1345CHAPTER 176 Whipple’s Disease

WD suggest the entire small bowel can be involved. Diagnostic misdirection can be caused by co-infection with Giardia lamblia, which is

occasionally identified. The intestinal phase can also be confused with

Crohn’s or celiac disease. In addition to rheumatologic and intestinal

disease, neurologic (6–63%), cardiac (17–55%), pulmonary (10–50%),

lymphatic (10–55%), ocular (5–10%), dermal (5–30%), and less commonly other sites are variably involved in classic WD.

Neurologic Disease CNS disease, defined by PCR-based detection of T.

whipplei in cerebrospinal fluid (CSF), develops in ~50% of patients,

many of whom are asymptomatic. A variety of neurologic manifestations have been reported and portend a poor prognosis. The most

common are cognitive changes including memory impairment progressing to dementia, personality and mood alterations, hypothalamic

involvement (e.g., polyuria/polydipsia, sleep-cycle disorders), and

supranuclear ophthalmoplegia. In addition, neuro-ophthalmologic

manifestations of WD include supranuclear gaze palsy (usually vertical), oculomasticatory and oculofacial myorhythmia (highly suggestive

of Whipple’s), nystagmus, and retrobulbar neuritis. Focal neurologic

presentations (dependent on lesion location), seizures, ataxia, meningitis, encephalitis, rhomobo- or limbic encephalitis, hydrocephalus,

myelopathy, myoclonus, choreiform movements, and distal polyneuropathy also have been described. Neurologic sequelae occur with CNS

disease, and the mortality risk is significant.

MRI results may be normal. Identified lesions (solitary or multifocal) are usually T2 and fluid-attenuated inversion recovery (FLAIR)

hyperintense and may enhance with gadolinium. All sites can be

involved, and the nature of lesions is variable (e.g., nodular, infiltrative,

tumor-like). Although imaging findings are myriad and are not diagnostic, the median temporal lobe, midbrain, hypothalamus, and thalamus are commonly affected. FDG-PET may reveal increased uptake.

CSF analysis may be normal; when abnormal, leukocytosis (generally

lymphocyte-predominant) and an elevated protein concentration are

common. A low CSF glucose level has been reported.

Cardiac Disease Endocarditis is increasingly recognized in WD (85% of

cases in males), causes 2.6−6.3% of culture-negative endocarditis cases,

and may be complicated by congestive heart failure (40% of cases),

embolic events, arrhythmias, mycotic aneurysm, or rarely hypotension.

Fever is often absent, and the Duke clinical criteria are rarely met.

Vegetations are identified by echocardiography in 50–75% of cases.

All valves, alone or in combination, can be affected; most commonly

involved are the aortic and mitral valves. Preexisting valvular disease is

found in only a minority of cases, although infection of bioprosthetic

T. whipplei has a tropism for myeloid cells, which it invades and

in which it can avoid being killed. Infiltration of infected tissue by

large numbers of foamy macrophages containing periodic acid–Schiff

(PAS)–staining inclusions (representing ingested bacteria) is a characteristic and most common finding. With gastrointestinal disease

progression, villus atrophy, lymphangiectasia, crypt hyperplasia, and

apoptosis of surface epithelial cells are observed in the small intestine,

with resultant diarrhea due to decreased absorption and increased leak

of water and solutes. Occasionally, involvement of lymphatic or hepatic

tissue may manifest as noncaseating granulomas that can mimic sarcoid or granulomatous vasculitis.

■ CLINICAL MANIFESTATIONS

Asymptomatic Colonization/Carriage Studies using primarily PCR have detected T. whipplei sequence in stool, saliva, duodenal

tissue, and (rarely) blood in the absence of symptoms. Although prevalence rates are still being defined, in Western European countries,

detection in saliva (0.2%) is less common than that in stool (1–11%)

and appears to occur only with concomitant fecal carriage. The prevalence of fecal carriage is elevated among individuals with exposure to

waste water or sewage (12–26%) and among children living in tropical

Africa and Asia (20–48%). A duration of carriage of 7 years for the

same strain has been described in a sewer worker. Evolution of the carrier state into chronic disease is uncommon. Bacterial loads are lighter

in asymptomatic carriage than in active disease.

Acute Infection T. whipplei has been implicated as a cause of acute

gastroenteritis in children. It was also detected via PCR in the blood

of 4.6% of febrile patients (75% of whom were <15 years of age) from

two rural villages in Senegal as opposed to 0.25% of healthy controls.

Further, T. whipplei has been implicated as a cause of acute pneumonia.

These data suggest that primary acquisition may result in symptomatic

pulmonary or intestinal infection or a febrile syndrome, which perhaps

are more common than is generally appreciated.

