Table 1.
Summary of in vitro and in vivo pre-clinical models of dalbavancin activity against biofilm-embedded bacteria.
| Reference | Microorganisms | Design | Results |
|---|---|---|---|
| Fernández et al., 2016 [32] & Schmidt-Malan et al., 2016 [34] | 171 staphylococcal clinical isolates from prosthetic joint infections | Adapted Calgary-device 1. Biofilms were 6 h mature before confronting antibiotics during 20 h. Comparators: DAL, VAN and TDZ, at increasing concentrations. | DAL: MBIC90 0.12–0.50 µg/mL, MBBC90 2–4 µg/mL VAN: MBIC90 2–4 µg/mL, MBBC90 >128 µg/mL TDZ: MBIC90 2–4 µg/mL, MBBC90 >32 µg/mL |
| Knafl et al., 2017 [36] | 10 MRSA plus 10 MRSE clinical strains | 96-well microtiter plate with a 24 h biofilm, exposed during 24 h to increasing concentrations of DAL. Measure of remaining biofilm was made by CV dying 2. No comparators. | MRSA: MIC range 0.031–0.064 µg/mL; MBC 1–4 µg/mL MRSE: MIC range 0.023–0.625 µg/mL; MBC 2–16 µg/mL |
| Neudorfer et al., 2018 [33] | Clinical isolates 58 E. faecalis 25 E. faecium |
Adapted Calgary-device 1. Biofilms were 6 h mature before confronting antibiotics during 20 h. Comparators: DAP and VAN | DAL: for VSE: MBIC90 0.25 µg/mL, MBBC90 1 µg/mL for VRE: MBIC90 > 16 µg/mL, MBBC90 >16 µg/mL VAN: for VSE: MBIC90 2 µg/mL, MBBC90 >128 µg/mL for VRE: MBIC90 > 128 µg/mL, MBBC90 > 128 µg/mL DAP: for VSE: MBIC90 4 µg/mL, MBBC90 128 µg/mL for VRE: MBIC90 4 µg/mL, MBBC90 128 µg/mL |
| Di Pilato et al., 2020 [35] | 9 clinical isolates plus 3 referral isolates (3 MSSA, 3 MRSA, 2 MSSE, 4 MRSE) |
Model 1. Adapted Calgary device. Biofilms were 7-days mature before confronting antibiotics during other 7 d. Model 2. Ti and Cr-Co disks cultured during 48 h and then confronted to antibiotics during 7 d. Both experiments used DAL and VAN at doses of 1, 4, and 16 µg/mL |
Model 1. Heterogeneous response to antibiotics. Overall, DAL showed a higher and faster reduction of biofilm-embedded bacteria over time as compared with VAN, both at lower and higher dosages. Model 2. Similar effect against biofilm formed over Ti and Cr-Co disks, except for medium dosages (4 µg/mL), where DAL showed higher reductions of biofilm-embedded bacteria |
| Žiemytė et al., 2020 [37] | Clinical isolates of MSSA, MRSA and MRSE | Experiments of biofilm inhibition and treatment (6–9 h-old biofilms). Measurement of biofilm growing over 20 h by electrical impedance. Treatment with increasing concentrations of DAL, CLX, VAN, LNZ, and RIF | 1. Biofilm inhibition. MBIC of DAL ranged 0.5–2 µg/mL. RIF and DAL showed the highest inhibitory efficacy as compared with CLX, VAN and LNZ. 2. Biofilm treatment. DAL stopped or reduced biofilm at 8–32 µg/mL. Comparators had no effect for S. aureus biofilm. For S. epidermidis biofilm, RIF and CLX were more effective than DAL at lower concentrations. |
| Darouiche et al., 2005 [38] |
S. aureus (MIC 0.06 µg/mL) |
Rabbit model of infection with catheter tips implanted in subcutaneous pockets. Treatments are administered pre-operatively so to avoid the infection of the foreign material. DAL is given at 10 mg/kg, and VAN at 20 mg/kg (and then again 24 h after surgery) | In animals treated with placebo, only 47% of catheter tips were infected. The rate of infection in the DAL group was 28% (p = 0.2 when compared to placebo), and 53% in the VAN group (p = 0.8). Serum Cmax of DAL was 80.3 µg/mL, and at day 3 it was 1.3 µg/mL. At day 7 it was only detectable in two rabbits of four (0.4 and 0.6 µg/mL). |
| Baldoni et al., 2013 [39] | MRSA ATCC 43300 MIC 0.078 µg/mL |
Tissue-cage infection model in guinea-pigs. Treatment starts 3 days after inoculation. Three regimes of DAL: 40 mg/kg—Cmax 44.6 µg/mL, AUC0–7d 3393 µg·h/mL 60 mg/kg—Cmax 55.6 µg/mL, AUC0–7d 4298 µg·h/mL 80 mg/kg—Cmax 68.8 µg/mL, AUC0–7d 4464 µg·h/mL 3 T½ 35.8 to 45.4 h. Other regimes: DAL + RIF, RIF |
DAL monotherapies had a discreet killing (inferior to RIF alone) with an infection eradication rate of 0%. The combination of RIF + DAL achieved an eradication rate similar to RIF alone (25–36%). Only high doses of DAL (80 mg/kg) avoided the emergence of rifampin resistance. |
| Barnea et al., 2016 [40] | MRSA (Clinical strain). MIC 0.06 µg/mL |
Rat animal infection model of wound infection and sternal osteomyelitis. Treatment started 24 h after inoculation. DAL was given as an initial bolus of 20 mg/kg followed by 10 mg/kg/d for 7 or 14 days. VAN was given at 50 mg/kg/12 h for 7 or 14 days. | DAL was similar to VAN and better than the absence of treatment. Administration of DAL and VAN avoided systemic dissemination of staphylococcal infection. Concentration of DAL in bone tissue at 4, 6 and 10 days was 9.5 µg/g, 9.2 µg/g, and 10.7 µg/g, respectively |
DAL: Dalbavancin. DAP: Daptomycin. VAN: Vancomycin. LNZ: Linezolid. TDZ: Tedizolid. CLX: Cloxacillin. RIF: Rifampin. MRSA: Methicillin-resistant Staphylococcus aureus. MSSA: Methicillin-susceptible S. aureus. MRSE: Methicillin-resistant Staphylococcus epidermidis. MSSE: Methicillin-susceptible S. epidermidis. VSE: Vancomycin-susceptible enterococci. VRE: Vancomycin-resistant enterococci. CV: Crystal violet. MIC: Minimal inhibitory concentration. 1 Pegged-lids confronted to 96-well microtiter plates. MBIC (minimal biofilm inhibitory concentration) is determined by turbidity after confronting the pegs with antibiotics. MBBC (minimal biofilm bactericidal concentration) is determined after incubating the pegged-lid in 96-well microtiter plates with fresh media after having confronted the pegs with antibiotics. 2 MBC was defined as a 50%-reduction in the optic density value as compared with positive controls in the 96-well microtiter plate. 3 PK of 80 mg/kg is comparable to data observed in blister of patients after a single dose of DAL 1000 mg (Cmax 67 µg/mL, and AUC0–7d 6438 µg·h/mL) [41].