Antibiotics and Stewardship: What s New in Pediatrics-Land?

Transcription

1 Antibiotics and Stewardship: What s New in Pediatrics-Land? Sean P. Elliott, MD Professor of Pediatrics Associate Chair of Education, Department of Pediatrics University of Arizona College of Medicine Tucson, AZ

2 Objectives Describe current steps to be a successful antibiotic steward Identify new antibiotics in the pipeline Evaluate the potential impact and pediatric indications of new antibiotics currently on the market

3 Conflict of Interest Disclosure I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or provider of commercial services discussed in this presentation. I do not intend to discuss an unapproved or investigative use of a commercial product or device in my presentation.

4 Antimicrobial Resistance Critical threat to public health Value of antibiotics to human health: Increase life expectancy 2 10 years $100,000/life-year $60 trillion to $300 trillion in the U.S. 1% reduction efficacy = $600 billion cost to human health Consume 51 tons daily 80% agriculture/aquaculture

5 Nature abhors a vacuum Development of resistance: Point mutations DNA Most = unimportant Affect gene: Viable Non-viable Accumulated point mutations = function change

6 Selective Pressure mutant bacteria resistant to antibiotic Mutants: Less virulent Grow slowly Less competitive Less viable Less clinically significant never acquire chance for a toe-hold

7 Selective Pressure Remove the competition: Overuse of antibiotics (wide-spectrum) Permit growth Permit evolution Allow microbiologic & clinical significance Transfer resistance Multidrug-Resistant Problem! WHO: 1 of 3 greatest threats to human health

8 MDRO Infections Clinical characteristics: Progressive Invasive Persistent Related clinical characteristics: End-organ damage Adverse drug effects Emergence of additional MDROs

9 Antibiotic Resistance Alter binding site Decrease accumulation: Efflux Prevent entry Inactivate drug

10 EIN Survey 267 survey respondents 54: +CRE in their practice (85 patients) Pediatric AND adult patients Median age 31 years 11% age < 18 years Infrequent travel out of U.S. 67% died 76% hospitalization prolonged due to CRE

11 Infection Prevention Hand Hygiene Isolation practices Cohorting Challenges: My hands are cleaner than yours I m only going into the room for a second I don t believe your science Commitment

12 Antibiotic Stewardship What is it? Impact of EHR Problems: Pushback Funding Commitment

13 Pediatrics 2015;135(1) Antibiotic Stewardship ASPs: Freestanding children s hospitals (41) Continuous monitoring Dedicated pharmacist/peds ID ASP = improved Abx use Needs: Better metrics to measure use (IV/PO) Use/Cost vs. appropriate Use/Mortality New focus?: patient safety, CDI, MDRO

14 Antibiotic Stewardship Narrow is Good Monitor local epidemiology and EBM: S pneumoniae PCN-S Ampicillin/Amoxicillin 1 st line Rx CAP Follow-up to modify Rx: De-escalation Cessation (RS/TCx negative) Anticipatory Guidance

15 Agricultural antibiotic use Little regulation/oversight Non-pharmaceutical grade abx $25/kg Subtherapeutic dosing = selective pressure 2005: FDA banned FQ in poultry 2012: nonbinding recs to avoid antibiotics Effects of ban: Monitoring? Costs passed to consumers? True benefit of prophylaxis?

16 The War on Superbugs The 10 X 20 Initiative IDSA Few drugs to treat ESKAPE pathogens: E. faecium S. aureus K. pneumoniae A. baumannii P. aeruginosa Enterobacter

17 The War on Superbugs Fix the pipeline: Global intervention Political Scientific Industry Economic Intellectual property Policy Medical & Philanthropic leaders

18 The War on Superbugs Kennedy s dream: Political statement Reality? < 10 years to achieve Similarity to 10 X 20 initiative Moral Commitment Collective Commitment

19 The War on Superbugs War-thinking: Response to Anthrax attacks Funding channels Support big and small companies Commitment medical setting Commitment regional setting Commitment national setting Commitment global setting

20 Executive Order 13676: Combating Antibiotic- Resistant Bacteria President Obama Sept. 18, 2014

21 National Action Plan

22 National Action Plan Implementation by 2020: Major reductions in MDRO/PRO threats Improved antibiotic stewardship Elimination of antibiotics in agri/aqua-culture Expanded surveillance for MDRO/PRO Development of 2 or more abx drug candidates Task Force: Depts of Defense, Agriculture, Health & Human Services, State, Justice, Veterans Affairs, and Homeland Security; EPA; National Science Foundation; U.S. Agency for International Development; Domestic Policy Council; etc., etc.

