The genus Enterococcus consists of bacteria naturally found in the human gastrointestinal tract, forming a part of the normal gut flora. While typically harmless, these organisms are opportunistic pathogens that can cause serious infections when they translocate to other body sites. Treating these infections is challenging due to the bacteria’s inherent ability to resist multiple classes of antibiotics. Enterococcus species are now among the most common causes of hospital-acquired infections worldwide, often affecting critically ill patients or those with underlying conditions.
Understanding Enterococci Infections
Enterococci are Gram-positive bacteria that possess a characteristic round shape and are classified as facultative anaerobes, meaning they can survive with or without oxygen. This hardiness allows them to thrive in diverse environments, including the hospital setting. The two species responsible for the vast majority of human infections are Enterococcus faecalis and Enterococcus faecium.
E. faecalis is historically the more common isolate, accounting for 80% to 90% of clinical cases, while E. faecium is often associated with more drug-resistant strains. These bacteria are responsible for a range of severe conditions, particularly in hospitalized patients with indwelling medical devices. Common infection sites include the urinary tract, the bloodstream (causing bacteremia and sepsis), and the heart valves, where they cause infective endocarditis requiring aggressive and often prolonged treatment.
Why Ceftriaxone is Not the Standard Treatment
Ceftriaxone, a widely used third-generation cephalosporin, is generally ineffective against Enterococcus species, which is a major point of confusion given its broad-spectrum activity against other Gram-positive bacteria. This lack of activity is an intrinsic property of the organism, built into its cell wall synthesis machinery. All Enterococci naturally produce an altered enzyme called Penicillin-Binding Protein 5 (PBP5).
PBP5 is the primary target that cephalosporin antibiotics must bind to and inhibit to successfully halt cell wall construction, which is how the drug kills bacteria. However, the structure of PBP5 has a significantly reduced affinity for Ceftriaxone and other cephalosporins. Even when the drug is present at high concentrations, the PBP5 enzyme continues to function, allowing the bacterial cell wall to be synthesized and the organism to survive and multiply.
This mechanism results in a high minimum inhibitory concentration (MIC) for Ceftriaxone, rendering it clinically useless as a single agent for treating enterococcal infections. In fact, using cephalosporins alone for a suspected infection can actively select for and promote the growth of Enterococci. Therefore, when treating a patient with a known or suspected Enterococcus infection, Ceftriaxone is routinely excluded from the therapeutic regimen.
Primary Antibiotic Strategies
For infections caused by strains that are still susceptible to common antibiotics, the first-line treatment relies on agents that target the bacterial cell wall. Ampicillin or Penicillin G are the preferred monotherapies for susceptible E. faecalis infections, particularly for less severe cases like uncomplicated urinary tract infections. These beta-lactam antibiotics are generally able to bind to the enterococcal PBP targets with enough potency to achieve a therapeutic effect in most E. faecalis strains.
When a patient has a documented severe penicillin allergy or the infecting strain is resistant to Ampicillin, the glycopeptide antibiotic Vancomycin becomes the alternative cell wall agent. Vancomycin interrupts cell wall synthesis at a different step than beta-lactams, making it an effective substitute for susceptible Enterococcus infections. The decision between Ampicillin and Vancomycin is heavily dependent on the patient’s allergy profile and the specific susceptibility of the isolate.
For serious, deep-seated infections such as endocarditis or meningitis, a single agent is often not enough to achieve a bactericidal (bacteria-killing) effect, so combination therapy is employed. The standard synergistic approach combines a cell wall agent, such as Ampicillin, with an aminoglycoside like Gentamicin. The cell wall agent damages the cell structure, which then allows the aminoglycoside to penetrate the bacterium and interfere with protein synthesis, achieving a much stronger and faster killing effect.
In cases of E. faecalis endocarditis that exhibit high-level resistance to aminoglycosides, a “double beta-lactam” regimen combining high-dose Ampicillin with Ceftriaxone is sometimes used to achieve synergy. This specific combination should not be confused with using Ceftriaxone alone.
Addressing Drug-Resistant Enterococci
The most challenging scenario involves drug-resistant strains, particularly Vancomycin-Resistant Enterococci (VRE). VRE strains, most commonly E. faecium, have acquired genetic material that alters the cell wall structure, preventing Vancomycin from binding effectively. Treating VRE infections requires the use of reserve antibiotics, which are often less potent, carry more side effects, or are only bacteriostatic, meaning they inhibit growth rather than actively killing the bacteria.
Linezolid, an oxazolidinone antibiotic, is an important option for VRE infections and is available in both intravenous and oral forms. It works by inhibiting the initiation of bacterial protein synthesis and is widely used for both E. faecalis and E. faecium. Daptomycin, a lipopeptide, offers a potent bactericidal alternative that works by disrupting the bacterial cell membrane.
Another option, Quinupristin/Dalfopristin, is a combination drug that has activity only against VRE strains of E. faecium and not E. faecalis. The choice between these agents is guided by the infection site, the patient’s renal function, and local resistance patterns, with Daptomycin often preferred for bloodstream infections when it is susceptible. Ultimately, determining the appropriate course of action for resistant strains relies heavily on culture and susceptibility testing (antibiogram), which provides healthcare providers with the specific profile of drugs that remain effective against the infecting organism.