''Capnocytophaga canimorsus'' is a

fastidious A fastidious organism is any organism that has complex or particular nutritional requirements. In other words, a fastidious organism will only grow when specific nutrients are included in its medium. The more restrictive term fastidious microorga ...

, slow-growing, Gram-negative rod of the genus ''

Capnocytophaga ''Capnocytophaga'' is a genus of Gram-negative bacteria. Normally found in the oropharyngeal tract of mammals, they are involved in the pathogenesis of some animal bite wounds and periodontal diseases. Taxonomy The term ''Capnocytophaga'' come ...

''.Pers C, Gahrn-Hansen B, and Frederiksen W. 1996. ''Capnocytophaga canimorsus'' Septicemia in Denmark, 1982-1995: Review of 39 Cases. ''Clinical Infectious Diseases'' 23: 71-75.Brenner DJ, Hollis DG, Fanning GR, and Weaver RE. 1989. ''Capnocytophaga canimorsus'' sp. nov. (Formerly CDC Group DF-2), a Cause of Septicemia following Dog Bite, and ''C. cynodegmi'' sp. nov., a Cause of Localized Wound Infection following Dog Bite. ''Journal of Clinical Microbiology'' 27 (2): 231-235. It is a

commensal Commensalism is a long-term biological interaction (symbiosis) in which members of one species gain benefits while those of the other species neither benefit nor are harmed. This is in contrast with mutualism, in which both organisms benefit fro ...

bacterium in the normal gingival flora of canine and feline species, but can cause illness in humans. Transmission may occur through bites, licks, or even close proximity with animals.Fischer LJ, Weyant RS, White EH and Quinn FD. Intracellular Multiplication and Toxic Destruction of Cultured Macrophages by ''Capnocytophaga canimorsus''. ''Infection and Immunity'' 63 (9): 3484-3490. ''C. canimorsus'' generally has low virulence in healthy individuals,Lion C, Escande F and Burdin JC. 1996. ''Capnocytophaga canimorsus'' Infections in Human: Review of the Literature and Cases Report. ''European Journal of Epidemiology'' 12 (5): 521-533. but has been observed to cause severe, even grave, illness in persons with pre-existing conditions. The

pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...

of ''C. canimorsus'' is still largely unknown, but increased clinical diagnoses have fostered an interest in the bacillus. Treatment with antibiotics is effective in most cases, but the most important yet basic diagnostic tool available to clinicians remains the knowledge of recent exposure to canines or felines.

History

''Capnocytophaga canimorsus'' was first observed in 1976 by Bobo and Newton. The pair isolated a previously unknown

Gram-negative Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...

bacterium from a patient presenting with

meningitis Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, headache, and neck stiffness. Other symptoms include confusion or ...

in addition to

sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...

. The patient had been previously exposed to two canine bites on two consecutive days from two different dogs. Noting the coincidence between the timing of the bites with the onset of symptoms, Butler ''et al''. analyzed 17 similar cases of patients presenting with either sepsis or meningitis from 1961 to 1975. The cases had been sent to the CDC for examination due to the presence of an unknown Gram-negative bacillus isolated from infected individuals. Butler notified the CDC of the high incidence of dog bites in connection with the infections. The CDC could not identify the organism, so they applied the name CDC group DF-2. DF-2 stands for dysgonic fermenter, meaning that the bacterium is a slow-growing, fermentative bacillus. In 1989, while analyzing the properties of the unknown bacterium, Weaver et al. noted many similarities to bacteria of the genus ''Capnocytophaga''. Later that same year, Brenner et al. proposed the name ''Capnocytophaga canimorsus'' after examining the morphology, G+C% content, and motility of the species.

Etymology

The name ''Capnocytophaga'' is derived from the Greek word ''kapnos'', meaning "smoke", and given here because of its dependence on carbon dioxide for growth. It was added to distinguish this genus from the

Cytophaga ''Cytophaga'' is a genus of Gram-negative, gliding, rod-shaped bacteria. This bacterium is commonly found in soil, rapidly digests crystalline cellulose ''C. hutchinsonii'' is able to use its gliding motility to move quickly over surfaces. A ...

genus, originating from the Greek words of ''kytos'' (meaning "cell"), and ''phagein'' (meaning "eat"). The species name of ''canimorsus'' comes from the Latin words ''canis'' and ''morsus'', meaning "dog" and "bite" respectively.

