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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 7  |  Issue : 1  |  Page : 16-19

Clinical profile of patients with heteroresistant vancomycin- intermediate Staphylococcus aureus bacteraemia compared to those with methicillin-resistant Staphylococcus aureus bacteraemia at a level-1 trauma centre of India


1 Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India
2 Department of Orthopedics, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication13-Aug-2019

Correspondence Address:
Dr. Purva Mathur
Room No. 211, Second Floor, Department of Laboratory Medicine, JPNA Trauma Centre, All India Institute of Medical Sciences, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpsic.jpsic_9_19

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  Abstract 


Introduction: Staphylococcus aureus is the common cause of bacteraemia, skin/soft-tissue infections and pneumonia in both developed and developing countries, with many of them being caused by methicillin-resistant S. aureus (MRSA) strains. Vancomycin has been a reliable therapeutic option for MRSA infections. Vancomycin-resistant S. aureus and heterogeneous vancomycin-intermediate S. aureus (hVISA) strains have been reported to be associated with vancomycin treatment failure. The present study was performed to determine the percentage of infections due to hVISA and also to compare the clinical characteristics of patients with hVISA infections.
Methods: The study was conducted at the department of microbiology of a 1600-bedded level 1 trauma centre of India. Vancomycin minimum inhibitory concentration (MIC) using Etest was performed for MRSA strains isolated from inpatients over 3 years, 2013 to 2015. Heteroresistance determination was done for strains with vancomycin MIC ≥1 μg/ml using Macro Etest method. Clinical data of all patients with MRSA and hVISA infection were compared.
Results: A total of 837 S. aureus strains were collected. Of these, 371 (44.3%) were MRSA; 108 (12.9%) had vancomycin MIC ≥1 μg/ml and 32 (3.8%) strains had hVISA. Presence of hVISA infection was found to be significantly associated with the presence of prosthetic implants and surgical-site infections. These patients had prolonged duration of hospital stay and were also associated with vancomycin treatment failure.
Discussion: Percentage of hVISA strains reported at our institution was 3.8%, which may be a reflection of community scenario. Mortality rate associated with hVISA bacteraemia was more than that observed with MRSA bacteraemia though not statistically significant. hVISA isolation was greater in high-bacterial–load infections such as blood and respiratory tract infections. Presence of high-bacterial-load MRSA infections for prolonged period despite adequate vancomycin treatment is an indirect clinical marker of hVISA infection.

Keywords: Bacteraemia, heterogeneous vancomycin-intermediate Staphylococcus aureus, risk factors, vancomycin-susceptible methicillin-resistant Staphylococcus aureus


How to cite this article:
Batra P, Mathur P, Paul R, Gupta P, Malhotra R. Clinical profile of patients with heteroresistant vancomycin- intermediate Staphylococcus aureus bacteraemia compared to those with methicillin-resistant Staphylococcus aureus bacteraemia at a level-1 trauma centre of India. J Patient Saf Infect Control 2019;7:16-9

How to cite this URL:
Batra P, Mathur P, Paul R, Gupta P, Malhotra R. Clinical profile of patients with heteroresistant vancomycin- intermediate Staphylococcus aureus bacteraemia compared to those with methicillin-resistant Staphylococcus aureus bacteraemia at a level-1 trauma centre of India. J Patient Saf Infect Control [serial online] 2019 [cited 2019 Dec 10];7:16-9. Available from: http://www.jpsiconline.com/text.asp?2019/7/1/16/264399




  Introduction Top


Staphylococcus aureus is one of the common causes of bacteraemia, skin/soft-tissue infections and pneumonia in both developed and developing countries. Data published by the Indian Network for Surveillance of Antimicrobial Resistance study conducted in 15 Indian tertiary care centres over 2 years, 2008–2009, showed that the prevalence of methicillin-resistant S. aureus (MRSA) was 41%, with the maximum isolation being from inpatients (43%).[1] MRSA is among the leading causes of pneumonia and skin/soft-tissue infections in the USA also, accounting for 20% of nosocomial bloodstream infections. Vancomycin has been the most reliable therapeutic option for MRSA infections, especially in the critical care settings.[2]S. aureus strains with reduced vancomycin susceptibility include vancomycin-resistant S. aureus (VRSA; minimum inhibitory concentration [MIC] ≥16 μg/ml) and vancomycin-intermediate S. aureus (VISA; MIC = 4–8 μg/ml).[3]

