J Antimicrob Chemother 2022; 77: 1452–1460

https://doi.org/10.1093/jac/dkac049 Advance Access publication 21 February 2022

Impact of ceftazidime/avibactam versus best available therapy on

mortality from infections caused by carbapenemase-producing
Enterobacterales (CAVICOR study)
Juan José Castón1,2,3,4*, Angela Cano1,2,3,4, Inés Pérez-Camacho5, Jose M. Aguado4,6,7, Jordi Carratalá 4,8,9,
Fernando Ramasco10, Alex Soriano 4,11, Vicente Pintado12, Laura Castelo-Corral13, Adrian Sousa14,
María Carmen Fariñas4,15,16, Patricia Muñoz 4,17,18,19,20, Vicente Abril López De Medrano21, Óscar Sanz-Peláez22,

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Ibai Los-Arcos 4,23,24, Irene Gracia-Ahufinger3,25, Elena Pérez-Nadales1,2,3, Elisa Vidal1,2,3,4, Antonio Doblas1,
Clara Natera1,2, Luis Martínez-Martínez3,4,25,26 and Julian Torre-Cisneros1,2,3,4

1
Infectious Diseases Unit, Hospital Universitario Reina Sofía, Cordoba, Spain; 2Instituto Maimónides de Investigación Biomédica de
Córdoba (IMIBIC), Córdoba, Spain; 3CIBER de Enfermedades Infecciosas-CIBERINFEC (CB21/13/00049), Instituto de Salud Carlos III,
Madrid, Spain; 4Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0008/REIPI RD16/0016/0001); 5Unidad de
Gestión Clínica de Enfermedades Infecciosas, Hospital Regional Universitario de Málaga, IBIMA, Málaga, Spain; 6Unidad de
Enfermedades Infecciosas, Hospital Universitario 12 de Octubre, Instituto de Investigación i+12, Universidad Complutense de Madrid,
Madrid, Spain; 7CIBER de Enfermedades Infecciosas-CIBERINFEC (CB21/13/00079), Instituto de Salud Carlos III, Madrid, Spain;
8
Department of Infectious Diseases, Bellvitge University Hospital, Bellvitge Biomedical Research Institute (IDIBELL), University of
Barcelona, Barcelona, Spain; 9CIBER de Enfermedades Infecciosas-CIBERINFEC (CB21/13/00009), Instituto de Salud Carlos III, Madrid,
Spain; 10Department of Anesthesiology and Intensive Care, Hospital Universitario La Princesa, Madrid, Spain; 11Department of Infectious
Diseases, Hospital Clínic de Barcelona, Barcelona, Spain; 12Infectious Diseases Department, Hospital Ramón y Cajal and Instituto Ramón
y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain; 13Section of Infectious Diseases, Hospital Universitario de A Coruña, A Coruña,
Spain; 14Infectious Diseases Unit-Internal Medicine Department, Hospital Álvaro Cunqueiro, Área Sanitaria de Vigo, Vigo, Spain;
15
Servicio de Enfermedades Infecciosas, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander, Spain;
16
CIBER de Enfermedades Infecciosas-CIBERINFEC (CB21/13/00068), Instituto de Salud Carlos III, Madrid, Spain; 17Clinical Microbiology
and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 18Instituto de Investigación Sanitaria Hospital
Gregorio Marañón, Madrid, Spain; 19Medicine Department, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain;
20
CIBER Enfermedades Respiratorias-CIBERES (CB06/06/0058), Instituto de Salud Carlos III, Madrid, Spain; 21Servicio de Enfermedades
Infecciosas, Consorcio Hospital General Universitario de Valencia, Valencia, Spain; 22Infectious Diseases Unit, Hospital Universitario de
Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria, Spain; 23Infectious Diseases Department, Hospital Universitari Vall d’Hebrón,
Barcelona, Spain; 24CIBER de Enfermedades Infecciosas-CIBERINFEC (CB21/13/00054), Instituto de Salud Carlos III, Madrid, Spain; 25Unit
of Microbiology, Hospital Universitario Reina Sofía, Córdoba, Spain; 26Department of Agricultural Chemistry, Soil Sciences and
Microbiology, University of Córdoba, Córdoba, Spain

*Corresponding author. E-mail: juanj.caston.sspa@juntadeandalucia.es

Received 2 December 2021; accepted 31 January 2022

Background: Infections caused by carbapenemase-producing Enterobacterales (CPE) are not well represented
in pivotal trials with ceftazidime/avibactam. The best strategy for the treatment of these infections is unknown.
Methods: We conducted a multicentre retrospective observational study of patients who received ≥48 h of
ceftazidime/avibactam or best available therapy (BAT) for documented CPE infections. The primary outcome
was 30 day crude mortality. Secondary outcomes were 21 day clinical response and microbiological response.
A multivariate logistic regression model was used to identify factors predictive of 30 day crude mortality. A pro-
pensity score to receive treatment with ceftazidime/avibactam was used as a covariate in the analysis.
Results: The cohort included 339 patients with CPE infections. Ceftazidime/avibactam treatment was used
in 189 (55.8%) patients and 150 (44.2%) received BAT at a median of 2 days after diagnosis of infection.
In multivariate analysis, ceftazidime/avibactam treatment was associated with survival (OR 0.41, 95%
CI 0.20–0.80; P = 0.01), whereas INCREMENT-CPE scores of .7 points (OR 2.57, 95% CI 1.18–1.5.58; P = 0.01)
and SOFA score (OR 1.20, 95% CI 1.08–1.34; P = 0.001) were associated with higher mortality. In patients

