Infection (2022) 50:1409–1423

https://doi.org/10.1007/s15010-022-01876-x

REVIEW

Update of clinical application in ceftazidime–avibactam

for multidrug‑resistant Gram‑negative bacteria infections
Sisi Zhen1 · Hui Wang1,2 · Sizhou Feng1

Received: 22 April 2022 / Accepted: 14 June 2022 / Published online: 4 July 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2022

Abstract
Purpose  Multidrug-resistant Gram-negative bacteria (MDR-GNB) have become a major global public health threat. Ceftazi-
dime–avibactam (CAZ–AVI) is a newer combination of β-lactam/β-lactamase inhibitor, with activity against carbapenem-
resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa (CRPA). The aim of this review is to
describe the recent real-world experience of CAZ–AVI for the infections due to MDR-GNB.
Methods  We searched PubMed, Embase and Google Scholar for clinical application in CAZ-AVI for MDR-GNB infections.
Reference lists were reviewed and synthesized for narrative review.
Results  MDRGNB infections are associated with higher mortality significantly comparing to drug-susceptible bacterial
infections. Fortunately, CAZ–AVI shows significant benefits for infections due to KPC or OXA-48 CRE, comparing to
colistin, carbapenem, aminoglycoside and other older agents, even in those with immunocompromised status. The efficacy of
CAZ–AVI varies in different infection sites due to CRE, which is lower in pneumonia. Early use is associated with improved
clinical outcomes. Noteworthy, when adopted as salvage therapy, CAZ–AVI is still superior to other GNB active antibiot-
ics. CAZ–AVI plus aztreonam is recommended as the first line of MBL-CRE infections. However, for infections caused by
KPC- and OXA-48-producing isolates, further investigations are needed to demonstrate the benefit of combination therapy.
Besides CRE, CAZ-AVI is also active to MDR-PA. However, the development of resistance in CRE and MDR-PA against
CAZ–AVI is alarming, and more investigations and studies are needed to prevent, diagnose, and treat infections due to
CAZ–AVI-resistant pathogens.
Conclusions  CAZ-AVI appears to be a valuable therapeutic option in MDR-GNB infections. Using CAZ-AVI appropriately
to improve efficacy and decrease the emergence of resistance is important.

Keywords  Ceftazidime–avibactam · Carbapenem-resistant Enterobacterales · Multidrug-resistant Pseudomonas

aeruginosa · Multidrug-resistant Gram-negative bacteria

Introduction

Since initial emergence in 1980s, Enterobacterales produc-

Sisi Zhen and Hui Wang are co-authors.
* Sizhou Feng
szfeng@ihcams.ac.cn; doctor_szhfeng@163.com
1
State Key Laboratory of Experimental Hematology,
National Clinical Research Center for Blood Diseases, Haihe
Laboratory of Cell Ecosystem, Institute of Hematology &
Blood Diseases Hospital, Chinese Academy of Medical
Sciences, Peking Union Medical College, Tianjin 300020,
China
2
Department of Hematology, The Affiliated Yantai
Yuhuangding Hospital of Qingdao University,
Yantai 264000, Shandong Province, China
ing extended-spectrum beta lactamase (ESBL) was reported
with increased frequency and became a major antimicrobial-
resistant pathogen [1]. Carbapenem was the last resort of
ESBL-producing Enterobacterales infections. However, the
extensive use of carbapenem led to a more serious problem:
the emergence of carbapenem-resistant Enterobacterales
(CRE). One of the most comprehensive continental surveys
is the European Survey of Carbapenemase-Producing Enter-
obacterales (CPE) initiative, which reported 850 of 2301
(37%) Klebsiella pneumoniae samples and 77 of 402 (19%)
E coli samples were carbapenemase (KPC, NDM, VIM, or
OXA-48-like) producers. The infection prevalence of CPE

