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OXA and relevant superbugs

OXA and relevant superbugs. Dr JD Deetlefs. In terms of gram (-) infections;. No new class of antibiotics since 1985 Resistance has steadily increased since then. The end is very near…. NDM1. NDM-1. OXA-48. (KPC,GES,VIM). The Enterobacteriacae.

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OXA and relevant superbugs

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  1. OXA and relevant superbugs Dr JD Deetlefs

  2. In terms of gram (-) infections; • No new class of antibiotics since 1985 • Resistance has steadily increased since then

  3. The end is very near… NDM1

  4. NDM-1 OXA-48 (KPC,GES,VIM)

  5. The Enterobacteriacae Family of rod-shaped gram-negative bacteria, most of which occur normally in the intestines of humans.

  6. Common antibiotic resistance mechanisms;

  7. Beta lactamases inactive Beta-lactam antibiotics Penicillin Cephalosporin

  8. Penicillinase the first Beta-lactamase Abraham and Chain in 1940 from Gram-negative E. coli.

  9. Antibiotic resistance: Timeline

  10. Cephalosporin’s - 1964

  11. Antibiotic resistance:Timeline

  12. ESBL’s (extended spectrum) • 1983 (Germany) • Beta – lactamases with increased activity against B-lactam antibiotics • Resistance to all B-lactams (cephalosporin’s + penicillin's) • > 200 enzymes described

  13. Classification;

  14. Carbapenems to the rescue • Available from 1989 • Beta –lactam antibiotics with extremely broad spectrum • Imipenem • Meropenem • Ertapenem • Doripenem

  15. Carbapenems • Cornerstone in treating ESBL’s • Very stable against all Beta - lactamases

  16. Carbapenemases

  17. Carbapenemases • Beta-lactamases with added ability to inactivate ALL beta-lactam antibiotics, including carbapenems = carbapenemases • 1996(US) -KPC

  18. Carbapenemase classification • Class A carbapenemases e.g. KPC • Class B enzymes e.g. VIM, IMP, NDM • Class D enzymes belonging to the OXA family

  19. Damage so far; • NDM-1 : 45 • OXA-48 : 39 • KPC : 3 • GES : 4 • VIM : 4

  20. New Delhi metallo-beta-lactamase-1 (NDM-1) “Nieu-Delhi MBL” First reported in Sweden in a K pneumoniaestrain from the urine culture of a patient from Indian origin Also isolated from E coli in the same patient’s gut Subsequently shown that probably emerged much earlier Now spread worldwide due to medical tourism, travel In New Delhi, found in potable as well as tap water samples Estimated that 10% of New Delhi’s population is colonised in GIT

  21. What makes NDM-1 special? Circular, double-stranded unit of DNA that replicates within a cell independently of the chromosomal DNA

  22. NDM-1 : Plasmid • The plasmid on which it occurs, is a broad host range IncL/M type • Thus can spread between Enterobacteriaceae, as well as Gram negative non-fermenters e.g. A baumannii

  23. NDM-1 : Plasmid • Large thus carries additional resistance mechanisms to other antibiotic classes (aminoglyocides,quinolones)

  24. NDM-1 has arrived: First report of a carbapenem resistance mechanism in South Africa. S Afr Med J 2011;101:873-875. W Lowman, C Sriruttan, T Nana, N Bosman, A Duse, J Venturas, C Clay, J Coetzee

  25. The New Kid on the Block: OXA-48 Described in Turkey, from there emerging in Europe, and described in North Africa 2011 at private hospital in Johannesburg, patient that came from India → Sudan → Egypt Highly resistant K pneumoniae, KPC /NDM-1 negative on PCR Sent isolate to Paris, France OXA-48 positive Multiplex PCR, Tested some historic isolates OXA-48 positive form other centers as well

  26. OXA-48 Also plasmid mediated Propensity for causing institutional outbreaks For the outbreak in Gauteng the index patient had relevant travel history (Egypt and Morocco) Not so for the other two centres (Cape Town and PE)

  27. MIC’s

  28. Significance : It kills patients • Mortality associated with Klebsiellapneumoniaebacteremia: • Susceptible K pneumoniae: 15% • ESBL producing K pneumoniae: 30% • Carbapenemase-producing K pneumoniae: 70%

  29. Treatment Options for CRE’s • Depends on the mechanisms of resistance and MIC levels • If ESBL overproduction / porin loss, and carbapenem MIC ≤ 4µg/ml, then can use carbapenem • Colistin + Tygecycline

  30. Mortality Rates According to Treatment Regimens GL Diakos, et al. Antimicrob Agents Chemother 2009;53:1868-73

  31. Tigecycline • Structurally related to the tetracyclines • Large volume of distribution,serum levels low • Minimal excretion in urine • Efficacy in the treatment of severe infections not yet determined

  32. Colistin • Dosing regimen remains controversial • Resistance to colistin is emerging • Monotherapy associated with poor outcomes, combination therapy more promising

  33. Alternative Treatment Options • Fosfomycin – clinical data limited, expensive • Rifampicin – in combination, limited data • Double carbapenem therapy (ertapenem-doripenem) • Carbapenemase-inhibitors undergoing phase I and II trials (e.g. NX104)

  34. Treatment recommendations; • If sensitive: carbapenem (MIC ≤4) + aminoglycoside • Carbapenem + colistin • Tigecycline as third option, in combination

  35. Risk Factors and Epidemiology of Carbapenemases • Risk factors include: • Prolonged hospitalisation • ICU stay • Invasive devices • Immunosuppression • Multiple antibiotics before culture

  36. Carbapenem exposure? • Numerous studies have shown that it is not a prerequisite for the development of CRE’s

  37. More bad news on the way…

  38. Serratiamarcescens

  39. What are we doing : Lab perspective • Active surveillance from our side – all isolates with reduced susceptibility to carbapenems (as routine); • MIC testing • PCR for KPC,NDM1 and OXA-48 (Gold standard) • Can be performed directly from stool swabs

  40. Multiplex PCR from culture – routine from 2012 • OXA-48 • KPC • NDM-1 • VIM • GES • IMP

  41. Hospital management • Isolation of patient, contact precautions as well as cohorting • Dedicated nursing staff on all shifts • Active and extensive surveillance of all contacts – esp for KPC, NDM and OXA-48: screen all the patients at present • Patients are considered colonized and infective for the duration of their hospitalization

  42. Current opinion; • Screening of staff - limited value • Environmental swabs – specific indications • Digestive decolonization not indicated – can compromise already limited treatment options Symposium on Carbapenemases,Paris, Feb 2012

  43. In Summary • CRE’s have arrived • Carbapenemases like NDM-1 and OXA-48 have outbreak potential that far surpasses that of any ESBL • Carbapenameses may (and probably will) become the ESBL’s of tomorrow • When that happens the end may by nearer than we think…

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