1241CHAPTER 157 Haemophilus and Moraxella Infections

should be evaluated and treated for N. gonorrhoeae and C. trachomatis infections if their last contact with the patient took place within

60 days before the onset of symptoms or the diagnosis of infection in

the patient. If the patient’s last potential sexual exposure to infection

was >60 days before onset of symptoms or diagnosis, the patient’s most

recent sex partner should be treated. Partner-delivered medications

or prescriptions for medications to treat gonorrhea and chlamydial

infection diminish the likelihood of reinfection (or relapse) in the

infected patient. In states where it is not prohibited, this approach is

an option for partner management. Patients should be instructed to

abstain from sexual intercourse until therapy is completed and until

they and their sex partners no longer have symptoms. Greater emphasis must be placed on prevention by public health education, individual

patient counseling, and behavior modification, particularly the use of

condoms. Sexually active persons, especially adolescents, should be

offered screening for STIs. For most male patients, NAAT of urine or a

urethral swab may be used for screening. Preventing the spread of gonorrhea may help reduce the transmission of HIV. No effective vaccine

for gonorrhea is yet available, but efforts to test several candidates are

underway including a field trial of a licensed group B meningococcal

vaccine (Bexsero), which in prototype form had been shown to reduce

the incidence of gonorrhea in a population given the vaccine to control

a group B meningococcal epidemic.

■ FURTHER READING

Bolan GA et al: The emerging threat of untreatable gonococcal infection. N Engl J Med 366:485, 2012.

St. Cyr S et al: Update to CDC’s Treatment Guidelines for Gonococcal

Infection, 2020. MMWR Morb Mortal Wkly Rep 69:1911, 2020.

Golden MR et al: Effect of expedited treatment of sex partners on

recurrent or persistent gonorrhea or chlamydial infections. N Engl J

Med 352:676, 2005.

Petousis-Harris EH et al: Effectiveness of a group B outer membrane

vesicle meningococcal vaccine against gonorrhoea in New Zealand: A

retrospective case-control study. Lancet 390:1603, 2017.

Rice PA: Gonococcal arthritis (disseminated gonococcal infection).

Infect Dis Clin North Am 19:853, 2005.

Taylor SN et al: Single-dose zoliflodacin (ETX0914) for treatment of

urogenital gonorrhea. N Engl J Med 379:1835, 2018.

Unemo M et al: Antimicrobial resistance expressed by Neisseria gonorrhoeae: A major global public health problem in the 21st century.

Microbiol Spectr 4:10.1128/microbiolspec.EI10-0009-2015, 2016.

Unemo MM et al: Gonorrhoea. Nat Rev Dis Primers 5:80, 2019.

HAEMOPHILUS INFLUENZAE

■ MICROBIOLOGY

Haemophilus influenzae was first recognized in 1892 by Pfeiffer, who

erroneously concluded that the bacterium was the cause of influenza.

H. influenzae is a small (1- × 0.3-μm) gram-negative organism of variable shape; thus, it is often described as a pleomorphic coccobacillus.

In clinical specimens such as cerebrospinal fluid (CSF) and sputum, H.

influenzae frequently stains only faintly with safranin and therefore can

easily be overlooked.

H. influenzae grows both aerobically and anaerobically. Its aerobic growth requires two factors: hemin (X factor) and nicotinamide

adenine dinucleotide (V factor). These requirements are used in

the clinical laboratory to identify the bacterium. However, using

157 Haemophilus and

Moraxella Infections

Timothy F. Murphy

phenotypic methods for differentiating among Haemophilus species

has limitations, as the growing number of whole-genome sequences

of Haemophilus isolates from the human respiratory tract is revealing

complex genetic relationships among Haemophilus species (see “Diagnosis,” below).

Six major serotypes of H. influenzae have been identified; designated

a through f, they are based on antigenically distinct polysaccharide

capsules. In addition, some strains lack a polysaccharide capsule and

are referred to as nontypable strains. Type b and nontypable strains are

the most relevant strains clinically (Table 157-1), although encapsulated strains other than type b can cause disease. H. influenzae was the

first free-living organism to have its entire genome sequenced.

The antigenically distinct type b capsule is a linear polymer composed of ribosyl-ribitol phosphate. Strains of H. influenzae type b

(Hib) cause disease primarily in infants and children <6 years of age.

