Table 2.
Summary of studies investigating the treatment of infection caused by methicillin-resistant Staphylococcus aureus according to the different sites of infection.
| Author, Year and Reference | Study Design | No. of Patients | Antibiotic and Dosing | Source of Infection | Isolates | Severity | Clinical Outcomes | Relapse Rate— Resistance Development |
Comments |
|---|---|---|---|---|---|---|---|---|---|
| Primary or CR-BSI; IE; Infections Associated with Intracardiac Device—Daptomycin + Fosfomycin | |||||||||
| Pujol et al., 2021 | RCT | 155 (74 DAP + FOS vs. 81 DAP) |
DAP 10 mg/kg/day + FOS 2 g q6 h vs. DAP 10 mg/kg/day |
100% BSIs CR-BSI 41.9–48.1% SSTI 13.5–23.5% IE 11.1–12.2% surgical site 4.9–9.5% UTI 3.7–8.1% other 7.4–9.9% unknown 9.9–18.9% |
100% MRSA | Median CCI: 3–4 Mean Pitt score: 1.15–1.22 |
Treatment success at 6-week: 54.1% vs. 42.0% (RR 1.29; 95%CI 0.93–1.80; p = 0.14) Complicated BSI: 16.2% vs. 32.1% p = 0.022 |
6-week microbiological failure rate: 0% vs. 11.1% p = 0.003 AEs rate: 17.6% vs. 4.9%p = 0.018 |
Daptomycin plus fosfomycin provided a 12% higher rate of treatment success than daptomycin alone. This antibiotic combination prevented microbiological failure and complicated BSI, but it was more often associated with AEs. |
| Mirò et al., 2012 | Case series + In vitro study |
3 (+14 in vitro tested isolates) |
DAP 10 mg/kg/day + FOS 2 g q6 h |
100% IEs | 67% MRSA 33% MSSA |
NA | Clinical cure: 100% |
AEs rate: 0.0% |
This combination was tested in vitro against 7 MSSA, 5 MRSA, and 2 intermediately glycopeptide-resistant S. aureus isolates and proved to be synergistic against 11 (79%) strains and bactericidal against 8 (57%) strains. |
| Garcia-de-la-Maria et al., 2018 | In vivo study (rabbit model) |
5 MRSA strains | DAP 6–10 mg/kg + FOS 2 g q6 h or cloxacillin 2 g q4 h |
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. | |||||
| Primary or CR-BSI; IE; Infections Associated with Intracardiac Device—Daptomycin + Ceftaroline or Ceftobiprole | |||||||||
| Geriak et al., 2019 | RCT | 40 (17 DAP + ceftaroline vs. 23 DAP/VAN monotherapy) |
DAP 6–8 mg/kg/day + ceftaroline 600 mg q8 h |
100% BSIs SSTIs 35–53% BJI 17–29% LRTI 6–26% UTI 17–18% IE 4–19% CR-BSI 6–13% IAI 9% |
100% MRSA | ICU admission 13–18%Median CCI 5–6 Immunosuppressed 4% |
In-hospital mortality rate: 0% vs. 26% p = 0.029 |
NA | This exploratory study showed with a very small number of patients that initial therapy with DAP + ceftaroline may be associated with reduced in-hospital mortality compared with the treatment standards of VAN or DAP monotherapy in patients with MRSA bacteremia. The survival benefit, if any, may be limited to patients with high-risk endovascular sources and those with IL-10 of >5 pg/mL on the day of first positive blood culture. |
| McCreary et al., 2019 | Retrospective matched cohort study | 171 (58 DAP + ceftaroline vs. 113 standard of care) |
DAP 8 mg/kg/day + ceftaroline 600 mg q8 h |
100% BSIs Endovascular 53% Secondary 42% CR-BSI 5% |
100% MRSA | ICU admission 16% CCI >3 49–57% Immunosuppressed 9% |
30-day mortality rate: 8.3% vs. 14.2% p = NS Lower 30-day mortality rate in subgroup of patients receiving combination therapy with a CCI ≥3, endovascular source, and receipt of DAP-ceftaroline within 72 h of index culture |
Relapse: 8.6% vs. 9.7% p= NS |
