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July 2000, Volume 26, Number 1, Pages 101-104
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Case Report
Agrobacterium yellow group: bacteremia and possible septic arthritis following peripheral blood stem cell transplantation
Y Chalandon1, D L Roscoe2 and S H Nantel1

1Division of Hematology and Leukemia/Bone Marrow Transplantation Program of British Columbia, Canada

2Division of Microbiology, Vancouver General Hospital, British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada

Correspondence to: Dr Y Chalandon, Division of Hematology and Leukemia/Bone Marrow Transplantation Program of British Columbia, Vancouver Hospital and Health Sciences Centre, 950 West 10th Avenue, Vancouver, British Columbia, V5Z 4E3, Canada

Abstract

A 47-year-old male patient developed sepsis and monoarticular arthritis following autologous stem cell transplantation for recurrent Hodgkin's disease. Blood cultures were positive for Agrobacterium yellow group. The knee pain and swelling responded promptly to the institution of empirical broad-spectrum antibiotics. Recurrent bacteremia developed necessitating Hickman line removal for eventual resolution of the infection. Transplant physicians should be aware of this unusual pathogen and the potential for both persistent line-related sepsis and possible septic arthritis. Bone Marrow Transplantation (2000) 26, 101-104.

Keywords

Agrobacterium; septic arthritis; autologous; transplantation; stem cell

Febrile neutropenia and central venous catheter-associated bacteremia are common complications following intensive chemotherapy and stem cell transplantation. Septic arthritis is distinctly unusual in these patients suggesting that commonly encountered organisms do not typically cause joint-related complications. Agrobacteria are anaerobic nonfermentative gram-negative bacilli found worldwide in soils and known to be plant pathogens, but infrequently have been reported to cause infections in humans. Some authors have described Agrobacteria as emerging opportunistic pathogens, primarily Agrobacterium radiobacter.1,2,3 Reported infection due to Agrobacterium yellow group is rare, with only one report in the literature describing four cases.4 Infection with unusual organisms may present with unique clinical problems. In this report we describe a case of Agrobacterium yellow group bacteremia associated with a possible septic arthritis, which required removal of the central venous catheter in addition to antibiotics for resolution.

Case report

A 47-year-old male developed recurrent nodular sclerosing Hodgkin's disease 2 years after attaining CR with multiagent chemotherapy (mechlorethamine, vincristine, procarbazine, prednisone (MOPP)/adriamycin, bleomycin, vinblastine (ABV) hybrid ´ 6 cycles). At relapse he had evidence of disease in the abdomen and right inguinal region. He received two cycles of standard chemotherapy (cyclophosphamide, vincristine, procarbazine, prednisone (CVPP)/MOPP) and had peripheral blood stem cells (PBSC) collected following mobilization with G-CSF 10 mug/kg/day ´ 6 days. In November 1998, he underwent autologous PBSC transplant following conditioning with cyclophosphamide, carmustine (BCNU), etoposide (VP-16) and cisplatin (CBVP). He did not receive any antibiotic prophylaxis. On day +2 he developed fever to 38.4°C, diarrhea and left knee pain. He had no previous history of arthritis. He was neutropenic (ANC = 0) and empirical broad spectrum antibiotics were commenced (ceftazidime 2 g i.v. every 8 h, tobramycin 110 mg i.v. every 8 h, vancomycin 1 g i.v. every 12 h. Tobramycin and vancomycin doses and intervals were then adjusted to maintain therapeutic blood levels). On day +3 in the face of progressive knee swelling, the knee joint was aspirated. Gram stain and cultures were negative. Crystals were not detected. Synovial fluid WBC count was 61 ´ 106/l with 66% neutrophils, 30% monocytes and 4% lymphocytes. Within 48 h the fever and knee pain/swelling resolved. Blood cultures drawn at the time of fever grew gram-negative bacilli, subsequently identified as Agrobacterium yellow group, and reported to be susceptible to ceftazidime and tobramycin (Table 1). Blood cultures were collected by aseptic technique into two aerobic and two anaerobic culture bottles and incubated in the BACTEC 9240 (BD Biosciences, Sparks, MD, USA). At 48 h, slender gram-negative bacilli were detected in the aerobic bottles, which were subcultured in 5% sheep's blood and MacConkey agars. After overnight incubation in 5% CO2, circular convex colonies 1-2 mm in diameter notable for a bright yellow pigment were present on the blood agar plate. There was no growth on the MacConkey agar. The oxidase and catalase tests were positive. Initial identification and susceptibility tests were done on an automated system (MicroScan, West Sacramento, CA, USA). The preliminary identification of the isolate was Chryseobacterium spp., but due to the relative biochemical inertness on this system the isolate was sent to our reference laboratory (Provincial Laboratory, British Columbia Center for Disease Control) who made the identification of Agrobacterium yellow group based on the following biochemical reactions: oxidative utilization (OF) of glucose, xylose, lactose, sucrose and maltose, but not mannitol; negative reactions for indole, citrate, lysine and ornithine decarboxylase, arginine dihydrolase, gelatinase and DNAse; weakly positive delayed urea (Christensen's); growth at 25° and 35°C, but not at 42°C; and no zone of inhibition to a polymixin disk. Tests for motility were positive and the isolate demonstrated one polar flagellum. Flexirubin pigment was not demonstrated.

