Cost-effectiveness analysis of linezolid versus vancomycin in the treatment of adult hospital-acquired and ventilator-associated methicillin-resistant staphylococcus Aureus Pneumonia (a systematic review)

Abstract

Background

Ventilator-Associated Pneumonia (VAP) is defined as pneumonia that occurs 48 to 72 h following endotracheal intubation and frequently involves pathogens demonstrating significant antibiotic resistance. Methicillin-Resistant Staphylococcus Aureus (MRSA) is the most common pathogen associated with pneumonia. The treatment of MRSA VAP is challenging and is associated with high rates of morbidity, mortality, and overall hospital costs. The selection of an appropriate therapeutic option serves to reduce mortality and overall healthcare expenses. Given the increasing emphasis on monitoring antibiotic consumption and the optimal utilization of limited resources, decision-makers are encouraged to employ economic evaluations to select a cost-effective treatment option and optimize outcomes based on available resources.

Objective

The main objective of this study is to identify and review the economic evaluations conducted regarding the treatment of MRSA VAP patients with linezolid, vancomycin, and teicoplanin, and to summarize the evidence and assess the methodologies employed.

Methods

This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The search strategy was initiated by formulating the PICOS question and based on the designed protocol, data were extracted from PubMed, Web of Science, Scopus, and Google Scholar databases up to June 8, 2025. The retrieved documents were limited to English and Persian languages. To maximize document retrieval, no restrictions were placed on the time frame or document type. Inclusion and exclusion criteria were applied for screening studies, and eligible studies were identified and their reporting quality was assessed with the CHEERS and Philips checklists.

Findings

The search yielded 1378 records, from which ten studies were ultimately utilized. Only three of ten studies were conducted within the MRSA VAP patient population, while the remaining were conducted within the patients with MRSA-related Hospital-Acquired Pneumonia (HAP). All ten included studies compared linezolid and vancomycin; teicoplanin was not discussed in any of the identified studies. Two studies also considered the duration of empirical antibiotic treatment. Nine studies were conducted using the cost-effectiveness method and one study using the cost-utility method. All studies utilized the decision tree analytical model. The majority of the studies have considered a short-term time horizon, and only two studies have utilized a lifetime horizon. All but one study assessed the robustness of their results through sensitivity analyses. The findings indicated that despite the high cost of the linezolid drug, its superior clinical efficacy, higher survival rates, and lower rates of adverse events and mortality make it cost-effective compared to vancomycin.

Conclusion

The results of the reviewed studies suggest that linezolid can be cost-effective compared to vancomycin in the treatment of the studied population. However, given the short-term time horizon and the limited costing perspective adopted by the studies, current clinical and economic realities, and each country’s acceptable threshold for new treatments, we must be cautious in interpreting such findings.

Clinical trial

Not applicable.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12962-026-00781-6.

Introduction

Hospital-Acquired Pneumonia (HAP) is defined as pneumonia that develops 48 h or more after hospital admission and was not incubating at the time of the patient’s admission [1, 2]. Ventilator-Associated Pneumonia (VAP) typically manifests 48 to 72 h following endotracheal intubation [2]. VAP is the most common nosocomial infection in intensive care units (ICUs) worldwide, with an incidence rate of 6–52%, and in certain circumstances, this rate increases to 76% [3]. Mechanical ventilation can increase the risk of pneumonia by 3- to 21-fold [4]. Both are difficult to treat and often involve pathogens with significant antibiotic resistance [5].

Methicillin-Resistant Staphylococcus Aureus (MRSA) is the most common pathogen associated with pneumonia [6] and is also a cause of severe nosocomial pneumonia [7]. The prevalence of MRSA varies across different regions worldwide, reported as 46% in the Western Pacific region, 34% in the United States, 26% in Europe, and 6% in Canada [4]. Severe HAP caused by MRSA leads to high rates of morbidity and mortality [8].

Several factors increase the risk of acquiring MRSA in a hospital setting. These include prior antibiotic use, which can disrupt normal microbial flora and promote resistant strains, as well as the use of invasive devices such as catheters and ventilators that provide a direct pathway for bacteria. Patients with open wounds or skin conditions, a history of MRSA infection or previous colonization, chronic illnesses such as diabetes, renal disease, neoplasm or those undergoing immunosuppressive therapy and patients admitted to the ICU are also at elevated risk. In addition, overcrowding in hospitals and limited adherence to infection control practices can facilitate MRSA transmission among patients and healthcare workers [9, 10].

Globally, 9% to 27% of patients in ICUs who are under mechanical ventilation develop VAP caused by MRSA, a serious infection in intubated patients and is associated with high morbidity and mortality rates. This rate is 77.5% in Asia and Latin America [11]. Respiratory tract infection is the second most common infection in Iranian hospitals (15%) [12]. According to the report of the National Surveillance System for nosocomial Infections in Iran in 2021, the longest length of hospitalization was related to ventilator-associated infections (31.7 days) and the highest percentage of deaths among patients with nosocomial infections was reported to be related to respiratory tract infections (63.28%). Also, in this report, the rate of MRSA was reported to be 49.61% [13].

MRSA VAP is difficult to treat because MRSA strains are often completely resistant to multiple antibiotics and do not respond purely to first-line antibiotics, necessitating the use of last-line antibiotics such as linezolid, vancomycin, teicoplanin, and daptomycin as first-line therapy [14]. The American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines recommend vancomycin or linezolid for MRSA pneumonia. In addition, switching to linezolid is also recommended if patients fail treatment with vancomycin [15].

