Managing serious Gram positive infection 2018 Matthew Dryden MD Director of Infection Royal Hampshire County Hospital, Winchester University of

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1 Managing serious Gram positive infection 2018 Matthew Dryden MD Director of Infection Royal Hampshire County Hospital, Winchester University of Southampton

2 Disclosures Consulting or lecture honoraria from Bayer, Wyeth, Janssen-Cilag, Pfizer, Astra Zeneca, Cubist, Merk, Motif Bio, Matoke Investigator on antibiotic trials for Bayer, Pfizer, Basilea, Wyeth, Astra Zeneca Recent General Secretary of British Society of Antimicrobial Chemotherapy

3 Post operative suppuration necessary to healing or a complication? My delight may be conceived when there were revealed to me beautiful tangles, tufts and chains of round organisms in great numbers, which stood out clear and distinct among the pus cells and debris... Alexander Ogston 1880

4 What Gram positives are we concerned about? MRSA, hvisa, VRSA Coagulase negative staphylococci Strep pneumoniae Other streptococci Enterococci, VRE

5 Problems with health care infections driven by antibiotic selection Community acquired. MRSA, hvisa, VRSA, cmrsa Coagulase negative staphylococci Strep pneumoniae Other streptococci Enterococci, VRE

6 MRSA as % of invasive S. aureus isolates

7 2014 invasive isolates VRE Macrolide res Strep. pneumonia

8 Variability in MRSA infections and pathogenicity Number of death certificates mentioning Staphylococcus aureus: by methicillin resistance, England and Wales, Number of PVL SA strains identified by the HPA s Staphylococcus Reference Unit2 Patients becoming more complex, vulnerable and harder to predict likely microbial aetiology3 HPA, Health Protection Agency; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus; PVL, Panton-Valentine leucocidin; SA, Staphylococcus aureus. 1.Office for National Statistics, Deaths involving MRSA: 2008 to Available at: Accessed March 2018; 2. The National Archives. Heath Protection Report 2011;5(7). Available at: Accessed February 2018; 3. Dryden, M. Personal opinion.

9 Intercontinental Exchanges of CA-MRSA Clones ST8, ST59, ST80, ST30 DeLeo FR, et al. Lancet 2010; 375:

10 Antimicrobial resistance in community acquired staphylococcal soft tissue infection Kearns A on behalf of the Community Skin Infection (CSI) study group Public Health England, Colindale, London, NW9 5EQ, UK

11 Clinical issues with invasive staphylococcal infection Which antibiotic? One drug or two? Duration of treatment Source control Test of cure

12 Staphylococcal bacteraemia Most patients should have TTE Consider imaging bone and back pain Failure to identify vertebral osteomyelitis or epidural abscess or BE can lead to catastrophic consequences Repeat BC on day 3

13 When might a TTE be avoided? Nosocomial or health care-associated acquisition of bacteremia Sterile follow-up blood cultures within four days after the initial positive culture No permanent intracardiac device No hemodialysis dependence No clinical signs of endocarditis or secondary foci of infection Removable focus of infection removed promptly, if present Defervescence within 72 hours of initial positive blood culture

14 Dual therapy? Rifampicin 700 adults with S. aureus bacteremia randomized to treatment with standard therapy plus rifampin (600 or 900 mg per day, orally or intravenously) or placebo, no significant difference in mortality or bacteriologic failure was observed after 12 weeks (17 versus 18 percent; hazard ratio 0.96, CI ). Lancet. 2018;391(10121):668. Gentamicin 48 patients with MSSA native valve endocarditis. Although patients who received nafcillin plus gentamicin for the first two weeks of therapy had more rapid clearing of bacteremia than those who received nafcillin alone, cure rates were comparable and combination nafcillin and gentamicin therapy was associated with a higher incidence of renal dysfunction. Ann Intern Med. 1982;97(4):496 Toxin related Gram positive infections staph PVL or GAS Role of contact tracing Decolonisation

15 PVL (MSSA or MRSA) Panton-Valentine Leukocidin (PVL) is a toxin produced by some strains of Staphylococcus aureus. The toxin can destroy white blood cells and cause extensive tissue necrosis and severe infection. PVL infections remain uncommon in the UK but are likely to become more common in the future PVL infection can cause recurrent deep, painful abscesses It should be considered when the severity and extent of lesions is greater than expected, when close contacts have similar lesions, if frequent relapses occur and if there is poor response to antibiotics Pets have been implicated in transmission PVL is not identified by most laboratories Treatment is with drainage + antibiotics eg a two - four week course of flucloxacillin + clindamycin or linezolid, plus five days of chlorhexidine wash and nasal mupirocin to clear the lesions completely.