Epidemiology

In the United States, 50% of Americans will be bitten by dogs during the course of their lifetimes; 1 million Americans are bitten by dogs annually.Janda JM, Graves MH, Lindquist D and Probert WS. 2006. Diagnosing ''Capnocytophaga canimorsus'' Infections. ''Emerging Infectious Diseases'' 12 (2): 340-342. Cases of human infection following exposure to ''C. canimorsus'' have been observed worldwide. Cases have been reported in the United States, Canada, Europe, Australia and S. Africa. Symptoms may appear within 2–3 days after exposure, or up to 4 weeks later. Middle-aged and elderly persons are at greater risk for contraction of disease; more than 60% of sufferers are 50 years of age or older. In addition, individuals who spend a greater portion of their time with canines and felines are also at higher risk. This includes veterinarians, breeders, pet owners, and keepers. Having certain pre-existing medical conditions exacerbates the risk. Chance of infection by any bacterial species after dog bites varies between 3 and 20%; for cats, it may be as high as 50%.Gaastra W and Lipman LJA. 2010. ''Capnocytophaga canimorsus''. ''Veterinary Microbiology'' 140: 339-346.

Morphology, culture, and isolation

''C. canimorsus'' is a fastidious, Gram-negative, fermentative, nonspore-forming rod. Bacilli are usually 1-3 μm in length. After growth on

agar Agar ( or ), or agar-agar, is a jelly-like substance consisting of polysaccharides obtained from the cell walls of some species of red algae, primarily from ogonori (''Gracilaria'') and "tengusa" (''Gelidiaceae''). As found in nature, agar is ...

plates, longer rods tend to have a curved shape. The bacteria do not have

flagella A flagellum (; ) is a hairlike appendage that protrudes from certain plant and animal sperm cells, and from a wide range of microorganisms to provide motility. Many protists with flagella are termed as flagellates. A microorganism may have f ...

, but move with a gliding motion, although this can be difficult to see. ''C. canimorsus'' requires the right medium for growth. The bacterium cultures well on blood agar plates (heart infusion agar with 5% sheep or rabbit blood) and chocolate agar plates.Shin H, Mally M, Meyer S, Fiechter C, Paroz C, Zaehringer U, Cornelis GR. 2009. Escape from Immune Surveillance by ''Capnocytophaga canimorsus''. ''Infection and Immunity'' 77: 2262-2271.de Boer MGJ, Lambregts PCLA, van Dam AP and van't Wout JW. 2007. Meningitis caused by ''Capnocytophaga canimorsus'': when to expect the unexpected. ''Clinical Neurology and Neurosurgery'' 109: 393-398. Colonies may not be visible for up to 48 hours due to slow growth. At 18 hours, colonies are usually less than 0.5 mm in diameter, and are spotty and convex. At 24 hours, colonies may be up to 1 mm in diameter. After 48 hours, colonies are narrow, flat, and smooth, with spreading edges. At this time, colonies may appear to be purple, pink, or yellow, but once they are scraped from the agar plate, they are always yellow in appearance.

Genome

The genome of ''C. canimorsus'' strain Cc5 consists of a single circular chromosome of 2,571,406 bp with a

G+C content G, or g, is the seventh letter in the Latin alphabet, used in the modern English alphabet, the alphabets of other western European languages and others worldwide. Its name in English is ''gee'' (pronounced ), plural ''gees''. History Th ...

of 36.11%, and it encodes 2,405

open reading frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readin ...

In animals

Members of the

genus Genus ( plural genera ) is a taxonomic rank used in the biological classification of extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruses. In the hierarchy of biological classification, genus com ...

''Capnocytophaga'' are found in the oral cavities of humans and animals. Most of these species are not found in humans. ''C. canimorsus'' is a

bacterium found in dogs and cats; it is not a member of the normal

microbiota Microbiota are the range of microorganisms that may be commensal, symbiotic, or pathogenic found in and on all multicellular organisms, including plants. Microbiota include bacteria, archaea, protists, fungi, and viruses, and have been found t ...

of humans. About 26% of dogs carry these commensal bacteria in their mouths. ''C. canimorsus'' rarely causes disease symptoms in animals. One case of ''C. canimorsus'' isolated from a dog bite wound on a small dog's head has been reported; the bacteria were localized to the wound and the dog did not present with

bacteremia Bloodstream infections (BSIs), which include bacteremias when the infections are bacterial and fungemias when the infections are fungal, are infections present in the blood. Blood is normally a sterile environment, so the detection of microb ...

