INTRODUCTION — Capnocytophaga canimorsus is a bacterial cause of fulminant sepsis among individuals who have been bitten by a dog; patients at greatest risk include immunocompromised individuals, particularly those with asplenia, functional asplenia, cirrhosis, or history of heavy alcohol use [1]. C. canimorsus and other Capnocytophaga species also cause a variety of other infections, including in immunocompetent hosts.
Issues related to Capnocytophaga infection will be reviewed here. Issues related to initial management of animal and human bites and to soft tissue infections due to dog and cat bites are discussed separately. (See "Animal bites (dogs, cats, and other animals): Evaluation and management".)
EPIDEMIOLOGY — Capnocytophaga species cause rare but severe infection in humans. The incidence of infection due to C. canimorsus in the general population is low. National surveillance for Capnocytophaga species is not performed in the United States; a national survey in the Netherlands noted 0.67 cases per million per year [2]. The prevalence among immunocompromised hosts is likely substantially higher than that of the general population. A case fatality rate of up to 31 percent has been reported [3-6]; mortality is high even among patients who are immunocompetent.
C. canimorsus is the most common cause of severe Capnocytophaga infection in humans and the cause of most dog bite-associated Capnocytophaga infections [6]. Risk factors for C. canimorsus infection include a history of a dog bite and immunocompromise, particularly asplenia, functional asplenia, cirrhosis, or history of heavy alcohol use. Most (72 to 74 percent) of these infections occur in men, with a peak among individuals 50 to 70 years old [2,3,7]. Approximately half (43 to 56 percent) of patients report a history of a dog bite; others report scratches from dogs or occasionally cats or exposure to dogs without bites or scratches [2-5,8].
Bacteremia due to Capnocytophaga species other than C. canimorsus is most commonly associated with polymicrobial soft tissue infections of the head and neck [6]. The major risk factor in this group is immunosuppression [6].
MICROBIOLOGY — Capnocytophaga is a genus in the family Flavobacteriaceae. Capnocytophaga species are slow growing, capnophilic ("carbon loving"), facultative anaerobes. They are long, thin, and generally fusiform gram-negative rods (picture 1), which may become pleomorphic with prolonged growth.
The Capnocytophaga genus consists of nine species: C. ochracea, C. gingivalis, C. sputigena, C. leadbetteri, C. haemolytica, C. granulosa, C. canimorsus, C. cynodegmi, C. canis, the putative novel species C. stomatis [9], and one unnamed taxon, AHN8471. These species are subdivided into two groups based on whether they inhabit the oral cavity of humans or inhabit the oral cavity of dogs and occasionally cats. C. canimorsus, C. cynodegmi, and C. stomatis are found in the oral cavity of dogs and cats, whereas all the other species are found in the human oral cavity.
The microbiome of the human oral cavity is remarkably heterogeneous, with over 400 species identified by 16S sequencing [10,11]. C. ochracea, C. gingivalis, and C. sputigena are normal flora of the subgingival sulcus of humans, whereas C. leadbetteri, C. haemolytica, and C. granulosa have been isolated from dental plaque in healthy humans [12,13].
C. canimorsus, C. cynodegmi, C. canis, and perhaps C. stomatis are normal flora of the dog oral cavity. C. canimorsus is responsible for the vast majority of Capnocytophaga infections resulting from dog bites, whereas C. cynodegmi rarely causes infection in humans. C. canimorsus is present in the oral cavity of 67 to 86 percent of dogs and 55 to 84 percent of cats [14-17]. Among C. canimorsus serovars, three (serovars A, B, and C) are responsible for >90 percent of human infections associated with dog bites, even though these three constitute only 8 percent of serovars carried by dogs [18,19], suggesting that serovar-specific virulence characteristics play a role in human infection and that the relatively low incidence of human C. canimorsus infection following dog bites is attributable in part to the low carriage rate of virulent serovars by dogs.
