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BRIEF REPORT Clinical and Microbiological Characteristics of Rhizobium radiobacter Infections Chih-Cheng Lai,1 Lee-Jene Teng,2,3 Po-Ren Hsueh,1,2 Ang Yuan,1 KuangChau Tsai,1 Jih-Luh Tang,1 and Hwei-Fang Tien1 Departments of 1Internal Medicine and 2Laboratory Medicine, National Taiwan University Hospital, and 3School of Medical Technology, National Taiwan University College of Medicine, Taipei, Taiwan Data obtained from 1996 to 2002 on 13 patients with Rhizobium radiobacter infections were analyzed. Ten patients (76%) had underlying hematological malignancy or solidorgan cancer. Six patients (46%) had febrile neutropenia during the course of R. radiobacter infection. The majority (54%) of infections were catheter-related bacteremia, and 92% of infections were hospital acquired. All the patients survived. Eighteen isolates were recovered from the 13 patients, and each isolate was susceptible to cefepime, piperacillin-tazobactam, carbapenems, and ciprofloxacin. The pulsed-field gel electrophoresis profiles differed among the isolates recovered from different patients, indicating the absence of nosocomial spread of the organism. Strains of the Rhizobium species (formerly Agrobacterium, which was reclassified based on 16S rDNA analyses) are aerobic, motile, oxidase-positive, and non–spore-forming gram-negative bacilli [1–4]. Among the species of Rhizobium (i.e., R. radiobacter, R. rhizogenes, R. rubi, R. undicola, and R. vitis), R. radiobacter is the species that most commonly causes disease in humans [3, 4]. Since the first case of human infection with R. radiobacter, in a patient with prosthetic aortic valve endocarditis, was reported in 1980 [5], R. radiobacter has been recognized as an opportunistic human pathogen [1, 6, 7]. Most of patients with R. radiobacter infection have debilitating underlying diseases [1, 6–20]. The clinical presentations associated with R. radiobacter infection are protean, and bacteremia caused Received 25 July 2003; accepted 21 August 2003; electronically published 4 December 2003. Reprints or correspondence: Dr. Po-Ren Hsueh, Depts. of Laboratory Medicine and Internal Medicine, National Taiwan University, No. 7, Chung-Shan South Rd., Taipei, Taiwan (hsporen @ha.mc.ntu.edu.tw). Clinical Infectious Diseases 2004; 38:149–53 2004 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2004/3801-0023$15.00 by this organism is usually secondary to the use of intravenous catheters (5, 8, 14, 16, 17). The majority of patients with R. radiobacter infection have appeared to respond well to antibiotic therapy. In addition, a significant aspect of therapy is the removal of foreign material, because patients who have persistent infection or who initially respond to therapy risk experiencing relapse until the foreign body is removed. The outcome of infection with R. radiobacter is favorable [1, 7]. In this report, we describe the clinical features of 13 patients with R. radiobacter infections who were treated at the National Taiwan University Hospital (NTUH) during the period 1996– 2002. Microbiological characteristics were also investigated, including antimicrobial susceptibilities and molecular types of the 18 isolates recovered from the 13 patients. Patients and methods. From 1 January 1996 through 31 December 2002, 13 patients with R. radiobacter infections who were hospitalized in the National Taiwan University Hospital were identified (table 1). Relevant information on the clinical presentation of these patients was collected. These data included the underlying diseases, associated medical condition (e.g., the use of an indwelling catheter or receipt of chemotherapy), clinical syndromes, hospital day on which a culture result positive for R. radiobacter was obtained, antibiotic regimens received, and outcome. Eighteen isolates of R. radiobacter were recovered from the 13 patients with infection. These were initially identified on the basis of colonial morphotypes, gram staining characteristics, oxidase reaction, and growth on triple-sugar agar. These isolates were also identified as R. radiobacter by their biochemical profiles, obtained with the Vitek GNI and API 20NE system (bioMérieux). The MICs of 13 