This page contains a Flash digital edition of a book.
Bacterial Infections


Figure 2: Single/Infrequent Dosing Yields Similar Cure Rates as Daily Dosing in Antibacterial Skin and Skin Structure Infections (Phase 2 Study SIMPLIFI)21


100


10 20 30 40 50 60 70 80 90


0 82 72 69 79 78 81


63 87


38 58


200 mg Clinically evaluable regimen (see Figure 221


72 88


46 58


1,200 mg Oritavancin dosing arm


68 87


39 48


Microbiologically evaluable 800 ± 400 mg


). However, even though the SIMPLIFI study was


not powered to detect differences in outcomes across the dosing arms, cure rates were numerically highest for patients receiving single-dose therapy. This finding directly supported the design of the current Phase 3 studies comparing 1,200 mg single dose oritavancin to twice-daily vancomycin in patients with ABSSSI. The safety profile among the three regimens in SIMPLIFI showed no statistical difference in adverse events, serious adverse events and there were no unexpected adverse events.


Accumulation of Oritavancin in Macrophages As mentioned, above, oritavancin’s long terminal half-life and accumulation in macrophages has raised concerns about potential immunosuppression. As expected from the known properties of macrophages, this has not been seen in vitro or in vivo. Millions of macrophages are present in the human body and millions are produced each day, and each has a life-span of approximately 120 days. Theoretically, when a one-time dose is administered, the drug will be engulfed by the macrophages that day. A number of these same macrophages will die the day oritavancin is administered and be replaced with new macrophages not containing oritavancin.24 In addition, macrophages in the body are differentiated into Kupfer cells in the liver and Langherhans cells in the skin, as some examples. Azithromycin, which is also sequestered in macrophages, has been


1. Allen NE, From vancomycin to oritavancin: the discovery and development of a novel lipoglycopeptide antibiotic, Anti-infect Agents Med Chem, 2010;9:23–47.


2. Belley A, McKay GA, Arhin FF, et al., Oritavancin disrupts membrane integrity of Staphylococcus aureus and vancomycin-resistant enterococci to effect rapid bacterial killing, Antimicrob Agents Chemother, 2010;54:5369–71.


3. Kim SJ, Cegelski L, Stueber D, et al., Oritavancin exhibits dual mode of action to inhibit cell-wall biosynthesis in Staphylococcus aureus, J Mol Biol, 2008;377:281–93.


4. Patti GJ, Kim SJ, Yu TY, et al., Vancomycin and oritavancin have different modes of action in Enterococcus faecium, J Mol Biol, 2009;392:1178–91.


5. Rubino CM, Van Wart SA, Bhavnani SM, et al., Oritavancin population pharmacokinetics in healthy subjects and patients with complicated skin and skin structure infections or bacteremia, Antimicrob Agents Chemother, 2009;53:4422–8.


6. Greenblatt DJ, Zhao Y, Duan SX, et al., Effect of oritavancin on human cytochromes P450 in vitro [Poster A1-1284], Presented at: the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, 12–15 September 2009.


7. Belley A, Neesham-Grenon E, McKay G, et al., Oritavancin kills stationary-phase and biofilm Staphylococcus aureus cells in vitro, Antimicrob Agents Chemother, 2009;53:918–25.


New Phase 3 Registration Programme A Phase 3 global registration programme is currently enrolling patients in two parallel studies (TMC-ORI-10-01 and TMC-ORI-10-02 clinicalTrials.gov registration numbers NCT01252719 and NCT01252732, respectively). for the ABSSSI indication. Approximately fifteen countries are recruiting patients for the programme, which is a comparative study of the 1,200 mg IV single dose of oritavancin compared to vancomycin given twice daily for seven to 10 days. The study is a double-blind randomised clinical trial. There are two primary endpoints in this trial. One is assessment at 48 to 72 hours, evaluating the absence of fever, cessation of lesion spread and no rescue antibiotics. And the second is assessment at 7 to 14 days (test of cure [TOC]) following end of treatment, evaluating a sustained clinical response. Secondary evaluations include: end of treatment (EOT) and an evaluation at day 10. Patients being enrolled in this programme may not receive antibiotics prescribed within 14 days of study entry unless it is determined that the isolated pathogen in vitro is resistant to the drug prescribed. Besides having signs and symptoms of an inflammatory response, the patient’s lesions must be accompanied by at least 75 cm2 of surrounding erythema and/or induration.


