February 2019

Application for inclusion of

- (J01DD52) ceftolozane- (J01DI54) delafloxacin (J01MA23) eravacycline (J01AA13) - (J01DH52) omadacycline plazomicin (J01GB14)

as RESERVE on the WHO Model List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc)

EML Secretariat on behalf of the EML working group

Table of contents

Table of contents 1 General items 1 Abbreviations used in this document 4 Ceftazidime / avibactam (J01DD52) 5 Ceftolozane / tazobactam (J01DI54) 8 Delafloxacin (J01MA23) 10 Meropenem / vaborbactam (J01DH52) 13 Eravacycline (J01AA13) 16 Omadacycline 18 Plazomicin (J01GB14) 19 References 21

General items

Summary statement of the proposal for inclusion, change or deletion.

The report of the 2017 WHO Expert Committee on the Selection and Use Essential Medicines [1] defines Reserve group antibiotics as follows: “The Reserve group includes antibiotic classes that should be treated as ‘last-resort’ options, or tailored to highly specific patient populations and settings, when other alternatives would be inadequate or had already failed (e.g. severe or life-threatening due to multidrug-resistant bacteria). To preserve their effectiveness, these medicines should be protected and prioritized as key targets of high- intensity national and international stewardship programmes involving monitoring and reporting of their use (and ideally also resistance to these classes).” In 2017 eight antibiotic classes were identified for this group (, fourth and fifth generation , lipopetides, (iv only), oxazolinidones, , glycylcyclines).

Key elements of this definition are the limitation of appropriate use to specific, limited situations and the clear statement that other antibiotics are preferable whenever possible. Finally, the definition links the group to stewardship actions to monitor appropriate use, emphasizing the need for intensive monitoring of use of this group. The 2017 EML did not list some of the antibiotics newly approved between 2014 and 2017. Furthermore, several new antibiotics have obtained FDA and / or EMA approval since 2017. This document proposes to list all of the following antibiotics on the EML complementary list, as RESERVE antibiotics according to the WHO AWaRe classification since they potentially fulfil the criteria mentioned above (‘last-resort’ options for multidrug-resistant bacteria). It should, however, be noted that not all of the molecules have the same therapeutic value. While certain medicines like ceftazidime/avibactam may offer clear advantages for the treatment of multidrug-resistant organisms (MDRO), this advantage is less clear for certain other medicines (e.g. delafloxacin). The expert committee should decide for each drug listed in the application whether it merits listing as RESERVE antibiotic on the EML.

It should also be noted that the indications proposed in this document may differ from the indications for which the drugs are approved by the regulatory authorities. This is due to the fact that regulatory approval relies on

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non-inferiority trials for specific syndromes that do not take into account . Because of their potential value as “last-resort” drugs for confirmed (or highly suspected) MDRO infections, it seems clear that their use should be reserved to very specific patient populations. Again, the expert committee should make a decision about proposed indications. It should also be noted that for all drugs, data on use in children remains scarce or non-existent.

Public health relevance of antibiotics active against multidrug-resistant Gram-negative bacteria

Antibiotic-resistant bacteria are a significant threat to public health, both in high-income as well as low- and middle-income countries (LMIC).[2-4] A recent study estimated that infections with antibiotic-resistant bacteria were responsible for approximately 33’000 attributable deaths in Europe in 2015.[2] Fewer data are available for LMIC, but a retrospective study in ten hospitals in India found that resistant pathogens were associated with 2- 3 times higher mortality than infections with susceptible strains after adjusting for several confounders.[3] Over the last decade there has been increasing spread of multidrug-resistant Gram-negative pathogens such as carbapenemase producing Enterobacteriaceae.[5] The Global Antimicrobial Resistance Surveillance System (GLASS) Report published in 2018 found high levels of resistance in Enterobacteriaceae and non- fermenters in many of the LMICs providing data for the report.[3] The 2015 WHO Global Action Plan on Antimicrobial Resistance calls for the development of new antimicrobial medicines.[4] To provide a framework for this endeavour WHO recently published a priority list of antibiotic-resistant bacteria. “Priority 1: critical” category includes four types of pathogens, all of which are Gram-negative: carbapenem resistant Acinetobacter baumannii, and Enterobacteriaceae; and third-generation resistant Enterobacteriaceae.[6]

Antibiotics proposed for inclusion on the EML complementary list, as RESERVE antibiotics

ANTIBIOTIC ANTIBIOTIC ATC DOSE FORM YEAR OF PROPOSED TARGET CLASS CODE FDA /EMA INDICATION* POPULATION APPROVAL ceftazidime/ third J01DD52 2g/0.5g 2015 Confirmed or Patients with avibactam generation powder for suspected severe cephalosporin / reconstitution with infections beta-lactamase for infusion MDRO caused by inhibitor susceptible to pathogens ceftazidime / outlined on avibactam the left ceftolozane/ third J01DI54 1 g/0.5g 2014 Confirmed or Patients with tazobactam generation powder for suspected severe cephalosporin / reconstitution infection with infections beta-lactamase for infusion MDRO caused by inhibitor susceptible to pathogens ceftolozane/ outlined on tazobactam the left delafloxacin fluoroquinolone J01MA23 450mg tablet 2017 Confirmed or Patients with suspected severe 300mg infection with infections powder for MDRO caused by reconstitution susceptible to pathogens for infusion delafloxacin outlined on the left eravacycline tetracycline J01AA13 50mg 2018 Confirmed or Patients with (fluorocycline) powder for suspected severe reconstitution infection with infections for infusion MDRO caused by susceptible to pathogens eravacycline outlined on the left meropenem/ carbapenem / J01DH52 2g/2g 2017 / Confirmed or Patients with vaborbactam beta-lactamase powder for 2018 suspected severe inhibitor reconstitution infection with infections for infusion MDRO caused by susceptible to pathogens meropenem/ outlined on vaborbactam the left omadacycline tetracycline Not yet 100mg 2018 / Confirmed or Patients with assigned lyophilized 2018 suspected severe powder for infection with infections reconstitution MDRO caused by pathogens

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150mg tablet susceptible to outlined on omadacycline the left plazomicin aminoglycoside J01GB14 500mg/10ml 2018 / Confirmed or Patients with concentrate 2018 suspected severe for solution infection with infections for infusion MDRO caused by susceptible to pathogens plazomicin outlined on the left

* For the officially approved indications (FDA and EMA) see below in the individual sections for each antibiotic.

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Abbreviations used in this document

Abbreviation AP Acute ATC Anatomical Therapeutic Chemical Classification BAT Best available therapy CAZ-AVI Ceftazidime-avibactam CE Clinically evaluable CI Confidence interval CPE Carbapenemase-producing Enterobacteriaceae C/T Ceftolozane / tazobactam Diff. Difference ESBL Extended spectrum beta-lactamase HABP Hospital-acquired Bacterial Pneumonia HAP Healthcare-associated pneumonia cIAI Complicated intraabdominal infection cUTI Complicated EMA European Medicines Agency FDA United States Food and Drug Administration KPC carbapenemase LMIC low- and middle-income countries MBL metallo-beta-lactamase MDRO multidrug-resistant organisms MRSA -resistant Staphylococcus aureus mMITT microbiologically modified intention-to-treat population M/V Meropenem / vaborbactam P/T / tazobactam RCT Randomized controlled trial TOC Test of cure UTI Urinary tract infection VAP Ventilator-associated pneumonia

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Ceftazidime / avibactam (J01DD52)

Summary • Proposed listing as individual drug (alternative to be discussed: create category of beta-lactam/ beta- lactamase inhibitor combinations with “extended spectrum”) • Diagnostics requirement: ideally used in settings with adequate microbiologic capacity to detect resistant pathogens • Monitoring: as for other RESERVE antibiotics • Confirmed or suspected severe infections with MDRO susceptible to ceftazidime / avibactam

Ceftazidime is third generation cephalosporin listed on the EML complementary list and classified within the WATCH group. Avibactam is a non-beta-lactam beta-lactamase inhibitor active against certain types of carbapenemases (e.g. KPC and OXA-48 but not active against metallo-beta-lactamases). It has FDA & EMA approval for cUTI & cIAI (for cIAI in combination with metronidazole).[7] EMA lists “HAP and other infections due to Gram-negative bacteria with limited treatment options” as further indication.

FDA and EMA indications for ceftazidime / avibactam

FDA EMA • Complicated Intra-abdominal Infections (cIAI), • Complicated Intra-Abdominal Infection (cIAI) used in combination with metronidazole • Complicated Urinary Tract Infection (cUTI), • Complicated Urinary Tract Infections (cUTI), including pyelonephritis including Pyelonephritis • Hospital-acquired pneumonia including • Hospital-acquired Bacterial Pneumonia and ventilator associated pneumonia (VAP) Ventilator-associated Bacterial Pneumonia • Infections due to aerobic Gram-negative (HABP/VABP) organisms in patients with limited treatment options • https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/206494s004lbl.pdf • https://www.ema.europa.eu/documents/assessment-report/zavicefta-epar-public-assessment-report_en.pdf

The table below lists the RCTs conducted to date comparing ceftazidime / avibactam to or best available therapy for cIAIs and cUTIs.[8-11] Of note, all but one of the RCTs [8] included patients based on clinical syndromes and not based on the presence of infections confirmed to be caused by multidrug-resistant organisms . In that “descriptive” trial of patients with cUTI (plus some patients with cIAI) caused by ceftazidime- resistant Gram negatives, ceftazidime / avibactam treatment resulted in similar clinical response compared to BAT.

So far, few data on the “real life” clinical use of ceftazidime / avibactam has been published. A retrospective single centre study at the University of Pittsburgh Medical Center in Pittsburgh, USA examined outcomes of 109 patients with bacteraemia caused by carbapenem-resistant K. pneumoniae bacteraemia (97% of which were KPC producers) over the time period from 2009 to 2017. The 30-day survival rate was 92% (12/13) in patients treated with CA vs. 69% (66/96) for patients treated with other regimens, but this obviously has to be interpreted with caution given the many potential confounding factors. [7]

Published data about use of CAZ-AVI in children is very scarce and limited to a phase I study and case reports.[12-14] However, two phase 2 RCTs have been conducted in children with cUTIs and cIAI and are awaiting publication (ClinicalTrials.gov Identifier: NCT02475733 and NCT02497781). Of note ceftazidime / avibactam may have a role in combination with to treat infections caused by Enterobacteriaceae producing metallo-beta-lactamases at least until the combination of aztreonam with avibactam becomes available.[15, 16]

5/23 February 2019

Summary of RCTs comparing ceftazidime / avibactam to other antibiotics

Trial Setting Study type Population Intervention Comparator Outcome Adverse events Wagenlehner 2012-2014 phase 3, 1033 patients with ceftazidime-avibactam FDA Safety population included et al.[11] multicentre, cUTI/acute 2000 mg/500 mg 500 mg every (1) % patients all patients who received 160 double-blind, pyelonephritis every 8 hours 8 hours with symptomatic resolution of any IV study therapy RECAPTURE centres in double-dummy UTI-specific symptoms, 1 25 non-inferiority improvement in flank pain at day 5 ≥1 AE RECAPTURE countries RCT visit • 185/511 (36.2%) 2 (2) % of patients with CAZ-AVI microbiological eradication and • 158/509 (31.0%) symptomatic resolution at TOC (21– doripenem 25 days post-randomization) in mMITT population ≥1 SAE • 21/511 (4.1%) CAZ- 276/393 (70.2%) CAZ-AVI vs AVI 276/417 (66.2%) (diff. 95% CI: 4.0 • 12/509 (2.4%) (−2.39 to 10.42) doripenem

EMA Clostridium difficile % patients infection with favorable microbiological • 2 (0.4%) CAZ-AVI response • 0 doripenem at TOC in mMITT population

304/393 (77.4%) CAZ-AVI vs. 296/417 (71.0%) doripenem (diff, 95% CI: 6.4 (.33 to 12.36)) Carmeli et 2013-2014 phase 3, 333 adult patients ceftazidime/avibactam Best available Clinical response at TOC visit, 7–10 No new safety concerns al. [8] multicentre, with cUTI (306) or 2000/500 over 2-h therapy (BAT) days after last infusion of study identified 53 centres open-label, cIAI (27) caused therapy in mMITT population REPRISE in 16 descriptive RCT by ceftazidime- CAZ-AVI vs BAT countries resistant 140/154 (91%) (CAZ-AVI) vs • Any AE 51/164 vs Enterobacteriaceae 135/148 (91%) (BAT) 66/168 or Pseudomonas • Most frequent AE aeruginosa nausea (8/164 vs 10/168) Mazuski et 2012-2014 phase 3, 1066 adult ceftazidime/avibactam Meropenem Clinical cure at TOC visit CAZ-AVI + metro vs al.[9] multicenter, patients with cIAI 2000/500 over 2-h + 1g/8h over 30 28–35 days after randomization meropenem 136 double-dummy, metronidazole minutes RECLAIM 1 centers in double-blind, 500mg/8h FDA ≥1 AE RECLAIM 2 30 non-inferiority mMITT population: • 243/529 (45.9%) vs. countries RCT clinical disease criteria and ≥1 227/529 (42.9%) pathogen at baseline ≥1 SAE • 42/529 (7.9%) vs. 337/413 (81.6%) CAZ-AVI 40/529 (7.6%) metronidazole vs. 349/410 (85.1%)

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meropenem (diff., 95% CI −3.5; −8.64 to 1.58)

EMA MITT and clinically evaluable at TOC Populations: • patients who received study drug and met the clinical disease criteria (MITT) 429/520 (82.5%) CAZ-AVI metronidazole vs. 444/523 (84.9%) meropenem (diff., 95% CI −2.4, −6.90 to 2.10)

• subset of MITT population with no protocol deviations affecting the efficacy of the study drug 376/410 (91.7%) CAZ-AVI metronidazole vs. 385/416 (92.5%) meropenem (diff., 95% CI −0.8, −4.61 to 2.89) Quin et 2013-2015 phase 3, 441 hospitalized ceftazidime/avibactam Meropenem Clinical cure rate at the TOC visit in 82/215 (38.1%) and al.[10] multicentre, adults with cIAI 2000/500 over 2-h + 1g/8h over 30 clinically evaluable (CE) subjects. 83/217 (38.2%) subjects China, double-blind, requiring surgical metronidazole minutes in the CAZ-AVI plus RECLAIM 3 Republic of double-dummy intervention 500mg/8h 166/177 (93.8%) vs 173/184 metronidazole and Korea, non-inferiority (94.0%) meropenem groups, Vietnam RCT (−0.2, 95% CI−5.53 to 4.97) respectively, experienced ≥1 AE

7/23 February 2019

Ceftolozane / tazobactam (J01DI54)

Summary • Proposed listing as individual drug (alternative: create category of beta-lactam/ beta-lactamase inhibitor combinations with extended spectrum) • Diagnostics requirement: ideally used in settings with adequate microbiologic capacity to detect resistant pathogens • Monitoring: as for other RESERVE antibiotics • Confirmed or suspected severe infections with MDRO susceptible to ceftolozane/tazobactam

Ceftolozane / tazobactam (C/T) is the combination of a new cephalosporin with a structure similar to ceftazidime with a beta-lactam inhibitor that has been in clinical use for decades (tazobactam). C/T retains in vitro activity against some strains of multidrug-resistant P. aeruginosa and against Enterobacteriaceae producing ESBL. It only has limited activity against Gram positive pathogens and anaerobes.[17]

C/T has been assessed in 2 RCT, one for cUTI and one for cIAI.[18, 19] Of note, in the cUTI trial levofloxacin was used as comparator agent, a highly debatable choice given that resistance to levofloxacin in Gram negatives isolated in urine cultures at baseline was nearly 10 time more prevalent at baseline (2.7% for C/T versus 26.7% for levofloxacin).[19] A RCT in VAP is currently being conducted (ClinicalTrials.gov Identifier: NCT01853982).

A retrospective cohort study in of 101 patients treated with C/T in 22 Italian centres for a variety of infections causes by P. aeruginosa, including 51% of XDR strains, showed overall clinical success of 83.2% and a good safety profile.[20] A secondary analysis of the 150 of 1346 (11.1%) patients with ESBL producing organisms in the original 2 RCTs reported high clinical cure rates with C/T (overall 97.4%), better than the comparators (82.6% for levofloxacin (cUTI only) and 88.5% for meropenem (cIAI only)).[21] The major methodologic limitations of these studies mean, however, that the data have to be interpreted with caution Data for children are scarce and no specific recommendations regarding use in the paediatric population can be made.[22, 23]

FDA and EMA indications for ceftolozane / tazobactam

FDA EMA • Complicated Intra-abdominal Infections, used • Complicated intra-abdominal infections in combination with metronidazole • Acute pyelonephritis • Complicated Urinary Tract Infections, • Complicated urinary tract infections including Pyelonephritis • https://www.ema.europa.eu/documents/product-information/zerbaxa-epar-product-information_en.pdf • https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206829lbl.pdf

8/23 February 2019

Trial Setting Study type Population Intervention Comparator Outcome Adverse events Wagenlehner 2011-2013 Phase 3, 1083 adults with Ceftolozane/tazobactam levofloxacin Composite cure: clinical cure and ≥1 AE et al. [19] multicentre, pyuria and 1.5 g/8h iv for 7 days 750 mg/24h iv microbiological eradication of all • C/T 185/533 (34.7%) 209 double-blind, diagnosis of for 7 days baseline uropathogens 5–9 days • Levofloxacin 184/535 ASPECT-cUTI centres in double-dummy, complicated after treatment in the (34.4%) 25 non-inferiority lower-urinary- microbiological mITT population countries. RCT tract infection or C/T 306/398 (76.9%) vs ≥1 SAE pyelonephritis levofloxacin 275/402 (68.4%) • C/T 15/533 (2.8%) (82% • Levofloxacin 18/535 pyelonephritis) Microbiological mITT population, (3.4%) resistance of Gram-negative • 2 SAE (Clostridium pathogens at baseline: difficile infection) in • C/T: 20/731 (2.7%) C/T group deemed • Levofloxacin: 195/731 (26·7%) related to study treatment

Most frequent AE in both treatment groups: headache and gastro intestinal symptoms Solomkin et 2011- Phase 3, 993 adults with Ceftolozane/tazobactam meropenem Clinical cure rates at TOC visit (24– ≥1 AE al. [18] multicentre, clinical evidence of 1.5 g/8h iv plus 1g/8h iv plus 32 days from start of therapy) in • C/T + metro 44.0% double-blind, cIAI for whom metronidazole placebo the microbiological ITT population • Meropenem 42.7% ASPECT-cIAI 196 non-inferiority operative or 500mg/8h iv for 4–10 for 4–10 (-14) centres RCT percutaneous (-14) days days 323/389 (83.0%) vs. 364/417 ≥1 SAE drainage of an (87.3%) (weighted difference, • 39/482 (8.1%) infectious −4.2%; 95% CI −8.91 to .54) • 36/497 (7.2%) focus was either • Drug-related SAEs: 1 planned or had Patients with ESBL-producing C. difficile in each been performed Enterobacteriaceae, clinical cure group recently (>96% • C/T 23/24 (95.8%) appendicitis) • Meropenem 23/26 (88.5%)

9/23 February 2019

Delafloxacin (J01MA23)

Summary • Proposed listing as individual drug (other fluoroquinolone antibiotics are categorized as “Watch”) • Diagnostics requirement: ideally used in settings with adequate microbiologic capacity to detect resistant pathogens • Monitoring: as for other RESERVE antibiotics • Confirmed or suspected severe infections with MDRO susceptible to delafloxacin

Delafloxacin is a new fluoroquinolone with additional activity against methicillin-resistant S. aureus compared to the older molecules of this class.[24, 25] It has been approved for treatment of skin and soft tissue infections based on two phase 3 multicentre, double blind non-inferiority trials.[26, 27] In these trials about one third and one fourth of patients had infections due to MRSA. A review of the safety data of both RCT and additional phase I and II trials showed few discontinuations (<1%) due to treatment-related adverse events and the proportion of patients with AEs was similar to the proportion observed in the comparator arms.[28] No fluoroquinolone specific AE such as tendinitis or neuropathy were observed in the delafloxacin arm. Gastrointestinal events (notably diarrhoea), headache, and infusion site pain were the most frequently reported AE. Adverse events associated with fluoroquinolones (tendinitis, myopathy, dysglycaemia, neuropathy, neurotoxicity) were not more frequent when compared with vancomcycin/aztreonam with the caveat that the combined phase 3 trials only included 1492 patients and rare, potentially severe events were unlikely to be detected. A trial comparing delafloxacin to moxifloxacin (or linezolid in the case of confirmed MRSA) in patients with community-acquired pneumonia (NCT02679573) has been completed in 2018 but results have not yet been published.

Delafloxacin may potentially also have a role in the treatment of gonorrhoea with good in vitro activity even against strains with reduced susceptibility to ciprofloxacin.[29] There are no data for use of delafloxacin and children and similar to other fluoroquinolones it is not recommended for use in patients younger than 18 years.

FDA EMA • Acute Bacterial Skin and Skin Structure Infections • Treatment of local infections of skin and (ABSSSI) subcutaneous tissues • https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208610Orig1s000,208611Orig1s000Approv.pdf • https://www.ema.europa.eu/en/medicines/human/paediatric-investigation-plans/emea-001080-pip01-10-0

10/23 February 2019

Phase 2 and phase 3 randomized controlled trials assessing delafloxacin:

Trial Setting Study type Population Intervention Comparator Outcome Adverse events (AE) Kingsley 2011 Phase 2, 256 adult patients with Delafloxacin iv iv 15 Investigator assessment of clinical ≥1 AE et al. multicentre, acute bacterial skin 300mg/12h for 5- mg/kg/12h response at the follow-up visit in • delafloxacin 58/78 (74.4%) [30] 23 centres in double-blind, and skin structure 14 days the ITT population (all randomized • vancomycin 63/96 (64.6%) the US three-arm infections Or patients) • linezolid 54/75 (72.0%) (1:1:1) RCT • diarrhoea 15.4% vs 4.2% Linezolid iv Cure vs 6.7% 600mg/12h • 57/81 (70.4%) • 50/77 (64.9%) ≥1 SAE • 53/98 (54.1%) • delafloxacin 5/78 (6.4%) • vancomycin 6/96 (6.3%) Delafloxacin vs linezolid (mean linezolid 2/75 (2.7%) difference: -25.4%; 95% CI, - 20.0%–9.1%)

Delafloxacin vs vancomycin (- 16.3%; 95% CI -30.3% to -2.3%) Pullman 2013-2014 Phase 3, 660 adult patients with Delafloxacin iv Vancomycin iv 15 FDA ≥1 AE et al.[26] multicentre, acute bacterial skin 300mg/12h for 5- mg/kg/12h plus Objective response (>20% • delafloxacin 154/324 34 study double-blind, and skin structure 14 days aztreonam iv erythema reduction) at (47.5%) PROCEED centers in non-inferiority infections 2g/12h for 5-14 48–72 h after initiation of study • vancomycin/aztreonam seven RCT days drug without evidence of clinical 193/326 (59.2%) countries MRSA infections were failure in the ITT population • diarrhoea 27 (8.3%) v 10 in 78 (32.1%) and 91 (3.1%) (36.8%) patients in Delafloxacin 259/331 (78.2%) vs the delafloxacin vancomycin/aztreonam 266/329 ≥1 SAE and (80.9%) (mean treatment • delafloxacin 12/324 (3.7%) vancomycin/aztreonam difference, -2.6%; 95% CI, -8.78% • vancomycin/aztreonam groups to 3.57%). 12/326 (3.7%)

EMA No cases of Clostridium difficile Investigator assessment infection, tendinitis, tendon of clinical cure (no remaining signs rupture, peripheral neuropathy, or symptoms) at the FU visit in the myopathy thought to be related ITT population to delafloxacin treatment.

Delafloxacin 172/331 (52.0%) vs. vancomycin/aztreonam 166/329 (50.5%) (mean treatment difference 1.5; 95CI –6.11 to 9.11) O’Riordan 2014-2016 Phase 3, 850 adult patients with Delafloxacin iv Vancomycin iv 15 FDA ≥1 AE et al. multicentre, acute bacterial skin 300mg/12h for 3 mg/kg/12h plus Objective response (>20% • delafloxacin 182/417 [27] double-blind, days with switch aztreonam iv erythema reduction) at (43.6%)

11/23 February 2019

76 study non-inferiority and skin structure to Delafloxacin po 2g/12h for 5-14 48–72 h after initiation of study • vancomycin/aztreonam centers in 16 RCT infections 450mg/12h days drug without evidence of clinical 167/425 (39.3%) PROCEED countries failure in the ITT population • diarrhoea 32 (7.7%) v 14 Overall 116/850 (3.4%) (21.0%) MRSA Delafloxacin 354/423 (83.7%) vs identified as pathogens vancomycin/aztreonam 344/427 ≥1 SAE (80.6%) (mean treatment • delafloxacin 16/417 (3.8%) difference, +3.1%; 95% CI, -2.0% • vancomycin/aztreonam to 8.3%). 17/425 (4.0%)

1 case of paraesthesia in each treatment group EMA potentially related to treatment. Investigator assessment of clinical cure (no remaining signs No cases of tendinitis, tendon or symptoms) at the FU visit in the rupture, myopathy or treatment- ITT population related hypo- or hyperglycaemia

Delafloxacin 244/423 (57.7%) vs 1 case of Clostridium difficile vancomycin/aztreonam 255/427 infection in delafloxacin group (59.7%) (mean treatment (prior treatment failure on difference, -2.0%; 95% CI, -8.6% trimethoprim/sulfamethoxazole to 4.6%). and clindamycin)

12/23 February 2019

Meropenem / vaborbactam (J01DH52)

Summary • Proposed listing as individual drug (alternative: create category of beta-lactam/ beta-lactamase inhibitor combinations with extended spectrum) • Diagnostics requirement: ideally used in settings with adequate microbiologic capacity to detect resistant pathogens • Monitoring: as for other RESERVE antibiotics • Confirmed or suspected severe infections with MDRO susceptible to meropenem / vaborbactam

Meropenem / vaborbactam is a combination of the carbapenem meropenem with the non-suicidal cyclic – based β-lactamase inhibitor vaborbactam.[31, 32] Vaborbactam inhibits Ambler class A and C β-lactamases of which KPC and some extended spectrum beta-lactamases are currently the clinically most relevant examples. Metallo-β- lactamases (e.g. NDM, VIM) and class D β-lactamases are not inhibited by vaborbactam.

As of December 2018, meropenem / vaborbactam was assessed in 2 phase RCT (see table below for details).[33, 34] The TANGO I trial showed non-inferiority of meropenem / vaborbactam versus piperacillin / tazobactam for the treatment of complicated urinary tract infections (infection with a pathogen resistant to standard antibiotics was not an inclusion criterion).[33] The TANGO II trial compared meropenem / vaborbactam to the best available therapy (often a combination of antibiotics) in patients with a variety of infections caused by carbapenem resistant Enterobacteriaceae and showed decreased mortality and increased cure rates with meropenem / vaborbactam.[34]

FDA EMA • Patients 18 years of age and older with complicated • Complicated urinary tract infection, including urinary tract infections (cUTI), including pyelonephritis pyelonephritis • Complicated intra-abdominal infection • Hospital-acquired pneumonia, including ventilator associated pneumonia • Bacteria in the blood associated with any of the infections listed above • Infections due to aerobic Gram-negative organisms in adults with limited treatment options

• https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209776Orig1s000TOC.cfm • https://www.ema.europa.eu/en/news/new-medicine-treat-infections-adults

13/23 February 2019

Randomized controlled trials assessing meropenem vaborbactam:

Trial Setting Study type Population Intervention Comparator Outcome Adverse events (AE) Kaye et 2014-2016 Phase 3, 550 patients ≥ 18 Meropenem / Piperacillin / FDA: overall success (clinical cure MV vs PT: al., multicentre, years with vaborbactam tazobactam (P/T) + microbiologic success) at the end • Any AE: 39.0% vs 35.5% 2018.[33] 60 sites in 17 multinational, complicated urinary (M/V) 2g/2g iv 4g/0.5g iv over 30 of IV treatment visit for • Study drug-related AE: countries double-blind tract infection over 3 hours minutes every 8 microbiologic modified ITT 15.1% vs 12.8% TANGO I (Asia, randomized every 8 hours hours population: • Severe AE: 2.6% vs. 4.8% Europe, 98.4% (M/V) vs 94.0% (P/T) (diff. • Life-threatening AE: 1.1% North- and 4.5% [95% CI,0.7%-9.1%]) vs 0% South • AE leading to study drug America) EMA: discontinuation: 2.6% vs (1) microbial eradication at test-of- 5.1% cure visit for microbiologic modified • Headache (most common ITT: AE): 8.8% vs 4.4% 66.7% (M/V) vs 57.7% (P/T) (diff. 9.0% [95%CI, −0.9% -18.7%)

(2) microbial eradication at test-of- cure visit for microbiologic evaluable populations: 66.3% (M/V) vs 60.4% (P/V) (diff. 5.9% [95%CI, −4.2% -16.0%]) Wunderink 2014-2017 Phase 3, 77 patients ≥ 18 Meropenem / “Best available day-28 all-cause mortality: MV vs PT: et al al., multicentre, years with cUTI/AP, vaborbactam therapy” (BAT) MV 15.6% (5/32) vs. BAT 33.3% • Any treatment-emergent 2018.[34] 27 sites in 8 multinational, HAP/VAP, (MV) 2g/2g iv (5/15) (diff.- 17.7%; 95%CI - (TE) AEs 84.0% (42/50) vs. countries open-label bacteraemia, cIAI over 3 hours monotherapy or 44.7-9.3%) 92.0% (23/25) TANGO II (North- and randomized due to every 8 hours combination: Severe TEAEs 14.0% (7/50) South clinical trial confirmed/suspected polymyxins, FDA: microbiologic-CRE-modified • vs. 28.0% (7/25) America, (2:1 carbapenem- carbapenems, intent-to-treat population Europe, randomization resistant aminoglycosides, • Drug-related TEAEs: 24.0% Israel) to MV vs BAT) Enterobacteriaceae tigecycline, overall success (clinical cure & (12/50) vs. 44.0% (11/25) (CRE) ceftazidime- microbiologic eradication) at TOC in • Serious AEs: 34.0% (17/50) (K. pneumoniae avibactam the cUTI/AP subgroup vs. 44.0% (11/25) 58.7%) 33.3% (4/12) (MV) vs. 50.0% (2/4) (BAT)

all-cause mortality in the combined HABP/VABP and bacteremia subgroups 22.2% (4/18) (MV) vs. 44.4% (4/9)(BAT) (diff. - 22.2%; 95% CI - 59.9 - 15.5%)

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clinical cure at TOC in the cIAI subgroup 100% (2/2) (MV) vs. 0% (0/2)

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Eravacycline (J01AA13)

Summary • Proposed listing as individual drug (alternative: create category with tigecycline and omadacycline) • Diagnostics requirement: ideally used in settings with adequate microbiologic capacity to detect resistant pathogens • Monitoring: as for other RESERVE antibiotics • Confirmed or suspected severe infections with MDRO susceptible to eravacycline

Eravacycline is a fully synthetic tetracycline antibiotic that has a spectrum of activity similar to tigecycline and maintains its activity in the presence of two common resistance mechanisms: ribosomal protection and active drug efflux. It retains activity against most ESBL producing Enterobacteriaceae and some strains of carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii but has limited activity against Pseudomonas aeruginosa.[35-38] It achieved non- inferiority compared with in one trial and meropenem in another trial in the treatment of complicated intrabdominal infections in hospitalized adults.[39, 40] A further trial has been conducted in adult patients with cUTI using levofloxacin as comparator, but the results have so far only been published on cinicaltrials.gov (NCT01978938).

Like for other tetracyclines, eravacycline use is not recommended in children < 8 years and pregnant or breastfeeding women due to the risk of tooth discoloration and enamel hypoplasia. A phase 1 multicenter study to assess the and safety of iv eravacycline in children 8 to <18 years is currently recruiting patients (ClinicalTrials.gov Identifier: NCT03696550).

FDA EMA • complicated intra-abdominal infections (cIAI) in • complicated intra-abdominal infections (cIAI) in adults adults • https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211109lbl.pdf • https://www.ema.europa.eu/en/medicines/human/EPAR/xerava

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Randomized controlled trials assessing eravacycline

Trial Setting Study type Population Intervention Comparator Outcome Adverse events Solomkin et 2013- Phase 3 541 adult Eravacycline 1 ertapenem Clinical response 25 to 31 calendar more treatment-emergent AE in the al. [39] 2014 double- hospitalized mg/kg/12h 1g/24h days after the first dose of the study eravacycline treatment group (113 /270) than blind, patients with drug the ertapenem treatment group (75/ 268). IGNITE-1 66 sites multicentre cIAIs Minimum 4 days Minimum 4 Difference mostly explained by nausea and in 11 non- requiring days clinical cure 87.0% (235 /270) for phlebitis; no difference in SAE countries inferiority urgent eravacycline and 88.8% (238/268) RCT surgical or for ertapenem Nausea was recorded for 22 patients (8.1%) percutaneous in the eravacycline group and 2 patients intervention; (difference −1.80%; 95% CI (0.7%) in the ertapenem group, and phlebitis 9% ESBL −7.4% to 3.8%) was recorded for 8 patients (3.0%) in the carriers eravacycline group and 1 patient (0.4%) in the ertapenem group. NCT01978938 2014- Phase 3 908 adult eravacycline 1.5 levofloxacin Participants in the microbiological SAE 2015 non- patients with mg/kg/24h with iv intent-to-treat (micro-ITT) • eravacycline 7/455 (1.5%) IGNITE-2 inferiority cUTI switch per os 750mg/24h population with a responder levofloxacin 6/450 (1.3%) 18 RCT possible after 3 for 7 days outcome at the post-treatment visit • countries doses (200mg/12h) Eravacycline 194/297 (65.3%) vs levofloxacin 213/302 (70.5%) Solomkin et 2016- Phase 3, 500 adult Eravacycline iv meropenem FDA: Clinical response at TOC visit Treatment-emergent adverse events (TEAE) al. [40] 2017 double- patients with 1.0 mg/kg/12h iv 1g/8h 25-31 days after the • eravacycline 37.2% (93/250) blind, suspected initiation of the study drug in the meropenem 30.9% (77/249) IGNITE-4 65 sites double- cIAI micro-ITT population •

