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Ceftazidime/Avibactam Allergan/Pfizer Approved February 25, 2015 EMA: June 2016 6

Ceftazidime/Avibactam Allergan/Pfizer Approved February 25, 2015 EMA: June 2016 6

Prof. Ignacio Martin-Loeches MD. PhD. St James’s Hospital Trinity College Dublin Ireland. DECLARATION OF INTERESTS

• INDUSTRY – Lectures: Aspen, Thermofisher, Polyphor, MSD. – Advisory board: Gilead, Accelerate, bioMérieux, MSD. • ACADEMIC – COBATRICE Chair ESICM – Council World Federation of Societies of Intensive and Critical Care Medicine (WFSICCM) – Deputy of Critical care group at the European Respiratory Society – Surviving sepsis campaign steering committee – Global sepsis Alliance – Editorial Board • Intensive Care Medicine • Medical Science • How many antibiotics are we consuming?

Between 2000 and 2010, total global consumption grew by 33%, from approximately 50 billion to 70 billion standard units (SU)*

TOP consumers 2010

CHINA 10 billion units USA INDIA (7 units per person) 6,8 billion units 12,9 billion units (22 units per (10,7 units per person) person)

*As defined by IMS, a standard unit is a measure of volume based broadly on the smallest identifiable dose given to a patient, dependent on the pharmaceutical form (a pill, capsule, or ampoule).

Source: Van Boeckel TP et al ., Lancet Infect Dis 2014;14: 742–502014 (based on IMS MIDAS data) Last-resort antibiotics Trends in consumption of in the hospital sector, selected EU countries, 2011–2015

Carbapenem consumption Greece

Denmark

Hungary strong association Netherlands

Bulgaria Percentage of -resistant invasive isolates Defined daily doses (DDD)/1 000 inhabitants/day Source (adapted from): Summary of the latest data on antibiotic consumption in the Source: Joint Interagency Consumption and European Union, ESAC-Net surveillance data, November 2016 Resistance Analysis (JIACRA) Report, June 2017 Between 1962 and 2000, no major classes of antibiotics were introduced

Peptidomimetic antibiotics target outer-membrane Srinivas N et al. Science. 2010

Fischbach MA et al. Science 2009 WHO priority pathogens list for R&D of new antibiotics

GAIN act USA (government) (Generating Antibiotic Incentive Now)

Innovative Medicine (public/private) Initiative IMI) – EU « New Drugs for Bad Bugs » (ND4BB)

Objective: 10 new drugs by 2020

http://www.who.int/mediacentre/news/releases/2017/-antibiotics-needed/en/ (25/2/2017) IDSA Calls for 10 new antibiotics by

9. / 2020 Melinta Approved Sept 2017 8. Melinta FDA apporved 2017 7. / Allergan/Pfizer Approved February 25, 2015 EMA: June 2016 6. Ceftolozane/ Cubist Pharmaceuticals: Approved December 19, 2014 EMA: Septemebr 18, 2015 5. The Medicines Company: Approved August 26, 2014 4. Phosphate Cubist Pharmaceuticals: Approved June 20, 2014 3. Durata Therapeutics: Approved May 23, 2014 2. Cubist Pharmaceuticals: Approved May 27, 2011 1. IDSA = Infectious Diseases Society of America. Forrest Laboratories: Approved October 29, 2010 http://www.nytimes.com/2010/02/27/business/27germ.html?_r=0 http://www.idsociety.org/10x20/ Practical issues in new antibiotic development

• Need new, simplified, affordable regulatory path to new drug approval. – Need FDA and EMA assistance • Financial: new antibiotic has net value of - $50 million at discovery vs. $1 billion for musculoskeletal drug – Antibiotics lose benefit with extensive use – Guidelines promote short course use (vs. chronic use of other drugs) – Max cost of $1000-$3000 / case (vs. up to $80,000 for chemotherapy)

Bartlett JG, et al. Clin Infect Dis 2013 Why such slow antibiotic development? Potential solutions

• Use molecular diagnostics to • Find new substances to screen target antibiotic use and • Private–public partnerships for withhold in viral development of new agents • Study short course therapy • Focus on resistant pathogens and use of biomarkers, to and unmet needs to support minimize overuse of higher prices antibiotics • Enhance public commitment to responsible antibiotic use • Enhance infection prevention

Spellberg B, et al. Am J Respir Crit Care Med 2015 Potential US FDA approval of selected “new” antibiotics

FDA approved 8/2017 (cUTI)

FDA approved 6/2017 (ABSSTI)

Theureutzbacher et al. CMI 2017 Unmet needs in the antibacterial pipeline

• Broad and narrow spectrum drugs active against DTR GNB • (Enterobacteriaceae, Pseudomonas, and Acinetobacter) – Including those that produce carbapenemase • where the only active agents are , amynoglycosides, and

• G + drugs active against MRSA and Enterococcus show improved efficacy in more difficult to treat

• Drugs more effective, safer and /or more convenient than current drugs

GRAM - GRAM +

DRUGS HERE AND THOSE COMING Staphylococcus aureus

Drug Here Drug On The Way Agent Route Agent Class Route Ceftaroline IV IV-PO IV IV Dalbavancin glycopeptide IV IV-PO Delafloxacin FQ IV-PO Rifampin IV-PO JNJ-Q2 FQ IV-PO SMX/TMP IV-PO Oritavancin Glycopeptide IV IV Omedacycline IV-PO

Tigecycline IV -mimetics IV

Vancomycin IV Tedizolid oxazolidinone IV-PO IV, IM Tetracycline IV/PO DRUGS HERE AND THOSE COMING Staphylococcus aureus

Drug Here Drug On The Way Agent Route Agent Class Route Ceftaroline IV Lefamulin pleuromutilin IV-PO Ceftobiprole IV Daptomycin IV Dalbavancin glycopeptide IV Linezolid IV-PO Delafloxacin FQ IV-PO Rifampin IV-PO JNJ-Q2 FQ IV-PO SMX/TMP IV-PO Oritavancin Glycopeptide IV Telavancin IV Omedacycline Tetracycline IV-PO

Tigecycline IV Brilacidin defensin-mimetics IV

Vancomycin IV Tedizolid oxazolidinone IV-PO Teicoplanin IV, IM Eravacycline Tetracycline IV/PO Ceftaroline in vitro & in animal models