DAP-ceftaroline treatment is often delayed in MRSA BSI. Combination therapy may be more beneficial if initiated earlier, particularly in patients at higher risk for mortality. |
| Nichols et al., 2021 | Retrospective case-control study | 140 (66 DAP + ceftaroline vs. 74 DAP/VAN or ceftaroline monotherapy) |
DAP + ceftaroline |
100% BSIs | 100% MRSA | ICU admission: 57–64% MV 11–18% Vasopressors: 15–17%Median CCI: 2–3 Immunosuppressed 13% |
Primary outcome (infection-related mortality, 60-day readmission, 60-day BSI recurrence): 21% vs. 24% p = 0.66 |
BSI recurrence: 3% vs. 7% p = 0.45 |
No difference was found in the composite outcome of 60-day bacteremia recurrence, readmission, or inpatient infection-related mortality for patients with MRSA bacteremia retained on combination therapy versus those de-escalated to monotherapy. |
| Johnson et al., 2021 | Retrospective cohort study | 60 (30 DAP + ceftaroline vs. 30 DAP/VAN ± GEN/RIF) |
DAP 10 mg/kg/day + ceftaroline 600 mg q8 h |
100% BSIs Endovascular 37–40% IE 23–50% CR-BSI 6.7–37% SSTI 13–23% LRTI 13% IAI 3.3% UTI 3.3% |
100% MRSA | ICU admission 53–57% Immunocompromised 10–13% Median CCI 5 |
Clinical failure rate: 20% vs. 43% p = 0.052 At multivariate analysis, DAP + ceftaroline was associated with 77% lower odds of clinical failure (OR 0.23; 95%CI 0.06–0.89) |
60-day recurrence: 0% vs. 30% p < 0.01 |
In patients with complicated MRSA-BSI with delayed clearance, DAP + ceftaroline trended towards lower rates of clinical failure than SoC and was significantly associated with decreased clinical failure after adjustment for baseline differences. |
| Ahmad et al., 2020 | Retrospective case-control study | 30 (15 DAP/VAN + ceftaroline vs. 15 switched to DAP/VAN monotherapy following BSI resolution) |
VAN 15–20 mg/kg q8–12 h or DAP 8–10 mg/kg/day + ceftaroline 600 mg q8–12 h |
100% BSIs IE 33–87% BJI 7–47% CNS infection 7% |
100% MRSA | Median CCI 0 | Mortality rate: 20% vs. 7% p = 0.24 |
Recurrence: 0% vs. 27% p = 0.27 |
In subjects with complicated and prolonged MRSA bacteremia requiring supplemental ceftaroline, clinical outcomes did not differ among patients prescribed DAP/VAN alone following bacteremia resolution vs. patients who continued combination therapy. |
| Sakoulas et al., 2014 | Retrospective multicenter study + in vitro analysis |
26 | DAP 4–10 mg/kg/day + ceftaroline 200 mg q12 h– 600 mg q8 h |
100% BSIs 54% IEs 42% BJI 4% SSTI |
76.9% MRSA 7.7% MSSA 7.7% VISA 7.7% MRSE |
NA | Mortality rate: 4% Time to bacteremia clearance: 10 (previous therapeutic regimens) vs. 2 days (DAP + ceftaroline) |
Ceftaroline plus daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen. |
|
| Cortes-Penfield et al., 2019 | Retrospective cohort study | 17 (5 DAP monotherapy vs. 12 DAP + ceftaroline 2–3° line) |
DAP 8 mg/kg/day + ceftaroline |
100% persistent BSIs BJI 47.1% IE 29.4% SSTI 23.5% |
100% MRSA | ICU admission 64.7% Mean CCI: 3.2–5 |
Mortality rate: 53% Duration of BSI: 11.1 (early combination therapy) vs. 17.3 days p = 0.11 |
NA | Early combination therapy with daptomycin and ceftaroline shortens prolonged MRSA bacteremia and may be helpful in securing favorable clinical outcomes. |
| Hornak et al., 2019 | Case series | 11 (6 DAP + ceftaroline; 5 VAN + ceftaroline) |
DAP or VAN + ceftaroline 200 mg q12 h– 600 mg q8 h |
