Early recognition of methicillin-resistant Staphylococcus aureus surgical site infections using risk and protective factors identified by a group of Italian surgeons through Delphi method

The Food and Drug Administration (FDA) recently proposed a new classification of skin and soft tissue infections namely acute bacterial skin and skin structure infections (ABSSSIs) which comprise erysipelas, cellulitis, major subcutaneous abscesses, and wound infections, including surgical site infections (SSIs). An ABSSSI is a bacterial infection of the skin with a lesion area of at least 75 cm², measured by redness, edema, or induration [1]. ABSSSIs constitute a significant burden for the healthcare system and their incidence is increasing. They have become a challenging clinical problem associated with high direct and indirect costs. Bacterial pathogens that commonly cause ABSSSIs include S. pyogenes and S. aureus, including a large number of methicillin-resistant S. aureus (MRSA) strains.

Given the associated morbidity, mortality, length of hospital stay, and overall direct and indirect costs, SSIs represent a significant problem [2‐4]. Moreover, MRSA infections can have an even greater impact on hospital budgets and on patients’ health, since they are more severe, may lead to longer hospital stays, and are associated with higher mortality.

Despite progresses in prevention, SSIs remain one of the most common adverse events in hospitals, accounting for 11 to 26% of all healthcare-associated infections [5]. In Italy, the rate of SSIs ranged from 5.4 to 12.8%, although recent studies have shown a reduction to 5%, [6, 7]. Surgical patients can develop several types of post-operative infection, with wound infections being the most common. The specific surgical procedures for each specialty are associated to different percentages of SSIs [8]. These complications add 10–20% additional extra costs to the total hospital bill [9].

In the USA, for any given type of operation, the development of a wound infection will approximately double the cost of hospitalization. These infections lead to 80,000 deaths per year and are associated with an annual treatment cost of US$2 billion [10]. A similar scenario has been found in Italy, where nosocomial infections occur in 500,000 out of 8,000,000 hospital admissions per year [11].

SSIs caused by S. aureus may be life threatening (estimated mortality rate 5%) and account for more than two extra weeks of hospitalization and around US$50,000 extra cost [12]. Rates of MRSA infection are increasing dramatically, and there is an urgent need to reduce hospitalizations and costs and implement more effective outpatient management and treatment strategies. Since cost containment and cost-efficient patient management are top priorities today, for the whole healthcare system, many hospitalized patients with SSIs could be safely treated, as outpatients, with current options of intravenous antibiotic therapy. This would reduce costs for hospitalization and could also improve patients’ outcome and satisfaction.

The exact incidence of SSIs is difficult to determine. In fact, the Diagnosis-Related Group (DRG) system underestimates the rate of SSIs, due to a very early discharge of surgical patients. Hospitals without a surveillance system report infection rates of less than 5%. This figure probably underestimates the problem, mostly because many SSIs are diagnosed after the patient has been discharged from hospital [8]. For example, Petrosillo et al. described that SSIs occurred in 5.2% out of 4665 patients and that, while 148 SSIs (61.4%) were diagnosed during the patients’ stay in hospital, 93 (38.6%) were recorded within 30 days after discharge [13]. This is comparable to the 34.8% result found in another Italian study on general surgery patients reported by Fiorio et al. [14]. However, in another similar surveillance study, higher post-discharge rates of SSI were found [15]. Marchi et al. reported data on non-prosthetic surgery from the Italian SSI surveillance program for the period 2009 to 2011, based on 60,460 operations from 355 surgical wards: SSIs were observed in 1628 cases (2.6%), with 60% of these being diagnosed on day 30 post-discharge surveillance [16].

Thus, up to 60% of SSIs are diagnosed after discharge from hospital, and this trend is increasing as the length of post-operative hospital stay is getting shorter and the number of 1-day surgery procedures is increasing [17].

According to current literature, active infection surveillance is useful in reducing the incidence of SSIs through surveillance-induced infection control efforts [18]. Operations performed in hospitals with at least 2 years of surveillance showed a 29% lower risk of SSIs, confirming that surveillance is a protective factor in preventing SSIs [16].

