Continuing Education Activity

Enterococci are Gram-positive facultative anaerobic cocci in short and medium chains, which cause difficult-to-treat infections in the nosocomial setting. They are a common cause of UTIs, bacteremia, and infective endocarditis and rarely cause intra-abdominal infections and meningitis. They have intrinsic resistance to some antibiotics and acquire and transfer resistance to other bacteria via mobile genetic elements. Their detection is aided by conventional Gram stain and cultures and newer techniques like MALDI-TOF, NAAT, and PCR. Antibiotic sensitivities should be obtained early on to help physicians formulate treatment plans. To avoid the high morbidity and mortality associated with this condition, it must be promptly diagnosed and treated. This activity reviews the evaluation and treatment of enterococcal infections and highlights the role of the interprofessional team in preventing the hospital-related spread of enterococci, especially VRE.

Objectives:

• Compare the diseases caused by enterococci.
• Identify the mechanism of resistance of enterococcus to commonly used antibiotics.
• Identify the various treatment regimens used for enterococcal infections.
• Identify how interprofessional team strategies can result in better care coordination for patients presenting with an enterococcal infection.

Introduction

Enterococci are Gram-positive facultative anaerobic cocci in short and medium chains, first discovered in 1899 in the human gastrointestinal tract. They were recognized as a separate genus from streptococci by DNA hybridization and 16S rRNA sequencing in 1984.[1] They are the first of the ESKAPE organisms (Enterococci spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.) highlighted by the WHO as rising causes of nosocomial and antibiotic-resistant infections in the last few decades threatening public health.[2]

Vancomycin-resistant enterococci (VRE) were first reported in 1933 in animals owing to avoparcin, a vancomycin analog used as an animal food additive. However, they were reported for the first time in humans in England in 1988, several years later.[3][4]

Etiology

Enterococci are found in the soil, water, food, sewage, plants, human skin, the oral cavity, and the large intestine, constituting less than 1% of the total microbiota.[3]

There are about 58 species recognized of enterococci so far, the most important and common being E. faecalis and E .faecium.[5] Others include E. avium, E. caccae, E. casseliflavus, E. dispar, E. durans, E. gallinarum, E. hirae, and E. raffinosus. These so-called non-faecium non-faecalis enterococci are increasingly recognized in reports as causes of the bloodstream and endovascular infections in humans nowadays.[6][7][8]

Enterococci are highly resilient and can survive difficult conditions like common antiseptics and disinfectants, promoting their widespread persistence on ordinary hospital inanimate items.[1][4] Moreover, they are easily transmissible via the hands of healthcare workers (HCWs).[9]

Enterococcal colonization of the gastrointestinal (GI) tract is the main predisposing factor for severe infections, which occur through gut translocation. Enterococci are phagocytosed and transported across the intestinal wall and resist killing by the lymph system.[10] 

The risk of VRE colonization and infections is associated with previous antibiotic exposure disrupting normal gut microbiomes, especially vancomycin, and cephalosporins. In addition, prolonged hospitalization, ICU stays, residence in long-term care (LTC) facilities, hemodialysis patients, diabetes, cancer, and transplant patients, stomach acid suppression, use of invasive devices, and exposure to contaminated surfaces, including shared medical equipment can also predispose individuals to get enterococci/VRE infections.[11][12]

Epidemiology

Currently, enterococci rank second in the USA, only after staphylococci, in nosocomial infections, antibiotic-resistant pathogenic diseases, central line-associated bacteremias, and hospital-associated endocarditis.[4][13] Reports suggest that 60% of all infections by enterococci are healthcare-acquired, including in the ICU setting. Enterococci are the third most common cause of community-acquired endocarditis in North America, after Staphylococcus aureus and Streptococcus viridans, higher than anywhere else globally.[10]

Enterococci cause 15 to 20% of hospital urinary tract infections (UTIs).[14] Currently, VRE is much less prevalent in Europe than in the USA, where they have grown to be around 30% of all enterococcal infections. There has also been a noticeable rise in the E. faecium species, constituting 35% of enterococcal isolates from nosocomial infections and 40% of bloodstream isolates in liver/stem cell transplant recipients.[15][16] 

E. faecium species are 80% vancomycin-resistant and 90% ampicillin-resistant compared to E. faecalis species, which are only 10% vancomycin-resistant and mostly ampicillin sensitive.[5]

