|Year : 2015 | Volume
| Issue : 2 | Page : 262-266
Vancomycin MIC creep in methicillin-resistant Staphylococcus aureus (MRSA) isolates from 2006 to 2010 in a hospital in China
W Chang1, Xiaoling Ma1, P Gao2, X Lv3, H Lu1, F Chen1
1 Department of Clinical Laboratory, Anhui Provincial Hospital, Hefei, PR China
2 Department of Clinical Laboratory, The Second People's Hospital of Wuhu, Wuhu, PR China
3 Department of Clinical Laboratory, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, PR China
|Date of Submission||05-Nov-2013|
|Date of Acceptance||16-Sep-2014|
|Date of Web Publication||10-Apr-2015|
Department of Clinical Laboratory, Anhui Provincial Hospital, Hefei
Source of Support: None, Conflict of Interest: None
Purpose: To assess whether vancomycin minimum inhibitory concentration (MIC) creeps among clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) in a regional hospital in China. Furthermore, to analyze the causes of vancomycin MIC creeps and the relationship between vancomycin MICs and the outcome among patients with MRSA infection. Materials and Methods: All clinical isolates of MRSA from 2006-2010 were retrieved and tested by the broth microdilution procedure to determine their vancomycin MIC. Meanwhile, related patient records were analyzed. Results: While all isolates were susceptive to vancomycin, the percentage of isolates with a vancomycin MIC = 1 mg/L increased significantly from 2006 (37.0%) to 2010 (75.7%). Meanwhile, vancomycin usage density (DDDs/1000 bed-days) had increased significantly from 2006-2010. Mean linear correlation analysis showed a statistically significant positive correlation (r = 0.905, P < 0.05) between the consumption of vancomycin and the percentage of MRSA isolates with a vancomycin MIC = 1 mg/L. Clinical records revealed high vancomycin MIC was associated with a higher microbiologic failure rate in MRSA bloodstream infections. Conclusions: The data demonstrated vancomycin MIC creep among clinical isolates in our hospital, and the MIC creep may be caused by the increasing usage of vancomycin. Furthermore, the analysis strongly suggested this shift of vancomycin MIC within the susceptible range may be associated with an increasing probability of treatment failure.
Keywords: Methicillin-resistant Staphylococcus aureus, MIC creep, outcome, vancomycin
|How to cite this article:|
Chang W, Ma X, Gao P, Lv X, Lu H, Chen F. Vancomycin MIC creep in methicillin-resistant Staphylococcus aureus (MRSA) isolates from 2006 to 2010 in a hospital in China. Indian J Med Microbiol 2015;33:262-6
|How to cite this URL:|
Chang W, Ma X, Gao P, Lv X, Lu H, Chen F. Vancomycin MIC creep in methicillin-resistant Staphylococcus aureus (MRSA) isolates from 2006 to 2010 in a hospital in China. Indian J Med Microbiol [serial online] 2015 [cited 2019 Sep 16];33:262-6. Available from: http://www.ijmm.org/text.asp?2015/33/2/262/148837
| ~ Introduction|| |
In recent years, a continuing increase in the prevalence of Methicillin-Resistant Staphylococcus aureus (MRSA) has been observed.  Vancomycin, a glycopeptide antibiotic, has been the primary choice for the treatment of MRSA infections. Although MRSAs with intermediate or resistant to vancomycin remain rare, many reports have described MRSA strains with vancomycin MICs increased to the high end of the Clinical and Laboratory Standards Institute (CLSI) susceptibility range with minimum inhibitory concentration (MIC) = 2 mg/L. This MIC shift has been defined as "MIC creep".  A growing number of studies suggest that the vancomycin MIC creep is associated with an increased probability of failure.  In response to evidence that vancomycin was poorly effective against MRSA isolates with MIC >4 mg/L, the CLSI lowered the vancomycin susceptibility breakpoint for S. aureus to ≤2 mg/L in 2006.
