The Journal of Antibiotics (2023) 76:20–26

https://doi.org/10.1038/s41429-022-00573-z

ARTICLE

In vitro analysis of synergistic combination of polymyxin B with 12

other antibiotics against MDR Acinetobacter baumannii isolated from
a Chinese tertiary hospital
Hui Liu1 Dan Hu1 Dongxin Wang1 Han Wu1 Yunjun Pan1 Xin Chen1 Lin Qi1,2 Lian Li
● ● ● ● ● ● ●
1,2 ●
Rongxin Liang1

Received: 31 August 2022 / Revised: 21 September 2022 / Accepted: 22 September 2022 / Published online: 28 October 2022
© The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2022

Abstract
In clinical practice, polymyxins are suggested to be used in combination with other antibiotics for improving their antibacterial
efficacy and preventing the emergency of antibiotic-resistant strains. However, even though synergistic combination of
polymyxin B with many antibiotics have been confirmed in various studies with different bacterial species and analyzing
methods, which antibiotic is the best option for combination therapy of polymyxin B against MDR A. baumannii remains
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uncertain. In this study, we systematically analyzed the synergistic combination of polymyxin B with 12 other antibiotics
against MDR A. baumannii isolated from a Chinese tertiary hospital using the checkerboard assay. The results suggest that, for
polymyxin B-based combination therapy against MDR A. baumannii as characterized in this hospital, cefperazone-sulbactam
may be the best partner, since it has the highest synergistic rate and the best synergistic effect with polymyxin B. Minocycline,
imipenem, meropenem, ceftazidime, cefepime, amikacin and sulfamethoxazole also have some synergistic effects with
polymyxin B, but piperacillin-tazobactam, ciprofloxacin, levofloxacin and tobramycin show no synergism. None of these 12
antibiotics has an antagonistic effect when combined with polymyxin B.

