Epidemiologically Important Gram-negative Bacteria. Anthony Harris, MD, MPH Department of Epidemiology and Preventive Medicine University of Maryland

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1 Epidemiologically Important Gram-negative Bacteria Anthony Harris, MD, MPH Department of Epidemiology and Preventive Medicine University of Maryland

2 The introduction of antibacterial drug therapy in the 1940s led to a dramatic reduction in illness. The emergence of drugresistant bacteria is reversing the trend

3 The current antibiotic crisis differs from those in the past because several different organisms are involved and because there are no immediate solutions on the horizon

4 The prevalence of antimicrobialresistant human pathogens is rapidly increasing, but the discovery and development of new antimicrobial drugs have slowed dramatically

5 Recent data shows the same trends AJIC 2004;32;470

6 31.9%

7 NHSN: Antibiotic-resistance Bacteria CLABSI (% imipenem resistant) VAP (% imipenem resistant) CAUTI (% imipenem resistant) Pooled (% imipenem resistant) Pseudomonas 23.0% 25.1% 26.4% 25.3% Klebsiella 10.8% Acinetobacter

8 Outline of talk Mechanisms of resistance E. coli ESBL Klebsiella KPC/CRE Pseudomonas Acinetobacter Reasons for spread of resistance Methods to reduce resistance

9 Mechanisms of Resistance Decreased permeability of the outer membrane important for Pseudomonas aeruginosa Alteration of the target site important for penicillin-resistant Streptococcus pneumoniae Efflux Production of a bacterial enzyme

10 B-lactamase Production Encoded within a chromosome inducible important for Citrobacter, Enterobacter, Serratia, Pseudomonas Acquired on a plasmid or transposon usually produced all the time (noninducible) potentially transferable to other bacteria

11 Plasmid-mediated B lactamases First described: TEM-1, TEM-2, and SHV-1 resistance to penicillins 1st generation cephalosporins 2nd generation cephalosporins easily inhibited by clavulinic acid, sulbactam or tazobactam Now, more than 200 B lactamases have been documented (

12 Extended Spectrum B lactamases (ESBL) plasmid mediated B lactamase leads to diminished sensitivity to cefotaxime, ceftazadime and aztreonam Present mostly in E. coli and Klebsiella

13 Treatment of ESBL Infections KEY POINT: SEE HOW YOUR LAB IS IDENTIFYING THEM IN YOUR COMPUTER Do not treat ESBL s with third generation cephalosporins Antibiotics of choice include Carbapenems: may be preferable to any other antibiotic B-lactam/B-lactamase inhibitor antibiotics quinolones

14 E. coli Most common pathogen of nosocomial infections Sites of nosocomial infection surgical site infections blood stream infections urinary tract infections Common pathogen in ICU s

15 Klebsiella Common isolate 5% of nosocomial infection site isolates 8% of hospital-acquired UTI and pneumonia Sites of nosocomial infection surgical site infections pneumonia UTI

16 KPC: Epidemiology First reports in 2004 in New York In 2007 CDC data,8% of all Klebsiella isolates were reported to be carbapenem resistant, compared to just under 1% in Srinivasan A, Infect Contrl Hospi Epi, 2008;29:1099.

17 KPC: Resistance Most commonly seen in Klebsiella pneumoniae KPC confers resistance to penicillins, cephalosporins and carbapenems Present on a plasmid

18 KPC: Microbiological detection Difficult to identify for laboratories which has important clinical implications Ertapenem better method than imipenem or other carbapenems Anderson KF,J Clin Micro, 2007;:2723.