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was shown to be 1.3 patients per 10,000 hospital admis-
sions and 2.5 patients per 100,000 hospital patient-days
[2]. Similarly, multidrug-resistant Gram-negative bacteria
(MDR-GNB) other than CRE, such as carbapenem-resistant
Pseudomonas aeruginosa (CRPA) or carbapenem-resistant
Acinetobacter baumannii (CRAB), are also prevalent [3–6].
MDR-GNB infections were associated with higher mor-
tality significantly comparing to drug-susceptible bacterial
infections. In the United States, it was estimated that more
than 2 million people suffered infections by multidrug-resist-
ant organism each year and about 23,000 died as a direct
result of these infections [7]. A number of studies had been
conducted to assess the outcomes of infections due to CRE
[8–12]. A meta-analysis suggested that mortality was higher
significantly in carbapenem-resistant Klebsiella pneumoniae
(CRKP) (466/1093, 42.6%) than carbapenem-susceptible
Klebsiella pneumoniae patients (231/859, 26.9%) (OR 2.18,
95% CI 1.60–2.90) [13].
Clinical outcomes of infections due to CRE or CRPA in
hematological patients had been described [14–17]. Tre-
carichi et al. [16] conducted a prospective study including
278 episodes of Klebsiella pneumoniae bacteremia in 13
hematological units, and found that the overall mortality at
21 days was significantly higher for patients with CRKP
bacteremia than those with carbapenem-susceptible Kleb-
siella pneumoniae bacteremia (84/161, 52.2% vs 17/117,
14.5%, P < 0.001). Similar outcomes were observed in 81
hematological malignancies patients infected with Pseu-
domonas aeruginosa [17]. Overall mortality rate at 30 days
was significantly higher in patients with CRPA (n = 23) com-
paring to those with carbapenem-susceptible Pseudomonas
aeruginosa (n = 58) (60.9% vs 17.2%, P < 0.001).
Considering the increasing prevalence, higher mortality,
and longer stay of hospital, WHO identified CRE, CRPA,
and CRAB as critical priority pathogens. Because of lack-
ing alternative drugs, patients are often dead without effec-
tive treatment, indicating that it is of utmost importance to
choose newer agents against them. Ceftazidime–avibactam
(CAZ–AVI) is one of the new antibiotics approved by FDA
and EMA based on the promising outcomes in clinical trials.
In this review, we describe the actual evidence of CAZ–AVI
in patients with infections due to CRE and multidrug-resist-
ant Pseudomonas aeruginosa (MDR-PA), aiming to provide
insights into the use of CAZ–AVI for these infections.
The clinical data of ceftazidime–avibactam
CAZ–AVI is a new β-lactam/β-lactamase inhibitor combi-
nation. Different from other β-lactamase inhibitor, avibac-
tam is a novel non-β-lactam β-lactamase inhibitor, which
can inhibit ESBL, Ambler class A (GEM, SHV, CTX-M
and KPC), class C (AmpC), and some class D (OXA-48)
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S. Zhen et al.
enzymes [18], but cannot inhibit the activity of metallo-β-
lactamases (MBLs) [19]. The addition of avibactam restores
ceftazidime activity against isolates previously resistant to
ceftazidime, including Enterobacterales and Pseudomonas
aeruginosa. However, Acinetobacter baumannii strains are
resistant to CAZ–AVI, because avibactam cannot inhibit
OXA-51, 23, 40, 24-like enzymes, which are always pro-
duced by Acinetobacter baumannii [20, 21]. Avibactam
is renally excreted, and its pharmacokinetics are similar
to those of ceftazidime, allowing for coformulation [22].
CAZ–AVI was approved by FDA for the use in complicated
intra-abdominal infections (cIAI), complicated urinary tract
infections (cUTI) including pyelonephritis, and hospital-
acquired bacterial pneumonia/ventilator-associated bacte-
rial pneumonia (HABP/VABP) with recommended dose
of 2.5 g q8h for 2 h. According to the Infectious Diseases
Society of America Guidance on the Treatment of Antimi-
crobial-Resistant Gram-Negative Infections published in
2022, CAZ–AVI was recommended as preferred treatment
for these infections: 1. pyelonephritis and cUTI caused by
CRE; 2. infections outside of the urinary tract caused by
CRE; 3. KPC-producing CRE infections outside of the uri-
nary tract and OXA-48-like-producing CRE infections if
carbapenemase production is present; 4. difficult-to-treat
infections due to Pseudomonas aeruginosa; furthermore,
CAZ–AVI together with aztreonam was recommended as
first-line therapy for MBL-producing CRE infections [23].
The clinical data in CRE infections
Clinical efficacy comparing to other drugs
Before newer β-lactam/β-lactamase inhibitors entered the
market, traditional drugs, including colistin, carbapenem,
aminoglycoside, tigecycline monotherapy, or combination
therapy, were common choices for CRE infections. Till now,
one prospective and several retrospective cohorts have been
conducted to compare the efficacy between CAZ–AVI and
colistin exclusively in different countries, among which
bacteremia and HABP were the most common types of
infections [24–27]. The first prospective, multicenter study
comparing CAZ–AVI to colistin for CRE infections was
conducted by Van Duin et al. involving 137 patients [24].
Bacteremia (n = 63, 46%) and respiratory infections (n = 30,
22%) were most common types. Among 54 CRKP isolates
tested for carbapenemase gene, 28 (52%) and 24 (44%)
were positive for ­blaKPC-2 and ­blaKPC-3. 98 CRE isolates
were tested the susceptibility to colistin. The susceptible
rates to colistin in CAZ–AVI group and colistin group were
77% (23/30) and 93% (63/68), respectively. IPTW-adjusted
all-cause hospital mortality at day 30 was 9% versus 32%
(difference, 23%, 95% CI, 9% ~ 35%, P = 0.001) in patients
treated with CAZ–AVI and colistin. Almangour et al. [26]
Update of clinical application in ceftazidime–avibactam for multidrug‑resistant Gram‑negative…
conducted a larger retrospective, multicenter study including
