Company

Ticker Symbol

Products

Details

Targanta Therapeutics Corp.

CSFB

Oritavancin

Deal size      $74.8mm

Target range $12-14

Target close  10/9/07

Panelist

Hospital affiliation

State

Deverick Anderson, MD

Duke University Medical Center

NC

Paul Axelson, MD

University of Pennsylvania School of Medicine

PA

Ben Barnett,MD

The University of Texas Medical School at Houston

TX

Adeel Butt , MD

University of Pittsburgh Medical Center

PA

Sonia Nagy Chimienti, MD

Beth Israel Deaconess Medical Center

MA

Erik Dubberke, MD

Barnes-Jewish Hospital, Washington University School of Medicine

MO

Kelly Gebo, MD

The Johns Hopkins University School of Medicine

MD

Suzanne Lavoie, MD

Virginia Commonwealth University Medical Center

VA

Jin Suh, MD

St. Luke's-Roosevelt Hospital Center, Columbia University Medical Center

NY

Question

Pages

Q1.  About Oritavancin: What have you heard about oritavancin?  How do you think it will best be used?  What are the strengths and weaknesses of the medication?  Where have you learned the most about the medication -- the medical literature? Conferences?

4-6

Q2.  Antibiotic landscape: Targanta is planning to submit an NDA in early 2008 for oritavancin to treat cSSSI.  The drug has also completed phase 2 trials for the treatment of bactermia. What other antibiotics are currently used in a manner similar to that proposed for oritavancin?  In other words, what antibiotics would be considered by an infectious disease specialist along with oritavancin for the treatment of a patient with cSSSI and with bactermia?  What factors would be important to help choose one antibiotic over another?

6-8

Q3.  Other glycopeptides antibiotics: Oritavancin is a member of the glycopeptides family of antibiotics.  Other glycopeptides antibiotics that are currently in development include dalbavancin, telavancin and ramoplanin.  Please compare and contrast these antibiotics to each other.  What are the strengths and weaknesses of each drug? 

8-10

Q4.  Activity against Staphylococcus: Please review this ICAAC 2007 abstract about oritavancin’s activity against staphylococci.  Please comment on its effectiveness against this type of bacteria, with particular focus on methicillin-resistant Staph aureus (MRSA) and vancomycin-resistant Staphylococcus.  How does oritavancin’s activity compare to vancomycin and other antibiotics used to treat these organisms?

10

Q5.  Activity against Streptococcus: Please review this ICAAC 2007 abstract about oritavancin’s activity against different Streptococci.  What do you think about its effectiveness against these organisms?  How does its activity and resistance profile compare to other antibiotics commonly used to treat these bacteria?  How important is this activity against Streptococcus relative to the overall function of the medication?  Do you think oritavancin might commonly be used for this indication?

10-11

Q6.  Activity against Enterococcus: Please review this ICAAC 2007 abstract about oritavancin’s activity against Enterococcci.  How does its function and resistance profile compare to other antibiotics commonly used to treat these organisms?  How does oritavancin work against vancomycin-resistance enterococcus?  How important is this activity against Enterococcus relative to the overall function of the medication?  Do you think oritavancin might commonly be used for this indication?

11-12

Q7. Activity against Clostridium difficile: Please review these two ICAAC 2007 abstracts about the activity of oritavancin against C. difficile.  How promising is this data?  How does its activity against C. difficile compare to metronidazole and vancomycin?  How significant is this activity of oritavancin relative to its overall function?  Should this indication for oritavancin be further explored? 

12-13

Q8.  FDA Approval process: In 2003, InterMune (a company which had previously owned oritavancin) had expected to submit an NDA for oritavancin.  However, this submission was delayed because the FDA requested additional safety information due to adverse events seen in two small phase III trials including rash and phlebitis.  Furthermore, in a single-dose, open-label, non-controlled, dose escalation study, 5 of the 11 subjects were found to have symptomatic, transient elevations in their hepatic transaminases (DMID. 2004; 50: 95-102).

How do you think this historical information will impact the FDA approval process for oritavancin?  What information will Targanta need to show regarding oritavancin in order to address these prior concerns?  Do you think the FDA might require a large post-marketing study to investigate the incidence of adverse events?  Please explain why or why not.

13-19

Q9.  Adoption of oritavancin I: Targanta is planning to submit an NDA in early 2008 for oritavancin to treat cSSSI.  If it were to receive FDA approval, what factors do you think will impact its adoption into clinical practice?  What would make physicians more or less likely to use this medication?  What information would they be looking for in order to make a decision about using the medication?

19-22

Q10. Adoption of oritavancin II: If oritavancin were to receive FDA approval, how widely and how quickly do you think the drug would be adopted into clinical practice?  What have you heard from colleagues regarding their attitudes towards this drug and their potential incorporation into clinical use?

22-23

Q11.  Other issues: For someone trying to understand oritavancin – its potential uses, its marketplace, and the likelihood of its approval of the FDA – is there anything else that would be important to know?

23-24

Appendices

25-33

IPO Panel: Targanta Therapeutics - Tier 1

Introduction

Welcome to this panel among infectious disease specialists in which we will discuss Targanta Therapeutics and its lead product, oritavancin. Our primary goals for this discussion are to discuss potential uses of the medication, review data recently presented about it at ICAAC 2007, examine its potential for adoption by clinicians, and explore any potential obstacles to FDA approval. The discussion is enhanced when you, as a panelist, not only respond to the posted questions, but also reply to comments made by our moderator and your fellow panelists. We look forward to a lively and interactive discussion. Please note: In your participation on this panel, Panel Intelligence expects and requires that you comply with the terms of the Consultant Confidentiality Agreement to which you previously agreed. If you have any questions about the terms of that agreement, please review them through the link provided on your Panel Intelligence home page after you've logged in.

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Q1. About oritavancin

What have you heard about oritavancin? How do you think it will best be used? What are the strengths and weaknesses of the medication? Where have you learned the most about the medication -- the medical literature? conferences?

Panelist 1: It is a lipoglycopeptide with enhanced activity against Staph and enterococcus, including vancomycin resistant strains.

Panelist 2: Oritavancin is an IV antibiotic with activity against resistant GPC - in particular MRSA and VRE. So far I have only seen minimal data.

Panelist 3: I have seen minimal data, but reportedly it is gylcopeptide with bacteriocidal activity against GPCs including MRSA/VRE

Panelist 6: a new agent with efficacy against GP organisms including resistant GP organisms.

Panelist 4: It seems like oritavancin has been in development for some time. It is an experimental semi-synthetic glycopeptide that has activity against gram positive organisms. It appears to have good activity against MRSA and VRE, as well as other gram positive pathogens. It has an additional mechanism of action over vancomycin, so that it may retain sensitivity when vanco the organism is resistant to vancomycin. Its hard to say how it will be used, but I would suspect it will be used initially to treat resistant organisms like VRE or MRSA. It is once a day, I believe, so that is an advantage. Other strengths are its unique mechanism, and lack of requirements for drug levels, I think. Weaknesses would be only the IV formulation, and once a day, over drugs in development with longer half-lives. I've learned about it mostly from talking to colleagues, and reading abstracts from conferences, or reviews on experimental agents.

Panelist 7: ORI is an old drug that we have known for many years as LY333328, or just '328 for short. Lilly developed it for a long time, encountered both FDA and bacterial resistance, and then sold all rights to it. These were the days when VRE was just becoming a major concern. Indeed '328 did have increased activity against some bugs, but it also had a high degree of protein binding and a long half life at sub-MIC concentrations. Concerns about inducing resistance, phlebitis, and what to do in the event of toxic overdosage outweighed any small activity advantage it offered.

Panelist 8: Oritavancin has been a been around for several years years-- its obvious strengths are broad spectrum gram positive activity, long half-life which will facilitate ?once weekly dosing and resistance profile. We've discussed it during ID conferences, reviewed literature, seen preliminary data from national meetings and I look forward to gaining experience with this product.

Panelist 9: I have not heard of this agent.

Use of oritavancin

If oritavancin were to receive FDA approval for cSSSI, how do you think it would fit in your current treatment algorithm for this type of infection.

Panelist 6: Would probably be a me-too drug. don't know enough about some other issues for clinical usage to say it would beat out some of the other drugs we have available.

Panelist 3: at the moment, we have a number of options for SSSI infections, so unless there was some really unique feature, I don't know that it would be on top of my prescribing algorithm

Panelist 7: Simple FDA approval would not make me consider it for this type of infection. However, the definition of cSSSI varies, and will impact answers to this question.

Panelist 4: I really can't see how it would fit in, as we have a number of agents available for this. However, if in the clinical trials there was something unique about it, or if perhaps there was a resistant isolate as described in some of the abstracts from yesterday, I could see it as a "niche" drug.

Panelist 9: it depends on the clinical efficacy, comparison to currently available agents (superiority vs equivalence), route of dosing (is there some benefit vs currently available agents), frequency of dosing (is there some benefit vs currently available agents). I can't comment on it's hierarchy in my treatment choices without that information.

Panelist 8: we have currently have somany options for cSSSI, i really can't see myself using ORI except for those cases where the pt refuses to stay in the hospital and perhaps one dose lasting a week is better than nothing at all.

Panelist 1: Unless there was a clear-cut advantage based on the clinical trial, it likely would be reserved for patients with resistant organisms not sesnitive to any other available antibitoics, or if the patient did not tolerate or had contraindications to other available antibiotics.

Panelist 5: It would be one of a number of abx approved for this condition. Its use will depend on individual circumstances of each patient.