19 KPC: Infection control Difficult to determine if infection control measures should be the same for KPC as for ESBL-producing Klebsiella

20 Pseudomonas Common isolate 9% of nosocomial infection site isolates most common cause of nosocomial gramnegative pneumonia Sites of nosocomial infection bacteremia surgical site infections pneumonia

21 Antibiotic Options for Pseudomonas Due to mechanism of resistance, resistance can evolve Hence, repeat cultures Role of double antibiotic coverage practiced by many but documentation of effectiveness poor

22 Antibiotic Options for Pseudomonas At University of Maryland : 83% susceptible to cefepime 70% susceptible to ciprofloxacin 74% susceptible to imipenem 76% susceptible to piperacillin/tazobactam

23 Pseudomonas bacteremia Combination Therapy: Fact or Fiction

24 Authors Year Combination beneficial Hilf et al Y 1986 Bodey et al N Chatzinikolao N u et al 1995 Vidal et al N 1994 Kuikka et al N

25 Conclusions of Bacteremia Data: Minimal to no effect of combination therapy on cure of infection or mortality Instituting effective treatment up-front is what is important Patients with pseudomonas pneumonia as primary source have poorer outcome

26 Acinetobacter Gram-negative coccobacillus Was often viewed as a colonizer HAS ARRIVED as a nosocomial pathogen Acinetobacter baumannii is the most common Outbreak of imipenem-resistant Acinetobacter in New York Difficult to eradicate colonized state Emergence in returning troops from the Middle East

27 Increasing Incidence in US CDC National Nosocomial Infections Surveillance report the following increases in Acinetobacter Proportion of Acinetobacter ICU pneumonia increased from 4% in 1986 to 7% in 2003 Proportion of Acinetobacter UTIs and SSIs also increased Increase noted at multiple US hospitals and not confined to 1 geographic region Gaynes R, Clinical Infectious Diseases 2005;41:848.

28 Increasing Incidence Worldwide SENTRY antimicrobial surveillance program involves 5 geographic regions 11% of Acinetobacter were carbapenem resistant Gales AC Clinical Infectious Diseases 2001;32(S2):104.

29 Increasing Incidence Middle East Worldwide Australia South Africa

30 Attributable Mortality Reference Clinical Setting Cases Controls Attributable Mortality Grupper, et al Playford et al Sunenshine et al Kwon et al Robenshtok et al Blot el a Nosocomial BSI ICU, med-surg wards Israel Infection/Colonization General ICU Australia MDR-AB infections 3* Care Hospitals Baltimore, MD CR-AB BSI 3* Care Hospitals Korea Nosocomial BSI Israel Nosocomial BSI ICU Belgium 52 cases of AB-BSI 52 Matched Controls w/o AB 66 cases of Infection or Colonization 96 cases of MDR- AB Infections 40 cases of CR-AB Infection 112 cases of AB- BSI 131 Matched controls w/o AB 36.5% 20% 91 Susceptible-AB 8.4% 89 Un-infected 14.8% 40 Imipenemsusceptible 90 controls w/ Klebsiella BSI 45 cases of BSI 90 Matched Controls w/ AB 25-30% 22.7% 7.8%

31 Transmissibility compared to other Organism A. baumanni i P. aeruginos a organisms HCW Room Entrie s Hand + Before (%) Gown and/or Glove + After % Hands + After Removal % 38.7% 4.5% 133 0% 8.2% 0.8% VRE # 94 0% 9% 0% MRSA # 81 2% 19% 2.6% # Snyder G, et al, Infect Control Hosp Epidemiol July 2008; 29(7): Morgan DJ et al, Infect Control Hosp Epidemiol. June 2010;

32 After Contact with Patients Infected/Colonized with MDR Acinetobacter baumannii 40% of Gloves/Gowns were Contaminated 4% of Hands were Contaminated after removal of gloves MRSA 18.5% of Gloves/Gowns 1% of Hands Contaminated VRE 8.5% of Gloves/Gowns No Hands Contaminated

33 Acinetobacter carbapenems are/were the antibiotic of choice Ampicillin-sulbactam susceptibility should be looked at Tigecycline data is not encouraging

34 Spread of Resistance Reasons for spread of resistant bacteria excessive antibiotic use overcrowding poor hygiene and failure of infection control practices

35 Hand-disinfection is the single most important means of preventing the spread of infection CDC

36 Do Certain Antibiotics Lead to Emergence of Resistance? Answer is likely yes but as to specific ones it is uncertain due to poor study design variable and incorrect control group selection lack of statistical control for confounding and collinearity of antibiotics lack of adjustment for time at risk lack of adjustment for severity of illness

37 As much as possible and consistent with first-rate medical care, we must starve these bacteria of the lifeblood that promotes their persistence- the unrelenting selective pressure exerted by overuse of antibiotics Lou Rice, CID 2000;31:762.

