Look, I know I have talked a lot about staphylococcus but there is a ton of details that go into the therapeutic aspects of it. When it comes to staphylococcus aureus bacteremia, specifically MRSA, vancomycin is the first line therapy per the IDSA guidelines (1). I have discussed the issues with vancomycin dosing, and how the goal troughs only guarantee you will achieve a specific pharmacodynamic parameter rather than achieving a therapeutic goal. Given the broad use of vancomycin, it is not a surprise that over the years (at least since the 1980s, when vancomycin became more broadly used) the MIC of MRSA to vancomycin has increased. This is referred to as the “MIC creep” and this was the subject of a fairly interesting review (2). One of the implications of a rising MIC in MRSA isolates is that current target troughs for vancomycin of 15-20mg/L allows isolates with MIC <0.5 to have a near 100% chance of achieving the goal AUC/MIC ratio of 400, which drops to nearly 0% when the MIC increases to 2.
Despite this concern, however, it seems the trend is going in the opposite direction. A meta-analysis of 55 studies (3) found that the MIC by both broth microdilution (BMD) and Etest were decreasing overall:
Of course, while the overall MIC is not going up, it stands to reason that higher MIC (at least 2) would be associated with treatment failure by the above logic. For instance, in vitro data has found that higher MIC was associated with treatment failure in vancomycin treated patients, with success being correlated with higher bactericidal activity (4):
There is quite a bit of retrospective data to suggest that higher MIC to vancomycin is associated with both higher mortality and higher rates of recurrences. For instance, a small cohort study (5) found that patients whose MIC to vancomycin was 2 by BMD were more likely to have poor treatment outcomes (74% vs 46%). Further, another cohort (6) suggests that high MIC by Etest (1.5) was associated with higher rates of complicated bacteremia (78.3% vs 13.2%, p <0.0001), as well as with higher mortality (17.4% vs 3.9%, p = 0.08). A larger, 15-year cohort study evaluated 414 episodes of MRSA bacteremia (7). While multivariate analysis found that higher MIC was protective against shock, logistic regression analysis found that an MIC greater than 1.5 was independently associated with higher mortality:
In another cohort (8), patients with high MIC by Etest experienced higher composite of failure, though when dividing the individual components of the primary outcome:
Furthermore, classification and regression tree analysis identified an MIC of 1.5 by Etest as the threshold of higher failure (71% vs 28.3%), and achieving a trough of 15 was not correlated with success. This also holds true for nosocomial MRSA, with one cohort (9) finding that patients with MIC >2 had higher 30-day mortality rate (HR 2.20, 95% CI 1.13-4.27 by univariate; HR 2.39, 95% CI 1.2-4.79 by multivariate analysis).
One interesting tidbit here is that this relationship seems to hold true even if the organism is susceptible to methicillin (i.e. you have an MSSA with an MIC to vancomycin of 2), regardless if someone is treated with an antibiotic other than vancomycin. In one cohort study (10), 284 patients treated with vancomycin were matched with an equal number treated with flucloxacillin. While patients who were treated with vancomycin were more likely to have hospital onset or device associated infections, logistic regression univariate and multivariate models found that high vancomycin MIC by Etest (>1.5) was associated with higher mortality:
Notably, vancomycin MIC had an impact on mortality, regardless of whether the patient was treated with flucloxacillin or vancomycin:
Several meta-analyses have found similar results. A review of 25 studies (11) found that vancomycin MIC was associated with higher mortality, regardless of the source of infection, only when MRSA strains were evaluated (OR 1.64, 95% CI 1.14-2.73). When looking at an Etest MIC >2, there was a higher mortality for staph aureus infections when compared to lower MICs (OR 1.74, 95% CI 1.34-2.21). Similarly, high MIC (those >1.5) was associated with treatment failure:
Another meta-analysis (12) evaluated several vancomycin MICs via different methodologies (BMD <1 and Etest <1.5 were categorized as low MIC) with primary outcome being treatment failure and mortality. In 20 studies, there was an increased risk of failure in those who had a high MIC to vancomycin (RR 1.40, 95% CI 1.15-1.71) as well as a higher risk of mortality (RR 1.42,9 95% CI 1.08-1.87).