Introduction reported in hospitals around the world, which greatly

In the past decades, due to the heavy use of antibiotics
in clinic practice, antibiotic resistance of Acinetobacter
baumannii has generally increased worldwide [1, 2]. Of
particular concern is the emergence of multidrug resistant
(MDR) A. baumannii, the extensive antibiotic resistance
nature of which has seriously narrowed the available anti-
biotic therapy alternatives and made the treatment of
bacterial infection caused by MDR A. baumannii a big
challenge faced by clinicians [3, 4]. Even worse, nosoco-
mial outbreaks of MDR A. baumannii have been frequently
These authors contributed equally: Hui Liu, Dan Hu
* Rongxin Liang
15586919387@163.com
1 been recommended by many authorities, such as Clinical and
Department of Clinical Laboratory, Renmin Hospital, Hubei
University of Medicine, Shiyan, Hubei 442000, PR China
2 used in clinical practice [7, 11, 12]. Theoretically, combina-
Department of Clinical Laboratory, Jinzhou Medical University
Graduate Training Base, Renmin Hospital, Hubei University of
Medicine, Shiyan, Hubei 442000, PR China
increases the risk of MDR A. baumannii infection and
makes the MDR A. baumannii infection a worldwide pro-
blem [5, 6]. The wide prevalence of MDR A. baumannii
and the high antibiotic resistance feature have made the
search for effective antibacterial therapy against MDR
A. baumannii an urgent need.
Polymyxins, including colision, polymyxin E and poly-
myxin B, have currently been regard as the last resort agents
for the treatment of MDR A. baumannii [7]. However,
the available pharmacodynamic (PD) and pharmacokinetic
(PK) data suggest that reliably efficacious plasma con-
centrations of polymyxin B are difficult to be maintained with
polymyxin B monotherapy [7–9]. While polymyxins are
highly nephrotoxic agents, the likeliness of renal impairment
is closely associated with the daily dose of polymyxin [10].
A strategy for promoting antibacterial efficacy without
increasing polymyxin exposure is the use of polymyxins in
combination with other agents. Actually, this strategy has
Laboratory Standards Institute (CLSI), and is increasingly
tion therapy has potential advantages such as increasing the
antibacterial efficacy, reducing the dosage of the antibiotics
In vitro analysis of synergistic combination of polymyxin B with 12 other antibiotics against MDR. . .
that have high toxicity, and even decreasing the development
of antibiotic resistance [13, 14].
Even though a large number of in vitro studies have
confirmed synergistic combination of different antibiotics
with polymyxin B against different bacterial species, the
determination of which antibiotic is more suitable for
combination therapy with polymyxin B against MDR
A. baumannii remains uncertain. Many studies have
examined just one or a few antibiotic combinations, and
different laboratories use different analytical methods, as
well as different clonal strains, the heterogeneity of the
existing data makes it difficult to compare the combination
effect of different antibiotics with polymyxin B against
MDR A. baumannii [15, 16].
In order to get a systematical evaluation of the syner-
gistic combination of polymyxin B with different antibiotics
against MDR A. baumannii, 12 antibiotics that are recom-
mended for routine reporting of antimicrobial susceptibility
testing of A. baumannii were selected and examined with
checkerboard assays to determine their synergistic rates and
synergistic effects with polymyxin B against the MDR A.
baumannii isolated from a Chinese tertiary hospital.
Materials and methods
Bacterial isolates and chemicals
A total of 128 non-duplicate MDR A. baumannii isolates
were obtained from various specimens of inpatients in
Shiyan Renmin Hospital, a Chinese tertiary hospital that
located in the center area of China, during the period
from 2018 to 2020. Species that identified with the
Vitek2 compact system (BioMerieux, France) were further
confirmed with MALDI-TOF mass spectrometry (Bruker,
China). Antibiotic susceptibility of those isolates referred
to the clinic antimicrobial susceptibility reports and
MDR was defined as being resistant to at least three of
the six antibiotic classes, including β-lactam/β-lactamase
inhibitor combinations, cephalosporins, carbapenems, ami-
noglycosides, tetracyclines, fluoroquinolones. A. baumannii
ATCC19606 was used as the control strain. All antibiotics
employed in this study were purchased from Solarbio
(Beijing, China) and dissolved with sterile water to prepare
stock solution.
Multilocus sequence typing and clonal complex
analysis
32 out of 128 isolates of MDR A. baumannii were randomly
selected and cultivated with LB broth for 24 h. Then bacteria
were collected and total DNA was extracted with Bacterial
Genomic DNA Extraction Kit (SAINT-BIO, Shanghai).
21
Multilocus sequence typing (MLST) of MDR A.baumannii
was determined by amplifying seven housekeeping genes
as described previously, including cpn60, fusA, gltA, pyrG,
recA, rplB, rpoB. The fragments containing seven house-
keeping genes were sent to Biomed (Beijing, China) for
purification and DNA sequencing service. The numbers of
alleles and sequence types (STs) were assigned by comparing
with MLST online database (https://pubmlst.org). The goe-
BURST algorithm was used to infer the evolutionary relat-
edness of the STs.
Susceptibility testing
MICs of polymyxin B and 12 other antibiotics were deter-
mined with the broth microdilution method according to the
CLSI guideline (https://clsi.org/). Briefly, bacterial cell sus-
pensions prepared with cation-regulated Mueller–Hinton
broth (CAMHB) were dispensed into the wells of 96-well
microtiter plate and made the final bacterial concentration of
5 × 105 CFU ml−1 for each well. Polymyxin B and 12 other
antibiotics were separately added into each well to get desired
concentration, ranging from 256 to 2 μg ml−1 with twofold
dilution for piperacillin-tazobactam (TZP) and sulfamethox-
azole (SXT), 128 to 1 μg ml−1 with twofold dilution for
cefperazone-sulbactam (SCF), ceftazidime (CAZ) and ami-
kacin (AK), 64 to 0.5 μg ml−1 with twofold dilution for
cefepime (FEP), 32 to 0.25 μg ml−1 with twofold dilution for
tobramycin (TOB), minocycline (MH), imipenem (IPM)
and meropenem (MEM), 16 to 0.125 μg ml−1 with twofold
dilution for levofloxacin (LEV) and polymyxin B (PB), and
8 to 0.0625 μg ml−1 with two-fold dilution for ciprofloxacin
(CIP). The plates were read after incubating for 24 h, and MIC
was defined as the lowest concentration of antibiotic required
to visibly inhibit the growth of bacteria.
Checkerboard studies
Basing on the susceptibility testing results, checkerboard
assays were further conducted to determine the pharmaco-
dynamic interaction of polymyxin B with 12 other antibiotics
on antibacterial activity. In this experiment, polymyxin B and
each other antibiotic were prepared by two-fold serial dilu-
tions and mixed to produce different concentration combi-
nations. The results were read after incubated for 24 h and
interpreted as follows: FICI ≤ 0.5, synergistic; 0.5 < FICI ≤
4.0, indifferent; and FICI > 4.0, antagonistic.
Synergistic combination analysis
Synergistic combination was analyzed from two aspects,
one was synergistic rate and the other was synergistic effect.
For each antibiotic combination, synergistic rate was cal-
culated as the percentage of the isolates with FICI ≤ 0.5.
22 H. Liu et al.

