Monotherapy is associated with a lower risk of mortality in patients infected with carbapenem-resistant Enterobacteriaceae without sepsis

doi:10.21203/rs.3.rs-2713388/v1

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Monotherapy is associated with a lower risk of mortality in patients infected with carbapenem-resistant Enterobacteriaceae without sepsis

https://doi.org/10.21203/rs.3.rs-2713388/v1

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Background: To determine the mortality-related risk factors for carbapenem-resistant Enterobacteriaceae (CRE) infection in hospitalized patients and to compare the clinical efficacy of different antimicrobial regimens, mainly from the perspective of mortality.

Methods: Data were retrospectively collected from a 3,000-bed regional medical center with CRE infections between January 2021 and June 2022. The clinical characteristics, microbiological characteristics, and antimicrobial therapies of the patients with different outcomes were analyzed. Mortality-related risk factors were analyzed by the Cox proportional regression model for multivariate analysis.

Results: 120 patients were included. All patients received definitive therapy, and 65.0% (78/120) received active drug treatment. Among those receiving active drug treatment, 65.4% (51/78) received combination therapy, and 34.6% (27/78) received monotherapy. The all-cause mortality of CRE infection was 20.8% (25/120). Multivariate analysis showed that the length of hospital stay after CRE infection (hazard ratio [HR], 0.868; 95% confidence interval [CI], 0.806-0.936; P = 0.000), Sequential Organ Failure Assessment (SOFA) score (HR = 1.169; 95%CI, 1.066-1.281; P = 0.001), central venous catheter (HR = 3.858; 95%CI, 1.411-10.547; P = 0.009), age (HR = 1.035; 95%CI, 1.002-1.070; P = 0.036), and combination therapy (HR = 3.152; 95%CI, 1.205-8.245; P = 0.019) were independent mortality risk factors after CRE infection. Subgroup analysis of the non-sepsis group among 78 patients who received active drug treatment showed significantly lower mortality in monotherapy than in combination therapy (0% versus 22.2%, P = 0.034). Patients who received carbapenem-containing therapy had significantly higher mortality than those who received carbapenem-sparing therapy (31.3% versus 13.9%, P = 0.022).

Conclusions: Patients with a higher SOFA score, central venous catheter, shorter hospital stay after CRE infection, older age, and combination therapy had poor outcomes. Since patients with non-sepsis have a lower mortality rate from monotherapy, combination antibiotic treatment should not be routinely recommended to treat CRE infections.

Carbapenem resistant Enterobacteriaceae (CRE)

Mortality

Risk Factors

Antimicrobial

The emergence of carbapenem-resistant Enterobacteriaceae (CRE) infection seriously threatens human health [1]. CRE is resistant to any approved carbapenem anti-biotics in China (meropenem, imipenem, ertapenem, panipenem, or biapenem) or is confirmed to produce carbapenemase [2]. The incidence rate and antimicrobial resistance of CRE infection have increased rapidly in recent years. Since the first report of carbapenem-resistant Klebsiella pneumoniae (CRKP) in Zhejiang province in 2007, almost all provinces in China have reported cases of CRE infection [3]. According to data from the China Antimicrobial Surveillance Network (CHINET) in 2021, the resistance rate of Klebsiella pneumoniae to carbapenem increased rapidly from 2.9% in 2005 to 24.4% in 2021 [4]. Antimicrobial resistance is also severe in other countries [1, 5]. Antimicrobial-resistant pathogens cause more than 2.8 million infections and more than 35 000 deaths annually in the United States [1].

Clinical studies have shown significant mortality among patients with CRE infection. In particular, severe bloodstream infections (BSIs) caused by CRE are associated with extremely high mortality, nearly 80% [6, 7]. A recent meta-analysis including 62 studies showed a mortality rate of 54.3% for BSIs associated with CRKP [6]. However, mortality-related risk factors for CRE infection are not fully understood. Currently, the main treatment options for CRE infections are carbapenem, tigecycline, colistin, aminoglycoside, and novel antimicrobials such as regimens based on ceftazidime/avibactam (CAZ-AVI) [1, 5]. Although several studies of antimicrobial regimens affect treatment outcomes in patients with CRE infection [8–10], the optimal antimicrobial regimen, the superiority of combination therapy or monotherapy, and the mode of administration of carbapenems remain controversial [11, 12]. Therefore, our study aimed to investigate mortality risk factors in patients with CRE infections and compare the effects of anti-microbial regimens on mortality and other clinical outcomes.

2.1. Study design and patient selection

We conducted a retrospective case-control study of patients with CRE infections at a 3,000-bed regional medical center, between January 2021 and June 2022. Exclusion criteria were patients who: (1) were ≤ 14 years old, (2) were colonized with CRE, (3) had other pathogen infections, (4) did not have complete medical records, and (5) did not receive ≥ 48 h of definitive therapy. Only the first episode of CRE infection was included in patients who experienced more than one CRE infection. The primary outcome was all-cause mortality. Secondary outcomes were treatment failure, clinical cure, and 7-day microbiological eradication.