Nontypable strains are primarily mucosal pathogens but occasionally

cause invasive disease.

■ EPIDEMIOLOGY AND TRANSMISSION

H. influenzae, an exclusively human pathogen, is spread by airborne

droplets or by direct contact with secretions or fomites. Colonization

with nontypable H. influenzae is a dynamic process; new strains are

acquired and other strains are replaced periodically.

The widespread use of Hib conjugate vaccines in many industrialized countries has resulted in striking decreases in the rate of

nasopharyngeal colonization by Hib and in the incidence of Hib infection (Fig. 157-1). Worldwide, invasive Hib disease occurs predominantly in unimmunized children and in those who have not completed

the primary immunization series. Most World Health Organization

member countries have introduced Hib conjugate vaccination, but a

large number of the world’s children remain unimmunized, principally

in countries without national vaccine programs. Certain groups have a

higher incidence of invasive Hib disease than the general population,

TABLE 157-1 Characteristics of Type b and Nontypable Strains of

Haemophilus influenzae

FEATURE TYPE b STRAINS NONTYPABLE STRAINS

Capsule Ribosyl-ribitol phosphate Unencapsulated

Pathogenesis Invasive infections due to

hematogenous spread

Mucosal infections due to

contiguous spread

Clinical

manifestations

Meningitis and invasive

infections in incompletely

immunized infants and

children

Otitis media in infants and children;

lower respiratory tract infections in

adults with chronic bronchitis

Evolutionary

history

Basically clonal Genetically diverse

Vaccine Highly effective

conjugate vaccines

Protein D used as carrier protein in

pneumococcal vaccine approved

in Europe: GSK Synflorix. Others

under development

Incidence

50

10

20

30

40

1987 1991 1995 1999

FIGURE 157-1 Estimated incidence (rate per 100,000) of invasive disease due to

Haemophilus influenzae type b among children <5 years of age: 1987–2000. Fewer

than 40 cases per year have been reported since 2000. (Data from the Centers for

Disease Control and Prevention.)

1242 PART 5 Infectious Diseases

including African-American and Australian Aboriginal children and

Native American groups. Although this increased incidence has not

yet been accounted for, several factors may be relevant, including age

at exposure to the bacterium, socioeconomic conditions, and genetic

differences.

■ PATHOGENESIS

Hib strains cause systemic disease by invasion and hematogenous

spread from the respiratory tract to distant sites such as the meninges,

bones, and joints. The type b polysaccharide capsule is an important

virulence factor affecting the bacterium’s ability to avoid opsonization

and cause systemic disease.

Nontypable strains cause disease by local invasion of mucosal surfaces. Otitis media results when bacteria reach the middle ear by way

of the eustachian tube. Adults with chronic obstructive pulmonary

disease (COPD) experience recurrent lower respiratory tract infection

due to nontypable strains. In addition, nontypable H. influenzae persist

in the lower airways of adults with COPD in both extracellular and

intracellular locations, contributing to the airway inflammation that

is a hallmark of the disease. Nontypable strains that cause infection in

adults with COPD differ in pathogenic potential and genome content

from strains that cause otitis media. In the middle ear, nontypable

strains form biofilms. More resistant to host clearance mechanisms and

to antibiotics than are planktonic bacteria, biofilms are associated with

chronic and recurrent otitis media. Nontypable H. influenzae persist in

the human respiratory tract and cause infection by altering expression

of genes through slipped-strand mispairing and through phase-variable

expression of DNA methylase genes that control the expression of

multiple genes that play a role in virulence.

The incidence of invasive disease caused by nontypable strains is

low but appears to be increasing over the past decade. Most strains that

cause invasive disease are genetically and phenotypically diverse.

■ IMMUNE RESPONSE

Antibody to the capsule is important in protection from infection

by Hib strains. The level of (maternally acquired) serum antibody to

the capsular polysaccharide, which is a polymer of polyribitol ribose

phosphate (PRP), declines from birth to 6 months of age and, in the

absence of vaccination, remains low until ~2 or 3 years of age. The age at

the antibody nadir correlates with that of the peak incidence of type b

disease. Antibody to PRP then appears partly as a result of exposure

to Hib or cross-reacting antigens. Systemic Hib disease is unusual

after the age of 6 years because of the presence of protective antibody.

