Antibacterial Treatment of Meticillin-Resistant Staphylococcus Aureus Complicated Skin and Soft Tissue Infections: a Cost and Budget Impact Analysis in Greek Hospitals

Complicated skin and soft tissue infections (cSSTIs) are among the most common infections treated in the hospital setting [1, 2]. They represent the more extreme end of the clinical spectrum of SSTIs [3] as they typically involve deep soft tissue and occur in patients with underlying disease, often requiring intravenous (IV) antibiotic therapy and/or surgical intervention [2]. As a result, their treatment incurs high healthcare costs. cSSTIs frequently complicate clinically significant medical conditions such as peripheral arterial disease, diabetes mellitus or renal insufficiency and can also cause complications in immunocompromised hosts [4].

Gram-positive pathogens are the predominant cause of cSSTIs. Staphylococcus aureus (S. aureus) was found to be the most frequently occurring pathogen among hospitalized SSTI patients on a global scale in the SENTRY Antimicrobial Surveillance Program [5], and in a large observational study with 1995 cSSTIs patients hospitalized in Europe [1]. Antibiotic resistance in isolates from SSTIs has increased significantly over time [6‐10], but the emergence of meticillin-resistant S. aureus (MRSA) is recognized as the greatest resistance concern [5], as it complicates the treatment of cSSTIs, limits therapeutic options and impacts treatment outcomes.

Systemic infections with MRSA are associated with a higher mortality rate, a longer length of stay (LOS) in hospital, and greater healthcare costs than non-MRSA infections [11].

In Greece, where antimicrobial drug resistance rates remain high [12], MRSA prevalence reaches 40%, which is among the highest in Europe [13] and comparable to figures reported for the USA [14]. The increase in MRSA, in part, reflects the changing epidemiology of soft tissue infections as a consequence of the recent dramatic increase in the incidence of community acquired MRSA (CA-MRSA), the pathogen most commonly isolated from SSTIs in many locations in the US [15]. CA-MRSA strains are distinct from hospital-acquired strains, cause mainly skin and soft tissue infections (ranging in severity from furuncles to necrotizing fasciitis), and are associated with the production of virulence factors like the Panton Valentine Leukocidin (PVL) toxin, which may further complicate treatment [16]. In Europe, the prevalence of infections due to CA-MRSA appear to vary across the continent, with Greece reporting one of the highest rates (30%) of S. aureus infection in outpatients compared to 6–18% in other Western European countries [16, 17].

Successful management of cSSTI involves prompt recognition, timely surgical debridement or drainage, resuscitation if required and appropriate antibiotic therapy [3]. Treatment for MRSA-related cSSTIs may include either IV or per os (PO) pharmaceutical treatment for 7–14 days and in most cases hospitalization is required. Vancomycin (VANCO) has historically been the standard of care for MRSA infections, but adverse effects, the need for IV access and growing resistance, tend to limit its use [7]. Newer antimicrobials such as daptomycin (DAPTO), linezolid (LINE) and telavancin have shown comparable efficacy to VANCO and are recommended in international guidelines [18].

Use of proper antimicrobial treatment is an illustrative example of the tradeoffs between increased pharmaceutical spending and decreased resource use costs. Given the scarcity of economic and human healthcare resources and the fact that the cost of available antimicrobial treatments varies, the purpose of the present study was to identify healthcare resource use and cSSTI total inpatient costs, along with other associated costs for different antibiotic treatments in the Greek hospital setting. A secondary objective was to perform a budget impact analysis for the inpatient treatment of MRSA-cSSTIs.

Treatment of cSSTIs due to MRSA has significant cost implications within the hospital setting, as a result of additional LOS and extensive use of appropriate healthcare resources. This study aimed to (a) map the costs associated with inpatient treatment of cSSTIs due to MRSA in Greece, and (b) to analyze costs associated with different antibacterial therapies and the potential budget impact of increasing the usage of the lowest cost agent.

For the baseline case scenario (depicting the current treatment scenario in Greece), LINE was shown to be the most cost-saving first-line antimicrobial agent compared to other treatment options. By extending the scope of its current use (from 19% of patients to a hypothetical 30%), the total (aggregate) budget impact was €896,065 over a 3-year period. Although LINE drug acquisition cost approximates the average cost of the remaining available treatments for cSSTI, its use may result in significantly reduced medical costs, namely hospitalization costs, compared to other selected antibiotic treatments. Using LOS data from a large phase IV study [20] for the treatment of documented MRSA-cSSTIs, LINE’s budget impact savings were further increased to €1,893,600 for the 3-year period (Table 6). Clinical data demonstrates 100% bioavailability [27] of the oral LINE formulation, thus allowing continuation of therapy in both the inpatient and outpatient setting when clinically appropriate and without dosage adjustment.

