A Review of the Combination Therapy of Low Frequency Ultrasound with Antibiotics

Table 3

Reports about effect of LFU on antibiotic release from implanted material.

Authors (year)	Type of research	Pathogens	Frequency, density, and time of LFU	Loaded antibiotics	Results
Hendriks et al. (2003) [40]	In vitro study of bone cement	NA	46.5 kHz; Time average acoustic intensity of 167 mW/cm^2; 1 : 3 duty cycle; 18 h	Gentamicin	Average gentamicin release was higher in the insonated samples for all three bone cements, although none of these differences were statistically significant.
Norris et al. (2005) [39]	In vitro studyon hydrogel polymer matrix	P. aeruginosa	43 kHz; CW, 15 min at three time points in 4 h period	Ciprofloxacin	Biofilm accumulation on ciprofloxacin-loaded hydrogels with ultrasound-induced drug delivery was significantly reduced compared to the accumulation of biofilms grown in control experiments.
Ensing et al. (2005) [41]	In vitro studyon bone cement samples and beads	NA	46.5 kHz; Average acoustic intensity of 167 mW/cm^2; 1 : 3 duty cycle; 18 h	Gentamicin	Pulsed ultrasound significantly enhanced gentamicin release from gentamicin-loaded beads, whereas gentamicin release from the gentamicin-loaded bone cements was not significantly enhanced.
Ensing et al. (2005) [43]	In vivo study of bone cement	E. coli	28.48 kHz; Mean acoustic intensity of 167 mW/cm^2; 1 : 3 duty cycle; 24–72 h	Gentamicin	Ultrasound in combination with gentamicin yielded a tendency towards enhanced bacterial killing in biofilms growing on acrylic bone cements.
Ensing et al. (2006) [42]	In vitro study	E. coli; S. aureusCoagulase-negative staphylococci; P. aeruginosa	46.5 kHz; mean acoustic intensity of 167 mW/cm^2; 1 : 3 duty cycle; 40 h	Gentamicin; Gentamicin/clindamycin	Application of pulsed ultrasound in combination with antibiotic release by antibiotic-loaded bone cements yielded a reduction of both planktonic and biofilm bacterial viability compared with antibiotic release without application of ultrasound.
Cai et al. (2007) [44]	In vivo study of bone cement	S. aureus	46.5 kHz; Average intensity of 300 mW/cm^2; 2 : 1 duty cycle; 12 h	Vancomycin	The enhanced reduction in hip aspirates from ultrasound group 0–12 h was 1.62  CFU/ml (), and that in hip aspirates from ultrasound group 12–24 was 2.77  CFU/ml ().
Yan et al. (2007) [46]	In vitro and in vivo study of antibiotic-loaded bone cement	S. aureus	25 kHz; 100 or 300 mW/cm^2 for in vitro study; 300 mW/cm^2 for in vivo study; CW, 0.5 h	Vancomycin	LFU increased the drug elution by 2.57–27.44% when compared with the controls in vitro. LFU increased local by 47.6 mg/mL and urinary elimination of vancomycin by 109.56 mg but failed to prolong local . Decreased bacterial vitality and relieved inflammation in the infected hip treated were also observed in ultrasound group.
Cai et al. (2009) [10]	In vitro study of bone cement	NA	46.5 kHz; Spatial-average-time-average intensity of 1.2 W/cm^2; 1 : 2 duty cycle; 40 min	Vancomycin	Intermittent watt-level ultrasonication improved the ultrasound-enhanced vancomycin release from cement in view of the prolonged and the inhibited subtherapeutic release compared with continuous ultrasonication.
Lin et al. (2015) [45]	In vitro and in vivo study of PMMA cement	S. aureus	1 MHz; 300 mW/cm^2; 3 : 10 duty cycle; 4–24 h	Vancomycin	In vitro study showed the eluted vancomycin from the vancomycin + ultrasound + microbubbles group was significantly more effective against the planktonic S. aureus than in any of the other study groups (). In vivo study showed the viable count of S. aureus that survived when vancomycin + ultrasound + microbubbles cylinders were implanted was significantly lower than in each of the other study groups ().
Wendling et al. (2016) [47]	In vitro study of PMMA cement	NA	25.5 kHz; CW, 5, 15, 45 min	Vancomycin	There were significant increases in elution amount for LFU treatment groups compared with the non-LFU groups (). The correlations between LFU duration and total elution amount were significant ().

CW: continuous wave ultrasound. NA: not applicable.