38 Campaign to Prevent Antimicrobial Resistance in Healthcare Settings 12 Steps to Prevent Antimicrobial Resistance: Hospitalized Adults 12 Contain your contagion 11 Isolate the pathogen 10 Stop treatment when cured 9 Know when to say no to vanco 8 Treat infection, not colonization 7 Treat infection, not contamination 6 Access the experts 5 Use local data 4 Practice antimicrobial control 3 Target the pathogen 2 Get the catheters out 1 Vaccinate Prevent Transmission Use Antimicrobials Wisely Diagnose & Treat Effectively Prevent Infections

39 Then What Antibiotic Recommendations Should I Be Making? Limit duration of antibiotics Limit unnecessary use of broad-spectrum agents Controversial issues: Two agents versus one Empiric antibiotic choice/inadequate therapy Importance of dosing frequency of antibiotics and their effect on resistance

40 How To Prevent Resistance Improve handwashing compliance Find novel ways to decrease patient-topatient transmission Limit duration of antibiotics

41 How To Prevent Resistance Limit unnecessary use of broadspectrum agents IN GENERAL, LIMIT THE USE OF ANTIBIOTICS BOTH IN THE HOSPITAL AND OUTSIDE THE HOSPITAL

42 Infection control questions about untreatable Gram-negative bacteria Should I be placing these patients on contact isolation precautions? Should I be performing active surveillance culturing? Should I be focusing my efforts on antimicrobial stewardship or infection control? Should we be cohorting these patients? Should I be culturing hospital personnel?

43 References: A good general review of resistance Kaye KS. Pathogens resistant to antimicrobial agents. Epidemiology, molecular mechanisms, and clinical management. Infect Dis Clin North Am. Infect Dis Clin North Am. 2004; 18:467 A good review of ESBL Paterson DL. Extendedspectrum beta-lactamases: a clinical update Clin Microbiol Rev. 2005;18:

44 References A good review of ESBL s Bradford, P. A Extendedspectrum ß-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin. Microbiol. Rev. 14: Article on Acinetobacter Maragakis L, and Perl TM. Acinetobacter baumannii. Clin Infect Dis 2008;46: Article on Acinetobacter Munoz-Price LS. Acinetobacter infection. N Engl J Med Mar 20;358: Pharmacodynamic article Craig WA. Does the dose matter. Clin Infect Dis Sep 15;33 Suppl 3:S233-7.

45 References A good review of Pseudomonas resistance mechanisms. Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis. 2002;34: Interesting article on the benefits of short term therapy (8 days) for ventilator-associated pneumonia JAMA. 2003;290:2588 Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. Am J Respir Crit Care Med 2000;162: Article that shows that patients with low-likelihood of ventilator-associated pneumonia did as well or better with 3 day course of antibiotics versus a longer course.

46 References Article on multi-drug resistant bacteria. Paterson DL. A step closer to extreme drug resistance in gram-negative bacilli. Clin Infect Dis. 2007;45:1179. Article on ESBLs and ESBL in the community. Pitout JD. ESBL Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis. 2008;8:159. Meta-analysis on the role of combination therapy. Safdar N. Does combination antimicrobial therapy reduce mortality in Gram-negative bacteraemia? A meta analysis. Lancet Infect Dis. 2004;4:519.

47 References Harris AD. How important is patient-to-patient transmission for ESBL. Am J Infect Control Mar;35: and Clin Infect Dis 2007;45:1347. Harris AD. What infection control interventions should be undertaken for multi-resistant Gram-negative bacteria. Clin Infect Dis. 2006;43 Suppl 2:S57 Article on KPC. Nordmann P. The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis. 2009;9:228. Guidance on KPC MMWR. MMWR. March 20, ;256. Editorial on KPC. Srinivasan A. Klebsiella pneumoniae carbapenemase-producing organisms: An ounce of prevention really is worth a pound of cure. Infect Control Hosp Epidemiol. 2008;29:1107.