antimicrobial agents (table 2) for the 18 isolates of R. radiobacter were determined by means of the agar dilution method according to guidelines established by the NCCLS [21, 22]. Genotypes of the 18 isolates of R. radiobacter were determined by PFGE. DNA extraction and purification were also performed, as described elsewhere [23]. The DNA was digested by the restriction enzyme PmeI, and the restriction fragments were separated in a CHEF-DRIII unit (Bio-Rad) [23]. Interpretation of the PFGE profiles followed the description by Tenover et al. [24]. Patients with intravascular device–associated infections caused by R. radiobacter were defined as those with a body temperature of 138.3C and malaise, chills, or tachypnea with no obvious identifiable source of infection except for the exit site or tunnel infection, as well as cultures of ⭓2 blood samples BRIEF REPORT • CID 2004:38 (1 January) • 149 M M M F F 9 10 11 12 13 37 2 59 53 74 46 21 50 61 30 81 82 66 Celiac sprue ALL NHL Cutaneous lymphoma Esophageal cancer AML NHL Breast cancer Breast cancer Pregnancy Rhabdosarcoma Laryngeal cancer CAD Underlying condition No Yes Yes No Yes Yes Yes Yes No No No No No Neutropenia 9/24/2002 9/21/2002 8/2/2002; 8/2/2002; 10/03/2002 10/19/2001 4/6/2000 5/3/1997 3/7/1997 1/23/1997 12/5/1996 11/22/1996 9/30/1996 Date of isolation, month/day/year Blood (PAC and PB); Blood (PAC); Blood (PAC) 11/15/2002; 11/19/2002; 12/2/2002 Blood (PAC); Blood (PAC) 11/7/2002; 11/11/2002 Blood (PAC and PB) Blood (PAC and PB) Blood (PAC); Blood (PB); Blood (PAC and PB) Blood (CVC) Blood (PAC) Sputum Pleural effusion Blood Blood Pleural effusion Blood Site of isolation Treatment CRB CRB CRB CRB CRB CRB Cefepime Ampicillin-sulbactam and gentamicin Cefatazidime, tobramycin Cefpirome Piperacillin-tazobactam Imipenem Ciprofloxacin Pneumonia Ceftazidime Pneumonia Cefoperazone drainage Bacteremia Cefmetazone Bacteremia Ceftriaxone Pneumonia Antibiotics drainage Bacteremia Amoxicillin-clavulanate Type of infection M1; M2; M3 CRB L1; L2 K J I1; I2; I3 H G F E D C B A Isolate a designation Yes No No No Yes Yes Yes No No No No No No Survival Survival Survival Survival Survival Survival Survival Survival Survival Survival Survival Survival Survival Catheter removal Outcome a Isolate designations used in this study; see figure 1. NOTE. Infections were nosocomial in all patients, with the exception of patient 5, whose infection was community-acquired. ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; CAD, coronary arterial disease; CRB, catheter-related bacteremia; CVC, central venous catheter; NHL, Non-Hodgkin lymphoma, PAC, Port-a-Cath; PB, peripheral blood. M 8 F 5 F F 4 M M 3 6 M 2 7 M 1 Age, Patient no. Sex years Table 1. Demographic and clinical characteristics of 13 patients with cultures positive for Rhizobium radiobacter who were treated at the National Taiwan University Hospital, 1996–2002. Table 2. In vitro susceptibilities of 18 isolates of Rhizobium radiobacter from 13 patients who were treated at the National Taiwan University Hospital, 1996–2002. MIC, mg/mL Antimicrobial agent Range MIC50 MIC90 No. (%) of susceptible a isolates Ampicillin-sulbactam 1–16 8 16 11 (61) Ceftazidime 2–32 8 16 13 (72) Cefotaxime 1–16 2 16 14 (78) Piperacillin-tazobactam ⭐0.03–8 0.5 8 18 (100) Cefepime 0.12–8 1 4 18 (100) Aztreonam 2–32 4 16 14 (78) Imipenem ⭐0.03–0.06 0.06 0.06 18 (100) Meropenem ⭐0.03–0.06 ⭐0.03 0.06 18 (100) Ciprofloxacin ⭐0.03–0.5 ⭐0.03 0.25 18 (100) Moxifloxacin ⭐0.03–0.25 ⭐0.03 0.25 …b Trovafloxacin ⭐0.03–0.5 0.06 0.5 … b Garenoxacin ⭐0.03–1 0.12 1 … b Amikacin 4–32 8 16 17 (94) a Susceptibility results were interpreted according to the MIC interpretative standards established by the NCCLS for Pseudomonas aeruginosa and organisms other than Enterobacteriaceae [22]. b Interpretative criteria for defining susceptibility to moxifloxacin, trovafloxacin, and garenoxacin were not provided by the NCCLS [22]. (obtained through the central catheter or from a peripheral source) positive for R. radiobacter. Episodes of infection that developed ⭓48 h after admission were regarded as nosocomial, while episodes of infection identified by positive cultures earlier than 48 h after admission were considered