230 patients with CRE infections. The most common infec-
tion type was HABP and VABP (n = 82, 36%), followed by
UTI (n = 44, 19%), wound infection (n = 37, 16%), and IAI
(n = 30, 13%). Carbapenemase type was reported for 49%
(73/149) and 46% (37/81) isolates in CAZ–AVI and colistin
group, in which 98% were b­ laOXA-48. If isolates were identi-
fied as non-susceptible to the study drug, the patient was
excluded. Clinical cure (71% vs 52%, P = 0.004, OR: 2.29,
95% CI 1.31–4.01) was significantly higher in CAZ–AVI
group than colistin-based group. Mortality was lower (35%
vs 44%, P = 0.156, OR: 0.67, 95% CI 0.39–1.16) in patients
treated with CAZ–AVI. As for the safety, acute kidney injury
(15% vs 33%, P = 0.002, OR 0.37, 95% CI 0.19–0.69) was
significantly less common in patients receiving CAZ–AVI.
Although larger, better designed studies are needed, for
infections due to KPC or OXA-48 CRE, especially for
colistin resistant strains infections, CAZ–AVI is a reason-
able alternative to colistin. However, for MBL-CRE, which
is naturally resistant to CAZ–AVI, CAZ–AVI monotherapy
is not recommended.
When comparing to other antibiotics such as carbap-
enem, aminoglycoside and so on, similar outcomes were
observed [28–34]. One meta-analysis encompassed 12 stud-
ies involving 4951 patients evaluating the efficacy and safety
of CAZ–AVI for GNB infections [35]. In the subgroup anal-
ysis of causative pathogen, CAZ–AVI demonstrated a higher
clinical response (RR 1.61, 95% CI 1.13–2.29, I2 = 61.7%)
and a lower mortality (RR 0.29, 95% CI 0.13–0.63, I2 = 0)
than control treatment (carbapenem, colistin, tigecycline,
and so on) for infections caused by CRE. Moreover, in the
subgroup analysis by infection type, CAZ–AVI was supe-
rior in clinical response for bacteremia from two studies
(140 patients) (RR 2.11, 95% CI 1.54–2.88, I2 = 0) and in
microbiological eradication in cUTI from three studies
(1186 patients) (RR 1.13, 95% CI 1.05–1.21, I2 = 43.6%).
Castón et al. [28] conducted the largest comparative series
of patients (n = 339) with infections caused by CPE treated
with CAZ–AVI or best available therapy (BAT). The most
common type of carbapenemase was OXA-48 (n = 255), fol-
lowed by KPC (n = 84). UTI was the most frequent type of
infection (n = 129, 38.1%), followed by bloodstream infec-
tion (BSI) (n = 111, 32.7%), IAI (n = 60, 17.7%), and pneu-
monia (n = 39, 11.5%). Although CAZ–AVI was always
used as monotherapy than BAT (133/189, 70.4% vs 64/150,
42.6%, P < 0.001), the 30-day crude mortality was signifi-
cantly lower in CAZ–AVI group (26/189, 13.7% vs 33/150,
22.0%, P = 0.04). In multivariate analysis, CAZ–AVI-con-
taining regimen was the only independent factor of 21-day
clinical response (OR 2.43, 95% CI 1.16–5.12, P = 0.02) and
microbiological eradication (OR 0.40, 95% CI 0.18 ~ 0.85,
P = 0.02). In patients with INCREMENT-CPE scores > 7
points, CAZ–AVI treatment was associated with lower
1411
mortality significantly than comparator (21.9%, 16/73
vs 46.9%, 23/49, P = 0.0004). This study described less
adverse events in CAZ–AVI group (11/189, 5.8% vs 30/150,
20%, P < 0.001). Gu et al. [30] also reported the advantage
of CAZ–AVI than others for CRE infections in a single-
center, retrospective study. The study included 90 infections
due to CRKP. Forty two were treated with CAZ–AVI and
forty eight were treated with others (carbapenem, colis-
tin, tigecycline, fosfomycin, fluroquinolone). The crude
30-day mortality (8/42, 19.0% vs 22/48, 45.8%, P = 0.007)
and 14-day clinical failure (14/42, 33.3% vs 24/48, 50.0%,
P = 0.046) were lower in CAZ–AVI group. Moreover, the
subgroup analysis showed CAZ–AVI was still associated
with decreased 30-day mortality in the bacteremia (OR 0.23,
95% CI 0.08–0.63, p = 0.004), septic shock (OR 0.23, 95%
CI 0.07–0.78, p = 0.019), SOFA score > 5 (OR 0.13, 95%
CI 0.04–0.36, P < 0.000), mechanical ventilation (OR 0.13,
95% CI 0.04–0.36), and Charlson comorbidity index (> 3,
OR 0.15, 95% CI 0.04–0.55, P = 0.004). Available data indi-
cate that CAZ–AVI is associated with improved clinical and
microbiology outcomes for KPC or OXA-48 CRE infections
comparing to traditional drugs and may be more valuable
for severe cases than mild cases. (The clinical data about
comparative efficacy between CAZ–AVI and others are sum-
marized in Table 1.)
The efficacy between CAZ–AVI and other newer
β-lactam/β-lactamase inhibitors for the treatment of CRE
infections is similar. Ackley et al. [36] conducted a multi-
center, retrospective cohort study to compare the efficacy of
CAZ–AVI (n = 105) and meropenem–vaborbactam (n = 26)
for CRE infections. 61% of the patients in the CAZ–AVI
group received combination therapy (with aminoglycosides,
colistin, tigecycline, and others) and 15% in the merope-
nem–vaborbactam group, respectively. Among 32 and
13 isolates tested for genetic mechanism in CAZ–AVI
and meropenem–vaborbactam group, 23 (71.9%) and 10
(76.9%) were positive for KPC. Clinical success at day 30
(61.9% vs 69.2%, P = 0.49), mortality at day 30 (19.1% vs
11.5%, P = 0.57), and mortality at day 90 (28.6% vs 26.9%,
P = 0.48) were similar between CAZ–AVI group and mero-
penem–vaborbactam group. Development of resistance
occurred in three patients who received CAZ–AVI mono-
therapy and in none-patients in the meropenem–vaborbac-
tam group.
Totally, although more data are needed, CAZ–AVI offers
therapeutic advantages comparing to other traditional anti-
biotics for the treatment of KPC- and OXA-48-producing
Enterobacterales infections, especially for severe patients.
Clinical experience in patients with pneumonia
The clinical and microbiological outcomes among
patients treated with CAZ–AVI for CRE infections vary in
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Table 1  Overview of retrospective/prospective comparative/case–control studies involving CAZ–AVI for the treatment of CRE infections
1412

