Targeted Therapy of Severe Infections Caused by Staphylococcus aureus in Critically Ill Adult Patients: A Multidisciplinary Proposal of Therapeutic Algorithms Based on Real-World Evidence

(1) Introduction: To develop evidence-based algorithms for targeted antibiotic therapy of infections caused by Staphylococcus aureus in critically ill adult patients. (2) Methods: A multidisciplinary team of four experts had several rounds of assessment for developing algorithms concerning targeted antimicrobial therapy of severe infections caused by Staphylococcus aureus in critically ill patients. The literature search was performed by a researcher on PubMed-MEDLINE (until August 2022) to provide evidence for supporting therapeutic choices. Quality and strength of evidence was established according to a hierarchical scale of the study design. Two different algorithms were created, one for methicillin-susceptible Staphylococcus aureus (MSSA) and the other for methicillin-resistant Staphylococcus aureus (MRSA). The therapeutic options were categorized for each different site of infection and were selected also on the basis of pharmacokinetic/pharmacodynamic features. (3) Results: Cefazolin or oxacillin were the agents proposed for all of the different types of severe MSSA infections. The proposed targeted therapies for severe MRSA infections were different according to the infection site: daptomycin plus fosfomycin or ceftaroline or ceftobiprole for bloodstream infections, infective endocarditis, and/or infections associated with intracardiac/intravascular devices; ceftaroline or ceftobiprole for community-acquired pneumonia; linezolid alone or plus fosfomycin for infection-related ventilator-associated complications or for central nervous system infections; daptomycin alone or plus clindamycin for necrotizing skin and soft tissue infections. (4) Conclusions: We are confident that targeted therapies based on scientific evidence and optimization of the pharmacokinetic/pharmacodynamic features of antibiotic monotherapy or combo therapy may represent valuable strategies for treating MSSA and MRSA infections.


Introduction
Staphylococcus aureus represents one of the major causes of infection among critically ill patients, with a remarkable burden of morbidity and mortality [1,2]. A recent study conducted among 15,202 critically ill patients admitted to 1150 different intensive care units (ICUs) found that 37.0% of clinical isolates retrieved from cultures were Gram-positives, of which S. aureus represented more than 50% [3].   Cefazolin is likely as effective as an ASP and may be considered as a first-line treatment for MSSA spinal epidural abscesses. In regard to BSI, a recent meta-analysis of ten observational studies compared the efficacy of cefazolin and oxacillin in the management of primary and secondary BSIs (34% skin and soft tissue infections, 27% IEs, and 18% pneumonia) caused by MSSA [16]. Cefazolin was significantly associated with lower mortality rate (RR 0.78; 95%CI 0.69-0.88), higher clinical cure rate (RR 1.09; 95%CI 1.02-1.17), and lower risk of drug withdrawal for adverse events (AEs; RR 0.27; 95%CI 0.16-0.47) compared to oxacillin [16]. Conversely, no difference in the relapse rate of BSIs was found between cefazolin and oxacillin treatment (RR 1.29; 95%CI 0.96-1.74). These findings were confirmed in a large multicentric retrospective study that included 3167 patients affected by primary or secondary MSSA BSIs (ICU admission 17.6%) [17]. In that study, cefazolin showed a significantly lower mortality rate both at 30-day (aHR 0.63; 95%CI 0.51-0.78) and at 90-day (aHR 0.77; 95%CI 0.66-0.90) compared to oxacillin or nafcillin. No difference in the relapse rate of BSI was found between the two therapeutic regimens (aOR 1.13; 95%CI 0.94-1.36). Conversely, a recent large multicentric retrospective study including 7312 patients with MSSA BSIs (ICU admission 13.5%) showed no difference in the 30-day mortality rate between cefazolin and flucloxacillin at propensity adjusted analysis (aOR 0.86; 95%CI 0.65-1.14) [18]. Likewise, no difference between cefazolin and antistaphylococcal penicillins (ASPs) was documented in several retrospective observational studies (ICU admission ranging from 5.2% to 41.8%) in terms of mortality rate, clinical cure rate, and relapse or recurrence rate of MSSA BSIs [19][20][21][22][23]. In a multicentric retrospective cohort study including 93 patients with complicated MSSA BSIs (41% related to bone and joint infections and 20% IE) [24], cefazolin showed a significantly lower clinical failure rate at 90-day (24% vs. 47%; p = 0.04) and AE rate (3% vs. 30%; p < 0.001) compared to oxacillin.