Chronic Infection •  “CLASSIC” WD So-called classic WD was

the initial clinical syndrome recognized, with consequent identification

of T. whipplei. This chronic infection is defined by involvement of the

duodenum and/or jejunum that develops over years. In most individuals, the initial phase of disease manifests primarily as intermittent,

often symmetrical, occasionally chronic, and rarely destructive migratory oligo- or polyarthralgias/seronegative arthritis involving the knees,

wrists, ankles, and metacarpal-interphalangeal joints most commonly.

Less frequently, spondylitis, sacroiliitis, discitis, tenosynovitis, bursitis,

and prosthetic hip infection also have been described. Intermittent fever,

myalgias, and skin nodules may accompany joint symptoms. Tests for

rheumatoid factor and antinuclear antibody are usually negative. This

initial stage is often confused with a variety of rheumatologic disorders and, on average, lasts 6–8 years before gastrointestinal symptoms

commence. Treatment of presumed inflammatory arthritis with immunosuppressive agents (e.g., glucocorticoids, anti-TNF-α, anakinra) can

accelerate progression of the disease process; thus, screening for WD

prior to initiation of immunosuppressant therapy may be appropriate,

depending on the clinical scenario. Alternatively, antimicrobial therapy for another indication may reduce symptoms, and this situation

should also prompt consideration of WD. The intestinal symptoms

that develop in the majority of cases are characterized by diarrhea

with accompanying weight loss and may be associated with fever

and abdominal pain. Occult gastrointestinal blood loss, vitamin deficiencies, hepatosplenomegaly (10–15%), and ascites (10%) are less

common. Anemia and hypereosinophilia may be detected. The most

common finding on abdominal CT is mesenteric and/or retroperitoneal lymphadenopathy (usually raising concern about lymphoma).

The endoscopic or video-capsule observation of pale, yellow, or shaggy

mucosa with erythema or ulceration past the first portion of the

duodenum suggests WD (Fig. 176-1). When endoscopy with duodenal

biopsy is nondiagnostic, a video-capsule study may assist in identifying more distal lesions for subsequent biopsy. 18F-Fluorodeoxyglucose

positron emission tomography (FDG-PET) studies in patients with

FIGURE 176-1 Endoscopic view of the jejunal mucosa demonstrating a thickened,

granular mucosa and “white spots” due to dilated lacteals. (Reprinted with

permission from J Bureš et al: Whipple’s disease: Our own experience and review

of the literature. Gastroenterol Res Pract, 2013.)

1346 PART 5 Infectious Diseases

valves has been described. Mural, myocardial, or pericardial disease

also occurs alone or in combination with valvular involvement. Constrictive pericarditis develops infrequently. Diagnosis of cardiac disease

is rarely made prior to surgical intervention.

Pulmonary Disease Some combination of interstitial disease, nodules,

parenchymal infiltrate, and pleural effusion is observed. An association

with pulmonary hypertension has also been reported. The clinical significance of T. whipplei sequence identified in bronchoalveolar lavage

fluid (BALF) from asymptomatic HIV-infected individuals or in a case

of interstitial lung disease is unresolved but suggests caution in diagnosing “isolated” pneumonia on the basis of sequence alone. Notably,

while the bacterium seems to exist in the airways of HIV-infected persons at higher rates, its presence is not clearly associated with increased

inflammation or a discernible decrease in lung function.

Lymphatic Disease Mesenteric and retroperitoneal lymphadenopathy

are common with intestinal disease, and mediastinal adenopathy may

be associated with pulmonary infection. Peripheral adenopathy is less

common.

Ocular Disease (Non–Neuro-Ophthalmologic) Uveitis is the most common

form of ocular disease, usually presenting as a change in vision or

“floaters.” Anterior (anterior chamber), intermediate (vitreous), and

posterior (retina/choroid) uveitis can occur alone or in combination.

Treatment with glucocorticoids alone can worsen uveitis and unmask

extraocular disease. Likewise, use of local or systemic glucocorticoids

after ocular surgery can precipitate ocular infection, likely as a result of

asymptomatic or subclinical disease. Keratitis, crystalline keratopathy,

and optic neuritis also have been reported. Patients may be misdiagnosed with sarcoid or Behçet’s disease prior to the recognition of

Whipple’s.

Dermatologic Disease Skin hyperpigmentation (melanoderma), particularly in light-exposed areas in the absence of adrenal dysfunction, is

suggestive of WD. A variety of other cutaneous manifestations have

been described, including erythematous macular lesions, nonthrombocytopenic purpura, subcutaneous nodules, and hyperkeratosis.

Miscellaneous Sites Thyroid, renal, testicular, epididymal, gallbladder,

skeletal muscle, and bone marrow involvement have all been described.