Publication Design Number of patients (% with combination) No. (%) and Baseline pathogens Resistance mecha- Outcomes (No. %) (CAZ–AVI vs. compara-
sources of infec- nisms tor)

13
tion
CAZ–AVI Comparator Clinical cure/success Mortality

van Duin 2018 [24] Multicenter, pro- 38 (NR) 99 colistin (NR) BSI 46%, K. pneumoniae 97%; KPC 38%, NR Day 30: 3/38 (8%)
spective Pneumonia 22%, Enterobacter spp. 3% non-carbapenemase vs 33/99 (33%),
UTI 14%, producing 1%; P = 0.64
Wound 10%, NR 61%,
Others 8%
Hakeam 2021 [25] Multicenter, retro- 32 (72%) 29 colistin (100%) 100% BSI K. pneumoniae 79%; OXA-48 51%; 15/32 (47%) vs 6/29 Day 30: 12/32 (38%)
spective E coli. 11%; NDM 21%; (21%), P = 0.049 vs 12/29 (41%),
Other 10% KPC 10%; P = 0.75
NR 18%
Fang 2021 [27] Multicenter, retro- 37 (70%) 78 colistin (88%) Pneumonia 57%; K. pneumoniae 100% NR 19/37 (51%) vs 9/78 Day 28: 3/37 (8%)
spective BSI 50%; (12%) vs 23/78 (29%),
IAI 28%; P = 0.013
UTI 10%;
Others 13%
Almangour 2022 Multicenter, retro- 149 (23%) 81 colistin (70%) HAP/VAP 36%; K. pneumoniae 87%; OXA-48 47%; 106/149 (71%) vs In hospital mortal-
[26] spective BSI 26%; E coli. 9%; KPC 1%; 42/81 (52%), ity: 52/149 (35%)
UTI 19%; Other 3% NR 52% P = 0.004 vs 36/81 (44%),
Wound 16%; P = 0.156
IAI 13%;
Others 13%
Shi 2021 [40] Sing center, retro- 43 (79%) 62 tigecycline (94%) HAP/VAP 100% K. pneumoniae 100% NR 22/43 (51%) vs Day 28: 13/43 (30%)
spective 18/62 (29%), vs 21/62 (34%),
P = 0.022 P = 0.695
Ackley 2020 [36] Multicenter, retro- 105 (61%) 26 MV (15%) BSI 40%; Klebsiella spp. 67%; KPC 24%; 65/105 (62%) vs Day 30: 20 /105
spective Non-BSI: Enterobacter spp. NR 76% 18/26 (69%), (19%) vs 3 /26
Pneumonia 30%; 21%; P = 0.49 (12%), P = 0.57;
SSTI 15%; E coli. 9%; Day 90: 30 /105
IAI 13%; Other 3% (29%) vs 7 /26
Others 1% (27%), P = 0.48
Tumbarello 2019 Multicenter, retro- 138 (79%) (104 104 (74%) BSI 86%, K. pneumoniae 100% KPC 100% NR Day 30: 47/138
[38] spective, matched matched) Pneumonia 5%, (34%);
IAI 5%, 38/104 (37%) vs
2%, 58/104 (56%),
others 1% P = 0.005
Karaiskos I (2021) Multicenter prospec- 147 (71 matched) 71 (NR) BSI 76%, K. pneumoniae 100% KPC 97%, Day 14: 119/147 Day 28:30/147
[53] tive, matched (54%) UTI 15%, OXA-48 3% (81%) (20%);
HAP/VAP 17%, 13/71 (18%) vs 29/71
IAI 7%, (41%), P = 0.005
others 5%
S. Zhen et al.
 Table 1  (continued)
Publication Design Number of patients (% with combination) No. (%) and Baseline pathogens Resistance mecha- Outcomes (No. %) (CAZ–AVI vs. compara-
sources of infec- nisms tor)
tion
CAZ–AVI Comparator Clinical cure/success Mortality