2.2. Microbiology

The agar disc diffusion and the Mueller-Hinton broth dilution methods were used to test the antimicrobial susceptibility according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. The CRE isolates were identified and collected in the microbiological laboratories. Resistance to carbapenem was defined as MIC ≥ 2 µg/mL for ertapenem or MIC ≥ 4 µg/mL for meropenem or imipenem, and KB (Kirby-Bauer) ≤ 18 mm for ertapenem or KB ≤ 19 mm for meropenem or imipenem according to the CLSI document (2017 M100S 27th, http://www.clsi.org). In addition, the CAZ-AVI breakpoint was defined according to the CLSI and European Committee on Antibiotic Susceptibility Testing guidelines (EUCAST)(http://www.eucast.org). The breakpoints of tigecycline and colistin were determined according to the U.S. FDA (https://www.fda.gov/home) and EUCAST (http://www.eucast.org), respectively [9].

2.3. Study definitions

All-cause mortality was defined as the death of patients due to various causes during CRE infection. Treatment failure was the worsening or persistence of signs or symptoms and/or relapse of infection at 14 days after antimicrobial treatment. In addition, death, hospice, or treatment discontinuation were also considered treatment failure [13]. Clinical cure was the resolution of signs and symptoms of infection 14 days after antimicrobial treatment [14]. The 7-day microbiological clearance was described as a negative culture for CRE seven days after antimicrobial therapy [14]. CRE colonization was defined as isolation from a non-sterile site (stool, soft tissue, respiratory samples, etc.) with no apparent signs of infection (fever, abnormal imaging, elevated white blood cell count, and elevated inflammatory markers) [15].

Antimicrobial exposure was antibiotic use ≥ 3 d within 30 days before CRE infection [8]. Active drug therapy was treatment with at least one in vitro active antibiotic after CRE infection. Empirical therapy was using antibiotics within 48 h before CRE culture reports were available [16]. The therapy was considered appropriate empirical therapy if the active drug was administered. Definitive therapy was the administration of anti-microbial agents after the availability of the antimicrobial susceptibility test (AST) [8], and it was considered to be appropriate definitive therapy or early appropriate definitive therapy if the active drug was administered within 48 h or five days, respectively [17]. Combination therapy was defined as treatment of an active drug in combination with another antibacterial agent (active or inactive), while monotherapy was defined as treatment with only one active antibiotic. Carbapenem-containing therapy was a treatment that included carbapenems, while carbapenem-sparing therapy was a treatment that did not include carbapenems. CAZ-AVI-based therapy was defined as treatment with CAZ-AVI or in combination with other antibiotics. Polymyxin B-based therapy was defined as treatment with polymyxin B or in combination with other antibiotics except for CAZ-AVI. Tigecycline-based therapy was defined as treatment with tigecycline or in combination with other antibiotics except for CAZ-AVI and polymyxin B [18]. If the antibiotic regimens were changed, the last regimen was included for analysis if the treatment failed. However, the previous regimen was included if there was microbiological eradication or a successful response within 14 days [9].

2. 4. Data Collection

The following medical data and records of included patients were collected: (1) Clinical characteristics: patient demographics, hospital-related factors, clinical severity assessment scores, preexisting medical conditions, invasive procedures, clinical index, and type of infection; (2) microbiological characteristics: type of pathogen, antibiotic resistance; (3) antibacterial regimens; and (4) treatment outcomes: primary outcome and secondary outcomes.

2.5. Statistical analysis

SPSS software (version 26) was used for analysis. The CRE patients were divided into survival and death groups to compare baseline features. Kolmogorov-Smirnov tests were used to assess data normality. Normally distributed variables are given as mean ± standard deviations (SD) and were evaluated by Student’s t-test. Nonnormally distributed continuous variables are presented as interquartile range and were assessed using the Mann-Whitney U test. Categorical variables were analyzed with the chi-square test or Fisher’s exact test. Mortality-related risk factors were evaluated using the Cox proportional regression model and presented by hazard ratios (HRs) and the corresponding 95% confidence intervals (95% CIs). Variables with a P value < 0.1 in univariate analyses were incorporated into a multivariate stepwise forward Cox regression model to establish independent risk factors for all-cause mortality in CRE-infected patients.

3.1. Clinical characteristics

In total, 637 hospitalized patients with CRE infections were screened, and 120 were enrolled in the analysis after applying the inclusion and exclusion criteria (Fig. 1). The patients were divided into death and survival groups. The demographic and clinical characteristics of the study cohort are listed in Table 1. The median age was 61.5 years [interquartile range (IQR), 49.3 to 70.5 years), and 83 patients (69.2%) were men. Of these patients, 85.0% (102/120) had hospital-acquired infections, while 15.0% (18/120) had community-onset healthcare-associated infections. The median Charlson comorbidity index, Acute Physiology and Chronic Health Evaluation (APACHE II) score, and SOFA score were 4.0 (IQR, 2.0 to 7.0), 11.0 (IQR, 5.0 to 16.0), and 2.0 (IQR, 0.3 to 5.0), respectively. The most common type of infection was pneumonia (67.5%, 81/120), followed by bloodstream infection (23.3%, 28/120) (Table 1). Additional variables included preexisting medical conditions, clinical index, CRE pathogen, antibiotic resistance, and the number of patients with an eradicable focus. Details are shown in the supplementary material (Supplementary Table A3). Furthermore, the demographic and clinical characteristics of 28 patients with CRE-BSIs were also analyzed (Supplementary Table A1).

