Infectious Disease and Microbiology - Alcaligenes Species

Basics

Alcaligenes is a genus of aerobic, gram-negative bacilli that are widely distributed in the environment but only rarely cause human infection. Clinically recognized species have included Alcaligenes denitrificans, A. faecalis, and A. piechaudii.

An important historical taxonomic issue involves A. xylosoxidans. This organism was previously placed within Alcaligenes, but molecular analysis, including 16S rRNA sequencing, supports its classification in the genus Achromobacter. It is therefore currently known as Achromobacter xylosoxidans.

Microbiologic Characteristics

Alcaligenes species are aerobic, gram-negative bacilli. They are environmental organisms and are generally considered opportunistic rather than highly virulent primary pathogens.

Their isolation from a clinical specimen must therefore be interpreted in the context of the patient’s symptoms, specimen source, and underlying risk factors.

Epidemiology

Alcaligenes species have a worldwide distribution, but clinically significant human infections are uncommon.

Because these organisms can survive in environmental and aqueous settings, healthcare-associated contamination has occasionally resulted in infection.

Rare outbreaks and episodes of bacteremia have been linked to contaminated medical solutions, including intravenous fluids.

Opportunistic Infection

Alcaligenes infections occur primarily as opportunistic infections.

Patients at greater risk may include those with:

• Prolonged hospitalization

• Intravascular devices

• Immunosuppression

• Serious underlying disease

• Recent invasive procedures

• Exposure to contaminated medical fluids or equipment

The presence of an indwelling vascular catheter may provide a route for bloodstream infection.

Sepsis and Bacteremia

One of the most important manifestations is bloodstream infection.

Clinical features may include:

• Fever

• Chills

• Hypotension

• Tachycardia

• Altered mental status

• Other manifestations of systemic infection

Severe cases can progress to sepsis or septic shock, particularly in medically vulnerable patients.

Contaminated Intravenous Fluids

A notable epidemiologic association is bacteremia resulting from contaminated intravenous fluids.

Because Alcaligenes species can persist in moist environments, contamination of medical solutions or equipment can occasionally produce healthcare-associated clusters of infection.

When multiple hospitalized patients develop infection with an unusual environmental gram-negative organism, a common contaminated source should be considered.

Localized Infections

In addition to bacteremia and sepsis, Alcaligenes species may occasionally produce localized infections.

The clinical presentation depends on the involved site and the patient’s underlying condition.

Potential infections may involve:

• Soft tissues

• Respiratory tract

• Urinary tract

• Intravascular devices

• Other normally sterile sites

However, these infections remain relatively uncommon.

Alcaligenes faecalis

A. faecalis is one of the better-known species associated with human disease.

Although frequently regarded as an environmental organism or occasional colonizer, it has been implicated in opportunistic infections, particularly in hospitalized or medically compromised patients.

Isolation from a normally sterile site such as blood should be taken more seriously than recovery from a potentially colonized specimen.

Achromobacter xylosoxidans - Important Taxonomic Distinction

The organism formerly called:

Alcaligenes xylosoxidans

is currently classified as:

Achromobacter xylosoxidans

This distinction is important because older textbooks and microbiology references may continue to list it under Alcaligenes.

Achromobacter xylosoxidans is particularly recognized as an opportunistic gram-negative pathogen and should not be considered a current member of the genus Alcaligenes.

Diagnosis

The primary method of diagnosis is:

Culture.

Depending on the clinical syndrome, appropriate specimens may include:

• Blood

• Catheter-associated specimens

• Respiratory secretions

• Urine

• Wound material

• Other normally sterile body fluids

Identification to the species level is helpful because antimicrobial susceptibility may differ substantially between isolates.

Interpreting a Positive Culture

Because Alcaligenes organisms may represent environmental contamination or colonization, a positive culture does not automatically establish infection.

True infection is more likely when:

• The organism is repeatedly isolated from blood

• It is recovered from a normally sterile site

• The patient has compatible clinical findings

• There is an infected catheter or another plausible source

• Multiple cultures grow the same organism

Clinical correlation is therefore essential.

Antimicrobial Susceptibility

Antimicrobial susceptibility can be unpredictable.

For this reason, definitive therapy should be based on:

Culture identification

• ●

In vitro susceptibility testing.

Empiric treatment may need to be modified once susceptibility results become available.

Treatment

Historically, carbapenems have been used for serious Alcaligenes infections.

Potential agents include:

• Imipenem

• Meropenem

Ureidopenicillins have also demonstrated activity against some isolates.

However, therapy should not be selected solely on the basis of genus identification because resistance patterns can vary.

Additional Antimicrobial Options

Depending on susceptibility testing, potentially useful agents may include:

• Ceftazidime

• Trimethoprim-sulfamethoxazole

• Fluoroquinolones

• Selected antipseudomonal β-lactams

Older literature also describes colistin as a possible option in selected resistant infections, although its role depends heavily on the specific organism and susceptibility profile.

Importance of Susceptibility Testing

A central principle in treating Alcaligenes infection is:

Do not assume susceptibility.

Treatment should be adjusted according to laboratory susceptibility results whenever possible.

This is particularly important in:

• Bacteremia

• Sepsis

• Healthcare-associated infection

• Immunocompromised patients

• Patients previously exposed to broad-spectrum antibiotics

Source Control

Antibiotics alone may not be sufficient when infection is associated with a contaminated device or fluid source.

Management may require:

• Removal of an infected vascular catheter

• Discontinuation of contaminated intravenous solutions

• Drainage of localized collections

• Removal of infected prosthetic material when appropriate

• Investigation of a possible healthcare-associated outbreak

Source control is especially important when bacteremia persists despite appropriate antimicrobial therapy.

Prevention

Prevention primarily involves rigorous healthcare infection-control practices.

Important measures include:

• Proper preparation and storage of intravenous fluids

• Sterile handling of vascular catheters

• Appropriate catheter care

• Hand hygiene

• Proper disinfection of medical equipment

• Prompt investigation of unusual clusters of gram-negative bacteremia

Identification of a contaminated common source may prevent additional infections.

High-Yield Healthcare Association

Hospitalized patient

• ●

Unusual gram-negative bacillus in blood cultures

• ●

Possible contaminated IV fluids

→ Consider Alcaligenes among the possible environmental pathogens.

High-Yield Taxonomy

Older name:

Alcaligenes xylosoxidans

Current classification:

Achromobacter xylosoxidans

This taxonomic change is particularly important when reading older microbiology sources.

High-Yield Treatment Principle

Alcaligenes infection

→ Culture and susceptibility testing

→ Select an active antimicrobial

→ Modify treatment according to susceptibility results

→ Obtain source control when a catheter, contaminated solution, or other removable focus is involved.

Exam Essentials

Genus:

→ Alcaligenes

Important species:

→ A. faecalis, A. denitrificans, and A. piechaudii

Microbiology:

→ Aerobic gram-negative bacillus

Distribution:

→ Worldwide

Human disease:

→ Rare and generally opportunistic

Important systemic manifestation:

→ Bacteremia and sepsis

Classic healthcare-associated source:

→ Contaminated intravenous fluids

Diagnosis:

→ Culture

Major treatment principle:

→ Therapy guided by antimicrobial susceptibility testing

Historically useful agents:

→ Carbapenems and ureidopenicillins

Other possible active agents:

→ Ceftazidime, TMP-SMX, and fluoroquinolones depending on susceptibility

Important former species:

→ Alcaligenes xylosoxidans

Current name:

→ Achromobacter xylosoxidans

Key clinical pearl:

→ When an unusual environmental gram-negative bacillus causes bacteremia in several hospitalized patients, investigate contaminated fluids, devices, or other common healthcare-associated sources.

Infectious Disease and Microbiology - Afipia Species

Basics

Afipia is a genus of aerobic gram-negative bacteria that includes Afipia broomeae, A. clevelandensis, and A. felis. These organisms have been investigated as possible human pathogens, but their overall role in clinical disease remains uncertain.

Historically, A. felis attracted considerable attention because it was once proposed as the cause of cat-scratch disease. Subsequent research showed that most cases of cat-scratch disease are actually caused by Bartonella species, particularly Bartonella henselae.

Microbiologic Characteristics

Afipia species are pleomorphic, aerobic, gram-negative bacilli. Because they may stain poorly with routine methods, they can sometimes be demonstrated more clearly with silver-based stains.

Their variable morphology and difficult visualization can make laboratory recognition challenging.

Clinical Significance

The pathogenic importance of Afipia species in humans is not fully established.

Although these organisms have occasionally been isolated or detected in patients with compatible clinical syndromes, they are not considered common human pathogens.

The most important historical association is with cat-scratch disease.

Cat-Scratch Disease Association

For a period of time, Afipia felis was believed to be the primary cause of cat-scratch disease.

Current evidence indicates that this is not the case.

Most cat-scratch disease is caused by:

Bartonella henselae

Other Bartonella species may occasionally be involved.

A. felis may possibly account for a small minority of cases or may be detected in unusual clinical circumstances, but its precise role remains uncertain.

Clinical Presentation

If Afipia is involved in a cat-scratch-like syndrome, the presentation may resemble typical cat-scratch disease.

Possible manifestations include:

• Regional lymphadenopathy

• Fever

• Malaise

• Tender or enlarged lymph nodes

• A papule or lesion near the site of inoculation

However, because Bartonella henselae is much more strongly associated with this syndrome, Bartonella infection should usually be considered first.

Diagnosis

Diagnosis is not straightforward because Afipia species are rarely encountered and routine clinical testing is limited.

Histologic examination of affected lymph nodes may help when the organism is suspected.

Silver stains can improve visualization because these gram-negative bacilli may be difficult to identify with standard staining techniques.

Histopathology

Affected lymph nodes may show inflammatory changes resembling those seen in cat-scratch disease.

Depending on the stage of disease, findings may include:

• Granulomatous inflammation

• Necrosis

• Suppurative changes

• Reactive lymphoid hyperplasia

These findings are not specific for Afipia, so clinical correlation and exclusion of more common causes are necessary.

Differential Diagnosis

The major differential diagnosis is:

Bartonella henselae infection

Other causes of chronic or subacute lymphadenopathy should also be considered, including:

• Tuberculosis

• Nontuberculous mycobacteria

• Toxoplasmosis

• Tularemia

• Lymphoma

• Other bacterial lymphadenitides

The patient’s exposure history and laboratory findings help guide the diagnosis.

Treatment

There is no well-established antimicrobial regimen for Afipia infection because convincing clinical data are limited.

Macrolide antibiotics may have activity and have sometimes been used when treatment is considered necessary.

Potential agents include:

• Azithromycin

• Clarithromycin

However, evidence supporting a specific regimen or duration is insufficient.

General Management

When a patient presents with a syndrome resembling cat-scratch disease, management should primarily be directed by the more likely etiologic agent, especially Bartonella henselae.

If Afipia is specifically identified, treatment decisions should be individualized according to:

• Clinical severity

• Site of infection

• Host immune status

• Microbiologic findings

• Response to therapy

Prognosis

Because Afipia-associated disease is rare and incompletely defined, prognosis is not well characterized.

If infection is limited to a cat-scratch-like lymphadenitis syndrome, the course would generally be expected to be relatively benign, but this remains based on limited clinical experience.

High-Yield Taxonomy

Important species include:

• Afipia broomeae

• Afipia clevelandensis

• Afipia felis

High-Yield Historical Association

A. felis

was once believed to cause:

Cat-scratch disease

But most cases are now known to be caused by:

Bartonella henselae

Exam Essentials

Genus:

→ Afipia

Organism type:

→ Pleomorphic aerobic gram-negative bacillus

Useful stain:

→ Silver stain

Historical disease association:

→ Cat-scratch disease

Current major cause of cat-scratch disease:

→ Bartonella henselae

Possible role of A. felis:

→ Rare or minority contributor, but uncertain

Diagnosis:

→ Histologic examination of affected lymph nodes, supported by specialized microbiologic methods

Treatment:

→ No established standard regimen

Potentially useful drug class:

→ Macrolides

Key clinical pearl:

→ If a patient has classic cat-scratch disease, think Bartonella first, not Afipia.

Infectious Disease and Microbiology - Aeromonas Species

Basics

Aeromonas is a genus of gram-negative bacilli that is widely distributed in aquatic environments. Important human pathogens include Aeromonas caviae, A. hydrophila, A. schubertii, and A. veronii, although several other species can also cause disease.

These organisms are particularly associated with gastrointestinal infection, water-exposed wounds, soft-tissue infection, and invasive disease in patients with major underlying illnesses.

