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Marrow Transplantation (2000) 26, 101–104  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt Case report Agrobacterium yellow group: bacteremia and possible septic following peripheral blood stem cell transplantation

Y Chalandon1, DL Roscoe2 and SH Nantel1

1Division of Hematology and Leukemia/Bone Marrow Transplantation Program of British Columbia; and 2Division of Microbiology, Vancouver General Hospital, British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada

Summary: Case report

A 47-year-old male patient developed and A 47-year-old male developed recurrent nodular sclerosing monoarticular arthritis following autologous stem cell Hodgkin’s disease 2 years after attaining CR with multiag- transplantation for recurrent Hodgkin’s disease. Blood ent chemotherapy (mechlorethamine, vincristine, procarba- cultures were positive for Agrobacterium yellow group. zine, prednisone (MOPP)/adriamycin, bleomycin, vinblas- The and swelling responded promptly to the tine (ABV) hybrid × 6 cycles). At relapse he had evidence institution of empirical broad-spectrum . of disease in the abdomen and right inguinal region. Recurrent bacteremia developed necessitating Hickman He received two cycles of standard chemotherapy line removal for eventual resolution of the . (cyclophosphamide, vincristine, procarbazine, prednisone Transplant physicians should be aware of this unusual (CVPP)/MOPP) and had peripheral blood stem cells and the potential for both persistent line- (PBSC) collected following mobilization with G-CSF 10 related sepsis and possible septic arthritis. Bone Marrow ␮g/kg/day × 6 days. In November 1998, he underwent auto- Transplantation (2000) 26, 101–104. logous PBSC transplant following conditioning with cyclo- Keywords: Agrobacterium; septic arthritis; autologous; phosphamide, carmustine (BCNU), etoposide (VP-16) and transplantation; stem cell cisplatin (CBVP). He did not receive any prophy- laxis. On day +2 he developed to 38.4°C, diarrhea and left knee pain. He had no previous history of arthritis. He was neutropenic (ANC = 0) and empirical broad spec- Febrile neutropenia and central venous catheter-associated trum antibiotics were commenced ( 2 g i.v. bacteremia are common complications following intensive every 8 h, tobramycin 110 mg i.v. every 8 h, chemotherapy and stem cell transplantation. Septic arthritis 1 g i.v. every 12 h. Tobramycin and vancomycin doses and is distinctly unusual in these patients suggesting that com- intervals were then adjusted to maintain therapeutic blood monly encountered organisms do not typically cause - levels). On day +3 in the face of progressive knee swelling, related complications. Agrobacteria are anaerobic nonfer- the knee joint was aspirated. and cultures were mentative gram-negative bacilli found worldwide in soils negative. Crystals were not detected. Synovial fluid WBC and known to be plant , but infrequently have count was 61 × 106/l with 66% neutrophils, 30% monocytes been reported to cause in humans. Some authors and 4% lymphocytes. Within 48 h the fever and knee have described Agrobacteria as emerging opportunistic pain/swelling resolved. Blood cultures drawn at the time of 1–3 pathogens, primarily Agrobacterium radiobacter. fever grew gram-negative bacilli, subsequently identified as Reported infection due to Agrobacterium yellow group is Agrobacterium yellow group, and reported to be susceptible rare, with only one report in the literature describing four to ceftazidime and tobramycin (Table 1). Blood cultures 4 cases. Infection with unusual organisms may present with were collected by aseptic technique into two aerobic and unique clinical problems. In this report we describe a case two anaerobic culture bottles and incubated in the BAC- of Agrobacterium yellow group bacteremia associated with TEC 9240 (BD Biosciences, Sparks, MD, USA). At 48 h, a possible septic arthritis, which required removal of slender gram-negative bacilli were detected in the aerobic the central venous catheter in addition to antibiotics for bottles, which were subcultured in 5% sheep’s blood and resolution. 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 Correspondence: Dr Y Chalandon, Division of Hematology and and catalase tests were positive. Initial identification and Leukemia/Bone Marrow Transplantation Program of British Columbia, Vancouver Hospital and Health Sciences Centre, 950 West 10th Avenue, susceptibility tests were done on an automated system Vancouver, British Columbia, V5Z 4E3, Canada (MicroScan, West Sacramento, CA, USA). The preliminary Received 6 April 1999; accepted 11 February 2000 identification of the isolate was Chryseobacterium spp., but Agrobacterium septic arthritis and autologous stem cell transplantation Y Chalandon et al 102 Table 1 Antibiotic susceptibility of Agrobacterium yellow group Discussion

