Outcomes in Patients With Staphylococcus aureus Bacteraemia Treated With Dalbavancin in Clinical Trials Urania Rappo , Pedro L. Gonzalez , Karthik Akinapelli , Jennifer S. McGregor , Sailaja Puttagunta , and Michael W. Dunne 1
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Urania Rappo Allergan plc Harborside 5 • 185 Hudson Street • Jersey City, NJ 07311 USA
[email protected] Phone: +1 201-427-8864
Allergan plc, Jersey City, NJ, USA; Independent Consultant, Hamden, CT, USA; Iterum Therapeutics, Old Saybrook, CT, USA
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INTRODUCTION
• Dalbavancin is a second-generation semisynthetic lipoglycopeptide antibiotic structurally related to teicoplanin • Dalbavancin binds to the terminal D-alanyl-D-alanine of the stem peptide in newly growing cell wall peptidoglycan, preventing cross-linking 1
(transpeptidation and transglycosylation) of disaccharide subunits, interrupting cell wall synthesis and resulting in bacterial cell death (Figure 1)1,2
Figure 1. The Mechanism of Action of Dalbavancin
Gram-positive
Gram-positive cell wall
Peptidoglycan
LTA
2
3
METHODS
• Patients enrolled in the ABSSSI, cSSSI, and catheter-related bloodstream infection studies were included in this analysis (Table 1) • Blood cultures were drawn at baseline (before study drug treatment) from 2 different anatomical sites (not through an existing intravascular line) and were then repeated every 48–72 hours until negative • If clinically indicated, blood cultures were to be collected at the time of treatment discontinuation or for determination of treatment failure • Patients in whom S aureus was identified in blood cultures taken at the baseline visit were selected for further assessment • Clearance of bacteraemia is provided for those patients with ≥1 follow-up postbaseline blood culture • Clinical resolution was typically defined as resolution of signs and symptoms of presenting illness and no requirement for new systemic or concurrent antibiotic (Table 1) Table 1. Studies Including Patients With Staphylococcus aureus Bacteraemia Treated With Dalbavancin or a Comparator Agent
Peptidoglycan Membrane
Protein Cytoplasmic membrane
Phospholipid
G NA
M NA
M NA
G NA
G NA
D-Glu
Gly Gly Gly Gly Gly
Lys D-Ala D-Ala y Gl
y Gl
y Gl
G NA
NA
Ala D-Glu y Gl
DUR001-301 Phase 3, randomized, double-blind, double-dummy study to compare the efficacy and safety of dalbavancin to a comparator regimen (vancomycin with possible switch to oral linezolid) for the treatment of ABSSSI5
M
M NA
Ala
y Lys Gl
G NA
M NA
D-Ala Gly Gly Gly Gly Gly
Ala D-Glu Lys D-Ala D-Ala
From Dunne et al. Clearance of Staphylococcus aureus bacteremia in patients treated with dalbavancin. Poster presented at IDWeek 2013, October 2–6, 2013, San Francisco, California, USA. http://www.idweek.org. Ala=alanine; Glu=glutamic acid; Gly=glycine; LTA=lipoteichoic acid; Lys=lysine; NAG=N-Acetylglucosamine; NAM=N-Acetylmuramic acid.
• Dalbavancin is a long-acting lipoglycopeptide approved by the US Food and Drug Administration and the European Medicines Agency
for treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults2,3 –– Dalbavancin has shown potent activity against Gram-positive pathogens responsible for ABSSSI, in particular Staphylococcus aureus, including methicillin-resistant S aureus (MRSA) and streptococci4-6 –– Plasma concentrations of dalbavancin exceed bactericidal concentrations for 14 days after administration of 1500 mg as a single dose or a 2-dose regimen (1000 mg followed by 500 mg a week later; Figure 2)2,7
Figure 2. S erum Concentrations of Dalbavancin 1500 mg After Intravenous Administration as 30-Minute Infusion in a Single or a 2-Dose Regimen Single-Dose Dalbavancin 1500 mg
400
2-Dose Dalbavancin 1000 mg on day 1, followed by 500 mg 1 week later Vancomycin 1000 mg twice daily
300
Bactericidal Concentration of Dalbavancin
Treatment
Total Dosed, n
S. aureus Bacteraemia in Dalbavancin/ Comparator Patients*
DUR001-302 Phase 3, randomized, double-blind, double-dummy study to compare the efficacy and safety of dalbavancin to a comparator regimen (vancomycin with possible switch to oral linezolid) for the treatment of ABSSSI5
DUR001-303 Phase 3b, double-blind, multi-center, randomised study to compare the efficacy and safety of single-dose dalbavancin to a 2-dose regimen of dalbavancin for the treatment of ABSSSI4
