Therapy Options for Acinetobacter Infections Viewed from the East

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

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 for the treatment of A. baumannii infections  Combination therapy is commonly used in ESCMIDclinical practice eLibrary

20 by author Combination therapy for XDR A. baumannii A Chinese consensus statement for XDR GNB infections

Combinations based on sulbactam or its fixed-dose combination: Cefoperazone sulbactam + tigecycline +

(cefoperazone-sulbactam or ampicillin-sulbactam) + tigecycline carbapenems

(cefoperazone-sulbactam or ampicillin-sulbactam) + doxycycline Cefoperazone-sulbactam + doxycycline +

Sulbactam + carbapenems carbapenems

Tigecycline-based combinations: Imipenem + rifampicin + (polymyxin or

Tigecycline + (cefoperazone-sulbactam or ampicillin-sulbactam) tobramycin)

Tigecycline + carbapenems

Tigecycline + polymyxin

Polymyxin-based combinations:

Polymyxin + carbapenems

Polymyxin + tigecycline ESCMID eLibrary

21 Chinese XDR Consensus Working by Group. Clin MicrobiolauthorInfect 2016; 22: S15–S25 Commonly used antimicrobials for combination therapy for the treatment of XDR A. baumannii in China

 Cefoperazone-sulbactam and Sulbactam  Doxycycline/minocycline  Tigecycline  Carbapenems  Aminoglycosides  Rifampicin ESCMIDfosfomycin eLibrary

22 by author Cefoperazone-sulbactam (CFP-SUL) and Sulbactam

 Relatively low resistance rate of CFP-SUL in CFP-SUL resistance rate in A. baumannii A. baumannii  The resistance rate is lower than ampicillin- 40 sulbactam: 38% vs 67% in 2015 30 (unpublished CHINET data) 20  The antimicrobial susceptibility of CFP-SUL R is routinely tested for gram-negative bacilli % 10 in China  CFP-SUL is available in several Asian 0 countries such as China, Japan, Korea, Thailand and Phillipines. Sulbactam alone available since 2014 in China CHINET national bacterial resistance surveillance data  Breakpoints of CFP-SUL used: ESCMIDS, ≤16/8 μg/ml; I, 32/16 μg/ml; R, ≥64/32 eLibrary μg/ml (Jones RN, JCM 1987) 23 by author In-vitro Activity of Combination of CFP-SUL and Minocycline against Carbapenem-Resistant A. baumannii

 53 nonduplicate CRAB clinical isolates  Results:  Synergism 39 isolates  Partial synergism 11 isolates  Indifference 3 isolates  Conclusion: The combination of CFP-SUL with minocycline had significant synergistic activity ESCMIDagainst CRAB eLibrary

24 Pei G. Microb Drug Resist 2012; by 18: 574-7 author In vitro activity of sulbactam in combination with imipenem, meropenem, panipenem or cefoperazone against A. baumannii

Imipenem-susceptible Imipenem-resistant (n=40)(%) (n=40)(%) Synergy 20–27 7–25 Partial synergy 42–67 40–57 Additive 7–17 20–25 Indifference 0–12

Conclusion: MICs of both the combined antimicrobials were reduced (FICI ≤1) in the majority of isolates, which could potentially improve the ESCMIDclinical outcomes of patients with eLibrary intractable infections

25 Ji J. Int J Antimicrob Agents by2013; 41: 393 –author401 Molecular Mechanisms of Sulbactam Antibacterial Activity and Resistance in A. baumannii

 The antibacterial activities of sulbactam are mediated through inhibition of the penicillin-binding proteins (PBPs) PBP1 and PBP3  Resistance mechanisms  High level resistance: pbp3 mutations  Low level resistance: mutations in the genes associated with cell wall biosynthesis or stress ESCMIDresponses eLibrary

26 Penwell WF, Antimicrob Agentsby Chemother author2015; 59:1680–9 Antimicrobial treatment of XDR A. baumannii at a hospital in Shanghai

 Antimicrobial therapy of 43 pts with XDR A. baumannii was retrospectively analyzed

Antimicrobials Efficacy rate % Alone 4, with AMK/ISP 2, with Cefoperazone-sulbactam (n=8) 62.5 Dox/Mino 2 Alone 12, with Dox/Mino 6, with Carbapenem (n=19) 47.3 ISP 1 Cefoperazone-sulbactam+ Alone 4, with Dox/Mino 3 42.9 carbapenem (n=7)

No antimicrobial treatment (n=7) 28.6

 Conclusion: High-dose cefoperazone-sulbactam and carbapenem alone or combined with other antibiotics could be considered ESCMIDchoices for treatment of XDR when eLibrary other options are not available.

27 Li Y, J Microbiol Immunol Infectby 2015; 48, 101author-8 A combination regimen for extensive burns with PDR (colistin and tigecycline not tested) A. baumannii infection

 9 cases with moderate or severe inhalation injuries  PDRAB infection first occurred in the respiratory system in all nine patients. Wound infection in six patients (66.7%), and 4 of those pts were blood cultures positive.  Antimicrobial dosage：  CFP-SUL 12 g/d (3.0 q8h)  Merpenem 6g/d  Minocycline 0.2 g/d PO  The treatment was effective in all nine patients, and bacterium ESCMIDwas eliminated in eight pts (89%) eLibrary

Ning F, Chin J Med 2014; 127(6):1177 28 by author The use of Minocycline or Doxycycline for Acinetobacter infections

