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ORIGINAL ARTICLE
Year : 2021  |  Volume : 15  |  Issue : 2  |  Page : 118-121

Raoultella terrigena infections in hematopoietic stem cell transplant recipients: High rate of mortality in multidrug-resistant strains - A retrospective observational study


1 Departement of Laboratories, National Center for Bone Marrow Transplant; Faculty of Medicine of Tunis, Tunis El Manar University, LR 18ES39, Tunis, Tunisia
2 Departement of Hematology, National Center for Bone Marrow Transplant, Tunis, Tunisia

Date of Submission11-Aug-2020
Date of Decision26-Oct-2020
Date of Acceptance25-Nov-2020
Date of Web Publication30-Jun-2021

Correspondence Address:
Dr. Ameni Mellouli
Service des Laboratoires, Centre National de Greffe de Moelle Osseuse, 1006, Tunis
Tunisia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_99_20

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  Abstract 

Background: Raoultella terrigena is a Gram-negative bacterium mainly reported as aquatic and soil organism. It is rarely involved in human infections. This study investigated the epidemiology of R. terrigena infections in the National Bone Marrow Transplant Center of Tunis (NBMTC) between January 2010 and March 2018, their associated antibiotics resistance patterns, and the molecular features of extended-spectrum β-lactamase (ESBL) producing strains. Materials and Methods: Our retrospective study concerned hematopoietic stem cell transplant (HSCT) adult recipients hospitalized at the NBMTC and infected with R. terrigena. The search of the ESBL and carbapenemases genes for multidrug-resistant strains was performed by PCR amplification. Results: Twelve strains of R. terrigena were responsible for infections in 10 hematopoietic stem cell transplant recipients (1.2% of total HSCT recipients). They were responsible for skin (n = 4) and urinary tract infections (n = 4). The first-line antibiotherapy was based on a monotherapy in one case and a dual therapy in eleven cases. Imipenem was the most prescribed antibiotic (n = 7/12). Mortality was attributable to R. terrigena infection in two over ten patients. Nine strains were producing ESBL. Five strains were resistant to ertapenem, two to imipenem, ten to ciprofloxacin, and five to amikacin. BlaCTX-M1, blaOXA-48, and blaKPC were found in seven, four, and one strains, respectively. Conclusion: Low prevalence of R. terrigena infections in HSCT recipients but high rates of attributable mortality and multidrug-resistant strains.

Keywords: Carbapenemases, extended-spectrum β-lactamase, hematopoietic stem cell transplantation, infection, Raoultella terrigena


How to cite this article:
Mellouli A, Chebbi Y, Raddaoui A, El Fatmi R, Ladeb S, Othmen TB, Achour W. Raoultella terrigena infections in hematopoietic stem cell transplant recipients: High rate of mortality in multidrug-resistant strains - A retrospective observational study. Indian J Transplant 2021;15:118-21

How to cite this URL:
Mellouli A, Chebbi Y, Raddaoui A, El Fatmi R, Ladeb S, Othmen TB, Achour W. Raoultella terrigena infections in hematopoietic stem cell transplant recipients: High rate of mortality in multidrug-resistant strains - A retrospective observational study. Indian J Transplant [serial online] 2021 [cited 2021 Jul 24];15:118-21. Available from: https://www.ijtonline.in/text.asp?2021/15/2/118/319896


  Introduction Top


Raoultella terrigena, first described in 1981, was known as Klebsiella terrigena. In 2001, it was reclassified according to 16S rDNA and rpoB gene sequencing studies under a new genus as R. terrigena in the Enterobacteriaceae family.[1] It is a Gram-negative, nonmotile, oxidase-negative, facultative anaerobic, and capsulated bacillus.

R. terrigena was primarily reported as aquatic and soil organism and considered as a nonpathogenic species, although it harbors numerous virulence factors found in Klebsiella pneumonia.[2] It is a very rarely isolated bacterium from clinical specimens.[3] Until now, very few reports of clinical infections caused by R. terrigena were cited in the literature.[2] These infections occurred often in immunocompromised patients.[4]

R. terrigena is naturally resistant to aminopenicillins through the production of low-level penicillinase. In recent years, works have appeared describing infections with Raoultella strains generating different mechanisms of resistance (extended-spectrum β-lactamases [ESBL], carbapenemases). These works are interested primarily in R. planticola and R. ornithinolytica.

