Antibiotic Resistant Pathogens “Be afraid. Be very afraid.”

1. Antibiotic Resistant Pathogens“Be afraid. Be very afraid.” Patty W. Wright, M.D. Division of Infectious Diseases Vanderbilt University September 2014 There are no financial disclosures for this lecture.

2. Objectives • To discuss the mechanisms by which bacteria become resistant to antibiotics. • To discuss the epidemiology of antibiotic resistant pathogens. • To review the clinical presentation and treatment of antibiotic resistant infections.

3. What Is an Antibiotic? • Antibiotics = chemical substances produced by a microorganism that can kill or inhibit the growth of other microorganisms • For example: penicillins • Newer, synthetic agents now exist which are antibacterials, but not true antibiotics • For example: quinolones

4. Antibiotic Mechanisms of Action • Inhibition of cell wall synthesis • Disruption of bacterial membranes • Inhibition of protein synthesis • Inhibition of nucleic acid synthesis • Antimetabolites http://en.wikipedia.org/wiki/File:Prokaryote_cell_diagram.svg

5. Inhibition of cell wall synthesis Beta-lactams Penicillins, Cephalosporins, Carbapenems Vancomycin Disruption of bacterial membranes Daptomycin Polymyxins Colistin Both mechanisms bactericidal Inhibition/Disruption of Cell Walls and Membranes

6. Includes Aminoglycosides Tetracyclines Clindamycin Macrolides Linezolid Result in production of defective proteins May be bactericidal or bacteriostatic Inhibition of Protein Synthesis

7. Inhibition of nucleic acid synthesis Quinolones Metronidazole Rifamycins Bacteriocidal Antimetabolites Sulfonamides, Trimethoprim Prevent bacterial synthesis of folic acid Bacteriostatic Inhibition of Nucleic Acid Synthesis and Antimetabolites

8. 5 Basic Mechanisms of Resistance • Alteration of antibiotic binding sites • Enzymatic destruction or modification of the antibiotic • Decreased uptake of the antibiotic • Efflux of the antibiotic out of the cell • Decreased affinity for the antibiotic in specific pathways

9. Mechanisms of Resistance • Alteration of antibiotic binding sites • Changes in the Penicillin Binding Proteins may lead to… • MRSA • Strep pneumo resistance to PCN • Enzymatic destruction or modification of the antibiotic • Common cause of inactivation of the aminoglycosides

10. Mechanisms of Resistance • Decreased uptake of the antibiotic • Vancomycin, rifampin, and clindamycin are not able to enter Gram negatives • Efflux of the antibiotic out of the cell • Common resistance mechanism of Pseudomonas andAcinetobacter • Decreased affinity for the antibiotic in specific pathways • Provides resistance to the antimetabolites (trim-sulfa)

11. Development of Resistance MedicineNet.com

12. Development of Resistance MedicineNet.com

13. Objectives • To discuss the mechanisms by which bacteria become resistant to antibiotics. • To discuss the epidemiology of antibiotic resistant pathogens. • To review the clinical presentation and treatment of antibiotic resistant infections.

14. Multidrug-Resistant Organisms (MDROs) Infectious agents that are resistant to key antimicrobials. May include resistance to: One or more antimicrobials All but one antimicrobial or class All antimicrobials and classes Three or more antimicrobial classes* Limited treatment options Associated morbidity/mortality *Management of MDRO in Healthcare Settings, 2006 HICPAC

15. MDR GN Different Antibiotic Options S = Sensitive (Antibiotic will treat) R = Resistant (Antibiotic will NOT treat) What options do we have to treat this patient?