Vaccines in which PRP is conjugated to protein carrier molecules have

been developed and are now used widely. These vaccines generate an

antibody response to PRP in infants and effectively prevent invasive

infections in infants and children.

Since nontypable strains lack a capsule, the immune response to

infection is directed at noncapsular antigens. These antigens have

generated considerable interest as immune targets and potential vaccine components. The human immune response to nontypable strains

appears to be strain-specific, a characteristic that accounts in part for

the propensity of these strains to cause recurrent otitis media and

recurrent exacerbations of chronic bronchitis in immunocompetent

hosts.

■ CLINICAL MANIFESTATIONS

Hib The most serious manifestation of infection with Hib is meningitis (Chap. 138), which primarily affects children <2 years of age. The

clinical manifestations of Hib meningitis are similar to those of meningitis caused by other bacterial pathogens. Fever and altered central

nervous system function are the most common features at presentation. Nuchal rigidity may or may not be evident. Subdural effusion, the

most common complication, is suspected when, despite 2 or 3 days of

appropriate antibiotic therapy, the infant has seizures, hemiparesis, or

continued obtundation. The overall mortality rate from Hib meningitis

is ~5%, and the morbidity rate is high. Of survivors, 6% have permanent sensorineural hearing loss, and about one-fourth have a significant disability of some type. If more subtle disabilities are sought, up to

half of survivors are found to have some neurologic sequelae, such as

partial hearing loss and delayed language development.

Epiglottitis (Chap. 35) is a life-threatening Hib infection involving

cellulitis of the epiglottis and supraglottic tissues. It can lead to acute

upper-airway obstruction. Its unique epidemiologic features are its

occurrence in an older age group (2–7 years old) than other Hib infections and its absence among Navajo Native Americans and Alaskan

Eskimos. Sore throat and fever rapidly progress to dysphagia, drooling,

and airway obstruction. Epiglottitis also occurs in adults.

Cellulitis (Chap. 129) due to Hib occurs in young children. The

most common location is on the head or neck, and the involved area

sometimes takes on a characteristic bluish-red color. Most patients

have bacteremia, and 10% have an additional focus of infection.

Hib causes pneumonia in infants. The infection is clinically indistinguishable from other types of bacterial pneumonia (e.g., pneumococcal

pneumonia) except that Hib is more likely to involve the pleura. Several

less common invasive conditions can be important clinical manifestations of Hib infection in children. These include osteomyelitis, septic

arthritis, pericarditis, orbital cellulitis, endophthalmitis, urinary tract

infection, abscesses, and bacteremia without an identifiable focus.

Non–type b encapsulated strains of H. influenzae (types a, c, d, e,

and f) are unusual causes of invasive infection manifested predominantly by bacteremia and pneumonia. H. influenzae type a infections

are seen with increased frequency in indigenous populations of North

America, and these strains are predominantly clonal. Most infections

due to non–type b encapsulated strains occur in the setting of underlying conditions.

Nontypable H. influenzae Nontypable H. influenzae is the most

common bacterial cause of exacerbations of COPD; these exacerbations are characterized by increased cough, sputum production, and

shortness of breath. Fever is low-grade, and no infiltrates are evident

on chest x-ray. Nontypable strains also cause community-acquired bacterial pneumonia in adults, especially among patients with COPD or

AIDS. The clinical features of H. influenzae pneumonia are similar to

those of other types of bacterial pneumonia, including pneumococcal

pneumonia.

Nontypable H. influenzae is one of the three most common causes

of childhood otitis media (the other two being Streptococcus pneumoniae and Moraxella catarrhalis) (Chap. 35). Infants are febrile

and irritable, while older children report ear pain. Symptoms of viral

upper-respiratory infection often precede otitis media. The diagnosis

is made by pneumatic otoscopy. An etiologic diagnosis, although not

routinely sought, can be established by tympanocentesis and culture of

middle-ear fluid. Clinical features associated with H. influenzae otitis

media include a history of recurrent episodes, treatment failure, concomitant conjunctivitis, bilateral otitis media, and recent antimicrobial

therapy. The increasing use of pneumococcal polysaccharide conjugate vaccines in many countries has resulted in an overall decrease in

otitis media and its complications. However, a relative increase in the

proportion of otitis media caused by H. influenzae in children failing

initial antimicrobial therapy or with recurrent episodes has occurred.