In regard to CNS infections, it should be mentioned that a study carried out among 17 patients with CNS infections caused by MS staphylococcal isolates showed that the percentage of cerebrospinal fluid (CSF) penetration could be higher for cefazolin than for cloxacillin (4.3% vs. 1.8%) [25].
Overall, oxacillin and cefazolin could be considered equivalent for the management of MSSA infections. Several real-world studies showed no significant difference between the two agents in terms of mortality, clinical cure, microbiological eradication, and relapse rate. However, cefazolin could provide some advantages in case of primary and/or secondary BSIs or CNS infections. In regard to the drug administration mode, it is worth mentioning that a retrospective cohort study including 107 patients with MSSA IE found that administration by CI was the only independent variable associated with 30-day microbiological cure with oxacillin at multivariate analysis (p = 0.01) and that CI granted significantly higher microbiological cure rate compared to intermittent infusion (94% vs. 79%; p = 0.03) [26]. These findings could support the use of CI for maximizing the achievement of optimal PK/PD with oxacillin. Notably, combination therapy did not add any advantage over cefazolin or oxacillin monotherapy in the management of MSSA infections. A recent meta-analysis of 12 studies found that combination therapy did not reduce significantly the mortality rate at day 30 (RR 0.92; 95%CI 0. 70-1.20), at day 90 (RR 0.89; 95%CI 0.74-1.06), or at any time (RR 0.91; 95%CI 0.76-1.08) in the treatment of MSSA bacteremia compared to monotherapy [27]. Furthermore, combination therapy was associated with a significantly higher risk of AEs (including nephrotoxicity) (RR 1.74; 95%CI 1.31-2.31; p < 0.001). Additionally, a retrospective observational study including 350 patients with MSSA bacteremia (ICU admission 19.5%) found that combination therapy of daptomycin with a beta-lactam failed in reducing mortality rate compared to beta-lactam monotherapy after propensity score-matched analysis (90-day mortality rate: HR 0.89; 95%CI 0.54-1.49) [28].

Targeted Treatment of MRSA Infections
The therapeutic algorithm for targeted treatment of infections caused by MRSA in critically ill patients was organized according to the types of infection site and is shown in Figure 2. The scientific evidence supporting the different choices is summarized in Table 2.
in Figure 2. The scientific evidence supporting the different choices is summarized in Table 2.  Combination therapy with high-dose daptomycin (10 mg/kg q24 h) plus CI fosfomycin (16 g/day after 6-8 g LD) or an anti-MRSA cephalosporin (ceftaroline 600 mg q8 h over 8 h after 600 mg LD or ceftobiprole 500 mg q8 h over 8 h after 500 mg LD) is suggested as first-line targeted therapy of primary BSIs (including catheter related), IEs, or infections associated with intracardiac/intravascular devices caused by MRSA. Vancomycin (2 g/day by CI after 2 g LD) or teicoplanin (6 mg/kg q12 h after an LD of 12 mg/kg q12 h for 4-5 doses) should be reserved as second line alternatives and could be suitable whenever vancomycin MIC is ≤1 mg/L ( Figure 2).
In a recent RCT [29], 155 patients with MRSA BSI were randomized to receive daptomycin in monotherapy or in combination therapy with fosfomycin. Combination therapy granted significantly lower rates of both complicated BSI (16.2% vs. 32.1%; p = 0.022) and 6-week microbiological failure (0% vs. 11.1%; p = 0.003) compared to monotherapy. Additionally, in patients receiving combination therapy a trend toward higher treatment success rate at 6-week was found (54.1% vs. 42.0%; p = 0.14). Conversely, combination therapy was associated with significantly higher AE rate (17.6% vs. 4.9%; p = 0.018). In the subgroup analysis of patients with Pitt score > 1, a significantly higher cure rate was observed with combination therapy compared to monotherapy (57.1% vs. 22.7%; p = 0.023). This is in agreement with the findings of an early case series of three patients with staphylococcal IEs, one of whom had prosthetic valve endocarditis (PVE), who were successfully treated with daptomycin plus fosfomycin [30].