⸻

Microbiologic Characteristics

Aeromonas species are gram-negative, non-spore-forming bacilli. They are facultative anaerobes and can grow in either aerobic or relatively low-oxygen conditions.

They are commonly recovered from aquatic environments and may resemble other enteric gram-negative organisms on routine culture. Species-level identification and susceptibility testing are often useful in serious infections.

⸻

Epidemiology

Aeromonas organisms are ubiquitous in:

• Fresh water

• Brackish water

• Soil

• Aquatic environments

They have even been isolated from chlorinated tap water.

Because these bacteria are environmentally widespread, exposure is common. They may also be found in the gastrointestinal tract of asymptomatic individuals, so isolation from stool does not always indicate clinically significant infection.

⸻

Major Routes of Infection

Human disease may develop after:

• Ingestion of contaminated food or water

• Traumatic exposure of wounds to fresh or brackish water

• Near-drowning or aspiration of contaminated water

• Exposure of tissue to medicinal leeches

• Hematogenous spread in severely ill patients

The route of exposure often predicts the clinical syndrome.

⸻

Gastroenteritis

Aeromonas can cause acute gastroenteritis ranging from mild, self-limited diarrhea to more severe inflammatory disease.

Symptoms may include:

• Watery diarrhea

• Abdominal cramps

• Nausea

• Vomiting

• Fever

In some patients, stools may become bloody or inflammatory.

Most cases are relatively mild and resolve with supportive care, but severe enteritis can occur in vulnerable patients.

⸻

Enteritis in Immunocompromised Patients

Acute enteritis caused by Aeromonas has been described more frequently in immunocompromised patients, including those with advanced HIV infection.

In these patients, diarrhea may be more prolonged or severe, and the risk of extraintestinal infection may be greater.

Careful assessment for dehydration and systemic illness is important.

⸻

Wound Infection

One of the most characteristic clinical associations is infection after exposure of damaged skin to contaminated water.

Typical scenarios include:

• Lacerations sustained in freshwater

• Flood-related injuries

• Fishing or boating injuries

• Trauma followed by immersion in water

The resulting infection may range from uncomplicated cellulitis to rapidly progressive deep tissue disease.

⸻

Cellulitis

Aeromonas cellulitis often begins after a wound is exposed to fresh or brackish water.

Clinical findings may include:

• Erythema

• Swelling

• Pain

• Warmth

• Purulent drainage

The infection may progress quickly, especially in immunocompromised patients or those with liver disease.

⸻

Osteomyelitis

Deeply contaminated wounds can occasionally result in bone infection.

Aeromonas osteomyelitis is usually associated with:

• Penetrating trauma

• Open fractures

• Water exposure

• Delayed treatment of soft-tissue infection

Prolonged antimicrobial therapy and surgical debridement may be required.

⸻

Myonecrosis and Necrotizing Infection

Aeromonas can produce severe soft-tissue infection, including myonecrosis and necrotizing fasciitis-like syndromes.

This is especially important in patients who are:

• Immunosuppressed

• Cirrhotic

• Malignancy-associated

• Severely debilitated

Rapidly increasing pain, swelling, bullae, tissue discoloration, or systemic toxicity should raise concern for a necrotizing infection requiring urgent surgical evaluation.

⸻

Medicinal Leech-Associated Infection

Aeromonas is part of the normal intestinal flora of medicinal leeches.

Therefore, patients receiving leech therapy after reconstructive or plastic surgery can develop Aeromonas wound infections.

This association is clinically important because infection can threaten grafts or reimplanted tissue.

Prophylactic antibiotics with activity against Aeromonas may be considered in settings where medicinal leeches are used.

⸻

Ecthyma Gangrenosum-Like Lesions

In severely immunocompromised patients, Aeromonas bacteremia can occasionally produce necrotic skin lesions resembling ecthyma gangrenosum.

These lesions may appear as:

• Hemorrhagic vesicles

• Necrotic plaques

• Ulcers with dark centers

Although classically associated with Pseudomonas aeruginosa, ecthyma-like lesions are not exclusive to Pseudomonas.

⸻

Bacteremia and Sepsis

Aeromonas can cause bloodstream infection, particularly in patients with:

• Cirrhosis

• Malignancy

• Immunosuppression

• Severe soft-tissue infection

• Advanced systemic illness

Bacteremia may progress to septic shock and multiorgan failure.

⸻

Cirrhosis and Spontaneous Peritonitis

Patients with chronic liver disease, especially cirrhosis, are at increased risk of invasive Aeromonas infection.

Clinical syndromes may include:

• Bacteremia

• Sepsis

• Spontaneous bacterial peritonitis

Aeromonas should therefore be considered in cirrhotic patients with compatible systemic infection, particularly when there is a relevant water exposure history.

⸻

Aspiration Pneumonia After Drowning

Aeromonas may cause severe pneumonia after aspiration of contaminated water during drowning or near-drowning.

Patients can develop:

• Fever

• Respiratory distress

• Hypoxemia

• Pulmonary infiltrates

• Severe pneumonia

This is an important environmental exposure clue.

Near-drowning in freshwater followed by pneumonia should prompt consideration of Aeromonas among the possible pathogens.

⸻

Intra-Abdominal Infection

Aeromonas may occasionally cause intra-abdominal disease, including abscess formation.

This is uncommon but may occur in patients with:

• Abdominal surgery

• Bowel disease

• Immunosuppression

• Perforation

• Systemic bacteremia

⸻

Diagnosis

Diagnosis is based on culture from the affected site.

Depending on the syndrome, specimens may include:

• Stool

• Blood

• Wound material

• Tissue

• Respiratory secretions

• Peritoneal fluid

• Bone or deep soft-tissue specimens

Because Aeromonas may colonize the gastrointestinal tract without causing disease, stool culture results must be interpreted together with the clinical picture.

⸻

Antimicrobial Susceptibility

Aeromonas species can produce beta-lactamases, so susceptibility to many beta-lactam antibiotics may be variable.

For serious infections, antimicrobial susceptibility testing is important.

Therapy should be tailored once culture and sensitivity results are available.

⸻

Treatment

Treatment depends on the type and severity of infection.

For invasive or systemic disease, a third-generation cephalosporin is commonly used, with or without an aminoglycoside depending on severity and susceptibility.

Fluoroquinolones also have reliable activity against many Aeromonas isolates and are frequently useful.

⸻

Third-Generation Cephalosporins

Potentially active agents include:

• Ceftriaxone

• Cefotaxime

• Ceftazidime

These may be used in serious infections when susceptibility is demonstrated.

In severe sepsis or rapidly progressive disease, combination therapy may be considered initially.

⸻

Fluoroquinolones

Fluoroquinolones such as ciprofloxacin are often active against Aeromonas and may be useful for:

• Soft-tissue infection

• Bacteremia

• Gastrointestinal infection when antibiotic therapy is indicated

• Water-associated wound infection

Susceptibility testing should guide definitive treatment.

⸻

Additional Antimicrobial Options

Other potentially active agents include:

• Imipenem

• Meropenem

• Ertapenem

• Aztreonam

• Trimethoprim-sulfamethoxazole

• Aminoglycosides

• Tetracyclines

• Tigecycline

The optimal agent depends on infection severity, anatomic site, and susceptibility results.

⸻

Treatment of Enteritis

Most uncomplicated Aeromonas gastroenteritis is self-limited.

The most important treatment is:

Fluid and electrolyte replacement.

Patients with diarrhea should receive appropriate rehydration with oral or intravenous fluids depending on severity.

Antibiotics are generally reserved for:

• Severe diarrhea

• Persistent disease

• Dysentery

• Immunocompromised patients

• Extraintestinal spread

⸻

Management of Wound Infection

Water-associated Aeromonas wound infections require careful source control.

Management may include:

• Thorough irrigation

• Removal of foreign material

• Debridement of devitalized tissue

• Culture of deep specimens

• Appropriate antibiotics

Rapid progression should prompt urgent surgical evaluation.

⸻

Necrotizing Soft-Tissue Infection

When necrotizing infection is suspected, antibiotics alone are not sufficient.

Immediate surgical exploration and debridement are essential.

Warning features include:

• Severe pain out of proportion to examination

• Rapid progression

• Bullae

• Skin necrosis

• Crepitus

• Hypotension

• Systemic toxicity

Early surgery can be lifesaving.

⸻

Prognosis

Most uncomplicated gastrointestinal infections have a good prognosis.

Outcome is less favorable in patients with:

• Septicemia

• Cirrhosis

• Severe immunosuppression

• Necrotizing soft-tissue infection

• Delayed surgical source control

• Multiorgan failure

Early recognition and appropriate therapy markedly improve outcomes.

⸻

Prevention

Prevention focuses on reducing exposure and protecting wounds.

Important measures include:

• Avoid exposing open wounds to fresh or brackish water

• Clean water-contaminated injuries promptly

• Use protective footwear around natural water sources

• Maintain proper wound care after aquatic injuries

• Use appropriate infection-prevention strategies during medicinal leech therapy

Patients with cirrhosis or major immunosuppression should be particularly cautious about contaminated water exposure.

⸻

High-Yield Water Exposure Pattern

Freshwater injury

Rapidly progressive cellulitis

Gram-negative bacillus

→ Think Aeromonas.

⸻

High-Yield Drowning Pattern

Near-drowning

Aspiration

Severe pneumonia

→ Consider Aeromonas, particularly after freshwater exposure.

⸻

High-Yield Liver Disease Pattern

Cirrhosis

Bacteremia or spontaneous bacterial peritonitis

→ Aeromonas is an important possible pathogen.

⸻

High-Yield Leech Association

Medicinal leech therapy

Postoperative wound infection

→ Think Aeromonas.

⸻

Exam Essentials

Genus:

→ Aeromonas

Important species:

→ A. hydrophila, A. caviae, A. veronii, and A. schubertii

Organism:

→ Gram-negative, non-spore-forming facultative anaerobic bacillus

Environmental reservoir:

→ Fresh water, brackish water, and soil

Major gastrointestinal disease:

→ Gastroenteritis

Classic exposure:

→ Water-contaminated wound

Major soft-tissue complications:

→ Cellulitis, myonecrosis, osteomyelitis, and necrotizing infection

Important special association:

→ Medicinal leeches

Important pulmonary association:

→ Aspiration pneumonia after drowning

Important systemic risk group:

→ Patients with cirrhosis or severe immunosuppression

Diagnosis:

→ Culture

Main treatment of uncomplicated enteritis:

→ Fluid and electrolyte replacement

Important antibiotics for invasive disease:

→ Third-generation cephalosporins or fluoroquinolones

Other potential agents:

→ Carbapenems, aztreonam, TMP-SMX, aminoglycosides, tetracyclines, or tigecycline depending on susceptibility

Critical treatment for necrotizing disease:

→ Urgent surgical debridement plus systemic antibiotics

Infectious Disease and Microbiology - Actinomadura Species

Basics

Actinomadura is a genus of aerobic, gram-positive, branching filamentous bacteria that can produce chronic infections in humans. Important pathogenic species include Actinomadura madurae, A. pelletieri, and A. latina, together with several less commonly encountered species.

These organisms are most strongly associated with actinomycetoma, a chronic infection involving the skin and deeper tissues. In more severe cases, infection may extend into muscle and bone or, rarely, produce pulmonary or disseminated disease.

Microbiologic Characteristics

Actinomadura species are filamentous bacteria that form branching structures resembling fungal hyphae. Despite this appearance, they are true bacteria rather than fungi.

Characteristic features include:

• Gram-positive staining

• Branching filamentous morphology

• Aerobic growth

• Slow and sometimes difficult laboratory recovery

Because their appearance overlaps with other aerobic actinomycetes, careful culture and species identification are often necessary.

Epidemiology

Actinomadura infections occur predominantly in tropical and subtropical regions.

Disease is especially associated with areas where people have frequent contact with contaminated soil and where traumatic implantation of environmental organisms into the skin is common.

Human infection is uncommon in the United States but may occur in travelers, immigrants, or patients with relevant environmental exposure.

Transmission

Infection usually follows direct traumatic inoculation of the organism from the environment into the skin.

Possible exposures include:

• Walking barefoot

• Agricultural work

• Thorn injuries

• Splinters

• Soil-contaminated wounds

Once introduced into tissue, the infection typically progresses slowly over months or years.

Person-to-person transmission is not considered an important route.

Actinomycetoma

The classic infection caused by Actinomadura is:

Actinomycetoma

This is a chronic granulomatous infection that commonly affects the skin and subcutaneous tissue and may progressively involve:

• Fascia

• Muscle

• Bone

The foot is a particularly common site in endemic regions.

Clinical Presentation of Actinomycetoma

Actinomycetoma usually develops gradually.

