Expert Review of Anti-infective Therapy

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Ceftazidime-avibactam and aztreonam

combination for Carbapenem-resistant
Enterobacterales bloodstream infections with
presumed Metallo-β-lactamase production: a
systematic review and meta-analysis

Nitin Gupta, Carl Boodman, Parikshit Prayag, Abi Manesh & Tirlangi Praveen
Kumar

To cite this article: Nitin Gupta, Carl Boodman, Parikshit Prayag, Abi Manesh & Tirlangi
Praveen Kumar (23 Jan 2024): Ceftazidime-avibactam and aztreonam combination for
Carbapenem-resistant Enterobacterales bloodstream infections with presumed Metallo-β-
lactamase production: a systematic review and meta-analysis, Expert Review of Anti-infective
Therapy, DOI: 10.1080/14787210.2024.2307912

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EXPERT REVIEW OF ANTI-INFECTIVE THERAPY
https://doi.org/10.1080/14787210.2024.2307912

REVIEW

Ceftazidime-avibactam and aztreonam combination for Carbapenem-resistant

Enterobacterales bloodstream infections with presumed Metallo-β-lactamase
production: a systematic review and meta-analysis
Nitin Guptaa, Carl Boodmanb,c, Parikshit Prayagd, Abi Maneshe and Tirlangi Praveen Kumar a

a
Department of Infectious Disease, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India; bDepartment of Clinical
Sciences, Institute of Tropical Medicine, Antwerp, Belgium; cDivision of Infectious Disease, Department of Internal Medicine, University of Manitoba,
Winnipeg, Manitoba, Canada; dDepartment of Infectious Diseases, Deenanath Mangeshkar Hospital, Pune, India; eDepartment of Infectious Diseases,
Christian Medical College, Vellore, India

ABSTRACT ARTICLE HISTORY

Introduction: Carbapenem-resistant Enterobacterales (CRE) due to Metallo-β-lactamase (MBL) production Received 8 September 2023
are treated with either polymyxins or the novel combination of ceftazidime-avibactam and aztreonam (AA). Accepted 17 January 2024
This study aims to evaluate the 30-day mortality of AA in patients with BSI caused by MBL-CRE infections. KEYWORDS
Methodology: In this systematic review and meta-analysis, all articles up to June 2023 were screened Aztreonam; ceftazidime-
using search terms like ‘CRE’, ‘MBL’, ‘AA’ and ‘polymyxins’. The risk ratio for AA vs polymyxins was avibactam; polymyxin;
pooled using a random-effect model, and the results were represented by a point estimate with a 95% hospital-acquired infection;
confidence interval. bloodstream infection; NDM;
Results: After removing the duplicates, the titles and abstracts of 455 articles were screened, followed metallobetalactamase
by a full-text screening of 50 articles. A total of 24 articles were included for systematic review, and four
comparative studies were included in the meta-analysis. All four studies had a moderate or serious risk
of bias. The pooled risk ratio for 30-day mortality for AA vs. polymyxins was 0.51 (95%CI: 0.34–0.76), p <
0.001. There was no significant heterogeneity.
Conclusion: The meta-analysis from studies with a high risk of bias shows that AA is associated with
lesser 30-day mortality when compared to polymyxins in patients with MBL-producing CRE BSI.
Registration with PROSPERO- CRD42023433608.

1. Introduction suggested to treat MBL CRE infections [4]. While some

studies have recently been published, there is a need for
Carbapenem-resistant Enterobacterales (CRE) infections are
systematic analysis of the published literature. While
a common cause of bloodstream infections (BSI) and are
a systematic review and meta-analysis (SRMA) published in
associated with high mortality rates [1]. Inappropriate defi­
2021 focussed on this novel combination, many studies
nitive therapy has been identified as a significant risk factor
have been published since then [4]. This SRMA, therefore,
for mortality in patients with CRE infections [1].
aims to assess the 30-day mortality of AA in patients with
Traditionally, polymyxins, such as polymyxin B and colistin
BSI caused by CRE infections with proven or presumed MBL
(Polymyxin E), are used to treat CRE BSI, but the outcomes
production.
with these treatments are suboptimal [2]. Furthermore,
polymyxins are associated with significant nephrotoxicity
[3]. Ceftazidime-avibactam, a combination of third- 2. Methodology
generation cephalosporins and non-beta lactam beta-
2.1. Registration
lactamase inhibitor, is a newer antibiotic increasingly used
to treat CRE infections [4]. Recent studies have shown its The trial protocol was registered with PROSPERO
activity and usefulness against two of the three carbapene­ (CRD42023433608).
mases, OXA-48 and KPC [4]. It is, however, inactive against
the third carbapenemase, the Metallo-β-lactamase (MBL)
2.2. Databases and time period
enzymes [4]. Aztreonam is a monobactam antibiotic active
against MBLs but susceptible to hydrolysis by enzymes such This SRMA included studies from two databases (PubMed and
as extended-spectrum beta-lactamases (ESBL), which often Embase). Pre-print servers were also checked to include other
co-exist with MBL in CRE [4]. Since avibactam can inhibit eligible articles not yet present in the two included databases.
ESBL, a novel strategy of a synergistic combination of All articles up to 19.06.2023 were screened to look for
aztreonam and ceftazidime-avibactam (AA) has been eligibility.