Table 1

Risk factors for all-cause mortality among 120 patients with CRE infections
Variables	Value(s) for the following patients (%):
Variables	Death (n = 25)	Survival (n = 95)	Total (n = 120)	P value
Demographics
Age (yr), median (IQR)	67.0 (58.5–74.0)	58 .0 (48.0–68.0)	61.5 (49.3–70.5)	0.013*
> 65 years old	17 (68.0)	38 (40.0)	55 (45.8)	0.012
Male	18 (72.0)	65 (68.4)	83 (69.2)	0.730
Hospital-related factors
Hospital-acquired infection	23 (92.0)	79 (83.2)	102 (85.0)	0.271
Community-onset healthcare-associated infection	2 (8.0)	16 (16.8)	18 (15.0)	0.271
Length of hospital stay after CRE infection, median (IQR)	6.0 (3.5–12.0)	16.0 (9.0–26.0)	13.0 (7.0-23.8)	0.000*
Admission to ICU	15 (60.0)	47 (49.5)	62 (51.7)	0.349
Length of ICU stay after CRE infection	0.0 (0.0–12.0)	0.0 (0.0–8.0)	13.0 (7.0-23.8)	0.625
Clinical severity assessment scores
Charlson comorbidity index, median (IQR)	6.0 (3.0-8.5)	4.0 (2.0–7.0)	4.0 (2.0–7.0)	0.083
Charlson index ≥ 3	23 (92.0)	65 (68.4)	88 (73.3)	0.018
APACHE II score, median (IQR)	20.0 (14.5–29.0)	9.0 (5.0–14.0)	11.0 (5.0–16.0)	0.000*
APACHE II score ≥ 15	19 (76.0)	21 (22.1)	40 (33.3)	0.000
SOFA score, median (IQR)	7.0 (4.0-12.5)	1.0 (0.0–3.0)	2.0 (0.3-5.0)	0.000*
SOFA score ≥ 2	24 (96.0)	41 (43.2)	65 (54.2)	0.000
Acute comorbidities
Septic shock	9 (36.0)	6 (6.3)	15 (12.5)	0.000*
Sepsis	17 (68.0)	26 (27.4)	43 (35.8)	0.000*
Invasive procedures
Mechanical ventilation	5 (20.0)	21 (22.1)	26 (21.7)	0.820
Central venous catheter	13 (52.0)	18 (18.9)	31 (25.8)	0.001*
Trachea cannula	9 (36.0)	28 (29.5)	37 (30.8)	0.530
Tracheotomy	5 (20.0)	16 (16.8)	21 (17.5)	0.769
Lumbar puncture	8 (32.0)	31 (32.6)	39 (32.5)	0.952
Thoracentesis	3 (12.0)	8 (8.4)	11 (9.2)	0.696
Arterial cannula	1 (4.0)	4 (4.2)	5 (4.2)	1.000
Drainage tube	1 (4.0)	4 (4.2)	5 (4.2)	1.000
Clinical index
WBC (10⁹/L)	13.6 (4.6–18.3)	8.8 (6.6–12.6)	9.3 (6.5–13.8)	0.042*
PCT (ng/ml)	1.0 (0.6-7.0)	0.41 (0.15–1.8)	0.6 (0.2–3.1)	0.004*
ALB (g/L), median (IQR)	28.3 (26.2–33.6)	33.4 (29.3–35.6)	32.7 (28.9–35.4)	0.002*
Type of infection
Bloodstream infection	10 (30.0)	18 (18.9)	28 (23.3)	0.035*
Pneumonia	19 (76.0)	62 (65.2)	81 (67.5)	0.308
Urinary tract infections	2 (8.0)	11 (11.6)	13 (10.8)	1.000
Intraabdominal infections	4 (16.0)	10 (10.5)	14 (11.7)	0.487
Intracranial Infections	1 (4.0)	2 (2.1)	3 (2.5)	0.507
Skin and soft tissue infections	1 (4.0)	11 (11.6)	12 (10.0)	0.456
7-day microbiological clearance	0 (0)	49 (51.6)	49 (40.8)	0.000*
Exposure to antibiotics in prior 30 days	14 (26.0)	56 (58.9)	70 (58.3)	0.790
Piperacillin/tazobactam	4 (16.0)	20 (21.1)	24 (20.0)	0.574
Cephalosporins	7 (28.0)	25 (26.3)	32 (26.7)	0.865
Carbapenems	2 (8.0)	17 (17.9)	19 (15.8)	0.357
Levofloxacin	2 (8.0)	5 (5.3)	7 (5.8)	0.635
Treatment
Empirical antibiotic treatment	20 (80.0)	77 (81.1)	97 (80.8)	0.905
Reasonable empirical antibiotic treatment	5 (20.0)	25 (26.3)	30 (25.0)	0.466
Appropriate definitive therapy (≤ 5 d)	16 (64.0)	47 (49.5)	63 (52.5)	0.196
Early appropriate definitive therapy (≤ 2 d)	10 (40.0)	45 (47.4)	55 (45.8)	0.511
CAZ-AVI-containing therapy	4 (16.0)	17 (17.9)	21 (17.5)	1.000
Polymyxin B-containing therapy	8 (32.0)	17 (17.9)	25 (20.8)	0.122
Tigecycline-containing therapy	6 (24.0)	16 (16.8)	22 (18.3)	0.397
Carbapenem-containing therapy	15 (60.0)	33 (34.7)	48 (40.0)	0.022*
Active drug treatment	19 (76.0)	59 (62.1)	78 (65.0)	0.195
One active drug treatment	17 (68.0)	54 (56.8)	71 (59.2)	0.313
Two or more active drug treatment	2 (8.0)	5 (5.3)	7 (5.8)	0.635
Combination therapy	17 (68.0)	34 (35.8)	51 (42.5)	0.004*
¹ IQR, Inter quartile range; ICU, Intensive Care Unit; APACHE, Acute Physiology and Chronic Health Evaluation; SOFA, Sequential Organ Failure Assessment; WBC, White blood cell count; PCT, Procalcitonin; ALB, Albumin; CAZ-AVI, ceftazidime/avibactam.

