High-Dose Daptomycin Is Effective as an Antibiotic Lock Therapy in a Rabbit Model of Staphylococcus epidermidis Catheter-Related Infection

TEXT

Bloodstream infections (BSIs) are a common complication of central venous catheters (CVCs), with incidence rates of 2.9 to 11.3 cases per 1,000 days of CVC use (1). The main microorganisms that cause long-term catheter-related BSIs (CRBSIs) are coagulase-negative staphylococci (CoNS), which account for ∼30% of health care-associated BSIs (2–5). The pathogenic property of CoNS is related mainly to their ability to form an adherent biofilm on the surface of indwelling medical devices (6). Antibiotic lock therapy (ALT) using vancomycin lock therapy (LT) is recommended in cases of uncomplicated CRBSIs caused by CoNS (7). Moreover, this treatment fails in the form of relapse in 20% of episodes, so new therapeutic alternatives need to be explored as elective therapies (2). Daptomycin has demonstrated high in vitro efficacy against staphylococcal biofilms because of rapid penetration into the matrix of the biofilm (8, 9).

ALT regimens last 14 days, resulting in reduced access to the device. Moreover, there are patients with no other available vascular access who urgently need vascular access and benefit from a shorter treatment period. Given the clinical importance of finding a faster and more effective ALT treatment to enable earlier access to the long-term catheter, thereby improving patient outcomes, reducing the risk of resistance, and preventing infection-related sequelae, the aim of this study was to compare the activity of vancomycin and different concentrations of daptomycin for the treatment of experimental Staphylococcus epidermidis catheter-related infection using ALT in a rabbit model.

The MICs of vancomycin and daptomycin against two strains of S. epidermidis (SE14 and SE94) were determined with the broth microdilution method according to EUCAST (10). Both strains were susceptible to vancomycin and daptomycin. To analyze the susceptibility on biofilm formation, we followed the protocol described by Chandra et al. (11). We found that minimum biofilm eradication concentrations at 90% (MBEC₉₀s) of vancomycin for the SE14 and SE94 biofilms growing in silicone discs were 10,000 and >10,000 mg/liter, respectively, and the MBEC₉₀s of daptomycin were 1,024 mg/liter for both strains. Our in vitro studies indicated that daptomycin exhibited better in vitro activity than vancomycin against the S. epidermidis biofilm. Unlike daptomycin, vancomycin diffused slowly into the deeper layers of the biofilm, and the biofilm bacteria showed decreased sensitivity to vancomycin (12).

To measure the effect of vancomycin 10 mg/ml and daptomycin 5 and 50 mg/ml on S. epidermidis biofilm, growth on silicone discs was visualized with confocal laser scanning microscopy (CLSM) using LIVE/DEAD staining to distinguish between dead cells and live cells. As shown in Fig. 1a and b, daptomycin 50 mg/ml significantly reduced the number of live cells; in contrast, dead cells increased in the other treatments. Moreover, the effect of the treatments visualized with CLSM revealed that both strains treated with daptomycin at a high concentration had a bacterial mortality of >90% (Fig. 1c). The differences between the results of colony counts and viability using CLSM indicated that some samples contained viable but nonculturable (VBNC) cells. The possible recurrence of staphylococci infections related to medical devices may be caused for this VBNC (13).

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FIG 1

Activity of vancomycin and daptomycin in silicone discs against S. epidermidis strains SE14 (a) and SE94 (b) after 24 h of treatment. VAN, vancomycin; DAP, daptomycin. *, P ≤ 0.05 versus control. **, P ≤ 0.05 versus control and VAN 10 mg/ml. ***, P ≤ 0.05 versus control, VAN 10 mg/ml, and DAP 5 mg/ml. (c) S. epidermidis stained with LIVE/DEAD BacLight viability kit to directly visualize the effect of the antibiotics tested. Red fluorescence, dead cells; green fluorescence, live cells (visualized at ×60 magnification).

Following methodology used in our previous studies of ALT therapy for catheter-related infection (14), after 48 h infection with an inoculum of 10⁸ CFU/ml of SE14 or SE94, treatments with vancomycin 10 mg/ml and daptomycin 5 and 50 mg/ml were analyzed using the percentage of negative cultures and the log₁₀ CFU (mean ± SD; 95% confidence interval [CI]) recovered from the catheter-tip cultures (Table 1). Higher concentrations of vancomycin were not used because of the precipitation of the drug (15). After 24 h of LT with daptomycin 50 mg/ml, the colony counts recovered from the catheter-tip cultures were significantly lower than those treated with vancomycin or daptomycin 5 mg/ml (P ≤ 0.001). Of note, daptomycin 50 mg/ml was the only LT that achieved a significant percentage of negative catheter-tip cultures in both strains after 24 h. At 72 h, no difference was seen between the two daptomycin doses, which were more effective than the vancomycin locks. This suggests that daptomycin at high concentrations rapidly penetrates the biofilm layer, thus reducing both the length and frequency of ALT with a rapid salvage of CVCs.

Clinical use of daptomycin LT for the treatment of CoNS-associated CRBSIs is scarce (16, 17). Therefore, global results from the few clinical cases in which daptomycin 5 mg/ml was used as ALT are similar to those with vancomycin, with a failure rate of close to 20% to 25%. However, in our results, a high therapeutic dose of daptomycin resulted in statistically significant reductions of catheter bacterial loads and negativization of catheter tips in just 24 h of treatment. That difference can be translated to superior efficacy in clinical practice, including a reduction in the duration of treatment or prevention of the spread of persistent cells.

In conclusion, daptomycin LT at high concentrations may be a promising treatment for CoNS-associated CRBSIs, offering a therapeutic advantage over low concentrations of daptomycin or vancomycin, thus warranting further consideration and clinical studies.