100% BSIs | 100% MRSA | Median CCI 4.5 Immunosuppressed 20% |
Microbiological cure rate:100% 30-day mortality rate: 11.1% |
30-/60-day relapse: 0.0% | Combination therapy demonstrated success in diverse cases of refractory MRSA BSIs, including instances of persistent bacteremia paired with incomplete source control. |
| Duss et al., 2019 | Case report + in vitro analysis |
1 | DAP 10 mg/kg/day + ceftaroline600 mg q8 h |
IE | MRSA | NA | Clinical cure In in vitro analysis, at high inoculum only combination between DAP and ceftaroline provides synergistic and bactericidal activity |
No relapse | A synergistic effect between daptomycin plus ceftaroline and increased bactericidal activity against MRSA was reported, suggesting that this combination may be effective for the treatment of invasive MRSA infection. |
| Cunha et al., 2015 | Case report | 1 | DAP 12 mg/kg/day + Ceftaroline 600 mg q12 h |
PVE | 100% MRSA | NA | Clinical cure | No relapse | Ceftaroline plus high-dose daptomycin could be a treatment option for PVE sustained by difficult-to- treat MRSA strains. |
| Tascini et al., 2020 | Case series | 12 | Ceftobiprole + DAP (in 11 patients) |
100% IEs 67% PVEs |
33.3% MRSA 33.3% MSSA 33.3% CoNS |
Immunosuppressed 16.7% | Clinical cure rate 83% | Relapse 0.0% | Ceftobiprole, especially in combination, could be a promising alternative treatment for infective endocarditis. |
| Oltolini et al., 2016 | Case report | 1 | DAP 10 mg/kg/day + ceftobiprole 500 mg q8 h |
IE | MRSA | NA | Clinical cure | No relapse | Ceftobiprole plus daptomycin could be a treatment option for IE sustained by difficult-to- treat MRSA strains. |
| Barber et al., 2014 | In vitro study | 20 MRSA isolates | DAP + ceftobiprole |
Ceftobiprole plus daptomycin represented the most potent combination with a 4-fold decrease in MIC and synergy against all strains evaluated in time–kill evaluations. Additionally, binding studies demonstrated enhanced daptomycin binding in the presence of subinhibitory concentrations of ceftobiprole. The use of combination therapy with ceftobiprole may provide a needed addition for the treatment of Gram-positive infections resistant to daptomycin or vancomycin. | |||||
| Primary or CR-BSI; IE; Infections Associated with Intracardiac Device—Vancomycin or Teicoplanin | |||||||||
| Schweizer et al., 2021 | Multicenter retrospective cohort | 7411 of which 606 switched to DAP during the first hospitalization and 108 within the first 3 days |
VAN vs. switch to DAP |
100% BSIs SSTI 46.4–48.5%BJI 20.4–29.2% Endovascular 18.1–29.9% LRTI 2.3–5.0% |
100% MRSA MIC > 1 mg/L for VAN: 8.2–16.0% |
ICU admission 5.5–7.1% Immunosuppressed 76.2% |
30-day mortality rate: 8.3% (early switch to DAP) vs. 17.4% (VAN) aHR 0.48 (95%CI 0.25–0.92) 30-day mortality rate: 12.9% (any switch) vs. 17.4% (VAN) aHR 0.87 (95%CI 0.69–1.09) |
NA | Switching to daptomycin within 3 days of initial receipt of vancomycin is associated with lower 30-day mortality among patients with MRSA BSI. |
| Tong et al., 2020 | RCT | 352 (174 DAP/VAN + beta-lactam vs. 178 DAP/VAN) |
DAP 6–10 mg/kg/day or VAN 1 g q12 h + Oxacillin 2 g q6 h or Cloxacillin 2 g q6 h or CEF 2 g q8 h vs. DAP 6–10 mg/kg/day or VAN 1 g q12 h |
100% BSI SSTI 23–28% primary BSI 20% BJI 15–18% CR-BSI 12–14% LRTI 6–7% IE 3–5% other 7–10% |
100% MRSA | Median CCI: 5 Median SOFA score: 1–2 |