. A few cases of infection have been reported in rabbits after being bitten by dogs. Clinical manifestations of ''C. canimorsus'' in rabbits causes a range of symptoms, including

disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems moving parts o ...

, cellular

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...

(tissue death), low blood pressure,

gangrene Gangrene is a type of tissue death caused by a lack of blood supply. Symptoms may include a change in skin color to red or black, numbness, swelling, pain, skin breakdown, and coolness. The feet and hands are most commonly affected. If the ga ...

, and

kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

High-risk categories

In addition to those at higher risk of developing complications from ''C. canimorsus'' due to greater contact with felines and canines, certain pre-existing conditions place individuals in a critically high-risk category. Among these are those who have undergone a splenectomy, alcoholics, and individuals with immunosuppression due to the use of steroids such as glucocorticoids. Individuals with

β-thalassemia Beta thalassemias (β thalassemias) are a group of genetic disorder, inherited hemoglobinopathy, blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the HBB, beta chains of hemoglobin that result in variable out ...

and smokers are also listed as high-risk. These individuals, like asplenics and alcoholics, have increased levels of alimentary iron in their bloodstream. ''C. canimorsus'' requires large amounts of iron to grow, so these conditions are optimal for the bacillus.

Asplenia

Of the cases presented in literature, 33% occurred in

asplenic Asplenia refers to the absence of normal spleen function and is associated with some serious infection risks. Hyposplenism is used to describe reduced ('hypo-') splenic functioning, but not as severely affected as with asplenism. ''Functional'' a ...

individuals, who have decreased

IgM Immunoglobulin M (IgM) is one of several isotypes of antibody (also known as immunoglobulin) that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antig ...

and

IgG Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG ...

production. They also have delayed macrophage assembly and produce less

tuftsin Tuftsin is a tetrapeptide (Thr-Lys-Pro-Arg, TKPR) located in the Fc-domain of the heavy chain of immunoglobulin G (residues 289-292). It has an immunostimulatory effect. It is named for Tufts University where it was first discovered in 1983.Najj ...

. Tuftsin is responsible for the stimulation of

phagocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...

, so its decrease in the presence of bacterial infection poses a problem. A functional spleen is important for the removal of pathogens. Because this particular pathogen seems to flourish in asplenic patients, both IgM antibodies and tuftsin may be critical in the process of marking this bacterium for destruction by phagocytosis. Asplenics often have double the amount of healthy iron in their bloodstreams, and are 60 times more at risk of developing fatal clinical manifestations of the bacterium. Individuals with asplenia often experience symptom onset within a day of exposure. The infection rapidly progresses toward multiple organ system failures and finally death. The mortality rate in individuals with asplenia is much higher than any other at risk-category for ''C. canimorsus'' infections.

Alcoholism

People who struggle with alcohol addiction represent around 24% of individuals presenting with ''C. canimorsus'' infections.

Alcoholism Alcoholism is, broadly, any drinking of alcohol (drug), alcohol that results in significant Mental health, mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognize ...

has been shown to result in decreased superoxide production in

neutrophils Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...

, as well as declines in

neutrophil elastase Neutrophil elastase (, ''leukocyte elastase'', ''ELANE'', ''ELA2'', ''elastase 2'', ''neutrophil'', ''elaszym'', ''serine elastase'', subtype ''human leukocyte elastase (HLE)'') is a serine proteinase in the same family as chymotrypsin and has bro ...

activity. This results in an increase in predisposition to

(bacteria in the blood). As a result, people suffering from alcoholism are more likely to suffer from the more dangerous aspects of ''C. canimorsus'' invasions. Finally, alcoholics are associated with increased blood iron content.

Immunosuppression

Immunosuppresant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified int ...

s are often used to treat

autoimmune diseases An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...

