Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, Washington, USA

Correspondence to: Dr W E Stamm, University of Washington, Division of Allergy and Infectious Diseases, Box 356523, 1959 NE Pacific Street, Seattle, WA 98195, USA

Human oral Capnocytophaga species have been only rarely described as a cause of sepsis in patients following stem cell or marrow transplantation, and pneumonia has not been reported in this setting. In addition, fluoroquinolone resistance is rarely seen in these species, and has never been reported in C. gingivalis. We report a case of pneumonia (confirmed by culture of bronchoalveolar lavage fluid) and sepsis due to fluoroquinolone- resistant Capnocytophaga gingivalis in a patient following autologous stem cell transplantation, who responded to treatment with linezolid and metronidazole. Capnocytophaga infections should be considered in patients with fever following stem cell or marrow transplantation, especially those with neutropenia and mucositis. Susceptibility testing is needed given the existence of multidrug-resistant isolates.

Bone Marrow Transplantation (2001) 28, 1171-1173.

Capnocytophaga gingivalis; pneumonia; fluoroquinolone resistance; transplantation

The genus Capnocytophaga is comprised of fastidious, capnophilic, fusiform gram-negative bacilli divided into two groups, those found primarily in the human oral cavity and those found primarily in the canine oral cavity. C. canimorsus and C. cynodegmi are the species predominantly of canine origin, and are associated most commonly with dog-bite infections. Species isolated from the human oral cavity, where they colonize the subgingival sulcus and other areas, include C. ochracea, C. gingivalis, C. sputigena, C. granulosa, and C. hemolytica.¹ Several human oral Capnocytophaga species have been reported to cause bacteremia and sepsis in immunocompromised hosts,^2,3,4 and one case of presumed pneumonia due to C. ochracea has been reported in an immunocompromised patient.² However, infections due to these organisms have been rarely described following stem cell or marrow transplantation,^4,5,6 and no cases of pneumonia have been reported in this setting. In addition, fluoroquinolone resistance is uncommon in human oral Capnocytophaga species, and to our knowledge has not been reported in C. gingivalis. We report pneumonia (confirmed by culture of bronchoalveolar lavage fluid) and sepsis due to fluoroquinolone-resistant C. gingivalis in a patient following autologous peripheral blood stem cell transplantation.

Case report

A 30-year-old male with acute myelogenous leukemia (AML) in first remission received an autologous peripheral blood stem cell transplantation after conditioning with busulfan and VP-16. Early post transplant, he developed fever to 39°C, chills, mild hypotension, and new patchy bibasilar pulmonary infiltrates on chest radiography, which were confirmed on computed tomography (CT) scan of the chest (Figure 1). Blood cultures initially showed no growth. Gentamicin was added to levofloxacin, which the patient had been taking prophylactically. Review of systems was otherwise notable for moderate mucositis, dry cough, mild dyspnea, and fatigue. Drug allergies included vancomycin and -lactam agents. Other medical history included presumed pulmonary aspergillosis, based on lung tissue histology revealing septate hyphae, which was diagnosed prior to transplant and had radiographically resolved on liposomal amphotericin followed by voriconazole. He also had mild veno-occlusive disease, hypothyroidism, and a single congenitally absent kidney. There was no relevant travel history or known exposures to tuberculosis. Physical examination was remarkable for moderate oral mucositis and scattered coarse breath sounds with bibasilar ronchi. Laboratory studies demonstrated a WBC count of 1.2 ´ 10⁹/l with 0% neutrophils.

Bronchoscopy with bronchoalveolar lavage (BAL) revealed many thin fusiform gram-negative rods (GNRs) and occasional gram-positive cocci in clusters on Gram stain. Fusiform GNRs began growing from blood agar (trypticase soy agar with 5% sheep blood) incubated anaerobically at 35°C in 5% CO₂ from multiple earlier blood cultures, and fusiform GNRs grew from culture of the BAL fluid at 6000 CFU/ml (along with Micrococcus at 80 CFU/ml and alpha-Streptococcus at 40 CFU/ml). Gentamicin was discontinued, and linezolid and metronidazole were added to treat suspected aspiration pneumonia and Capnocytophaga sepsis. The patient's fever resolved within 24 h and radiographic abnormalities began resolving over the next week. The fusiform GNRs were identified as C. gingivalis on the basis of their morphology and the following biochemical reactions: catalase and oxidase negative; absence of nitrate reduction; absence of esculin, starch, or gelatin hydrolysis; and absence of -galactosidase activity by the o-nitrophenyl--D-galactopyranoside (ONPG) test. Antimicrobial susceptibilities determined using the E test are summarized in Table 1.

Discussion

Sepsis is a common manifestation of infection due to human oral Capnocytophaga species in immunocompromised hosts, particularly in the setting of neutropenia and oral mucositis,^3,5 which were risk factors for infection in our patient. Sepsis due to Capnocytophaga has rarely been described in the setting of stem cell or marrow transplantation.^4,5,6 Bilgrami et al⁴ reported bacteremia due to a Capnocytophaga species of human origin (which could not be further speciated) in a patient following autologous marrow transplantation for Hodgkin's lymphoma. Baquero et al⁵ described bacteremia due to C. ochracea in a patient following autologous marrow transplantation for AML. Rubie et al⁶ reported sepsis due to C. ochracea in a child following allogenic marrow transplantation for aplastic anemia. In a review of Capnocytophaga infections in the immunocompromised by Bilgrami et al, most patients had leukemia as the underlying illness, followed by solid tumors, and then other diseases such as multiple myeloma, lupus, and myelofibrosis.⁴ Lin et al² reported a series of Capnocytophaga infections in patients with immunocompromising conditions including hematologic and solid-organ malignancies, bronchiectasis and Tetralogy of Fallot.