In fact, almost any organ can be involved in classic WD, with varying

frequency, variable combinations, and myriad signs and symptoms. As

a result, WD should be considered in the setting of a chronic multisystemic process. Despite its rarity, the combination of rheumatologic

and intestinal disease with weight loss, with or without neurologic and

cardiac involvement, warrants heightened suspicion.

ISOLATED INFECTION This entity has been defined as infection in the

absence of intestinal symptoms, although an occasional small-bowel

biopsy may be PAS-positive or more commonly PCR-positive in this

setting. “Isolated infection” is something of a misnomer since multiple

nonintestinal sites of T. whipplei infection are not uncommon. Infection at the same nonintestinal sites (single or multiple) that are variably

involved in classic WD may also present as “isolated infection.” Further,

intestinal disease can subsequently develop. Endocarditis, neurologic

disease, uveitis, rheumatologic manifestations, and pulmonary involvement are most commonly described. Signs and symptoms are similar

to those described for T. whipplei infection of these sites in classic WD.

With enhanced PCR-based diagnostic capabilities, T. whipplei infection

without concomitant intestinal involvement (of which endocarditis is

the best example) will probably be diagnosed increasingly often.

REINFECTION/RELAPSING DISEASE/IMMUNE RECONSTITUTION

INFLAMMATORY SYNDROME (IRIS) It has been suggested that, if an

underlying host immune defect places an individual at risk for chronic

infection, then that person may be at risk for reinfection due to occupational exposure or contact with family members who are asymptomatically colonized. One case of apparent reinfection that was due to a

different genotype supports this contention.

Optimal treatment regimens and durations are still being defined.

However, it is clear, especially in the setting of occult or overt

CNS disease, that treatment with oral tetracycline or trimethoprimsulfamethoxazole (TMP-SMX) alone may result in disease relapse.

Relapses or perhaps reinfections occurring years to decades after initial

therapy have been described.

As in patients treated for HIV or mycobacterial disease, IRIS has

been described in up to 17% of patients treated for T. whipplei infection. Prior immunosuppressive therapy increases the likelihood of

IRIS, in which inflammation recurs after an initial clinical response

to treatment and loss of PCR detection of T. whipplei. Manifestations

include the development of fever, arthritis, skin lesions, subcutaneous

nodules, pleuritis, uveitis, and orbital and periorbital inflammation;

some cases have been fatal.

■ DIAGNOSIS

Considering T. whipplei infection and ensuring that the appropriate

tests are performed are the critical steps in making the diagnosis, which

otherwise will likely be missed. Serology is of little value since patients

with active infection usually mount a poor IgM/IgG response to T.

whipplei and a positive result most likely reflects prior exposure and

clearance. The clinical presentation will in part dictate which clinical

specimens are most likely to enable the diagnosis. In the presence (and

perhaps the absence) of gastrointestinal symptoms, postbulbar duodenal biopsies should be performed, although a normal macroscopic

appearance is common. As a general rule, diagnostic yield is greater

for tissue specimens than for body fluids. Biopsy of normal-appearing

skin may detect T. whipplei in the setting of classic WD and serve as

a minimally invasive means to establish the diagnosis. It is prudent

to collect CSF even in the absence of CNS symptoms; asymptomatic

disease is common, the CNS is the most common site for relapse, and

thus the information gained by CSF examination could influence the

design and duration of the treatment regimen.

The diagnosis of classic WD was originally based on histologic

findings in intestinal biopsy specimens. Although this diagnostic procedure remains important, it is not optimally sensitive. Infiltration of

the lamina propria with macrophages containing PAS-positive inclusions that are resistant to diastase is observed. However, PAS is nonspecific, also yielding positive results with mycobacteria (which can

be differentiated with Ziehl-Neelsen stain and culture), Rhodococcus

equi, Bacillus cereus, Corynebacterium species, and Histoplasma species. T. whipplei can be detected by silver stain, Brown-Brenn (weakly

positive), or acridine orange and is not stained by calcofluor. Staining

of other tissues or fluids (e.g., ocular aspirations) for PAS-positive

inclusions in macrophages can be performed to support the diagnosis. The sensitivity of identification of PAS-positive inclusions in WD

may be decreased by anti-TNF-α therapy. Electron microscopy can be

used to identify the trilaminar cell wall of T. whipplei. When available,

immunohistochemistry has greater specificity and sensitivity than PAS

staining and can be performed on archived fixed tissue. Alternatively,

the use of fluorescence in situ hybridization (FISH) has been reported

as a complementary diagnostic tool with various tissue samples.

