Elizabethkingia are opportunistic pathogens preferentially causing illness among neonates and, usually, immune compromised individuals with underlying medical conditions. This course will focus on one species of Elizabethkingia, namely Elizabethkingia meningosepticum. Outbreaks of this bacteria have occurred throughout the world and in the United States and yet we have hardly heard of it. These pathogens are associated with a high mortality rate. Early detection and treatment with an effective antibiotic regimen is important to increase the probability of good outcomes.
After completing this course, the learner will be able to meet the following 13 objectives:
Elizabethkingia are bacteria belonging to the family of Flavobacteriaceae. The genus Elizabethkingia currently includes four species (Table 1):
E. meningosepticum is the only encapsulated species and the most relevant in clinical practice. The ability to produce proteolytic enzymes may be associated with its virulence and the ability to cause severe human infections.
Serologic procedures were conducted for typing strains isolated in epidemiological studies. Six serotypes have been described, A to F, of which serotype C is most commonly responsible for cases of neonatal infections.
DNA hybridization studies on a limited number of strains of E. meningosepticum have identified two main genomic groups:
E. meningosepticum is a non-fermenting, nonmotile, oxidase-positive, gram-negative, rod-shaped, aerobic bacillus.
E. meningosepticum typically grows within 24 hours of incubation on blood and chocolate agar. E. meningosepticum strains either are not pigmented or produce a very pale yellow, nondiffusible pigment which may not be easily evident at 24 hours. An additional 24 to 48 hours of incubation at room temperature may increase pigmentation, allowing faster identification and aiding in the appropriate empiric therapy until final results become available. Strains growing better at 40o C are mostly associated with invasive meningitis.
Colonies of E. meningosepticum grow poorly or not at all on MacConkey agar and are considered glucose oxidizers. They do not grow on colistin nalidixic agar (CNA) because, although they are resistant to colistin, they are susceptible to quinolones such as nalidixic acid. E. meningosepticum may show colistin resistant and vancomycin sensitive/intermediate growth which is paradoxic for a gram negative bacterium.
Little information exists about the pathogenesis of Elizabethkingia infections. Early experimental animal studies supported the low virulence of these microorganisms but these studies lacked accurate information. Adult rabbits and newborn hamsters survived without evidence of infection after intravenous and subcutaneous inoculation, respectively. Intracerebral inoculation led to a mortality rate of 27% but microorganisms were not recovered at autopsy.
Colonization of the respiratory tract usually precedes invasive infection particularly in high risk populations such as neonates and adults in ICUs. Early and late onset neonatal meningitis is hypothesized to have been preceded by colonization of the infant at the time of delivery since this has been described for other common neonatal pathogens. However, this hypothesis has not been studied.
E. meningosepticum are widely distributed in nature e.g., freshwater, saltwater and soil. They may normally be present in fish and frogs. They are not normally present in human microflora.
Strains of E. meningosepticum, sharing the same phenotypic, chemotaxonomic and genomic characteristics of human pathogens, have been isolated from infected birds. Although community acquired infections have been described after exposure to contaminated water, in most cases the source remains unknown.
Since first recognition of E. meningosepticum as a cause of neonatal meningitis in 1958, outbreaks have occasionally been described since 1961. Nosocomial outbreaks have been an important source of morbidity and mortality in neonates and immunocompromised individuals since 1956.
Hospital infections include:
E. meningosepticum can be transmitted from individual to individual. This bacilla has always affected humans but it is an opportunistic pathogen. It does not usually cause illness in individuals who are otherwise healthy.
Environmental studies have revealed that E. meningosepticum can:
Colonization of patients via contaminated medical equipment/devices include:
E. meningosepticum has been isolated from the female genital tract. Whether this site is a source of neonatal colonization with subsequent development of early and late onset meningitis has not been studied.
In outbreaks, respiratory tract colonization occurs more often than infection.
Among all Elizabethkingia, E. meningosepticum is the most important human pathogen.
Risk factors which should raise suspicion for E. meningosepticum infections include:
General symptoms of E. meningosepticum are very non-specific and may mimic many other infections. Generalized symptoms may include:
The most severe and common clinical presentation during the neonatal period is E. menigosepticum meningitis. Onset of infection may be insidious and may resemble the common signs and symptoms of early and late onset neonatal meningitis due to other pathogens common in this age group. Infections usually affect premature infants during the first few weeks of life and often occur as outbreaks. Among the various serotypes of E. meningosepticum (A to F), type C has been the cause of most reported outbreaks.
