From MIC creep to MIC decline: Staphylococcus aureus antibiotic susceptibility evolution over the last 4 years
Authors: J. Ruiz, E. Villarreal, M. Gordon, J. Frasquet, A. Castellanos, P. Ramirez
Journal: Clinical Microbiology and Infection (2016)

Staphylococcus aureus is a major cause of nosocomial bacteraemia worldwide, and it has been associated with a high morbidity and mortality rate. Since its discovery in 1880 this microorganism has been able to develop resistance to different antibiotics to which it has been exposed. However, the main events in the evolution of S. aureus have been the emergence of resistance to methicillin and the progressive increase of vancomycin MICs, which has been described as ‘MIC creep’. Results of recent studies have suggested an association between high vancomycin MIC and worse outcomes [[1]Kalil A.C. Van Schooneveld T.C. Fey P.D. Rupp M.E. Association between vancomycin minimum inhibitory concentration and mortality among patients with Staphylococcus aureus bloodstream infections: a systematic review and meta-analysis.JAMA. 2014; 312: 1552-1564Crossref PubMed Scopus (136) Google Scholar]. In a retrospective study, we have investigated the dynamics of S. aureus antibiotic susceptibility and its possible relationship with hospital antibiotic consumption in patients with nosocomial S. aureus bacteraemia from January 2010 to December 2014. The study was performed in a public, tertiary-care, university-affiliated hospital with 975 acute-care beds in Spain. Hospital antibiotic consumption obtained from the stock management program calculated as Defined Daily Doses (DDD) and DDD per 100 patient-days. Resistance to vancomycin, daptomycin and linezolid was investigated according to the standard procedures. Vancomycin and daptomycin MICs were determined by the microdilution method in accordance with CLSI criteria by using commercial panels (ESTEN 2009; SensititreTM, Izasa, Spain) read visually. Trends in antibiotic use and resistance during the study period were examined with the Kendall correlation test, using the year as a covariate. Autoregressive integrated moving average (ARIMA) models were performed for 6-month periods to investigate the relationship between S. aureus vancomycin MIC and methicillin-resistant S. aureus (MRSA) prevalence and hospital consumption of antibiotic used for Gram-positive infections during the same period and the previous 6-month period. Pearson correlation coefficient tests for S. aureus vancomycin and daptomycin MICs were also calculated. A total of 209 consecutive episodes of nosocomial bacteraemia due to S. aureus were included; 58 (27.2%) were caused by MRSA. We observed a decrease in vancomycin MIC during the study period (p <0.001). This reduction was particularly relevant in bacteraemia due to S. aureus with MIC >1.5 mg/L. In 2010, all patients with S. aureus bacteraemia had a vancomycin MIC value >1.5 mg/L, whereas only 6.9% of patients in 2014 showed a vancomycin MIC value >1.5 mg/L (Table 1). Reduction in vancomycin MIC was observed for both methicillin-susceptible S. aureus (p 0.005) and MRSA (p 0.03). There were no differences in vancomycin MIC between medical, critical care, haematological, surgical and paediatric units (p 0.339). No changes in the percentage of MRSA among the total number of S. aureus bacteraemia were observed (p 0.759).Table 1Antibiotic consumption and MICaMIC in mg/L. to vancomycin, daptomycin and linezolid20102011201220132014pbp-value for Kendall correlation test.Total Staphylococcus aureus bacteraemia, n3231414263-DDD/100 patients-day (Total DDD) Vancomycin1.37 (4296)1.32 (3677)0.92 (2648)1.63 (4558)1.55 (4345)0.806 Teicoplanin1.02 (2917)1.09 (3048)0.75 (2155)0.71 (1981)0.47 (1484)0.086 Linezolid4.30 (13 526)4.04 (11 224)3.13 (9006)5.52 (15 443)5.77 (16 154)0.462 Daptomycin0.36 (1129)0.50 (1386)0.64 (1849)1.55 (4342)2.49 (6970)0.023 Cloxacillin0.24 (759)0.32 (879)0.53 (1534)0.87 (2441)1.36 (3797)0.015 Quinolones10.37 (32 593)11.65 (27 526)13.08 (37 698)21.77 (60 862)21.39 (61 502)0.029Antibiotic resistance % MRSA25.029.029.014.026.20.759 Vancomycin MIC, mean (SD)2.12 (0.73)1.62 (0.59)1.47 (0.46)1.16 (0.33)1.16 (0.35)<0.001 % S. aureus vancomycin MIC >1.0 (n)100.0 (31)66.7 (30)67.5 (40)33.3 (39)50.0 (58)<0.001 % S. aureus vancomycin MIC >1.5 (n)100.0 (31)53.3 (30)32.5 (40)7.7 (39)6.9 (58)<0.001 Daptomycin MIC, mean (95% CI)0.28 (0.18)0.28 (0.18)0.42 (0.29)0.39 (0.32)0.32 (0.23)0.906 % S. aureus daptomycin MIC >0.25 (n)30.0 (20)20.0 (5)60.7 (28)46.0 (39)40.0 (60)0.807 Linezolid % S. aureus with linezolid MIC >2.06.000.000.000.001.590.309Abbreviations: DDD, Defined Daily Doses; MRSA, methicillin-resistant S. aureus.a MIC in mg/L.b p-value for Kendall correlation test. Open table in a new tab Abbreviations: DDD, Defined Daily Doses; MRSA, methicillin-resistant S. aureus. Daptomycin MIC was available in 151 patients, and a progressive increase of this value was observed during the study