Clinical Features and Outcomes of Patients with Elizabethkingia Meningoseptica Infection: An Emerging Pathogen

Background: Elizabethkingia meningoseptica, formerly known as Chryseobacterium meningosepticum, is a non-motile, non-fastidious, catalase and oxidase-positive, aerobic, glucose-non-fermentative Gram-negative bacillus �rst de�ned by Elizabeth O. King in 1959. It has recently emerged as an opportunistic pathogen infecting people in the the extremes of age and the immunocompromised, especially in nosocomial settings. There has been an increased interest in this pathogen due to its rising occurrence around the world, its ubiquity in nature, and inherent capacity for antimicrobial resistance. Methods: We describe a retrospective case series at the Aga Khan University Hospital in Karachi, Pakistan on patients admitted from January 2013 to December 2018 with Elizabethkingia meningoseptica infections. All patients identi�ed to have any clinical culture specimen positive for Elizabethkingia meningoseptica were included. Data was collected on a structured proforma from the Hospital Information Management Systems (HIMS). Results:


Background
Elizabethkingia meningoseptica, formerly known as Chryseobacterium meningosepticum, is a non-motile, nonfastidious, catalase and oxidase-positive, aerobic, glucose-non-fermentative Gram-negative bacillus rst de ned by Elizabeth O. King in 1959.Formerly the most pathological member of the Chryseobacterium genus, it was reclassi ed into the genus Elizabethkingia in 2005.[1] Elizabethkingia genus has been noted for its genes that grant it great degree of genetic variability and subsequent antimicrobial resistance.This fact combined with lack of literature, wide distribution in nature, and lack proper treatment regimens have led to high mortality rates in hospital-settings, particularly in Intensive Care Units since 2004.[2] This has led to increased interest in E. meningoseptica as an emerging pathogen in the past decade.E. meningoseptica are most frequently isolated from soil, saltwater and freshwater and from dry and moist clinical environmental and equipment surfaces, intravenous lipid solutions, and municipal water supplies including those which have been adequately chlorinated.[3] Although nearly ubiquitous in nature, it is an uncommon human pathogen.E. meningoseptica predominately causes outbreaks of meningitis in immunocompromised patients, particularly in premature newborns and infants in neonatal intensive care units of developing countries.[4] The bacterium is a rare cause of nosocomial pneumonia, endocarditis, and meningitis in immunocompromised adults.Recently in the past few years, it has been found to cause soft tissue infection and sepsis in immunocompetent adults.[5] In a study from Wisconsin, 48 cases of Elizabethkingia were reported during an outbreak, which resulted in 17 deaths in a 5-month period beginning in November 2015.[9] Most data on E. meningoseptica related septicemia is derived from Taiwan.A large case series showed that yearly incidence of E. meningoseptica bacteraemia increased substantially from 2002 (from 6.8-13.1 to 26.6-39.9per 100,000 admissions; P = 0.006).[10] A recent review of literature suggests that almost all cases of septicemia from E. meningoseptica occur in a nosocomial setting.[3] Moreover, Elizabethkingia, alongside its genetic relative chryseobacterium spp., are inherently extensively drug resistant.They are resistant to broad spectrum of antibiotic classes, including marcolides, tetracyclines, linezolid, polymyxin group, chloramphenicol, aminoglycosides, and beta-lactam drugs.[11] Vancomycin, rifampicin, new uoroquinolones, piperacillin-tazobactam, and minocycline the current preferred empirical choices for E. meningoseptica infections.[3] Tigecycline as the preferred drug of choice for infections is currently being studied.[3] Elizabethkingia meningoseptica is an important emerging opportunistic bacterium that primarily occurs in nosocomial settings.Given its ubiquitous nature, arsenal of multidrug resistant genes, and a nity to infect primarily the immunocompromised; it is paramount that more resources be devoted to study this emerging pathogen.It is also unclear as to which treatment regimen is most effective and what are the factors associated with adverse outcomes.The aim of this study is to describe the clinical features and outcomes of Elizabethkingia meningoseptica infections in a tertiary care center at Karachi, Pakistan.Furthermore, a systematic review of literature regarding this pathogen is also presented in this study.

Methods
This was a retrospective case series of patients admitted between January 2013 and December 2018 with Elizabethkingia meningoseptica infections at the Aga Khan University (AKU) Hospital in Karachi, Pakistan.All patients identi ed to have any clinical culture specimen positive for Elizabethkingia meningoseptica were included.Data was collected on a structured proforma from the Hospital Information Management Systems (HIMS).Identi cation and susceptibility of Elizabethkingia meningoseptica isolated from cultures is performed by automated systems in accordance with Clinical Laboratory Standards Institute (CLSI) recommendations at Aga Khan University Hospital.All patients who were found to be colonized but not infected were excluded.Data was analyzed using SPSS ver 19.Descriptive analysis was performed for demographic features with median and IQR reported for quantitative variables such as age and lengths of hospital stay and frequencies (percentage) for qualitative variables such as gender, co-morbid conditions, mortality and complications etc.All p value ≤ 0.05 will be taken as signi cant.Ethical exemption was taken for the study by the Ethics Review Committee (ERC) of Aga Khan University (AKU) (ERC #2019-1786-4439).Data was kept con dential and no personal identi ers were used.