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1452
Ceftazidime/avibactam and CPE infections
with INCREMENT-CPE scores of .7 points, ceftazidime/avibactam treatment was associated with lower mortal-
ity compared with BAT (16/73, 21.9% versus 23/49, 46.9%; P = 0.004). Ceftazidime/avibactam was also an inde-
pendent 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).
Conclusions: Ceftazidime/avibactam is an effective alternative for the treatment of CPE infections, especially in
patients with INCREMENT-CPE scores of .7 points. A randomized controlled trial should confirm these findings.
Introduction
Infections caused by carbapenemase-producing Enterobacterales
(CPE) have emerged as an important problem for public health.1
This is due to the fact that these infections present a growing inci-
dence and they are associated with high mortality.2 Initially, the
therapeutic regimens for these infections were based on the
‘best available therapy’ (BAT), which included drugs considered
as second-line antibiotics because of their toxicity or clinical effi-
cacy, i.e. gentamicin, colistin, tigecycline and fosfomycin.
Ceftazidime/avibactam exhibits activity against class A
β-lactamases, including Klebsiella pneumoniae carbapenemase
(KPC), class C and some class D β-lactamases, such as OXA-48.3
This drug has been approved for the treatment of complicated
intra-abdominal infections (IAIs), complicated urinary tract in-
fections (cUTIs), hospital-acquired pneumonia and infections
due to aerobic Gram-negative organisms with limited treatment
options.4–6
However, infections caused by CPE are not well represented in
pivotal clinical trials and there are not comparative clinical trials
between ceftazidime/avibactam and BAT in this setting.
Although clinical experience has been increasing in recent years,
including studies focusing on one type of carbapenemase, or
comparative studies with a single type of antibiotic,7–11 informa-
tion available is still limited. For that reason, the aim of this study
was to investigate whether treatment of infections caused by
CPE with ceftazidime/avibactam is associated with lower mortal-
ity than those treated with BAT. Additionally, we investigated
whether ceftazidime/avibactam is associated with higher rates
of clinical response and microbiological eradication compared
with BAT.
Materials and methods
Study design and population
CAVICOR is a retrospective cohort study involving 14 tertiary hospitals
that are part of the Spanish Public Healthcare System. We included hos-
pitalized patients from 1 June 2014 until 31 December 2019 with: (i) age
.18 years at hospital admission; (ii) cUTI, hospital-acquired pneumonia
(including ventilator-associated pneumonia), IAI or bloodstream infec-
tion (BSI) and confirmed CPE [KPC or OXA-48 group carbapenemases
(OXA)]; and (iii) treatment for ≥48 h with ceftazidime/avibactam or
BAT. The clinical data of these patients from each centre were recorded
in a central database. All the data collected were pseudonymized.
Exclusion criteria were: (i) patients whose culture episode did not
meet criteria for infection; (ii) those whose infection was caused by CPE
other than KPC or OXA-48 group-producing species; (iii) polymicrobial in-
fection (except for IAI); (iv) patients who were participating in a clinical
trial involving active treatment for the infections; and (v) patients with
‘do not resuscitate’ orders or with life expectancy of ,30 days.
Definitions
The definitions of cUTI, pneumonia, IAI and BSI have been described pre-
viously.12 Patients with BSI were analysed as such, regardless of the pri-
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mary source. Infection onset was defined as the collection date of the
index culture.
Twenty-one day clinical response was considered when none of these
criteria was present: (i) the patient died before Day 21; (ii) treatment with
ceftazidime/avibactam or BAT at Day 21 for persistence of symptoms or
signs of infection; and (iii) relapse of the infection (defined as the onset of
a second infection caused by the initially isolated pathogen in a patient
whose antibiotic treatment was previously discontinued by clinical im-
provement, regardless of the presence or not of a negative previous con-
trol culture).
Microbiological eradication was defined as absence of the initial
pathogen in cultures taken from the site of the index infection at least
5 days from the start of treatment. This variable was determined only
in patients in whom a control culture was obtained.
A therapeutic regimen including a single in vitro active drug was con-
sidered as monotherapy. Combination therapy was defined as the add-
ition, for more than 48 h, of other antimicrobials with in vitro activity
against the clinical isolate. Treatment of CPE infections was at the discre-
tion of the physician in charge.
Acute renal failure was defined by modified KDIGO guidelines as a
1.5× increase in baseline serum creatinine levels within 7 days of treat-
ment initiation.13 Adequate source control was considered when it was
performed in the first 24 h after the diagnosis of infection in patients
with severe sepsis or septic shock, or in the first 3 days in the remaining
cases.
The study was approved by the local Ethics Committee (code
FCO-CAV-2018-01), which exempted the need to seek written informed
consent due to the observational and non-interventional nature of the
study. The study was also authorized by the Spanish Regulatory Agency
(Agencia Española del Meciamento y Productos Sanitarios).
Outcome and explicative variables
The primary outcome variable was 30 day crude mortality after diagnosis
of infection. Secondary outcome variables were 21 day clinical response
and microbiological failure. The variables considered as possible predic-
tors of the primary and secondary endpoints are listed in Table 1.
Patients discharged before 30 days after infection onset were fol-
lowed up through the consultation of available outpatients medical
records.
Microbiology
The detection of carbapenemases was carried out when any isolate iden-
tified as a species within the order Enterobacterales showed an MIC of imi-
penem or meropenem ≥1 mg/L, if using any dilution method, and/or
inhibition zone of ≤22 mm, if using a disc diffusion method for imipenem
or meropenem (10 μg discs). Each hospital conducted antibiotic suscepti-
bility testing and carbapenemase detection according to its own protocols.
On available isolates, additional tests were performed in a centralized ref-
erence laboratory for this study (at the Hospital Universitario Reina Sofía,
1453
Castón et al.