The development and implementation of specific PCR-based diagnostics have significantly increased the sensitivity and specificity of T.

whipplei identification. PCR can be applied to affected tissues (with

greater sensitivity for non-formalin-fixed than for formalin-fixed tissue) in support of histologic findings and to various body fluids (e.g.,

CSF; aqueous or vitreous humor; joint, pericardial, or pleural fluid;

BALF; blood; urine). It is important to note that the interpretation of

a PCR-based diagnostic approach must take into account limitations

such as false-positive results due to sample contamination, falsenegative results due to low organism load, poor sample quality, inadequate DNA extraction, and variability in performance of various PCR

assays. As with all diagnostic tests, consideration of pretest probability

is critical for interpretation and a negative result does not exclude WD.

Urine PCR for T. whipplei infection may hold promise for the noninvasive diagnosis of classic and isolated WD. In a recent study of 12

cases, urine PCR was positive in 9 (75%) of 12 cases prior to treatment

compared to 0 (0%) of 110 controls, including 11 controls that were

presumed carriers in which feces PCR was positive, although there was

no evidence of disease. In addition, urine PCR is a potential tool to

evaluate success of WD therapy. Saliva and fecal PCR is inappropriate

1347CHAPTER 177 Infections Due to Mixed Anaerobic Organisms

as the sole diagnostic tool for WD due to a low positive predictive

value, which more commonly identifies colonization, not disease; a

positive result requires confirmation from appropriate end-organ tissue or body fluid.

T. whipplei has been successfully cultured from blood, CSF, synovial

fluid, BALF, valve tissue, duodenal tissue, skeletal muscle, and lymph

nodes, but culture is not practical since it takes months to obtain a

positive result.

Affected anatomic sites in WD patients may demonstrate uptake

on FDG-PET, which in turn could guide tissue sampling for use in

specific tests.

TREATMENT

Whipple’s Disease

Data on treatment are emerging, but the optimal regimen and duration for chronic infection, which may depend on the sites involved

(e.g., CNS and heart valve), are unclear. Appropriate treatment usually results in a rapid—and at times remarkable—clinical response

(e.g., in CNS disease), but eradication requires prolonged treatment. Maintenance of a durable response has been more challenging because of both relapse and host predisposition to reinfection.

Rates of relapse, particularly of CNS disease, were unacceptable

with oral tetracycline or TMP-SMX monotherapy. Sequence data

now indicate that TMP is not active against T. whipplei (given the

absence of dihydrofolate reductase in T. whipplei) and that resistance to SMX and sulfadiazine can occur. However, a randomized

controlled trial in 40 patients, who received either ceftriaxone

(2 g IV q24h) or meropenem (1 g IV q8h) for 2 weeks followed by

oral TMP-SMX (160/800 mg) twice a day for 1 year, demonstrated

outstanding efficacy. The only case in which therapy failed—an

asymptomatic CNS infection that was not eradicated by either

regimen—was subsequently cured with oral minocycline and

chloroquine (250 mg/d after a loading dose). A follow-up trial

reported similar efficacy with a regimen of ceftriaxone (2 g IV

q24h) for 2 weeks followed by oral TMP-SMX for 3 months. One

issue in these trials was that the doses—and perhaps the duration

of ceftriaxone and meropenem treatment as well—were not optimal

for CNS infection. By contrast, in a small retrospective series, outcome was better in patients treated with oral doxycycline (100 mg

twice a day) plus hydroxychloroquine (200 mg three times a day;

to raise phagosome pH and increase drug activity in vitro) than in

patients initially treated with TMP-SMX.

Until more data become available, it seems prudent—at least in

asymptomatic/symptomatic CNS disease (which is present in many

cases of WD)—first to administer CNS-optimized doses of IV

ceftriaxone (2 g q12h) or meropenem (2 g q8h) for 2–4 weeks and

then to treat with oral doxycycline, or minocycline plus hydroxychloroquine for at least 1 year, if tolerated. Although TMP-SMX has

been frequently used as the oral alternative with reported success, a

number of relapses or reinfections with TMP-SMX treatment have

been reported, thereby suggesting caution for its use in patients

with infection in critical locations such as the CNS and the heart.

Although data on the use of PCR to guide therapy do not exist,

it seems reasonable that continued T. whipplei detection by PCR,

especially in the CSF and perhaps urine, should dictate at least

continuation of therapy or perhaps consideration of an alternative

regimen when in conjunction with a poor clinical response.

As molecular diagnostics become more available, T. whipplei

may be increasingly recognized as a cause of endocarditis, and

thus, timely recognition may result in cure with medical management alone. Surgery may be needed in the setting of endocarditis

with significant valve dysfunction or myocardial abscess. Current

European guidelines for the treatment of endocarditis caused by

T. whipplei recommend oral doxycycline plus hydroxychloroquine

for ≥18 months or, alternatively, ceftriaxone (2 g q24h IV) or penicillin (2 million units q4h IV) plus streptomycin (1 g q24h IV) for

2–4 weeks followed by oral TMP-SMX (800 mg q12h); a small study

from Spain reported that treatment durations of 12–13 months with

these regimens or variations were efficacious.

