Effectiveness of traditional non-carbapenem β-lactams vs. novel β-lactams for the treatment of carbapenem-resistant Pseudomonas aeruginosa: a retrospective cohort study

doi:10.21203/rs.3.rs-5015025/v1

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Research Article

Effectiveness of traditional non-carbapenem β-lactams vs. novel β-lactams for the treatment of carbapenem-resistant Pseudomonas aeruginosa: a retrospective cohort study

https://doi.org/10.21203/rs.3.rs-5015025/v1

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Background

The World Health Organization (WHO) has identified carbapenem-resistant Pseudomonas aeruginosa (CRPA) as one of the three critical priority pathogens. There is scarce literature evaluating the treatment outcomes in patients with CRPA infections treated with traditional non-carbapenem β-lactam (NCBL) agents. Thus, this study aims to assess the effectiveness of traditional NCBL compared to Noval β-lactam agents (NVL) for treating non-carbapenem β-lactam -susceptible CRPA.

Methods

A single-center retrospective cohort study was conducted between January 2016 and December 2022. The study included adult patients 18 years and older with infection due to CRPA who were treated based on microbiology sensitivity with traditional NCBL or NVL for more than 48 hours. The primary outcome was 30-day mortality.

Results

124 patients were included: 98 (79%) in the NCBL group and 26 (20.9%) in the NVL group. 78 (62.9%) patients were male. The median (interquartile range (IQR)) age of included patients was 64 (45, 77) years. A total of 84 (67.7%) patients were critically ill, with an overall median (IQR) APACHE II score of 18 (13.5, 23). The rates of 30-day mortality in NCBL and NVL groups were 41 (41.8%) and 12 (46.2%), respectively; P = 0.692.

Conclusion

In patients with CRPA infections susceptible to traditional NCBL, there was no statistical significant difference in 30-day mortality among patients who were treated with traditional NCBL compared with NVL. Further studies with larger sample sizes are needed to confirm these findings.

Carbapenem

resistance

Pseudomonas aeruginosa

Cephalosporins

Piperacillin/Tazobactam

Carbapenem resistance Pseudomonas aeruginosa (CRPA) is ranked second highest among the four common Gram-negative species isolated in the United States. (1, 2) In 2019, the Centers for Disease Control and Prevention (CDC) reported that multidrug-resistant P. aeruginosa is a severe threat to the healthcare system. (3) The World Health Organization (WHO) has identified CRPA as one of the three critical priority pathogens.(4) Patients with CRPA infections have a longer stay and increased mortality compared to susceptible P. aeruginosa isolates.(5–8)

Carbapenem resistance (Carb-R)/cephalosporin sensitive (Ceph-S) P. aeruginosa mechanism of resistance was mainly attributed to overexpression of efflux systems and decreased expression of OprD (9). While the epidemiology of carbapenemase-producing CRPA varies based on geographic region, 69% were reported in South and Central America, and 30% were reported in the Middle East, with adjusted mortality higher than that of non-carbapenemase-producing CRPA infections.(10) Thus, many practitioners use novel β-lactams to overcome the carbapenemase-producing CRPA type of resistance.

Although novel β-lactams (NVL) showed better outcomes compared to more traditional regimens such as colistin or aminoglycosides-regimens to treat CRPA, (11, 12) many studies found that overutilization of NVL leads to emergent resistance to these agents. (13–15) Therefore, 2024 IDSA guidelines recommended susceptible traditional beta-lactams for CRPA, although comparative effectiveness studies to guide treatment decisions for infections caused by P. aeruginosa resistant to carbapenems but susceptible to traditional non-carbapenem β-lactams are unavailable. (16) This study aims to assess the effectiveness of traditional non-carbapenem β-lactam (NCBL) compared to NVL agents for treating non-carbapenem β-lactam -susceptible CRPA.

