MRSA across roads: new antibiotic options

MRSA across roads: new antibiotic options Javier Garau, MD, PhD University of Barcelona 18th Infection and Sepsis Symposium, BUGS, MUGS AND DRUGS, Porto, 27th February 2013

DISCLOSURES I have accepted grants, speaking invitations and conference invitations from Astellas, AstraZeneca, Bayer, GSK, Novartis, Pfizer and Vifor Pharma I have had recent or ongoing consultancy with Astellas, AstraZeneca, Bayer, Durata, GSK, Janssen, Novartis, Pfizer, Theravance and Vifor Pharma

Current treatment options for MRSA infections and their limitations Agents with anti-mrsa activity include: Vancomycin Linezolid Teicoplanin Tigecycline Daptomycin Co-trimoxazole Telavancin Tedizolid Ceftaroline Ceftobiprole Oritavancin Dalbavancin Limitations of current therapy: Progressive limitations of vancomycin Daptomycin not effective in pneumonia Non-susceptible daptomycin MRSA after glycopeptide exposure Plasmid-mediated resistance to linezolid Poor outcomes in left-sided infective endocarditis

The Clinical Significance of Vancomycin Minimum Inhibitory Concentration in Staphylococcus aureus Infections: A Systematic Review and Meta-analysis Quality of reporting of meta-analysis profile showing flow of studies included in the meta-analysis. van Hal SJ et al. CID 2012

Vancomycin MIC was significantly associated with treatment failure irrespective of source of infection or MIC methodology Mantel-Haenszel analysis of events denoting S. aureus vancomycin treatment failure (irrespective of definition, source of infection and MIC methodology used) comparing high vancomycin MIC (>1.5 lg/ml) with low MIC (<1.5 lg/ml) infections. Squares indicate point estimates, and the size of the square indicates the weight of each study. Abbreviations: CI, confidence interval; M-H, Mantel-Haenszel; MIC, minimum inhibitory concentration. van Hal SJ et al. CID 2012

The Clinical Significance of VAN MIC in S.aureus Infections: A Systematic Review and Meta-analysis. Conclusion Patients with MRSA BSI and higher vancomycin MIC values by Etest have a higher likelihood of mortality and treatment failure. The cause is not well defined; most likely reflects an interaction among pathogen-specific variables, host responses, and suboptimal vancomycin exposure. Non vancomycin anti-mrsa therapies should be considered for patients with MRSA BSI with high vancomycin MIC, especially for values >2.0 μg/ml by Etest. There are currently no data to support better survival rates with alternative antibiotics for MRSA BSI. van Hal SJ et al. CID 2012

Differential characteristics of patients with bacteremia caused by MSSA strains with a MIC to vancomycin >1.5 μg/ml compared with <1.5 μg/ml by Etest* *Values are no. (%) except as indicated. MSSA, methicillin-susceptible Staphylococcus aureus; IV, intravenous. Antistaphylococcal -lactams refers to parenteral cloxacillin, cefazolin, amoxicillin-clavulanate, piperacillin-tazobactam, or imipenem/meropenem. Including non -lactam antibiotics with in vitro activity against MSSA (mostly levofloxacin, moxifloxacin or, clindamycin). Delay since isolation of MSSA in blood cultures. Removal of catheter in the first 48 hours since isolation of MSSA in blood cultures. Aguado JM et al. EID 2011

Antibiotic choice may not explain poorer outcomes in patients with S aureus bacteremia and high VAN MIC concentrations. We assessed 532 patients with SAB from 8 hospitals. All patients with MRSA bacteremia were treated with VAN, and patients with MSSA bacteremia received either flucloxacillin or VAN. Increasing VAN MIC was associated with increased mortality in VAN-treated patients. However, even in patients with MSSA bacteremia treated with flucloxacillin, mortality was also higher if the vancomycin Etest MIC of their isolate was >1.5 μg/ml, compared with those with lower MIC isolates (26.8% vs 12.2%; P <.001). After adjustment in a multivariate model, age, hospital-onset SAB and vancomycin MIC were independently associated with mortality, but methicillin resistance and antibiotic choice were not. Holmes NE et al. JID 2011

In Vivo Efficacy of Tedizolid, Linezolid and Vancomycin The antibacterial efficacies of tedizolid phosphate (TZD), linezolid and vancomycin regimens simulating human exposures at the infection site against MRSA were compared in an in vivo mouse pneumonia model Immunocompetent BALB/c mice were orally inoculated with one of three strains of MRSA Drug regimens used produced epithelial lining fluid exposures comparable to human exposures observed following intravenous regimens of 200 mg Q24 TZD, 600 mg Q12 linezolid and 1g Q12 VAN Tessier PR et al. AAC 2012

