Should MRSA bloodstream infection be treated with vancomycin, daptomycin or something else? In this article an infectious diseases pharmacist with research and clinical experience in the area provides insights on the pharmacologic options for MRSA bloodstream infection.
Authored By: Kimberly Claeys, Pharm.D., BCPS
Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) represents one of the most common healthcare associated infections seen by clinical pharmacists and result in significant morbidity and mortality. The Infectious Disease Society of America (IDSA) even has a guideline dedicated to the management of MRSA infections.
We all know that vancomycin is our go-to agent for the management of MRSA BSIs and according to the IDSA MRSA guidelines it is recommended for BSIs and/or infective endocarditis with an A-II level of evidence. We are also familiar with the fact that vancomycin is not without its limitations. For instance, there are numerous studies (some conflicting), which detail the impact of MRSA vancomycin minimum inhibitory concentrations (MICs) on patient mortality. There is also as the need to strictly dose and then monitor vancomycin levels in order to optimize the pharmacokinetic/pharmacodynamic (PK/PD) index of efficacy while minimizing toxicity.
Daptomycin is also recommend within the IDSA MRSA guidelines and is approved for the treatment of S. aureus BSIs. In clinical practice we often reserve daptomycin for difficult-to-treat cases or those with possible vancomycin failure. Although this is current clinical practice, does this represent best clinical practice?
Below is a quick recap of the available literature comparing these two agents for the treatment for MRSA BSI and some of the important PK/PD considerations for the use of vancomycin.
VANCOMYCIN VERSUS DAPTOMCIN: RETROSPECTIVE DATA EVERYWHERE
Straight out of Detroit, MI
Aside from the initial 2005 clinical trial comparing daptomycin to vancomycin in S. aureus (both methicillin-sensitive [MSSA] and MRSA) BSIs and infective endocarditis, the majority of comparative effectiveness trials have been retrospective and a lot of that data has been from a single geographic location in Michigan. Let’s start with the studies from the research group in Detroit:
In 2013 Kullar and colleagues published a quasi-experimental study where clinical success was compared pre- (n = 100) and post-implementation (n= 70) of a new MRSA BSI treatment pathway. This new pathway recommended an early change to high dose daptomycin in MRSA BSI where the vancomycin MIC was reported as > 1 mg/L. Clinical success was defined as a composite of: resolution/improvement in baseline signs and symptoms, absence of new signs and symptoms, and/or eradication of MRSA from bloodstream after at least 7 days of therapy. Success was significantly higher in the post-pathway implementation group (75.0% versus 41.4%, p < 0.001). This was largely driven by the fact that more patients in the pre-pathway group experienced persistent bacteremia beyond 7 days of vancomycin therapy (43.4% versus 21%, p < 0.001).
An important limitation of this study, however, was the unbalanced nature of the pre- and post-pathway groups. More patients in the pre-pathway group had primary sites of MRSA that included infective endocarditis and bone/joint while post-pathway patients had more catheter-associated MRSA BSIs.
Next was the matched cohort study of early (within 72 hours) daptomycin versus vancomycin by Murray and colleagues. A total of 170 patients with MRSA BSI and vancomycin MIC > 1 mg/L were matched 1:1 using age, Pitt Bacteremia Score, and primary source of MRSA. Clinical outcomes were again compared between vancomycin-treated versus daptomycin-treated patients with the primary outcome of clinical failure, a composite metric of 30-day all-cause mortality and/or persistent bacteremia lasting > 7 days. The investigators reported significantly higher clinical failure rates in vancomycin-treated patients (48.2% versus 20.0%, p <0.001) and increased 30-day all-cause mortality (12.9% versus 3.5%, p = 0.047). Again, persistent bacteremia was a major driver for increased clinical failure in the vancomycin-treated patients (42.4% versus 18.8%, p = 0.001).
Besides the usual pitfalls of retrospective observational studies, a major limitation was the reliance on automated susceptibility testing (AST) MICs.
To offset this potential limitation, a third study, which included 262 patients, was completed. This time clinical isolates from all patients included in the final analysis were collected in order to determine “true” MIC by broth microdilution (BMD). This study was matched by propensity score according to: age, Pitt Bacteremia Score, primary source of MRSA, and hospital of care. The primary outcome was clinical failure, again a composite metric. This time clinical failure included the following parameters: 30-day all-cause mortality, bacteremia persistent ≥7 days, or a change in antibiotic therapy secondary to persistent signs and symptoms of infection.
A total of 262 patients were included in the final analysis. To be included in the daptomycin-treatment arm patients had to be changed to daptomycin within 72 hours of start of MRSA therapy. Clinical failure was significantly higher in the vancomycin-treated patients (45.0% versus 29.0%, p = 0.007).