Continued monitoring of the incidence and etiology of otitis media

will be important.

Nontypable H. influenzae also causes puerperal sepsis and is an

important cause of neonatal bacteremia. These nontypable strains,

provisionally named Haemophilus quentini, are closely related to but

distinct from H. haemolyticus, tend to be of biotype IV and cause invasive disease after colonizing the female genital tract.

Nontypable H. influenzae causes sinusitis (Chap. 35) in adults and

children. In addition, the bacterium is a less common cause of various

invasive infections. These infections include bacteremia, empyema,

adult epiglottitis, pericarditis, cellulitis, septic arthritis, osteomyelitis,

endocarditis, cholecystitis, intraabdominal infections, urinary tract

infections, mastoiditis, and aortic graft infection. Most H. influenzae

invasive infections in countries where Hib vaccines are used widely are

caused by nontypable strains, and a recent increased incidence of such

infections has been observed. Although most strains of nontypable H.

influenzae that cause invasive infections are genetically diverse, recent

1243CHAPTER 157 Haemophilus and Moraxella Infections

localized clusters of infections have been caused by clonally related

strains. Continued monitoring will be important. Many patients with

H. influenzae bacteremia have an underlying condition, such as HIV

infection, cardiopulmonary disease, alcoholism, or cancer.

■ DIAGNOSIS

The most reliable method for establishing a diagnosis of invasive H.

influenzae infection is recovery of the organism in culture in a normally sterile body site, such as blood, CSF, or joint fluid.

H. influenzae isolated from the respiratory tract must be distinguished from a complex flora and from other Haemophilus species.

Particular caution must be used to distinguish H. influenzae from

Haemophilus haemolyticus, a respiratory tract commensal that has

identical growth requirements. H. haemolyticus has classically been

distinguished from H. influenzae by the hemolysis of the former

species on horse blood agar. However, a significant proportion of

isolates of H. haemolyticus have now been recognized as nonhemolytic. Analysis of various genotypic markers, including 16S ribosomal

sequences, superoxide dismutase, outer-membrane protein P6, protein

D, and fuculose kinase, can be used to distinguish these two species.

The availability of whole-genome sequences of an increasing number

of Haemophilus isolates from the human upper respiratory tract has

revealed complex genomic relationships among Haemophilus species,

suggesting a genetic continuum between some Haemophilus species.

The presence of gram-negative coccobacilli in Gram-stained CSF

is strong evidence for Hib meningitis. Recovery of the organism from

CSF confirms the diagnosis. Cultures of other normally sterile body

fluids, such as blood, joint fluid, pleural fluid, pericardial fluid, and

subdural effusion, are confirmatory in other infections.

Detection of PRP is an important adjunct to culture in rapid

diagnosis of Hib meningitis. Immunoelectrophoresis, latex agglutination, coagglutination, and enzyme-linked immunosorbent assay are

effective in detecting PRP. These assays are particularly helpful when

patients have received prior antimicrobial therapy and thus are especially likely to have negative cultures.

Because nontypable H. influenzae is primarily a mucosal pathogen,

it is a component of a mixed flora; thus etiologic diagnosis is challenging. Nontypable H. influenzae infection is strongly suggested by

the predominance of gram-negative coccobacilli among abundant

polymorphonuclear leukocytes in a Gram-stained sputum specimen

from a patient in whom pneumonia is suspected. Although bacteremia

is detectable in a small proportion of patients with pneumonia due

to nontypable H. influenzae, most such patients have negative blood

cultures.

A diagnosis of otitis media is based on the detection by pneumatic

otoscopy of fluid in the middle ear. An etiologic diagnosis requires

tympanocentesis but is not routinely sought. An invasive procedure

is also required to determine the etiology of sinusitis; thus, treatment

is often empirical once the diagnosis is suspected in light of clinical

symptoms and sinus radiographs.

TREATMENT

Haemophilus influenzae

Initial therapy for meningitis due to Hib should consist of a cephalosporin such as ceftriaxone or cefotaxime. For children, the dosage

of ceftriaxone is 75–100 mg/kg daily given in two doses 12 h apart.

