Are Two Antibiotics Better Than One?

Methicillin-resistant Staphylococcus aureus (MRSA) is a common community and nosocomial pathogen capable of causing a wide variety of infections. Mortality rates associated with MRSA bacteremia have been reported as high as 50%. Despite the prevalence of MRSA, significant controversy exists regarding optimal treatment strategies, particularly for patients with complicated and/or persistent infections. Vancomycin remains an impressive workhorse in the MRSA treatment landscape; however, its utility is limited by slow bactericidal activity, evolving dosing strategies that necessitate labor-intensive therapeutic drug monitoring, nephrotoxicity, and suboptimal clinical outcomes data despite decades of use. Daptomycin is an alternative first-line agent for the treatment of MRSA bacteremia and is associated with less nephrotoxicity and more convenient dosing strategies compared with vancomycin. Nonetheless, the outcomes of patients treated with standard daptomycin doses are underwhelming, as only 44% of patients with MRSA bacteremia achieved clinical success following receipt of a 6-mg/kg daily dose.¹ Of concern, gene mutations that confer daptomycin tolerance and enhanced S aureus survival have been reported.^2,3 Unlike treatment with vancomycin, higher doses of daptomycin (ie, ≥8 mg/kg/day) demonstrate more rapid in vitro killing and suppression of resistance and are associated with improved clinical outcomes.^4,5

An alternative approach is combination therapy with a β-lactam, which offers similar advantages as high-dose daptomycin but may allow for use of lower vancomycin or daptomycin doses.⁶ Historically, combination approaches have been employed for treatment refractory or persistent MRSA bacteremia; however, new data indicate that such approaches could have benefit if employed much earlier.

The Infectious Diseases Society of America clinical practice guidelines for the treatment of MRSA infections recommend high-dose daptomycin (ie, 10 mg/kg/day) in combination with another antibiotic as salvage therapy for persistent MRSA bacteremia and/or vancomycin treatment failures.⁷ Unfortunately, there are minimal data to demonstrate which antibiotic combinations are preferred or when combination therapy should be initiated or stopped. Moreover, the role of novel MRSA-active antibiotics is not represented, as the guidelines were published only months after ceftaroline received approval from the US Food and Drug Administration and years before even newer agents were introduced on the market. Interestingly, patients often receive empiric “combination therapy” in clinical practice with vancomycin plus either cefepime or piperacillintazobactam. Recent data suggest that patients receiving at least 24 hours of cefepime have improved clearance of MRSA bloodstream infections compared with patients receiving vancomycin monotherapy, and this may be a preferred empiric regimen if cefepime has adequate in vitro activity against gram-negative nosocomial pathogens within the institution.⁸

β-Lactam antibiotics are likely the preferred partner agents for vancomycin and daptomycin because of their enhanced safety compared with other antibiotic classes that may be considered for synergy and because of the favorable economic profile of older β-lactam agents such as cefazolin. The absence of real-world clinical data for the use of novel MRSA-active agents for complicated infections, taken with compelling in vitro synergy data and desire to use antibiotics judiciously, warrants the investigation of β-lactam combination therapies. Briefly, we review the available in vitro and clinical data for β-lactam combination therapies in the treatment of MRSA bacteremia.

In Vitro Data

Several mechanisms of synergy exist between β-lactams and vancomycin or daptomycin. Notably, increasing glyco- and lipopeptide resistance is associated with improved susceptibility to β-lactam antibiotics through a phenomenon called the seesaw effect. Possible explanations include increased expression of penicillin-binding protein (PBP) 2, decreased PBP4, and/ or inactivation of the mecA gene in vancomycin-intermediate S aureus (VISA) or vancomycin-resistant strains.^9,10 Among the 4 PBPs produced by S aureus, PBP1 blockade is most strongly associated with daptomycin potentiation. Therefore, β-lactams with affinity for PBP1 (eg, cefazolin, nafcillin, meropenem) enhance anti-MRSA activity of daptomycin, whereas those with minimal affinity (eg, ceftriaxone, cefoxitin) do not.^11,12 Interestingly, ceftaroline is more active against MRSA isolates with higher vancomycin and daptomycin minimum inhibitory concentrations because of enhanced PBP2 binding.^10,13 Other bacterial genetic and metabolic adaptions may confer changes to the bacterial cell wall. Indeed, ceftaroline enhances daptomycin-induced cell membrane depolarization and reduces cell wall thickness of both daptomycin-susceptible and -nonsusceptible strains of S aureus, including biofilm-producing MRSA.^14,15 This potent synergy may result in clinical de-escalation or sparing of higher daptomycin doses.⁶

