All the patients were at increased risk for the development of CoNS infections for different reasons. Patients from the transplant haematology ward were neutropenic or were receiving immunosuppressant drugs, while patients from the ICU were critically ill and were being treated with broad spectrum antibiotics for different infections. Importantly, they all had a central vein catheter. One observation of concern is that only two of the thirteen patients had previous exposure to glycopeptides. This is in contrast to other reports describing the selection of resistance after exposure to vancomycin or teicoplanin in CoNS [8
]. In the current study, the great number of CoNS isolated from blood were considered to be contaminants, particularly in the haematology ward where blood cultures are drawn for routine for surveillance other than to diagnose infection. In this ward therapy protocols schedule an association of antimicrobials on signs of infections. This may lead to underestimate the frequency of CR-BSI interfering with cultures. In ICU blood cultures are drawn on signs of infection, so the number of clinically relevant CoNS out of the total amount of blood cultures is higher, although the level of contamination is also high. It can be very difficult to draw blood from venipuncture in haematology or critically ill patients, so a certain level of contamination is probably unavoidable, but our data impose to be more strict in sending in blood for cultures in order to limit false positive cultures that may lead to overtreatment.
Our data support the idea that CoNS with reduced susceptibility to glycopeptides are endemic in these wards and are maybe resident on skin and nares of personnel and patients. Indeed, genomic analysis revealed that different strains were responsible for most infections. Only two isolates displayed a clonal relationship. As a direct contact between the two patients was excluded, ward or personnel contamination should be implicated. Nevertheless, as far as we are aware, there is no indication for screening and decontamination of CoNS in patients and personnel from critical areas such as the haematology ward and the ICU. This could be an issue for further studies.
After this study, the actual therapy strategy in the two wards is to start empirical treatment with glycopeptides if CR-BSI is suspected and promptly shift to a different drug according to susceptibility test if the diagnosis is confirmed or if treatment fails. Nevertheless if the signs of infection are severe or if clinical conditions do not allow to wait, therapy with linezolid is started and eventually de-escalated on sensitivity report.
The majority of isolates were S. epidermidis
and this species was slightly more frequently associated with BSI than S. haemolyticus
. It was widely accepted that S. haemoyiticus
is uniquely predisposed among CoNS to develop glycopeptides resistance as this was the first CoNS species in which vancomycin and teicoplanin resistance was identified [21
]. Nowadays S. epidermidis
is often reported to be a nosocomial pathogen bearing multi-resistance [22
]. Moreover there are many studies suggesting the possible relationship between methicillin resistance and reduced susceptibility to glycopeptides in CoNS [9
Not all clinical isolates demonstrated MICs for vancomycin and teicoplanin in the intermediate susceptibility range, but they were all shifted towards the cut-off level. Moreover, these isolates were also able to grow on Vanco-screen agar. It has been previously shown that staphylococci able to grow on Vanco-screen agar may display hetero-resistance to glycopeptides [27
]. Heteroresistance was first defined as the presence of >10-6
stable cell subpopulations of a strain that is apparently susceptible to vancomycin on the basis of conventional criteria, but for which the vancomycin MIC for the subpopulation of cells is greater than or equal to 8 mg/liter [12
]. Since 2006 CLSI breakpoints have changed, actual definition might be that although the MIC for the entire population is within the range of susceptibility according to the CLSI criteria, subpopulations grow in the presence of ≥ 4 mg/L of vancomycin. The hetero-resistant phenotype may be associated with treatment failure and/or may be precursor of glycopeptide resistance and should be considered in both empirical and rational therapy decisions.
In our series, CoNS remained homogeneously susceptible in vitro
to linezolid, tigecycline and daptomycin. Of these three drugs only daptomycin is suitable for the treatment of BSI, given its pharmacokinetic profile. Linezolid was used off label to treat most patients. The use of linezolid for the treatment of catheter related Gram positive blood stream infections is still a matter of discussion, as there have been suggestions that it is associated with a higher mortality rate depending on the type of infection [28
]. Nevertheless, in a recent cohort study, empiric therapy with linezolid was associated with greater survival and more successful microbiological eradication compared to standard therapy in the treatment of methicillin-resistant S. aureus
]. Further, in a pharmacoeconomic evaluation study linezolid was considered more efficient than teicoplanin in the treatment of Gram-positive bacteremia [30
Tigecycline is not registered for the treatment of bacteremia, and its use should be limited to real clinical necessity to preserve its activity against multi-resistant Gram negative bacteria. Clinical efficacy of daptomycin has been demonstrated in patients with S. aureus
]. To our knowledge no clinical data exist on daptomycin efficacy against CoNS with elevated MICs for glycopeptides. A remarkable characteristic related to low-level resistance to glycopeptides in CoNS is cell wall thickness [27
]. Due to its mechanism of action, this characteristic may interfere with daptomycin also, at least in clinical setting or subsequent to extensive use.