In regard to preclinical models, a rabbit model of experimental MRSA endocarditis investigated the efficacy of daptomycin plus fosfomycin vs. daptomycin alone and showed that combo therapy granted significantly better efficacy in terms of both proportion of sterile vegetations (100% versus 72%; p = 0.046) and bacterial burden reduction within the vegetations (p = 0.025) [31]. Daptomycin plus fosfomycin significantly improved the efficacy of daptomycin monotherapy at 6 mg/kg/day in terms of both the proportion of sterile vegetations (100% versus 72%, p = 0.046) and the decrease in the density of bacteria within the vegetations (p = 0.025). Daptomycin plus fosfomycin was as effective as daptomycin monotherapy at 10 mg/kg/day (100% versus 93%, p = 1.00) and had activity similar to that of daptomycin plus cloxacillin when daptomycin was administered at 6 mg/kg/day (100% versus 88%, p = 0.48). Daptomycin nonsusceptibility was not detected in any of the isolates recovered from vegetations. In conclusion, for the treatment of MRSA experimental endocarditis, the combination of daptomycin plus fosfomycin showed synergistic and bactericidal activity.         Antibiotic combination showed excellent synergistic or additive effects on the original and the linezolid-resistant strain but showed indifferent effect for fosfomycin-resistant strain. In the Galleria mellonella infection model, the survival rate of the antibiotic combined was improved compared with that of the single drug. There was a good correlation between in vivo efficacy and in vitro susceptibility.      Antibiotic combination showed excellent synergistic or additive effects on the original and the linezolid-resistant strain but showed indifferent effect for fosfomycin-resistant strain. In the Galleria mellonella infection model, the survival rate of the antibiotic combined was improved compared with that of the single drug. There was a good correlation between in vivo efficacy and in vitro susceptibility.     catheter-related biofilm rat model found that viable bacteria counts in biofilm were significantly reduced after treatment (p < 0.05).

Xie et al., 2021
In vitro/ in vivo preclinical study One MRSA strain LIN 2.5-10 mg/kg + FOS 50-200 mg/kg Antibiotic combination showed excellent synergistic or additive effects on the original and the linezolid-resistant strain but showed indifferent effect for fosfomycin-resistant strain. In the Galleria mellonella infection model, the survival rate of the antibiotic combined was improved compared with that of the single drug. There was a good correlation between in vivo efficacy and in vitro susceptibility.   Several clinical studies may support the efficacy of combining daptomycin with ceftaroline in the management of MRSA BSIs, IE, or PVE [32][33][34][35][36][37][38][39][40][41]. An RCT including 40 patients randomized to combination therapy with daptomycin plus ceftaroline or to daptomycin/vancomycin monotherapy of MRSA BSIs (ICU admission up to 18%) showed that combination therapy was associated with significantly lower in-hospital mortality rate (0% vs. 26%; p = 0.029) [32]. The surprising findings led the investigators to stop early the study due to an unacceptable higher risk of mortality in the monotherapy arm. Conversely, two large retrospective studies found no difference in terms of mortality rate, hospital readmission, and BSI recurrence of combination therapy with daptomycin plus ceftaroline vs. standard of care monotherapy with vancomycin, daptomycin, or ceftaroline in the treatment of MRSA BSI [33,34]. However, in a subgroup of patients with severe disease (median Charlson Comorbidity Index ≥ 3) and with a primary endovascular source of infection, treatment with daptomycin plus ceftaroline within 72 h from index cultures resulted in a trend toward reduced mortality rate (4.3% vs. 20.8%; p = 0.16) [33]. A retrospective cohort study compared combination of daptomycin plus ceftaroline vs. standard of care with daptomycin or vancomycin plus gentamycin or rifampicin in the treatment of complicated MRSA BSI (ICU admission up to 57%) [35]. Combo therapy with daptomycin plus ceftaroline was associated with 77% lower odds of clinical failure at multivariate analysis (OR 0.23; 95%CI 0.06-0.89) and with a significantly lower risk of 60-day recurrence (0% vs. 30%; p < 0.01). Cunha et al. reported one case of MRSA aortic PVE successfully treated with a 6-week combination therapy course of high-dose daptomycin (i.e., 12 mg/kg/day) plus ceftaroline [41].