The Utility of Other MRSA Agents
Given what we know from the data above, it would be reasonable to assume another agent would provide better results. This was evaluated in a matched cohort study of 85 patients treated with daptomycin and 85 treated with vancomycin (13). Here, daptomycin was associated with less clinical failure at 30 days compared to vancomycin (20% vs 48.2% p <0.001). Multivariate logistic regression analysis found that vancomycin was associated with higher risk of 30-day clinical failure (aOR 4.5, 95% CI 2.1-9.8). Survival at 90 days was significantly higher in the daptomycin group:
It should be noted that the average AUC was ~211 in the vancomycin group, suggesting these patients may have been underdosed. In another retrospective, case-control study (14) both agents were compared in patients whose MRSA MIC to vancomycin was between 1 and 2. The composite outcome of 60-day mortality, microbiological failure, and bacteremia recurrence was lower in the daptomycin group (31% vs 17%, p =0.084), with the outcome being largely driven by mortality benefit (20% in the vanco group vs 9% in the dapto group, p=0.046). In univariate analysis, the use of vancomycin was associated with failure (OR 3.13, 95% CI 1.0-9.76). It should be noted, however, that those who received daptomycin were more likely to have osteomyelitis and have an ID consult, which may have influenced the results.
Finally, a propensity matched cohort study (15) found that clinical failure was higher in the vancomycin treated cohort compared to the daptomycin one (45% vs 29%, p=0.007), a pattern that held true even when the vancomycin BMD MIC was 0.5 (54.5% vs 32%, p=0.027):
Multivariate analysis also found that vancomycin therapy was associated with clinical failure:
Given this, it seems reasonable to use daptomycin in severe infections where the vancomycin MIC is creeping up. Despite this, however, there is some data that does not suggest MIC plays a role in outcomes. For instance, in one retrospective cohort study (16) comparing 163 patients with MIC <1 and >2, multivariate survival analysis did not find that vancomycin MIC >2 was associated with higher 28-day all-cause mortality (aHR 1.57, 95% CI 0.73-3.37). Further, in another meta-analysis of 13 studies, high and low MIC mortality was not statistically different (27.7% vs 23.3%, respectively 17). Finally, in a review of 38 studies (18), high vancomycin MIC (>1.5) was not associated with higher mortality (risk difference 1.6%, 95% CI -2.3 to 5.6). This held true when analyzing MICs >2 (risk difference 3.3, 95% CI -3.4 to 9.9%).
One thing to note is the variability in the MIC methodology, which may account for the difference in the data with the later studies and why the target seems to shift between 1.5 and 2. While broth microdilution method is considered the gold standard for MIC testing, Etest is also another methodology that is frequently used. In several studies, Etest tends to provide values that were higher when compared to broth microdilution (19, 20), suggesting that a cut-off of 2 in the Etest is roughly equivalent to that of 1.5 in the BMD.
- MIC creep refers to the overall increase in MIC to certain antibiotics for a strain of bacteria
- For Staph aureus, in relation to vancomycin, it means that the same goal trough at a higher MIC leads to a lower probability of achieving your goal pharmacokinetic parameters
- Higher MIC to vancomycin for MRSA (i.e. 1.5 for BMD and 2 for Etest) are associated with poorer outcomes such as higher mortality, higher rates of relapse
- Daptomycin may be the antibiotic of choice if the vancomycin MIC is above 1.5-2.
- Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer AW, Levine DP, Murray BE, J Rybak M, Talan DA, Chambers HF; Infectious Diseases Society of America. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011 Feb 1;52(3):e18-55. doi: 10.1093/cid/ciq146. Epub 2011 Jan 4. Erratum in: Clin Infect Dis. 2011 Aug 1;53(3):319. PMID: 21208910.
- Dhand A, Sakoulas G. Reduced vancomycin susceptibility among clinical Staphylococcus aureus isolates (‘the MIC Creep’): implications for therapy. F1000 Med Rep. 2012;4:4. doi: 10.3410/M4-4. Epub 2012 Feb 1. PMID: 22312414; PMCID: PMC3270590.
- Diaz R, Afreixo V, Ramalheira E, Rodrigues C, Gago B. Evaluation of vancomycin MIC creep in methicillin-resistant Staphylococcus aureus infections-a systematic review and meta-analysis. Clin Microbiol Infect. 2018 Feb;24(2):97-104. doi: 10.1016/j.cmi.2017.06.017. Epub 2017 Jun 23. PMID: 28648858.
- Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC Jr, Eliopoulos GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol. 2004 Jun;42(6):2398-402. doi: 10.1128/JCM.42.6.2398-2402.2004. PMID: 15184410; PMCID: PMC427878.
- Hidayat LK, Hsu DI, Quist R, Shriner KA, Wong-Beringer A. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med. 2006 Oct 23;166(19):2138-44. doi: 10.1001/archinte.166.19.2138. PMID: 17060545.
- Aguado JM, San-Juan R, Lalueza A, Sanz F, Rodríguez-Otero J, Gómez-Gonzalez C, Chaves F. High vancomycin MIC and complicated methicillin-susceptible Staphylococcus aureus bacteremia. Emerg Infect Dis. 2011 Jun;17(6):1099-102. doi: 10.3201/eid/1706.101037. PMID: 21749780; PMCID: PMC3358192.
