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JAC Advance Access originally published online on June 13, 2008
Journal of Antimicrobial Chemotherapy 2008 62(4):773-775; doi:10.1093/jac/dkn246
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Vancomycin MICs did not creep in Staphylococcus aureus isolates from 2002 to 2006 in a setting with low vancomycin usage

Juan-Ignacio Alós1,*, Ana García-Cañas1, Paloma García-Hierro1 and Francisco Rodríguez-Salvanés2

1 Servicio de Microbiología, Hospital Universitario de Getafe, Carretera de Toledo km. 12.5, 28905 Getafe, Madrid, Spain 2 Departamento de Bioestadística, Hospital Universitario de La Princesa, Madrid, Spain

* Corresponding author. Tel: +34-91-683-3541; Fax: +34-91-683-3541; E-mail: nachoalos{at}microb.net

Received 4 April 2008; returned 28 April 2008; revised 21 May 2008; accepted 23 May 2008


   Abstract
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Objectives: The aim of this study was to evaluate MIC trends for clinical isolates of Staphylococcus aureus to vancomycin over a 5 year period (2002–06) in a hospital in Spain.

Methods: All clinical isolates of S. aureus (one per patient) from clinical samples of patients at Hospital Universitario de Getafe from January 2002 to December 2006 were used. MICs of vancomycin were determined by the CLSI broth microdilution procedure. For analysis of MIC trends over the 5 years, we grouped the isolates into those with MIC ≤1 mg/L [2428 methicillin-susceptible S. aureus (MSSA) and 518 methicillin-resistant S. aureus (MRSA)] and those with MIC ≥2 mg/L (MIC = 2 mg/L: 141 MSSA and 47 MRSA; MIC = 4 mg/L: 5 MSSA and 1 MRSA). MICs for the different groups in the different years were compared with the linear-trend {chi}2 test.

Results: A total of 3141 strains of S. aureus collected over the 5 year period was included in this analysis. Of these, 2574 (82%) strains were MSSA and 566 (18%) strains were MRSA. One of the 566 MRSA strains (0.18%) and 5 of the 2574 MSSA strains (0.19%) were vancomycin-intermediate (not significant). The rest were susceptible. The overall percentage of MRSA isolates with a vancomycin MIC of ≥2 mg/L was much higher than that of MSSA during the 5 year period [8.5% (48/566) versus 5.7% (146/2574); P = 0.012]. No statistically significant change in the percentage of isolates with a vancomycin MIC of ≥2 mg/L was observed over the years for MRSA ({chi}2 = 0.01; P = 0.91) or MSSA ({chi}2 = 0.08; P = 0.78). Annual consumption of parenteral vancomycin in our hospital in daily defined doses/100 stays was: 2002 (1.91), 2003 (1.63), 2004 (1.74), 2005 (2.06) and 2006 (1.64).

Conclusions: In a setting of low consumption of vancomycin and with a large collection of S. aureus clinical isolates, we have demonstrated the stability of vancomycin MICs over time.

Keywords: antimicrobial susceptibility , gentamicin , antimicrobial resistance


   Introduction
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Staphylococcus aureus is among the most common organisms in hospital- and community-acquired infections. In recent years, a large and continuing increase in the prevalence of methicillin-resistant S. aureus (MRSA) has been observed. In addition, the emergence of S. aureus with reduced susceptibility or resistance to vancomycin and other glycopeptides is a cause for concern.1

Vancomycin is the antibiotic of choice for the treatment of serious infections caused by MRSA. However, vancomycin treatment failure in MRSA bacteraemia is not uncommon, even when MRSA is susceptible to vancomycin. Recently, a direct influence of vancomycin MIC on the mortality associated with MRSA bacteraemia was described.2 This is worrying, especially as these MICs are within the susceptible range.

There are reports of an increase in MICs of vancomycin over time, in what has been described as ‘MIC creep’,3–5 but other studies differ with these results.6

The aim of this study was to evaluate MIC trends for clinical isolates of S. aureus to vancomycin over a 5 year period (2002–06) in the Microbiology Service of Hospital Universitario de Getafe, Getafe, Madrid, Spain.


   Materials and methods
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All clinical isolates of S. aureus (one per patient) from clinical samples of patients at Hospital Universitario de Getafe from January 2002 to December 2006 were used in this study.

Isolates were identified as S. aureus according to standard methods.

MICs of vancomycin were determined by the CLSI broth microdilution procedure,7 using commercialized panels (Wider, MIC/ID Gram-positive, CA, USA); the test medium was cation-adjusted Mueller–Hinton broth. Panels incorporated a log2 dilution of vancomycin (concentration range: 1–16 mg/L).