Study design and settings

A retrospective cohort study was conducted at King Faisal Specialist Hospital and Research Center-Jeddah (KFSHRC-J), a tertiary care and teaching hospital with 388 beds. The study was approved by the institutional review board of KFSHRC-J (IRB 2023-81). The study included adult patients 18 years and older with infection due to CRPA between January 2016 and December 2022 and treated based on the susceptibility data with NCBL including ceftazidime, cefepime, or piperacillin/tazobactam or NVL including ceftolozane-tazobactam (C-T) or ceftazidime-avibactam (CAZ/AVI) for more than 48 hours. Patients were followed until discharge or death. Patients were excluded if isolates' sensitivity was intermediate or resistant to all antipseudomonal non-carbapenem β-lactam agents (Fig. 1).

Study outcomes

The primary outcome was 30-day mortality. Secondary outcomes include 30-day infection-related mortality, clinical cure rate, microbiologic eradication, 90–day recurrence, 30-day readmission due to infection, intensive care unit (ICU), and hospital length of stay(LOS). Data collection

The data was collected using the electronic medical records system and entered in REDCap (10.8.0 - © 2021 Vanderbilt University). All patients’ records were assigned unique codes. All patients with documented CRPA sensitivity to one of the non-carbapenem β-lactams were allocated into two groups (NCBL vs NVL) based on their definitive treatment. Variables extracted from the medical record include demographics, comorbidities, indwelling devices, the severity of illness, infection, and infusion type; microbiological data; and clinical outcomes data. Data on empiric, definitive, and concurrent antibiotics were collected (Table e1 supplementary appendix). The antibiotic dosing appropriateness was evaluated based on the patient's renal function status (Table e2, Table e3 supplementary appendix)

Microbiology

Antibiotic susceptibility testing was conducted using the automated systems Vitek 2 system (bioMérieux, Marcy-l'Étoile, France). Microbial susceptibility breakpoints were determined based on the Clinical and Laboratory Standards Institute (CLSI) guidelines. C-T and CAZ/ AVI Minimum Inhibitory Concentration (MIC) of ≤ 4/4 was considered susceptible. While Cefepime and ceftazidime MIC of ≤ 8 and piperacillin-tazobactam MIC of ≤ 16 were considered susceptible. (17)

Definitions

Clinical cure was defined as the resolution of signs and symptoms of infection with the study drug without treatment needing modification due to toxicity or failure. (18) Laboratory and radiologic findings were included in the evaluation of the clinical cure, including resolution of fever, decrease or lack of progression of radiographic abnormalities, improvement or normalization of arterial blood gas, and improvement or return to baseline of the white blood cells, procalcitonin, and C-reactive protein (CRP), when applicable. Infection-related mortality was considered if patients had direct complications of infection or persistent signs of infection, including fever, persistent positive blood cultures, leukocytosis, and elevated CRP at the time of death. (19) Microbiologic eradication was defined as no further growth of the baseline pathogen. In contrast, microbiologic failure was defined as a positive repeat culture of the same causative pathogen at the same infection site. 90-day recurrence of infection was defined as positive cultures of the same species, as the index culture isolates after evidence of at least one negative growth of microorganisms during 90 days of the primary infection episode. Sepsis and septic shock were defined based on sepsis- 3 definition. (20)

Statistical analysis

Data analysis was done using STATA software version 18. Categorical data were reported as frequencies (n) and percentages (%). Continuous data were reported as median and interquartile ranges (IQR). The Mann-Whitney U test and the Chi-square tests were used in univariate analysis. Multivariable analysis was done using a logistic regression model. A p-value less than 0.05 was considered significant.

Among 289 cases screened, 124 patients met the inclusion criteria: 79% in the NCBL group and 20.9% in the NVL group (Fig. 1). 62.9% of included cases were male, and the median (IQR) age was 64 (45, 77) years. 42.7% of patients were admitted to the hospital due to infection; the infection type was mainly hospital-acquired pneumonia (46.8%). The median (IQR) for charlson's comorbidity index (CCI) score was 5 (2, 7), and was similar between groups. 67.7% of patients were admitted to the ICU with an overall mean APACHE II score of 18 (13.5, 23), which was higher in the NCBL group 18 (14, 24) vs. 14 (10, 21) in NVL; P = 0.017. Cefepime was the main definitive antibiotic used in the NCBL group (42.7%), while CAZ/AVI was mainly used in the NVL group (76.9%). The median (IQR) duration of definitive therapy was comparable between groups 8 (5, 11) (Table 1).