Primary outcome (90-day mortality, relapse, persistent BSI, microbiological failure): 35% vs. 39% (−4.2%; 95%CI −14.3% to 6%) 90-day mortality: 21% vs. 16% (4.5%; 95%CI −3.7% to 12.7%) |
Persistent BSI: 11% vs. 20% (−8.9%; 95%CI −16.6% to −1.2%) AKI: 23% vs. 6% (17.2%; 95%CI 9.3% vs. 25.2%) |
Among patients with MRSA bacteremia, addition of an antistaphylococcal β-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings. |
| Community-Acquired Pneumonia—Ceftaroline or Ceftobiprole | |||||||||
| Sotgiu et al., 2018 | Systematic review with meta-analysis | 6 retrospective observational studies providing data on patients with documented MRSA pneumonia (345 patients) |
Ceftaroline 600 mg q12 h |
CAP/HAP/VAP caused by MRSA | Pooled success rate in CAP subgroup: 81.3% (95%CI 80.0–82.7) Pooled success rate in MRSA subgroup: 71.7% (95%CI 59.7–82.3) |
||||
| Bassetti et al., 2020 | Retrospective cohort study | 89 | Ceftaroline 600 mg q8 h (60% combination therapy) |
100% severe CAP 12% bacteraemic |
Isolated pathogens in 34.8% of included cases 10.1% MRSA |
ICU admission 37% Septic shock 12% Immunosuppressed 40% Mean CCI 4 ± 3 |
30-day mortality rate: 20% Clinical failure rate: 36% The only independent predictor of clinical failure was the time elapsing from severe CAP diagnosis to ceftaroline therapy (OR for each passing day 1.5, 95%CI 1.1–1.9, p = 0.003). |
NA | Ceftaroline could represent an important therapeutic option for severe CAP. |
| Nicholson et al., 2012 | RCT | 638 (314 ceftobiprole vs. 324 ceftriaxone plus LIN) |
Ceftobiprole 500 mg q8 h vs. Ceftriaxone 2 g/day ± Linezolid 600 mg q12 h |
100% CAP 4% Bacteraemic |
Isolated pathogens in 28.8% of included cases | PSI ≥ 4: 22% SIRS 52–55% |
Clinical cure: 86.6% vs. 87.4% (95%CI −6.9% to 5.3%) Microbiological eradication: 88.2% vs. 90.8% (95%CI −12.6% to 7.5%) |
NA | Ceftobiprole was non-inferior to the comparator (ceftriaxone ± linezolid) in all clinical and microbiological analyses conducted, suggesting that ceftobiprole has a potential role in treating hospitalized patients with CAP. |
| Durante-Mangoni et al., 2020 | Retrospective cohort study | 29 | Ceftobiprole 250 mg/die– 500 mg q8 h |
19.3% CAP | 24.1% MRSA | Septic shock 13.8% | Clinical cure rate: 68.9% (66.7% in CAP subgroup) |
NA | Ceftobiprole, even outside current indications, may be a safe and effective treatment for resistant Gram-positive cocci infections where other drugs are inactive or poorly tolerated and for salvage therapy. |
| Infection-Related Ventilator-Associated Complications—Linezolid or Linezolid + Fosfomycin | |||||||||
| Kato et al., 2021 | Systematic review with meta-analysis | 7 RCTs (1239 patients) and 8 retrospective observational studies (6125 patients) |
LIN 600 mg q12 h vs. VAN 1 g q12 h or 15 mg/kg q12 h |
HAP/VAP caused by MRSA | Clinical cure and microbiological eradication rates were significantly increased in patients treated with LIN in RCTs (clinical cure: RR 0.81; 95%CI 0.71–0.92; microbiological eradication: RR 0.71; 95%CI 0.62–0.81) and retrospective studies (clinical cure: OR 0.35; 95%CI 0.18–0.69). However, mortality was comparable between patients treated with VAN and LIN in RCTs (RR 1.08; 95%CI 0.88–1.32) and retrospective studies (OR 1.20; 95%CI 0.94–1.53). Likewise, there was no significant difference in AEs between VAN and LIN in retrospective studies (thrombocytopenia: OR 0.95; 95%CI 0.50–1.82; nephrotoxicity: OR 1.72; 95%CI 0.85–3.45). According to our meta-analysis of RCTs and retrospective studies conducted worldwide, we found robust evidence to corroborate the IDSA guidelines for the treatment of proven MRSA pneumonia. |