Data on isolated infection and certain site-specific treatment

issues are even more limited. Anecdotal reports describe successful treatment of uveitis with oral TMP-SMX with or without

rifampin, whereas treatment with tetracycline alone has resulted in

relapse. Although a role for adjunctive intraocular therapy has been

reported, the data are unclear on this point. There is a single case

report of clearance of infection in a chronically relapsing patient

by the addition of interferon gamma to antimicrobials. The supplementation to antimicrobials may be a consideration to address

refractory disease or potential issues with antibiotic resistance.

Although data on the treatment of foreign body–associated

infection are virtually nonexistent, medical treatment for a prosthetic hip infection was apparently successful; however, follow-up

was limited.

The occurrence of a Jarisch-Herxheimer reaction within 24 h of

treatment initiation has been described, with rapid resolution. The

addition of glucocorticoids may be beneficial in the management

of IRIS, and thalidomide has been used in steroid-refractory cases.

Importantly, although data are lacking, due to the inherent risk

of relapse or reinfection, lifelong suppressive therapy with doxycycline after completion of the initial treatment regimen has been

advocated. Regardless of the therapeutic approach chosen, an effort

to ensure compliance and close follow-up for potential relapse or

reinfection, which can occur many years after an apparent cure, will

maximize the chances for a good outcome.

■ FURTHER READING

Bally JF et al: Systematic review of movement disorders and oculomotor abnormalities in Whipple’s disease. Mov Disord 33:1700, 2018.

Crews NR et al: Diagnostic approach for classic compared with localized Whipple disease. Open Forum Infect Dis 5:ofy136, 2018.

Damaraju D et al: Clinical problem-solving: A surprising cause of

chronic cough. N Engl J Med 373:561, 2015.

Guérin A et al: IRF4 haploinsufficiency in a family with Whipple’s

disease. Elife 7:e32340, 2018.

Gunther U et al: Gastrointestinal diagnosis of classical Whipple

disease: Clinical, endoscopic, and histopathologic features in 191

patients. Medicine 94:e714, 2015.

Lagier JC, Raoult D: Whipple’s disease and Tropheryma whipplei

infections: When to suspect them and how to diagnose and treat

them. Curr Opin Infect Dis 31:463, 2018.

Mcgee M et al: Tropheryma whipplei endocarditis: Case presentation

and review of the literature. Open Forum Infect Dis 6:ofy330, 2018.

Meunier M et al: Rheumatic and musculoskeletal features of Whipple

disease: A report of 29 cases. J Rheumatol 40:2061, 2013.

Moter A et al: Potential role for urine polymerase chain reaction in

the diagnosis of Whipple’s Disease. Clin Infect Dis 68:1089, 2019.

Watanuki S et al: Sutton’s Law: Keep going where the money is. J Gen

Intern Med 30:1711, 2015.

Anaerobes comprise the predominant class of bacteria of the normal

human microbiota that reside on mucous membranes and predominate in many infectious processes, particularly those arising from

mucosal surfaces. These organisms generally cause disease subsequent

to the breakdown of mucosal barriers and the leakage of the microbiota

177 Infections Due to Mixed

Anaerobic Organisms

Neeraj K. Surana, Dennis L. Kasper

1348 PART 5 Infectious Diseases

into normally sterile sites. Infections resulting from contamination by

the microbiota are usually polymicrobial and involve both aerobic and

anaerobic bacteria. However, the difficulties encountered in handling

specimens in which anaerobes may be important and the technical

challenges entailed in cultivating and identifying these organisms

in clinical microbiology laboratories continue to leave the anaerobic

etiology of an infectious process unproven in many cases. Therefore,

an understanding of the types of infections in which anaerobes can

play a role is crucial in selecting appropriate microbiologic tools to

identify the organisms in clinical specimens and in choosing the most

appropriate treatment, including antibiotics and surgical drainage or

debridement of the infected site. This chapter focuses on infections

caused by anaerobic bacteria other than Clostridium species, which are

covered elsewhere (Chaps. 134 and 154).