• Active & bactericidal vs. – Staphylococci, including MRSA – Streptococci including penR pneumococci – H. influenzae and M. catarrhalis including ß-lactamase-producers – Enterobacteriaceae EXCEPT if ESBL, high level AmpC or carbapenemase – Not active vs. non-fermenters, Bacteroides • Hard to select resistance in MRSA1,2 • In vivo efficacy vs. – MRSA & VISA in lung, endocarditis and other models1,2 – -resistant S. pneumoniae (PRSP) in a rabbit pneumonia3

Zhanel G et al. Drugs. 2009;69:809–831. Kanafini ZA. Future Microbiol. 2011;6:9–18. Croisier-Bertin D et al. Antimicrob Agents Chemother. 2011;55:3557–3563. Potency of ceftaroline against S.pneumoniae

The enhanced binding affinity for penicillin binding proteins (PBP2) provides ceftaroline with potent activity against resistant strains of S. pneumoniae, including isolates resistant to and quinolones, as well as multidrug- resistant strains of

S.pneumoniae

1. Garrison MW, Kawamura NM, Wen MM. Expert Rev Anti Infect Ther. 2012 Oct;10(10):1087-103. 18 Study design

• 1240 patients were enrolled in two large international Phase III, multicentre, randomised, double-blind, comparative trials (FOCUS 1 & 2)

PORT III and IV severity classification End of treatment 1:1 randomisation

Ceftaroline fosamil Patients 600 mg IV q12h 10% non-inferiority design aged ≥18 years (400 mg q12h for moderate renal impairment) with CAP and Test of Late PORT risk (5–7 days of therapy) class III / IV cure follow-up requiring 8–15 days 21–35 days hospitalisation 1 g IV q24h after end of after end of treatment treatment

MRSA patients were excluded from the FOCUS studies All patients in FOCUS 1 received 2 doses (24 h course) of adjunctive (500 mg q12h) starting with first dose of study drug Adapted from File TM Jr, et al. Clin Infect Dis 2010;51:1395–405. CAP, community-acquired pneumonia; MRSA, -resistant Staphylococcus aureus; PORT, Pneumonia Outcomes Research Team Baseline patient characteristics (MITTE)

Ceftaroline fosamil 600 mg Ceftriaxone 1 g Characteristic (N=580) (N=573) PORT risk class, n (%) III 360 (62.1) 353 (61.6) IV 220 (37.9) 220 (38.4) Renal impairment, n (%) Mild (CrCl, 51–80 mL/min) 199 (34.3) 190 (33.2) Moderate (CrCl, 31–50 mL/min) 88 (15.2) 85 (14.8)

Severity of disease was higher than that studied in previous registration trials

Adapted from File TM Jr, et al. Clin Infect Dis 2010;51:1395–405; File TM Jr, et al. J Antimicrob Chemother 2011;66 (Suppl 3):iii19–32; Low DE, et al. J Antimicrob Chemother 2011;66(Suppl 3):iii33‒44. CrCl, creatinine clearance; MITTE, modified intent-to-treat efficacy; PORT, Pneumonia Outcomes Research Team FOCUS 1&2: Early clinical response at Day 4 (EmMITT*)

Ceftaroline fosamil, n/N 49/69 58/85 107/154

Ceftriaxone, n/N 41/72 51/83 92/155

Neither FOCUS trial established that ceftaroline fosamil was statistically superior to ceftriaxone in terms of clinical response rates at Day 4. The suggestion of benefit seen with ceftaroline fosamil at Day 4 does NOT imply an improved overall end outcome

Eckburg PB et al. Infect Dis Clin Pract 2012;20:254–60 * EmMITT, exploratory microbiological modified intent-to-treat (n=309) ASIA-CAP: Subgroup analysis

Patients clinically cured at the test-of-cure visit, by analysis population and patient subgroup

Zhong NS, et al. Lancet Infect Dis. 2015;15:161–171. Changes in Therapy Recommendations in the 2019 ATS/IDSA Guidelines for Community-Acquired Pneumonia

• For patients without risk factors for P. aeruginosa, the β-lactam options have been updated. Intravenous has been removed, while ceftaroline has been added. Ceftaroline was not approved during the previous guideline period. In clinical trials, ceftaroline showed superior clinical outcomes compared to ceftriaxone in CAP caused by S pneumoniae and MSSA

• For inpatients with P aeruginosa risk factors, the previous guidelines recommended double gram-negative coverage, but the new guideline recommends 1 antipseudomonal β-lactam

Twenty-year trend in mortality among hospitalized patients with pneumococcal community-acquired pneumonia

Cillóniz C, Liapikou A, Martin-Loeches I, García-Vidal C, Gabarrús A, et al. PLOS ONE 2018 Tedizolid: Novel Oxazolidinone

• Proposed indication: treatment of acute bacterial skin and skin structure infections (ABSSSI)

• Clinical development program – ABSSSI • Approved – Hospital-acquired/ventilator associated bacterial pneumonia (HABP/VABP) • Phase 3 finished

NDA=new drug application; IV=intravenous; HAP=hospital-acquired pneumonia; VAP=ventilator-associated pneumonia. 1. www.Cubist.com ; assessed December 17, 2013. Tedizolid Pulmonary Disposition in Healthy Volunteers

• Pulmonary Pharmacokinetics1 – The pulmonary disposition of oral tedizolid was assessed in a prospective, open- label, multiple-dose pharmacokinetic study of adult healthy volunteers

BAL Time Point 2 hours 4 hours 12 hours 24 hours

ELF (μg/mL) 9.05 (3.83) 4.45 (2.18) 5.62 (1.99) 1.33 (0.59)

AM (μg/mL) X20 to x40 !!! 3.67 (1.02) 4.38 (2.18) 1.42 (0.63) 1.04 (0.52) Total plasma (μg/mL) 2.01 (0.55) 1.51 (0.33) 0.946 (0.31) 0.398 (0.17)

Free plasma (μg/mL) 0.213 (0.058) 0.159 (0.035) 0.100 (0.033) 0.042 (0.018)

• Tedizolid concentrations in the ELF and AM were higher than free plasma concentrations, suggesting extensive extracellular (i.e., ELF) and intracellular (i.e., AM) pulmonary penetration in typical sites of infection 2 • Tedizolid exposure in ELF and AM cells was above MIC90 for the entire dosing period  Mean ELF, AM, and plasma concentrations at each BAL time point. Data presented as mean (SD)  AM = alveolar macrophage; BAL = bronchoalveolar lavage; ELF = epithelial lining fluid; WBC = white blood cell count