The identification of SSIs involves interpretation of clinical and laboratory findings. The Centers for Disease Control and Prevention (CDC) National Nosocomial Infections Surveillance (NNIS) system has developed standardized surveillance criteria for defining SSIs [19]. Using these criteria, SSIs are classified as either incisional or organ/space. Incisional SSIs are further divided into those involving only skin and subcutaneous tissue (superficial incisional SSIs) and those involving deeper soft tissues of the incision (deep incisional SSIs). Organ/space infections are not included in ABSSSIs.

According to the NNIS system reports, the most commonly encountered pathogens in SSIs are Gram-positive cocci, particularly Staphylococcus aureus (S. aureus), coagulase-negative staphylococci (CoNS), Streptococcus pyogenes (S. pyogenes), and Enterococcus spp., followed by Escherichia coli, Pseudomonas aeruginosa and Enterobacter spp. [20]. The source of pathogens is often the endogenous flora of the patient’s skin, mucous membranes, or hollow viscera [21]. Microorganisms of endogenous flora are usually aerobic Gram-positive cocci (e.g., staphylococci), but may also include fecal flora (e.g., anaerobic bacteria and Gram-negative aerobes) [22].

Exogenous sources of pathogens involved in SSIs include surgical personnel (especially members of the surgical team), the operating room environment (including air), and all tools, instruments, and materials brought to the sterile field. Exogenous flora consists primarily of aerobes, especially Gram-positive organisms (e.g., staphylococci and streptococci) [23].

Besides S. aureus and CoNS, Staphylococcus epidermidis may be responsible for severe infections following implantation of any prosthesis in general surgery, cardiac surgery, orthopedics, etc. Such infections may require removal of the prosthesis.

Table 1 lists the more frequent pathogens, according to surgical procedure.

S. aureus is consistently the leading cause of nosocomial infections, including SSIs. The incidence of MRSA strains is rising dramatically, and the amount of hospitalizations has more than doubled, in the past decade. Remarkably, MRSA is the main pathogen causing SSIs in many academic and community hospitals [24]. This represents a significant, independent risk factor for adverse clinical and economic outcomes. Kirkland et al. estimated that the excess hospital costs associated with MRSA SSIs ranged from US$3089 to US$35,367 [3]. Engemann et al. found that, among surgical patients, those with MRSA infections were hospitalized 5 days longer than those with methicillin-sensitive S. aureus (MSSA) infections [25]. Hospital charges for MRSA patients were also US$62,908 greater than for patients without an infection and US$40,000 greater than for patients with MSSA infections.

Other studies support the findings that patients with MRSA infections require more health-care resources than patients with MSSA infections [26]. Weigelt et al. determined that the risk-adjusted attributable increase in duration of hospitalization was approximately 1 day and, in terms of costs for the hospitalization, over US$1000. They also found that significant independent risk factors, increasing costs, and time spent in hospital for SSIs due to MRSA, included illness severity, transfer from another healthcare facility, a previous hospital admission (30 days), and other polymicrobial infections (p < 0.05) [27].

MRSA is a versatile and dangerous bacterial pathogen that shows virulence, antibiotic resistance, and survival fitness [28]. Selection pressure, exercised by broad-spectrum antibiotic treatment and cross-transmission through healthcare workers’ hands, facilitates its spreading. Hence, profiles to identify patients at high risk of MRSA carriage might improve prevention of MRSA infections because MRSA carriers, without symptomatic infection, are an important pathogen reservoir [29].

Efforts should be made to identify patients at risk of colonization and subsequent infection by multi-drug-resistant microorganisms such as MRSA, and to control hospital-acquired SSIs. Remarkably, surveillance systems, even without any specific intervention, have been associated with a reduction in SSIs [30]. Because all authors do not recommend a universal rapid MRSA screening, other methods to pick out patients at high risk of MRSA colonization and subsequent SSIs could be very useful.