Vancomycin is a bactericidal glycopeptide that has been recommended for decades by the IDSA guidelines for the treatment of MRSA due to its excellent antibacterial activity [16, 17]. However, its poor penetration into lung tissue and low concentrations at the site of infection can be a major challenge in the treatment of pneumonia [18]. Vancomycin is also associated with adverse effects, such as nephrotoxicity, and leads to increased treatment costs, sometimes to $2500 per patient. Moreover, vancomycin-resistant microorganisms are currently on the rise [19–21].

Linezolid is another treatment option for patients with MRSA-associated pneumonia. Linezolid is a bacteriostatic oxazolidinone that was approved by the US Food and Drug Administration in 2000 for the treatment of gram-positive infections, including those caused by MRSA [17, 22]. Notable features of linezolid include excellent tissue penetration and 100% oral bioavailability [23].

Teicoplanin is also a glycopeptide antibiotic widely used in European countries, mainly considered for treating Gram-positive infections ranging from moderate to severe including MRSA. Multiple studies have demonstrated good therapeutic results for teicoplanin in MRSA VAP treatment [24, 25].

Several meta-analyses [26–29] have compared the efficacy and safety of linezolid with vancomycin and teicoplanin. However, these reports do not lead us to a unified conclusion for choosing a superior treatment option [30].

Successful antimicrobial treatment in bacterial infections has a positive economic impact that reduces the incidence, mortality rates, and overall healthcare costs [31]. Many factors can play a role in selecting the right treatment regimen and cost is an important factor in the discussion regarding alternative antibiotic options [32].

The increasing emphasis on monitoring antibiotic consumption and optimal use of limited resources is forcing decision-makers to use economic evaluations to select cost-effective treatment methods and optimize outcomes with available resources Economic evaluations compare alternative options with respect to the economic benefits versus the health benefits. Pharmacoeconomic analyses and economic models are tools that compare the costs of various technologies used in healthcare against their economic, clinical, and human benefits [4].

In this study, we identified economic evaluation studies that compared linezolid, vancomycin, and teicoplanin drug treatments in patients with MRSA VAP. Our aim in this study was to identify economic evaluations based on modelling, summarize the evidence and evaluate the methods used. The databases we searched were different from those of Wegner et al. and our search continued until June 8, 2025.

Methods

Study design

This review was conducted as a systematic review utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy was developed by considering the PICOS (Population, Intervention, Comparator, Outcome, Study design) question (Table 1).

Table 1.

PICOS question description

Patients/ Population	Adult hospitalized patients with Ventilator-Associated Pneumonia or Hospital-acquired pneumonia caused by Methicillin-Resistant Staphylococcus Aureus
Intervention	Intravenous linezolid treatment
Comparators	Intravenous vancomycin or teicoplanin treatment
Outcome	Quality of life outcomes such as QALY/LYG and Cost per clinical outcomes such as treatment, death, survival, adverse events, …
Study design	Full model-based economic evaluation studies (cost-effectiveness analysis, cost-utility analysis, cost-benefit analysis)

Search strategy

First, the keywords “Ventilator-Associated Methicillin-resistant Staphylococcus Aureus Pneumonia, teicoplanin, vancomycin, linezolid, and Cost-effectiveness analysis” were searched in the Medical Subject Headings (MeSH) and the search strategy was designed using MeSH terms, synonyms, and entry terms, Boolean operators (including AND and OR).

Then based on the designed strategy, the search was executed on June 8, 2025, across the following databases: PubMed, Scopus, Web of Science, and Google Scholar. To maximize document retrieval, no restrictions were imposed regarding the time frame or document type. However, the retrieved documents were limited to English and Persian languages. Systematic review search strategy is available in the Supplementary Material I.

Eligibility criteria and selection of studies

Studies were selected according to the criteria stated below:

Inclusion criteria

Type of studies:

Full model-based economic evaluation studies (cost-effectiveness analysis, cost-utility analysis or cost-benefit analysis) comparing linezolid with vancomycin or teicoplanin in the treatment of hospitalized adult patients with VAP (ventilator-associated pneumonia) or HAP (hospital-acquired pneumonia) caused by methicillin-resistant Staphylococcus aureus.

Exclusion criteria

Studies were excluded if they met the following criteria:

1. Studies that were not published in either Persian or English.

2. Studies for which full text access was unavailable or were limited to abstracts only or editorial interpretations.

3. Studies related to other hospital infections or causative agents or drugs other than linezolid, vancomycin, and teicoplanin.

4. Studies focused on the treatment of pediatric patients due to differences in treatment protocols.

5. Studies concentrating on management outcomes, prevention, or diagnostic methods instead of HAP/VAP treatment.

Study selection and quality assessment

Duplicate records were identified and eliminated using the EndNote software’s Duplicates feature.

Screening of studies according to the specified inclusion and exclusion criteria was performed first based on the title, then based on the abstract, and finally based on the full text. Records that did not meet the eligibility criteria were excluded at each stage.

Throughout all stages of the review, the scientific sources were independently examined by two researchers. Consensus was reached for the inclusion or exclusion of studies. In cases of disagreement, a third researcher was consulted to resolve the discrepancy.

The reporting quality of economic evaluation studies is assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) tool. This checklist consists of seven questions with 28 criteria that assess the reporting quality of each economic evaluation study in terms of title/abstract/introduction/methods/results/discussion/other relevant information [33].

We also used a second tool (Philips checklist) to assess the quality of study reporting. The Philips checklist is a standardized tool for assessing the quality and reliability of health economic evaluation studies, which provides a comprehensive assessment of the methodology, data, and reporting of the study. This checklist helps decision-makers assess the validity of study results. This checklist is designed as a questionnaire that researchers and decision-makers can use to comprehensively review various aspects of a study, including problem definition, method selection, data collection, analysis, reporting, and generalizability of results. Its main purpose is to help identify strengths and weaknesses of studies and ensure the validity of the results to support clinical and policy decisions.