Shields 2017 [29] Single center, retro- 13 (38%) 96 (70%) BSI 100% K. pneumoniae 100% KPC 97%; Day 30: 11/13 (85%) Day 30: 1/13 (8%)
spective NR 3% vs 39/96 (41%), vs 30/96 (31%),
P = 0.006 P = 0.1;
Day 90: 1/13 (8%)
vs 43/96 (45%),
P = 0.01
Alraddadi 2019 [31] Single center, retro- 10 28 (89%) BSI 58%, K. pneumoniae 79%, OXA-48 71%, Day 30: 4/10 (40%) Day 30: 5/10 (50%)
spective HAP 50%; E coli. 21% NDM 16%, vs 11/28 (39%), vs 16/28 (57%),
UTI 29%; NDM + OXA-48 P > 0.99 P = 0.7
IAI 21%, 3%,
SSTI 13% non-carbapenemase
producing 11%
Tsolaki 2020 [33] Two centers, retro- 41 (78%) 36 (97%) BSI 65%, K. pneumoniae 100% KPC 94%; 33/41(80%) vs Day 28: 6/41 (15%)
spective VAP 34%, NR 6% 19/36(53%), vs 14/36 (39%),
IAI 10%, P = 0.01 P = 0.035
UTI 4%,
Others 3%
Gu 2021 [30] Sing center, retro- 42 (62%) 48 (NR) Pneumonia 74%; K. pneumoniae 100% NR 28/42 (67%) vs Day 30: 8/42 (19%)
spective BSI 50%; 24/48 (50%), vs 22/48 (46%),
UTI 7%; P = 0.046 P = 0.007
CNS 6%
IAI 2%;
SSTI 4%
Chen 2021 [32] Multicenter, retro- 35 (NR) 152 (NR) BSI 100% Enterobacterales NR 25/35 (71%) vs Day 30: 6/35 (17%)
spective 100% 48/152 (32%), vs 72/152 (47%),
Update of clinical application in ceftazidime–avibactam for multidrug‑resistant Gram‑negative…

P = 0.002
Shen 2021 [34] Sing center, retro- 9 (56%) 80 (31%) BSI 100% K. pneumoniae 100% NR NR Day 28: 2/9 (22%) vs
spective 40/80 (50%)
Castón 2022 [28] Multicenter, retro- 189 (30%) 150 (57%) UTI 38%; K. pneumoniae 92%; OXA-48 75%; 169/189 (89%) vs Day 30: 26/189
spective BSI 33%; Enterobacter spp. 4%; KPC 25% 119/150 (79%), (14%) vs 33/150
IAI 18%; E. coli. 3%; P = 0.01 (22%), P = 0.04
Pneumonia 12% Other 1%
Caston 2017 [41] Multicenter, retro- 8 (NR) 23 (74%) BSI 100% K. pneumoniae 81%; OXA-48 61%; 6/8 (75%) vs 8/23 Day 30: 2/8 (25%),
spective (hemato- Other 19% KPC 39% (35%), P = 0.031 vs 12/23 (52%),
logical patients) P = 0.19

CAZ–AVI ceftazidime–avibactam, CRE carbapenem-resistant Enterobacterales, NR unreported; BSI: bloodstream infection, UTI urinary tract infection, KP Klebsiella pneumonia, K. pneumo-
niae Klebsiella pneumonia, E. coli Escherichia coli, HAP/VAP hospital-acquired pneumonia/ventilator-associated pneumonia, SSTI skin and soft-tissue infection, IAI intra-abdominal infection,
MV meropenem–vaborbactam