period, although no significant variation was achieved (p 0.083). In 2010, only 30.0% of the strains had a MIC value >0.25 mg/L, and in 2014 daptomycin MIC value was >0.25 mg/L in 40.0% of the studied strains. In patients with both MIC to vancomycin and daptomycin, a relationship between both values was found (p 0.004). No significant changes were detected in linezolid resistance during the study period (p 0.223). We observed a significant increase in daptomycin (p 0.023), cloxacillin (p 0.015) and quinolones (p 0.029) use during the observation period (Table 1). The most relevant increase was observed for daptomycin, rising from 1129 DDD in 2010 to 6970 DDD in 2014. No significant changes were observed in vancomycin, teicoplanin and linezolid consumption. The ARIMA model only found a relationship between S. aureus vancomycin MIC and teicoplanin consumption (Slope (β): –0.497; p 0.032). No relationship was found between antibiotic consumption and MRSA rate (p >0.05). No relationship could be established between the previous 6-month antibiotic exposure and S. aureus resistances. Potential relationship between quinolone use and MRSA incidence was included in our analysis. However, we did not find any association between these two variables. The main finding of our study is the detection of a progressive reduction in S. aureus vancomycin MIC during the study period. According to our results this reduction could only be associated with teicoplanin consumption but not vancomycin exposure. MRSA prevalence remained unchanged and no relationship was found with antibiotic consumption. Antibiotic resistance has become a major clinical and public health problem. Several authors have demonstrated a direct relationship between antimicrobial consumption and antibiotic resistance in Gram-negative bacteria. However, information about this relationship for Gram-positive bacteria is limited and to some extent contradictory. In a multicentre study, Grau et al. [[2]Grau S. Fondevilla E. Freixas N. et al.Relationship between consumption of MRSA-active antibiotics and burden of MRSA in acute care hospitals in Catalonia.Spain. J Antimicrob Chemother. 2015; 70: 1193-1197PubMed Google Scholar] did not find a relationship between antimicrobial exposure and the incidence of MRSA. On the other hand, teicoplanin has been associated with the emergence of vancomycin-resistant enterococci [[3]Lai C.C. Chu C.C. Cheng A. Huang Y.T. Hsueh P.R. Correlation between antimicrobial consumption and incidence of health-care-associated infections due to methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci at a university hospital in Taiwan from 2000 to 2010.J Microbiol Immunol Infect. 2013; 30: 5Google Scholar]. However, these studies did not consider the investigation of S. aureus MIC as a potential indicator of antibiotic resistance. Vancomycin exposure has been related with the promotion of vancomycin-intermediate S. aureus strains and with a reduced susceptibility to both vancomycin and daptomycin [[4]Charles P.G. Ward P.B. Johnson P.D. Howden B.P. Grayson M.L. Clinical features associated with bacteremia due to heterogeneous vancomycin-intermediate Staphylococcus aureus.Clin Infect Dis. 2004; 38: 448-451Crossref PubMed Scopus (330) Google Scholar]. Conversely, the progressive reduction of S. aureus vancomycin MIC found in our study could only be related to a reduction in the use of teicoplanin. Nevertheless, although no statistically significant relationship was found, there was a tendency in the relationship between the percentage of strains with vancomycin MIC >1 mg/L and glycopeptide consumption. Therefore, association between antibiotic use and Gram-positive bacteria antibiotic susceptibility seems to be a real threat. As previous studies, we found a positive correlation between vancomycin and daptomycin S. aureus MIC [[5]Patel N. Lubanski P. Ferro S. Bonafede M. Harrington S. Evans A. et al.Correlation between vancomycin MIC values and those of other agents against gram-positive bacteria among patients with bloodstream infections caused by methicillin-resistant Staphylococcus aureus.Antimicrob Agents Chemother. 2009; 53: 5141-5144Crossref PubMed Scopus (29) Google Scholar]. It has been proposed that elevation in vancomycin MIC could be related to a bacterial wall thickening, which could also affect daptomycin and cloxacillin response. In our centre MIC was not calculated by E-Test, which is considered the best technique to assess exact MIC. However, it should be considered that the vast majority of clinical laboratories use automated systems, using the E-Test technique as routine only in a few cases. This study was able to detect a reversal in the recent evolution of S. aureus susceptibility to vancomycin. Although it has not been possible to establish a clear relationship with the antibiotic consumption, we found evidence showing the effect of antimicrobial policy on S. aureus antibiotic susceptibility.