Panelist 2: I agree with the other panelists. cSSSI is a crowded field. Unless there is proven superiority to other agents, I'm not sure that we will use it much

Off label use?

If oritavancin were to receive FDA approval for cSSSI, is it possible that it might be used off-label to treat other infections? If so, please describe which ones.

Panelist 3: drugs are always used off label, particularly in salvage therapy. I suspect the first few cases of off label use would be difficult to treat endocarditis/epidural abscess as potentially an adjunct therapy or replacement therapy for those unable to tolerate vanco/dapto for allergic or toxicity reasons

Panelist 7: Agree with 3. After approval, I believe it would be rarely used for cSSSI, and almost exclusively used for other types of infections.

Panelist 6: Of course. If it has that great activity against gram positives then it will be used for bacteremia and difficult to treat infections. Problem will be that it won't go on (at least our) formulary ...with just the cSSSI indication so we won't use it "off label" except in rare circumstances.

Panelist 5: No, it should not be.

Panelist 4: I believe that it would be used off-label, no matter what the approved indications are for, as long as it is available in a given hospital for use. The types of infections it would be used for depend on its PK characteristics, penetration into various tissue compartments, etc. I can see it being used for select bacteremias, line infections, etc., that involve gram positive organisms resistant to vanco and the others.

Panelist 1: Yes, it will be used off label. Unlikley it will become a major player for treating cSSSI. Will be used to treat refractory / resistant infections as long as there is reasonable data adequate levels of antibiotic are able to get to the site of infection. I find it hard to believe same panelist only use antibitoics based on labeling. Example: only FDA-approved treatment for C. diff is oral vanc. How many of you use only oral vanc to treat C. diff?

Panelist 9: as with all other compounds, if the drug is superior and is found to work well with minimal side effects, I suspect it would be used off-label in some circumstances, if other options were not available.

Panelist 2: I agree with the other panelists. It will definitely be used off label. In fact, it will probably primarily be used off label, as I don't think it will be used often for cSSSI. It will most likely be used in some scenarios of refractory infections due to highly resistant gram-positive organisms.

Panelist 8: yes, physicians do it all the time. I'd try it for culture approven (resistant) osteomyelitis, endocarditis; situations where long-term antibiotic therapy might be indicated.

Panelist 5: Not much at all. My knowledge is limited to what I obtained from the internet, the company website and conference coverage. My impression is that it has broad gram positive coverage and low incidence of side effects.

Q2. Antibiotic landscape

Targanta is planning to submit an NDA in early 2008 for oritavancin to treat complicated skin and skin structure infections (cSSSI). The drug has also completed phase 2 trials for the treatment of bactermia. What other antibiotics are currently used in a manner similar to that proposed for oritavancin? In other words, what antibiotics would be considered by an infectious disease specialist along with oritavancin for the treatment of a patient with cSSSI and for the treatment of a patient with bactermia? What factors would be important to help choose one antibiotic over another in these cases?

Panelist 1: Other potential antibioitics used in a similar manner include anti-staph penicillins, 1st generation cephalosporins, vanc, synercid, linezolid, bactrim, clindamycin, daptomycin, and tigecycline. Choice of antibiotics depends on risk factors for resistant organismsm, demonstrated efficacy for patient populations, need for IV or oral abx, availability of antibiotics, efficacy of antibiotics, and cost-effectiveness of antibiotics. For OSSA, primary compounds are anti-staph penicillins and 1st gen ceph, if sensitivities of organism known unlikely ortivancin would be used (SSSI or bactermia). For SSSI and bacteremia confirmed with MRSA/VRE or suspected MRSA/VRE, ortivancin might be considered if patient was hospitalized (IV administration) and ortivancin was demonstrated to have superior clinical efficacy, better side effect profile, or shown to be cost-effective.

Panelist 2: The antibiotic landscape of cSSSI is a crowded one. Just focusing on antibiotics with activity against MRSA, the following have recently received FDA indications for cSSSI - linezolid, daptomycin, tigecycline. With surge of CA-MRSA, TMP-SMX, clinda, doxycycline/minocycline are being used more as well. For bacteremia with resistant GPC - we are limited to only 2 antibiotics with data - vancomycin and daptomycin. Thus, another agent with BSI data would be welcome. Factors that determine what agents would be used include, efficacy, administration (oral v. IV), cost, and hosptial formulary.

Panelist 3: There are a number of old and new abx for GPC including vanc, bactrim, clinda, linezolid, tigecycline, daptomycin. Oral is important and reducing side effects and drug drug interactions also important. Finally, cost is a driver for reimbursement. If it's not covered patients wont want it.

Panelist 6: I think there are a number of drugs approved for cSSSI including: linezolid, daptomycin, vancomycin

Panelist 4: Other antibiotics used for these indications are vancomycin, daptomycin, linezolid, quinupristin-dalfopristin, and tigecycline. ALso older agents like tmp-smx, doxycycline and rifampin can be used for MRSA. THere are many factors that go into choosing an antibiotic. One is familiarity of the agent, long-term clinical use and results, etc. Sometimes known side effects can be easier to live with than perhaps the unknown. Other factors are patient specific factors such as liver or renal disease, severity of illness, etc. COst is a big issue, and forumlary status in the hospital. Method of intake, either iv or po, frequency of dosing, need for drug levels, etc are important.

Panelist 7: Other panelists have compiled an exhaustive list.

Panelist 8: all new antibiotics initally go for the easiest indication--cSSSI. There are many, many options available for this indication. The list would be long-- penicllins, cephalosporins, clinda, vancomycin, etc. I would prefer to use a more narrow spectrum antibiotic. ORI is too broad for my taste, even for bacteremias. On the otherhand, if you're using it empirically until an organism has been identified, it can play an important there, as well as for outpatient administration.

Panelist 9: the other panelists have already listed the main agents in this area: vancomycin, daptomycin, linezolid, dalbavancin are those that are more recent and targeted to resistant gram positive infections. things to consider in prescribing this category of drugs include frequency of dosing, side effect profile, intravenous vs oral route, and cost.

Other antibiotics

Please compare the activity and side effect profile to these other antibiotics that are approved for cSSSI: Cubicin® (daptomycin), Zyvox® (linezolid), and Tygacil™ (tigecycline).

Panelist 3: These are all effective drugs. Linezolid has significant toxicity with possible thrombocytopenia, lft abnormalities. It can also be difficult to use in ESRD patients. Tigecycline can cause N/vomiting as well as LFT abnormalities (a particularly difficult issue in ICU patients). daptomycin is difficult to administer in ESRD (I dont think we have good data yet on this and given low barrier to resistance I'm concerned about using in this population

Panelist 7: I don't believe that I have enough reliable information about the side effects of Ori to respond.

Panelist 4: So far, we don't have much information about the activity and side effect profile of oritavancin, so I can't comment there. daptomycin is very active, but there is some emerging resistance and it has some dosing issues in special populations. Have not seen much CPK elevation that is reported. Linezolid is also very active, and can be given orally. Limited by drug interactions with SSRI, thrombocytopenia with longer use. Tigecycline is a very broad spectrum agent, in fact too broad for routine use for cSSSI infections. Side effects are mostly GI.

Panelist 9: I have no knowledge of side effects of ortivancin to comment. with regard to the other abx: daptomycin: I have concerns about emergence of resistance, particularly with MRSA. I have not seen much CPK abnormality with my prescribing, which is good. Can't use it for pulmonary infections. linezolid: great efficacy for MRSA and VRE but really problematic with regard to thrombocytopenia (develops within weeks in most people, and is a huge problem in BMT patients I frequently care for). also an issue is the SSRI interaction (many patients are on these meds; not a huge problem, as we usually halve the dose of the SSRI and watch carefully, but it is a concern) and the cost, which is prohibitive for some. tigecycline: I have not prescribed it much but I understand that side effects are not significant, other than GI issues (usually minor n/v).

Panelist 8: as stated by the other panelists- need more info on ORI. Linezolid has the oral/IV formulation, tigecycline is has much broader coverage.

Panelist 2: Linezolid has the side effect of thrombocytopenia with prolonged usage and interacts with SSRIs. Advantage is that there is a PO formulation. Dapto has side effect of increased CPK. I agree with the other panelist in that I haven't seen much of this either. has indication for endocarditis/bacteremia and the other two don't. Tigecycline can cause elevation of LFTs.

Panelist 6: side effects are outlined by other panelists. I still haven't seen enough about s/e of oritavancin to comment on it.

Panelist 1: Agree with several other posters, difficult to make comaprisons based on data available. Linezolid limited by potential drug interactions and thrombocytopnia (not too much of a problem for duration of treatment for cSSSI). Advantage is orally available. Some resistance has developed. Daptomycin fairly well tolerated, only available IV. Tiga limited by GI upset, too broad.

Panelist 5: Daptomycin has an indication for bloodstream infection, so it is superior (so far) in that regard. Linezolid is limited by its side effect of thrombocytopenia, but advantage is that it has an oral formulation Tigecycline has very broad spectrum, so when multiple organisms are suspected, it is the drug of choice. In terms of MRSA cSSI, the coverage is probably similar for all.

Panelist 5: Daptomycin, Linezolid, Vancomycin are similar drugs. Cost, spectrum of activity and rate of side effects will determine what is ultimately chosen for patients.

Q3. Other glycopeptides antibiotics

Oritavancin is a member of the glycopeptides family of antibiotics. Other glycopeptides antibiotics that are currently in development include dalbavancin, telavancin and ramoplanin. Please compare and contrast these antibiotics to each other. What are the strengths and weaknesses of each drug?