Table 1. Baseline characteristics of the study patients Table 1. Continued

Ceftazidime/ Ceftazidime/
avibactam avibactam
Variable (n=189) BAT (n=150) P value Variable (n=189) BAT (n=150) P value

Male sex, n (%) 125 (66.1) 86 (57.3) 0.09 21 day clinical cure, n (%) 169 (89.4) 119 (79.3) 0.01
Age (years), median (IQR) 67 (56–77) 70 (59–80) 0.65 Microbiological response, n (%) 100 (52.9) 50 (33.3) ,0.001
Comorbidities, n (%) Infection relapse, n (%) 24 (12.7) 13 (8.6) 0.24
Diabetes mellitus 51 (27.0) 56 (37.3) 0.04 Crude mortality (30 days), n (%) 26 (13.7) 33 (22) 0.04
Solid tumour 24 (12.7) 10 (6.6) 0.06
Chronic renal failure 62 (32.8) 40 (26.6) 0.30
COPD 32 (16.9) 31 (20.7) 0.48

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Córdoba): identification at species level was confirmed by MALDI-TOF
Liver disease 20 (10.6) 17 (11.3) 0.82 (Bruker Daltonik, Bremen, Germany); and detection of carbapenemase
Chronic heart failure 34 (18) 36 (24.0) 0.39 was performed by the modified carbapenem inhibition method (mCIM)14
Peripheral vascular disease 18 (9.5) 17 (11.3) 0.58 and a colorimetric test (β CARBA test, Bio-Rad, Madrid, Spain). The type of
Neutropenia 10 (5.3) 3 (2.0) 0.09 carbapenemase was investigated by immunochromatography (NG Test
Haematological malignancy 12 (6.3) 1 (0.7) 0.005 CARBA 5, NG Biotech, France). Ceftazidime/avibactam susceptibility testing
Stem cell transplantation 7 (3.7) 1 (0.7) 0.06 was performed by broth microdilution using commercial panels
(SensititreTM, Thermo Fisher, Madrid, Spain) and results were interpreted
Solid organ transplantation 29 (15.3) 16 (10.7) 0.20
in accordance with the EUCAST clinical breakpoints.15
Charlson comorbidity index ≥3, n 106 (56.1) 91 (60.6) 0.39
(%)
Immunosuppressive therapy, n (%) 54 (28.5) 29 (19.3) 0.05 Statistical analysis
Surgery in previous month, n (%) 45 (23.8) 50 (33.3) 0.05 Continuous variables were described as median and IQR. The Student’s
Bladder catheter in previous week, 101 (53.4) 84 (56.0) 0.71 t-test or the Mann–Whitney U-test were used to compare normally and
n (%) non-normally distributed continuous variables, respectively. To compare
Acute renal failure, n (%) 67 (35.4) 32 (21.3) 0.003 categorical variables, the chi-squared test or Fisher’s exact test were
Septic shock, n (%) 36 (19.0) 13 (8.7) 0.006 used. OR and 95% CI were calculated for all associations. Variables with
a two-sided P value of ,0.05 were considered statistically significant.
In ICU at time of diagnosis of 29 (15.3) 20 (13.3) 0.18
A multivariate logistic regression model was used to identify predict-
infection, n (%)
ive factors of 30 day crude mortality. Variables emerging from univariate
Type of infection, n (%) analysis with P values of ,0.10 and those with potential clinical relevance
Bloodstream 72 (38.1) 39 (26) 0.02 were included in the multivariate model in a backward stepwise manner.
Urinary tract 67 (35.4) 62 (41.3) 0.26 Because patients treated with ceftazidime/avibactam may differ on
Intra-abdominal 27 (14.3) 33 (22.0) 0.06 some relevant baseline characteristics compared with patients pre-
Pneumonia 23 (12.2) 16 (10.7) 0.66 scribed BAT, a propensity score to receive ceftazidime/avibactam was cal-
Clinical status culated by obtaining a non-parsimonious multivariate model by logistic
SOFA score, median (IQR) 3 (1–6) 2 (1–5) 0.03 regression, in which the outcome variable was the treatment type. The
APACHE II score, median (IQR) 14 (9–19) 12 (7–18) 0.01 explanatory variables included age, gender, type of ward, Charlson co-
morbidity index, severity of systemic inflammatory response syndrome
INCREMENT-CPE score .7, n (%) 73 (38.6) 49 (32.7) 0.25
(SIRS), acute and chronic renal failure, BSI, immunosuppressive therapy
Pitt score, median (IQR) 1 (1–3) 1 (1–4) 0.88
and SOFA score. Similarly, a multivariate analysis was used to identify inde-
Renal replacement therapy, n (%) 21 (11.1) 9 (6.0) 0.10 pendent risk factors for 21 day clinical response, including propensity score
Mechanical ventilation, n (%) 36 (19.0) 25 (16.6) 0.59 to receive ceftazidime/avibactam. To investigate risk factors associated
Source control of infection, n (%) 142 (75.1) 114 (76) 0.835 with microbiological failure, a multivariate regression logistic analysis was
Type of CPE, n (%) performed including microbiological evaluable population only. The
K. pneumoniae 170 (89.9) 141 (94.0) 0.18 Kaplan–Meier method was used for survival analysis. Analysis for a ‘centre
Enterobacter spp. 9 (4.8) 3 (2) 0.17 effect’ was performed using the Cochran–Mantel–Haenszel test. Moreover,
E. coli 6 (3.2) 5 (3.3) 0.93 to control for the site effect we classified centres into those with low
Klebsiella oxytoca 3 (1.6) 0 (0.0) 0.43 (low-mortality-risk centres) and high (high-mortality-risk centres) mortality
using TreeNet considering all other variables. This dichotomous variable
Others 1 (0.5) 1 (0.7) 0.87
was included in the multivariate analysis of risk factors of 30 day mortality.
Presence of ESBL, n (%) 134 (70.8) 95 (63.3) 0.10
The same procedure was performed to evaluate the site effect on 21 day
Type of carbapenemase, n (%) clinical response and microbiological failure (after using TreeNet to classify
OXA-48 139 (73.5) 116 (77.3) 0.45 the centres as low or high risk of 21 day clinical response or microbiological
KPC 50 (26.5) 34 (22.7) 0.44 failure, respectively). All statistical analyses were performed with SPSS soft-
Variables related to treatment ware, version 20 (IBM Corp., Armonk, NY, USA).
Monotherapy, n (%) 133 (70.4) 64 (42.6) ,0.001
Days of treatment, median (IQR) 11 (8–15) 10 (7–13) 0.08
Adverse events, n (%) 11 (5.8) 30 (20.0) ,0.001
Results
During the study period, 339 patients met inclusion criteria and
Continued received treatment with ceftazidime/avibactam or BAT. One