Only one case of pneumonia in an immunocompromised host due to human oral Capnocytophaga species has been reported, but not following stem cell or marrow transplantation. In that report by Lin et al, a patient with bronchiectasis and Tetralogy of Fallot developed clinical and radiographic evidence of pneumonia following endotracheal intubation for corrective surgery, and C. ochracea was presumed to be the etiologic agent after its isolation from sputum and blood cultures; this patient did not have neutropenia or mucositis.² Because C. gingivalis, Micrococcus, and alpha-Streptococcus have all been found to colonize the human oral cavity, we assume that in our patient, an aspiration event may have been the inciting factor leading to pneumonia. Mucositis and neutropenia likely contributed to the development of pneumonia, bacteremia, and sepsis.

Antimicrobial management of pneumonia in the early period following bone marrow transplantation is guided by degree of suspicion regarding a particular pathogen and by early use of diagnostic procedures, primarily BAL. Pneumonia during the initial neutropenic period is usually bacterial, especially gram-negative species, or fungal, especially Aspergillus species, in etiology. Empiric antimicrobial therapy should thus be effective against gram-negative bacteria, including Pseudomonas, and possibly Aspergillus. Specific antimicrobial therapy should be determined by the results of the BAL and additional studies. Isolation of Capnocytophaga as the sole etiologic agent in our patient allowed therapy to be guided by in vitro susceptibility testing. Human oral Capnocytophaga species are generally sensitive to ampicillin-sulbactam, clindamycin, erythromycin, tetracycline, chloramphenicol, fluoroquinolones, and imipenem, but resistant to aminoglycosides. Fluoroquinolones, clindamycin, imipenem, or most broad-spectrum -lactam/-lactamase inhibitor combinations are reasonable choices for empiric therapy in bone marrow transplant patients until susceptibility results are available. Susceptibilities vary for penicillin, ampicillin, aztreonam, cephalosporins, vancomycin, and metronidazole,^2,7,8 and therefore these agents should be avoided empirically for infections due to human oral Capnocytophaga species.

Fluoroquinolone resistance is uncommon, and to our knowledge has not been reported in C. gingivalis. Fluoroquinolone resistance was reported by Baquero et al⁵ in an isolate of C. ochracea and by Gomez-Garces et al⁹ in an isolate of C. sputigena. Prophylactic use of levofloxacin in our patient may have selected for fluoroquinolone resistance. Linezolid, which was empirically chosen in this patient because of a vancomycin allergy, had good in vitro activity against the C. gingivalis isolate. In vitro susceptibility testing to linezolid or its use in infections due to Capnocytophaga has not been previously described. Linezolid may be an effective alternative antibiotic choice against multidrug-resistant Capnocytophaga isolates or in patients with multiple drug allergies.

Capnocytophaga infections should be considered in patients with fever following stem cell or marrow transplantation, especially those with neutropenia and mucositis. Susceptibility testing is needed given the existence of multidrug-resistant isolates. Isolation of this organism in patients already receiving antibiotics may signal resistance and should prompt a change in empiric antibiotic coverage pending susceptibility testing.

Acknowledgements

We thank Yolanda Houze for characterization of the Capnocytophaga gingivalis isolate and Susan Swanzy for performing in vitro susceptibility testing, both from the University of Washington Microbiology Laboratory. We also thank Debra Mattson for providing clinical data pertaining to the case report.

1 Gill VJ. Capnocytophaga. In: Mandel GL, Bennett JE, Dolin R (eds). Principles and Practice of Infectious Diseases, 5th edn. Churchill Livingstone: Philadelphia, 2000, 2441-2444.

2 Lin R, Hsueh P, Chang S et al. Capnocytophaga bacteremia: clinical features of patients and antimicrobial susceptibility of isolates. J Formos Med Assoc 1998; 97: 44-48, MEDLINE

3 Parenti DM, Snydman DR. Capnocytophaga species: infections in nonimmunocompromised and immunocompromised hosts. J Infect Dis 1985; 151: 140-147, MEDLINE

4 Bilgrami S, Bergstrom SK, Peterson DA et al. Capnocytophaga bacteremia in a patient with Hodgkin's disease following bone marrow transplantation: case report and review. Clin Infect Dis 1992; 14: 1045-1049, MEDLINE

5 Baquero F, Fernandez J, Dronda F et al. Capnophilic and anaerobic bacteremia in neutropenic patients: an oral source. Rev Infect Dis 1990; 12: S157-S160, MEDLINE

6 Rubie H, Attal M, Lemozy J et al. Prophylaxie antibactérienne initiale après allogreffe de moelle osseuse etude pilote de vancomycine systémique. Path Biol 1988; 36: 912-914,

7 Rummens JL, Gordts B, van Landuyt HW. In vitro susceptibility of Capnocytophaga species to 29 antimicrobial agents. Antimicrob Agents Chemother 1986; 30: 739-742, MEDLINE

8 Roscoe DL, Zemcov SJV, Thornber D et al. Antimicrobial susceptibilities and -lactamase characterization of Capnocytophaga species. Antimicrob Agents Chemother 1992; 36: 2197-2200, MEDLINE

9 Gomez-Garces JL, Alos JI, Sanchez J, Cogollos R. Bacteremia by multidrug-resistant Capnocytophaga sputigena. J Clin Microbiol 1994; 32: 1067-1069, MEDLINE

Figure 1 CT scan of the chest showing patchy bibasilar consolidation.

Table 1 Antimicrobial susceptibilities for the Capnocytophaga gingivalis isolate