The pediatric dosage of cefotaxime is 200 mg/kg daily given in four

doses 6 h apart. Adult dosages are 2 g every 12 h for ceftriaxone and

2 g every 4–6 h for cefotaxime. An alternative regimen for initial

therapy is ampicillin (200–300 mg/kg daily in four divided doses)

plus chloramphenicol (75–100 mg/kg daily in four divided doses).

Therapy should continue for a total of 1–2 weeks.

Administration of glucocorticoids to patients with Hib meningitis reduces the incidence of neurologic sequelae. The presumed

mechanism is reduction of the inflammation induced by bacterial

cell-wall mediators of inflammation when cells are killed by antimicrobial agents. Dexamethasone (0.6 mg/kg per day intravenously in

four divided doses for 2 days) is recommended for the treatment of

Hib meningitis in children >2 months of age.

Invasive infections other than meningitis are treated with the

same antimicrobial agents. For epiglottitis, the dosage of ceftriaxone is 50 mg/kg daily, and the dosage of cefotaxime is 150 mg/kg

daily, given in three divided doses 8 h apart. Epiglottitis constitutes

a medical emergency, and maintenance of an airway is critical. The

duration of therapy is determined by the clinical response. A course

of 1–2 weeks is usually appropriate.

Many infections caused by nontypable strains of H. influenzae,

such as otitis media, sinusitis, and exacerbations of COPD, can be

treated with oral antimicrobial agents. Approximately 20–35% of

nontypable strains produce β-lactamase (with the exact proportion

depending on geographic location), and these strains are resistant

to ampicillin. Several agents have excellent activity against nontypable H. influenzae, including amoxicillin/clavulanic acid, various

extended-spectrum cephalosporins, and the macrolides azithromycin and clarithromycin. Fluoroquinolones are highly active against

H. influenzae and are useful in adults with exacerbations of COPD.

However, fluoroquinolones are not currently recommended for

the treatment of children or pregnant women because of possible

effects on articular cartilage.

In addition to β-lactamase production, alteration of penicillinbinding proteins—a second mechanism of ampicillin resistance—

has been detected in isolates of H. influenzae. Although rare in the

United States, these β-lactamase-negative ampicillin-resistant strains

are common in Japan and are increasing in prevalence in Europe.

Resistance to macrolides is also being observed with increasing frequency globally. Continued monitoring of the evolving antimicrobial

susceptibility patterns of H. influenzae will be important.

■ PREVENTION

Vaccination (See also Chap. 123) Three conjugate vaccines that

prevent invasive infections with Hib in infants and children are

licensed in the United States. In addition to eliciting protective antibody, these vaccines prevent disease by reducing rates of pharyngeal

colonization with Hib. The widespread use of conjugate vaccines

has dramatically reduced the incidence of Hib disease in developed

countries. Even though the manufacture of Hib vaccines is costly,

vaccination is cost-effective. The Global Alliance for Vaccines and

Immunizations has recognized the underuse of Hib conjugate vaccines.

The disease burden has been reduced in developing countries that

have implemented routine vaccination (e.g., The Gambia, Chile). An

important obstacle to more widespread vaccination is the lack of data

on the epidemiology and burden of Hib disease in many developing

countries.

All children should be immunized with an Hib conjugate vaccine,

receiving the first dose at ~2 months of age, the rest of the primary

series at 2–6 months of age, and a booster dose at 12–15 months of age.

Specific recommendations vary for the different conjugate vaccines.

The reader is referred to the recommendations of the American Academy of Pediatrics (Chap. 123 and www.cispimmunize.org).

Currently, no vaccines are available specifically for the prevention

of disease caused by nontypable H. influenzae. However, a vaccine that

contains protein D—a surface protein of H. influenzae—conjugated

to pneumococcal polysaccharides is licensed in other countries and

is used widely throughout the world. The vaccine has shown partial

efficacy in preventing H. influenzae otitis media in clinical trials. Vaccine formulations that include surface protein antigens are currently in

clinical trials, and additional progress in the development of vaccines

against nontypable H. influenzae is anticipated.