in 11 dummy, Gastrointestinal disorders most frequent countries. multicentre, Eravacycline 177/250 (90.8%) vs. TEAE: nausea (12), vomiting (9), diarrhoea non- Meropenem 187/249 (96.1%) (6) inferiority RCT (difference -0.5, 95% CI -4.1-to 5.8)

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Omadacycline

Summary • Proposed listing as individual drug (alternative: create category with tigecycline and eravacycline,) • Diagnostics requirement: ideally used in settings with adequate microbiologic capacity to detect resistant pathogens • Monitoring: as for other RESERVE antibiotics • Confirmed or suspected severe infections with MDRO susceptible to omadacycline

Omadacycline has a broad spectrum of activity against many Gram-positive and Gram-negative pathogens, including MRSA.[41] Several RCT have been conducted or are currently ongoing, but as of the writing of this report the results have not yet been published in the peer-reviewed literature. • Oral Omadacycline vs. Oral Linezolid for the Treatment of ABSSSI (NCT02877927), Phase 3, double-blind, multicentre non-inferiority RCT (2016-2017) in 735 adult patients with ABSSSI, Primary outcome: Early clinical response (87.5% vs. 82.5%, +5.0%, 95% CI -02 to 10.3). • Omadacycline Versus Linezolid for the Treatment of ABSSSI (NCT02378480), Phase 3, double-blind, multicentre non-inferiority RCT (2015-2016): results not yet available • Omadacycline vs Moxifloxacin for the Treatment of CABP (NCT02531438), Phase 3, double-blind, multicenter non- inferiority RCT (2015-2017) in 774 adult patients with CAP. Primary outcome: Number of participants with early clinical response 81.1% vs 82.7% (-1.6, 95% CI -7.1 to 3.8) • Oral Omadacycline vs. Oral Nitrofurantoin for the Treatment of Cystitis (NCT03425396): trial still recruiting

FDA EMA • Community-acquired bacterial pneumonia (CABP) Not yet approved at the time of the writing of this document. Under review for Acute bacterial skin and skin structure infections • • Community-acquired bacterial pneumonia (ABSSSI) (CABP) • Acute bacterial skin and skin structure infections (ABSSSI) • https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209816_209817lbl.pdf

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Plazomicin (J01GB14)

Plazomicin is a next-generation aminoglycoside which is not affected by many aminoglycoside-modifying enzyme of Enterobacteriaceae that inactivate other types of aminoglycosides.[42, 43] This makes it a potentially useful drug for the treatment of carbapenemase producing Enterobacteriaceae since aminoglycosides are not affected by carbapenemase production (metallo-betalactamases may be an exception since they often are associated with genes for methylases affecting and inactivating all types of aminoglycosides, including plazomicin).

FDA EMA • Patients 18 years of age or older for the Not yet approved at the time of the writing of this treatment of complicated urinary tract infections document. (cUTI), including pyelonephritis caused by the • Complicated urinary tract infections (cUTI), following susceptible microorganism(s): including pyelonephritis, Escherichia coli, Klebsiella pneumoniae, Proteus • Bloodstream infections (BSI) due to certain mirabilis, and Enterobacter cloacae Enterobacteriaceae • Infections due to Enterobacteriaceae in adult patients with limited treatment options • https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303orig1s000lbl.pdf

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Trial Setting Study type Population Intervention Comparator Outcome Adverse events Connolly et 2010-2012 Phase 2, Adult inpatients plazomicin iv 10 levofloxacin 750 Microbiological N/A al.[44] multicenter, and outpatients mg/kg/24h mg/24h iv for 5 eradication in the MITT and the 27 study sites double-blind with documented days ME populations at TOC, 5 to 12 in 4 countries RCT or suspected cUTI plazomicin iv 15 days after the last treatment. S (USA, India, or AP mg/kg/24h Colombia, Randomization Chile) 1:1:1 Study not 388 adult patients plazomicin iv 15 meropenem iv N/A N/A yet with cUTI or AP mg/kg/24h 1g/8h published for 4–7 days for 4–7 days followed by optional followed by optional EPIC oral therapy, for a oral therapy, for a total of 7–10 days of total of 7–10 days Conference therapy of therapy abstract: Open Forum Infectious Diseases, Volume 4, Issue suppl_1, 1 October 2017, Pages S532

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