Susceptibility testing — Careful antibiotic susceptibility testing is warranted. To date, beta-lactamase production is rare in C. canimorsus, it has been described almost exclusively in other Capnocytophaga species [6,20]. Among non-C. canimorsus isolates characterized in case series, 24 to 44 percent produce beta-lactamase, including class D beta-lactamase, conferring resistance to penicillin, cephalosporins, and imipenem [6,20]. All beta-lactamase/carbapenemase-resistant isolates were susceptible to clindamycin. (See 'Treatment' below.)
In another study, the presence of beta-lactamase genes among isolates of Capnocytophaga species that originate in the human oral cavity was highest among patients with periodontitis (82 percent of isolates), intermediate among patients with hematologic diseases (50 percent of isolates), and lowest among healthy volunteers (16 percent of isolates) [21]. Three Capnocytophaga isolates of human-derived species that produce extended-spectrum beta-lactamases have been identified in France [22-24]; these isolates were susceptible to imipenem, and two of the three were susceptible to amoxicillin-clavulanate.
PATHOGENESIS — The pathogenesis of Capnocytophaga species, particularly their ability to cause fulminant sepsis in asplenic and functionally asplenic patients, is not well understood. Pathogenesis investigations have largely focused on C. canimorsus. Virulence factors that have been characterized are described here.
C. canimorsus forages sugars from glycoproteins in human cells, including phagocytes [25,26]. The genome contains 13 loci that encode polysaccharide utilization loci [26], which enable the utilization of host starch as an energy source for the bacterium. These polysaccharide utilization proteins cover the bacterial surface, constituting more than half of the bacterial surface proteome [26]. Similar polysaccharide utilization loci are present in members of the Flavibacteria and Bacteroides. One of the polysaccharide utilization systems in C. canimorsus utilizes N-acetylglucosamine harvested from host glycoproteins to synthesize the bacterial peptidoglycan [27]; included among these host glycoproteins is human immunoglobulin (Ig)G [28]. Of note, in cirrhosis and other liver disease, glycosylation of many serum glycoproteins is altered, with measurable increases in N-acetyl glucosamine-containing glycoproteins [28], leading to speculation that bacterial degradation of IgG per se and/or the increase in the serum of glycoprotein molecules metabolized by these organisms may contribute to pathogenesis [29].
C. canimorsus inhibits the ability of macrophages to kill bacteria and inhibits phagocytosis by polymorphonuclear leukocytes. C. canimorsus and other Capnocytophaga species possess a polysaccharide capsule on the surface that impedes complement-mediated killing and phagocytosis by macrophages and a surface lipooligosaccharide that inhibits Toll-like receptor 4 signaling [17,19,30-32].
CLINICAL MANIFESTATIONS
Septic shock — The most severe presentation of Capnocytophaga infection is acute onset of severe sepsis accompanied by fever, disseminated purpuric lesions, hypotension, acute renal insufficiency, and altered mental status [3,5,33]. The rash may evolve to purpura fulminans or frank gangrene. The systemic inflammatory response leads to microvascular injury and endothelial damage that may cause disseminated intravascular coagulation and multiorgan failure. C. canimorsus is the species of Capnocytophaga most commonly associated with septic shock, but other species of Capnocytophaga may cause a similar syndrome.
Patients at greatest risk for septic shock include immunocompromised individuals, particularly those with asplenia, functional asplenia, cirrhosis, or history of heavy alcohol use. In large case series, up to two-thirds of the patients with C. canimorsus septicemia were immunocompromised: 10 to 33 percent were asplenic, 7 to 22 percent had a history of alcohol abuse, and 5 percent were receiving treatment with corticosteroids [3-5]. Additional immunocompromised states that have been reported include oral mucositis and/or oral ulceration in the setting of granulocytopenia, acute myelogenous leukemia, acute lymphocytic leukemia, solid tumors, systemic lupus erythematosus, multiple myeloma, and acute myelofibrosis [34-36]. In addition, there are case reports of sepsis due to Capnocytophaga species in patients with chronic lymphocytic leukemia and following bone marrow transplantation [37,38].
