VRE. By Theresa Deike. Disease Etiologic Agent

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1 VRE By Theresa Deike Disease Etiologic Agent Vancomycin-resistant Enterococci, or VRE, is a major nosocomial disease at hospitals throughout the world (1). While over 54 different species of vancomycin resistant enterococci have been shown to cause the disease, Enterococcus faecalis and Enterococcus facecium are the two most common species in the US (1). Both E. faecalis and E. facecium belong to the domain bacteria, kingdom Eubacteria, subkingdom Posibacteria, Phylym Firmicutes, class Bacilli, order Lactobacillales, family Enterococcacea and genus Enterococcus (2). Both species are prolific colonizers, especially of immunocompromised patients, and are difficult to treat due to their intrinsic and acquired resistance to antibiotics(3). Disease Transmission and Reservoirs VRE infections are spread by direct contact with the causative microbe (4). As the primary reservoir of Enterococci in humans is the lower GI tract, any surfaces that come into contact with the feces or skin near the groin of the patient can become contaminated (5). This proves problematic in healthcare settings especially as many carriers of the bacterium are asymptomatic and proper infection control protocols are not in place as the patient is not displaying symptoms (3). In hospitals and other long term care facilities, patients are primarily infected via the contaminated hands of healthcare providers (3). Studies have shown that many healthcare providers believe the movement of patients and adjustment of patient machines and airways to be clean procedures that do not require strict cleaning or handwashing after the completion of the task (3). This allows for the spread of the causative bacteriums to other areas outside of the GI tract such as the mouth and throat as the providers do not realize they are spreading the disease (1,3). The introduction of E. faecalis and E. facecium to these areas allows for cross colonization and the exchange of bacterial resistance to unrelated bacteria in the area (1,3). The improper cleaning of infected medical equipment such as toilets, sheets, shower chairs, patient gowns, and beds has been shown to be a major cause of infection for bedridden patients in nursing homes and the ICU (1,3). Patients who obtain the bacteriums via these infected surfaces are primarily colonized initially in the lower GI tract or female reproductive tract due to the direct contact with the anus, urinary meatus, and vagina (3,5). Entercocci remains viable on contaminated surfaces for days to weeks which greatly increases the risk of nosocomial infection for immunocompromised patients when these surfaces are not properly cleaned (3). Once a patient has been infected with VRE, the disease can persist for months to years due to the suppression of healthy gut flora (1). Much like C. difficle infections,

2 the repeated use of antibiotic use kills the normal gram positive bacteria of the gutallowing for the overgrowth of the Enterococci (1,3). As VRE infects primarily immunocompromised patients, persons with cancer, hematological malignancies, recent organ transplants or surgeries, and patients who have prolonged stays in the ICU or long term care facilities are at greatest risk (1). As decolonization efforts in these patients are largely transitionary and the bacteriums can remain viable for extended periods in the external environment, VRE infection is these patients can reemerge within days (1). While infection with VRE can occur outside of hospital settings, through the consumption of infected animal products or improperly treated water, the strains encountered are far less virulent and are typically easier to treat than those causing nosocomial infection (6). This is due in part to the introduction of glycopeptide antibiotics to animal feed(1). The most common animal reservoirs are chickens, pigs, and cattle3. The disease has been shown to infect domesticated animals as well who obtain the bacterium via infected meat products (1,6). Characteristics of Enterococcus faecalis and Enterococcus facecium All species of Enteroccoci are gram positive bacteriums found as single or paired chains of cocci (6,7). The species are prolific hydrolzers of esculin in the presence of bile and are able to tolerate high salt concentrations as well as a variety of temperatures (3). Both catalase negative and facultatively anaerobic, the species differ primarily in their resilience and pathogenicity (7). Enterococci species are resilient with mechanisms for both acquired and intrisic resistance to a variety of antibiotics due to their high genome plasticity (1). This includes the regular usage of plasmids, transposons, and insertion sequences to disseminate and integrate antibiotic resistance and other genes related to pathogenicity and virulence between species (1,9). While E. faecalis is more pathogenic than E. facecium, E. facecium composes the majority of VRE infections in North America1. Though currently making up 15% of nosocomial VRE infection in the US the prevalence of VRE E. faecalis infections is growing (8). A primary difference between the two species is the difference in susceptibility to β- lactam antibiotic activity. While all species of Enteroccocus present with low-level intrinsic resistance to β-lactams due to the presence penicillin-binding proteins, the production of these protiens is increased with E. facecium (3,8). As a result, E. facecium is more difficult to treat due to its increased resistance (1). E. facecium most commonly infects the urinary tract and skin which places immunocompromised surgery patients and persons with urinary catheters at increased risk due to the limited treatment options (9). The increased pathogenicity of E. faecalis is due in part to the production of highly specialized Gelatinase not present in other species of Enterococci (9). Gelatinase is a zinc metalloprotease known for the degradation of host substrates such as collagen, fibrinogen, and fibrin. By degrading these substances, the pathogenicity of the