The clinical features and outcomes of human infections caused by R. terrigena as well as antibiotic susceptibility have been rarely reported. A retrospective study was conducted in the National Bone Marrow Transplant Center (NBMTC) of Tunis to investigate the epidemiology of R. terrigena infections in HSCT recipients, to estimate antibiotics susceptibility, and to determine the genes encoding ESBL and carbapenemases.


  Materials and Methods Top


Patients

The NBMTC is a university hospital center referral for allografts in Tunisia. Our study took place in the adult ward, which includes a transplant unit with nine laminar flow cabins and a hematology unit with 10 conventional rooms. On average, 41 geno-identical human leukocyte antigen allografts and 61 autografts are performed per year in the NBMTC.

Our retrospective study concerned adult patients hospitalized at the hematology and transplant unit of NBMTC and infected with R. terrigena between January 2010 and March 2018.

The same patient could be included more than once for different infectious episodes if there was an interval of 1 month between episodes.

Our patients, hospitalized in single rooms, underwent a systematic screening of digestive colonization, at admission and then weekly until their discharge. After the first rectal swab, patients received a digestive tract decontamination using enteral colistin, gentamicin, and amphotericin B to eliminate Gram-negative bacilli and fungi. R. terrigena digestive colonization was diagnosed if the strain was found in rectal swabs or in stool cultures.

Detailed information on patients was collected from medical records. These data included age, gender, underlying disease, transplant procedures, prior hospitalization, history of renal failure and/or biliary tract diseases, prior antibiotic usage, neutrophil counts, presence of indwelling catheter, graft versus host disease (GVHD), infectious episode (clinical presentation, treatment, and outcome). The day of infusion of HSCT was considered day 0.

Microbiology

Different samples were obtained according to the presumed infection (blood cultures, urine cultures, skin samples, punctures…) in case of fever or any signs of infection.

The Bacterial identification was done according to conventional methods and by Api20E (Biomérieux). Antimicrobial susceptibility testing was performed by the diffusion method on agar medium according to the Antibiotic Committee/ French Society of Microbiology standards.

ESBL identification was performed by the double-disk synergy test. The minimal inhibitory concentrations (MIC) of imipenem and ertapenem were performed by the E-test method (BioMérieux®) for strains resistant to ertapenem.

The search for the ESBL genes (blaSHV, blaTEM, blaCTXM, and its subgroups and blaOXA-10) in ESBL strains and carbapenemases genes (blaOXA-48, blaKPC, blaGES, blaIMP, and blaVIM) in strains resistant to carbapenems was performed by PCR amplification.[5],[6],[7],[8],[9]

Definitions

Neutropenia was defined as an absolute neutrophil count of <500 cells/mm3.

Sepsis and septic shock were defined according to The Third International Consensus Definitions for Sepsis and Septic Shock.[10]

Mortality was considered attributable to R. terrigena infection if there was no other apparent cause.

Statistical analysis

Absolute and relative frequencies were calculated for the qualitative variables. Averages, medians, and extreme values were determined for the quantitative variables. Clinical features were estimated according to the number of patients. Data were analyzed with IBM SPSS Statistics 19 (Statistical Package for the Social Sciences, United States) software version 19.0 for windows.

Patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

Patient's confidential data was not used, only publicly accessible documents were used, and institutional ethics approval was deemed not necessary. All protocols were followed as per declaration of Helsinki.


  Results Top


Prevalence and timing of Raoultella terrigena infection

During the study period, 848 patients received HSCT. Among them, ten (1.2%) developed 12 R. terrigena infectious episodes (1.4%). Nine patients developed one infectious episode and one patient developed three infectious episodes (two skin infections and one urinary tract infection). These infections were more frequent after allograft (1.9% of total allograft) than after autograft (0.6% of total autograft) of HSCT.

The median time of R. terrigena infection was day +70.83 post graft, ranging from −9 to +555 days. Eight infectious episodes occurred within 100 days.

Patients' characteristics

R. terrigena infections occurred in patients with a mean age of 37.4 years (16–62 years) and a sex ratio man/woman of 1.5. These patients received an allograft (n = 7) or an autograft (n = 3) of HSCT and were followed for acute leukemia (n = 4), lymphoma (n = 2), myeloma (n = 2), aplastic anemia (n = 1) and myelodysplastic syndrome (n = 1).

A history of hospitalization within 3 months of the infectious episode was noticed in six among 10 patients with a median length of stay of 64.7 days. Prior antibiotic usage within a month before the infection was observed in seven of the cases with a median time of use of 14.3 days. Imipenem, ciprofloxacin, ceftazidime, amikacin, and colistin were the most prescribed antibiotics. Prior fecal colonization with R. terrigena was detected in eight infectious episodes. The average time between colonization and infection was 5.6 days (−36 days to −1 day before infection). Neutropenia and mucositis were observed in three and nine patients, respectively. GVHD was noticed in eight infectious episodes. It preceded the infection in only one case.

