Vancomycin-Resistant Enterococci

Etiology

Enterococci have developed a variety of mechanisms of resistance to several antibiotics like aminoglycosides, B-lactams, tetracyclines, quinolones, and vancomycin (glycopeptide). Intrinsically, they have penicillin-binding proteins with low-affinity to beta-lactams, can produce beta-lactamases, and have decreased cellular permeability to several. Specifically, vancomycin-resistant Enterococcus resistance is due to the changes in the formation of peptidoglycan that makes up the bacterial cell wall. Normally, vancomycin binds to the D-Ala-D-Ala terminus of the protein precursors to peptidoglycan. Resistance develops as this terminus is changed to D-Ala-D-lactate so that vancomycin binds with less affinity. This is coded by genotypes identified alphabetically as VanA to VanG. Of these, the plasmid-based VanA and VanB genotypes are by far the most common, followed distantly in prevalence by the chromosomal phenotypes VanD and VanC respectively. VRE has slightly different resistance formation with Aminoglycosides, all except for Streptomycin, the formation of resistance is mainly due to inactivating enzyme 2"-phosphotransferase-6′-acetyltransferase. Streptomycin resistance on the other is through the production of streptomycin adenyltransferase.[4][5][6][7]

Epidemiology

Beginning in the 1980s, isolates of vancomycin-resistant Enterococcus were demonstrated in Europe, likely arising due to the use of the glycopeptide antibiotic avoparcin in livestock to promote growth. Development in the United States was probably due to increasing use of vancomycin in the clinical setting. Throughout the 1990s and 2000s, multiple epidemics have plagued hospitals due to person-to-person transmission. After fecal shedding, vancomycin-resistant Enterococcus is found on the skin and spreads via exposed or contaminated surfaces. 

According to the National Healthcare Safety Network, enterococci species ranked as the second overall healthcare-associated infection between 2011 and 2014. In particular, E. Faecalis was a cause in 7.4% of cases. Furthermore, Enterococci species were found to be the number one isolate for central line-associated bloodstream infections (CLABSI), number three for catheter-associated urinary tract infection (CAUTI), number eleven for ventilator-associated pneumonia (VAP) and number two for surgical site infections (SSI). While the majority of Enterococcus isolates are E. faecalis, the majority of vancomycin-resistant Enterococcus isolates are E. faecium. From 2011 to 2014 the resistance of E. faecium to vancomycin was as high as 83.8 % of isolates for CLABSI and 86.2 % for CAUTI. In 2013 the CDC categorized vancomycin-resistant Enterococcus as a “serious threat,” suggesting the need for increased monitoring and prevention activities. 

There are many risk factors for vancomycin-resistant Enterococcus colonization and subsequent infections. The most commonly observed risk factor is previous antimicrobial therapy. This mechanism likely is due to alteration in bowel flora. Furthermore, patients at increased risk are those with severe underlying illnesses or immunosuppression. This also includes patients with a long hospital stay, admission to long-term care facilities, extended use of antibiotics, and proximity to other patients with vancomycin-resistant Enterococcus.[8][9]

History and Physical

Patients with an underlying vancomycin-resistant Enterococcus infection will present with a variety of history and physical exam findings dependent on the clinical manifestations as described below. Specifically, the focus should be placed on using the patient’s medical history and physical exam to elucidate the source of infection. 

Clinical Manifestations

Enterococcus can cause a wide range of clinical diseases. The most common clinical presentation is bacteriuria, though it is becoming increasingly clear that many of these cases are due to colonization rather than infection. Other frequent causes of infection are bacteremia without endocarditis, followed by endocarditis. 

