91桃色

Leclercia adecarboxylata is a gram-negative bacillus firstly described by H. Leclerc in 1962, and previously known as “Enteric group 410” or “Escherichia adecarboxylata” [1], since Leclercia spp. shares a lot of structural and microbiological characteristics with the genus Escherichia. Due to those similarities, L. adecarboxylatainfections might be more common than what believed so far since past clinical cases might have been erroneously defined as Escherichia spp. infections. Moreover, most bacterial assays often could not distinguish these morphologically and metabolically similar bacteria [2,3]. In present days, the availability of more sensitive testing methods (e.g.: DNA hybridization, computer identification studies) like Matrix Assisted Laser Desorption/Ionization Time of Flight (“MALDI-TOF”) mass spectrometry allowed a more precise species identification, eventually leading to the present categorization [4]. Given this increasing number of accurate identifications, L. adecarboxylatahas been recently recognized as an emerging bacterium [4].

Hence, we decided to review the most original and relevant articles available in the literature to provide a state of art to the current knowledge of this emerging pathogen.

References for this review were identified from PubMed, Embase, and Cochrane with the following research term combination: “Leclercia adecarboxylata” OR “Leclercia” OR “Leclercia infection”. Only papers in English were included. The final reference list was generated based on timeline, originality, and relevance to the scope of this Review.

Etiology and microbiology

Leclercia adecarboxylata is a gram-negative, motile, facultative- anaerobic, oxidase-negative, mesophilic bacillus belonging to the Enterobacteriaceae family [4]. It shares many structural and microbiological properties with the genus Escherichia [1,4], but, thanks to more sensitive testing methods such as DNA hybridization and computer identification studies, a reclassification of this bacteria was achieved [4]. However, L. adecarboxylataand Escherichia also harbor some differences: in particular, unlike Escherichia strains, Leclercia might occasionally test positive for urease hydrolysis and differ for malonate utilization and production of yellow pigment; they also grow in the presence of potassium cyanide and, unlike Escherichia, resulting negative to lysine and ornithine decarboxylase tests [5].

Given its low virulence, L. adecarboxylatararely causes monomicrobial infection, mostly in immunocompromised patients, while it is thought that this pathogen generally requires other coinfecting microorganisms to establish infection in immunocompetent subjects [2]. In the setting of polymicrobial infections, the most co-pathogens found are Enterococci, Acinetobacter, Pseudomonas aeruginosa, Klebsiella, Fusarium and Staphylococcus epidermidis [3,6]. Some cases of monomicrobial infection were also described in immunocompetent patients even without significant underlying comorbidities: particularly, only in one case the patient reported a clinical history of chronic diseases [7], while in the other cases no medical history was observed [8-10].

Leclercia adecarboxylata shows generally high susceptibility to antibiotics, however, some Multidrug-Resistant (MDR) strains have been widely described even in local outbreaks [2,6,11-13]. Particularly, specimens harbouring blaTEM-1 and blaCTX-M group 1 and intl1 genes (dfrA12-orfF-aadA2) as genetic determinants for resistance might become difficult-to-treat pathogens [11].

L. adecarboxylata is a ubiquitous microorganism, which may be found in both aquatic environments and soil, as well as in the commensal gut flora of certain animals [1]. Asymptomatic carriage or colonization in healthy individuals is also described, rising concerns in regards to the spreading of the infection to immunocompromised people [14].

Prolonged antibiotic therapies, invasive interventions to the gastrointestinal tract, concomitant use of immunomodulators and the simultaneous presence of vascular graft or hemodialysis catheter could represent a risk factor for developing L. adecarboxylatainfections.

Indeed, several articles associate L. adecarboxylatawith haematological malignancies, solid cancer in general, or immunomodulator therapy. Moreover, several other underlying conditions might favor L. adecarboxylatainfections: for instance, wounds may be represented an access into the tissue, thus easing the pathogenicity as well as catheters in catheter-related bacteraemia or peritonitis could be developed in patients undergoing dialysis or chemotherapy [2]. A recent L. adecarboxylataoutbreak was reported in 25 patients receiving total parenteral nutrition (TPN): this pathogen was isolated after an extensive epidemiological investigation in one sealed, unopened bottle of TPN belonging to the same batch administered to all patients [12].