Panelist 1: ramoplanin active against VRE but not available for systemic administation. dalbavancin can be adminstered once weekly, may be superior to vanc for treating CR-BSI. May not be effetive against vanA VRE telavancin has activity against VRE.

Panelist 2: I agree with Panelist 1. Dalbavancin is intriguing b/c it can be administered once weekly. Telavancin probably has better activity against VRE than dalba. Ramoplanin has activity against VRE and may have some ability to penetrate biolfilms. I believe it is being studied against CDiff as well.

Panelist 3: delbavacin is attractive because it is once weekly, though drug-drug interctions need to be sorted out more thoroughly. ramaplanin good vs. vre telavancin also good vs. VRE, I think superior to dalbavancin

Panelist 6: I don't have a lot of information about these other agents.

Panelist 4: The big difference for dalbavancin is its administration once weekly. This would be very attractive for outpatient therapy, obviously. It has good MRSA coverage, not sure about VRE. Telavancin works by disrupting cell membranes, in addition to being cell wall active, which may help with resistance and cidal effects. Don't know much more about it. Don't really know anything about ramoplanin, but I would think it may be like teicoplanin?

Panelist 9: the only agent of these three that I have familiarity with is dalbavancin. at once weekly dosing it is intriguing for outpatient treatment. main concern is drug-drug interactions and side effects, given the long half-life of the drug

Panelist 7: Dalba & tela are similar in many respects to the teicoplanins widely used in Europe. Ori has a somewhat different chemical nature in that it is not as "lipo" as the other lipoglycopeptide agents, and this gives it a somewhat different penetration and pharmacokinetic profile. I don't recall specifics about the differences, but I think it was just different, not necessarily better or worse. Ramoplanin is in an entirely different class, and I am only familiar with its use as an oral agent against potentially pathological bowel flora.

Panelist 8: i have more familiarity with dalbavancin and teicoplanin, the former has the most clinical data-- long half life which affords weekly dosing, fairly well tolerated. All are fairly similar-- better activity against faecalis than faecium, minimal anaerobic activity and may cover c. diff. The main "potential" strengths would be activity against resistant organsism--MRSA, VRE, ?resistant c. diff.

Panelist 9: the only agent of these three that I have familiarity with is dalbavancin. at once weekly dosing it is intriguing for outpatient treatment. main concern is drug-drug interactions and side effects, given the long half-life of the drug

Ranking the glycopeptides

Imagine a scenario in which dalbavancin, telavancin, and oritavancin all became available. If you could only have regular access to one of these drugs, which one would you pick and why? After answering this question, please list which drug would be your second choice and why.

Panelist 3: I am more familiar with the dalbavancin data, and think that this drug is probably the most interesting with the once weekly dosing.

Panelist 7: I don't have enough basis to choose at this point - aside from their various pharmacokinetic advantages, each of these drugs has yet to demonstrate *overall* superiority over vancomycin.

Panelist 4: I guess my first choice would be dalbavancin given that it can be given once weekly. THis would be very helpful for outpatient IV administration. Next, I would probably choose oritavancin, just because I am more familiar with the data presented here. I don't know enough about telavancin to have much of an opinion about it, but its dual-mechanism of action is interesting.

Panelist 9: I do not have enough familiarity with either of these agents to decide on one as my choice. I need more clinical data.

Panelist 8: that this stage, i'd go with the drug with the best/most clinical data-- dalbavancin, which isn't saying much i'm afraid.

Panelist 2: It depends on what type of infection I was treating. If it were anything beside cSSSI I'm not sure I would use any of those three. For cSSSI, I would probably choose dalba first - once weekly dosing and some clinical data. Next would be telavancin b/c I have only seen in vitro data for orita.

Panelist 6: I have little information about these other drugs and couldn't rank them.

Panelist 1: As previously stated, difficult based on available data. Treatment also likely individualized to patient (type/site of infection, organism, other meds, etc). Dalb as advantage of infrequent dosing. Concern about lack of activity vanA. Seccond choice ortivancin

Panelist 5: I do not know the other drugs in enough detail to make that decision yet.

Panelist 5: Unable to compare since they are not in clinical use yet.

Please review the attached abstract  (Appendix A)

Q4. Activity against Staphylococcus

Please review this ICAAC 2007 abstract about oritavancin’s activity against staphylococci. Please comment on its effectiveness against this type of bacteria, with particular focus on methicillin-resistant Staph aureus (MRSA) and vancomycin-resistant Staphylococcus. How does oritavancin’s activity compare to vancomycin and other antibiotics used to treat these organisms?

Panelist 1: Based on low MICs it appears ortivancin will be effective against sensitive and resistant staph strains, including strains resistant to daptomyvin, linezolid, and vanc. Without knowing what acheivable serum levels of ortivancin are it is difficult to state how these MICs may transplant to clinical efficacy.

Panelist 2: The MIC data suggests that it has good activity in the lab. MIC data does not always translate into clinical efficacy for several reasons including penetration and bioavailability.

Panelist 6: data is encouraging about Staph susceptibility.

Panelist 4: Oritavancin appears to be very active against staph aureus strains that are both sensitive to oxacillin MRSA. The MICs reported seem to be very low for oritavancin, but probably since there is little clinical data, we don't know what likely breakpoints for resistant/susceptible will be in clinical settings. I don't see any data specific for vanco resistant staph, but in the few isolates that are resistant to dapto or linezolid, the oritavancin MICs seem low. The activity in vitro for oritavancin seems very high in these isolates; it remains to be seen what happens in vivo.

Panelist 7: To echo the reservations of panelists 1 & 2, this data doesn't mean much without knowing the achievable levels, the penetration characteristics, and the therapeutic index.

Panelist 8: the MICs are promising- they always are with any new antibiotic that hasn't yet had resistance selection pressure-- lets see how they fare after a few years of antibiotic mismanagement by surgeons...

Panelist 9: as was mentioned by the other panelists, the MICs look good, but without knowledge of tissue penetration and serum drug levels, we can't make conclusions about clinical efficacy. further data is needed.

Panelist 3: looks good against resistant staph, though wil definitely need more invivo data

Panelist 5: I don’t see much difference in MIC between MRSA and non-MRSA. There isn’t enough info to compare wit other drugs.

Please review the attached abstract  (Appendix B)

Q5. Activity against Streptococcus

Please review this ICAAC 2007 abstract about oritavancin’s activity against different Streptococci. What do you think about its effectiveness against these organisms? How does its activity and resistance profile compare to other antibiotics commonly used to treat these bacteria? How important is this activity against Streptococcus relative to the overall function of the medication? Do you think oritavancin might commonly be used for this indication?

Panelist 1: Appears there are low MICs for all organisms tested, including those resistant to other antibiotics. Again, difficult to translate in vitro MICs to clinical efficacy without know more about pharmacokinetics of ortivancin. If do MICs translate to clinical efficacy, ortivancin may be good option for sterptococcal infections, including resistant S. pneumonia infecitons

Panelist 2: Similar to the previous abstract, the MIC data is encouraging and shows that the agent is active against multiple organisms in the micro lab. En vivo efficacy is still to be seen. I am concerned that this drug would be overused if it were billed as an agent for streptococcal infections - resistant or not.

Panelist 3: THis appears to be a good drug for strep including ones reistant to other organisms. Like the previous paenlist I am concerned it would be overused by those looking for broad spectrum coverage for strep.

Panelist 6: other than resistant SP, the other streps have limited resistance and usually this is treatable with a number of different agents currently available. concerning is that the range of MIC for I SP and R SP included some with a (relatively) high MIC so that intrinsically we may have some resistance making it harder to use as an initial drug.

Panelist 4: Again, oritavancin appears to have very good activity against a variety of strep species in vitro. Most impressive is the activity against pcn resistant strep pneumo, but it is also active against strep broadly. I can't really see much of a role here for this agent, except in limited circumstances, but the data is useful to profile the overall gram positive activity of the drug. Activity against staph and enterococcus is more important.

Panelist 7: Nothing surprising in this data - I would expect it to have the same activity as vancomycin.

Panelist 8: I agree with my fellow panelists-- preliminary data looks good-- as it should, no surprises. Again, I have reservations about mismanagement of ORI..

Panelist 9: I agree with the other panelists. MIC's look good. we need PK data/clinical efficacy data. not sure of the role for this agent, unless there is someone who will need long term abx for a complicated skin infection, who for some reason can't tolerate the other agents currently in use.

Panelist 5: I doubt it would be used for Strep. There are much cheaper and very efficacious alternatives available.

Please review the attached abstract  (Appendix C)

Panelist 9: again, MIC/in vitro data looks good. Need clinical data to make determinations regarding use in clinical practice. if the data are similar in vivo, it would be a great addition to treatment of these types of infections.

Q6. Activity against Enterococcus

Please review this ICAAC 2007 abstract about oritavancin’s activity against Enterococcci. How does its function and resistance profile compare to other antibiotics commonly used to treat these organisms? How does oritavancin work against vancomycin-resistance enterococcus? How important is this activity against Enterococcus relative to the overall function of the medication? Do you think oritavancin might commonly be used for this indication?

Panelist 1: Appears ortivancin is effective in vitro against sensitive and resistant enterococcal strains. Again, pharmacokinetic data needed to better translate to clinical efficacy (or in vivo animal models or clinical trial data).