The vancomycin MIC by BMD was used to stratify outcomes and clinical failure remained higher in the vancomycin-treated patients. Since this was a contemporary cohort, with the majority of patients treated after the release of the two previously mentioned papers, clinical failure in the vancomycin-treated patients was largely driven by change in therapy (28.2% versus 15.3%, p = 0.05) as opposed to persistent bacteremia. Regardless, 30-day all-cause mortality remained higher in the vancomycin-treated group (15.3% versus 6.1%, p = 0.01).
Here are the links and references for the three aforementioned studies:
- Kullar R, Davis SL, Kaye KS, Levine DP, Pogue JM, Rybak MJ. 2013. Implementation of an antimicrobial stewardship pathway with daptomycin for optimal treatment of methicillin-resistant Staphylococcus aureus bacteremia. Pharmacotherapy 33:3-10.
- Murray KP, Zhao JJ, Davis SL, Kullar R, Kaye KS, Lephart P, Rybak MJ. 2013. Early use of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bacteremia with vancomycin minimum inhibitory concentration >1 mg/L: a matched cohort study. Clin Infect Dis 56:1562-1569.
- Claeys KC, Zasowski EJ, Casapao AM, Lagnf AM, Nagel JL, Nguyen CT, Hallesy JA, Compton MT, Kaye KS, Levine DP, Davis SL, Rybak MJ. 2016. Daptomycin Improves Outcomes Regardless of Vancomycin MIC in a Propensity-Matched Analysis of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections. Antimicrob Agents Chemother 60:5841-5848.
Additional retrospective analysis
Aside from the aforementioned trilogy from Detroit there have been several retrospective comparative trials mirroring the results described above (with another from Detroit!).
In a 2012 study by Moore and colleagues, 118 vancomycin-treated patients were matched to 59 daptomycin-treated patients. To be included daptomycin had to be started within 14 days of MRSA infection. Matching criteria included age, APACHE II and risk level of MRSA source (low/intermediate/high). The primary outcome of interest of clinical failure, a composite of: 60-day all-cause mortality, microbiologic failure (persistence), and/or MRSA BSI recurrence. Median time to change to daptomycin therapy was 5 days (interquartile range [IQR] 3 – 9 days) and 48% of these patients had positive MRSA blood cultures at the time of the switch.
Patients in the vancomycin-treated group experienced higher clinical failure rates, but the difference was not statistically significant (31.0% versus 17.0%, p = 0.084). There was, however, a significantly higher rate of 60-day all-cause mortality among vancomycin-treated patients (20.0% versus 9.0 %, p = 0.049).
In 2014 Weston and colleagues examined the potential role of daptomycin for the treatment of MRSA BSI in patients with varying renal function. Among the 100 vancomycin- and 50-daptomycin-treated patients, approximately half had renal impairment with a glomerular filtration rate of < 50 mL/min/1.73m2. Clinical failure composite was defined as: in-hospital mortality, 30-day MRSA BSI recurrence, and/or bacteremia > 5 days.
Vancomycin-treated patients experienced higher clinical failure rates (51% versus 34%, p = 0.048) and, importantly, the results were not different when outcomes were stratified by renal function according to KDOQI stages.
Most recently in 2016, Moise and colleagues published a retrospective multicenter matched cohort study in patients with MRSA BSI with elevated vancomycin MICs. This study included a total of 170 patients from 11 institutions across the United States. Patients were excluded from the analysis if they received > 5 days of therapy with vancomycin before daptomycin therapy. Patients were matched according to age, severity of illness, infection type, infectious diseases consult, and institution. The composite outcome of clinical failure included: 60-day all-cause mortality, persistent bacteremia or signs and symptoms of infection > 7 days, failure at end of treatment, and 30-day recurrence/relapse of MRSA BSI.
The composite outcome was not significantly different between vancomycin-treated and daptomycin-treated patients (39.0% versus 31.0%, p = 0.259). Higher failure rates at end of therapy were noted in the vancomycin-treated group (24.0% versus 11.0%, p = 0.025) – the main driver for this outcome was the need to change antibiotic therapy. Of note, 76% of patients had clearance of bacteremia by day 4 and attributable mortality was the same for vancomycin- versus daptomycin-treated patients. A potential limitation to consider is the concomitant use of beta-lactam agents was significantly higher among vancomycin-treated patients (71% versus 46%, p = 0.001), meaning the potential benefit of the seesaw effect could skew outcomes.