3.2. Microbiological characteristics

The predominant CRE was Klebsiella pneumoniae (81.7%, 98/120), followed by Escherichia coli (9.2%, 11/120), Enterobacter cloacae (5.0%, 6/120), Klebsiella oxytoca (1.7%, 2/120), Klebsiella aerogenes (0.8%, 1/120), Proteus mirabilis (0.8%, 1/120), and Morganella morganii (0.8%, 1/120). Morganella morganii and Proteus mirabilis are naturally resistant to imipenem, polymyxin B, and tigecycline. Therefore, these two isolates were excluded from Table 2. For 118 isolates, the resistance rates to the antibiotics tested were as follows: polymyxin B (10.6%, 7/66), tigecycline (3.4%, 6/118), aztreonam (89.8%, 106/118), imipenem (81.4%, 96/118), ertapenem (90.7%, 107/118), meropenem (80.5%, 95/118), levofloxacin (80.5%, 95/118), ciprofloxacin (88.1%, 104/118), amikacin (52.5%, 62/118), and sulfamethoxazole (75.4%, 89/118). The resistance rates to polymyxin B and tigecycline were much lower than those of other antibiotics. And the resistance rate of K. pneumoniae to antibiotics was generally higher than that of Escherichia coli (Table 2).

Table 2

The drug resistance of CRE strains involved in the study
	No. of resistant isolates/no. of tested isolates (%)
Antibiotics	All strains (n = 118¹)	Klebsiella pneumoniae (n = 98)	Escherichia coli (n = 11)	Other Enterobacteriaceae (n = 9)
Polymyxin B²	7/66 (10.6)	7/63 (11.1)	0/2 (0)	0/1 (0)
Tigecycline	4/118 (3.4)	4/98 (4.1)	0/11 (0)	0/9 (0)
Aztreonam	106/118 (89.8)	95/98 (96.9)	5/11 (45.5)	6/9 (66.7)
Imipenem	96/118 (81.4)	87/98 (88.8)	5/11 (45.5)	4/9 (44.4)
Ertapenem	107/118 (90.7)	92/98 (93.9)	7/11 (63.6)	8/9 (88.9)
Meropenem	95/118 (80.5)	86/98 (87.8)	5/11 (45.5)	4/9 (44.4)
Levofloxacin	95/118 (80.5)	88/98 (89.8)	4/11 (36.4)	3/9 (33.3)
Ciprofloxacin	104/118 (88.1)	93/98 (94.9)	7/11 (63.6)	4/9 (44.4)
Amikacin	62/118 (52.5)	60/98 (61.2)	1/11 (9.1)	1/9 (11.1)
Sulfamethoxazole	89/118 (75.4)	77/98 (78.8)	9/11 (81.8)	3/9 (33.3)
¹Morganella morganii and Proteus mirabilis were excluded due to the natural resistance
²The drug resistance of polymyxin B in some patients was not available

3.3. Risk factors of mortality

The all-cause mortality rate of included patients was 20.8% (25/120). Compared to surviving patients, patients who did not survive were older (median age, 67.0 versus 58.0; P = 0. 013). Patients who did not survive exhibited higher APACHE II scores (median scores, 20.0 versus 9.0; P = 0.000), SOFA scores (median scores, 7.0 versus 1.0; P = 0.000), white blood cell count (median, 13.6 versus 8.8; P = 0.042), procalcitonin (median, 75.3 versus 62.7; P = 0.004), and lower albumin (median, 28.3 versus 33.4; P = 0.002). Patients who did not survive also exhibited higher incidences of septic shock (36.0% versus 6.3%; P = 0.000), sepsis (68.0% versus 27.4%; P = 0.000), a central venous catheter (52.0% versus 48.9%; P = 0.000), and bacteremia (30.0% versus 18.9%; P = 0.035). However, the 7-day microbiological clearance was lower in patients who did not survive (0.0% versus 51.6%; P = 0.000). Patients who expired received more carbapenem-containing therapy (60.0% versus 34.7%; P = 0.022) and combination therapy (68.0% versus 35.8%; P = 0.004) relative to survivors (Table 1).

Multivariate Cox regression analysis of 120 patients indicated that the SOFA score (HR = 1.169; 95%CI, 1.066–1.281; P = 0.001), central venous catheter (HR = 3.858; 95%CI, 1.411–10.547; P = 0.009), age (HR = 1.035; 95%CI, 1.002–1.070; P = 0.036), and combination therapy (HR = 3.152; 95%CI, 1.205–8.245; P = 0.019) were positively associated with all-cause mortality. In contrast, the length of hospital stay after CRE infection (HR = 0.868; 95%CI, 0.806–0.936; P = 0.000) was negatively correlated with all-cause mortality (Table 3).

Table 3

Multivariate Cox regression analysis of mortality-related risk factors among 120 patients with CRE infections.
Variables	HR (95% CI)	P value
Length of hospital stay after CRE infection	0.868 (0.806–0.936)	0.000
SOFA score	1.169 (1.066–1.281)	0.001
Central venous catheter	3.858 (1.411–10.547)	0.009
Age	1.035 (1.002–1.070)	0.036
Combination therapy	3.152 (1.205–8.245)	0.019
¹ HR, hazard ratio; CI, confidence interval; SOFA, Sequential Organ Failure Assessment.