Panelist 2: The MICs for both resistant and susceptible enterococci are encouraging. If this agent also performs this well in vivo, then it will be an excellent addition - particularly for treatment of serious VRE infections.

Panelist 3: data looks encouraging, particularly for VRE, though in vitro and in vivo are not always the same

Panelist 6: Seems to overall have good activity. Only concern are some strains with a MIC of 4. Need more data from clinical trials.

Panelist 4: Once again, oritavancin has shown low MICs to both species of enterococcus in vitro, including strains that are resistant to vanco, and a limited number of strains resistant to dapto and linezolid. THis may translate into very potent effects in vivo for these organisms. It appears to have high activity against VRE. This activity is very important for this drugs functionality, because this is where it will most likely be used, along with staph strains. It may very well be used commonly for this indication if this can be translated to clinical data.

Panelist 7: This abstract does not provide the vanc susceptibility cutoffs used. Probably no matter - the pattern clearly shows that the primary mechanism giving rise to vanco resistance (Van A) also present a challenge to Ori. There will undoubtedly be a quantitative difference between the in vitro MICs to vanc and Ori, but as other panelists have said, what matters is what happens in vivo, and that is a long and tenuous extrapolation from the current data.

Panelist 7: This abstract does not provide the vanc susceptibility cutoffs used. Probably no matter - the pattern clearly shows that the primary mechanism giving rise to vanco resistance (Van A) also present a challenge to Ori. There will undoubtedly be a quantitative difference between the in vitro MICs to vanc and Ori, but as other panelists have said, what matters is what happens in vivo, and that is a long and tenuous extrapolation from the current data.

Panelist 8: definitely see a niche for ORI here-- resistant organisms in severely ill patients, given the in-vitro data, i'd try it in-vivo

Panelist 9: again, MIC/in vitro data looks good. Need clinical data to make determinations regarding use in clinical practice. if the data are similar in vivo, it would be a great addition to treatment of these types of infections.

Panelist 5: Not very excited about the data for VRE. For susceptible enterococci, there are already drugs available and this is an addition.

Please review the attached abstracts  (Appendix D)

Q7. Activity against Clostridium difficile

Please review these two ICAAC 2007 abstracts about the activity of oritavancin against C. difficile. How promising is this data? How does its activity against C. difficile compare to metronidazole and vancomycin? How significant is this activity of oritavancin relative to its overall function? Should this indication for oritavancin be further explored?

Panelist 1: It appears ortivancin may be effective against C. diff. More data needed on stool levels and whether there are any potential compounds in stool that my bind or inactivate ortivancin. Although it is not clear how the spore assay translates to in vivo models, ortivancin may decrease sporulation activity of C. diff. This would be beneficial in preventing spread of C. diff in healthcare settings. This should be studied further.

Panelist 2: These are very interesting data. I do think that this indication should be pursued. I still have reservations about how easily in vitro studies translate into in vivo reality, though. I'm also not clear how oritavancin would be administered in vivo. I assume PO (we will essentially have a patient "drink" a bag of IV vancomycin if we need to use PO vanco), but don't know for sure. Does anyone else know?

Panelist 3: I agree with panelist 2, how will this drug be administered? Orally? An interesting indication given the difficulties recently with C diff, but I think animal studies would be more helpful than in vitro for this indication.

Panelist 6: These abstracts offer some interesting information about the activity of this agent against CD. I don't know how to interpret the difference btwn BM and AI methods - as it pertains to human/animal use. Clinical/animal data is necessary. Interesting data about invitro sporulation of CD spores with exposure to this drug. But would this also occur in vivo and what doses would be needed?

Panelist 4: THis data is promising, espeicially the data on its activity against CD spores, which may decrease epidemic outbreaks. It appears that oritavancin has equal if not better activity vs CD compared to metro or vanco, in vitro. This is difficult to translate to clinical settings, however, as it is not reported on the PK, distribution, etc., of oritavancin to the gut. This may be significant in the overall function for the drug, but this would likely be a secondary use for specific situations. I'm not sure I would pursue this indication further, unless there really was something to the issue of activity againgt spores.

Panelist 7: Nothing to add to previous comments. I do not know whether Ori will be digested in the GI tract, and this would be an all-important question for this indication.

Panelist 8: Interesting data especially regarding the resistant CD spores in the 2nd abstract; would see a potential role her with emergence of resistant c diff. I also curious about how it would be administered for this indication, and also the COST. Why do we teach students to use metron. again after a c. diff pt relapses? Metron. costs less, alot less.

Panelist 9: intriguing data, particularly as pertains to spores. this would be an interesting drug to pursue for treatment of patients with relapsing disease. we still would use metronidazole as first line therapy, and I suspect that unless there were a cost benefit, we'd use vancomycin as second line. but for folks with relapses that are difficult to manage, this might be a good agent to explore. currently we just do long tapers of vanco po for this type of patient. also, as was mentioned, the route of administration is going to be important. clinical data is obviously needed as well.

Panelist 5: I doubt much will be found here. The MIC is not better than MET or VANC to the degree that this will be a major drug.

Q8. FDA Approval process

In 2003, InterMune (a company which had previously owned oritavancin) had expected to submit an NDA for oritavancin. However, this submission was delayed because the FDA requested additional safety information due to adverse events seen in two small phase III trials including rash and phlebitis. Furthermore, in a single-dose, open-label, non-controlled, dose escalation study, 5 of the 11 subjects were found to have symptomatic, transient elevations in their hepatic transaminases (DMID. 2004; 50: 95-102). How do you think this historical information will impact the FDA approval process for oritavancin? What information will Targanta need to show regarding oritavancin in order to address these prior concerns? Do you think the FDA might require a large post-marketing study to investigate the incidence of adverse events? Please explain why or why not.

Panelist 1: This past studies will likely alert the FDA to potential adverse events due to ortivanin, particularly in light of several recent concerns of inadequate post-marketing surveillance. However, as there are few alternate drugs available for MRSA, VRE, and C. diff, the FDA probably recognizes the need for additional compounds effective against these organisms. FDA will likely like data demonstrating it is not hepatotoxic and will likely require post-marketing surveillance.

Panelist 2: Given these prior studies, I would imagine that the FDA will examine future clinical data very closely - both prior to approval and post-marketing. I agree with Panelist 1 that the FDA will surely consider this drug an important addition to fighting resistant organisms, but I don't think that will override safety concerns.

Panelist 3: I think the FDA is being more careful with its approval process. Given the niche that this drug will fill, it will be seen as attractive. That said, the hepatotoxicity issue will be important to follow particularly because many of the patietns taking this drug will be on other medicines, including antiretorivrals for HIV.

Panelist 6: I think that this data will be looked at very closely by the FDA. Pre-approval (and larger) studies as well as post-approval marketing should be required by the FDA. Despite its activity, given the recent information and post-marketing side effects seen, I think that easy approvals without rigorous post-marketing studies are going to be few and far between.

Panelist 4: This historical information will probably be explored in depth by FDA, but I have no real knowledge of how this process may work. Targanta will need to show data from all their clinical trials specifically addressing rash and phlebitis, as well as liver function tests in patients on the drug. There would likely be a requirement for post-marketing study for liver tests as well as other unknown side effects, given recent experience with drugs being withdrawn after approval. I personally think this is important, as approval trials are often done in hundreds of patients but after approval the number of patients treated is very large, and can uncover rare but important side effects.

Panelist 7: As we've seen with drugs like daptomycin, cidofavir, and foscarnet, the FDA will approve anything if the indication is strong enough. At least 2 companies "owned" Ori before InterMune, and either they or the FDA judged the indications to be insufficient. Have the indications changed? Some, yes, but I'm not sure they've changed enough.

Panelist 8: I'm glad the FDA has gotten more stringent. I'm tired of receiving "dear doc.." new warning letters from pharmaceut companies. when they lose credibility with the public, we physicians take a hit as well. Targenta needs to do the obvious-- accumulate as much clinical data as possible looking at adverse reactions, drug-drug interactions, looking a sub-populations, etc. etc; difficult to do with in-vitro data

Panelist 9: I suspect the FDA will consider this previous data carefully in the approval process, particularly in light of issues with many other medications in recent years. I suspect they will require post-marketing data as well. I do think however they will be interested in this drug, given the organisms against which it is effective.

Please review this abstract about a phase 3 study  (Appendix E)

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Please review this abstract about another phase 3 study  (Appendix F)

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Clinical data

Many panelists mentioned wanting to see clinical data about oritavancin. You have just reviewed two abstracts containing information about the phase 3 studies that have been performed regarding the drug. What is your opinion about these studies? What do you think of the results?

Panelist 7: There isn't enough information in these abstracts to reach firm conclusions about their quality or their significance. This drug has been around and under development for so long, that I would insist on seeing *ALL* relevant clinical studies performed with this drug in all their gory detail before reaching conclusions on any subset of them.

Panelist 3: This is a limited amount of data that doesn't really explain adverse events (what were the most common ones?) or explore drug-drug interactions. More data is needed in bigger studies with more information on other outcomes (particularly toxicity)

Panelist 4: The amount of information in these abstracts is limited, but there is a suggestion that ORI is non-inferior to vanco for cSSSI infections caused by Gram positive infections. However, there is not much that would suggest ORI has much of an advantage over vanco. The shorter duration of total therapy is driven by the lack of a PO phase in the ORI arm, which is not that big a difference. We really need to see data on the tolerability and side effects. Also, it would be nice to see the microbiology of these infections.

