Acinetobacter baumannii: from S to PDR P. Plésiat French National Reference Center for Antibiotic Resistance University Hospital Jean Minjoz 25030 Besançon, France No conflict of interest!
IDSA CID 2009, 48:1
CDC 2014!
: Prevalence of A. baumannii in June 2012 : 0.6%! Jones R. et al. IJAA 2003, 22:551!
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)
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)!
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?)
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!
France: 13.6%! Resistance rates to fluoroquinolones!
France: 5.9%! Resistance rates to carbapenems!
France: 11.5%! Resistance rates to aminoglycosides!
France: 4.1%! Resistance rates to 3 antibiotic groups!
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
Prevalence of A. baumannii in NI (June 2012)! (Prevalence of A. baumannii in 2012 : 0.6%)!
Acquired resistance in A. baumannii! Intrinsic mechanisms - Mutations - Insertion sequences - Phenotypic adaptation Additive! Synergistic! Complementary effects!
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)
ADC overproducing mutants! Mueller-Hinton! MH + cloxacillin 250 mg/l! Pout blaadc Variants ADC-7, -11, -29,-30, -33, -50, -56 blaadc ISAba1/x
Extended-spectrum ADCs (ESAC)! Increased resistance to :
OXA-51 overproducing mutants! P out OXA-51 Variants : OXA-64, -66, -69 ISAba1/9 OXA-51 ISAba1/OXA-66
***! **! Coyne S. et al. AAC 2011, 55: 947!
Courtoisy of P. Courvalin!
Transfers of resistance genes! Enterobacteriaceae Pseudomonas sp. Acinetobacter sp.
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
ß-lactamases in A. baumannii# (CNR 2014, n=270)! ESBLs +! Carbapenemases! 2%! ADC! 14%! ESBLs! 3%! Carbapenemases ±! ADC! 81%!
No of strains 14 12 10 8 6 4 2 2014 2013 2012 0 SHV- 12 + CTX- M 15 GES- 11 PER- 1
Carbapenemases in A. baumannii! OXA- 23 OXA- 24/40 OXA- 58 OXA- 72 OXA- 23 + TEM- 1 OXA- 23 + GES- 11 OXA- 23 + PER- 7 OXA- 58 + PER- 1 IMP- 1 NDM- 1 NDM- 9 NDM- 1 + OXA- 23 NDM- 1 + OXA- 58 OXA- 51 OXA- 51 + TEM- 1 OXA- 51 + RTG- 2 OXA- 51 + ADC- 30 2012 2013 2014 0 50 100 150 200 250 300 350 400 450 No of strains
Transferable class D carbapenemases! Poirel L. et al. AAC 2010, 54:24!
Transferable class D carbapenemases! OXA-23! FEP! PIP! TZP! CTX! TIC! TCC! CAZ! MEM! IPM! ATM! MH MH + 250 mg/l cloxacillin
Transferable class D carbapenemases! OXA-23/ADC++! FEP! PIP! TZP! CTX! TIC! TCC! CAZ! MEM! IPM! ATM! MH MH + 250 mg/l cloxacillin
Transferable class D carbapenemases! OXA-23/PER-7! FEP! PIP! TZP! CTX! TIC! TCC! CAZ! MEM! IPM! ATM! MH ArmA
Transferable class D carbapenemases! OXA-58! FEP! PIP! TZP! CTX! TIC! TCC! CAZ! MEM! IPM! ATM! MH MH + 250 mg/l cloxacillin
OXA-23 map (2014)!
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!
PFGE profiles of CRAB! ST 2 85 1 1 125 20 20 1 2 79 115 2 2 2 2 2 2 2 2 2 2 2 2 107 25 25 108 10 ID 3144 3145 3048 3270 3435 3458 3073 3027 3167 3221 3281 3283 3410 3210 3187 3182 3189 3393 3395 3211 3416 3150 3153 3041 3400 3169 3222 3408 OXA type 23 23 23 23 23 23 23 23 23 23/58 23 23 23 23 23 23 23 23 23 23 23 23 23 24 23 58 24 23 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!
Transferable class D carbapenemases! NDM-1! FEP! PIP! TZP! CTX! TIC! TCC! CAZ! MEM! IPM! ATM! MH MH + 250 mg/l cloxacillin
Genetic environment of blandm-1!
NDM-1 map (2014)!
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
http://integrall.bio.ua.pt/!
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!
AbaR-associated AME genes! Krizova L. et al. AAC 2011, 55:3201! Seputiene V. et al. AAC 2012, 56:1969!
Salmonella enterica P. aeruginosa Acinetobacter baumannii
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 (2003-2009)! 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!
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!
China! Zhu L. et al. PLoS One 2013, 6:e66584! Australia! Nigro S.J. et al. JAC 2011,66:1504!
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: 951-953
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)!
16 RNA methylase ArmA! 200 180 160 140 120 100 80 60 40 20 0 2012 2013 2014 OXA-23 + ArmA OXA-23
Fighting multidrug resistance! Treatment! improvement! Acquisition of resistance! genes or mutations by strains! Spread of epidemic clones among populations! Hygiene measures!
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 ).
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
LPS modification and colistin resistance! Mutations in! - Sensor kinase gene pmrb" - Response regulator gene pmra! Arroyo L.A. et al. AAC 2011, 55:3743!