Furthermore, multivariate Cox regression analysis of 28 patients with CRE-BSIs showed that the length of hospital stay after CRE infection (HR = 0.860; 95%CI, 0.766–0.966; P = 0.011), the SOFA score (HR = 1.378; 95%CI, 1.124–1.691; P = 0.002), and white blood cell count (HR = 1.026; 95%CI, 0.998–1.056; P = 0.070) were independent mortality factors after CRE-BSIs (Supplementary Table A2).

3.4. Therapeutic characteristics

All patients received definitive antibiotic therapy, 97 received empirical antibiotic therapy, 30 received reasonable empirical antibiotic treatment, and 78 (65.0%) received active drug treatment. A total of 55 patients (45.8%) received early appropriate definitive therapy (≤ 2 d), as defined in Materials and Methods, and 63 (52.5%) received appropriate definitive therapy (≤ 5 d). There were no significant differences between the patients who received reasonable and unreasonable empirical antibiotic treatment (16.7% versus 22.2%, P = 0.466). Similarly, there was no significant difference between the patients who received early appropriate and inappropriate definitive therapy (18.2% versus 23.1%, P = 0.511) (Table Ⅰ). The detailed antimicrobial regimens and clinical outcomes of patients are shown in Table 4.

Table 4

Antimicrobial regimens and clinical outcomes among 120 patients with CRE infections
Antimicrobial regimens	n (%)	All-cause mortality	Treatment failure	Clinical cure	7-day microbiological clearance
Non-active drug treatment	42 (35.0)	6 (14.3)	14 (33.3)	28 (66.7)	16 (38.1)
Carbapenem	14 (11.7)	4 (28.5)	7 (50.0)	7 (50.0)	5 (35.7)
Piperacillin/tazobactam	17 (14.2)	1 (5.9)	4 (23.5)	13 (76.5)	5 (29.4)
Cephalosporin	6	1	2	4	3
Others	5	0	1	4	3
Monotherapy with one active drug	27 (22.5)	2 (7.4)	6 (22.2)	21 (77.8)	15 (55.6)
CAZ-AVI	9 (7.5)	1 (11.1)	3 (33.3)	6 (66.7)	5 (55.6)
Carbapenem	9 (7.5)	1 (11.1)	2 (22.2)	7 (77.8)	4 (44.4)
Piperacillin/tazobactam	3	0	0	3	3
Others	6	0	1	5	3
Combination therapy with only one active drug	44 (36.7)	15 (34.1)	21 (47.7)	23 (52.3)	14 (31.8)
Polymyxin B + non-active drug	16 (13.3)	6 (37.5)	8 (50.0)	8 (50.0)	5 (31.1)
Tigecycline + non-active drug	12 (10.0)	5 (41.7)	5 (41.7)	7 (58.3)	4 (33.3)
CAZ-AVI + non-active drug	8 (6.7)	2 (25.0)	4 (50.0)	4 (50.0)	3 (37.5)
Carbapenem + non-active drug	2	0	1	1	1
Levofloxacin + non-active drug	2	0	0	2	1
Sulfamethoxazole + non-active drug	2	1	1	1	0
Amikacin + non-active drug	2	1	2	0	0
Two or more active drug treatment	7 (5.8)	2 (28.6)	3 (42.9)	4 (57.1)	4 (57.1)
CAZ-AVI + Polymyxin B	2	1	2	0	0
CAZ-AVI + Tigecycline	2	0	0	2	2
Tigecycline + Carbapenem	1	0	0	1	1
Tigecycline + Amikacin	1	0	0	1	1
Tigecycline + Levofloxacin	1	1	1	0	0

The antibiotic regimens were divided into four categories: non-active drug treatment (35.0%, 42/120), monotherapy with one active drug (22.5%, 27/120), combination therapy with one active drug (36.7%, 44/120), and treatment with two or more active drugs (5.8, 7/120). All-cause mortality rates were 14.3%, 7.4%, 34.1%, and 28.6%, respectively. Compared to the other three categories, the monotherapy with one active drug group had the lowest rates of all-cause mortality (7.4%, 2/27) and treatment failure (22.2%, 6/27) but the highest rates of clinical cure (77.8%, 21/27) and 7-day microbiological clearance (55.6%, 15/27). The most common antibiotics given in this group were CAZ-AVI (7.5%, 9/120) and carbapenems (meropenem, imipenem) (7.5%, 9/120). In the combination therapy with only one active drug group, polymyxin B (13.3%, 16/120) and tigecycline (10.0%, 12/120) were the antibiotics most used (Table 4).

3.5. Comparison between monotherapy and combination therapy

All-cause mortality was significantly higher in the monotherapy group than in the combination therapy group (7.4% versus 33.3%, P = 0.011). The clinical characteristics, microbiological characteristics, and clinical outcomes between these two groups were compared. Compared to patients treated with monotherapy, patients treated with combination therapy were associated with substantially higher median APACHE II score (14.0 versus 8.0, P = 0.027) and SOFA score (3.0 versus 1.0, P = 0.017) and higher incidences of tracheotomy (23.5% versus 3.7%, P = 0.028) and bacteremia (39.2% versus 11.1%, P = 0.010). Patients with combination therapy exhibited a significantly higher percentage of K. pneumonia strain (88.2% versus 63.0%, P = 0.009) and higher incidences of resistance to meropenem KB ≤ 6 (92.2% versus 48.1%, P = 0.000) and imipenem MIC ≥ 16 (86.3% versus 44.4%, P = 0.000) (Table 5). Additional variables were analyzed, including preexisting medical conditions, clinical index, and the number of patients with eradicable focus (Supplementary Table A4).