Harbart et al. found that age 75 years or older, previous hospitalization (in the preceding 12 months), and recent antibiotic therapy (in the preceding 6 months) were the strongest risk factors for MRSA colonization in surgical patients, then confirmed in a validation cohort [31].

Applying the Delphi method, we recently identified the most common risk factors for colonization and/or infection by MRSA as being patient from a long-term care facility, previous hospitalization (within the preceding 30 days), Charlson score >5, chronic obstructive pulmonary disease and thoracic surgery, antibiotic therapy with beta-lactams (especially cephalosporin and carbapenems) and/or quinolones in the preceding 30 days, age 75 years or older, current duration of hospital admission >16 days, and prosthetic implant surgery. Furthermore, protective factors were an adequate antibiotic prophylaxis, laparoscopic surgery, and the presence in the hospital of an active surveillance program for infection control [8].

Clinical MRSA isolates show a decreased susceptibility or increased resistance to anti-MRSA drugs. Thus, treatment of ABSSSIs is now challenged by toxicity, few oral options, and greater need for hospitalization and its associated costs [32].

The Infectious Diseases Society of America (IDSA) recommended beta-lactam or clindamycin for mild/moderate non-purulent ABSSSIs, and vancomycin plus piperacillin/tazobactam for severe non-purulent ABSSSIs treatments [33]. In purulent ABSSSIs, doxycycline or trimethoprim/sulfamethoxazole should cover MRSA for moderate cases and vancomycin, daptomycin, linezolid, or ceftaroline in severe cases. Antimicrobials available in Italy for treating ABSSSIs with activity against MRSA and other resistant Gram-positive pathogens include vancomycin, teicoplanin, daptomycin, linezolid, and ceftaroline. Of these antimicrobials, only linezolid is available in an oral formulation.

Table 2 reports the main characteristics of anti-MRSA drugs for SSIs. Some of these drugs have significant potential toxicity (e.g., myopathy from daptomycin, renal function impairment from vancomycin, bone marrow suppression from linezolid) and drug interactions (e.g., linezolid and selective serotonin re-uptake inhibitors). While doxycycline and trimethoprim/sulfamethoxazole are active against MRSA, their activity against beta-hemolytic streptococci is poor, limiting their use as monotherapy for ABSSSIs.

Dalbavancin, a novel lipoglycopeptide antibiotic active against both MSSA and MRSA, was approved by the FDA in May 2014 and by the European Medicines Agency (EMA) in February 2015 for the treatment of ABSSSIs caused by susceptible Gram-positive organisms [34]. Several clinical trials have demonstrated its tolerability, efficacy, and non-inferiority compared to standard therapy for ABSSSIs. The DISCOVER 1 and DISCOVER 2 studies showed that once-weekly intravenous dalbavancin was not inferior to twice-daily intravenous vancomycin, followed by oral linezolid for the treatment of ABSSSIs. Adverse events were reported less frequently in patients treated with dalbavancin, than in those treated with vancomycin-linezolid [35]. Dalbavancin’s high-protein binding and prolonged half-life allow for easily and consistently attainable therapeutic levels. It has a well-established activity against the Gram-positive organisms commonly involved in superficial and deep SSIs, including MRSA and other multidrug-resistant pathogens, and the MIC₉₀ values for these organisms have remained stable over the past decade.

Dalbavancin, as an anti-MRSA agent, displays advantageous factors, such as bactericidal effect, full activity on biofilm [36], which could be increased by combination with rifampicin, lack of drug-drug interactions, lack of renal toxicity, and no adverse events associated with an early discharge from hospital, because of its prolonged half-life. Indeed, the most unique feature of dalbavancin is its once-weekly dosing, previously approved as a 1000 mg dose followed by 500 mg 1 week later, and then the one-shot, single-dose of 1500 mg, recently approved by the EMA [37].

The aim of this study was to create a score for the early recognition of SSIs caused by MRSA in order to facilitate the prompt initiation of adequate antibiotic therapy.