Capnocytophaga species

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MICROBIOLOGY

Capnocytophaga spp. are long, thin gram-negative bacilli that are slow growing, with gliding ability on agar media. They are facultatively anaerobic and require enrichment with CO2 (5-10%) for optimum growth (capnophilic). The organisms grow best at 35 to 37 °C on either blood or chocolate agar. They do not grow on MacConkey agar. Visible colonies typically take 2 to 4 days of incubation (83) and some strains can be pigmented in orange or pink. Some selective media have been tested for clinical isolation from polymicrobial samples (30, 112), but no medium was specific enough to allow growth of all Capnocytophaga species. Most of them contained antimicrobial agents known to be inactive onCapnocytophaga sp., as VCAT, CAPE, bacitracin chocolate blood agar, VK, TSBV, CapR and TBBP media (31).

EPIDEMIOLOGY

Capnocytophaga species constitute part of the normal oral microflora of humans and animals (61), and are often considered as opportunistic pathogens, that was confirmed by recent studies of microbial profiles using the human oral microbe identification microarray (23, 54, 128, 131). Metagenomic analysis of the canine oral cavity, as revealed by high-throughput pyrosequencing of the 16S rRNA gene, showed that Capnocytophaga are part of canine oral flora (3.8%) (116). Clinical isolates of Capnocytophaga spp are classified into two broad groups: (1) those species found in the human oral cavity: C. gingivalis, C. granulosa, C. haemolytica, C. leadbetteri, C. ochracea and C. sputigena and (2) those species that colonize the oral cavities of dogs (and occasionally cats): C. canimorsus (75) and C. cynodegmi (83, 118, 130). Some species remains unclassified according to sequence analysis of 16S rRNA gene, as AHN9607/AHN9576/AHN9798/AHN8471/ChDC (35).

Ma et al. (71) analyzed the community in dental plaque of elder people, over 60 years of age, with root caries and isolated Capnocytophaga sp. in 14% of cases. Teeth with high plaque mass exhibited high levels of C. gingivalis (43). Capnocytophaga strains were more often isolated in samples from children (17), with oncological diseases (71%) other than leukaemia (57%). Concomitant chemotherapy had no influence on oral Capnocytophaga carriage, but previous antibiotherapy was reported to decrease their prevalence in oral samples (59).

Umeda et al. (124) compared C. canimorsus isolates genetically using 16S rRNA gene sequence analysis and pulsed-field gel electrophoresis (PFGE). C. canimorsus was detected in 69.7% of dogs and 54.8% of cats. Analysis of samples of tooth plaque from a total of 131 canines determined that 49.2% of canines sampled carried a species of Capnocytophaga and 21.7% of the canines sampled in this study carried C. canimorsus (26). C. canimorsus was classifiable into two main groups (I and II) with differing γ-glutamyl aminopeptidase activity. The authors suggested that group I can be transmitted to humans and group II is indigenous only to the oral cavities of dogs and cats.

van Dam et al. (126) used the PCR-restriction fragment length polymorphism (PCR-RFLP), a species-specific PCR on rpoB, and rrs sequencing, to test 29 strains of Capnocytophaga canimorsus and other canine Capnocytophaga spp. from human blood cultures and grouped them into three PCR-RFLP types. These authors also suggested the presence of different gene copies in a few strains, indicating that this method was less appropriate for species identification.

CLINICAL MANIFESTATIONS

The species that colonize the human oral cavity are thought to have a role in the pathogenesis of various forms of periodontal disease (48, 84). However, there is no evidence of its implication it in dental caries in children, as demonstrated by microbiome analysis (54, 128).

Systemic infections have been reported in cancer patients (57) especially with severe chemotherapy (113). These Capnocytophaga species can also cause a wide variety of infections in immunocompetent, as immonocompromised hosts, including bacteremia (6, 20, 91), endocarditis (7, 16, 47), pericardial abscess or coronary heart disease (9), lung infections, mediastinal or iliopsoas abscesses (19), empyema (52), various bone infections (67, 93, 98), keratitis (86), endophthalmitis (82, 105), peritonitis (21), facial cellulitis (50, 65), suppurative lymphadenitis or abscesses (29, 88), meningitis (11, 81, 97) or extracerebral intracranial abscess (104). Peri-partum infections or preterm birth have been described (69), leading to chorioamnionitis (80) and sepsis in the newborn (51). Santa-Cruz et al.(107) showed that the presence of Capnocytophaga was significantly associated with low-birth weight (p=0.008) in a Spanish Caucasian population with medium-high educational level, in the bivariate and/or multivariate model.

