In vitro synergy of polymyxins with other antibiotics for Acinetobacter baumannii: A systematic review and meta-analysis

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International Journal of Antimicrobial Agents journal homepage: http://www.elsevier.com/locate/ijantimicag

Review

In vitro synergy of polymyxins with other antibiotics for Acinetobacter baumannii: A systematic review and meta-analysis Wentao Ni a,1 , Xiaodi Shao b,1 , Xiuzhen Di b , Junchang Cui a , Rui Wang b , Youning Liu a,∗ a b

Department of Respiratory Diseases, Chinese People’s Liberation Army General Hospital, Beijing 100853, China Department of Clinical Pharmacology, Chinese People’s Liberation Army General Hospital, Beijing 100853, China

a r t i c l e

i n f o

Article history: Received 7 August 2014 Accepted 1 October 2014 Keywords: Acinetobacter baumannii Polymyxin Antibiotic combination Synergy

a b s t r a c t In order to provide preliminary guidance for rational antibiotic combination therapy in the clinic, a systematic review and meta-analysis was performed to evaluate the in vitro synergistic activity of polymyxins combined with other antibiotics against Acinetobacter baumannii. An extensive literature search was undertaken without restriction according to region, publication type or language. All available in vitro synergy tests on antibiotic combinations consisting of polymyxins were included. The primary outcome assessed was the in vitro activity of combination therapy on bacterial kill or inhibition. In total, 70 published studies and 31 conference proceedings reporting testing of polymyxins in combination with 11 classes consisting of 28 antibiotic types against 1484 A. baumannii strains were included in the analysis. In time–kill studies, high in vitro synergy and bactericidal activity were found for polymyxins combined with several antibiotic classes such as carbapenems and glycopeptides. Carbapenems or rifampicin combination could efficiently suppress the development of colistin resistance and displayed a >50% synergy rate against colistin-resistant strains. Synergy rates of chequerboard microdilution and Etest methods in most antibiotic combinations were generally lower than those of time-kill assays. The benefits of these antibiotic combinations should be further demonstrated by well-designed clinical studies. © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction Acinetobacter baumannii is an opportunistic bacterial pathogen that can be easily found in many healthcare environments. Before the 1970s, A. baumannii was susceptible to most traditional antibiotics such as broad-spectrum ␤-lactams, cephalosporins and tetracyclines [1]. Nevertheless, because of its excellent environmental resilience and remarkable ability to develop resistance, A. baumannii has become one of the notorious superbugs in recent years [2]. Outbreaks of serious nosocomial infections caused by multidrug-resistant (MDR) A. baumannii have been continuously reported from hospitals worldwide, resulting in high mortality rates and bed-day costs [3]. The lack of new potent agents against MDR Gram-negative bacteria has forced clinicians to re-introduce polymyxins, a group of polypeptide antibiotics that was discovered in the 1940s [4].

∗ Corresponding author. Tel.: +86 10 6693 7909; fax: +86 10 8821 4425. E-mail address: [email protected] (Y. Liu). 1 These authors contributed equally to this study.

The polymyxins consist of five chemical compounds (A–E), but only polymyxin E (colistin) and polymyxin B are currently available on the market. Lots of in vitro susceptibility studies show that polymyxins have potent antibacterial activity against MDR A. baumannii through disorganising its outer membrane [4]. However, dosing-related nephrotoxicity and neurotoxicity limit its wider clinical application, and the increased usage has led to the emergence of resistant and heteroresistant isolates [5]. Therefore, to improve clinical treatment success and to restrict the emergence of resistance, combination therapies based on polymyxins have been proposed as good options for treating MDR A. baumannii infections [6]. In vitro synergy studies can provide preliminary guidance for rational drug combination use in the clinic. A number of in vitro tests have been performed on polymyxins in combination with other antibiotics against A. baumannii, yielding various results. The heterogeneity in these tests is likely to arise through the limited number of strains, susceptibility differences, testing methods and clonal diversity of strains among different hospitals and laboratories [7]. To determine which antibiotic combinations might be suitable options to treat MDR A. baumannii infections, we

http://dx.doi.org/10.1016/j.ijantimicag.2014.10.002 0924-8579/© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Please cite this article in press as: Ni W, et al. In vitro synergy of polymyxins with other antibiotics for Acinetobacter baumannii: A systematic review and meta-analysis. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.10.002

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systematically searched and analysed the literature to evaluate the in vitro synergistic activity of polymyxins with other antibiotics against A. baumannii.

recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST): susceptible, ≤2 mg/L; and resistant, ≥4 mg/L.