As the causative agent of neonatal meningitis, E. menigosepticum demonstrates mortality rates up to 57% and produces severe post-infectious sequelae including brain abscesses, hydrocephalus, deafness and developmental delay. The case-fatality rate has been high in neonates and early and late complications are common among survivors.
Proposed risk factors in neonates associated with poor neurological outcomes, mainly hydrocephalus and deafness, include:
Early diagnosis and the institution of appropriate antibiotic therapy are associated with a better prognosis yet the overall mortality of neonates from early reports is above 60%.
Other common manifestations of E. meningosepticum infection in the neonatal period are:
E. meningosepticum can affect immunocompromised individuals of all age groups whether hospitalized or not. Among hospitalized immunocompromised individuals, clinical presentation varies according to the source of exposure (indwelling devices, infusion of contaminated solutions, head and neck surgery, peritoneal dialysis, polypectomy etc.) and underlying risk factors. Underlying immunodeficiencies and invasive surgical procedures determine the severity and the site of infection. Signs and symptoms of E. meningosepticum in all age groups may include:
Nosocomial pneumonia, mainly among intubated, immunocompromised adults, has a mortality rate of 60%. E. meningosepticum has been isolated from endotracheal and nasal secretions and is not considered the true pathogen. Bacterial load, immune status and selective antibiotic pressure may prompt invasive disease. Reported predisposing immunodeficiencies have ranged from carcinoma, tuberculosis, leukemia, aplastic anemia, asplenia, congenital immunodeficiency and corticosteroid therapy.
In older immunocompetent pediatric patients and adults, community acquired Elizabethkingia infections occur infrequently. Such infections are seen mainly in geriatric patients and the most common clinical presentation is pneumonia.
Only recently has Elizabethkingia infections been found in the immunocompetent and diabetic adult patients. Signs and symptoms may include:
Rapid bacteriologic identification is essential as E. meningosepticum is typically resistant to the common antimicrobials used to empirically treat gram-negative rod infections. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) can provide the diagnosis within 24 hours of admission. Its utility in protein profiling has emerged as a powerful tool for the rapid identification of bacteria and yeast isolates. MALDI-TOF MS can be performed very quickly, requiring a mean of a few minutes per sample to identify an isolate with high accuracy thus aiding in early identification of an unusual and inherently resistant organism, allowing adjustment of the antibiotic regimen.
Using MALDI-TOF MS, colonies from a bacterial culture plate are placed on disposable VMS target plates by using disposable loop, overlaid with 1 µl α-cyano-4-hydroxycinnamic acid matrix and then air dried before being processed by the spectrometer. The result is a spectral fingerprint which is unique to each species as the mass peaks reflect ribosomal and other constitutive proteins. The spectral signature is cross-referenced in a database to identify the organism according to its genus or species. In general, a confidence level of ≥75% is acceptable for identification. MALDI-TOF MS can be performed on all isolates (blood, CSF, tissue, as well as, sputum samples) identifying the same bacterium with identical spectrum, as well as antimicrobial susceptibility profile.
All isolates of Elizabethkingia speciated as E. meningosepticum are sent to state clinical microbiology laboratories where these isolates undergo pulsed field gel electrophoresis (PFGE).
All isolates of Elizabethkingia are shipped to the CDC for more extensive testing and confirmation that includes using optical gene mapping. The CDC laboratory is the only laboratory in the United States that can distinguish between the species and their strains of Elizabethkingia.
Ideal antibiotic therapy is based on determination of the etiological agent and its relevant antibiotic sensitivity. Empiric treatment is often started before laboratory microbiological reports are available when treatment should not be delayed due to the seriousness of the disease. The effectiveness of individual antibiotics varies with the location of the infection, the ability of the antibiotic to reach the site of infection and the ability of the bacteria to resist or inactivate the antibiotic. Some antibiotics actually kill the bacteria (bactericidal), whereas others merely prevent the bacteria from multiplying (bacteriostatic) so that the host's immune system can overcome them.
