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The role of daptomycin based combination therapy in prosthetic bone-joint infection caused by Resistant Enterococci (VRE) Vasant JA1, Beckley GM1, Albur M1, Noel AR2 , Bowker KE2, MacGowan AP1,2, Darley ESR1 1. North Bristol NHS Trust, Bristol, UK; 2. Antimicrobial Reference Laboratory, Bristol, UK

INTRODUCTION RESULTS: In vitro experimental data

• VRE are a common cause of nosocomial infection and are of particular concern due to a very limited range of active • Time-kill curves (TKC) for the mean results of the 3 isolates at different drug concentrations and combinations are shown in Figures 1a antimicrobials. (D-TG), 1b (D-TAR), and 1c (D-AMP) with a legend key in Table 2. • Daptomycin is the only available cidal drug for such isolates however daptomycin non-susceptibility is now emerging. • Daptomycin alone exhibited no bactericidal activity at any concentration. • In lieu of novel agents combination therapy is an attractive option. • Only tigecycline showed modest bactericidality with one log drop at 24 & 48 hours. • Recent in vitro work has suggested potential synergy for combinations of daptomycin with aminoglycosides1 and beta- • Based on “classic” interpretive criteria the combinations of daptomycin with tigecycline, ceftaroline or did not produce lactams2, however experience of daptomycin in combination with other agents is lacking. synergy at any combination (Table 3). • The area-under-bacterial-kill-curve (AUBKC) at 24, 48 and 72 hours showed modest but significantly better antimicrobial activity of

daptomycin with tigecycline as compared to daptomycin alone at Dtr and Dss (p<0.05) (Table 3). METHODS • The AUBKC at 48 and 72 hours showed a modest but significant antimicrobial additive effect for the combinations of daptomycin with

tigecycline and daptomycin with amoxicillin at Dpk (p<0.05) compared to daptomycin alone (Table 3), but not for daptomycin with Clinical data: We present the clinical and microbiological outcomes of two patients with prosthetic bone-joint infection ceftaroline. caused by VRE with reduced susceptibility to daptomycin, both treated with combination high dose daptomycin and • The AUBKC at 72 hours of combination daptomycin with tigecycline at Dpk was also superior to tigecycline alone (p=0.01). tigecycline therapy. • There was no evidence of antagonism of any daptomycin combination at any concentration or evidence for the emergence of secondary daptomycin resistance over a 72 hours period for either monotherapy or combination therapy. In vitro data: • Bactericidal activity of daptomycin (D) with tigecycline (TG), ceftaroline (TAR) and amoxicillin (AMP) alone and in Fig 1a Fig 1b Fig 1c combination was assessed by time-kill methodology for the clinical VRE isolates and an faecalis control strain (ATCC 29212). Susceptibilities of all three isolates are shown in Table 1.

• Concentrations used for daptomycin were peak (Dpk) 9.3mg/L, steady-state (Dss) 4.0mg/L and trough (Dtr) 2.2mg/L reflecting free drug serum concentrations based on actual patient data from therapeutic drug monitoring. • Fixed concentrations of 0.3mg/L (TG), 8mg/L (TAR) and 50mg/L (AMP) were used representing phamacokinetically achievable average free drug concentrations. • A 44 drug exposure matrix for each drug combination was used along with a growth control (GC). Bactericidality was measured by sampling at the following time points: 0, 2, 4, 6, 12, 24, 48 and 72 hours. Table 1. Antimicrobial susceptibilities of study isolates Table 2. Legend key for TKC graphs • Emergence of secondary daptomycin resistance was determined by subculturing onto plates containing daptomycin Antibiotic ATCC 29212 52277 VRE 1 57412 VRE 2 GC Growth control TAR Ceftaroline fixed concentration 8mg/L both 2 and 4 times above the baseline MIC. 1mg/L R R Dtr Daptomycin trough DtrTAR Daptomycin trough + ceftaroline fixed concentration 8mg/L Vancomycin 2mg/L 256 mg/L >256mg/L Dss Daptomycin steady state DssTAR Daptomycin steady state + ceftaroline fixed concentration 8mg/L 0.25mg/L R 16mg/L Nitrofurantoin 8mg/L Not done Not done Dpk Daptomycin peak DpkTAR Daptomycin peak + ceftaroline fixed concentration 8mg/L Tigecycline 0.12mg/L 0.064mg/L 0.19mg/L TG Tigecycline fixed concentration 0.3mg/L AMP Amoxicillin fixed concentration 50mg/L Daptomycin No Data 8mg/L 6 mg/L CASE 1 DtrTG Daptomycin trough + tigecycline fixed concentration 0.3mg/L DtrAMP Daptomycin trough + amoxicillin fixed concentration 50mg/L Moxifloxacin 0.25mg/L Zone 32mm R Gentamicin 8mg/L R R DssTG Daptomycin steady state + tigecycline fixed concentration 0.3mg/L DssAMP Daptomycin steady sate + amoxicillin fixed concentration 50mg/L 1mg/L S S DpkTG Daptomycin peak + tigecycline fixed concentration 0.3mg/L DpkAMP Daptomycin peak + amoxicillin fixed concentration 50mg/L • A 78 year old female underwent an elective scoliosis repair with metalwork insertion but had fevers and a leaking wound Synercid R S S 3 weeks post-operatively.

