1246 PART 5 Infectious Diseases

agar surface without disruption (the “hockey puck sign”). In addition,

after 48 h of growth, M. catarrhalis colonies take on a pink color and

tend to be larger than neisserial colonies. A variety of biochemical tests

can distinguish M. catarrhalis from neisseriae. Kits that rely on these

biochemical reactions are commercially available.

TREATMENT

Moraxella catarrhalis

M. catarrhalis rapidly acquired β-lactamases during the 1970s and

1980s; antimicrobial susceptibility patterns have remained relatively

stable since that time, with >90% of strains now producing

β-lactamase and thus resistant to amoxicillin. Otitis media in

children and exacerbations of COPD in adults are generally managed empirically with antimicrobial agents that are active against

S. pneumoniae, H. influenzae, and M. catarrhalis. Most strains

of M. catarrhalis are susceptible to amoxicillin/clavulanic acid,

extended-spectrum cephalosporins, newer macrolides (azithromycin, clarithromycin), trimethoprim-sulfamethoxazole, and fluoroquinolones. However, recent reports from several centers in Asia

show substantial resistance to macrolides and fluoroquinolones,

indicating emerging resistance. Continued monitoring of global

antimicrobial susceptibility patterns of M. catarrhalis will be critical.

■ FURTHER READING

Ahearn CP et al: Insights on persistent airway Infection by nontypeable Haemophilus influenzae in chronic obstructive pulmonary

disease. Pathog Dis 75:ftx042, 2017.

Blakeway LV et al: Virulence determinants of Moraxella catarrhalis:

Distribution and considerations for vaccine development. Microbiology 163:1371, 2017.

Jalalvand F, Riesbeck K: Update on non-typeable Haemophilus

influenzae-mediated disease and vaccine development. Expert Rev

Vaccines 17:503, 2018.

Lewis DA, Mitja O: Haemophilus ducreyi: From sexually transmitted

infection to skin ulcer pathogen. Curr Opin Infect Dis 29:52, 2016.

Perez AC, Murphy TF: A Moraxella catarrhalis vaccine to protect

against otitis media and exacerbations of COPD: An update on current progress and challenges. Hum Vacc Immunother 3:2322, 2017.

THE HACEK GROUP

HACEK organisms are a group of fastidious, slow-growing, gramnegative bacteria whose growth requires an atmosphere of carbon

dioxide. These organisms do not grow on media routinely used for

enteric bacteria (e.g., MacConkey agar). Species belonging to this

group include several Haemophilus species, Aggregatibacter (formerly

Actinobacillus) species, Cardiobacterium species, Eikenella corrodens,

and Kingella kingae. HACEK bacteria normally reside in the oral cavity

and have been associated with local infections in the mouth. They are

also known to cause severe systemic infections—such as bacteremia

and bacterial endocarditis, which can develop on either native or prosthetic valves (Chap. 128). In a nationwide survey in Denmark, HACEK

bacteremias were most often due to Haemophilus species, followed by

158 Infections Due to the

HACEK Group and

Miscellaneous Gram-Negative

Bacteria

Tamar F. Barlam

Aggregatibacter species. HACEK bacteremia is strongly predictive of

underlying infective endocarditis (overall positive predictive value,

60%). However, this association varies significantly by organism. For

example, in one study, infective endocarditis was diagnosed in 100% of

patients with Aggregatibacter actinomycetemcomitans bacteremia, 55%

with Haemophilus parainfluenzae bacteremia, but in no patients with

Eikenella bacteremia.

In large series, 0.8–6% of cases of infective endocarditis are attributable to HACEK organisms, most often Aggregatibacter species,

Haemophilus species, and Cardiobacterium hominis. Invasive infection

typically occurs in patients with a history of cardiac valvular disease

or prosthetic valves, often in the setting of a recent dental procedure

or nasopharyngeal infection. The aortic and mitral valves are most

commonly affected. The clinical course of HACEK endocarditis tends

to be subacute, particularly with Aggregatibacter or Cardiobacterium.

However, K. kingae endocarditis may have a more aggressive presentation. Compared with non-HACEK endocarditis, HACEK endocarditis

occurs in younger patients and has been more frequently associated

with embolic, vascular, and immunologic manifestations. Systemic

embolization is common. The overall prevalence of major emboli associated with HACEK endocarditis ranges from 28% to 71% in different

series. On echocardiography, valvular vegetations are seen in up to 85%

of patients. Aggregatibacter and Haemophilus species cause mitral valve

vegetations most often; Cardiobacterium is associated with aortic valve

vegetations.