The emergence of MRSA with reduced vancomycin susceptibility has become a worldwide concern. However, very few investigations have been done in this particular field in mainland China. The objective of this study was to evaluate vancomycin MIC trends for clinical MRSA isolates over a five-year period (2006-2010) in a major regional hospital in the central China. Additionally, related clinical records were also collected to analyze the relationship between vancomycin MIC and drug usage. Meanwhile, this study investigated the relationship between vancomycin MIC and an increased probability of failure among MRSA bloodstream infected patients treated with vancomycin.
| ~ Materials and Methods|| |
The Committee of Medical Ethics of Anhui Provincial Hospital approved of the study. This was a retrospective folder review and was in compliance with the Declaration of Helsinki. Furthermore, no personal identifiers from patients involved in this study were included and all the data were analyzed anonymously. Therefore, The Committee of Medical Ethics of Anhui Provincial Hospital waived the requirement for informed consent.
All MRSA isolates were collected from clinical samples of patients from January 2006 to December 2010 at Anhui Provincial Hospital, a major regional hospital that provides healthcare services to patients from Anhui, Jiangsu and Henan provinces (where lives a total of one-tenth of the Chinese population) with 1300 beds. Only one isolate per patient was included in this analysis. For patients with more than one isolate, only the first isolate was tested. According to the standard method, S. aureus isolates were identified by gram's stain, microscopic examination and coagulase test and then reaffirmed by automated microbial analyzer (Vitek2 Compact, BioMerieux, French). MRSA was screened by oxacillin and cefoxitin discs, and further confirmed by mecA polymerase chain reaction (PCR). 
Antimicrobial susceptibility testing was performed by broth microdilution according to the CLSI recommendation. The testing was performed and read by one observer who was blinded to the isolates information. The susceptibility breakpoint for vancomycin was MIC ≤2 mg/L. Reference strain ATCC 29213 was used for quality control.
According to WHO Collaborating Centre for Drug Statistics Methodology (http://www.whocc.no/atcddd/), the usage of vancomycin in hospital is described by the defined daily doses per 1000 bed-days (DDDs/1000 bed-days). The consumption of vancomycin in our hospital for systemic treatment and selective digestive decontamination was obtained from the records of the Pharmacy Service. The number of in-patients every year was collected from the Medical Records Room.
A further study was conducted among patients with MRSA bloodstream infections from 2006-2010. All the data were collected and analyzed anonymously. The inclusion criteria of patients studied were as follows: 18-years-old and above, non-neutropenic, with an MRSA culture that met the American Centers for Disease Control and Prevention (CDC) criteria for bloodstream infection (CDC issues updated Bloodstream Infection Prevention Guidelines, 2011), and had received vancomycin treatment within 48 hours of the index blood culture. During the study period, 173 patients met the inclusion criteria. All data were extracted from patients' medical records by a trained reviewer. Collected data contain the following parts: Age, gender, medical history, antibiotic treatment data (date, time, dosing regimen and duration) and outcome. In our study, vancomycin treatment failure included death related to the infection and/or microbiological failure for patients who had received vancomycin for at least 5 days. Microbiologic failure was defined as a persistently positive culture results obtained 5 days after the initiation of vancomycin treatment and before the treatment completion. If a patient met more than one criterion, the outcome would only be classified as one clinical failure.
To analyze MIC trends over the 5-year period, the isolates were divided into three groups: MIC ≤0.5 mg/L, MIC = 1 mg/L and MIC = 2 mg/L. MIC trends were assessed using non-parametric methods (the Spearman's ranking correlation coefficient). Statistical significance was defined as P < 0.05. Association between DDDs/1000 bed-days for vancomycin and the susceptibility of MRSA to vancomycin was assessed using Linear Regression Analyze. Clinical data for the different groups were studied and compared with the χ2 test.
| ~ Results|| |
Changes in vancomycin MIC
A total of 1132 isolates were collected from 2006-2010. The number of tested isolates each year was 196, 159, 273, 220 and 284, respectively. All strains were susceptible to vancomycin using current CLSI guidelines. The vancomycin MIC distribution is displayed in [Figure 1]. The percentage of isolates with an MIC = 1 mg/L significantly increased from 2006 (37.0%) to 2010 (75.7%). Meanwhile, the percentage of isolates with an MIC ≤0.5 mg/L decreased significantly from 59.8% to 15.5%.