13
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different types of infection. In previous studies, pneumonia
or mechanical ventilation had been illustrated to be a risk
factor for CAZ–AVI treatment failure [37–39]. Preclinical
human studies (phase I) suggested that CAZ–AVI pen-
etrates in the long with PK patterns profile similar between
epithelial lining fluid and plasma, and the epithelial lining
fluid/plasma ratio of CAZ–AVI concentrations ranges from
0.31 to 0.35. Although the epithelial lining fluid exposures
of CAZ–AVI exceed level required for efficacy in plasma,
there is no evidence to support similar exposures in pneu-
monia patients, especially in those with mechanical ventila-
tion. This study also found that epithelial lining fluid con-
centrations increased dose-proportionally for both drugs,
with twofold increase in area under curve for patients who
received 3 g ceftazidime plus 1 g avibactam comparing
to who received 2 g ceftazidime plus 0.5 g avibactam. If
higher doses of CAZ–AVI are more effective in pneumonia,
patients still need evaluated.
Fortunately, when comparing to tigecycline-based
regimen, CAZ–AVI still shows better clinical outcomes
for patients with pneumonia due to CRE. Shi et al. [40]
conducted a retrospective cohort to compare the efficacy
between CAZ–AVI-based regimen (n = 43) and tigecycline-
based regimen (n = 62) for HABP or VABP due to CRKP in
intensive-care units. Most population received CAZ–AVI
or tigecycline combination therapy (79.1% vs 93.5%,
P = 0.027). Although there was no significant difference in
28-day survival rates between the two groups, CAZ–AVI
regimen was significantly associated with 28-day clinical
success (OR 3.405, 95% CI 1.304–8.889, P = 0.012) and
microbiological success (OR 7.778, 95% CI 2.717–22.265,
P < 0.001) in propensity score analysis.
CAZ–AVI-based therapy for pneumonia due to CRE
shows lower clinical success comparing to other types of
infections, while comparing to tigecycline, it seems to be a
better choice. The optimal dose for pneumonia or those with
mechanical ventilation needs further exploration.
Clinical experience in special populations
Patients with hematological malignancies and solid organ
transplantation receptors are in high risk of severe infections
because of impairment of the immune system and frequent
neutropenia. True-world clinical experience considering the
experience of CAZ–AVI in hematological patients is limited
till now. A multicenter, retrospective study conducted by
Castón et al. [41] retrospectively reported the outcomes of 31
hematological patients infected with CRE BSI. The 14-day
clinical success rate (75.0% vs 34.8%) and 30-day survival
rate (75.0% vs 47.8%) of 8 patients in CAZ–AVI group were
higher than the other patients (n = 23) in the control group.
Clerici et al. [42] conducted a retrospective study including
126 hematological patients and evaluate CAZ–AVI efficacy
13
S. Zhen et al.
in those with febrile neutropenia. CAZ–AVI was adminis-
tered in 10 of 109 patients who received hematopoietic stem
cell transplantation for empirical or definitive therapy. They
found that CAZ–AVI was effective in bacteremia clearance.
We conducted a retrospective cohort in our hospital, includ-
ing 47 hematological patients with CRE or CRPA BSI. A
favorable survival rate was observed as 83.8% in 37 patients
with CRE BSI, supporting more clinical experiences for the
application of CAZ–AVI in hematological diseases patients
(the data are being published).
Real-world clinical practice of using CAZ–AVI for
CRE infections in solid organ transplantation receptors
was also described recently in several observational stud-
ies and case series [43–46]. Zhang et al. [44] compared
the efficacy of CAZ–AVI and other antibiotics for CRKP
infection after kidney transplantation and found patients
receiving CAZ–AVI had lower 30-day mortality (3/22,
13.6% vs 14/32, 43.8%, P = 0.019) and higher 14-day clini-
cal cure (18/22, 81.8% vs 17/32, 53.1%, P = 0.030) signifi-
cantly. Chen et al. [45] included 10 (9 infected with CRKP
and 1 with CRPA) lung transplant recipients treated with
CAZ–AVI. The 30-day clinical survival was high to 100%
and nine patients achieve negative of microbiological culture
with a median time of 6.7 days. Another study reported that
the clinical response at 30 days among liver transplanta-
tion recipients treated with CAZ–AVI as salvage therapy
for CRKP infections was 58.8% (10/17) [43]. It seems that
CAZ–AVI can be a promising choice for CRE infections,
even in those with impairment of immune system. Larger
multicenter studies are needed to be conducted to solidate
this.
The optimization of usage
CAZ–AVI monotherapy or  CAZ–AVI‑based combination
therapy  Prior to the introduction of CAZ–AVI into the
market, combination therapy with two or more antibiotics
with in vitro activity was deemed to be superior to mono-
therapy, especially in those with septic shock or high mor-
tality scores. While for CAZ–AVI-containing regimen,
monotherapy supports similar efficacy as combination with
traditional drugs (carbapenem, colistin, and so on) for infec-
tions due to KPC- or OXA-48-producing Enterobacterales
according to available experience [37, 47–50]. In a recent
meta-analysis, including 13 studies and 503 patients with
carbapenem-resistant pathogens infections, there was no dif-
ference in mortality regarding CAZ–AVI monotherapy and
CAZ–AVI-based combination therapy (OR 0.96, 95% CI
0.65–1.41) [51]. Tumbarello et al. [52] conducted the larg-
est retrospective study involving 577 adults infected with
KPC-KP. Bacteremia was the most frequent type of infec-
tion (n = 391), and non-bacteremia included cUTIs (n = 71),
pneumonia (n = 59), IAIs (n = 35), and others (n = 21). Mor-
Update of clinical application in ceftazidime–avibactam for multidrug‑resistant Gram‑negative…
tality at day 30 was 25.3% (146/577), which did not differ
between those with CAZ–AVI alone and those with combi-
nation therapy (3/165, 26.1% vs 103/412, 25.0%, P = 0.79).
Notably, CAZ–AVI combination therapy was more fre-
quently in patients with higher Charlson comorbidity
indexes and in those with pneumonia significantly (P < 0.01
for both). A prospective cohort also described similar out-
come when comparing CAZ–AVI-containing monotherapy
and combination therapy [53]. On the contrary, a retrospec-
tive cohort performed at two tertiary hospitals in China first
reported that 30-day mortality rates for patients receiving
CAZ–AVI-based combination therapy were significantly
lower than those with CAZ–AVI monotherapy (10/41,
24.4% vs 11/21, 47.6%, P = 0.028) for CRKP infection [54].
The multivariate analysis still revealed that combination
with another in vitro non-susceptible antimicrobial, such as
carbapenems, tigecycline, and fosfomycin, was significantly
associated with lower 30-day mortality (HR 0.167, 95% CI
0.060–0.465, P = 0.001). Considering the existing of con-
founders such as illness severity and types of infections,
more evidence is required to explore the potential benefit of
combination for KPC- or OXA-48 CRE infections.
For MBL-producing strains infections, clinical data
have shown promising outcomes with the combination of
CAZ–AVI and aztreonam in several case reports and small
cohort studies [55–60]. Falcone et al. [61] conducted the first
prospective study involving 102 patients with bacteremia
due to MBL-producing Enterobacterales, with 82 produc-
ing NDM and the others producing VIM. 51.0% (n = 52) of
patients receiving CAZ–AVI plus aztreonam, while 49.0%
(n = 50) are receiving other active antibiotics consisting of
colistin, tigecycline, aminoglycosides, and carbapenem.
The 30-day mortality (10/52, 19.2% vs 22/50, 44.0%,
P = 0.007) and acute kidney injury (1/52, 1.9% vs 10/50,
20.0%, P = 0.003) were significantly lower in CAZ–AVI
plus aztreonam group than comparative group. A PS-based
matched analysis including 50 pairs of patients reported that
the regimen of CAZ–AVI plus aztreonam was associated
with a lower mortality rate at day 30 (HR 0.31, 95% CI
0.15–0.66, P = 0.002), lower clinical failure at day 14 (OR
0.36, 95% CI 0.18–0.70, P = 0.003), and shorter length of
hospital stay (HR 0.48, 95% CI 0.29–0.78, P = 0.003) com-
pared to other active antibiotics. The clinical data support
that CAZ–AVI plus aztreonam is a potential therapeutic
choice in MBL-producing isolates infections. The data in
our hospital indicated that MBL-CRE accounted for 56%
(n = 37) in 66 CRE isolated from blood and tested by PCR
for identification of carbapenemase genes. In terms of the
types of isolates, the proportions of MBL-CRE were 77%
(24/31), 33% (9/27), 43% (3/7) and 100% (1/1) in Escheri-
chia coli, K. pneumonia, Enterobacter cloacae, and Raoul-
tella planticola, respectively. Therefore, combination with
aztreonam actively is important, especially in those hospitals
1415
with higher proportion of MBL-CRE (The data are being
published.)
Moreover, combination therapy may decrease the recur-
rence of CRE infections and CAZ–AVI resistance. Ackley
et al. [36] retrospectively included 105 patients treated with
CAZ–AVI for CRE infections. The recurrence of CRE infec-
tions (6/64, 9.4% vs 9/41, 22.0%) and CAZ–AVI resistance
(0/64, 0% vs 3/41, 7.3%) were numerically lower in combi-
nation therapy group than monotherapy group.
In conclusion, CAZ–AVI plus aztreonam shows signifi-
cant dominance in clinical efficacy for MBL-CRE infections.
For KPC- or OXA-48 CRE infections, whether combination
CAZ–AVI with an in vitro non-susceptible antimicrobial
drug could have better clinical effectiveness than CAZ–AVI
monotherapy is controversial. Well-designed prospective
studies or randomized control trials with more participants
should be designed for further investigation.
Timing of CAZ–AVI therapy  As is known, appropriate and
timely treatment is critical to patients with bacteremia [62].
A retrospective study enrolling 102 KPC-CRE bacteremia
found that the survivors had shorter median time (8.5 h vs
48 h, P = 0.014) from blood cultures collection to appropri-
ate antibiotic therapy than those who died [63]. Receipt of
appropriate treatment within 48 h decreased 30-day mortal-
ity rate (29.1% vs 63.8%, P < 0.001), and was independently
negatively associated with the overall 30-day mortality by
Cox regression analysis (HR 1.382, 95% CI 1.132–1.687,
P = 0.001). Consistent with these reports, Jorgense et al. [64]
demonstrated receiving CAZ–AVI within 48 h of infection
onset was associated with lower clinical failure (OR 0.409,
95% CI 0.180–0.930, P = 0.0329) for patients infected with
MDR-GNB. Therefore, to improve the prognosis of infec-
tions due to CRE, it is of great importance to use appropri-
ate antibiotics including CAZ–AVI as soon as possible after
blood culture collection.
Although early use is critical, it is noteworthy that after
failure of other regimens, CAZ–AVI as salvage therapy is
still associated with clear benefits comparing to other com-
mon regimens. Tumbarello et al. [38] reviewed 104 patients
infected with bacteremia due to KPC-KP, who receiving
CAZ–AVI as a salvage regimen after a first-line treatment
with other antimicrobials. CAZ–AVI was administrated with
other active antibiotics in 82 patients. When comparing to a
matched cohort involving 104 KPC-KP bacteremia treated
with drugs other than CAZ–AVI, the data indicated that
receipt of CAZ–AVI was associated with a lower 30-day
mortality significantly (36.5% vs 55.7%, P = 0.005). Mul-
tivariate analysis of the 208 cases of KPC-KP bacteremia
identified receipt of CAZ–AVI as the sole independent pre-
dictor of survival. Even among patients with single-drug
salvage regimens (n = 49), CAZ–AVI group still displayed
lower 30-day mortality (9/22, 40.9% vs 21/27, 77.8%,
13