- Soriano A, Marco F, Martínez JA, Pisos E, Almela M, Dimova VP, Alamo D, Ortega M, Lopez J, Mensa J. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis. 2008 Jan 15;46(2):193-200. doi: 10.1086/524667. PMID: 18171250.
- Lodise TP, Graves J, Evans A, Graffunder E, Helmecke M, Lomaestro BM, Stellrecht K. Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin. Antimicrob Agents Chemother. 2008 Sep;52(9):3315-20. doi: 10.1128/AAC.00113-08. Epub 2008 Jun 30. PMID: 18591266; PMCID: PMC2533486.
- Wang JL, Wang JT, Sheng WH, Chen YC, Chang SC. Nosocomial methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in Taiwan: mortality analyses and the impact of vancomycin, MIC = 2 mg/L, by the broth microdilution method. BMC Infect Dis. 2010 Jun 7;10:159. doi: 10.1186/1471-2334-10-159. PMID: 20529302; PMCID: PMC2890009.
- Holmes NE, Turnidge JD, Munckhof WJ, Robinson JO, Korman TM, O’Sullivan MV, Anderson TL, Roberts SA, Gao W, Christiansen KJ, Coombs GW, Johnson PD, Howden BP. Antibiotic choice may not explain poorer outcomes in patients with Staphylococcus aureus bacteremia and high vancomycin minimum inhibitory concentrations. J Infect Dis. 2011 Aug 1;204(3):340-7. doi: 10.1093/infdis/jir270. PMID: 21742831.
- van Hal SJ, Lodise TP, Paterson DL. The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis. Clin Infect Dis. 2012 Mar;54(6):755-71. doi: 10.1093/cid/cir935. Epub 2012 Feb 2. PMID: 22302374.
- Jacob JT, DiazGranados CA. High vancomycin minimum inhibitory concentration and clinical outcomes in adults with methicillin-resistant Staphylococcus aureus infections: a meta-analysis. Int J Infect Dis. 2013 Feb;17(2):e93-e100. doi: 10.1016/j.ijid.2012.08.005. Epub 2012 Oct 22. PMID: 23089040; PMCID: PMC3780595.
- Murray KP, Zhao JJ, Davis SL, Kullar R, Kaye KS, Lephart P, Rybak MJ. 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. 2013 Jun;56(11):1562-9. doi: 10.1093/cid/cit112. Epub 2013 Feb 28. PMID: 23449272.
- Moore CL, Osaki-Kiyan P, Haque NZ, Perri MB, Donabedian S, Zervos MJ. 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. 2012 Jan 1;54(1):51-8. doi: 10.1093/cid/cir764. Epub 2011 Nov 21. PMID: 22109947.
- Claeys KC, Zasowski EJ, Casapao AM, Lagnf AM, Nagel JL, Nguyen CT, Hallesy JA, Compton MT, Kaye KS, Levine DP, Davis SL, Rybak MJ. Daptomycin Improves Outcomes Regardless of Vancomycin MIC in a Propensity-Matched Analysis of Methicillin-Resistant Staphylococcus aureus Bloodstream Infections. Antimicrob Agents Chemother. 2016 Sep 23;60(10):5841-8. doi: 10.1128/AAC.00227-16. PMID: 27431221; PMCID: PMC5038271.
- Honda H, Doern CD, Michael-Dunne W Jr, Warren DK. The impact of vancomycin susceptibility on treatment outcomes among patients with methicillin resistant Staphylococcus aureus bacteremia. BMC Infect Dis. 2011 Dec 5;11:335. doi: 10.1186/1471-2334-11-335. PMID: 22142287; PMCID: PMC3254119.
- Ishaq, H., Tariq, W., Talha, K.M. et al. Association between high vancomycin minimum inhibitory concentration and clinical outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: a meta-analysis. Infection 49, 803–811 (2021). https://doi.org/10.1007/s15010-020-01568-4
- Kalil AC, Van Schooneveld TC, Fey PD, Rupp ME. Association between vancomycin minimum inhibitory concentration and mortality among patients with Staphylococcus aureus bloodstream infections: a systematic review and meta-analysis. JAMA. 2014 Oct 15;312(15):1552-64. doi: 10.1001/jama.2014.6364. PMID: 25321910.
- Sader HS, Rhomberg PR, Jones RN. Nine-hospital study comparing broth microdilution and Etest method results for vancomycin and daptomycin against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2009 Jul;53(7):3162-5. doi: 10.1128/AAC.00093-09. Epub 2009 Apr 27. PMID: 19398641; PMCID: PMC2704704.
- Kruzel MC, Lewis CT, Welsh KJ, et al. Determination of vancomycin and daptomycin MICs by different testing methods for methicillin-resistant Staphylococcus aureus. J Clin Microbiol. 2011;49(6):2272-2273. doi:10.1128/JCM.02215-10