Urinary tract infection

Enterococcus is frequently cited as one of the three most likely etiologies of both uncomplicated and complicated UTI, especially healthcare-associated UTIs. Of these, the vast majority is E. faecalis, though the majority of vancomycin-resistant isolates are E. faecium. It is usually associated with indwelling urinary catheters and instrumentation. The severity of the disease can range from uncomplicated cystitis to complicated cystitis to pyelonephritis, perinephric abscess, or prostatitis. There is an increasing awareness that many reported “urinary tract infections” are, in fact, colonization. Asymptomatic pyuria and bacteriuria should not be treated unless the patient is exhibiting signs and/or symptoms of a UTI or sepsis.

Intra-abdominal and pelvic infections

As commensals, vancomycin-resistant Enterococcus is commonly isolated from intra-abdominal and pelvic infections. The usual infections include abscesses, wounds, or peritonitis. Often they are part of a polymicrobial infection with other gram-negative or anaerobic organisms. Nonetheless, intra-abdominal and pelvic abscesses are commonly associated with enterococcal bacteremia prompting antibiotic coverage of Enterococcus.

Bacteremia

Bacteremia is a common and life-threatening manifestation of vancomycin-resistant Enterococcus. Nosocomial bacteremic infections are regularly acquired due to intravascular catheters or urinary catheters. In the community, bacteremia is commonly due to translocation from the GI and genitourinary (GU) tract. E. faecium in the bloodstream is associated with increased mortality likely due to the higher levels of resistance. 

Infective endocarditis

Enterococci are the second most common cause of infective endocarditis. Common sources are central lines, GI or GU tracts after manipulation, damaged mitral or aortic valve infections, or liver transplantation. Community-acquired endocarditis can occur, and it is usually due to E. faecalis in patients with no risk factors. Clinically, they present subacutely with fevers and constitutional symptoms. Typical signs of infection include fevers or a new murmur. Typical stigmata of endocarditis such as petechiae, Osler nodes, and Roth spots are rare and, as with other etiologies, typically occur with subacute infection rather than acute infection. 

Uncommon sites of infection

Vancomycin-resistant Enterococcus is an uncommon cause of central nervous system (CNS) infections. However, when it does occur, the majority are caused by E. faecium over E. faecalis. Infection usually is associated with neurosurgical intervention such as shunts. Like most CNS infections, common presentations include altered mental status and fevers. Vancomycin-resistant Enterococcus also is found in skin infections as a part of a microbial infection. They can be found in decubitis ulcers, osteomyelitis, and soft tissue abscesses. Finally, pneumonia secondary to enterococci is very rare. When it does occur, it is usually seen as VAP in severely debilitated and immunocompromised patients who have received broad-spectrum antibiotics in the past.[7]

Evaluation

Workup for vancomycin-resistant Enterococcus will begin with the determination that the patient has an underlying infectious disease process. Next, each potential source of infection needs to be evaluated. Specimens from the potential source should be sent for routine cultures before administration of empiric antibiotics to determine the exact species and drug susceptibilities. Sensitivities for fosfomycin, daptomycin, nitrofurantoin, and chloramphenicol are not standard in all laboratories and should be added as clinically appropriate.[10][11]

Treatment / Management

Antibiotic therapy for the treatment of vancomycin-resistant Enterococcus depends on the type of infection and drug susceptibility of the organism or organisms involved. In monomicrobial infections, the antibiotic choice should be tailored to tissue for penetration, culture, and local resistance patterns. Moreover, treatment can be controversial as vancomycin-resistant Enterococcus often can be found as a colonizer in polymicrobial infections. Initiation of vancomycin-resistant Enterococcus coverage should be initiated based on clinical suspicion or failure of prior antibiotic regimens. [12][13][14]

The vast majority of enterococcal infections are due to E. faecalis. E. faecalis tends to be susceptible to beta-lactams and aminoglycosides. Vancomycin resistance is more frequent in undifferentiated E. faecalis than resistance to aminopenicillins, stressing that beta-lactams should remain the first choice in most infections before culture data. Conversely, most strains of E. faecium are highly resistant to beta-lactams and aminoglycosides. In general, if vancomycin-resistant Enterococcus is highly resistant to other antimicrobial therapies; the two major treatments are linezolid and daptomycin. A meta-analysis of these two therapies has shown that the overall mortality, clinical cure, microbiological cure, and relapse rate were not significantly different. Importantly, the most common genotypic causes of vancomycin resistance are VanA and VanB which are inducible resistance genes. As a result, patients with initially vancomycin sensitive isolates that do not respond to treatment should be re-cultured.

