Capnocytophaga

INTRODUCTION — Capnocytophaga species cause infections among individuals who are exposed to dogs, or rarely cats, especially after a bite. C. canimorsus and other Capnocytophaga species cause a variety of infections, including fulminant sepsis.

Patients at greatest risk for severe infection include immunocompromised individuals, particularly those with asplenia, functional asplenia, liver disease (eg, cirrhosis), or alcohol use disorder [1,2]. However, immunocompetent individuals can also develop severe infection.

Issues related to Capnocytophaga infection will be reviewed here. Issues related to initial management of animal bites and to soft tissue infections due to dog and cat bites are discussed separately. (See "Animal bites (dogs, cats, and other mammals): Evaluation and management".)

EPIDEMIOLOGY — Capnocytophaga species cause rare but often severe infection in humans.

The incidence of infection due to Capnocytophaga species in the general population is low. A national survey in the Netherlands noted 0.67 cases per million per year; national surveillance is not performed in the United States [3]. The incidence among immunocompromised hosts and pregnant individuals is likely substantially higher than that of the general population. (See 'Risk factors' below.)

RISK FACTORS

Dog bites — Dog bites are the most common source of Capnocytophaga infection.

Approximately half (43 to 56 percent) of patients report a history of a dog bite; others report scratches from or exposure to dogs without bites [3-11]. Occasionally, cat bites or other exposures to cats may cause infection.

C. canimorsus is the cause of most dog bite-associated Capnocytophaga infections and the most common cause of severe Capnocytophaga infection in humans [1]. (See 'Species' below.)

Detailed discussion of animal bites is found separately. (See "Animal bites (dogs, cats, and other mammals): Evaluation and management", section on 'Spectrum of antibiotic coverage'.)

Asplenia, cirrhosis, or alcohol use — Severe infections from dog bites usually occur in patients with immunocompromise, particularly asplenia, functional asplenia, liver disease (eg, cirrhosis), or heavy alcohol use [4-7,9,10,12-14].

Most of these infections occur in men, with a peak among individuals 50 to 70 years old [3,5,15].

Neutropenia — Patients with severe immunosuppression, especially neutropenia, appear to be at increased risk [1,16-21]. Underlying illnesses in this population include history of hematopoietic stem cell transplant, solid organ transplant, or immunosuppressive medications (eg, chemotherapy, corticosteroids). Mucositis is commonly present and is thought to be the point of entry in many cases.

Head, neck, or oral infection — Bacteremia due to Capnocytophaga species other than C. canimorsus is commonly associated with polymicrobial soft tissue infections of the head and neck, such as neck or facial abscess, osteomyelitis of the mandible, dental root infection, or periodontitis [1,16,22]. The major risk factor in this group is immunosuppression [1].

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.

Species — 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 [23], 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, C. canis, 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.

●Oral flora in humans – The microbiome of the human oral cavity is remarkably heterogeneous, with over 400 species identified by 16S sequencing [24,25]. 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 [26,27].

●Oral flora in dogs and cats – 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.

C. canimorsus is present in the oral cavity of 67 to 86 percent of dogs and 55 to 84 percent of cats [28-32]. 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 [33,34], 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.

Identification in culture — Capnocytophaga spp are more fastidious than many other bacteria and require enriched agar. 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.

Antibiotic susceptibility — All Capnocytophaga isolates should undergo susceptibility testing (see 'Susceptibility testing' below). However, susceptibility testing is complicated by lack of guidelines for defining susceptibility from organizations such as the Clinical and Laboratory Standards Institute (CLSI) or the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

●Beta-lactams – Beta-lactam susceptibility of Capnocytophaga species is variable, often depending on the species. Some strains produce beta-lactamases that confer resistance to some or all of the penicillins and cephalosporins. Beta-lactamase inhibitors (eg, clavulanate, sulbactam, tazobactam) typically retain the ability to overcome this resistance.

To date, beta-lactamase production is rare in C. canimorsus, the most common cause of severe infection from dog bites. Isolates that do not produce beta-lactamase typically remain susceptible to penicillins and cephalosporins [32].

Beta-lactamase production has been described almost exclusively in Capnocytophaga species other than C. canimorsus [1,35-37]. Among non-C. canimorsus isolates characterized in case series, 24 to 44 percent produce beta-lactamase [1,37]. In one study, the presence of beta-lactamase genes among isolates of Capnocytophaga species of 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) [37].

Three Capnocytophaga isolates of human-derived species that produce extended-spectrum beta-lactamases have been identified in France [38-40]; these isolates were susceptible to imipenem. Rare isolates that produce class D beta-lactamase have been reported; such isolates are resistant to beta-lactams with or without beta-lactamase inhibitors, and carbapenems, but all have retained susceptibility to clindamycin [1,37].