Necrotizing Fasciitis-Daptomycin ± Clindamycin
Real-world clinical evidence supporting the use of combination therapy with daptomycin plus ceftobiprole for MRSA BSIs and/or IE is limited only to one case series and one single case report [42,43]. In a case series of 12 staphylococcal IE (of which two-thirds were PVE) treated with ceftobiprole (5/12 underwent surgical intervention because of vegetation size or severe valve dysfunction with heart failure), 11/12 were treated with ceftobiprole plus daptomycin with a clinical cure rate of 83% and none with BSI relapse [42]. Interestingly, an in vitro study assessing the synergic activity of four different antibiotic combinations against 20 MRSA strains found that combo of ceftobiprole plus daptomycin was always synergic against all of the evaluated strains with a four-fold MIC decrease [44].
Overall, combination therapy with daptomycin plus fosfomycin or ceftaroline/ceftobiprole could be the preferred therapeutic strategy for the management of BSIs, IEs and/or infections associated with intracardiac/intravascular devices caused by MRSA. These combinations could grant lower risk of both clinical/microbiological failure and recurrence compared to monotherapy. In regard to PVE, a recent meta-analysis of four studies found no benefits of either gentamicin (OR 0.98; 95%CI 0.39-2.46) or rifampicin (OR 1.29; 95%CI 0.71-2.33) addition in reducing clinical failure in the treatment of staphylococcal PVE [47]. Conversely, the unfavorable PK/PD profile coupled with the safety issues should limit the role of glycopeptides in the treatment critically ill patients with MRSA BSIs, IEs, and/or infections associated with intracardiac/intravascular devices.

Community-Acquired Pneumonia
CI ceftaroline (600 mg q8 h over 8 h after 600 mg LD) or CI ceftobiprole (500 mg q8 h over 8 h after 500 mg LD) are suggested as first-line therapy of severe CAP in patients with risk factors or clinical/radiological features evocative for MRSA etiology (Figure 2).
A recent meta-analysis of 14 studies in patients with pneumonia (of which five were retrospective and provided data on clinical outcome in 345 patients with documented MRSA pneumonia) reported that the pooled success rate of ceftaroline was of 71.7% (95%CI: 59.7-82.3) [48]. A retrospective cohort study including 89 patients affected by severe CAP (10.1% due to MRSA; ICU admission 37%) treated with ceftaroline found a clinical failure rate of 36% [49]. Interestingly, the only independent predictor of clinical failure was the time elapsed from the diagnosis of severe CAP and the start of treatment with ceftaroline (OR for each passing day 1.5; 95%CI 1.1-1.9; p = 0.003) [49].
One RCT [50] and one retrospective observational study [51] may support the use of ceftobiprole for severe MRSA CAP. A phase III RCT [50] randomized 638 patients with CAP (4% bacteraemic; 2% MRSA) to ceftobiprole or ceftriaxone plus linezolid. No significant difference between the two groups was found in terms of overall clinical cure rate (86.6% vs. 87.4%) and/or microbiological eradication rate (88.2% vs. 90.8%). A retrospective cohort study [51] including 29 patients treated with ceftobiprole (19.3% CAP; septic shock 13.8%), of whom 24% were affected by MRSA pneumonia, found a clinical cure rate of 68.9% (66.7% in the subgroup of patients affected by CAP). No clinical failure occurred in the subgroup of patients affected by MRSA pneumonia.
Overall, ceftaroline and ceftobiprole could be reasonable options for the treatment of severe MRSA CAP in critically ill patients. Both agents showed similar penetration rate in the epithelial lining fluid (ELF) (20-25%) [52,53]. In regard to mode of administration, some studies suggested that in the treatment of critically ill patients, CI may allow the attainment of higher PK/PD targets with ceftaroline against MRSA compared to intermittent infusion [54,55]. Likewise, the same could be anticipated for ceftobiprole, even if real-world evidence is currently lacking.