Table 1

Baseline Characteristics for Patients with Carbapenem Resistant Pseudomonas aeruginosa
Parameter	Total (n = 124)	NCBL (n = 98)	NVL (n = 26)	P-value
		n (%) OR Median [IQR]
Gender
-Female	46 (37.1)	37 (37.8)	9 (34.6)	0.768
-Male	78 (62.9)	61 (62.2)	17 (65.4)	0.768
Age (years)	64 [45, 77]	64.5 [49, 77]	56 [41, 78]	0.411
BMI (kg/m²)	26.3 [22.4, 30.9]	26.3 [22.5, 31.3]	26.6 [21.5, 29.1]	0.535
Reason for Hospital Admission
-Infections	53 (42.7)	42 (42.9)	11 (42.3)	0.960
-Neurology	18 (14.5)	16 (16.3)	2 (7.7)	0.267
-Cardiology	16 (12.9)	12 (12.2)	4 (15.4)	0.671
-Nephrology	13 (10.5)	10 (10.2)	3 (11.5)	0.843
-Oncology	11 (8.9)	7 (7.1)	4 (15.4)	0.189
-Others	13 (10.5)	11 (11.2)	2 (7.7)	0.601
Carlson Comorbidity Index score	5 [2, 7]	5 [3, 7]	4.5 [2, 7]	0.434
The type of catheter**
-Peripheral line	67 (54.0)	64 (65.3)	3 (11.5)	< 0.001*
-Central venous catheter	72 (58.1)	57 (58.2)	15 (57.7)	0.965
-Foley catheter	15 (12.1)	9 (9.2)	6 (23.1)	0.053
-Arterial Line	1 (0.8)	1 (1.0)	0 (0.0)	NA
-Other	4 (3.2)	1 (1.0)	3 (11.5)	0.007*
ICU admission	84 (67.7)	69 (70.4)	15 (57.7)	0.218
On mechanical ventilation	79 (63.7)	65 (66.3)	14 (51.9)	0.239
Vasopressors during therapy	44 (35.5)	36 (36.7)	8 (29.6)	0.572
APACHE II score**	18 [13.5, 23]	18 [14, 24]	14 [10, 21]	0.017*
Infection type
-Hospital-acquired pneumonia	58 (46.8)	51 (45.9)	12 (44.4)	0.888
-Ventilator-associated pneumonia	39 (31.5)	33 (29.7)	8 (29.6)	0.992
-Urinary tract infection	23 (18.5)	23 (20.7)	4 (14.8)	0.488
-Wound	24 (19.4)	22 (19.8)	6 (22.2)	0.781
-Intraabdominal	3 (2.4)	4 (3.6)	0 (0.0)	0.317
-Other	8 (6.5)	5 (4.5)	3 (11.1)	0.188
Presence of bacteremia	27 (21.8)	18 (18.4)	9 (34.6)	0.074
Renal replacement therapy	38 (30.6)	31 (31.6)	7 (26.9)	0.643
Infusion type
-Intermittent infusion	94 (75.8)	89 (90.8)	5 (19.2)	< 0.001*
-Extended infusion	30 (24.2)	9 (9.2)	21 (80.8)	< 0.001*
Number of Patients treated with the study Drugs > 48 hours
Piperacillin- Tazobactam	23 (18.5)	23 (23.5)	NA
Cefepime	53 (42.7)	53 (54.1)	NA
Ceftazidime	22 (17.7)	22 (22.4)	NA
Ceftolazon- Tazobactam	6 (4.8)	NA	6 (23.1)
Ceftazidime- Avibactam	20 (16.1)	NA	20 (76.9)
Duration of therapy (days)***	8 [5, 11]	9.5 [7, 14]	10 [7, 14]	0.060
APACHE II: Acute Physiology and Chronic Health Evaluation; BMI: Body Mass Index; IQR: Interquartile Range; NCBL: non-carbapenem β-lactam; NVL: Noval β-lactam. Indicates statistical significance (P < 0.05); at the time of the study enrolment; ** for definitive treatment

For outcome analysis, no statistical significant difference was found in 30-day mortality (41.8% vs. 46.2%; P = 0.692), 30-day infection-related mortality (29.6% vs. 38.5%; P = 0.387), or clinical cure rate (47.7% vs. 59.3%; P = 0.283) in the NCBL vs. NVL group, respectively. However, microbiological eradication (33.7% vs. 57.7%; P = 0.025) was higher and 90-day infection recurrence (61.2% vs.38.5%; P = 0.037) was lower in NVL compared to NCBL (Table 2).