Chemoprophylaxis The risk of secondary disease is greater than

normal among household contacts of patients with Hib disease. Therefore, all children and adults (except pregnant women) in households

with an index case and at least one incompletely immunized contact

<4 years of age should receive prophylaxis with oral rifampin. When

two or more cases of invasive Hib disease have occurred within 60 days

1244 PART 5 Infectious Diseases

at a child-care facility attended by incompletely vaccinated children,

administration of rifampin to all attendees and personnel is indicated,

as it is for household contacts. Chemoprophylaxis is not indicated

in nursery and child-care contacts of a single index case. The reader

is referred to the recommendations of the American Academy of

Pediatrics.

HAEMOPHILUS DUCREYI

Haemophilus ducreyi is the etiologic agent of chancroid (Chap. 136),

a sexually transmitted disease characterized by genital ulceration and

inguinal adenitis. In addition to being a cause of morbidity in itself,

chancroid is associated with HIV infection because of the role played

by genital ulceration in HIV transmission. Chancroid increases the

efficiency of transmission of and the degree of susceptibility to HIV

infection. H. ducreyi has also been recognized as an important cause of

non-sexually transmitted cutaneous ulcers.

■ MICROBIOLOGY

H. ducreyi is a highly fastidious coccobacillary gram-negative bacterium whose growth requires X factor (hemin). Although, in light

of this requirement, the bacterium has been classified in the genus

Haemophilus, DNA homology and chemotaxonomic studies have

established substantial differences between H. ducreyi and other Haemophilus species. Taxonomic reclassification of the organism is likely

in the future but awaits further study. Ulcers contain predominantly T

cells. The fact that patients who have had chancroid may have repeated

infections indicates that infection does not confer protection.

■ EPIDEMIOLOGY AND PREVALENCE

The prevalence of chancroid has steadily declined in the United States

and worldwide over the past decade and a half. The infection appears

to be more common in developing countries. Transmission is predominantly heterosexual, and cases in males have outnumbered those in

females by ratios of 3:1 to 25:1 during outbreaks. Contact with commercial sex workers and illicit drug use are strongly associated with

chancroid. Most cases in developed countries are sporadic.

H. ducreyi has emerged as a major cause of cutaneous ulcers in

children in developing countries, particularly in the South Pacific and

Africa. Strains that cause cutaneous ulcers have genome sequences

that are nearly identical to class I strains (of two related classes) of H.

ducreyi that cause genital ulcers.

■ CLINICAL MANIFESTATIONS AND

DIFFERENTIAL DIAGNOSIS

Infection is acquired as the result of a break in the epithelium during

sexual contact with an infected individual. After an incubation period

of 4–7 days, the initial lesion—a papule with surrounding erythema—

appears. In 2 or 3 days, the papule evolves into a pustule, which

spontaneously ruptures and forms a sharply circumscribed ulcer that

generally is not indurated (Fig. 157-2). The ulcers are painful and

bleed easily; little or no inflammation of the surrounding skin is evident. Approximately half of patients develop enlarged, tender inguinal

lymph nodes, which frequently become fluctuant and spontaneously

rupture. Patients usually seek medical care after 1–3 weeks of painful

symptoms.

The presentation of chancroid does not usually include all of the

typical clinical features and is sometimes atypical. Multiple ulcers can

coalesce to form giant ulcers. Ulcers can appear and then resolve, with

inguinal adenitis (Fig. 157-2) and suppuration following 1–3 weeks

later; this clinical picture can be confused with that of lymphogranuloma venereum (Chap. 189). Multiple small ulcers can resemble

folliculitis. Other differential diagnostic considerations include the

various infections causing genital ulceration, such as primary syphilis,

secondary syphilis (condyloma latum), genital herpes, and donovanosis. In rare cases, chancroid lesions become secondarily infected with

bacteria; the result is extensive inflammation.

Non-sexually transmitted cutaneous ulcers caused by H. ducreyi

resemble those of yaws caused by Treponema pallidum subspecies pertenue, which is endemic in regions where H. ducreyi cutaneous ulcers

are seen. Ulcers caused by H. ducreyi are less likely than those of yaws

to show central granulating tissue and less likely to have indurated

edges, but substantial overlap in clinical characteristics exists.

