Intrinsic resistance: the native organism

Soon after the introduction of penicillin in the early 1940s, there were reports that penicillin treatment for enterococcal endocarditis produced worse outcomes than penicillin treatment for streptococcal endocarditis . It is consistent with this observation that enterococci are considerably less susceptible to penicillins than streptococci. For example, for E. faecalis, the minimal inhibitory concentration (MICs) of penicillin is usually 8 µg per milliliter, and for E. faecium, until recently, it was 4 to 32 µg per milliliter; the concentrations of ampicillin that are needed to inhibit enterococci are about half those of penicillin. It usually takes much more penicillin (often more than 100 µg per milliliter) to kill an enterococcus than to inhibit it, and this lack of bactericidal (killing) activity presumably explains the poor efficacy of penicillin (and vancomycin) as mono therapy for patients with enterococcal endocarditis. Even those enterococci that are susceptible to killing by penicillin can develop tolerance to this bactericidal effect. The greater clinical efficacy in treating enterococcal endocarditis with the use of penicillin plus streptomycin (despite low-level in vitro resistance to the latter) was reflected in vitro by the presence of synergism and a bactericidal effect.

This finding led to the recognition of this combination as the standard of care, despite the toxicity of streptomycin. Among other antimicrobial drugs, none are more effective against enterococci than ampicillin or penicillin, and indeed, enterococci are, as a group, inherently resistant to cephalosporins, antistaphylococcal penicillins, low concentrations of clindamycin and aminoglycosides, and in vivo trimethoprim. Thus, for decades, the regimen of choice for patients with enterococcal endocarditis has been penicillin or ampicillin (with substitution of vancomycin in a patient allergic to penicillin or for the occasional ampicillin-resistant enterococcus ARE) combined with an aminoglycoside. Mono-therapy with penicillin, ampicillin, or vancomycin has appeared to be sufficient for most other enterococcal infections.

Intrinsic resistance includes enterococci that exhibit a low-level resistance to many of the antibiotics used for Gram-positive infections. The genes for intrinsic resistance, like other species characteristics, appear to reside on the chromosome. The various intrinsic (inherent) traits expressed by enterococci include resistance to semisynthetic penicillinase-resistant penicillins, cephalosporins, low levels of aminoglycosides, and low levels of clindamycin. Ampicillin and penicillin G are somewhat more effective against enterococci than other β-lactams.

A tolerance phenomenon also can occur with β-lactams. Streptococci show MICs that are 10 to 100 times lower than those for enterococci. Resistance to cephalosporins is relatively greater than for ampicillin or penicillin, making cephalosporins a poor choice for treatment. The E. faecium species appears to have a higher intrinsic resistance to β--lactams than other species. A low-level intrinsic resistance also is seen with aminoglycosides due to decreased ability of the antibiotic to penetrate the outer cell envelope of enterococci. This penetration is necessary for the antimicrobial actions of the aminoglycoside, since the drug acts intracellularly. Synergistic combinations of cell-wall active antibiotics (eg, penicillins, carbapenems, or glycopeptides with aminoglycosides) are useful when bactericidal activity is needed as in the treatment of bacteremia, endocarditis, or meningitis. E faecalis appears to have a higher level of intrinsic resistance to aminoglycosides than other species. Enterococci are marginally susceptible to fluoroquinolones and are not susceptible in vivo to sulfamethoxazole/trimethoprim due to endogenous sources of folate.

Clindamycin generally is considered to be inactive against enterococcal organisms at clinically achievable concentrations. Antibiotics other than those used for Gram-positive infections and aminoglycosides have shown limited efficacy in the treatment of enterococci.