|Figure 1: Trends in vancomycin susceptibility of MRSA strains over a 5-year period, Anhui Province|
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Changes in vancomycin consumption
[Figure 2] lists the vancomycin consumption in the hospital. It showed that the vancomycin usage density (DDDs/1000 bed-days) had increased significantly from 2006 (1.2) to 2010 (5.3). [Figure 3] shows the correlations between antibiotic usage and sensitivity to vancomycin. Correlation analysis between the consumption of vancomycin and the percentage of MRSA isolates with a vancomycin MIC = 1 mg/L revealed a statistically significant positive correlation (r = 0.905, P < 0.05).
|Figure 2: Annual vancomycin usage density in the Anhui Provincial Hospital, 2006-2010|
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|Figure 3: Correlation analysis between the consumption of vancomycin and the percentage of MRSA isolates with different vancomycin MIC|
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Vancomycin MIC and the therapeutic efficacy
To investigate the association between vancomycin MIC and the risk of treatment failure, the isolates were divided into two groups: MIC ≥1 mg/L and MIC ≤0.5 mg/L. [Table 1] compared the treatment outcomes between high and low vancomycin MIC groups. In univariate analysis, there was no significant difference in age, gender or comorbid disease between the two groups. 4 of 90 patients with low vancomycin MIC suffered a Microbiologic failure. In the study, 12 of 83 patients with high vancomycin MIC still had a persistently positive culture results. This difference is statistically significant. Furthermore, Average length of use antibiotic was greatly extended. The median hospital length of stay was longer for the high vancomycin MIC group than for the low vancomycin MIC group (46 days versus 29 days). In addition, patients with high vancomycin MIC had a higher mortality rate than those with low MIC, but this was no significant different.
|Table 1: Comparison of outcomes and clinical characteristics between high (MIC≥1 mg/L) and low (MIC≤0.5 mg/L) MIC groups |
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| ~ Discussion|| |
Over the last 10 years, MRSA has been one of the most common causes of serious hospital- and community-acquired infections in most areas of China.  In these areas, vancomycin has always been the primary antibiotic of choice for the treatment of serious MRSA infections. Although new anti-staphylococcal antibiotics such as linezolid and daptomycin have been developed recently, vancomycin remains as the only widespread therapeutic preference due to new drugs' high cost and the absence of large clinical trials.  However, vancomycin treatment failure is not uncommon, despite that MRSA strains are susceptible to vancomycin in vitro. More and more clinicians started to question the continued utility of vancomycin for MRSA infections. Recent studies described a reduction in the efficacy of vancomycin against MRSA strains, and suggested that subtle changes in the MIC may explain clinical failures.  Therefore, it is necessary to examine the changes in vancomycin susceptibility and to explore the impact of these changes on the clinical outcome.
This study reported an increase in the percentage of isolates with MIC = 1 mg/L from 2006-2010, accompanied by a decrease in the percentage of isolates with an MIC ≤0.5 mg/L. Similar results have also been shown by others. Golan et al.,  reported a statistically significant increase in vancomycin MIC from 2001-2005 in a regional medical center in the United States. Similarly, Wang et al. reported an MIC increase in both MRSA and MSSA.  In Europe, very gradual increases in vancomycin MICs have been documented from France.  However, conflicting results have been noted in which MIC creep could not be detected. A Spanish study for isolates collected from 2002-2006 did not reveal any notable changes in the vancomycin MIC pattern.  An analysis of SENTRY surveillance data collected from 1998-2003, which included 35458 S. aureus isolates, detected no change in vancomycin MICs over this time by standard CLSI methods.  These variations are accounted for by differences in the epidemiological and clinical factors between study sites, including variation in susceptibility testing methods, different clonal dissemination and dosing of vancomycin.  It is important to point out that the changes of vancomycin MICs vary widely from one area to another. Therefore, surveillance to monitor this phenomenon in all geographical regions is highly warranted. In China, with the abuse of antibiotics, drug-resistant strains of bacteria grew especially severe. According to our research, vancomycin MIC creep is occurring in mainland China.