Housman ST, et al. Antimicrob Agents Chemother. 2012 Pharmacokinetic and relative penetration ratios for single doses of tedizolid and linezolid in the murine pneumonia model under various conditions

ELF penetration Drug Model Blood fAUC ELF AUC ratio

Tedizolid Immunocompetent 4.7 (0.1) 43.9 (2.8) 9.34

Neutropenic 3.35 (0.1) 35.6 (0.2) 10.63

Uninfected 2.77 (0.1) 17.0 (0.1) 6.14

Linezolid Immunocompetent 115.9 (44.0) 155.8 (14.2) 1.34

Neutropenic 53.4 (4.7) 61.4 (17.9) 1.15

Uninfected 36.3 (0.9) 62.5 (17.7) 1.72

Keel RA et al. Antimicrob. Agents Chemother 2012; 56: 3420-3422 Platelet Counts– Pooled Phase 3 Studies At any post-baseline assessment through last dose of study druga 20

15 P=.0002

12.6 10

P=.0175 5 6.4 4.5 Patients With TEAEs (%) 2.1 0 Below LLN Substantially Abnormal (<75% of LLN)

6-Day TZP 200 mg once daily 10-Day LZD 600 mg twice daily

TEAE=treatment-emergent adverse events; GI=gastrointestinal; LLN=lower limit of normal; TZP=tedizolid; LZD=linezolid. aPlatelet counts were collected on Study Day 7-9, Study Day 11-13, and after the last dose of study drug. 1. DeAnda C, et al. Integrated results from 2 phase 3 studies comparing tedizolid phosphate 6 days vs. linezolid 10 days in patients with ABSSSI. Poster presented at: 53rd Interscience Congress on Antimicrobial Agents and Chemotherapy (ICAAC); September 10-13, 2013; Denver, CO. (L-203). A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate (TZD) and Linezolid (LZD) for Treatment of Ventilated Gram-Positive (G+) Nosocomial Pneumonia 726 patients were randomized (TZD n = 366; LZD n = 360)

• “TZD was not noninferior to LZD based on the investigator-assessed clinical response at TOC” Wunderink et al. Open Forum Infectious Diseases 2019 Therapy of MRSA infections

Bacteremia Pneumonia Sepsis cSSSI Endocarditis CNS infections

Vancomycin Vancomycin Linezolid Ceftaroline Daptomicin Ceftaroline Daptomicin Ceftaroline Tedizolid Linezolid Vancomycin Tedizolid

Unmet needs for new antibiotics

• Survey of EIN members, 562 responded – Rate unmet needs on scale of 1–5 (low–high) • Saw new antibiotic development as the best strategy to meet unmet needs of resistance

EIN, Emerging Infections Network Hersh AL, et al. Clin Infect Dis 2012;54:1677-8, Mutidrug resistant (MDR) versus difficult to treat (DTR) pathogens

Multi-drug resistant (MDR) nonsusceptible to at least one antimicrobial in three or more antimicrobial categories Difficult to treat resistant (DTR) pathogens Extensive-drug resistant (XDR) Resistant to all first-line high efficacy, low-toxicity nonsusceptible to at least one antimicrobial in all but two or fewer agents, but susceptible to ‘reserve agents’, including antimicrobial categories colistin, and tigecycline Pan-drug resistant (PDR) nonsusceptible to all antimicrobial agents

Magiorakos AP et al. Clin Microbiol Infect 2012 Strich JR et al. Semin Respir Crit Care Med 2019 Cantón R et al. Curr Opin Crit Care 2020 Relevance of difficult to treat (DTR) pathogens

% of ICU stays associated with inpatients with bacteremia from Gram-negative bacteria (E. coli, K. pneumoniae, Enterobacter spp., P. aeruginosa and A. baumannii)

First line agents: carbapenems, other β-lactams, and fluoroquinolones

P. aeruginosa best exemplified the concept of a DTR pathogen

Resistant to all carbapenems, other b-lactams, and fluoroquinolones

Pseudomonas aeruginosa , a paradigm of difficult to treat (DTR) pathogen

Strich JR et al. Semin Respir Crit Care Med 2019 Relevance of difficult to treat (DTR) pathogens

% of ICU stays associated with inpatients with bacteremia from Gram-negative bacteria (E. coli, K. pneumoniae, Enterobacter spp., P. aeruginosa and A. baumannii)

First line agents: carbapenems, other β-lactams, and fluoroquinolones

P. aeruginosa best exemplified the concept of a DTR pathogen

Resistant to all carbapenems, other b- lactams, and fluoroquinolones

Pseudomonas aeruginosa , a paradigm of difficult to treat (DTR) pathogen

Strich JR et al. Semin Respir Crit Care Med 2019 Mortality and Health Care Burden of HABP/VABP

• HABP/VABP are associated with high mortality, and increased length of ICU stay and health care costs

> 2 days of Invasive MV > 2 days in ICU Characteristic No VAP VAP No ICU-HAP ICU-HAP

ICU length of stay (days), median [IQR] 6 [3-13] 21 [13-35] 3 [1-5] 13.5 [6-28]

ICU mortality rate (%) 25.9% 32.5% 6.8% 25.6%

Hospital length of stay (day), median [IQR] 16 [7-32] 32 [19-54] 15 [8-27] 26 [14-52]

Hospital mortality rate (%) 34.9% 42.5% 14.8% 35.8%

1Saied et al. Crit Care Med 2018 New Agents being developed to treat resistant Gram-negative bacteria

Agent Related-class Developer Ceftolozane-tazobactam BLBLI Merck Ceftazidime-avibactam BLBLI Pfizer Murepavadine OMPTA Polyphor - BLBLI Merck -avibactam BLBLI Pfizer Shionogi Eravacycline Tetracycline Tetraphase Achaogen Meropenem-vaborbactam BLBLI Melinta CARBAPENEMASE Ceftazadime/Avibactam (Cephalosporin/Inhibitor)