The microbiology laboratory should be alerted when a HACEK

organism is being considered. Most cultures that ultimately yield a

HACEK organism become positive within the first week, especially

with improved culture systems such as BACTEC. Studies have not

shown that prolonged incubation increases laboratory recovery of

clinically significant HACEK isolates. Polymerase chain reaction (PCR)

techniques, such as gene amplification of 16S rRNA, can facilitate

the diagnosis of HACEK infection of blood or cardiac valves. Other

tools, such as matrix-assisted laser desorption ionization–time of

flight (MALDI-TOF) mass spectrometry performed directly on agar

colonies, can increase the accuracy and speed of diagnosis of HACEK

infections.

Because of HACEK organisms’ slow growth, antimicrobial susceptibility testing may be difficult, and β-lactamase production may not

be detected. Resistance is most commonly noted in Haemophilus and

Aggregatibacter species. Etest methodology may increase the accuracy

of susceptibility testing. In recent studies, ceftriaxone and levofloxacin

have been active against all isolates. The overall prognosis in both

native-valve and prosthetic-valve HACEK endocarditis is excellent and

is significantly better than that in endocarditis caused by non-HACEK

pathogens.

Haemophilus Species Haemophilus parainfluenzae is the most

common Haemophilus species isolated from cases of HACEK endocarditis. Of patients with HACEK endocarditis due to Haemophilus

species, 60% have been ill for <2 months before presentation, and

19–50% develop congestive heart failure. Mortality rates as high as

30–50% were reported in older series; however, more recent studies

have documented mortality rates of <5%. H. parainfluenzae has been

isolated from other infections, such as meningitis; brain, dental, pelvic,

and liver abscess; pneumonia; urinary tract infection; and septicemia.

Aggregatibacter Species Aggregatibacter species are the most common cause of HACEK endocarditis; the species most frequently

involved are A. actinomycetemcomitans, A. (formerly Haemophilus)

aphrophilus, and A. paraphrophilus. Aggregatibacter is associated with

prosthetic-valve endocarditis more often than are Haemophilus species. A. actinomycetemcomitans can be isolated from soft tissue infections and abscesses in association with Actinomyces israelii. Typically,

patients who develop Aggregatibacter endocarditis have periodontal

disease or have recently undergone dental procedures in the setting of

underlying cardiac valvular damage. The disease is insidious; patients

may be sick for several months before diagnosis. Frequent complications include embolic phenomena, congestive heart failure, and renal

failure.

1247CHAPTER 158 Infections Due to the HACEK Group and Miscellaneous Gram-Negative Bacteria

Infective endocarditis, unlike other infections with K. kingae, occurs

in older children and adults. The majority of patients have preexisting

valvular disease. There is a high incidence of complications, including

arterial emboli, cerebrovascular accidents, tricuspid insufficiency, and

congestive heart failure with cardiovascular collapse.

TREATMENT

HACEK Endocarditis

(Table 158-1) Ceftriaxone (2 g/d) is first-line therapy for HACEK

endocarditis, with a favorable outcome in 80–90% of cases. Data on

the use of levofloxacin (750 mg/d) for HACEK endocarditis remain

limited, but this drug can be considered an alternative for treatment

of patients intolerant of β-lactam therapy. Of note, Eikenella is resistant to clindamycin, metronidazole, and aminoglycosides.

Native-valve endocarditis should be treated for 4 weeks with

antibiotics, whereas prosthetic-valve endocarditis requires 6 weeks

of therapy. The cure rates for HACEK prosthetic-valve endocarditis appear to be high. Unlike prosthetic-valve endocarditis

caused by other gram-negative organisms, HACEK endocarditis is

often cured with antibiotic treatment alone—i.e., without surgical

intervention. In a recent case-control study, 1-year mortality was

significantly lower than infective endocarditis caused by viridans

group Streptococcus.

OTHER FASTIDIOUS GRAM-NEGATIVE

BACTERIA

Capnocytophaga Species Like HACEK organisms, this genus of

fastidious, fusiform, gram-negative coccobacilli is facultatively anaerobic and requires an atmosphere enriched in carbon dioxide for optimal

growth. Capnocytophaga species such as C. ochracea, C. gingivalis,

C. haemolytica, and C. sputigena are part of the oral flora; most infections are contiguous with the oropharynx (e.g., periodontal disease,

respiratory tract infections, cervical abscesses, endophthalmitis). These

organisms have also been associated with sepsis in immunocompromised hosts, particularly neutropenic patients with oral ulcerations,

meningitis, endocarditis, cellulitis, osteomyelitis, and septic arthritis.