After identifying eligible studies, their reporting quality was assessed by two researchers independently using the CHEERS 2022 and Philips checklists. Any disagreements were resolved through discussion and the authors reached consensus, and in cases of disagreement, a third researcher was used. The completed Cheers and Philips checklists of studies reviewed is available in the Supplementary Materials II & III.

Data extraction

A data extraction form was prepared and implemented in Microsoft Word software. This form was designed to include all the essential parameters required for a comprehensive and systematic review of economic evaluations. The data extraction form encompassed the following items:

Title, Author(s) name(s), Publication year, Journal, Country, Type of economic evaluation, The designed economic model, Intervention and Comparators, Population characteristics, Perspective, Source of effectiveness data, Source of cost data, costing year and the Currency utilized in the study, Time horizon, and the Discount rate applied to both costs and Quality-Adjusted Life Years (QALY), Measure of effect, Acceptable cost-effectiveness threshold, Sensitivity analyses performed, Final study results, Funding source, and Authors’ conflicts of interest.

The data extraction process was performed independently by two researchers. The extracted data were compared and any discrepancies were resolved through discussion and consensus between the two researchers. In instances where disagreements persisted, a third researcher was consulted to achieve resolution.

Results

Study screening process

The initial search conducted across the specified databases led to the retrieval of 1378 records. This total comprised 198 records from PubMed, 140 from Web of Science (WOS), 682 from Scopus, and 358 from Google Scholar.

Following the elimination of 189 duplicate records, 1189 records proceeded to the screening phases. The title review resulted in the exclusion of 383 records, and abstract screening led to the elimination of 771 additional records. From the 35 remaining records, 25 were deemed ineligible during the full-text review. Consequently, 10 eligible economic evaluation studies were ultimately identified for inclusion in this systematic review. A list of the 25 studies that were excluded during the full-text review phase is provided in a supplementary material IV, along with specific reasons for exclusion.

The reasons for exclusion during the final screening stage (full-text review) were detailed as follows:

• Study design (6 cases).

• Interpretation or editorial letters (2 cases).

• Difference in the type of infection or the antibiotic under investigation (7 cases).

• Studies that did not constitute a complete economic evaluation or lacked an economic model (8 cases).

• Studies focused on prevention and diagnosis rather than treatment (2 cases).

The flow diagram (Fig. 1) presents the number of records retrieved, those screened for eligibility, and the counts of excluded and included items.

Fig. 1.

Flow diagram for evidence extraction and quality assessment (PRISMA Flow Diagram)

Characteristics of the reviewed studies

Key details extracted from the ten selected studies are presented in (Table 2 and 3). All included studies were conducted after the year 2000.

Table 2.

Overview of economic evaluation studies

Year	Economic Methodology and Model	Interventions and comparators	Target Population	The Duration of Treatment		Costing Perspective	Time horizon		Outcomes	Serious Adverse Events	Discount Rate	Robustness Assessment (Sensitivity Analysis)
				First-Line Treatment: considered patient treatment only up to the end of the first line of therapy	First and Second-Line Treatment		Short-Term Horizon	Dual Time horizon (Short-Term and Long-Term Horizons)
2005–2009 4 S* [4, 21, 36, 38]	CEA 9 S [4, 20, 21, 35–40]	linezolid versus vancomycin (All Studies)	VAP caused by confirmed MRSA 3 S [4, 38, 40]	only first-line treatment [20]	First-line treatment = 14 days. The second-line treatment = 14 days [39]***	Healthcare Payer Perspective 7 S [20, 21, 34, 35, 37, 39, 40]	A 4-week time horizon 3 S [35, 37, 39] A 30-day time horizon 2 S [20, 40]	A 10-day horizon and a Lifetime horizon (with 9 years of post-treatment survival) [38]	Clinical Cure 7 S [20, 35–40]	“Adverse Event Rate” for each intervention 4 S [20, 34, 39, 40]	3% for both costs and QALYs [34]	Univariate SA 8 S [20, 21, 34–38, 40]
			HAP caused by confirmed MRSA 5 S [20, 21, 35, 37, 39]	13 days (with the empirical treatment) [34]	First-line treatment = 10 days. The second line treatment = 10 days [35] ***		The end of the first-line treatment (11 days) [4]					Scenario Analysis 5 S [35–39]
2014–2016 5 S [20, 34, 35, 37, 39]				11.3 days for linezolid and 10.7 days for vancomycin [21]	First-line treatment = 10 days. The second line treatment = 10 days [37]***	Healthcare System Perspective 3 S [4, 36, 38]	The end of the first-line treatment (11.3 days for linezolid and 10.7 days for vancomycin) [21]	A 60-day horizon and a Lifetime horizon (with 15 years of post-treatment survival) [34]	Survival 3 S [4, 21, 36]	“Adverse Event Rate” cumulatively for each intervention 4 S [20, 35–37]		Probabilistic SA (PSA) 4 S [34, 35, 37, 40]
	CUA [34]		HAP suspected of MRSA with empirical treatment period 2 S [34, 36]	10 days [38]	From the start of the empirical therapy until successful completion of the first or second-line treatment, or failure of the second line of treatment [36]				QALY 2 S [34, 38]			bivariate SA [36]
				11 days [4]			The successful completion of the first or second line, or failure of the second line [36]					multi-factorial (multivariate) SA [21]
2024 [40]				7 days [40] **					LYG 2 S [36, 38]			Threshold SA [34]

* S=Study or Studies

** Although this study mentioned switching to second-line treatment (due to treatment failure or adverse events), this transition was not incorporated into the study model

*** If the treatment failed or adverse events occurred, patients were switched on day 7 of the first-line treatment to the second-line treatment (the alternative antibiotic)

Table 3.