1454
Ceftazidime/avibactam and CPE infections
hundred and eighty-nine out of 339 (55.8%) patients received
treatment with ceftazidime/avibactam whereas 150 (44.2%) re-
ceived BAT. The baseline characteristics of these patients are
shown in Table 1. Median age was 70 years (IQR 54–79). The me-
dian Charlson comorbidity score was 3 (IQR 2–5). Most frequent
infections were cUTI (n = 129; 38.1%) and BSI (n = 111; 32.7%)
(Figure 1). Sources of bacteraemia are summarized in Table S1,
available as Supplementary data at JAC Online. Thirty-eight per-
cent (15/39) of pneumonia cases were ventilator associated. The
baseline characteristics of the patients by type of infection are
summarized in Table S2.
The median number of days from diagnosis of infection to ini-
tiation of therapy was 2 (IQR 1–4). The median duration of treat-
ment was 10 days (IQR 7–14). The antibiotics combined with
ceftazidime/avibactam were amikacin (n = 17; 30.3%), tigecyc-
line (n = 15; 26.8%), colistin (n = 10; 17.9%), gentamicin (n = 6;
10.7%), fosfomycin (n = 6; 10.7%), tobramycin (n = 1; 1.8%) and
aztreonam (n = 1; 1.8%). The regimens used in patients included
in the BAT group are described in Table S3.
Bacterial isolates were available for studies in the refer-
ence laboratory from 174 cases (102 and 72 from patients
treated with ceftazidime/avibactam and BAT, respectively).
In those cases, the microorganisms (163 K. pneumoniae, 8
Enterobacter cloacae and 3 Escherichia coli) and enzymes
(109 OXA-48, 62 KPC, 1 OXA-48 plus KPC and 2 other carba-
penemases) originally identified in the participating centres
were confirmed in the reference laboratory. Detailed charac-
terization of these isolates will be presented separately
(manuscript in preparation).
Figure 1. Flow chart showing patient enrolment. CAZ-AVI, ceftazidime/avibactam. aP , 0.001. bP = 0.01. cP = 0.01.
Mortality
In the entire cohort, 30 day crude mortality was 17.4% (n = 59).
The highest rate of mortality was observed in patients with pneu-
monia [28.2% (11/39)] and the lowest mortality in patients with
IAI [10% (6/60)]. Table 2 shows a comparison of demographics,
clinical- and treatment-related variables of patients with and
without 30 day crude mortality. Patients treated with
ceftazidime/avibactam were less likely to die than patients in
the BAT group (26/189, 13.7% versus 33/150, 22%; P = 0.04).
These differences were due to a significantly higher 30 day crude
mortality in patients with INCREMENT-CPE score of .7 points
treated with BAT compared with ceftazidime/avibactam (23/49,
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46.9% versus 16/73, 21.9%; P = 0.004) (Figure 2). Similarly, in
patients with BSI, ceftazidime/avibactam treatment was
associated with lower 30 day crude mortality than BAT (10/72,
13.9% versus 12/39, 30.8%; P = 0.03) (Table S2).
Overall, single-drug regimens were not associated with higher
mortality than combination therapy, neither in patients who re-
ceived ceftazidime/avibactam (19/133, 14.3% versus 7/56,
12.5%; P = 0.82) nor in those treated with BAT (12/64, 18.7% ver-
sus 21/86, 24.4%; P = 0.40). However, among patients with
INCREMENT-CPE scores of .7 points, monotherapy with
ceftazidime/avibactam was associated with lower 30 day mor-
tality than the patients in the BAT group treated with combin-
ation regimens (19/133, 14.3% versus 14/30, 46.7%; P , 0.001).
According to the type of carbapenemase, mortality was sig-
nificantly lower in infections caused by OXA-48 strains included
in the BAT group (n = 116) when this therapy included a
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Castón et al.