2. Materials and methods

2.5. Quantitative data synthesis

2.1. Search strategy A literature search was performed in July 2014 by two separate reviewers, without restriction according to region, publication type or language. Primary sources were the electronic databases PubMed and Embase. To reduce publication bias, Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Infectious Diseases Society of America (IDSA) and European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) conference proceedings for the years 2006–2013 were also reviewed. Keywords and Boolean operators used for searches were (colistin OR colistimethate OR polymyxin) AND (Acinetobacter baumannii OR baumannii OR A. baumannii) AND (in vitro OR combination OR chequerboard OR time-kill OR Etest OR microdilution OR agar dilution OR susceptibility). No special search features were used. The related articles function was also used to broaden the search, and the reference lists of the retrieved articles were reviewed for additional studies. When multiple reports describing the same strain population were published, the most recent or complete report was used.

All statistical analyses were performed with Comprehensive Meta-Analysis v.2.2 (Biostat Inc., Englewood, NJ). The event rate (synergy rate) with 95% confidence interval (CI) was calculated for each study, and various pooled event rates were calculated both by the fixed-effects model and random-effects model. The I2 test was used to assess heterogeneity, where I2 values of 0% indicate no observed heterogeneity whereas larger values indicate increasing heterogeneity. Results of the fixed-effects model are quoted unless substantial heterogeneity is present, in which cases results of the random-effects model are stated [8]. In the statistical analyses, groups were divided by synergy testing method and the classes of antibiotics that polymyxins were combined with. For studies using more than one testing method, the results of different methods were separately collected and analysed in different groups. In each group, the results were subgrouped by antibiotic type and resistance to polymyxins. In time-kill studies performing multiple tests on the same bacterial population and the same antibiotic combination, the one that used a more common bacterial load or clinically achievable drug concentration was chosen.

2.2. Inclusion and exclusion criteria

3. Results

All available in vitro synergy tests of antibiotic combinations consisting of polymyxins were included in this study. Studies using non-traditional testing methods [except for the chequerboard method, Etest and the time-kill assay, which included both the static time-kill and in vitro dynamic pharmacokinetic/pharmacodynamic (PK/PD) model], those testing polymyxins in combination with agents or compounds that are not available on the market worldwide, and those examining combinations with three or more drugs were excluded.

In total, 859 potentially relevant studies were initially identified by the PubMed and Embase searches (Fig. 1). Most of these studies were excluded as they did not report any in vitro tests assessing the synergy of polymyxin combination therapies for A. baumannii. Finally, 70 published studies and 31 conference proceedings fulfilled the pre-determined inclusion criteria and were included in the analysis. Table 1 summarises the main characteristics of each included study. In total, 105 time-kill assays, 77 chequerboard microdilution tests and 33 Etests were performed, testing polymyxins in combination with 11 classes consisting of 28 antibiotic types against 1484 A. baumannii strains.

2.3. Outcome measurements The primary outcome was the in vitro activity of combination therapy on bacterial kill or inhibition. With time-kill assays, synergy for the combination was defined as >2 log10 CFU/mL decrease in comparison with that by the most active constituent of the combined antibiotics, and antagonism was defined as >2 log10 CFU/mL increase. For the chequerboard method and Etest, the fractional inhibitory concentration index (FICI) was calculated with the following formula: FICI = (MICAB /MICA ) + (MICBA /MICB ), where MICAB is the minimum inhibitory concentration (MIC) of drug A tested in combination, MICA is the MIC of drug A tested alone, MICBA is the MIC of drug B tested in combination and MICB is the MIC of drug B tested alone. Synergy was defined as a FICI ≤0.5, indifference as a FICI between >0.5 and 4 and antagonism as a FICI > 4. The secondary outcomes were bactericidal activity, defined as >3 log10 CFU/mL reduction in the colony count relative to the initial inoculum, and the effect of combination therapy on resistance development. 2.4. Data extraction For the analysis, the following data were independently extracted by two reviewers: (i) author identification; (ii) year of publication; (iii) synergy testing method; (iv) type of antibiotic(s) used; (v) number of isolates tested; and (vi) MICs of isolates for polymyxins. The breakpoints for polymyxins were those