General characteristics of the reviewed economic evaluations

Reference Author/Year	Journal	Country	Population	Comparison	Economic Analysis Model	Decision Analysis Model	Perspective	Time Horizon	Currency/ Cost Year	Discount Rate (Costs)	Discount Rate (QALY)	Funding Source	Conflict of Interest
Buendía et al.[40] 2024	BMC Infectious Diseases	Colombia	A mathematical model of MRSA VAP patients, age 18+ (No real participants)	Linezolid vs. Vancomycin	CEA	Decision Tree	Third Payer in Colombia	30 days	USD, 2022	NR	N/A	Personal Budget	No
Grau et al.[38] 2005	Journal of chemotherapy	Spain	VAP patients in ICU With 4 subgroups (Based on the results of Kollef et al. [41] study)	Linezolid vs. Vancomycin	CEA	Decision Tree	Spain National Health System (SNS)	First: End of treatment (10 days); Second: Life Time (9 years post-treatment survival)	Euro, 2003	NR	NR	NR	Yes
Machado et al.[4] 2005	Brazilian Journal of Infectious Diseases	Brazil	Patients with VAP MRSA in ICU (Based on the results of Kollef et al. [41] study)	Linezolid vs. Vancomycin Brand vs. Vancomycin Generic	CEA	Decision Tree	Health care System (Brazil)	Until end of the treatment/death (Approx. 11 days)	Brazilian Real, 2004	NR	N/A	NR	Yes
Lin et al.[20] 2016	Journal of Microbiology, Immunology and Infection	Taiwan	A simulation of HAP MRSA patients	Linezolid vs. Vancomycin	CEA	Decision Tree	Health care Payer in Taiwan	7–30 days post end of treatment	USD (Currency conversion year NR)	NR	N/A	Pfizer	Yes
Collins et al.[34] 2015	Value in Health	USA	A hypothetical cohort of adult HAP patients (Suspected MRSA)	Linezolid vs. Vancomycin	CUA	Decision Tree	Health Care Payer in the United States	First: Life Time (15 years post-treatment survival); Second: 60 days	USD, 2014	3%	3%	Budget Not Received	No
Tan et al.[39] 2014	Value in Health Regional Issues	China	A hypothetical model of HAP MRSA patients	Linezolid vs. Vancomycin	CEA	Decision Tree	Health Care Payer in China	4 weeks	Chinese Renminbi¥, 2012	NR	N/A	Pfizer	Yes
Patel et al.[35] 2014	Critical Care	USA	A hypothetical simulation of HAP patients with confirmed MRSA, age 18+ (No real participants)	Linezolid vs. Vancomycin	CEA	Decision Tree	Health Care Payer in the United States	4 weeks	USD, 2012	NR	N/A	Pfizer	Yes
Patel et al.[37] 2014	Infection and Drug Resistance	Germany	A hypothetical simulation of HAP patients with confirmed MRSA, age 18+ (No real participants)	Linezolid vs. Vancomycin	CEA	Decision Tree	Health Care Payer in Germany	4 weeks	Euro, 2012	NR	N/A	Pfizer	Yes
De Cock et al.[36] 2009	Infection	Germany	A hypothetical simulation of HAP patients (Suspected/Proven MRSA) (No real participants)	Linezolid vs. Vancomycin	CEA	Decision Tree	German Health Care System	End of treatment (First line or Second line failure/success)	Euro, 2006 & 2007	NR	N/A	Pfizer	Yes
Mullins et al.[21] 2006	Clinical Therapeutics	USA	MRSA HAP patients, age 16+ (Based on the results of Wunderink et al. [42] study)	Linezolid vs. Vancomycin	CEA	Decision Tree	Health Care Payer in the United States	Until end of treatment/death	USD (Currency conversion year NR)	NR	N/A	Pfizer	Yes

NR: Not Reported - N/A: Not Applicable - HAP: Hospital-Acquired Pneumonia - VAP: Ventilator-Associated Pneumonia - MRSA: Methicillin-Resistant Staphylococcus Aureus - CEA: Cost-Effectiveness Analysis – CUA: Cost-Utility Analysis

The United States of America holds the largest number of studies in this field, with three studies [21, 34, 35]. Following the USA, Germany contributed two studies [36, 37], and Spain [38], Brazil [4], China [39], Taiwan [20], and Colombia [40] have each conducted one study. Although teicoplanin was one of the keywords in our search, to the date of our search we did not find any modeling-based economic evaluation studies that considered teicoplanin as a comparator and in all ten final studies, vancomycin and linezolid were compared.

Sensitivity analysis was performed in all studies except for the study by Machado et al. [4]. A summary of the results of the sensitivity analyses is available in the Supplementary Material V.

Reported results in the studies

Quality of study reporting

We assessed the reporting quality of the ten remaining studies from the final screening phase using the Cheers checklist and summarized the results in the Table 4.

Table 4.

