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Resistance to antibiotics : Preserving a precious resource Laurent Gutmann Hopital Européen Georges Pompidou 1) The main question: Why do we have to preserve the antibiotics 1) Infections are still present and will not disappear ! In the community -Pneumonia: -Meningitis : -Urinary tract infections: -Gastrointestinal infections: -Cutaneous : Streptococcus pneumoniae… Tuberculosis XDR Meningococcus, S;pneumoniae Escherichia coli….. Salmonella…. Staphylococcus aureus …. In the hospital -In the intensive care units and after complex surgery -Nosocomial infections : intubation for assisted lung ventilation; intravenous and urinary catheters ; immunodepression Enterobacteriaceae, Pseudomonas , S.aureus 2) Antibiotics are widely Used in the community and the hospital (≈ 50/50) : 600 Tons in human in france. How do we prescribe antibiotics Regular prescriptions: although should be done according to the best recommendations' Over the counter especially in low developed countries A major problem : no control whatever is the antibiotic old !, recent! , quantities! Are human the only consumers ?? -Animals (more than in humans) -Agriculture 2) What are the consequences of the “intensive” usage of antibiotics This knowing that we cannot stop using antibiotics -We need to cure infections in humans -This can also be true for animals This is the dilemma Use !! ↔ Preserve !! AB exerts a strong selection pressure on the bacteria 1) Mutations Selection of resistant bacteria Gut.. 2) Acquisition of genetic material harboring resistance mechanisms - Multiresitance AB Enterobacteriaceae Pseudomonas CARBAPENEMS b-LACTAMS + Inhibitor of b-lactamases 3e g CEPHALOSPORINES CARBAPENEMASES CEPHALOSPORINASE + efflux 1e and 2e CEPHALOSPORINE PENICILLINS TEM/SHV variant Hospital BLSE BLSE CTXM Community PENICILLINASE and TEM/SHV 1950-1984 1984-2006 2000-2008 At the present time there is no antibiotic for which resistance has not appeared After a certain number “of tons of usage” This included the most recent : Carbapenems, oxazolidinone, fluoroquinolones Bacteria which become a problem in human Gram positive Gram negative Community Community -S. aureus CAMRSA -S.pneumoniae (5-30%) -Enterobacteriacae (4-20%) -H. influenzae -Gonococcus Hospital Hospital -S. aureus MRSA (5-30%) -E. faecalis and faecium -Enterobacteriaceae (5-50%) -Pseudomonas ; -Acinetobacter (50% in ICU in the US) 3) Dissemination a major threat The resistance is amplified by the dissemination Of genes between bacteria in different reservoir And by the inter-human transmission and others types of transmission This is true in the hospital in the community and from one to the other including the intercontinental travelling Since we can harbor these resistant bugs on the skin and in the gut Hand transmission !!!!!! Pool of antibiotic resistance genes Farm:animal Food: meat Humans Environmental Soil, Dust, Wastes, Sewages Wild life (Birds, Rodents, Insects….) Fruits,Vegetab les…. Food Humans Some examples of species and resistance which have and which are disseminating being a real problem for the humans NDM-1 and KPC among the most dangerous carbapenemases present in the Multiresistant strains of E.coli ,and or Klebsiella pneumoniae KPC Deshpande et al SENTRY 2007 EARSS 2007 Staphylococcus aureus Methi R: always present And now in the community Conclusions The selective pressure is such that there always will be new resistance toward new molecules However to combat the existing resistances we need new antibiotics -Search for novel drugs is needed Against known targets Search for novel targets is needed but difficult!!! -Chemistry is the essential tool: New or modified molecules -Structural biology is becoming an essential tool for drug design Good Usage of antibiotics which is a fundamental issue to slow down the appearance of new resistances We need Good Practices to decrease the dissemination of the existing resistant bacteria SARM chez les animaux Methicillin resistant Staphylococcus aureus: , pigs and pets .Am Assoc Swine Vet 2008 P15-20 Resistance to Streptococcus pneumoniae Plan antibiotiques1 PCV72 55 200 souches étudiées 60 52 53 48 48 43 38 36 38 35 32 30 32 31 2009 40 25 17 20 20 4 5 1988 0,5 0,7 1 1986 10 1987 12 1984 7 A major problem in meningitis 2007 2006 2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995 1994 1993 1992 1991 1990 1989 0 1985 % de PSDP 43 2008 50 Multiresistance linked to integrons D’costa et al science 2006