Infection-Related Ventilator-Associated Complications
Linezolid (600 mg q12 h) in monotherapy or in combination therapy with CI fosfomycin (16 g q24 h after 6-8 g LD) is suggested as first-line targeted therapy of IVACs caused by MRSA. CI ceftaroline (600 mg q8 h over 8 h after 600 mg LD) or CI ceftobiprole (500 mg q8 h over 8 h after 500 mg LD) could be suggested as potential alternatives, especially in case of bacteraemic infections [56] (Figure 2).
Two meta-analyses [57,58] may support the use of linezolid for treating IVACs due to MRSA. In the first one, Kato et al. [57] analyzed seven RCTs and eight retrospective cohort and/or case-control studies comparing linezolid and vancomycin for the treatment of hospital-acquired or ventilator-associated pneumonia caused by MRSA. Clinical cure and microbiological eradication rates were significantly increased in patients treated with linezolid in both the RCTs (clinical cure: RR 0. 81 Only preclinical studies may support the role of combining fosfomycin with linezolid for the treatment of MRSA infections [59][60][61][62][63]. A systematic review of seven in vitro preclin-ical studies documented a synergic effect between linezolid and fosfomycin against 95% of 166 Staphylococcus aureus strains, regardless of being planktonic or embedded within the biofilm [59]. In the same review, two in vivo preclinical studies were reported to grant higher efficacy when linezolid was combined with fosfomycin compared to each single agent alone [59]. One meta-analysis [48] and one retrospective cohort study (CAPTURE) [64] may support the use of ceftaroline for the management of severe HAP due to MRSA, including IVACs. A recent meta-analysis of 14 studies in patients with pneumonia (of which five were retrospective and provided data on clinical outcome in 345 patients with documented MRSA pneumonia) reported that the pooled success rate of ceftaroline was 83.0% (95%CI: 65.0-95.0) in HAP/VAP and 71.7% (95%CI: 59.7-82.3) in MRSA pneumonia [48]. A retrospective cohort study including 40 patients affected by HAP/VAP treated with off-label ceftaroline (67.5% ICU admission) found that the clinical success rate was 75% overall (81% and 62% for HAP and VAP, respectively) and 58% in the MRSA subgroup [64].
One post hoc retrospective analysis of a phase III RCT [65], one retrospective cohort study [51], and one in vitro study [66] may support the use of ceftobiprole for severe hospital-acquired pneumonia (HAP) due to MRSA, including IVACs. A post hoc analysis of a phase III RCT including 307 high-risk patients with HAP found that early response (at day 4) was higher among ceftobiprole-treated patients than among comparator-treated patients (12.5% difference; 95%CI 3.5-21.4) [65]. A retrospective cohort study [51] including 29 patients treated with ceftobiprole (48.3% HAP, of which one case of IVAC; septic shock 13.8%), of which 24% were affected by MRSA pneumonia, found a clinical cure rate of 68.9% (85.7% in the subgroup of patients affected by HAP). No clinical failure occurred in the subgroup of patients with MRSA pneumonia. Among 66 MRSA isolates retrieved from HAP, 63/66 (95.5%) were susceptible to ceftobiprole (MIC50 1 mg/L; MIC90 2 mg/L), and 3/66 were ceftobiprole-resistant but with a borderline MIC of 4 mg/L [66].
Overall, linezolid could be considered the preferred therapeutic option for the management of IVACs caused by MRSA. Real-world evidence showed higher clinical cure rate and microbiological eradication rate compared to vancomycin. Linezolid showed very high penetration rate into the ELF of critically ventilated patients (97%), and this may grant effective PK/PD target attainment against MRSA with an MIC up to 2 mg/L [67][68][69]. Fosfomycin showed high penetration rate into the ELF of critically septic patients (>50%) [70] and may theoretically represent a valuable add-on for combo therapy with linezolid according to even physicochemical properties and synergic activity. Novel anti-staphylococcal cephalosporins could be a promising but second-line alternative for IVACs due to MRSA, considering that studies supporting the use of these agents in ICU scenario are limited (mainly assessed in CAP) compared to those available for linezolid. ELF penetration rates were quite limited (20-25%) [52,53], but CI administration may be suggested for maximizing PK/PD target attainment in ventilated critical care patients with normal and/or augmented renal clearance [55].