• Approved for: – Complicated intra-abdominal infection (cIAI) – Complicated (cUTI), including – Hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP) – indicated for the treatment of infections due to aerobic Gram-negative organisms in adult patients with limited treatment options • GNB coverage: – Active against ESBL, AmpC and some CPE (KPC, OXA-48) – Pseudomonas sp. with class A/C beta-lactamases • Gaps – ESBL-Acinetobacter, Burkholderia, Stenotrophomonas, NDM, Pseudomonas with ceftaz-efflux pumps, anaerobes, MRSA

Lagace-Wiens et al. Infect Drug Res 2014;9:13-25 Plasma and ELF concentration–time profiles Phase I study in healthy volunteers Geometric mean (SD) plasma and median ELF concentrations (semi-log scale)

Cohort A: AVI 500 mg+CAZ 2000 mg Cohort B: AVI 1000 mg+CAZ 3000 mg

1000 Plasma geometric mean concentration (n=22) 1000 Plasma geometric mean concentration (n=20) ELF median concentration (n=5)* ELF median concentration (n=5) Individual ELF data Individual ELF data 100 100

10 10

CAZ 1 1

0.1 0.1 Concentration (mg/L) Concentration (mg/L) 0.01 0.01 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time after start of infusion (h) Time after start of infusion (h) 100 Plasma geometric mean concentration (n=22) 100 Plasma geometric mean concentration (n=20) ELF median concentration (n=5)* ELF median concentration (n=5) Individual ELF data Individual ELF data 10 10

AVI 1 1 0.1

(mg/L) 0.1

0.01 Concentration 0.01 Concentration (mg/L)

0.001 0.001 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time after start of infusion (h) Time after start of infusion (h)

• Ceftazidime and avibactam penetrated well into human ELF; plasma and ELF concentrations increased approximately dose- proportionally for both agents • Plasma levels of ceftazidime-avibactam are a good surrogate measure for lung penetration

Nicolau D et al. ICAAC 2013; Poster A-1027 Primary endpoint efficacy: Clinical cure rates at TOC (CE and cMITT populations)

CE population cMITT population

(n=199/257) (n=211/270) (n=245/356) (n=270/370)

CE, clinically evaluable; CI, confidence interval; cMITT, clinically modified intention-to-treat; HAP, hospital-acquired pneumonia; TOC, test of cure; VAP, ventilator-associated pneumonia.

Torres Et al. Lancet Infect Dis 2018 Key patient and disease characteristics at baseline (cMITT population)

Ceftazidime-avibactam (N=356) Meropenem (N=370) Parameter Age, years, mean (SD) 62.1 (16.6) 61.9 (17.4) Male, n (%) 268 (75) 274 (74) Race, n (%) White 150 (42) 163 (44) Black or African American 1 (<1) 2 (1) Asian 201 (56) 199 (54) Other 4 (1) 6 (2) Body mass index, kg/m2, mean (SD) 24.0 (6.1) 23.9 (5.2) APACHE II score category, n (%) <10 1 (<1) 1 (<1) 10–19 309 (87) 316 (85) 20–30 46 (13) 53 (14) Estimated CrCl, mL/min, mean (SD) 102.6 (67.5) 100.1 (53.1) Renal status, n (%) Normal renal function or mild impairment (CrCl 50–150 mL/min) 286 (80) 292 (79) Moderate or severe impairment (CrCl 16–50 mL/min) 18 (5) 18 (5) Augmented (CrCl >150 mL/min) 50 (14) 58 (16) NP subtype, n (%) VAP 118 (33) 128 (35) Non-VAP 238 (67) 242 (65) Mechanical ventilation at baseline, n (%) Ventilated 154 (43) 159 (43) Non-ventilated 202 (57) 211 (57) Prior systemic antibiotic use (in the 48 hours before randomisation), n (%) None 122 (34) 117 (32) >0 to ≤24 hours 185 (52) 209 (56) >24 to ≤48 hours 49 (14) 44 (12)

Torres Et al. Lancet Infect Dis 2018 Clinical efficacy of Ceftazidime/avibactam (Phase III Studies)

Indication Key Findings

I • As effective as meropenem when combined Reclaim Complicated Intra- Abdominal Infections with in patients with cIAI

II Recapture Complicated Urinary • As effective as in patients with cUTI Tract Infections

III Hospital Acquired • As effective as meropenem in patients with HAP/VAP Reprove Pneumonia, incl. Ventilator Associated

IV • Non-inferior to BAT in cIAI/cUTI caused by Pathogen directed Reprise ceftazidime- resistant gram-negative pathogens (ceftazidime-R) (97% of patients were receiving carbapenem as BAT ) Clinical outcomes, drug toxicity and emergence of ceftazidime- avibactam resistance among patients treated for carbapenem-resistant Enterobacteriaceae infections

April 2015-Feb 2016 Pittsburg university Clinical success 59% (22/37) 30-day Survival 76% (28/37)

Recurrence; 23% (5/22) of clinical successes within 90-days

Microbiologic failure rate 27% (10/37).

Ceftazidime-avibactam resistance was detected in 30% (3/10) of microbiologic failures after 10, 15 and 19 days.

PK/PD optimization/ COMBO++++

Shields RK et al – Clinical infectious diseases 2016;63:1615-18 Ceftazidime–avibactam in CRE Klebsiella pneumoniae bacteremia clinical success

Rates of 30-day clinical success across treatment regimens Clinical success

Among patients with CRE Klebsiella pneumoniae bacteremia, rates of clinical success at 30-day were significantly higher among patients receiving ceftazidime-avibactam compared to those who received a carbapenem plus aminoglycoside (P=0.04) or colistin (P=0.009) and other regimens (P=0.004)

C-A, ceftazidime–avibactam; CB+AG, carbapenem and aminoglycoside; CB+COL, carbapenem and colistin; CRE, carbapenem-resistant Enterobacteriaceae Shields RK, et al. Antimicrob Agents Chemother 2017. Jul 25;61(8) e00883-17 Colistin versus Ceftazidime-avibactam in the Treatment of Infections due to Carbapenem-Resistant Enterobacteriaceae

• 38 patients were treated first with ceftazidime-avibactam and 99 with colistin • Bloodstream (n=63, 46%) and respiratory (n=30, 22%) infections • All-cause hospital mortality at 30-days – ceftazidime-avibactam 9% – colistin 32% (p=0.0012) • Disposition at 30 days, patients treated with – ceftazidime-avibactam had 64% probability of a better outcome as compared to patients treated with colistin. • Partial credit analyses indicated uniform superiority of ceftazidime-avibactam to colistin