Clinical manifestations and diagnosis

L. adecarboxylata is implicated in several clinical syndromes, such as endocarditis [4,15,16], bacteraemia [2,7], wound infection and cellulitis [10,17,18], pharyngeal and peritonsillar abscesses [9], urinary tract infections [19], pneumonia [20] and peritonitis [21,22]. Cases of keratitis with corneal abscess from L. adecarboxylatainfection have also been reported in patients with a history of exposure to the aquatic environment [17]. Most of the cases described regards immunocompromised adults, however, wound infections and peritonitis were reported even in immunocompetent children [18,21]. Two cases of pediatric septic arthritis of the knee caused by L. adecarboxylata, following an injury with residual foreign bodies, were reported in otherwise healthy Australian children without any significant pre-existing condition [23].

Other common clinical presentations are catheter-associated urinary tract infections in males, with translocation through the genitourinary tract, ventilator-associated pneumonia, peritonitis and vascular graft infections. Bacteremia can also occur after translocation across the intestinal mucosal barrier, in the setting of megacolon, prolonged antibiotic therapies or mucosal alterations due to invasive interventions to the gastrointestinal tract [2,14,24]. As reported before, most infections have been linked to immunosuppression, but also to the simultaneous presence of central vascular catheter [7] as it appears from several reports, catheters could be considered as important reservoirs for L. adecarboxylatabloodstream infection regardless of the patients’ immune status [6,11,25]. In light of this, Dotis, et al., recently conducted a systematic review of the case reports in international literature, identifying 13 cases of peritonitis in patients with peritoneal dialysis. All the patients included had a favourable outcome and showed a good response to the antibiotic therapy [26].

Currently, considering the wide distribution and use of MALDI- TOF, the diagnosis of a L. adecarboxylatainfection does not require any significant clinical or microbiological efforts. This pathogen might be isolated also from several biological specimens, such as blood culture, wound pus, faeces, urine, gallbladder, peri-ciliary and ciliary abscesses, synovial fluid, peritoneal fluid from peritoneal dialysis, sputum, cerebrospinal fluid, catheters, skin wounds, peritoneal fluid and abscesses (e.g.: peritonsillar and periovarian) [7].

The isolates more commonly mentioned in literature usually show a high susceptibility to antibiotics [2,3] and might be controlled with a variety of antibiotics, such as beta-lactams, witnessing therapeutic to therapeutic failures or needing second line treatments. [11]. A more comprehensive evaluation regarding natural antimicrobial susceptibility patterns was reported by Stock et al from 94 L. adecarboxylatastrains, collected from several human specimens: the bacteria were naturally resistant to numerous antibiotic molecules, such as oxacillin, clarithromycin, erythromycin, roxithromycin, ketolides, rifampin, glycopeptides, streptogramins, fusidic acid, lincosamides, penicillin G, and fosfomycin but susceptible to most beta-lactams, quinolones, aminoglycosides, tetracyclines, nitrofurantoin folate pathway inhibitors, azithromycin and chloramphenicol.

However, some multi-resistant strains have been reported in the literature. Recently a case of Catheter-Related Bloodstream Infection (CRBSI) was described in a patient affected by gastric and duodenal diffuse large B-cell lymphoma with TPN through a tunneled central venous catheter. A multi-drug resistant L. adecarboxylatawas isolated from either peripheral and CVC blood culture, with an antibiogram showing full resistance to amoxicillin/clavulanate, fosfomycin, and trimethoprim-sulfamethoxazole [13]. In addition, Extended-Spectrum Beta-Lactamase (ESBL), New Delhi Metallo-Beta-Lactamase 1 (NDM)-producing and carbapenem-resistant L. adecarboxylataare also described. Three cases of ESBL producer isolates were in fact reported: the first case was described from a patient with acute myeloid leukaemia [27], the second in a 47-year-old female with breast cancer [11] and the third one in a 50-year-old female with end-stage renal disease [6]. In relation to NDM-producing L. adecarboxylata, two cases were reported: the first regarding a patient hospitalized for a foot trauma-related injury [28] while the second concerned an outbreak of 25 patients in intravenous TPN [12]. Regarding carbapenem-resistant L. adecarboxylatastrain, one case was reported from a healthy newborn in China, with a resistance pattern to both meropenem and ertapenem [29]. However, as only case reports and case series report resistant L. adecarboxylatastrains, it is impossible to infer whether risk factors are implicated in this concerning process.