Table 5

Comparison between monotherapy and combination therapy among 78 CRE-infected patients who received an active therapy
Variables	Monotherapy (n = 27)	Combination therapy (n = 51)	P value
Demographics
Age (yr), median (IQR)	57.0 (47.0–69.0)	60.0 (49.0–68.0)	0.883
Male	17 (63.0)	41 (80.4)	0.094
Hospital-related factors
Hospital-acquired infection	24 (88.9)	45 (88.2)	1.000
Length of Hospital stay after CRE infection, median (IQR)	11.0 (6.0–27.0)	17.0 (7.0–25.0)	0.389
Admission to ICU	10 (37.0)	26 (51.0)	0.240
Length of ICU stay after CRE infection	0.0 (0.0–8.0)	0.0 (0.0–10.0)	0.305
Clinical severity assessment scores
Charlson comorbidity index, median (IQR)	4.0 (2.0–7.0)	4.0 (3.0–7.0)	0.992
APACHE II score	8.0 (4.0–15.0)	14.0 (8.0–21.0)	0.027*
SOFA score	1.0 (0.0–4.0)	3.0 (1.0–6.0)	0.017*
Acute comorbidities
Septic shock	4 (14.8)	10 (19.6)	0.760
Sepsis	8 (29.6)	24 (47.1)	0.137
Invasive procedures
Mechanical ventilation	5 (18.5)	13 (25.5)	0.487
Central venous catheter	5 (18.5)	18 (35.3)	0.122
Trachea cannula	9 (33.3)	12 (23.5)	0.353
Tracheotomy	1 (3.7)	12 (23.5)	0.028*
Lumbar puncture	5 (18.5)	20 (39.2)	0.062
Thoracentesis	3 (11.1)	4 (7.8)	0.688
Arterial cannula	0 (0)	4 (7.8)	0.292
Drainage tube	0 (0)	4 (7.8)	0.292
Type of infection
Bacteremia	3 (11.1)	20 (39.2)	0.010*
Pneumonia	15 (55.6)	34 (66.7)	0.334
Urinary tract infections	6 (22.2)	3 (5.8)	0.057
Intraabdominal infections	6 (22.2)	5 (9.8)	0.175
Intracranial Infections	0 (0)	2 (3.9)	0.541
Skin and soft tissue infections	3 (11.1)	3 (5.9)	0.412
CRE pathogen
K. pneumoniae	17 (63.0)	45 (88.2)	0.009*
E. coli	4 (14.8)	4 (7.8)	0.437
E. cloacae	3 (11.1)	1 (1.9)	0.117
Antibiotic resistance
Meropenem KB ≤ 6	13 (48.1)	47 (92.2)	0.000*
Imipenem MIC ≥ 16	12 (44.4)	44 (86.3)	0.000*
Tigecycline resistant	3 (11.1)	0 (0)	0.038
Amikacin resistant	12 (44.4)	26 (51.0)	0.583
Outcome
All-cause mortality	2 (7.4)	17 (33.3)	0.011*
Treatment failure	6 (22.2)	23 (45.1)	0.047*
7-day Microbiological clearance	15 (55.6)	18 (35.3)	0.085
¹ IQR, Inter quartile range; ICU, Intensive Care Unit; APACHE, Acute Physiology and Chronic Health Evaluation; SOFA, Sequential Organ Failure Assessment.

Patients who received active treatment (n = 78) were divided into sepsis and non-sepsis groups. In the non-sepsis group, monotherapy had significantly lower mortality than combination therapy (0% versus 22.2%, P = 0.034). However, no significant differences were observed between the two treatments (25.0% versus 45.8%, P = 0.420). In addition, the tigecycline-based combination group showed substantially higher mortality than other regimens (44.4% versus 5.4%, P = 0.009) (Table 6).

Table 6

The comparison of antimicrobial regimens between sepsis and non-sepsis patients who received an active drug treatment.
Antimicrobial regimens	Sepsis patients				Non-sepsis patients
Antimicrobial regimens	Death (n = 13)	Survival (n = 19)	Total (n = 32)	P value	Death (n = 6)	Survival (n = 40)	Total (n = 46)	P value
Monotherapy	2	6	8	0.420	0	19	19	0.034*
CAZ-AVI	1	3	4	0.629	0	5	5	1.000
Carbapenem	1	2	3	1.000	0	6	6	0.579
Other Monotherapy	0	1	1	1.000	0	8	8	0.571
Combination therapy	11	13	24	0.420	6	21	27	0.034*
CAZ-AVI-based	3	5	8	1.000	0	4	4	1.000
Polymyxin B-based	2	5	7	0.091	1	8	9	1.000
Tigecycline-based	2	4	6	1.000	4	5	9	0.009*
Other combination therapy	1	2	3	1.000	1	4	5	0.520

3.6. Therapies containing CAZ-AVI, polymyxin B, tigecycline, and carbapenem

The clinical outcomes among patients who received CAZ-AVI, polymyxin B, tigecycline, and carbapenem-containing therapies are shown in Figure Ⅱ. CAZ-AVI-containing therapy presented a lower mortality rate and a higher 7-day microbiological clearance. In contrast, polymyxin B and carbapenem-containing therapy showed higher mortality and treatment failure rates and lower rates of 7-day microbiological clearance (Fig. 2).