CONTACT Tirlangi Praveen Kumar praveenkuma.124@gmail.com Department of Infectious Disease, Kasturba Medical College, Manipal, Manipal Academy
of Higher Education, Manipal 576104, India
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14787210.2024.2307912
© 2024 Informa UK Limited, trading as Taylor & Francis Group
2 N. GUPTA ET AL.
Article highlights
● Bloodstream infections (BSI) by Metallo-β-lactamase (MBL) producing
Carbapenem-resistant Enterobacterales (CRE) are commonly treated
with either polymyxins or the novel combination of ceftazidime-avi­
bactam and aztreonam (AA).
● In this systematic review, a total of 24 articles were included after
screening 512 articles.
● Of the 42 cases with BSI in which AA was used and mortality was
reported, 19% of the patients died. Of the 42 cases in two single-arm
studies, the 30-day mortality was 26%.
● From the four comparative studies, the pooled 30-day mortality with
AA was 26%, while it was 55% for polymyxins.
● The pooled risk ratio for 30-day mortality for AA vs. polymyxins was
0.51 (95%CI: 0.34-0.76), p<0.001. All the studies had moderate or
serious risk of bias, but there was no significant heterogeneity.
2.3. Search string
The following search string was used to retrieve articles:
(‘enterobacteriaceae’[MeSH Terms] OR Enterobacteriaceae
[Text Word] OR ‘enterobacterales’[MeSH Terms] OR
Enterobacterales[Text Word] OR ‘escherichia’[MeSH Terms]
OR Escherichia[Text Word] OR ‘klebsiella’[MeSH Terms] OR
Klebsiella[Text Word]) AND (‘carbapenems’[MeSH Terms] OR
Carbapenem[Text Word] OR CRE) OR (Metallo[All Fields]
AND (‘beta-lactamases’[MeSH Terms] OR Beta Lactamase
[Text Word]) OR (‘beta-lactamase NDM’[All Fields] OR new
delhi metallo beta lactamase[Text Word] OR NDM OR IMP
OR VIM) AND ((‘aztreonam’[MeSH Terms] OR aztreonam[Text
Word]) AND (‘avibactam’[All Fields] OR avibactam[Text
Word])) AND ((‘polymyxins’[MeSH Terms] OR polymyxin
[Text Word]) OR (‘colistin’[MeSH Terms] OR colistin[Text
Word])).
2.4. Eligibility criteria
Studies on individuals of any age and sex (including pregnant
individuals) who were diagnosed with BSI due to CRE with
proven or presumed MBL production were screened for elig­
ibility. Those studies on patients with BSI due to CRE-
producing MBL, where outcomes after initiation of AA were
mentioned, were included in the final analysis. Those patients
with BSI due to multiple organisms (simultaneously) were
excluded. Studies on non-human subjects were excluded. In-
vitro studies, pk-pd modeling studies, reviews, systematic
reviews, and conference abstracts were excluded.
2.5. Definitions
BSI infection due to CRE was defined as the isolation of
Enterobacterales from blood and proven resistance to car­
bapenems on susceptibility testing. Proven MBL produc­
tion was defined as CRE shown to be producing MBL by
any phenotypic or genotypic methods. Presumed MBL pro­
duction was defined as CRE, which was resistant to cefta­
zidime-avibactam but sensitive to synergy testing
(ceftazidime avibactam and aztreonam). The sensitive and
resistant antibiotic classification was based on the pre-
determined cutoffs used by the study. The primary out­
come of the study was 30-day mortality. 30-day mortality
was defined as any mortality within 30 days of recruitment
due to any cause.
2.6. Search strategy
The articles were retrieved from the two databases using the
search strings. They were reviewed for duplicates. After remov­
ing the duplicates, the title and abstract were screened for
eligibility independently by two authors (NG and TPK). Any
conflicts were resolved by the third author (CB). After the
initial screening, full-length articles were retrieved for screen­
ing by the same set of reviewers. The articles that met the
inclusion criteria were included in the final analysis.
2.7. Data extraction and analysis
In a separate table, data from case reports where AA was used
to treat BSI was extracted and compiled independently by two
authors (NG and TPK). Author details, country of reporting,
age, gender, isolated organism, mechanism of carbapenem
resistance, duration of AA, concurrent antibiotic and mortality
were recorded for each of the included cases. Those cases
where AA was used for syndromes other than BSI were com­
piled in a supplementary table. Single-arm studies using AA to
treat BSI were also assessed for inclusion. Author details,
number of cases and 30-day mortality were recorded.
Comparative studies where AA and polymyxin were used to
treat BSI were used for meta-analysis. Age, country of
reporting, year of study and publication, type of study, sample
size, age group and the common organisms were noted for all
the included comparative studies.
2.8. Critical appraisal of the included articles
Each included article for meta-analysis was appraised using
ROBINS-1 for non-randomized studies of interventions indepen­
dently by two reviewers (NG and TPK) [5]. Results from all com­
parative studies were compared to determine differences in the
clinical outcomes between the two groups. The risk ratio was
pooled using a random-effect model (MH method), and the results
were represented by a point estimate with a 95% confidence
interval. The heterogeneity across studies was tested using I2
and Cochran Q tests. A p value < 0.05 for the chi-square test of
the Q statistic or an I2 > 60% were considered statistically signifi­
cant heterogeneity. Review Manager (version 5.3, Cochrane
Nordic, Copenhagen, Denmark) was used for the meta-analysis.
3. Results
3.1. Results of screening
A total of 60 articles from PubMed, 444 articles from Embase and
eight articles were included from searching the citations [6]. After
deleting 57 duplicates, 455 articles were included for title-
abstract screening. After the title-abstract screening, 50 articles
were included in the full-text screening. After excluding 26 arti­
cles, 24 articles were finally included for systematic review [7–30].