Table 1 Synergistic
Antbiotic Resistant ratea Synergistic rateb Synergistic effectc
combinations of polymyxin B
with 12 other antibiotics against Total ST92 (23) ST75 (9) Combinated Reduction fold of MIC with
MDR A. baumannii obtained isolates (128) with PB 1/4 MIC of PB
from a Chinese tertiary hospital
TZP 100.0% 100.0% 100.0% 0.0% –
CAZ 100.0% 100.0% 100.0% 31.2% 8.3
SCF 100.0% 100.0% 100.0% 75.8% 10.9
FEP 100.0% 100.0% 100.0% 24.2% 4.8
IPM 100.0% 100.0% 100.0% 45.3% 9.6
MEM 100.0% 100.0% 100.0% 39.1% 8.4
AK 65.6% 47.8% 88.9% 17.2% 9.5
TOB 100.0% 100.0% 100.0% 0.0% –
CIP 100.0% 100.0% 100.0% 0.0% –
LEV 100.0% 100.0% 100.0% 0.0% –
MH 29.7% 26.1% 33.3% 69.5% 6.3
SXT 100.0% 100.0% 100.0% 4.7% –
PB 0.0% 0.0% 0.0% – –
a
Resistant rate, the percentage of antibiotic-resistant isolates for each group
b
Synergistic rate, calculated as the percentage of the isolates with FICI ≤ 0.5
c
Synergistic effect, measured as the mean value of the reduction fold of MIC by 1/4 MIC of polymyxin B