Comparative In Vivo Efficacy of Epithelial Lining Fluid Exposures of Tedizolid, Linezolid and Vancomycin for MRSA in a Mouse Pneumonia Model ELF concentration time course of 20 mg/kg Q24 tedizolid, 120 mg/kg 454 Q12 LZD and 25 mg/kg Q12 VAN over 24h in mice. Changes in bacterial density after 24h for tedizolid, LZD, and VAN treated groups (bar level represents average change in log10 CFU of group from initial density, error bars 1 SD). = Significant different from tedizolid and LZD, p 0.016. = Significantly different from LZD, p 0.026. The VAN regimen was less protective than either the TZD or linezolid regimens, with overall survival of 47 61.1% versus 94.7% and 89.5%, respectively. Tessier PR et al. AAC 2012

In vitro activity of dalbavancin, oritavancin, telavancin and vancomycin against Gram-positives Zhanel GG et al. Drugs 2010

Chemical structure of ceftaroline Adapted from Zhanel GG et al. Drugs 2009

Comparative in vitro MIC 90s of Ceftaroline and Other Comparators against Gram-Positive Bacteria a Ceftaroline MIC breakpoints areas follows: S. aureus < 1 for skin isolates only, S. pneumoniae < 0.25 lg/ml for community-acquired bacterial pneumonia isolates only, Streptococcus pyogenes < 0.015 for skin isolates only, and Streptococcus agalactiae <0.03 lg/ml for skin isolates only. Saravolatz LD et al. CID 2012

Activity of Ceftaroline and Comparator Antimicrobial Agents Against 3329 Streptococcus pneumoniae Isolates Recovered in the United States During 2008 2010 a As defined by CLSI criteria. b FDA break points were applied when available: S. pneumoniae, susceptible 0.25 μg/ml; no resistance category. c Penicillin parenteral (non-meningitis), as defined by the CLSI. d Penicillin (oral penicillin V), as defined by the CLSI. e FDA break points were applied when available Farrell DJ et al. CID 2012;55(S3):S206 14

Binding affinities of ceftaroline, cefotaxime, and ceftriaxone for pneumococcal PBPs Among 3 PenR S. pneumoniae, ceftaroline had a high affinity for PBP2X, a primary target for cephalosporin PBP binding activity, and high affinities for PBP2B and PBP1B, are also major targets for PBP binding activity of cephalosporins. 15 Kosowska-Shick K et al. AAC 2010

MIC50/MIC90 and MBC50/MIC90 values for all antimicrobials tested for their activities against CA- MRSA,VISA, and hvisa Saravolatz L et al. AAC 2010

In vitro activity of ceftaroline against 623 diverse strains of anaerobic bacteria Against gram-positive strains, the activity of ceftaroline was similar to that of amoxicillin/clavulanate and 4 to 8 times greater than ceftriaxone. Against gram-negative organisms, ceftaroline showed good activity against β- Lactamase negative strains, Citron DM et al. AAC 2010

Comparative in vitro MIC 90s of Ceftaroline and Other Comparators against Gram-negative Bacteria Ceftaroline breakpoints are as follows: Enterobacteriaceae sensitive < 0.5, and resistant > 2 lg/ml for CABP and skin isolates. Haemophilus influenzae < 0.12 lg/ml for CABP isolates only Saravolatz LD et al. CID 2012

1. f % T > MIC targets of 35, 44 and 51 for CPT are associated with net bacterial stasis and a 1- and 2-log 10 CFU reduction from baseline of SP, respectively, based on data from a neutropenic murine infection model. Van Wart SA et al. 2012 ICAAC

Ceftaroline PK/PD An in vitro pharmacodynamic study (hollow fibre model) examining simulated regimens of 600 mg of ceftaroline every 12 h and 600 mg of ceftaroline every 8 h. For the studied strains with an MIC of 0.5 mg/l, the every 12 h regimen produced a free T>MIC of 83%, whereas the every 8 h regimen produced a free T>MIC of 100%. At an MIC of 1 mg/l, the Q 8 h regimen produced a free T>MIC of 92%. In severe infections such as endocarditis, the more aggressive dose of 600 mg every 8 h to ensure an optimal percentage T>MIC is recommended. Vidaillac et al. Int J Antimicrob Agents 2010;. Ho TT et al. JAC 2012