Statistical summary of the results of studies reviewed with the CHEERS checklist

Domain	% Yes (range)	Most Common Finding
TITLE (Q1)	100% (10/10)	Clear and informative title (100%)
ABSTRACT (Q2)	100% (10/10)	Structured abstract (100%)
INTRODUCTION (Q3)	100% (10/10)	Clear background and objectives (100%)
METHODS (Q4–Q21)	83.88% (0-100)	Strong reporting in health economic analysis plan, population, location, comparators, perspective, time horizon, selection and measurement and valuation of outcomes and costs, rationale & description of model (100%) Analytics & assumptions of model and characterizing uncertainty (90%) only Machado not reported Engagement approach (50%) only Buendía, Tan, Patel (USA), Patel (Germany), De Cock reported The weakest reporting in distributional effects (40%) only Buendía, Collins, Patel (USA), Patel (Germany) reported and characterizing heterogeneity (30%) only Grau, Collins, Tan reported, but only Collins reported discount rate (10%)
RESULTS (Q22–Q25)	72.5% (0-100)	Strong reporting in study parameters and summary of main results (100%) Effect of uncertainty (90%) only Machado not reported, but effect of engagement never reported (0%)
DISCUSSION (Q26)	100% (10/10)	All studies discussed findings, limitations, and generalizability (100%)
OTHER RELEVANT INFORMATION (Q27–Q28)	90% (9/10)	Source of funding and conflicts of interest (90%) only Machado not reported

Based on the results of the Cheers checklist, all ten studies had complete coverage in determining classical components of economic evaluation: the target population, setting, perspective, comparators, time horizon, outcomes, and costs.

However, major methodological limitations were identified: “the discount rate” which affects the present value of costs and consequences in long-term analyses and is very important has only been applied in one study, and the “characterizing heterogeneity” which helps to understand the different effects of the intervention in subgroups has been reported in only three studies.

The “characterizing distributional effects”, which was mentioned in only four studies, addresses how the cost-benefit of an intervention is distributed across different population groups (e.g., age, gender, socioeconomic groups) and helps policymakers assess the equitable outcomes of the intervention across different population groups. Lack of transparency in this aspect may lead policymakers to choose interventions that exacerbate health inequalities rather than improve them.

The “engagement approach” was used in only half of the studies and the lack of transparency in this approach in the other half of the studies raises the question of whether the interests and concerns of affected individuals were properly considered in the design and implementation of the study.

In the “Results” section, the “effect of engagement”, which none of the studies reported, refers to the impact of stakeholder engagement on the results of an economic evaluation. Reporting this effect shows how the participation of different individuals or groups can influence the understanding of the results, identify influential factors or set priorities. Failure to report this deprives us of understanding how stakeholder engagement affects the validity and applicability of the results.

Therefore, the main issue is not in conducting economic analysis, but in the transparency and completeness of reporting.

Although the use of the CHEERS checklist is appropriate for assessing the quality of reporting, it does not fully assess the methodological robustness of decision analysis models. Using an additional assessment tool, such as the Philips Checklist for decision analysis modeling studies, provides deeper insight into structural assumptions, model validity, and analytical rigor. Therefore, we also assessed the ten remaining studies from the final screening phase using the Philips checklist and summarized the results in the Table 5.

Table 5.

Statistical summary of the results of studies reviewed with the Philips checklist

Domain	% Yes (range)	Most Common Finding
Structure (S1-S18)	0–100%	Clear problem (100%), diagram (100%), but no alternative structures (0%)
Data (D19-D49)	0–100%	Sources listed (100%), but no systematic search (80% No), no utilities (70% N/A)
Consistency (C50-C57)	0–30%	Almost universally missing validation (0–30% Yes)
Additional (C58-C61)	0–100%	Perspective and ICER reported (100%), but productivity costs never addressed (0%)
PSA performed	50%	Collins, Buendia, Patel (Germany), Mullins, Patel (USA) – 5/10
QALYs used	20%	Grau, Collins – 2/10
Discounting applied	10%	Collins only – 1/10
External validation	0	None
Programming verification	0	None

Across all 10 studies, the Philips Checklist revealed consistent strengths in defining the decision problem (100%), providing model diagrams (100%), and reporting ICERs (100%). However, major methodological limitations were identified: no study performed external validation (0%), none described programming verification (0%), and only 40% conducted probabilistic sensitivity analysis. Utilities (QALYs) were used in only 20% of studies, and discounting was applied in just 10%. These findings highlight a need for improved reporting of model validation procedures and uncertainty analysis in economic evaluations of treatment MRSA VAP.

Findings

The final findings of ten studies are summarized in (Table 6). All studies acknowledged the higher per-unit drug cost of linezolid compared to vancomycin. Nevertheless, the consensus was that despite this higher unit price, linezolid resulted in lower overall hospitalization costs, reduced costs stemming from treatment failure, and fewer hospitalization days compared to vancomycin.

Table 6.