Pathophysiology

Enterococci do not produce toxins like staphylococci and streptococci, but their virulence comes from other properties like durability, structure, and antibiotic resistance.[4]

Enterococcal surface components include the polysaccharide capsule, adhesins, pili, and the aggregation substance.[1] Their ability to form biofilms promotes adherence to catheters, dental prostheses, and heart valves and limits antibiotic penetration, causing persistent infections that are often even polymicrobial.[17]

Enterococci secrete virulence factors like bacteriocins, hemolysin/cytolysin, gelatinase, and serine protease. Moreover, they are also capable of producing toxic oxygen metabolites, leading to cell injury.

Enterococci are intrinsically resistant to cephalosporins, clindamycin, aminoglycosides, and trimethoprim-sulfamethoxazole.[5] They also gain antibiotic resistance through their ability to acquire and transfer resistance-related mobile genetic elements (MGE) via various mechanisms like plasmids, conjugation, and transposons.[1] This latter property is believed to be due to the absence of CRISPR-Cas gene loci, which usually limit invading harmful DNA.

Table

Antibiotic Strain

 Table 1. Mechanism of resistance to specific antibiotics [31] [32] [33]

*Sometimes, vancomycin-resistant genes are indolent, causing initial phenotypic vancomycin susceptibility that can later reverse in some emerging strains called vancomycin-variable enterococci (VVE).[34] Interestingly, studies also discovered vancomycin-dependent enterococci (VDE), which actually need vancomycin for growth, often after prolonged exposure to oral vancomycin regimens, rendering them difficult to isolate.[35] They are treated similarly to VRE. Enterococci are the main reason for vancomycin resistance in Staphylococcus aureus via horizontal VanA gene transfer when they co-exist.[36]

History and Physical

A thorough history must be obtained from patients, including a comprehensive fever history, antibiotic history including duration of antibiotic use, history of infection with multidrug-resistant organisms, history of previous hospitalizations or stays at skilled nursing facilities or nursing homes, appropriate cancer screening, HIV screening, past and recent surgical history, history of medical conditions like uncontrolled diabetes, recent cardiac valve replacement, nonhealing wounds and external lines like Mediport, Foley catheter, or peripherally inserted central lines (PICC). In addition, a physical examination of each organ system must be detailed, especially if the source of bacteremia is unknown.

• Urinary tract infections (UTI) are the most common infections caused by enterococci, usually occurring in chronically ill patients in the nosocomial setting associated with obstruction, urinary catheterization, or instrumentation.[37] They can also cause complicated UTIs such as pyelonephritis, perinephric abscesses, and chronic prostatitis, which can all act as sources of bacteremia. Complicated UTIs are associated with diabetes mellitus, pregnancy, indwelling urinary catheters and devices, immunocompromised state, neurogenic bladder, urinary obstruction, and nephrolithiasis.
• Bacteremia is usually secondary to IV catheters, UTIs including catheter-associated urinary tract infections (CAUTI), intra-abdominal including biliary tract infections, wound infections including burns and ulcers, and bone infections.
• The prevalence of enterococcal infective endocarditis (IE) is consistently rising, present in 8 to 32% of enterococcal bacteremia cases, and it usually has a subacute course.[38][39] Interestingly, enterococci was the most common pathogen causing IE in subjects who underwent transcatheter aortic valve implantation (TAVI), probably owing to their advanced age and comorbidities.[40] Infective endocarditis can present with a temperature ≥ 38 degrees C (100.4 degrees F), Osler nodes, Roth spots, Janeway lesions, new heart murmur or worsening of preexisting murmur, hematuria, hematuria, and splinter hemorrhages.
• Intra-abdominal collections and peritonitis are associated with enterococci as well.
• Meningitis is uncommon and is mainly associated with intraventricular shunts, neurosurgical procedures, CSF leakage, trauma, anatomical defects in CNS, and high-grade bacteremia in immunocompromised patients. Interestingly, some reports showed an association with Strongyloides hyperinfection.[41][42] Patients can present with altered mental status, headache, neck stiffness, fever, lethargy, nausea, and vomiting.
• They are also sometimes seen in surgical-site infections, diabetic and decubitus ulcers, prosthetic joint infections, endophthalmitis, and dental and root canal failure infections.[43]
• Some outbreaks of neonatal enterococcal sepsis have been reported in the USA.