Capnocytophaga species have been isolated from many other sites as

well, usually as part of a polymicrobial infection. There is a high prevalence of resistance to β-lactams and macrolides in Capnocytophaga;

the oral cavity serves as a reservoir for resistance genes to those agents.

C. canimorsus and C. cynodegmi are endogenous to the canine

and feline mouth (Chap. 141). Patients infected with these species

frequently have a history of dog or cat bites or of exposure without

scratches or bites. Asplenia, glucocorticoid therapy, and alcohol abuse

are predisposing conditions that can be associated with severe sepsis

with shock and disseminated intravascular coagulation. Patients typically have a petechial rash that can progress from purpuric lesions to

gangrene.

A. actinomycetemcomitans has been isolated from patients with

brain abscess, meningitis, endophthalmitis, parotitis, osteomyelitis,

urinary tract infection, pneumonia, and empyema, among other infections. A. aphrophilus is often associated with bone and joint infection

and is an important cause of brain abscess. In one series, A. aphrophilus

was isolated from brain abscesses in 10% of cases—a rate that is disproportionate to its isolation from oral flora. This species has also been

described as a cause of abscess in other organ systems.

Cardiobacterium Species Cardiobacterium species, most often

C. hominis, cause endocarditis primarily in patients with underlying

valvular heart disease or with prosthetic valves. These organisms

most frequently affect the aortic valve. Many patients have signs and

symptoms of long-standing infection before diagnosis, with evidence

of arterial embolization, vasculitis, cerebrovascular accidents, immune

complex glomerulonephritis, or arthritis at presentation. Embolization, mycotic aneurysms, and congestive heart failure are common

complications. A second species, C. valvarum, has been described in

association with endocarditis.

Eikenella corrodens E. corrodens is most frequently recovered from

sites of infection in conjunction with other bacterial species. Clinical

sources of E. corrodens include sites of human bite wounds (clenchedfist injuries), endocarditis, soft tissue infections, osteomyelitis, head

and neck infections, respiratory infections, chorioamnionitis, gynecologic infections associated with intrauterine devices, meningitis, brain

abscesses, and visceral abscesses. This organism is the least common

cause of HACEK endocarditis.

Kingella kingae More than half of cases of K. kingae infection are

bone and joint infections; the majority of the remaining infections are

infective endocarditis, bacteremia, and meningitis. Invasive K. kingae

infections with bacteremia are associated with upper respiratory tract

infections and stomatitis in 80% of cases. Rates of oropharyngeal colonization with K. kingae are highest in the first 3 years of life (detected in

~5–10% of children) and appear higher in children regularly attending

daycare; colonization coincides with an increased incidence of skeletal

infections and other invasive infections due to this organism from the

age of 6 months to 4 years. K. kingae can be transmitted from child

to child and has been the cause of outbreaks among young children.

K. kingae bacteremia can present with a petechial rash similar to that

seen in Neisseria meningitidis sepsis.

Because of improved microbiologic methodology and molecular

methods such as real-time PCR, the isolation of K. kingae is increasingly common. Inoculation of clinical specimens (e.g., synovial fluid)

into aerobic blood culture bottles enhances recovery of this organism.

PCR studies of blood or joint fluid can identify K. kingae in culturenegative cases. Some studies have demonstrated that K. kingae has

surpassed Staphylococcus aureus as the leading cause of septic arthritis

and osteomyelitis in children.

TABLE 158–1 Treatment of Infections Caused by HACEK-Group and Other Fastidious Gram-Negative Organisms

ORGANISMS PREFERRED THERAPY ALTERNATIVE AGENTS COMMENTS

Haemophilus spp.

Aggregatibacter spp.

Cardiobacterium spp.

Eikenella corrodens

Kingella kingae

Ceftriaxone (2 g/d) Ampicillin/sulbactam (3 g of ampicillin

q6h)

Levofloxacin (750 mg/d)

Ampicillin/sulbactam resistance has been described in

Haemophilus and Aggregatibacter spp.

Data on use of levofloxacin for endocarditis therapy are

limited. Fluoroquinolones are not recommended for treatment

of patients <18 years of age.

Penicillin (16–18 million units q4h) or ampicillin (2 g q4h) can be

used if the organism is susceptible. However, because of the

slow growth of HACEK bacteria, antimicrobial testing may be

difficult, and β-lactamase production may not be detected.