Heteroresistant VISA (hVISA) is the stage that precedes the development of VISA. These strains have vancomycin MIC within the susceptible range, but there are subpopulations of VISA at proportions ranging from 1/105 to 1/106 organisms. Strains of MRSA with reduced vancomycin susceptibility were first reported from Japan in 1997.[4] Bloodstream infections due to hVISA are associated with prolonged duration of bacteraemia, greater bacterial load and hospital stay and vancomycin treatment failure.[3],[5],[6]

hVISA has been reported from various countries including Japan, Tehran, Korea, Hong Kong, Thailand, Spain, Greece, Germany, Italy and the United Kingdom, with the rate of heteroresistance ranging from 0% to 74%.[7] Few studies conducted in India have reported vancomycin heteroresistance to range from 10% to 15%,[7],[8] but there are no studies from India showing the clinical impact of hVISA isolation. This wide variation in prevalence is influenced by several factors such as geographical area, site of infection and screening method used.[6] Thus, the present study was conducted to determine the frequency of infections due to S. aureus with reduced vancomycin susceptibility. The clinical characteristics of patients with hVISA bacteraemia were also compared with that of patients with vancomycin-susceptible MRSA (VS-MRSA) bacteraemia.


  Methods Top


A prospective study was performed at the department of microbiology of a 1600-bedded multispeciality level 1 trauma centre. All the S. aureus strains isolated over 3 years (2013–2015) were included in the study. MRSA screening was performed using the cefoxitin (30 μg) disc. MIC to vancomycin was determined for isolates obtained from inpatients. Heteroresistance determination was also done for strains with vancomycin MIC ≥1 μg/ml using the Macro Etest method.[9]

Method of heteroresistance determination (Macro Etest method)

As described by Charles et al[9]; Several colonies of the strain were picked and suspended in normal saline to obtain a 2-McFarland-standard bacterial density. Of this suspension, 100 μL was evenly spread onto a 90-mm brain heart infusion agar plate and allowed to dry. Vancomycin and teicoplanin Etest strips were then applied onto the surface of the plates in parallel but in opposite directions, and the plates were incubated at 35°C for 48 h. Zones were read at complete inhibition while carefully observing for visual hazy growth and microcolonies. A strain was considered to be hVISA positive if microcolonies were detected at 8 μg/ml for both vancomycin and teicoplanin or at 12 μg/ml for teicoplanin alone.

Clinical data

Clinical data of all patients with MRSA and hVISA infections were obtained from the hospital records. All patients with hVISA bacteraemia were considered as cases, whereas those with VS-MRSA bacteraemia were considered as controls. Data collected included demographic details of the patients, presence of prosthetics/implants, duration of bacteraemia, duration of inpatient stay, duration of intensive care unit stay, mechanical ventilation, Acute Physiology and Chronic Health Evaluation score, mortality and presence of pneumonia or surgical-site infection. Death was attributed to infection if the patient had signs of infection with persistent positive blood cultures with no other plausible cause of death. These findings were compared between the two groups of patients to assess the clinical significance.

Statistical analysis

A univariate analysis was performed to identify risk factors for hVISA infections, using Chi-square test for categorical variables and Student's t-test for continuous variables. Data were analysed using SPSS Statistics for Windows, Version 17.0 (SPSS Inc., Chicago: USA). P < 0.05 was considered statistically significant.


  Results Top


A total of 837 non-duplicate strains of S. aureus were collected over the study period. Of these, 229 (27.3%) were from outpatients and the rest 608 (72.6%) were from inpatients. Of these, 371 (44.3%) MRSA strains were isolated; 77 (9.1%) from outpatients and 294 (35.1%) from inpatients. The MIC of vancomycin was determined in the 294 MRSA inpatient strains. Of these, vancomycin MIC was ≥1 μg/ml in 108 (36.7%) strains. Of these 294 strains, 32 (10.8%) were found to be hVISA. The year-wise distribution of the isolates (both MRSA and hVISA) is shown in [Figure 1]. The number of MRSA and hVISA isolates seemed to increase constantly over the study period. The sample-wise distribution of the isolates is shown in [Figure 2].
Figure 1: Year-wise distribution of the inpatient isolates

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Figure 2: Sample-wise distribution of the inpatient isolates