Central Nervous System Infections
Linezolid (600 mg q12 h) is suggested in monotherapy as targeted therapy of primitive CNS infections caused by MRSA ( Figure 2) and in combination therapy with fosfomycin (16 g/day CI after 6-8 g LD) as targeted therapy of post-operative neurosurgical MRSA infections.
Three retrospective studies, two case series, and two case reports may support the use of linezolid for the management of CNS infections caused by MRSA [71][72][73][74][75][76][77][78]. In a retrospective cohort of 66 patients with MRSA CNS infections (78.8% bacteraemic), salvage therapy with linezolid after previous failure of glycopeptide treatment had good efficacy with an in-hospital mortality rate of 13.6% and a relapse rate of 16.7% [71]. Among 26 patients treated with linezolid for Staphylococcus aureus meningitis (81% post-operative), the clinical cure rate was 69%, and the microbiological eradication rate was 93% [72]. A retrospective case-control study including 17 patients with MRSA meningitis found significantly higher microbiological cure rate at 5-day among those receiving linezolid compared to those receiving vancomycin (77.8% vs. 25.0%; p = 0.044) [73].
Overall, linezolid could be considered the preferred therapeutic option for the management of CNS infections caused by MRSA. Real-world evidence showed greater clinical cure rate and microbiological eradication rate compared to glycopeptides. Linezolid showed good penetration rate into the cerebrospinal fluid (CSF) of neurocritical patients (57%) [79] and is expected to attain optimal PK/PD targets at the infection site. High-dose fosfomycin (i.e., 24 g/day) may theoretically represent a valuable add-on for combination therapy with linezolid in case of post-operative neurosurgical MRSA infections thanks to a good CSF penetration rate (27%) and to the fact that CSF concentrations were shown to remain above the clinical breakpoint for MRSA during the overall treatment period [80].

Necrotizing Skin and Soft Tissue Infections
High-dose daptomycin in monotherapy (10 mg/kg q24 h) or in combination therapy with clindamycin (600 mg q6 h) is suggested as first-line targeted therapy of necrotizing skin and soft tissue infections caused by MRSA (Figure 2).
A recent meta-analysis of seven studies (907 patients) compared daptomycin and vancomycin in the treatment of bacteraemic MRSA infections and found that treatment success rate with daptomycin was significantly higher in intermediate-risk sources, of which 28-33% were soft tissue infections, (OR 4.40; 95%CI 2.06-9.40; p < 0.001) [81]. A large European registry including 6075 patients treated with daptomycin, of which 1927 had complicated skin and soft tissue infections (31.5% MRSA), reported an overall clinical success of 84.7% (87.0% in subgroup of patients with MRSA skin and soft tissue infections) [82]. Notably, daptomycin switch to due to previous clinical failure with other antibiotic therapy was reported in as high as 53.7% of patients [82].
A recent retrospective cohort study including 190 patients affected by necrotizing soft tissue infections of lower limbs found that clindamycin was associated with 2.92 times reduced odds of having an amputation when compared with their counterparts, including in adjusted analysis (p = 0.015) [83]. No significant difference in mortality rate between patients receiving clindamycin as part of their initial antibiotic regimen and those treated with comparators was reported (8.3% vs. 11.6%; p = 0.45) [83].
Interestingly, a retrospective case-control study [84] including 62 critically ill patients affected by necrotizing soft tissue infections (22.6% caused by Staphylococcus aureus) found that an intensive multidisciplinary management (including early surgical debridement followed by daily inspection of surgical wounds, close microbiological surveillance, and targeted antibiotic strategy including high-dose daptomycin for MRSA coupled with clindamycin plus anti-pseudomonal beta-lactam) was more effective than standard management (in which on-demand consultation with emergency surgeon and infectious disease specialist coupled with the use of vancomycin as targeted therapy for MRSA), allowing for earlier control of infection and faster reduction of multiple organ dysfunction (∆SOFA −5.2 ± 3.5 pts. vs. −2.1 ± 3.0 pts.; p = 0.003). Additionally, significant lower 7-day (3.1% vs. 20.0%; p = 0.049) and ICU mortality rate (15.6% vs. 40.0%; p = 0.032) was found in patients receiving intensive multidisciplinary management.