Panelist 9: these abstracts to not provide sufficient data on efficacy, tolerability, and superiority to currently available agents. larger studies with clinical significance are needed.

Panelist 8: the abstracts provide preliminary summaries of preliminary data. is the company planning on submitting a couple of abtracts for FDA approval or to hospital P and T committees?

Panelist 2: The data presented is limited but suggests that Orita may be at least equivalent to the comparator. I would like to see what organisms caused the infections and what type of side effects the patients in the vanco arm that the orita group did not have.

Panelist 6: These abstracts outline some data about O - with an overall success rate similar to vancomycin. The data about side/effects is limited so difficult to draw significant conclusions.

Panelist 1: Non-inferior to vanc = not too exciting. To change prescribing patterns we would like to see superiority studies. Shortened duration of therapy of some help, but having orally available alternatives decreases impact of shortened duration of IV therapy.

Panelist 5: Abstracts are never a substitute to peer reviewed publications. In any case, far more data is required for FDA approval as well as incorporation of a drug into routine clinical practice.

Please review this excerpt from Targanta's prospectus  (Appendix G)

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Clinical data for FDA approval

In the excerpt from its prospectus that you just reviewed, Targanta described its interactions with the FDA regarding its clinical data. Please share your opinion about this information presented by the company. What do you think about the information that is being requested by the FDA? Do you agree with Targanta’s conclusions?

Panelist 7: The FDA knows how to do antibiotics, and they fully understand the need for drugs that do what Ori supposedly can do. Their request for additional analysis and justification is a response to being pushed in a direction they are reluctant to go. The fact that other agents have been approved with non-inferiority deltas in excess of 10% really has no bearing on this approval; the panel that granted the other approval may not even have any overlap with the panel overseeing this decision. Targanta had to be optimistic in their prospectus, and they had to come to the conclusions they came to about the FDA, or we wouldn't be having this discussion. Therefore, the company's published statements do not influence my optimism about FDA actions on their behalf. The basic question here is: will Ori be approved? From my limited vantage point, without access to a lot of the information that will determine this outcome, the FDA requests and the long so-far-unsuccessful history of this drug make it look like a steep uphill battle.

Panelist 3: I agree with panelist 7, the FDA is doing their job. While the company has to view the glass as "half full" in their prospectus, my guess is that they know they are facing a tough battle since there are so many other useful drugs out there fore SSSI's. I can't say they won't win eventually, but they will need to have more data on efficacy. Also, I suspect they will need more data on the adverse events.

Panelist 4: The FDA requests, which I read over several times, is hard for me to understand. It appears that FDA is asking for analysis of the benefit of ORI compared to historical vancomycin and placebo, in a population similar to that enrolled in ORI clinical trials. I don't have experience with this type of analysis, but it seems like it might be very difficult to do this. The full FDA approval may not turn on efficacy anyway; there may be safety or toxicity concerns that are not fully addressed in these clinical trials. The issues of the non-inferiority margin of 10 or 15 % can probably be clarified to FDA's satisfaction, in my opinion.

Panelist 9: I agree with the FDA's requests for more information on the benefit vs other currently available agents. Also agree with the new standard of less than 10% difference in non-inferiority. If that is the new standard, then all new drugs should adhere to that, regardless of prior decisions or prior standards. I do not agree with Targanta's conclusions.

Panelist 8: it's hard to believe that over 1500 pts have been on ORI; 5 days response on ORI vs. 11 days with vanco/ceph looks impressive on the surface. the FDA is like our IRB committee, sometimes arbitrary and usually unpredictable. but their request is reasonable under recent circimstances and targenta should provide the information if available.

Panelist 2: This is a difficult question to answer. In the end, the FDA will get what the FDA wants, I guess. I agree with previous panelists' comments that the request is thus reasonable. Targanta must remain optimistic in their prospectus for their investors.

Panelist 6: Regardless of the what information the FDA requests, Targanta must deliver if they want to get approval. Even if the previous non-inferiority standard was > 10%, there have now been several approved antibiotics which, in post marketing showed significant side effects. I feel like we aren't hearing the whole story.

Panelist 1: Usually a company consults with the FDA prior to initiating a phase III trial, to make sure all of the endpoints are the endpoints the FDA is looking for. I see this as a warning sign. I doubt the FDA would raise the bar after previously recommending a less stringent cut-off (although it is a government agency). Not consulting with the FDA prior to spending millions of dollars to conduct a phase III trial is bad business.

Please review this additional excerpt from Targanta's prospectus  (Appendix H)

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Targanta’s actions

The attached excerpt from the prospectus contains information about actions taken by Targanta since its acquisition of oritavancin, that may address some concerns that have been raised in the discussion. Please share your opinion about this information. How significant is each point? Do they sufficiently address some of your concerns? Is there anything else that Targanta is overlooking?

Panelist 3: Quite honestly I think Targanta is trying to make the drug look good (which is their job) but have not really addressed the issues that the FDA has raised. From my opinion, they've missed the mark.

Panelist 7: Agree with 3 again. Targanta is doing some of the things they have to do, but in the final analysis they're not improving the drug or learning new information about it, merely repackaging old information. We don't have info about *how* they addressed the phlebitis issue - that may have been solved by altering the solution composition or rate of admin, and that info would be of value. But it doesn't appear that they addressed it by investigation, only by reanalysis of InterMune data, so Targanta's actual contribution to this issue is very limited. The types of statements they make about potency borders on insulting. They know full well that "superior potency" is a measure of little meaning unless it is coupled with (a) info stating that the potentcy is against bugs I would actually use this drug against, (b) info about the safely achievable blood levels, and (c) info about the ability of the drug to penetrate in effective concentrations into sites of infection like bone, brain, veg, & prosthetic materials. Furthermore, with a lipophilic drug like Ori, they could artificially increase the apparent potency in lab tests merely by reducing protein concentrations in the broth media, or in some cases, even the type of tubes used for the tests (e.g. glass v plastic). Targanta is not "overlooking" this information - they have to know it is important. By not providing it up front, they raise suspicions about the info they are not providing.

Panelist 6: I have to agree with Panelist 3 and 7. The information given is merely Targanta's explanation without giving us clear clinical and evidence based data on which to assess these issues. I am happy that the FDA agreed with their re-assessment of the phlebitis risk, but I would like more info on which to make my own decision. Secondly, as pointed out by panelist #7; potency is a very tricky assessment to make and would have liked to obtain direct information about how the testing was done and some of the other information was addressed.

Panelist 4: I also have some reservations about the statements made here. Regulatory: Again, we are not seeing the actual data that is referred to, so cannot make an independent judgement on this. It is unclear if the data is new, or a re-analysis of old data, or what, if any, changes were made to the drug or its formulation to address the problem of phlebitis. The FDA agreeing to lift a voluntary hold does not sound like a ringing endorsement to me. More information is needed. Potency: Again, more details are needed to make an independent assessment, but it sounds sort of strange for them to say that somehow they have demonstrated that the drug is now up to 32 times more potent in vitro than previously reported by Lilly. Regarding relative potency against other antibiotics, this in vitro data does not necessarily translate to in vivo, when drug PK, and tissue penetration must be considered. Economic: Can't really say, but perhaps Lilly is willing to negotiate a lower price because they know something we don't? One issue that is not addressed is the liver enzyme elevation referred to in earlier trials. This is important.

Panelist 1: I agree with the prior comments on this issue. Not enough data to determine validity of the prospectus. The statement on potnency can be misleading.

Panelist 9: these are promising actions, particularly the phlebitis action. Not knowing the details, I cannot comment on how this will affect clinical use, but if the FDA is satisfied, it suggests that there may have been some decrease in the incidence or severity. we will need to see clinical data to appreciate what this means. Similarly, the cost issue will be one that will only be solved when we see pricing information. THe in vitro data is promising as well, but we still need good clinical data to make determinations regarding the role and hierarchy of this agent in clinical practice.

Panelist 2: I agree with the other panelists' comments. The statements in the prospectus make it sound that the company is optimistic about obtaining FDA approval and thus releasing Oritavancin soon. These are entirely different issues than trying to convince physicians to actually use the drug. The data available (including the statements made in the prospectus) do not really do anything to convince me to use the drug. I would like to see the recent data on phlebitis and actually see how the drug does in vivo against organisms like MRSA and VRE.

Panelist 8: Would like to kow more about the regulatory data submiited regarding the increased rate of injection-site phlebitis. The prospectus suggest that the FDA was satisfied with the data-- whatever that was. But if ORI will require CVL to prevent or reduce rates these adverse events, it hurts the product. Little skeptical that Targenta's new potency data revealed that ORI is actually 32x more potent than Lilly/Intermue realized...hmmm. I suppose from an investor point of view, these points are somewhat reassuring, but as a clinician, I'd want to review more details of the injection site reactions, and potency data.

Panelist 5: Targanta should anticipate FDA’s concerns and answer them proactively. Especially the concern about liver enzyme abnormalities, and longer term safety needs to be addressed.

Labeling

Will the history of adverse events with this drug impact the labeling of this drug? If so, please explain how. Do you think they may have specific warnings associated with the medication? If so, what might the warnings be?

Panelist 3: I think the phlebitis is an issue. Hepatotoxicity is also a major issue, particularly in patients taking other antiepileptis and antibiotics for other conditions. Interactions with antiretrovirals will also need to be evalated.

Panelist 7: Yes - most of the adverse effects that can attributed to the administration of Ori will be mentioned in the label, even minor ones. This is done to encourage docs to report it when they encounter what might be an adverse reaction.

