Trends Sci. 2025; 22(8): 9681

Infections caused by Enterobacterales represent a significant global health issue, particularly due to the prevalence of carbapenem-resistant Enterobacterales. Enterobacterales, an ordo of gram-negative bacteria, is associated with several diseases in humans and animals, such as bacteremia, pulmonary infections, and urinary tract infections [1]. Carbapenem-resistant Enterobacterales (CRE) have emerged as a substantial public health concern, causing significant morbidity and mortality in hospital settings [2,3]. A meta-analysis revealed a global prevalence of carbapenem-resistant Enterobacterales (CRE) at 43.06 %, with Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae as the predominant species [4]. A further analysis revealed carbapenem resistance in 31.4 % of Escherichia coli and 25.8 % of Klebsiella pneumoniae isolates [5]. Infections caused by Enterobacterales are prevalent in children, with Escherichia coli representing 47.69 % of cases, followed by Salmonella at 24.62 % and Klebsiella at 15.38 % [6]. Urinary tract infections were the predominant symptoms in both adults and children [5,6].

Infections caused by carbapenem-resistant Enterobacterales (CRE) are linked to markedly elevated death rates in contrast to infections from carbapenem-susceptible Enterobacterales (CSE), attributable to restricted treatment alternatives [7-10]. CRE infections provide a 3.39-fold increased risk of total death compared to CSE infections [9]. Carbapenems are last-resort antibiotics extensively employed to address bacterial infections caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacterales. Consequently, if a bacterial strain exhibits resistance to this antibiotic, it will pose significant challenges [11]. Klebsiella pneumoniae and Escherichia coli are the principal etiological agents of CRE infections, employing resistance mechanisms including enzyme production, efflux pumps, and porin mutations [12,13]. Carbapenemases encompass KPC, MBLs, and OXA-48-like enzymes that disseminate rapidly via plasmids [13].

The fast worldwide proliferation of carbapenemase-producing Enterobacterales needs immediate investigation to identify effective treatments [2,13]. Current therapy comprise polymyxins, tigecycline, fosfomycin, and aminoglycosides [8]. Combination treatment of 2 or more pharmacological agents has demonstrated enhanced efficacy relative to monotherapy [14]. For carbapenem-resistant Enterobacteriaceae (CRE) with carbapenem minimum inhibitory concentrations (MICs) ≤ 8 mg/L, the combination of carbapenems with colistin, high-dose tigecycline, or aminoglycosides may be efficacious [15]. Recently introduced antibiotics, including ceftazidime-avibactam, meropenem-vaborbactam, plazomicin, and eravacycline, provide supplementary alternatives for the treatment of CRE [7,8]. Additional interesting pharmaceuticals under research are imipenem-relebactam and cefiderocol [8]. Strategies to address CRE including repurposing existing antibiotics, combining antibiotic therapies, or are seen as viable approaches in [13]. Treatment techniques must be tailored according to resistance mechanisms, susceptibility profiles, illness severity, and patient characteristics [7,8].

To address the lack of a widely recognized worldwide protocol for the management of carbapenem-resistant Enterobacterales (CRE) infections, considering their considerable global health impact and correlation with elevated morbidity and death rates. This study aims to assess the relative efficacy of monotherapy, dual therapy, and multiple antibiotic regimens as reported in observational studies, offering essential insights into treatment alternatives customized to CRE infection as a consideration in the clinical setting.

Materials and methods

Study methodology

This meta-analysis and systematic review were performed following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The protocol for this review has been registered in PROSPERO under ID Number CRD42024629626. The independent variable consisted of the type of antibiotic therapy (dual-antibiotic or multi-antibiotic therapy compared to single-antibiotic therapy), whereas the dependent variable was the survival rates of patients with CRE infections.