communityacquired. Neutropenia was defined as a neutrophil count of !1.0 ⫻ 10 9 cells/L. Antibiotic therapy was considered appropriate if the chosen drug proved to be active against the isolate on the basis of the results of susceptibility testing. Antibiotypes were considered identical if the MICs of all antimicrobial agents tested were identical or had a discrepancy of !1 dilution. Isolates were defined as being the same strain or originating from a single clone if they had identical antibiotypes and PFGE profiles. Results. The clinical characteristics of the 13 patients with infections are provided in table 1. All 13 patients received their diagnosis after 1996, and 5 patients (38%) were identified in 2002. The mean age of the patients was 51 years (range, 2–82 years). Ten patients (76%) had underlying hematological malignancies or solid-organ cancer, and 1 patient (7%) had a celiac sprue. Six patients (46%) had febrile neutropenia during R. radiobacter infection. Clinical infections included bacteremia associated with a central venous catheter or Port-A-Cath (Smiths Industries Medical Systems, Deltec) in 7 patients, primary bacteremia in 3 patients, and pneumonia in 3 patients. Twelve of the 13 patients acquired R. radiobacter infections during hospital stays or via chemotherapy-related indwelling catheters. All but 3 patients wee treated with appropriate antibiotics after blood cultures were reported to be positive for R. radiobacter. Of the 7 patients with catheter-related bacteremia, 4 patients had their catheters removed, and 3 recovered without removal of the catheter. All patients survived. All the isolates were gram-negative bacilli, oxidase-positive, indole-negative, and glucose-nonfermenters. Colonies that grew on trypticase soy agar supplemented with 5% sheep’s blood were mucoid and slightly pink. The reaction profiles generated by Vitek GNI and API 20NE system were identical. The following characteristics suggest our isolates were R. radiobacter: positive reactions for urease, phenylalanine deaminase, esculin hydrolysis, and acids from maltose, sucrose, mannitol, and xylose. All isolates were susceptible to cefepime, piperacillin-tazobactam, imipenem, meropenem, and ciprofloxacin (table 2). Susceptibilities to ampicillin-sulbactam, ceftazidime, cefotaxime, aztreonam, and amikacin varied. Moxifloxacin, trovafloxacin, and garenoxacin had good in vitro activities against these isolates, with MIC90 values of ⭐1 mg/mL. Among the 18 isolates recovered from the 13 patients, a total of 13 PFGE profiles (figure 1) were identified. PFGE profiles differed among the isolates recovered from different patients. Both antibiotypes and genotypes were identical for 2 isolates from each of 2 patients (isolates I1 and I3 from patient 9 and isolates M1 and M3 from patient 13) who experienced 2 episodes of Port-A-Cath–related bacteremia at intervals of 2 months and 17 days, respectively. Discussion. In the present report, the majority of the patients had hematological malignancies or solid-organ cancer, and most of them had received chemotherapy. Furthermore, there were 3 patients that did not have any cancer and had never received immunosuppressive agents. Our findings are consistent with those of other investigators [1, 7, 10, 13, 14, 18, 20]. We emphasize that R. radiobacter should be included in the list of pathogens that cause bacteremia even in immunocompentent patients, especially in the presence of an intravenous catheter. PFGE analysis has been extensively applied for epidemiological typing and the taxonomic study of clinical isolates [23, 24, 25]. No previous reports have described the use of this technique to type clinical isolates of R. radiobacter. In the present study, 5 of the 13 patients became infected during a 5month interval toward the end of 2002, and all 5 of these patients had Port-A-Cath–related bacteremia. This raised the possibility of an outbreak (of bacteremia or pseudobacteremia). However, the PFGE profiles of the isolates recovered from the 5 patients seen in 2002 and those recovered from different patients within the 6-year time period of the study differed, indicating that the isolates were clonally unrelated. The identical PFGE profiles of the 3 isolates