Capnocytophaga spp. Ampicillin/sulbactam

(1.5–3 g of ampicillin q6h)

Ceftriaxone (2 g/d q12–24h) Penicillin (12–18 million units q4h) should be used if the isolate

is known to be susceptible.

Pasteurella multocida Ampicillin/sulbactam

(1.5–3 g of ampicillin q6h)

Ceftriaxone (1–2 g/d q12–24h) Penicillin should be used if the isolate is known to be

susceptible. P. multocida is also susceptible to tetracyclines

and fluoroquinolones.

1248 PART 5 Infectious Diseases

TABLE 158-2 Treatment Options for Other Selected Gram-Negative

Bacteriaa

ORGANISM TREATMENT OPTIONS

Achromobacter xylosoxidans Carbapenems, tigecycline, colistin

Aeromonas spp. Fluoroquinolones, third- and fourthgeneration cephalosporins, carbapenems,

aminoglycosides

Elizabethkingia/

Chryseobacterium spp.

Fluoroquinolones, minocycline, tigecycline,

piperacillin/tazobactam

Rhizobium radiobacter Fluoroquinolones, third- and fourth-generation

cephalosporins, carbapenems

Shewanella spp. Fluoroquinolones, third- and fourth-generation

cephalosporins, β-lactam/β-lactamase

inhibitors, carbapenems, aminoglycosides

Chromobacterium violaceum Carbapenems, fluoroquinolones,

trimethoprim-sulfamethoxazole

a

Treatment should be based on in vitro susceptibility testing; multidrug resistance is

common among these organisms.

TREATMENT

Capnocytophaga Infections

(Table 158-1) Because of increasing β-lactamase production, a penicillin derivative plus a β-lactamase inhibitor—such as ampicillin/

sulbactam (1.5–3.0 g of ampicillin every 6 h)—is currently recommended for empirical treatment of infections caused by Capnocytophaga species. If the isolate is known to be susceptible, infections

with C. canimorsus should be treated with penicillin (12–18 million

units every 4 h). Capnocytophaga is also susceptible to clindamycin

(600–900 mg every 6–8 h) and third-generation cephalosporins such

as ceftriaxone (2 g every 12–24 h). Antibiotics should be given prophylactically to asplenic patients who have sustained dog-bite injuries.

Pasteurella multocida P. multocida is a fastidious, bipolar-staining,

gram-negative coccobacillus that colonizes the respiratory and gastrointestinal tracts of domestic animals; oropharyngeal colonization

rates are 70–90% in cats and 50–65% in dogs. P. multocida can be

transmitted to humans through bites or scratches, via the respiratory

tract from contact with contaminated dust or infectious droplets, or via

deposition of the organism on injured skin or mucosal surfaces during

licking. Most human infections affect skin and soft tissue; almost twothirds of these infections are caused by cats. Patients at the extremes

of age or with serious underlying disorders (e.g., cirrhosis, diabetes)

are at increased risk for systemic manifestations, including meningitis, peritonitis, osteomyelitis and septic arthritis, endocarditis, septic

shock, ecthyma, necrotizing fasciitis, and purpura fulminans, and are

more likely not to have evidence of an animal bite. However, cases have

also occurred in healthy individuals of all ages. If inhaled, P. multocida

can cause acute respiratory tract infection, particularly in patients with

underlying sinus and pulmonary disease.

TREATMENT

Pasteurella multocida Infections

(Table 158-1) P. multocida is susceptible to penicillin, ampicillin,

ampicillin/sulbactam, second- and third-generation cephalosporins,

tetracyclines, and fluoroquinolones. β-Lactamase–producing strains

have been reported.

OTHER GRAM-NEGATIVE BACTERIA

Achromobacter xylosoxidans Achromobacter (previously Alcaligenes) xylosoxidans is an aerobic nonfermenting gram-negative organism that is probably part of the endogenous intestinal flora. It has been

isolated from a variety of water sources, including well water, IV fluids,

and humidifiers. Immunocompromised hosts, including patients with

cancer and postchemotherapy neutropenia, cirrhosis, chronic renal

failure, and cystic fibrosis, are at increased risk for infection. Nosocomial outbreaks and pseudo-outbreaks of A. xylosoxidans infection have

been attributed to contaminated fluids, and clinical illness has been

associated with isolates from many sites, including blood (often in the

setting of intravascular devices). Community-acquired A. xylosoxidans

bacteremia usually occurs in the setting of pneumonia. Metastatic

skin lesions are present in one-fifth of cases. The reported mortality

rate is as high as 67%—a figure similar to rates for other bacteremic

gram-negative pneumonias.

