Abstract
Effective antimicrobials are crucial for managing Staphylococcus aureus implant-associated bone infections (IABIs), particularly for infections due to rifampin-resistant S. aureus (RRSA). Failure to remove the implant results in persistent infection; thus, prolonged suppressive antibiotic therapy may be a reasonable alternative. However, a high incidence of adverse events can necessitate the discontinuation of therapy. In this scenario, commercial Staphylococcal bacteriophage Sb-1 combined with antibiotics is an option, showing a promising synergistic activity to facilitate the treatment of biofilm infections. Therefore, we evaluated the efficacy of the inhibitory activity of five antibiotics (doxycycline, levofloxacin, clindamycin, linezolid, and rifampin) alone or combined with phage Sb-1 (106 PFU/mL) in a simultaneous and staggered manner, to combat five clinical RRSA strains and the laboratory strain MRSA ATCC 43300 in 72 h by isothermal microcalorimetry. The synergistic effects were observed when phage Sb-1 (106 PFU/mL) combined with antibiotics had at least 2 log-reduction lower concentrations, represented by a fractional biofilm inhibitory concentration (FBIC) of <0.25. Among the antibiotics that we tested, the synergistic effect of all six strains was achieved in phage/doxycycline and phage/linezolid combinations in a staggered manner, whereas a distinctly noticeable improvement in inhibitory activity was observed in the phage/doxycycline combination with a low concentration of doxycycline. Moreover, phage/levofloxacin and phage/clindamycin combinations also showed a synergistic inhibitory effect against five strains and four strains, respectively. Interestingly, the synergistic inhibitory activity was also observed in the doxycycline-resistant and levofloxacin-resistant profile strains. However, no inhibitory activity was observed for all of the combinations in a simultaneous manner, as well as for the phage/rifampin combination in a staggered manner. These results have implications for alternative, combined, and prolonged suppressive antimicrobial treatment approaches.
Highlights
Staphylococcus aureus implant-associated bone infections (IABIs) represent a substantial challenge in orthopedic and trauma-related surgery, with severe consequences for the patients, such as long hospital stays and repeated surgeries [1]
A broth microdilution assay was performed to confirm that the minimum inhibitory concentrations (MICs) of rifampin were greater than or equal to 1 μg/mL for the clinical strains according to EUCAST breakpoints [20], which was interpreted as rifampin-resistance
Most strains exhibited susceptibility to the tested antibiotics according to EUCAST breakpoints (EUCAST, 2020), while doxycycline (2 μg/mL), levofloxacin (1 μg/mL), linezolid (4 μg/mL), clindamycin (0.5 μg/mL), and rifampin (0.5 μg/mL) were considered resistant
Summary
Staphylococcus aureus implant-associated bone infections (IABIs) represent a substantial challenge in orthopedic and trauma-related surgery, with severe consequences for the patients, such as long hospital stays and repeated surgeries [1]. Current treatment approaches for S. aureus implant-associated infections are based on surgical debridement with retention or removal of the infected tissue in order to reduce the bacterial burden as much as possible and on prolonged administration of biofilm-active antibiotics; the recommended antimicrobials are rifampin-based combination therapy due to its excellent bone penetration ability and oral bioavailability [4,5]. The rifampin-resistant S. aureus (RRSA) IABIs are considered as difficult to eradicate in patients with limiting therapeutic interventions. Antibiotic suppressive therapy, as the alternative treatment strategy, is used to achieve sustained remission in chronic IABIs patients retaining the foreign body, as due to various reasons they are unable to remove the implant with the rifampin-resistant
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