The Perfect Storm

1. The Perfect Storm Robert S Jones, MSc, DO, FACP, FIDSA Day in Pediatrics Friday, October 3, 2014

4. Antibiotic Armageddon Robert S. Jones MSc DO FACP FIDSA RHPN Infectious Diseases October 3, 2014

5. Armageddon: An all-destroying war: a final and decisive war or conflict

6. Instructional Objectives • How does resistance occur? • What are some basic antibiotic principles? • How big is the problem? • What can we do as physicians to prevent resistance? • How does technology play a role? • What is the drug supply/pipeline for the future?

7. We are here Antibiotic Armageddon New Antimicrobials Resistance Year

8. Antibiotic resistance (AR) is a growing problem that has recently been identified as a major public health threat and priority by several expert committees, including those of the Institute of Medicine, the American Society for Microbiology, as well as by the U.S. Office of Technology Assessment American Society of Microbiology. Report of the ASM Task Force on Antibiotic Resistance. Washington, D.C., 1994. U.S. Congress, Office of Technology Assessment. Impacts of Antibiotic Resistant Bacteria (OTA-H-629). Washington, D.C., 1995. American Society of Microbiology. New and Reemerging Infectious Diseases: A Global Crisis and Immediate Threat to the Nation’s Health, The Role of Research. Washington,D.C., 1997. Institute of Medicine, Forum on Emerging Infections. Antimicrobial Resistance: Issues and Options. Washington, D.C., 1998

9. Q1. What percentage of antibiotics used in the hospital are inappropriate? • 10% • 20% • 30% • 40% • 50% • 60%

10. Bacterial Resistance • When antibiotic use began, the genes encoding antibiotic resistance already existed unseen, either as mutants in infecting strains awaiting antibiotic selection or elsewhere in the larger bacterial world awaiting antibiotic mobilization • Three billion years of bacterial evolution had invented them, but only 70 years of antibiotic use has now selected, mobilized, and spread these resistance genes through infecting bacteria

11. Concern of Resistance • Antimicrobial resistance is not a new problem • Articles published >50 years ago in NEJM decried the overuse of antibiotics and the irrational use of fixed combinations • An article on the transmissibility of staphylococci noted that the administration of tetracycline to hospitalized patients increased the rate of nasopharyngeal colonization with S. aureus, much with showed resistance to tetracycline Bernsten CA, McDermott W. Increased transmissibility of staphylococci to patients receiving an antimicrobial drug. N Engl J Med 1960;262:637-42. Reversing the tide of antibiotic resistance. N Engl J Med 1960;262:578-9

12. Three basic mechanisms of resistance • Altering the target site of the antibiotic • Preventing access to the target site • Inactivating the antibiotic

13. Conventional Antibiotics and their Targets DNA Topoisomerase Inhibitors Quinolones 2-Pyridones RNA Synthesis Inhibitor Rifamycins Cell Membrane Agents Polymyxins Defensins Magainins Protein Synthesis 30S Inhibitors Tetracyclines Glycylglycines Aminoglycosides 50S Inhibitors Macrolides Chloramphenicol Lincosamides Streptogramin B Others Oxazolidinones Everninomycin DNA RNA 30S Cell Membrane DHFA THFA 50S Ribosomes Folic Acid Metabolism Inhibitors Sulfonamides Trimethoprim Cell Wall Cell Wall Synthesis Inhibitors Penicillins Bacitracin Cephalosporins Vancomycin Monobactams Teicoplanin Carbapenems Cycloserine Ramoplanin Phosphomycin

15. Staphylococcal Resistance • In 1944 it was first recognized that S aureuscould produce beta-lactamase and was resistant to penicillin • From 1944-1947, staphylococci in the hospital went from 100% susceptible to <25% susceptible • By 1960 almost 95% of community isolates were penicillin resistant and we began to see the beginning of MRSA • In 1961 we started to see MRSA

16. Rapid Development of Ciprofloxacin Resistance in Methicillin-Susceptible and Resistant Staphylococcus aureus • Prospective study on the development of ciprofloxacin resistance in S. aureusin the Atlanta VA • After the introduction of ciprofloxacin to the formulary all S. aureus isolates were screened for resistance • All resistant isolates, both MRSA and MSSA were collected (6/88-7/89) Blumbert, etal JID 1991;163:1279-1285

