Introduction

The first carbapenemase-producing Enterobacteriaceae (CPE) were identified in Japan in the 1990s, ^{Reference Ito, Arakawa and Ohsuka1} and multiple CPE isolates have since emerged worldwide. ^{Reference Ma, Song and Li2} Among these, KPC (class A), NDM, VIM, IMP (class B), and OXA-48-like (class D) represent the most important carbapenemases in terms of diffusion and clinical impact. ^{Reference Alvisi, Curtoni and Fonnesu3} CPE isolates may accumulate resistance to beta-lactams and other families of antibiotics. From an epidemiological perspective, these microorganisms pose a significant threat because their resistance determinants are primarily co-transmitted via mobile genetic elements, especially plasmids. Although CPE colonization does not always lead to active infection, asymptomatic carriers can still spread the pathogen to other patients and the hospital environment. It is therefore important to detect CPE carriers in the hospital environment to prevent transmission and outbreaks. Screening is also important so healthcare providers will know to be alert for signs of active infection in CPE carriers. Once a patient develops a CPE infection, treatment options are severely limited, and for some patients, effective antimicrobial therapy may not be available. ^{Reference Magiorakos, Burns and Rodríguez Baño4} The mortality rate for CPE infection can be over 25%. ^{Reference Hoellinger, Deboscker and Danion5}

Since the SARS-Cov-2 pandemic, the prevalence of carbapenemase producers has accelerated worldwide and has reached dramatic numbers. ^{Reference Ma, Song and Li2} A recent global estimate based on data from 204 countries (1990–2021) reported 1.03 million deaths associated with these microorganisms in 2021, including 216,000 directly attributable deaths. ^{Reference Naghavi, Vollset and Ikuta6} Projections indicate that by 2050, these numbers could escalate to 1.91 million attributable deaths and 8.22 million associated deaths. ^{Reference Naghavi, Vollset and Ikuta6} A 2025 assessment by the European Centre for Disease Prevention and Control (ECDC) concluded that the incidence of CPE is continuing to rise throughout the European Union, and the probability of further spread is high. ⁷ The report further noted that there is increasing evidence of plasmid-mediated spread of CPE that is responsible for outbreaks in hospitals and within healthcare systems. ⁷ Similar to the global and European trends, the number of CPE cases are increasing over time in Spain. ^{Reference Brolund, Lagerqvist and Byfors8} The prevalence of healthcare-associated CPE infections in patients admitted to Spanish hospitals in 2022 was 5.6%. ^{Reference Gallego-Berciano, Parra and Gallego-Munuera9} The most common mechanism of carbapenem resistance in Spain was KPC-producers (69.5%), followed by OXA-48 producers (22.9%). ^{Reference Watanabe, Cano and Escudero-Sánchez10} The cost per case (infected and/or colonized) varies depending on the healthcare system, center type, and time to detection, among other factors, but estimates suggest costs of up to 96,878€ in Spain. ^{Reference Ferrer, Garnacho-Montero and Rascado11}

The main types of screening methods for CPE that can be performed from direct samples are culture-based methods, immunological methods, proteomic-based methods, and molecular techniques. Culture on selective chromogenic media is a method whereby samples are cultured on a medium containing an antibiotic as a selective agent, and each bacterial species produces a different color. Disadvantages of this method are limited sensitivity and a turnaround time of up to 2 days. Immunochromatography-based methods are easy to use and provide excellent sensitivity and specificity values. ^{Reference Boutal, Moguet and Pommiès12} As a limitation, they can only be used from positive blood cultures or rectal samples. Proteomic-based methods, such as matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), are reliable methods for detecting carbapenemase activity; however, MALDI-TOF MS is not fully automated, does not characterize the group of carbapenemase produced, and is limited for use only on positive blood cultures or clinical samples with high bacterial load. ^{Reference Oviaño and Bou13} Other phenotypic tests based on carbapenemase hydrolysis such as carbapenemase-producing-CRE phenotypic assays (eg, the Carba NP test or modified carbapenem inactivation method) require long incubation (>4 hr) and may miss or have poor sensitivity for detecting rare or variant enzymes. Molecular techniques include polymerase chain reaction (PCR), whole genome sequencing, and microarrays. The Xpert® Carba-R Assay developed by Cepheid® is a molecular PCR test for the rapid and accurate detection and differentiation of genes encoding the five most prevalent carbapenemases. ^{Reference Traczewski, Carretto and Canton14}

A CPE screening strategy or protocol should include a description of the type of assay to be used, the definition of a high-risk patient, a description of contact precautions (CP), and timing of those CP (ie, either while waiting for results or only after results have been obtained). Given all the elements involved, there is no universal consensus on the optimal CPE screening strategy. General CPE screening guidelines by the ECDC recommend implementing preventive CP (PrevCP) and screening with a “rapid and sensitive” method for high-risk hospitalized patients upon hospital admission. ^{Reference Magiorakos, Burns and Rodríguez Baño4} But screening protocols at the national level, if defined at all, differ based on the healthcare setting resources and organization, as well as the regional epidemiology of CPE. Spanish guidelines recommend the use of culture for CPE screening ^{Reference Rodriguez-Bano, Cisneros and Cobos-Trigueros15} without further details on whom and when to screen or in terms of the overall screening strategy. A more comprehensive national guideline on CPE screening strategies is provided by the “Zero Resistance Project,” which recommends screening by culture only in intensive care units (ICU). ¹⁶

Standard CPs to reduce CPE transmission include, but are not limited to, adequate hand washing with properly worn gloves, gowns, and aprons by relevant staff members, various packages of disposable one-off use supply items, careful handling of infectious waste, screening of contact patients when positive carriers are detected, in-depth cleaning after an outbreak, and cohorting or isolation of carriers (or, alternatively, forced bed closures when cohorting or isolation is not feasible). PrevCP are these CPs implemented before results of the screening test are available. However, in Spain, PrevCP is rarely practiced, and CPs are only implemented after a positive CPE test. In the opinion of the authors, CPE screening in real-world clinical practice in Spain is consistently performed only for patients admitted to ICUs. Access to rapid detection techniques such as multiplex rapid PCR is limited because of hospital budget constraints and because it is not recommended in Spanish guidelines. Since culture is less costly, it is the preferred detection method. Therefore, current standard of care (SoC) of high-risk hospitalized patients (HRHP) in Spain is a mixture of three co-existing situations: (1) PrevCP and screening by culture; (2) screening by culture and CPs only after a positive result; and (3) no screening or CPs.

Given the economic constraints in hospital and healthcare systems, cost analyses are useful to guide the selection of specific CPE screening methods and strategies. The aim of the present analysis is to assess the cost impact of implementing a CPE screening strategy which consists of PrevCP + rapid molecular Xpert Carba-R PCR CPE screening of all HRHP at hospital admission versus current SoC in Spain.