Acinetobacter baumannii: from S to PDR
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1 Acinetobacter baumannii: from S to PDR P. Plésiat French National Reference Center for Antibiotic Resistance University Hospital Jean Minjoz Besançon, France No conflict of interest!
2
3 IDSA CID 2009, 48:1
4 CDC 2014!
5 : Prevalence of A. baumannii in June 2012 : 0.6%! Jones R. et al. IJAA 2003, 22:551!
6 Wild-type susceptibility of A. baumannii! ß-lactams - (Ampicillin-sulbactam) - (Ticarcillin-clavulanate) - Piperacillin-tazobactam - Cefotaxime - Ceftazidime - Cefepime - (Ceftolozane-tazobactam) - Imipenem - Meropenem - (Doripenem) Aminoglycosides - Gentamicin - Netilmicin - Tobramycin - Amikacin Fluoroquinolones - Ofloxacin - Ciprofloxacin - Levofloxacin Others - Colistin - Cotrimoxazole - Tetracycline - Doxycycline - Minocycline - (Tigecycline)
7 Wild-type A. baumannii" FEP (cefepime), PIP (piperacillin), TZP (piperacillin-tazobactam), CTX (cefotaxime), TIC (ticarcillin),! TCC (ticarcillin-clavulanate), CAZ (ceftazidime), MPM (meropenem), IPM (imipenem), GM (gentamicin),! TOB (tobramycin), ATM (aztreonam), KM (kanamycin), CS (colistin), CIP (ciprofloxacin), AKN (amikacin)!
8 Mechanisms involved in intrinsic resistance" 1. Poor outer membrane permeability (OmpA-like porin) 2. Constitutively-expressed efflux system AdeIJK (RND) 3. Active efflux pump AceI (PACE) 4. Large genome of 3.95 ± 0.1 Mbp 5. OXA-51 type ß-lactamase Latent mechanisms" 6. Wide-spectrum class C ß-lactamase ADC 7. Efflux systems of RND (AdeABC, AdeAA 2 B), MATE (AbeM, AbeM-2,-3,-4), MFS (CraA, AmvA), and SMR (AbeS) families 8. Carbapenem-specific OprD-like porins (CarO?)
9 I! MDR: I or R 3 groups! II! III! IV! XDR: I or R 6 groups! PDR: I or R to all drugs! V! VI! VII! VIII! Magiorakos A.P. et al. CMI 2012, 18:268!
10 France: 13.6%! Resistance rates to fluoroquinolones!
11 France: 5.9%! Resistance rates to carbapenems!
12 France: 11.5%! Resistance rates to aminoglycosides!
13 France: 4.1%! Resistance rates to 3 antibiotic groups!
14 Resistance rates in Europe! MDR strains: from 0% to 86.6% XDR strains? PDR (< 1%?) MDR Not MDR XDR PDR Poor response to treatments Use of nonconventional drug combinations Prolonged hospital stays Deaths (impacted by underlying disease) Increased hospital costs EARSS 2013
15 Prevalence of A. baumannii in NI (June 2012)! (Prevalence of A. baumannii in 2012 : 0.6%)!
16
17 Acquired resistance in A. baumannii! Intrinsic mechanisms - Mutations - Insertion sequences - Phenotypic adaptation Additive! Synergistic! Complementary effects!
18 Resistant mutants! Mechanisms Fq cy Tcc Tzp Caz Fep Ipm Mpm Tob Akn Lvx Cip Cs ß-lactamase ADC ++ I/R I/R I/R S/I/R Efflux pumps AdeABC ++ S/I S/I R I/R AdeIJK +/- S/I S/I AdeFGH ++ Impermeability OprD-like porin??? LPS modification +/- R Targets alteration GyrA/B, ParC ++ I/R R Tcc (ticarcillin-clavulanate), Tzp (piperacillin-tazobactam), Caz (ceftazidime), Fep (cefepime), Ipm (imipenem), Mpm (meropenem), Tob (tobramycin), Amk (amikacin), Lvx (levofloxacin), Cip (ciprofloxacin), Cs (colistin)
19 ADC overproducing mutants! Mueller-Hinton! MH + cloxacillin 250 mg/l! Pout blaadc Variants ADC-7, -11, -29,-30, -33, -50, -56 blaadc ISAba1/x
20 Extended-spectrum ADCs (ESAC)! Increased resistance to :
21 OXA-51 overproducing mutants! P out OXA-51 Variants : OXA-64, -66, -69 ISAba1/9 OXA-51 ISAba1/OXA-66
22 ***! **! Coyne S. et al. AAC 2011, 55: 947!