Clinical presentation and treatment

Urinary tract infection and skin infection were both responsible for four infectious episodes. Bloodstream infection was found in three cases. However, the respiratory infection was present in only one case. Bacteremia was related to a catheter in one of the three cases. Most infectious episodes were asymptomatic (n = 7/12) because of prior use of corticosteroid therapy. Fever was the major infectious sign (n = 4/5).

The first-line antibiotherapy was based on a monotherapy in one case and a dual therapy in eleven cases. The median time to start it was 1 day (0–2 days). Imipenem was the most prescribed antibiotic (n = 7/12), particularly in association with amikacin (n = 3/7). In fact, this prescription was based on multidrug-resistant bacteria screening results. A second-line antibiotherapy was indicated in eight cases either because of antimicrobial resistance (n = 6), worsening of symptomatology, or side effects (n = 2). Imipenem and ciprofloxacin were the most prescribed antibiotics, used in five and four cases, respectively.

Outcome

R. terrigena infections evolved into disseminated intravascular coagulation and septic shock in one and two patients, respectively. Mortality was attributable to R. terrigena infection in two cases. Dead patients had as underlying hematologic malignancies: acute lymphoblastic leukemia and myelodysplastic syndrome. One of them experienced a delay of 2 days to start an adequate antibiotherapy. The death occurred after ESBL producing R. terrigena urinary tract infection and bacteremia complicated with septic shock.

Antibiotic resistance and molecular analysis

Out of our 12 strains of R. terrigena, ten strains were resistant to piperacillin-tazobactam, nine to ceftazidime and cefotaxime, five to ertapenem, and two to imipenem. MICs of ertapenem ranged from 1.5 to 32 mg/L. MICs of imipenem were above 32 mg/L.

Resistance to ciprofloxacin, gentamicin, amikacin, and fosfomycin involved ten, eight, five, and one strains, respectively.

The double disk synergy test was positive in nine strains. Predominant ESBL gene was blaSHV (n = 9/9), flowed by blaCTXM (n = 7/9), (7/7blaCTXM-1 subgroup), blaTEM (n = 5/9) and blaOXA-10 (n = 1/9) [Table 1]. The co-existence of two genes was identified in eight strains.
Table 1: Distribution of genes encoding extended-spectrum β-lactamases and carbapenemases in Raoultella terrigena strains

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Among the five carbapenem-resistant strains, four had the blaOXA-48 gene only (n = 3) or associated with the blaKPC gene (n = 1). One carbapenem-resistant strain did not harbor any carbapenemase gene [Table 1].


  Discussion Top


Our study was the first one concerned R. terrigena infections in HSCT recipients. We were interested in the clinical and bacteriological features of these infections. In the literature, few studied were focus on R. terrigena infections. It was often a case report.[1],[2],[3],[11]

However, there were some limitations in this study such as the retrospective nature and the only recourse to conventional methods for identification of R. terrigena. Our strains differed from typical K. pneumonia strains. It lacked urease. Conventional tests and commercial kits are inadequate to discriminate between Raoultella spp. and Klebsiella spp. It was stated that commercial kits such as API 20E® (BioMerieux) usually failed to correctly identify these two species. Studies showed that VITEK2® automatized system and MALDI-TOF MS determined isolates correctly at the genus level as Raoultella but not at the species level. For the identification of Raoultella species, 16 S rRNA sequencing is the method of choice.[1],[2]

In our study, R. terrigena caused infections in ten patients (1.2% of total HSCT recipients). R. terrigena is an environmental organism, infrequently responsible for human infections that occur mainly in immunocompromised patients.[12] Indeed, four cases were described in the literature. The first case was a 45-year-old liver transplant recipient who developed infective endocarditis due to R. terrigena.[11] In the second case, R. terrigena caused sepsis in a 69-year-old male who underwent major surgery (Whipple's procedure).[3] The third case was a premature newborn who had urinary tract infection with R. terrigena and the fourth case was a subungual abscess in a patient who hurt himself working on a farm.[1],[2] The pathogenic role of Raoultella spp in human infection is still difficult to elucidate. It is considered as opportunistic pathogen that affects mainly patients with immunosuppression or comorbidities, particularly solid tumors.[2]

The prevalence of R. terrigena infection was higher in allograft (1.9% of total allograft) than in autograft (0.6% of total autograft) patients. The allograft is a highly immunosuppressive condition that induces long-lasting neutropenia, GVHD, and long time for engraftment.[12]

Acute leukemia was the predominant underlying disease in our patients (n = 4/10). In fact, this hematological disease is associated with deep and prolonged immune deficiency, leading to an increased susceptibility to infections.