carbapenem compared with non-carbapenem regimens (9/62, Table 2. Comparison of patients with and without 30 day crude mortality
14.5% versus 16/54, 29.6%; P = 0.04) (Figure 3). On the other
hand, the risk of mortality of infections caused by OXA-48 was Survivors
higher in the BAT group compared with ceftazidime/avibactam Non-survivors (n=280;
only when the INCREMENT-CPE score was .7 points (17/32, Variable (n=59; 17.4%) 82.6%) P value
53.1% versus 11/48, 22.9%; P = 0.006). Similar results were found
Male sex, n (%) 35 (59.3) 176 (62.9) 0.61
when specifically comparing patients treated with carbapenems
Age (years), median (IQR) 71 (55.5–82) 68 (58–77) 0.60
within the BAT group and ceftazidime/avibactam (7/13, 53.8%
Comorbidities, n (%)
versus 11/48, 22.9%; P = 0.04).
Diabetes mellitus 18 (30.5) 89 (31.8) 0.84
In the multivariate analysis after adjustment by propensity
Solid tumour 6 (10.1) 28 (10) 0.97
score (Table 3), SOFA score at the diagnosis of infection (OR
Chronic renal failure 22 (37.3) 80 (28.5) 0.19
1.20, 95% CI 1.08–1.34, P = 0.001) and INCREMENT-CPE score
COPD 15 (25.4) 48 (17.1) 0.24

