Large variations in clinical antibiotic activity against Staphylococcus aureus biofilms of periprosthetic joint infection isolates

Abstract

Staphylococcus aureus biofilms have a high tolerance to antibiotics, making the treatment of periprosthetic joint infection (PJI) challenging. From a clinical perspective, bacteria from surgical specimens are cultured in a planktonic state to determine antibiotic sensitivity. However, S. aureus exists primarily as established biofilms in PJI. To address this dichotomy, we developed a prospective registry of total knee and hip arthroplasty PJI S. aureus isolates to quantify the activity of clinically important antibiotics against isolates grown as biofilms. S. aureus planktonic minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were assessed using clinical laboratory standard index assays for 10 antibiotics (cefazolin, clindamycin, vancomycin, rifampin, linezolid, nafcillin, gentamicin, trimethoprim/sulfamethoxazole, doxycycline, and daptomycin). Mature biofilms of each strain were grown in vitro, after which biofilm MIC (MBIC) and biofilm MBC (MBBC) were determined. Overall, isolates grown as biofilms displayed larger variations in antibiotic MICs as compared to planktonic MIC values. Only rifampin, doxycycline, and daptomycin had measurable biofilm MIC values across all S. aureus isolates tested. Biofilm MBC observations complemented biofilm MIC observations; rifampin, doxycycline, and daptomycin were the only antibiotics with measurable biofilm MBC values. 90% of S. aureus biofilms could be killed by rifampin, 50% by doxycycline, and only 15% by daptomycin. Biofilm formation increased bacterial antibiotic tolerance nonspecifically across all antibiotics, in both MSSA and MRSA samples. Rifampin and doxycycline were the most effective antibiotics at killing established S. aureus biofilms. ß

Complete Killing of Agar Lawn Biofilms by Systematic Spacing of Antibiotic-Loaded Calcium Sulfate Beads

“…This is indicated by the lack of growth in the zone of biofilm killing on replica plates as well as by the lack of growth in cultures taken from the zones immediately surrounding the beads, where high concentration of antibiotics was present (Figure 2A,B and Figure S3). Total eradication of biofilms in orthopedic infections by systemic administration of antibiotics is extremely challenging, since the concentrations required to eradicate biofilms of clinical strains are often greater than 1000 µg/mL for vancomycin as well as a wide range of antibiotic classes [14,48], in part due to the presence of persister cells [49]. However, concentrations of vancomycin achieved in the serum and knee joint fluid by IV administration are much lower, approximately 25 and 7 µg/mL, respectively [50].…”

“…Biofilms are microbial communities adhering to biotic or abiotic surfaces. In vitro studies and anecdotal clinical evidence suggests that bacteria within biofilms can resist killing at high antibiotic concentrations and often require a prolonged or repeated courses of antibiotics [12,13] at concentrations that are often outside the therapeutic window by systemic administration [14]. Bacteria within a biofilm become tolerant and can survive antibiotic treatments without necessarily having an acquired, heritable, resistance phenotype [15,16].…”

Structural and Functional Dynamics of Staphylococcus aureus Biofilms and Biofilm Matrix Proteins on Different Clinical Materials

“…Least active was vancomycin, as well. Furthermore, in another study, doxycycline displayed higher activity than vancomycin against different Staphylococcus aureus clinical isolates [112].…”

New developments and future challenges in prevention, diagnosis, and treatment of prosthetic joint infection

“…The minimum inhibitory concentrations (MIC) that are used as susceptibility tests for cultured bacteria do not reflect the susceptibility of the bacteria within a biofilm, which can require many‐fold higher concentrations to achieve the minimum biofilm eradication concentration (MBEC). In vitro studies from clinical isolates of S. aureus isolated from PJI suggest that rifampin and doxycycline, are among the few common antibiotics with measurable biofilm bactericidal concentrations (90% of S. aureus biofilms tested could be killed by rifampin and 50% by doxycycline) 111 . These findings are supported by clinical studies that show rifamycin‐based antibiotics such as rifampin improve treatment of PJI, however, as a monotherapy, rapid resistance develops, emphasizing the importance of combination antimicrobial therapy in S. aureus PJI 21,112 …”