Here are the links and references for the three aforementioned studies:
- Moore CL, Osaki-Kiyan P, Haque NZ, Perri MB, Donabedian S, Zervos MJ. 2012. Daptomycin versus vancomycin for bloodstream infections due to methicillin-resistant Staphylococcus aureus with a high vancomycin minimum inhibitory concentration: a case-control study. Clin Infect Dis 54:51-58.
- Weston A, Golan Y, Holcroft C, Snydman DR. 2014. The efficacy of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bloodstream infection in patients with impaired renal function. Clin Infect Dis 58:1533-1539.
- Moise PA, Culshaw DL, Wong-Beringer A, Bensman J, Lamp KC, Smith WJ, Bauer K, Goff DA, Adamson R, Leuthner K, Virata MD, McKinnell JA, Chaudhry SB, Eskandarian R, Lodise T, Reyes K, Zervos MJ. 2016. Comparative Effectiveness of Vancomycin Versus Daptomycin for MRSA Bacteremia With Vancomycin MIC >1 mg/L: A Multicenter Evaluation. Clin Ther 38:16-30.
SO DAPTOMYCIN IS BETTER, RIGHT?
Recognizing limitations of our data
This brief review of available literature provides a compelling argument for use of daptomycin in MRSA BSI over traditional vancomycin therapy. There are, however, several practical considerations and limitations in study design that should be addressed.
One of the most obvious considerations when trying to aggregate the available data is the fact that the primary outcomes of these studies varied considerably. Although the term “clinical failure” was used throughout (Kullar examined clinical success, but this is arguably dichotomous and mutually exclusive), the clinical failure composites were composed of varying and inconsistent metrics. From one study to the next there is no consistent definition of clinical failure.
Additionally, when clinical failure was significantly different, the main driver of that failure varied between studies, with some having persistent bacteremia as the main cause while others were driven by a switch in antibiotic therapy.
Time to start of daptomycin therapy also varied considerably, with one study allowing up to 14 days of alternative MRSA therapy before daptomycin was initiated.
Another consideration is the time period under study. While some of these studies used contemporary cohorts of patients from the last 5 years, others included patients that spanned a decade. This may not seem like a long time, but there is still the potential for the temporal changes in practice to cause significant bias in the final analysis. For instance, more aggressive source control, more infectious disease consults, and shorter time to change to an alternative agent from vancomycin are all considerations.
So although quite compelling, the results detailed above are difficult to aggregate and drawn sufficient conclusions to change treatment paradigms for MRSA BSI.
This brings us to the following publication:
- Weston A, Boucher HW. 2013. Early high-dose daptomycin for methicillin-resistant Staphylococcus aureus bloodstream infections with elevated vancomycin minimum inhibitory concentrations: ready for prime time? Clin Infect Dis 56:1570-1572.
Dosing and target attainment considerations
From a practical standpoint, dosing of both vancomycin and daptomycin varied considerably throughout the available studies. Daptomycin doses ranged from 5 mg/kg to 10 mg/kg, with scattered mention of dosing weights.
Many clinicians have become comfortable with the concept of high-dose daptomycin therapy from a safety perspective, but from a health-system perspective doses may be limited based on cost of the agent. Perhaps more importantly, vancomycin dosing and monitoring strategies have changed considerably and continue to evolve.
For several of the above studies, the PK/PD target for vancomycin changed from goal steady state trough values of > 10 mg/L to trough values of 15 mg/L to 20 mg/L. During this time we have also found out that trough values of 15 mg/L to 20 mg/L are associated with significantly higher rates of nephrotoxicity, an important consideration when comparing outcomes between the two agents.
We have known for some time that the ideal PK/PD target for vancomycin is the area-under-the-concentration-time curve (AUC) in relation to MIC (AUC/MIC ratio) of > 400, but daily practice has not followed suit due to the difficulty implementing a two-level AUC monitoring and dosing program in clinical practice.
As Lodise and colleagues have shown, up to 60% of patients with vancomycin trough values < 15 mg/L still achieve a target AUC/MIC of > 400. The same group also demonstrated that, when the MRSA vancomycin MIC is 2 mg/L, vancomycin struggles to obtain our PK/PD target, with probability of target attainment of only 57%, often producing doses with unacceptably high risk of nephrotoxicity.
Inability to measure the true AUC in vancomycin-treated patients represents a limitation of our currently available literature from both the perspectives of efficacy and toxicity. A thorough review of the literature supporting vancomycin AUC monitoring is beyond the scope of this article, but a nice review of innovative practices as well as background materials as a provided here in these papers:
- Pai MP, Neely M, Rodvold KA, Lodise TP. 2014. Innovative approaches to optimizing the delivery of vancomycin in individual patients. Adv Drug Deliv Rev 77:50-57.