3.1. Time-kill data synthesis For polymyxin–carbapenem combinations (Fig. 2), pooling data from 273 strains in 26 studies showed that the synergy rate was 80.6% (95% CI 64.2–90.6%); 2 isolates showed antagonism, with a rate of 7.1% (95% CI 4.4–11.4%). The rate of bactericidal activity for 170 isolates increased from 26.2% (95% CI 18.6–35.5%) for the most active single agent to 71.8% (95% CI 63.3–79.0%) in combinations. Heterogeneity (I2 ) for these studies was 53.4%. The synergy rate of combinations with colistin was 84.9% (95% CI 74.6–91.5%), which was higher than that of polymyxin B combinations (63.4%, 95% CI 37.8–83.2%). Meropenem and doripenem showed synergy rates of 85.2% (95% CI 68.3–93.9%) and 86.6% (95% CI 70.3–94.7%), respectively, whilst imipenem displayed a synergy rate of 66.8% (95% CI 44.2–83.7%). When examining polymyxin-resistant strains (nine studies on 58 isolates), the synergy rate was 79.8% (95% CI 63.2–90.1%), similar to that of polymyxin-susceptible strains. For polymyxin–rifampicin combinations (Fig. 3), 22 studies tested 280 isolates and yielded a synergy rate of 57.2% (95% CI 50.5–63.6%), whilst 1 isolate was antagonistic, with an antagonism rate of 6.2% (95% CI 3.7–10.4%). Rates of bactericidal activity for 153 isolates increased from 26.4% (95% CI 10.2–53.1%) for the best single agent to 86.7% (95% CI 73.2–94%) in combinations. Heterogeneity (I2 ) for these studies was 44.3%. The synergy rate in combinations

Please cite this article in press as: Ni W, et al. In vitro synergy of polymyxins with other antibiotics for Acinetobacter baumannii: A systematic review and meta-analysis. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.10.002

Polymyxin

Polymyxin resistancea

Combination antibiotic(s)

No. of isolates

Synergy testing method (s)

Outcome reported

Tascini et al. [9] Hogg et al. [10] Giamarellos-Bourboulis et al. [11] Yoon et al. [12] Wareham and Bean [13] Timurkaynak et al. [14] Petersen et al. [15] Foleno et al. [16] Tascini et al. [17] Leu et al. [18] Biancofiore et al. [19] Tripodi et al. [20] Tan et al. [21] Li et al. [22] Song et al. [23] Sands et al. [24] Kroeger et al. [25] Scheetz et al. [26] Morgan et al. [27] Antonopoulou et al. [28] Pankuch et al. [29] Guelfi et al. [30] Moland et al. [31] Lee et al. [32] Burgess et al. [33]

1998 1998 2001 2004 2006 2006 2006 2006 (IDSA) 2006 (ECCMID) 2006 (ECCMID) 2007 2007 2007 2007 2007 2007 2007 2007 2007 (IDSA) 2007 (ECCMID) 2008 2008 2008 2008 2008 (ICAAC)

PMB COL COL PMB PMB COL COL COL COL COL COL COL COL COL COL PMB COL PMB COL COL COL PMB PMB COL COL

S S, R S S, R S S, R

5 13 39 8 5 5 9 20 1 10 1 9 13 8 8 19 1 4 32 18 51 10 1 2 5

Chequerboard Chequerboard Time–kill Chequerboard, time–kill Etest Chequerboard Chequerboard Chequerboard Chequerboard Chequerboard Chequerboard Time–kill Chequerboard, time–kill Chequerboard Time–kill Chequerboard PK/PD time–kill Time–kill Etest Time–kill Time–kill Chequerboard Time–kill Time–kill Time–kill

FICI FICI Tks, b FICI, tks, b FICI FICI FICI FICI FICI FICI FICI Tks, b FICI, tks, b FICI Tks FICI Tks Tks FICI Tks Tks FICI Tks Tks Tks, b