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of .7 points (OR 2.57, 95% CI 1.18–5.58, P = 0.01) were
Liver disease 6 (10.2) 31 (11.1) 0.83
independent predictors of mortality, whereas treatment with
Chronic heart failure 19 (32.2) 51 (18.2) 0.04
ceftazidime/avibactam was associated with survival (OR 0.41,
Peripheral vascular disease 10 (16.9) 25 (9.0) 0.06
95% CI 0.20–0.80; P = 0.01). Survival curve analysis confirmed
Neutropenia 2 (3.4) 11 (3.9) 0.84
the reduced mortality risk associated with ceftazidime/
Haematological malignancy 2 (3.4) 11 (3.9) 0.84
avibactam treatment (Figure 2).
Stem cell transplantation 1 (1.7) 7 (2.5) 0.71
Solid organ transplantation 7 (11.9) 38 (13.6) 0.71
Clinical response Charlson comorbidity index ≥3, 41 (69.5) 156 (55.7) 0.05
Overall, the 21 day clinical response rate was 84.9% (n = 288). n (%)
Table S4 shows the characteristics of the patients according to Immunosuppressive therapy, n (%) 16 (27.1) 67 (23.9) 0.63
21 day clinical response. In patients treated with ceftazidime/ Surgery in previous month, n (%) 10 (16.9) 85 (30.3) 0.03
avibactam, 21 day clinical response was more frequent than in Bladder catheter in previous 39 (66.1) 146 (52.5) 0.05
those treated with BAT (169/189, 89.4% versus 119/150, week, n (%)
79.3%; P = 0.01). According to the type of infection, the patients Acute renal failure, n (%) 29 (49.1) 70 (25) ,0.001
with pneumonia included in the ceftazidime/avibactam group Septic shock, n (%) 31 (11.2) 18 (30.5) ,0.001
had a higher rate of 21 day clinical response than patients trea- In ICU at time of diagnosis of 16 (27.1) 33 (11.8) 0.003
ted with BAT (21/23, 91.3% versus 9/16, 56.2%; P = 0.01). infection, n (%)
The only independent predictor of clinical response in the Type of infection, n (%)
multivariate analysis was ceftazidime/avibactam-containing Bloodstream 22 (37.3) 89 (31.8) 0.42
therapy (OR 2.43, 95% CI 1.16–5.12; P = 0.02), whereas SOFA Urinary tract 20 (33.9) 109 (38.9) 0.47
score (OR 0.78, 95% CI 0.71–0.87; P , 0.001) and single-drug Pneumonia 11 (18.6) 28 (10) 0.06
treatments (either with BAT or ceftazidime/avibactam) (OR Intra-abdominal 6 (10.1) 54 (19.2) 0.09
0.42, 95% Clinical status
CI 0.20–0.86; P = 0.02) were independently associated with clin- SOFA score, median (IQR) 5 (3–8) 2 (1–5) ,0.001
ical failure (Tables S4 and S5). In this analysis we could not rule APACHE II score, median (IQR) 18 (13–23) 12 (8–17) ,0.001
out the hypothesis of homogeneity of results between centres INCREMENT-CPE score .7, 39 (66.1) 83 (29.7) ,0.001
because the variable centre (dichotomized) was significant in n (%)
the multivariate analysis (OR 0.39, 95% CI 0.19–0.79; P = 0.009). Pitt score, median (IQR) 4 (2–7) 1 (0–3) ,0.001
Renal replacement therapy, n (%) 10 (16.9) 20 (7.2) 0.01
Mechanical ventilation, n (%) 21 (35.6) 40 (14.2) ,0.001
Microbiological response Source control of infection, n (%) 45 (76.3) 211 (75.9) 0.95
In 192 patients out of 339 patients of the cohort (56.6%), repeat High-mortality-risk centre, n (%) 47 (79.7) 177 (63.2) 0.01
cultures were obtained. Microbiological eradication rate was Type of CPE, n (%)
78.1% (n = 150 patients) and it was significantly more frequent K. pneumoniae 56 (94.9) 255 (91.1) 0.32
in patients treated with ceftazidime/avibactam than in those Klebsiella oxytoca 0 (0.0) 3 (1.1) 0.68
treated with BAT (100/120, 83.3% versus 50/72, 69.4%; E. coli 1 (1.7) 10 (3.6) 0.45
P = 0.02). Sixteen out of 42 patients with microbiological failure Enterobacter spp. 1 (1.7) 11 (3.9) 0.39
had cUTI (38.1%), 12 (28.6%) IAI, 9 (21.4%) BSI and 5 (11.9%) Others 1 (1.7) 1 (0.4) 0.22
pneumonia. IAI was the only type of infection associated with Presence of ESBL, n (%) 36 (61.0) 193 (68.9) 0.21
microbiological failure compared with the rest of the infections Type of carbapenemase, n (%)
(12/42; P = 0.001). In the multivariate analysis, IAIs (OR 5.98; OXA-48 42 (71.2) 213 (76.1) 0.41
95% CI 1.92–18.59; P = 0.002) were associated with microbio- KPC 17 (28.8) 67 (23.9) 0.45
logical failure, whereas ceftazidime/avibactam-containing ther- Variables related to treatment,
apy was the only factor independently associated with n (%)
microbiological response (OR 0.40; 95% CI 0.18–0.85; P = 0.02)
(Tables S6 and S7). Continued

1456
Ceftazidime/avibactam and CPE infections

Table 2. Continued Discussion

Survivors
To our knowledge this is the largest comparative series of pa-
Non-survivors (n=280;
tients with infections caused by CPE treated with ceftazidime/
Variable (n=59; 17.4%) 82.6%) P value
avibactam or BAT. Our results indicate that in these patients
the use of ceftazidime/avibactam is associated with lower mor-
Monotherapy 31 (52.5) 166 (59.2) 0.34 tality compared with BAT. Moreover, ceftazidime/avibactam
CAZ-AVI-containing therapy 26 (44.1) 163 (58.2) 0.04 treatment was an independent predictor of clinical response
21 day clinical cure, n (%) 21 (35.6) 267 (95.4) ,0.001 and microbiological eradication in this setting.
Microbiological response, n (%) 18 (30.5) 132 (47.1) ,0.001 In our cohort, the 30 day crude mortality rate of 17.5% was
Infection relapse, n (%) 2 (3.4) 35 (12.5) 0.04 lower than in previously reported series.7–9,16 This could be ex-
plained by lower mortality in patients treated with BAT in our co-
hort compared with other studies,10,17 probably due to the high