Evaluation

Before antibiotic treatment is initiated, culture and gram stains from body fluids and blood must be obtained. Chest X-ray, echocardiogram, CT scan of the abdomen, or colonoscopy may be necessary per the infection's clinical context.

• Enterococci are gram-positive, non-spore-forming cocci, usually appearing as short chains, diplococci, or single ovoid cells. They are facultative anaerobes that grow on culture media, tolerating a high 6.5% salt concentration and a wide range of temperatures. Although mostly non-hemolytic, some enterococci show alpha and beta hemolysis.[5]
• They are bench diagnosed as catalase-negative, urease-negative, Lancefield group D antigen-positive, esculin hydrolyzing in 40% bile salts, and PYR hydrolyzing, distinguishing it from Streptococcus gallolyticus. Selective media and commercial kits use many of these properties for enterococci identification. Intra-species differentiation is based on the fermentation of carbohydrates, hydrolysis of arginine, tolerance to tellurite, motility, and pigmentation.[44]
• Genetic methods have replaced traditional biochemical tests. They include gene probes, polymerase chain reaction (PCR), 16s rRNA sequencing, nucleic acid amplification testing (NAAT), matrix-assisted laser desorption ionization-time of flight (MALDI-TOF), and other new technologies.[45][46][47][48] These can quickly identify enterococci among other microorganisms in a short time through species-specific protein segments and even detect their antimicrobial susceptibilities. 
• Enterococcus should be routinely tested for sensitivity to penicillin, vancomycin, and high-level aminoglycoside resistance (HLAR).[49] In the case of beta-lactam or vancomycin resistance, in vitro susceptibility to daptomycin and linezolid is warranted.
• The DENOVA tool can be used to predict endocarditis in patients with enterococcal bacteremia (based on the Duration of symptoms, Embolizations, Number of positive cultures, Origin, valve disease, and Auscultation murmurs). Some authors recommend transthoracic echocardiograms for all community-acquired and nosocomial enterococcal bacteremia.[39][38]
• As a part of the evaluation, reports have proposed routine colonoscopies for cases of enterococcal bacteremia or IE of unclear source, given the high prevalence of new colonic neoplasms in this population, similar to the guidelines for Streptococcus bovis and Clostridium septicum.[50][51][52]

Treatment / Management

The treatment of enterococcal infection depends on the type of infection and susceptibility of the organism to antibiotics. Compared to Enterococcus faecium, infections due to Enterococcus faecalis tend to be more virulent, and bacteremia is more likely to be associated with endocarditis. Even though penicillin and ampicillin inhibit enterococci, they are not often bactericidal. Vancomycin and aminoglycosides are also less bactericidal. Aminoglycoside has poor permeability, so it can be combined with a simultaneous cell-wall active agent to achieve the necessary intracellular aminoglycoside concentration.[49] 

Penicillin or ampicillin are typically used to penetrate the cell wall with an aminoglycoside. Vancomycin combination with aminoglycoside increases the risk of nep[hrotoxicity. Therefore, vancomycin may only be used in cases of hypersensitivity with an inability to desensitize or in cases of high-level beta-lactam resistance.[53] E. faecalis is also more susceptible to ampicillin and more resistant to quinupristin-dalfopristin. The typically recommended regimes for infections are described in the following table:

Table

Disease Sensitive strains

Table 2. Routine recommended antibiotics regimens and duration for common enterococcal infections

(a) Given the bacteriostatic effect of beta-lactams on enterococci at the usual doses, combination therapy with a beta-lactam (usually ampicillin) plus an aminoglycoside (specifically gentamicin or streptomycin) for 4 to 6 weeks has been the standard to achieve bacteriocidal action against enterococci in cases of IE. This prolonged use of aminoglycosides often causes nephrotoxicity and ototoxicity, as highlighted in the old paper “Deaf or Dead” Most recently, a two beta-lactam combination with ampicillin and ceftriaxone for six weeks duration has shown to be an equal alternative, with less toxicity leading to less interruption, and an effective option for HLAR isolates.[57][58][59][60][61][62][63][18] However, it is level B evidence, not definitive, and holds more for E. faecalis than E. faecium.[64][65] 