The classic clinical triad includes:

• Localized swelling

• Draining sinus tracts

• Granules discharged through the sinuses

The affected area may initially be painless, but progressive disease can lead to extensive tissue destruction, deformity, and disability.

Without appropriate treatment, infection may spread from superficial tissues into deeper structures, including bone.

Species Associations

Actinomadura madurae is one of the best-recognized causes of actinomycetoma.

Actinomadura pelletieri is also an important cause and may produce more aggressive inflammatory disease.

Other species, including A. latina, are much less commonly reported but can produce similar clinical syndromes.

Bone and Deep-Tissue Involvement

Long-standing infection can extend into:

• Muscle

• Tendons

• Fascia

• Bone

When bone becomes involved, chronic osteomyelitis may develop.

This can lead to:

• Bone destruction

• Deformity

• Impaired mobility

• Chronic draining sinuses

Advanced disease may become difficult to eradicate with medical therapy alone.

Pulmonary Infection

Pulmonary Actinomadura infection is rare.

It may occur after inhalation or as part of disseminated infection.

Possible manifestations include:

• Chronic cough

• Fever

• Dyspnea

• Pulmonary infiltrates

• Nodular or cavitary disease

Pulmonary infection usually warrants aggressive antimicrobial therapy because of the risk of progression and dissemination.

Disseminated Disease

Disseminated Actinomadura infection is uncommon but can occur, particularly in patients with impaired host defenses.

Possible sites include:

• Lungs

• Skin

• Bone

• Soft tissues

• Other internal organs

Systemic disease generally requires prolonged multidrug treatment.

Diagnosis

Diagnosis is based primarily on culture of material obtained from the infected site.

Useful specimens include:

• Drainage from sinus tracts

• Granules

• Tissue biopsy

• Bone specimens

• Respiratory specimens in pulmonary disease

Because superficial drainage may become contaminated by other organisms, deep tissue or granule specimens are often preferable.

Microscopy and Histopathology

Microscopic examination may show branching gram-positive filaments.

Histopathology may demonstrate:

• Granules surrounded by inflammatory cells

• Granulomatous inflammation

• Chronic suppurative inflammation

• Fibrosis

• Tissue destruction in advanced disease

The presence and morphology of granules may help distinguish actinomycetoma from fungal mycetoma.

Differential Diagnosis

The major distinction is between:

Actinomycetoma

and

Eumycetoma

Actinomycetoma is caused by bacteria such as:

• Actinomadura

• Nocardia

• Streptomyces

Eumycetoma is caused by true fungi.

Other conditions that may resemble mycetoma include:

• Chronic osteomyelitis

• Tuberculosis

• Botryomycosis

• Sporotrichosis

• Foreign-body granuloma

• Chronic bacterial abscesses

Treatment

Actinomadura infections can be difficult to treat and may respond slowly to antimicrobial therapy.

Prolonged combination treatment is often required, particularly for extensive actinomycetoma or disseminated disease.

Therapy should ideally be guided by species identification, susceptibility testing when available, clinical response, and the extent of tissue involvement.

Streptomycin-Based Therapy

Historically, streptomycin combined with another active agent has achieved moderate success.

Common combinations have included:

Streptomycin

plus

Trimethoprim-sulfamethoxazole

or

Dapsone

These regimens may require prolonged courses because deeply established infection resolves slowly.

Trimethoprim-Sulfamethoxazole

TMP-SMX is one of the most frequently used agents in combination regimens for actinomycetoma.

It may be paired with:

• Streptomycin

• Amoxicillin

• Other active agents

Long treatment durations are often necessary.

Other Antimicrobial Regimens

Additional combinations that have been used include:

• Penicillin + gentamicin + TMP-SMX, followed by prolonged TMP-SMX and amoxicillin

• Amoxicillin-clavulanate

• Clindamycin

• Carbapenems

• Fusidic acid

The optimal regimen varies because susceptibility patterns differ among Actinomadura species.

Severe or Disseminated Infection

Pulmonary or disseminated disease generally requires aggressive multidrug therapy.

Management may include:

• Combination antimicrobial therapy

• Prolonged treatment

• Surgical removal of localized infected tissue when feasible

• Correction of underlying immunosuppression if present

Early specialist involvement is valuable because treatment failure and relapse can occur.

Surgical Treatment

Surgery has an important role in many cases of actinomycetoma.

Possible procedures include:

• Excision of localized lesions

• Drainage

• Debridement of infected tissue

• Resection of involved bone

• More extensive surgery for advanced destructive disease

Surgery is particularly useful when infection is localized but poorly responsive to antibiotics.

General Management Principles

Treatment is most successful when several strategies are combined:

• Appropriate prolonged antimicrobial therapy

• Surgical source control when necessary

• Early recognition before extensive tissue destruction

• Careful follow-up for relapse

Advanced disease with major bone involvement is considerably more difficult to cure.

Prognosis

Localized disease treated early generally has a better prognosis.

Factors associated with poorer outcome include:

• Long duration before diagnosis

• Extensive sinus formation

• Bone involvement

• Large lesions

• Disseminated infection

• Inadequate surgical source control

• Poor response to antimicrobial therapy

Relapse may occur even after prolonged treatment.

Prevention

No vaccine is available.

Risk reduction in endemic regions includes:

• Wearing protective footwear

• Avoiding barefoot exposure to soil

• Prompt cleaning of penetrating injuries

• Using protective clothing during agricultural work

• Early evaluation of chronic painless swellings or draining sinus tracts

High-Yield Clinical Pattern

Person from a tropical or subtropical region

• ●

Chronic painless swelling of the foot

• ●

Multiple draining sinuses

• ●

Granules in the discharge

→ Think mycetoma.

If caused by a branching gram-positive bacterium:

→ Think actinomycetoma.

High-Yield Microbiology

Actinomadura:

• Bacterium, not fungus

• Gram positive

• Aerobic

• Filamentous

• Branching

This morphology can resemble fungal hyphae but represents bacterial filaments.

High-Yield Disease Association

Actinomadura species are classically associated with:

→ Actinomycetoma

The infection may progress from:

Skin

→ Subcutaneous tissue

→ Muscle

→ Bone

Exam Essentials

Genus:

→ Actinomadura

Important species:

→ A. madurae, A. pelletieri, and A. latina

Organism type:

→ Aerobic branching filamentous bacterium

Gram stain:

→ Gram positive

Major geographic distribution:

→ Tropical and subtropical regions

Classic disease:

→ Actinomycetoma

Typical tissues involved:

→ Skin, subcutaneous tissue, muscle, and bone

Classic clinical triad of mycetoma:

→ Swelling + draining sinuses + granules

Diagnosis:

→ Culture, supported by microscopy and histopathology

Major treatment challenge:

→ Frequently refractory and requires prolonged therapy

Common therapeutic approach:

→ Combination antimicrobial treatment, often including TMP-SMX with another active agent

Historically useful combination:

→ Streptomycin + TMP-SMX or dapsone

Important additional treatment:

→ Surgical resection or debridement when feasible

Infectious Disease and Microbiology - Actinobacillus Species

Basics

Actinobacillus is a genus of gram-negative bacteria that was historically associated mainly with animal disease but can occasionally cause human infection. Several species are clinically relevant, including Actinobacillus equuli, A. hominis, A. suis, and A. ureae.

An important historical species, Actinobacillus actinomycetemcomitans, is no longer classified within this genus. It is now known as Aggregatibacter actinomycetemcomitans. Despite the taxonomic change, older medical literature may still use the former name.

Microbiologic Characteristics

Actinobacillus species are aerobic, gram-negative bacilli that are nonmotile. Their morphology may vary from short rods to coccoid or coccobacillary forms.

Some species are relatively fastidious and may require enriched culture conditions. Their growth characteristics can therefore help distinguish them from other gram-negative organisms.

Epidemiology

Actinobacilli were first recognized as pathogens of cattle, but they have also been isolated from other animals and humans.

Human infection is uncommon and often occurs after direct exposure to animals. Animal bites, particularly horse bites and other traumatic inoculations, are important routes of transmission for several species.

Because of this zoonotic association, a history of recent animal exposure can be an important diagnostic clue.

Important Species

Clinically important species include:

• Actinobacillus equuli

• Actinobacillus hominis

• Actinobacillus suis

• Actinobacillus ureae

The organism formerly called Actinobacillus actinomycetemcomitans is now classified as:

Aggregatibacter actinomycetemcomitans

This organism remains medically important because of its association with endocarditis and periodontal disease.

Aggregatibacter actinomycetemcomitans

Although no longer classified as Actinobacillus, Aggregatibacter actinomycetemcomitans remains strongly associated with the historical Actinobacillus literature.

It is part of the HACEK group of organisms associated with endocarditis.

HACEK traditionally includes:

• Haemophilus species

• Aggregatibacter species

• Cardiobacterium species

• Eikenella species

• Kingella species

These organisms are gram-negative bacteria that can cause indolent infective endocarditis and may require prolonged culture incubation or modern molecular methods for detection.

Endocarditis

Aggregatibacter actinomycetemcomitans is a recognized cause of infective endocarditis.

The disease may have a relatively subacute course, with symptoms such as:

• Fever

• Malaise

• Weight loss

• New or changing cardiac murmur

• Embolic manifestations

• Signs of heart failure in advanced disease

Blood cultures are the major diagnostic tool.

Because HACEK organisms are associated with endocarditis, persistent bacteremia with one of these organisms should prompt careful cardiac evaluation.

Periodontitis

Aggregatibacter actinomycetemcomitans is strongly associated with periodontal infection.

It may be isolated in conjunction with other oral organisms, including Actinomyces israelii.

Clinical disease may include:

• Gingival inflammation

• Periodontal pocket formation

• Loss of periodontal attachment

• Alveolar bone destruction

The organism is particularly associated with aggressive forms of periodontitis in some patients.

Wound Infections

Actinobacillus species can produce localized wound infection following traumatic inoculation.

Animal bites are especially important.

Clinical findings may include:

• Pain

• Erythema

• Swelling

• Purulent drainage

• Cellulitis

• Occasionally deeper soft-tissue involvement

Culture of wound material is useful when infection is clinically significant.

Animal Bite-Associated Disease

Actinobacillus suis and Actinobacillus equuli are particularly associated with animal bite-related wound infections.

Horse bites are a classic exposure.

Infection can result from direct inoculation of organisms present in the animal’s oral flora into damaged human tissue.

Because animal bite wounds are often polymicrobial, other aerobic and anaerobic organisms may also be present.

Actinobacillus hominis

A. hominis has been associated with bacteremia, particularly in patients with significant underlying illness.

Reported risk factors include:

• Chronic pulmonary disease

• Hepatic failure

• Debilitating medical conditions

Bloodstream infection may therefore be a marker of severe underlying disease.

Actinobacillus ureae

A. ureae can occasionally cause invasive infection.

Reported manifestations include:

• Bacteremia

• Meningitis

Central nervous system infection is rare but potentially severe.

Endophthalmitis

Actinobacillus-related ocular infection has occasionally been reported.

Endophthalmitis may occur after:

• Trauma

• Surgery

• Hematogenous spread

Symptoms can include severe eye pain, redness, photophobia, and visual loss.

Urgent ophthalmologic treatment is necessary because intraocular infection can rapidly threaten vision.

Diagnosis

Diagnosis is based primarily on culture.

Appropriate specimens depend on the clinical syndrome and may include:

• Blood

• Wound material

• Cerebrospinal fluid

• Ocular specimens

• Periodontal material

• Tissue samples

Species-level identification is useful because clinical associations and antimicrobial susceptibilities vary.

Culture Characteristics

On approximately 1-day-old culture plates, Actinobacillus colonies may appear translucent and measure around 1–2 mm in diameter.

The organism historically called A. actinomycetemcomitans is more fastidious.

It is an obligate capnophile, meaning that increased carbon dioxide improves its growth.

Early colonies may be very small, often less than 0.5 mm in diameter. After several days they may enlarge to approximately 2–3 mm and develop:

• Rough surfaces

• Pitting of the agar

These characteristics can help laboratory identification.

Differential Diagnosis

Depending on the clinical syndrome, the differential may include other gram-negative coccobacilli and HACEK organisms.

For endocarditis, consider:

• Haemophilus

• Cardiobacterium

• Eikenella

• Kingella

• Other causes of culture-positive or culture-negative endocarditis

For bite wounds, consider:

• Pasteurella

• Streptococci

• Staphylococci

• Anaerobic oral flora

• Other zoonotic gram-negative bacteria

Treatment

Treatment depends on the species, infection site, and susceptibility profile.