3 bacterium greatly increases and allows for the formation of biofilms on surfaces not readily colonized by E. facecium (9,1). This includes surfaces such as the heart, brain and kidneys (9). Virulence Factors In order for an Enterococcus infection to be classified as VRE, the bacterium must display specific resistance to the antibiotic Vancomycin, which is not found in all species of Enteroccoci (6,8). Both E. faecalis and E. facecium carry a variety of genes for Glycopeptide resistance (1). While VanA resistance is primarly only carried by E. facecium, the seven other phenotypic variants of Glycopeptide resistance have been found in both species1. These genes function by disrupting the formation of the bacterial cell wall (1,3). Glycopeptide antibiotics such as Vancomycin bind to the D-ala-D-lac termini of pentapeptide precursors blocking peptidoglycan synthesis and cross linking of the cell wall (1). Without a functional cell wall the bacterium dies (1). Up until the 1990s, Vancomycin was the antibiotic of choice for most infection. Its overuse and improper patient use in the United States has resulted in North America having the highest rates of nosocomial VRE in the world (1). Common between most species of VRE is the appearance of additional resistance to Aminoglycosides (1). E. faecalis and E. facecium have moderate resistance to Aminoglycosides, primarily Gentamicin, due to the presence of genes that encode for enzymes directly capable of deactivating the antibiotic and the modification of ribosomal attachment sites (1,3). All Enterococci species have low levels of resistance to Aminoglycosides as a result of decreased permeability for the antibiotic across the cellular membrane (1). Diagnosis Diagnosis of all Vancomycin Enteroccocci species occurs primarily through the culture of peri-rectal swabs or patient stool samples (10). VRE is only properly diagnosed in 45% of blood and urine samples so the routine screening of skin and stool samples is key for patient management during an outbreak in a care facility (3). The two main types of culture used for diagnosis are Bile esculin azide agar and brain heart infusion agar both containing 6 μg/ml of vancomycin to confirm Vancomycin resistance (10). Diagnosis from these cultures is then confirmed via the MIC Method (10). The Mic Method, or the Minimum Inhibitory Concentration Assay, is a procedure that determines the lowest concentration of an antibiotic to kill a bacterium (11). The MIC levels for vancomycin and teicoplanin are commonly assessed to begin the distinction between Enterococci species (10). If the bacterium is found to be susceptible to teicoplanin, likely the bacterium carries the VanB resistance gene and will carry additional antibiotic resistance (3). The vancomycin MIC test primarly disginushes other Enterococci species from E. faecalis and E. facecium, which have a higher MIC for vancomycin than the other species (3).

4 Additional testing for motility and pigment production has been used to distinguish between less common Enterococci species (3,5,10.) However, with the reduction in cost of PCR and ELISA assays these tests are often used to both in the diagnoses the specific pathogen and determine suspecitibility to antibiotics (3). Routine examination of patient samples helps to make certain that a bacterium has not developed resistance to a particular antibiotic used during the treatment process (3,5). Signs and Symptoms While not all patients infected with VRE display symptoms, the disease most commonly presents with fever, malaise, tachycardia, and redness or heat at the site of infection (12,3). Other symptoms depend primarily on the location of VRE colonization as they will present similarly ot any other bacterial infection (12). For example, if a patient presents with bacterima likely the patient will present with fever, shivering, or hypotension as the infection moves to the bloodstream (1,12). Bacteriema is primarily only found in debilitated immunocompromised patients receiving multiple antibiotics (3). Both E. faecalis and E. facecium have been found to cause Bacteriema (3). Enteroccoci species, both vancomycin and non-vancomyicn resistant, are one of the most common causes of central line and urinary catheter infection which can lead to development of this presentation (3). Colonization of Enterocci on the skin has been shown to cause osteomyelitis, septic arthritis, and abscesses of soft tissues (3).This manifestation primarily impacts persons with preexisting decubiti and diabetic uclers or who have recently undergone surgery (3).. Likely the microbe is part of a polymicrobial infection particularly for skin and suture infections (1,3). When Enterococcal endocarditis occurs, the patient most commonly presents with a fever heart mummers, and weight loss- all symptoms appearing in a subacute manner (3). Rarely patients will develop petechiae, Roth s spots, and Osler s nodes (3). Infective endocarditis is caused almost exclusively by E. faecalis and makes up the second most common cause of endocarditis overall (3). Rarely, VRE will result in CNS infection (3). These outbreaks are caused by the E. facecium species in patients with more serious underlying diseases such as cancer and preexisting cardiac disease (3). Symptoms include altered mental status, acute fever, low blood glucose levels, increased CSF protein, pleocytosis, and occasional coma (3). History and Current Outbreaks E. faecalis and E. facecium were both isolated in 1988 by a team led by AH Uttley (1). The disease was first discovered in England and France in 1986 (1). It s first appearance in the United States occurred shortly after in 1987 (1). The initial outbreaks in Europe and the US differed in that the US outbreaks occurred due to an overuse of vancomycin in healthcare settings whereas the outbreak in Europe was a