17. Rapid Development of Ciprofloxacin Resistance in Methicillin-Susceptible and Resistant Staphylococcus aureus • Results: • After 3 months of ciprofloxacin use, high-level resistance (MIC90, 64µg/ml) developed in MRSA • Resistance rose from 0% to 79% in MRSA in a one year period • High-level ciprofloxacin resistance also developed in MSSA, increasing to 13.6% over the same period • Conclusion: ciprofloxacin resistance can develop rapidly in S. aureus Blumbert, etal JID 1991;163:1279-1285

18. How quickly does resistance develop? Depends on: the drug and the bug indication (widespread vs restricted use) concerns for impact on resistance DrugOrganismTime to resistance Ciprofloxacin MRSA < 1 year Ciprofloxacin pneumococci > 10 years Nitrofurantoin UTI organisms decades Penicillin S. pyogenesdecades

19. Emergence of superbugs • NDM-1 (New Delhi metallobeta-lactamase 1): refers to transmissible genetic element encoding multiple resistance genes, not a specific bacteria • MDR TB • Malaria • ESKAPE • E. faecium(VRE) • S. aureus • Klebsiellapneumoniae • Acinetobacterbaumannii • Pseudomonas aeruginosa • Enterobacterspecies

20. New drugs No drugs “E.S.C.A.P.E.” Bugs • Enterococcusfaecium • Staph. aureus (MRSA) • Clostridium difficile • Acinetobacterbaumanii (MDR) • Pseudomonas (MDR) • Enterobacteriaciae (MDR)

22. The Origin and Spread of NDM-1. Moellering RC Jr. N Engl J Med 2010;363:2377-2379.

23. NDM-1 • New Delhi metallo-B-lactamase containing plasmid • First detected in 2008 in India • Spreading in fall of 2010 to UK, Canada, Japan and US as residents and visitors travel • Carries 14 drug resistance genes making them resistant to nearly all known antibiotics • Promiscuous plasmid that is easily spread between unrelated GNRs • Most commonly seen in E. coli and Klebsiellapneumoniae

24. Highly resistant Escherichia coli Proportion of invasive isolateswithresistance to fluoroquinolones in 2009 • Map 4 Proportion of 3rdgenerationcephalosporinsresistantisolates in 2009 Source: ECDC, Antimicrobialresistance surveillance in Europe 2009

25. Other Factors • Medical advances • People are living longer • As the body ages, its host defenses diminish • Advances in treatment of cancer, cardiovascular disease and renal disease extends peoples lives by 10-20 years • Improvements in trauma and surgery • Introduction of intensive care units • Exposure over time to numerous antibiotic treatments (OP, IP, long-term care) • 1988 the National Academy of Sciences/Institute of Medicine estimated that nearly half of the total annual production of antibiotics is directed to use in farm animals • Reliable testing for viral illnesses and other diseases

26. “When you grow up every 20 minutes, you get smart pretty fast.” Louis Rice MD, Brown University

27. Resistance • The association between increased rates of antimicrobial use and resistance has been documented for nosocomial infections and resistant community-acquired infections • Most antimicrobial use in humans is for treatment of OP infections • Otitis media is the second leading cause of office visits to physicians and accounts for over 40% of all outpatient antimicrobial use in children

28. Some Facts About Resistance • Drug-resistant infections take a staggering toll in the United States and across the globe. Just one organism, methicillin resistant Staphylococcus aureus (MRSA), kills more Americans every year than emphysema, HIV/AIDS, Parkinson’s disease, and homicide combined • Nearly 2 million Americans per year develop hospital-acquired infections (HAIs), resulting in 99,000 deaths – the vast majority of which are due to antibacterial-resistant pathogens • Based on studies of the costs of infections caused by antibiotic-resistant pathogens versus antibiotic-susceptible pathogens, the cost to the U.S. health care system of antibiotic resistant infections is $21 billion to $34 billion each year and more than 8 million additional hospital days

29. Impact of (resistance) MRSA on SSIs *P<.001. †P=.001. Engemann JJ et al. Clin Infect Dis. 2003;36:592-598.

30. Percentage of MRSA and VRE isolates from TRHMC

31. What can we do? • Need new technologies • Education • Follow treatment guidelines • Infection control programs • Know local resistance patterns (antibiogram) • Evidence based medicine • Antibiotic stewardship program • Immunize our patients

32. The Laboratory • The FilmArray is a multiplex PCR reaction designed for simultaneous detection and identification of: • Adenovirus • Coronavirus HKU1 • Coronavirus NL63 • Human Metapneumovirus • Influenza A • Influenza B • Parainfluenza 1 • Parainfluenza 2 • Parainfluenza 3 • Parainfluenza 4 • Rhinovirus/Enterovirus • Respiratory Syncytial Virus