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The maximum number of MRSA and hVISA isolates were obtained from patients with bloodstream infection, 176 (59.8%) and 15 (46.8%), respectively. Therefore, the clinical characteristics of patients with MRSA bacteraemia and hVISA bacteraemia were compared [Table 1]. Presence of hVISA infection was found to be significantly associated with the presence of prosthetic implants and surgical-site infections. Patients with hVISA infection were associated more frequently with vancomycin treatment failure (assessed by the prolonged duration of bacteraemia and prolonged duration of hospital stay). These patients were also at significantly greater risk of developing pneumonia.
Table 1: Clinical features of bacteraemia due to heteroresistant vancomycin-intermediate Staphylococcus aureus and methicillin-resistant Staphylococcus aureus isolates with the P value

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  Discussion Top


This study has certain important observations. First, the percentage of hVISA strains reported at our institution was substantial, 3.8%. This was, however, less than that reported from a few other centres.[10],[11] Our centre being a level-1 trauma centre receives only trauma patients who are otherwise healthy and do not have previous antibiotic exposure. Thus, the level of antibiotic resistance and proportion of hVISA noted maybe a reflection of the community scenario.

Second, unlike few investigators,[12],[13],[14],[15] the presence of hVISA infection was found to be significantly associated with vancomycin treatment failure (assessed by prolonged duration of bacteraemia), presence of prosthetic implants and prolonged duration of hospitalisation. The mortality rate associated with hVISA bacteraemia was more than that observed with MRSA bacteraemia, but this was not statistically significant as observed in other studies.[6] It has been suggested by many authors that hVISA and VISA strains have reduced virulence factors, leading to reduced mortality but an increase in persistent infections.[16]

None of the isolates were resistant to vancomycin by the conventional methods, but 3.8% of the isolates were hVISA. The presence of VISA is routinely screened for on the basis of the vancomycin MIC; however, screening for hVISA is not routinely performed because the vancomycin MIC is generally reported in the susceptible range by the conventional methods. hVISA screening requires additional testing methods which are more labour intensive, expensive and time-consuming when compared with the routine susceptibility testing methods. In addition, the methods used for evaluating hVISA are not standardised. The reference method for the detection of hVISA is using the Population Analysis Profile (PAP); however, this method is technically demanding.[5] The Macro Etest method used in the current study has a reliable sensitivity of 89.1%.

In our study, the most common source of isolation was blood followed by respiratory tract. Very few isolates were obtained from soft-tissue infections. This indicates that there is greater isolation of hVISA from infections with high bacterial load such as bloodstream and respiratory tract infections. hVISA bacteraemia was associated significantly with the development of pneumonia and surgical-site infection. A significant association between the hVISA isolation and presence of prosthetic devices highlights the importance of removal of infected prosthetic implants as they frequently lead to the formation of biofilms.[13] This finding is in concordance with that observed by Charles et al.[14]

This is the first study of its kind from the Indian subcontinent. In addition, of all the studies conducted, this is the first study involving such a large population size.[1],[13] Through our study, we can conclude that presence of high-bacterial-load MRSA infections for prolonged period despite adequate vancomycin treatment is an indirect clinical marker of hVISA infection.

This study has few drawbacks: first, the PAP method (reference method) for the detection of hVISA was not performed and thus many strains of hVISA may have been missed. Second, molecular methods for mecA gene detection or determination of cell wall thickness (the most important mechanism of hVISA production) using electron microscopy were not performed. Third, because the current study is a retrospective study, some of the clinical data such as dosage of vancomycin administered could not be analysed. In addition, being a retrospective study, the strains obtained from the year 2013 were obtained from stocks. Maintenance of strains in stock could have affected the glycopeptide resistance as shown by few studies.[17] Thus, it is possible that the level of resistance determined for that year would have been greater.