In addition to reducing LOS and healthcare costs, the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines suggest that conversion from parenteral to oral therapy using antimicrobials with excellent bioavailability, when the patient’s condition allows, can reduce complications that may arise as a result of IV access. An antimicrobial management program which outlines clinical criteria and guidelines for oral switch could play an important role in safeguarding the balance between incremental antimicrobial acquisition costs and the development of resistance at an institutional level [28].

Hospitalization has been recognized within international literature as the main cost driver in the treatment of MRSA infections, comprising up to 81% of total treatment costs and making early discharge a reasonable target for savings [29, 30]. A recent retrospective chart review in 12 European countries [26] has shown that by applying early discharge criteria in MRSA-cSSTIs more than one-third of hospitalized patients in usual clinical practice could be discharged from the hospital (37.9% overall and 41.1% for Greece with a mean ± SD potential LOS reduction of 6.2 ± 8.2 and 7.5 ± 10.6 days, respectively).

A treatment strategy that would focus on early discharge followed by outpatient parenteral treatment (OPAT) use or use of orally available antimicrobials could be of benefit. However, OPAT treatment is rather costly and is not commonly used in the Greek NHS setting [31].

As with every study of this kind, the outcomes must be interpreted in light of a number of limitations. First of all, the study design assumes equal effectiveness among the different treatment schedules. This probably leads to conservative estimations, considering that data from a recent systematic meta-analysis of 14 studies of six antibiotics (n = 1,840) suggested differences in efficacy of different MRSA-cSSTI pharmaceutical treatments [32], mostly in favor of LINE. The assumption that all patients are cured after receiving second-line treatment and that no patients died represents a simplification of reality. The majority of studies in cSSTIs do report high clinical success and very low mortality rates [15] which are similar for patients treated with LINE or VANCO [20], however, second-line efficacy data are lacking. All model assumptions were based on a previously published model [19] and were considered reasonable by the panel of experts. Moreover, the option of outpatient oral and IV treatment continuation was not taken into consideration as this falls beyond the scope of the study (hospital setting). However, this could have a substantial impact on total cost of treatment [33], especially from an overall healthcare system perspective. Recent evidence shows that the administration of antibacterial treatment administered on an outpatient basis can reduce per patient costs up to 30% [19].

Another limitation to be considered is the lack of Greek-specific pharmaceutical use and MRSA-cSSTI prevalence data. The use of an expert panel approach implies a level of uncertainty with respect to the data acquisition process [34]. Furthermore, results may not be fully transferable to other treatment settings, as significant variation exists in clinical practice [31]. The actual magnitude of this uncertainty is very difficult to quantify. However, the multidisciplinary make-up of the team of experts and the consistency of estimations produced by expert panels in Greece, as reported by previous research [35] enhance the robustness of results. Moreover, recently published data on patients’ age and sex, mean LOS and IV use in Greece from a retrospective study in 12 European countries [31] are consistent with the results of the expert panel.

In actual terms, the economic benefits of LINE are heavily based on its ability to reduce LOS and associated hospital costs. This was evident in the case where equal LOS was hypothesized for all comparators, which resulted in VANCO being the least costly choice. Newer agents have been shown to reduce LOS and thus may offset (partially or fully) the costs of medication.

Finally, the use of the recently introduced DRGs costing system leads to an underestimation of the relevant costs. This is because the current DRG price lists in Greece do not include staff costs. This is likely to result in an underestimation of the actual cost of treating cSSTIs due to MRSA, especially within the hospital setting. It has to be noted that the average hospitalization cost per day for cSSTIs based on the DRG reimbursement system was found to be approximately half the respective cost compared to recently published literature in the Greek setting [31] and the World Health Organization for inpatient cost per day (309.65 adjusted for inflation in 2012) [25, 26]. Furthermore, as with most pharmacoeconomic studies, drug acquisition costs used in the cost calculations lack consideration for price variation over time.

Notwithstanding its limitations, this study is an illustrative example of the importance of global hospital budget, where higher drug acquisition costs would be offset by the marked reduction in hospital and fixed costs due to early discharge.

According to current clinical practice, as depicted by the panel of experts in the present study, LINE is associated with the lowest total costs in the management of the “typical” MRSA-cSSTI patient. The lower costs for patients treated with LINE can be attributed to a switch to oral therapy and earlier hospital discharge. International experience shows that early discharge, when certain criteria are met, can reduce healthcare costs without compromising quality of care. In light of considerable hospital budget constraints, the development of hospital strategies to facilitate early discharge of patients, for example by introducing clinical criteria and guidelines for switching to oral treatments for MRSA-cSSTIs, could result in substantial savings for the Greek global hospital budget.