||||
| Jiang et al., 2013 | Systematic review with meta-analysis | 12 RCTs (4725 patients) |
LIN vs. VAN or TEI |
HAP | There was no statistically significant difference between the two groups in the treatment of nosocomial pneumonia regarding the clinical cure rate (RR 1.08; 95%CI 1.00–1.17; p = 0.06). Linezolid was associated with better microbiological eradication rate in nosocomial pneumonia patients compared with glycopeptide antibiotics (RR 1.16; 95%CI 1.03–1.31; p = 0.01). There were no differences in the all-cause mortality (RR 0.95; 95%CI 0.83–1.09; p = 0.46) between the two groups. However, the risks of rash (RR 0.41; 95%CI 0.24–0.71; p = 0.001) and renal dysfunction (RR 0.41; 95%CI = 0.27–0.64; p < 0.0001) were higher with glycopeptide antibiotics. | ||||
| Antonello et al., 2020 | Systematic review of in vitro studies | 9 in vitro/in vivo preclinical studies | LIN + FOS |
S. aureus isolates (166 strains) |
Combination therapy including FOS and LIN had a synergistic effect in vitro approximately in 95% of cases (synergistic effect of the combination against 100% of the tested isolates was reported in 6 in vitro studies) and even against staphylococcal biofilm cultures. Furthermore, the only 2 in vivo studies performed proved FOS + LZD combination to have higher efficacy than FOS or LIN alone. | ||||
| Chen et al., 2018 | In vitro study | 11 S. aureus strains (5 MSSA and 6 MRSA) | LIN + FOS |
Synergistic effects were observed for eight strains, and no antagonism was found with any combination. Moreover, LIN combined with FOS at 4× MIC showed the best synergistic antibacterial effect, and this effect was retained after 24 h. In addition, both the antibiotics alone and in combination showed increased post-antibiotic effect and post-antibiotic subminimum inhibitory concentration effect values in a concentration- and time-dependent manner. | |||||
| Li et al., 2020 | In vitro/in vivo preclinical study | 4 S. aureus strains (2 MSSA and 2 MRSA) | LIN 10 mg/kg + FOS 200 mg/kg |
The combination of linezolid and fosfomycin was synergistic and bacteriostatic against four tested strains. Treatment of Galleria mellonella larvae infected with lethal doses of S. aureus resulted in significantly enhanced survival rates when low-dose of combination has no significant differences with high-dose combination. Combination therapy including linezolid and fosfomycin has synergistic effect against S. aureus in vitro and in an experimental G. mellonella model, and it suggests that a high dose of linezolid and fosfomycin may not be necessary. | |||||
| Chai et al., 2016 | In vitro/in vivo preclinical study | 3 MRSA strains | LIN 40 mg/kg q12 h + FOS 300 mg/kg q12 h |
A FICI ≤ 0.5 was found for LIN + FOS combination, showing the best synergistic effect in all strains. The combination of LIN and FOS in a 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. | |||||
| Infection-Related Ventilator-Associated Complications—Ceftaroline or Ceftobiprole | |||||||||