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CAZ-AVI, ceftazidime/avibactam.
Safety
Adverse events (AEs) were reported in 41 (12.1%) patients.
Treatment with ceftazidime/avibactam was less related to
AEs than BAT (11/189, 5.8% versus 30/150, 20%; P , 0.001).
The most frequent AEs were renal failure (18/41, 43.9%) and
diarrhoea (9/41, 21.9%). Renal failure was significantly more
frequent in patients treated with BAT compared with those
treated with ceftazidime/avibactam (3/189, 1.6% versus
15/150, 10%; P ≤ 0.01). Diarrhoea was more frequent in the
ceftazidime/avibactam group, although no significant differ-
ences were found between groups (5/11, 45.4% versus 4/30,
13.3%; P = 0.07). Two out of nine episodes of diarrhoea were
caused by Clostridioides difficile and in all cases the patients
had received ceftazidime/avibactam previously. In 10 patients,
AEs led to treatment discontinuation [eight patients treated
with BAT (seven renal failures and one episode of vomiting),
and C. difficile colitis in two patients treated with ceftazidime/avi-
bactam]. There were no deaths secondary to any AE.
percentage of patients in the BAT group who received treatment
with carbapenems because they had infections caused by OXA-48
isolates with in vitro susceptibility to these drugs. In fact, our re-
sults show how mortality in the BAT group was lower when a car-
bapenem was included in the therapy regimen. Despite the low
mortality of patients in the BAT group, ceftazidime/avibactam
treatment was an independent predictor of survival. Although
other studies have previously described that ceftazidime/
avibactam is associated with lower mortality than BAT in infec-
tions caused by CPE, these studies either compared ceftazidime/
avibactam with a single class of antibiotics such as colistin10 or in-
cluded only a specific population (e.g. critically ill mechanically
ventilated or haematological patients)18,19 or only one type of in-
fection (BSI).17 In our study, the impact of ceftazidime/avibactam
on survival was especially important in the subgroups of patients
with INCREMENT-CPE scores of .7 points and patients with BSI,
suggesting that these groups of patients should probably be man-
aged with ceftazidime/avibactam-containing therapy.
In accordance with previous reports8,9,11,20 in our series,
single-drug treatment with ceftazidime/avibactam was not

Figure 2. Kaplan–Meier survival curves in patients treated with ceftazidime/avibactam (CAZ-AVI; continuous line) or BAT (discontinuous line) for in-
fections caused by CPE. (a) Survival in patients with INCREMENT-CPE score of ≤7 points (log rank 0.73). (b) Survival in patients with INCREMENT-CPE
score of .7 points (log rank 0.004).

