NIH Sleuths Track Source Of Sphingomonas Outbreak (CME/CE)

CME Author: Zeena Nackerdien

Study Authors: Ryan C. Johnson, Clay Denning, et al.

Target Audience and Goal Statement:

Infectious disease specialists

The goal was to explore a study using a systematic genomic investigation to understand the dynamics of an indolent Sphingomonas koreensis outbreak within a single hospital.

Questions Addressed:

Healthcare-associated infections (HAIs), particularly of multidrug-resistant bacteria, affect at least 2 million people annually in the U.S. While epidemiologic chains of transmission have been clarified for outbreaks of Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus and Mycobacterium tuberculosis, knowledge gaps exist regarding the characteristics of many opportunistic Gram-negative human pathogens. Infections by these organisms are of special concern, as they are extremely efficient at upregulating genes that code for mechanisms of antibiotic drug resistance, especially in the presence of antibiotic selection pressure.

The Gram-negative sphingomonas species are usually omnipresent in natural and man-made aqueous environments, with the most human pathogen identified as S. paucimobilis; however, reports of a cluster of Sphingomonas koreensis infections in 2016 at the National Institutes of Health (NIH) Clinical Center prompted the investigators to address the following questions:

• Can culture-based and genomics-based techniques be used to characterize isolates from four of the six inpatients at the NIH Clinical Center who developed infections with sphingomonas species?
• Could the hospital implement remediation strategies based on results from microbiologic culturing and fine-scale genomic analyses?

Synopsis and Perspective:

When a cluster of sphingomonas infections was identified in 2016, it sparked an epidemiological investigation that led to finding 12 patients over 11 years who had been infected with genetically similar strains of S. koreensis. Nine of the 12 patients had undergone stem cell transplants and the median length of stay was 44 days (range, 0 to 374). Patients had infection-related conditions ranging from S. koreensis pneumonia to S. koreensis bacteremia.

The strain was cultured at a very low concentration in one of the patients and thought to be the result of either contamination or colonization. Of the remaining 11 patients, 8 patients with S. koreensis infections recovered, and 3 patients died (all 3 patients had S. koreensis sepsis and severe, unrelated infections).

Julia A. Segre, PhD, of the National Human Genome Research Institute of the National Institutes of Health (NIH) in Bethesda, Maryland, and colleagues used whole-genome DNA sequencing to analyze clinical isolates of multidrug-resistant S. koreensis identified from 2006 to 2016 at the NIH clinical center. Shotgun metagenomic sequencing was also used to culture S. koreensis from sinks in patient rooms and to identify a reservoir of the bacteria within the infrastructure of the hospital. Shotgun metagenomics sequencing facilitated the determination of diversity and abundance, with the addition of functional analysis. Comparisons were then made with environmental and clinical S. koreensis isolates obtained from other sources. More than 80 sequenced isolates and 49 metagenomic samples were evaluated in this study.

Genetic sequencing classified two cases as different from one another (i.e., S. yanoikuyae and S. trueperi). The remaining four S. koreensis isolates had >99.92% similarity, suggesting that they belonged to the same clonal strain. Moreover, the isolates were resistant to numerous classes of antibiotics, e.g., aminoglycosides (amikacin and gentamicin), beta-lactams (aztreonam, piperacillin–tazobactam, cefepime, ceftazidime, ceftriaxone, and meropenem), and fluoroquinolones (levofloxacin). This result illustrates the difficulty of treating these infections. Based on retrospective analyses of banked clinical isolates of sphingomonas from the same institution, it appears that this isolate had been intermittently recovered over the past decade. S. koreensis from non-NIH sources were genetically distinct from the isolates characterized in this study.

Quantitative profiles or phylogenetic trees of single-nucleotide variations (SNVs) of the core genome were used to identify individual S. koreensis strains and their relative abundance within each sample. Using this approach, sinks were found to be colonized by numerous S. koreensis strains. Together with metagenomics analyses, this strategy enabled the identification of reservoirs in select plumbing fixtures, thereby enabling the initiation of remediation strategies. For instance, components from two sinks were immersed in 71^o C baths for 20 minutes following microbial culture. Thereafter, cultures of the heated components were negative.

One limitation of the study was that investigators could not unequivocally match any isolate from a sink in a patient room to a clinical isolate. Because the investigators were not aware of strain diversity in early samples, there was also no metagenomic data for the initial isolates from patients and sinks.

“S. koreensis is a waterborne organism, which also poses risk for HAIs, particularly in immunocompromised patients,” the authors said. Exposure is through water droplets or water aerosols “that are inhaled or that breach normal defenses through non-intact mucous membranes or invasive devices,” they noted. The authors added that community-acquired sphingomonas infections are rarely reported.

Source Reference: New England Journal of Medicine, Dec. 27, 2018; 379:2529-2539.

Study Highlights: Explanation of Findings

Genomic and metagenomic methods employed in this study provided a higher-level comprehension of an intermittent sphingomonas cluster. Four highly similar S. koreensis strains were isolated from patients’ sinks in 2016, suggesting they belong to the same clonal strain. Additionally, eight older S. koreensis strains were identified dating back to 2006, shortly after the opening of the new hospital building. The older isolates shared a high degree of nucleotide identity with one another and with the 2016 isolates (>99.8% average nucleotide identity). The findings suggested that the rarely reported S. koreensis is an opportunistic human pathogen with a pervasive presence in the NIH Clinical Center.

The genetically diverse population (ascertained from whole-genome sequencing of 68 S. koreensis isolates obtained from patients and the plumbing system) is a phenomenon frequently seen in microbial outbreaks. A key strength of this study lies in the fact that understanding the genetic diversity of bacterial species causing an outbreak could be used to tackle issues such as patient-to-patient transmission and the point of origin.

Interestingly, this aerobic Gram-negative rod was originally described in 2001 following isolation from natural mineral water in Korea. Sporadic reports in the literature detail isolated cases of meningitis and dialysis-associated peritonitis linked to S. koreensis. The current data provided a valuable “genetic barcode” to also draw an inference regarding the potential for the existence of an entire S. koreensis reservoir at the peripheries of the NIH Clinical Center water-distribution system.

Following evaluations of the chlorine concentration and water temperature, the investigators found that chlorine concentrations of hot-water samples were below the U.S. Centers for Disease Control and Prevention (CDC)-recommended threshold of ≥0.5 mg/L. Beginning in December 2016, hot water was calibrated to maintain levels of chlorine above 0.5 mg/L. In keeping with the hospital standard of ≥51^o C, the water temperature was determined at the heat exchanger and adjusted from 46-49^o C to a temperature of ≥60^o C.

Other studies have illuminated the threats posed by potable water and splashback from the drain to patients. The remediation strategies adopted by the NIH Clinical Center to prevent further S. koreensis infections are also applicable to other waterborne pathogens.

The authors hypothesized that “a single S. koreensis strain entered the water system soon after construction of the new NIH Clinical Center hospital building in 2004. Reports describe colonization of pipes with waterborne bacteria in newly constructed, unused facilities in which water has stagnated.”

To date, no new sphingomonas infections have been reported at the Clinical Center since the implementation of remediation strategies in 2016, according to another article.

Molly Walker wrote the original story for MedPage Today.

• Reviewed by
  Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner