Ceftazidime-avibactam (+/- aztreonam) use in Paediatrics Case study: Ceftazidime-avibactam (+/- aztreonam) use in Paediatrics James Hatcher and Irasha Hettiarachchi

Complex medical background 12 year old boy Consanguineous Somali parents Born in UK but has travelled to Somalia Chronic severe neutropenia Exocrine pancreatic insufficiency Small joint arthritis Episodes of colitis – IBD or neutropenic colitis Recurrent infections At least 2 episodes of Salmonella gastroenteritis

Treatment of neutropenia Very high dose GCSF = no response High dose IvIg and methylprednisolone = no response Ciclosporin = developed encephalopathy Responded to a combination of rituximab, MMF and methotrexate. Neutrophils remained normal until April 2015

2015 -2018 Referred for bone marrow transplantation Relapsing episodes of neutropenia 2018 progression of disease Febrile neutropenic colitis Perianal soft tissue collection Descending colon with thickened wall in keeping with severe focal inflammation

Acute deterioration May 2019 Admitted with abdominal pain and septic MRI showed large intra-abdominal collection at site of stricture presumably due to perforation Neutrophils 0.0 laparotomy - large collection with adhesions. Clearance of abscess, resection of stricture, creation of colostomy. Granulocyte infusions started (rituximab cover)

Stabilisation at local PICU Blood culture and intra-abdominal pus Multi-drug resistant Enterobacter ludwigii CT scan showed continued collection

Microbiology Testing Metallo-beta-lactamase positive on PCR Antibiotic Disc Diffusion Sensitivity Pattern Penicillins (+/- inhibitors) and monobactams Amoxicillin Resistant Co-amoxiclav Piperacillin/tazobactam Mecillinam Aztreonam Cephalosporins (+/- inhibitors) Ceftazidime Ceftriaxone Cefpodoxime Cefepime Ceftolozane/tazobactam Ceftazidime/avibactam Carbapenems Ertapenem Meropenem Aminoglycosides Amikacin Sensitive Gentamicin Tobramycin Miscellaneous Ciprofloxacin Co-trimoxazole Tigecycline Fosfomycin Chloramphenicol Microbiology Testing Metallo-beta-lactamase positive on PCR IMP enzyme positive Antibiotic Minimum Inhibitory Concentration (MIC) Testing Meropenem 2 mg/L = sensitive Colistin 0.5 mg/L = sensitive Fosfomycin 16 mg/L = sensitive Ceftazidime >256 mg/L = resistant Tigecycline 4 mg/L = resistant

Enhanced (synergy) zones to placing discs of ceftazidime/avibactam and aztreonam discs next to each other No zone to ceftazidime/avibactam No zone to aztreonam

Placing the ceftazidime/avibactam and aztreonam MIC strips on top of each other allows a crude MIC to be interpreted Cross MIC strips show the zone of synergy

Antimicrobial Therapy Commenced on meropenem and colistin at local PICU Amikacin added when results extended sens known Due to continued instability therapy changed: Ceftazidime/avibactam Aztreonam Metronidazole Teicoplanin Amikacin Patient stabilised with this combination to consider transfer to Great Ormond Street (GOSH) Blood cultures now negative

Transfer to GOSH June 2019 Aim to stabilise with hope to proceed to rapid HSCT Clinical deterioration following transfer ARDS Pancytopenia and coagulopathy Inotrope dependence Fistula / dehiscence from surgical wound Bone marrow aspirate consistent with bone marrow failure

Received a dose of 1.812.5mg every 8 hours Adult dose of ceftazidime/avibactam 2.5g every 8 hours Paediatric dose of ceftazidime/avibactam 3 months – 6 months: 50mg/kg every 8 hours 6 months – 18 years: 62.5mg/kg every 8 hours

Ongoing spikes of temps throughout admission CRP remained high. Renal function remained normal

Progressive wound dehiscence and abdominal distension Progressive circumferential necrosis extended from around his stoma Not stable for surgical debridement Radiologically inserted drain into complex collection Still growing IMP positive Enterobacter species Enterococcus faecium and Rhizopus sp. On 18S PCR

Move to Palliative care Diagnosed with Adenosine deaminase 2 deficiency (ADA2) Rare genetic immunodeficiency Failed extubation Worsening wound necrosis No improvement in neutrophil count Ongoing clinical sepsis Transferred back to local PICU and died in July 2019

Ceftazidime-Avibactam Beta-lactam/beta-lactamase inhibitor combination – fixed dose 4:1 Avibactam stable against beta-lactamases: Ambler class A (TEM, SHV, CTX-M, KPC) Ambler class C (AmpC) Ambler class D (OXA) No activity against MBLs (NDM, VIM, IMP)

Ceftazidime-avibactam NICE. ES16 Nov 2017.

Ceftazidime-Avibactam Phase III clinical trial programme Seven prospective, international, multicentre, randomised Phase III studies RECLAIM 1, 2 and 3: Adults with cIAI RECAPTURE 1 and 2: Adults with cUTI (including acute pyelonephritis) REPROVE Adults with nosocomial pneumonia (including VAP) REPRISE Adults with CAZ-resistant pathogens Double-blind randomisation (1:1): CAZ 2000 mg + AVI 500 mg + metronidazole 500 mg IV q8h or MER 1000 mg IV + placebo q8h Primary objective: RECLAIM 1 and 2: Assess non-inferiority of CAZ-AVI re: clinical cure at TOC visit in patients with ≥1 identified pathogen (mMITT populations) RECLAIM 3: Proportion of patients with clinical cure at TOC visit (CE populations) Double-blind randomisation (1:1) : CAZ 2000 mg + AVI 500 mg q8h IV or DOR 500 mg + placebo q8h IV Primary objective: Assess non-inferiority of CAZ-AVI on co-primary endpoints in mMITT analysis set: Resolution of UTI-specific symptoms Resolution/improvement of flank pain Per-patient microbiol eradication and symptomatic resolution Double-blind randomisation (1:1) : CAZ 2000 mg + AVI 500 mg q8h IV or MER 1000 mg + placebo q8h IV Plus open-label empiric linezolid + aminoglycoside Primary objective: Assess non-inferiority of CAZ-AVI on clinical cure rate at TOC visit in cMITT and CE populations Open-label randomisation (1:1) : CAZ 2000 mg + AVI 500 mg + metronidazole 500 mg q8h IV or Best available therapy Primary objective: Estimate per-patient clinical response to CAZ-AVI and best available therapy at TOC visit in cUTI and cIAI caused by CAZ-resistant Gram-negative pathogens Slide ID: PD Abbreviations AVI, avibactam; CAZ, ceftazidime; CE, clinically evaluable; cIAI, complicated intra-abdominal infection; cMMIT, clinically modified intent-to-treat; cUTI, complicated urinary tract infection; DOR, doripenem; IV, intravenous; MER, meropenem; mMITT, microbiological modified intent-to-treat; q8h, every 8 h; TOC, test of cure; UTI, urinary tract infection; VAP, ventilator-associated pneumonia. Highlighted references: Box (top centre): NCT01499290 p1 (purpose), p3. (more information); NCT01499290 p1 (purpose), p3. (more information); NCT01500239 p1 (purpose), p3-4. (locations); NCT01595438. p1. (purpose) and p4. (more information); NCT01599806. p1. (purpose), p4. (more information); NCT01644643. p1. (purpose)., p4 (more information). NCT01808092. p1. (purpose), p3. (more information); Cerexa FDA Briefing Package. NDA 206494. December 2014. Accessed January 2015 [www.fda.gov Cerexa_CAZ-AVI for Injection]. p121. section 5.3.3. Box (column 1, middle row): NCT01499290. p1. (purpose); NCT01500239. p1. (purpose); NCT01726023. p.1. (purpose). Box (column 1, bottom row): NCT01499290. p1. (purpose), p2. (purpose, table); NCT01500239. p1. (purpose), p2. (purpose, table); NCT01726023. p1. (purpose), p2. (purpose, table); Cerexa FDA Briefing Package. NDA 206494. December 2014. Accessed January 2015 [www.fda.gov Cerexa_CAZ-AVI for Injection]. p105 table 55. Box (column 2, middle):NCT01595438. p1. (purpose); NCT01599806.p1. (purpose). Box (column 2, bottom): NCT01595438. p1. (purpose), p3. (purpose, table). ; NCT01599806. p1. (purpose), p2. (purpose, table); Cerexa FDA Briefing Package. NDA 206494. December 2014. Accessed January 2015 [www.fda.gov Cerexa_CAZ-AVI for Injection]. p105 table 55. Box (column 3, middle): NCT01644643. p1. (purpose). Box (column 3, bottom): NCT01644643. p1. (purpose), p2. (purpose, table); Cerexa FDA Briefing Package. NDA 206494. December 2014. Accessed January 2015 [www.fda.gov Cerexa_CAZ-AVI for Injection]. p105 table 55. Box (column 4, middle): NCT01808092. p1. (purpose). Box (column 4, bottom): NCT01808092. (purpose), p2. (purpose, table); Cerexa FDA Briefing Package. NDA 206494. December 2014. Accessed January 2015 [www.fda.gov Cerexa_CAZ-AVI for Injection]. p105 table 55. CE, clinically evaluable; cMMIT, clinically modified intent-to-treat; mMIITT, microbiological modified intent-to-treat

Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party. JAC. 2018

Comparison with cefepime Shown to be safe and effective Similar AE to ceftazidime PK data being reported separately

NDM + ESBL positive Kleb pneumo Example of synergistic combination of ceftazidime/avibactam (CAZ/AVI) and aztreonam (ATM) for colisitin resistant Klebsiella pneumoniae metallo-beta lactamase producers Figure 1 Example of synergistic combination of ceftazidime/avibactam (CAZ/AVI) and aztreonam (ATM) for an NDM + ESBL-producing K. pneumoniae. Susceptibility testing of ATM alone (a), combination of CAZ/AVI with ATM (b) and CAZ/AVI alone (c). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC. Unless provided in the caption above, the following copyright applies to the content of this slide: © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. NDM + ESBL positive Kleb pneumo Journal of Antimicrobial Chemotherapy, Volume 73, Issue 2, February 2018, Pages 542–544, https://doi.org/10.1093/jac/dkx393

Aztreonam + Avibactam CRE Enterobacterales isolates n=120 (mostly KPC) Antimicrobial MIC50 (μg/ml) MIC90 %susceptible (EUCAST) %resistant Aztreonam/avibactam 0.12 0.5 - Aztreonam >16 1.7 97.5 Meropenem 8 >32 12.5 46.7 Gentamicin >8 40.8 56.7 Amikacin 32 59.2 25.8 Tigecycline 2 85.0 3.3 Colistin 0.25 81.7 18.3 Adapted from: Sader et al. Antimicrobial Activities of Aztreonam-Avibactam and Comparator Agents against Contemporary (2016) Clinical Enterobacteriaceae Isolates. AAC 2018

MIC range MIC50 (μg/ml) MIC90 Good in vitro activity of AZT-AVI against MBL Enterobacterales Poor in vitro activity of AZT-AVI against Pseudomonas most likely related to co-existing porin related mechanisms Organism Mechanism MIC range MIC50 (μg/ml) MIC90 Enterobacterales NDM (n=72) ≤0.015 – 8 0.12 0.5 IMP (n=27) 0.03 – 4 0.25 1 VIM (n=64) ≤0.015 – 2 Pseudomonas aeruginosa NDM (n=3) 16 - >128 - IMP (35) 2 – 128 32 64 VIM (270) 0.25 - 128 16 Adapted from: Kazmierczak et al. Multiyear, Multinational Survey of the Incidence and Global Distribution of Metallo--Lactamase-Producing Enterobacteriaceae and Pseudomonas aeruginosa. AAC 2015

Summary Ceftazidime-avibactam has been shown to be safe in both adults and paediatrics Increasingly being used up front against some carbapenamases-producing organsims Potential for combination with aztreonam in difficult to treat MBL infections

Further reading Hawkey et al. Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party. J Antimicrob Chemother 2018; 73 Suppl 3 Sternbach et al. Efficacy and safety of ceftazidime/avibactam: a systematic review and meta-analysis. J Antimicrob Chemother 2018; 73: 2012-2029 Bradley et al. Safety and Efficacy of Ceftazidime-avibactam in the Treatment of Children >3months to <18 Years With Complicated Urinary Tract Infection: Results from a Phase 2 Randomized, Controlled Trial. Pediatr Infect Dis J. 2019 Sep; 38(9): 920-928