(b) VRE treatment options are outlined below: 

• Linezolid is the only FDA-approved agent for VRE. It has also been studied in combination with gentamicin, doxycycline, or rifampicin.[66]
• Daptomycin has been used alone or in combination with ceftaroline, ampicillin, ertapenem, tigecycline, and fosfomycin. For high MICs, a high dose of > 6 mg/kg/day is used.[67]
• Quinupristin/dalfopristin was used against E. faecium only but was subsequently withdrawn from the market for causing phlebitis and myalgias.
• Oritavancin[66]
• Most recently, tedizolid was shown to be efficacious, but robust clinical data is still lacking.[66]
• Tigecycline is the last salvage treatment for VRE.

There have been several studies comparing linezolid and daptomycin for VRE bacteremia and endocarditis, with mixed results. However, linezolid and high-dose daptomycin are both equally more effective than low-dose daptomycin.[67][68]

Newer Therapies

Commensal probiotic cocktails are suggested to prevent and reverse gut colonization with VRE. They mainly contain four species; Clostridium bolteae, Parabacteroides distasonis, Bacteroides sartorii, and Blautia producta, which secretes a lantibiotic that is highly effective against VRE.[69]

Methods to significantly limit enterococcal adherence with its related infections and biofilm formation include:

a) Use of surface coatings with specific antimicrobial and antiadhesive properties on catheters and implants like non-leachable cationic film coatings.[17]

b) Vaccination or antibody therapy directed against the enterococcal pilus tip EbpA.[17]

Propionate, one of the short-chain fatty acids (SCFA), has shown antimicrobial effects on enterococci in the mouth to treat dental plaques and infections.[70] Highly specific lytic bacteriophage therapy has shown to be rapidly efficacious when used against enterococcal infections, both in vitro and in vivo, with one study even on humans with chronic prostatitis.[71][72] 

Phage therapy has also been shown to induce anti-phage modifications in the enterococcal cell wall, rendering them less capable of intestinal colonization, expansion, or antibiotic resistance.[73] Phage endolysins can be used successfully against resistant enterococci without actual phage therapy, per several studies.[71] CRISPR gene activating modalities have been proposed to limit horizontal antibiotic resistance gene transfer among enterococci.[74] 

An idea exists for developing monoclonal antibodies targeting enterococcal signal transduction pathways to interfere with the antibiotic resistance gene.[36]

Differential Diagnosis

Preliminary culture data from urine, blood, cerebrospinal fluid, tissue, fluid, or wounds are generally read as Gram-positive cocci in chains. Differentials at this point can include Group A, B, and C Streptococci, and Streptococcus bovis, in addition to enterococcal species. However, when a nosocomial infection is likely in a critically ill patient, one should empirically cover for Enterococcus before the final culture read is available.

UTI, bacteremia, infective endocarditis, meningitis, intra-abdominal, and wound infections can be caused by hundreds of pathogens that can mimic an enterococcal infection. Again, if suspicion of resistant species exists in the appropriate clinic context, empiric broad-spectrum antibiotic coverage is warranted until sensitivities can be obtained.

Prognosis

In systematic reviews, VRE infections have demonstrated a two-fold increase in morbidity, mortality, and economic burden compared to vancomycin-sensitive isolates, even after VRE treatments were made available.[75] VRE infections also increased the overall length of hospital stay, LTC facility discharges, and readmissions.[13]

Enterococcal endocarditis has a mortality rate of 11 to 35%, while the mortality rate for enterococcal bacteremia is 25%, and for enterococcal meningitis is 20%.[1]

Complications

A study suggested an association between E. gallinarum gut translocation and autoantibodies production, as seen in inflammatory bowel disease.[5] 

Extracellular superoxide produced by E. faecalis causes DNA instability and inflammatory changes in the colonic mucosa, leading to colorectal cancer.[1] This finding was supported by a higher burden of E. faecalis in the stools of colon cancer patients than in controls. 