Figure 1. Risk of bias assessment for comparative studies using the ROBINS-1 tool.
Cases where AA was used for infections other than BSI have been
compiled in Supplementary Table S1.
3.2. Case reports/series
The 43 cases from 18 case reports/series in patients with BSI are
compiled in Table 1 [7–24]. Klebsiella pneumoniae (Kp) was the
most common organism in the reported cases (53%, 23/43). Of
the 42 cases with BSI in which AA was used and mortality was
reported, 19% (n = 8) of the patients died.
3.3. Single-arm observational studies
This SR included two single-arm studies in patients with BSI
treated with AA [25,26]. In the study by Bavaro et al. from Italy,
of the 21 patients with BSI due to Kp, 30-day mortality was
48% [25]. In the study by Zhang et al. from China, 30-day
mortality in 21 patients with MBL CRE was 5% [26].
3.4. Comparative studies
Only one of the four comparative observational studies was
prospectively conducted (Table 2) [27]. All studies were con­
ducted on adults between 2018 and 2022 in India, Italy or
Greece. Individual data on the organisms responsible for BSI
were not available for the specific subgroups that were included
in the meta-analysis. Kp and Escherichia coli were the most com­
mon organisms. Except for one study, all studies focused on BSI.
In the study by Amarthya et al., patients with all infectious
syndromes were enrolled including BSI [29]. Pneumonia (71%)
followed by BSI (33%) were the most common syndromes that
were treated by either intervention in that study [29]. The data on
patients with BSI was obtained from the study group. The study
by Prayag et al. did not mention outcomes in the AA group, and
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 3
these were obtained by contacting the group [28]. All four studies
were critically analyzed using the ROBINS-1 tool (Figure 1).
3.5. Risk of bias analysis
All the studies had a serious risk of bias except for the prospec­
tive observational study by Falcone et al., which had a moderate
risk of bias [27]. Confounding was addressed in all except one
retrospective study by Falcone et al. [30]. Co-interventions were
not balanced in all the studies, leading to a higher risk of bias.
3.6. Meta-analysis
The meta-analysis showed that the pooled risk ratio for 30-day
mortality for AA vs polymyxin was 0.51 (95%CI: 0.34–0.76),
p < 0.001 (Figure 2). There was no significant heterogeneity,
as evidenced by an I2 of 24%.
4. Discussion
In the individual case reports/series, AA use in patients with
MBL production was associated with 19% mortality (Table 1).
In single-arm studies, mortality ranged from 5% to 48%
[25,26]. In the comparative studies, the use of AA in patients
with BSI due to MBL-producing CRE resulted in lower mortality
when compared to polymyxin-based therapy. The pooled
mortality in the AA arm was 26% compared to 55% in the
polymyxin arm. The pooled risk ratio for 30-day mortality
favoring AA was 0.51 (95%CI: 0.34–0.76).
Carbapenem resistance in Enterobacterales is mediated
primarily by MBLs in certain regions such as India [31].
Global production of novel antimicrobials for CRE, such as
meropenem-vaborbactam or imipenem-relebactam, is biased
toward CRE mechanisms that are more common in high-
income countries. While MBL causes a significant healthcare
4 N. GUPTA ET AL.