Table 2

Outcomes for Patients with Carbapenem Resistant Pseudomonas aeruginosa
Parameter	Total (n = 124)	NCBL (n = 98)	NVL (n = 26)	P-value
	n (%) OR Median [IQR]
Primary outcomes
30- days Mortality	53 (42.7)	41 (41.8)	12 (46.2)	0.692
Secondary outcomes
30- days Mortality related to infection	39 (31.5)	29 (29.6)	10 (38.5)	0.387
Clinical cure by the end of treatment	69 (50.0)	53 (47.7)	16 (59.3)	0.283
Microbiological outcome
-Eradication	48 (38.7)	33 (33.7)	15 (57.7)	0.025*
90-day infection recurrence	70 (56.5)	60 (61.2)	10 (38.5)	0.037*
30-days hospital readmission	29 (23.4)	26 (26.5)	3 (11.5)	0.108
30-days readmission due to infection	13 (10.5)	13 (13.3)	0 (0.0)	0.050
ICU LOS (days)	22.5 [10.5, 48]	21 [10, 47]	30 [14, 73]	0.288
Hospital LOS (days)	78 [32, 137.5]	78.5 [34, 137]	62 [25, 198]	0.652
IQR: Interquartile Range; LOS: length of stay; NCBL: non-carbapenem β-lactam; NVL: Noval β-lactam. *Indicates statistical significance (P < 0.05).

In the univariate analysis, among patients who died vs. those who survived, ICU admission (59.2% vs. 79.3%; P = 0.018), vasopressor use (21.1% vs. 54.7%; P = < 0.001), and APACHE II score (17(12, 21) vs. 20(15, 25); P = 0.02) were mainly contributing factors for the 30-day mortality (Table 3). However, in the multivariable logistic model, only vasopressor use contributed to 30-day mortality, with an odd ratio (95% confidence interval) of 3.6 [1.4, 9.2]; P = 0.006. (Table 4)

Table 3

Univariate Analysis of 30-day all-cause mortality
Parameter	Died (n = 71)	Survived (n = 53)	P-value
	n (%) OR Median [IQR]
NCBL antibiotics use	57 (80.3)	41 (77.4)	0.692
NVL antibiotics use	14 (19.7)	12 (22.6)
Age (years)	62 [43, 77]	64 [49, 77]	0.705
Carlson Comorbidity Index score	5 [2, 6]	6 [3, 7]	0.260
ICU admission	42 (59.2)	42 (79.3)	0.018*
Vasopressors use	15 (21.1)	29 (54.7)	< 0.001*
APACHE II score	17 [12, 21]	20 [15, 25]	0.020*
Infection type
-Hospital-acquired pneumonia	31 (43.7)	27 (50.9)	0.421
-Ventilator-associated pneumonia	19 (26.8)	20 (37.7)	0.193
-Urinary tract infection	17 (23.9)	6 (11.3)	0.074
-Wound	14 (19.7)	10 (18.9)	0.906
-Intraabdominal	2 (2.8)	1 (1.9)	0.739
-Other	4 (5.6)	4 (7.6)	0.668
Duration of definitive therapy (days)	7 [5, 12]	8 [6, 11]	0.460
Infusion type
-Intermittent infusion	56 (78.9)	38 (71.7)	0.356
-Extended infusion	15 (21.1)	15 (28.3)
APACHE II: Acute Physiology and Chronic Health Evaluation; IQR: Interquartile Range; ICU: Intensive care unit; NCBL: non-carbapenem β-lactam; NVL: Noval β-lactam. *Indicates statistical significance (P < 0.05).