Ullman et al. [34] Attridge et al. [35] Pankey and Ashcraft [36] Lim et al. [37] Principe et al. [38] Arroyo et al. [39] Mukhopadhyay et al. [40] Burgess et al. [41]

2008 (ICAAC) 2008 (ICAAC) 2009 2009 2009 2009 2009 2009 (ICAAC)

COL COL PMB PMB COL COL COL COL

S S S S S, R S, R R S

3 5 8 3 24 35 5 5

PK/PD time–kill PK/PD time–kill Etest, time–kill Time–kill Chequerboard Chequerboard Chequerboard Time–kill

b Tks, b FICI, tks, b Tks FICI FICI FICI Tks, b

Pongpech et al. [42] Rodriguez et al. [43] Sopirala et al. [44] Urban et al. [45] Pankuch et al. [46] ˜ et al. [47] Pachón-Ibánez Dizbay et al. [48] Özbek and S¸entürk [49] Özbek and Ötük [50] Gordon et al. [51] Srisupha-Olarn and Burgess [52] Tan et al. [53] Dorobisz et al. [54] Korber-Irrgang and Kresken [55] Lim et al. [56] Lim et al. [57] Steed et al. [58]

2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 2010 (ICAAC) 2010 (ICAAC) 2010 (ICAAC) 2010 (ECCMID) 2010 (ECCMID) 2010 (ECCMID) 2010 (ECCMID)

COL COL COL PMB COL COL COL COL COL COL COL COL COL COL PMB PMB COL

S S, R S S S, R S S S S, R S S S R

30 14 32 5 25 4 25 6 50 6 3 2 6 10 29 5 8

Chequerboard, time–kill Time–kill Chequerboard, Etest, time–kill Time–kill Time–kill Time–kill Etest Chequerboard Chequerboard Chequerboard, time–kill PK/PD time–kill PK/PD time–kill Chequerboard, Etest, time–kill Chequerboard Time–kill Time–kill Time–kill

FICI, tks Tks, b FICI, tks Tks, b Tks Tks FICI FICI FICI FICI, tks, b Tks, b Tks, b FICI, b FICI Tks Tks Tks

Shields et al. [59]

2011

COL

S

Rifampicin, ampicillin/sulbactam Rifampicin Rifampicin Imipenem, rifampicin Imipenem, rifampicin, azithromycin Doxycycline, meropenem, rifampicin, azithromycin Tigecycline Ceftobiprole Rifampicin Imipenem, sulbactam Meropenem, rifampicin Imipenem, rifampicin, ampicillin/sulbactam Minocycline Rifampicin Rifampicin Tigecycline Ceftazidime Tigecycline Tigecycline Imipenem, sulbactam, rifampicin Meropenem Meropenem Tigecycline Sulbactam Rifampicin, ampicillin/sulbactam, cefepime, doxycycline, meropenem, levofloxacin, amikacin Meropenem Rifampicin Meropenem Rifampicin, tigecycline, meropenem Tigecycline Tigecycline Rifampicin Imipenem, clarithromycin, ceftazidime, ceftriaxone, vancomycin, linezolid Imipenem, meropenem Imipenem, rifampicin Imipenem, tigecycline Rifampicin, doripenem Doripenem Rifampicin Rifampicin, tigecycline Tigecycline Tigecycline Vancomycin Meropenem Rifampicin Ampicillin/sulbactam, doripenem Daptomycin Rifampicin, tigecycline Rifampicin, meropenem, cefepime Rifampicin, ampicillin/sulbactam, imipenem, tobramycin Imipenem, doripenem, rifampicin, tigecycline, ampicillin/sulbactam

17

Etest, time–kill

FICI, tks

S, R S S S S S S S S S S, R S S, R S S S S

S R S

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Please cite this article in press as: Ni W, et al. In vitro synergy of polymyxins with other antibiotics for Acinetobacter baumannii: A systematic review and meta-analysis. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.10.002

Table 1 Summary of characteristics of included studies.