16 Amount of PVL Effect of antibiotics on staphylococcal PVL production Dumitrescu O, et al. Antimicrobial Agents And Chemotherapy. 2007,

17 Odds of death after bacteraemia 441 cases of S aureus bacteraemia, 130 (29%) patients died within 30 days. The death rate was 34% (76/227) for MRSA and 27% (58/214) for MSSA Wylie et al BMJ Aug 5; 333(7562): 281. doi: /bmj F

18 Duration of treatment for uncomplicated bacteraemia 14 days from last positive BC Infective endocarditis has been excluded via echocardiography. No indwelling devices (such as prosthetic heart valves or vascular grafts) are present. Follow-up blood cultures drawn two to four days after initiating intravenous antistaphylococcal therapy and removing the presumed focus of infection (if present) are negative. The patient defervesced within 48 to 72 hours after initiating intravenous antistaphylococcal therapy and removal of the presumed focus of infection (such as debridement of soft tissue infection or intravascular catheter removal). There is no evidence of metastatic staphylococcal infection on physical examination.

19 Longer treatment required for: Infective endocarditis Cardiac device infection Osteomyelitis Prosthetic joint infection Septic arthritis Meningitis Pneumonia

20 Vanc Teic

21 Higher Teicoplanin MIC is Associated With Unfavourable Outcome and Increased Mortality In a retrospective cohort study of 101 bacteraemia patients, 56 had a lower teicoplanin MIC ( 1.5 mg/l) for MRSA and 45 had a higher MIC (>1.5 mg/l) for MRSA % of patients P<0.001 P=0.022 MIC 1.5 µg/ml vs >1.5 µg/ml influences clinical outcome determined by E-test; OR: ( ; P=0.001) * Clinical cure or improvement; Unfavourable outcome: clinical failure = inadequate response to teicoplanin therapy (e.g. resistance to teicoplanin, worsening, recurrence or new onset of signs and symptoms requiring change of antibiotic; positive MRSA blood culture at EOT Chang HJ, et al. JAC 2012;67:

22 Retrospective 30-day in-hospital mortality rate in methicillinsusceptible Staphylococcus aureus bacteraemia Treatment regimen Number of patients Mortality naf/cef only 38 3% (1/38) vanc plus naf/cef 135 7% (10/135) vanc only 94 20% (19/94) (chi-square test for trend p<0.01) Association Adjusted hazard ratio and 95% Confidence Interval Receipt of nafcillin or cefazolin vs. vancomycin alone 0.21 (0.09, 0.47) Switch from vancomycin to nafcillin or cefazolin vs. remaining on vancomycin alone 0.31 (0.10, 0.95) Schweizer et al. BMC Infectious Diseases 2011; 11:279.

23 Vancomycin vs. β-lactams for MSSA bacteraemia: Cohort, 7 years all cases No. cases No. deaths Deaths, % p Vanco β-lactam Case control matched for underlying status Vanco β-lactam <0.001 Kim et al. AAC 2008;52:192 7

24 Antibiotic Company Iclaprim Motifbio Delafloxacin Melinta Year Approved 2019? 2017 Indication Drug Class Spectrum Advantages Disadvantages dihydrofolate Gram +& Alternative class Rapidly bactericidal Not approved yet! ABSSI/CAP reductase inhibitor Gram - Gram + & IV /oral Favourable MICs Tendonitis etc fluoroquinolone ABSSSI Gram Dalbavancin Actavis 2014 ABSSSI lipoglycopeptide Gram + Single dose intravenous therapy Red man syndrome Renal adj Oritavancin Medicines Company 2014 ABSSSI lipoglycopeptide Gram + Single dose intravenous therapy Artificially prolong aptt, infusionrelated reactions?same as linezolid Tedizolid Merck 2014 ABSSSI oxazolidinone Gram + Telavancin Theravance 2013 ABSSSI and lipoglycopeptide Gram + cephalosporin Gram + & HABP / VABP Ceftaroline Pfizer (AZ) 2010 ABSSSI/CABP GramTigecycline Pfizer 2005/6 csssi IAI glycylcycline Gram + & Once a day oral formulation; 6 day treatment for ABSSSI Dual mechanism of action, inhibiting cell wall synthesis and cell membrane function, active against VISA and hvisa Potent activity against MRSA and Streptococci pneumoniae isolates, including drug resistant strains QTc prolongation, potential birth defects Mortality with chr renal failure Same as B lactams Once daily Efficacy v MDR Concerns in bacteraemia Familiarity - 14 years of clinical experience; generic pricing Familiarity - 17 years of clinical experience; oral formulation available; generic pricing Decreased efficacy with moderate renal impairment GramDaptomycin Merck (Cubist) 2003 csssi, S. aureus bacteremia cyclic lipopeptide Gram + Linezolid Pfizer 2000 csssi, CAP, HABP, VRE oxazolidinone Gram + Vancomycin Eli Lilly 1958 csssi lipoglycopeptide Gram + Familiarity - 59 years of clinical experience; generic Serotonin syndrome; adverse events in renal impairment; hypoglycemia if coadministered with insulin/oral hypoglycemics Nephrotoxicity risk with higher doses; ototoxic