Enterococcal cytolysin causes liver cell injury, especially in patients with alcoholic hepatitis, correlating with both-disease severity and mortality. Hence one of the therapies suggested for this patient population is cytolytic enterococci-specific bacteriophages.[76]

Fecal enterococci abundance has been associated with high graft versus host disease (GVHD) in the allogeneic hematopoietic transplant patients population. Interestingly, the predominance of enterococci over regular clostridia species in the gut of patients with GVHD was associated with diets with higher lactose intake. Hence lactose-free diet or lactase-based therapy is suggested for these patients to prevent the overgrowth of enterococci.[77][78]

E. faecalis and E. faecium strains have been utilized as human probiotics in common preparations for diarrhea, irritable bowel syndrome, hypercholesterolemia, and immunity boosters. They have also been used in animals to promote growth and as starters for fermenting food. So far, no infections or safety concerns of these specific probiotics have been reported. However, they need to be monitored closely for the potential development of problematic lineages from old or new strains.[79][80]

Deterrence and Patient Education

Patients must be educated to practice good hand hygiene, keep the catheter sites clean, monitor for erythema around those sites, and alert their doctors if they feel ill or have spiking fevers. Patients should also be aware of the duration that catheters and prosthetic devices have been in place and make sure providers note them down, too.

Pearls and Other Issues

1. Enterococci are Gram-positive facultative anaerobic cocci in short and medium chains commonly associated with nosocomial infections.
2. VRE is seen in patients with prolonged hospitalization, ICU stays, residence in long-term care (LTC) facilities, hemodialysis patients, and diabetes, cancer, and transplant patients.
3. E. faecium species are 80% vancomycin-resistant and 90% ampicillin-resistant compared to E. faecalis species, which are only 10% vancomycin-resistant and mostly ampicillin sensitive.
4. Virulence factors include structural durability, bacteriocins, hemolysin/cytolysin, gelatinase, serine protease, and biofilm production. Antibiotic resistance is intrinsic or acquired through the transfer of resistance-related mobile genetic elements (MGE) via various mechanisms like plasmids, conjugation, and transposons.
5. Vancomycin resistance is attributed to the vanA gene, which replaces the D-Ala-D-Ala terminus of peptidoglycan with D-Ala-D-lactate, which binds to vancomycin with significantly lower affinity. VanA gene confers vancomycin resistance to MRSA via horizontal transmission.
6. Enterococci can cause UTIs, bacteremia, IE, meningitis, intra-abdominal infections, and wound infections. Resistant strains require prolonged courses of antibiotics.
7. Enterococcus should be routinely tested for sensitivity to penicillin, vancomycin, and high-level aminoglycoside resistance (HLAR). In the case of beta-lactam or vancomycin resistance, in vitro susceptibility to daptomycin and linezolid is warranted. 
8. Hand hygiene is paramount to preventing patient-to-patient transmission of VRE. Surveillance stool cultures may be required in high-risk patients in ICUs, transplant patients, and LTC patients to prevent the colonization of the GI tract and subsequent infections.

Enhancing Healthcare Team Outcomes

The Infectious Disease team, Infection Prevention Committee, and Antimicrobial Stewardship Program are crucial in tackling enterococcus and VRE infections and implementing preventive measures to limit hospital-related outbreaks. Clinicians, nurses, and pharmacists form an important interprofessional team to treat enterococcal infections.[9][81]

• The CDC recommends prompt active screening via rectal and perirectal swabs or stool samples, with subsequent reporting of VRE in high-risk patients such as those in the ICU, transplant or oncology wards, hemodialysis or immunocompromised patients, prolonged hospitalizations, and admissions from LTC, as it has shown to be cost-effective for preventing colonization, infections, and deaths.[82][83][84]
• Specific environmental cleaning modalities, such as the non-touch automated mobile ultraviolet units and routine chlorhexidine bathing, especially in the ICU, are recommended for reducing the VRE burden. 
• HCW training on hand hygiene is associated with a 47% decline in acquiring VRE in hospitals.[9][85]
• Contact isolation for VRE patients is used in most hospitals; however, there is no consistent data to support it.[86][87]
• Antibiotic stewardship programs that limit the use of cephalosporins, antibiotics against anaerobes, vancomycin, and broad-spectrum antibiotics, play an essential role in preventing the emergence and spread of this pathogen.[9]

Review Questions

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• Comment on this article.

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Disclosure: Mina Said declares no relevant financial relationships with ineligible companies.

Disclosure: Ekta Tirthani declares no relevant financial relationships with ineligible companies.

Disclosure: Emil Lesho declares no relevant financial relationships with ineligible companies.