In Vivo Efficacy of Ceftaroline, Compared with Linezolid and Vancomycin against MRSA and VISA in a Rabbit Endocarditis Model Bacterial titers in vegetations after 4 days of treatment Ceftaroline regimen mimicking the human dose of 10 mg/kg q 12h (600 mg q12h) Linezolid regimen mimicking the human dose of 10 mg/kg q12h (600 mg q12h) Vancomycin administered by a constant IV infusion in order to reach a steady-state 20 X MIC in serum Jacqueline C et al. AAC 2007

In Vivo Activity of Ceftaroline, against Vancomycin-S and -R Enterococcus faecalis Strains in a Rabbit Endocarditis Model Bacterial titers in vegetations after 4 days of treatment EF 12704 is susceptible to vancomycin (Vans), and EF NJ1 exhibits a Vanr VanA phenotype. The MICs of ceftaroline, linezolid, and vancomycin for strains EF 12704 and EF NJ1 were 2 and 1 mg/liter, 2 and 1 mg/liter, and 2 and 256 mg/liter. Jacqueline C et al. AAC 2009

Efficacy of ceftaroline in the treatment of experimental MRSA acute osteomyelitis. Rabbit model of acute osteomyelitis. Efficacy assessed following 4 days of treatment by colony counts of infected bone tissues (joint fluid, femoral bone marrow and bone). Vancomycin was ineffective against the MRSA strain and poorly active against GISA infections in this model. Ceftaroline and linezolid demonstrated significant activity in bone marrow and bone, and were significantly better than vancomycin treatment. Ceftaroline was the only drug to exhibit significant activity against MRSA in infected joint fluid. Jacqueline C et al. JAC 2010

FOCUS 1 & 2: Study design Phase III, multicentre, randomised, double-blind, comparative Multinational: Africa, Asia, Eastern Europe, Western Europe, Latin America and USA Port III and IV severity classification 1:1 randomisation End of treatment (EOT) Patients aged 18 yr with CAP and POR risk class III/IV requiring hospitalisation Ceftaroline 600 mg IV q12h (400 mg q12h for moderate renal impairment) (5 7 days of therapy) Ceftriaxone 1 g IV q24h 10% non-inferiority design TOC (Test of cure) 8 15 days after EOT LFU (Late follow-up) 21 35 days after EOT All patients in FOCUS 1 received 2 doses (24 h course) of adjunctive clarithromycin (500 mg q12h) starting with first dose of study drug File TM et al. Clin Infect Dis. 2010;51:1395 1405.

Disposition of patients in studies of ceftaroline versus ceftriaxone in the treatment of community-acquired pneumonia (CAP) MITTE population, MITT patients with Pneumonia Outcomes Research Team (PORT) risk class III or IV; mmitte population, MITT patients who met minimum criteria for CAP of PORT risk class of III or IV and had >1 typical bacterial pathogen isolated. File TM et al. CID 2010

FOCUS 1 & 2: Baseline patient characteristics were similar and well balanced Ceftaroline 600 q12 N=580 File TM et al. Clin Infect Dis. 2010;51:1395 1405.

FOCUS 1 & 2: Severity of disease was higher than that studied in previous registration trials Ceftaroline 600 q12 N=580 File TM et al. Clin Infect Dis. 2010;51:1395 1405. File TM et al. J Antimicrob Chemother. 2011;66 (Suppl. 3):iii19 32. Low DE et al. J Antimicrob Chemother. 2011;66 (Suppl. 3):iii33 44.

S. pneumoniae was the most commonly isolated pathogen in the FOCUS trials At least one baseline pathogen was identified in 333 patients in the integrated analysis 293 patients (88.0%) had CAP caused by typical pathogens 40 patients (12.0%) had CAP caused by a mixed infection (typical and atypical pathogens) Most common pathogens Streptococcus pneumoniae (41.7%; 139 of 333 patients) Staphylococcus aureus (16.5%; 55 of 333 patients) Other pathogens isolated Haemophilus influenzae Haemophilus parainfluenzae Klebsiella pneumoniae Escherichia coli File TM et al. Clin Infect Dis. 2010;51:1395 1405.