25 A case for a b-lactam? Ceftaroline Effective Bactericidal Well tolerated low toxicity No levels required Easy to administer Standard of care vs. MSSA infections Broader cover Vulnerable patients with co-morbidities Early therapeutic response

26 Designed to be different from other cephalosporins 26 Zhanel GG et al. Drugs. 2009;69:

27 Competition assays with ceftaroline for PBP2a of MRSA Moisan et al. JAC 2010;65:

28 Ceftaroline Indications:1 Acute bacterial skin and skin structure infections (ABSSSI) Community-acquired bacterial pneumonia* Efficacy: Bactericidal activity against MRSA, multidrug-resistant Streptococcus pneumonia and some Gram-negative organisms (broad-spectrum)2 Clinical cure in csssi3 Ceftaroline 91.1% vs vancomycin/aztreonam 93.3% (MRSA csssi: 95.1% vs 95.2%) Resistance:4 Ceftaroline-resistant MRSA isolates have been identified in Europe and Asia with MICs between 4 and 8 µg/ml Safety:1 Serious hypersensitivity reactions have been reported In pooled phase 3 trials, direct Coombs test seroconversion occurred in 10.8% of ceftarolinetreated patients vs 4.4% of comparator drugs * Ceftaroline is not indicated for treatment of CAP caused by MRSA 1. TEFLARO Prescribing Information. Forest Laboratories, 2013; 2. Girish C, et al. J Pharmacol Pharmacother 2011;2: ; 3. Corey GR, et al. J Antimicrob Chemother 2010;65(Suppl 4):iv41-51; 4. Long SW, et al. Antimicrob Agents Chemother 2014; 58:

29 Ceftaroline 600 q12h dosing is optimised for time-dependent pharmacodynamics Mean free drug serum concentration-time profile1 Ceftaroline free drug concentration, mg/l S. aureus MIC90 1 µg/ml2 1.0 S. pneumoniae MIC mg/l Keel RA et al. Antimicrob Agents Chemother. 2011;55: Flamm RK et al. Clin Microbiol Infect. 2012;18(suppl S3): Farrell DJ et al. Clin Microbiol Infect. 2012;18(suppl S3): Time, h

30 CANVAS 1 and 2: pooled comorbidity data DM PVD Ceftaroline fosamil No. of patients cured/total no. of patients Difference, % (95% CI) PP-ZFO-EUR-0031 Date of preparation: March (%) of patients (%) of patients Integrated analysis: clinical cure rates by underlying comorbidity (CE population at TOC visit) 96/ / (-12.2 to 5.0) Vancomycin plus aztreonam No. of patients cured/total no. of patients Difference, % (95% CI) 80/90 75/ (-10.0 to 9.7) CANVAS, Ceftaroline versus Vancomycin in Skin and Skin-Structure Infection; CE, clinically evaluable; CI, confidence interval; cssti, complicated skin and soft tissue infection; DM, diabetes mellitus; PVD, peripheral vascular disease; TOC, test of cure. Corey R, et al. Clin Infect Dis 2010;51:

31 Early response data: overall response Clinical responders at Day 4 (%) FOCUS 1 and 2 Early clinical response at Day 4 in the EmMITT population 100 (N=309) FOCUS 1 Ceftaroline 600 mg FOCUS 2 FOCUS 1&2 Integrated Ceftriaxone 1 g FOCUS 1 responder* FOCUS 2 responder* FOCUS 1 and 2 responder* Ceftaroline (600 mg), n/n (%) 49/69 (71.0) 58/85 (68.2) 107/154 (69.5) Ceftriaxone (1 g), n/n (%) 41/72 (56.9) 51/83 (61.4) 92/155 (59.4) Neither FOCUS trial established that ceftaroline was statistically superior to ceftriaxone in terms of clinical response rates at Day 4 The suggestion of benefit seen with ceftaroline at Day 4 does not imply an improved overall end outcome *Responder defined by clinical stability and improvement of symptoms. EmMITT, exploratory microbiological modified intent-to-treat; FOCUS, Ceftaroline Community-Acquired Pneumonia Trial Versus Ceftriaxone in Hospitalized Patients. Eckburg PB, et al. Infect Dis Clin Pract 2012;20:

32 Early response data: by pathogen FOCUS 1 and 2 Early clinical response by pathogen at Day 4 in the EmMITT population (N=309) S. pneumoniae MSSA H. influenzae K. pneumoniae E. coli Ceftaroline (600 mg), n/n (%) 54/74 (73.0) 14/24 (58.3) 16/21 (76.2) 14/18 (77.8) 4/12 (33.3) Ceftriaxone (1 g), n/n (%) 42/75 (56.0) 17/31 (54.8) 20/28 (71.4) 7/12 (58.3) 7/13 (53.8) There was a high rate of early response, irrespective of pathogen The suggested benefit at Day 4 does not imply an improved overall end outcome EmMITT, exploratory microbiological modified intent-to-treat; MSSA, methicillin-sensitive Staphylococcus aureus. Eckburg PB, et al. Infect Dis Clin Pract 2012;20:

33 CAPTURE Registry: real-world data in patients with cssti and comorbidities Initial 1-year results (data collected from August 2011 to August 2012) reported on 647 patients treated for cssti High clinical success rates were observed for ceftaroline fosamil overall (85%) and across patient groups, including patients with comorbidities 100 Pathogens All pathogens MRSA MSSA Clinical success rate (%) Clinical success rate (%) Comorbidities DM PVD Obesity CAPTURE, Ceftaroline Assessment Program and Teflaro Utilization Registry; cssti, complicated skin and soft tissue infection; DM, diabetes mellitus; PVD, peripheral vascular disease; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus. Santos PD, et al. J Chemother 2013;25:341 6.

34 CAPTURE Registry: real-world data in patients with CAP and comorbidities Initial 18-month results (data collected from August 2011 to February 2013) reported on 398 patients treated for CAP High clinical success rates were observed for ceftaroline fosamil overall (79%) and across patient subgroups (those with comorbidities and different pathogen types) Clinical success rates were highest in patients with Streptococcus pneumoniae infections and CAP patients with structural lung disease or congestive heart failure Comorbidities and pathogen types Clinical success rate (%) All Structural CongestiveStroke All patients lung heart failure S. aureus disease MRSA MSSA All S. pneumoniae NOTE: There are no clinical data to support the use of ceftaroline fosamil for MRSA in CAP caution is advised when treating such patients (Zinforo SmPC, 2017). Clinical success is defined as the following: clinical cure with no further need for antibiotic therapy or clinical improvement with switch to oral agents at the end of ceftaroline fosamil treatment. CAP, community-acquired pneumonia; CAPTURE, Ceftaroline Assessment Program and Teflaro Utilization Registry; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillinsusceptible Staphylococcus aureus. Ramani A, et al. J Chemother 2014;26:

35 Emergence of High-level Ceftaroline Resistance in MRSA Isolates in the USA Caused by PBP2a Mutations Natural history of 6 MRSA clinical isolates collected from the blood and respiratory tract of a 20-year-old cystic fibrosis patient over 154 days with their PBP2a active-site amino acid mutations and ceftaroline MICs Site Sputum Sputum Sputum Sputum Blood Sputum Isolate no PBP2a amino acid changes Y446N E447K Y446N Y446N E447K E239K Y446N E447K MIC (mg/l) > >32 >32 Days post initial admission High-level ceftaroline-resistance (MIC >32 mg/l) in MRSA was detected in isolates collected from a cystic fibrosis patient in the USA Two amino acid-altering mutations (Y446N and E447K) uniquely present in the ceftaroline-binding pocket of PBP2a were found to be responsible for ceftaroline resistance Long SW et al. Antimicrob Agent Chemother 2014;58:

36 Combination treatment Ceftaroline restores daptomycin activity against daptomycinnonsusceptible vancomycin-resistant Enterococcus faecium. Sakoulas G, Rose W, Nonejuie P, et al. Antimicrob Agents Chemother 2014; 58:1494.

