Carbapenem-resistant Enterobacterales (CRE) is an urgent public
health threat of significant global concern that accounted for
more than 1100 deaths per the 2019 CDC report for antibiotic
resistance.1 CRE is associated with higher mortality rate, with
an approximately 2-fold increase in mortality compared with
infections with carbapenem-susceptible Enterobacterales.2
Carbapenemases produced by CRE have been classified into
three different groups according to Ambler classification: class
A [e.g. Klebsiella pneumoniae carbapenemase (KPC)], class B or
MBL (e.g. VIM) and class D [e.g. oxacillinase (OXA-48)].2,3 Local
data that describe the molecular epidemiology of CRE in Saudi
Arabia found that OXA-48 accounted for 71.2% (n = 292) of
410 carbapenemase-producing CRE isolates, followed by NDM
(n = 85; 20.7%) and NDM + OXA-48 (n = 33; 8%).4
 The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/
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Alqahtani et al.
The new β-lactam/β-lactamase inhibitors have gained significant
interest for their favourable outcomes in terms of clinical
efficacy and safety profile.5 Ceftazidime/avibactam is a combination
of a third-generation cephalosporin, ceftazidime, and the
novel, non-β-lactam β-lactamase inhibitor avibactam, which
possesses the ability to treat carbapenemase-producing CRE
(CP-CRE).5 Ceftazidime/avibactam was approved by the FDA in
2015 for complicated urinary tract infections (cUTIs), complicated
intra-abdominal infections (cIAIs) and, in 2018, for the
treatment of hospital-acquired pneumonia (HAP) and ventilator-
associated pneumonia (VAP).6
Few observational studies have evaluated the clinical outcomes
for treatment of CP-CRE harbouring OXA-48 with ceftazidime/avibactam.7,8
Findings of these studies showed lower
30 day mortality with ceftazidime/avibactam ranging between
8.3% and 22%.7,8 Notably, the small sample size of both studies
would affect its generalizability and increase the value in other
studies with larger sample sizes.
Considering the high prevalence of Gram-negative resistant
pathogens, particularly CP-CRE, at our institution,9 the aim of
this study was to evaluate the clinical efficacy of ceftazidime/avibactam
for treatment of CP-CRE harbouring OXA-48 and/or NDM.
Methods
Study design and setting
This was a retrospective, observational, single-centre study conducted at
King Abdulaziz Medical City (KAMC) from January 2018 to November
2020. KAMC is a Joint Commission International (JCI)-accredited
1500-bed tertiary care academic medical centre in Riyadh, Saudi Arabia.
Study population
The inclusion criteria of patients were if they were adults (age ≥18 years)
and had received ceftazidime/avibactam alone or in combination for
≥72 h as treatment of a confirmed infection secondary to CP-CRE with
a detected gene encoding for carbapenemase production. At least one
isolate was collected and isolated from each case for microbiological
analysis. All patients were stratified into two groups: those who had received
ceftazidime/avibactam alone (monotherapy group) and those
who had combination therapy added to ceftazidime/avibactam for treatment
of CP-CRE as per definition (combination therapy group). Patients
with polymicrobial infections and those who did not receive aztreonam
in combination with ceftazidime/avibactam for CP-CRE encoded with
NDM were excluded. The study was approved by the institutional review
board at King Abdullah International Medical Research Center (KAIMRC).
Clinical data were collected from electronic medical records and
de-identified for further review. Relevant information, including demographic
data, baseline comorbidities, Charlson comorbidity index, infection
and treatment-related variables, was recorded.
Microbiological tests
Microbiological tests for bacterial identification and susceptibility testing
were performed in the laboratory department in accordance with
CLSI protocols. Susceptibility tests were conducted by an automated
susceptibility testing system via the VITEK 2 system (bioMérieux,
Marcy-l’Étoile, France). Per local microbiology lab protocol, isolates were subjected
for further work-up when susceptibility tests showed resistance to
ertapenem, meropenem or imipenem/cilastatin, defined as when MICs
are at the resistance cut-off of the susceptibility breakpoints determined
by CLSI protocol (≥1 mg/L for meropenem and imipenem/cilastatin and
2
≥0.5 mg/L for ertapenem). Such isolates would undergo PCR-based testing
to identify the presence of any gene coding for carbapenemase production
and thus classified as CP-CRE. Ceftazidime/avibactam MICs were determined
by Etest (bioMérieux). Broth microdilution was used to determine colistin
MICs. The results were interpreted in accordance with the CLSI clinical
breakpoints (≤2 mg/L interpreted as susceptible or intermediately susceptible,
after recent updates of CLSI in 2020). Carbapenemase gene content
was detected using the GeneXpert Carba-R PCR assays (Cepheid,
Sunnyvale, CA, USA) targeting blaKPC, blaOXA-48-like, blaVIM, blaNDM and blaIMP.