Clinical Cure Rates by Study Population at the Test-of-Cure Visit Data are proportion (%) of patients, unless otherwise indicated. CE, clinically evaluable population; CI, confidence interval; FOCUS, Ceftaroline Community Acquired Pneumonia Trial versus Ceftriaxone in Hospitalized Patients; ME, microbiologically evaluable population; MITTE, modified intent-to-treat efficacy population; mmitte, microbiological modified intent-to-treat efficacy population. File TM et al. CID 2010

Clinical Cure Rates by the Most Common Baseline Pathogens at Test-of-Cure Visit, Integrated Microbiological Modified Intent-to-Treat Efficacy Population a MDRSP was defined in these studies as strains resistant to 2 antimicrobial classes of drugs, including penicillin, macrolides, tetracycline, fluoroquinolones, chloramphenicol, trimethoprim-sulfamethoxazole, and cephalosporins. b Patients with confirmed or suspected community-acquired pneumonia caused by MRSA at baseline were excluded from the study File TM et al. CID 2010

Clinical Cure Rates in Select Patient Subgroups, Integrated Clinically Evaluable Population a Represents crude difference as a result of small sample size. Pathogens causing bacteremia included Streptococcus pneumoniae (17 ceftaroline, 12 ceftriaxone; 1 MDR S. pneumoniae in each group), Staphylococcus aureus (3 ceftaroline, 4 ceftriaxone; 1 MRSA in ceftriaxone group), Haemophilus influenzae (1 in each group), and 1 Klebsiella pneumoniae in the ceftaroline group. One patient had bacteremia caused by S. pneumoniae and S. aureus. b Prior antibiotic treatment defined as receipt of a systemic antibacterial within <96 h before the first dose of study drug. Patients were permitted to receive a single dose of a short-acting antibiotic. Patients were not permitted to receive cefixime, ceftriaxone, fluoroquinolones, azithromycin, clarithromycin extended-release, dirithromycin, telithromycin, ertapenem, penicillin G benzathine procaine, doxycycline (200 mg), or minocycline extended-release. File TM et al. CID 2010

FOCUS 1 & 2: Ceftaroline demonstrates consistently high clinical cure rates across all relevant populations studied Favours ceftriaxone 1 g Favours cftaroline Favours ceftriaxone 1g Favours ceftaroline File TM et al. Clin Infect Dis. 2010;51:1395 1405.

FOCUS 1 & 2: FDA mandated post-hoc, retrospective analysis of Day 4 response: rationale for early response analysis Important changes in US FDA guidance on efficacy assessment in clinical trials of new antibiotics for the treatment of CAP occurred after the start of the FOCUS trials 1,2 Two particularly important changes were: 1,2 A revision in disease definition (from CAP to CABP ) Inclusion of a new requirement for an assessment of early clinical response at Day 4 Recommendation based on historical data indicating that antibacterial therapy showed a treatment effect on fever (acute symptoms) after approximately 72 96 hours in patients with predominantly pneumococcal pneumonia The FDA required that trials were analysed according to the new guidance 3 1. FDA. Guidance for industry community-acquired bacterial pneumonia: developing drugs for treatment, 2009. 2. Eckburg PB et al. Infect Dis Clin Pract. 2012 [epub June 2012]. 3. FDA. Briefing document. Anti-infective drugs advisory committee meeting, 2009.

FOCUS 1 & 2: rationale for early response analysis (continued) At the request of the FDA, a retrospective combined analysis of the FOCUS trials was performed using a clinical response endpoint at Day 4 in a subgroup of patients who met the FDA definition of CABP 2 To be a Day 4 responder, a patient had to: 2 Be in a stable condition, based on temperature, heart rate, respiratory rate, blood pressure, oxygen saturation, and mental status Show improvement in at least 1 of 4 symptoms present at baseline (cough, dyspnoea, pleuritic chest pain, sputum production) with worsening of none This early response analysis was performed in the exploratory microbiological modified intent-to-treat (EmMITT) population 2 1. File TM et al. Clin Infect Dis. 2010;51:1395 1405. 2. Eckburg PB et al. Infect Dis Clin Pract. [epub June 2012].

FOCUS 1 & 2: Response rates at Day 4 by pathogen Ceftaroline 600 q12 Eckburg PB et al. Infect Dis Clin Pract. [epub June 2012

CANVAS 1 and 2: Phase 3, Multicenter, Randomized, Double-Blind Studies to Evaluate the Safety and Efficacy of Ceftaroline versus Vancomycin plus Aztreonam in cssti Corey GR et al. CID 2010

CANVAS 1 and 2. Demographic and baseline characteristics (E-MITT population) Friedland HD et al. AAC 2012

Results of CANVAS Studies: Clinical Cure Rates for Clinically Evaluable Population at the Test-of-Cure Visit and for Subgroups According to Type of Infection and Presence of Diabetes Mellitus, Peripheral Vascular Disease, or Bacteremia File TM et al. CID 2012