Our study results further showed an association between the usage of vancomycin in our health care system and an increase in vancomycin resistance amongst MRSA. In our hospital, the consumption of vancomycin had increased significantly from 2006-2010. Correlation analysis unveiled a statistically significant association between the vancomycin usage density and the percentage of MRSA isolates with a vancomycin MIC = 1 mg/L and MIC ≤0.5 mg/L. The results indicated that the increase of vancomycin usage may have contributed to MIC creep. Recent studies revealed that suboptimal drug exposure, resulting from usual dosing regimens of vancomycin, might lead to biofilm matrix production increase, which further renders the MRSA strains less resistant to the vancomycin.  The increase in the cell wall thickness can reduce antibiotic penetration and elevate vancomycin MIC.  All of these changes are the prerequisite for emergence of vancomycin-intermediate S. aureus (VISA) strains.  Therefore, a more appropriate approach for antibiotic therapies management is desired.
S. aureus antibiotic resistance has posed great challenges to the treatment of serious infections such as endovascular infection, for which bactericidal therapy is pivotal for a successful clinical outcome.  Our analysis strongly suggested that MIC creep increased the microbiologic failure rate, thereby raising the probability of treatment failure. Our study also proved that MIC creep prolonged the median hospital length of stay, thus increase the risk of treatment failure and treatment costs. Many reasons may help to explain the phenomenon. Lodise et al.,  identified the vancomycin MIC breakpoint associated with an increased probability of failure using classification and regression tree (CART) analysis. According to the researches on vancomycin PK-PD, the optimal pharmacodynamic parameter that predicts vancomycin activity is the area under the curve (AUC) to MIC ratio, with a ratio >400 associated with treatment success in patients with pneumonia and BSI. Even one intermediate dilution MIC slight change can affect the AUC/MIC achieved in an individual patient; similarly, a shift in an MIC population can drastically affect the anticipated target attainment rate associated with a specific AUC/MIC target.  According to a recent research  , the probability of achieving this target is extremely low when the MIC value reaches 2 μg/mL, even when maintaining vancomycin troughs of 15-20 μg/mL. This may help to explain why patients with high vancomycin MIC had reduced antibiotic efficacy compared to patients with low vancomycin MIC.
Some studies demonstrated that mortality associated with MRSA bacteremia was higher when vancomycin was used to treat infections with strains that had a high vancomycin MIC. A recent meta-analysis also revealed that higher vancomycin MIC values (>1.5 μg/mL), irrespective of MIC testing methodology and infection source, were predictive of mortality.  In our research high vancomycin MIC was associated with a higher mortality, but this increase was no statistic significant difference. There are several reasons which may account for this finding. First, the size of the sample is small. Secondly, a few researches revealed that reduced vancomycin susceptibility Staphylococcus aureus is associated with changes in bacterial features and virulence potential. And the phenotypic features are likely to impact host-pathogen interactions in MRSA infections and reduce fatality rate. 
This study has two limits. First, all the data were collected from one regional hospital, though our hospital is a well-equipped teaching hospital that provides health care services to patients from neighboring provinces. Thus geographical restriction may have a limited impact on the applicability of these results to isolates from other areas in China. Second, additional studies need to be done to investigate whether the different clonal disseminations in MRSA strains correlates with the emergence of the MIC creep. Although, we didn't investigate the genetic relatedness of these MRSA strains, we do a long-term nosocomial infection surveillance through phenotypic and genotypic methods. There has not been an outbreak of MRSA in our hospital during the experimental period. Moreover, all clinical isolates of MRSA were collected from different wards. Therefore, we speculated that the impact of clonal dissemination of strains appeared limited.
In summary, this study found vancomycin MIC creep among MRSA isolates over a time of 5 years in a major regional hospital in China. We have further demonstrated that this phenomenon may be influenced by changes in drug consumption during the period from 2006-2010. The results also indicated that vancomycin susceptibility may associate with the increase of probability of treatment failure.
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[Figure 1], [Figure 2], [Figure 3]