Combination Therapy in Methicillin-Resistant Staphylococcus aureus Bacteremia: History
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Chienhsiu Huang
,
Ihung Chen
,
Lichen Lin

Combination therapy with daptomycin plus ceftaroline to treat methicillin-resistant Staphylococcus aureus bacteremia has been reported to reduce methicillin-resistant Staphylococcus aureus bacteremia-related mortality. The combination therapy group had an in-hospital mortality, duration of bacteremia, and adverse event rate similar to those patients who had monotherapy. There was less bacteremia recurrence in the combination group. Initial combination therapy with ceftaroline for the treatment of methicillin-resistant Staphylococcus aureus bacteremia showed a trend of reducing the risk of in-hospital mortality. 

  • vancomycin
  • daptomycin
  • ceftaroline
  • Methicillin-resistant Staphylococcus aureus

1. Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a serious infectious disease associated with a high risk of mortality [1][2][3]. The primary parenteral therapy for MRSA infection is vancomycin. Treatment with vancomycin will clinically or microbiologically fail in invasive MRSA infections [4][5][6][7][8]. Daptomycin is an alternative first-line option that is reserved for MRSA bacteremia that has relapsed or persisted despite vancomycin treatment. However, the failure of daptomycin in the treatment of MRSA bacteremia is common, and nonsusceptibility has emerged [9][10][11]. The clinical practice guidelines by the infectious diseases society of America for the treatment of MRSA infections in adults and children recommends the following management strategies for persistent MRSA bacteremia and vancomycin treatment failure in adult patients: 1. If the isolate is susceptible, high-dose daptomycin in combination with another agent (such as a beta-lactam antibiotic) should be considered (B-III strength of recommendation). 2. If a reduced susceptibility to vancomycin and daptomycin are present, options may include quinupristindalfopristin, trimethoprim-sulfamethoxazole, linezolid, or telavancin (C-III strength of recommendation) [12]. Ceftaroline is a fifth-generation cephalosporin that is active against gram-positive pathogens such as Staphylococcus aureus (SA) and Streptococcus pneumoniae as well as their resistant strains (e.g., MRSA, vancomycin-resistant SA, and multidrug-resistant Streptococcus pneumoniae) [13]. The in vitro activity of ceftaroline is also active against common gram-negative pathogens such as Escherichia coli, Klebsiella pneumoniae, and Haemophilus influenzae; it is not active against extended spectrum beta-lactamase-producing gram-negative organisms [14]. Ceftaroline is the only commercially available beta-lactam with bactericidal activity against MRSA; it also increases the bactericidal effect of daptomycin by enhancing daptomycin binding to bacterial cell membranes [15][16][17]. Ceftaroline is currently approved in the United States for bacterial pneumonia and skin/soft tissue infections [18][19]. Observational studies have shown that ceftaroline may be effective in the treatment of MRSA bacteremia. However, studies comparing ceftaroline to standard-of-care therapy for MRSA bacteremia are limited, and ceftaroline is not United States Food and Drug Administration-approved for this indication. Thus, combination therapy with ceftaroline plus daptomycin is an option because both agents have an individual efficacy against MRSA [20][21][22]. In the study by Zasowski et al., ceftaroline was noninferior to daptomycin in the treatment of MRSA bacteremia [23]. Studies have shown that combination therapy, such as the combination of daptomycin and ceftaroline, can reduce the duration of MRSA bacteremia and mortality due to MRSA bacteremia [24][25][26][27][28].