The susceptibility breakpoint for vancomycin was ≤2 mg/L.7

Brain heart infusion with 6 mg/L vancomycin was used to screen vancomycin resistance, as recommended by the CLSI.7 When grown in this medium, MIC was obtained by Etest (AB Biodisk, Solna, Sweden). Etest MIC values were rounded up to the next highest 2-fold MIC value.

For analysis of MIC trends over the 5 years, we grouped the isolates into those with MIC ≤1 mg/L and those with MIC ≥2 mg/L. MICs for the different groups in the different years were compared with the linear-trend {chi}2 test. Statistical significance was defined as P < 0.05.

To study the distribution of vancomycin MICs according to gentamicin susceptibility, a specific source (blood cultures versus other samples) and a specific service (ICU and Burn Unit versus other services) were also studied and compared using the {chi}2 test.

Information on the consumption of vancomycin in our hospital for systemic treatment and for selective digestive decontamination (SDD) was obtained from the records of the Pharmacy Service.


   Results
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A total of 3141 strains of S. aureus collected over the 5 year period was included in this analysis. Of these, 2574 strains (82%) were methicillin-susceptible S. aureus (MSSA) and 566 strains (18%) were MRSA. The number of isolates tested in each year was: 2002, 449 MSSA and 84 MRSA; 2003, 520 MSSA and 135 MRSA; 2004, 543 MSSA and 111 MRSA; 2005, 608 MSSA and 134 MRSA and 2006, 454 MSSA and 102 MRSA.

MIC50s, MIC90s and the number of strains with the different vancomycin MICs are presented in Table 1. One of the 566 MRSA strains (0.18%) and 5 of the 2574 MSSA strains (0.19%) were vancomycin-intermediate (not significant). The rest were susceptible using the 2006 CLSI guidelines.6


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  		Table 1. Number of strains of MSSA and MRSA by year with the indicated MICs of vancomycin, MIC50s and MIC90s

 
The overall percentage of MRSA isolates with a vancomycin MIC of ≥2 mg/L was much higher than that of MSSA during the 5 year period [8.5% (48/566) versus 5.7% (146/2574); P = 0.012].

No statistically significant change in the percentage of isolates with an MIC of vancomycin ≥2 mg/L was observed over the years for MRSA ({chi}2 = 0.01; P = 0.91) or for MSSA ({chi}2 = 0.08; P = 0.78) (Figure 1).


Figure 1
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  		Figure 1. Percentage of strains, by year, of MRSA and MSSA with vancomycin MICs of ≥2 mg/L.

 
Of 2285 strains of MSSA tested for susceptibility to gentamicin, 2212 were gentamicin-susceptible and 73 were gentamicin-resistant. Among the gentamicin-susceptible strains, 2073 had MICs of vancomycin ≤1 mg/L and 139 MICs ≥2 mg/L, and among the gentamicin-resistant strains, 65 had MICs ≤1 mg/L and 8 MICs ≥2 mg/L (P = 0.109). Of 479 strains of MRSA tested for susceptibility to gentamicin, 370 were gentamicin-susceptible and 109 were gentamicin-resistant. Among the gentamicin-susceptible strains, 335 had MICs of vancomycin ≤1 mg/L and 35 MICs ≥2 mg/L, and among the gentamicin-resistant strains, 96 had MICs ≤1 mg/L and 13 MICs ≥2 mg/L (P = 0.45).

Among the MSSA strains, 227 were isolated from blood and 2347 from other types of clinical samples. Of the blood isolates, 219 had vancomycin MICs ≤1 mg/L and 8 had MICs ≥2 mg/L, and of the other isolates, 2188 had vancomycin MICs ≤1 mg/L and 159 MICs ≥2 mg/L (P = 0.057). Among the MRSA strains, 58 were isolated from blood and 508 from other types of clinical samples. Of the blood isolates, 49 had MICs of vancomycin ≤1 mg/L and 9 MICs ≥2 mg/L, and of the other isolates, 448 had MICs of vancomycin ≤1 mg/L and 60 MICs ≥2 mg/L (P = 0.413).

Among the MRSA strains, 125 were isolated from the ICU and Burn Unit and 441 from other services. Of the ICU and Burn Unit isolates, 105 had MICs of vancomycin ≤1 mg/L and 20 MICs ≥2 mg/L, and of the isolates from other services, 393 had MICs of vancomycin ≤1 mg/L and 48 MICs ≥2 mg/L (P = 0.120).