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Polymyxin resistancea

Combination antibiotic(s)

No. of isolates

Synergy testing method (s)

Outcome reported

Liang et al. [60] Sheng et al. [61] Lim et al. [62] Hornsey and Wareham [63] Tan et al. [64] Santimaleeworagun et al. [65] Wareham et al. [66] Wang and Su [67] Speil et al. [68] Principe et al. [69] Poudyal et al. [70] Teo et al. [71] Speil et al. [72] Hornsey et al. [73] Peck et al. [74] Kempf et al. [75] Ozseven et al. [76] Quale et al. [77] Mutlu Yilmaz et al. [78] Deveci et al. [79] Miyasaki et al. [80]

2011 2011 2011 2011 2011 2011 2011 2011 2011 (ICAAC) 2011 (ICAAC) 2011 (ECCMID) 2011 (ECCMID) 2011 (ECCMID) 2012 2012 2012 2012 2012 2012 2012 2012

COL COL PMB COL PMB COL COL PMB PMB COL COL PMB PMB COL COL COL PMB PMB COL COL COL

S S S S S, R S S S S

4 17 31 2 16 8 6 35 21 24 3 24 21 1 6 1 34 25 1 10 20

Time–kill Chequerboard, time–kill Time–kill Chequerboard Chequerboard, Etest, time–kill Chequerboard Chequerboard Chequerboard Chequerboard Chequerboard PK/PD time–kill Time–kill Chequerboard Chequerboard, time–kill Time–kill Etest Chequerboard Time–kill Chequerboard, time–kill Chequerboard Etest

Tks, b FICI, tks, b Tks, b FICI Tks FICI FICI FICI FICI FICI Tks, b Tks FICI FICI, tks Tks FICI FICI Tks FICI, tks FICI FICI

Vidaillac et al. [81]

2012

COL

S, R

4

Chequerboard, time–kill

FICI, tks, b

Kongsanae et al. [82] Rao et al. [83] Medeiros and Lincopan [84] Malmberg et al. [85] Moraitou et al. [86] Lim et al. [87] Cai et al. [88] Clock et al. [89] Cıkman et al. [90] Netto et al. [91]

2012 2012 (ICAAC) 2012 (ICAAC) 2012 (ECCMID) 2012 (ECCMID) 2012 (ECCMID) 2012 (ECCMID) 2013 2013 2013

COL PMB PMB COL COL PMB PMB PMB COL PMB

S, R S

30 1 8 1 42 2 35 48 33 2

Chequerboard, time–kill Time–kill Chequerboard Time–kill Etest PK/PD time–kill Time–kill Chequerboard Etest Time–kill

FICI, tks Tks FICI Tks FICI Tks, b Tks FICI FICI Tks

Principe et al. [92] Lee et al. [93] Ni et al. [94] Karaoglan et al. [95]

2013 2013 2013 2013

COL COL COL COL

S, R S, R S S, R

24 2 70 50

Chequerboard, time–kill PK/PD time–kill Chequerboard Etest

FICI, tks, b Tks, b FICI FICI

Cetin et al. [96] Zhang et al. [97] O’Hara et al. [98] Hornsey et al. [99] Yilmaz et al. [100] Leite et al. [101] Arhin et al. [102] Mansour et al. [103] Oleksiuk et al. [104] Hagihara et al. [105] Leu et al. [106] Nastro et al. [107] Thamlikitkul and Tiengrim [108] Galani et al. [109]