16. Epidemiology of Antibiotic Resistant Pathogens • Getting an antibiotic increases a patient’s chance of becoming colonized or infected with a resistant organism • Increasing use of antibiotics increases the prevalence of resistant bacteria in hospitals www.cdc.gov

17. Antibiotic Exposure Increases Risk of Resistance Patel G et al. Infect Control Hosp Epidemiol 2008;29:1099-1106 Zaoutis TE et al. Pediatrics 2005;114:942-9 Talon D et al. ClinMicrobiol Infect 2000;6:376-84

18. Effect of Antibiotics onAntimicrobial Resistance in Individual Patients Costelloe C et al. BMJ. 2010;340:c2096. systematic review and meta-analysis

19. Association of VancomycinUse with Resistance (JID 1999;179:163)

20. Annual Prevalence of ImipenemResistance in P. aeruginosa vs. CarbapenemUse Rate r = 0.41, p = .004 (Pearson correlation coefficient) 45 LTACHs, 2002-03 (59 LTACH years) Gould et al. ICHE 2006;27:923-5

21. Infection with Resistant Pathogens Is Associated with Higher Mortality

22. Mortality of resistant (MRSA) vs. susceptible (MSSA) S. aureus • Mortality risk associated with MRSA bacteremia, relative to MSSA bacteremia: OR: 1.93; p < 0.001.1 • Mortality of MRSA infections higher than MSSA: relative risk [RR]: 1.7; 95% confidence interval: 1.3–2.4).2 1. Clin. Infect. Dis.36(1),53–59 (2003). 2. Infect. Control Hosp. Epidemiol.28(3),273–279 (2007).

23. MRSA MRSA and Mortality: Bacteremia Cosgrove SE et al Clin Infect Dis 2003;36:53+

24. MRSA MRSA and Mortality: Surgical Site Infections Engemann JJ et al CID 2003;36:592+

25. Mortality Associated with CarbapenemResistant (CR) vs Susceptible (CS) Klebsiellapneumoniae (KP) p<0.001 p<0.001 OR 3.71 (1.97-7.01) OR 4.5 (2.16-9.35) Patel G et al. Infect Control Hosp Epidemiol 2008;29:1099-1106

26. Improving Antibiotic Use Reduces Resistance

27. P. aeruginosa susceptibilities before and after implementation of antibiotic restrictions (CID 1997;25:230) P<0.01 for all increases

28. Improving Antibiotic Use Is a Public Health Imperative • Antibiotics are the only drug where use in one patient can impact the effectiveness in another • If everyone does not use antibiotics well, we will all suffer the consequences • “Using antibiotics properly is analogous to developing and maintaining good roads”

29. Antibiotic Prescribing • Doctors prescribe antibiotics to children 62% of the time if they perceive parents expect & 7% of the time if they feel parents do not expect them • Antibiotics were prescribed in 68% of acute respiratory tract visits • 80% of those were unnecessary • $1.1 billion spent annually on unnecessary antibiotics for adults upper respiratory tract infections Pediatrics 103:711-718, 1999 J Fam Pract: 50(10): 853-8, 2001 Arch Int Med: 163(4): 487-94, 2003

30. ALL MDROs New Antibacterial Agents Approved 1983-2011: The Pipeline is Dry • Only 15-16 antibiotics are in development • Only 8 of these have activity against key Gram neg bacteria • None have activity against bacteria resistant to all current drugs Adapted from Spellberg B et al. Clin Infect Dis. 2004;38:1279-86.

31. Objectives • To discuss the mechanisms by which bacteria become resistant to antibiotics. • To discuss the epidemiology of antibiotic resistant pathogens. • To review the clinical presentation and treatment of antibiotic resistant infections.

32. Selected Specific Mechanisms of Resistance

33. Case • A 57 yo male with diabetes and renal failure is being treated for a foot ulcer with associated bone infection. He has received vancomycin after hemodialysis for almost 12 weeks. He continues to have poor wound healing and undergoes repeat I&D. Cultures grow S. aureuswith intermediate sensitivity to vancomycin.

34. Vancomycin Resistance in S. aureus VISA: vancomycin intermediate S. aureus VRSA: vancomycin resistant S. aureus NEJM. 2009; 360: 439

35. A 71 yo nursing home patient is admitted with pneumonia. Sputum cultures grow Klebsiellapneumoniae reported as sensitive to ceftriaxone and ciprofloxacin, but resistant to cefepime and ceftazidime. He is treated with ceftriaxone, but continues to have fever and respiratory decline. Case

36. Enzymatic Destruction:Beta-lactamases • Breakdown beta-lactams faster than they can bind the penicillin binding proteins • Classes A, B, C, D • A and C most common • Point mutations in Class A may lead to extended-spectrum beta-lactamases (ESBLs), which inhibit penicillins, cephalosporins and monobactams • Class B contain zinc & hydrolyze all but monobactams (aztreonam) • Easily transmitted to other bacteria

37. How Does Clinical Practice Contribute to the Development of Resistance?

38. Case • A 55 yo female presents with urinary frequency and burning. She is placed on cephalexin. Urine cultures grow Enterococcus. The doctor notes that the lab report does not mention sensitivity results for cephalexin (as it does for ampicillin), but decides not to change the patient’s antibiotics. The patient returns the next week with a kidney infection. Repeat urine cultures again grow Enterococcus.

