Enterococci are microorganisms that have a remarkable ability to adapt to their environment. Two species have a notable clinical implication, enterococcus faecalis and enterococcus faecium. Risk factors for colonization and infection should be recognized, including prior treatment with antibiotics such as cephalosporins or quinolones. Because of their natural resistance to several classes of antibiotics and increased resistance to penicillins, initial empirical treatment of severe infection in a patient with risk factors will often include a glycopeptide. A restriction in the empirical use of cephalosporins or quinolones and antibiogram-targeted antibiotic therapy are essential measures to prevent the emergence of resistant enterococci strains, particularly resistant to vancomycin.
Enterococci are Gram-positive bacteria in the form of diplococci or chain hulls. They are anaerobic facultative, immobile and devoid of capsule. This family includes about 30 species that have long been classified as streptococci because of their similarities with group D streptococci. The two main clinically important species are enterococcus faecalis and enterococcus faecium, the first found more frequently than the latter (90% vs. about 10%).
These germs are undemanding and can survive under hostile conditions, such as highly alkaline or salt-rich environments (e.g., bile salts), or extreme temperatures (10 °C to 60 C). They can also survive for a long time on all kinds of surfaces. On the other hand, they are not very virulent by nature compared to other Gram-positive bacteria since the lethal dose, that is to say the number of bacteria which kills 50% of the animals, is definitely higher. They are both part of the commensal flora of our intestines and behave like opportunistic germs. The infections most often caused by these germs are urinary tract infections, peritonitis, intra-abdominal abscess, nosocomial bacteremia or endocarditis. The most commonly found portal of entry is digestive but catheters can also be a source of infection in a medical setting. Their nature gives them a certain number of native resistance and tolerance capacities to different classes of antibiotics, which determines the therapeutic management. Using a clinical case encountered in hospital practice, we will explore various possible scenarios.
Ms. R., age 45, is hospitalized in the ICU because of severe diabetic acid-ketosis decompensation that developed in the context of a cefuroxime-treated pulmonary infection, 2 x 500 mg per day for three years. days. She has been known for type 1 diabetes for 30 years.
After stabilizing her condition, she was transferred to a department of internal medicine five days later. Twenty-four hours after her transfer, she presents a feverish state at 39 °C associated with an episode of solemn shivers. There is no clear infectious focus but there is a systolic murmur in the mitral focus not previously described. Following blood cultures, urine culture, ablation and catheter culture, empiric treatment with piperacillin-tazobactam is initiated in the context of a probable nosocomial infection. Two pairs of blood cultures performed are positive for enterococci. An echocardiogram is requested and the antibiotic treatment is adjusted according to the following scenarios.
FIRST SCENARIO: THIS IS AN ENTEROCOCCUS FAECALIS “SENSIBLE”
Enterococci are characterized by native resistance to cephalosporins mediated by a penicillin binding protein (PLP). The minimum inhibitory concentration (MIC) of penicillins and carbapenems is 10 to 100 times higher for enterococci than for other streptococci due to a lower affinity of PLP for these betalactamines. In addition, enterococci are considered to be beta-lactam tolerant because they are killed only by minimal bactericidal (MBC) concentrations of antibiotics well above the MIC (CMB / MIC> 32). Thus, while they are considered sensitive to penicillins or carbapenems on the antibiogram (Table 2), this does not mean that these antibiotics will be bactericidal. If a bactericidal effect is necessary, as in a case of severe infection, it is therefore recommended to combine an aminoglycoside penicillin to benefit from a synergistic effect.
Aminoglycosides are not effective against enterococci at doses used against other organisms due to less permeability of the wall, but their use in combination with an agent blocking the synthesis of peptidoglycans (a betalactamine or a glycopeptide) allows better penetration of aminoglycosides and restores their full effectiveness. The two aminoglycosides that are recommended for this synergistic effect are gentamycin and, more rarely, streptomycin. In recent years, more and more strains of enterococci having acquired a high level of resistance to aminoglycosides have been observed. On the other hand, their side effects, in particular their nephrotoxicity and ototoxicity may pose difficulties of use in frail and elderly patients.
