“Unmasking the Uncommon”: A case series of multi-drug resistant Elizabethkingia meningoseptica causing late-onset sepsis and meningitis in preterm neonates

Introduction

Elizabethkingia meningoseptica is an uncommon cause of infection that mostly affects immunocompromised individuals.¹ In neonates, premature birth weight and very low birth weight are major risk factors. E. meningoseptica infections present as early onset sepsis and meningitis with a high mortality rate. Reports of late-onset sepsis and meningitis are rare.² E. meningoseptica is found in both natural and hospital environments, and is isolated from contaminated water supplies, equipment surfaces and tubing, infant formulas, and IV solutions.^3,4 Its ability to form biofilms allows it to persist in hospital environments, with outbreaks being reported, especially in Neonatal Intensive Care Units (NICU).⁵ Its intrinsic resistance and recent reports of multi-drug resistant strains (MDR) are a cause for growing concern.¹ In the absence of established guidelines for antibiotic susceptibility testing (AST) and lack of evidence-based treatment regimens, treatment failures are common with negative patient outcomes.¹

We present three cases of late-onset sepsis in high-risk neonates born at a district government hospital and admitted to the NICU simultaneously. All had a similar MDR AST profile but were successfully treated.

Case report

Discussion

Elizabethkingia meningoseptica is an emerging nosocomial pathogen widespread in natural environments. It can persist under harsh conditions in healthcare facilities and has been isolated from hospital water supplies and critical care equipment such as mechanical ventilators and indwelling catheters, resulting in outbreaks.^3,4,6 In neonates, E. meningoseptica infection typically manifests as either early onset sepsis or meningitis. Predisposing factors in neonates include prematurity, very low birth weight, central venous catheters, immunosuppression, and prolonged and prior exposure to higher antibiotic concentrations.^1,3 Neurological complications are common in 30.4% of survivors who develop hydrocephalus and 6.5% experience varying degrees of hearing loss.^2,3

Recent reports show a notable increase in E. meningoseptica infections, possibly due to advanced automated methods.³ E. meningoseptica is resistant to a wide range of antimicrobials including most β-lactams (including cephalosporins and carbapenems), as well as in combination with β-lactamase inhibitors (except for piperacillin-tazobactam), macrolides, tetracyclines, polymyxins, chloramphenicol, and aminoglycosides.^1,3,7 Thus, most empirical treatments for gram-negative infections are ineffective. Global reports show a geographical variability in susceptibilities to fluoroquinolones, piperacillin/ tazobactam and TMP-SMX. Recent literature from USA⁸ and Australia⁷ have reported up to 89% susceptibility and 75% clinical success with piperacillin/tazobactam, unlike our isolates which were 100% resistant. Similar to global studies, our isolates expressed susceptibility to Levofloxacin and Minocycline.⁷

Uniquely, susceptibility to antibiotics used to treat gram-positive infections such as Vancomycin, Clindamycin and Rifampicin has been reported in Elizabethkingia spp. Initially, susceptibility to vancomycin was demonstrated by disk diffusion, using the CLSI interpretative criteria for Staphylococcus spp. Discrepancies recognized in results of susceptibility testing for vancomycin in E. meningoseptica by disk diffusion and detection of MIC breakpoints by broth microdilution or agar dilution, resulted in the former method being abandoned. While lacking interpretative breakpoints in CLSI and EUCAST, treatment failures are seen with elevated MICs of ≥4μg/mL and isolates are considered non-susceptible.⁷ Though initially advocated as the mainstay agent in the treatment of invasive E. meningoseptica infections, increasing reports of therapeutic failures are alarming.⁹ There is a high prevalence of VanW gene in Elizabethkingia isolates from Australia and South East Asia, conferring a VanB type phenotype as seen in Gram positive organisms.¹⁰ The wide variation in susceptibility highlights the need for MIC profiling.

The potential for multi-drug resistance and the absence of established guidelines for antibiotic susceptibility testing make management even more challenging. While some studies advocate a combination of minocycline and TMP-SMX with isolates demonstrating 90% susceptibility to TMP-SXM,⁸ we noted our cluster of isolates to be resistant to TMP-SMX. Our patients showed good clinical outcomes with monotherapy of vancomycin in 2 cases and ciprofloxacin in 1 case. Fluoroquinolone monotherapy has proven to be effective in E. meningoseptica infections, however combination therapy is preferred to avoid high-level resistance developing due to single-step mutations.^7,10 Vancomycin alone has been reported to have a high mortality (78%) in the management of neonatal meningitis.⁹ Based on the available data, a combination of vancomycin and ciprofloxacin, linezolid, or rifampicin has demonstrated good clinical efficacy in the treatment of E. meningoseptica meningitis and bacteremia.^1,3 The use of rifampicin-containing therapies may be curbed due to a paucity of data in effective management of Gram-negative infections,¹⁰ as well as reserved in counties endemic with tuberculosis.

Attempts must be made to trace the source of the infection and to take stringent steps to prevent the transmission of this infection. Recommendations for environmental screening include water sampling and environmental swabs from sinks, faucets, patient beds, tubings and devices.⁶ Infection prevention recommendations include consistently using alcohol-based hand rubs following hand washing and using sterile water to change diapers. It is also important to periodically repair, clean, super chlorinate, and replace sink taps. Continuous training is essential to reinforce proper hand hygiene practices and contact precautions for hospital personnel. ¹¹

There are a few reports of E. meningoseptica causing late-onset sepsis and meningitis.^1,2 Interestingly, all of our patients had late-onset sepsis and meningitis. Cases 1 and 3 presented with bacteremia, whereas case 2 showed meningitis. Prematurity was a common risk factor for all neonates. Additionally, cases 1 and 3 had other predisposing factors such as the use of central venous catheters and prolonged and prior exposure to higher antibiotic concentrations. Timely identification of cultures allows for prompt and tailored therapy with good patient outcomes. Long-term follow-up is required to assess the potential neurological complications. Neonates were admitted to the NICU during the same period. We hypothesized that our cases were nosocomial infections; however, environmental screening failed to identify the source of infection. Due to lack of funds, sequencing was not performed to determine the epidemiological relationship of the strains.

The presence of gram-negative bacilli causing bacteremia or meningitis in neonates with risk factors must alert clinicians to E. meningoseptica. Prompt and appropriate antibiotic therapy is key to curbing long-term morbidity and mortality.

Ethics and consent

This study was approved by the Institutional Ethics Committee (Kasturba Medical College, Mangalore), Reg No. ECR/541/Inst/KA/2014/RR-20, DHR Reg. No. EC/NEW/INST/2020/742. Approval was given on 20.12.2023 with protocol number IEC KMC MLR-12/2023/513.

Written informed consent for publication of clinical details and/or clinical images was obtained from the parents of the patients.