E. meningosepticum has unusual resistance patterns and mechanisms and are resistant to most β-lactam drugs, including the carbapenems and aztreonam. Many possess two different types of β-lactamases, namely:
Class A extended-spectrum β-lactamases (ESBLs)
Class B metallo-β-lactamases (MBLs)
Class B MBLs confer resistance to carbapenems, which are widely used to treat infections caused by multidrug-resistant gram-negative bacteria. Two types of MBLs, BlaB and GOB, have been identified in isolates of E. meningosepticum. Although they have similar molecular weights, these two enzyme types show only very low molecular similarity. Sequencing and analysis of genes encoding BlaB and GOB has revealed heterogeneity, with up to 12 BlaGOB and 14 BlaB alleles identified. E. meningosepticum is intrinsically resistant to most β-lactams, including carbapenems, due to production of chromosomal MBLs.
Bellais et al. reported that all E. meningosepticum isolates harbored two types of MBLs simultaneously: BlaB belonging to subclass B1 and GOB belonging to subclass B3. However, a recent survey in China reported that only 55 of 170 E. meningosepticum isolates harbored both types of MBLs and 38 isolates harbored only one type of MBL. Furthermore, no MBL genes were detected in the remaining 77 isolates, even though many of these isolates were resistant to imipenem. PCR experiments detected both genes encoding BlaB and GOB MBLs in all E. meningosepticum isolates. DNA sequence analysis revealed that E. meningosepticum isolates possessed 7 types of BlaB gene, including 5 novel variants (BlaB-9 to BlaB-13) and 11 types of BlaGOB gene, including 10 novel variants (BlaGOB-8 to BlaGOB-17). The most common combination of MBLs was BlaB-12 plus GOB-17.
These organisms are generally resistant to the conventional chemotherapeutic agents used in the treatment of neonatal meningitis, such as ampicillin, gentamicin, kanamycin, and chloramphenicol. Different resistance patterns have been reported in different outbreaks worldwide.
The appropriate choice of antimicrobial agents effective for the treatment of E. meningosepticum infections is quite difficult to make due to the following reasons:
Hoque et al. reported a strain of multiresistant E. meningosepticum isolated from eight neonates in a NICU from September 1994 to May 1996. The strain was resistant to ampicillin, ceftazidime, imipenem, gentamicin, ciprofloxacin and trimethoprim/ sulfamethoxazole (TMP/SMX) but was susceptible to piperacillin and amikacin and had variable susceptibility to rifampicin and vancomycin.
Güngör et al. reported that although all of their isolates in an NICU were susceptible to ciprofloxacin in vitro, three patients did not respond to ciprofloxacin therapy given for 6 or 7 days. They switched the therapy to vancomycin and rifampin and all three patients survived with one having a complication (hydrocephalus).
According to the results of the SENTRY Antimicrobial Surveillance Program, Elizabethkingia are known to exhibit resistance to:
Elizabethkingia are known to be susceptible to:
Ceyhan et al. reported that although all of their isolates remained susceptible to vancomycin, rifampicin and linezolid during an outbreak, resistance to imipenem and amikacin was increased in the second and third clusters. This may be due to an inducible resistance against these antibiotics. The possibility of this type of resistance should be considered when choosing an antibiotic regimen to treat E. meningosepticum infection. Four of 13 cases (1 in the second cluster and 3 in the third cluster) died despite antibacterial treatment which had appeared to be effective in sensitivity testing. This may be due to the neonates' prematurity and severe disease and also may represent a difference of in vitro activity.
In conclusion, there is no optimal regimen for the treatment of Elizabethkingia infections, and antimicrobial therapy should be based on MIC results from properly performed susceptibility tests.
E. meningosepticum is usually resistant to cephalosporins, aminoglycosides and carbapenems.
Among the extended spectrum ß-lactam penicillins, piperacillin is the most active agent. In one series of 52 isolates, all were susceptible. More recent studies have reported an increase in isolates resistant or of intermediate susceptibility. Bolash et al. reported that the susceptibilities of E. meningosepticum to piperacillin and ticarcillin were similar. Previous reports had found none of the isolates tested susceptible to ticarcillin.
The addition of a ß-lactamase inhibitor, either tazobactam or clavulanate to piperacillin, amoxicillin or ticarcillin does not confer any significant advantage. However, in a study of 7 distinct isolates of E. meningosepticum, addition of clavulanic acid had a significant impact lowering the MICs of cephalosporins, particularly ceftazidime. Clavulanic acid lowered ceftazidime, cefotaxime and cefoperazone MICs. None of the strains appeared to harbor plasmids, but a broad-substrate, constitutive, chromosomal ß-lactamase was detected.