from patient 9 and another 3 BRIEF REPORT • CID 2004:38 (1 January) • 151 Figure 1. Representative PFGE profiles digested with PmeI of 13 clones from 18 isolates of Rhizobium radiobacter recovered from 13 patients treated at the National Taiwan University Hospital, 1996–2002. Lane M, molecular size markers. Lanes 1–13, pulsotypes of I to XIII, respectively. See table 2 for designations of isolates. isolates from patient 13 lead to the conclusion that the 2 episodes of bacteremia were caused by the same strain and were not due to reinfection with different clones of R. radiobacter. The infections were strongly related to the presence of foreign plastic materials (e.g., an intravascular catheter, nephrostomy tube, or prosthetic valve) [1]. In the present report, 10 patients presented with bacteremia, and 7 of them had intravascular catheters. Five out of 10 patients were reported to be neutropenic. All 10 patients received intravenous antibiotics, but 3 of the patients were not treated with the removal of the catheter. It appears that antimicrobial therapy is usually successful, and catheter removal should be considered only if bacteremia continues despite appropriate antimicrobial therapy or if the patient becomes unstable, as was the case with patient 9 and patient 13. In addition to bacteremia, respiratory tract infection was also present in 3 patients. This suggests that R. radiobacter should be added to the list of pathogens that induce pneumonia, especially in patients with malignancy. In this report, none of the cultures of various clinical specimens performed at the microbiological laboratories of the NTUH yielded Rhizobium until September 1996. After that time, increasing numbers of positive cultures—particularly from blood specimens—that yielded Rhizobium isolates were noted. Furthermore, all but 1 of the infections were nosocomial, unlike in a previous study [7]. The reason for this may be the 152 • CID 2004:38 (1 January) • BRIEF REPORT small number of cases, but these results may imply that R. radiobacter should be considered a possible pathogen in cases of hospital-acquired infection. Surveillance studies to determine the reservoirs in the hospital setting for nosocomial transmission of this organism should be conducted. An analysis of the antimicrobial susceptibility test results provides several insights. First, previous findings suggested that clinical isolates of Rhizobium species that were resistant to aztreonam were common because monobactams could be produced by some soil strains of Rhizobium [4]. However, according to the NCCLS breakpoints for organisms other than Enterobacteriaceae, only 4 of 19 isolates were not susceptible to aztreonam (MICs, ⭓16 mg/mL). Second, the susceptibility patterns of the isolates to third-generation cephalosporins were variable. Testing of antimicrobial susceptibility to these agents using the standard dilution method should be performed for every R. radiobacter isolate of clinical significance. Third, cefepime, piperacillin-tazobactam, carbapenems, and fluoroquinolones seemed to be promising agents for treating infections caused by R. radiobacter, according to the susceptibility test results. Additional studies (on animals or humans) should be performed to elucidate the correlation between in vitro susceptibility testing and clinical efficacy. Fourth, the antimicrobial susceptibilities of the isolates at different intervals, ranging from weeks (in the case of patient 13) to months (in the case of patient 9), remained nearly identical, despite intervening therapy. In conclusion, R. radiobacter should be considered a potential community-acquired or hospital-acquired pathogen in the presence of foreign plastic materials, especially in immunocompromised patients. In addition, removal of the foreign material may be necessary if there is a poor response to the appropriate antimicrobials. References 1. Edmond MB, Riddler SA, Baxter CM, Wicklund BM, Pasculle AW. Agrobacterium radiobacter: a recently recognized opportunistic pathogen. Clin Infect Dis 1993; 16:388–91. 2. Lautrop H. Agrobacterium spp. Isolated from clinical specimens. Acta Pathol Microbiol Scand 1967; 187:63–4. 3. 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