IV dalbavancin: 1000 mg on Day 1, 500 mg on Day 8, IV placebo q12h to match vancomycin, possible switch to oral placebo q12h after 3 days of IV therapy, treatment duration 10–14 days IV comparator: IV vancomycin 1000 mg or 15 mg/kg q12h, IV placebo to match dalbavancin, possible switch to oral linezolid 600 mg q12h after 3 days of IV vancomycin therapy, treatment duration 10–14 days IV dalbavancin: 1000 mg on Day 1, 500 mg on Day 8, IV placebo q12h to match vancomycin, possible switch to oral placebo q12h after 3 days of IV therapy, treatment duration 10–14 days IV comparator: IV vancomycin 1000 mg or 15 mg/kg q12h, IV placebo to match dalbavancin, possible switch to oral linezolid 600 mg q12h after 3 days of IV vancomycin therapy, treatment duration 10–14 days
Decrease in lesion area, absence of fever, absence or improvement in local signs of fluctuance/warmth, improved (≤ mild) signs of local tenderness/swelling/induration, improved (≤ mild) purulent drainage, no concurrent antibiotics, and patient survival
Decrease in lesion area, absence of fever, absence or improvement in local signs of fluctuance/warmth, improved (≤ mild) signs of local tenderness/swelling/induration, improved (≤ mild) purulent drainage, no concurrent antibiotics, and patient survival
IV dalbavancin, 2-dose regimen: 1000 mg on Day Decrease in lesion area, absence of fever, 1, 500 mg on Day 8 absence or improvement in local signs of fluctuance/warmth, improved (≤ mild) signs of local tenderness/swelling/induration, IV dalbavancin, single-dose regimen: 1500 mg on improved (≤ mild) purulent drainage, no concurrent antibiotics, and patient Day 1 survival
568
284
3
VER001-9 Phase 3, randomised, double-blind, multi-center study to evaluate the safety and efficacy of dalbavancin versus linezolid in the treatment of cSSSI with suspected or confirmed Gram-positive bacterial pathogens9
200 150
IV dalbavancin: 1000 mg on Day 1, 500 mg on Day Resolution of signs and symptoms such 8, possible switch to oral placebo q12h, treatment that patient did not receive new systemic duration 14 days antibiotics
284
735
368
3
7
50
0
7
14
Time (d) Adapted from Dunne et al. Clearance of Staphylococcus aureus bacteremia in patients treated with dalbavancin. Poster presented at IDWeek 2013, October 2–6, 2013, San Francisco, California, USA. http://www.idweek.org.
VER001-4 Phase 2, randomized, open-label, multi-center study to evaluate the safety and efficacy of dalbavancin versus vancomycin in the treatment of catheter-related bloodstream infections with suspected or confirmed Grampositive bacterial pathogens8
• Phase 2 and 3 efficacy studies have been conducted and completed with dalbavancin to explore the clinical outcomes and microbiological clearance in patients with ABSSSI, complicated skin and skin structure infections (cSSSI), or catheter-related bloodstream infections4,5,8,9 –– This analysis focuses on the patients with S aureus bacteraemia at baseline in these studies
IV comparator: IV vancomycin: 1000 mg q12h, or dose-adjusted for renal impairment. Could switch to IV nafcillin or oxacillin 2g q4h or q6h after pathogen identification and susceptibility testing
• Overall, 59 patients had follow-up blood cultures available for assessment • A total of 39 patients with S aureus bacteraemia at baseline received dalbavancin
–– 8 of the 39 patients received dalbavancin 1500 mg as a single dose • S aureus bacteraemia, including those with MRSA, cleared in all patients with follow-up blood cultures receiving dalbavancin (Table 2) –– S aureus bacteraemia cleared in 8 of 8 patients receiving single-dose dalbavancin • None of the clinical failures in the dalbavancin group was a result of persistent underlying bacteraemia • The reasons for clinical failure in patients receiving dalbavancin included: –– Local signs of tenderness to palpation and swelling/induration were worse than mild –– Local signs of fluctuance and localised heat/warmth had not resolved –– Receipt of concomitant antibiotic –– Unplanned surgical intervention for ABSSSI >72 hours after study drug Table 2. Documented Clearance and Clinical Outcomes in Patients With S aureus Bacteraemia Receiving Dalbavancin or Comparator Dalbavancin
Comparator
48–72 h
EOT
≥20% Reduction in Lesion Size
Clinical Success†
3/3 7/7 15/15
3/4 6/7 14/15
2/3 5/6 14/14
4/4
—
10/10 39/39 (100)
Infection
Clearance of Bacteraemia*
48–72 h
EOT
≥20% Reduction in Lesion Size
Clinical Success†
2/3 6/6 N/A
1/3 5/6 N/A
3/3 5/6 N/A
3/4
2/2
—
2/2
—
9/9
9/9
—
8/12
23/26 (88)
33/36 (92)
19/20 (95)
6/9 (67)
18/23 (78)
ABSSSI, n/N DUR001-301 DUR001-302 DUR001-303 cSSSI, n/N Catheter-related bloodstream infections, n/N
367
6
VER001-4 Total, n/N (%)
695
ABSSSI=acute bacterial skin and skin structure infection; cSSSI=complicated skin and skin structure infection; EOT=end of treatment; N/A=not applicable, no comparator drug. *Patients with a follow-up blood culture (postbaseline) † Clinically evaluable population (those with missing data excluded from the analysis) of patients with a positive blood culture at baseline.