In general, all cephalosporins have unpredictable and usually poor activity against these pathogens. Cefoperazone, cefotaxime and ceftriaxone showed similar activity with some isolates highly susceptible and many of intermediate susceptibility. However, the MIC50 for E. meningosepticum are above the NCCLS susceptibility breakpoint for almost all the strains tested. Ceftazidime, and the first and second-generation cephalosporins are generally less active. In one study, eight of 12 isolates were reported as being susceptible to cefoperazone-sulbactam. Fourth generation cephalosporins, cefepime and cefpirome have also poor activity against E. meningosepticum.
Aztreonam has shown poor activity against the few isolates tested. Furthermore, as a result of the production of metallo-ß-lactamases, Elizabethkingia are highly resistant to both imipenem and meropenem.
Fluoroquinolones have shown good activity against E. meningosepticum, especially ofloxacin, levofloxacin and ciprofloxacin.
Interpretation of the in vitro performance of vancomycin against E. meningosepticum can be controversial since MIC breakpoints recommended by the NCCLS are for gram-positive microorganisms.
Other non-ß -lactam antibiotics most consistently active against E. meningosepticum are:
Among aminoglycoside antibiotics such as amikacin, therapeutic failure has occurred.
The optimal antimicrobial therapy for infections due to Elizabethkingia, is difficult to determine. Empiric therapy is based on the unusual susceptibility pattern, the availability of effective antimicrobials, the age of the patient, clinical presentation and reported experience.
Definitive therapy should rest upon the susceptibility results of the isolated organism. Important considerations to remember when managing these infections include:
Meningitis is not only the most common but also the most difficult E. meningosepticum infection to treat successfully. Delay in implementing appropriate therapy and the lack of effective antimicrobials commonly permits the persistence of positive CSF cultures for much longer periods than for other gram-negative pathogens causing neonatal meningitis.
Although vancomycin MICs are high and its indication is controversial, this drug has been the most effective agent reported in the literature for the management of meningitis, especially in combination with rifampin. Vancomycin resistance acquired during therapy has been described and this possibility should be considered in the event of treatment failures. A recent report advised against using vancomycin for E. meningosepticum meningitis based on the high MICs of this drug for this pathogen. Rifampin is very active against Elizabethkingia but when used as a single agent it may rapidly induce resistance.
Susceptibility of E. meningosepticum to TMP/SMX varies significantly in recent reports, ranging from 23 to 100% resistance. Linder et al. reported a successful outcome in eight of nine infants treated with TMP/SMX but none of these infants had a positive CSF culture or confirmed meningitis. TMP/SMX has excellent penetration into the CSF and anecdotal evidence for its effectiveness in E. meningosepticum meningitis is available. Special considerations, when using TMP/SMX during the neonatal period, is it association with hematological abnormalities and kernicterus.
Piperacillin should be use cautiously in CNS infections since the achievable concentration of this drug in the CSF could be sub-therapeutic. Furthermore, of the 8 reported cases who received piperacillin, five developed hydrocephalus and one died.
The use of intraventricular antibiotics has been associated with an increased risk of hydrocephalus and should not be considered unless intravenous therapy has failed to eradicate infection. In older patients, empiric treatment with minocycline and quinolones can also be considered. Minocycline has good in vitro activity against the great majority of isolates, good penetration into the CSF and is available as a parenteral formulation. Given that tetracyclines are primarily bacteriostatic, combination with another active agent such as rifampin is advisable.
The pharmacodynamics of quinolones in bacterial meningitis have shown that in order to achieve bactericidal effectiveness, the concentration of antibiotics in the CSF needs to exceed the MBC for the entire dosing interval. Quinolones are lipophilic agents and peak CSF concentrations, up to 26% of the serum concentration are reached rapidly. Although there are discrepancies in the literature, in general the MIC50 of ciprofloxacin is below the NCCLS susceptibility breakpoint for the majority of the isolates tested. Ciprofloxacin is currently FDA approved for neonatal treatment of multidrug-resistant, gram-negative infections. Nevertheless, clinical experience with quinolones in E. meningosepticum neonatal meningitis is not widely available in the English literature. Sakuma et al, recently reported the successful treatment of a 5-day-old infant with E. meningosepticum meningitis treated with intravenous ciprofloxacin and TMP/SMX. The use of TMP-SMX should be used cautiously in this age group.
Most strains of E. meningosepticum are highly resistant to all cephalosporins. Based on in vitro susceptibilities, it has been proposed that ceftizoxime might be effective treatment, however, there is not enough clinical experience reported in the English literature to support the use of this agent in neonatal meningitis. A single case of E. meningosepticum meningitis treated with cefepime was reported in the Literature. Lu et al. described a 21 year-old women with insulin-dependent diabetes and E. meningosepticum meningitis, successfully treated with a 21-day-course of cefepime. The recovered strain was sensitive to cefepime, meropenem, imipenem/cilastatin, and moxalactam.