2013 2013 2013 2013 2013 (IDSA) 2013 (IDSA) 2013 (ICAAC) 2013 (ICAAC) 2014 2014 2014 2014 2014 2014

PMB PMB COL COL COL COL COL COL COL PMB COL COL COL COL

S S, R R S S S, R S, R

Rifampicin, meropenem, minocycline Imipenem, tigecycline Rifampicin, tigecycline Vancomycin, teicoplanin Rifampicin, tigecycline Imipenem, sulbactam, fosfomycin Teicoplanin Rifampicin Tigecycline Doripenem Doripenem Doripenem Rifampicin Telavancin Imipenem, rifampicin, tigecycline Sulbactam Imipenem Rifampicin Tigecycline Sulbactam Rifampicin, tigecycline, imipenem, amikacin, doxycycline Vancomycin, trimethoprim, trimethoprim/sulfamethoxazole Rifampicin Tigecycline Imipenem, vancomycin Daptomycin Rifampicin Doripenem Rifampicin, tigecycline Doripenem Ampicillin/sulbactam Imipenem, meropenem, ceftazidime, tigecycline, amikacin, rifampicin Doripenem Rifampicin Tigecycline Tigecycline, piperacillin/tazobactam, cefoperazone/sulbactam Ampicillin/sulbactam, cefoperazone/sulbactam Minocycline, fosfomycin Vancomycin, doripenem Telavancin Tigecycline, sulbactam Imipenem, rifampicin, vancomycin, amikacin Oritavancin Imipenem, meropenem Sulbactam, doripenem Tigecycline Imipenem Rifampicin Sulbactam Daptomycin

20 25 3 2 18 13 11 11 18 4 6 4 11 14

Chequerboard, Etest Chequerboard Chequerboard, time–kill Chequerboard, time–kill Etest Chequerboard Chequerboard, time–kill Chequerboard Time–kill Time–kill Chequerboard Etest Chequerboard Time–kill

FICI FICI FICI, tks, b FICI, tks, b FICI FICI FICI, tks FICI Tks, b Tks FICI FICI FICI Tks, b

S S, R S, R S S, R R S S, R S S S, R

S S S S, R S S, R S

S, R S S R S, R S, R

PMB, polymyxin B; COL, colistin; IDSA, Infectious Diseases Society of America; ECCMID, European Congress of Clinical Microbiology and Infectious Diseases; ICAAC, Interscience Conference on Antimicrobial Agents and Chemotherapy; PK/PD, pharmacokinetic/pharmacodynamic; FICI, fractional inhibitory concentration index; Tks, time–kill synergy; b, bactericidality. a Breakpoints for polymyxins were those recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST): susceptible (S), ≤2 mg/L; and resistant (R), ≥4 mg/L.

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Table 1 (Continued)

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Fig. 1. Flow diagram of included studies.

with colistin was 64.9% (95% CI 54.2–74.2%) and the rate in combinations with polymyxin B was 52.6% (95% CI 44.2–60.9%). When specifically examining polymyxin-resistant strains (six studies on 47 isolates), the overall synergy rate was 56.8% (95% CI 41.1–71.2%), which was similar to that of susceptible strains. For polymyxin–tigecycline combinations (Fig. 4), testing on 135 isolates in 13 studies yielded a synergy rate of 41.6% (95% CI 33.1–50.5%); 2 isolates were antagonistic, with a rate of 9.1% (95% CI 4.4–18.1%). Bactericidal activity for 84 isolates increased from 16.8% (95% CI 7.6–33.1%) for the single most active agent to 60.3% (95% CI 39.3–78.2%) in combinations. Heterogeneity (I2 ) was 24.0%. Considering that only three studies consisting of nine strains tested the colistin–tigecycline combination and two studies tested polymyxin-resistant isolates, these subgroup analyses were not performed. For colistin–glycopeptide combinations (Fig. 5), synergy tests were performed in nine studies with 46 isolates, yielding a synergy rate of 70.8% (95% CI 53.1–83.9%); no isolates showed antagonism. Heterogeneity (I2 ) for these studies was 22.81%. The rate of bactericidal activity for 29 isolates increased from 8.4% (95% CI 2.4–25.2%) for colistin used alone to 73.3% (95% CI 53.9–86.6%) in antibiotic combinations. Data for colistin-resistant strains were available for three studies, with a lower synergy rate of 25.0%. Fourteen studies evaluated the in vitro synergy of polymyxins combined with other antibiotic classes for A. baumannii. Among these, four studies including 38 strains evaluated the colistin–sulbactam combination and three studies including 22 strains evaluated the colistin–ampicillin/sulbactam combination, yielding a pooled synergy rate of 70.8% (95% CI 44.5–88.0%). Tests on 23 isolates in five studies showed that the synergy rate of