Van Duin D et al. Clin Infect Dis. 2017 Ceftolozane/Tazobactam Overview

Class In vitro activity In vivo efficacy . Antipseudomonal cephalosporin Pseudomonas aeruginosa, including Activity in mouse models of + β-lactamase inhibitor drug-resistant strains sepsis, pneumonia, urinary . Fixed 2:1 ratio , including ESBL- tract infection, burn wound positive strains infection, and thigh infection Klebsiella pneumoniae, including Positive outcomes and adhered to ESBL-positive strains an expected safety profile in Phase 2 and 3 trials in adult Minimal activity against Gram- patients with cUTI and cIAI positive bacteria + Limited activity against anaerobes No activity against KPC, MBL Linear PK Lung penetration Mechanism of action Development stage Rapid tissue distribution . Rapidly bactericidal Completed Phase 3 trials for Minimal accumulation . Inhibits synthesis treatment of cIAI and cUTI Extensive renal excretion . Active against organisms with Phase 3 trial underway for porin deficiencies or mutations nosocomial pneumonia Low protein binding . Inhibits β-lactamases, Minimal CYP450 drug-drug broadens coverage to most interactions ESBL-producing Enterobacteriaceae

Zhanel et al. Drugs. 2014;74:31-51.

Kollef et al. Poster #1917 Martin-Loeches et al. Poster #O0302 Presented at ECCMID 2019 Presented at ECCMID 2019 Martin-Loeches et al. Poster #O0302 Presented at ECCMID 2019 Martin-Loeches et al. Poster #O0302 Presented at ECCMID 2019 Ceftolozane/Tazobactam vs. Meropenem for VAP, vHAP and Treatment Failure HAP

Kollef M et al. Lancet Infect Dis. 2019 ICU Nosocomial Pneumonia: Ventilated HAP Has the Highest Mortality

• All-cause mortality in ICU acquired pneumonia: 20 to 50%1 – HAP in ICU has similar mortality rate as VAP – All-cause mortality (ACM) appears greatest in ventilated HAP, slightly less in VAP, and least for nonventilated HAP in ICU2-3

28-day All Cause Mortality in ICU Nosocomial Pneumonia3

Ventilated HAP 39%

Ventilated Acquired Pneumonia (VAP) 27%

Non-ventilated HAP in ICU 22%

Ferrer M et al. Curr Opin Crit Care 2018; 24: 325-31 2. Considerations for design for the study of HABP and VABP foundation for the NIH Biomarkers Consortium HABP/VABP Project Team May 26, 2017. Ref Accessible at https://fnih.org/what-we-do/biomarkers-consortium/programs/ventilator-acquired-bacterial-pneumonia .Accessed 30-Dec- 2018 3.Talbot GH et al. J Infect Dis 2019 Jan 11 42 Difference in All Cause Mortality in nonventilated HABP, ventilated HABP and VABP: Are They All the Same Disease?

ASPECT, REPROVE, RESTORE,Talbot et al. J Infect Dis 2019 Difference in All Cause Mortality in nonventilated HABP, ventilated HABP and VABP: Are They All the Same Disease?

• All cause mortality (ACM) at day 28 differs for VABP and ventilated HABP

vHAP VAP REPROVE, ASPECT,RESTORE Zaragoza et al. Crit Care 2020 What about Pseudomonas aeruginosa

1. MexAB-OprM 2. MexCD-OprJ Table adapted from3. CastanheiraMexEF-OprN M, et al. 2014 Activity greatly decreased >> Retains activity 4. MexXY

Castanheira M, et al. Antimicrob Agents Chemother. 2014;58:6844-6850. What about Pseudomonas aeruginosa

Outer Membrane β-lactamase Resistance Mechanisms Efflux Pump Efflux Pump Porin Loss Enzyme OprD AmpC MexXY MexAB Ceftolozane Ceftazidime /tazobactam Imipenem Meropenem

Activity greatly decreased >> Retains activity Table adapted from Castanheira M, et al. 2014

61 1. Castanheira M, et al. Antimicrob Agents Chemother. 2014;58:6844-6850. Co-Resistance among Commonly Prescribed 1st line Beta-Lactams, but not Ceftolozane/Tazobactam: Potential Implications

• P. aeruginosa co-resistance is common among 1st line β- lactams

• P. aeruginosa non- susceptible to piperacillin- tazobactam, ceftazidime or meropenem are less susceptible to the other β- lactams, but not ceftolozane/tazobactam

Moise P, Gonzalez M, Alekseeva I et al. Critical Care 2020, 24(Suppl 1):P425 S. Lob ET AL. Activity of Ceftolozane-Tazobactam Against a Worldwide Collection of Clinical Gram-Negative Isolates – SMART 2017. Presented at ECCMID 2019 Comparing the two new BL/BLI drugs

• Ceftazidime–avibactam • Ceftolozane–tazobactam – Active ESBLs – Stable against pseudomonal resistance mechanisms – Active class A ( KPC) and D (Opr-D, AmpC, efflux (OXA-48) pumps) – 2000 mg CAZ + 500 mg AVI – 2000 mg CToZ + 1000 mg for NP TAZ for VAP/NP – Predictable PK – Active vs. ESBLs – Rapid lung distribution – Predictable PK – Renal excretion – Rapid lung distribution – Renal excretion – OXA type ESBL – No KPC activity

NP, nosocomial pneumonia Imipenem/Relebactam (MK-7655)- Merck

• Irreversible inhibitor of class A (ESBL, KPC) and Class C (AmpC) β-lactamases (64-fold decrease of imipenem MICs in KPC producing Klebsiella pneumoniae) • Good activity against AmpC overproducing P. aeruginosa (imipenem MICs decreased 8x from >16 µg/ml to 2 µg/ml) • Not active against class B (VIM, NDM), not active against class D (OXA-48) • Little/no activity against MDR A. baumannii (OXA-23 !) Diazabicyclooctane (DBO) Piperidine analogue ongoing RESTORE-IMI-2: Imipenem/Relebactam vs Piperacillin/Tazobactam for HAP/VAP

Phase 3, randomized, controlled, double-blind, multicenter trial in adult patients with HAP or VAP