Results Synergistic combinations of polymyxin B with 12

Molecular epidemiological characteristics of MDR
A. baumannii
Two STs have been identified with 32 isolates of MDR
A. baumannii selected for MLST analysis. ST92 was the
dominant ST, taking up to 71.9%, and its single locus
variant (SLV) ST75 accounted for the remaining 28.1%.
Both of those two STs were grouped into the clonal com-
plex (CC) CC92, one of the largest CC for A. baumannii in
the database of PubMLST.
Antibiotic resistance profiles of MDR A. baumannii
Antibiotic resistance rates of 128 MDR A. baumannii isolates
to PB and 12 other antibiotics are listed in Table 1. The data
showed that MDR A.baumannii obtained from this hospital
exhibited high resistance rates to TZP, SCF, CAZ, FEP, IPM,
MEM, TOB, CIP, LEV and SXT (100% to all). The per-
centage of the isolates that were resistant to AK and MH were
65.6% and 29.7% respectively, and no isolate appeared to be
resistant to polymyxin B. Comparing the antibiotic resistance
profile of ST92 and ST75, great similarity could be found,
with both of those two STs showing high antibiotic resistance
rates to TZP, CAZ, SCF, FEP, IPM, MEM, CIP, LEV, TOB
and SXT (100% to all), and low to MH (26.1% for ST92,
33.3% for ST75) and PB (0% for both). Notably, significant
difference in antibiotic resistance rate to AK could be
detected between those two STs, with ST75 showing much
higher rate than ST92, with 88.9% vs 47.8%.
other antibiotics against MDR A. baumannii isolated
in one hospital
Synergistic combinations of polymyxin B with 12 other
antibiotics against MDR A. baumannii isolated in one
hospital were analyzed with the checkerboard assay. The
results showed that SCF had the highest synergistic
rate with polymyxin B, reaching up to approximate
75.8%, followed by MH, IPM and MEM, with about
69.5%, 45.3% and 39.1% respectively. CAZ had the
synergistic rate of 31.2% with polymyxin B, while FEP,
AK and SXT had just 24.2%, 17.2% and 4.7%, respec-
tively (as shown in Table 1). No synergism was noted in
combinations of polymyxin B with TZP, CIP, LEV and
TOB, with any isolate.
Among the seven antibiotic combinations that have a
synergistic rate of >10%, SCF showed the best synergistic
effect with polymyxin B, with the antibiotic susceptibility
raised by approximate 10.9-fold by 1/4 MIC of polymyxin
B. AK, IPM and MEM had similar synergistic effect, with
the antibiotic susceptibility raised by 9.5-, 9.6- and 8.4-fold
by 1/4 MIC of polymyxin B, respectively (as shown in
Table 1). Though CAZ had lower synergistic rate with
polymyxin B than MH, it had much better synergistic effect
with polymyxin B, with the antibiotic susceptibility raised
by approximate 8.3-fold by 1/4 MIC of polymyxin B,
compared with 6.3-fold for MH. FEP had relative poorer
synergistic effect with polymyxin B among the seven
combinations, with the antibiotic susceptibility raised by
just 4.8-fold by 1/4 MIC of polymyxin B.
In vitro analysis of synergistic combination of polymyxin B with 12 other antibiotics against MDR. . .
The checkerboard assay has also revealed that none of
these 12 antibiotics had antagonistic effect with polymyxin
B against MDR A.baumannii isolated in this hospital.
Discussion
Like many healthcare facilities around the world, many
hospitals in China have also experienced worrysome
nosocomial infections, particularly that caused by MDR
A. baumannii [17, 18].
In this study, MLST analysis has revealed that the
genetic background of MDR A. baumannii obtained from
a Chinese tertiary hospital is quite simple, with just
two sequence types (92ST and 75ST) that show close
evolutionary relationship and belong to the same clonal
complex (CC92). Also, antibiotic susceptibility analysis
has shown that those two STs have great similarity in their
antibiotic resistance profiles, both of them with high
resistance rates to antibiotics including TZP, CAZ, SCF,
FEP, IPM, MEM, LEV, CIP, TOB, and SXT, and low-
resistance rates to MH and PB. Both the molecular epi-
demiological characteristic and antibiotic susceptibility
related phenotype suggest that nosocomial spreading and
nosocomial infection of MDR A. baumannii have occurred
in this hospital.
With the aim to explore the effective antibacterial strategy
against MDR A. baumannii as characterized in this hospital,
synergistic combination of polymyxin B with 12 other anti-
biotics were analyzed with MDR A. baumannii obtained
from this hospital. The results have demonstrated that SCF