Susceptibility results for both isolates from both episodes of bacteremia are reported in Table 1. Only the first isolate was available for susceptibility testing by an agar gradient diffusion method (Etest, ABBiodisk, Solna, Sweden) according to the manufacturer's recommendations. Results are reported in Table 1. Specific interpretations for susceptibility testing of this organism are not available and guidelines for interpretations were based on those for non-Enterobacteriaceae.5 Antibiotics were continued and on day +9 fever recurred. Therapeutic dose amphotericin B (0.5 mg/kg/day i.v. every 24 h) was added. Ceftazidime was replaced with imipenem (500 mg i.v. every 6 h) and G-CSF (5 mug/kg/day s.c) was commenced to speed neutrophil recovery. Blood cultures from days +9, 10 and 11 eventually grew the same Agrobacterium. The Hickman catheter was removed and the tip was cultured following the technique of Maki et al,6 but the culture remained negative after 7 days of incubation. However, the patient became afebrile within 12 h of removal and subsequent blood cultures were negative. The WBC started to rise the day following removal of the central catheter and the patient became non-neutropenic 48 h after removing the line. Echocardiography was negative for vegetations. After 5 days, a new Hickman line was placed to allow for 3 further weeks of antibiotic therapy with tobramycin and imipenem to treat presumed septic arthritis.

Discussion

We describe the case of an immunocompromised patient who developed Agrobacterium yellow group bacteremia post-PBSC transplant for recurrent Hodgkin's disease. Agrobacterium yellow group has only previously been reported in patients receiving peritoneal dialysis.4 Agrobacteria are gram-negative, aerobic bacteria found ubiquitously in soil. Recognized as plant pathogens, human infections have rarely been reported. Best known for its ability to induce tumors in susceptible plants, Agrobacterium tumefaciens is now known to be genetically identical to A. radiobacter, the most commonly reported species associated with human infections. Agrobacteria have biochemical characteristics similar to other gram-negative bacilli commonly isolated from the environment and often require tests not routinely available in the clinical diagnostic laboratory, as occurred in this instance. Agrobacterium yellow group are a distinct entity without species designation and are commonly confused with Sphingomonas paucimobilis.7 The actual incidence of infection with this organism may be under reported due to the difficulty in making an exact identification.

This presentation of Agrobacterium infection was unusual due to the association of a possible septic arthritis of the left knee, which to our knowledge has not been described previously. Despite the negative synovial fluid culture, Agrobacterium-induced septic arthritis was strongly suspected. First, the fluid was inflammatory showing 61 ´ 103/ml WBC with a majority of neutrophils with no crystals seen at a time when the patient was profoundly neutropenic and febrile. Second, the patient had good response to antibiotics and did not receive non-steroidal anti-inflammatory agents or steroids. The negative culture results in this case may have been due to the antibiotic therapy which was started 18 h prior to joint aspiration. It is also possible that Agrobacterium is difficult to culture from synovial fluid, with local factors in the joint fluid, such as defensin, humoral factors or neutrophils impairing growth of Agrobacterium in culture, and organisms may have been trapped in the clotted synovial fluid sample. The possibility that this could have been a reactive arthritis to Agrobacterium as occurs during infection with other pathogens such as Chlamydia (Reiter's syndrome) or enteric bacteria was also considered.8 The presumed mechanism for reactive arthritis is an immune-mediated inflammatory response to infection at a site distant from primary infection. However, this seems unlikely in the patient we describe. First, the signs and symptoms of arthritis in this case occurred at the time of bacteremia, while in reactive arthritis symptoms usually appear 1 to 4 weeks after infection. Second, rapid improvement of knee pain and swelling occurred after initiation of antibiotic therapy. Antibiotics have no role in the treatment of enteric reactive arthritis and it is controversial for Chlamydia.9 Third, the arthritis involved only one joint, the knee, which is less commonly involved in reactive arthritis where multiple joints are generally involved.10 Finally and most importantly, an immune-mediated reaction like the one responsible for reactive arthritis would be highly unlikely in a patient profoundly immunocompromised by underlying Hodgkin's disease and by the immunosuppression induced by the conditioning regimen.

