the process of bacterial colonization and infection. The CD OMP is considered a potential vaccine candidate. The presence or absence of fimbriae does not seem to influence the capacity of the bacterium to adhere.8M catarrhalis also expresses both transferrin and lactoferrin receptors on its surface. These proteins provide the cell with the capacity to acquire iron by sequestering it from the host carrier proteins.9 Those receptors are virulence factors and immunogenic, and as such, are potential vaccine candidates.10 Some M catarrhalis strains produce a protein that confers resistance to complement. Complement-resistant strains inhibit the terminal pathway of complement (ie, the formation of the membrane attack complex of complement).11The endotoxin of M catarrhalis, a lipopolysaccharide, may also play a role in the disease process.

Clinical Manifestations

The most significant infections caused by M catarrhalis are upper respiratory tract infections, including otitis media and sinusitis in children and lower respiratory tract infections in adults.

M catarrhalis is the third most common cause of otitis media in children, following Streptococcus pneumoniae and nontypable Haemophilus influenzae. Otitis media is the most frequent infection caused by M catarrhalis in children, and as such, causes significant morbidity and necessitates the widespread use of antibiotics.3,12 Since 1980, there has been an increase in the isolation of M catarrhalis from middle ear exudates.13Presently, it accounts for 15% to 20% of pathogens recovered from middle ear fluids of children with AOM; however, these isolation rates might be an underestimation. In a study using PCR, M catarrhalis DNA was detected in 46.4% of 97 middle ear specimens compared to 54.6% for H influenzae DNA and 29.9% for S pneumoniae DNA. The increase in the isolation rate of M catarrhalis has been accompanied by the appearance of beta-lactamase–producing strains, which now account for approximately 95% to 100% of the isolates. The organism may occur as a single pathogen or in combination with other organisms. Otitis media caused by M catarrhalis cannot be distinguished clinically from otitis caused by S pneumoniae or H influenzae. However, the severity of otitis media symptoms appear to be lower for M catarrhalis, and it is more likely to remit spontaneously than is disease caused by S pneumoniae or H influenzae.14

Sinusitis is a very common infection in early childhood accounting for about 5% to 10% of upper respiratory tract infections.15 It is often underdiagnosed in children because the symptoms are nonspecific. In acute sinusitis (when symptoms are present for 10–30 days) and subacute sinusitis (30–120 days) in children, S pneumoniae,H influenzae, and M catarrhalis are the most frequently isolated pathogens. S pneumoniae is found in 30% to 40% of patients, whereas H influenzae and M catarrhalis each account for about 20% of cases.15,16 The clinical manifestations of sinusitis caused by M catarrhalis are similar to those caused by S pneumoniae and H influenzae.

Although bronchopulmonary infections caused by M catarrhalis have generally been noted in adults with chronic lung disease, pneumonia has also been reported in children. However, establishing a microbiological diagnosis of lower respiratory tract infection in children is notoriously difficult. Lower respiratory tract infections due to M catarrhalis appear to be relatively rare during childhood with most infections occurring in children younger than 1 year.17 Expectorated sputum and tracheal aspirates are more likely to yield a clinically significant isolate than nasopharyngeal aspirates. Therefore, data concerning the role of M catarrhalis in lower respiratory tract infection are not conclusive. Because sputum samples are usually not available in children, most documented pneumonia cases were severe and occurred primarily in immunocompromised patients. In one report, five premature infants younger than 6 months with preexisting lung disease were diagnosed as having pneumonia following a 2- to 4-day prodrome of cough, tachypnea, and retractions. M catarrhalis was recovered from bronchial aspirations. All patients required assisted ventilation for marked hypoxia.18 Associated M catarrhalis bacteremia has been reported in other patients with pneumonia. In adults, M catarrhalis pneumonia is more common in patients with chronic lung disease, AIDS, and malignancy.

Underlying conditions associated with increased predisposition to M catarrhalis infections in children include AIDS, leukemia, and immunoglobulin deficiencies. M catarrhalis has also been reported as a cause of bacterial tracheitis,19,20 as well as a variety of other infections including urethritis,21conjunctivitis,22 pyogenic arthritis,23peritonitis,24 preseptal cellulitis,25 bacteremia,26,27 and urinary tract infection.28 Meningitis caused by M catarrhalis occasionally results from hematogenous spread,29,30 or as a complication of ventriculoperitoneal shunt infection.31 Endocarditis is rare, and the few reported cases were associated with a high mortality rate.32 Urethritis caused by M catarrhalis can be mistaken for gonococcal urethritis. Conjunctivitis caused by M catarrhalis in the newborn can mimic ophthalmia neonatorum caused by Neisseria gonorrhoeae.

Bacteremia caused by M catarrhalis is less well understood and has been reported sporadically in a variety of clinical settings, in both children and adults. The clinical severity of M catarrhalis bacteremia has varied from self-limited febrile illness to lethal sepsis. Some reviews indicate that a significant proportion of children with M catarrhalis bacteremia had an underlying immune defect (malignancy, AIDS, neutropenia, low IgG level) or a predisposing respiratory factor (chronic lung disease, tracheostomy, mechanical ventilation). However, some healthy, immunocompetent patients with no predisposing factors have presented with M catarrhalis bacteremia. In most such patients, the source of the infection was an upper airway focus (otitis, sinusitis) or pneumonia.27 Children with M catarrhalis bacteremia may present with different clinical manifestations. Some children present with petechial or purpuric rashes resembling infection caused by N meningitidis. Other patients present with nonspecific symptoms and no focus of infection, similar to patients with occult pneumococcal bacteremia.

Treatment

Before 1970, all strains of M catarrhalis were susceptible to penicillin and ampicillin. However, β-lactamase-producing strains progressively increased during the 1980s. Presently, almost all M catarrhalis isolates are producers of β-lactamases (prevalence over 90%) reducing susceptibility to penicillins only. The β-lactamase inhibitors clavulanic acid and sulbactam are active against the β-lactamase enzymes produced by M catarrhalis.

In vitro, M catarrhalis isolates are generally susceptible to ampicillin/sulbactam and amoxicillin/clavulanic acid; erythromycin; azithromycin; clarithromycin; trimethoprim-sulfamethoxazole; chloramphenicol; tetracycline; aminoglycosides; fluoroquinolones (eg, ciprofloxacin); and both second- and third-generation cephalosporins (cefuroxime, cefaclor, cefprozil, cefpodoxime, cefixime, and loracarbef). Cefaclor is less active than cefuroxime against M catarrhalis. Most β-lactamase-producing strains respond to treatment with β-lactam/β-lactamase inhibitor combination, as well as second- and third-generation cephalosporins.33 However, antimicrobial treatment should be guided by in vitro susceptibility testing, especially for invasive infections. M catarrhalis strains are resistant to vancomycin, oxacillin, and clindamycin.

Prevention

The mode of transmission of the organism is by direct contact with contaminated respiratory tract secretions and/or droplet spread. Therefore, good hand-washing technique and sterilization of instruments used in intubations and aspiration may reduce or prevent nosocomial infections caused by M catarrhalis. Cessation of smoking, as well as prevention of passive smoking, may reduce M catarrhalis infections. Presently, no vaccine is available for the prevention of M catarrhalis infections. Certain protein components of the organism are considered potential vaccine candidates; however, little or nothing is known about the optimal routes for vaccine delivery or whether there is need for adjuvants. One of the major challenges that still exists is to find mechanisms that will effectively deliver protein antigens to mucosal surfaces. Several strategies have been investigated and resulted in varying degrees of success.34