R. terrigena was known as a soil microorganism,[13] which explained the large predominance of skin infections in our series (n = 4). As reported previously, R. terrigena had preference for indwelling catheter and urinary tract,[2] that's why urinary tract infections (n = 4) and bacteremia (n = 3) were frequent in our study.

In our study, mortality was attributable to R. terrigena infection in two cases. The death occurred after ESBL producing R. terrigena urinary tract infection and bacteremia complicated with septic shock. In the four case reports,[1],[2],[3],[11] only one patient who suffered from a fatal endocarditis due to ESBL producing strain and who received a liver transplantation died after multi-organ failure.[11] In the other three reports, the outcome was favorable.[1],[2],[3]

Isolated ESBL producing R. terrigena strains exhibited co-resistance to aminoglycosides and fluoroquinolones (n = 6/9). This is explained by the fact that the coding genes for ESBL are associated with resistance genes to different families of antibiotics on the same plasmid. Very limited studies have been undertaken on the sensitivity of R. terrigena to antimicrobial agents.

Molecular analysis of ESBL producing R. terrigena strains in our study showed the predominance of blaSHV gene (n = 9) followed by blaCTXM gene (n = 7). All the CTX-M enzymes belonged to the CTX-M-1 subgroup. Concerning blaSHV, the typing of this gene is necessary to differentiate the natural penicillinase from the other β-lactamases of the SHV group. CTX-M type ESBL, and more particularly CTX-M-15, are described as the most prevalent ESBL in K. pneumoniae and other Enterobacteriaceae species in Tunisia as well as in many parts of the world.[14]

Amplification of carbapenemase encoding genes revealed the presence of blaOXA-48 in four strains and blaKPC in one strain. Indeed, OXA-48 is the most widespread carbapenemase in Tunisia and North African countries.[14],[15] KPC type enzyme is rare in our country.[14]

Limitations

It was a single centre study with limited number of patients.


  Conclusion Top


In our study, we noted a low prevalence of R. terrigena infections but a considerable rate of attributable mortality and high rate of multidrug-resistant strains. The use of more sophisticated methods of bacterial identification is necessary to better understand the epidemiology of this pathogen.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Demiray T, Köroğlu M, Özbek A, Hafizoğlu T, Altındiş M. The first case of Raoultella terrigena infection in an infant. Turk J Pediatr 2015; 57:624-7.  Back to cited text no. 1
    
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Shaikh MM, Morgan M. Sepsis caused by Raoultella terrigena. J R Soc Med 2011;2:1-3.  Back to cited text no. 3
    
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Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:801-10.  Back to cited text no. 10
    
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Goegele H, Ruttmann E, Aranda-Michel J, Kafka R, Stelzmueller I, Hausdorfer H, et al. Fatal endocarditis due to extended spectrum betalactamase producing Klebsiella terrigena in a liver transplant recipient. Wien Klin Wochenschr 2007;119:385-6.  Back to cited text no. 11
    
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Yemişen M, Balkan İİ, Salihoğlu A, Eskazan AE, Mete B, Ar MC, et al. The changing epidemiology of bloodstream infections and resistance in hematopoietic stem cell transplantation recipients. Turk J Hematol 2016;33:216-22.  Back to cited text no. 12
    
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Boattini M, Almeida A, Cardoso C, Cruz CS, Machado C, Vesza Z, et al. Infections on the rise: Raoultella spp., clinical and microbiological findings from a retrospective study, 2010–2014. Infect Dis 2016;48:87-91.  Back to cited text no. 13
    
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Ben Tanfous F, Alonso CA, Achour W, Ruiz-Ripa L, Torres C, Ben Hassen A. First Description of KPC-2-Producing Escherichia coli and ST15 OXA-48-Positive Klebsiella pneumoniae in Tunisia. Microb Drug Resist 2017;23:365-75.  Back to cited text no. 14
    
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Saïdani M, Hammami S, Kammoun A, Slim A, Boutiba-Ben Boubaker I. Emergence of carbapenem-resistant OXA-48 carbapenemase-producing Enterobacteriaceae in Tunisia. J Med Microbiol 2012;61:1746-9.  Back to cited text no. 15
    



 
 
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