Eligibility criteria

The inclusion criteria were established utilizing the PICOS framework. The criteria for study inclusion are as follows: (1) the population comprises patients with Carbapenem-Resistant Enterobacterales (CRE) infections; (2) the intervention entails dual-antibiotic therapy and multi-antibiotic therapy; (3) comparator groups consist of populations receiving single antibiotic therapy; (4) outcome measures focus on survival rates; (5) the study design is observational studies. The exclusion criteria are: (1) irrelevant outcomes; (2) insufficient data; and (3) irretrievable studies.

Data sources and search strategies

The literature search was conducted on December 14, 2024, utilizing the following databases: PubMed, Cochrane CENTRAL, ScienceDirect, Scopus, and EBSCOhost. Search keywords were developed in line with the MeSH (Medical Subject Headings) browser and integrated using Boolean operators. The keywords used included: (“Enterobacterales” OR “Enterobacteriaceae” OR “Escherichia coli” OR “Proteus mirabilis” OR Enterobacter OR “Serratia marcescens” OR “Citrobacter” OR “Klebsiella”) AND (“ESBL” OR “Beta lactamase” OR “β-lactamase”) AND (“Monotherapy” OR “Mono” OR “Combination”) AND (“Antibiotic”) AND (“Cohort” OR “Case control” OR “Retrospective” OR “Observational”) AND (Survive OR Survival OR Died OR Mortality OR Death). The search details for each database can be seen in Table S1.

Study selection results

Three independent reviewers (MFH, DEP and SAA) will apply the eligibility criteria and select studies for inclusion in the systematic review and meta-analysis. All studies from databases were collected in Rayyan.ai (Rayyan Systems Inc., Doha, Qatar). All collected articles were screened for year, title, and abstract by 3 independent reviewers after duplicates were removed. Each reviewer will independently screen the titles and abstracts of identified records and select potentially relevant studies. Full texts of these potentially relevant studies will then be retrieved and independently assessed for eligibility by both reviewers. The reviewers will be blinded to each other’s decisions during this process. Any disagreements between the reviewers during the study selection process will be resolved through discussion until consensus is reached. If consensus cannot be reached, a fourth reviewer (ES) will be consulted.

Data extraction

The data obtained from the chosen studies comprised the author’s name and publication year, sample size in the intervention group, sample size in the control group, age, treatment regimens, type of infection, type of bacteria, and duration of observation. Survival rate data were extracted for each study.

Study quality and risk of bias

The studies obtained were subsequently evaluated for quality and risk of bias. Fifty-one studies were evaluated utilizing the Newcastle-Ottawa Score (NOS). Bias assessment encompasses 3 primary domains: selection, comparability, and outcome in cohort studies, as well as exposure in case-controlled studies. Each domain comprises multiple criteria, with a maximum score of 9 points representing the highest quality. Selection, scoring up to 4 points, evaluates the representativeness of research groups and the participant selection method. This includes assessing the representativeness of cases or exposed groups, the source of controls, and the validation of exposure through reliable data. Comparability, with a scoring range of up to 2 points, assesses the extent to which the study addresses confounding variables. Points are awarded for the consideration of relevant factors that may impact the study’s findings, facilitating a balanced comparison. The outcome or exposure, which can receive a maximum of 3 points, evaluates the quality of outcome assessment in cohort studies or exposure ascertainment in case-control studies. This includes considerations of follow-up adequacy, consistency in outcome measurement, and bias reduction. Research exhibiting elevated NOS scores, reaching a maximum of 9 points, is deemed to possess a reduced risk of bias and enhanced methodological quality.

Quantitative data synthesis (meta-analysis)

Statistical analysis was conducted using Review Manager 5.4.1. (Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark). We will use a random-effects meta-analysis to combine individual study data, given the likely clinical and methodological diversity among the included studies. This approach assumes that the true effect size varies from study to study and provides a more conservative estimate of the effect size and its confidence interval.