23 Courtoisy of P. Courvalin!
24 Transfers of resistance genes! Enterobacteriaceae Pseudomonas sp. Acinetobacter sp.
25 Transferable ß-lactamases in A. baumannii! R R R TIC S-R S-R S-R TZP S R R CAZ S S I-R IPM 1970 s 1990 s 2000 s TEM-1,2 SHV-1 RTG
26 ß-lactamases in A. baumannii# (CNR 2014, n=270)! ESBLs +! Carbapenemases! 2%! ADC! 14%! ESBLs! 3%! Carbapenemases ±! ADC! 81%!
27 No of strains SHV CTX- M 15 GES- 11 PER- 1
28 Carbapenemases in A. baumannii! OXA- 23 OXA- 24/40 OXA- 58 OXA- 72 OXA TEM- 1 OXA GES- 11 OXA PER- 7 OXA PER- 1 IMP- 1 NDM- 1 NDM- 9 NDM- 1 + OXA- 23 NDM- 1 + OXA- 58 OXA- 51 OXA TEM- 1 OXA RTG- 2 OXA ADC No of strains
29 Transferable class D carbapenemases! Poirel L. et al. AAC 2010, 54:24!
30 Transferable class D carbapenemases! OXA-23! FEP! PIP! TZP! CTX! TIC! TCC! CAZ! MEM! IPM! ATM! MH MH mg/l cloxacillin
31 Transferable class D carbapenemases! OXA-23/ADC++! FEP! PIP! TZP! CTX! TIC! TCC! CAZ! MEM! IPM! ATM! MH MH mg/l cloxacillin
32 Transferable class D carbapenemases! OXA-23/PER-7! FEP! PIP! TZP! CTX! TIC! TCC! CAZ! MEM! IPM! ATM! MH ArmA
33 Transferable class D carbapenemases! OXA-58! FEP! PIP! TZP! CTX! TIC! TCC! CAZ! MEM! IPM! ATM! MH MH mg/l cloxacillin
34 OXA-23 map (2014)!
35 Genetic diversity of CRAB CC1 CC1 CC2 CC2 OXA-23 OXA-24 OXA-23 + OXA-58 OXA-23 + PER-7 OXA-58 Jeannot K. et al. Plos One 2014,e115452!
36 PFGE profiles of CRAB! ST ID OXA type / LocaPon S. L. du Var T- Marseille Aubervilliers S. Omer Lyon Marseille Aubervilliers Nancy Fort de France Fort de France Lens Lens Ferolles- APlly Niort A- Marseille T- Marseille Maubeuge Lyon Calais Calais Reims HN- Marseille HN- Marseille Aubervilliers Reims RP- Marseille Fort de France Roubaix Jeannot K. et al. Plos One 2014,e115452!
37 Transferable class D carbapenemases! NDM-1! FEP! PIP! TZP! CTX! TIC! TCC! CAZ! MEM! IPM! ATM! MH MH mg/l cloxacillin
38
39 Genetic environment of blandm-1!
40 NDM-1 map (2014)!
41 Aminoglycoside-modifying enzymes! Enzyme Reference gene Resistance AAC(3)-I aacc1 G AAC(3)-II aacc2 G, T, N AAC(3)-III aacc3 K, G, T AAC(3)-VI aac(3)-vi (K), G, (T), (N) AAC(6 )-Ib aaca4 T, N, A AAC(6 )-Ib' aaca4' G, T, N AAC(6 )-II aaca3 G, T, N APH(3')-VI apha6 K, A ANT(4 )-II ant(4')-iia T, A ANT(2")-I aadb K, G, T ANT(3")-I aada1 ST, SP
42
43 N (G)! K,T,N,A! G! K! K,G,T! K,A! St, Sp! 106 mdr A. baumannii isolates! European countries (clones I, II, III)! PCR screening of AME genes! 95% isolates 1! 84% isolates 2 (up to 5)! aacc1 and aada1 always together" Nemec A. et al. J. Med. Microbiol. 2004, 53:1233!