39. Intrinsic Resistance • Some bacteria are intrinsically resistant to the certain antibiotics. • A literal ton of cephalosporins will not treat Enterococcus. • One bug spray may work for fleas, but not wasps.

40. Case • A 67 yo female develops pneumonia and dehydration following admission for a MI. She is placed on renally-dosed piperacillin-tazobactam. Sputum cultures grow Enterobacter, sensitive to pip-tazo. The patient’s renal function improves with hydration; however, her pip-tazo dose is not adjusted. A few days later the patient becomes sicker and is found to have Enterobacter, resistant to pip-tazo, in her blood cultures.

41. Underdosing • Bacteria may develop resistance to certain antibiotics. • The proper dosing of antibiotics is important to prevent the development of resistance. • Dosing decisions are often made on the basis of drug levels (such as vancomycin troughs). It is critical that they are drawn correctly.

42. Underdosing • You might kill the first few ants with the toxic ant food, but the rest of them figure it out and won’t eat anymore. • This happens a lot faster if the ants only take a little nibble of the poison instead of a feast.

43. Case • A 84 yo female develops abdominal pain and fever. CT scan of the abdomen shows diverticulitis and a left upper quadrant abscess. She is placed on ciprofloxacin and metronidazole. Surgery is consulted, but declines to operate due to the patient’s age and multiple medical problems. She is treated with 4 wks of antibiotics; however, a repeat CT shows persistence of the abscess. http://www.meddean.luc.ed

44. Poor Penetration • Antibiotics may not be able to penetrate into the site of the infection. • Abscesses, infected joints, CNS infections, etc • Infections of prosthetic devices, like central lines and artificial heart valves, are very difficult to treat without removal. • It doesn’t matter how much bug spray is outside, as long as the bees are safe inside the hive.

45. Case • A 4 yo female presents with a cough which has been present for several months. Her mother reports that the cough is worse at night and after she exercises. She does not have any associated fevers. The patient has been treated with a variety of oral antibiotics without improvement.

46. Incorrect Diagnosis • The patient does not actually have a bacterial infection. • Cancer, rheumatologic disorders, and other infections due to viruses, fungi, or mycobacteria may masquerade as a bacterial infection. • You can spray the “termites” with all the bug spray you want, but if the damage to the wood was actually due to water, then the poison is not going to help.

47. Case • A 43 yo patient with leukemia develops a very low WBC count and fever following chemotherapy. The patient is placed on broad-spectrum antibiotics (meropenem and vancomycin) without improvement in her fevers. Blood and urine cultures are negative. Unfortunately, the patient becomes septic and dies. Repeat cultures taken in the ICU prior to death are also without growth.

48. Immunodeficiency • A functioning immune system is often more important than the antibiotics. • Multiple levels and types of immunodeficiency lead to various risks, i.e. BMT vs. AIDS vs. DM vs. pregnancy, etc. • If you are staked to the ant hill with your hands tied behind your back, it really doesn’t matter how much bug spray you own.

49. A 51 yo male develops MSSA endocarditis involving a bicuspid aortic valve s/p a localized skin infection. He is treated with iv nafcillin with clearance of his blood cultures. One of the medicine residents reports reading an article that states you can treat endocarditis with 2 weeks of therapy. The patient completes 2 weeks of nafcillin and returns a week later with recurrent fever and chills. Case

50. The proper duration of treatment is important. Some infections take longer to treat than others: Endocarditis Osteomyelitis Prosthetic device infections Brain abscesses If you are supposed to treat the aphids daily for 2 weeks, but only do it for 2 days, some of them will survive to breed and eat your roses. Incorrect Duration