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38 Use off licensed indications CNS Orthopaedic Endocarditis

39 Oxazolidinones Linezolid Tedizolid

40 Oxazolidinones Wide experience now: IV and oral Reduction in IV lines and duration of hospital stay Patient mobilisation Clinical role: oral and prolonged treatment;?superior in pneumonia and MRSA cssti Other indications? Caveat: Bone marrow suppression and neuropathy for linezolid Tedizolid advantages over linezolid: pk, lower dose, safer, short course

41 Tedizolid Linezolid Tedizolid Has Increased Binding Activity versus Linezolid Greater interactions of tedizolid translates into higher potency Locke JB, et al. AAC 2010;54:

42 Tedizolid Use was Associated with Overall Reduced Risk of Myelosuppression Patients with low platelet counts (%) Patients with reduced platelet counts during the entire study period P= Tedizolid 200 mg, 6 days Linezolid 600 mg, 10 days P= Tedizolid was associated with a significantly lower risk of developing thrombocytopenia Tedizolid is not known to increase the risk of anemia, leukopenia, or pancytopenia LLN = lower limit of normal; N1 = any post-baseline observation through last dose of active drug. Prokocimer P, et al. JAMA 2013;309(6): Shorr EF, et al. AAC 2014; doi: /aac Moran G, et al. LID 2014;14(8):

43 Iclaprim Iclaprim Motifbio 2019? ABSSI/CAP dihydrofolate Gram +& reductase Gram - Alternative class Rapidly bactericidal Not approved yet! inhibitor Huang D et al. A Pooled Analysis of the Phase 3 REVIVE Trials: Randomized, Double-blind Studies to EValuate the Safety and Efficacy of Iclaprim Versus Vancomycin for treatment of Acute Bacterial Skin and Skin Structure Infections IJAA

44 Iclaprim

45 Daptomycin Daptomycin Merck (Cubist) 2003 Dapto non-inferior to anti-staph pen + gent or vanc + gent for staph bacteraemia. Fowler VG et al N Engl J Med. 2006;355(7):653. csssi, S. aureus bacteremia cyclic lipopeptide Gram + Familiarity - 14 years of clinical experience; generic pricing Decreased efficacy with moderate renal impairment

46 Trend for Lower Microbiological Success for Daptomycin vs Comparators for MRSA SSTIs Microbiological success rate for daptomycin was slightly lower vs comparator drugs* (3 RCTs, n=203; OR 0.91, 95% CI 0.77 to 1.06; p=0.10) *Vancomycin, semisynthetic penicillins, teicoplanin Fowler VG et al N Engl J Med. 2006;355(7):653. Wang SZ et al. BMJ Open 2014;4:e

47 Significantly Higher Creatinine Phosphokinase Elevation for Daptomycin vs Comparators in SSTI Patients Creatinine phosphokinase elevations were significantly more common for daptomycin vs comparator agents* in patients with SSTIs (5 RCTs, n=1521; OR=1.95, 95% CI 1.04 to 3.65, p=0.04) Incidence of treatment-emergent adverse events (AEs) was comparable or daptomycin vs comparators (5 RCTs, n=1521; OR=1.06, 95% CI 0.71 to 1.59, p=0.76) No significant differences were observed for discontinuation due to AEs and all-cause mortality between the daptomycin and comparator groups (6 RCTs, n=1710; OR=0.76, 95% CI 0.46 to 1.10, p=0.12) *Vancomycin, semisynthetic penicillins, teicoplanin Fowler VG et al N Engl J Med. 2006;355(7):653. Wang SZ et al. BMJ Open 2014;4:e

48 VRE infections: There are limited options for treatment of serious VRE infections. Monotherapy with daptomycin or tigecycline or linezolid may be sufficient in some cases All strains (60) were susceptible to LZD and DPT (MIC(90), 4 and 2μg/ml, respectively) and only a single strain presented intermediate susceptibility to tigecycline (MIC(90), 0.25μg/ml). 30% of strains were resistant to Q-D (MIC(90), 4μg/ml), and CFT was constantly inactive (MIC(90), 64μg/ml). Finally, TLV showed low-level MICs (MIC(90), 0.5μg/ml) against vanb-positive isolates but not against vana-positive isolates (MIC(90), 8μg/ml). Med Mal Infect 2011; 41:405.