Septic arthritis due to gram-negative organisms is seen in 9-17% of cases of infectious arthritis,11 often in elderly patients with chronic debilitating disease or chronic arthritis in the infected joint,12 and in intravenous drug users or immunocompromised patients.13 The most common gram-negative organisms involved are Neisseria gonorrhoeae in sexually active age groups, and prior to the availability of vaccine, Haemophilus influenzae in the young. Pseudomonas spp., Neisseria meningitidis and Salmonella spp. complete the list of common gram-negative rods associated with infectious arthritis.14 Agrobacterium yellow group could be added to the list of gram-negative bacilli causing septic arthritis among immunocompromised patients. The typical duration of antimicrobial therapy is 2-3 weeks.15 However, in our case we chose 4 weeks because of the relapse on initially appropriate therapy and the profound state of immunosuppression secondary to high-dose therapy and PBSC transplant. The patient was treated with two antibiotics to which the organism was susceptible to decrease the risk of development of resistance.

The other interesting feature of this case is presumed Agrobacterium infection of the Hickman catheter. When fever recurred 7 days after the start of antibiotics, blood cultures drawn from the line were positive for the same organism and remained positive for 3 consecutive days despite modification of antibiotics. Moreover, following line removal the patient improved rapidly with defervescence and subsequent negative cultures. The fact that the culture of the tip of the Hickman line was negative was surprising as this patient demonstrated bacteremia for 3 consecutive days and blood cultures became negative after removal of the line. This has been described in a previous report when bacteria may escape detection by conventional culturing of the catheter.3 The sensitivity of catheter tip cultures is reported to range from 78 to 97%.16,17,18 In our case, a false-negative result may be due to failure to use techniques which would allow detection of organisms present in the internal lumen of catheter. In one report, 16 patients with catheter-related infection had negative tip culture, but were found to have positive hub culture.17 The propensity to colonize foreign devices may be due to the ability of Agrobacterium to adhere to silicone tubes, similar to Staphylococcus aureus and Staphylococcus epidermidis as shown by Alnor et al.3 Central venous catheter infection due to Agrobacterium spp. has mainly been described with Agrobacterium radiobacter.1,3 The infection could be controlled only after removing the catheter in 57 to 83% of the cases.1,2,3,19,20 Central venous catheter infection with Agrobacterium yellow group, to our knowledge, has never been described. The only report of human infection with this pathogen to date was peritonitis in four patients receiving continuous ambulatory peritoneal dialysis.4 In three out of four of these cases the peritoneal catheter had to be removed because of recurrence of infection after good response to intraperitoneal antibiotic therapy (and also oral antibiotic in one case). It seems, as it was the case with the patient we described, that Agrobacterium yellow group is difficult to eradicate from an indwelling foreign body with antibiotics alone. Removal of a central line should be considered if fever persists for longer than 48 to 72 h.

Antibiotic susceptibility of Agrobacterium spp. is variable.2 In a report of the University of Minnesota Hospital, the isolates were resistant to tobramycin and variably resistant to cephalothin.2 In the report of Edmond et al, the isolates were resistant to tobramycin, but also to third-generation cephalosporins other than ceftriaxone.1 Most reports suggest that Agrobacterium spp. are susceptible to trimethoprim-sulfamethoxazole (TMP-SMX) with the exception of two reports.21,22 There is very little information in the literature about antibiotic susceptibility of Agrobacterium yellow group, with Swann et al4 reporting on four clinical isolates and reference strains. They do not provide the interpretative criteria used, but their isolates are reported to be broadly resistant to all cephalosporins tested, to piperacillin, netilmicin, amikacin and chloramphenicol. MIC data which suggests susceptibility is given for sulfamethoxazole (<2 mug/ml), trimethoprim (4 mug/ml) and gentamicin (4 mug/ml). The isolate from our case was initially susceptible to ceftazidime and tobramycin (Table 1), but subsequently was reported to be intermediate to ceftazidime. This minor category change from susceptible to intermediate tested by the automated microbroth dilution method reflects the fact that the MIC of these antibiotics was near the threshold, as demonstrated by E-test MIC results. As it was still susceptible to imipenem, this antibiotic was chosen to replace ceftazidime. Optimal therapy for Agrobacterium is unknown due to limited data. As suggested by Hulse et al,2 antibiotic susceptibility is not predictable a priori, and Agrobacterium is potentially multiply resistant to antibiotics.2 It is even less well documented in Agrobacterium yellow group and this pathogen seems to have more resistance than the Agrobacterium spp. (Table 1).4 Treatment should be guided by antibiotic susceptibility as no prospective study has demonstrated the optimal antibiotic regimen. When such uncommon organisms are detected in patients, the susceptibility of the bacteria is perhaps best determined by standard MIC tests since interpretative criteria are not available.