The type of data used is dichotomous and the outcomes will be synthesized using odds ratio (OR) with a 95 % Confidence Interval (CI). If heterogeneity is low, the meta-analysis forest plot will use a fixed effect model. The I² statistic will be calculated to evaluate the degree of heterogeneity, ranging from 0 to 100 %, indicating the extent of heterogeneity from none to high. Typically, an I² value greater than 50 % indicates moderate to high heterogeneity. Meta-regression towards age was conducted using Comprehensive meta-analysis v3.

Results and discussion

Study selection and quality assessment

After the search process in 5 databases, 1,023 articles were collected. A total of 267 duplicate articles, were removed. leaving 756 articles for manual selection based on title and abstract. A total of 532 articles were excluded because they met the exclusion criteria or did not meet the inclusion criteria by reading the title and abstract. This left 224 articles to be accessed but only 84 articles that can only read in full-text for the comprehensive assessment. A total of 28 articles had irrelevant outcome and insufficiency data in 5 articles. The final results were 51 studies, which were included in the quantitative synthesis. The flow of article searches and study selection can be seen in the PRISMA 2020 diagram in Figure 1.

Figure 1 Prisma 2020 diagram.

According to Figure 2, the predominant overall score among studies is 8, with 9 being the second most prevalent score. A limited number of studies indicate scores of 6 and 7. Research with elevated scores (8 - 9) exhibits a decreased risk of bias, as it reflects more robust selection methodologies, enhanced comparability among groups, and more explicit result reporting. Research with lower scores (6 - 7) may exhibit an elevated risk of bias (moderate risk of bias), possibly because to insufficient control of confounding factors or methodological deficiencies. The majority of research in this study exhibits low to moderate bias risk, suggesting that their results are generally trustworthy; nevertheless, certain studies may necessitate more careful interpretation. Thirty-seven inclusion studies demonstrated a low risk of bias, while the remaining studies exhibited a moderate risk of bias. This suggests that the evidence quality in this review is relatively high.

Figure 2 NOS score of risk assessment.

Studies characteristics

A total of 6,545 participants, aged 18 to 76 years, were included from the 51 articles, encompassing patients with CRE infections. The interventions employed consist of single antibiotic therapy, dual-antibiotic therapy, and multi-antibiotic therapy, with observation periods spanning 14 to 30 days. Detailed tables of study characteristics can be seen in Table S2. Research indicates that elderly patients in intensive care units exhibit a diminished immune response, with Gram-negative bacteria identified as the primary agents of bloodstream infections in this population, characterized by elevated antibiotic resistance levels [67]. This statement parallels the findings of the study, which involved predominantly middle-aged to elderly patients (45 - 74 years old) suffering from bloodstream infections. Long-term care facilities frequently act as reservoirs for bacteria that exhibit resistance to multiple drugs, thereby increasing patients’ susceptibility to bacterial infections, including carbapenem-resistant Klebsiella pneumoniae [68]. This finding aligns with the study, which indicated that most patients were ICU patients infected with Klebsiella pneumoniae.

Meta-analysis and meta-regression on patients age

Comparison of monotherapy and combination therapy antibiotic treatments indicates that 3combination therapy is superior regarding the survival rate of patients infected with CRE (Figure 3). The meta-analysis results indicate that combination therapy significantly enhances the survival rate (OR = 0.69, 95 % CI (0.62, 0.78), p < 0.00001, I² = 49 %) in comparison to antibiotic monotherapy. The results are corroborated by a low level of heterogeneity (I² = 49 %), suggesting that the variations among studies are minimal, thereby affirming the reliability and consistency of the meta-analysis finding [69].