■ HISTORICAL PERSPECTIVE

Anaerobic organisms were first identified by Antonie van Leeuwenhoek

in 1680—nearly a century before oxygen itself was discovered. Leeuwenhoek set up culture medium (crushed pepper powder and clean rainwater) in two glass tubes—one open to ambient air and the other sealed

closed—that he incubated for several days. Although he did not expect

to observe anything in the sealed tube, he was surprised to find “animalcules” in both tubes. He noted that these bacteria in the sealed tube were

“bigger than the biggest sort” in the tube left open to air. It was not until

the mid- to late nineteenth century that Leeuwenhoek’s findings were

confirmed by Pasteur and others. However, these principles described

by Leeuwenhoek underlie the basic pathogenesis of anaerobic infections: development of an anaerobic environment in a closed space is

due to consumption of oxygen by aerobic organisms and results in the

outgrowth of anaerobic organisms.

■ DIFFERENCES BETWEEN ANAEROBIC AND

AEROBIC ORGANISMS

Anaerobic bacteria can be categorized as obligate anaerobes (killed in

the presence of ≥0.5% oxygen), aerotolerant organisms (can tolerate

the presence of oxygen but cannot use it for growth), and facultative

anaerobes (can grow in the presence or absence of oxygen). Most

clinically relevant anaerobes, such as Bacteroides fragilis, Prevotella

melaninogenica, and Fusobacterium nucleatum, are relatively aerotolerant. These organisms contrast with obligate aerobes, which require high

concentrations of oxygen for growth, and microaerophilic organisms,

which are damaged by atmospheric concentrations of oxygen (~21%)

but require low concentrations of oxygen (typically 2–10%) for growth.

Given that molecular oxygen can reduce to superoxide (O2

−) and

hydrogen peroxide (H2

O2

), which are damaging to cells, the ability

to tolerate the presence of oxygen is due, in part, to the expression of

superoxide dismutase and catalase. The variation in anaerobic organisms tolerating anywhere from <0.5 to 8% O2

 may reflect the amount

of these enzymes that is produced.

Furthermore, aerobic and anaerobic organisms differ in their

energy metabolism. Cellular respiration requires establishment of an

electrochemical gradient across the membrane, resulting in an electric

potential (often related to a proton gradient) across the membrane. In

aerobic respiration, electrons are shuttled through an electron transport

chain, with oxygen as the final electron acceptor. Anaerobic organisms

can metabolize energy by either anaerobic respiration or fermentation.

Given that the final electron acceptor in anaerobic respiration (e.g.,

sulfate, nitrate, carbon dioxide, or fumarate) is not as highly oxidizing

as oxygen, this pathway is less efficient than aerobic respiration and

produces less ATP per glucose molecule. In contrast, fermentation does

not use an electrochemical gradient. Rather, it releases energy from an

organic molecule (e.g., pyruvate and its derivatives) via substrate-level

phosphorylation and is therefore a less efficient process than either

aerobic or anaerobic respiration; for comparison, fermentation results

in ~5% of the energy released by aerobic respiration. For these reasons,

facultative anaerobes will preferentially utilize oxygen if it is available;

in oxygen-limiting situations, organisms will use anaerobic respiration

rather than fermentative processes, if possible.

TABLE 177-1 The Anaerobic Human Microbiota: An Overview

ANATOMIC SITE

TOTAL

BACTERIAa

ANAEROBIC/

AEROBIC

RATIO POTENTIAL PATHOGEN(S)

Nose 103

–104 2:1 Peptostreptococcus spp.,

Prevotella spp.

Oral cavity

Saliva 108

–109 10:1 Fusobacterium nucleatum,

Prevotella melaninogenica,

Prevotella oralis group,

Bacteroides ureolyticus

group, Peptostreptococcus

spp. 

Tooth surface 1010–1011 1:1

Gingival crevices 1011–1012 103

:1

Gastrointestinal tract

Stomach 100

–103 1:10 Lactobacillus spp.

Duodenum 101

–105 1:1 Lactobacillus spp.,

Streptococcus spp.

Jejunum 103

–106 1:1 Streptococcus spp.,

Lactobacillus spp.,

Peptostreptococcus spp.

Ileum 104

–109 10:1 Bacteroides spp.,

Streptococcus spp.,

Enterococcus spp.

Cecum and colon 1011–1012 103

:1 Bacteroides spp.

(principally members

of the B. fragilis group),

Prevotella spp., Clostridium

spp.

Female genital tract 107

–109 10:1 Peptostreptococcus

spp., Bacteroides spp.,

Prevotella bivia

Skin 104

–106 100:1 Cutibacterium acnes

a

Per gram or milliliter.

