New Antibiotic Availability and Usage

1. New Antibiotic Availability and Usage Lennox K. Archibald, MD, PhD, FRCP, DTM&H Hospital Epidemiologist Shands Hospital University of Florida

2. Disclosures None No conflict of interest

3. “As we face the new millennium, we must renew our commitment to the prevention and control of infectious diseases, recognizing that the competition between humans and microbes will continue long past our lifetimes and those of our children.” Jeffrey P. Koplan, Director, CDC

4. ...no man is an island, entire of itself; every man is a piece of the continent, a part of the main... (From “Devotions” by John Donne (1572-1631)

5. World-wide problem Major risk factors Antimicrobial use (misuse) Infection control practices (non-compliance) Antimicrobial Resistance

6. Elderly Immunosuppressive Rx Organ transplant Malignancy HIV / AIDS Diabetes Chronic renal disease Pregnant women Infants and children Alcohol / substance use Chronic lung disease Chronic heart disease Other chronic illnesses Antimicrobial Resistance: Vulnerable Patient Populations

7. >2 million hospitalized patients affected per year >90,000 deaths per year 85% bacterial pathogens 70% pathogens resistant to >1 agent Antimicrobial Resistancein the U.S.

8. Definition of Emerging Infections ...."Emerging infections are defined as "new, re-emerging or drug-resistant infections whose incidence in humans has increased within the past two decades or whose incidence threatens to increase in the near future." A number of factors were identified as reasons why emerging infections are a modern-day reality; no one factor could account for the problem"..... Reference: Lederberg J, Shope RE, Oaks SC, eds. Emerging infections: microbial threats to health in the United States. Washington, DC: National Academy Press, 1992

9. Selective Pressures- Antimicrobial Use and Resistance Fruit Animal husbandry Foreign travel Outpatient care Daycare Fisheries Marine paint Hospitals

10. Where do we stand at the moment?

11. Rates of Resistance Versus Rates of Infection • Over past decade, CDC has documented downward trend in infection rates in four major anatomic sites: • Bloodstream • Respiratory tract • Urinary tract • Wounds • At same time, infection rates due to resistant pathogens are increasing

12. “For as long as CDC has measured the prevalence of hospital-acquired infections caused by multidrug-resistant organisms, it has been increasing.” Muto CA. Infect Control Hospital Epidemiol 2005; 26:10-12.

13. Trend in licensed hospital beds, NNIS Hospitals P <0.01 ICU beds Hospital beds Archibald et al. Clin Infect Dis. 1997 Feb;24(2):211-5.

14. CDC Data What are the sentinel bugs?

15. Distribution of the most common HA pathogens isolated from the four major infection sites, ICU, NNIS hospitals, 1990-1998 37% CoNS* 14% Enterococcus sp. 13% S. aureus 5% Candida albicans 5% Enterobacter sp. 26% Other 16% Enterococcus sp. 13% CoNS* 12% S. aureus 10% P. aeruginosa 9% Enterobacter sp. 40% Other SSI 7% BSI 17% OTHER 22% UTI 23% 18% Escherichia coli 16% Candida albicans 14% Enterococci 11% P. aeruginosa 6% K. pneumoniae 35% Other 18% S. aureus 17% P. aeruginosa 11% Enterobacter sp. 7% K. pneumoniae 5% Acinetobacter sp. 42% Other PNEU 31% *coagulase-negative staphylococcus

16. Pathogen Staphylococcus aureus Escherichia coli Coagulase-negative staphylococci Enterococcus spp. Pseudomonas aeruginosa Enterobacter spp. Klebsiella pneumonia Percentage* (n=101,821) 13 12 11 10 9 6 5 Resistance methicillin ampicillin methicillin vancomycin imipenem ceftazidime ceftazidime Seven Pathogens Associated with 66% Hospital-Acquired Infections  Increasing resistance over past 20 years 66% Total Source: All sites of nosocomial infection, Hospital-wide Component, National Nosocomial Infection Surveillance System, January to March 1996: Am J Infect Control 1996:24;380-8

17. Sentinel Bug/Drug Combinations of Public Health Significance (Healthcare Settings) • Staphylococcus aureus---methicillin • Enterococcus spp.---vancomycin • Pseudomonas aeruginosa---3rd generation cephalosporins (3rd GC) • Pseudomonas aeruginosa/Imipenem • Escherichia coli & other GNR/3rd GC • GNR/Quinolones

18. Sentinel Bug/Drug Combinations of Public Health Significance (Community) • Staphylococcus aureus/methicillin group penicillins • Streptococcus pneumoniae/penicillin • Salmonella spp./ Quinolones • Relevant to outpatient, freestanding centers, LTCF, homecare

19. Hospital-associated Pneumonia:Pathogens • S. aureus: 18% • P. aeruginosa 17% • Enterobacter spp. 11% • K. pneumoniae 7% • Acinetobacter spp. 5%

20. Methicillin-resistant S. aureus (MRSA) Infections in NNIS Hospitals, by ICU Status, 1986-1998 % resistant

21. Methicillin (oxacillin)-resistant Staphylococcus aureus (MRSA) among ICU patients, 1995-2004 Source: National Nosocomial Infections Surveillance (NNIS) System