Table 1. Details of individual cases where ceftazidime-avibactam and aztreonam were used for treatment.
Age Isolated Duration
Case Author Ref Country (years) Gender Syndrome organism Genotyping (days) Concurrent antibiotics Mortality
1 Abid 2018 [7] USA 74 F BSI En clo IMP NR Amikacin N
2 Alghoribi 2021 [8] Saudi 40 F BSI (IE) Kp NDM 50 N N
Arabia
3 Amarsy 2021 [9] France 54 M BSI Kp NDM NR N N
4 Amarsy 2021 [9] France 64 M BSI Kp NDM NR N Y
5 Ibarias 2020 [10] Mexico 35 M BSI Kp NDM 10 N N
6 Benchetrit [11] France 67 F BSI Kp NDM 15 N N
2019
7 Maria Peri [12] Italy 78 M BSI Eco NDM 1 N Y
2020
8 Mehdawi 2020 [13] Saudi 45 F BSI + CNS Kp NDM NR Colistin + Gentamicin N
Arabia
9 Nori 2020 [14] USA 68 F BSI + VAP En clo NDM NR Tigecycline Y
10 Nori 2020 [14] USA 63 F BSI + UTI En clo NDM NR N Y
11 Nori 2020 [14] USA 54 M BSI + VAP En clo NDM NR Tigecycline + N
Gentamicin
12 Osipov 2020 [15] Russia 59 F BSI Kp NDM 14 NR N
13 Osipov 2020 [15] Russia 19 M BSI Kp NDM 8 NR N
14 Osipov 2020 [15] Russia 58 M BSI Kp NDM 12 NR N
15 Osipov 2020 [15] Russia 19 F BSI Kp NDM 11 NR N
16 Osipov 2020 [15] Russia 58 M BSI Kp NDM 15 NR N
17 Osipov 2020 [15] Russia 60 M BSI Kp NDM 27 NR N
18 Osipov 2020 [15] Russia 60 F BSI Kp NDM 17 NR N
19 Osipov 2020 [15] Russia 18 F BSI Kp NDM 15 NR N
20 Shah 2021 [16] USA 80 M BSI + UTI Kp N/D 13 Colistin NR
21 Sieswerda [17] Holland 60 F BSI+UTI Kp NDM 14 N Y
2019
22 Sempere 2022 [18] Spain 65 M BSI En clo VIM NR N N
23 Sempere 2022 [18] Spain 75 M SSI +BSI En clo VIM NR N Y
24 Sempere 2022 [18] Spain 30 F BSI En clo VIM NR Amikacin N
25 Sempere 2022 [18] Spain 64 M UTI +BSI En clo VIM NR N N
26 Sempere 2022 [18] Spain 40 M BSI En clo VIM NR N Y
27 Sempere 2022 [18] Spain 38 F BSI En clo VIM NR Amikacin N
28 Sempere 2022 [18] Spain 57 F BSI En clo VIM NR Amikacin N
29 Sempere 2022 [18] Spain 78 M BSI En clo VIM NR N N
30 Sempere 2022 [18] Spain 70 M IAI +BSI Eco VIM NR N N
31 Sempere 2022 [18] Spain 60 M SSTI +BSI Ko VIM NR N N
32 Sempere 2022 [18] Spain 64 F BSI Ko VIM NR N N
33 Shaw 2018 [19] Spain 59 M IAI +BSI Kp NDM 28 N
34 Shaw 2018 [19] Spain 70 M UTI +BSI Kp NDM 14 N N
35 Shaw 2018 [19] Spain 80 M BSI Kp NDM 3 N Y
36 Shaw 2018 [19] Spain 82 F UTI +BSI Kp NDM 14 N N
37 Shaw 2018 [19] Spain 58 M IAI + BSI Kp NDM 18 N N
38 Hobson [20] France 3 F BSI Momo NDM 10 N N
39 Davido [21] France 69 M BSI Kp NDM 10 N N
40 Cairns [22] Australia 73 M BSI +UTI En clo IMP 42 N N
41 Cairns [22] Australia 64 M BSI + UTI En clo IMP 28 N N
42 Perrotta [23] Italy 57 M BSI + UTI Kp NDM 10 N N
43 Yasmin [24] USA 4 M BSI En spp NDM 14 N N
Abbreviations: Ref- References, U.S.A.- United States of America, M- Male, F-Female, BSI- Blood Stream infection, CNS- Central nervous system infection, IE- Infective
Endocarditis, SSTI- Skin and soft tissue infection, OM- Osteomyelitis, VAP- Ventilator associated pneumonia, UTI- Urinary tract infection, IAI- Intra-abdominal
infection, En spp- Enterobacter species, En clo- Enterobacter cloacae, Eco- Escherichia coli, Kp- Klebsiella pneumoniae, Ko- Klebsiella oxytoca, Momo- Morganella
morganii, NDM- New Delhi Metallo beta-lactamase, VIM-Verona Integron-encoded Metallo beta-lactamase, Y-Yes, N- No, NR- Not reported.

Table 2. Details of comparative studies on BSI due to CRE with proven or presumed MBL production.
Author Ref Country Year of Study Type of Study Sample size Age group Eco Kp
Falcone 2021 [20] Italy and Greece 2018–2019 Prospective Observational study 89 >18 years 3* 93*
Prayag 2023 [21] India 2021–2022 Retrospective Observational study 74 >18 years 26 (35%) 41 (55%)
Amarthya 2023 [22] India 2020–2022 Retrospective Observational study 29 >18 years 0 29 (100%)
Falcone 2020 [23] Italy and Greece 2018–2019 Retrospective Observational study 21 >18 years 4* 31*
Abbreviations:Ref- References, Eco-Escherichia coli, Kp- Klebsiella pneumoniae.
*These numbers represent the organism distribution of the entire study and are not restricted to patients who received ceftazidime-avibactam and aztreonam
combination or polymyxins.

burden in the global south, it lacks novel, effective, and afford­
able treatment [32]. New Delhi MBL (NDM) is the most com­
mon type of MBL reported in the literature, including in this
SR. In a previous SRMA, 85% of the MBL-producing isolates of
Enterobacterales were sensitive to AA [4].
In the case reports/series, MBL production was confirmed in
all but one case [16]. Both single-arm studies had proven MBL
production. In the comparative studies, all except one had
confirmed MBL production by genotyping [27,28,30]. Kp was
the most common organism in all the comparative studies.