In approximately half of cases, there is a history of dog bite or other contact with dog saliva [3-5] and occasionally a history of cat scratch or contact with cat saliva. The delay between dog bite and clinical presentation ranges from 1 to 30 days, with an average of 5 to 6 days [5].
Other presentations — Capnocytophaga species can cause a variety of other clinical presentations. In one case series, diagnoses included sepsis or septic shock (41 percent of patients), fever of unknown origin (13 percent), meningitis (13 percent), cellulitis (11 percent), and respiratory tract infection (7 percent) [7]. C. canimorsus can cause pneumonia (which may be complicated by empyema), soft tissue infection, meningitis, endocarditis, septic arthritis, purpura fulminans, cholecystitis, and peritonitis associated with peritoneal dialysis [3,39-44]. In older adults, it is a rare cause of meningitis (<1 percent) [45].
There are case reports of Capnocytophaga species from the human oral cavity (C. ochracea, C. gingivalis, C. sputigena, C. leadbetteri, C. haemolytica, and C. granulosa) associated with wound infections, pneumonia, soft tissue abscesses, ocular infections, bacteremia, septic arthritis, osteomyelitis, endocarditis, peritonitis associated with peritoneal dialysis, lymphadenitis, abdominal abscess, lung abscess, empyema, aortitis, and thrombotic thrombocytopenia purpura [46-52]. Most of these infections occur in immunocompromised hosts, but any can also occur in otherwise healthy individuals.
In addition, Capnocytophaga species in the human oral cavity colonize the subgingival sulcus and supragingival plaque and can cause localized juvenile periodontitis and other types of periodontal disease; C. ochracea and C. granulosa are the most prevalent species isolated [53,54]. These species are also occasionally isolated from the vagina and can cause intrauterine device infection, preterm labor, chorioamnionitis, and neonatal sepsis [55].
In the setting of meningitis, the cerebrospinal fluid may demonstrate a lower pleocytosis (200 to 2000 white blood cells/mL) and/or a higher percentage of lymphocytes (15 to 30 percent) than meningitis caused by other bacteria, more typical of that seen in Listeria monocytogenes meningitis [3,56-58].
Sensorineural hearing loss has been described as a permanent complication of several cases of C. canimorsus meningitis [57,58]; it is unclear whether it occurs more commonly with this infection than other bacterial causes of meningitis.
DIAGNOSIS — The diagnosis of Capnocytophaga infection is established via culture. The organisms grow slowly and identification of the organism may take several days. Therefore, the microbiology laboratory should be alerted when Capnocytophaga infection is suspected; in such cases, specimens should be held for extended incubation.
C. canimorsus is more fastidious than other species and requires enriched agar; blood cultures turn positive after 1 to 14 days (mean 6 days) of incubation [5]. Capnocytophaga organisms grow on blood or chocolate agar with optimal growth at 35 to 37°C in the presence of 5 to 10 percent CO2. Colonies on plates typically take two to four days to reach sufficient size for analysis. The colonies of zoonotic species C. canimorsus and C. cynodegmi are unpigmented, whereas colonies of human species of Capnocytophaga may be pigmented.
Microscopic examination of a buffy coat or peripheral smear for fusiform gram-negative organisms within the cytoplasm of polymorphonuclear leukocytes (picture 2) can expedite the diagnosis of Capnocytophaga infection in some cases, particularly among asplenic patients [5,59-61].
Commercial biochemical identification panels may be unreliable for identification of the Capnocytophaga species. Molecular probes, matrix-assisted laser desorption-ionization mass spectrometry, or sequencing of 16S ribosomal RNA are more reliable [33,62-65]. In several case reports, in cases of meningitis, polymerase chain reaction (PCR) of cerebrospinal fluid was used to make a rapid diagnosis of C. canimorsus [66]; however, commercially available PCR diagnostics may not contain primers specific for Capnocytophaga species, so broad-range PCR technology may be required, and the sensitivity and specificity of PCR in this setting is not well defined.