| Sotgiu et al., 2018 | Systematic review with meta-analysis | 6 retrospective observational studies providing data on patients with documented MRSA pneumonia (345 patients) |
Ceftaroline 600 mg q12 h |
CAP/HAP/VAP caused by MRSA | Pooled success rate in HAP/VAP subgroup: 83.0% (95%CI 65.0–95.0) Pooled success rate in MRSA subgroup: 71.7% (95%CI 59.7–82.3) |
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| Kaye et al., 2015 | Retrospective cohort study | 40 | Ceftaroline | 67.5% HAP 32.5% VAP |
47.5% MRSA | ICU admission 42.5% | Overall clinical cure rate: 75.0% (61.5% in VAP subgroup) Clinical success rate in MRSA subgroup: 57.9% |
NA | Ceftaroline is an effective treatment option for HAP and VAP when a susceptible etiologic pathogen is identified, including MRSA. |
| Scheeren et al., 2019 | Retrospective analysis of an RCT | 307 (169 ceftobiprole vs.138 comparator) |
Ceftobiprole 500 mg q8 h vs. Ceftazidime + Linezolid |
100% HAP | 23.7% S. aureus | Mechanical ventilation 22.5% | Early clinical response (at day 4): difference 12.5% (95%CI 3.5–21.4) |
NA | Ceftobiprole treatment may have advantages over other antibiotics in terms of achieving early improvement in high-risk patients with HAP. |
| Durante-Mangoni et al., 2020 | Retrospective cohort study | 29 | Ceftobiprole 250 mg/die– 500 mg q8 h |
47.8% HAP/VAP | 24.1% MRSA | Septic shock 13.8% | Clinical cure rate: 68.9% (85.7% in HAP/VAP subgroup) No clinical failure in MRSA subgroup |
NA | Ceftobiprole, even outside current indications, may be a safe and effective treatment for resistant Gram-positive cocci infections where other drugs are inactive or poorly tolerated and for salvage therapy. |
| Antonelli et al., 2019 | In vitro study | 66 MRSA isolates from HAP | Ceftobiprole | Overall susceptibility to ceftobiprole: 95.5%; MIC50: 1 mg/L; MIC90: 2 mg/L | |||||
| Central Nervous System Infections—Linezolid or Linezolid + Fosfomycin | |||||||||
| Chen et al., 2020 | Retrospective cohort study | 66 | LIN | Brain abscess 28.8% Spinal epidural abscess 27.3% Meningitis 18.2% Meningitis + brain/epidural abscess 13.6% Spine device-related infection 7.6% |
100% MRSA Bacteraemic 78.8% |
Liver cirrhosis 21.2% | In-hospital mortality rate: 13.6% |
Relapse rate: 16.7% |
LIN demonstrated promising effect as a salvage therapy for central nervous system infection caused by MRSA, whether due to drug allergy or glycopeptide treatment failure. |
| Pintado et al., 2020 | Retrospective multicentric cohort study | 26 | LIN 600 mg q12 h (62% monotherapy) |
100% meningitis 81% post-operative |
15 MRSA 11 MSSA Bacteraemic 8% |
Immunosuppressed 8% | Clinical cure rate: 69% Microbiological cure rate: 93% 30-day mortality rate: 23% |
NA | Linezolid appears to be effective and safe for therapy of S. aureus meningitis. |
| Sipahi et al., 2013 | Retrospective case-control study | 17 | LIN 600 mg q12 h vs. VAN 500 mg q6 h |
Meningitis 100% | 17 MRSA | NA | Microbiological cure at 5-day: 77.8% vs. 25.0% p = 0.044 |
NA | Findings suggested that LIN is superior to VAN for treating MRSA meningitis, especially in cases in which there is a high MIC (2 mg/L) for VAN. |
| Rebai et al., 2019 | Case series | 10 | LIN 600 mg q12 h |
Meningitis 60%Ventriculitis 20% Subdural empyema 20% |
7 MRSA 3 MRSE |
NA | Microbiological cure rate: 100% |