1416
P = 0.008). Guimarães et al. [65] also demonstrated that
CAZ–AVI was a promising salvage therapy for KPC-KP
infections. CAZ–AVI as salvage therapy for KPC-KP infec-
tions was superior to alternative drugs, even in patients with
bacteremia.
Similarly, favorable outcomes were observed in patients
with OXA-48-CRE infections when using CAZ–AVI as
salvage therapy. Sousa et al. [66] prospectively enrolled
57 patients with OXA-48-CRE infections, who received
CAZ–AVI after previous treatment failure. Most patients
received CAZ–AVI as monotherapy (46/57). Sepsis or septic
shock occurred in 31 (54%) patients. Clinical and micro-
biological cure were achieved in 77% and 65% of patients.
Mortality rates at 14 days and 30 days were 14% and 22%,
respectively. Six patients experienced recurrence of OXA-
48-CRE infections within 90 days from the end of treatment,
without increasing MIC (the minimum inhibitory concentra-
tion) to CAZ–AVI comparing to the original isolates. After
retreated with CAZ–AVI monotherapy, all but one patient
achieved clinical and microbiological cure. The remain-
ing patient, who had a complicated sternal osteomyelitis,
was clinically and microbiologically cured following three
courses with CAZ–AVI monotherapy. Moreover, none of
these episodes developed resistance to CAZ–AVI.
Early use of CAZ–AVI is associated with improved
clinical outcomes in CRE infections. If other antimicrobials
had failed, CAZ–AVI as salvage therapy still shows clear
benefits in KPC- and OXA-48-producing Enterobacterales
infections.
Limitation: the emergence of resistance to CAZ–AVI
As is shown above, CAZ–AVI brings large clinical benefits
for the CPE infections. However, as the popular use of this
drug, resistance to CAZ–AVI has been reported in multi-
ple centers. The overall resistance rate after exposure to
CAZ–AVI ranged between 1.4 and 12.8% in studies enroll-
ing more than 20 patients with CRE infections [36–39, 48,
52, 53, 67]. To support more information of treatment-
associated resistance to CAZ–AVI, we collected available
literature online, including 8 cohorts and 18 case reports
[36–39, 48, 52, 53, 67–86].
Seventy-one CRE (susceptible to CAZ–AVI) were
observed developing resistance to CAZ–AVI after exposure
to this drug till now, which harbored KPC-3 (n = 30) mostly,
followed by KPC-2 (n = 11), and the rest of isolates (n = 30)
were not reported for subtypes of KPC. The isolates before
developing resistance to CAZ–AVI mainly belonged to
ST258 (n = 13) and ST512 (n = 12). Other strains belonged
to ST39 (n = 5), ST151 (n = 2), ST307 (n = 2), ST11 (n = 2),
and ST101 (n = 1). The ST strains were not reported in 34
isolates. Regarding to the species, most were KP (n = 67),
and 1 was Citrobacter freundii, while 3 isolates were not
13
S. Zhen et al.
reported. After exposure to CAZ–AVI, 92 isolates were
reported, in which 55 were detected for the mechanism of
resistance to CAZ–AVI. Acquired resistance was mostly
associated with substitution of D179Y in KPC-3 (n = 32) or
KPC-2 (n = 5), alone or together with other substitutions or
resistance determinants.
Reported mechanisms of resistance in CRE include enzy-
matic resistance causing antibiotics inactivation, membrane
impermeability of porin mutation, or increased efflux activ-
ity and target protein mutations [87]. As is mentioned above,
numerous mutations in b­ laKPC genes, especially b­ laKPC-3 and
­blaKPC-2 genes conferring CAZ–AVI resistance, have been
published. Most of KPC variants reported have substitutions,
insertions or deletions in four loops, including the Ω-loop
(Arg164 to Asp179), the Val240 loop located between β3-
and β4-strand (Cys238 to Thr243), and the Lys270 loop
located between the β5-strand, the α11- helix (Ala267 to
Ser275), and Trp105 loop. The Ω-loop region in CAZ–AVI
is an important activity site of lactamase [88]. The muta-
tions of KPC-3 or KPC-2 occurring at 164–179 site, such
as Asp179Tyr, Asp179Ala, Asp164Ser, and so on, result in
flexibility of the Ω-loop region, which decrease the bind-
ing of avibactam and ceftazidime hydrolysis activity, lead-
ing to CAZ–AVI resistance [89]. Besides KPC, amino acid
substitutions in other Class A β-lactamase such as CTX-M-
14 and VEB-1 also contribute to CAZ–AVI resistance [78,
90]. Class B β-lactamase is naturally resistant to CAZ–AVI,
because avibactam could not inhibit the activity of MBLs
[19]. Chromosome- or plasmid-mediated AmpC β-lactamase
mutations have been reported in CRE. The changes in the
Ω-loop region (such as amino acids 168, 176, 309–314, and
366) cause resistance in C. freundii and E. cloacae [91].
Structural alterations in or surrounding the R2 binding site
lead to non-susceptibility in E. coli [92]. As for Class D-β-
lactamase, avibactam can inhibit OXA-48, but cannot inhibit
some OXA-48 variants (OXA-163, OXA-405 and so on)
[93]. Permeability defects related to non-functional porins
also contribute to the resistance. Take K. pneumoniae for
example, OmpK 35 and OmpK 36 allow diffusion of avi-
bactam across the outer membrane, while mutation of the
OmpK 35/36 gene invalidates [94]. However, this resistance
mechanism alone cannot increase MIC of CAZ–AVI. Only
together with other mechanisms, mutation of porins can sig-
nificantly increase the MIC to CAZ–AVI [95]. The presence
of penicillin binding protein 3 formed by four amino acid
insertion is also associated with decreasing CAZ–AVI sus-
ceptibility in E. coli [96].
The infection due to CAZ–AVI-resistant isolates becomes
a concerning issue with higher mortality. As was reported
by Tumbarello and colleagues [52], 30-day mortality rates
among patients infected with CRE who developed resist-
ance and those susceptible to CAZ–AVI were 45% (9/20)
and 24% (137/557), respectively. Lacking valuable choice
Update of clinical application in ceftazidime–avibactam for multidrug‑resistant Gram‑negative…
is a concerning problem. Notably, the mutation of D179Y
restored susceptibility to carbapenems. Theoretically, car-
bapenems can be a choice of these infections. However,
this is not recommended, because the susceptibility to car-
bapenem is unstable, which can be rapidly restored under
the selective pressure of carbapenem. Some suggested dual
carbapenem and CAZ–AVI therapy, while the clinically effi-
cacy and safety of this regimen is not determined. Athans
et al. [72] reported that one case was clinically cured using
meropenem–vaborbactam as salvage therapy for CAZ–AVI-
resistant Klebsiella pneumonia infection, which indicated
that meropenem–vaborbactam may be an alternative choice.
Currently, there is no best choice for treating CAZ–AVI-
resistant CRE infections. Therefore, increasing hospital sur-
veillance and preventing the transmission of resistance are
essential. Moreover, selecting factors associated with resist-
ance and optimizing antibiotics to decrease the emergency
of resistance are also beneficial.
Many laboratories usually detect CRE by susceptibility
tests and phenotypic carbapenemase tests such as mCIM
and β-CarbaTM  test or  immunochromatography  assays.
Studies have found that some of the strains (such as those
with KPC-31, KPC-94, and KPC-95) cannot be detected by
the traditional phenotypic carbapenemase tests [75, 81, 97].
Accurate molecular approach—PCR—should be imple-
mented together with traditional methods to prevent CRE
from escaping regular surveillance.
In terms of the risk factors of CAZ–AVI resistance,
some authors proposed that suboptimal dose exposure to
CAZ–AVI is one of the predictors [98]. Shields et al. [39]
found that renal replacement therapy was independently
associated with emergence of resistance to CAZ–AVI
(P = 0.009) in a retrospective study including 77 patients
with CRE infections, suggesting that renal replacement
therapy may lead to suboptimal dose. Fontana et al. [97]
reported that resistance to CAZ–AVI tended to occur among
those with a long previous exposure time to this drug. How-
ever, Shen et al. [83] reported a strain developed resistance
only after 3 days exposure to CAZ–AVI in one case. The
exposure duration associated with resistance is difficult to
define. Moreover, Ackley et al. [36] reported higher resist-
ance rate in those treated with monotherapy than combina-
tion therapy numerically (3/41, 7.3% vs 0/64, 0%), but this
was limited by its small sample and confounding factors
between the two groups.
Notably, CAZ–AVI resistance in KPC-KP producers
developed independently from previous exposure. Hum-
phries et al. [99] and Gaibani et al. [100] reported 1 and 3
cases infected with KPC-KP isolates resistant to CAZ–AVI
without prior treatment of CAZ–AVI, respectively.
The emergence of CAZ–AVI resistance among CRE is
becoming a concerning problem, decreasing the efficacy of
1417
this drug. Isolates belonging to ST258 or ST512, or pro-
ducing KPC, especially KPC-3, are more likely to develop
resistance to CAZ–AVI after exposure to this drug. Preferred
choice for infections due to CAZ–AVI-resistant pathogens
has not been determined. Optimizing usage of CAZ–AVI
to prevent the emergence of resistance and improving sur-
veillance methods is necessary. For isolates without prior
exposure to CAZ–AVI but developing resistance, further
investigation is warranted.
The clinical data in MDR‑PA infections
Besides CRE, CAZ–AVI was also active to MDR-PA. Cur-
rently, some published studies from different countries have
illustrated the therapeutic effect in CRPA or MDR-PA infec-
tions. Corbella et al. [101] conducted a retrospective cohort
on patients with MDR or extremely resistant (XDR) PA
infections treated with CAZ–AVI in Spain. The source of
infection included pneumonia (21/61, 34.4%), UTI (16/61,
26.2%), skin and soft-tissue infection (14/61, 23.3%), IAI
(7/61, 11.5%), and others. Half of them had sepsis at presen-
tation. CAZ–AVI was initiated at a median of 7.0 days from
symptom onset. The 14-day clinical cure rate and 30-day
all-cause mortality rate were 54.1% and 13.1%, respectively.
Chen et al. [102] enrolled 136 patients with CRPA infec-
tions in a single center in China to provide comparison of
CAZ–AVI and polymyxin. Almost all patients had pneu-
monia infections (n = 135, 99.3%), while 49 (36.0%) had
BSI. The 14-day mortality rate (5.9% vs 27.1%, P = 0.002),
30-day mortality rate (13.7% vs 47.1%, P < 0.001), and in-
hospital rate (29.4% vs 60.0%, P = 0.001) were lower in
the CAZ–AVI group than in the polymyxin B group. Fur-
thermore, after adjusting for confounders, the difference in
30-day mortality between the two groups was still signifi-
cant (14.3% vs 42.9%, P = 0.018). Regarding to the bacte-
rial eradication, the frequency was significantly higher in
those with CAZ–AVI than polymyxin B (45.1% vs 12.9%,
P < 0.001). Multivariate Cox analysis identified CAZ–AVI
therapy and central venous catheterization as independ-
ent predictors of 30-day survival, and age as the predic-
tor of 30-day mortality. A multicenter retrospective study
conducted in 6 medical centers in the USA enrolled 203
patients [64]. CRE and CRPA were isolated from 117 and
63 culture specimens, respectively. For CRPA infections, the
most frequent infection source was respiratory tract (60.3%),
followed by urinary tract (11.1%) and so on. The 30-day
mortality and 30-day recurrence rates were 17.5% (11/63)
and 6.3% (4/63). Another multicenter retrospective study
involving 41 MDR-GNB (other than CRE) patients treated
with CAZ–AVI monotherapy (8/41, 19.5%) or combination
therapy (33/41, 80.5%) from 13 hospitals in Italy [103].
The most common causative episodes were Pseudomonas
13