There are no standardized methods for in vitro susceptibility testing, which is difficult to perform given the slow rate of growth and the requirement for enriched media.
TREATMENT — Patients with severe Capnocytophaga infection should be treated initially with a beta-lactam-beta-lactamase combination (such as piperacillin-tazobactam) or a carbapenem (such as imipenem), pending susceptibility testing. If antibiotic susceptibilities are performed, the regimen can be adjusted accordingly at the time these data become available. Patients with nonsevere infection may be treated with oral therapy (such as amoxicillin-clavulanate or clindamycin).
Production of beta-lactamase by Capnocytophaga strains has been observed [67]; the prevalence of beta-lactam resistance among C. canimorsus isolates is uncertain but likely rare. Susceptibility testing should be performed whenever possible; in addition, for wound infections that do not respond clinically to standard antibiotic therapy (particularly those due to C. cynodegmi or C. stomatis) phenotypic resistance testing is warranted. If an isolate is found to be resistant to penicillins, cephalosporins, and carbapenems, clindamycin may be the antibiotic of choice; susceptibility testing should be performed. (See 'Susceptibility testing' above.)
Capnocytophaga species are resistant to aztreonam by broth or agar dilution methods; susceptibility to aminoglycosides and trimethoprim-sulfamethoxazole is equivocal [67-69]. Resistance to fluoroquinolones has been reported in more than half of the cases in one series, as well as in a case report [35,44].
The duration of therapy should be based on the clinical presentation and the clinical response to treatment. There are no clinical trials examining duration of therapy.
PREVENTION — Antibiotic prophylaxis with amoxicillin-clavulanate for five days following a dog bite is appropriate for patients at highest risk (including patients with asplenia, patients with alcohol use disorder, patients receiving corticosteroids, or patients who are otherwise immunocompromised).
SUMMARY
●Capnocytophaga canimorsus is a bacterial cause of fulminant sepsis among individuals who have been bitten by a dog; patients at greatest risk include immunocompromised individuals, particularly those with asplenia, functional asplenia, cirrhosis, or history of heavy alcohol use. (See 'Introduction' above.)
●Clinical manifestations of severe infection include sepsis accompanied by fever, disseminated purpuric lesions, hypotension, acute renal insufficiency, and altered mental status. The rash may evolve to purpura fulminans or frank gangrene. The systemic inflammatory response leads to microvascular injury and endothelial damage that may cause disseminated intravascular coagulation and multiorgan failure. (See 'Clinical manifestations' above.)
●Other presentations of Capnocytophaga infection include bacteremia, soft tissue infection, peritonitis, meningitis, respiratory tract infection, preterm labor, chorioamnionitis, and neonatal sepsis. (See 'Other presentations' above.)
●The diagnosis is established via culture; growth of the organism is slow. Blood cultures require a mean incubation period of six days, and colonies on plates typically take two to four days to reach sufficient size for analysis. For meningitis, cerebrospinal fluid polymerase chain reaction may be a more rapid diagnostic modality. (See 'Diagnosis' above.)
●Microscopic examination of a buffy coat or peripheral smear for fusiform gram-negative organisms within the cytoplasm of polymorphonuclear leukocytes (picture 2) can expedite the diagnosis of Capnocytophaga infection in some cases, particularly among asplenic patients. (See 'Diagnosis' above.)
●Patients with severe Capnocytophaga infection should be treated with a beta-lactam-beta-lactamase combination (such as piperacillin-tazobactam) or a carbapenem (such as imipenem). Patients with nonsevere infection may be treated with oral therapy (such as amoxicillin-clavulanate or clindamycin). (See 'Treatment' above.)
●Antibiotic prophylaxis with amoxicillin-clavulanate for five days following a dog bite is appropriate for patients at highest risk (including patients with asplenia, patients with alcohol use disorder, patients receiving corticosteroids, or patients who are otherwise immunocompromised). (See 'Prevention' above.)