3.7. The role of carbapenems in the treatment of CRE infections

Patients who received carbapenem-containing therapy had significantly higher mortality than those who received carbapenem-sparing therapy (31.3% versus 13.9%, P = 0.022), as shown in Table 1. Survival analysis also revealed that carbapenem-containing treatment was associated with higher mortality than carbapenem-sparing therapy (P = 0.024) (Fig. 3). The characteristics and clinical outcomes of the patients receiving these two therapies were compared (Table 5), and no significant differences were found between the two groups. Active carbapenem treatment did not lead to a significant difference in mortality (P = 0.352).

The clinical outcomes among the 21 patients who received polymyxin B with carbapenem and tigecycline with carbapenem regimens were compared. The regimen of tigecycline with carbapenem showed lower rates of mortality and treatment failure but a higher rate of 7-day microbiological clearance (Fig. 4)

4.1. Mortality-related risk factors of CRE infections

The rate of all-cause mortality for all types of infection was 20.8% (25/120), and the mortality of BSIs was 35.7% (10/28), which was consistent with previously reported rates of approximately 30–80% [6, 19]. Many factors affect the prognosis of patients with CRE infection, including the severity of the disease, microbial characteristics, antibiotic treatment, and other patient risk factors. Independent risk factors associated with in-creased mortality in our cohort were higher SOFA score, central venous catheter, shorter hospital stay after CRE infection, older age, and combination therapy.

Several scores reflecting the severity of the disease, the APACHE II score [20], the Charlson index [21], the Pitt bacteremia score [22], and the SOFA score [23], were repeatedly reported as independent risk factors for death after CRE infection. The univariate analysis showed that the APACHE II score ≥ 15 (OR = 1.201; 95%CI, 1.115–1.295), the Charlson score ≥ 3 (OR = 1.136; 95%CI, 0.987–1.308), and the SOFA score ≥ 2 (OR = 1.433; 95%CI, 1.241–1.656) significantly increased mortality among patients with CRE infection. The SOFA score is an important indicator of sepsis. When the SOFA score is ≥ 2 with signs of infection, sepsis is considered. Septic shock is standard in critically ill patients and closely relates to patients' prognosis and mortality [24]. Life-support interventions, such as central venous catheters, can cause mucosal damage and increase the incidence of BSIs, as most bacteria enter the bloodstream through the mucosal barrier [25]. Additionally, three studies [26–28] showed that the median hospital stay after CRE infection in the death and survivor groups was (10.5 vs. 46, P < 0.001), (11.3 vs. 52.8, P < 0.001), and (21 vs. 37, P < 0.001), respectively. Similarly, our study showed that survivors had a significantly more extended hospital stay after CRE infection. However, longer hospital stays and device use (e.g., urinary or central venous catheters) predispose to recurrent CRE infection [29]. If available, it is preferable to discharge patients with CRE infection after ensuring adequate treatment.

4.2. Monotherapy and combination therapy

Although the 2021 Infectious Diseases Society of America (IDSA) guidelines do not recommend routinely using combination antibiotic therapy to treat CRE infections [1], some literature has shown that combination therapy is more effective. Seven studies [8, 9, 16, 17, 22, 28, 30] demonstrated significantly lower mortality in combination therapy. In comparison, three studies [10, 31, 32] reported lower mortality in monotherapy when the regimens were not based on CAZ-AVI or the number of patients receiving CAZ-AVI was small. Five studies [8, 33–36] identified no substantial difference between CAZ-AVI monotherapy and combination therapy. Only one study [37] reported significantly lower mortality in CAZ-AVI combination therapy. The multivariate analysis revealed that combination therapy was an independent mortality risk factor for CRE infection (OR = 12.641, P = 0.021). When comparing monotherapy and combination therapy characteristics, patients who received combination therapy were more severely ill (with higher APACHE II and SOFA scores), more resistant to carbapenem, and had more BSIs. Therefore, the lower mortality rate of monotherapy in this study could be due to the mild illness of the patients, the lower resistance to carbapenems of CRE strains, and the easily controllable source of infection. A subgroup analysis of sepsis and non-sepsis patients found that monotherapy had significantly lower mortality in patients without sepsis than in combination therapy. At the same time, monotherapy had substantially lower mortality than combination therapy, while there was no difference in patients with sepsis. Therefore, patients with mild disease and an easily controllable source of infection can be treated with monotherapy, while patients with severe disease can be treated with combination therapy.

4.3. Antimicrobial regimens for CRE infections

In addition to the debate of monotherapy and combination therapy, there are still controversies on how to adjust the doses of carbapenems, the efficacy of "old" antibiotics (polymyxin, tigecycline), and the efficacy and safety of new antibiotics such as CAZ-AVI.