If vancomycin-resistant Enterococcus is isolated and highly susceptible, therapy should be narrowed. For UTIs, monotherapy with high dose ampicillin, 18 to 30 g/day intravenous (IV), should be started. If the UTI is uncomplicated but resistant to ampicillin, then nitrofurantoin 100 mg per os (PO) twice a day or fosfomycin 3g PO single dose are the preferred agents. However, it is important to note that UTIs could be secondary to colonization and removal of the catheter could be therapeutic. For bacteremia, monotherapy with ampicillin often can be used as well. However, this does not provide bactericidal activity, so an aminoglycoside such as gentamycin can usually be added. Ampicillin with ceftriaxone is an alternative regimen as it has similar efficacy to ampicillin and gentamycin but is less nephrotoxic. 

If sensitivities are not available, or for high levels of resistance to beta-lactams or aminoglycosides, linezolid, 600 mg PO or IV twice a day, can be used. A synthetic oxazolidinone antibiotic, this is a bacteriostatic drug that binds to the ribosome, preventing peptide bond formation. For endocarditis, linezolid has been shown to be an effective first-line medication, although it is a bacteriostatic drug. Adverse effects, especially after prolonged use, include thrombocytopenia, anemia, peripheral neuropathy, and risk of inducing serotonin syndrome. Alternatives should be considered with patients who regularly take serotonergic medications.

Another alternative is an off-label use of high dose daptomycin 8 to 12 mg/kg IV (with renal adjustment) once a day. A lipopeptide antibiotic, it is bactericidal and causes cell membrane depolarization. Importantly, if patients are persistently bacteremic or the minimum inhibitory concentration is high for daptomycin, then combination therapy with ampicillin or ceftaroline can be used. Patients should be evaluated for myopathy, and weekly creatine kinase levels should be obtained. Furthermore, daptomycin is not effective on pulmonary infections as surfactant inactivates it, but this is rarely a concern with vancomycin-resistant Enterococcus because enterococcal pneumonia is exceedingly rare.

Tigecycline, a glycylcycline antibiotic, can be used for patients who are intolerant to other agents. It also can be used if other infections are present with the vancomycin-resistant Enterococcus as it has good coverage against gram positives, some gram negatives, and anaerobes. Although it is off-label, it is specifically considered a preferred agent for polymicrobial intraabdominal infections. It should not be used for vancomycin-resistant Enterococcus bacteremia as it distributes primarily to tissues and achieves low serum concentrations. Typical dosing is 100 mg IV once followed by 50 mg IV twice a day. Patients should be monitored for major adverse effects such as nausea and vomiting.

Chloramphenicol, at 50 to 100 mg/kg/day divided into doses every 6 hours (4 g/day max dose), has been used successfully to treat vancomycin-resistant Enterococcus bacteremia for many years and has excellent tissue penetration, including the CNS. Due to its high incidence of toxicity and adverse effects, such as aplastic anemia or bone marrow suppression, it should not be used as a first-line agent when other options are available and should generally be initiated in consultation with an infectious-disease specialist. It remains an option in resource-poor environments where modern drugs may not be available.[7][15][16][7]

Differential Diagnosis

• Bacterial sepsis

• Hospital-acquired  infections

• Infective endocarditis

• Peritonitis and abdominal sepsis

• Pyogenic hepatic abscesses

• Septic arthritis

• Uti and cystitis in females

• Uti in males

• Wound infection

Complications

• Endocarditis
• Colitis
• Osteomyelitis
• Sepsis
• Pneumonia