For HACEK endocarditis, ceftriaxone is a commonly preferred treatment because of its reliable activity and convenient dosing.

Therapy should be guided by current susceptibility data and the specific clinical syndrome.

Ceftriaxone

Ceftriaxone is a major treatment option for HACEK endocarditis.

Its advantages include:

• Reliable activity against many HACEK organisms

• Good bloodstream penetration

• Convenient once-daily dosing

Duration depends on whether native or prosthetic valve endocarditis is present and on current guideline recommendations.

Other Antimicrobial Options

Depending on susceptibility results and the site of infection, other potentially active agents include:

• Ampicillin

• Penicillin G

• Aminoglycosides

• Ciprofloxacin

• Trimethoprim-sulfamethoxazole

• Azithromycin

Azithromycin has demonstrated good in vitro activity against some isolates, although clinical experience varies by syndrome.

Combination Therapy

Older regimens sometimes used:

Ampicillin or penicillin G

plus

An aminoglycoside

particularly for severe invasive disease.

However, modern therapy should be individualized, and susceptibility testing is especially important because resistance patterns can vary.

Management of Bite Wounds

Animal bite-related infections require more than antimicrobial selection alone.

Important management principles include:

• Thorough wound irrigation

• Debridement when necessary

• Evaluation for tendon, joint, or bone involvement

• Tetanus prophylaxis when indicated

• Consideration of rabies risk depending on the animal and epidemiologic setting

Culture is particularly useful when infection is already established.

Prognosis

Most localized wound infections have a good prognosis when treated promptly.

More serious outcomes are possible in:

• Endocarditis

• Bacteremia

• Meningitis

• Endophthalmitis

• Deep bite-related infections

Delayed diagnosis or major underlying disease may worsen prognosis.

High-Yield Taxonomy

Old name:

Actinobacillus actinomycetemcomitans

Current name:

Aggregatibacter actinomycetemcomitans

This taxonomic change is important because older examinations and textbooks may use the former terminology.

High-Yield Endocarditis Association

HACEK organism

• ●

Subacute endocarditis

• ●

Fastidious gram-negative coccobacillus

→ Think Aggregatibacter actinomycetemcomitans among the possibilities.

High-Yield Bite Association

Horse or other animal bite

• ●

Gram-negative coccobacillary wound pathogen

→ Consider Actinobacillus equuli or Actinobacillus suis.

Exam Essentials

Genus:

→ Actinobacillus

Morphology:

→ Aerobic gram-negative coccobacillary or short bacillary organism

Motility:

→ Nonmotile

Important zoonotic association:

→ Animal bites

Former major species:

→ Actinobacillus actinomycetemcomitans

Current classification:

→ Aggregatibacter actinomycetemcomitans

Important disease caused by Aggregatibacter actinomycetemcomitans:

→ Endocarditis and periodontitis

HACEK association:

→ Yes

A. hominis:

→ Bacteremia, especially in patients with serious underlying disease

A. ureae:

→ Bacteremia and meningitis

A. suis and A. equuli:

→ Animal bite-associated wound infection

Diagnosis:

→ Culture

Preferred major therapy for HACEK endocarditis:

→ Ceftriaxone

Other potentially active agents:

→ Ampicillin, penicillin G, ciprofloxacin, TMP-SMX, selected aminoglycosides, and azithromycin depending on susceptibility

Infectious Disease and Microbiology - Acremonium Species

Basics

Acremonium is a genus of filamentous fungi that was formerly known as Cephalosporium. The genus contains roughly 100 species, but only a small number are clinically important. Medically relevant species include Acremonium alabamense, A. falciforme, A. kiliense, A. recifei, A. roseogriseum, and A. strictum. Among these, A. kiliense has historically been one of the most frequently encountered pathogenic species.

Microbiologic Characteristics

Acremonium species are molds composed of septate hyphae. Their microscopic appearance may resemble Fusarium, although Acremonium generally grows more slowly.

Colonies are commonly white and may appear velvety, cottony, or fasciculate. They are usually flat or only slightly elevated in the center. Some species are able to tolerate cycloheximide, a feature that can be useful in laboratory identification.

Because morphology can overlap with other hyaline molds, definitive identification may require specialized mycologic methods.

Epidemiology

Acremonium species are widespread environmental fungi. They have been isolated from soil, sewage, insects, plant rhizospheres, and a variety of other organic substrates.

Human infection is uncommon despite frequent environmental exposure. Disease usually develops after direct inoculation, ocular contamination, surgery, implantation of prosthetic material, or in the setting of significant immunosuppression.

Clinical Infections

Acremonium can cause both localized and invasive disease. Superficial and localized infections are more common than disseminated infection.

Important clinical manifestations include:

• Mycetoma

• Onychomycosis

• Fungal keratitis

• Ocular infection

• Soft contact lens colonization

Rarely, Acremonium produces severe invasive or disseminated disease.

Mycetoma

Acremonium can cause chronic infection of the skin and subcutaneous tissues known as mycetoma.

The infection typically develops slowly after traumatic inoculation of environmental material into the skin. Patients may develop swelling, chronic nodules, sinus tracts, and drainage.

Disease can persist for prolonged periods and may eventually involve deeper tissues or bone.

Onychomycosis

Acremonium is an uncommon cause of fungal nail infection.

Clinical features can include:

• Nail discoloration

• Thickening

• Brittleness

• Separation of the nail plate

Because Acremonium may occasionally represent contamination, repeated isolation or compatible direct microscopy is helpful before attributing nail disease to the organism.

Mycotic Keratitis

Acremonium can cause fungal keratitis, particularly after:

• Corneal trauma

• Exposure to contaminated environmental material

• Contact lens use

• Ocular surgery

Symptoms may include pain, redness, photophobia, tearing, and decreased visual acuity.

Prompt ophthalmologic evaluation is important because fungal keratitis can progress to deeper ocular infection and visual loss.

Contact Lens Colonization

Acremonium species can colonize soft contact lenses and lens-care equipment.

Colonization does not always indicate invasive keratitis, but it may create a reservoir for corneal infection, particularly when lens hygiene is poor or contaminated solutions are used.

Proper contact lens cleaning and replacement practices are therefore important preventive measures.

Invasive Pulmonary Disease

Invasive pulmonary Acremonium infection is rare and usually occurs in patients with major immune compromise, especially profound neutropenia.

Clinical manifestations may include:

• Persistent fever

• Cough

• Dyspnea

• Pulmonary infiltrates

• Nodules or cavitary lesions

Because these findings can resemble invasive aspergillosis, fusariosis, or other mold infections, microbiologic confirmation is important.

Central Nervous System Infection

Rare CNS manifestations include:

• Meningitis

• Cerebritis

• Brain abscess

These infections usually occur in severely immunocompromised patients or after direct inoculation or dissemination from another site.

Neurologic disease can be difficult to treat and may require prolonged systemic antifungal therapy together with surgical intervention when feasible.

Endocarditis

Acremonium has been reported as a rare cause of prosthetic valve endocarditis.

Risk factors include:

• Prosthetic cardiac material

• Previous cardiac surgery

• Prolonged intravascular access

• Immunosuppression

Fungal endocarditis often requires both prolonged antifungal therapy and surgical valve intervention.

Osteomyelitis and Arthritis

Acremonium may cause osteomyelitis or post-traumatic septic arthritis, particularly after:

• Penetrating trauma

• Contaminated wounds

• Surgery

• Direct inoculation

These infections may have a chronic and indolent course.

Successful management frequently requires both antifungal therapy and surgical debridement.

Endophthalmitis

Postoperative endophthalmitis caused by Acremonium has been described after ocular surgery.

Symptoms may include:

• Eye pain

• Redness

• Reduced vision

• Intraocular inflammation

This condition requires urgent ophthalmologic management because permanent visual loss may occur.

Peritoneal Dialysis-Associated Peritonitis

Acremonium can rarely cause peritonitis in patients undergoing peritoneal dialysis.

Presentation may include:

• Abdominal pain

• Cloudy dialysate

• Fever

• Peritoneal leukocytosis

Management may require systemic antifungal therapy and, in some cases, removal of the peritoneal dialysis catheter.

Disseminated Infection

Disseminated Acremonium infection is uncommon but may occur in patients with profound neutropenia or other severe immunosuppressive states.

Possible sites of dissemination include:

• Lungs

• Brain

• Skin

• Bone

• Heart

• Other internal organs

The prognosis is substantially worse when infection is disseminated.

Risk Factors for Invasive Disease

Important predisposing factors include:

• Prolonged neutropenia

• Hematologic malignancy

• Hematopoietic stem-cell transplantation

• Solid-organ transplantation

• Prolonged corticosteroid therapy

• Major immunosuppression

• Indwelling medical devices

• Recent surgery

• Trauma with environmental contamination

Localized superficial infections, however, can occur in immunocompetent individuals.

Diagnosis

Diagnosis is primarily based on culture from the affected site.

Specimens may include:

• Corneal scrapings

• Nail material

• Tissue biopsy

• Blood cultures

• Cerebrospinal fluid

• Respiratory samples

• Peritoneal fluid

• Bone or joint specimens

Because Acremonium can occasionally represent environmental contamination, the clinical context and repeated recovery from appropriate specimens are important.

Histopathology

Tissue examination may show septate hyaline fungal hyphae.

The morphology can resemble other hyalohyphomycetes, particularly:

• Fusarium

• Aspergillus

Therefore, histopathology is useful for demonstrating tissue invasion, but culture or molecular identification may be needed to determine the exact genus or species.

Differential Diagnosis

Important fungal differentials include:

• Fusarium

• Aspergillus

• Scedosporium

• Other hyaline molds

For keratitis, bacterial and herpetic infections must also be considered.

For chronic subcutaneous disease, the differential includes other causes of mycetoma, including bacterial actinomycetoma and infections caused by other filamentous fungi.

Treatment

Treatment can be difficult because antifungal susceptibility varies among Acremonium species.

Historically, amphotericin B has been considered a major therapeutic option, particularly for invasive disease.

However, clinical response may be inconsistent, and susceptibility testing can be helpful in serious infections.

Amphotericin B

Amphotericin B may be used for:

• Invasive infection

• Disseminated disease

• CNS disease

• Severe ocular or deep tissue infection

A lipid formulation may be preferred in many patients when prolonged treatment is needed because of reduced nephrotoxicity compared with conventional amphotericin B deoxycholate.

Azole Therapy

Newer azoles may have activity against Acremonium, although clinical experience is more limited and susceptibility can be variable.

Potential agents include selected triazoles such as:

• Voriconazole

• Posaconazole

The choice should ideally be guided by:

• Site of infection

• Susceptibility testing

• Clinical response

• Drug interactions

• Renal and hepatic function

Surgical Management

Surgical treatment is often important when infection is localized and accessible.

Possible interventions include:

• Drainage of abscesses

• Debridement of infected tissue

• Resection of infected bone

• Removal of infected prosthetic material

• Valve surgery for fungal endocarditis

• Ophthalmologic surgery for severe ocular infection

Antifungal therapy alone may be insufficient when devitalized tissue or infected foreign material remains in place.

General Management Principles

Successful treatment depends on three main factors:

• Appropriate antifungal therapy

• Source control

• Reversal of immunosuppression when possible

Recovery from neutropenia can significantly improve outcomes in patients with invasive mold infection.

Prognosis

Localized superficial infections usually have a better prognosis than invasive disease.

The outcome is worse in patients with:

• Persistent neutropenia

• Disseminated infection

• CNS involvement

• Prosthetic valve infection

• Delayed diagnosis

• Inability to remove infected foreign material

High-Yield Clinical Pattern

Neutropenic patient

• ●

Persistent fever

• ●

Pulmonary or disseminated mold infection

• ●

Slow-growing septate hyaline fungus

→ Consider Acremonium among the differential diagnoses.

High-Yield Ocular Pattern

Contact lens user or patient with corneal trauma

• ●

Painful keratitis

• ●

Filamentous fungus isolated from corneal scraping

→ Consider Acremonium as a possible cause.

Exam Essentials

Former name:

→ Cephalosporium

Organism type:

→ Filamentous mold

Hyphae:

→ Septate and hyaline

Growth:

→ Generally slower than Fusarium

Common environmental sources:

→ Soil, sewage, insects, and plant-associated environments

Important species:

→ A. kiliense among the historically important pathogenic species

Common localized infections:

→ Mycetoma, onychomycosis, and keratitis

Important invasive infections:

→ Pulmonary disease, CNS infection, endocarditis, osteomyelitis, endophthalmitis, and disseminated infection

Major risk factor for dissemination:

→ Profound neutropenia

Diagnosis:

→ Culture, supported by histopathology

Traditional major antifungal:

→ Amphotericin B

Possible alternative agents:

→ Selected newer azoles based on susceptibility

Important additional therapy:

→ Surgical drainage, debridement, or resection when feasible

Infectious Disease and Microbiology - Acinetobacter Species

Basics

Acinetobacter is a genus of aerobic gram-negative bacteria that includes several species capable of causing human disease. Clinically important members include Acinetobacter baumannii, A. calcoaceticus, A. haemolyticus, A. johnsonii, A. junii, A. lwoffii, and A. radioresistens, together with several less commonly identified or unnamed species.