Panelist 4: Yes, I would think that the label will contain all observed adverse events, with a special focus on the liver and phlebitis. Depending on the extent of the liver problems this could end up being very prominent in the label. Not sure if the phlebitis problems is big enough to require a central line to be used for the infusions or not.

Panelist 9: yes, the adverse effects will impact the labeling. the FDA is going to be more careful about this, not less careful, given what we know about use of drugs in real life. the phlebitis is a real issue, and depending upon how common this will be in practice, it will certainly affect use. it's not a deal-breaker; patients treated with nafcillin through peripheral IV's have problems with it. we just use PICC/central access for it to overcome the issue. we need more data in real-life use of ORI to see how big of an issue this will be. the hepatotoxicity will be an issue, however, again depending on the frequency.

Panelist 8: hepatoxicity, phlebitis, other drug-drug interactions... requiring a CVL/PICC will defeat the purpose of once weekly dosing.

Panelist 2: Phlebitis and the need for central lines went a long way to kill quinupristin/dalfopristin. Nevertheless, these side effects will have to be clearly spelled out on the drug labels. I would imagine that the FDA will be requiring more specific labeling of side effects for all drugs in the future.

Panelist 6: Given the recent history with different drugs and increased side effects noted in post-marketing I would agree that side effects will be prominent in this drug.

Panelist 1: Yes. Look at daptomycin. There have been no indications of rhabdo with changing the dosing. But we are instructed to monitor and check once weekly CPKs.

Panelist 5: Absolutely. In the current regulatory environment, even a small number of side effects are important – especially liver related, since at least two drugs have been taken off the market in recent years for relatively rare hepatotoxicity.

Other concerns

Do you have any other concerns about oritavancin that have not been mentioned thusfar in the discussion that might impact the likelihood of its approval by the FDA?

Panelist 3: side effects, toxicity, and cost are big issues to address!

Panelist 7: Agree with 3

Panelist 7: Agree with 3

Panelist 4: Toxicity and tolerability are big issues here. I think this could be as big, if not bigger, an issue than the efficacy for FDA approval, given the number of drugs taken off the market after approval recently.

Panelist 9: tolerability is the biggest concern, efficacy (superiority) is next, and cost is third. route of administration and dosing frequency will either distinguish it or not, all other aspects being equal.

Panelist 8: ditto, agree with 3

Panelist 2: As has been the concensus among the other panelists - safety/tolerability, efficacy, cost, and administration are all important

Panelist 6: not much to add

Panelist 1: as per other panelists. Also, I would like to also see tolerance studies: how easy is it for organisms to develop resistance?

Panelist 5: No

Panelist 4: The information contained in these abstracts is limited, but at least it gives a hint that oritavancin may be non-inferior to vancomycin in cSSSI infections caused by gram positive organisms. I'm not sure that these studies demonstrate any advantage of oritavancin over vanco, however. The shorter total duration of therapy for the ORI group is due to the lack of a PO phase, which may be a slight advantage, but not that great. We need more information about side effects, etc.

Panelist 5: If 5 of 11 (nearly 50%) had SYMPTOMATIC elevation of liver enzymes, then FDA would come down really hard on this drug. They do not want be burnt again like at least two previous drugs where patients died of hepatotoxicity. Company should really re-think about resubmitting the NDA. A larger trial before submission may help with this, but 11 patient trial is just not enough –actually it gives strong evidence NOT to approve this drug.

Q9. Adoption of oritavancin I

Targanta is planning to submit an NDA in early 2008 for oritavancin to treat cSSSI. If it were to receive FDA approval, what factors do you think will impact its adoption into clinical practice? What would make physicians more or less likely to use this medication? What information would they be looking for in order to make a decision about using the medication?

Panelist 1: efficacy against comparator drugs, organsisms cultured during the trial, cost, likelihood of resistance to ortivancin developing, tolerability / adverse events

Panelist 2: Their are so many agents for cSSSI that the only way to ensure its frequent use would be to show superiority to other agents. Without that kind of data (doubt that we'll see it), it will depend on cost, efficacy, emergence of resistance, ease of administration, and safety.

Panelist 3: I agree with prior panelists, development of resistance, toxicity, side-effects and cost will all drug utilization.

Panelist 6: I think the information given here is mainly in vitro. More in vivo info; method of administration (po v iv); side effect profile and method of metabolism are needed before i would adopt its use. Also, price, availability of alternative agents and ease of use will be important factors.

Panelist 4: The main factor may be formulary coverage, and cost initially. Also, the side effect profile and tolerability, drug interactions, etc., will need to be carefully considered. It may be restricted in some places to resistant organisms at first.

Panelist 7: I have not yet personally encountered, or heard of a colleague encountering, a situation that begs for the use of Ori. This could change quickly, of course, if Ori is shown to have superiority over available agents. Superiority, however, is a complex measure that is only tangentially addressed by the in vitro data so far discussed in this forum.

Panelist 7: Correction - by "a situation" I specifically meant a cSSSI. Of course, we have probably all seen a real need for better agents against MRSA and VRE.

Panelist 8: the market seems glutted with cSSSI indications-- it boils down to 1. efficacy, 2. efficacy again, 3. safety. if ORI has clinical data against gold standard and its better tolerated, it'll get usage, but right now it's a niche drug for resistant gram (+) pathogens

Panelist 9: I agree with panelist 2. the main issues in my mind are cost and resistance. daptomycin was supposed to be a miracle drug, and I have found it lacking in clincal use. we have had patients develop non-susceptibility during use, we have had poor success with bone and joint infections, and I frankly do not think it clears bacteremia from staph as well as vancomycin does. I only use it for VRE when I can't use linezolid. that being said, this new drug will need to be better than the currently available drugs in order to be used broadly. side effects are going to have to be minimal, and cost cannot be prohibitive.

Experience with Cubicin (daptomycin)

Panelist 9 shared some thoughts about Cubicin in the answer to Q8. Cubicin received FDA approval in 2003 to treat skin infections and in 2006 to treat S. aureus bacteremia including right-sided endocarditis. How do you think the cost of Cubicin has impacted its adoption into clinical practice? What can be learned from the introduction of and experience with Cubicin that can be applied to the prospective launch of oritavancin if it is approved?

Panelist 3: I think daptomycin has become more useful as a drug as we have had more difficult SA infections to treat.I dont use it as a SSSI drug, in fact my only experience with it is in difficult to treat MRSA infections

Panelist 7: Cream floats. Cost will have some impact, but eventually the extent to which any given drug is used will depend on its relative utility in clinical practice - factoring in everything that matters: efficacy, safety, availability of more desirable alternatives, etc.

Panelist 4: The cost of daptomycin has limited its use in my opinion. It is used for specific organisms, such as difficult to treat MRSA as mentioned before, or VRE. I agree, however, that if a drug clearly has benefit over another, than cost will be a secondary concern. But vancomycin is so established in this area, that just offering a little advantage will not result in widespread use or adoption on hospital formularies if the cost is too high.

Panelist 9: cost is an issue, but efficacy is the larger issue in my mind. I am not convinced that dapto is better than vanco; I only use it for intolerance to vanco (renal failure, the rare patient who has a true allergy, etc) because I have not had great success with clearance of bacteremia (despite the data), or with bone/joint infections (and there is ample data emerging in abstract form about efficacy in this area). I do not use it for CSSI because frankly we have better and cheaper drugs. I'm not sure that the dapto launch will affect ORI. each drug is evaluated independently by clinicians, based on clinical data. if the drug is good, and has a favorable side effect profile and reasonable cost, it will be used by clinicians.

Panelist 8: cost is always an issue-- consequently it's on our hospital formulary but heavily guarded.

Panelist 2: The two main issues that have impacted the use of dapto are 1) efficacy and 2) cost. I have never used it for cSSSI and doubt I will. We have used it at our institution for difficult to treat MRSA infections (after vanco "failure", if you will). The recent indication for bacteremia has been good for the drug in that now more than ID physicians know about it. It is no more efficacious than vanco and clearly more expensive, so it remains under ID approval only to ensure it is being used appropriately.

Panelist 6: As many of the other panelists, I have only used daptomycin for treatment of SA bacteremia in light of vanco failure or vanco intolerance. It's cost and side effects limit its use.

Panelist 1: In response to panelist 7, mmmmmmm, cream. I see two key issues. One, as ID physicians, we can be our own worst enemy for new antibotic development. We see a need for new antibiotic because of increasing resistance. But when one is available we keep it in reserve as to minimize the development of resistance. This is a necessary evil as far as I am concerned. The other issue is lack of superiority data. Vancomycin is a crappy antibiotic. If all you show is you are non-inferior to vanc, big deal. If an antibiotic were shown to be superior, cost would be a minor issue.

Panelist 5: Targenta should conduct clinical trials for bloodstream infections to see if ORV is a viable option.

Cost of oritavancin

How might the cost of oritavancin impact its adoption? If it was expensive, do you think it might be limited to cSSSIs that were resistant to other therapies? Conversely, does it offer significant benefit such that it might be used more widely despite the cost?

Panelist 3: I think cost will play a big role in adoption of the drug. If there are cheaper alternatives that are as effective, it will be tough to convince insurers to pay for it and it will probably only be used for difficult to treat SSSI's

Panelist 7: Cost will be arbitrated first by hospital formulary committees, and they will make it inconvenient to obtain if the upfront costs are prohibitive. With Ori, however, the costs of administration and blood level monitoring should be lower than vancomycin, and this advantage will factor into the decisions.

