Emerging Multidrug‐Resistant Organisms (MDROs)

David M. Mushatt, MD, MPH&TM, FIDSA Chief, Tulane Adult ID Section World Economic Forum Global Risk Annual Report:

 “arguably the greatest risk . . . to human health comes in the form of antibiotic-resistant bacteria. We live in a bacterial world where we will never be able to stay ahead of the mutation curve. A test of our resilience is how far behind the curve we allow ourselves to fall.” Public Health Significance

 Antimicrobial resistance:  Kills: higher rates of death (generally about double)  Increases time of infectivity  Can divert resources from other health-related development goals  Increases the cost of care  More expensive treatments, prolonged treatments, prolonged hospitalizations  Threatens global trade and security

WHO Antimicrobial Resistance Fact Sheet, 2013 Lives Devastated/Lost Due to Antibiotic-Resistant Organisms Risk Factors for MDR Emergence

 Antibiotic (Ab)use in Humans  Antibiotic (Ab)use in Animals  Failures in Infection Prevention and Infection Control  Transmission of Resistant Pathogens Explosion of Antibiotic Resistance

• Era of – MRSA (50‐60% locally) – VISA (“MIC Creep”), VRSA – VRE – Multidrug‐Resistant GNRs (MDROs) • Pseudomonas aeruginosa • ESBL‐containing Klebsiella pneumoniae and E. coli • Acinetobacter baumannii • Carbapenemase Resistant Enterobacteriaceae (CRE) – KPC and NDM‐Enterobacteriaceae

Emergence of Multidrug‐Resistant Organisms (MDROs) Declining New Antibacterial Drug Approvals, U.S. Approvals

Spellberg, CID 2004, Modified What You Don’t Want to See!!

Dig a little deeper, and a LOT further back

• “the majority of these strains were multidrug resistant indicating that antibiotic resistance is a common and widespread phenotype in pristine, unimpacted environments” • “we describe a novel macrolide kinase variant and an inducible daptomycin hydrolase, demonstrating not only that resistance is prevalent in the absence of anthropogenic antibiotics, but hitherto undiscovered mechanisms of resistance” • “the antibiotic resistome is an ancient and pervasive component of the microbial pangenome”

Plasmid‐mediated Colistin Resistance (mcr ‐1) December 31, 2016 New Delhi Metallo‐Beta‐Lactamase (NDM)

• CDC’s MMWR January 13, 2017 / 66(1);33 • 70s female s/p multiple hospitalizations in India • Dies from septic shock in Reno, Nevada • CRE Klebsiella pneumoniae grows from wound • Resistant to 26 antibiotics, including all aminoglycosides and polymyxins tested • Intermediate R to tigecycline • RESISTANT TO ALL ABX IN US!! What Can Be Done?

 Decrease rates of antibiotic usage / Improve Antibiotic Stewardship  By physicians  By public: requires education  Restrict use of antibiotics in agriculture  80% of antibiotics used in U.S. are for animals  Promote drug development  Regulatory policy changes (bring drugs to market faster)  Improve diagnostics  Prevent infections  Global Coordination

What Can Be Done?

 Reduce Selection Pressure:  Decrease unnecessary use of antibiotics / Improve Antibiotic Stewardship https://wwwn.cdc.gov/arinvestments Summary of Core Elements of Hospital Antibiotic Stewardship Programs JCAHO Required as of Jan. 1, 2017

• Leadership Commitment: Dedicating necessary human, financial and information technology resources • Accountability: Appointing a single leader responsible for program outcomes. Experience with successful programs show that a physician leader is effective • Drug Expertise: Appointing a single pharmacist leader responsible for working to improve antibiotic use. • Action: Implementing at least one recommended action, such as systemic evaluation of ongoing treatment need after a set period of initial treatment (i.e. “antibiotic time out” after 48 hours) • Tracking: Monitoring antibiotic prescribing and resistance patterns • Reporting: Regular reporting information on antibiotic use and resistance to doctors, nurses and relevant staff • Education: Educating clinicians about resistance and optimal prescribing Antibiotic Shortages Reasons for Shortages Challenges in Treating MDROs  Few effective antibiotics  Toxicity of available antibiotics  Diagnostic limitations  What is the specific resistance mechanism?  What is the turnaround time for advanced diagnostics? Polymyxins