33. The Laboratory • New technologies for quicker and more accurate identification • C diff • Influenza • Blood cultures (FISH for Enterococcus, yeast, Staph) • MRSA • RSV antigen • MRSA screen • Enterovirus PCR on spinal fluid • EBV and CMV antibody • HSV-1 and HSV-2 • PBP2 test on cultures

34. Common Errors in Interpreting Culture Reports • Confusing direct smear with culture • Confusing Staph. aureus with coag. neg. Staph. • Very different organisms • Very different clinical implications • Confusing MRSA, MRSE, MSSA, MSSE • Waiting for susceptibilities on organisms that may not be tested (CNS, etc.) • Assuming a culture is final when sensi’s appear on 1 organism from polymicrobial culture • Confusing bottles vs. sets (bacteremia) • Confusing UA with UC

36. Appropriate Antibiotic Use

37. There’s More to I.D. than…. “Pan-culture” “Vanco-Zosyn”

38. Q2. Vancomycinis a “stronger” antibiotic than Nafcillinfor Staphylococcus aureus • True • False

39. Principles of Selection

40. Host Characteristics • Immune status • Site of infection • Function of body systems responsible for absorption and elimination of drug • Allergies • Age • Pregnancy

41. Important Drug Features • Pharmacokinetics (absorption, distribution into body tissues and elimination) • Pharmacodynamics (mechanism of action, bacteriocidal or bacteriostatic nature of the antimicrobial effect, and the rate at which it occurs)

42. Identification of Organism • Gram stain • Collect specimen prior to starting antibiotics when possible • Collect appropriate specimens (site and type of culture, AFB, Fungal, Anaerobes, etc) • Immunologic or Molecular methods • Bacteriologic statistics: application of knowledge of the organisms most likely to cause infection in a given clinical setting

43. Site of Infection • Probably most important aspect of host factors

44. Basic Principles • Define the pathogen • Any culture (from relevant site) beats none • Contact outside labs for early culture results • Reculture if new fever (etc.), new abx • Treat the patient, not the culture • Match aggressiveness of Rx to severity and tempo of disease • Source control • Drain, debride, discontinue devices • Imaging, interventionalists

45. Basic Principles (cont.) • Antibiotics are not always benign; use with care • Allergy and ADEs (rash, GI, fever, cytopenias, renal, etc.) • Drug-drug interactions • TMP-SMZ, FQs, flagyl+ warfarin --> high INR, bleeding • Linezolid + SSRIs --> seretonin syndrome • FQs, macrolides + (multiple drugs) --> long QT, torsades • FQs, doxy, mino+Ca, Mg, Al, Fe --> drug inactivation • Resistance: current bug, next bug, C. difficile, population • Treat as narrowly and briefly as possible • Contain the contagion (infection control) • Prevention (immunize, hygiene, vents & lines…)

46. Q3. Penicillin allergy reporting is inaccurately reported in more than 85% of patients • A. True • B. False

47. . • A total of 150 patients (mean age 42 years; SD 16 years • 46% men; 47% black) were enrolled • The false-positive rate for self-reported penicillin allergy was 137 of 150 (91.3%; 95% CI 85.3% to 95.1%). Raja AS, Lindsell CJ, Bernstein JA, Codispoti CD, Moellman JJ. The use of penicillin skin testing to assess the prevalence of penicillin allergy in an emergency department setting. Ann Emerg Med. 2009 Jul;54(1):72-7

48. Penicillin skin testing • We will be offering skin testing in select populations within the next several months • Not appropriate for everyone • Not universally acurate

49. Antibiotic Selection Questions • Do I need to use an antibiotic? If so . . . • What would be the best drug? • What is the best dose for what I’m treating? • What is the best route of administration? • How long should I treat? • What are the potential side effects and collateral damage? • Does the patient have allergies or potential drug interactions? • What are the other host factors to consider?

50. Q4. What is the optimal treatment for acute uncomplicated cystitis? • Nitrofurantoin monohydrate/macrocrystals 100mg twice daily for 10 days • Rimethoprim-sulfamethoxazole (160/800 mg (DS tablet) twice daily for 3 days • Moxifloxacin 400mg daily for 3 days • Ciprofloxacin 500 mg twice daily for 3 days • Amoxicillin 500 mg three times a day for 7 days