Clinical response at different time points (E-MITT population) a Defined as a patient who exhibits cessation of lesion spread, is afebrile (temperature 37.6 C), and is not considered a clinical failure by the investigator on day 3. b Difference in clinical response rates, i.e., ceftaroline group comparator group. Differences for CANVAS 1 and 2 are crude differences; those for integrated CANVAS are weighted differences (stratified by study). c Calculated by a two-sided test of ceftaroline vs.comparator using the Miettinen and Nurminen method, with a Δ value of 0. A P value of 0.05 is suggestive of superiority of ceftaroline in day 3 response rate. Integrated analysis was stratified by study. Analyses were exploratory and conducted retrospectively. Friedland HD et al. AAC 2012

Clinical response rates in integrated CANVAS of patients positive for selected baseline isolates at day 3 (E-MITT population) a The table lists all Enterobacteriaceae isolates, including those producing ESBLs. One patient had both MSSA and MRSA and was counted once in the S. aureus total. Friedland HD et al. AAC 2012

Methicillin-resistant Staphylococcus aureus bacteraemia and endocarditis treated with ceftaroline salvage therapy a All MICs determined using Etest. b All ceftaroline infusions administered over 1 h. No ceftaroline therapeutic drug monitoring was performed. c Progression of ocular lesions while on therapy with vancomycin and appearance of new pulmonary nodules/lesions consistent with embolization. Ho TT et al. JAC 2012

Ceftarolin in MRSA bacteremia/endocarditis Pertinent clinical data 1. Mitral valve replacement on day 32 (day 13 of ceftaroline). Culture and histopathology of the valve, negative for MRSA. The patient completed 6 weeks of ceftaroline 2. TEE: 1.0 1.0 cm vegetation mitral papillary muscle; vancomycin changed to a 3.5 g continuous infusion targeting serum concentrations of 20 30 mg/l. After 15 days of persistent MRSA bacteraemia, therapy was changed to 600 mg of ceftaroline 3. The patient completed 3 weeks of ceftaroline therapy and was discharged with 3 weeks of linezolid. 4. DM and chronic renal disease. Blood cultures remained persistently positive for MRSA through hospital day 11 (on VAN). Then, changed to 6 mg/kg DAPTO every 48 h with continually positive blood cultures; changed to 600 mg of ceftaroline every 12 h on day 11 of therapy. Blood cultures performed after 2 days of ceftaroline therapy were negative 5. TEE revealed a 1.5 2 cm aortic vegetation. VAN adjusted to maintain trough of 15 20 mg/l. The patient remained bacteraemic for 12 days. Changed to 600 mg of ceftaroline q8h, with sterilization of blood cultures the following day. The patient received 2 weeks of ceftaroline therapy and was placed back to VAN to finish a 6 week course of therapy. 6. The patient was transitioned to 600 mg of ceftaroline every 8 h on hospital day 8; blood cultures cleared by day 13. The patient completed 22 days of ceftaroline therapy before being transitioned to daptomycin for home intravenous therapy. Ho TT et al. JAC 2012

Early Experience with Ceftaroline fosamil Therapy at an Academic Hospital System Retrospective cohort review of pts who received > 48 hrs of CPT at the Detroit Med Ctr from January 2011-May 2012. Results: 43 pts were treated: 51% had bacteremia (7 endocarditis, 8 pneumonias, 4 ABSSSI, 2 spinal abscesses, & 1 IV catheter-related infection), & 49% without bacteremia (14 pneumonias & 6 ABSSSI). - 16% were treated within its label; 91% were SA (32 MRSA & 7 MSSA) infections. There were 22 SA bacteremia (SAB): 4 MSSA, 1 hvisa, & 1 VISA. 30% were polymicrobial with Gram-Negative bacteria. - Median duration of CPT, 6.5 days (4-10). Median CPT MIC for SA, 0.5 mg/l (0.5-1). - The most common CPT dosage was 600mg q12h & adjusted for renal function. The median length of time to clearance of SAB was 5 days (3-6). 93% achieved CC or improvement at the end of CPT therapy. - 2 pts (5%) expired in the hospital & 11 pts were re-admitted within 30 days after discharge, 4/11 (10%) had re-admission for the same infection. Casapao AM et al. 2012 ICAAC

Ceftaroline. Treatment-emergent Adverse Events in Phase 3 Trials Ceftaroline, n=1013; comparators, n=1012 Saravolatz LD et al. CID 2012

SUMMARY Increasing limitations of vancomycin therapy New glycolipopeptides in the horizon Ceftaroline, new B-lactam active against MDR grampositive bacteria. - High affinity for S aureus PBP2a - Most potent drug against Streptococcus pneumoniae - Low protein binding, excreted by the kidneys; usual dose of 600 mg/q12h - Approved for the treatment of ABSSSIs and CABP - Safety profile similar to comparators