Synergy may also be explained by immune system regulation. Sakoulas and colleagues found that exposure to nafcillin significantly increased the activity of host defense peptides, particularly human cathelicidin LL-37, against S aureus, resulting in enhanced killing.¹⁶ The effect was more pronounced at higher doses; however, synergistic effects were observed at extremely low nafcillin concentrations. Importantly, the effect was also observed with ampicillin, piperacillin, cefazolin, ceftriaxone, and ceftaroline. The combinations of vancomycin and cefazolin, cefepime, ceftaroline, and nafcillin all demonstrated improved in vitro killing against vancomycin-susceptible, heterogeneous VISA, as well as VISA strains, compared with vancomycin alone.¹⁷

Clinical Data

Retrospective analyses of patients receiving vancomycin or daptomycin plus a β-lactam show shorter durations of bacteremia but no impact on rates of clinical failure compared with monotherapy.^18,19 Notably, however, bacteremia persisted for a median of 10 days prior to combination therapy initiation in these studies.¹⁹ Indeed, ceftaroline has been used successfully with vancomycin and daptomycin as salvage therapy for patients with refractory, persistent MRSA bacteremia.^19-22 Ceftaroline is an attractive choice to use in combination because it is the only β-lactam with in vitro activity against MRSA in addition to the synergistic laboratory effects previously described. The question of whether ceftaroline monotherapy would demonstrate improved clinical outcomes compared with vancomycin or daptomycin monotherapy or combination regimens remains unanswered. Patients are more likely to benefit from combination therapy earlier in the treatment course, particularly patients at higher risk of mortality.^19,23 A retrospective evaluation of 171 patients with MRSA bacteremia found mortality was reduced by 80% at 60 days for patients with a primary endovascular source receiving combination therapy with daptomycin plus ceftaroline within 72 hours of index blood culture.²⁴ In a recent prospective trial, patients with MRSA bacteremia were randomized to daptomycin (6-8 mg/kg/day) plus ceftaroline (600 mg every 8 hours) or standard monotherapy within 72 hours.²⁵ No patients (0 of 17) in the combination therapy arm died compared with 26% (6 of 23) of patients in the standard therapy arm, resulting in early termination of the study. All deaths were among patients with an endovascular source, and the majority (5 of 6) had serum IL-10 concentrations >5 pg/mL. The median duration of combination therapy was 8 days before de-escalation to monotherapy, which is notable because evidence to support the duration of combination therapy is lacking. Short durations of early combination followed by definitive monotherapy may be economically advantageous and spare unnecessary antibiotic exposures and toxicities.²⁵

An earlier prospective clinical trial that evaluated β-lactam combination therapy for MRSA bacteremia enrolled 60 patients who were randomly assigned to receive vancomycin or vancomycin plus flucloxacillin for 7 days within 48 hours of the first positive blood culture.²⁶ Patients receiving combination therapy had a 24-hour shorter duration of bacteremia, and fewer patients experienced persistent bacteremia. No difference in mortality was observed, owing to the small sample size. A subsequent openlabel trial (NCT02365493) of adult patients with MRSA bacteremia was designed to further elucidate the clinical effectiveness of early combination therapy based on these data. Patients were randomized within 72 hours of the first positive blood culture to either standard therapy (vancomycin or daptomycin monotherapy) or combination therapy with vancomycin or daptomycin plus 7 days of an antistaphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin).²⁷ The primary outcome is a composite measure of all-cause mortality, persistent bacteremia at 5 days or greater, microbiological relapse (defined as a MRSA-positive blood culture at least 72 hours after a negative culture), and microbiological treatment failure (defined as MRSA isolated from any sterile site except urine at least 14 days after randomization). The trial closed enrollment in December 2018 per recommendations of the data safety monitoring committee, and the infectious disease community eagerly awaits results.

Conclusions

Based on available and emerging data, it is reasonable to employ combination therapy with a PBP1-active β-lactam or ceftaroline early in the MRSA bacteremia treatment course, particularly in patients at the highest risk of treatment failure or death. Seven days of combination therapy may be sufficient if employed early in the treatment course, but more clinical data are needed to determine the optimal drug pairings and duration of combination therapy. Empiric monotherapy with ceftaroline compared with vancomycin or daptomycin monotherapy or combination regimens needs to be explored.

McCreary serves as an antimicrobial stewardship/ infectious diseases clinical pharmacist at the University of Pittsburgh Medical Center in Pennsylvania. *She is a member of the Society of Infectious Diseases Pharmacists.Barber is an assistant professor at the University of Mississippi School of Pharmacy and a clinical specialist in infectious diseases at the University of Mississippi Medical Center. *She is a member of the Society of Infectious Diseases Pharmacists.

References:

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