NA | LIN could be an alternative to VAN for the treatment of post-neurosurgical infections caused by MRSA with a high rate of efficacy. |
| Viaggi et al., 2011 | PK study | 7 | LIN 600 mg q12 h |
100% external ventricular drainage | Prophylaxis of CNS infection | ICU admission 100% | AUCCSF/AUCpkasma
0.57 |
NA | The wide variability in the CSF concentration profile and drug PK among patients suggests the adoption of TDM-guided strategy. |
| Saito et al., 2010 | Case series | 2 | LIN 600 mg q12 h |
100% intracranial abscess | 2 MRSA | ICU admission 100% | Clinical cure 100% | None | LIN showed high CSF penetration allowing for the effective treatment of post-neurosurgical infections caused by MRSA. |
| Kallweit et al., 2007 | Case report | 1 | LIN 600 mg q12 h |
Meningitis | MRSA | NA | Clinical cure | None | LIN showed high CSF penetration allowing for the effective treatment of post-neurosurgical infections caused by MRSA. |
| Kessler et al., 2007 | Case report | 1 | LIN 600 mg q12 h |
Meningitis | MRSA | NA | Clinical cure | None | LIN showed high CSF penetration allowing for the effective treatment of post-neurosurgical infections caused by MRSA. |
| Pfausler et al., 2004 | PK study | 6 | FOS 8 g q8 h |
100% ventriculitis | 2 MSSA 2 MSSE 2 NA |
ICU admission 100% | AUCCSF/AUCpkasma
0.27 ± 0.08 |
NA | High-dose FOS could provide sufficient antimicrobial concentrations in the CSF for the overall treatment period. |
| Antonello et al., 2020 | Systematic review of in vitro studies | 9 in vitro/in vivo preclinical studies | LIN + FOS |
S. aureus isolates (166 strains) |
Combination therapy including FOS and LIN had a synergistic effect in vitro approximately in 95% of cases (synergistic effect of the combination against 100% of the tested isolates was reported in 6 in vitro studies) and even against staphylococcal biofilm cultures. Furthermore, the only 2 in vivo studies performed proved FOS + LZD combination to have higher efficacy than FOS or LIN alone. | ||||
| Chen et al., 2018 | In vitro study | 11 S. aureus strains (5 MSSA and 6 MRSA) | LIN + FOS |
Synergistic effects were observed for eight strains, and no antagonism was found with any combination. Moreover, LIN combined with FOS at 4× MIC showed the best synergistic antibacterial effect, and this effect was retained after 24 h. In addition, both the antibiotics alone and in combination showed increased post-antibiotic effect and post-antibiotic subminimum inhibitory concentration effect values in a concentration- and time-dependent manner. | |||||
| Li et al., 2020 | In vitro/in vivo preclinical study | 4 S. aureus strains (2 MSSA and 2 MRSA) | LIN 10 mg/kg + FOS 200 mg/kg |
The combination of linezolid and fosfomycin was synergistic and bacteriostatic against four tested strains. Treatment of Galleria mellonella larvae infected with lethal doses of S. aureus resulted in significantly enhanced survival rates when low-dose of combination has no significant differences with high-dose combination. Combination therapy including linezolid and fosfomycin has synergistic effect against S. aureus in vitro and in an experimental G. mellonella model, and it suggests that a high dose of linezolid and fosfomycin may not be necessary. | |||||
| Chai et al., 2016 | In vitro/in vivo preclinical study | 3 MRSA strains | LIN 40 mg/kg q12 h + FOS 300 mg/kg q12 h |