■ ANAEROBES OF THE HUMAN MICROBIOTA

Most human mucocutaneous surfaces harbor a rich indigenous normal microbiota composed of aerobic and anaerobic bacteria. These

surfaces are dominated by anaerobic bacteria, which often account for

99.0–99.9% of the cultivable microbiota and range in concentration

from 103

/mL in the nose to 1012/mL in gingival scrapings and the colon

(Table 177-1). It is interesting that anaerobes inhabit many areas of the

body that are exposed to air: skin, nose, mouth, and throat. Anaerobes are thought to reside in the portions of these sites that either are

relatively well protected from oxygen (e.g., gingival crevices) or have a

local anaerobic environment conferred by neighboring aerobic organisms (e.g., tooth surfaces). The ability to cultivate these organisms is

improving, and—with strict attention to anaerobic conditions—more

than 80% of the microscopic counts in fecal samples can be cultured.

However, culture-independent approaches (e.g., sequencing of the 16S

rDNA gene) show that the overwhelmingly diverse low-abundance

bacterial species present in the microbiota remain uncultivated. Several

projects, including the Human Microbiome Project (funded by the U.S.

National Institutes of Health) and MetaHIT (financed by the European

Commission), have characterized the normal microbiota of healthy

individuals and have demonstrated the presence of >10,000 different

bacterial species in the collective human microbiota. The human gut

alone harbors >1000 bacterial species, with 100–200 species present in

any given individual.

The major reservoir of anaerobic bacteria is the lower gastrointestinal tract, but these organisms are also present in considerable numbers

in the oral cavity, skin, and female genital tract (Table 177-1). In the

oral cavity, the ratio of anaerobic to aerobic bacteria ranges from 1:1 on

the surface of a tooth to 1000:1 in the gingival crevices. Prevotella and

Porphyromonas species make up much of the indigenous oral anaerobic

microbiota. Fusobacterium and Bacteroides (non–B. fragilis group) species are present in lower numbers. Anaerobic bacteria are not found in

appreciable numbers in the normal stomach and proximal small intestine. In the distal ileum, the microbiota begins to resemble that of the

1349CHAPTER 177 Infections Due to Mixed Anaerobic Organisms

colon, where the ratio of anaerobes to aerobic species is high (~1000:1).

The predominant anaerobes in the human intestine belong to the phyla

Bacteroidetes and Firmicutes and include a number of Prevotella and

Bacteroides species (e.g., members of the B. fragilis group, such as B.

fragilis, B. thetaiotaomicron, B. ovatus, B. vulgatus, B. uniformis, and

Parabacteroides distasonis) as well as various Clostridium, Peptostreptococcus, Blautia, and Fusobacterium species. In the female genital tract,

there are ~109

 organisms/mL of secretions, with an anaerobe-to-aerobe

ratio of ~10:1. The predominant anaerobes in the female genital tract

are Prevotella, Bacteroides, Fusobacterium, Clostridium, and the anaerobic Lactobacillus species. The skin microbiota contains anaerobes as

well; Cutibacterium acnes (which was previously Propionibacterium

acnes and will be considered as one of the Propionibacterium species

for the remainder of this chapter) is the predominant species, and other

species of propionibacteria and peptostreptococci are present in lower

numbers.

■ ANAEROBES AND HUMAN HEALTH

Commensal anaerobes have been implicated as crucial mediators of

physiologic, metabolic, and immunologic functions in the mammalian

host. The intestinal microbiota is essential for fermenting dietary carbohydrates into forms that are more usable by the host, among which

polysaccharides are the most abundant biological source of energy. Of

the organisms found within the intestines, Bacteroides species express

the widest array of polysaccharide-degrading enzymes, providing

important nutrients for both the host and other commensal organisms.

For example, B. thetaiotaomicron expresses 172 glycosyl hydrolases.

The anaerobic intestinal microbiota is also responsible for the production of secreted products that promote human health (e.g., vitamin K

and bile acids useful in fat absorption and cholesterol regulation).

One of the most important roles that anaerobes serve as components

of the normal colonic microbiota is the promotion of resistance to

colonization. The presence of commensal bacteria effectively interferes

with colonization by potentially pathogenic bacterial species through

the depletion of oxygen and nutrients, the production of enzymes and

toxic end products, and the modulation of the host’s intestinal innate

immune response. For example, the normal intestinal microbiota plays

an important role in protection against enteric infections, including

those due to Salmonella enterica serotype Typhimurium and Clostridium difficile.

The anaerobic intestinal microbiota also has immunomodulatory

properties that help regulate the immune system. The first example

of this role was demonstrated with B. fragilis, which can balance the

effector functions of T cells in the peripheral immune system and

induce colonic regulatory T cells via expression of polysaccharide A

(PSA). Moreover, B. fragilis expresses a glycosphingolipid that regulates the number of colonic invariant natural killer T cells. There are

now numerous examples of commensal anaerobes that can modulate

different aspects of the intestinal and extraintestinal immune system—

everything from specific effector T cells to dendritic cells to antimicrobial peptides.