polymyxins in combination with cephalosporins was 83.5% (95% CI 62.0–94.0%). Four studies consisting of 27 strains tested the colistin–tetracycline combination, and synergy was found in 26 strains. Two studies tested the polymyxin–amikacin combination and six of seven strains showed synergy. In addition, four studies tested colistin in combination with tobramycin, levofloxacin, clarithromycin or linezolid, and synergistic activity was found in 5/8, 4/5, 5/5 and 5/5 strains, respectively. 3.2. Chequerboard microdilution data synthesis The polymyxin–carbapenem combination was tested in 17 studies with 274 strains. The pooled synergy rate was 39.6% (95% CI 19.6–63.9%) and the rate of colistin combinations was higher than that of polymyxin B combinations. For polymyxins and rifampicin in combination, 11 studies tested 140 isolates and yielded a synergy rate of 60.3% (95% CI 34.4–81.5%). Tests on 297 isolates in 11 studies showed that the synergy rate of polymyxins in combination with tigecycline was 10.4% (95% CI 4.3–23.2%). Of note, 100% synergy rate was observed in one study (21 isolates) and excluding it yielded a synergy rate of 9.5% (95% CI 6.0–14.5%). Ten studies with 68 isolates were tested for the colistin–glycopeptide combination, and seven studies with 70 isolates were tested for polymyxins combined with sulbactam or ampicillin/sulbactam, yielding synergy rates of 56.0% (95% CI 3.4–75.6%) and 54.1% (95% CI 18.9–85.6%), respectively. Several studies reported the synergy rate of polymyxins in combination with other antibiotics, including minocycline, doxycycline, fosfomycin, amikacin and azithromycin, and the synergy rates were 28.9%, 0, 15.2%, 0 and 60%, respectively. In all studies, no antagonism with a FICI >4 was reported.

Please cite this article in press as: Ni W, et al. In vitro synergy of polymyxins with other antibiotics for Acinetobacter baumannii: A systematic review and meta-analysis. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.10.002

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Fig. 2. Forest plot and pooled synergy rates for polymyxin–carbapenem combinations. Subgroups within studies according to polymyxin resistance profile and types of carbapenem are listed separately and denoted by continuous numbering in parentheses. CI, confidence interval.

Fig. 3. Forest plot and pooled synergy rates for polymyxin–rifampicin combinations. Subgroups within studies according to polymyxin resistance profile are listed separately and denoted by continuous numbering in parentheses. CI, confidence interval.

Please cite this article in press as: Ni W, et al. In vitro synergy of polymyxins with other antibiotics for Acinetobacter baumannii: A systematic review and meta-analysis. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.10.002

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Fig. 4. Forest plot and pooled synergy rates for polymyxin–tigecycline combinations. Subgroups within studies according to polymyxin resistance profile are listed separately and denoted by continuous numbering in parentheses. CI, confidence interval.

3.3. Etest data synthesis Four studies with 38 isolates testing polymyxin–carbapenem combinations reported a pooled synergy rate of 32.4% (95% CI 10.1–67.2%). Seven studies reporting on polymyxin–rifampicin combinations provided a pooled synergy rate of 30.8% (95% CI 11.2–61.2%). Nine studies with 250 isolates testing polymyxin–tigecycline combinations yielded a synergy rate of 13.5% (95% CI 3.4–40.8%), and seven studies with 145 isolates testing polymyxin in combination with a ␤-lactam antibiotic/␤lactamase inhibitor yielded a synergy rate of 13.8% (95% CI 2.3–51.7%). One study examining a colistin–doxycycline combination reported synergy of 1 of 20 isolates. Another two studies tested combinations with amikacin and azithromycin, observing no synergistic activity. 3.4. Effect of antibiotic combinations on resistance development The rate of resistance development between colistin monotherapy and combination therapy was compared in four studies. Rodriguez et al. observed the emergence of resistant subpopulations when heteroresistant strains were exposed to colistin alone, whilst colistin–rifampicin and colistin–imipenem combinations successfully suppressed the emergence of resistant populations