5 result of glycopeptide antibiotics in animal feed (1). Early European infections were due in part to the consumption of infected meat products not due to human overuse (1). Both North America and Europe experience a rapid spread of nosocomial VRE infections from the 1990s to early 2000s (3). This was due in part to the increased misuse of glycopeptide antibiotics in healthcare settings (1). As VRE is now endemic in healthcare centers there is increased concern for the spread of additional antibiotic resistance. According to O Driscoll and Crank, in 2002 VRE was shown to be able to give transmitting vana resistance genes to methicillin-resistant Staphylococcus aureus (MRSA). Currently, the United States has one of the highest levels of VRE infection in the world (1,3). Despite this fact, the Texas Department of Health Services does not require care facilities to report outbreaks of VRE (13). The CDC reports that in 2015, 127 faculties in Texas reported the presence of Endocarditis caused by Enteroccoci, with overall hospital acquired infection levels decreasing by 3% (14). Treatment and Prevention Treatment of VRE begins following the results of antibiotic sensitivity testing of patient cultures (1). What antibiotics to use for VRE infection and when is an area of debate for scientists as they do not want to further limit available treatment options for VRE (1). Currently the only FDA approved antibiotic for VRE infections is Linezaolid and it is often the first line of defense if it is deemed that antibiotics are necessary for treatment (1). It as broad spectrum capabilities efficient against both E. faecalis and E. facecium (1). If this treatment proves ineffective, patients will likely be given penicillin and an aminoglycoside (3). Many efforts for the treatment and prevention of VRE infection are focused at improving patient and provider education to help prevent the spread of the disease (5). The CDC has worked with many international health agencies to develop a common set of recommended guidelines for care providers to help prevent the spread (5,15). The main goal is to break the chain of infection to prevent re-infection and the continued spread of the disease (15). Patients and their caregivers are informed of the importance of hand hygiene and through cleaning when admitted to at risk facilities, as proper hand washing has proven to be one of the most effective prevention methods (5). To identify asymptomatic patients, hospitals are recommended to preform regular screening of at risk patient s stool samples (5). Testing is recommended upon admission then once weekly until discharge (5). A final test is done prior to the patient s departure to prevent the spread to other units of facilities (5). In addition to regular screening, it is recommended that infected patients be isolated in rooms with no carpeting and a dedicated restroom (5,15). These precautions when combined with daily baths and regular replacement of medical equipment have been proven to be effective in preventing the spread of the bacteriums (5,15). There currently exist no guidelines as to how long a patient has to remain isolated with

6 these contact precautions after previously infected patients no longer present with the bacterium in their stool (15). Trials are currently underway to develop a vaccination effective against E. facecium (16). Scientists are aiming to produce antibodies against novel heteroglycan or glucosylated lipoteichoic acid, LTA, as the antibodies have been shown in other species to be more effective at killing E. facecium (16). Rabbit trials have subjects undergo 5 weeks of injections with the first two weeks consisting of IM injection and the last 3 weeks requiring the administration of the vaccination by an IV (16). While this successfully led to the production of antibodies in rabbits, scientists are still looking for more effective ways to provide this protection for humans (16). Conclusion Vancomycin-resistant Enterococci are a growing nosocomial infectious throughout the world. Impacting primarily immunocompromised patients, the bacteria are highly resilient and pathogenic. Both species of Enterocci that most commonly cause VRE in humans, E. faecalis and E. facecium, are prolific colonizers, especially of immunocompromised patients, and are difficult to treat due to their intrinsic and acquired resistance to antibiotics. As many patients are asymptomatic, healthcare providers can unknownng transmit the disease between patients. Prevention efforts are aimed primarily at early detection and proper education. End Notes 1. O Driscoll, T., & Crank, C. W. (2015). Vancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management. Infection and Drug Resistance 2. Cetinkaya, Yesim et all (2000 Vancomycin-Resistant Enterococci. Clin. Microbiol. Rev. 3. CDC (nd) Healthcare Associated Infections Site Government of South Austrailia (2017, March 22). Clinical Guideline Management of Patients with Vancomycin-resistant Enterococci (VRE) Clinical Guideline 5. Castillo-Rojas, G., Mazari-Hiríart, M., Ponce de León, S., Amieva-Fernández, R. I., Agis-Juárez, R. A., Huebner, J., & López-Vidal, Y. (2013). Comparison of Enterococcus faecium and Enterococcus faecalis Strains Isolated from Water and Clinical Samples: Antimicrobial Susceptibility and Genetic Relationships. 6. MSDS Online (2010) Enterococcus faecalis and faecium