Annual consumption of parenteral vancomycin in our hospital in daily defined doses (DDD)/100 stays was: 2002 (1.91), 2003 (1.63), 2004 (1.74), 2005 (2.06) and 2006 (1.64). Oral vancomycin consumption for SDD in DDD/100 stays of ICU and Burn Unit patients was: 2002 (63.5), 2003 (54.2), 2004 (49.5), 2005 (44.4) and 2006 (58.2).


   Discussion
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Studies reporting MIC creep have shown conflicting results.3–6 In this study, the vancomycin MICs among a large number of S. aureus isolates from a hospital over a period of 5 years were analysed. No increase in the vancomycin MIC for MRSA or MSSA was evident during the study period. Vancomycin activities remained stable over time in terms of inhibitory effect. In our case, all the susceptibility tests were performed by the same experienced personnel using a consistent procedure recommended by the CLSI.

Similarly, no vancomycin MIC creep was observed in bacteraemic MRSA isolates from 1999 to 2006 in a hospital in Texas, USA. Vancomycin activity remained stable in terms of inhibitory and bactericidal effects.6 In contrast, in a recent study,4 increased vancomycin MIC for S. aureus was demonstrated by a shift in the vancomycin MICs from ≤0.5 to 1 mg/L, based on an analysis of routine susceptibility testing data obtained from 2000 through 2004 using the broth microdilution method. With our study design, we did not detect anything like this. The authors of the study also detected increasing numbers of isolates with vancomycin MICs ≥2 mg/L during the study period—something that did not occur in our study. As in our study, they obtained higher MICs of vancomycin for MRSA than for MSSA isolates.

In contrast to the study of Robert et al.,5 we did not observe a difference in the distribution of MICs of vancomycin in our strains according to gentamicin susceptibility.

Limitations of our study include the geographical restriction to a single hospital, the fact that our first dilution was 1 mg/L, which does not permit detection of changes in lower MICs, and the use of the traditional 2-fold dilution in MIC testing. We could not detect shifts in vancomycin MICs as a result of a decrease in the percentage of isolates with an MIC of ≤0.5 mg/L and an increase in the percentage of isolates with MIC = 1.0 mg/L, as Steinkraus et al.3 had done.

The percentage of isolates with MIC of vancomycin ≥2 mg/L detected in our study, 8.5% of MRSA and 5.7% of MSSA, is worrying. These figures could be of clinical significance, based on the conclusions of Soriano et al.2

In our hospital, we have a low prevalence of MRSA compared with other centres.8 It is probably for this reason that the consumption of parenteral vancomycin is not high. We have demonstrated the stability of vancomycin MICs over time in a setting of low consumption of vancomycin with a large collection of S. aureus clinical isolates.


   Funding
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
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 References
 
No external funding was received.


   Transparency declarations
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None to declare.


   Acknowledgements
 
We wish to thank Javier Sánchez Rubio for providing data on the level of consumption of vancomycin in our hospital.


   References
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1 Sievert DM, Rudrik JT, Patel JB, et al. Vancomycin-resistant Staphylococcus aureus in the United States, 2002–2006. Clin Infect Dis (2008) 46:668–74.[CrossRef][Web of Science][Medline]

2 Soriano A, Marco F, Martínez JA, et al. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis (2008) 46:193–200.[CrossRef][Web of Science][Medline]

3 Steinkraus G, White R, Friedrich L. Vancomycin MIC creep in non-vancomycin-intermediate Staphylococcus aureus (VISA), vancomycin-susceptible clinical methicillin-resistant S. aureus (MRSA) blood isolates from 2001–05. J Antimicrob Chemother (2007) 60:788–94.[Abstract/Free Full Text]

4 Wang G, Hinler JF, Ward KW, et al. Increased vancomycin MICs for Staphylococcus aureus clinical isolates from a university hospital during a 5-year period. J Clin Microbiol (2006) 44:3883–6.[Abstract/Free Full Text]

5 Robert J, Bismuth R, Jarlier V. Decreased susceptibility to glycopeptides in methicillin-resistant Staphylococcus aureus: a 20 year study in a large French teaching hospital, 1983–2002. J Antimicrob Chemother (2006) 57:506–10.[Abstract/Free Full Text]

6 Holmes RL, Jorgensen JH. Inhibitory activities of 11 antimicrobial agents and bactericidal activities of vancomycin and daptomycin against invasive methicillin-resistant Staphylococcus aureus isolates obtained from 1999 through 2006. Antimicrob Agents Chemother (2008) 52:757–60.[Abstract/Free Full Text]

7 Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically: Approved Standard M7-A7 (2006) Wayne, PA, USA: CLSI.

8 National Nosocomial Infections Surveillance System. National Nosocomial Infections Surveillance (NNIS) System report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control (2004) 32:470–85.[CrossRef][Web of Science][Medline]


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