ESCMID Online Lecture Library © by Author

APPROACHES FOR DEFINING SAFE AND EFFECTIVE REGIMENS FOR CHILDREN IN THE CONTEXT OF AMR

Professor Mike Sharland,© by St George’s author University of London

ESCMID/ASM Conference on Drug Development to Meet the Challenge of ESCMID OnlineAntimicrobial Lecture Resistance Library 21 ‐ 23 September 2016, Vienna, Austria 2016 GARPEC PPS Neonate

Neonate: Antimicrobial Prescribing (90% DU)

Gentamicin 12,2

Ceftizoxime 12,0

Meropenem 9,2

Ampicillin 8,5

Amoxicillin and enzyme inhibitor 6,6

Amikacin 6,4

Fluconazole 4,7

Latamoxef 3,8

Benzylpenicillin 3,8

Nystatin 3,5

Nevirapine 3,5 Vancomycin 2,6© by author Cefotaxime 2,6

Cefazolin 2,1

Mezlocillin 2,1 Piperacillin andESCMID enzyme inhibitor Online1,9 Lecture Library Other 1,9

Metronidazole 1,6

Flucloxacillin 1,6

0 2 4 6 8 10 12 14 Percentage (%) GARPEC 2016 PPS - Child

Children: Antimicrobial Prescribing (90% DU) Ceftriaxone 7,0 Meropenem 6,9 Vancomycin 5,1 Vidarabine 4,5 Sulfamethoxazole and trimethoprim 4,2 Azithromycin 4,0 Amoxicillin and enzyme inhibitor 3,8 Amikacin 3,5 Cefepime 3,0 Latamoxef 2,8 Cefotaxime 2,7 Abacavir 2,6 Piperacillin and enzyme inhibitor 2,4 Metronidazole 2,3 Fluconazole 2,1 Clindamycin 2,1 Mezlocillin 2,0 Oseltamivir 1,9 Cefuroxime 1,9 Amoxicillin 1,8 Nystatin 1,7 Ciprofloxacin 1,6 Gentamicin 1,5 Isoniazid 1,4 Other 1,4 Ganciclovir 1,4 Rifampicin 1,3 Linezolid 1,2 © by author Oxacillin 1,2 Ampicillin 1,2 Pyrazinamide 1,1 Erythromycin 1,1 Trimethoprim 1,0 Cefazolin 0,9 Flucloxacillin 0,9 ESCMIDEthambutol Online Lecture Library 0,8 Cefoperazone, combinations 0,8 Ceftriaxone, combinations 0,8 Cefalexin 0,7 Amphotericin B 0,6 Sulfadiazine 0,6 Cefalotin 0,6 012345678 Percentage (%) Background

• There is no global consensus on the conduct of clinical trials (CTs)in children with specific clinical infection syndromes (CIS). There is no comprehensive regulatory guidance on the design of antibiotic (AB) CTs in neonates and children (EMA IDWP/FDA CTTI). • CTsofABefficacyreportedorcurrentlyon‐going in paediatrics are now very few compared to adults. • January 2016 ‐ 64 neonatal and pediatric AB open trials registered on ClinTrialsgov (2013 – over 4000 open adult trials) – only 12 recruiting neonates – 2 preterms (26% global population under 15..) • Half of trials pharma but© focussed by author on SSTI (13) and cIAI (10) – areas of moderate clinical need. Other half strategic/academic of “varying” quality. • ESCMIDCurrent approach Online is not Lecture an optimal Library model for families/pharma/pediatricians – anyone… KEY COMPONENTS OF EFFICACY ASSESSMENT IN PAEDIATRIC ANTIBIOTIC CTs © by author ESCMID Online Lecture Library HARMONISATION IN STUDY DESIGN AND OUTCOMES IN PAEDIATRIC ANTIBIOTIC CTs: SR –LID 2016

WIDER AIM: To assess the degree of harmonization in CTs addressing efficacy of antibacterial agents in children and neonates

SPECIFIC OBJECTIVES: To systematically review the extent to which antibiotic trials of efficacy in children from 2000‐2015© by author apply consistent definitions for patient selection and endpoints

ESCMIDuse the Onlinestandardised inclusion/exclusion Lecture criteriaLibraryand endpoints for the major CIS as defined by the FDA and EMA for adults

Folgori L et al, Lancet Infect Dis 2016 RESULTS

Basic characteristics of included studies

CONSORT N° of Enrolled Pharma led Ongoing Including CIS* items reported studies pts studies trials neonates (%)** CAP 24 19,985 74 5 1 0 VAP/HAP 4 116 61 3 0 2 UTI 19 3,948 61 5 1 0 IAI 14 1,706 65 3 4 1 Sepsis 18 1,829 65 2 3 16 SSTI 7 1,489 73 4 1 1 Totals (%) 86*** 29,073 66 22 (26) 10 (12) 20 (23) *Clinical Infection Syndrome; **expressed as mean of included studies; ***82 single studies

Setting of included studies © by author ESCMID Online Lecture Library Proportion of the key study design criteria used in paediatric trials compared to the adult EMA/FDA guidance

CAP (24 studies) n studies that used the n studies that did not use FDA EMA criteria (%) the criteria (%) Inclusion criteria Clinical findings  23 (96) 1 (4) Haematological tests 3 (12) 21 (88) Biochemical tests 2 (8) 22 (92) Microbiology  1 (4) 23 (96) Imaging  10 (42) 14 (58) Exclusion criteria Clinical findings 19 (79) 5 (21) Haematological tests 2 (8) 22 (92) Biochemical tests 5 (21) 19 (79) Microbiology  12 (50) 12 (50) Imaging 4 (17) 20 (83) Underlying conditions  21 (88) 3 (12) History of recent infection © by author10 (42) 14 (58) History of recent AB** 10 (42) 14 (58) Allergy to study drugs 16 (67) 8 (33) Endpoints Clinical improvement  16 (67) 8 (33) ESCMIDTreatment failure/Changed Online AB  Lecture13 (54) Library11 (46) Microbiological efficacy 4 (17) 20 (83) Mortality  7 (29) 17 (71) SAE*** 6 (25) 18 (75) Comorbidities/sequelae 7 (29) 17 (71) Process outcome 4 (17) 20 (83) RESULTS

• QUALITY ASSESSMENT: ‐ the studies reported on a mean of 66% (range 30‐97%) of CONSORT items, with a slight difference between the various CIS

• INCLUSION CRITERIA: ‐ Primary diagnosis based on very variable combinations of clinical signs and laboratory tests ‐ Clinical findings used as inclusion criteria in 88% of CTs, followed by haematological and/or biochemical (42%) and microbiological tests (27%)

• EXCLUSION CRITERIA: ‐ Chronic/underlying conditions and a history of a recent infection/antibiotic use were considered exclusion criteria in 69 (84%) and 42 (51%) included trials respectively • PRIMARY AND SECONDARY ENDPOINTS© by author ‐ Clear primary endpoint not defined properly in 39 (48%) included trials ‐ Clinical efficacy the most commonly used outcome (66%) whereas microbiological efficacy ESCMIDand death were assessed Online in 33% and 18% Lectureof the studies. Library ‐ Wide variation identified for timing of evaluating the endpoints TIMING FOR EVALUATION OF CLINICAL ENDPOINTS

• Several limitations of current pediatric AB research from CTs impede translation into clinical practice

• Poor adherence of identified publications to CONSORT guidelines on trial reporting

• The variation found in defining study outcomes, test‐of‐cure (TOC) endpoints and clinical resolution ‐ Underlines the need for establishment of a standardized approach to evaluate the efficacy of an antibiotic in paediatrics © by author • There is a need for a new framework that is both relevant to regulatory trials to support the licensing process for new AB and strategic trials of the optimal use of ESCMIDolder AB Online Lecture Library KEY COMPONENTS OF SAFETY ASSESSMENT IN PAEDIATRIC ANTIBIOTIC CTs © by author ESCMID Online Lecture Library SR of SAFETY

To summarise the key components of safety assessment in paediatric AB CTs in relation to study design, population, safety definition, AB class‐related AEs

To discuss a way forward for possible harmonisation of study design© by and conductingauthor for future paediatric antibiotic CTs ESCMID Online Lecture Library SEARCH STRATEGY and SELECTION CRITERIA

• The following databases have been systematically searched using a strategy combining MeSH and free text terms for safety AND antibiotics in children and neonates : ‐ Medline ‐ Cochrane ‐ Clinicaltrials.gov

• Search limited to CT published or registered after 2000

• Considered eligible for inclusion studies reporting : 1. inclusion and exclusion criteria 2. primary and secondary endpoints, one of which is Safety 3. study design: RCT

• Excluded studies reporting data on 1. prophylaxis 2. topical/inhalational © by author 3. Febrile Neutropenia/Cystic Fibrosis 4. other study design

• ESCMIDAge range 0 ‐ 18 years Online Lecture Library • Studies presenting data from both adults and children included only if age‐related data could be identified PRELIMINARY RESULTS

STUDY SELECTION: • Our search identified 3,006 papers (Medline and Cochrane) and 1,010 CTs (clinicaltrials.gov) • 62 papers and 65 CTs fulfilled our inclusion and exclusion criteria and have been included in the analysis

PRELIMINARY DATA EXTRACTED FROM 62 PUBLISHED PAPERS SELECTED

SPONSOR n (%): • Industry: 23 (37%) • No‐profit: 39 (63%) n (%) of CTs PER ANTIBIOTIC CLASS: n (%) of ENROLLED PATIENTS PER ANTIBIOTIC CLASS

MONO vs COMBINED ANTIBIOTIC REGIMENS n (%): • Monotherapy 120 (90,9) • Combination 12 (9,1)

Patients with Serious Adverse Event and Drug‐related Adverse Events by antibiotic class, n (%):

ADVERSE EVENT BY SYSTEM, n (%):

• Overall pediatric AE/SAE rates are low, class predictable and extremely rarely were safety issues specific to the pediatric population

• Safety evaluation very poorly described and reported in CTs

• Sample size for safety studies for similar drugs vary considerably; both open label and blinded studies reported • Detectable level of SAE/AE© by unclear author from study design • Potential for optimal study design based on safety extrapolation fromESCMID adult trials Online Lecture Library AMR –Data from ECDC HAI PPS – children and neonates (all 29 EU/EEA Member States ) LID submitted 2016

• Data obtained from 17,273 children • Highest HAI prevalence in larger hospitals and in PICU/NICU • Independent risk factors for HAI:

‒ medical devices ‐ CVC ‒ young age (particularly neonates) ‒ prolonged length of stay

• Substantially different ESCMID Online Lecture patternLibraryof HAIs in children compared to adults ‐ BSI

33rd Annual Meeting of the ESPID, Leipzig 2015 © by author ESCMID Online Lecture Library Kent A, Expert Rev Anti Infect Ther 2014 Strategic trials to re‐evaluate Rao SC, Cochrane Database Syst Rev. 2011 Kaye KS, Pharmacotherapy 2015 efficacy/safety for older ABs

Paediatric studies have lower rates of AG/GP ototoxicity and nephrotoxicity

Consider pushing therapeutic index eg higher Cmax Combinations © by author • Combination therapy with 2 or more active drugsESCMID associated with Online potentially increased Lecture Library efficacy in the treatment of CRE infections • Optimal neo/ped combinations unclear

Daikos GL, Antimicrob Agents Chemother 2014 Tumbarello M, Clin Infect Dis 2012 Dose – Strategic trials required

• Increasing dosage (low rate of toxicity)

• Re‐evaluate therapeutic index

• Extended‐infusion dosing strategies

‒ Can produce longer duration of free drug exposure above MIC in isolates with higher MICs ‒ Resulted in decreased mortality compared to intermittent infusions Duration

Optimal duration to maximise efficacy and reduce resistance selection NeoVanc© by authorNeed for multiple strategic trials to define appropriate drugs, dose and duration of therapy for MDROs ESCMID Online Lectureinfections in children Library and neonates neoAMR project DNDi GARD Kaye KS, Pharmacotherapy 2015 Izadpanah M, J Res Pharm Pract 2015 Barker C, Curr Opin Infect Dis 2012 Asín‐Prieto E, J Infect Chemother 2015 NEW ANTIBIOTICS CURRENTLY IN CLINICAL DEVELOPMENT • April 2016, 37 antibiotics are listed on the Pew Charitable Trusts Antibiotic Pipeline • Very few data available limited to their in‐vitro activity and early PK • Among them, only 3 had an established PIP: – Carbavance (Meropenem+Vaborbactam)  Gram‐negative infections – Eravacycline  UTIs and cIAI – Solithromycin  CAP and gonococcal infections • 1 of the 37 antibiotics listed on the Pew antibiotic pipeline (Solithromycin)is being© investigated by author in children (maybe a few more) • A clear assessment is required about which AB are of critical importance to treat serious MDR infections in neonates and children –ESCMID then obtain enough Online data to allow Lecture them to enter Library routine care • Proportionate approach required of risks/benefits related to unmet need. http://www.pewtrusts.org/~/media/assets/2016/05/antibiotics‐currently‐in‐clinical‐development.pdf?la=en Strengthening Publications Reporting Infection in Newborns Globally –SPRING Group ‐ LID 2016

New positive initiatives led by multiple stakeholders – FDA/CTTI and C‐PathinUSAandEMA/EnprEMAin Europe Very clear recognition that neonates and children will need both new and old AB to treat MDRGN infections in HIC and LMIC settings – Advocacy issue – learn from HIV

PRAGMATIC international© by author expert consensus guidance (including multiple stakeholders) on the ESCMIDcore requirements Online that areLecture required Libraryfor regulatory approval of new AB and entry into clinical care © by author ESCMID Online Lecture Library GARPEC Website www.garpec.org