Figure 2. Forest plot comparing aztreonam plus ceftazidime-avibactam and polymyxins in adult patients with bloodstream infection due to Carbapenem-resistant
Enterobacteriaceae with presumed metallo-beta-lactamase production.
The study by Amarthya et al. exclusively enrolled CRKP
patients, while the two studies by Falcone et al. predominantly
had Kp with a handful of Ec cases [27–30]. In the study by
Prayag et al., 35% of the patients had BSI due to Ec [28]. It is
important to note that reports of AA resistance in Ec due to
PBP-3 inserts have been documented in India [33]. However, it
is unlikely to have impacted mortality outcomes in this study
as all patients were given AA only if they were susceptible to
synergy testing.
While this meta-analysis shows that AA fares better in
terms of 30-day mortality when compared to polymyxins,
certain caveats should be considered. All the studies were
observational in nature with small sample sizes and thus
were associated with the inherent flaws of such design,
such as confounding and selection bias. While most studies
adjusted for these biases and confounding by using pro­
pensity matching and multivariable logistic regression ana­
lysis, one of the studies did not adjust for these [30]. In the
cox-regression analysis of that study, the treatment arm
had no impact on the 30-day mortality [30].
It is possible that AA was used by physicians in patients
where the chance of survival was deemed to be more likely.
This, along with differences in patient severity, would likely
explain the differences in mortality that were observed in the
AA arm of the four studies. It must also be noted here that
international consensus guidelines prefer polymyxin over
colistin for invasive infections [34]. All the comparative studies
used colistin in either all their patients or in some patients.
While a recently published SR has not shown any difference in
outcomes between polymyxin and colistin, it is possible that
the mortality rate in the polymyxin arm might have been
exaggerated due to the preferential use of colistin in the
studies [35]. Also, it is possible that polymyxins might have
been used in patients with organisms that were resistant to
polymyxin. Only one study mentioned checking polymyxin
susceptibility by the recommended micro broth dilution test
[30]. The rest of the studies used a variety of commercial
systems for checking polymyxin susceptibility.
Outcomes in the polymyxin arm could have been influ­
enced by the use of polymyxin monotherapy in a small per­
centage of patients in two studies [27,29]. A meta-analysis
showed that polymyxin monotherapy was associated with
higher mortality when compared to combination polymyxin
therapy [36]. In the study by Amarthya et al. and Falcone et al.
(2021), polymyxin monotherapy was prescribed to 20% and
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 5
7% of the patients, respectively [27,29]. In other studies by
Prayag et al. and Falcone et al., polymyxin was always used in
combination therapy [28,30].
Polymyxin use is not only associated with poor out­
comes but a high rate of nephrotoxicity [3]. In one SR,
intravenous polymyxin use was associated with nephro­
toxicity in 39% of the patients [3]. In another SR, nephro­
toxicity with ceftazidime-avibactam was found to be
significantly lower than polymyxins [37]. In our SR,
23–33% of patients in the polymyxin arm and 2–6% in
the ceftazidime-avibactam arm (with or without aztreo­
nam) reported nephrotoxicity [27,28]. It must also be
noted here that nephrotoxicity varies with the formulation
of polymyxin used. In a systematic review, the nephrotoxi­
city with colistin (polymyxin E) was found to be signifi­
cantly higher than polymyxin-B [35]. The higher rates of
adverse events in the polymyxin arm could have had an
impact on the mortality outcomes as well.
This meta-analysis was not without limitations. All the
included studies were observational studies with a high risk
of bias. MBL production was not proven in all isolates, and it
could affect the result in either direction. Adjunctive therapy
was used commonly in both arms, but they were not balanced
or adjusted. Polymyxin susceptibility was not done by recom­
mended methods. The formulation of polymyxin used was not
consistent across studies. Despite the limitations, to the best
of our knowledge, this is the first meta-analysis evaluating
ceftazidime-avibactam and aztreonam in a comprehensive
manner.
This meta-analysis with low heterogeneity shows that AA is
associated with better clinical outcomes when compared to
polymyxins in patients with BSI due to MBL producing CRE.
Since most of the included studies had a higher risk of bias, it
isn’t easy to understand the true difference between these
two strategies, necessitating the need for high-quality rando­
mized controlled trials.
5. Expert opinion
Carbapenem-resistant Gram-negative infections, currently
endemic to countries such as India, are slowly evolving to be
a global problem. The limited number of antibiotics available
to treat the metallo-beta-lactamase (MBL) variant of these
infections is concerning. In this systematic review and meta-
analysis, we discuss the two main choices for treatment:
6 N. GUPTA ET AL.
polymyxins and the combination of ceftazidime-avibactam
and aztreonam (AA). The results of this study showed that
there is a clear trend toward better outcomes with AA.
However, since the number of studies was limited and all
the included studies had a high risk of bias, we concluded
that the results of our study should be confirmed by
a randomized controlled trial (RCT).