- Neely MN, Youn G, Jones B, Jelliffe RW, Drusano GL, Rodvold KA, Lodise TP. 2014. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrob Agents Chemother 58:309-3.
- Patel N, Pai MP, Rodvold KA, Lomaestro B, Drusano GL, Lodise TP. 2011. Vancomycin: we can’t get there from here. Clin Infect Dis 52: 969-74.
A closer look at data from the microbiology lab
Methods used to measure vancomycin MIC are also a major consideration and potential limitation of available literature.
There have been several publications focused on the discordance between automated testing systems, E-test, and the “gold-standard” BMD method. It is well known that E-test will produce MICs that are one to two dilutions higher than BMD, however, these reports also demonstrate significant discordance between the three major automated testing systems, BMD, and E-test.
The MicroScan system overcalls MIC by one dilution up to 74% of the time while Pheonix and Vitek 2 more likely under-call the MIC by one dilution (76% and 20% of the time, respectively). The important consideration is that these are measures of absolute agreement, but essential agreement (MIC + 1 log2 dilution) is the main driver for measuring precision of these instruments in clinical practice. If we were to look only at essential agreement, these systems would be in agreement 93.6% to 100% of the time. Given the importance of MRSA vancomycin MICs on ability to obtain PK/PD efficacy targets and overall association with patient outcomes, having an accurate estimate of MIC becomes essential to optimizing patient care.
These publications provide additional insight into this:
- Bland CM, Porr WH, Davis KA, Mansell KB. 2010. Vancomycin MIC susceptibility testing of methicillin-susceptible and methicillin-resistant Staphylococcus aureus isolates: a comparison between Etest(R) and an automated testing method. South Med J 103:1124-1128
- Rybak MJ, Vidaillac C, Sader HS, Rhomberg PR, Salimnia H, Briski LE, Wanger A, Jones RN. 2013. Evaluation of vancomycin susceptibility testing for methicillin-resistant Staphylococcus aureus: comparison of Etest and three automated testing methods. J Clin Microbiol 51:2077-2081
IF NOT DAPTOMYCIN, WHAT ELSE?
Looking back to our IDSA MRSA guidelines, vancomycin and daptomycin are the only two agents with sufficient data to recommend for treatment of MRSA BSI. That being said, these guidelines were last updated in 2011 and we have seen an increase in the number of agents on the market that demonstrate bactericidal activity against MRSA. Of these new agents, ceftaroline shows the most promise for clinical use in terms of emerging evidence.
Ceftaroline Fosamil was approved for treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia in 2010. Since this time there have been several retrospective studies evaluating its use in MRSA bacteremia, even allowing it to gain approval for use in MRSA BSIs secondary to skin infections in 2015.
Clinically, ceftaroline has often been used in combination as salvage therapy after vancomycin failure. In a retrospective study of 527 patients that received ceftaroline during their care, 129 patients were identified as having S. aureus BSI (92.5% were MRSA). Of these patients, 109 (78.3%) experienced improved clinical outcomes when ceftaroline was either added or substituted as primary therapy.
Potential limitations of this study include the fact that ceftaroline was often used in combination with other agents, usually after vancomycin therapy, and it is unclear how many patients were actively bacteremic (i.e. had MRSA positive blood cultures at time of ceftaroline therapy).
Ceftaroline has also been studied in case series either alone or in combination with other MRSA-active agents (i.e. daptomycin or TMP/SMX) with positive results with respect to clinical and microbiological cure. A full review of alternative treatments for MRSA BSI is also beyond the scope of this article, but suggested reviews are listed below:
- Kullar R, Sakoulas G, Deresinski S, van Hal SJ. 2016. When sepsis persists: a review of MRSA bacteraemia salvage therapy. J Antimicrob Chemother 71:576-586.
- Holubar M, Meng L, Deresinski S. 2016. Bacteremia due to Methicillin-Resistant Staphylococcus aureus: New Therapeutic Approaches. Infect Dis Clin North Am 30:491-507.
- High dose daptomycin has been shown to decrease clinical failure compared to vancomycin in MRSA BSIs. Recent data suggests that these improved clinical outcomes are regardless of vancomycin MIC.
- Variation in existing literature is seen in regards to definition of clinical failure, dosing for both antibiotics, timing of daptomycin, and vancomycin MICs. This limits our confidence in aggregating the data and in suggesting a change to daptomycin as first line therapy.
- Vancomycin remains the mainstay treatment and we are becoming increasingly aware of limitations in clinical practice, from determining the appropriate MIC to monitoring vancomycin exposure optimally.
- There is potential for other options besides strictly using vancomycin or daptomycin. With respect to monotherapy, ceftaroline may be a viable option but more clinical evidence is needed.
[Last updated: 11/27/2016]
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