2. Ceftaroline plus Vancomycin or Daptomycin Combination Therapy versus Vancomycin or Daptomycin Monotherapy

The standard-of-care therapy for MRSA bacteremia is associated with high morbidity and mortality. Medical experts should explore the use of two antibiotics in combination. Four meta-analyses of combination therapy in the treatment of MRSA bacteremia were published in the literature [29][30][31][32]. Ye et al. (2020) included six studies of vancomycin combined with beta-lactam antibiotics and showed that there was significantly reduced persistent bacteremia and a shortened duration of bacteremia in the combination therapy group. There was no statistically significant difference in the incidence of nephrotoxicity, 30-day mortality, MRSA-related mortality, or bacteremia relapse between the two groups [29]. The study of Wang et al. (2020) included 15 studies of patients treated with daptomycin or vancomycin in combination with beta-lactam antibiotics and showed that the combination therapy significantly reduced the bacteremia recurrence and persistent bacteremia and shortened the duration of bacteremia. There was no statistically significant difference in the risk of crude mortality between the two groups. However, a subgroup analysis of three studies showed that the combination of daptomycin plus beta-lactam antibiotics could reduce the risk of crude mortality [30]. The study by Kale-Pradhan et al. (2020) included nine studies of patients treated with daptomycin or vancomycin in combination with beta-lactam antibiotics and demonstrated that the combination therapy was associated with significantly lower rates of bacteremia relapse and persistent bacteremia. Mortality was not significantly different between the two groups [31]. Yi et al. (2021) included 13 studies of patients treated with daptomycin or vancomycin in combination with beta-lactam antibiotics and found no statistically significant difference in 30-day mortality, in-hospital mortality, or mortality within 60–90 days between the two groups. Combination therapy is associated with a shorter duration of bacteremia, a lower risk of persistent bacteremia, and a lower risk of bacteremia recurrence within 60–90 days [32]. The previous four meta-analyses showed that adding a beta-lactam antibiotic to vancomycin or daptomycin decreased the recurrence of bacteremia and shortened the bacteremia duration in the treatment of patients with MRSA bacteremia. There was no evidence that combination therapy could reduce the risk of MRSA bacteremia mortality. Researchers only included ceftaroline in combination with vancomycin or daptomycin versus vancomycin or daptomycin in the current meta-analysis. The results were the same as those of the previous four meta-analyses. Combination therapy in the treatment of MRSA bacteremia did not reduce the risk of mortality, implying no significant benefit for patients with MRSA bacteremia.
Lodise et al. suggested that the administration of MRSA bacteremia therapy within the first 24–48 h was strongly related to clinical outcomes [33]. Studies have shown that high-risk MRSA bacteremia patients benefit the most from combination therapy when it is administered early in the treatment course (within 72 h) [34]. It is important to initiate combination therapy early in the treatment of MRSA bacteremia, and it should be initiated within the first 72 h of onset, ideally within the first 24 h to prevent complications from persistent bacteremia [35][36][37]. Many studies have stressed that administering initial therapy within 72 h of the index culture is strongly related to MRSA bacteremia mortality. Researchers analyzed two studies in the current meta-analysis, namely, the study of McCreary et al. and the study of Geriak et al. [38][39]. In the study of McCreary et al., the patients receiving daptomycin with ceftaroline combination therapy for MRSA bacteremia had a lower all-cause mortality at day 30 than those who received standard-of-care monotherapy. A subgroup analysis showed that there was a numerically lower mortality in the patients who received daptomycin plus ceftaroline within 72 h of the index culture. The study suggested that daptomycin and ceftaroline may have mortality benefits when initiated early for MRSA bacteremia [39]. In the study of Geriak et al., vancomycin or daptomycin was used as a monotherapy, and a regimen of daptomycin plus ceftaroline was used as a comparator for the initial treatment of MRSA bacteremia. That study observed an unanticipated in-hospital mortality difference of 0% (0/17) for combination therapy and 26% (6/23) for monotherapy, causing the early termination of the study [38]. That study also showed that daptomycin and ceftaroline combination therapy have mortality benefits as initial therapy within 72 h of the index culture in the treatment of MRSA bacteremia. The current meta-analysis recommended initial combination therapy with ceftaroline for MRSA bacteremia rather than ceftaroline as salvage therapy because initial combination therapy with ceftaroline may reduce the risk of MRSA bacteremia mortality. The current challenges with vancomycin or daptomycin plus ceftaroline combination in the treatment of MRSA bacteremia include a lack of ceftaroline data for the treatment of MRSA bacteremia, and a lack of data on the efficacy and safety of initial combination therapy for MRSA bacteremia. Researchers call into question whether combination therapy works. Which combinations are best for MRSA bacteremia patients? What is the appropriate duration of combination therapy? Is combination therapy necessary for the entire course of treatment? Whether a de-escalation treatment regimen is considered a reasonable alternative to long-term combination therapy in patients with an early clinical response remains to be determined. In the future, four issues need to be explored by medical experts, which are as follows: 1. Initial and early combination therapy with daptomycin or vancomycin plus ceftaroline may be beneficial for mortality in MRSA bacteremia patients. Blinded, randomized, prospective studies are needed to confirm the efficacy and safety of combination therapy in MRSA bacteremia patients. 2. Appropriate dosing strategies for daptomycin or vancomycin plus ceftaroline combination therapy have not been determined. 3. Combination therapy is not necessary for the entire course of treatment. If de-escalation therapy is considered a reasonable alternative to long-term combination therapy in patients with an early clinical response, further investigation is warranted to determine the optimal timing of de-escalation. These drugs, including their dosage regimen and duration of therapy, are optimal for de-escalation therapy. 4. In the study of Geriak et al., a higher mortality was seen in patients with serum interleukin-10 concentrations >5 pg/mL [38]. The researchers recommend the use of biomarkers as potential risk indicators for the administration of combination therapy in high-risk patients. Biomarkers related to MRSA bacteremia are a new, attractive area that is worth exploring. The medical community urgently needs advanced knowledge of biomarkers related to MRSA bacteremia to guide clinical decision-making and the management of MRSA bacteremia patients.

This entry is adapted from the peer-reviewed paper 10.3390/antibiotics11081104

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