 Minocycline is an “old drug” that was first introduced in the 1960s.  It is approved for the treatment of A. baumannii infections by FDA of the US.  In China, Minocycline is only available for oral formulation, but has both oral and intravenous preparations of Doxycycline.  Minocycline susceptibility is routinely tested for Acinetobacter  Intravenous doxycycline is used for XDR A. baumannii infections.  Usually combined with CFP-SUL, carbapenems, or with both ESCMIDof them eLibrary

29 Goff DA & Kaye KS. Clin Infect Disby 2014; 59: s365 author-6 What is the difference of doxycyline and minocycline?

 A. baumannii clinical isolates are highly susceptible to both of them  Minocycline has better activity (n=5478)

MIC50, µg/ml MIC90, µg/ml Susceptibility % Minocycline 1 8 79 Doxycycline 2 >8 60 Imipenem >8 >8 37 Ampicillin-sulbactam >16/4 >16/4 26

 Doxycycline may have less central nervous adverse ESCMIDeffect of dizziness eLibrary

30 Castanheira M. Clin Infect Dis 2014;by 59: s367-73 author A. baumannii including XDR isolates have a relatively high susceptible rate to minocycline in China

54 R S, ≤4 µg/ml % 44 34 n 24 14 4

MIC distribution of minocycline against 256 XDRAB CHINET national bacterial CARSS national bacterial resistance ESCMIDresistance surveillance data eLibrary surveillance data Hu FP, Clin Microbiol Infect 2016; 22: S9–S14 Xu A, Clin Microbiol Infect 2016; 22: S1-8 31 by author Doxycycline/Minocycline for MDR-AB infections

 Ten retrospective studies regarding doxycycline and minocycline for the treatment of 156 pts with A. baumannii infections were reviewed  Combination therapy in 86% pts  Clinical success: 77% (120/156)  Respiratory infections: 72% (87/121)  Bloodstream infection: 87% (21/ 24) ESCMIDMicrobiological eradication: eLibrary 71% (72/101)

32 Falagas ME. Int J Antimicrob Agentsby 2015; 45: 455author–460 Tigecycline in combination for the treatment of Acinetobacter infections

 Tigecycline+colistin  The most studied combination and showed promising efficacy  Tigecycline+cefoperazone-sulbactam  One of the commonly used combination regimens in China  Tigecycline was launched in China in 2011  Other combinations:  Tigecycline+carbapenems (meropenem, imipenem)  Tigecycline+sulbactam ESCMID Tigecycline+rifampin eLibrary Cai Y, Infect Dis 2016; DOI: 10.3109/23744235.2016.1155735 33 Garnacho-Montero J, Expert Revby Anti Infect Ther author 2015; 13:769–77 Antimicrobial susceptibility in Acinetobacter in China

100 90 CHINET 2015 80 74.8 70.5 66.2 66.6 68.5 70 62 64.5 58.7 60.8 60 n 49.1 45.8 50 42.8 38.1 40 30 20

R esistance rate（％） R esistance 9.7 10 0.2 0 MIC distribution of minocycline SXT PIP/TAZ against 256 XDRAB Amikacin Getamycin Imipenem CefopimeAMP/SUL Tigecycline Minocycline ceftazidimeMeropenemPiperacillin Polymyxin B Ciprofloxacin CARSS national bacterial ESCMIDCefperazone/sulbactam eLibraryresistance surveillance data

Xu A, Clin Microbiol Infect 2016; 22: S1-8 by author In-vitro activity of Tigecycline and CFP-SUL combination against MDR A. baumannii

 The combination showed 29% of synergy Control against 72 MDR strains 1/2MIC TGC (all were CRAB) 1/2MIC SCF  Time-kill assays 1 MIC TGC confirmed the 1 MIC SCF synergistic interaction 1/2 MIC in 3 of 4 XDR A. combination baumannii 1 MIC ESCMID eLibrarycombination

35 Liu B, J Chemother 2015; 27: 271by-6 author In-vitro activity of Tigecycline and CFP-SUL combination against MDR A. baumannii

 The combination of tigecycline + CFP-SUL had better synergistic effects than tigecycline+ SUL against XDR-AB

Control 1/2 MIC CFP 1/2 MIC TGC + CFP

1/2 MIC TGC + SUL ESCMID eLibrary1/2 MIC TGC + CFP-SUL

36 Liu B, J Chemother 2015; 27: 271by-6 author High dose tigecycline in critically ill pts with severe infections of MDR bacteria

 54 pts received a standard dose (SD) and 46 high dose (HD) of TGC were enrolled in the ICU of a teaching hospital in Rome  SD: 50 mg q12h  HD: 100 mg q12h  CRAB (n=34) and CRKP (n =45) were the main isolated pathogens Results:  In the VAP subgroup (63 pts: 30 received SD and 33 HD), the HD group had a trends of better clinical and microbiological outcomes. The only independent predictor of clinical cure was the use of high tigecycline dose (P=0.009)  There were no pts requiring TGC discontinuation or dose reduction ESCMIDbecause of adverse events, indicating eLibrary the safety of higher dose

37 De Pascale et al. Critical Care 2014,by 18: R90 author SUMMARY

 Acinetobacter has an increasing trends of isolation in clinical specimens  Acinetobacter is highly resistant to antimicrobial agents and hypervirulent Acinetobacter emerged  Antimicrobial therapy options for Acinetobacter infections are rare  Although controversies exist, combination therapy is commonly used in clinical practice  Commonly used antimicrobials for combination therapies in China include:  Cefoperozone-sulbactam, Sulbactam, Minocycline/Doxycycline, ESCMIDTigecycline, Carbapenems, Aminoglycosides,eLibrary Fosfomycin, Rifampicin

38 by author