Summary of results from the reviewed economic evaluations

Reference	Outcome Criterion	Sensitivity Analysis Performed	Final findings
Buendía et al.[40] 2024 (Colombia)	Clinical Cure Rate	• One-way SA, • Probabilistic SA*	Linezolid is the dominant treatment compared to vancomycin with a $517 lower cost and a 10% incremental benefit. The mean incremental NET BENEFIT of linezolid is US$1048 (1009–1088) CI 95%. The PSB for vancomycin is US $1036, while linezolid reduces the PSB to zero, eliminating any decision-making uncertainty. The baseline results of the study were “robust to changes in all assumptions and parameters.”
Grau et al.[38] 2005 (Spain)	• Clinical Cure Rate • QALY • LYS	• Univariate SA • Scenario Analysis (8 scenarios)	Linezolid is dominant in the treatment of patients with MRSA VAP, with an ICER of less than €30,000 (the Spanish acceptable threshold for new treatments is €30,000). ICER Per life year saved = € 289.51 ICER Per QALY = € 348.85 The additional LYS with LIN = 2.175 The additional QALY with LIN = 1.805 The results were stable under sensitivity analysis.
Machado et al.[4] 2005 (Brazil)	Death or Survival	NR	Despite its higher drug cost, linezolid has a lower overall cost per recovered patient, making it more cost-effective than vancomycin. Invested amount per cured patient: Linezolid (R$ 7,764.72), Brand-name Vancomycin (R$ 13,231.65), Generic Vancomycin (R$ 11,277.59).
Lin et al.[20] 2016 (Taiwan)	Clinical Cure Rate	• One-way SA (5%, 10%, 20% changes)	The hospitalization costs associated with linezolid were lower ($4998 versus $5496) while the total cost of linezolid treatment per patient is $376 more than vancomycin, and the treatment rate with linezolid is also higher than vancomycin (57.6% vs. 46.6%). Incremental Cost Per Cure (ICPC) = $3421 Depending on the willingness to pay for clinical treatment, linezolid can be affordable in Taiwan. Clinical parameters (number of days in intensive care unit and rate of clinical improvement) had the greatest impact on ICPC.
Collins et al.[34] 2015 (USA)	QALY	• Univariate SA • Probabilistic SA* • Threshold Analysis	The model was sensitive to changes in time horizon, mortality and population. Over the lifetime time horizon, in the ITT population and assuming no difference in mortality rates between drugs, linezolid prevails with an ICER Per QALY=$6,089 and ICER Per life saved=$68,615. In the mITT population, linezolid was dominated both ICER Per QALY and ICER Per life saved. At a 60-day time horizon, in the mITT population and assuming the same mortality rate between drugs, vancomycin prevails.
Tan et al.[39] 2014 (China)	Clinical Cure Rate	• Scenario Analysis (8 scenarios)	In four cities in China, linezolid is a cost-effective option compared to brand-name vancomycin with relatively low ICERs (less than ¥20,000 per patient improved). ICER per additional successfully treated patient: Beijing= ¥1,861 Nanjing= ¥163 Xi’an= ¥16,509 Guangzhou= Linezolid Dominated ICERs were stable under sensitivity analyses.
Patel et al.[35] 2014 (USA)	Clinical Cure Rate	• Univariate SA • Probabilistic SA* • Scenario Analysis (3 scenarios)	Linezolid is superior to vancomycin in terms of lower cost ($824) and higher clinical response (2.7%). The results were stable under sensitivity analyses (at a WTP of $0, linezolid has a 64.4% chance of being cost-effective).
Patel et al.[37] 2014 (Germany)	Clinical Cure Rate	• Univariate SA • Probabilistic SA* • Scenario Analysis (3 scenarios)	Linezolid is superior to vancomycin in terms of lower cost (€123) and higher clinical response (2.7%). The results were stable under sensitivity analyses (at a WTP of €0, linezolid has a 53.9% chance of being cost-effective).
De Cock et al.[36] 2009 (Germany)	• Clinical Cure Rate • Survival • LYG	• One-way SA • Two-way SA • Scenario Analysis (2 scenarios)	Linezolid is associated with 8.7% greater clinical improvement (73.6% vs. 64.9%) and 13.2% higher survival than vancomycin (79.3% vs. 66.1%) and 2.3 Additional Life-Years Gained than vancomycin and has a small additional cost (€ 420). Adverse Event Management Cost = Linezolid (€222) vs. Vancomycin (€271). Average total costs per episode of patient treatment = Linezolid (€12,829) vs. Vancomycin (€12,409). LOS = Linezolid (11.2) vs. Vancomycin (10.8). ICER Per Life Gained = € 180 ICER Per Death Avoided = € 3,171 ICER Per Additional Cure = € 4,813 The results were stable under sensitivity analysis.
Mullins et al.[21] 2006 (USA)	Survival	• Univariate SA • Multifactorial SA	Linezolid is cost-neutral compared to vancomycin ($32,636 for Linezolid vs. $32,024 for Vancomycin) but provides a higher clinical response/survival rate (Survival: Linezolid = 80% vs. Vancomycin = 63.5%). Given the cost-neutral finding, Linezolid’s significantly higher clinical response/survival rate made it a cost-effective alternative. ICER per life year saved= $3,600 The results were stable under sensitivity analysis.

* Probabilistic SA with 10,000 Monte Carlo Simulations - NR: Not Reported - SA: Sensitivity Analysis

Buendía et al. [40] calculated the Net Monetary Benefit (NMB). The NMB is defined as the difference between incremental effectiveness in monetary terms and the incremental monetary costs, measured in currency units (such as dollars) [43].

They also calculated the burden of uncertainty and the Payer Specific strategy (PSB). The PSB represents the financial risks imposed on the payer and demonstrates the risk (financial burden) if the payer selects a non-cost-effective option.

Discussion

This systematic review aimed to examine the economic evaluation of linezolid compared to vancomycin and teicoplanin in the treatment of patients suffering from MRSA VAP. In this pursuit, ten studies were identified that performed economic modeling comparing linezolid and vancomycin but only three studies [4, 38, 40] were found that exclusively examined this specific patient population. Consequently, we were obliged to include studies that analyzed patients with HAP caused by MRSA to ensure there was sufficient evidence to review.

It is worth noting that the study by Grau et al. [38] covered four subgroups of VAP patients (All patients with VAP, Patients with VAP with a gram-positive agent, Patients with VAP with gram-positive Staphylococcus aureus, the MRSA VAP population). Furthermore, Collins et al. [34] selected the Intent-to-Treat (ITT) population for the base-case analysis but reported the results from the modified Intent-to-Treat (mITT) populations in their probabilistic sensitivity analysis.