Other risk factors have been described as diabetic status (18) or HIV infection or therapy (68, 90, 122).

The species that are found in the oral cavity of dogs and cats, especially C. canimorsus, have been associated with severe sepsis following dog bites or cat scratches. The main identified risk factors are patients who have undergone splenectomy for a variety of reasons (102, 109), patients who are HIV infected (103), patients receiving cytotoxic or biological drugs (94) or who are chronic alcoholics (13, 15, 64, 66, 91, 108). Zoonotic infections with Capnocytophaga sp. originated from contact with a patient’s household pets were described in undergoing continuous ambulatory peritoneal dialysis (3). A vector-born C. canimorsus sepsis was recently reported after a bite into the neck by a large pine weevilHylobius abietis (123). Specific severe clinical symptoms were frequently associated with C. canimorsus infection, as fulminant sepsis (121), purpura (14, 22, 62, 72), disseminated intravascular coagulation (46), and liver and kidney failure (120, 129). Some cases of mortal severe sepsis due to C. canimorsus infection after a dog bite who died less than 12 hours after admission, were reported (87, 126).

LABORATORY DIAGNOSIS

Capnocytophaga spp. have been recovered from a variety of oral/dental sites as well as lower respiratory tract specimens (tracheal aspirates, bronchoscopy), aspirates of wounds and abscesses, osteoarticular samples, cerebrospinal and peritoneal fluids, ocular specimens and blood. A significant number of infections are polymicrobial, including other bacteria that colonize the human or animal oropharynx. In asplenic patients with high-grade bacteremia, the organism may be seen on Gram stains of buffy coats prepared from peripheral blood(1).

Diagnosis is usely performed by biochemical tests (including automated tests) (130), matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) (8) or 16S rRNA gene amplification (27, 40, 97). Identification and quantification of putative periodonto-pathogen bacteria, including Capnocytophaga species, by commercially available rapid PCR-based methods (eg. Micro-IDent and micro-IDent Plus) have also proved their efficiency (43, 125).

The differentiation between C. sputigena and C. ochracea remains difficult by using biochemical tests, but results of phenotypic identification of Capnocytophaga sp. (other thanCapnocytophaga canimorsus) are largely congruent with 16S rRNA gene sequence analysis. C. canimorsus differs from C. gingivalis, C. ochracea, C. sputigena by the positive catalase and oxidase – together with the typical morphology of spindle-shaped cells in the Gram stain. The MALDI-TOF MS is a rapid method that always allows Capnocytophagaidentification at the genus level, and constitutes a valuable diagnostic tool in the clinical laboratory (130).

Using PCR methods, Suzuki et al.(118) succeeded to show a higher prevalence of C. canimorsus (74% of dogs and 57% of cats) and C. cynodegmi (86% of dogs and 84% of cats) in the oral cavities of dogs and cats. The identification to species level often requires use of 16S rRNA gene analysis (25, 37).

PATHOGENESIS

The species that colonize humans are opportunistic pathogens invading tissues as a result of interruption of the normal mucosal barriers in the healthy human oropharynx from trauma, disease or ulceration/mucositis.

Cooperation with other oral microorganism could be important, as it was shown that the induction of coaggregation and intracellular interaction by release of a soluble component byC. ochracea played a significant role in the formation of biofilm by F. nucleatum and C.ochracea (85).

Fernandez-Feo et al.(33) showed, by oral microbiome analysis, that Capnocytophaga sputigena was able to degrade gliadin and gliadin derivatives. Szimula et al. (119) demonstrated that Sjogren's syndrome Antigen A (SSA)/Ro60-reactive T cells were activated by a mimicry peptide originated from C. ochracea.