●Other antibiotics – In addition to beta-lactam/beta-lactamase inhibitor combination antibiotics (eg, amoxicillin-clavulanate, ampicillin-sulbactam), clindamycin and carbapenems almost always retain activity against Capnocytophaga species [16,32,35]. Susceptibility to fluoroquinolones, aminoglycosides, macrolides, and trimethoprim-sulfamethoxazole is variable [14,18,41-43]. The organisms are resistant to aztreonam.

PATHOGENESIS — The pathogenesis of Capnocytophaga species, particularly their ability to cause fulminant sepsis in asplenic and functionally asplenic patients, is not adequately understood.

●C. canimorsus – Pathogenesis investigations have largely focused on C. canimorsus, the predominant species from dog exposures. Virulence factors that have been characterized are described here.

C. canimorsus forages sugars from glycoproteins in human cells, including phagocytes [44,45]. The genome contains 13 polysaccharide utilization loci [45], 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 [45]. 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 [46]; included among these host glycoproteins is human immunoglobulin (Ig)G [47]. Of note, in cirrhosis and other liver diseases, glycosylation of many serum glycoproteins is altered, with measurable increases in N-acetyl glucosamine-containing glycoproteins [47], 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 [48].

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 [31,34,49-51].

●Human oral flora isolates – Capnocytophaga isolates from human oral flora are normal commensals of low virulence. However, in patients with significant immunocompromise, they can become opportunistic pathogens if oral mucosal barriers are interrupted (eg, from mucositis, ulceration, disease) [32]. Since C. canimorsus, the most virulent Capnocytophaga species, is normally absent in human oral flora, infections caused by human oral flora are typically less severe than those that result from a dog bite.

CLINICAL MANIFESTATIONS

Septic shock — The most severe presentation of Capnocytophaga infection is acute onset of bacteremia, severe sepsis or septic shock accompanied by fever, disseminated purpuric lesions, hypotension, acute renal insufficiency, and altered mental status [4,5,7,12,52-56]. The rash may evolve to purpura fulminans or frank gangrene (picture 2 and picture 3 and picture 4). Disseminated intravascular coagulation and multiorgan failure may occur.

Patients at greatest risk for septic shock include immunocompromised individuals, particularly those with asplenia, functional asplenia, cirrhosis, or heavy alcohol use. (See 'Risk factors' above.)

In approximately half of cases of sepsis, there is a history of dog bite or other contact with a dog or 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 five to six days [7]. (See 'Dog bites' above.)

Other presentations — Capnocytophaga species can cause a variety of other clinical presentations besides sepsis.

Numerous types of infection have been reported:

●Head and neck infection – Facial cellulitis, neck or facial abscess, osteomyelitis of the mandible, dental root infection, periodontitis, and ocular infection have been reported [1,4,57-59]. These infections are usually caused by Capnocytophaga species that arise from the human oral cavity, as described above. (See 'Head, neck, or oral infection' above and 'Microbiology' above and 'Pathogenesis' above.)

●Endocarditis – Capnocytophaga endocarditis is reported most commonly in patients with exposure to dogs. In a systematic review of 18 patients with endocarditis, 12 (67 percent) reported a dog bite or close contact with a dog [22,60]. Surgery for valve replacement was required in half of patients. In some cases, the diagnosis was made following valve replacement when histopathology stains of the resected valve revealed the organism.

●Meningitis – There are several case reports of meningitis due to Capnocytophaga [15,55,61-64]. 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 [5,9,10,65].

Sensorineural hearing loss has been described as a permanent complication of C. canimorsus meningitis [10,55,65]; it is unclear whether it occurs more commonly with this infection than other bacterial causes of meningitis.

●Other presentations – Many other syndromes have been reported, including fever of unknown origin, skin and soft tissue infection (eg, cellulitis, wound infection, soft tissue abscess), pulmonary infection (eg, pneumonia, empyema, lung abscess), bone and joint infection (eg, septic arthritis, osteomyelitis), aortitis, obstetric and gynecologic syndromes (eg, intrauterine device infection, preterm labor, chorioamnionitis, neonatal sepsis), hematologic disorders (eg, thrombotic thrombocytopenia purpura), and gastrointestinal infection (eg, cholecystitis, peritonitis in patients on peritoneal dialysis, intraabdominal abscess) [4,5,16,43,57,60,66-78].