  Conclusion Top


Given the difficulties with laboratory screening for hVISA, presence of bacteraemia despite prolonged vancomycin treatment may be considered a potential clinical marker for hVISA. Treatment of such patients may need to be reassessed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Joshi S, Ray P, Manchanda V, Bajaj J, Chitnis D, Gautam V, et al. Methicillin resistant Staphylococcus aureus (MRSA) in India: Prevalence and susceptibility pattern. Indian J Med Res 2013;137:363-9.  Back to cited text no. 1
    
2.
Tverdek FP, Crank CW, Segreti J. Antibiotic therapy of methicillin-resistant Staphylococcus aureus in critical care. Crit Care Clin 2008;24:249-60, vii-viii.  Back to cited text no. 2
    
3.
Charles PG, Ward PB, Johnson PD, Howden BP, Grayson ML. Clinical features associated with bacteremia due to heterogeneous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis 2004;38:448-51.  Back to cited text no. 3
    
4.
Rybak MJ, Leonard SN, Rossi KL, Cheung CM, Sader HS, Jones RN, et al. Characterization of vancomycin-heteroresistant Staphylococcus aureus from the metropolitan area of Detroit, Michigan, over a 22-year period (1986 to 2007). J Clin Microbiol 2008;46:2950-4.  Back to cited text no. 4
    
5.
Chaudhari CN, Tandel K, Grover N, Sen S, Bhatt P, Sahni AK, et al. Heterogeneous vancomycin-intermediate among methicillin resistant Staphylococcus aureus. Med J Armed Forces India 2015;71:15-8.  Back to cited text no. 5
    
6.
Casapao AM, Leonard SN, Davis SL, Lodise TP, Patel N, Goff DA, et al. Clinical outcomes in patients with heterogeneous vancomycin-intermediate Staphylococcus aureus bloodstream infection. Antimicrob Agents Chemother 2013;57:4252-9.  Back to cited text no. 6
    
7.
Loomba PS, Taneja J, Mishra B. Methicillin and vancomycin resistant S. aureus in hospitalized patients. J Glob Infect Dis 2010;2:275-83.  Back to cited text no. 7
    
8.
Singh A, Prasad KN, Misra R, Rahman M, Singh SK, Rai RP, et al. Increasing trend of heterogeneous vancomycin intermediate Staphylococcus aureus in a tertiary care center of Northern India. Microb Drug Resist 2015;21:545-50.  Back to cited text no. 8
    
9.
Satola SW, Farley MM, Anderson KF, Patel JB. Comparison of detection methods for heteroresistant vancomycin-intermediate Staphylococcus aureus, with the population analysis profile method as the reference method. J Clin Microbiol 2011;49:177-83.  Back to cited text no. 9
    
10.
Tenover FC, Biddle JW, Lancaster MV. Increasing resistance to vancomycin and other glycopeptides in Staphylococcus aureus. Emerg Infect Dis 2001;7:327-32.  Back to cited text no. 10
    
11.
Fridkin SK. Vancomycin-intermediate and -resistant Staphylococcus aureus: What the infectious disease specialist needs to know. Clin Infect Dis 2001;32:108-15.  Back to cited text no. 11
    
12.
Geisel R, Schmitz FJ, Thomas L, Berns G, Zetsche O, Ulrich B, et al. Emergence of heterogeneous intermediate vancomycin resistance in Staphylococcus aureus isolates in the Düsseldorf area. J Antimicrob Chemother 1999;43:846-8.  Back to cited text no. 12
    
13.
Maor Y, Hagin M, Belausov N, Keller N, Ben-David D, Rahav G, et al. Clinical features of heteroresistant vancomycin-intermediate Staphylococcus aureus bacteremia versus those of methicillin-resistant S. aureus bacteremia. J Infect Dis 2009;199:619-24.  Back to cited text no. 13
    
14.
Charles PG, Ward PB, Johnson PD, Howden BP, Grayson ML. Clinical features associated with bacteremia due to heterogeneous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis 2004;38:448-51.  Back to cited text no. 14
    
15.
Lesens O, Methlin C, Hansmann Y, Remy V, Martinot M, Bergin C, et al. Role of comorbidity in mortality related to Staphylococcus aureus bacteremia: A prospective study using the Charlson weighted index of comorbidity. Infect Control Hosp Epidemiol 2003;24:890-6.  Back to cited text no. 15
    
16.
Turner J, Howe RA, Wootton M, Bowker KE, Holt HA, Salisbury V, et al. The activity of vancomycin against heterogeneous vancomycin-intermediate methicillin-resistant Staphylococcus aureus explored using an in vitro pharmacokinetic model. J Antimicrob Chemother 2001;48:727-30.  Back to cited text no. 16
    
17.
Boyle-Vavra S, Berke SK, Lee JC, Daum RS. Reversion of the glycopeptide resistance phenotype in Staphylococcus aureus clinical isolates. Antimicrob Agents Chemother 2000;44:272-7.  Back to cited text no. 17
    


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