TREATMENT

Achromobacter xylosoxidans Infections

(Table 158-2) Treatment is based on in vitro susceptibility testing

of all clinically relevant isolates; multidrug resistance is common.

Carbapenems, tigecycline, and colistin are typically the most active

agents.

Aeromonas Species Aeromonas is a facultative anaerobic gramnegative bacterium. Aeromonas infections are most often caused by

A. hydrophila, A. caviae, A. veronii, and A. dhakensis. Aeromonas proliferates in potable water, freshwater, and soil. It remains controversial

whether Aeromonas is a cause of bacterial gastroenteritis; asymptomatic

colonization of the intestinal tract with Aeromonas occurs frequently,

and no clonally related diarrheal outbreak has been documented. However, rare cases of hemolytic-uremic syndrome following bloody diarrhea have been shown to be secondary to the presence of Aeromonas.

Aeromonas causes health care–associated sepsis and bacteremia in

infants with multiple medical problems and in immunocompromised

hosts, particularly those with cancer or hepatobiliary disease, including cirrhosis. A. caviae is associated with health care–related bacteremia. Community-acquired infections include bacteremia, spontaneous

bacterial peritonitis, biliary tract infections, and skin and soft tissue

infections. Severe soft tissue infections such as necrotizing fasciitis are

more common in Taiwan than in Western countries; Aeromonas was

the most common pathogen associated with skin and soft tissue infections after the tsunami in Thailand. Along with other gram-negative

organisms such as Shewanella and Chromobacterium, Aeromonas

infections are associated with floods and other hydrologic disasters.

Aeromonas infection and sepsis can occur in patients with trauma

(including severe trauma with myonecrosis), patients with seawatercontaminated wounds, and burn patients exposed to the organism by

environmental (freshwater or soil) wound contamination. Reported

mortality rates range from 25% among immunocompromised adults

with sepsis to >90% among patients with myonecrosis. Patients with

A. dhakensis bacteremia have higher 14-day mortality rates than do

those whose bacteremia is attributable to other species. Aeromonas can

produce ecthyma gangrenosum (hemorrhagic vesicles surrounded by a

rim of erythema with central necrosis and ulceration; see Fig. A1-34)

resembling the lesions seen in Pseudomonas aeruginosa infection. This

organism causes nosocomial infections related to catheters, surgical

incisions, or use of leeches. Other manifestations include meningitis,

peritonitis, pneumonia, and ocular infections.

TREATMENT

Aeromonas Infections

(Table 158-2) Aeromonas species are generally susceptible to fluoroquinolones (e.g., ciprofloxacin at a dosage of 500 mg every 12 h PO or

400 mg every 12 h IV), third- and fourth-generation cephalosporins,

carbapenems, and aminoglycosides, but resistance to all those agents

has been described. Because Aeromonas can produce various βlactamases, including carbapenemases, susceptibility testing must be

used to guide therapy. Antibiotic prophylaxis (e.g., with ciprofloxacin) is indicated when medicinal leeches are used.

1249CHAPTER 159 Legionella Infections

Elizabethkingia/Chryseobacterium Species Elizabethkingia

meningoseptica (formerly Chryseobacterium meningosepticum), a

nonfastidious aerobic nonfermentative gram-negative bacillus, is an

important cause of nosocomial infections, including outbreaks due to

contaminated fluids (e.g., contaminated sinks, disinfectants, and aerosolized antibiotics) and sporadic infections due to indwelling devices,

feeding tubes, and other fluid-associated apparatuses. Most published

reports have originated from Asia, particularly Taiwan. A report from

South Korea described infections with a high case-fatality rate associated with mechanical ventilation. Outbreaks due to this organism

have persisted until extensive cleaning of environmental surfaces

and equipment has been performed. Nosocomial E. meningoseptica

infection usually involves preterm neonates, patients with underlying immunosuppression (e.g., related to malignancy or diabetes), or

patients exposed to antibiotics in intensive care. E. meningoseptica

has been reported to cause meningitis (primarily in neonates), pneumonia, sepsis, endocarditis, bacteremia, eye infections, and soft tissue

infections. Other species of Elizabethkingia are emerging, identified

using MALDI-TOF and 16s rRNA sequencing. In a report of 86 clinical isolates, only 12 (19.8%) of the isolates were E. meningoseptica;

the majority were E. anophelis (51 isolates; 59.3%). More than threequarters of the isolates were from the lower respiratory tract, and

9.3% were from blood cultures. In a U.S. study of 11 patients with E.

anophelis infection, all had bloodstream infections. In that series, the

patients had comorbidities and recent health care exposure; there was

a mortality rate of 18.2%.

