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. 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. Objectives

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

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

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

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

8. 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 5 Basic Mechanisms of Resistance

9. 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 Mechanisms of Resistance

10. 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 and Acinetobacter Decreased affinity for the antibiotic in specific pathways – Provides resistance to the antimetabolites (trim-sulfa) Mechanisms of Resistance

11. Development of Resistance MedicineNet.com

12. Development of Resistance MedicineNet.com

13. 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. Objectives

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

16. 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 Epidemiology of Antibiotic Resistant Pathogens www.cdc.gov

17. Antibiotic Exposure Increases Risk of Resistance Pathogen and Antibiotic ExposureIncreased Risk Carbapenem Resistant Enterobactericeae and Carbapenems 15 fold ESBL producing organisms and Cephalosoprins6- 29 fold 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. Clin Microbiol Infect 2000;6:376-84

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

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

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

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

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

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

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. Adapted from Spellberg B et al. Clin Infect Dis. 2004;38:1279-86. 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 ALL MDROs

31. 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. Objectives

32. Selected Specific Mechanisms of Resistance

33. 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. aureus with intermediate sensitivity to vancomycin. Case

34. Vancomycin Resistance in S. aureus VISA MIC 4-8 mcg/ml Thickened cell walls Vancomycin cannot penetrate Often associated with decreased susceptibility to daptomycin VRSA MIC ≥ 16 mcg/ml Acquired VanA gene from VRE Causes alteration of the binding site NEJM. 2009; 360: 439 VISA: vancomycin intermediate S. aureus VRSA: vancomycin resistant S. aureus

35. Case A 71 yo nursing home patient is admitted with pneumonia. Sputum cultures grow Klebsiella pneumoniae 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.

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. 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. Case

39. 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. Intrinsic Resistance

40. 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. Case

41. 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. Underdosing

42. – 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. Underdosing

43. 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. Case http://www.meddean.luc.ed

44. 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. Poor Penetration

45. 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. Case

46. 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. Incorrect Diagnosis

47. 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. Case

48. 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. Immunodeficiency

49. Case 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.

50. Incorrect Duration 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.

51. A 44 yo male with a h/o iv drug abuse is injured in a motor vehicle accident. He develops an infection of his leg wound with MRSA. He is treated with iv vancomycin while hospitalized. Because of his history of drug abuse, the physician wants to avoid sending the patient home with an iv line, so he writes the patient a script for vancomycin 1000mg po Q12hrs. The patient returns with recurrent infection. Case

52.  Some antibiotics have good oral bioavailability. Some don ’ t … or in the case of vancomycin, none. ◦ Agents with good po bioavailability include:  Quinolones, linezolid, TMP/sulfa, metronidazole, doxycycline, clinda ◦ If you are supposed to feed the roaches the poison, but you shake it on them instead, it ’ s probably not going to work. Poor Bioavailability

53. A 44 yo male with a h/o iv drug abuse is injured in a motor vehicle accident. He develops an infection of his leg wound with MRSA. He is treated with iv vancomycin while hospitalized. Because of his history of drug abuse, the physician wants to avoid sending the patient home with an iv line, so he writes the patient a script for linezolid 600mg Q12hrs. The patient returns with recurrent infection. Same Case … Different Drug

54. Patient non-adherence – Multiple potential causes of non-adherence: Inability to afford meds Drug abuse Mental illness Side effects Difficult dosing regimen – The bug spray doesn ’ t work if the hornets are in your backyard and the spray is at the hardware store. Non-adherence

55. Summary: Mechanisms of Action Mechanisms of action of common antibiotics and antibacterial agents – Inhibition of cell wall synthesis – Disruption of bacterial membranes – Inhibition of protein synthesis – Inhibition of nucleic acid synthesis – Antimetabolites

56. Bacterial resistance to antibiotics may occur by – Decreased uptake of the antibiotic – Efflux of the antibiotic out of the cell – Alteration of antibiotic binding sites – Enzymatic destruction or modification of the antibiotic – Decreased affinity for the antibiotic in specific pathways Summary: Mechanisms of Resistance

57. Antibiotics fail for a variety of reasons. Different antibiotics provide coverage for different bacteria. Proper antibiotic dose, duration, and route of administration are all important to prevent the development of resistance. Host factors, such as immunosuppression or barriers to adherence, are also important to the success of antibiotic therapy. Summary: Factors Leading to Clinical Failure