■ DIAGNOSIS

Clinical diagnosis of chancroid is often inaccurate, and laboratory

confirmation should be attempted in suspected cases. An accurate

diagnosis of chancroid relies on culture of H. ducreyi from the lesion

or from an aspirate of suppurative lymph nodes. Since the organism

can be difficult to grow, the use of selective and supplemented media

is necessary. No polymerase chain reaction (PCR) assay for H. ducreyi

is commercially available; such tests can be performed by Clinical

Laboratory Improvement Amendment (CLIA)–certified clinical laboratories that have developed their own assays.

A probable diagnosis of sexually transmitted chancroid can be

made when the following criteria are met: (1) one or more painful

genital ulcers; (2) no evidence of T. pallidum infection by dark-field

examination of ulcer exudate or by a negative serologic test for syphilis

performed at least 7 days after ulcer onset; (3) a typical clinical presentation for chancroid; and (4) a negative test for herpes simplex virus in

the ulcer exudate.

A serologic test for syphilis does not distinguish cutaneous ulcers

due to H. ducreyi from those due to yaws. A PCR assay has been used in

clinical studies to establish an H. ducreyi etiology, but, as stated above,

no such assay is commercially available.

TREATMENT

Haemophilus ducreyi

Treatment regimens for both genital and cutaneous infections

include (1) a single 1-g oral dose of azithromycin; (2) ceftriaxone

(250 mg intramuscularly in a single dose); (3) ciprofloxacin (500 mg

by mouth twice a day for 3 days); and (4) erythromycin base (500 mg

by mouth three times a day for 7 days). Isolates from patients who

do not respond promptly to treatment should be tested for antimicrobial resistance. In patients with HIV infection, healing may be

slow and longer courses of treatment may be necessary. Clinical

treatment failure in HIV-seropositive patients may reflect co-infection,

especially with herpes simplex virus. Contacts of patients with

chancroid should be identified and treated, whether or not symptoms are present, if they have had sexual contact with the patient

during the 10 days preceding the patient’s onset of symptoms.

FIGURE 157-2 Chancroid with characteristic penile ulcers and associated left

inguinal adenitis (bubo).

1245CHAPTER 157 Haemophilus and Moraxella Infections

No. of COPD exacerbations

0

10

20

30

40

50

60

70

80

90

NTHI M.cat S.pn PA

Exacerbations associated with new isolates

FIGURE 157-3 Cumulative results of a prospective study (1994–2004) of bacterial

infection in chronic obstructive pulmonary disease (COPD) showing etiology of

exacerbations. The numbers of exacerbations shown indicate the acquisition

of a new strain simultaneous with clinical symptoms of an exacerbation. NTHI,

nontypable H. influenzae; M.cat, M. catarrhalis; S.pn, Streptococcus pneumoniae;

PA, Pseudomonas aeruginosa. (Reproduced with permission from JC Goldstein, TF

Murphy: Moraxella catarrhalis, a human respiratory tract pathogen. Clin Infect Dis

49:124, 2009.)

MORAXELLA CATARRHALIS

■ MICROBIOLOGY

M. catarrhalis is an unencapsulated gram-negative diplococcus whose

ecologic niche is the human respiratory tract. The organism was

initially designated Micrococcus catarrhalis. Its name was changed

to Neisseria catarrhalis in 1970 because of phenotypic similarities to

commensal Neisseria species. On the basis of more rigorous analysis

of genetic relatedness, Moraxella catarrhalis is now the widely accepted

name for this species.

■ EPIDEMIOLOGY

Nasopharyngeal colonization by M. catarrhalis is common in infancy,

with colonization rates ranging between 33% and 100% and depending on geographic location. Several factors probably account for this

geographic variation, including living conditions, day-care attendance,

hygiene, household smoking, and population genetics. The prevalence

of colonization decreases steadily with age.

The widespread use of pneumococcal conjugate vaccines in some

countries has resulted in alterations in patterns of nasopharyngeal

colonization in resident populations. A relative increase in colonization

by nonvaccine pneumococcal serotypes, nontypable H. influenzae, and

M. catarrhalis has occurred. These changes in colonization patterns

may be altering the distribution of pathogens of both otitis media and

sinusitis in children.

■ PATHOGENESIS

M. catarrhalis causes mucosal infections of the respiratory tract by contiguous spread from its colonizing site in the upper airway. A preceding

viral upper respiratory tract infection is a common inciting event for

otitis media. In exacerbations of COPD, the acquisition of new strains

is critical for pathogenesis. Strains exhibit substantial genetic diversity

and differences in virulence properties.