It must be noted here that there are multiple anticipated
challenges in conducting an RCT, such as the lack of funding
and difficulty in enrollment. AA has emerged as the preferred
choice for treating gram-negative infections in several MBL
endemic regions. This is primarily due to several of the guide­
lines recommending AA for MBL infections and the relatively
poor experience of physicians with alternative antibiotics such
as polymyxins. In such a situation, convincing physicians, and
patients to enroll in a trial that gives the patient only a 50%
chance of receiving AA may be difficult. Well-conducted pro­
spective cohort studies that address the limitations of the
previous studies may be a feasible alternative.
In our opinion, AA seems to perform better owing to its
favorable side effect profile and fewer adverse clinical out­
comes in patients with MBL infections. Despite these advan­
tages, there are several challenges for low resource settings,
such as limited availability and high cost. Additionally, the
combination is supposed to be used in patients with suscep­
tible MBL or OXA-48 infection, which requires synergy testing.
These tests are often unavailable in resource-poor settings
leading to indiscriminate and empiric use of the AA combina­
tion. Reports of Klebsiella pneumoniae resistant to this combi­
nation have started to emerge and are only expected to
increase with its rampant use. There is a need for capacity
building and advocacy to promote the judicious use of anti­
biotics and increase the availability of in-vitro susceptibility.
This will not only help improve individual outcomes but will
also help in surveillance purposes. Surveillance of the emer­
gence of resistance and antimicrobial stewardship interven­
tions to control their emergence is anticipated to become very
important in the near future.
AA uses the activity of aztreonam against MBL and avi­
bactam on other enzymes. The ceftazidime component has
no apparent role in the treatment. A single drug combina­
tion of aztreonam-avibactam is the need of the hour but
has not been marketed widely. Advocacy to ensure access
to this antibiotic and the regulation of its cost will be
paramount.
In our study, polymyxin use was associated with higher
mortality, but improper susceptibility methods and lack of
clarity on its use (polymyxin vs. colistin, monotherapy vs.
combination, etc.) make it difficult to interpret the data.
There is a need for better evaluation of polymyxin as an
alternative drug, especially in the event of increasing resis­
tance to ceftazidime-avibactam. A limited number of drugs in
the armamentarium to treat MBL infection necessitates invest­
ment in research and innovation to discover and develop
newer molecules to deal with such infections.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
ORCID
Tirlangi Praveen Kumar http://orcid.org/0000-0002-5926-5885
References
1. Hu Q, Chen J, Sun S, et al. Mortality-related risk factors and novel
antimicrobial regimens for carbapenem-resistant
Enterobacteriaceae infections: a systematic review. Infect Drug
Resist. 2022 Nov 28;15:6907–6926. doi: 10.2147/IDR.S390635
2. Clancy CJ, Potoski BA, Buehrle D, et al. Estimating the treatment of
carbapenem-resistant Enterobacteriaceae infections in the United
States using antibiotic prescription data. Open Forum Infect Dis.
2019 Jul 28;6(8):ofz344. doi: 10.1093/ofid/ofz344
3. Wagenlehner F, Lucenteforte E, Pea F, et al. A systematic review on
estimated rates of nephrotoxicity and neurotoxicity in patients
treated with polymyxins. Clin Microbiol Infect. 2021 May 1;27
(5):671–686. doi: 10.1016/j.cmi.2020.12.009
4. Mauri C, Maraolo AE, Di Bella S, et al. The revival of aztreonam in
combination with avibactam against Metallo-β-Lactamase-
Producing Gram-Negatives: a systematic review of in vitro studies
and clinical cases. Antibiotics. 2021 Aug 20;10(8):1012. doi: 10.
3390/antibiotics10081012
5. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for asses­
sing risk of bias in non-randomised studies of interventions. BMJ.
2016 Oct 12;355:i4919. doi: 10.1136/bmj.i4919
6. Haddaway NR, Page MJ, Pritchard CC, et al. PRISMA2020: an
R package and Shiny app for producing PRISMA 2020-compliant
flow diagrams, with interactivity for optimised digital transparency
and Open Synthesis. Campbell Syst Rev. 2022;18(2):e1230. doi: 10.
1002/cl2.1230
7. Abid MB, Buchan B, Ledeboer N, et al. 1192. Identification of
a novel Enterobacter cloacae isolate producing an IMP-13
metallo-β-lactamase. Open Forum Infect Dis. 2018 2018 Nov 26;5
(Suppl 1):S360–1. doi: 10.1093/ofid/ofy210.1025
8. Alghoribi MF, Alqurashi M, Okdah L, et al. Successful treatment of
infective endocarditis due to pandrug-resistant Klebsiella pneumo­
niae with ceftazidime-avibactam and aztreonam. Sci Rep. 2021 May
6;11(1):9684. doi: 10.1038/s41598-021-89255-8
9. Amarsy R, Jacquier H, Munier AL, et al. Outbreak of
NDM-1-producing Klebsiella pneumoniae in the intensive care
unit during the COVID-19 pandemic: another nightmare.
A J Infect Control. 2021 Oct;49(10):1324–1326.
10. Bocanegra-Ibarias P, Camacho-Ortiz A, Garza-González E, et al.
Aztreonam plus ceftazidime-avibactam as treatment of
NDM-1-producing Klebsiella pneumoniae bacteraemia in
a neutropenic patient: Last resort therapy? J Glob Antimicrob
Resist. 2020 Dec;23:417–419.
11. Benchetrit L, Mathy V, Armand-Lefevre L, et al. Successful treat­
ment of septic shock due to NDM-1-producing Klebsiella pneumo­
niae using ceftazidime/avibactam combined with aztreonam in
solid organ transplant recipients: report of two cases.
Int J Antimicrob Agents. 2020 Jan;55(1):105842.