4.3.1 Carbapenems

Due to increasing resistance to CRE, carbapenems are no longer reserved as a last resort therapy for high-risk CRE infections. Still, the issue of carbapenems in treating CRE infections has been widely debated in recent years [11]. Some studies [30, 38, 39] indicated that carbapenem-containing therapy was associated with significantly lower mortality than carbapenem-sparing therapy, while other studies [22, 40] did not show substantial differences. Our study found that carbapenem-containing treatment significantly increased the mortality among patients with CRE infection and did not show superiority compared to CAZ-AVI-containing, tigecycline-containing, and polymyxin B-containing therapies. However, treatment with active carbapenem did not lead to higher mortality. Xiao et al. [9] observed significantly lower mortality rates in patients with meropenem MICs < 8 mg/L than in those with meropenem MICs ≥ 8 mg/L (22.7% versus 48.5%; P < 0.042). Daikos et al. [7] also found that isolates with a meropenem MIC ≤ 4 mg/L were more likely to benefit than those with a meropenem MIC ≥ 4 mg/L in patients with CRE-BSIs. Therefore, carbapenem-containing therapy should be administered to CRE infection caused by isolates with a meropenem MIC of 1–8 mg/L. When the MICs of meropenem are relatively high, high-dose continuous-infusion meropenem optimized using real-time TDM can be considered [41]. Alternatively, two carbapenems and their combination with other active agents can be tried to improve the efficacy and prognosis of patients [39].

4.3.2 Polymyxins and tigecycline

Polymyxins and tigecycline are first-line agents to treat CRE infections. However, these monotherapies are often unsatisfactory, and their efficacy is uncertain even when combined with other antibiotics [42]. The combination of polymyxin and tigecycline showed good in vitro synergistic effects [43], but the clinical impact of synergy has not yet been identified. Unfortunately, in our study, only a few patients received tigecycline combined with polymyxin. The tigecycline-based combination in our study was mainly tigecycline with a carbapenem, which did not show better clinical efficacy in non-sepsis patients compared to other regimens.

4.3.3 CAZ-AVI

CAZ-AVI, as a new antimicrobial combination, was approved in 2015 by the U.S. Food and Drug Administration (FDA) to treat complicated intra-abdominal and urinary tract infections and hospital-acquired pneumonia [44]. Several studies [8, 26, 34, 36, 45, 46] have reported that CAZ-AVI has significantly lower mortality than other antimicrobial agents. The ESCMID guidelines recommend that older antibiotics, including polymyxin and tigecycline, be considered in patients with non-severe infections due to CRE. They suggest new antibiotics such as meropenem/vaborbactam or ceftazidime/avibactam be used in critically ill patients [5]. Although preliminary evidence suggests that CAZ-AVI may be an effective treatment for CRE infection, clinical experience is still limited in China. More post-marketing data from real-world studies and randomized clinical trials are needed to evaluate its efficacy and safety in treating CRE infections.

4.4 Limitations

Our study has some limitations. First, the retrospective study design was prone to selection and recall bias. Second, other mortality risk factors, such as carbapenemase production and meropenem MIC, could not be included due to the lack of data. Third, our laboratory did not detect the resistance of CAZ-AVI, so the resistance rate was not available. Fourth, this was a single-center study with a small sample size, and the number of patients receiving each antibiotic was too small to conduct subgroup com-parisons.

Patients with a higher SOFA score, central venous catheter, shorter hospital stay after CRE infection, older age, and combination therapy had poor outcomes. Patients who received combination therapy were critically ill and had more uncontrollable sources of infection. Since patients with non-sepsis have a lower mortality rate from monotherapy, combination antibiotic treatment should not be routinely recommended to treat CRE infections.

Acknowledgments

None.

Author Contributions

Conceptualization, Q.H. and S.D.; methodology, J.C.; formal analysis, J.C.; investigation, J.C. and S.D.; resources, Q.H. and S.D.; data curation, J.C. and Q.H.; writing-original draft preparation, J.C.; writing-review and editing, Q.H. and P.Z.; supervision, Q.H., S.-D. and P.Z.; funding acquisition, Q.H. and S.D. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by grants from Xiangya Hospital Management Research Fund of Central South University (2019GL08), the Natural Science Foundation of Hunan Province, China (2022JJ30922), and the Program of Natural Science Foundation of Hunan Province, China (2022JJ80045).

Ethics approval and consent to participate

The study was approved by the Medical Ethics Committee of Xiangya Hospital, Central South University (Ethics Approval Number: 202109174). Safety and fairness were fully considered in the trial design of this study. The content and results of the study would not cause harm or risk to the subjects, and there was no conflict of interest. Informed consent was obtained from all subjects involved in the study.

Consent for publication

Not applicable

Competing interests

The authors declare no conflict of interest.

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No competing interests reported.

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Monotherapy is associated with a lower risk of mortality in patients infected with carbapenem-resistant Enterobacteriaceae without sepsis

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Abstract

Figures

1. Introduction

2. Materials And Methods

2.1. Study design and patient selection

2.2. Microbiology

2.3. Study definitions

2. 4. Data Collection

2.5. Statistical analysis

3. Results

3.1. Clinical characteristics

3.2. Microbiological characteristics

3.3. Risk factors of mortality

3.4. Therapeutic characteristics

3.5. Comparison between monotherapy and combination therapy

3.6. Therapies containing CAZ-AVI, polymyxin B, tigecycline, and carbapenem

3.7. The role of carbapenems in the treatment of CRE infections

4. Discussion

4.1. Mortality-related risk factors of CRE infections

4.2. Monotherapy and combination therapy

4.3. Antimicrobial regimens for CRE infections

4.3.1 Carbapenems

4.3.2 Polymyxins and tigecycline

4.3.3 CAZ-AVI

4.4 Limitations

5. Conclusions

Declarations

References

Additional Declarations

Supplementary Files

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