has the highest synergistic rate with polymyxin B, reaching
up to 75.8%, followed by MH, IPM, MEM, CAZ, FEP, AK
and SXT. Also, SCF has the best synergistic effect with
polymyxin B, with the susceptibility of SCF that in syner-
gistic combination with polymyxin B increased by about
10.9-fold by 1/4 MIC of polymyxin B, that is followed by
IPM, AK, MEM, CAZ, MH and FEP.
Synergistic combination of polymyxin B with some
antibiotics as examined in this research has also been
reported in various studies with A. baumannii strains
obtained from different regions of the world. Some are in
agreement with our study. For example, synergistic com-
bination of polymyxin B with IPM has been confirmed in
two studies with A. baumannii obtained from New York,
UK and Isparta, Turkey, and with MEM in two studies
with A. baumannii obtained from Isparta, Turkey and São
Paulo, Brazil, respectively [19–21]. Also, synergistic
effect of polymyxin B with MH has been demonstrated in
a study with A. baumannii obtained from Jinan, China,
and with CAZ and AK in a study with A. baumannii
obtained from São Paulo, Brazil, respectively [22, 23].
Giving that A. baumannii strains obtained from different
23
geographical regions are likely to have different molecular
epidemic characteristics, synergistic combinations con-
firmed with A. baumannii strains obtained from different
cities can be assumed to be specific and charcateristic to
the area [24–27].
However, some reports are different from our study.
For example, even though high synergistic rate of poly-
myxin B with SCF against MDR A. baumannii has been
demonstrated in this study, synergistic effect between those
two antibiotics could not be detected with any tested isolate
in a study with MDR A. baumannii obtained from Kars,
Turkey [28]. Also, though the synergistic combination of
polymyxin B with CIP failed to be confirmed in this study, a
synergistic rate of 14.29% for this combination had been
obtained in a previous study with 21 MDR A. baumannii
isolates obtained from Annaba, Algeria [29]. The dis-
crepancy between those studies may due to the different
molecular characters of A. baumannii strains obtained from
different regions, and suggests that synergistic combina-
tions of those antibiotics with polymyxin B may be bacterial
strain related. For a better understanding of synergistic
combination of polymyxin B with those antibiotics against
MDR A. baumannii, further studies with well characterized
MDR A. baumannii strains obtained from different regions
may be required.
In a previous study, meta-analysis was performed, by
incorporating all published data about in vitro synergistic
combinations of polymyxin B with different antibiotics
against A. baumannii obtained from different regions of
the world, to evaluate the general synergistic rate of poly-
myxin B with those antibiotics against A. baumannii [30].
Consistent with our results, the general synergistic rate of
carbapenems with polymyxin B in this meta-analysis was
approximate 39.6%, compared with 45.3% for IPM and
39.1% for MEM in our study. Two possible reasons may
account for this similarity, one is that the combination of
polymyxin B with carbapenems has general synergistic
effect against the A. baumannii strains occuring all over the
world, with the synergistic rate of approximate 39.6%, the
other is that A. baumannii strains used in this study may
represent the most epidemic clonal complex around the
world. Actually, the clonal complex that the A. baumannii
strains in this study belong to is the main clonal complex for
A. baumannii in Pubmlst dataset, and also the epidemic
clonal complex that is widely spreading in Asia, Europe and
America [31–34].
Basing on the result of this meta-analysis, carbapenems
were proposed as the best partner for combination therapy
of polymyxin B against A. baumannii, as they had rela-
tively higher synergistic rates with polymyxin B compared
with the other antibiotics included in analysis [30].
However, in this study, we have found that polymyxin B
has the higher synergistic rate and the better synergistic
24
effect with SCF than with IPM, with 75.8% vs 45.3% in
synergistic rate and 10.9- vs 9.6-fold increased in sus-
ceptibility by 1/4 MIC of polymyxin B, than with MEM,
with 75.8% vs 39.1% in synergistic rate and 10.9- vs
8.4-fold increased in susceptibility by 1/4 MIC of poly-
myxin B, respectively. Though MH has a relatively poorer
synergistic effect with polymyxin B compared with car-