DIAGNOSIS

When to suspect Capnocytophaga infection — Capnocytophaga should be suspected as a cause of infection in patients with unexplained severe sepsis or septic shock, a history of close contact with a dog (especially a dog bite), and/or asplenia, functional asplenia, liver disease (eg, cirrhosis), or alcohol use disorder. (See 'Dog bites' above and 'Asplenia, cirrhosis, or alcohol use' above and "Animal bites (dogs, cats, and other mammals): Evaluation and management", section on 'Spectrum of antibiotic coverage'.)

The organism should also be considered as a cause of sepsis or head and neck infection in patients with severe immunocompromise (eg, neutropenia), especially if the oral mucosa is compromised by conditions such as mucositis. (See 'Neutropenia' above and 'Head, neck, or oral infection' above.)

Establishing the diagnosis — The diagnosis of Capnocytophaga infection is usually established via culture, although diagnoses are occasionally made via other methods:

●Culture – The organisms grow slowly in culture. The microbiology laboratory should be alerted when Capnocytophaga infection is suspected so extended incubation and specific culture techniques can be used. (See 'Identification in culture' above.)

In patients with bacteremia, blood cultures typically turn positive at around six days of incubation (range, 1 to 14 days) [7].

●Peripheral smear or buffy coat – In some patients, particularly among asplenic patients, an early preliminary diagnosis can be made from visualizing the organisms on a peripheral smear or buffy coat sample. Positive samples reveal fusiform gram-negative organisms within the cytoplasm of polymorphonuclear leukocytes (picture 5) [7,11,79,80].

●Other tests – Molecular probes, matrix-assisted laser desorption-ionization mass spectrometry, or sequencing of 16S ribosomal RNA have been successfully used to diagnose infection [56,81-84]. In several case reports of meningitis, polymerase chain reaction (PCR) of cerebrospinal fluid was used to make a rapid diagnosis of C. canimorsus [85]; 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.

Commercial biochemical identification panels may be unreliable for identification of the Capnocytophaga species.

Susceptibility testing — 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. Typical antibiotic susceptibility patterns are discussed in detail above. (See 'Antibiotic susceptibility' above.)

We request susceptibility testing from the microbiology laboratory for the following antibiotics: penicillin, amoxicillin-clavulanate, cefazolin, ceftriaxone, clindamycin, a fluoroquinolone (eg, ciprofloxacin, levofloxacin), a carbapenem (eg, imipenem, meropenem), a macrolide (eg, azithromycin), and an aminoglycoside (eg, gentamicin).

TREATMENT — Antibiotic therapy is the mainstay of treatment of infections due to Capnocytophaga species.

In some cases, surgery may be part of the treatment plan, such as valve replacement in patients with endocarditis or wound debridement in patients with an infected dog bite. In a systematic review of 128 infected patients, early wound cleansing and surgical removal of the focus of infection correlated with improved survival [54].

Dog bites — Patients with an infected dog bite should receive antibiotics that cover Capnocytophaga species along with other pathogens that are commonly isolated from infected animal bites. A typical regimen is oral amoxicillin-clavulanate or intravenous ampicillin-sulbactam (table 1 and table 2). Debridement is often indicated in patients with infected bites. (See "Animal bites (dogs, cats, and other mammals): Evaluation and management", section on 'Antibiotic therapy'.)

Some patients who present with a recent dog bite that does not show evidence of infection qualify for prophylactic antibiotics, as discussed below and separately. (See 'Prevention' below and "Animal bites (dogs, cats, and other mammals): Evaluation and management", section on 'Antibiotic prophylaxis'.)

Confirmed infection — In patients with Capnocytophaga infection proven by culture, initial antibiotics are selected while antibiotic susceptibility testing results are still pending. Because susceptibility testing is not routinely performed for Capnocytophaga isolates, susceptibility testing should be requested from the microbiology laboratory, as described above. (See 'Susceptibility testing' above.)

Patients with severe infection should be treated with a beta-lactam-beta-lactamase inhibitor (eg, ampicillin-sulbactam, piperacillin-tazobactam) or a carbapenem (eg, imipenem, meropenem), pending susceptibility testing results. We favor ampicillin-sulbactam because it has a narrower spectrum of coverage than piperacillin-tazobactam and carbapenems. An exception is patients with meningitis due to Capnocytophaga species, for whom a carbapenem is preferred because beta-lactam-beta-lactamase inhibitor combinations do not reliably achieve high enough concentrations in cerebrospinal fluid.

Nonsevere infections may be treated with oral therapy (eg, amoxicillin-clavulanate). Clindamycin is an alternative but we favor beta-lactam-beta-lactamase inhibitors due to risk of Clostridium difficile from clindamycin.

Once antibiotic susceptibility test results are available, the regimen can be adjusted. (See 'Antibiotic susceptibility' above.)