49 VRE infections Combination therapy is often indicated for severe or complicated infections such as endocarditis. Several antibiotic combinations have been used in isolated case reports with some efficacy, including the following: high-dose ampicillin with an aminoglycoside, ampicillin with ceftriaxone or imipenem, high-dose daptomycin with ampicillin and gentamicin or with gentamicin and rifampin daptomycin with tigecycline quinupristin-dalfopristin with high-dose ampicillin doxycycline and rifampin linezolid with tigecycline limited efficacy, limited susceptibility, and extensive toxicities with many of these agents and combinations present barriers to effective treatment. oritavancin has been shown to have in vitro activity against some isolates of VRE prolonged course of oritavancin in the treatment of a serious VRE infection, prosthetic valve endocarditis. Ceftaroline restores daptomycin activity against daptomycin-nonsusceptible vancomycinresistant Enterococcus faecium. Sakoulas G, Rose W, Nonejuie P, et al. Antimicrob Agents Chemother 2014; 58:1494.

50 Dalbavancin / Oritavancin Dalbavancin Actavis 2014 ABSSSI lipoglycopeptide Gram + Oritavancin Medicines Company 2014 ABSSSI lipoglycopeptide Gram + Single dose intravenous therapy Single dose intravenous therapy Suitable for outpatient ID offices? Non-compliant patients Saves in patient days Oritavancin is a novel lipoglycopeptide with activity against Gram-positive organisms including streptococci, methicillin-resistant Staphylococcus aureus, vancomycin-resistant S aureus (VRSA), and vancomycin-resistant enterococci (VRE) Red man syndrome Renal adj Artificially prolong aptt, infusionrelated reactions

51 Dalbavancin +/- beta lactams a. - hvisa, b.- hvisa DNS, c.- VISA DNS, d.- VISA DNS Xhemali et al JAC 2018 in press

52 Delafloxacin a novel anionic fluoroquinolone Enhanced antimicrobial activity against both gram-positives, gram-negatives, atypicals and anaerobic bacteria Active against MSSA and MRSA Available as IV and oral formulation Improved safety profile 52

53 In vitro activity of delafloxacin against FQs-resistant S. aureus Almer et al., 2004: 71 strains. Origin: US Nilius et al., 2003: 19 strains. Origin: US Compound MIC50 (µg/ml) MIC90 (µg/ml) Compound MIC50 (µg/ml) MIC90 (µg/ml) Delafloxacin Delafloxacin Trovafloxacin 1 2 Levofloxacin Levofloxacin 8 16 Trovafloxacin 2 8 Ciprofloxacin Ciprofloxacin Moxifloxacin 4 8 Gatifloxacin 8 16 Gemifloxacin

54 Cardiac Safety Some FQs can precipitate episodes of Torsades de Pointes (TdP), a life threatening or even fatal episodes of ventricular arrhythmia. Some FQs prolong the QT interval by blocking voltage-gated potassium channels, especially the rapid component of the delayed rectifier potassium current IKr, expressed by herg. Concerns over the potential for proarrhythmia have prompted the withdrawal of grepafloxacin from the market. According to the available case reports and clinical studies, moxifloxacin carries the greatest risk of QT prolongation and should be used with caution in patients with predisposing factors for TdP. Although gemifloxacin, levofloxacin, and ofloxacin are associated with a lower risk of QT prolongation compared with moxifloxacin, they should also be used with caution in patients at risk for QT prolongation. Unlike other FQs, delafloxacin did not affect QT/QTc interval 54

55 Delafloxacin Clinical Development Program 2658 subjects exposed to delafloxacin 30 studies 23 Phase I studies 7 Phase II/III studies N=1158 N= PK studies N=881 1 photosens.study Oral Delafloxacin N=52 Phase II 2 studies in ABSSSI N=406 Phase II 2 studies other indications (CAP* and ABECB**) N= studies renal &hepatic impairment N=83 1 DDI study N=22 1 QT interval study Oral delafloxacin N=68 1 TQTc interval study IV delafloxacin N=52 Phase III 2 studies in ABSSSI N=1510 Phase III 1 study other indication (uncomplicated gonhorrea) N=460 *Community-acquired pneumonia; ** Acute bacterial exacerbation of chronic bronchititis 55

56 Summary Epidemiology of Gram positive infection is changing Patients with invasive staphylococcal disease need careful assessment and management Pathogenic strains eg PVL are emerging Wide variety of new antimicrobial agents (unlike for Gram negatives). All non inferior to comparators in registration trials All of these are welcome and have a clinical role to play.

57 Thank you