, such as lupus. When individuals undergo treatment with immunosuppresants such as glucocorticoids, their bodies' defenses are lowered. As a result, exposure to ''C. canimorsus'' is more infectious in these individuals than in healthy individuals. Immunosuppressed patients make up about 5% of individuals presenting with ''C. canimorsus'' symptoms.

Symptom onset and clinical manifestations

Symptoms appear within 1–8 days after exposure to ''C. canimorsus'' but usually present around day 2. Symptoms range from mild, flu-like symptoms to full-blown

fulminant Fulminant () is a medical descriptor for any event or process that occurs suddenly and escalates quickly, and is intense and severe to the point of lethality, i.e., it has an explosive character. The word comes from Latin ''fulmināre'', to strik ...

sepsis. Individuals often complain of any combination of: fever, vomiting, diarrhea,

malaise As a medical term, malaise is a feeling of general discomfort, uneasiness or lack of wellbeing and often the first sign of an infection or other disease. The word has existed in French since at least the 12th century. The term is often used ...

, abdominal pain,

myalgia Myalgia (also called muscle pain and muscle ache in layman's terms) is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likel ...

, confusion,

dyspnea Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathing, breathe well enough. The American Thoracic Society defines it as "a subjective experience of brea ...

, headaches, and skin rashes such as

exanthema An exanthem is a widespread rash occurring on the outside of the body and usually occurring in children. An exanthem can be caused by toxins, drugs, or microorganisms, or can result from autoimmune disease. The term exanthem is from the Greek ...

. More severe cases of

endocarditis Endocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves. Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or the ...

, disseminated intravascular coagulation, and

have been reported. Prior treatment with methylprednisolone has been shown to prolong bacteremia in these infections, which enables the progression of endocarditis.

Differential diagnosis

Diagnosing infections with ''C. canimorsus'' can be difficult. Common practice for culturing isolates is to keep agar plates for one week; sometimes, cultures of ''C. canimorsus'' are not visible at that point due to slow growth or inappropriate media. ''C. canimorsus'' requires very specific culture media and conditions; enriched media are necessary. ''C. canimorsus'' displays enhanced growth in high concentrations of carbon dioxide, so culturing the bacteria in candle extinction jars or carbon dioxide incubators is necessary. To diagnose this bacillus, certain reactions may be tested. The bacterium should test positive for catalase and oxidase, arginine dihydrolase, maltose, and lactose. It should test negative for nitrate reduction, urease, and H₂S production. ''C. canimorsus'' can be distinguished from other Gram-negative bacteria by testing negative for inulin and sucrose. Due to the relatively slow growth of this bacterium, diagnosis often relies upon the clinician having knowledge that the patient was previously in contact with a canine or feline. Once aware of this, clinicians can request that agar plates be kept longer than one week to ensure proper isolation of the bacterium. Sometimes, even these methods fail. Cases have been noted where cultures repeatedly came up negative for ''C. canimorsus'', only to determine its presence with 16S rRNA gene sequencing. PCR assays of species-specific genes may also be beneficial. For individuals presenting with meningitis, ''C. canimorsus'' can be diagnosed with a cerebrospinal fluid

Gram stain In microbiology and bacteriology, Gram stain (Gram staining or Gram's method), is a method of staining used to classify bacterial species into two large groups: gram-positive bacteria and gram-negative bacteria. The name comes from the Danish ...

. These methods are more costly, but are the best way to ensure species-level identification. Isolates are usually obtained from blood cultures (88% of the time) and less frequently from bite wounds. In incidents where the patient is in full septic shock, whole blood smears may be effective.

Treatment

Immediate cleansing of wounds caused by canines and felines can be successful in keeping ''C. canimorsus'' infections at bay. Irrigation of wounds with saline is recommended and individuals are encouraged to seek medical help for the administration of antibiotics. Antibiotics are recommended if wounds are deep or individuals postpone seeking medical attention. Antibiotics that contain beta-lactamase inhibitors (''i.e.'', oral

Augmentin Amoxicillin/clavulanic acid, also known as co-amoxiclav or amox-clav, sold under the brand name Augmentin, among others, is an antibiotic medication used for the treatment of a number of bacterial infections. It is a combination consisting of ...

or parenteral

Unasyn Unasyn is the trade name for two related antibiotic drugs: * Ampicillin/sulbactam, a fixed-dose combination medication of the penicillin antibiotic combination ampicillin/sulbactam * Sultamicillin Sultamicillin, sold under the brand name Unasyn am ...

) cover ''C. canimorsus'', as well as other organisms common in bites. Penicillin G is the drug of choice, although some isolates have been found to show resistance. ''C. canimorsus'' is susceptible to ampicillin, third-generation

cephalosporins The cephalosporins (sg. ) are a class of β-lactam antibiotics originally derived from the fungus ''Acremonium'', which was previously known as ''Cephalosporium''. Together with cephamycins, they constitute a subgroup of β-lactam antibiotics ...

tetracyclines Tetracyclines are a group of broad-spectrum antibiotic compounds that have a common basic structure and are either isolated directly from several species of ''Streptomyces'' bacteria or produced semi-synthetically from those isolated compounds. T ...

, clindamycin, and chloramphenicol. It has shown resistance to gentamicin. Treatment is recommended for a minimum of three weeks. Hospitalization is required in more severe infections. For cases of sepsis, high doses of penicillin are required. Third-generation cephalosporins are often given prior to diagnosis because they cover a broad range of Gram-negative bacteria. After diagnosis, provided the strain is not beta-lactamase-producing, medication should be switched to penicillin G. Presumably, penicillin G could be given with a beta-lactamase inhibitor combination, such as Unasyn, for patients with a beta-lactamase-producing strain. Mortality of meningitis-related infections is much lower than mortality associated with sepsis. Because ''C. canimorsus'' induces fulminant sepsis, earlier diagnosis is associated with greater survival.

Evasion of immune system

''C. canimorsus'' has been observed to multiply in the presence of mouse J774.1 macrophages.

Macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

s recognize and kill pathogens by engulfing them. They also secrete cytokines necessary to begin the immune pathway cascade. ''C. canimorsus'' bacteria are not internalized by macrophages; in fact, macrophage monolayers break down in their presence, suggestive of a

cytotoxin Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating c ...

.Shin H, Mally M, Kuhn M, Paroz C and Cornelis GR. 2007. Escape from Immune Surveillance by ''Capnocytophaga canimorsus''. ''The Journal of Infectious Diseases'' 195: 375-386. In the presence of ''C. canimorsus'', cytokine activity is greatly downregulated, because the macrophages fail to produce TNF-α, IL-8, IL-6 and IL-1α, interferon-γ, and nitric oxide. In addition, toll-like receptor 4 (

TLR4 Toll-like receptor 4 is a protein that in humans is encoded by the ''TLR4'' gene. TLR4 is a transmembrane protein, member of the toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. Its activation leads to an ...

) normally recognizes pathogens and begins a signalling cascade to induce production of pro inflammatory

cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

via the NF-κB pathway. In cells infected with ''C. canimorsus'', TLR4 did not activate the signalling pathway, so did not elicit an inflammatory response by the immune system. Because this species does not elicit a strong inflammatory response, the bacteria have ample time for replication before detection by the host immune system.

Electron micrograph A micrograph or photomicrograph is a photograph or digital image taken through a microscope or similar device to show a magnified image of an object. This is opposed to a macrograph or photomacrograph, an image which is also taken on a mi ...

s of J774.1 monolayers infected with ''C. canimorsus'' have shown cells of the bacteria within the macrophage's

vacuole A vacuole () is a membrane-bound organelle which is present in plant and fungal cells and some protist, animal, and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic mo ...

s, surrounded by bacterial septa. This suggests that ''C. canimorsus'' replicates intracellularly in macrophages. ''C. canimorsus'' cells also show resistance to killing by complement and killing by

polymorphonuclear leukocyte Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They hav ...

s (PNMs). ''C. canimorsus'', when in the presence of PMNs, feeds on them by deglycosylating host glycans. In fact, in the presence of PMNs, ''C. canimorsus'' experiences robust growth. ''C. canimorsus'' has the ability to evade these necessary immune functions, and, therefore, must be taken seriously. Greater knowledge about the pathogenesis of this bacterium is required to prevent and treat the diseases associated with it.

References

External links

* * * {{Taxonbar, from=Q310984 Flavobacteria Bacterial diseases Zoonoses Bacteria described in 1989 Cat diseases