346 2-dose dalbavancin
• In the ABSSSI studies, there were more patients in the dalbavancin group who had ≥20% reduction in lesion size at 48–72 hours (23 of 26 patients, 88%) than those in the comparator 15
349 single-dose dalbavancin
854
IV linezolid: 600 mg q12h; possible switch to oral linezolid 600 mg q12h, treatment duration 14 days
IV dalbavancin: weekly: 1000 mg on Day 1, 500 mg Absence of fever, resolution of signs on Day 8 (n=33). Daily: 650 mg on Day 1, 65 mg on and symptoms of catheter-site infection, Days 2–14 (this arm was discontinued; n=7). Total and no additional systemic antibiotics dose received: 780 mg (n=1), 845 mg (n=1), 1000 mg (n=3), 1170 mg (n=1), 1500 mg (n=34).
Efficacy Outcomes
VER001-9
group (6 of 9 patients, 67%) • Patients in the dalbavancin group had higher rates of clinical success at the end of treatment (33 of 36 patients, 92%) than those in the comparator group (18 of 23 patients, 78%)
CONCLUSIONS
571 (71 at 1000 mg) (500 at 1500 mg)
4
283
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• All patients with S aureus bacteraemia treated with dalbavancin (single- or 2-dose regimen) who had follow-up blood cultures had clearance of their bloodstream infection • Clinical outcomes were similar in patients receiving single- or 2-dose dalbavancin regimen to those in patients receiving daily treatment with comparator agents for 10–14 days • Dalbavancin is indicated for the treatment of ABSSSI in adults caused by designated susceptible strains of Gram-positive microorganisms and offers an alternative to treat S aureus bacteraemia in these patients; dalbavancin can be given as a single dose of 1500 mg or as 1000 mg followed 1 week later by 500 mg
REFERENCES
Catheter-related bloodstream infection
100
RESULTS
Clearance of Bacteraemia*
cSSSI
250
0
Study Number and Title
Definition of Clinical Success (End of Treatment Visit)
Received Dalbavancin/ Comparator, n
ABSSSI
Cytoplasm
Dalbavancin Plasma Concentration (mg/L)
3
74
40
10
34
9
ABSSSI=acute bacterial skin and skin structure infection; cSSSI=complicated skin and skin structure infection; IV=intravenous; N/A= not applicable; q4h=every 4 hours; q6h=every 6 hours; q12h=every 12 hours. *Patients with follow-up blood culture (post-baseline).
Presented at the 27th European Congress on Clinical Microbiology and Infectious Diseases (ECCMID 2017), April 22–25, 2017, Vienna, Austria
1. Economou NJ, et al. J Am Chem Soc. 2012;134(10):4637-4645. 2. Xydalba. Dalbavancin. Europe: Durata Therapeutics International BV; 2016. 3. Dalvance® (dalbavancin). Full Prescribing Information, Durata Therapeutics US Ltd., Parsippany, NJ, 2016. 4. Dunne MW, et al. Clin Infect Dis. 2016;62(5):545-551.
5. 6. 7. 8. 9.
Boucher HW, et al. N Engl J Med. 2014;370(23):2169-2179. Huguet A, et al. J Appl Microbiol. 2013;114(5):1294-1299. Dorr MB, et al. J Antimicrob Chemother. 2005;55 Suppl 2:ii25-30. Raad I, et al. Clin Infect Dis. 2005;40(3):374-380. Jauregui LE, et al. Clin Infect Dis. 2005;41(10):1407-1415.
DISCLOSURES
Urania Rappo, Pedro L. Gonzalez, and Jennifer S. McGregor, are employees of Allergan plc. Urania Rappo and Pedro L. Gonzalez hold stock in Allergan plc. Karthik Akinapelli, Sailaja Puttagunta, and Michael W. Dunne are employees of Iterum Therapeutics.
ACKNOWLEDGMENTS
Editorial support was provided by Lee B. Hohaia, PharmD, and John E. Fincke, PhD, at Complete Healthcare Communications, LLC (Chadds Ford, PA), a CHC Group company, and funded by Allergan plc (Dublin, Ireland).
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