Among these organisms, A. baumannii is the most important cause of serious healthcare-associated infection and is also the species most strongly associated with multidrug resistance.

Microbiologic Characteristics

Acinetobacter species are aerobic, nonmotile, encapsulated gram-negative organisms. During rapid growth they may appear more rod-shaped, whereas in the stationary phase they often have a coccobacillary appearance.

They are capable of colonizing human skin and mucosal surfaces and may therefore be recovered from patients without necessarily causing invasive disease. This ability to colonize patients and survive in the healthcare environment contributes substantially to their importance as nosocomial pathogens.

Epidemiology

Acinetobacter species have a worldwide distribution. They are particularly important in hospitals, where they can survive on environmental surfaces and medical equipment for prolonged periods.

Healthcare-associated infections occur most frequently in:

• Intensive care units

• Patients receiving mechanical ventilation

• Patients with prolonged hospitalization

• Patients with invasive devices

• Severely ill or immunocompromised individuals

A. baumannii has become especially important because hospital strains may acquire resistance to multiple antimicrobial classes.

Major Risk Factors

Important factors that predispose to Acinetobacter infection include prolonged hospitalization, ICU admission, mechanical ventilation, endotracheal intubation, urinary catheterization, vascular catheters, major surgery, severe trauma, burns, and previous exposure to broad-spectrum antibiotics.

Alcohol use disorder has historically been associated with community-acquired Acinetobacter pneumonia, although most serious contemporary infections are healthcare-associated.

Combat injuries and heavily contaminated traumatic wounds can also become infected with A. baumannii and related species.

Pneumonia

Acinetobacter can cause severe pneumonia, particularly in hospitalized and mechanically ventilated patients.

Ventilator-associated pneumonia is one of the most important clinical syndromes associated with A. baumannii. Patients may present with fever, increasing respiratory secretions, hypoxemia, leukocytosis, and new or progressive pulmonary infiltrates.

Because Acinetobacter can colonize respiratory secretions, isolation from tracheal aspirates does not always prove infection. The microbiologic result must therefore be interpreted together with the clinical and radiographic findings.

Community-acquired pneumonia caused by Acinetobacter is much less common but has historically been described in individuals with heavy alcohol use or major underlying illness.

Bacteremia

Acinetobacter bacteremia usually occurs in hospitalized patients and is frequently associated with:

• Central venous catheters

• Pneumonia

• Wound infection

• Urinary tract infection

• Severe systemic illness

Patients may progress to septic shock and multiorgan dysfunction, particularly when infection is caused by a highly resistant strain or when appropriate therapy is delayed.

Tracheobronchitis

Acinetobacter may cause tracheobronchitis, especially in patients with artificial airways or prolonged tracheal intubation.

Children with tracheostomies or other airway devices may also develop infection or colonization.

The distinction between airway colonization and true lower respiratory infection is clinically important.

Skin, Soft-Tissue, and Wound Infection

Acinetobacter can cause cellulitis and other skin and soft-tissue infections, particularly when associated with:

• Vascular catheters

• Major trauma

• Burns

• Surgical wounds

• Combat-related wounds

Burn wounds and traumatic wounds provide an especially favorable environment for colonization and invasive infection.

Local infection around an intravascular catheter may occasionally resolve only after the catheter is removed.

Urinary Tract Infection

Acinetobacter urinary tract infections usually occur in patients with complicated urinary systems rather than in otherwise healthy individuals.

Major risk factors include:

• Urinary catheterization

• Structural urinary tract disease

• Prolonged hospitalization

• Critical illness

• Previous antimicrobial therapy

Urinary isolates should be interpreted carefully because catheterized patients may have asymptomatic bacteriuria or colonization.

Meningitis

Acinetobacter can cause meningitis, particularly following:

• Neurosurgical procedures

• Cranial trauma

• Ventricular drains

• Other intracranial devices

Post-neurosurgical meningitis caused by multidrug-resistant A. baumannii can be particularly difficult to treat because antimicrobial penetration into cerebrospinal fluid may be limited.

Diagnosis

Diagnosis is based primarily on microbiologic culture from the clinically involved site.

Possible specimens include:

• Blood

• Respiratory secretions

• Bronchoalveolar lavage

• Urine

• Wound material

• Cerebrospinal fluid

• Catheter-tip cultures when clinically appropriate

Because Acinetobacter frequently colonizes hospitalized patients, a positive culture does not automatically establish infection.

The clinician must determine whether the isolate represents:

True infection or colonization.

Antimicrobial Susceptibility Testing

Susceptibility testing is essential because Acinetobacter, particularly A. baumannii, can display highly unpredictable resistance patterns.

Resistance may involve:

• Carbapenems

• Cephalosporins

• Fluoroquinolones

• Aminoglycosides

• Multiple β-lactams

For serious infection, definitive treatment should therefore be based on the susceptibility profile whenever possible.

Treatment

Treatment depends on the site and severity of infection and, most importantly, on antimicrobial susceptibility results.

Historically, carbapenems such as imipenem or meropenem were among the most reliable agents for susceptible Acinetobacter infections.

However, carbapenem-resistant A. baumannii has become a major worldwide problem, so carbapenems should not be assumed to be active without susceptibility confirmation.

Sulbactam

Sulbactam is unusual among β-lactamase inhibitors because it has intrinsic antibacterial activity against Acinetobacter.

This characteristic makes sulbactam-containing regimens particularly important in treatment.

Sulbactam generally has greater direct activity against Acinetobacter than:

• Clavulanic acid

• Tazobactam

Modern treatment of difficult A. baumannii infection often incorporates sulbactam-based therapy when the organism is susceptible or when high-dose sulbactam strategies are appropriate.

Other Potentially Active Agents

Depending on susceptibility results, active agents may include:

• Third- or fourth-generation cephalosporins

• Aminoglycosides

• Fluoroquinolones

• Doxycycline

• Minocycline

• Tigecycline

• Polymyxins

• Sulbactam-containing regimens

No single drug should be assumed effective against a resistant hospital strain.

Aminoglycosides

Amikacin or another active aminoglycoside may sometimes be added to treatment of severe systemic infection when susceptibility is demonstrated.

Combination therapy may be considered for:

• Septic shock

• Highly resistant infection

• Severe pneumonia

• Bacteremia

However, aminoglycoside toxicity and limited penetration into some tissues must be considered.

Polymyxins

Polymyxins such as colistin or polymyxin B may retain activity against extensively drug-resistant Acinetobacter.

They have historically been used as salvage agents, but their use is limited by toxicity, particularly nephrotoxicity and neurotoxicity.

They should therefore be used selectively and with careful monitoring.

Tigecycline and Tetracycline Derivatives

Tigecycline and certain tetracycline derivatives may show activity against Acinetobacter.

These agents may be useful in selected infections, but they are not ideal for all sites.

For example, tigecycline produces relatively low serum concentrations and therefore may be less appropriate as sole therapy for bloodstream infection.

Drug choice should always take infection site into account.

Catheter-Associated Infection

When a vascular or urinary catheter is clearly the source of infection, source control is important.

Management may include:

• Removal or replacement of the infected catheter

• Appropriate systemic antimicrobial therapy

Catheter removal alone is generally insufficient when bacteremia or invasive infection is present.

Antimicrobial Resistance

A. baumannii is generally more resistant than many other Acinetobacter species.

Clinically important resistance patterns include:

Multidrug-resistant Acinetobacter:

→ Resistance to multiple major antimicrobial classes

Carbapenem-resistant Acinetobacter:

→ Resistance to imipenem, meropenem, or related carbapenems

Extensively drug-resistant strains:

→ Susceptibility remains to very few agents

Resistance mechanisms may include β-lactamases, carbapenemases, altered membrane permeability, efflux pumps, and target modifications.

Infection Control

Strict infection-control practices are essential because Acinetobacter can persist on dry hospital surfaces and spread between patients.

Important measures include:

• Careful hand hygiene

• Contact precautions when indicated

• Proper cleaning and disinfection of equipment

• Environmental cleaning

• Appropriate management of ventilators and respiratory equipment

• Minimizing unnecessary invasive devices

• Antimicrobial stewardship

• Surveillance during outbreaks

ICUs require particular vigilance because vulnerable patients and frequent device use facilitate transmission.

Prevention

Prevention depends primarily on reducing healthcare-associated transmission.

Important strategies include minimizing unnecessary catheterization, shortening the duration of mechanical ventilation when possible, adhering to ventilator-associated pneumonia prevention measures, maintaining proper wound care, and following strict infection-control protocols.

Judicious antibiotic use is also important because excessive broad-spectrum antimicrobial exposure promotes selection of resistant Acinetobacter strains.

High-Yield Clinical Pattern

ICU patient

• ●

Mechanical ventilation

• ●

New pneumonia

• ●

Multidrug-resistant gram-negative coccobacillus

→ Think Acinetobacter baumannii.

High-Yield Resistance Pattern

Hospital-acquired infection

• ●

Carbapenem resistance

• ●

Few remaining antimicrobial options

→ Consider multidrug-resistant or carbapenem-resistant A. baumannii.

High-Yield Drug Feature

Sulbactam is not merely a β-lactamase inhibitor in Acinetobacter infection.

It also has:

Direct antibacterial activity against Acinetobacter.

High-Yield Infection Sites

Common Acinetobacter infections include:

• Ventilator-associated pneumonia

• Bacteremia

• Wound and burn infections

• Catheter-associated infections

• Complicated urinary tract infection

• Post-neurosurgical meningitis

Exam Essentials

Major pathogenic species:

→ Acinetobacter baumannii

Organism:

→ Aerobic gram-negative coccobacillus

Motility:

→ Nonmotile

Normal colonization:

→ Skin and mucosal surfaces

Major setting:

→ Healthcare-associated infection, especially ICU

Classic pulmonary syndrome:

→ Ventilator-associated pneumonia

Important wound association:

→ Burns and traumatic or combat wounds

Important CNS association:

→ Post-neurosurgical meningitis

Diagnosis:

→ Culture with susceptibility testing

Historically important susceptible-drug class:

→ Carbapenems

Important problem:

→ Carbapenem-resistant A. baumannii

β-lactamase inhibitor with intrinsic Acinetobacter activity:

→ Sulbactam

Potential agents for resistant infection:

→ Sulbactam-based therapy, selected tetracyclines, aminoglycosides, polymyxins, or other active agents according to susceptibility

Important non-drug treatment:

→ Source control, including removal of infected catheters when appropriate

Major prevention:

→ Strict hospital infection-control practices, especially in ICUs

Infectious Disease and Microbiology - Acanthamoeba Species Basics Acanthamoeba is a genus of free-living protozoa that is widely distributed in the environment. Several species have been associated with human infection, including A. astronyxis, A. castellanii, A. culbertsoni, A. divionensis, A. glebae, A. griffini, A. healyi, A. hatchetti, A. palestinensis, A. polyphaga, and A. rhysodes. These organisms do not require a human or animal host to complete their life cycle and can persist independently in environmental sources. Acanthamoeba species exist as both trophozoites and cysts. The trophozoite is the active, feeding form, whereas the cyst is more resistant to environmental stress and contributes to the organism’s persistence in unfavorable conditions.

Microbiologic Characteristics Acanthamoeba species are free-living protozoa with a worldwide environmental distribution. They are commonly encountered in soil, dust, freshwater, brackish water, sewage, hot tubs, and other moist environments. Their ability to form resistant cysts allows them to survive under conditions that would eliminate many other microorganisms. The organisms are relatively resistant to standard concentrations of chlorine used in drinking water and swimming pools, which helps explain their persistence in treated water systems.

Epidemiology Acanthamoeba infections occur worldwide because the organisms are ubiquitous in the environment. Human exposure is common, but clinical disease is relatively uncommon and usually develops when the organism gains access to susceptible tissues. Acquisition may occur through inhalation, contamination of damaged skin, or direct contact with contaminated soil or water. Contact lens–associated infection is particularly important. Using tap water, nonsterile saline, or contaminated lens-cleaning solutions can introduce Acanthamoeba onto the corneal surface. Although disseminated and central nervous system disease primarily affects immunocompromised or debilitated patients, infection can occasionally occur in people without an obvious underlying immune defect.

