Therapy Options for Acinetobacter infections viewed from the east Minggui Wang, M.D. Huashan Hospital, Fudan University ESCMIDShanghai ,eLibrary China 1 by author OUTLINE Three problems of Acinetobacter infections in clinical Increasing trends of Acinetobacter infections Highly resistant to antimicrobial agents of Acinetobacter Emergence of hypervirulent Acinetobacter Antimicrobial therapy of Acinetobacter infections Controversies for combination or monotherapy? Commonly used antimicrobials for combination therapies in East Cefoperozone-sulbactam, sulbactam, minocycline/doxycycline, ESCMIDtigecycline, carbapenems, aminoglycosides,eLibrary fosfomycin, rifampicin 2 by author Gram-negative bacilli account for over 70% of all clinical isolates in China Percentage of Gram-negative bacilli in total CHINET 2015 clinical isolates (%) 73 73 72 72 72 Gram-positive cocci 71 30％ 70 70 （26481/88778） 68 Gram-negative bacilli 67 ％ 66 70 CHINET national bacterial （62297/88778） resistance surveillance data 2005ESCMID2006 2007 2008 2009 2010 2011 2012 2013 2014 2015eLibrary 3 by author Constituent ratio of A. baumannii, P. aeruginosa and K. pneumoniae among all clinical isolates in China since 2005 16 P. aeruginosa A. baumannii K. pneumoniae % K. pneumoniae 14 12 12.1 12 11.5 A. baumannii 11.3 11.1 11 10.7 10 10 9.2 P. aeruginosa 8.7 8.8 8 CHINET national bacterial resistance surveillance data ESCMID6 eLibrary 4 byHu FP, authorClin Microbiol Infect 2016; 22: S9–S14 Antimicrobial resistance in Acinetobacter spp. in China (%) (n=9503, A. baumannii 93%) CHINET 2015 100 90 80 74.8 68.5 70.5 64.5 66.2 66.6 70 62 58.7 60.8 60 49.1 45.8 50 42.8 38.1 40 30 20 R esistance rate（％） R esistance 9.7 10 0.2 0 SXT Amikacin PIP/TAZ Getamycin Imipenem CefopimeAMP/SUL Piperacillin Tigecycline Minocycline ceftazidimeMeropenem ESCMIDPolymyxin B eLibraryCiprofloxacin Cefoperazone/sulbactam by author Corelation of increasing trends of imipenem-resistance with constituent ratio of A. baumannii clinical isolates in China since 2005 13 Imipenem-resistance rate 70 CHINET DATA 12 60 Ratio % 11 CR 50 % 10 Constituent ratio 40 9 30 8 7 20 ESCMID6 eLibrary 10 6 Modifiedby from Huauthor FP, Clin Microbiol Infect 2016; 22: S9–S14 Corelation of increasing trends of imipenem-resistance with constituent ratio of K. pneumoniae clinical isolates in China since 2005 15 18 14 CHINET DATA 16 Constituent ratio Ratio 13 14 % CR 12 12 % 11 10 10 Imipenem-resistance rate 8 9 8 6 7 4 6 2 ESCMID5 eLibrary 0 7 Modifiedby from Huauthor FP, Clin Microbiol Infect 2016; 22: S9–S14 Corelation of increasing trends of imipenem-resistance with constituent ratio of P. aeruginosa clinical isolates in China since 2005 16 45 CHINET DATA 40 14 Ratio 35 % Imipenem-resistance rate CR 12 30 % 25 10 20 8 Constituent ratio 15 10 6 5 ESCMID4 eLibrary 0 8 Modifiedby from Huauthor FP, Clin Microbiol Infect 2016; 22: S9–S14 A report of bacterial resistance in China 2005~2014 Antimicrobial resistance in five most common bacteria: E.ESCMID coli, K. pneumoniae, A. baumannii eLibrary, P. aeruginosa and S. aureus 9 byHu FP, authorClin Microbiol Infect 2016; 22: S9–S14 Pan-drug resistance (PDR) in P. aeruginosa and A. baumannii (colistin and tigecycline not included for AST) CHINET DATA 25 P.aeruginosa 21 21 A. baumannii 20 20 20 18 18 % 17 15 11 10 5 3.23 2.1 1.7 1.7 1.8 1.5 1.5 1.6 1.7 ESCMID0 eLibrary 10 by author Emergence of hypervirulent and extensively drug resistant A. baumannii A. baumannii is generally described as a low-virulence organism, however it could be a highly virulent pathogen A recent report from the US described that 6 patients with relatively minor underlying disease were died from an outbreak of XDR A. baumannii with hypervirulent. ESCMID eLibrary Jones CL, Clin Infect Dis 2015; 61:145-54 11 Paterson by DL & Harris PNA.author Clin Infect Dis 2015; 61:155-6 Characteristics of the hypervirulent A. baumannii strains Five clade B strains: n=208 ST10, uncommon ST type Encoded 208 genes homologous to known virulence factors One clade A strain: ST2, an international ESCMIDclonal complexes eLibrary Jones CL, Clin Infect Dis 2015; 61:145-54 12 by author OUTLINE Three problems of Acinetobacter infections in clinical Increasing trends of Acinetobacter infections Highly resistant to antimicrobial agents of Acinetobacter Emergence of hypervirulent Acinetobacter Antimicrobial therapy of Acinetobacter infections Controversies for combination or monotherapy? Commonly used antimicrobials for combination therapies in East Cefoperozone-sulbactam, sulbactam, minocycline/doxycycline, ESCMIDtigecycline, carbapenems, aminoglycosides,eLibrary fosfomycin, rifampicin 13 by author Antimicrobial therapy options for different resistance level A. baumannii infections Garnacho-Montero