Duration of antibiotic therapy — The duration of therapy should be based on the clinical syndrome and the clinical response to treatment. For example, certain conditions (eg, endocarditis) require longer durations than others. There are no clinical trials examining duration of therapy.

Many patients who initially receive intravenous therapy can be transitioned to oral therapy once they are stable. However, certain conditions often require the full course of antibiotics to be administered intravenously (eg, endocarditis, meningitis).

PROGNOSIS — In patients with severe sepsis or septic shock, case fatality rates of up to 56 percent have been reported, and mortality rates are high even among patients who are immunocompetent [2,4-7,54,86].

For patients without severe sepsis, mortality data are scarce. In such patients, mortality likely depends on the specific type of infection and the patient’s immune status.

PREVENTION — For patients with dog bites, prompt and aggressive wound care is necessary to prevent infection. In addition, antibiotic prophylaxis is often provided for patients who are immunocompromised or whose wounds have certain high-risk features. Details regarding wound management and antibiotic prophylaxis for uninfected animal bites are provided separately. (See "Animal bites (dogs, cats, and other mammals): Evaluation and management", section on 'Antibiotic prophylaxis' and "Animal bites (dogs, cats, and other mammals): Evaluation and management", section on 'Wound management'.)

Prevention of infection caused by human oral flora strains of Capnocytophaga has not been studied. Appropriate oral care, especially in immunocompromised patients, is likely to be beneficial.

SUMMARY AND RECOMMENDATIONS

●Epidemiology and risk factors – Infections due to Capnocytophaga species are rare. Dog bites are the most common cause of infection, and patients with asplenia, cirrhosis, or alcohol use are prone to severe infections. Neutropenia and head, neck, or oral infections are risk factors for infections not due to dog bites. (See 'Epidemiology' above and 'Risk factors' above.)

●Microbiology – Different species are found in the oral flora of dogs compared to humans. C. canimorsus, the most common species in dogs, is the most common cause of severe infections. (See 'Microbiology' above.)

●Clinical manifestations – The most severe form of infection is bacteremia and septic shock with disseminated purpuric lesions. Other types of infection include head and neck infection, endocarditis, and meningitis. (See 'Clinical manifestations' above.)

●Diagnosis

•When to suspect – Infection due to Capnocytophaga species should be suspected in patients with unexplained severe sepsis or septic shock, a history of close contact with a dog (especially a dog bite), and/or asplenia, functional asplenia, liver disease (eg, cirrhosis), or alcohol use disorder. It should also be considered as a cause of sepsis or head and neck infection in patients with severe immunocompromise (eg, neutropenia) and mucositis. (See 'When to suspect Capnocytophaga infection' above.)

•Methods of diagnosis – Blood culture is the most common method of diagnosis; blood cultures typically turn positive at around six days of incubation (range, 1 to 14 days). Occasionally, an early diagnosis can be made from visualizing the organisms on a peripheral smear or buffy coat sample (picture 5). (See 'Establishing the diagnosis' above.)

●Treatment

•Dog bites – Patients with an infected dog bite should receive antibiotics that cover Capnocytophaga species along with other pathogens that are commonly isolated from infected animal bites. A typical regimen is oral amoxicillin-clavulanate or intravenous ampicillin-sulbactam (table 1 and table 2). (See "Animal bites (dogs, cats, and other mammals): Evaluation and management", section on 'Antibiotic therapy'.)

•Confirmed infection – Pending susceptibility results, we suggest treating patients with severe infection with ampicillin-sulbactam; piperacillin-tazobactam or a carbapenem (eg, imipenem, meropenem) are reasonable alternatives (Grade 2C). For patients with meningitis due to Capnocytophaga species, a carbapenem is preferred because beta-lactam-beta-lactamase inhibitor combinations do not reliably achieve high enough concentrations in cerebrospinal fluid. (See 'Confirmed infection' above.)

We suggest treating nonsevere infections with oral amoxicillin-clavulanate; clindamycin is a reasonable alternative (Grade 2C). (See 'Confirmed infection' above.)

Once antibiotic susceptibility test results are available, the regimen can be adjusted. (See 'Confirmed infection' above.)

•Duration – The duration of therapy should be based on the clinical syndrome and the clinical response to treatment. (See 'Duration of antibiotic therapy' above.)

●Prevention – For patients with dog bites, prompt and aggressive wound care is necessary to prevent infection. In addition, antibiotic prophylaxis is often provided for patients who are immunocompromised or whose wounds have certain high-risk features. (See "Animal bites (dogs, cats, and other mammals): Evaluation and management", section on 'Antibiotic prophylaxis'.)