Panelist 4: The cost will affect its adoption, in that hospital formulary committees will look at that when making decisions. I would like to think that its use would be limited to resistant organisms not because of cost, but because of good medical practice and antibiotic stewardship, but cost is a more realistic barrier. Right now, I cannot see any significant benefit that it would be used widely despite a high cost over what we have now.

Panelist 9: if all other factors are equivalent, cost will be the deciding factor. if it is more expensive than currently available agents, we won't use it. our hospital formularies simply won't include it. if it is expensive, it will only be used if it is better than other agents and if patients have failed those other agents and have no other options.

Panelist 8: costs can be prohibitive if its providing only marginal benefits over "gold standard" options. the utility of ORI may lie in home infusions, outpatient management, or pts nearing hospital discharge.

Panelist 2: Cost will clearly impact its usage. If it is equivalent to cheaper drugs, it makes no sense to use the more expensive agent. It is more complicated than just price, though. Hospital committees and group bargaining can help lower prices. Still, I see little use for this drug for cSSSI in anything but the most severe and/or resistant infections...and even then, once the cheaper meds failed.

Panelist 6: Without clear superiority to other drugs, if the indication is cSSSI then cost will definately be an issue.

Panelist 1: Cost and how it impacts formulary changes will depend more on the clinical data. non-inferior plus $$$$$$ = minimal use (reserved for refractory infections).

Panelist 5: Since there are multiple options for cSSI, the cost has to be extremely competitive with the current agents for hospitals and formularies to stock this drug.

Panelist 5: Cost, route of administration, spectrum of activity, incidence of adverse effect

Q10. Adoption of oritavancin II

If oritavancin were to receive FDA approval, how widely and how quickly do you think the drug would be adopted into clinical practice? What have you heard from colleagues regarding their attitudes towards this drug and their potential incorporation into clinical use?

Panelist 1: If ortivancin is found to be superior to comparator drugs, much more liekly to be incorporated into clinical practice rapidly. Otherwise efficacy, cost effetiveness,and side effect profile in addition to likelihood of resistance developing will be weighed into treatment decision making.

Panelist 2: It depends on the indication. If it receives FDA approval for cSSSI - It will essentially be a "me too" drug in an already crowded field. If it receives indication for bacteremia, it will be used regularly - particularly if there is data to suggest it is superior to vanco!

Panelist 3: If superior to vanco will be used quickly in bacteremias. We need drugs for complicated MRSA infections, particularly in those on dialysis. This is a difficulty of dapto and could be a real area for this drug. Soft tissue infections have lots of options at the moment

Panelist 6: Agree with the earlier posters. Important info needed would be side effect profile; metabolism; risk for development of resistance; method of administration. All this being added to a crowded field of agents for cSSSI. For bacteremia we are limited with bactericidal agents against MRSA to vanco and dapto. Both have problems so this could be a drug with widespread use...depending on the above.

Panelist 4: I'm not sure how widely or quickly it would be adopted into clinical use. People are used to using vancomycin, and many ID doctors may be concerned with overuse and the induction of resistance for a drug that has some very important properties that allow it to be used when first line agents fail. I haven't really heard much from colleagues about how it will be incorporated into use yet.

Panelist 7: Like vancomycin, I suspect that many institutions would regulate the use of Ori. Its rate of adoption would then depend on whether it is viewed as a second-line agent to vanco, or superior.

Panelist 8: similar to all the prior responses-- needs to establish better efficacy and tolerance to comparator options to get people talking-- for non-ID physicians, it's the potential once weekly or less dosing to treat endocarditis and osteomyelitis that piques their interest.

Panelist 9: I have heard nothing from colleagues about this drug, which is unusual, as we have an active research group at our institution in the area of MRSA/VRE treatment. I doubt this will be widely used unless clinical data are superb. and I don't see that data yet.

Formulary adoption

If oritavancin were to receive FDA approval, how likely do you think it would be adopted by your hospital’s formulary? Please explain the reasoning behind your answer. What information would need to be available to the hospital formulary committee in order to increase the potential for adoption?

Panelist 3: it would depend a lot on cost as well as efficacy data. If it's no more effective (or has less toxicity) and is more expensive its unlikey to be adopted by P&T committee

Panelist 7: In our tertiary academic medical center, its use will almost certainly require authorization by ID subspecialists. The extent to which authorization will be granted will most likely depend on information that is not yet available, or that will change quickly as experience with the drug is gained.

Panelist 4: It may be adopted but it will almost surely be restricted at our hospital to ID specialists for approval. I do not believe it offers such advantages that it will be approved for routine use. The cost and toxicity will be factors, of course, in addition to efficacy and indications.

Panelist 9: our hospital would only include it on formulary if it had a role (better than other drugs for a certain indication, ability to be used for organisms that are resistant to all other available drugs) and if the cost was reasonable. again, as we've said, if it's equal to the other available drugs, not better, it has to be the cheaper or the same cost, otherwise their is no need for it.

Panelist 8: most hospital P/T committees work in similar fashion, as confirmed by the other panelists' reponses: can the product provide a niche not fullfilled by existing products? is it safer? can it save the hospital money?

Panelist 2: Cost data drives a lot of P/T decisions, so it will depend to a large extent on cost. That, coupled with no particular benefit over other choices, makes me think it is unlikely to be approved. Should it be approved, it would require authorization via ID consultation - as others have stated.

Panelist 6: Will be limited to ID approval for certain in the beginning. If it is only approved for cSSSI, then it won't be added at all without some clinical or cost superiority. The data we have been given doesn't show that.

Panelist 1: Based on data presented, it would probably be added to the formulary but use restricted to refractory infections or patients who don't tolerate other antibiotics. Approval would require an ID specialist.

Panelist 5: Without more data about efficacy (published data in peer reviewed journals) and the cost information, it is impossible to make this call.

Panelist 5: If oritavancin were to receive FDA approval, how widely and how quickly do you think the drug would be adopted into clinical practice? What have you heard from colleagues regarding their attitudes towards this drug and their potential incorporation into clinical use?

Q11. Other issues

For someone trying to understand oritavancin – its potential uses, its marketplace, and the likelihood of its approval of the FDA – is there anything else that would be important to know?

Panelist 1: results of in vivo animal models and clinical data. results of in vitro studies to attempt to induce reistance.

Panelist 2: I completely agree with Panelist 1. Oritavancin appears to have excellent activity against resistant organisms in the lab - but that's only a piece of the puzzle. Would want to see in vivo data and safety profile, in particular.

Panelist 3: I think its important to know the efficacy (as you've looked at) however the toxicities, side effects and drug-drug interactions are important. Cost of the drug is another very important issue that's often overlooked. If it's too expensive, it will only be used for cases where there are few other optionss

Panelist 6: As said in the previous questions issues i need more data about are: 1) administration (iv v po) 2) metabolism and drug-drug interactions 3) in vivo efficacy shown thru clinical trials 4) side effect profiles 5) cost

Panelist 4: Of course, we have not discussed any clinical data yet, only in vitro. So we need to know a lot more about its side effects, need for monitoring, cost, etc.

Panelist 7: Go to people who worked in the companies that previously owned Ori, buy them a few drinks, and ask them what's important to know.

Panelist 8: NEED MORE CLINICAL DATA... and how it compares to similar products, not vanco but the other new investigational glycopeptide agents that we mentioned in the first question-- which is better? Not necessarily for FDA approval but for the next step--to get it onto our hospital formularies.

Panelist 9: we need to know clinical data, efficacy compared to currently available agents, side effect profile, route of delivery, and frequency of dosing.

Panelist 5: If more data is available, it should be disseminated.

Presentation Number:

E-1617

Poster Board Number:

234

Presentation Title:

In Vitro Activity Profile of Oritavancin against Resistant Staphylococcal Populations from a Recent Surveillance Initiative

Keywords:

Staphylococci,oritavancin,surveillance

Author Block:

D. F. SAHM1, G. MOECK 2, F. F. ARHIN 2, D. C. DRAGHI 1;
1Eurofins Medinet Anti-Infective Services, Herndon, VA, 2Targanta Therapeutics, St. Laurent, Canada.

Financial Disclosures:

 D.F. Sahm, None.

Background: Oritavancin (ORI) is a potent bactericidal lipoglycopeptide that is under clinical development for use in the treatment of infections caused by gram-positive bacteria. ORI will be used in settings where resistant (R) staphylococci are likely to be encountered. This surveillance (SUR) study profiled ORI activity in vitro against drug-R staphylococci. Methods: Recent (2005-2006) clinical isolates of S. aureus (SA; n = 5,008) and coagulase-negative staphylococci (CoNS; n = 862) from hospital sites in the US (95), EU (48), and Israel (1) were centrally tested by broth microdilution (CLSI; M7-A7) against ORI and other relevant comparators. ORI assays included 0.002% polysorbate-80 throughout. Analysis of ORI activity included MIC results for specific resistance phenotypes including multi-drug resistant (MDR) SA defined as R to ≥3 of the following agents: ciprofloxacin, clindamycin, erythromycin, gentamicin, oxacillin (Ox), quinupristin-dalfopristin, trimethoprim-sulfa, vancomycin, daptomycin (DAP; non-susceptible [NS], and linezolid (LIN; NS).
Results:

ORI MICs (μg/ml) against DAP NS SA (n=3) ranged from 0.06 to 0.25. Two DAP NS CoNS had ORI MICs of 0.015 and 0.5. ORI MICs for 4 LIN NS CoNS ranged from 0.12 to 0.25. Conclusions: ORI MICs against a variety of R phenotypes encountered in this SUR initiative demonstrated that ORI had potent activity against a wide spectrum of staphylococci likely to be encountered in a variety of clinical settings.