Chryseobacterium indologenes has caused bacteremia, sepsis, peritonitis, meningitis, and pneumonia, typically in immunocompromised

patients with indwelling devices. Mortality rates have been as high as

50% in some reports; it is unclear whether a poor prognosis is related

to underlying comorbidities or to the multidrug-resistant phenotype

of the organism.

TREATMENT

Elizabethkingia/Chryseobacterium Infections

(Table 158-2) These organisms are often susceptible to fluoroquinolones, minocycline, tigecycline, and rifampin. They may be

susceptible to β-lactam/β-lactamase inhibitor combinations such

as piperacillin/tazobactam, but multidrug-resistant isolates are

increasing and can possess extended-spectrum β-lactamases and

metallo-β-lactamases. In vitro susceptibility testing often indicates

activity of agents used against gram-positive bacteria (e.g., vancomycin), but it is unclear that those agents are reliable clinically.

Combination therapy may be needed for successful treatment.

Susceptibility testing should be performed to guide the choice of

optimal agents.

MISCELLANEOUS ORGANISMS

Rhizobium (formerly Agrobacterium) radiobacter has usually been

associated with infection in the presence of medical devices, including intravascular catheter–related infections, prosthetic-joint and

prosthetic-valve infections, and peritonitis caused by dialysis catheters. Cases of endophthalmitis after cataract surgery also have been

described. Most R. radiobacter infections occur in immunocompromised hosts, especially individuals with malignancy or HIV infection.

Elderly patients with septic shock, watery diarrhea, and acute renal

failure also have been reported. Strains are usually susceptible to

fluoroquinolones, third- and fourth-generation cephalosporins, and

carbapenems (Table 158-2).

Shewanella species are ubiquitous nonfermentative gram-negative

organisms found in seawater and marine environments. Human

disease is caused primarily by S. putrefaciens and S. algae; S. algae

may be the more virulent species. Most infections involve skin and

soft tissue, ranging from impetigo to necrotizing fasciitis. Patients

are exposed to the organism through contact of bites, open wounds,

or devitalized tissue with seawater, marine animals, or fresh seafood

or through ingestion of seawater or of raw or undercooked seafood,

especially shellfish. Shewanella species also cause chronic ulcers of the

lower extremities, osteomyelitis, biliary tract infections, pneumonia,

bacteremia, sepsis, and potentially chronic otitis media. A fulminant

course is associated with cirrhosis, hemochromatosis, diabetes mellitus, malignancy, or other severe underlying conditions. In one series of

cases from Martinique, 13% of infections were fatal. These organisms

are often susceptible to fluoroquinolones, third- and fourth-generation

cephalosporins, β-lactam/β-lactamase inhibitors, carbapenems, and

aminoglycosides (Table 158-2).

Chromobacterium violaceum is a facultative anaerobic organism

found in soil and water in tropical or subtropical regions. After exposure, it can cause rare but serious—often fatal—skin and soft tissue

infections of limbs although several recent reports suggest a more

benign course with lower mortality. Life-threatening infections with

severe sepsis and metastatic abscesses occur most often in patients

with underlying illness, particularly in children with defective neutrophil function (e.g., those with chronic granulomatous disease).

C. violaceum is frequently resistant to multiple drugs; carbapenems

are most often used empirically. Fluoroquinolones and trimethoprimsulfamethoxazole also can be active (Table 158-2).

Ochrobactrum anthropi causes infections related to central venous

catheters in compromised hosts; other invasive infections such as

bacteremia have been described. Pseudomonas (formerly Flavimonas)

oryzihabitans can cause catheter-related bloodstream infections in

immunocompromised patients. Sphingobacterium is a rare cause

of human infection in immunocompromised hosts. It can colonize

hospital water systems, respiratory tract equipment, and laboratory

instruments. Sphingomonas paucimobilis is found in soil and water

sources and is a rare cause of infection in both healthy and immunocompromised patients. This organism can cause bloodstream infections, respiratory distress, and sepsis. It has a predilection for bone

and soft tissue infection, osteomyelitis, and septic arthritis. A different

species, Sphingomonas koreensis, was associated with a small cluster

of nosocomial cases at one hospital and was traced to a reservoir in

the plumbing system. Ralstonia species also can contaminate water

supplies, including hospital water systems. Cases of bacteremia, osteomyelitis, pneumonia, and meningitis have been described. Other

organisms implicated in human infections include Weeksella species;

Bergeyella species; various CDC groups; and Oligella urethralis. The

reader is advised to consult subspecialty texts and references for further

guidance on these organisms.