12. Peri AM, Piazza A, De Zan V, et al. Autochthonous ST405 NDM-5
producing Escherichia coli causing fatal sepsis in Northern Italy.
Int J Antimicrob Agents. 2020 May;55(5):105953.
13. Mehdawi F, Al-Ahmadi M, Marhabi H. Effective treatment of ven­
triculitis with OXA-48 carbapenem-resistant Klebsiella pneumonia,
followed by bacteremia with NDM carbapenem-resistant Klebsiella
pneumonia-case report. J Infect Public Health. 2020 Feb 1;13
(2):343. doi: 10.1016/j.jiph.2020.01.101
14. Nori P, Szymczak W, Puius Y, et al. Emerging co-pathogens: New
Delhi metallo-beta-lactamase producing enterobacterales infec­
tions in New York City COVID-19 patients. Int J Antimicrob
Agents. 2020 Dec;56(6):106179.
15. Osipov I, Salogub G, Ivanov V, et al. Ceftazidime-avibactam and
aztreonam in the treatment of severe infections associated with
XDR Klebsiella pneumoniae in neutropenic patients with hemato­
logical malignancy: single-center study. Hemasphere. 2020 Jan
1;4:742–743.
16. Shah PJ, Tran T, Emelogu F, et al. Aztreonam, ceftazidime/avibac­
tam, and colistin combination for the management of
carbapenemase-producing klebsiella pneumoniae bacteremia:
a case report. J Pharm Pract. 2021 Aug;34(4):653–657.
17. Sieswerda E, van den Brand M, van den Berg RB, et al. Successful
rescue treatment of sepsis due to a pandrug-resistant,
NDM-producing Klebsiella pneumoniae using aztreonam powder
for nebulizer solution as intravenous therapy in combination with
ceftazidime/avibactam. J Antimicrob Chemother. 2020 Mar 1;75
(3):773–775. doi: 10.1093/jac/dkz495
18. Sempere A, Viñado B, Los-Arcos I, et al. Ceftazidime-avibactam plus
aztreonam for the treatment of infections by VIM-type-producing
gram-negative bacteria. Antimicrob Agents Chemother. 2022 Oct
18;66(10):e0075122. doi: 10.1128/aac.00751-22
19. Shaw E, Rombauts A, Tubau F, et al. Clinical outcomes after com­
bination treatment with ceftazidime/avibactam and aztreonam for
NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae
infection. J Antimicrob Chemother. 2018 Apr 1;73(4):1104–1106.
doi: 10.1093/jac/dkx496
20. Hobson CA, Bonacorsi S, Fahd M, et al. Successful treatment of
bacteremia due to NDM-1-Producing Morganella morganii with
aztreonam and ceftazidime-avibactam combination in a pediatric
patient with hematologic malignancy. Antimicrob Agents
Chemother. 2019 Jan 29;63(2):e02463–18. doi: 10.1128/AAC.
02463-18
21. Davido B, Fellous L, Lawrence C, et al. Ceftazidime-avibactam and
aztreonam, an interesting strategy to overcome β-lactam resistance
conferred by metallo-β-lactamases in enterobacteriaceae and pseu­
domonas aeruginosa. Antimicrob Agents Chemother. 2017 Aug
24;61(9):e01008–e01017. doi: 10.1128/AAC.01008-17
22. Cairns KA, Hall V, Martin GE, et al. Treatment of invasive IMP-4
Enterobacter cloacae infection in transplant recipients using cefta­
zidime/avibactam with aztreonam: a case series and literature
review. Transpl Infect Dis. 2021 Apr;23(2):e13510.
23. Perrotta F, Perrini MP. Successful treatment of Klebsiella pneu­
moniae NDM sepsis and intestinal decolonization with ceftazi­
dime/avibactam plus aztreonam combination in a patient with
TTP complicated by SARSCoV-2 nosocomial infection. Medicina
(Kaunas). 2021 Apr 28;57(5):424. doi: 10.3390/medicina57
050424
24. Yasmin M, Fouts DE, Jacobs MR, et al. Monitoring ceftazidime-
avibactam and aztreonam concentrations in the treatment of
a bloodstream infection caused by a multidrug-resistant
Enterobacter sp. Carrying both Klebsiella pneumoniae carbapene­
mase-4 and New Delhi metallo-β-lactamase-1. Clin Infect Dis. 2020
Aug 14;71(4):1095–1098. doi: 10.1093/cid/ciz1155
25. Bavaro DF, Belati A, Diella L, et al. Prompt and appropriate anti­
microbial therapy improves outcomes of NDM-Producing and