• MRI spine revealed discitis and empirical treatment was commenced with -. Table 3. Mean bactericidality (log kill) and AUBKC of study isolates. P values shown represent value for difference between AUBKC at 72 hours for highlighted antimicrobial combinations • Tissues from debridement isolated a vancomycin resistant with a daptomycin of MIC 8mg/L and tigecycline MIC of 0.064mg/L. Antibiotic 2hr log-kill 4hr log-kill 6-hr log-kill 12hr log-kill 24hr log-kill 48hr log-kill 72hr log-kill AUBKC 24 AUBKC 48 AUBKC 72 • Therapy was changed to high dose daptomycin (8mg/kg OD) and tigecycline for a 23 day period. Gc mean 0.5 1.1 1.8 2.3 2.1 2.1 2.1 189.5 386.0 582.5 Dtr mean 0.1 0.6 1.0 2.3 2.1 2.1 2.1 183.7 380.2 576.6 • Despite a decrease in CRP from 246 to 15, repeat debridement 8 weeks post surgery was required clinically. Dss mean 0.1 0.3 0.7 2.1 1.9 2.1 2.0 179.8 373.7 568.4 • Further tissues did not initially isolate a VRE however did grow a and therapy was changed to Dpk mean 0.1 0.1 0.4 1.7 1.6 2.1 1.9 173.0 363.4 557.4 TG mean 0.0 -0.1 1.9 -0.4 -1.0 -0.9 -0.4 142.8 265.5 395.2 P=0.007

linezolid and piperacillin-tazobactam. DtrTG mean -0.1 -0.1 -0.3 -0.5 -1.1 -1.3 -1.2 132.9 248.6 363.6 P=0.023 • Due to further clinical deterioration the metalwork was removed and tissues unfortunately re-grew VRE. DssTG mean 0.0 -0.3 -0.3 -0.3 -1.1 -1.4 -1.0 135.0 251.0 368.7 P=0.019 DpkTGmean -0.1 -0.3 -0.4 -1.1 -1.2 -2.1 -1.2 126.9 233.8 340.2 TAR mean 0.0 0.1 0.8 2.1 1.9 1.8 1.9 179.4 369.3 559.5 DtrTAR mean 0.0 0.0 0.7 2.2 1.7 1.7 2.0 178.1 363.3 552.3

DssTAR mean -0.1 -0.1 0.4 1.8 1.7 1.6 1.7 173.2 357.7 542.2 P=0.036 CASE 2 DpkTAR mean -0.1 -0.1 0.2 1.7 1.6 1.8 1.7 170.3 357.2 545.0 AMP mean -0.1 -0.1 -0.1 1.4 1.2 1.3 1.6 165.0 340.5 520.4 DtrAMP mean 0.0 -0.1 1.1 1.1 0.7 1.0 1.3 162.9 329.0 502.4 • A 76 year-old male presented post primary total knee replacement with a discharging wound. DssAMP mean 0.0 -0.2 -0.3 0.6 1.0 0.6 0.5 154.2 318.1 477.1 DpkAMP mean -0.1 -0.4 -0.4 -0.2 0.7 0.0 0.4 144.8 298.4 448.7 • Tissues from debridement grew a mixture of vancomycin-susceptible and vancomycin resistant Enterococcus faecium with daptomycin MICs of 4mg/L and 6mg/L respectively and a tigecycline MIC 0.19mg/L. • Combination treatment with high-dose daptomycin (10mg/kg OD) and tigecycline was commenced for a period of 20 DISCUSSION days after metalwork removal. • The CRP fluctuated between 42 and 96 with initial clinical response, however further debridement was required and • These cases highlight the challenges of prosthetic joint infection caused by resistant bacteria. subsequent tissues persistently grew VRE (daptomycin MIC rising to 16mg/L) signifying microbiological failure of cure. • Both patients had a short-term clinical response to high dose daptomycin and tigecycline combination therapy, however eventually • Treatment was changed to linezolid. showed microbiological failure of cure. • After a further 4 weeks therapy was changed to oral minocycline and the patient is continuing on a prolonged oral • In both cases were modified for a variety of other reasons including secondary infections and requirement for an oral switch. course pending second-stage procedure. • The role of surgery and source control (metalwork removal) is also key and it is therefore difficult to define the role that individual antimicrobials played. REFERENCES • Our in vitro experimental data supports the likelihood of antimicrobial additivity of daptomycin-tigecycline combination therapy with no antagonism or emergence of secondary resistance. 1) Furustrand Tafin U et al. Gentamicin improves the activities of daptomycin and vancomycin against in vitro and in an experimental foreign-body infection model. Antimicrobial Agents & Chemotherapy. 2011. 55(10):4821-7. • There was no evidence to support an additive effect of ceftaroline with daptomycin. 2) Smith JR et al. B-lactam combinations with daptomycin provide synergy for against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium. Journal of Antimicrobial • Within the published literature there are only a handful of other cases where daptomycin-tigecycline combination therapy has been used Chemotherapy. 2015. 70(6):1738-43. 3,4 5 3) Schutt AC and Bohm NM. Multidrug resistant Enterococcus faecium treated with combination high-dose daptomycin and tigecycline therapy. The annals of pharmacotherapy. for Enterococcal infections reported with varying success rates , and limited other published in vitro data . 2009. 43: 2108-12. • More studies in the form of multi-center prospective controlled studies are urgently needed to address the growing problem of infections 4) Jenkins I. Linezolid- and vancomycin-resistant Enterococcus faecium endocarditis: successful treatment with tigecycline and daptomycin. Journal of Hospital Medicine. 2009. 2(5): 343-4. 5) Hindler JA et al. In vitro activity of daptomycin in combination with B-lactams, gentamicin, rifampicin and tigecycline. Antimicrobial Agents & Chemotherapy. 2015. 59(7): 4279-88. caused by multi-drug resistant bacteria including VRE.