As with other cases of gram-negative meningitis it is recommended that therapy continue for two to three weeks after sterilization of the CSF is accomplished. Recommendations for treatment of other E. meningosepticum infections follow those for meningitis and are modified by the age of the patient. Minocycline or a quinolone, in combination with rifampin, seems appropriate empiric therapy in patients older than 8 years. Although minocycline has good activity, in severe infections piperacillin is recommended since tetracyclines are bacteriostatic agents. Management of catheter related infections should follow the general considerations indicated for other gram-negative pathogens.
In gram-negative neonatal meningitis:
Management of catheter related infections should follow the general recommendations for other gram-negative pathogens:
No vaccines are currently available for any Elizabethkingia species.
Clinical studies demonstrate the importance of rapid instigation of epidemiological investigation, while also ensuring that fundamental infection control procedures are in place during an outbreak and to prevent an outbreak. It is worthwhile for the infection control team to ensure that the hospital water tanks are inspected and chlorinated yearly and any necessary repair work carried out.
Patients known to be infected or colonized with E. meningosepticum should be placed in isolation following the institutional guidelines for multiple antibiotic-resistant organisms. Particular attention should be placed when handling respiratory equipment, especially nebulizers with a reservoir. Elizabethkingia can multiply to substantial concentrations in nebulizer fluid and increase the risk of spreading nosocomial pneumonia.
Outbreaks of gram-negative bacterial infections are usually due to transient carriage of the organisms on the hands of healthcare workers. Susceptible patients may become colonized after acquiring the organism from a healthcare worker but infection may or may not develop.
Gram-negative bacteria can have an inanimate reservoir such as hospital sinks. It is generally considered that this is not an important factor in endemic hospital-acquired infections. In those susceptible to infection, however, small numbers of potentially pathogenic organisms present on healthcare workers' hands after washing them in contaminated tap water may cause infection.
To detect the source of an outbreak of E. meningosepticum, it is important to obtain cultures from food and infant formulas, wet areas, dry surfaces, equipment and the hands of healthcare workers who have contact with patients. Obtaining cultures on a periodic basis is necessary.
Measures that have been used to eradicate E. meningosepticum outbreaks in pediatric wards include:
Other studies have shown successful control of an outbreak with milder measures including:
All healthcare facilities and staff should follow standard precautions when caring for patients with E. meningosepticum infections, which include:
In conclusion, surveillance for the reservoir and maintenance of rigorous infection control measures are essential to control E. meningosepticum outbreaks in the hospital setting.
Patients with any Elizabethkingia infection who have high risk factors have an increased mortality.
Several predictors of poor outcome include:
Healthcare facility response measures should include:
Elizabethkingia meningosepticum has been deemed a potentially important threat to patients in critical care areas because of its multidrug-resistant phenotype and its ability to adapt to various environments. An increased incidence of E. meningosepticum bacteremia has increased over the last decade. Patients at high risk of E. meningosepticum infection include preterm infants, the immunocompromised and those exposed to antibiotics in critical care units. Vancomycin, rifampicin, newer fluoroquinolones, piperacillin–tazobactam, minocycline and possibly tigecycline are preferred empirical choices for E. meningosepticum infection according to in-vitro susceptibility data. Combination therapy has been used for infections not responding to single agents. Saline, lipid and chlorhexidine gluconate solutions, as well as, contaminated sinks are only a few of the implicated sources of infection following outbreak investigations. In addition to reinforcement of standard infection control measures, actions that have successfully terminated E. meningosepticum outbreaks include pre-emptive contact isolation, systematic investigations to identify the source of the bacterium and thorough cleaning of equipment and environmental surfaces. As the clinical complexity and incidence of E. meningosepticum infections increase, there is a need for heightened awareness of the potential for this bacterium to cause outbreaks. Thus, timely initiation of active surveillance for infected/colonized patients should occur, as well as, investigations to identify the likely source of the bacterium, which will, in turn, allow implementation of appropriate infection control measures.
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This course is applicable for the following professions:
Advanced Registered Nurse Practitioner (ARNP), Clinical Nurse Specialist (CNS), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Registered Nurse (RN)
Medical Surgical, Pediatrics