Clearly, the gut microbiota confers many benefits, and its dysregulation may play a role in the pathogenesis of diseases characterized by

inflammation and aberrant immune responses, such as inflammatory

bowel disease, rheumatoid arthritis, multiple sclerosis, asthma, and

type 1 diabetes. Furthermore, the gut microbiota has been associated

with obesity and metabolic syndrome. A more complete discussion of

the intersection between the microbiota and human health is covered

elsewhere (Chap. 471).

■ ETIOLOGY

There are >10,000 species of bacteria—the overwhelming majority of

which are anaerobes—in the human microbiota, with each individual

colonized by hundreds of species. Anaerobic infections occur when the

harmonious relationship between the host and the host’s microbiota is

disrupted. Any site in the body is susceptible to infection with these

indigenous organisms if they are introduced into otherwise sterile tissue, either through disruption of mucosal surfaces (e.g., intestinal perforation, ischemia, surgery) or via direct inoculation of organisms into

tissue (e.g., bite wounds, trauma). Because the sites that are colonized

by anaerobes contain many species of bacteria, the resulting infections

are often polymicrobial, involving multiple species of anaerobes in

combination with synergistically acting facultative and/or microaerophilic organisms.

Despite the complex array of bacteria in the normal microbiota,

relatively few genera are isolated commonly from human infections

(Fig. 177-1). While the specific organisms identified vary with the

site and source of infection, the etiologic agents typically reflect the

neighboring microbiota. For example, organisms normally found

in the oro- and nasopharyngeal microbiota (e.g., P. melaninogenica,

Fusobacterium necrophorum, F. nucleatum, Peptostreptococcus species,

Porphyromonas gingivalis, Porphyromonas asaccharolytica, and Actinomyces species) can cause disease in contiguous areas, including odontogenic infections, peripharyngeal space infections, chronic sinusitis,

and pleuropulmonary infections. In female genital tract infections,

organisms normally colonizing the vagina (e.g., Prevotella bivia and

Prevotella disiens) are the most common isolates. Escherichia coli and B.

fragilis, both of which are components of the intestinal microbiota, are

the most commonly identified isolates from intraabdominal abscesses.

Indeed, the B. fragilis group, which encompasses 25 species and

includes B. thetaiotaomicron, B. vulgatus, B. uniformis, and B. ovatus,

contains the anaerobic organisms among the most frequently isolated

from clinical infections.

It is useful to think about anaerobic infectious etiologies with regard

not only to their anatomic location but also to their microbiologic features. While many anaerobic gram-negative bacilli cause disease (e.g.,

Prevotella, Bacteroides, Fusobacterium, and Porphyromonas species),

Veillonella species, which are part of the oral and intestinal microbiota, are among the few anaerobic gram-negative cocci that have

been implicated in human disease. Similarly, the peptostreptococci

(e.g., P. micros, P. asaccharolyticus, and P. anaerobius) and Finegoldia

magnus (which was previously Peptostreptococcus magnus and will be

considered as part of the peptostreptococci for the remainder of this

chapter) are the chief anaerobic gram-positive cocci that have pathogenic potential. Clostridium species are the primary anaerobic sporeforming gram-positive rods that produce human disease (Chap. 154).

Uncommonly, anaerobic gram-positive non-spore-forming bacilli

cause infection; C. acnes, a component of the skin microbiota and a

cause of foreign-body infections, and Actinomyces species are relevant

examples.

■ PATHOGENESIS

First and foremost, anaerobic infections require an anaerobic environment with a lowered oxidation-reduction potential. In some circumstances, this environment can occur directly—e.g., in tissue ischemia,

trauma, surgery, or a perforated viscus. In many other situations, the

infection is polymicrobial, and the facultative organisms maintain a

lowered oxidation-reduction potential in the local microenvironment

that allows for the propagation of obligate anaerobes. Once the proper

anaerobic environment is established, the organisms must still contend

with the host’s immune defenses. Similar to aerobic organisms, anaerobes express an array of virulence factors that help evade host defenses,

Gram-positive cocci

Other gram-positive rods

Other gram-negative rods

Other Bacteroides spp.

Prevotella spp.

Fusobacterium spp.

Porphyromonas spp.

Clostridium spp.

Veillonella spp.

Bacteroides fragilis

FIGURE 177-1 Distribution of anaerobic organisms isolated from clinical materials.

(Data combined from Y Park et al: Clinical features and prognostic factors of

anaerobic infections: A 7-year retrospective study. Korean J Intern Med 24:13, 2009;

and Japanese Association for Anaerobic Infections Research: Anaerobic infections

(general): Epidemiology of anaerobic infections. J Infect Chemother 17[Suppl 1]:4,

2011.)