J & Amaya-Villar R. Curr Opin Infect Dis 2010; 23: 332 Nonmulti-resistant A. baumannii infection First choice: β-lactam active following antibiogram results Alternative: follow antibiogram results Multiresistant A. baumannii infection First choice: Carbapenem (if susceptible) Alternative: Sulbactam Carbapenem-resistant A. baumannii infection First choice: Colistin Consider addition of rifampicin in susceptible strains Considered addition of aerosolized colistin in patients with tracheobronchitis or ventilator-associated pneumonia Alternative: Tigecycline In complicated intra-abdominal and skin-structure infections, tigecycline ESCMIDmay be considered first-line agent eLibrary especially in polymicrobial infections Optimal dose in cases of pneumonia is unknown 14 by author Controversies on the combination therapy for XDR or PDR A. baumannii infections Support Opposition Necessary for Lack of large randomized combination: Treatment clinical trial data (evidence- options are limited based data) Potential advantages of Disadvantages of combination: improved combination efficacy due to synergy adverse events Combination therapy is potential drive towards commonly used in resistance ESCMIDclinical practice eLibrary 15 Paul M, J Antimicrob Chemother by2014; 69:author 2305–9 Support of combination therapy Polymyxin B in Combination vs alone in Critically Ill Patients with A. baumannii or P. aeruginosa Infections A retrospective cohort study in two ICUs from teaching hospitals in Brazil 101pts: 33 (32.7%) were treated with polymyxin B in combination and 68 (67.3%) with polymyxin B in monotherapy. Results: The overall 30-day mortality was 59.4% (60 pts), comprising 42.4% (14/33) and 67.6% (46/68) in combination and monotherapy groups, respectively (P=0.03). The mortality rates were 18.5/1,000 patient days and 36.4/1,000 patient days in the combination and monotherapy groups, respectively (P=0.02). Combination therapy was independently associated with lower 30-day mortality (P=0.001). This is the first clinical study to show a benefit of combination over monotherapy with polymyxin B for severe XDR A. baumannii or P. ESCMIDaeruginosa infections eLibrary 16 Rigatto MH, Antimicrob Agents Chemotherby2015; 59:author 6575–80 Support of combination therapy Colistin versus Colistin plus Fosfomycin for Treatment of Carbapenem-Resistant A. baumannii Infections 94 pts infected with CRAB were randomized to receive colistin alone or colistin+fosfomycin (4g q12h ivgtt) for 7-14 d in Viet Nam Combination Monotherapy P Microbiological eradication (%) 100 81.2 0.01 End of study treatment Favorable clinical response (%) 59.6 55.3 0.835 End of study treatment 28-day all-cause mortality (%) 46.8 57.4 0.409 The pts who received combination therapy had a significantly more ESCMIDfavorable microbiological response eLibrary 17 Sirijatuphat R, Thamlikitkul V, Antimicrobby Agents Chemotherauthor 2014; 58: s598–s601 Opposition of combination therapy Monotherapy versus combination therapy for sepsis due to MDR A. baumannii A prospective cohort study in 28 Spanish hospitals. Monotherapy (MT): 68 (67.3%) pts; Combination therapy (CT) 33 (32.7%) . Pneumonia was the most common infection (50.5%) The most common drugs used in MT: colistin (67.6%) and carbapenems (14.7%); The most frequent combinations: colistin + tigecycline (27.3%), carbapenem+ tigecycline (12.1%) Results: Crude 30 day mortality was 23.5% and 24.2% for the MT and CT groups (P=0.94). Multivariate analysis showed no trend towards reduced 30 day mortality with CT (P=0.53) Conclusions: The data do not support an association of CT with ESCMIDreduced mortality in MDRAB infections.eLibrary 18 Lopez-Cortes LE, J Antimicrob Chemotherby2014; 69: author3119–26 Opposition of combination therapy Colistin and Rifampicin Compared With Colistin Alone for the Treatment of Serious Infections of XDR A. baumannii This is a multicenter, randomized clinical trial in ICU of 5 tertiary care hospitals in Italy Colistin + RFP Colistin P (n=104) (n=105) 28-day mortality (%) 43.3 42.9 0.95 A. baumannii eradication (%) 60.6 44.8 0.034 Conclusions: In serious XDR A. baumannii infections, 30-day mortality is not reduced by addition of rifampicin to colistin. These results indicate that, at present, rifampicin should not be routinely combined with colistin in clinical practice. ESCMID The increased rate of A. baumannii eradicationeLibrary with combination treatment could still imply a clinical benefit. 19 Durante-Mangoni E, Clin Infect Disby 2013; 57(3):349 –author58 Antimicrobial therapy of XDR A. baumannii in East Extensively drug resistant (XDR) A. baumannii is common, while polymyxins are not available in some countries such as China, so we are facing more difficult situation