■ FURTHER READING

Chambers ST et al: HACEK infective endocarditis: Characteristics and

outcomes from a large multi-national cohort. PLoS One 8:e63181,

2013.

Choi MH et al: Risk factors for Elizabethkingia acquisition and clinical

characteristics of patients, South Korea. Emerg Infect Dis 25:42, 2019.

Kormondi S et al: Human pasteurellosis health risk for elderly persons

living with companion animals. Emerg Infect Dis 25:229, 2019.

Lutzen L et al: Incidence of HACEK bacteremia in Denmark: A 6-year

population-based study. Int J Infect Dis 68:83, 2018.

Bacteria of Legionella species cause two primary human diseases:

Legionella pneumonia (often referred to as Legionnaires’ disease) and

Pontiac fever; collectively, these diseases are referred to as legionellosis.

Legionnaires’ disease was first described in 1976 in an outbreak among

members of the American Legion participating in a conference at a

hotel in Philadelphia, Pennsylvania. Since their original description,

159 Legionella Infections

Steven A. Pergam, Thomas R. Hawn

1250 PART 5 Infectious Diseases

Legionella-related infections have increased in frequency throughout

the world as techniques to diagnose them have improved, clinical

awareness has increased, cities have grown, and water systems have

both aged and become more complex. Most cases of legionellosis are

linked to waterborne exposures. These infections can be either sporadic or due to common-source community or nosocomial exposures.

Outbreaks of legionellosis are well described. After exposure, legionellosis occurs primarily among persons with risk factors for disease,

including older adults and those with primary organ dysfunction,

immunocompromise, or other chronic illnesses. Clinical awareness

is important, as the similarity of signs and symptoms of legionellosis

to those of other respiratory illnesses can lead to delayed treatment.

Despite appropriate therapy, Legionella pneumonia is associated with

significant morbidity and mortality.

■ PATHOGEN AND PATHOGENICITY

Legionellae are aerobic gram-negative bacteria that are ubiquitous in

aquatic environments, damp soil, and compost. Of the more than 60

Legionella species, approximately half have been documented to lead

to clinical disease, but most clinical disease is driven by Legionella

pneumophila, primarily serotype 1. The primary habitats for growth

and replication of Legionella are amoebae and other free-living protozoa, in which these bacterial species can thrive intracellularly; humans

are accidental hosts. Legionellae are reliant on host-derived amino

acids and nutrients for intracellular replication. The organisms have a

biphasic life cycle: a replicative phase in nutrient-rich conditions (e.g.,

in their protozoal hosts) and a noninfective transmissive phase under

scarcity of resources. Therefore, they can persist in complex biofilms in

both natural and engineered water systems (e.g., premise plumbing—a

building’s hot and cold water piping systems) and are phagocytized by

waterborne protozoa. In premise plumbing systems, where temperature and nutrients support the protozoal hosts of legionellae, the bacteria can replicate to concentrations sufficient to cause human infection.

After exposure to Legionella through inhalation or aspiration of

small aerosol particles, the organisms attach to immune cells and are

phagocytized. After phagocytosis, they can evade intracellular defenses

and replicate in human alveolar macrophages and monocytes. Pathogenic Legionella species have numerous virulence systems that they

use to evade the human immune system, including the development

of Legionella-containing vacuoles within immune cells, downregulation of cytokine receptors, inhibition of host protein synthesis, and

avoidance of lysosomal degradation. Despite their ability to replicate

and persist in the intracellular environment, innate immune components that target intracellular pathogens—specifically, pattern recognition receptors, including Toll-like receptors and nucleotide-binding

oligomerization domain–like receptors—activate immune responses.

Adaptive CD4 and CD8 cytotoxic T-cell involvement and these innate

immune responses eventually lead to the production of interferon γ

and tumor necrosis factor, the promotion of neutrophil recruitment

into the lung, and other proinflammatory responses. This cascade can

be beneficial and result in clearance of the pathogen. However, these

inflammatory responses can also cause immunopathology and adverse

outcomes. L. pneumophila is more cytopathogenic than most nonpneumophila Legionella species, a characteristic that may be partially

responsible for its association with severe disease.