Conclusion


In conclusion, oritavancin as single dose 1,200 mg IV therapy, has the following attributes that should make it a major contributor to the antibiotic armamentarium of Gram-positive drugs: a single dose for serious infections, multiple mechanisms of action, rapid bactericidal activity, no changes in susceptibility upon therapy to date, no myelosuppression, no CPK elevation, no renal monitoring, no expected CYP450 drug interactions, no electrocardiogram (ECG) conduction defects and no need for drug level monitoring.


If the Phase 3 registration programme confirms the safety and efficacy of a single, 1,200 mg IV dose of oritavancin, the possibility exists that this single dose, effective, and safe therapy, may potentially change the paradigm for antibiotic delivery by providing effective therapy without unnecessary hospitalisation in selected patients for complicated skin and soft tissue infections. n


8. McKay GA, Beaulieu S, Arhin FF, et al., Time-kill kinetics of oritavancin and comparator agents against Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium, J Antimicrob Chemother, 2009;63:1191–9.


9. McKay GA, Beaulieu S, Parr TR, Jr., Moeck G, In vitro post antibiotic effect studies of oritavancin against S. aureus and enterococci [Poster A-50], 47th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Chicago, Illinois, 17–20 September 2007.


10. Lehoux D, Arhin FF, Fadhil I, et al., Oritavancin demonstrates rapid and sustained bactericidal activity in the rat granuloma pouch model of Staphyloccocus aureus infection [Poster B-0404], 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, 27–30 September 2006.


11. Ambrose PG, Mouton JW, Khalmeter G, et al., Applying pharmacodynamics for susceptibility breakpoint selection and susceptibility testing. In: Nightingale CH, Ambrose PG, Drusano GL, Murakawa T (eds), Antimicrobial pharmacodynamics in theory and clinical practice, 2nd edition, New York: Informa Healthcare, 2007;21–44.


12. Craig WA, Pharmacodynamics of antimicrobials: General concepts and applications. In: Nightingale CH, Ambrose PG, Drusano GL, Murakawa T (eds), Antimicrobial pharmacodynamics in theory and clinical practice, 2nd edition, New York: Informa


Healthcare USA, Inc, 2007;1–19.


13. Van Bambeke F, Carryn S, Seral C, et al., Cellular pharmacokinetics and pharmacodynamics of the glycopeptide antibiotic oritavancin (LY333328) in a model of J774 mouse macrophages, Antimicrob Agents Chemother, 2004;48:2853–60.


14. Rodvold KA, Gotfried MH, Loutit JS, Porter SB, Plasma and intrapulmonary concentrations of oritavancin and vancomycin in normal healthy adults [Abstract O254], Presented at: 14th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 2004.


15. Rubino CM, Bhavnani SM, Forrest A, et al., Use of pharmacokinetic-pharmacodynamic principles for decision support for short-course oritavancin dosing regimens for complicated skin and skin structure infections [Abstract O152], Presented at: 18th European Congress of Clinical Microbiolgoy and Infectious Diseases [ECCMID], 19–22 April 2008.


16. Bhavnani SM, Lehoux D, Rubino CM, et al., Use of pharmacokinetics-pharmacodynamics to support oritavancin dose selection for patients with complicated skin and skin-structure infection: clinical confirmation of proof of concept [Poster A1-1288], Presented at: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, California, 12–15 September 2009.


approved and available for more than 10 years. Thus far, no short-term or long-term immunosuppression has been seen following therapeutic courses of azithromycin. Oritavancin has been dosed in 1,617 patients and 360 subjects over the past 15 years. Thus far, it too has not demonstrated any immunosuppression despite its long half-life.


100


EUROPEAN INFECTIOUS DISEASE


Rate of clinical cure (%)


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92