In accordance with the results of our meta-analysis, several studies also indicate that combination therapy offers superior treatment benefits compared to monotherapy, as it enhances efficacy and decreases the risk of resistance, resulting in improved mortality outcomes [70,71]. Combination antibiotic therapy provides synergistic effects through the use of multiple drugs with diverse mechanisms of action, enhancing efficacy against resistant bacteria and decreasing the probability of resistance emergence [70,72]. Combination therapy, which employs 2 or more antibiotics targeting distinct mechanisms within bacterial cells, can achieve a synergistic effect, leading to a more comprehensive therapeutic outcome [73,74]. The combined effects lead to bacteria experiencing effective mutations against all agents simultaneously, a mechanism that is infrequently observed in antibiotic monotherapy [70]. Combination therapy enhances the effectiveness of drugs, leading to improved therapeutic success and higher patient recovery rates, which in turn reduces mortality rates [75]. The findings align with Schmid et al. [71], which indicated that combination therapy reduced mortality in infections caused by resistant gram-negative bacteria, especially in bloodstream infections and those involving carbapenemase-producing Enterobacterales.

This study identifies CTN+TGC (Colistin + Tigecycline) as the most prevalent drug combination, with TGC + CBM (Tigecycline + Carbapenem) following closely behind. Numerous studies demonstrate the efficacy of these drug combinations. Zhou et al. [76] demonstrated that the combination of CTN and TGC produced significant effects compared to monotherapy with either drug, effectively reducing the density of carbapenem and colistin-resistant E. coli within 48 h. Cai et al. [77] reported that the combination of CTN and TGC led to a greater reduction in bacterial density and significantly decreased the area under the bactericidal curve compared to colistin alone. The combination of TGC and CBM has been shown to produce superior effects compared to monotherapy. Fergadaki et al. [78] demonstrated that the combination of tigecycline and meropenem displayed superior bactericidal activity relative to monotherapy, particularly against carbapenemase-producing Klebsiella pneumoniae isolates. This combination effectively reduced bacterial load in tissues and enhanced survival rates in experimental infection models. Combination therapy utilizing carbapenems and tigecycline demonstrates greater efficacy than monotherapy in decreasing mortality rates among patients with pneumonia infections [72].

This study identifies colistin and tigecycline as the most prevalent monotherapy regimens. In contrast to the outcomes of combination therapy, monotherapy is frequently linked to reduced clinical and microbiological success rates when compared to combination therapy [79]. Wang et al. [80] demonstrated that monotherapy with Tigecycline resulted in a mortality rate 2.73 times greater than that of tigecycline-based combination therapy for bloodstream infections. A study by Cheng et al. [81] indicated that monotherapy with colistin was associated with a 1.03 times higher mortality risk ratio compared to combination therapy with colistin in infections caused by carbapenem-resistant gram-negative bacteria. Monotherapy is frequently inadequate for treating infections caused by multidrug-resistant (MDR), extensively drug-resistant (XDR), or pan-drug-resistant (PDR) bacteria, as it lacks the necessary broad spectrum to address these infections [72,79].

Figure 3 Forest plot of survival rate monotherapy vs combination therapy.

The meta-analysis assessment on survival rates between dual antibiotic combination therapy and multiple combination therapy (more than 2 antibiotic regimens) revealed no significant difference (Figure 4). Nonetheless, the meta-analysis indicated a positive trend in survival rates for the double combination group relative to the double combination group (OR = 1.17, 95 % CI (0.95, 1.46), p = 0.15, I² = 44 %). The result exhibited a low degree of heterogeneity (I² = 44 %), signifying a high level of confidence in the findings [69].

Figure 4 Forest plot of survival rate dual combination therapy vs multiple combination therapy.

To detect potential publication bias and Outcome Variability, a funnel plot analysis was performed. The first funnel plot in Figure 5(A) compares the survival rates of monotherapy versus combination therapy, while the second funnel plot in Figure 5(B) compares dual combination therapy versus multiple combination therapy. In both plots, the symmetry around the vertical line at OR = 1 suggests no significant publication bias. The concentration of data points at the top of the plots indicates larger sample sizes and more precise estimates. Most data points cluster around the OR = 1 line, indicating no strong evidence favoring 1 therapy over the other in terms of survival rates. Both plots also have a few outliers, which may represent studies with extreme results or potential biases. Overall, the interpretation of both funnel plots is similar, with no significant publication bias and no strong preference for either therapy in terms of survival rates. The main distinction is the specific therapies being compared in each plot.