■ EPIDEMIOLOGY

Legionella species are responsible for >50% of all waterborne outbreaks

and >10% of disease related to drinking water in the United States. A

National Academies of Sciences, Engineering, and Medicine report

estimates that 50,000–70,000 Americans develop Legionnaires’ disease

per year. Incidence rates of legionellosis in the United States are reportedly 2–3 cases per 100,000 persons, but higher rates have been reported

in other parts of the world. Numerous global epidemiologic studies

assessing legionellosis have shown an increasing prevalence over the

past few decades; this increase has been hypothesized to be due to a

variety of causes, including an aging population, improved diagnostics,

global temperature changes, and an aging water infrastructure. Legionellosis is associated with substantial health care costs.

Legionella species are found throughout the world, but most epidemiologic data focus on legionellosis in large metropolitan areas in

Australia/New Zealand, Europe, and North America. Rates of infection

in other parts of the world are unknown, as surveillance systems and

laboratory testing are less readily available in large portions of Africa

and Asia. More than 80% of cases of Legionnaires’ disease are linked

to L. pneumophila—in particular to serotype 1, which is the most

frequently isolated Legionella pathogen. Although L. pneumophila predominates as a cause of disease, species predilection varies regionally.

In Australia and New Zealand, for example, the rate of disease due to

Legionella longbeachae approaches or exceeds that for L. pneumophila.

As previously mentioned, most reported cases are due to L. pneumophila serotype 1—a reflection of its pathogenicity. However, this

predominance is also due to the frequency and ease of use of urinary

antigen testing that targets this pathogen and allows more effective diagnosis in the community. It is unclear how large a role non-pneumophila

species and non–serotype 1 L. pneumophila play in disease. However,

in studies in Europe, where respiratory cultures are more frequently

collected, nearly 10% of Legionnaires’ disease patients were infected

with species other than L. pneumophila. In the United States, nearly

10% of culture-confirmed cases are due to non–serogroup 1 L. pneumophila. Immunosuppressed patients, such as cancer patients and

transplant recipients, may be more likely to develop pneumonia caused

by non-pneumophila species such as Legionella micdadei, Legionella

bozemanii, and L. longbeachae.

Despite increases in cases in the United States (Fig. 159-1) and

throughout the world, incident cases are still thought to be underreported. Many cohort studies of community-acquired pneumonia do not

require routine testing for Legionella or assess only for L. pneumophila

serotype 1 (by urinary antigen testing) and therefore may underestimate

true prevalence. For example, a large administrative database of studies

shows that, of patients with clinically proven community-acquired

pneumonia, only 26% underwent Legionella-specific testing; even

patients with documented risk factors for legionellosis are not always

tested for Legionella. In studies that routinely assess for legionellosis,

the prevalence of Legionella pneumonia ranges between 2 and 10% of

all community-acquired pneumonia cases. In addition, extrapulmonary presentations and Pontiac fever are less likely to be identified or

to result in presentation for health care, and this trend leads to further

underestimation of the true burden of legionellosis.

Seasonality and Climate Geoclimatic changes, storms, and seasonality are thought to be important components of Legionella’s

epidemiology. The incidence of Legionella disease increases in the

summer and fall—specifically, in warmer weather and with increased

rain and humidity. Studies that screen all respiratory samples for

Legionella find that legionellosis is indeed diagnosed most frequently

in the United States during warmer summer/fall months and periods

of greater humidity. Furthermore, seasonal storms, which may disrupt

water pipes or cause increased flooding, can result in contamination of

water systems with soil and lead to Legionella exposures. There is concern that, with ongoing climate shifts and rising global temperatures,

cases of legionellosis may continue to increase.

Community and Health Care–Associated Outbreaks Small

and large clusters and point-source outbreaks of Legionella cases lead

to public health investigations, but these situations account for only

~5–10% of all Legionella cases yearly. Outbreaks occur when two or

more people become ill after shared exposures in a community. In

health care systems, a single proven case should trigger a Legionella

investigation. The Centers for Disease Control and Prevention (CDC)

recommends an outbreak investigation if a singular patient with Legionella is identified who did not leave the facility/campus for the 10 days

prior to illness onset. Additionally, an outbreak investigation within a

health care system is warranted if there are at least two possible Legionella patients who spent any time in the hospital/long-term care facility

within 12 months of each other (see “Clinical Presentations” below).

Most common outbreaks are linked to water sources dispersing

aerosol droplets that increase the area of particle spread (e.g., cooling