Antibiotics Isolate No 1 Isolate No 2 We describe the case of an immunocompromised patient who developed Agrobacterium yellow group bacteremia MicroScana Etest MIC MicroScan post-PBSC transplant for recurrent Hodgkin’s disease. ␮ g/ml Agrobacterium yellow group has only previously been reported in patients receiving peritoneal dialysis.4 Agrobac- R ND R Ceftazidime S 24.0 I teria are gram-negative, aerobic found ubiquitously S ND I in soil. Recognized as plant pathogens, human infections Cefuroxime I 24.0 R have rarely been reported. Best known for its ability to Ciprofloxacin I 3.0 R induce tumors in susceptible plants, Agrobacterium tumefa- Gentamicin S 1.0 S ciens is now known to be genetically identical to A. radio- Imipenem S 1.0 S Tobramycin S 1.0 S bacter, the most commonly reported species associated TMP-SMX S 0.25 S with human infections. Agrobacteria have biochemical characteristics similar to other gram-negative bacilli com- aSusceptibility interpretations are not available for this organism and were monly isolated from the environment and often require tests based on interpretation for non-Enterobacteriaceae. not routinely available in the clinical diagnostic laboratory, = = = MIC minimum inhibitory concentrations; R resistant; I intermediate; as occurred in this instance. Agrobacterium yellow group S = susceptible; TMP-SMX = trimethoprim-sulfamethoxazole; ND = not determined. 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 due to the relative biochemical inertness on this system the exact identification. isolate was sent to our reference laboratory (Provincial Lab- This presentation of Agrobacterium infection was oratory, British Columbia Center for Disease Control) who unusual due to the association of a possible septic arthritis made the identification of Agrobacterium yellow group of the left knee, which to our knowledge has not been based on the following biochemical reactions: oxidative uti- described previously. Despite the negative synovial fluid lization (OF) of glucose, xylose, lactose, sucrose and malt- culture, Agrobacterium-induced septic arthritis was ose, but not mannitol; negative reactions for indole, citrate, strongly suspected. First, the fluid was inflammatory show- lysine and ornithine decarboxylase, arginine dihydrolase, ing 61 × 103/ml WBC with a majority of neutrophils with gelatinase and DNAse; weakly positive delayed urea no crystals seen at a time when the patient was profoundly (Christensen’s); growth at 25° and 35°C, but not at 42°C; neutropenic and febrile. Second, the patient had good and no zone of inhibition to a polymixin disk. Tests for response to antibiotics and did not receive non-steroidal motility were positive and the isolate demonstrated one anti-inflammatory agents or steroids. The negative culture polar flagellum. Flexirubin pigment was not demonstrated. results in this case may have been due to the antibiotic Susceptibility results for both isolates from both episodes therapy which was started 18 h prior to joint aspiration. It of bacteremia are reported in Table 1. Only the first isolate is also possible that Agrobacterium is difficult to culture was available for susceptibility testing by an agar gradient from synovial fluid, with local factors in the joint fluid, diffusion method (Etest, ABBiodisk, Solna, Sweden) such as defensin, humoral factors or neutrophils impairing according to the manufacturer’s recommendations. Results growth of Agrobacterium in culture, and organisms may are reported in Table 1. Specific interpretations for suscepti- have been trapped in the clotted synovial fluid sample. The bility testing of this organism are not available and guide- possibility that this could have been a to lines for interpretations were based on those for non- Agrobacterium as occurs during infection with other patho- Enterobacteriaceae.5 Antibiotics were continued and on day gens such as Chlamydia (Reiter’s syndrome) or enteric bac- +9 fever recurred. Therapeutic dose amphotericin B (0.5 teria was also considered.8 The presumed mechanism for mg/kg/day i.v. every 24 h) was added. Ceftazidime was reactive arthritis is an immune-mediated inflammatory replaced with imipenem (500 mg i.v. every 6 h) and G- response to infection at a site distant from primary infec- CSF (5 ␮g/kg/day s.c) was commenced to speed neutrophil tion. However, this seems unlikely in the patient we recovery. Blood cultures from days +9, 10 and 11 eventu- describe. First, the of arthritis in this ally grew the same Agrobacterium. The Hickman catheter case occurred at the time of bacteremia, while in reactive was removed and the tip was cultured following the tech- arthritis symptoms usually appear 1 to 4 weeks after infec- nique of Maki et al,6 but the culture remained negative after tion. Second, rapid improvement of knee pain and swelling 7 days of incubation. However, the patient became afebrile occurred after initiation of antibiotic therapy. Antibiotics within 12 h of removal and subsequent blood cultures were have no role in the treatment of enteric reactive arthritis negative. The WBC started to rise the day following and it is controversial for Chlamydia.9 Third, the arthritis removal of the central catheter and the patient became non- involved only one joint, the knee, which is less commonly neutropenic 48 h after removing the line. Echocardiography involved in reactive arthritis where multiple are gen- was negative for vegetations. After 5 days, a new Hickman erally involved.10 Finally and most importantly, an line was placed to allow for 3 further weeks of antibiotic immune-mediated reaction like the one responsible for therapy with tobramycin and imipenem to treat presumed reactive arthritis would be highly unlikely in a patient pro- septic arthritis. foundly immunocompromised by underlying Hodgkin’s