Ittig et al. (53) demonstrated that C. canimorsus LPS was 100 fold less endotoxic than Escherichia coli LPS. However, C. canimorsus lipid A was 20,000 fold less endotoxic than theC. canimorsus lipid A-core. The clinical course of C. canimorsus infection strongly indicated that the organism was able to avoid the immune system (at least in the early stages of infection). The absence of a proinflammatory response was due to the fact that C. canimorsus did not interact with human Toll-like receptor 4 (TLR4) (36). Upon presence of the LPS core on the lipid A, the binding to human myeloid differentiation factor 2 (MD-2) was dramatically increased, explaining the difference in endotoxicity. C. canimorsus have the unusual property to feed on cultured mammalian cells, including phagocytes, by harvesting the glycan moiety of cellular glycoproteins. Polysaccharide utilization loci (PULs) encoding surface exposed feeding complexes were found responsible by genomic and proteomic analysis (76, 95, 110) first demonstrated that Capnocytophaga canimorsus do not elicit an inflammatory response, and secondly that the archetype strain Cc5 were highly resistant to killing by complement and phagocytosis by human polymorphonuclear leukocytes (111). These authors concluded that a polysaccharide structure, likely an LPS, protects C. canimorsus from deposition of the complement membrane attack complex and from efficient phagocytosis by PMNs. Mally et al. (74) reported a case of C. canimorsus with a sialidase, able to inhibit the bactericidal activity of macrophages and to block the release of nitric oxide by LPS-stimulated macrophages. This surface-exposed sialidase allowed C. canimorsus to utilize internal aminosugars of glycan chains from host cell glycoproteins, what also contributed to bacterial persistence in a murine infection model (73), which may explain its capacity to escape from the host immune system.

SUSCEPTIBILITY IN VITRO AND IN VIVO

In vitro susceptibility testing of Capnocytophaga is complicated by their relatively slow growth and need for fastidious growth requirements (facultative anaerobic; 5-10% CO2). No guideline for testing the antimicrobial susceptibilities of these organisms have been issued by the Clinical and Laboratory Standards Institute (CLSI) or other European guidelines (EUCAST, CA-SFM).

Before the 2000s, there were relatively few studies of the in vitro antimicrobial susceptibilities of Capnocytophaga species (5, 45, 55, 99, 100, 106, 127). Prior to 1987, beta-lactamase-producing strains of Capnocytophaga spp. (34) were rare (<2%). Beta-lactamase-negative strains remain highly susceptible (MIC90 ≤ 1.0 μg /mL) to penicillin, amoxicillin, amoxicillin/clavulanate, piperacillin, ticarcillin and imipenem. An intrinsic activity of beta-lactamase inhibitors on Capnocytophaga strains was even reported (55).

However, in the past decades there have been increasing reports of serious infections due to beta-lactamase-producing strains (32, 59, 79, 89). The first report from Canada (99) demonstrated beta-lactamase production in 6 of 19 (32%) isolates studied in their laboratory in Vancouver. More recent reports from that European country continued to document a rapid escalation in beta-lactamase-producing strains of Capnocytophaga spp., including 8 of 11 blood isolates from patients with neutropenia (79) and 34 of 43 (79%) strains of C. ochracea/sputigena isolated from throat swabs of pediatric cancer patients undergoing chemotherapy in Rennes, France (55). Beta-lactamase-producing strains were usually reported more resistant to all cephalosporins (55, 99) than beta lactamase-negative strains. There was at least one report of a multidrug resistant Capnocytophaga sputigena bacteremia (39), including to third-generation cephalosporins and ciprofloxacin. Several beta-lactamases have been described as CSP-1 (41), one case of TEM-17 (101), or beta-lactamases belonging to the CfxA group (CfxA, CfxA2, CfxA3) (44, 56). Theses cefuroximases include enzymes (group 2e of the Bush’s classification) with more significant activity against cephalosporins and monobactams, rather than penicillins (resistance to aminopenicillins, first generation cephalosporins, cefuroxime and some oral 3rd generation cephalosporins, with inhibition by low concentrations of clavulanic acid). They are encoded by genes localized on chromosome and/or plasmid (44). The beta-lactamase CSP-1, isolated from C. sputigena, confers resistance to amoxicillin and 1st and 2nd generation cephalosporins. It presents 32% homology with CfxA, 41% with CblA and 38% with CepA (41).