Randomized (1:1) Imipenem/Cilastatin/Relebacta m 500mg/500mg/250 mg IV q6h Stratified by Pneumonia (n=268) 537 patients type with (HABP, VABP/vHABP) HABP/VABP APACHE score Piperacillin/tazobactam (<15, ≥15) 4.5 g IV q6h (n=269)

Duration of treatment: 7-14 days* of IV study Primary and Key Secondary Endpoint drug (no oral switch)

Day 28 all-cause mortality Clinical Response at Early Follow Up (EFU) visit

HABP=hospital-acquired bacterial pneumonia; VABP=ventilator-associated bacterial pneumonia; vHABP=ventilated hospital-acquired bacterial pneumonia 35

Titov I et al, Clin Infect Dis 12-Aug-2020 Advances article at https://doi.org/10.1093/cid/ciaa803 Imipenem/Relebactam vs. Piperacillin/Tazobactam for HAP/VAP

Day 28 All Cause Mortality by Randomization Strata

N=264 N=267 N=139 N=140 N=125 N=127 N=142 N=131 N=122 N=136

Adjusted Difference: -5.3%; % Difference: 3.7%; % Difference: -15.4%; % Difference: 1.2%; % Difference: -11.2%; 95% CI: - 11.9, 1.2 95% CI: -3.7, 11.2 95% CI: -16.2, -4.4 95% CI: -6.8, 9.1 95% CI: -21.6, -0.5

Titov I et al, Clin Infect Dis 12-Aug-2020 Advances article at

Imipenem/Relebactam vs. Piperacillin/Tazobactam for HAP/VAP

Day 28 All Cause Mortality by Pneumonia Type

N=142 N=131 N=31 N=35 N=91 N=101

% Difference: 1.2%; 95% CI: -6.8, 9.1 % Difference: -19.9%; 95% CI: -41.1, 3.6 % Difference: -8.2%; 95% CI: -19.7, 3.7

Titov I et al, Clin Infect Dis 12-Aug-2020 Advances article at

Meropenem-vaborbactam,

• Novel -based beta-lactamase inhibitor (fixed-dose combination product) – Potentiates the activity of meropenem • Optimized for inhibition of the carbapenemase KPC, common in carbapenemase-producing Enterobacteriaceae – Enterobacteriaceae – Klebsiella pneumoniae • Potential new option for the treatment of severe gram-negative infections, including carbapenem-resistant Enterobacteriaceae Pharmacokinetics of novel vaborbactam

Evidences of exposure to vaborbactam (uncombined with meropenem or any other antibiotic), as measured by Cmax and area under the concentration vs. time curve [ AUC ]: No evidence of accumulation with Median plasma concentration-time profiles multiple doses

Proportional increase of Cmax and AUC with dose

Rubino CM et al. Antimicrob Agents Chemother 2018 Meropenem-vaborbactam, TANGO I

Kaye KS et al. Effect of meropenem-vaborbactam vs piperacillin-tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection: the TANGO I randomized clinical trial. JAMA 2018; 319(8): 788-99

TANGO II

Aim: To evaluate the efficacy and safety of meropenem–vaborbactam monotherapy versus best available therapy (BAT) in adults with serious infections due to carbapenem resistant Enterobacteriaceae (CRE)

Design: Phase 3, randomized, prospective, multicentre, multinational, open label, active-controlled trial. meropenem-vaborbactam was administered for up to 14 days1

Patient population: 77 patients ≥ 18 years with confirmed or suspected CRE requiring 7 days of intravenous (IV) therapy

Comparators: vs versus BAT for CRE 79 carbapenem, aminoglycoside, , colistin, tigecycline or ceftazidimeavibactam). Interrupted by the DSMB: evidence of superiority against BAT (superiority efficacy results) (EOT and TOC)

Wunderink RG et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem- resistant Enterobacteriaceae infections: the TANGO II randomized clinical trial. Infect Dis Ther 2018; 7(4): 439-55

Efficacy endpoints in patients with HABP/VABP or bacteremia by timepoint (mCRE-MITT)

Wunderink R. Infect Dis Ther 2018 TANGO II: clinical cure by subgroup at test of cure (mCRE-MITT)

Clinical cure by subgroup at test of cure (mCRE-MITT)

mCRE-MITT, Microbiologic-CRE-Modified Intent-To-Treat (primary analysis population ); SIRS, systemic inflammatory response syndrome Cefiderocol

Siderophore cephalosporin

“Trojan Horse”

C-3 side chain Prevents recognition by β-lactamases

7 3

Catechol moiety Additional stability against C-7 side chain β-lactamases enhances stability Binds to ferric ions against β-lactamases

High stability and R to β-lactamase and rapid active uptake through the ferric iron transport system (almost not affected by classical efflux pump systems)

Ito-Horiyama T. AAC. 2016 Cefiderocol

Siderophore cephalosporin

“Trojan Horse”

C-3 side chain Prevents recognition by β-lactamases

7 3

Catechol moiety Additional stability against C-7 side chain β-lactamases enhances stability Binds to ferric iron ions against β-lactamases

High stability and R to β-lactamase and rapid active uptake through the siderophore ferric iron transport system (almost not affected by classical efflux pump systems)

Ito-Horiyama T. AAC. 2016 Cefiderocol

• Highly stable to various types of carbapenemase KPC, OXA, IMP, VIM and NDM • Potent activity against Gram-negatives including CR strains – – Pseudomonas aeruginosa – Escherichia coli APEKS – Klebsiella pneumoniae – Stenotrophomonas maltophilia • Not active against Gram-positives or anaerobes Cefiderocol: in vitro activity against CRE

Cumulative MIC curves for cefiderocol and CFID comparators against 169 CRE isolates FEP (meropenem-I/R; MIC > 2 µg/ml) CAZ/AVI CLOZ/TAZ COL MEM Cefiderocol is active against all CRE types (KPC, NDM, VIM, I MP, OXA-48) CI MIC: <0.125 to 4 P µg/ml)

M. Hackel et al., AAC 2017; 61 (9 e00093-17) Cefiderocol: in vitro activity against P. aeruginosa

CFID

COL CLOZ/TA FEP Z MEM

CIP Cumulative MIC for cefiderocol a nd comparators against 353 meropenem I/R P. aeruginosa Isolates MIC > 2 µg/ml) CAZ/AVI Cefiderocol MIC90 of 4 µg/ml Against MBL producing P. aeruginosa