Antimicrobial therapy
Ceftazidime/avibactam is a restricted medication at KAMC for critical care,
haematology/oncology and infectious disease (ID), and it can be dispensed
for 72 h without an ID approval. Therapy with ceftazidime/avibactam
was usually started by the primary treating physician, which was
often followed by an ID consultation. Dosage set was 2.5 g every 8 h to
be infused over 2 h. Other antibiotics that were frequently used as a combination
therapy for CP-CRE were colistin, amikacin, gentamicin, tigecycline
and aztreonam.
Definitions
The infection source was determined based on the CDC/National
Healthcare Safety Network criteria. Treatment regimens were classified
as monotherapy (treatment with ceftazidime/avibactam alone) or combination
therapy, defined as the addition of other IV antimicrobials with
in vitro activity against the clinical isolate or the addition of aztreonam
to ceftazidime/avibactam for isolates with NDM genes detected.
Concomitant treatment with metronidazole (when required for anaerobic
coverage) was not considered as combination therapy. Acute kidney injury
(AKI) was defined as an increase in serum creatinine by 0.3 mg/dL
over 48 h or a reduction in urine output to 0.5 mL/kg/h over 6 h.
Outcomes
Primary outcomes were determined to be clinical cure at completion of
therapy and 30 day mortality rate. For the secondary outcomes, 60 day
mortality and relapse rate within 30 days of completion of ceftazidime/
avibactam therapy for primary infection were determined. Safety outcomes
include development of adverse drug reactions related to
ceftazidime/avibactam. Clinical cure was defined as clinical improvement
with no signs or symptoms of systemic infection (absence of fever,
leucocytosis and elevated inflammatory markers) at the completion of
therapy. Relapse was defined as reinfection with the same organism
within 30 days after completion of ceftazidime/avibactam therapy. s
A total of 233 confirmed infections with CRE were identified between
January 2018 and November 2020. Twenty-two patients
were excluded for not fully meeting the inclusion criteria. A total
of 211 patients received ceftazidime/avibactam for CP-CRE infection
during the study period (Figure 1).
For those who received ceftazidime/avibactam as monotherapy
(n = 119), the average age was 66 years and the majority
of these were male (55.6%). Combination therapy was prescribed
for 92 patients (61% male) with an average age of 56 years. HTN
and DM followed by heart disease were the most frequently seen
comorbidities in monotherapy and combination therapy groups
[(70% versus 48%; P = 0.015); (69% versus 49%; P = 0.031);
(54% versus 48%; P = 0.259)], respectively. There were 61
(51.3%) patients with a Charlson index score of 5 or higher in
the monotherapy group and 36 (39%) in the combination group
(P = 0.08). Infection biochemical markers, including leucocytosis,
elevated procalcitonin, high erythrocyte sedimentation rate and
C-reactive protein, were elevated in both groups with no statistically
significant differences (Table 1).
Compared with the monotherapy group, more patients in the
combination group were in ICUs when cultures were collected
(61% versus 43%; P = 0.025). The number of patients receiving
invasive MV and vasopressors was significantly higher in the combination
group compared with the monotherapy group (55% versus
39%; P = 0.021 and 46% versus 32.8%; P = 0.051, respectively).
The most frequently isolated pathogens from 211 patients
were K. pneumoniae (189/211; 90%), Escherichia coli (9/211,
4.3%) and Enterobacter spp. (9/211; 4.3%). The majority of collected
specimens were from the respiratory tract (sputum, tracheal
aspirate, bronchoalveolar lavage) (31.3%), followed by
urine (27.5%) and blood (25.6%). More than 80% of isolates
(171/211; 81%) carried OXA-48 genes, followed by NDM ±
OXA-48 (40/211; 19%). Ceftazidime/avibactam susceptibility
was done for 76 isolates (44 and 32 in the monotherapy group
and combination groups, respectively); these were all susceptible
and carried the OXA-48 gene. Pneumonia (HAP and VAP) was the
most frequently encountered ID (31.3%) followed by UTIs (26.5%)
and bacteraemia (25.6%) (Figure 2). The appropriateness of ceftazidime/avibactam
dosing was observed in 77.7% of the total cohort;
however, 6% received higher doses since they were
determined to have resolved AKI secondary to sepsis, and 17% received
lower doses than recommended. The median time between
identifying CP-CRE and ceftazidime/avibactam initiation
was 24 h in both groups. The mean duration of ceftazidime/avibactam
therapy was prolonged in combination therapy (17 versus
14 days; P = 0.08). Combination therapy was prescribed for 92 patients,
45% of whom received aztreonam; 27%, colistin; 20%, gentamicin;
and the remaining received tigecycline (17.4%) and
amikacin (11%) (Table 2).