bapenems, with just about 6.3 fold increased in suscept-
ibility by 1/4 MIC of polymyxin B, the synergistic rate of
MH with polymyxin B is much higher than that of IPM,
with 69.5% vs 45.3%, and than that of MEM, with
69.5% vs 39.1%, respectively. Those results suggest that
SCF and MH may be more suitable for polymyxin B
based combination therapy against MDR A. baumannii
than carbapenems and further researches are deserved
to determine their clinical value on the treatment of MDR
A. baumannii infection.
Cephalosporins, including CAZ and FEP, were also
included into our study and showed synergistic rates
of 31.2% and 24.2% with polymyxin B against MDR A.
baumannii respectively. Though SXT had a relatively
lower synergistic rate of 4.7%, the synergistic effect of
it with polymyxin B against MDR A. baumannii was
first determined in this study. All of the data have potential
value on the treatment of MDR A. baumannii infection.
Except with AK, where it has been shown to have
a synergistic rate of 17.2% with polymyxin B against
MDR A. baumannii, giving that both AK and polymyxin
B have nephrotoxicity and the combination of these
two antibiotics are likely to enhance the side effect, this
combination is not recommended to be used in clinical
practice.
In summary, our study gives a complete analysis of the
synergistic combinations of polymyxin B with 12 different
antibiotics against MDR A. baumannii, which could provide
some useful insights for the selection of antibiotics that
are most suitable for combination therapy of polymyxin
B. Also, some synergistic combinations against MDR
A. baumannii, to the best of our knowledge, are first noted
in our study, which could provide additional therapeutic
alternatives for the combination therapy of polymyxin B
against MDR A. baumannii.
There are two limitations of this study that should be
considered. One is that this study was just based on
the isolates of MDR A. baumannii obtained from one
hospital of China. It seems that these isolates have a
close evolutionary relationship, similar antibiotic resis-
tance profiles and related antibiotic-resistant mechanisms.
Strains obtained from different regions may have different
molecular epidemic characteristics and different conclu-
sions may be obtained with strains obtained from different
regions. For this concern, further studies with different
MDR A. baumannii strains are required. The other is that
H. Liu et al.
this study has just evaluated the in vitro synergistic
combination of polymyxin B with 12 other antibiotics.
However, the question that which combination of anti-
biotic concentration should be employed for clinical use of
those antibiotic combinations is still uncertain. Giving that
different combinations of antibiotic concentration influ-
ence not only the antibacterial efficacy but also the side
effect on patients, so it is necessary to make it clear which
combination will benefit the patients the best. Further-
more, for each combination therapy, not only the anti-
bacterial activity, but also the toxicity and adverse effects
should be considered. One of the most serious adverse
effects of polymyxin B therapy is the does related
nephrotoxicity, so any antibiotic that can aggravate the
nephrotoxicity of polymyxin B should not be used in
combination with it. For optimizing those polymyxin
B based combination therapies, further pharmacokinetic
and pharmacodynamic studies are required to determine
the appropriate combination of antibiotic concentration
and to analyze the toxicity profile of each combination.
Also, animal models and clinical trails are required to
evaluate the clinical value of those combinations in the
treatment of MDR A. baumannii infection.
Acknowledgements The authors are grateful to the Shiyan Renmin
Hospital of Hubei University of Medicine and the Jinzhou Medical
University.
Author contributions HL, DH, LL and RX designed the study. HL
and DH were in charge of this study and performed the majority of
those experiments. RX drafted the manuscript and revised it criti-
cally for important intellectual content. DX, HW, YJ, XC and LQ
participated in the collection and identification of MDR A.baumannii
isolates.
Funding This work was supported by the Science Foundation of Hubei
Health Commission in Hubei province (Grant No: WJ2021F040).
Compliance with ethical standards
Conflict of interest The authors declare no competing interests.
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