Bone Marrow Transplantation Agrobacterium septic arthritis and autologous stem cell transplantation Y Chalandon et al 103 disease and by the induced by the con- antibiotics alone. Removal of a central line should be ditioning regimen. considered if fever persists for longer than 48 to 72 h. Septic arthritis due to gram-negative organisms is seen Antibiotic susceptibility of Agrobacterium spp. is vari- in 9–17% of cases of infectious arthritis,11 often in elderly able.2 In a report of the University of Minnesota Hospital, patients with chronic debilitating disease or chronic arthritis the isolates were resistant to tobramycin and variably resist- in the infected joint,12 and in intravenous drug users or ant to cephalothin.2 In the report of Edmond et al, the iso- immunocompromised patients.13 The most common gram- lates were resistant to tobramycin, but also to third-gener- negative organisms involved are in ation other than ceftriaxone.1 Most reports sexually active age groups, and prior to the availability of suggest that Agrobacterium spp. are susceptible to tri- vaccine, Haemophilus influenzae in the young. Pseudo- methoprim-sulfamethoxazole (TMP-SMX) with the excep- monas spp., and spp. tion of two reports.21,22 There is very little information in complete the list of common gram-negative rods associated the literature about antibiotic susceptibility of Agrobacter- with infectious arthritis.14 Agrobacterium yellow group ium yellow group, with Swann et al4 reporting on four clini- could be added to the list of gram-negative bacilli causing cal isolates and reference strains. They do not provide the septic arthritis among immunocompromised patients. The interpretative criteria used, but their isolates are reported to typical duration of antimicrobial therapy is 2–3 weeks.15 be broadly resistant to all cephalosporins tested, to piperac- However, in our case we chose 4 weeks because of the illin, netilmicin, and chloramphenicol. MIC data relapse on initially appropriate therapy and the profound which suggests susceptibility is given for sulfamethoxazole state of immunosuppression secondary to high-dose therapy (Ͻ2 ␮g/ml), trimethoprim (4 ␮g/ml) and gentamicin (4 ␮ and PBSC transplant. The patient was treated with two anti- g/ml). The isolate from our case was initially susceptible biotics to which the organism was susceptible to decrease to ceftazidime and tobramycin (Table 1), but subsequently the risk of development of resistance. was reported to be intermediate to ceftazidime. This minor The other interesting feature of this case is presumed category change from susceptible to intermediate tested by Agrobacterium infection of the Hickman catheter. When the automated microbroth dilution method reflects the fact fever recurred 7 days after the start of antibiotics, blood that the MIC of these antibiotics was near the threshold, as cultures drawn from the line were positive for the same demonstrated by E-test MIC results. As it was still suscep- organism and remained positive for 3 consecutive days tible to imipenem, this antibiotic was chosen to replace cef- tazidime. Optimal therapy for Agrobacterium is unknown despite modification of antibiotics. Moreover, following 2 line removal the patient improved rapidly with defer- due to limited data. As suggested by Hulse et al, antibiotic a priori Agrobacterium vescence and subsequent negative cultures. The fact that susceptibility is not predictable , and is potentially multiply resistant to antibiotics.2 It is even the culture of the tip of the Hickman line was negative less well documented in Agrobacterium yellow group and was surprising as this patient demonstrated bacteremia for 3 this pathogen seems to have more resistance than the Agro- consecutive days and blood cultures became negative after bacterium spp. (Table 1).4 Treatment should be guided by removal of the line. This has been described in a previous antibiotic susceptibility as no prospective study has demon- report when bacteria may escape detection by conventional strated the optimal antibiotic regimen. When such uncom- culturing of the catheter.3 The sensitivity of catheter tip cul- 16–18 mon organisms are detected in patients, the susceptibility tures is reported to range from 78 to 97%. In our case, a of the bacteria is perhaps best determined by standard MIC false-negative result may be due to failure to use techniques tests since interpretative criteria are not available. 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 Acknowledgements found to have positive hub culture.17 The propensity to colonize foreign devices may be due to the ability of Agro- Yves Chalandon is supported by a grant from the ‘Fond de perfec- bacterium to adhere to silicone tubes, similar to Staphylo- tionnement 1998/1999’ from University Hospital of Geneva, aureus and epidermidis as shown Switzerland. The authors would like to thank Ingrid Pocock, by Alnor et al.3 Central venous catheter infection due to Special Bacteriology, Provincial Laboratory, BCCDC, for Agrobacterium spp. has mainly been described with Agro- identification of the isolate. bacterium radiobacter.1,3 The infection could be controlled only after removing the catheter in 57 to 83% of the cases.1–3,19,20 Central venous catheter infection with Agro- References bacterium yellow group, to our knowledge, has never been described. The only report of human infection with this 1 Edmond MB, Riddler SA, Baxter CM et al. Agrobacterium pathogen to date was peritonitis in four patients receiving radiobacter: a recently recognized opportunistic pathogen. continuous ambulatory peritoneal dialysis.4 In three out of Clin Infect Dis 1993; 16: 388–391. four of these cases the peritoneal catheter had to be 2 Hulse M, Johnson S, Ferrieri P. Agrobacterium infections in removed because of recurrence of infection after good humans: experience at one hospital and review. Clin Infect Dis 1993; 16: 112–117. response to intraperitoneal antibiotic therapy (and also oral 3 Alnor D, Frimodt-Moller N, Espersen F et al. Infections with antibiotic in one case). It seems, as it was the case with the the unusual human pathogens Agrobacterium species and patient we described, that Agrobacterium yellow group is Ochrobactrum anthropi. Clin Infect Dis 1994; 18: 914–920. difficult to eradicate from an indwelling with 4 Swann RA, Foulkes SJ, Holmes B et al. ‘Agrobacterium yel-