The expression of several adhesin molecules with differing specificities for various host cell receptors reflects the importance of adherence

to the respiratory epithelial surface in the pathogenesis of infection.

M. catarrhalis invades multiple cell types. Its intracellular residence

in lymphoid tissue provides a potential reservoir for persistence in

the human respiratory tract. Like many gram-negative bacteria, M.

catarrhalis sheds vesicles into the surrounding environment. The

vesicles are internalized by host cells and mediate several virulence

mechanisms, including induction of inflammation and delivery of

β-lactamase, that can promote the survival of co-pathogens.

■ CLINICAL MANIFESTATIONS

In children, M. catarrhalis causes predominantly mucosal infections

when the bacterium migrates from the nasopharynx to the middle ear

or the sinuses (Chap. 35). The inciting event for both otitis media and

sinusitis is often a preceding viral infection. Overall, cultures of middle-ear

fluid obtained by tympanocentesis indicate that M. catarrhalis causes

15–20% of cases of acute otitis media. More sensitive molecular analysis of middle ear fluid detects M. catarrhalis alone or with other pathogens in 30 to 50% of middle ear fluid samples from children with otitis

media. Acute otitis media caused by M. catarrhalis or nontypable H.

influenzae is clinically milder than otitis media caused by S. pneumoniae, with less fever and a lower prevalence of a red bulging tympanic

membrane. However, substantial overlap makes it impossible to predict

etiology in an individual child on the basis of clinical features.

A small proportion of viral upper respiratory tract infections are

complicated by bacterial sinusitis. Cultures of sinus puncture aspirates

show that M. catarrhalis accounts for ~20% of cases of acute bacterial

sinusitis in children and for a smaller proportion in adults.

M. catarrhalis is a common cause of exacerbations in adults with

COPD. The bacterium has been overlooked in this clinical setting

because it has long been considered to be a commensal and because it

is easily mistaken for commensal Neisseria species in cultures of respiratory secretions (see “Diagnosis,” below). Several independent lines of

evidence have established M. catarrhalis as a pathogen in COPD. These

include (1) the demonstration of M. catarrhalis in the lower airways

during exacerbations, (2) the association of exacerbation with acquisition of new strains, (3) elevations of inflammatory markers in association with M. catarrhalis, and (4) the development of specific immune

responses following infection. M. catarrhalis is the second most common bacterial cause of COPD exacerbations (after H. influenzae), as

shown in a 10-year prospective study; the distribution of exacerbations

associated with new-strain acquisitions is shown in Fig. 157-3. Not

included are culture-negative cases or cases from which a pathogen

had been previously isolated. With the application of rigorous clinical

criteria for defining the etiology of exacerbations (both culture-positive

and culture-negative), ~10% of all exacerbations in the same study

were caused by M. catarrhalis. The clinical features of an exacerbation

due to M. catarrhalis are similar to those of exacerbations due to other

bacterial pathogens, including H. influenzae and S. pneumoniae. The

cardinal symptoms are cough with increased sputum production, sputum purulence, and dyspnea in comparison with baseline symptoms.

Pneumonia due to M. catarrhalis occurs in the elderly, particularly

in the setting of underlying cardiopulmonary disease, but is infrequent.

Invasive infections, such as bacteremia, endocarditis, neonatal meningitis, and septic arthritis, are rare.

■ DIAGNOSIS

Tympanocentesis is required for etiologic diagnosis of otitis media, but

this procedure is not performed routinely. Therefore, treatment of otitis

media is generally empirical. Similarly, an etiologic diagnosis of sinusitis requires an invasive procedure and thus is usually not available to

the clinician. Isolation of M. catarrhalis from an expectorated sputum

sample from an adult experiencing clinical symptoms of an exacerbation is suggestive, but not diagnostic, of M. catarrhalis as the cause.

Upon culture, colonies of M. catarrhalis resemble those of commensal neisseriae that are part of the normal upper airway flora. As mentioned above, the difficulty in distinguishing colonies of M. catarrhalis

from neisserial colonies in cultures of respiratory secretions explains in

part why M. catarrhalis has been overlooked as a pathogen. In contrast

to these Neisseria species, M. catarrhalis colonies can be slid across the