1457
Castón et al.
Figure 3. Kaplan–Meier survival curves in patients with infections due to
OXA-48-producing Enterobacterales included in the BAT group (n = 116)
with (n = 62/116, 53.4%) and without (n = 54/116, 46.5%) carbapenem-
containing therapy (log rank 0.04).
associated with higher 30 day crude mortality than when
ceftazidime/avibactam was used in combination. However, in the
subgroup of patients with INCREMENT-CPE score of .7 points our
results show a lower 30 day crude mortality rate in patients mana-
ged with ceftazidime/avibactam monotherapy than patients in the
BAT group treated with combination regimens when the
INCREMENT-CPE score was .7 points. This result has not been pre-
viously reported, probably because the percentage of patients who
received ceftazidime/avibactam in monotherapy in previous studies
was lower than the percentage found in our cohort.10,15
INCREMENT-CPE score of .7 points and SOFA score at onset of
infection were independently associated with higher risk of
30 day crude mortality. INCREMENT-CPE score is a predictive
model of mortality that has previously been associated with
higher mortality in both OXA-48 and KPC infections.9,11,21,22
Ceftazidime/avibactam has been associated with clinical cure in
studies focused on patients with BSI and in critically ill popula-
tions.17,18 In our study, including a greater variety of patients,
ceftazidime/avibactam treatment was also an independent pre-
dictive factor of 21 day clinical cure. The management of these in-
fections with a single-drug regimen was associated with 21 day
Table 3. Multivariate analysis of factors associated with 30 day mortality in the 339 patients with infections caused by CPE
Without propensity score adjustment
Variable OR 95% CI
CAZ-AVI-containing therapy 0.42 0.22–0.80
SOFA score at diagnosis of infection 1.22 1.10–1.35
INCREMENT-CPE score .7 points 2.13 1.01–4.46
CAZ-AVI, ceftazidime/avibactam.
1458
clinical failure, probably due to the higher proportion of patients in-
cluded in the BAT group who were managed with monotherapy.
In our series, the microbiological eradication rate was 78.1%.
Ceftazidime/avibactam treatment was a predictor of microbio-
logical eradication despite combined therapy being more fre-
quent in the BAT group than in patients who received
ceftazidime/avibactam. APACHE II score at diagnosis of infection
and IAI were associated with microbiological failure. It is prob-
able that patients with more severe infections have longer hospi-
talization time and therefore repeat cultures are more likely to be
performed in these patients. On the other hand, IAIs are polymi-
crobial infections with a high inoculum of bacteria where ad-
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equate source control is not always possible, which makes
microbiological eradication difficult.
AEs were significantly more frequent in the BAT group, renal
failure being the predominant toxic effect in these patients. A
high proportion of patients in the BAT group received colistin or
aminoglycosides and it is well known that aminoglycosides and
colistin are associated with renal toxicity.23,24
Our study has several limitations. First, it was an observational
and retrospective study, in which confounding by indication was
a potential issue. For that reason, a propensity score for receiving
ceftazidime/avibactam has been included in the analysis.
Second, the treatments were not randomly assigned and, there-
fore, a different distribution in unmeasured variables cannot be
ruled out. Third, it could be possible that the observed differences
may, in part, be related to underdosing of the drugs included in
the BAT group. Fourth, due to greater experience with these
infections, better management of the patients included in the
ceftazidime/avibactam group could have occurred because the
start of the use of this drug was later than for the drugs included
in the BAT group. By contrast, our study includes the largest
comparative series of patients to evaluate the effectiveness of
ceftazidime/avibactam versus BAT without restrictions by sever-
ity and type of infection or by type of carbapenemase.
In conclusion, the results of this observational, retrospective
study evidenced that ceftazidime/avibactam was associated
with improved survival compared with BAT for the treatment of
infections caused by CPE, especially in the group of patients
with INCREMENT-CPE scores of .7 points. Additionally,
ceftazidime/avibactam treatment was associated with more
clinical improvement and microbiological eradication, as well as
fewer AEs. Nevertheless, because resistances can emerge, cau-
tion in the use of ceftazidime/avibactam with a case-by-case
evaluation must be recommended. All these results should be
confirmed in randomized controlled trials.
Adjusted for the propensity score for therapy
with CAZ-AZI
P value OR 95% CI P value
0.008 0.41 0.20–0.80 0.01
,0.001 1.20 1.08–1.34 0.001
0.04 2.57 1.18–5.58 0.01
Ceftazidime/avibactam and CPE infections
Acknowledgements
We thank Belén Gutiérrez for her support in the statistical analysis.
Funding
This work was supported by Pfizer (grant number WI299308) and the
Fondo Europeo de Desarrollo Regional (FEDER) and Consejería de
Transformación Económica, Industria, Conocimiento y Universidades de
la Junta de Andalucía (programa Operativo FEDER Andalucía 204-2020,
Universidad de Córdoba, Project UCO-1265849, CAVICOR Cohort).
Transparency declarations
J.J.C. has received a research grant and honoraria for educational activ-
ities from Pfizer; J.M.A. has received honoraria for speaking or participat-
ing in advisory boards and/or research grants from the following
pharmaceutical companies: Gilead Sciences, Pfizer, Roche, MSD,
Novartis; V.P. has participated in accredited educational activities spon-
sored by MSD, Pfizer and Shionogi and has received honoraria for advisory
boards from Pfizer, Shionogi and Correvio; V.A.L.M. has received honoraria
for educational activities and advisory boards from Pfizer, Shionogi,
Menarini, MSD and Angelini Pharma; O.S.P. has received honoraria for
educational activities from Pfizer; I.L.A. has been a speaker for Merck
and Pfizer and has received travel support from Gilead, Merck and
Novartis; L.M.M. has been a consultant for MSD and Shionogi, has served
as speaker for Merck, AstraZeneca and Astellas, and has received re-
search support from Shionogi, Janssen-Cilag and Pfizer. J.T.C. has re-
ceived a grant from Pfizer and honoraria for speaking or participating in
advisory boards from Pfizer, MSD, Shionogi, Angelini Pharma and
Menarini. All other authors: none to declare.
Members of the CAVICOR research team
Luis Francisco Caballero Martínez and José María Reguera (Hospital
Regional Universitario de Málaga, IBIMA, Málaga, Spain); Laura Corbella
(Hospital Universitario 12 de Octubre, Instituto de Investigación i+12,
Madrid, Spain); Sara Grillo and Fe Tubau [Bellvitge University Hospital,
Bellvitge Biomedical Research Institute (IDIBELL), University of
Barcelona, Barcelona, Spain]; Alvar Santa Cruz, Laura Cotter, Juan
Álvarez, Diego Gutierrez, Luis Anibal Gómez, Juan de Ancos, Olaya
Alonso, Carlos Andrés Puga, Ayla Yarci and Antonio Manuel Fraile
(Hospital Universitario La Princesa, Madrid, Spain); Antonio Moreno,
Montse Sola, Laura Morata, Marta Bodro, Carol García-Vidal, Ana del Rio
and José Antonio Martínez (Hospital Clínic, Barcelona, Spain); Rosa
Escudero and Desirèe Gijón (Hospital Ramón y Cajal and Instituto
Ramón y Cajal de Investigación Sanitaria, Madrid, Spain); Efrén Sánche,
María Dolores Sousa, Lucía Ramos and Enrique Míguez (Hospital
Universitario de A Coruña, A Coruña, Spain); Fran Arnaiz de las Revillas,
Jorge Calvo, Marta Fernandez Martinez and Claudia Gonzalez Rico
(Hospital Universitario Marqués de Valdecilla, Santander, Spain); Ana
Álvarez Uría-Miyares, Maricela Valerio, Marina Machado, Sofía de la Villa,
Alicia Galar, María Palomo, María Olmedo and Sara Rodríguez (Hospital
General Universitario Gregorio Marañón, Madrid, Spain); Olalla Lima and
María Teresa Pérez-Rodríguez, (Hospital Álvaro Cunqueiro, Vigo, Spain);
Neus Gómez Muñoz (Consorcio Hospital General Universitario de
Valencia, Valencia, Spain); Benito Almirante, María Nieves Larrosa and
Belén Viñado (Hospital Universitari Vall d’Hebron Barcelona, Spain);
Raúl Gilarraz and Silvia Marrero (Hospital Universitario de Gran Canaria
Dr. Negrín, Las Palmas de Gran Canaria, Spain); and María
Córdoba-Fernández (Hospital Universitario Reina Sofía, Córdoba, Spain).
Supplementary data
Tables S1 to S7 are available as Supplementary data at JAC Online.
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