Results
Sixteen patients with E. meningoseptica were identi ed.The median age was 35 years with 44% males and 56% females, from the ages of 4 days to 83 years.The most common co-morbids were diabetes (31%) and hypertension (37.5%).The average Charlson's co-morbidity index was found to be 3.25.Three patients had some form of pre-existing malignancy, and ve patients had a history of repeated hospitalizations.Fifty six percent (n = 9) had bacteremia with E. meningosepticum.Among other sites of infection, three had urinary tract infection, n = 3 had meningitis and one had pneumonia.61% (n = 8) had monomicrobial growth whereas 38% had polymicrobial growth in culture.43% of patients required a Foley's catheter.56% (n = 9) required intubation and mechanical ventilation.E. meningosepticum was sensitive to beta lactam and quinolones in 68% (n = 11).These patients were treated with levo oxacin.Three of the E.meningosepticum isolates were extensively drug resistant (XDR) with sensitivity only to minocycline, which was the drug used for de nitive treatment.
Only one out of the four patients infected by the XDR strain expired.This case presented with a history of left middle cerebral artery infarction and septic shock.Four out of 16 patients died, and median length of hospital stay was 13 days.The most common co-infection was with Trichosporon beigelii (n = 2) and multi-drug resistant Acinetobacter (n = 2).Both co-infections in case of Trichosporon beigelii were found in urine cultures.In one case, the urine culture yielded a three: Candida tropicalis, Trichosporon beigelii, and E. meningoseptica.This patient had a history of colon carcinoma and colostomy and he expired.
All four patients who died had a history of repeated hospitalizations and signi cant comorbids.All of them had been mechanically ventilated and underwent invasive catheterization.E. meningoseptica was isolated in blood of three and tracheal aspirate in one patient who had undergone esophagectomy, thoracotomy, and tracheostomy.There were four con rmed samples collected from outpatient services.Three of these cases were women.Two were isolated from urine, both were women, and two from blood.One patient was of 12-year girl with a known history of neurogenic bladder with recurrent urinary tract infections, seizure disorder and had a polymicrobial infection with E. coli.
There were three neonates with E. meningoseptica infections identi ed in the neonatal intensive care unit (NICU).One of these presented with meningitis and CSF culture con rmed growth of E. meningoseptica.The other neonate presented with congenital abnormalities of the web of the larynx and in severe respiratory distress.
Con rmed cultures were blood were shown nine days after admission.This was likely a hospital acquired infection.The third case was of a 33-week preterm who had been born with bilateral intraventricular hemorrhages and showed signs of respiratory distress.Blood cultures were con rmed E. meningoseptica growth on the 3rd day of life.Both of the cases which had both positive blood cultures and respiratory distress were intubated in the NICU, likely pointing towards hospital acquired infection.

Discussion
A review literature was conducted to identify clinical case series reporting infections with Elizabethkingia meningoseptica and their outcomes (Table 1).While many isolated case reports and series were found [12][13][14][15][16][17], only one [18] looked at Elizabethkingia cases that were more than four in number.Much of the literature covered one or two cases in any given hospital or area, and none of the articles searched yielded a case series of more than 4 cases.There were no case series or reports on Elizabethkingia cases from Pakistan.Our study identi ed 16 patients in the last 6 years with Elizabethkingia meningosepticum infections.Unlike other case series with predominantly neonatal age group [18]; our patients had a median age of 35 years.Similar to case reports published, the sites of infection were urinary tract infection and meningitis [15,16].The outcomes have been variable with signi cant mortality among neonates [18].However, those patients whose isolates had susceptibility to quinolones and were treated with Cipro oxacin had better survival [13].This is similar to patients who were treated with a quinolone in our study.aminoglycosides and beta lactams, with the notable exception of piperacillin-tazobactam, and show sensitivities to uroquinolones and tetracyclines [11].This fact stood to reason in this study as well.All cases were resistant to aminoglycosides, colistin and carbapenems.All the cases showed sensitivity to either piperacillin-tazobactam, uroquinolones, or tetracyclines, minocycline in particular.
This study is a single center retrospective analysis and therefore is associated with several limitations.Four cases were outpatients and were lost to follow-up.However, this study is the rst case series to date from Pakistan reporting the clinical features and treatment outcomes of Elizabethkingia meningoseptica infections.Moreover, it offers insight into the sensitivity pattern of this organism in our region.

Conclusion
E.meningosepticum is an emerging nosocomial infection and associated with good survival especially if isolates are susceptible to quinolones and can be treated with them. Declarations

Table 1
Summary of studies reporting Elizabethkingia infections and their outcomes E. meningosepticum is intrinsically resistant to most commonly used antimicrobial resistance; therefore, options of treating it are quite limited.Most studies have established that clinical isolates are always resistant to