Table 4

Multivariable logistic model for factors affecting 30- days all-cause mortality
Parameter	OR [95% CI]	P-value
ICU admission	1.1 [0.4, 3.0]	0.854
Vasopressors use	3.6 [1.4, 9.2]	0.006*
APACHE II score	1.0 [1.0, 1.1]	0.261
APACHE II: Acute Physiology and Chronic Health Evaluation; IQR: Interquartile Range; ICU: Intensive care unit; OR: Odd Ratio; CI: Confidence Interval

In the univariate analysis of factors associated with infection recurrence, the use of NCBL antibiotics (85.7% vs. 70.4%; P = 0.037) and infusion type were the independent risk factors of this outcome (Table 5). While in the subgroup analysis of the outcome of ICU patients, no statistically significant differences were observed in all outcomes (Table e4 supplementary appendix)

Table 5

Univariate Analysis of infection recurrence
Parameter	Infection recurrence (n = 70)	Non-recurrence (n = 54)	P-value
	n (%) OR Median [IQR]
NCBL antibiotic use	60 (85.7)	38 (70.4)	0.037*
NVL antibiotic use	10 (14.3)	16 (29.6)	0.037*
Charlson Comorbidity Index score	6 [3, 7]	5 [2, 7]	0.257
Infection type
-Hospital-acquired pneumonia	36 (51.4)	22 (40.7)	0.237
-Ventilator-associated pneumonia	27 (38.6)	12 (22.2)	0.052
-Urinary tract infection	12 (17.1)	11 (20.4)	0.355
-Wound	12 (17.1)	12 (22.2)	0.478
-Intraabdominal	1 (1.4)	2 (3.7)	0.414
-Other (bacteremia, CAP, sepsis, respiratory, surgical culture shin)	3 (4.3)	5 (9.3)	0.264
Polymicrobial infections	23 (32.9)	21 (38.9)	0.486
Duration of definitive therapy (days)	7 [6, 12]	8.5 [5, 11]	0.850
Infusion type
-Intermittent infusion	58 (82.9)	36 (66.7)	0.037*
-Extended infusion	12 (17.1)	18 (33.3)	0.037*
CAP: Community Acquired Pneumonia; IQR: Interquartile Range; NCBL: non-carbapenem β-lactam; NVL: Noval β-lactam. *Indicates statistical significance (P < 0.05).

This retrospective cohort study showed that treating CRPA infections with traditional NCBL has a comparable outcome to NVL antibiotics.

In our research, around 42% of CRPA patients died within 30 days, with no statistically significant difference in 30-day mortality among patients treated with traditional NCBL versus NVL. The overall mortality rate in our study was higher than the reported CRPA mortality in the literature, around 15–18%. (5, 7, 8)

The severity of illness is the main factor associated with mortality in our cohort; however, many factors reported in the literature are associated with CRPA mortality. A multicenter cohort study that aimed to identify the risk factors related to CRPA bacteremia, mortality found that multiple organ failure and higher Pitt bacteremia scores were mainly attributed to the increased mortality. (21) Another study aimed to identify predictors of outcome in hematological malignancy patients found that the main risk factors contributing to the 28-day mortality were older age, the active stage of hematological diseases, high procalcitonin, septic shock, and neutropenia. (8)

Although our study did not detect differences in mortality among the study groups, microbiological eradication was statistically significantly higher in the NVL group compared to the traditional NCBL group; indeed, microbial eradication was reported to be similar or higher when NVL were used. (22, 23) On the other hand, our study found that 90-day infection recurrence was higher in the NCBL group, with type of infusion as a factor related to the recurrence. Several studies support the use of extended-infusion β-lactam to improve patient outcomes in patients with antibiotic-resistant infections. (24, 25) since most patients treated in the NCBL arm used intermittent infusion, that might explain the higher recurrence rate in this group. Moreover, some researchers hypothesize that the duration of therapy might be associated with the infection recurrence rate in patients with pseudomonal infections. However, our study did not detect the duration of treatment as a factor of infection recurrence. Similarly, a systematic review and meta-analysis that evaluated the outcome of patients with pseudomonal bacteremia using short vs. long-duration therapy found no difference between groups in the rate of infection recurrence. (26) Indeed, the increase in microbiological eradication in the NVL group and the increased recurrence of infection in the NCBL group might affect the prescriber's decision regarding agent selection in treating resistant organisms.