M. Hackel et al., AAC 2017; 61 (9 e00093-17) Cefiderocol: in vitro activity against A. baumannii CFID

COL Cumulative MIC curves for cefiderocol and comparators against 768 meropenem I/R A. baumannii CLOZ/TAZ isolates MIC > 2 µg/ml)

CAZ/AVI FEP

Cefiderocol MIC90 of 8 µg/ml MEM against carbapenemase (OXA- CI 23, OXA-58) producing A. P baumannii

M. Hackel et al., AAC 2017; 61 (9 e00093-17) APEKS-cUTI targeted “at risk” population for MDR cUTI

Portsmouth et al. Lancet Infect Dis 2018 Efficacy and Safety of Cefiderocol vs. High-Dose Meropenem in Patients with Nosocomial Pneumonia—Results of a Phase 3, Randomized, Multicenter, Double-Blind, Non-Inferiority Study

Wunderink et al. Open Forum Infect Dis. 2019 Efficacy and Safety of Cefiderocol vs. High-Dose Meropenem in Patients with Nosocomial Pneumonia—Results of a Phase 3, Randomized, Multicenter, Double-Blind, Non-Inferiority Study

Wunderink et al. Open Forum Infect Dis. 2019 CREDIBLE-CR

• Open label, RCT n=152 (2:1 randomization) – CR strains – Enterobacteriaceae (CRE) • Approx 35% of isolates A. baumannii – Pseudomonas aeruginosa • Clinical cure rates: – Acinetobacter baumannii – Stenotrophomonas maltophilia • Cefidericol (52.5%) • Cefidericol vs BAT • BAT (50.0%) • BAT mainly colistin based • Multiple infectious syndromes included (pneumonia, sepsis, UTI, etc)

Unadjusted Hazard Ratio for death at Day 49: 1.77; 95% CI: 0.87-3.57. p=0.11

FDA briefing document available at: www.fda.gov/media/131703/download Eravacycline: a novel cycline with spectrumbroad encompassing MDR gram-negative

• Structure close to tigecycline • Binding to 30S ribosome (Inhibition of Tigecycline protein synthesis (bacteriostatic) • Evades most resistant mechanisms of other (tetracycline active efflux pumps, ribosomal protection proteins) C7: Fluor No activity against P. aeruginosa, Burkholderia spp Eravacycline

Spectrum: Gram+, Gram- (CRE (class A, B, D), Acinetobacter spp.), anaerobes C9: Pyrrolidonyl No dosis adjustment if moderate renal/liver acetamide failure) MIC50/MIC90 of E.coli, K. pneumoniae (ESBL): 0.25/0.5 µg/ml) 2-8x more active than tigecycline against CRE, and A. baumannii () Plazomicin • Active against isolates resistant to other AGs (genta, tobra, amika-R; • Active against all AG modifying enzymes (AME) except AAC(2’)-Ia, -Ib, -Ic (++ Providencia) and against 16S ARN methylases (NDM CRE) • Active against AmpC, ESBL, CRE (KPC) • Inactive vs NDM • Active against S. aureus, coag neg Staphylococci • Limited activity against Acinetobacter, S pneumoniae, Enterococcus sp.

Livermore et al. JAC 2011, Walkty et al. AAC 2014, Landman et al. JAC 2011 Plazomicin Bloodstream infection or HAP or VAP caused by suspected or confirmed CRE

McKinnell et al. N Engl J Med. 2019 Outer Membrane Protein Targeting Antibiotics (OMPTA)

D115N A243T G247S F315Y D319N . High affinity binding to the periplasmic domain of LptD1 demonstrated (ACS Chemical Biology, 2018) 219-43 Aa duplication Potent in vitro activity against Pseudomonas aeruginosa strains Type Strain ATCC/DSM MIC (µg/mL) Pseudomonas aeruginosa ATCC 27853 0.06 Pseudomonas aeruginosa PAO1 0.25 Pseudomonas putida DSM 291 0.06 Pseudomonas fluorescens DSM 6147 0.06 Pseudomonas aureofaciens ATCC 15926 0.06 Pseudomonas syringae ATCC 12271 0.008

Escherichia coli ATCC 25922 >64 Klebsiella pneumoniae ATCC 13883 >64 Acinetobacter baumannii ATCC 19606 >64 Burkholderia cepacia ATCC 25416 >64 Stenotrophomonas maltophilia ATCC 13637 >64 Staphylococcus aureus ATCC 29213 >64

In vitro time-kill study comparing murepavadin to meropenem against ATCC 27853

Growth control Growth control 10 10 POL7080 8xMIC Meropenem 8xMIC 9 POL7080 4xMIC 9 Meropenem 4xMIC POL7080 2xMIC Meropenem 2xMIC 8 8 POL7080 1xMIC Meropenem 1xMIC 7 POL7080 0.5xMIC 7 Meropenem 0.5xMIC [log10] [log10] POL7080 0.25xMIC Meropenem 0.25xMIC 6 6

5 5 CFU/ml CFU/ml

4 4

3 log reduction3 3 log reduction3 LOQ LOQ 0 2 4 6 8 10 24 0 2 4 6 8 10 24 Time (h) Time (h) In vitro time-kill study comparing murepavadin to meropenem against isolate 22 (XDR)

Growth control Growth control 10 10 POL7080 8xMIC Meropenem 8xMIC 9 POL7080 4xMIC 9 Meropenem 4xMIC POL7080 2xMIC Meropenem 2xMIC 8 8 POL7080 1xMIC Meropenem 1xMIC 7 POL7080 0.5xMIC 7 Meropenem 0.5xMIC [log10] [log10] POL7080 0.25xMIC Meropenem 0.25xMIC 6 6

5 5 CFU/ml CFU/ml

4 4

3 log reduction3 3 log reduction3 LOQ LOQ 0 2 4 6 8 10 24 0 2 4 6 8 10 24 Time (h) Time (h) Murepavadin displays a potent in vitro bactericidal activity against P. aeruginosa 1 0 2 Risk Factors for MDR:IDSA/ATS

Organ failure New guidelines for HAP/VAP: USA vs. Europe.