Bone Marrow Transplantation Agrobacterium septic arthritis and autologous stem cell transplantation Y Chalandon et al 104 low group’ and Pseudomonas paucimobilis causing peritonitis 14 Smith JW, Piercy EA. Infectious arthritis. In: Mandell GL, in patients receiving continuous ambulatory peritoneal Benett JE, Dolin R (eds). Principles and Practice of Infectious dialysis. J Clin Pathol 1985; 38: 1293–1299. Disease. Churchill Livingstone: New York, 1995, pp 1034. 5 National Committee for Clinical Laboratory Standards. Per- 15 Syrogiannopoulos GA, Nelson JD. Duration of antimicrobial formance standards for antimicrobial susceptibility testing. therapy for acute suppurative osteoarticular infections. Lancet Wayne, PA, 1999; 19: M100–S9. 1988; 1: 37–40. 6 Maki DG, Weise CE, Sarafin HW. A semiquantitative culture 16 Brun-Buisson C, Abrouk F, Legrand P et al. Diagnosis of cen- method for identifying intravenous catheter-related infection. tral venous catheter-related sepsis: critical level of quantitative New Engl J Med 1977; 296: 1305–1309. tip cultures. Arch Intern Med 1987; 147: 873–877. 7 Schreckenberger PC, von Graevenitz A. Acinetobacter, Achro- 17 Douard MC, Clementi E, Arlet G et al. Negative catheter-tip mobacter, Alcaligenes, Moraxella, Methylobacterium and culture and diagnosis of catheter-related bacteremia. Nutrition other nonfermentative gram-negative rods. In: Murraz PR, 1994; 10: 397–404. Baron EJ, Pfallen MA et al. (eds). Manual of Clinical Micro- 18 Fan ST, Teoh-Chan CH, Lau KF. Evaluation of central venous biology. ASM Press: Washington, 1999, pp 539–560. catheter sepsis by differential quantitative . Eur 8 Rahman MU, Hudson AP, Schumacher HR Jr. Chlamydia and J Clin Microbiol Infect Dis 1989; 2: 142–144. Reiter’s syndrome (reactive arthritis). Rheum Dis Clin North 19 Yu WL, Wang DY, Lin CW. Agrobacterium radiobacter bac- Am 1992; 18: 67–79. teremia in a patient with chronic obstructive pulmonary dis- 9 Sieper J, Braun J. Reactive arthritis. Curr Opin Rheumatol ease. J Formos Med Assoc 1997; 96: 664–666. 1999; 11: 238–243. 20 Castagnola E, Conte M, Venzano P et al. Broviac catheter- 10 Cohen JI, Bartlett JA, Corey GR. Extra-intestinal manifes- related bacteraemias due to unusual pathogens in children with tations of Salmonella infections. Medicine 1987; 66: 349–388. cancer: case reports with literature review. J Infect 1997; 34: 11 Cooper C, Cawley MI. Bacterial arthritis in an English health 215–218. district: a 10 year review. Ann Rheum Dis 1986; 45: 458–463. 21 Freney J, Gruer LD, Bornstein N et al. Septicemia caused by 12 Newman ED, Davis DE, Harrington TM. Septic arthritis due Agrobacterium sp. J Clin Microbiol 1985; 22: 683–685. to gram-negative bacilli: older patients with good outcome. J 22 Cain JR. A case of septicaemia caused by Agrobacterium Rheumatol 1988; 15: 659–662. radiobacter (letter). J Infect 1988; 16: 205–206. 13 Sack K. : . Am J Med 1997; 102: 30S–34S.

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