Major Clinical Infections Acanthamoeba produces three particularly important clinical syndromes: granulomatous amebic encephalitis, keratitis, and chronic cutaneous or soft-tissue disease. Granulomatous amebic encephalitis is typically seen in patients with impaired immunity. The illness usually has an insidious and progressive course rather than the abrupt presentation seen with many bacterial or viral encephalitides. Neurologic symptoms may evolve over more than a week and can continue for several weeks or months before diagnosis. Acanthamoeba keratitis usually occurs after corneal trauma or in contact lens users. Contaminated cleaning solutions, tap-water rinsing of lenses, swimming while wearing lenses, and poor contact lens hygiene are important risk factors. The keratitis may resemble herpes simplex keratitis because dendritic or pseudodendritic corneal lesions can occur. Acanthamoeba can also cause chronic skin and soft-tissue infection. Manifestations include persistent ulcerative lesions, abscesses, plaques, or erythematous nodules. Cutaneous disease is particularly important in immunocompromised patients and may sometimes accompany disseminated infection.

Granulomatous Amebic Encephalitis Granulomatous amebic encephalitis is a severe, usually subacute or chronic central nervous system infection. It occurs most often in individuals with major underlying illness or impaired cellular immunity. The presentation is variable and can include progressive headache, behavioral changes, altered mental status, focal neurologic deficits, seizures, ataxia, cranial nerve abnormalities, and eventually coma. Because the disease evolves slowly, the diagnosis may initially be confused with brain tumor, fungal infection, tuberculosis, or another chronic encephalitis. The prognosis is generally poor, particularly when diagnosis is delayed.

Acanthamoeba Keratitis Keratitis is one of the most clinically recognizable Acanthamoeba infections and often occurs in otherwise healthy individuals. The strongest risk factor is contact lens use, particularly when lenses are exposed to nonsterile water. Important exposures include rinsing lenses or lens cases with tap water, swimming or showering while wearing lenses, using contaminated cleaning products, or poor lens-case hygiene. Patients may develop severe eye pain, photophobia, tearing, redness, and reduced visual acuity. Pain may be disproportionately severe compared with the initial clinical appearance. Early disease may show punctate epithelial abnormalities or dendritiform lesions and can therefore be mistaken for herpes simplex keratitis. As infection progresses, stromal inflammation and a characteristic ring-shaped corneal infiltrate may develop. Early recognition is important because delayed treatment can lead to corneal destruction and permanent visual impairment.

Cutaneous and Disseminated Disease Cutaneous Acanthamoeba infection may present with slowly progressive erythematous papules, nodules, ulcers, or abscess-like lesions. These lesions can be chronic and may involve the face, trunk, or extremities. In markedly immunocompromised patients, skin disease may represent part of disseminated infection. Organisms can spread hematogenously to other sites, including the central nervous system. Persistent unusual skin lesions in an immunocompromised patient should therefore prompt consideration of opportunistic free-living amebic infection.

Diagnosis Diagnosis depends on identifying the organism in tissue or clinical specimens. Acanthamoeba may be cultured using specialized media, although culture is not always rapidly available. Cysts or trophozoites can sometimes be demonstrated directly in tissue specimens. Brain tissue, corneal tissue, or corneal scrapings may show the organism on histopathologic examination. Useful stains include silver-methenamine and periodic acid–Schiff stains. Organisms may rarely be visualized in fresh cerebrospinal fluid, but CSF examination has relatively low sensitivity. For keratitis, corneal scrapings or biopsy specimens may be evaluated using microscopy, culture, histopathology, and polymerase chain reaction. PCR can provide highly useful confirmation when available. Serologic testing has little clinical value and is generally not useful for establishing the diagnosis.

Diagnostic Approach to Keratitis Acanthamoeba should be strongly suspected in a contact lens wearer with severe keratitis, especially when symptoms persist despite antibacterial or antiviral therapy. A particularly suggestive pattern is severe ocular pain combined with a history of contact lens exposure to tap water or recreational water. Corneal scraping should be obtained for microbiologic evaluation when the diagnosis is suspected. PCR, culture, and direct visualization can all contribute to confirmation.

Differential Diagnosis Granulomatous encephalitis may resemble other chronic or subacute central nervous system infections, including fungal meningitis or encephalitis, tuberculosis, toxoplasmosis, and other free-living amebic infections. Neoplastic and inflammatory neurologic disorders may also mimic the presentation. Acanthamoeba keratitis can be confused with herpes simplex keratitis, bacterial keratitis, fungal keratitis, and other causes of corneal ulceration. Chronic cutaneous disease may mimic fungal infection, atypical mycobacterial infection, bacterial abscesses, inflammatory dermatoses, or malignancy.

Treatment Treatment of Acanthamoeba infection can be difficult because the organisms have both trophozoite and cyst forms, and the cysts are relatively resistant to therapy. For granulomatous amebic encephalitis, no single standardized regimen has been proven consistently effective. Therapy generally uses combinations of agents with demonstrated in vitro or reported clinical activity. Drugs that have activity against Acanthamoeba include pentamidine, azole antifungals, sulfonamides, flucytosine, and, to a lesser extent, amphotericin B. Combination therapy is usually favored for serious systemic or neurologic disease because monotherapy is unlikely to be reliably effective. Treatment should be individualized with infectious disease and neurologic expertise whenever possible.

Treatment of Acanthamoeba Keratitis Keratitis generally requires prolonged topical combination therapy. Older regimens included topical propamidine combined with neomycin, gramicidin, and polymyxin. Modern treatment commonly relies heavily on topical biguanides because they have activity against both trophozoites and cysts. Frequently used agents include: • Polyhexamethylene biguanide at approximately 0.02% • Chlorhexidine at approximately 0.02% These may be combined with diamidines such as propamidine in selected cases. Treatment is often prolonged because viable cysts may persist even after initial clinical improvement. Severe disease or inadequate response may require ophthalmologic surgical management, including corneal transplantation in selected cases.

General Prevention Prevention is especially important because Acanthamoeba is widespread and difficult to eliminate completely from the environment. Contact lens users should use only sterile, commercially prepared solutions for lens cleaning, rinsing, and storage. Tap water should never be used to clean or store contact lenses or lens cases. Contact lenses should generally be removed before swimming, showering, entering hot tubs, or participating in water activities unless appropriate protective measures are used. Lens cases should be cleaned according to manufacturer instructions, allowed to dry completely, and replaced regularly. Standard precautions are sufficient for hospitalized patients because routine person-to-person spread is not a major mode of transmission. Avoiding exposure of open wounds or vulnerable tissues to contaminated warm freshwater may also reduce risk.

High-Yield Clinical Pattern Contact lens wearer ● Severe eye pain ● Exposure of lenses to tap water, swimming water, or contaminated cleaning solution → Think Acanthamoeba keratitis.

High-Yield Neurologic Pattern Immunocompromised patient ● Slowly progressive encephalitis over days to weeks ● Granulomatous CNS disease → Consider Acanthamoeba granulomatous amebic encephalitis.

High-Yield Diagnostic Features Acanthamoeba may be identified by: • Corneal scraping or biopsy • Brain or skin biopsy • Specialized culture • Histopathology • PCR Serologic testing: → Generally not useful.

Exam Essentials Organism type:

→ Free-living protozoan Distribution:

→ Worldwide Environmental reservoirs:

→ Soil, freshwater, brackish water, dust, sewage, and hot tubs Major infections:

→ Granulomatous amebic encephalitis, keratitis, and chronic cutaneous disease Major risk group for encephalitis:

→ Immunocompromised or debilitated patients Major risk factor for keratitis:

→ Contact lens use with contaminated or nonsterile water exposure Keratitis may mimic:

→ Herpes simplex keratitis Important diagnostic methods:

→ Corneal scraping, biopsy, culture, histopathology, and PCR Useful histologic stains:

→ Periodic acid–Schiff and silver-methenamine stains Serology:

→ Not clinically useful Important topical agents for keratitis:

→ Biguanides such as chlorhexidine or polyhexamethylene biguanide Key prevention:

→ Use only sterile solutions for contact lens care and avoid tap-water exposure.

Infectious Disease and Microbiology - Absidia corymbifera

BASICS

Genus

Absidia

Species

Absidia corymbifera is the principal species of Absidia historically recognized as pathogenic to humans.

It was previously referred to as:

Absidia ramosa

In more recent taxonomic classifications, organisms historically called Absidia corymbifera have been reclassified, but the older name is still encountered in medical literature.

⸻

MICROBIOLOGIC CHARACTERISTICS

Absidia corymbifera is a:

• Filamentous fungus

• Mold

• Member of the order Mucorales

Its morphology resembles other mucormycetes such as Rhizopus.

Characteristic microscopic features include:

• Broad hyphae

• Hyaline appearance

• Pauciseptate or nonseptate hyphae

• Hyphal diameter approximately 6–15 μm

The hyphae commonly branch at relatively wide angles, as is typical of mucormycetes.

⸻

CULTURE CHARACTERISTICS

The fungus grows rapidly in culture.

Typical growth may be visible within:

Approximately 4 days

Colonies are often:

• Light gray

• Grayish-brown

• Woolly or cotton-like

It can grow over a relatively broad temperature range, approximately:

25–45°C

Rapid growth helps distinguish mucormycetes from many slower-growing molds.

⸻

EPIDEMIOLOGY

Absidia corymbifera is:

Ubiquitous in the environment.

It can be found in:

• Soil

• Decaying organic matter

• Plant material

• Environmental debris

Because it is widely distributed, its isolation from a nonsterile specimen does not always indicate invasive disease.

It may occasionally represent:

Environmental contamination or colonization.

⸻

MODE OF ACQUISITION

The most common route of acquisition is believed to be:

Inhalation of airborne sporangiospores.

Other routes can include:

• Direct inoculation into damaged skin

• Traumatic implantation

• Contamination of wounds

The route of exposure influences the clinical syndrome that develops.

⸻

RISK FACTORS

Severe invasive infection occurs predominantly in patients with impaired host defenses.

Important risk factors include:

• Profound neutropenia

• Hematologic malignancy

• Hematopoietic stem-cell transplantation

• Solid-organ transplantation

• Prolonged corticosteroid therapy

• Severe immunosuppression

• Advanced HIV infection

• Uncontrolled diabetes mellitus

• Diabetic ketoacidosis

• Major trauma or burns

• Iron overload

• Deferoxamine exposure

The risk rises substantially when several of these factors coexist.

⸻

PATHOGENESIS

Like other mucormycetes, Absidia can invade blood vessels.

Angioinvasion produces:

• Thrombosis

• Tissue ischemia

• Infarction

• Necrosis

This explains the rapidly progressive and destructive nature of mucormycosis.

Vascular invasion also facilitates:

Hematogenous dissemination to distant organs.

⸻

INFECTIONS

Absidia corymbifera is an uncommon cause of:

Mucormycosis

Clinical disease may involve many organ systems.

Major forms include:

• Rhinocerebral mucormycosis

• Pulmonary mucormycosis

• Cutaneous mucormycosis

• Disseminated mucormycosis

Less common manifestations include:

• Central nervous system infection

• Meningitis

• Post-traumatic infection

• Deep soft-tissue infection

⸻

RHINOCEREBRAL MUCORMYCOSIS

Rhinocerebral disease typically begins in the:

Nasal cavity or paranasal sinuses

and may extend rapidly into:

• Orbit

• Facial structures

• Skull base

• Brain

It is classically associated with:

Poorly controlled diabetes and diabetic ketoacidosis.

Possible symptoms include:

• Facial pain

• Headache

• Nasal congestion

• Fever

• Periorbital swelling

• Diplopia

• Visual loss

Black necrotic tissue involving the nasal mucosa or palate is a major warning sign.

⸻

PULMONARY MUCORMYCOSIS

Pulmonary disease occurs especially in:

• Neutropenic patients

• Patients with hematologic malignancies

• Transplant recipients

Symptoms may include:

• Fever

• Cough

• Dyspnea

• Pleuritic chest pain

• Hemoptysis

Pulmonary infection can rapidly invade blood vessels and cause:

• Pulmonary infarction

• Massive hemorrhage

• Dissemination

⸻

CUTANEOUS MUCORMYCOSIS

Cutaneous infection may follow:

• Trauma

• Burns

• Contaminated dressings

• Surgery

• Direct inoculation

Lesions may begin as:

• Erythema

• Swelling

• Painful plaques

and progress to:

• Ulceration

• Necrosis

• Black eschar

Localized cutaneous disease can extend deeply into:

• Subcutaneous tissue

• Fascia

• Muscle

• Bone

⸻

DISSEMINATED MUCORMYCOSIS

Dissemination occurs most often in patients with severe immunosuppression.