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 7
KPC-Producing Klebsiella pneumoniae bloodstream infections in
patients hospitalized for COVID-19: a comparative retrospective
case-series. Antibiot Basel Switz. 2022 Oct 31;11(11):1519. doi: 10.
3390/antibiotics11111519
26. Zhang L, Zhen S, Shen Y, et al. Bloodstream infections due to
carbapenem-resistant Enterobacteriaceae in hematological
patients: assessment of risk factors for mortality and treatment
options. Ann Clin Microbiol Antimicrob. 2023 May 18;22(1):41.
doi: 10.1186/s12941-023-00586-y
27. Falcone M, Daikos GL, Tiseo G, et al. Efficacy of ceftazidime-
avibactam plus aztreonam in patients with bloodstream infec­
tions caused by Metallo-β-lactamase-Producing Enterobacterales.
Clin Infect Dis. 2021 Jun 1;72(11):1871–1878. doi: 10.1093/cid/
ciaa586
28. Prayag PS, Patwardhan SA, Panchakshari S, et al. Ceftazidime-
avibactam with or without Aztreonam vs polymyxin-based combi­
nation therapy for Carbapenem-resistant Enterobacteriaceae:
a retrospective analysis. Indian J Crit Care Med. 2023, Jun;27
(6):444–450.
29. Sree RA, Gupta A, Gupta N, et al. Ceftazidime-avibactam alone or
in combination with aztreonam versus polymyxins in the man­
agement of carbapenem-resistant Klebsiella pneumoniae noso­
comial infections (CAPRI study): a retrospective cohort study
from South India. Infection. 2023 Sep 11. doi: 10.1007/s15010-
023-02094-9
30. Falcone M, Tiseo G, Antonelli A, et al. Clinical features and out­
comes of bloodstream infections caused by New Delhi metallo-β-
lactamase-producing enterobacterales during a regional outbreak.
Open Forum Infect Dis. 2020 Feb;7(2):ofaa011.
31. Chatterjee N, Nirwan PK, Srivastava S, et al. Trends in carbapenem
resistance in pre-COVID and COVID times in a tertiary care hospital
in North India. Ann Clin Microbiol Antimicrob. 2023 Jan 3;22(1):1.
doi: 10.1186/s12941-022-00549-9
32. Boyd SE, Livermore DM, Hooper DC, et al. Metallo-β-lactamases:
structure, function, epidemiology, treatment options, and the
development pipeline. Antimicrob Agents Chemother. 2020 Sep
21;64(10). doi: 10.1128/AAC.00397-20
33. Bakthavatchalam YD, Shankar A, Manokaran Y, et al. Can fosfomy­
cin be an alternative therapy for infections caused by E. coli har­
bouring dual resistance: NDM and four-amino acid insertion in
PBP3? JAC Antimicrob Resist. 2023 Mar 4;5(2):dlad016. doi: 10.
1093/jacamr/dlad016
34. Tsuji BT, Pogue JM, Zavascki AP, et al. International consensus
guidelines for the optimal use of the polymyxins: endorsed by
the American college of clinical pharmacy (ACCP), European
society of clinical microbiology and infectious diseases
(ESCMID), infectious diseases Society of America (IDSA), interna­
tional society for anti-infective pharmacology (ISAP), society of
critical care medicine (SCCM), and society of infectious diseases
pharmacists (SIDP). Pharmacother J Hum Pharmacol Drug Ther.
2019;39(1):10–39.
35. Vardakas KZ, Falagas ME. Colistin versus polymyxin B for the treat­
ment of patients with multidrug-resistant gram-negative infections:
a systematic review and meta-analysis. Int J Antimicrob Agents.
2017 Feb 1;49(2):233–238. doi: 10.1016/j.ijantimicag.2016.07.023
36. Hou SY, Wu D, Feng XH. Polymyxin monotherapy versus
polymyxin-based combination therapy against
carbapenem-resistant Klebsiella pneumoniae: a systematic review
and meta-analysis. J Glob Antimicrob Resist. 2020 Dec;23:197–202.
doi: 10.1016/j.jgar.2020.08.024
37. Yang P, Li Y, Wang X, et al. Efficacy and safety of ceftazidime–
avibactam versus polymyxins in the treatment of carbapenem-
resistant Enterobacteriaceae infection: a systematic review and
meta-analysis. BMJ Open. 2023 May 1;13(5):e070491. doi: 10.1136/
bmjopen-2022-070491