Acknowledgements

Yves Chalandon is supported by a grant from the 'Fond de perfectionnement 1998/1999' from University Hospital of Geneva, Switzerland. The authors would like to thank Ingrid Pocock, Special Bacteriology, Provincial Laboratory, BCCDC, for identification of the isolate.

References

1 Edmond MB, Riddler SA, Baxter CM et al. Agrobacterium radiobacter: a recently recognized opportunistic pathogen. Clin Infect Dis 1993; 16: 388-391, MEDLINE

2 Hulse M, Johnson S, Ferrieri P. Agrobacterium infections in humans: experience at one hospital and review. Clin Infect Dis 1993; 16: 112-117, MEDLINE

3 Alnor D, Frimodt-Moller N, Espersen F et al. Infections with the unusual human pathogens Agrobacterium species and Ochrobactrum anthropi. Clin Infect Dis 1994; 18: 914-920, MEDLINE

4 Swann RA, Foulkes SJ, Holmes B et al. 'Agrobacterium yellow group' and Pseudomonas paucimobilis causing peritonitis in patients receiving continuous ambulatory peritonealdialysis. J Clin Pathol 1985; 38: 1293-1299, MEDLINE

5 National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing. Wayne, PA, 1999; 19: M100-S9,

6 Maki DG, Weise CE, Sarafin HW. A semiquantitative culture method for identifying intravenous catheter-related infection. New Engl J Med 1977; 296: 1305-1309, MEDLINE

7 Schreckenberger PC, von Graevenitz A. Acinetobacter, Achromobacter, Alcaligenes, Moraxella, Methylobacterium and other nonfermentative gram-negative rods. In: Murraz PR, Baron EJ, Pfallen MA et al. (eds). Manual of Clinical Microbiology. ASM Press: Washington, 1999, 539-560.

8 Rahman MU, Hudson AP, Schumacher HR Jr. Chlamydia and Reiter's syndrome (reactive arthritis). Rheum Dis Clin North Am 1992; 18: 67-79, MEDLINE

9 Sieper J, Braun J. Reactive arthritis. Curr Opin Rheumatol 1999; 11: 238-243, MEDLINE

10 Cohen JI, Bartlett JA, Corey GR. Extra-intestinal manifestations of Salmonella infections. Medicine 1987; 66: 349-388, MEDLINE

11 Cooper C, Cawley MI. Bacterial arthritis in an English health district: a 10 year review. Ann Rheum Dis 1986; 45: 458-463, MEDLINE

12 Newman ED, Davis DE, Harrington TM. Septic arthritis due to gram-negative bacilli: older patients with good outcome. J Rheumatol 1988; 15: 659-662, MEDLINE

13 Sack K. Monoarthritis: differential diagnosis. Am J Med 1997; 102: 30S-34S, MEDLINE

14 Smith JW, Piercy EA. Infectious arthritis. In: Mandell GL, Benett JE, Dolin R (eds). Principles and Practice of Infectious Disease. Churchill Livingstone: New York, 1995, 1034.

15 Syrogiannopoulos GA, Nelson JD. Duration of antimicrobial therapy for acute suppurative osteoarticular infections. Lancet 1988; 1: 37-40, MEDLINE

16 Brun-Buisson C, Abrouk F, Legrand P et al. Diagnosis of central venous catheter-related sepsis: critical level of quantitative tip cultures. Arch Intern Med 1987; 147: 873-877, MEDLINE

17 Douard MC, Clementi E, Arlet G et al. Negative catheter-tip culture and diagnosis of catheter-related bacteremia. Nutrition 1994; 10: 397-404, MEDLINE

18 Fan ST, Teoh-Chan CH, Lau KF. Evaluation of central venous catheter sepsis by differential quantitative blood culture. Eur J Clin Microbiol Infect Dis 1989; 2: 142-144,

19 Yu WL, Wang DY, Lin CW. Agrobacterium radiobacter bacteremia in a patient with chronic obstructive pulmonary disease. J Formos Med Assoc 1997; 96: 664-666, MEDLINE

20 Castagnola E, Conte M, Venzano P et al. Broviac catheter-related bacteraemias due to unusual pathogens in children with cancer: case reports with literature review. J Infect 1997; 34: 215-218, MEDLINE

21 Freney J, Gruer LD, Bornstein N et al. Septicemia caused by Agrobacterium sp. J Clin Microbiol 1985; 22: 683-685, MEDLINE

22 Cain JR. A case of septicaemia caused by Agrobacterium radiobacter (letter). J Infect 1988; 16: 205-206, MEDLINE

Tables

Table 1  Antibiotic susceptibility of Agrobacterium yellow group

Received 6 April 1999; accepted 11 February 2000
July 2000, Volume 26, Number 1, Pages 101-104
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