The infection may spread hematogenously to:

• Brain

• Liver

• Spleen

• Kidneys

• Heart

• Skin

Disseminated disease carries a very high mortality rate.

⸻

CENTRAL NERVOUS SYSTEM DISEASE

CNS involvement may occur by:

• Direct extension from rhinocerebral infection

• Hematogenous dissemination

• Rarely, traumatic inoculation

Meningitis after severe head injury has been described but is uncommon.

⸻

DIAGNOSIS

Diagnosis requires a combination of:

• Clinical suspicion

• Histopathology

• Culture

Because mucormycosis progresses rapidly, treatment should not be delayed while waiting for definitive culture results when clinical suspicion is high.

⸻

CULTURE

Culture can identify the organism.

However:

A positive culture alone does not always prove invasive infection because the organism may be an environmental contaminant.

Conversely:

A negative culture does not exclude mucormycosis.

Tissue examination is therefore very important.

⸻

HISTOPATHOLOGY

Characteristic tissue findings include:

• Broad hyphae

• Irregular width

• Pauciseptate or nonseptate appearance

• Wide-angle branching

• Angioinvasion

• Tissue necrosis

Demonstration of fungal invasion into tissue or blood vessels strongly supports true invasive disease.

⸻

DIFFERENTIAL DIAGNOSIS

Important fungal differentials include:

• Rhizopus

• Mucor

• Lichtheimia

• Cunninghamella

• Aspergillus

• Fusarium

A particularly important distinction is:

Mucormycetes:

→ Broad, irregular, pauciseptate hyphae with wide-angle branching

Aspergillus:

→ Narrower, regularly septate hyphae with acute-angle branching

⸻

TREATMENT

Mucormycosis is a medical and surgical emergency.

Successful management depends on three major principles:

1. Prompt antifungal therapy

2. Aggressive surgical debridement when feasible

3. Correction of underlying predisposing factors

⸻

FIRST-LINE ANTIFUNGAL THERAPY

A lipid formulation of amphotericin B is generally preferred for invasive mucormycosis.

Typical dosing:

Liposomal amphotericin B approximately 5 mg/kg/day IV

Higher doses may be considered in selected severe infections, particularly CNS disease.

Historically, amphotericin B deoxycholate was used at:

Approximately 1–1.5 mg/kg/day

However, lipid formulations are generally preferred because they permit higher dosing with less nephrotoxicity.

⸻

POSACONAZOLE

Posaconazole has activity against many mucormycetes.

It may be used as:

• Step-down therapy

• Salvage therapy

• An alternative when amphotericin B cannot be continued

Older regimens used:

Posaconazole approximately 800 mg/day

Modern dosing depends on formulation and should follow current prescribing guidance.

⸻

ISAVUCONAZOLE

Isavuconazole is another important agent active against mucormycetes.

It may be considered for:

• Primary treatment in selected patients

• Step-down therapy

• Salvage treatment

Choice between amphotericin B, posaconazole, and isavuconazole depends on:

• Disease severity

• Site of infection

• Renal function

• Drug interactions

• Antifungal susceptibility

• Clinical response

⸻

SURGICAL MANAGEMENT

Surgery is often crucial.

Aggressive debridement is especially important in:

• Rhinocerebral disease

• Cutaneous disease

• Necrotic soft-tissue infection

• Localized pulmonary disease in selected patients

Necrotic tissue has poor blood supply, limiting delivery of systemic antifungal therapy.

Therefore:

Antifungal therapy alone may be insufficient when extensive necrotic tissue remains.

⸻

REVERSAL OF UNDERLYING RISK FACTORS

Whenever possible:

• Correct diabetic ketoacidosis

• Control hyperglycemia

• Reduce or discontinue corticosteroids

• Reduce immunosuppression

• Treat neutropenia

• Discontinue deferoxamine

• Correct severe metabolic abnormalities

Recovery of neutrophil function can be particularly important for survival.

⸻

DURATION OF THERAPY

There is no single fixed duration.

Treatment is generally continued until:

• Clinical signs resolve

• Radiographic abnormalities improve substantially

• Surgical disease is controlled

• Immunosuppression has improved when possible

Therapy frequently lasts:

Several weeks to months

rather than a predetermined total cumulative dose.

⸻

GENERAL PREVENTION

There is no vaccine.

Preventive strategies focus on reducing susceptibility and exposure.

Important measures include:

• Avoid unnecessary immunosuppression

• Optimize management of HIV infection

• Control diabetes

• Avoid prolonged severe neutropenia when possible

• Minimize corticosteroid exposure

• Avoid deferoxamine in patients at risk when alternatives are appropriate

• Protect wounds from environmental contamination

⸻

PROGNOSIS

Prognosis depends strongly on:

• Site of infection

• Speed of diagnosis

• Extent of tissue invasion

• Degree of immunosuppression

• Ability to surgically remove infected tissue

• Reversal of underlying risk factors

Localized cutaneous disease generally has a better prognosis than:

• Pulmonary disease

• Rhinocerebral disease with CNS extension

• Disseminated mucormycosis

Delayed therapy markedly worsens outcomes.

⸻

HIGH-YIELD MICROBIOLOGY

Absidia corymbifera:

• Mold

• Mucorales

• Broad hyphae

• Pauciseptate or nonseptate

• Hyaline

• Rapidly growing

• Environmental organism

⸻

HIGH-YIELD PATHOLOGY

Broad, irregular, pauciseptate hyphae

+

Wide-angle branching

+

Angioinvasion

→ Think mucormycosis

⸻

HIGH-YIELD CLINICAL PATTERN

Immunocompromised patient

+

Rapidly progressive necrotic infection

+

Broad nonseptate fungal hyphae

→ Think Mucorales infection

⸻

HIGH-YIELD RISK PATTERN

Diabetic ketoacidosis

+

Facial pain/sinus disease

+

Black necrotic nasal or palatal lesion

→ Rhinocerebral mucormycosis

⸻

EXAM ESSENTIALS

Organism:

→ Absidia corymbifera

Older name:

→ Absidia ramosa

Organism type:

→ Filamentous mold

Order:

→ Mucorales

Hyphae:

→ Broad, hyaline, pauciseptate/nonseptate

Typical hyphal width:

→ Approximately 6–15 μm

Growth:

→ Rapid

Major route of infection:

→ Inhalation of spores

Major disease:

→ Mucormycosis

Common forms:

→ Rhinocerebral, pulmonary, cutaneous, disseminated

Major risk group:

→ Immunocompromised patients

Important pathogenic mechanism:

→ Angioinvasion with thrombosis and tissue necrosis

Diagnosis:

→ Tissue histopathology + culture

Preferred major antifungal class:

→ Amphotericin B, especially lipid formulations

Important alternatives/step-down agents:

→ Posaconazole or isavuconazole

Critical additional treatment:

→ Surgical debridement

Major management principle:

→ Reverse underlying immunosuppression or metabolic risk factors whenever possible

Infectious Disease and Microbiology - Yellow Fever

BASICS

Description

Yellow fever is an acute mosquito-borne viral infection caused by the yellow fever virus. Clinical illness ranges from an asymptomatic or mild febrile syndrome to a severe systemic disease characterized by jaundice, hepatic injury, hemorrhage, renal dysfunction, shock, and multiorgan failure.

The term “yellow” refers to the jaundice that develops in severe disease.

⸻

EPIDEMIOLOGY

Yellow fever occurs primarily in tropical regions of:

• Sub-Saharan Africa

• Tropical South America

Transmission occurs mainly in areas located approximately between 15° north and 15° south of the equator.

The infection may occur as:

• Sporadic cases

• Local outbreaks

• Large epidemics

The true incidence is substantially higher than the number of reported cases because many infections are mild, unrecognized, or occur in areas with limited surveillance.

Historically, Africa has accounted for the majority of cases and deaths.

Travel-associated risk varies according to:

• Destination

• Season

• Vaccination status

• Mosquito exposure

• Local outbreak activity

Transmission has traditionally been highest:

• In parts of West Africa during the rainy season

• In parts of Brazil and South America during periods of increased mosquito activity

⸻

RISK FACTORS

Major risk factors include:

• Residence in or travel to an endemic region

• Lack of yellow fever vaccination

• Mosquito exposure

• Travel during periods of increased mosquito activity

• Outdoor activities without appropriate mosquito precautions

• Travel to areas experiencing an outbreak

Unvaccinated travelers entering endemic regions are at greatest risk.

⸻

ETIOLOGY

Yellow fever is caused by:

Yellow fever virus

The virus is:

• An enveloped RNA virus

• A member of the Flaviviridae family

• Related to other flaviviruses such as dengue, Zika, West Nile, and Japanese encephalitis viruses

⸻

TRANSMISSION

Yellow fever is transmitted through the bite of infected mosquitoes.

Important mosquito vectors include:

• Aedes species

• Haemagogus species in the Americas

Humans and nonhuman primates participate in transmission cycles.

Three epidemiologic transmission patterns are recognized:

1. Sylvatic or jungle cycle

The virus circulates between mosquitoes and nonhuman primates.

Humans become infected when they enter forested environments.

2. Intermediate or savannah cycle

Occurs mainly in Africa.

Mosquitoes transmit infection between humans and nonhuman primates in areas between jungle and urban environments.

3. Urban cycle

The virus is transmitted from:

Human → Aedes aegypti mosquito → Human

This cycle can produce large urban outbreaks.

⸻

PATHOPHYSIOLOGY

After an infected mosquito bite, the virus initially replicates in local tissues and regional lymph nodes.

Viremia subsequently develops and the virus disseminates through the bloodstream.

Important organs affected include:

• Liver

• Kidneys

• Heart

• Adrenal glands

• Spleen

Severe hepatic injury produces:

• Jaundice

• Impaired clotting-factor synthesis

• Coagulopathy

Hemorrhage is promoted by:

• Thrombocytopenia

• Platelet dysfunction

• Reduced hepatic production of coagulation factors

• Disseminated intravascular coagulation in severe disease

⸻

INCUBATION PERIOD

The incubation period is generally:

3–6 days

Symptoms usually begin abruptly.

⸻

CLINICAL COURSE

Yellow fever traditionally progresses through three clinical phases:

1. Infection phase

2. Remission phase

3. Intoxication phase

Not every patient progresses through all three phases.

Most infections are mild or asymptomatic.

⸻

INFECTION PHASE

The illness usually begins suddenly with:

• High fever

• Chills

• Severe headache

• Myalgias

• Back pain

• Malaise

• Prostration

• Nausea

• Vomiting

Patients may also develop:

• Photophobia

• Arthralgia

• Loss of appetite

This phase usually lasts approximately 3–4 days.

⸻

REMISSION PHASE

After several days of fever, symptoms may temporarily improve.

The patient may become:

• Afebrile

• Less symptomatic

• Apparently recovering

This remission may last:

• Several hours

• Up to approximately 1–2 days

Most patients recover during this stage.

A minority, however, progress to severe disease.

⸻

INTOXICATION PHASE

Patients who enter the toxic phase become severely ill.

Fever returns and systemic organ dysfunction develops.

Important manifestations include:

• Jaundice

• Severe hepatic dysfunction

• Renal failure

• Hemorrhage

• Hypotension

• Shock

• Myocarditis

• Encephalopathy

This is the most dangerous phase of yellow fever.

⸻

HEMORRHAGIC MANIFESTATIONS

Bleeding may occur from:

• Gums

• Nose

• Gastrointestinal tract

• Venipuncture sites

• Other mucosal surfaces

Clinical manifestations include:

• Petechiae

• Purpura

• Hematemesis

• Melena

• Hematochezia

Vomiting of dark blood has historically been called:

“Black vomit”

This is a classic manifestation of severe yellow fever.

⸻

HEPATIC MANIFESTATIONS

Severe liver involvement produces:

• Jaundice

• Markedly elevated aminotransferases

• Coagulopathy

• Hepatic dysfunction

A useful clue is that AST may become markedly elevated, sometimes exceeding ALT because of both hepatic and extrahepatic tissue injury.

Severe hepatic failure is associated with poor prognosis.

⸻

RENAL MANIFESTATIONS

Renal involvement may cause:

• Oliguria

• Acute kidney injury

• Azotemia

• Proteinuria or albuminuria

Severe patients may require renal replacement therapy.

⸻

CARDIAC INVOLVEMENT

Myocarditis may occur.