Despite the known efficacy and safety of the antibiotic teicoplanin in treating MRSA VAP/HAP, confirmed by existing Randomized Clinical Trials (RCTs) [11, 44, 45], our systematic search of the scientific literature did not identify any modelling-based economic evaluation studies that considered teicoplanin as a comparator.

Late initiation of antibiotic therapy is often cited as a major risk factor for excess mortality. Infections caused by multidrug-resistant organisms highlight the need to avoid delaying antibiotic administration and to select the appropriate antibiotic. However, validation studies of American guidelines suggest that empirical antibiotic treatment based purely on risk factors may lead to the overutilization of broad-spectrum antibiotics [46].

In most cases, specialists decide to start antibiotic treatment based on clinical signs and symptoms consistent with VAP. However, before starting treatment, they request tests such as culture of the patient’s tracheal secretions to check for the type of infection and microorganism, white blood cell count (WBC), examination of blood inflammatory factors, and Chest X Ray (CXRay). However, in our review, only two of the ten studies [34, 36] considered the duration of empirical treatment; other studies did not incorporate this period into the economic model or if the experimental treatment period was included in the decision tree model, it was not considered in the calculation of costs and outcomes.

The selection of a modeling technique depends on various factors, such as who the decision maker is and what the purpose of the analysis is, how a decision maker assesses health outcomes, money, risks, and available resources. Decision trees and Markov models are the most common analytical approaches in economic evaluations [47]. Model complexity depends on the outcomes occurring over long time periods, the extent of patient transitions between health states, and the interaction of various elements within the model [48].

The Decision Tree model was the analytical model utilized across all studies in our review. This model is frequently employed in pharmaco-economic studies. These models are not very complex and are usually used for diseases that are not chronic and do not switch between health states much. In this model, the decision node relates to the number of interventions or strategies, and the chance nodes refer to uncertain events that have probabilistic values and quantities [49].

The simplest decision tree structure, done by Machado et al. [4], consists of a decision node (Linezolid vs. Vancomycin) and a chance node for each intervention (clinical cure or death). To incorporate complexity, six studies [20, 35–37, 39, 40] included adverse events in their models, and of these, four studies [35–37, 39] further incorporated a switch to second-line therapy due to treatment failure or adverse event occurrence.

The costing perspective is concerned with the breadth of types of costs considered, ranging from a narrow focus (e.g., direct costs) to the broadest perspective (e.g., societal or human capital costs) [49]. When a limited perspective is adopted, resulting costs may not fully reflect the actual financial burden imposed by the intervention, potentially can affect the correct decision-making process regarding the cost-effectiveness of interventions [50].

All included economic evaluations adopted a limited costing perspective (Healthcare Payer or System) and calculated only direct medical costs. Since cost is a significant factor in selecting therapeutic alternatives, this narrow scope means that the real and long-term costs associated with the interventions were not fully captured. Adopting a broader perspective could potentially alter the study outcomes and subsequent decisions regarding cost-effectiveness.

Similarly, the time horizon is a pivotal methodological determinant. Only two out of the ten studies [34, 38] adopted a lifetime horizon. Employing a short time horizon may significantly underestimate the true long-term benefits of successful treatments. For instance, if the outcome measure is QALY, the value of saving a life will be much greater if the time horizon is considered to be “the patient’s lifetime” rather than just “until the disease improves” [50].

This reality was demonstrated in the results of Collins et al. [34]. When the lifetime horizon was utilized, the incremental cost per QALY gained with linezolid was $6,089, and the incremental cost per life saved was $68,615. However, using the 60-day time horizon, the incremental cost per QALY gained soared to $19,608,688, and the incremental cost per life saved reached $443,662. Such a drastic difference in calculated costs can change the decision about affordability and necessitates caution when interpreting results based on short time frames.

Collins et al. [34] estimated the life expectancy for these patients using published severe sepsis reports [34, 51]. Reports have shown that the life expectancy of patients who develop severe sepsis is reduced compared to baseline [34, 52]. Assuming the average patient age in their model was 61, they projected that survivor of HAP would live for an additional 15 years. To calculate QALYs, they utilized quality of life data for survivors of acute respiratory failure requiring mechanical ventilation, estimating that each additional year of survival would generate a QALY of 0.92 [34].

Grau et al. [38] also adopted a lifetime time horizon and assumed survival after VAP to be 9 years and referencing Hamel et al. [53] that quality of life for survivors of acute respiratory failure decreases by 8% (0.92). Considering a lifetime time horizon, they found linezolid is dominant in the treatment of patients with MRSA VAP.

The other eight studies adopted a short-term time horizon. This narrow scope fails to capture the full economic burden of the disease and the long-term economic benefits associated with successful treatment, potentially leading to an underestimation of the true cost-effectiveness of interventions.

Also, in the economic modeling of the reviewed studies, clinical data and effectiveness of interventions, including clinical improvement rates and mortality and adverse events, were mainly adapted from the RCTs conducted in different countries and in distinct healthcare systems. This presents a significant challenge to the external validity of the findings, as treatment and care utilization patterns, as well as cost estimations, vary substantially across different countries and even between cities within the same country.

Furthermore, most of these economic modeling studies did not include actual participating patients and most used a hypothetical patient model based on clinical trials, which could affect the results of the studies. Although the robustness of the study outcomes is evaluated through sensitivity analyses, these contextual factors can influence the generalizability of the results when applied to different national decision-making settings.

