Antimicrobial Distribution From Local Delivery Depends on Dose

Abstract

Background Tissue distribution after local delivery has been quantified over a period of 5 hours on 7-T MRI in a rabbit model using gadolinium-labeled diethylenetriamine pentaacetic acid (Gd-DTPA) as an antimicrobial surrogate; however, it is unknown how the Gd-DTPA load in a local depot will affect the duration of high-concentration Gd-DTPA in local tissues after surgical débridement. Questions/purposes We determined whether the Gd-DTPA load in bone cement affected its local tissue distribution over a period of 1 month after local delivery.

Biofilm Antimicrobial Susceptibility Increases With Antimicrobial Exposure Time

“…Local delivery is expected to achieve levels above MBEC for several days. In vivo pilot data from quantitative MRI and in vivo tissue levels are consistent with levels from local delivery of 100 to 2000 lg/ mL lasting 5 days or more indicating the concentrations consistent with expected MBECs can be achieved from local delivery [12,15]. Although MBEC is the concentration that potentially will eradicate biofilm in 24 hours, it is not known if treatment duration longer than 24 hours would require the same antimicrobial concentration.…”

“…We attribute this to contamination of the 2000-lg/mL subcultures, falsely leading to the reading of 4000 lg/mL. The MBECs we measured at Day 5 are levels that could plausibly be sustained in vivo from local delivery for 5 days [12,15]. For the S. aureus strains that we studied, MBECs for combined antimicrobial formulations were lower than for single drug exposures (sign test, p \ 0.0386), which is consistent with synergy against planktonic S. aureus strains reported by other authors [21].…”

“…However, based on previously published quantitative MRI findings and in vivo tissue levels, concentrations in the range of 100 to 2000 lg/mL in a surgical wound are plausible for 5 days using high-dose delivery formulations. We consider 5 days a reasonable clinical goal for local antimicrobial delivery [12,15]. Third, we used a S. epidermidis strain, which is resistant by MIC (32 lg/mL) and forms biofilms that are tobramycin-tolerant to [ 8000 lg/mL; MBEC was measured in our laboratory outside the scope of this study to be approximately 40,000 lg/mL for tobramycin.…”

“…We chose to study this microorganism because of its known robust biofilm production. Although it is a laboratory strain not obtained directly from a clinical infection, this finding indicates that microorganisms with extremely high MBECs for a single drug can be eradicated by dual therapy at levels plausibly achievable by local delivery [12,15], in this case tobramycin and vancomycin. Based on the hundreds of strains that exist for (MICs) and 1-, 3-, staphylococcal species and their ability to develop persister cells tolerant to antimicrobials, it seems possible that biofilm microorganisms with similar antimicrobial tolerance could be responsible for recalcitrant clinical infections, underscoring consideration for codelivery of antimicrobials with different mechanisms of action such as vancomycin and tobramycin.…”

Antimicrobial Release From Prefabricated Spacers Is Variable and the Dose Is Low

“…As such it determines the antimicrobial release capability from the surfaces studied, not antimicrobial levels that will occur clinically. It is reasonable to expect that the amount of gentamicin delivered in vivo from different delivery vehicles would be proportional to the in vitro release data [13], but the actual levels that are achieved cannot be inferred from elution studies. Fourth, as an in vitro study our findings cannot be used to Table 2.…”