To come back to our case, given the microbiological result and the possibility of endocarditis, the doctors in charge reduced the spectrum of antibiotic therapy and prescribed intravenous amoxicillin (6 × 2 to 4 × 2 g / day). associated with intravenous gentamicin (3 mg / kg / day divided into three equal doses). Amoxicillin is indeed beta-lactam, which has the lowest MIC. The choice of intravenous penicillin 6 × 2 or 4 × 3 million IU / day would also have been possible.
The patient described in our clinical situation had received cefuroxime to treat a pulmonary infection. Prior antibiotic therapy is an established risk factor for developing enterococcal infection, especially if it is a third-generation cephalosporin such as ceftriaxone or a quinolone (e.g., ciprofloxacin) against which enterococci are present. are naturally resistant. Such treatments promote positive selection and proliferation of these enterococci. In hospitals, cephalosporins and quinolones are frequently used as an empirical treatment, especially in digestive and urological surgery.6 However, in persons at risk of developing enterococcal infection, as described below), it should be avoided these antibiotics in particular and to use ant biotherapy that is effective against enterococci before the results of blood cultures are available. A specialist opinion of infectious diseases can be useful in this situation.
With regard to simple urinary tract infections, a recent study has shown that cultures made on urine collected mid-jet returning positive for an enterococcus very rarely reflect the presence of a urinary infection to this germ. This is mostly the case of contamination and this even if the found concentration is greater than 105 CFU / ml, a concentration that signs the infection for other germs, including E. coli. These cases should not be treated in the absence of signs of severity.
THIRD SCENARIO: THIS IS A VANCOMYCIN RESISTANT ENTEROCOCCUS FAECIUM (VRE)
Enterococcus faecium is naturally more resistant to betalactamines and aminoglycosides than enterococcus faecalis (Table 1). These antibiotics are therefore not part of the empirical treatment recommended for these germs, which must include from the outset the use of a glycopeptide such as vancomycin.
However, in recent years, multiresistant strains of enterococcus faecium have developed, which have acquired new resistance factors, such as glycopeptide resistance. This phenomenon is well illustrated by the strain of E. faecium “clonal complex 17” (CC-17). A clonal complex is a group of bacteria genotypically close enough to be assigned a common origin. This strain CC-17 has adapted perfectly to the hospital environment by acquiring resistance factors such as cytolysin, molecule promoting cell lysis or Esp (Enterococcal surface protein) which allows better colonization of the urinary tract and catheters by the formation of a protective biofilm. This strain was found in particular in the epidemic that hit the CHUV and the Payerne Hospital in 2011. To date, according to genotypic and phenotypic criteria conferring them various resistance properties (operons), there are eight types acquired resistance to vancomycin (VanA, VanB, VanD, VanE, VanG, VanL, VanM, and VanN). The type of VanC resistance is intrinsic and specific to certain strains of enterococci. VanA isolates are generally resistant to vancomycin and teicoplanin, while VanB isolates remain sensitive to teicoplanin, which is of great therapeutic interest.
The spread of ERV in the United States is due to the wide use of cephalosporins and vancomycin in hospitals, and currently more than 30% of nosocomial enterococcal infections are caused by ERVs. In Europe, there is no large-scale use of vancomycin but a continued misuse of broad-spectrum antibiotics that selects ERVs.12 Currently, about 3% of nosocomial enterococcal infections are due to VRE and the vast majority are enterococcus faecium. The proportion of isolated ERVs is very uneven in the different European countries; it ranges from less than 1% to more than 25% in some countries, such as Ireland, according to EARS-Net (European Surveillance System for Antimicrobial Resistance, www.ecdc.europa.eu). There is also a worrying increase in nosocomial infections at VRE in Germany, with a rate of more than 10% in 2012.
The treatment of these organisms is based on linezolid 600 mg / 12 h or teicoplanin 400 mg / 12-24 h (in case of sensitivity and VRE type VanB). In the presence of endocarditis, the use of daptomycin 6-9 mg / kg / 24 h is proposed in view of its bactericidal effect not found with linezolid. However, its use is based on retrospective studies and clinical case reports and is not part of official recommendations. The opinion of a specialist in infectiology is necessary.