It should be noted that most of the economic evaluations reviewed were conducted mainly between 2005 and 2016, which creates limitations in the application of clinical and economic findings to the present time. Since that period, vancomycin administration has increasingly shifted from trough-based monitoring toward AUC-guided dosing, a strategy associated with improved pharmacokinetic target achievement and recommended to improve therapeutic precision and reduce vancomycin-induced nephrotoxicity. Economic results from previous studies may underestimate the efficacy and safety of vancomycin. The incremental cost-effectiveness of linezolid over vancomycin could be affected by dose adjustment patterns based on AUC-guided dosing.

Also, the epidemiology and resistance patterns of MRSA are dynamic and context-dependent, changing over time and under different conditions, influenced by changes in dominant clones, local antimicrobial stewardship interventions, and healthcare-associated transmission. Such changes may affect response rates, adverse events, length of stay, and overall resource utilization. Therefore, the generalizability of clinical and economic findings from previous studies to the present day should be interpreted with caution, especially in institutions where the microbiological landscape differs from the original study populations.

In addition, the wider acceptance and availability of generic linezolid than brand-name linezolid has reduced its cost compared to the period in which these studies were conducted. Because drug price is a major determinant of cost-effectiveness, the results of previous studies may no longer reflect today’s conditions. Accordingly, our findings should be interpreted as evidence-based findings for the periods studied and not necessarily as definitive conclusions on current cost-effectiveness.

Most importantly, interpretation of the current findings requires critical consideration of “potential publication bias” arising from “financial conflicts of interest.” Evidence suggests that in the field of economic evaluations, studies that report unfavorable or uneconomical outcomes are less likely to be published, a phenomenon that can affect estimates of the true cost-effectiveness of an intervention.

As a significant portion of the evidence in this review was funded by Pfizer, the manufacturer of linezolid, there is a potential for structural conflicts of interest that could influence the direction of study design and the interpretation of modeling parameters and reporting of results, and could act as a potential source of bias.

Given the presence of “potential publication bias” and “financial conflicts of interest” in the evidence from this review, it is not unexpected to doubt the generalizability of the current findings. Therefore, this analysis emphasizes the need to adopt a critical approach to this evidence and interpret its results cautiously, and emphasizes the need to conduct independent studies to resolve existing uncertainties regarding the cost-effectiveness of linezolid. It is also recommended that policy-making based on these results should be conducted with greater scientific caution regarding the possibility of overestimation of the clinical and economic benefits of this drug.

Our study has limitations

1. Search Scope: Our literature search was restricted to four major databases: PubMed, Web of Science, Scopus, and Google Scholar. However, the databases we reviewed are very extensive and we can largely claim that we have included all studies related to our topic.

2. Language Restriction: The search strategy was limited to documents published only in English and Persian languages. However, it is important to note, that to maximize document retrieval, no restrictions were placed on the time frame or document type.

Despite these limitations, the reporting quality of all identified studies was systematically assessed using the CHEERS and Philips checklists.

Conclusion

Cost remains a paramount factor in the selection of comparable treatments. The risk of choosing non-cost-effective treatments imposes a significant fiscal burden on the health system. Therefore, the results derived from economic evaluations are crucial for selecting cost-effective therapeutic options and promoting the optimal consumption of limited resources.

On the other hand, the increasing emphasis on monitoring antibiotic usage to combat antibiotic resistance and optimal use of limited resources, necessitates the application of these findings, especially for healthcare planning, updating clinical guidelines, reforming treatment patterns, and determining the inclusion of new antibiotics in insurance coverage, particularly in developing countries.

Of the ten studies we reviewed, the results of three studies [35, 37, 40] suggested the absolute dominance of linezolid compared to vancomycin, demonstrating lower cost and higher efficacy.

Six studies [4, 20, 21, 36, 38, 39] concluded that despite the high unit cost of the linezolid drug, its superior clinical efficacy and higher survival rates, coupled with a lower rate of adverse events and reduced mortality, render it a cost-effective option compared to vancomycin.

Conversely, one study [34] indicated that vancomycin demonstrated superiority over linezolid in patients with confirmed MRSA Hospital-Acquired Pneumonia.

All studies reviewed used approximately similar models and obtained approximately similar results, indicating the overall superiority of linezolid over vancomycin, but given the limitations of the studies in terms of short-term time horizon and limited cost perspective, changing MRSA resistance patterns and new vancomycin dosing regimens (AUC-guided vancomycin dosing), we should be cautious in interpreting such findings and since economic evaluations are conducted in different countries with different economic conditions, the applicability of these findings depends on the economic conditions and payment thresholds of each country, and the results of a limited number of studies cannot be used for all health systems in different countries.

This lack of generalizability highlights the need for health policymakers in each country to define preferences and estimate the willingness-to-pay (WTP) threshold for new treatments in different diseases, as well as to conduct studies based on current clinical and economic realities, which deserves to be addressed in future studies. Determining these preferences can be a good guide for health system decision-makers regarding the use of economic evaluation results.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

E. M. wrote the main manuscript text and prepared figures and tables. All authors reviewed the manuscript.

Funding

No financing.

Data availability

The datasets that support the results of this article are available in the supplementary materials: Systematic review search strategy is available in the Supplementary Material I. The completed Cheers checklist of studies reviewed is available in the Supplementary Material II. The completed Philips checklist of studies reviewed is available in the Supplementary Material III. A list of 25 studies that were excluded during the full-text review phase, along with specific reasons for exclusion is available in the Supplementary Material IV. A summary of the results of the sensitivity analyses is available in the Supplementary Material V.

Declarations

Ethical approval

Since this study did not involve human participants and the selected sources are publicly available, ethical approval was not required.

Competing interests

The authors declare no competing interests.