Multi-resistant Gram-negatives bacteria: Move over MRSA - new kids on the superbug block 8th Annual Infection Prevention Conference 23rd June 2011, Harrogate Kevin Kerr Harrogate and District NHS Foundation Trust/ Hull York Medical School 1

Extended-spectrum beta-lactamase What is an ESBL? Extended-spectrum beta-lactamase Enzyme capable of conferring resistance to: Penicillins 1st, 2nd, 3rd generation cephalosporins Aztreonam (But not cephamycins or carbapenems) Inhibited by clavulanic acid in vitro Plasmid mediated 2

The ESBL family TEM SHV CTX-M PER VEB TLA BES FEC GES SFO CME BEL PME RAHN CSP Klebsiella species esp K. pneumoniae Escherichia coli Proteus spp. Morganella morganii Providencia spp. Pseudomonas aeruginosa Acinetobacter spp. Enterobacter spp. Citrobacter spp. Salmonella spp. Capnocytophaga ochrachea Vibrio spp Aeromonas spp Rahnella 4

5

Public and media perception of ESBLs Google News Archives Hits MRSA 14 300 C. difficile 2 300 ESBL 658 7

MRSA HCAI TOP TRUMPS ESBL Transferable Resistance WINS Difficult to detect in the lab No national guidance on which patients to screen No national mandatory surveillance of bacteraemias No national guidance on Infection Control No national guidance on treatment Few treatment options Eradication of carriage not possible 8 8

Risk factors for ESBL Studies vary Study populations Case Selection Control groups Sample size Prior hospital stay especially on ITU/SCBU Mechanical ventilation Poor APACHE score Poor nutritional status Enteral/parenteral feed CVC Urinary catheter Recent surgery Decubitus ulcers Haemodialysis Previous antibiotic use Total use 3rd generation cephalosporins Quinolones Nursing home residence 10

Treatment options for ESBL 11

Mortality associated with ESBL infection Country Patient category Mortality rate ESBL (%) Mortality rate non-ESBL (%) P value Korea1 Haematological malignancy 44.8 14.2 <0.001 Korea2 Community 12.1 16.0 n.s. Spain3 Oncology 41 21 0.003 Israel4 30 11 Canada5 Mixed hospital 13 7 Italy6 29.7 6.1 1 Kang et al Ann Hematol 2011. In press 2 Lee et al Diag Micro Infect Dis 2011;70:150-3 3 Gudiol et al J Antimicrob Chemother;66:657-66 4 Marchain et al Antimicrob Ag Chemother;54:5099-5104 5 Otner-Agostini et al Can J Inf Dis Med Micro 2009;3:43-44 6 Tumbarello et al Antimicrob Ag Chemother 2010;54:4085-91

Thank heavens for carbapenems... KPC Plasmid-mediated resistance to carbapenems K. pneumoniae Spreading rapidly

Gaibani et al Euro Surveill 2011;16(8):pii=19800

Carbonne et al Euro Surveill 2010;15:(48):pii=19734

NDM-1 as at December 2010

J Antimicrob Chemother 2010;65:1604-1607 Antibiotic MIC (mg/L) Interpretation Ampicillin >32 R Co-amoxiclav >256/2 Piperacillin/tazobactam >256/4 Cefoxitin >256 Cefotaxime Ceftazidime Cefepime 128 Aztreonam .256 Imipenem 32 Meropenem 16 Ertapenem 64 Ciprofloxacin Gentamicin Amikacin Trimethoprim Tetracycline Tigecycline 2 Colistin J Antimicrob Chemother 2010;65:1604-1607

Carbapenemase-producers: other therapeutic options Combinations of traditional antibiotics Colisitin + rifampicin Colistin + vancomycin Sulfactams New tetracyclines E101 Fluorocyclines GSK2251052 New aminoglycosides (ACHN-490) New beta-lactamase inhibitors (eg nxl-104)

Infection control – one size does not necessarily fit all 2004 2005 2006 MRSA 0.55 0.57 0.45* ESBL 0.04 0.06 0.08* *P = 0.0001 Bertrand et al Eur J Clin Microbiol Inf Dis 2008;27:1113-1117

Pitout et al Clin Infect Dis 2004;38:1736-1741 Esbl Pitout et al Clin Infect Dis 2004;38:1736-1741 26

28 Saudi paper 2007 13% of individuals 0f 56 Kader et al Infect Control Hosp Epidem 2007;28:1114-1116 28

...and even more spanners

Tackling multi-resistant Gram-negatives...why bother? 31 31

Controlling MR-GNB: what can be done? Control antibiotic use especially if the problem is polyclonal Isolation of patients and contact precautions especially if clonal spread suspected 32

Antimicrobial stewardship Tängdén et al J Antimicrob Chemother 2011;66:1161-7 33

Tängdén et al J Antimicrob Chemother 2011;66:1161-7

Tängdén et al J Antimicrob Chemother 2011;66:1161-7

Antimicrobial stewardship Does my patient really need an antibiotic? Prescribe in accordance with your local antibiotic policy If prescribing empirically, “de-escalate” broad spectrum therapy when the microbiology results are known Colonisation does not equal infection 36

Controlling MR-GNB: what can be done? Control antibiotic use if polyclonal Infection control measures if clonal spread suspected 37

Infection control measures Eliminate environmental reservoirs Isolation of infected/colonised patients Increased hand hygiene Gut decolonisation? 38

Infection control measures Eliminate environmental reservoirs Screening and isolation of infected/colonised patients Increased hand hygiene 39

MR-GNB control at Harrogate District Hospital (HDH) 40

303 patients admitted with acute diarrhoea 96 (31.7%) were carriers of MR-GNB Cf MDR in 618/5764 (10.7%) of clinically relevant isolates 14 (15%) were aged ≤25 yrs; 10 (10.4%) never been hospitalised Vidal-Navarro J Antimicrob Chemother 2010;65:2455-2468 41

Screening for MR-GNB: unanswered questions Who to screen? How to screen? When to screen? How often to screen? Who pays? 42

Screening for MR-GNB: unanswered questions What do you do with the results?

Isolation of patients as a control measure Only 6.8% clearance. Some remained pos over the three year period Schwaber et al Clin Infect Dis 2011;52:848-855 44

Infection control measures Eliminate environmental reservoirs Screening and isolation of infected/colonised patients Increased hand hygiene 45

Conclusions 1 MR-GNB are widespread in hospital and community settings Carbapenems are the drugs of last resort for serious ESBL-associated infection… …but resistance to carbapenems has emerged and is spreading rapidly Some MR-GNB infections are becoming untreatable 46

Conclusions 2 There is no systematic surveillance for ESBLs and other MR-GNBs in many countries There is no agreement on how to screen and which patients to screen for MR-GNB carriage in hospitals Eradication of faecal MR-GNB carriage does not appear possible... ...so “traditional” infection control measures are important 47

Conclusions 3 ESBLs have entered the food chain (and are also found in food-borne pathogens such E. coli O157 and Salmonella spp) We are doing too little to control MR-GNBs at a national and international level More resources for control and treatment are needed but other HCAI may distort priorities 48