7 7. Hayakawa, Kayoko et Comparison of the Clinical Characteristics and Outcomes Associated with Vancomycin-Resistant Enterococcus faecalis and Vancomycin-Resistant E. faecium Bacteremia. Clin. Microbiol. Rev Thurlow, Lance et all (2012) Gelatinase Contributes to the Pathogenesis of Endocarditis Caused by Enterococcus faecalis Clin. Microbiol. Rev. 11, CDC (nd) Healthcare Associated Infections Site. 10. Cornell (nd) Minimum Inhibitory Concentration Assay 11. Healthy WA (nd) Vancomycin-resistant Enterococci (VRE) 12. Texas Department of State Health Services (nd) Vancomycin-resistant Enterococci 13. CDC (nd) Healthcare Associated Infections Site Shenoy, E. S., Paras, M. L., Noubary, F., Walensky, R. P., & Hooper, D. C. (2014). Natural history of colonization with methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE): a systematic review. Kodali, 15. S., Vinogradov, E., Lin, F., Khoury, N., Hao, L., Pavliak, V.,... Donald, R. G. K. (2015). A Vaccine Approach for the Prevention of Infections by Multidrug-resistant Enterococcus faecium. References Castillo-Rojas, G., Mazari-Hiríart, M., Ponce de León, S., Amieva-Fernández, R. I., Agis- Juárez, R. A., Huebner, J., & López-Vidal, Y. (2013). Comparison of Enterococcus faecium and Enterococcus faecalis Strains Isolated from Water and Clinical Samples: Antimicrobial Susceptibility and Genetic Relationships. PLoS ONE, 8(4), e CDC (nd) Healthcare Associated Infections Site. Retrieved March 6, 2018, from Cornell (nd) Minimum Inhibitory Concentration Assay. Retrieved March 6, 2018, from

8 tm Government of South Austrailia (2017, March 22). Clinical Guideline Management of Patients with Vancomycin-resistant Enterococci (VRE) Clinical Guideline. Retrieved March 9, 2018, from b2c8cd/m anagement of patients with Vancomycin-resistant Enterococci %28VRE%29 Clinical Guideline_ pdf?MOD=AJPERES&CACHEID=ROOTWORKSPACEe7b a72496fcbfd30eb2c8cd-lTFKG3u Cetinkaya, Yesim et all (2000 Vancomycin-Resistant Enterococci. Clin. Microbiol. Rev. Hayakawa, Kayoko et all (2012) Comparison of the Clinical Characteristics and Outcomes Associated with Vancomycin-Resistant Enterococcus faecalis and Vancomycin- Resistant E. faecium Bacteremia. Clin. Microbiol. Rev Healthcare-associated Infections. (2011, May 10). Retrieved March 8, 2018, from Healthy WA (nd) Vancomycin-resistant Enterococci (VRE)Retrieved March 6, 2018, from VRE ITS (nd) Enterococcus faecalis. Retrieved March 6, 2018, from = #null Kodali, S., Vinogradov, E., Lin, F., Khoury, N., Hao, L., Pavliak, V.,... Donald, R. G. K. (2015). A Vaccine Approach for the Prevention of Infections by Multidrug-resistant Enterococcus faecium. The Journal of Biological Chemistry, 290(32), MSDS Online (2010) Enterococcus faecalis and faecium. Retrieved March 6, 2018, from index/enterococcus-faecalis-and-faecium/ O Driscoll, T., & Crank, C. W. (2015). Vancomycin-resistant enterococcal infections: epidemiology, clinical manifestations, and optimal management. Infection and Drug Resistance, 8, Shenoy, E. S., Paras, M. L., Noubary, F., Walensky, R. P., & Hooper, D. C. (2014). Natural history of colonization with methicillin-resistant Staphylococcus aureus

9 (MRSA) and vancomycin-resistant Enterococcus (VRE): a systematic review. BMC Infectious Diseases, doi: / Texas Department of State Health Services (nd) Vancomycin-resistant Enterococci Retrieved March 6, 2018, from Thurlow, Lance et all (2012) by Enterococcus faecalis Clin. Microbiol. Rev. Gelatinase Contributes to the Pathogenesis of Endocarditis 11,

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Safe Patient Care Keeping our Residents Safe 2016 Use Standard Precautions for ALL Residents at ALL times #safepatientcare Do bugs need drugs? Dr Deirdre O Brien Consultant Microbiologist Mercy University