• Colistin – Colistimethate (prodrug of colistin for IV use) • Polymyxin B Polymyxins

• Discovered in 1947 • Derived from products of Bacillus species • Commonly used parenterally until early 1960s • Little use by 1980 because of nephrotoxicity • Now increased use with emergence of multi- drug resistant gram negative bacilli Mechanism of Action

• Cyclic polypeptide detergents • Penetrate into cell membrane, interact with phospholipids, and disrupt membrane • Bind to lipid A portion of endotoxin in cell wall (lipopolysaccharide) Antimicrobial Spectrum

• Broad range of gram-negative aerobic bacilli • Parenteral use reserved for resistant organisms – Pseudomonas aeruginosa – Acinetobacter baumannii Downsides

Toxicities • Reversible dose-related nephrotoxicity • Neurotoxicity: – Paresthesias of lips, tongue, extremities – Peripheral neuropathy – neuromuscular blockade Dosing • Optimal dosing still uncertain ESKAPE: •Enterococcus faecium •Staphylococcus aureus •Klebsiella pneumoniae •Acinetobacter baumannii •Pseudomonas aeruginosa •Enterobacter species

Clinical Infectious Diseases 2010;50:1081–1083 Ann Intern Med. 2016;165:363‐372 New Antibiotics Since 2010

Gram‐negative Agents 1. ceftolozane‐tazobactam 2. ceftazidime‐avibactam Gram‐positive Agents 3. ceftaroline 4. oritavancin 5. dalbavancin 6. tedizolid Newest Antibiotics

Clostridium difficile infection 7. fidaxomicin Tuberculosis (TB) 8. bedaquiline Newest Antibiotics

• “recently approved antibiotics have generally been lacking in biological innovation or public health importance” • The authors fault the – “me‐too” pattern of drug development – vague clinical outcomes selected as endpoints in most of the premarketing trials – premium pricing despite unclear evidence of improved clinical benefit

Deak D et al. Ann Intern Med 2016 May 31 Newest Antibiotics

• All but bedaquiline are members of established drug classes • Clinical trials took 5 to 9 years (median 6.2) • Fast‐track FDA approval for all 8 drugs took about 8 months • Almost all the drug approvals were based on noninferiority trials in fewer than 1000 patients • Prices for 7 of the new agents are considerably higher than for their comparator drugs, ranging from twice as high to almost 6000 times higher

New Approaches

New Antibiotics Non‐Antibiotic Angles of Attack From Soil to Pills

• Eleftheria terrae, was found to produce the best antibiotic candidate, which became teixobactin

iChip technology at work. Losee L. Ling et al Nature 517, 455–459 (22 January 2015)

Lugdunin

• Sampling of 187 hospital patients • People whose noses naturally contained Staph. lugdunensis were 6 times less likely to have S. aureus than people whose noses lacked S. lugdunensis • S. lugdunensis found to produce lugdunin, a cyclic peptide that inhibits Staph aureus

Zipperer, A. et al. Nature http://dx.doi.org/10.1038/nature18634 (2016) Brazilian Peppertree Bacteriophage Viruses Can ‘Eat' Bacteria from Within Novel Approaches

• Developing microbe‐attacking treatments with diminished potential to drive resistance – Immune‐based therapies, such as infusion of monoclonal antibodies and white cells that kill microbes – Antibiotics or biologic agents that don’t kill bacteria but alter their ability to trigger inflammation or cause disease • Developing treatments attacking host targets rather than microbial targets to avoid selective pressure driving resistance – Direct moderation of host inflammation in response to infection (e.g., cytokine agonists or antagonists, PAMP receptor agonists) – Sequestration of host nutrients to prevent microbial access to nutrients – Probiotics that compete with microbial growth