In our study, the overall cure rate for CRPA among patients was 50% and around 59% in patients treated with NVL antibiotics. Our findings were similar to the reported cure rate in literature for MDR/XDR P. aeruginosa infections treated with NVL, which was ranging between 50% and 80%. (27–30) On the other hand, our study reported an infection-related readmission rate of around 29%, mainly among the NCBL group. Our finding was lower than reported in the literature, which was reaching 61% of infection-related readmission among patients with an MDR infection history. (31)

Around 67% of included patients in our study were critically ill, however, the subgroup analysis did not show differences in outcomes between critically ill patients who were treated with traditional NCBL versus NVL antibiotics. Although evidence is limited, 2024 IDSA recommend the newer sensitive β-lactams over traditional NCBL in critically ill patients to account for the emergent of resistance from these agents upon treatment. (16, 32)

This study is the first to assess the effectiveness of traditional sensitive NCBL for CRPA isolates; however, the study has several limitations. The retrospective design of the study might lead to selection bias. The sample size might not be sufficient to test the association between study groups. The study did not investigate the mechanism of CRPA resistance. Microbiological eradication and failure were assessed only in patients with repeated cultures. Data on source control was not collected. Future antimicrobial stewardship studies are needed to design effective interventions to limit the overuse and misuse of antibiotics for resistant isolates.

In patients with CRPA infections, there was no significant difference in 30-day mortality among patients treated with traditional sensitive NCBL compared with NVL. However, infection recurrence rate at 90 days was higher in patients treated with sensitive traditional NCBL. Further studies with larger sample sizes are needed to confirm these findings.

Carb-R

Carbapenem resistance

Ceph-S

Cephalosporin sensitive

CRP

C-reactive protein

CRPA

Carbapenem-resistant Pseudomonas aeruginosa

CDC

Centers for Disease Control and Prevention

CLSI

Clinical and Laboratory Standards Institute

CAZ/AVI

Ceftazidime- avibactam

C-T

Ceftolazone -tazobactam

IDSA

Infectious disses society of America

KFSHRC-J

King Faisal Specialist Hospital and Research Center-Jeddah (KFSHRC-J)

WHO

World Health Organization

NCBL

non-carbapenem β-lactam

NVL

Noval β-lactam agents

MDR

Multidrug resistance

MDRO

Multidrug resistance organisms

XDR

Extensive drug resistance

Frequencies

IQR

Interquartile ranges

P. aeruginosa

Pseudomonas aeruginosa

Ethics approval and consent to participate

IRB approval was obtained from the Office of Research Affairs (ORA) in KFSHRC Jeddah (RAC: #2023-81). The data were kept confidential; no one except the research team had access to the files. Due to the retrospective nature of the study, consent to participate from human participants was waved. This study was implemented following Good Clinical Research Practice (Declaration of Helsinki) and the rules and guidelines of the Ethics Committee in KFSHRC.

Consent for publication

Not applicable

Clinical trial number

Not applicable

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors declare that they have no competing interests

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Authors' contributions

N.A. conceptualized, supervised, and manuscript writing and critically reviewed the manuscript; T.A. critically reviewed the manuscript; H.L. data acquisition and manuscript writing; R.H. data analysis; S.A., M.A., and RA data acquisition. M.M. and A.A. proposal writing. All authors read and approved the final manuscript.

Acknowledgments

The authors wish to thank King Saud University, Riyadh, Saudi Arabia, for supporting this research project (RSP2024R74). We appreciate Dr. Abdullah ALraddadi, an infectious disease fellow at King Faisal Specialist Hospital and Research Center in Jeddah, Saudi Arabia, thoughts on the study results that helped in discussion writing.

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Effectiveness of traditional non-carbapenem β-lactams vs. novel β-lactams for the treatment of carbapenem-resistant Pseudomonas aeruginosa: a retrospective cohort study

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