Presentation Number:

E-1616

Poster Board Number:

233

Presentation Title:

Anti-Streptococcal Activity Profile of Oritavancin, a Potent Lipoglycopeptide Under Development for Use against Gram-Positive Infections

Keywords:

streptococci,oritavancin,surveillance

Author Block:

D. C. DRAGHI1, G. MOECK 2, F. F. ARHIN 2, D. F. SAHM 1;
1Eurofins Medinet Anti-Infective Services, Herndon, VA, 2Targanta Therapeutics, St. Laurent, Canada.

Financial Disclosures:

 D.C. Draghi, None.

Background: Oritavancin (ORI), a bactericidal lipoglycopeptide, is under clinical development for use in treating infections caused by a variety of gram-positive species, including those exhibiting key resistance phenotypes. This study established a current in vitro activity profile of ORI against S. pneumoniae (SP) and various beta-hemolytic streptococci. Methods: Recent (2005-2006) clinical isolates of SP (n = 1,010) and β-hemolytic streptococci (287 S. pyogenes [SPY], 101 S. agalactiae [SAG], 60 Group C, G and F streptococci [BS]) collected from 172 hospital sites in the US, 32 sites in EU, and 1 site in Israel were centrally tested by broth microdilution (CLSI; M7-A7) against ORI and ten relevant comparators. ORI assays included 0.002% polysorbate-80 throughout. Analysis of ORI activity included evaluation against specific resistance phenotypes such as multi-drug resistant SP (MDR; resistant to ≥ 2 agents listed: penicillin (PEN), cefuroxime, erythromycin (ERY), and trimethoprim-sulfamethoxazole). Results:

S=susceptible; NS=non-susceptible (includes intermediate and resistant)
Conclusions: Based on MIC ranges and MIC90s, ORI showed potent activity against all streptococcal pathogens tested, regardless of their resistance phenotype to other drug classes. These in vitro findings indicate that ORI could serve as a highly active therapeutic choice for infections involving these organisms.

Presentation Number:

E-1615

Poster Board Number:

232

Presentation Title:

Anti-Enterococcal Activity Profile of Oritavancin, a Potent Lipoglycopeptide Under Development for Use against Gram-Positive Infections

Keywords:

Enterococci,oritavancin,surveillance

Author Block:

D. C. DRAGHI 1, D. F. SAHM1, F. F. ARHIN 2, G. MOECK 2;
1Eurofins Medinet Anti-Infective Services, Herndon, VA, 2Targanta Therapeutics, St. Laurent, Canada.

Financial Disclosures:

 D.F. Sahm, None.

Background: Oritavancin (ORI) is a bactericidal lipoglycopeptide under clinical development for the treatment of infections caused by a variety of gram-positive species, including enterococci. This surveillance initiative established a current in vitro activity profile of ORI against both E. faecalis (EF) and E. faecium (EM) populations, including those resistant (R) to currently available agents that may be used to treat enterococcal infections. Methods: Recent (2004-2005) clinical isolates of EF (n=909) and EM (n=389) collected from hospital sites in the US (60), EU (36), and Israel (1) were centrally tested by broth microdilution (CLSI; M7-A7). ORI assays included 0.002% polysorbate-80 throughout. Specific susceptible (S) and R phenotypes (e.g. non-susceptibility [NS] to linezolid [LIN], daptomycin [DAP], and vancomycin [VAN]) were examined for ORI. Additional analysis was performed for Van A (VAN-R, teicoplanin [TEI]-R) and Van B (VAN-R, TEI-S) phenotypes.
Results:

NA=not applicable for <10 isolates
NS=non-susceptible (intermediate and R)
ORI MICs were 0.12 and 0.5 for 2 DAP-NS EF and ranged from 0.015-0.5 for DAP-NS EM (n=11). ORI MICs were 0.03, 0.06, and 0.5 for LIN-NS EF (n=3); and ranged from 0.004-0.25 for LIN-NS EM (n=6).
Conclusions: ORI showed potent activity against all enterococci encountered in this study, including strains NS to VAN (both Van A and Van B phenotypes), LIN, or DAP. Based on these findings, ORI may provide a useful alternative for the management of infections caused by enterococci, including those resistant to other agents frequently used to manage such infections.

Presentation Number:

E-1618

Poster Board Number:

235

Presentation Title:

In Vitro Susceptibility of Genotypically Distinct Clostridium difficile Strains to Oritavancin

Keywords:

Clostridium difficile,antimicrobial susceptibility testing

Author Block:

R. O'CONNOR, J. FREEMAN, S. BAINES, M. WILCOX;
Leeds Teaching Hosp. & Univ. of Leeds, Leeds, United Kingdom.

Financial Disclosures:

  M. Wilcox, Research funding from Astra-Zeneca, Bayer, Genzyme, Nabriva, Pfizer, Vicuron and Wyeth; Honoraria for consultancy work and financial support to attend meetings.

Background: Clostridium difficile (CD) infection is a nosocomial disease of increasing importance. First line treatment is limited to metronidazole (MET) or vancomycin (VAN). Oritavancin (ORI) is a lipoglycopeptide with activity against Gram +ve bacteria, including drug resistant pathogens. MICs of ORI, MET and VAN against genotypically distinct CD strains, including epidemic CD PCR ribotypes 001 and 027 were determined by agar incorporation (AI) and broth macrodilution (BM). In AI methods, the impact of supplements on ORI MICs was tested to address ORI binding to surfaces.
Methods: 33 genotypically distinct CD strains were identified by PCR ribotyping. CD strains were prepared for inoculation onto AI plates or BM tubes in Schaedler’s anaerobic broth. For AI methods, ORI, MET and VAN stocks were prepared in water or 0.002% Polysorbate 80 (P80) and used to prepare Wilkins Chalgren AI plates with and without 2% lysed horse blood (LHB). BM MICs of ORI, MET and VAN were determined using Brucella broth with haemin and vitamin K; ORI was prepared in 0.002% P80 and P80 was maintained at 0.002% throughout the ORI assay. Inoculated AI plates and BM tubes were cultured anaerobically at 37°C for 48 h. Results: BM MIC90s were lower than AI MIC90s for all strains and agents tested. ORI BM MIC90s were 16-32x lower than ORI AI MIC90s. ORI BM MIC90s were 2-8x lower than those of MET and VAN. MET and VAN BM MICs were lower than AI MICs (8x and up to 2x respectively). ORI AI MIC90s were 2-4x higher than those of MET and VAN and were unaffected by 0.002% P80 and/or 2% LHB.

Conclusions: ORI was more active than MET or VAN against CD isolates as measured by BM. ORI activity against CD is significantly underestimated by AI methods, regardless of use of P80 or LHB.

Presentation Number:

E-1627a

Presentation Title:

Activity of Metronidazole, Vancomycin and Oritavancin against Epidemic Clostridium difficile Spores

Keywords:

Clostridium difficile,antibiotic

Author Block:

S. D. BAINES1, R. O'CONNOR 1, W. N. FAWLEY 2, J. FREEMAN 2, M. H. WILCOX 2;
1Univ. of Leeds, Leeds, United Kingdom, 2Leeds Teaching Hosp., Leeds, United Kingdom.

Financial Disclosures:

 S.D. Baines, None.

Background: Clostridium difficile (CD) infection is a major healthcare burden. CD spores (SP) are refractory to metronidazole (MET) and vancomycin (VAN) treatment, potentially increasing risk of recurrence or transmission. We compared the activity of oritavancin (ORI), a new lipoglycopeptide, MET and VAN against epidemic CD spores using spiral gradient endpoint (SGE), agar-based culture, and phase contrast microscopy (PCM). Methods: i) SGE was used to determine MICs of MET, VAN and ORI for vegetative cells (VC) and SP of CD ribotypes 001, 106, and 027. ii) SP of CD 001, 106 and 027 were added to 1mL water ±0.002% polysorbate-80 with MET (9.3 mg/L), VAN (350 mg/L) or ORI (350 mg/L). 1 and 30 mins after exposure, SP-drug solutions were filtered through cellulose acetate filters (CAF). CAF were incubated anaerobically on Brazier’s agar (37°C, 48h) to determine % viable CD SP. iii) Germination and outgrowth were determined by using PCM for control and CD 027 SP exposed to MET, VAN and ORI. Results: i) ORI MICs were 5-, 13-, 6-fold lower for CD 001, 106, and 027 SP compared with VC, respectively. No enhanced activity of MET or VAN against CD SP was observed. ii) Recovery of SP exposed to MET and VAN at 1 and 30 min was 95-110% and 70-80%, respectively. No CD SP were recovered from suspensions exposed to ORI. iii) Supra-MICs of MET, VAN and ORI prevented CD 027 SP outgrowth but not germination. Outgrowth of CD 027 SP pre-exposed to ORI was substantially reduced vs. control (peak %VC 30 vs. 87, P= 0.058) and significantly lower than CD 027 SP pre-exposed to MET (peak %VC 91, P= 0.043) and VAN (peak %VC 94, P= 0.041). Conclusions: ORI had enhanced activity against CD SP compared to MET and VAN using three experimental procedures. ORI (but not MET and VAN) inhibitory activity against SP persisted after washing and filtration. These data are consistent with possible binding of ORI to CD SP. The potential therapeutic benefit of increased activity of ORI against CD SP warrants further study.