A FICI ≤ 0.5 was found for LIN + FOS combination, showing the best synergistic effect in all strains. The combination of LIN and FOS in a 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. | |||||
| Necrotizing Fasciitis—Daptomycin ± Clindamycin | |||||||||
| Samura et al., 2022 | Systematic review with meta-analysis | 7 studies (2 RCTs and 5 retrospective observational; 907 patients) |
DAP vs. VAN |
100% BSI due to MRSA (28–32.8% complicated SSTI) |
DAP was associated with significantly lower mortality (OR 0.53, 95%CI 0.29–0.98) and higher treatment success (OR 2.20, 95%CI 1.63–2.96) compared to VAN. For intermediate-risk sources (including complicated SSTI), DAP was a factor increasing treatment success compared with VAN (OR 4.40, 95%CI 2.06–9.40). | ||||
| Cogo et al., 2015 | Multicenter retrospective registry | 1927 | DAP ≥ 4–6 mg/kg/day |
100% complicated SSTI |
S. aureus 51.9% (MRSA 31.5%) |
NA | Overall clinical success rate: 84.7% Clinical success rate in MRSA subgroup: 87.0% |
NA | DAP treatment resulted in high clinical success rates in patients with different complicated SSTI subtypes, the majority of whom having failed previous antibiotic therapy, with no safety issues. |
| Gatti et al., 2019 | Retrospective case-control study | 62 (32 receiving IMM vs. 30 SM) |
DAP 8–10 mg/kg/day vs. VAN 20 mg/kg/day |
100% NSTI |
S. aureus 22.6% (MRSA 3.2%) |
ICU admission 100%MV 90.3% Vasopressors 83.9% Immunosuppression 24.2% |
ICU mortality rate: 15.6% vs. 40% (p = 0.032) 7-day mortality rate: 3.1% vs. 20% (p = 0.049) |
NA | IMM was more effective than SM as it allowed the earlier control of infection and the faster reduction of multiple organ-dysfunction (ΔSOFA −5.2 ± 3.5 pts. versus −2.1 ± 3.0 pts.; p = 0.003). |
AE: adverse event; AKI: acute kidney injury; AUC: are under concentration-time curve; BJI: bone and joint infection; BSI: bloodstream infection; CAP: community-acquired pneumonia; CCI: Charlson comorbidity index; CEF: cefazolin; CI: continuous infusion; CNS: central nervous system; CR-BSI: catheter-related bloodstream infection; CSF: cerebrospinal fluid; DAP: daptomycin; EOT: end of treatment; FICI: fractional inhibitory concentration index; FOS: fosfomycin; GEN: gentamycin; HAP: hospital-acquired pneumonia; HR: hazard ratio; IAI: intrabdominal infection; ICU: intensive care unit; IE: infective endocarditis; IHD: intermittent hemodialysis; II: intermittent infusion; IMM: intensive multidisciplinary management; LIN: linezolid; LRTI: lower respiratory tract infection; MIC: minimum inhibitory concentration; MRSA: methicillin-resistant S. aureus; MRSE: methicillin-resistant S. epidermidis; MSSA: methicillin-susceptible S. aureus; MSSE: methicillin-susceptible S. epidermidis; MV: mechanical ventilation; NA: not assessed; NS: not significant; NSTI: necrotizing soft tissue infections; OR: odds ratio; PK: pharmacokinetic; PSI: pneumonia severity index; PVE: prosthetic valve endocarditis; RCT: randomized controlled trial; RIF: rifampicin; RR: risk ratio; SIRS: systemic inflammatory response syndrome; SM: standard management; SoC: standard of care; SSTI: skin and soft tissue infection; TDM: therapeutic drug monitoring; TEI: teicoplanin; UTI: urinary tract infection; VAN: vancomycin; VPA: ventilator-associated pneumonia; VISA: vancomycin-intermediate S. aureus.