Possible manifestations include:

• Bradycardia

• Arrhythmias

• ECG abnormalities

• Reduced cardiac function

• Cardiovascular collapse

⸻

RELATIVE BRADYCARDIA

A classic clinical finding is:

High fever + unexpectedly slow pulse

This is called:

Faget sign

or

pulse-temperature dissociation.

It is suggestive but not specific for yellow fever.

⸻

NEUROLOGIC MANIFESTATIONS

Severe or late disease can cause:

• Confusion

• Agitation

• Delirium

• Seizures

• Encephalopathy

• Coma

Neurologic abnormalities generally indicate severe systemic illness.

⸻

PHYSICAL EXAMINATION

Possible findings include:

• Fever

• Relative bradycardia

• Conjunctival injection

• Jaundice

• Abdominal tenderness

• Hepatomegaly

• Petechiae

• Purpura

• Mucosal bleeding

• Gastrointestinal bleeding

• Hypotension

• Signs of shock

Severe cases may progress to:

• Acute respiratory distress syndrome

• Multiorgan failure

• Coma

⸻

DIAGNOSIS

Diagnosis requires consideration of:

Compatible illness + epidemiologic exposure

Important questions include:

• Recent travel

• Residence in an endemic area

• Vaccination status

• Mosquito exposure

• Local yellow fever outbreaks

• Timing of illness after travel

Laboratory confirmation is especially important because many infections can resemble yellow fever.

⸻

LABORATORY FINDINGS

Common nonspecific findings include:

• Leukopenia

• Thrombocytopenia

• Elevated AST and ALT

• Elevated bilirubin

• Prolonged coagulation studies

• Evidence of DIC

• Metabolic acidosis

• Elevated creatinine

• Azotemia

• Proteinuria or albuminuria

Severe thrombocytopenia and hepatic dysfunction increase the risk of hemorrhage.

⸻

PCR

During the early viremic phase, yellow fever viral RNA may be detected by:

RT-PCR

PCR is most useful early in illness while viremia is present.

Availability may be limited to specialized or public-health laboratories.

⸻

SEROLOGY

Serologic diagnosis commonly relies on detection of:

Yellow fever-specific IgM antibodies

IgM can be detected using assays such as:

ELISA

Interpretation may be complicated by cross-reactivity with other flaviviruses, including:

• Dengue

• Zika

• West Nile virus

• Japanese encephalitis virus

Previous flavivirus vaccination may also complicate serologic interpretation.

Confirmation may require specialized neutralization testing.

⸻

TISSUE TESTING

In fatal or diagnostically difficult cases, viral antigen can be demonstrated by:

• Immunohistochemistry

• Molecular testing

Possible tissues include:

• Liver

• Kidney

• Myocardium

⸻

LIVER BIOPSY

Liver biopsy should generally be avoided during acute severe yellow fever because of the major risk of:

Fatal hemorrhage

This is an important clinical point.

⸻

PATHOLOGY

Characteristic hepatic abnormalities include:

• Hepatocyte apoptosis

• Steatosis

• Midzonal hepatic necrosis

Classic eosinophilic apoptotic hepatocytes are known as:

Councilman bodies

The midzonal pattern of hepatic injury is a characteristic pathologic feature of yellow fever.

⸻

ECG FINDINGS

Possible ECG abnormalities include:

• Sinus bradycardia

• ST-T abnormalities

• Other changes associated with myocarditis

⸻

DIFFERENTIAL DIAGNOSIS

Yellow fever can resemble many tropical and systemic infections.

Important differential diagnoses include:

• Dengue

• Severe malaria

• Leptospirosis

• Viral hepatitis

• Typhoid fever

• Ebola virus disease

• Marburg virus disease

• Lassa fever

• Rift Valley fever

• Crimean-Congo hemorrhagic fever

• South American viral hemorrhagic fevers

• Other causes of acute hepatic failure

Travel history is essential for narrowing the differential.

⸻

TREATMENT

There is currently no established specific antiviral therapy for yellow fever.

Treatment is therefore:

SUPPORTIVE

Patients with severe disease require careful management of organ dysfunction.

⸻

SUPPORTIVE CARE

Important measures include:

• Fluid resuscitation

• Electrolyte correction

• Oxygen support

• Hemodynamic monitoring

• Treatment of hypoglycemia

• Correction of metabolic acidosis

• Renal support

• Management of hemorrhage

• Mechanical ventilation when necessary

Severely ill patients should receive intensive-care management.

⸻

SHOCK

Treatment may require:

• Careful intravenous fluid resuscitation

• Vasopressors when hypotension persists

• Monitoring of urine output

• Correction of acid-base abnormalities

• Treatment of concurrent organ failure

Fluid therapy must be balanced carefully because capillary leak and organ dysfunction can predispose to pulmonary edema.

⸻

COAGULOPATHY

Significant bleeding or severe coagulation abnormalities may require:

• Fresh frozen plasma

• Other blood products when clinically indicated

• Vitamin K in selected patients

Management should be guided by active bleeding and coagulation studies.

⸻

RENAL FAILURE

Severe acute kidney injury may require:

Hemodialysis or another form of renal replacement therapy.

⸻

RESPIRATORY FAILURE

Patients who develop:

• Severe hypoxemia

• ARDS

• Respiratory failure

may require:

• Endotracheal intubation

• Mechanical ventilation

⸻

MEDICATION PRECAUTIONS

Avoid medications that increase bleeding risk.

In particular, avoid:

• Aspirin

• Other salicylates

• NSAIDs when significant hemorrhagic risk exists

Acetaminophen may also require caution in severe hepatic injury because of potential hepatotoxicity.

Medication selection should therefore be individualized in patients with hepatic dysfunction.

⸻

ADMISSION

Hospitalization is generally appropriate for patients with suspected clinically significant yellow fever, particularly outside endemic settings.

Urgent admission is required when there is:

• Jaundice

• Hemorrhage

• Hypotension

• Renal dysfunction

• Altered mental status

• Respiratory compromise

• Severe vomiting

• Evidence of multiorgan disease

Severe cases require ICU care.

⸻

PREVENTION

Prevention relies on two major strategies:

1. Vaccination

2. Mosquito-bite avoidance

⸻

YELLOW FEVER VACCINE

The yellow fever vaccine is a:

Live attenuated 17D vaccine

It is highly effective.

A single dose produces protective immunity in the great majority of recipients.

Protection generally develops within approximately:

10 days

Current international guidance recognizes that a single dose provides long-lasting protection for most people.

Routine booster vaccination every 10 years is no longer required for most individuals, although additional doses may be recommended in selected circumstances.

⸻

INTERNATIONAL CERTIFICATE OF VACCINATION

Some countries require proof of yellow fever vaccination for:

• Entry from endemic countries

• Travel through high-risk areas

• Prevention of importation into regions capable of sustaining transmission

The International Certificate of Vaccination or Prophylaxis generally becomes valid:

10 days after primary vaccination

Under current International Health Regulations, the certificate is generally considered valid for the lifetime of the vaccinated person.

Travelers should verify the current entry requirements of their destination before travel.

⸻

MOSQUITO-BITE PREVENTION

Travelers should use:

• EPA- or locally approved insect repellents

• Long sleeves

• Long trousers

• Permethrin-treated clothing or equipment when appropriate

• Window screens

• Air conditioning

• Mosquito nets where needed

Mosquito precautions remain important even after vaccination because mosquitoes transmit many diseases other than yellow fever.

⸻

VACCINE ADVERSE EFFECTS

Most vaccine reactions are mild.

Common reactions include:

• Headache

• Myalgia

• Low-grade fever

• Local injection-site discomfort

Serious reactions are extremely rare.

⸻

YELLOW FEVER VACCINE-ASSOCIATED NEUROLOGIC DISEASE

Rare neurologic complications include:

• Encephalitis

• Meningoencephalitis

• Guillain-Barré-like syndromes

• Other neurologic syndromes

Symptoms generally develop within days to several weeks following vaccination.

The risk is very low but is higher in certain age groups.

⸻

YELLOW FEVER VACCINE-ASSOCIATED VISCEROTROPIC DISEASE

This is an extremely rare but potentially fatal complication in which the vaccine strain produces an illness resembling severe wild-type yellow fever.

Features may include:

• High fever

• Hypotension

• Liver injury

• Thrombocytopenia

• Respiratory failure

• Multiorgan dysfunction

Risk is increased in certain patients, including:

• Older adults

• Individuals with significant thymus disorders

Because of its severity, vaccination should be based on careful risk-benefit assessment when risk factors are present.

⸻

VACCINE CONTRAINDICATIONS AND PRECAUTIONS

Because yellow fever vaccine is live attenuated, caution is required in patients with significant immune dysfunction.

Contraindications or major precautions may include:

• Severe immunosuppression

• Certain thymus disorders

• Severe allergy to vaccine components

• Infancy below the recommended vaccination age

• Pregnancy in situations where exposure risk is low

Decisions should be individualized according to:

Risk of yellow fever exposure vs risk of vaccination.

⸻

HIV

People living with HIV require individualized assessment.

Vaccination may be considered in selected patients who:

• Are clinically stable

• Do not have severe immunosuppression

• Have adequate CD4 counts

Severely immunocompromised patients generally should not receive a live yellow fever vaccine.

⸻

PREGNANCY

Pregnancy is generally considered a precaution rather than an absolute contraindication when yellow fever exposure is significant.

If travel to a high-risk area can be postponed, postponement may be preferred.

If travel cannot be avoided and the risk of yellow fever is substantial, vaccination may be considered after individualized risk-benefit assessment.

⸻

PROGNOSIS

Most infected individuals either remain asymptomatic or recover from the initial febrile illness.

Patients who progress to the intoxication phase have a substantially worse prognosis.

Mortality in severe yellow fever may reach approximately:

20–50%

Death usually results from:

• Shock

• Hepatic failure

• Renal failure

• Hemorrhage

• Multiorgan dysfunction

⸻

IMMUNITY AFTER INFECTION

Survivors generally develop:

Strong, long-lasting immunity

Recurrent yellow fever after natural infection is extremely unusual.

⸻

COMPLICATIONS

Important complications include:

• Fulminant hepatitis

• Severe jaundice

• Coagulopathy

• DIC

• Gastrointestinal hemorrhage

• Acute kidney injury

• Myocarditis

• Arrhythmias

• Shock

• ARDS

• Encephalopathy

• Seizures

• Multiorgan failure

Secondary bacterial infections may complicate prolonged severe illness.

⸻

HIGH-YIELD CLINICAL PATTERN

Traveler from tropical Africa or South America

+

Fever

+

Jaundice

+

Hemorrhage

+

Renal dysfunction

→ Think yellow fever

⸻

HIGH-YIELD DISEASE COURSE

Initial fever and myalgias

↓

Temporary improvement

↓

Return of fever + jaundice + hemorrhage + organ failure

→ Intoxication phase of yellow fever

⸻

HIGH-YIELD PHYSICAL SIGN

High fever + relative bradycardia

→ Faget sign

⸻

HIGH-YIELD PATHOLOGY

Midzonal hepatic necrosis

+

Councilman bodies

→ Characteristic of yellow fever

⸻

HIGH-YIELD DIAGNOSTIC APPROACH

Early illness:

→ RT-PCR

Later illness:

→ Yellow fever IgM serology

Remember:

Flavivirus serology can cross-react.

⸻

HIGH-YIELD PREVENTION

Most effective preventive measure:

→ Yellow fever vaccination

Additional essential measure:

→ Mosquito-bite prevention

⸻

EXAM ESSENTIALS

Causative agent:

→ Yellow fever virus

Virus family:

→ Flaviviridae

Genome:

→ RNA

Vector:

→ Mosquito

Major urban vector:

→ Aedes aegypti

Major endemic regions:

→ Sub-Saharan Africa and tropical South America

Incubation period:

→ Approximately 3–6 days

Classic severe manifestations:

→ Fever + jaundice + hemorrhage

Characteristic pulse finding:

→ Relative bradycardia / Faget sign

Characteristic liver pathology:

→ Midzonal necrosis

Characteristic apoptotic hepatocytes:

→ Councilman bodies

Diagnostic test during viremia:

→ RT-PCR

Important later diagnostic test:

→ IgM serology

Specific antiviral therapy:

→ None established

Main treatment:

→ Supportive care

Major prevention:

→ Live attenuated yellow fever vaccine

Vaccine type:

→ 17D live attenuated vaccine

Time for primary vaccine certificate to become valid:

→ 10 days

Routine 10-year booster for most people:

→ No longer required

Severe-stage mortality:

→ Approximately 20–50%

Major complications:

→ Hepatic failure, hemorrhage, renal failure, shock, ARDS, multiorgan failure