Antibiotics other than beta-lactams that are very active against Capnocytophaga spp. include clindamycin (MIC90 ≤ 0.03 mg/L). Older studies (117) documented susceptibility to erythromycin (MIC90 = 1.0 mg/L), but in recent case reports (10, 28), erythromycin resistance seems to become common. Ehrmann et al. (32) reported increasing prevalence of macrolide resistance: 29% of isolates from subgingival samples were MLS resistant independently of species identification, beta-lactamase production or patient group (periodontitis, hematology or healthy patients). The MLS-resistant isolates carried the erm(F) or erm(C) gene (93% and 7%,respectively).

Most fluoroquinolones still remain susceptible (ciprofloxacin, levofloxacin; (MIC90 ≤ 0.5 mg/L). Gomez-Garces et al. (39) reported a case of bacteremia caused by a multi-resistant strain of C. sputigena in a patient with hematological malignancy with a MIC of ciprofloxacin of 16 mg/L. In a published multicenter study from Spain, 9 of 16 (56%) isolates were resistant to ciprofloxacin (77).

There are only 3 published reports of in vitro susceptibility testing of C. canimorsus and C. cynodegmi (12, 15, 127). The results of these studies were similar to susceptibility data for human Capnocytophaga spp. except that there were no reports of beta-lactamase-producing C. canimorsus.

Only few studies report results of in vitro susceptibility of combination of antibiotics. Alou et al. (4) explored the in vitro killing activity by concentrations similar to those found in crevicular fluid of tinidazole in combination other antibiotics. They demonstrated that when combinations with tinidazole were used, reductions were significantly higher for all antibiotics: ≥5.28 log10 CFU/ml with clindamycin, ≥4.78 log10 CFU/ml with amoxicillin/clavulanic acid, and ≥6.17 log10 CFU/ml with levofloxacin.

ANTIMICROBIAL THERAPY

In view of the increasing evidence of beta-lactamase producing strains of Capnocytophaga spp., it is prudent to treat patients with serious infections with amoxicillin combined with clavulanic acide (or other beta-lactams + beta-lactamase-inhibitor combinations or imipenem in case of severe infections (58, 63). Initial empirical treatment of the febrile neutropenic patient with such widely used combinations as vancomycin plus ceftazidime may result in failure to adequately treat beta-lactamase-producing Capnocytophaga spp. In case of meningitis or bacteremia caused by C. canimorsus or C. cynodegmi, empirical treatment by 3rd generation cephalosporins can be used, but with the other species, in vitrosusceptibility must be confirmed before initializing beta-lactam treatment (39, 58).

Most of the strains remain also fully susceptibile to cefoxitin, linezolide and clindamycin, but treatment failures can be observed with vancomycin, polymyxin B, trimethoprime and aminoglycosides (58). In odontogenic or ophthalmic infections, topical clindamycin and/or azithromycin can be alternative drugs of choice (2, 42, 92). Fluoroquinolones (preferentiallyciprofloxacin) or metronidazole (16) might be used only after testing in vitro susceptibilities, because some cases of resistant strains have been reported (38, 96).

VACCINES

There are no vaccines commercially available for Capnocytophaga spp.

PREVENTION

To contribute to a better mouth hygiene, D-tagatose-based toothpaste (70) or blue light at 455 nm (114) have been reported to have the potential for preventing and removing plaque development and for altering the subgingival microbiota.

In case of bites, initial wound management consisting in irrigation and debridement was at least equally important with antibiotics for prevention of infection (115). To prevent overwhelming postsplenectomy infection (OPSI), asplenic patients required specific advice around travel and animal handling as they were at increased risk of OPSI (60). Several authors suggested that prophylactic antibiotics should be administered to all at-risk patients who seek medical attention following a dog bite (24, 49, 91). This recommendation was particularly applicable to patients who have undergone splenectomy and were at risk of overwhelming infection due to C. canimorsus.

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