Martin-Loeches I et al Curr Opin Crit Care. 2018 MDR prescription

Martin-Loeches et al. Curr Opin Crit Care 2018 Koulenti ICM 2014 Know your ‘local’ pathogen

Medical ICU Enterococcus Surgical ICU Susceptibility (%) spp. Acinetobacter Trauma ICU spp. 100 * P. aeruginosa * * 80

60 S. aureus

40 *

20

0 Methicillin Vancomycin Imipenem Ceftazidime

*Significant difference between ICUs

Namias et al. J Trauma 2000; Difficult to treat (DTR) pathogens: new active alternatives

Gram-negative ESKAPE microorganisms

New compounds resisting resistance mechanisms

• Ceftolozane tazobactam • Cetazidime-avibactam • Meropenem-vaborbactam • Imipenem-relebactam • Cefiderocol First and second line treatment for ESBLs (extented spectrum b-lactamases) infections

Enterobacteriacae ESBL producing Piperacillin/ tazobactam MIC ≤16mg/L First Line Second Line Piperacillin/tazobactam Meropenem +  Carbapenems or Tigecycline  Ceftolozane/ tazobactam or Fosfomycin Ceftazidime/avibactam

Piperacillin/ tazobactam MIC > 16mg/L and/or severe infection • Carbapenems • Ceftolozane/ tazobactam • Ceftazidime/avibactam Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or K pneumoniae Bloodstream Infection and Ceftriaxone Resistance: A Randomized Clinical Trial.

Harris et al. JAMA. 2018 First and second line treatment for ESBLs (extented spectrum b-lactamases) infections

Enterobacteriacae ESBL producing Piperacillin/ tazobactam MIC ≤16mg/L First Line Second Line Piperacillin/tazobactam Meropenem + Amikacin  Carbapenems or Tigecycline  Ceftolozane/ tazobactam or Fosfomycin Ceftazidime/avibactam

Piperacillin/ tazobactam MIC > 16mg/L and/or severe infection • Carbapenems • Ceftolozane/ tazobactam • Ceftazidime/avibactam First and second line treatment for ESBLs (extented spectrum b-lactamases) infections

Enterobacteriacae ESBL producing Piperacillin/ tazobactam MIC ≤16mg/L First Line Second Line Piperacillin/tazobactam Meropenem + Amikacin  Carbapenems or Tigecycline  Ceftolozane/ tazobactam or Fosfomycin Ceftazidime/avibactam

Piperacillin/ tazobactam MIC > 16mg/L and/or severe infection • Carbapenems • Cefiderocol • Ceftolozane/ tazobactam • Meropenem/vaborbactam • Ceftazidime/avibactam • Imipenem/cilastatin-relebactam P. aeruginosa empiric combination options in countries with high MDR rate

Backbone 2° agent Ceftolozane–tazobactam Cefiderecol Imipenem relabactam Piperacillin–tazobactam Amikacin Meropenem Colistin Imipenem Fosfomycin Ceftazidime

The antimicrobial regimen should be promptly narrowed or discontinued based on culture and susceptibility profile results and on clinical stability

MDR, multi-drug resistant Where is the role of new antibiotics for Carbapenem resistant ? News antibiotics for CP-CRE

A D C KPC OXA-48 VIM/IMP/NDM Ceftazidime Avibactam Meropenem Vaborbactam Imipenem Relebactam Cefiderocol Plazomicina Eravacycline

Active Activity depending on MICs and/or target concentrations Not active E M P I R I C A L

T A R G E T E D

Zaragoza et al. Crit Care 2020 Mortality Rates Among VAP Patients, According to Whether Therapy Was Escalated or De-Escalated

Inappropriate initial treatment leads to higher mortality MORTALITY(%)

Kollef MH, et al. Chest. 2006;129:1210-1218. Inappropriate Antibiotic Therapy Was Related to Mortality

A meta-analysis of 57 studies assessed the consequences of appropriate* vs inappropriate initial antibiotic therapy in the treatment of Gram-negative bacterial infections in the hospital setting1

Appropriate Initial Antibiotic Therapy Inappropriate Initial Antibiotic Therapy

Has been related to decrease in mortality of 62% in 39 studies Has been related to increased mortality of 2.5x and increased length of stay by a median of 3 days

*In the majority of studies, appropriate antibiotic therapy was defined based on susceptibility and timeliness of treatment. 1. Raman G et al. BMC Infect Dis. 2015;15(395):1-11. Kumar et al Crit Care Med 2006 Martin-Loeches et al. ICM 2020 Martin-Loeches et al. ICM 2020 Conclusions

• Great news, some new agents in development and in clinical trials

• Superiority to current regimens for CRE infection not completely assessed • Need for RCT, trials in settings other than cIAI, cUTI (e.g. BSI and VAP, MDR infections) • Trials designed for equivalence are a problem

• Most are modifications of older agents, or with new β-lactamase inhibitors • Few options for resistance mechanisms other than beta-lactamases (porin/efflux)

• High costs (may limit access to new agents in resource-poor-settings)

• Need to evaluate their respective potential at individual institutions based on appreciation of local problem pathogens Aiming for ‘normal’

THINK GLOBALLY, ACT LOCALLY Antibacterials in Development

Active vs Gram- Drug Name (Company) Class Potential Indications negative Pathogens LptD POL7080 (Polyphor/Roche) Yes (Pseudomonas) VABP inhibitor Debio 1452 (Debiopharm Group) Fabl Inhibitor No ABSSSI CG-400549 (CrystalGenomics) Fabl Inhibitor No ABSSSI Brilacidin (Cellceutix) Defensin-mimetic No ABSSSI Ceftaroline-avibactam (AZ/Actavis) Cepalo + BLI Yes cUTI (Melinta) Oxazolidinone Yes ABSSSI, CAPB TAKSTA (, Cempra) Fusidane No PJI Glycopeptide- TD-1792 (Theravance) cephalosporin No ABSSSI, HABP/VABP heterodimer (TiaGen Biotech) Quinolone Yes CABP, DFI, ABSSSI (MerLion Fluoroquinolone Yes cUTI, cIAI, ABSSSI Pharmaceuticals) Avarofloxacin (Furiex/Actavis) Fluoroquinolone Yes CABP/ABSSSI Zalbofloxacin (Dong Wha Pharma) Fluoroquinolone No CABP Type 2 topoisomerase ABSSSI, Resp GSK2140944 (GSK) No inhibitor infection, CABP http://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2014/03/12/tracking-the-pipeline-of-antibiotics-in-development

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