Figure 5 (A) Funnel plot of survival rate monotherapy vs combination therapy; (B) Funnel plot of survival rate dual combination therapy vs multiple combination therapy.

Dual therapy antibiotics are believed to enhance survival rates more effectively than multiple combinations, as fewer and simpler regimens can mitigate the risk of drug toxicity [82]. This may happen because the medicine combination enhances the synergistic benefits of the healing mechanisms while simultaneously posing the danger of synergistic drug toxicity. Research indicates that the cumulative toxicity of many antibiotics may exceed the toxicity of each antibiotic administered individually [82]. The toxicity of antibiotic combinations varies based on the specific antibiotic, dosage, and usage conditions. [83]. This results in considerable variability in effects among people; hence, whereas dual combination antibiotics demonstrate a higher survival rate, the difference relative to multiple combination treatment is not substantial.

One of the factors that can potentially affect the success of therapy is the age of the patient. Studies examining the correlation between age and infection survival rates in hospitalized patients yield inconsistent findings. Therefore, a meta-regression on age was conducted to determine how significant an effect age has on the outcome of mono vs combination therapy. The results of the meta-regression analysis (Figure 6) showed that age had no significant influence on the effectiveness of combination therapy versus monotherapy in patients infected with Enterobacterales. The regression coefficient for age was −0.0191 with a p-value of 0.0826, which showed a negative trend meaning as age increases, the survival rate decreases but was not statistically significant. Simultaneous tests showed that all coefficients, including age, were not significantly different from zero (p = 0.0826). Although there was variability between studies (I² = 45.92 %), the model explained only a small amount of variability (R² = 0.07), indicating that other factors may play a greater role in influencing the effectiveness of therapy. The regression graph also shows that the relationship between age and log odds ratio tends to be weak and inconsistent.

Figure 6 Meta-regression analysis of the log odds ratio in relation to age.

The dose and ratio of antibiotic combinations significantly determine whether their harmful effects are synergistic or antagonistic [84], therefore the management of drug dosage and adherence to combination antibiotic regimens are critical for controlling drug effects in patients. Administering multiple antibiotic combination therapy (more than 2 antibiotic regimens) is more complex than dual combination therapy, resulting in a higher risk of non-adherence among patients. This elevates the risk of toxicity within the multiple combination group [85], making dual combination therapy safer. In addition, the use of 2 antibiotics is expected to be more cost-effective compared to the use of more than 2 drugs, as it reduces the risk of resistance and increases treatment effectiveness, which can reduce the need for additional care or further treatment [86,87].

Overall, the use of dual combination antibiotics shows the best effect in increasing patient survival rates. However, this study did not compare the effects of antibiotics based on the classification of severity levels and comorbidities, raising concerns about potentially inaccurate comparisons that may not align with the conditions of each patient. This is due to inconsistencies in reporting patient severity at hospital presentation among the inclusion studies. In addition, this study also does not compare the safety rate of both combination types, so further research is needed for a more detailed investigation.

Conclusions

The use of combination antibiotics markedly enhances the survival rate when compared to monotherapy antibiotics. Nonetheless, the use of a dual antibiotic combination yields a superior survival rate in comparison to multiple antibiotics, albeit not to a significant extent. Further studies are recommended to explore the safety and cost-effectiveness of both combination types. Furthermore, it is advisable for subsequent studies to present more comprehensive findings that include classifications of patient severity and comorbidities. Furthermore, conducting a network meta-analysis is essential to provide more precise recommendations regarding which combination therapies exhibit greater potential.

Acknowledgements

The authors thank everyone who contributed to the successful completion of this study. Special thanks are due to Faculty of Medicine, University of Jember, Indonesia for providing the necessary resources and support throughout the research process. We also thank our colleagues and collaborators for their helpful discussions and comments.

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Supplementary Materials

Table S1 Search strategies.

Table S2 Extraction table.