22. World-wide Prevalence of MRSA by Country Lancet 2006; 368:876

23. Vancomycin-resistant Enterococcal (VRE) Infections in NNIS Hospitals % resistant

24. Vancomycin-resistant Enterococci among ICU patients, 1995-2004 Source: National Nosocomial Infections Surveillance (NNIS) System

25. Estimated Change in Change in Predictor Rate of VRE P-value Non-ICU VRE rate +++ 0.0001 Cephalosporin use (3rd) ++ 0.0002 (in all unit types) Vancomycin use ++ 0.0001 Type of ICU + 0.01 Independent Predictors* of Vancomycin-Resistant Enterococci in Adult Intensive Care Units * Preliminary Logistic Regression analysis (n=75) controlling for each factor, plus ICU “A” or “B” Source: NNIS/ICARE (preliminary)

26. Use of Vancomycin in U.S.*, and VRE at NNIS** Hospitals U.S. Hospitals All NNIS Hospitals 120 20 100 15 80 Kilograms of vancomycin (x100) resistant 60 10 enterococci % vancomycin- purchased* 40 5 20 0 0 84 85 86 87 88 89 90 91 92 93 94 95 96 97 Year * Kirst et al., Historical usage of vancomycin Antimicrob Agents Chemo 1998:1203-4 ** National Nosocomial Infections Surveillance System (CDC)

27. Fluoroquinolone-resistant Pseudomonas aeruginosa among ICU patients, 1995-2004 Source: National Nosocomial Infections Surveillance (NNIS) System

28. 3rd generation cephalosporin-resistant Klebsiella pneumoniae among ICU Patients,1995-2004 Source: National Nosocomial Infections Surveillance (NNIS) System

29. Extended Spectrum -lactamases (ESBLs) Risk Factors for Colonization/Infection* • Hospitalization • Nursing home residency • Length of hospital/ICU stay • Severity of illness • Antibiotic exposure (esp. ceftazidime, aztreonam) • Invasive devices/instrumentation

30. Imipenem-Resistant P. aeruginosa

32. P <.01 Archibald et al. JID 2005

35. Fluoroquinolone-resistant Pseudomonas aeruginosa among ICU patients, 1995-2004 Source: National Nosocomial Infections Surveillance (NNIS) System

36. 3rd generation cephalosporin-resistant Klebsiella pneumoniae Among ICU Patients,1995-2004 Source: National Nosocomial Infections Surveillance (NNIS) System

37. Rate of Antimicrobial Use in Adult Intensive Care Unit (ICU) Areas (n=108) and non-ICU Areas (n=40) P <0,05 Wilcoxon rank sum Source: ICARE Phase 2

38. Hospital-Associated Pneumonia • Leading cause of ICU antimicrobial prescribing

39. Resistant PathogensCommunity-acquired • Streptococcus pneumoniae • Salmonella • Shigella • Gonococci • Haemophilus influenzae • Mycobacterium tuberculosis • Staphylococcus aureus • ***HIV*** • Malaria

40. The Reality?

41. The Best of Times • Over 100 antimicrobial agents available in the U.S. • New antifungals and antivirals • DNA probes and PCR provide accurate laboratory diagnosis of infections in hours

42. However… • No new classes of agents 1968-2000 • Since 2000, only 3 new classes approved by FDA—effective largely against MRSA &VRE: streptogramins, linezolid, daptomycin • Apart from tigecycline, no new class of agents against Gram-negative organisms

43. The Worst of Times • New pathogens continue to emerge • Resistance continues to increase: bacteria, fungi, viruses, and parasites • Reports of MRSA from community settings • Pressures to reduce laboratory costs are curtailing diagnostic services • Not much new for gram negative infections

44. Other Emerging Gram-negative pathogens • Acinetobacter spp. • Stenotrophomonas spp. • Extended spectrum beta-lactamase producing pathogens: • Enterobacter cloacae • Klebsiella pneumoniae • Carbapenemase-producing Klebsiella pneumoniae

45. Resistant PathogensCommunity-acquired • Streptococcus pneumoniae • Salmonella • Shigella • Gonococci • Haemophilus influenzae • Mycobacterium tuberculosis • Staphylococcus aureus • ***HIV*** • Malaria

46. Emergence of Multidrug Resistance in S. pneumoniae • 1930s: Sulfonamide / sulfa drugs discovered & used • 1940s: PCN introduced for Rx • 1943: First sulfa-resistant clinical isolate reported • 1967: First PCN-resistant clinical isolate reported (New Guinea) • 1977: Outbreak of multi-drug resistant pneumococci (South Africa) • 1990s: Global spread of resistant pneumococci

47. Gram-negative Pathogens • 1986 through 2003: 65% of pneumonia episodes • Proportion of Acinetobacter spp. pneumonias increased from 4% in 1986 to >7.0% in 2003

48. Why Are Gram-negative Infections Increasing? • Adhere to host tissue via microbial adhesions • Interact with receptors on mucosal surfaces • Adhesin/receptor interactions define bacterial populations

49. Why Are Gram-negative Infections Increasing? • Changes in adhesins associated with resistant microorganisms or their interactions • Hence the underlying role of antimicrobial use!! • Thus, control must include control of antimicrobial use in ICUs

50. Antimicrobial Resistance Issues in Developing Countries • Unnecessary intensive care units • Indiscriminate antimicrobial use • Blind empiricism • Unnecessary prophylaxis • Inability to detect true resistance • Enhancement of laboratory capacity • Quality assurance (costly)