23 Pipeline Problems Since 1970 s: few new classes Pharmaceutical Co.: Withdraw engagement Non-recuperated costs years discovery to production

24 Pediatric Antibiotic Discovery Delayed research Lack of Pediatric indication Toxicity profile Perceived lack of indication: MDRO and Pediatrics? Pendulum swing: G+ to G- NICU (breeding ground MDROs) Immature immune response

25 Pediatric Antibiotic Discovery What s available? Old drugs, new uses Accelerate pediatric safety testing Advocate pediatric indication Explore new classes & approaches Cationic anti-microbial peptides (CAMPs): Direct effect of CAMPs against microbes Enhance production of CAMPs by patient s innate immune system.

26 Oxazolidinones Linezolid (Zyvox ) PO/IV, 100% absorption & bioavailability Use: MRSA, PRSP, VRE; no gram neg. Static not cidal Protein synthesis inhibition Resistance (rare): altered binding site Adverse reactions: MAO inhibitor Thrombocytopenia

27 Fluoroquinolones (cidal) Ciprofloxacin, Levofloxacin, Moxifloxacin Spectrum: Gram negative bacteria (Pseudomonas) Atypical bacteria Less active against gram positive (staph/strep) Use: cystic fibrosis, Pseudomonas UTI and osteochondritis, otitis externa, CAP

28 Cubicin Daptomycin Indication: Adult SSTI and bacteremia (Gram + only) VISA, VRSA, VRE Not indicated: pneumonia IV only Cidal (cell-wall porin-producer) No safety info - Pediatrics

29 Tigecycline Tetracycline-derived FDA approved: CAP but not HAP, cssti, ciai Black box warning: Increased mortality (0.7%) HAP > CAP SSTIs Use only when no alternates available No Pediatric indication

30 Ceftaroline Broad-spectrum cephalosporin Cidal: S. pneumoniae (PRSP) H. influenzae MSSA MRSA Gram-negatives β-lactamase resistant (H. influenzae)

31 Ceftaroline Ceftaroline vs Ceftriaxone: Non-inferiority Similar safety profile Modified intent-to-treat evaluation: better outcomes Pediatric RCT study - CAP: Similar adverse outcomes Similar efficacy +Coombs conversion w/o hemolytic anemia

32 Ceftaroline No Pediatric indication Future use? Pediatric safety study FDA indication Theoretic: MRSA or PRSP pneumonia Hypothetically: SSTI, invasive disease IV only

33 Inhaled antibiotics Inhaled tobramycin: Chronic Pseudomonas Improves lung function (10% FEV1) Reduces acute pulmonary exacerbations Adverse effects: Slight bacterial resistance Mild tinnitus New: powdered form (faster, +cough )

34 Inhaled antibiotics Inhaled aztreonam: Monobactam Anti-Pseudomonal drug (IV) Prolonged anti-pseudomonal effect: After Tobramycin inhaled Association with IV anti-pseudomonal drugs 2.5% FEV1, better respiratory scores More frequent, needs system cleaning New: use in MDRO, NTM (MAI)

35 Inhaled antibiotics Inhaled colistin: IV colistin = nephrotoxic & neurotoxic Activity against MDRO, Pseudomonas Adverse effects: Higher rates bronchospasm Minimal toxicity Few studies high dropout rate New: resistance reported in China

36 Other Adult-based antibiotics Ceftazidime/avibactam: Combined with metronidazole Compared to meropenem Equivalent outcomes: complicated IAI Ceftobiprole medocaril: Broad-spectrum cephalosporin Cidal Gram + (incl. MRSA, P/C-R S pneumo.) Gram (incl. R-Pseudomonas) HAP/VAP: safe & effective

37 Other Adult-based antibiotics Ceftolozane/Tazobactam: MDR-Pseudomonas ESBL-Enterobacteriaceae Tedizolid: 6-day regimen vs 10-day linezolid Gram + only IV/PO SSTI: non-inferior

38 Other Adult-based antibiotics Dalbavancin: Approved: Adults w/ SSTI-Gram + 2 doses, 1 week apart No drug/lab monitoring Compared to Vanco/Linezolid Non-inferior LTX-109: Novel topical anti-mssa/mrsa Nasal decolonization efficacy