44 AbaR-associated AME genes! Krizova L. et al. AAC 2011, 55:3201! Seputiene V. et al. AAC 2012, 56:1969!
45 Salmonella enterica P. aeruginosa Acinetobacter baumannii
46 K,T,N,A! K,G,T! G! K,T,N,A! K! K,G,T! St! St! St, Sp! 97 A. baumannii isolates (80% mdr)! US military treatment facilities ( )! Microarray screening 236 resistance genes! PCR sequencing! 43 AG resistance genes! 89% isolates 1! 80% isolates 2 (up to 6)! K, A! Taitt C.R. et al. AAC 2014, 58:767!
47 FEP! PIP! TZP! CTX! TIC! TCC! CAZ! MPM! IPM! GEN! TOB! ATM! FOS! COL! CIP! AKN! pacicu2 conjugative plasmid! Hamidian M. et al. JAC 2014, 69:955!
48 China! Zhu L. et al. PLoS One 2013, 6:e66584! Australia! Nigro S.J. et al. JAC 2011,66:1504!
49 16S rrna methylases! RmtD + SPM-1! (Brazil, P. aeruginosa)! RmtB! (Asia, Europe, Enterobacteriaceae)! RmtC! (Japan, P. mirabilis)! RmtA! (Asia, P. aeruginosa)! ArmA! (Europe, Asia, Enterobacteriaceae)! Doi Y. et al. AAC 2007, 51: 3388 Yamane et al. Emerg. Infect. Dis. 2005, 11:
50 ArmA A. Baumannii! FEP! PIP! TZP! TIC! TCC! CAZ! IPM! GM! FEP! PIP! TZP! MPM! TIC! TCC! CAZ! MPM! TOB! AZT! IPM! GM! TOB! DOX! CIP! AKN! SXT! LVX! CIP! AKN! FEP (cefepime), PIP (piperacillin), TZP (piperacillin-tazobactam), TIC (ticarcillin), TCC (ticarcillin-clavulanate), CAZ (ceftazidime), MPM (meropenem), IPM (imipenem), GM (gentamicin), TOB (tobramycin), AZT (aztreonam), DOX (doxycyclin), SXT (cotrimoxazole), LVX (levofloxacin), CIP (ciprofloxacin)!
51 16 RNA methylase ArmA! OXA-23 + ArmA OXA-23
52 Fighting multidrug resistance! Treatment! improvement! Acquisition of resistance! genes or mutations by strains! Spread of epidemic clones among populations! Hygiene measures!
53 Conclusions Increasing prevalence of XDR A. baumannii worldwide, exihibiting resistance to all ß-lactams, fluoroquinolones, and aminoglycosides XDR strains emerging within a few successful clonal complexes (EC I, EC II) Recent acquisition of resistance genes from various reservoirs (OXA-type carbapenemases, NDM, 16S RNA methylases ) Most strains remain susceptible to polymyxins (colistin) and tigecycline (breakpoints pending) XDR prompts clinicians to use of unorthodox drug combinations to treat XDR infections (colistin + rifampicin, colistin + carbapenem ).
54 Damien Fournier Katy Jeannot Catherine Llanes Caroline Brechet Marjorie Robert Emeline Gilliot Amélie Mille Pauline Chatelain Meryem Berrazeg Arnaud Bolard Charloae Richardot Aurélie Noguès Paulo Juàres
55 LPS modification and colistin resistance! Mutations in! - Sensor kinase gene pmrb" - Response regulator gene pmra! Arroyo L.A. et al. AAC 2011, 55:3743!
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