[43]. Poudyal et al. also found that colistin–doripenem combination was highly active in suppression of colistin resistance [70]. The other two studies [53,93] reported that changes in susceptibilities in subpopulations were detected at 72–96 h by real-time population analysis profiles when colistin was used alone. In contrast, no resistant A. baumannii colonies were detected at any time in colistin–rifampicin combination therapy. 4. Discussion Despite polymyxins having good in vitro antimicrobial activity against MDR A. baumannii, re-growth is commonly observed in time–kill assays and the plasma concentration achieved in patients is low, highlighting a need for caution with monotherapy [93]. Given these situations, combination therapies are now increasingly used [6]. This meta-analysis showed that several antibiotics in combination with polymyxins could act synergistically together against A. baumannii in vitro. For polymyxin–carbapenem and colistin–glycopeptide combinations, synergy rates were found in >70% isolates. Compared with monotherapy, significantly enhanced bactericidal activity could be observed in most combination therapies, from 8.4–26.4% to 60.3–86.7%. A previous meta-analysis came to the conclusion that there was an advantage for meropenem and doripenem in combination over imipenem

Fig. 5. Forest plot and pooled synergy rates for colistin–glycopeptide combinations. Subgroups within studies according to colistin resistance profile are listed separately and denoted by continuous numbering in parentheses. CI, confidence interval.

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[7]. The present study verified this with more included isolates and found the synergy rate of colistin–carbapenem combinations was higher than that of polymyxin B combinations, even when excluding studies testing the polymyxin–imipenem combination. For the polymyxin–rifampicin combination, a synergy difference between colistin and polymyxin B combination was also demonstrated, indicating colistin has better synergistic activity. The potent synergy and bactericidal activity of colistin in combination with glycopeptides and linezolid provide us an interesting angle on treatment especially when facing mixed infections caused by Gram-positive bacteria and MDR A. baumannii. Although the mechanisms of these combinations producing synergistic activity have not been fully understood, this effect is considered to be mediated by the permeabilising effect of colistin on the bacterial outer membrane, permitting the entry of large hydrophobic molecules such as glycopeptides and trimethoprim [51]. In addition, the synergy rate for colistin-resistant strains was very low, which further confirmed this conclusion. However, before these unconventional combinations are applied to clinical practice, more in vivo PK/PD studies are warranted and the risk of nephrotoxicity should be evaluated carefully. The resistance rate of colistin is increasing year by year and surveillance of some regions has reported a quite high rate of >30% [110]. Moreover, heteroresistance is more common in clinical isolates [110]. Although in vitro studies may not completely reflect the whole clinical picture, many have demonstrated that selection of resistant isolates following colistin exposure was very easy, whilst combination therapies could successfully suppress the emergence of resistant subpopulations. Even to those resistant strains, polymyxin–carbapenem and polymyxin–rifampicin combinations displayed a >50% synergy rate, without any antagonism. This provides us potential options in treating severe infections caused by pandrug-resistant A. baumannii. According to the pooled synergy data in this review, there is great discordance between different testing methods. For example, by the time-kill method, the synergy rate of polymyxin–carbapenem combinations was 80.6%, whilst by the chequerboard microdilution and Etest methods the synergy rates were 39.6% and 32.4%, respectively. For polymyxin–rifampicin combinations, synergy rates both of time-kill and chequerboard microdilution methods were ca. 60%, whilst the rate of Etest was only 30.8%. It appears that synergy rates of the time-kill method in most antibiotic combinations were generally higher than those of chequerboard microdilution and E-test methods. The same result was also obtained in synergy tests for other bacterial species [7]. Although time-kill assays can provide us more information about the interaction between drugs and bacteria in a larger reaction system, the testing processes are laborious, time consuming and require expertise in the specific procedures [44]. Therefore, universally accepted standards for synergy testing should be established and better methods that can accurately predict in vivo efficacy are desperately needed. In conclusion, this current review demonstrated the high in vitro synergy and bactericidal activity of polymyxins in combination with several antibiotics against A. baumannii. Carbapenems or rifampicin combination could efficiently suppress the development of colistin resistance and displayed a >50% synergy rate against colistin-resistant strains. However, the in vitro results may not be directly used in clinical practice, since in vivo conditions such as dynamic drug concentrations, virulence of bacteria and host immune response at the infection site cannot be completely mimicked in vitro. The benefits of these antibiotic combinations should be demonstrated through adequate multicentre randomised clinical studies.

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Please cite this article in press as: Ni W, et al. In vitro synergy of polymyxins with other antibiotics for Acinetobacter baumannii: A systematic review and meta-analysis. Int J Antimicrob Agents (2014), http://dx.doi.org/10.1016/j.ijantimicag.2014.10.002