1418
aeruginosa (33/41, 80.5%) and ESBL-producing Enterobac-
terales (4/41, 9.8%), whereas the remaining four patients had
polymicrobial infections. The clinical cure rate was 87.8%
(29/33) in patients infected with Pseudomonas aeruginosa,
and among 4 patients experienced clinical failure, 3 patients
presented with sepsis or septic shock. Several case series and
case reports also highlighted the efficacy of CAZ–AVI for
CRPA infections, even in central nervous system infection
had been described [104–108].
With the increasing use of this drug, the emergence of
resistance to CAZ–AVI in vivo or in vitro studies is concern-
ing. Ruedas-López et al. [109] and Fraile-Ribot et al. [110]
reported the resistance after CAZ–AVI treatment of Pseu-
domonas aeruginosa infections. Moreover, some studies also
reported that Pseudomonas aeruginosa developed cross-
resistance to ceftazidime, CAZ–AVI and ceftolozane/tazobac-
tam during treatment of cephalosporins or other antibiotics
[111–113]. Generally, like CRE, the most common resistance
mechanism to CAZ–AVI in Pseudomonas aeruginosa is enzy-
matic inactivation. The hyperproduction or structural modifi-
cation of AmpC, and the variants of OXA-2 or OXA-10 are
common causes [111, 113, 114]. Moreover, one recent study
reported that KPC-90 variants confer resistance to CAZ–AVI
in CRPA [115]. Another study in China found that CAZ–AVI
resistance was associated with ­blaKPC-2 copy-number variation
[116]. In addition to β-lactamase, the membrane impermeabil-
ity due to porin mutations and high rates of OprD loss play a
role in CAZ–AVI resistance [87]. Efflux pumps do not appear
to play a major role in CAZ–AVI resistance.
CAZ–AVI appears to be a valuable therapeutic option for
infections due to MDR-PA, but the emergence of resistance
is alarming.
Summary
The increasing prevalence of CRE and MDR-PA is a major
threat to human health globally. Fortunately, CAZ–AVI shows
significant benefits for infections due to CRE and MDR-PA,
even in those with immunocompromised status, supporting a
new therapeutic option. The efficacy of CAZ–AVI varies in
different infection sites due to CRE. Early use is associated
with improved clinical outcomes. Noteworthy, when adopted
as salvage therapy, CAZ–AVI is still superior to other GNB
active antibiotics. CAZ–AVI plus aztreonam is the first line
of MBL-CRE infections. However, for infections caused by
KPC- and OXA-48-producing isolates, further investigations
are needed to demonstrate the benefit of combination therapy.
The development of resistance in CRE and MDR-PA against
CAZ–AVI is alarming, and more investigations and studies
are needed to prevent, diagnose, and treat infections due to
CAZ–AVI-resistant pathogens.
13
S. Zhen et al.
Author contributions  SZ and HW drafted the manuscript, and Sizhou
Feng critically revised and approved the final version to be published.
Funding  This work received grant from funding CAMS Innovation
Fund for Medical Sciences (CIFMS) 2021-I2M-C&T-B-080 and
2021-I2M-017.
Declarations 
Conflict of interest  There are no conflicts of interest to report.
Ethical approval  Not required.
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