Overall, high-dose daptomycin could be suggested as targeted therapy of severe necrotizing skin and soft tissue infections caused by MRSA. Real-world data reported better clinical outcome compared to vancomycin in bacteraemic cases. Daptomycin showed very high penetration rate (i.e., 70-100%) in soft tissues [85,86], and this could maximize PK/PD target attainment at the infection site.

Expert Opinion
S. aureus represents a leading cause of infection among critically ill patients [3], and the widespread diffusion of MRSA is especially worrisome [4]. Several diagnostic platforms based on molecular methods are currently available for rapid detection of S. aureus and associated mec genes responsible for the methicillin-resistant phenotype. These systems work with positive blood cultures or directly with some clinical specimens [87] and can be very useful to rapidly assess, with high sensitivity, the presence of MSSA or MRSA as causes of infection, significantly shortening the time to targeted therapy. However, these systems cannot detect resistances to anti-MRSA cephalosporins and to non-beta-lactam agents, which should be tested by conventional phenotypic susceptibility testing.
In this context, the adoption of criteria that may provide the best therapeutic strategy in each of the different challenging scenarios may be fundamental [10,88].
In regard to MSSA infections, CI oxacillin or CI cefazolin monotherapy may represent the best choice for the management of the different types of infection, as no real-world evidence currently support the role of combination therapy.
In regard to MRSA infections, therapeutic choices should be guided by the infection site. Current evidence suggests that combination of high-dose daptomycin plus fosfomycin or ceftaroline/ceftobiprole may have very high probability of favorable clinical outcome and/or microbiological outcome in the treatment of primary BSIs or IE [29,32] and may represent a promising option for the management of infections associated with intracardiac/intravascular devices, including PVE [89]. Conversely, neither gentamicin nor rifampicin were shown to add significant advantages in this scenario [47]. It should also be noticed that several preclinical studies showed synergic activity between daptomycin and fosfomycin or ceftaroline [59,90,91], but the progressive emergence of fosfomycin-resistant and/or ceftaroline-resistant MRSA strains is quite worrisome [92][93][94][95]. Vancomycin and teicoplanin may be potential alternatives but were not considered as preferred agents due to the unfavorable PK/PD features (low bactericidal effect, risk of nephrotoxicity) [96][97][98]. Linezolid may be the preferred option in the treatment of deep-seated MRSA infections similar to CNS infections and/or IVACs based on the high penetration rates into the CSF and/or the ELF and on the favorable PK/PD features and [67,68,79,99]. Ceftaroline or ceftobiprole could be suggested as potential second-line alternatives in MRSA IVACs, especially in case of bacteraemic infections, although no pivotal trials were conducted in ICU scenario and real-world evidence are limited. High-dose daptomycin could be preferred in the treatment of severe MRSA necrotizing skin and soft tissue infections [100], especially when the pathophysiological alterations commonly retrieved in this type of infection may affect optimal PK/PD target attainment [101].
It should be mentioned that in patients allergic to oxacillin and/or cefazolin, good alternative options for the treatment of MSSA infections may be daptomycin, linezolid, or glycopeptides.
In conclusion, we are confident that these algorithm-based strategies could be helpful in improving clinical outcome in the treatment of challenging scenarios of S. aureus infections.

Conclusions
In an era characterized by the widespread diffusion of MRSA, implementing a multidisciplinary task force for targeting therapy in critically ill patients has become a real need. Our approach is focused on mirroring antibiotic therapy and on optimizing PK/PD target attainment at the infection site. These strategies could be helpful either in improving clinical outcome or in minimizing resistance spread. Availability of rapid molecular diagnostic tests for prompt identification of the causative pathogens will be fundamental for implementing antimicrobial stewardship programs based on the proposed algorithms.