Regarding treatment options, there are no shared guidelines nor any recommendation for L. adecarboxylatainfections. Most isolates described are sensitive towards most of all tested antibiotics [2]. However, as described by Spiegelhauer et al., several strains of L. adecarboxylatadisplayed resistance to ampicillin (9/30 isolates resistant) and inherent resistance to fosfomycin, unlike other Enterobacteriaceae (8/10 isolates resistant) [30], so these antibiotics should not be used as the first line for treatment. Stock et al. described the natural susceptibility patterns of L. adecarboxylata, showing that most of the isolated strains were sensible to beta-lactams suggesting that Leclercia could be treated with this antibiotic class [11]. Lastly, in regards to infection where a graft is present (e.g. Tenckhoff or vascular catheter), a strict recommendation to remove the catheter is uncertain; although some evidence suggests that removal was necessary to achieve therapeutic success [31], the ability of L. adecarboxylatato produce biofilm remains unknown, even if the role of L. adecarboxylatain catheter-related bloodstream infections is increasing (Figure 1) [2].

Figure 1: Take home messages: What is currently known about Leclercia adecarboxylata.

Infections caused by L. adecarboxylatahave likely been underestimated for decades due to the difficulty in identifying the microorganism, leading to underreporting in the medical literature [29,32-40]. An electronic search was employed to find the published articles which reported L. adecarboxylatainfections throughout the United States National Library of Medicine, PubMed (last accessed October 2023). All prospective studies, retrospective studies, case series, or case reports published in peer-reviewed medical journals, regarding the search topic were included. We excluded articles published in non-English languages, pre-print or ahead of print analysis, pre- clinical studies (including in vitro or animal model studies), short communications, letters to the editor, and commentaries. Our findings are summarized in Table 1.

A total of 160 papers were identified through our search, but, eventually, only 64 were included as describing a clinical case of L. adecarboxylatainfection. While 99 patients were affected by a generally multi-sensible L. adecarboxylatainfection, the number of multi-drug resistant strain is rising over time [41-62]. Among the documented cases of pediatric infection, even a colonization of a carbapenem- resistant L. adecarboxylataisolated from a healthy newborn has been reported in 2023 [29,63-70]. All things considered; it is hard and incorrect to define L. adecarboxylataas an “opportunistic pathogen” as often happen in literature [71-80], even if most of the infections occur in immunocompromised hosts.

Carbapenems are always considered when treating a multidrug- resistant Gram-negative bacterial infection, but carbapenem-resistant Enterobacteriaceae have become a major public health threat, leading to severe infections, limited treatment options, and mortality rates of 26%- 44% [29]. As previously shown despite most cases of L. adecarboxylatainfection are susceptible to common antibiotics, some drug-resistant strains have recently been detected in literature [29]. Moreover, even animal studies raise concern on the emergence of resistant strain of L. adecarboxylataas suggested by a recent paper regarding a genomic investigation of a multiple fluoroquinolone-resistance from a diseased synanthropic pigeon [81,82].

L. adecarboxylata infections occur rarely in immunocompetent patients and the pathogen usually shows good sensibility patterns to most antimicrobial agents. However, severe infections from difficult-to- treat strains are increasing. Given the absence of specific guidelines on L. adecarboxylatamanagement and treatment, there is a need to create a multicentric international network sharing experiences to increase knowledge about this emerging pathogen.

Conceptualization, E. F.; writing-original draft preparation, M.D.G., G.T., C.C., and E.F.; validation, M.D.G., G.T., C.C., and E.F.; investigation, M.D.G., G.T., C.C., and E.F.; data curation, M.D.G., G.T., C.C., and E.F.; writing-review & editing, M.D.G., G.T., C.C., S.C., F.C., A.C., F.C., and E.F.; visualization, M.D.G., G.T., C.C., S.C., F.C., A.C., F.C., and E.F.; supervision, A.C., F.C., and E.F. All authors have read and agreed to the published version of the manuscript.

None to declare, this research received no external funding or financial support

None to declare, all authors have no competing interests.

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