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CORRESPONDENCE
Year : 2019  |  Volume : 37  |  Issue : 1  |  Page : 91-94
 

Bad bug, no test: Tigecycline susceptibility testing challenges and way forward


Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India

Date of Web Publication16-Aug-2019

Correspondence Address:
Dr. Anushree Amladi
Department of Clinical Microbiology, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_19_207

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 ~ Abstract 


Tigecycline is a reserve antibiotic increasingly used for the treatment of multidrug-resistant bacteria, especially Klebsiella pneumoniae and Acinetobacter baumannii. At present, there are concerns regarding the testing and interpretation of tigecycline susceptibility to bugs such as K. pneumoniae and A. baumannii, which limit clinicians in appropriate usage. Use of appropriate method for testing such as broth microdilution is essential. In addition, tigecycline susceptibility testing is a challenge due to inconsistent results from various antimicrobial susceptibility testing automated platforms. There is a great need to define a suitable methodology along with interpretive criteria, especially for K. pneumoniae and A. baumannii. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Food and Drug Administration (FDA) breakpoints show wide variation and are defined for different set of organisms. Non-species-related pharmacokinetic/pharmacodynamic (PK/PD) breakpoints defined by the EUCAST can be used for organisms such as K. pneumoniae and A. baumannii.


Keywords: Acinetobacter baumannii, European Committee on Antimicrobial Susceptibility Testing, interpretation, Klebsiella pneumoniae, tigecycline


How to cite this article:
Shankar C, Pragasam AK, Veeraraghavan B, Amladi A. Bad bug, no test: Tigecycline susceptibility testing challenges and way forward. Indian J Med Microbiol 2019;37:91-4

How to cite this URL:
Shankar C, Pragasam AK, Veeraraghavan B, Amladi A. Bad bug, no test: Tigecycline susceptibility testing challenges and way forward. Indian J Med Microbiol [serial online] 2019 [cited 2019 Oct 21];37:91-4. Available from: http://www.ijmm.org/text.asp?2019/37/1/91/264490




There is a drastic increase in the incidence of extensively drug-resistant Gram-negative bacteria in the recent times, especially in India. Klebsiella pneumoniae and Acinetobacter baumannii are the two most common pathogens with high drug-resistant rates of up to 40% and 70% carbapenem resistance, respectively.[1] Very few agents are available for the management of these drug-resistant infections. Tigecycline and colistin are the drugs of last resort for treatment as single agents/in combination with other antibiotics. However, both these agents have shortcomings in terms of susceptibility testing, which significantly impact on its right use. Tigecycline is approved for the treatment of Gram-positive and Gram-negative bacteria causing intra-abdominal infections and skin and soft tissue infections.[2] However, it is used off-label for the treatment of other infections such as septicaemia.

Literature evidence of susceptibility to tigecycline varies among members of Enterobacteriaceae, and it is around 97%–98% for multidrug-resistant (MDR) Escherichia coli, while it is 82%–92% among MDR K. pneumoniae.[3],[4],[5] For A. baumannii, there are no breakpoints defined. Tigecycline Evaluation and Surveillance Trial/Antimicrobial Testing Leadership and Surveillance (TEST/ATLAS) studies report susceptibility by determining MIC50 and MIC90. This ranges from ≤0.5 to 2 μg/ml and 1 to 8 μg/ml, respectively.[3],[6],[7] A recent study from two centres in India reports >95% susceptibility to tigecycline among Enterobacteriaceae and 84% susceptibility among carbapenem-resistant Enterobacteriaceae using the Food and Drug Administration (FDA) criteria,[8] while for Acinetobacter spp., the MIC50 and MIC90 values were found to be 1 and 2 μg/ml, respectively.

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) collated database on MIC distribution of tigecycline for various organisms from global studies shows that greater proportion of K. pneumoniae isolates were within wild-type cut-off while Citrobacter koseri is highly susceptible with <1% of the isolates having MIC of >1 mg/L.[9] Although earlier studies reported lack of A. baumannii isolates with MIC of ≥4 mg/L, the EUCAST data show the steady increase in MIC among A. baumannii isolates. Furthermore, in contrast to E. coli and K. pneumoniae, A. baumannii is evenly distributed throughout various MIC and is not clustering around a certain MIC value [Figure 1].
Figure 1: European Committee on Antimicrobial Susceptibility Testing collated database on MIC distribution of tigecycline from various global studies[9] Wild-type cut-off for Escherichia coli: ≤0.5 mg/L (blue-dotted lines); Klebsiella pneumoniae and Citrobacter koseri ≤1 mg/L (red dotted lines). Epidemiological Cut Off (ECOFF) for Escherichia coli: 0.5 mg/L; Klebsiella pneumoniae and Citrobacter koseri 1 mg/L. No breakpoints for Acinetobacter baumannii

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 ~ Testing Challenges Top


Susceptibility to tigecycline can be tested by disc diffusion (DD) and broth microdilution (BMD) for MIC determination. Several factors influence the performance of tigecycline susceptibility testing; this include (i) date of preparation of the medium, (ii) ion content of the medium and/or (iii) organism-expressing heteroresistance to tigecycline.[10] The use of freshly (≤12 h) prepared broth is required for tigecycline BMD. It is hypothesised that the composition of medium was also shown to affect tigecycline MICs. In particular, high manganese concentration in Mueller–Hinton agar plates has been reported to show increase in tigecycline MICs.[10]

BMD is considered as the reference method for tigecycline susceptibility testing. [Table 1] shows the performance of various automated systems in determining tigecycline susceptibility for Enterobacteriaceae. Automated systems including Microscan Walkaway system, VITEK 2 and BD Phoenix have reported high rates of unacceptable major error (false-resistant) compared to BMD [Table 1]. However, performance of Microscan Walkaway system is comparable to BMD for all organisms tested with lack of very major errors except for Enterobacteriaceae group,[11] whereas VITEK 2 performance for tigecycline seems to be variable for Enterobacteriaceae group with wide differences in susceptibility ranging from 0% to 96% [Table 1]. It also shows poor essential agreement with BMD,[12],[13],[14] while BD Phoenix performance for Enterobacteriaceae shows very low susceptibility with poor categorical agreement for members of Enterobacteriaceae.[13] Although BD Phoenix has good essential agreement, the susceptibility is much lower than BMD.[13]E-test overcalls resistance and hence does not correlate with BMD results.[11],[12],[13] Although E-test can be used to select out heteroresistant colonies, its susceptibility performance is poor.[11]
Table 1: Performance of various methods to determine susceptibility to tigecycline when compared to broth micro dilution

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 ~ Interpretation Challenges Top


In addition to testing methodology, interpretation of susceptibility testing is also a challenge due to inconsistency in the breakpoints described, especially for Enterobacteriaceae, as proposed by various organisations [Table 2]. Susceptibility testing of tigecycline either by DD or by BMD has been interpreted based on clinical breakpoints designated by the United States-FDA for the members of Enterobacteriaceae.[15] This was derived from the clinical trial data based on the clinical outcomes of tigecycline therapy. The CLSI could not publish susceptible breakpoints for tigecycline as the drug manufacturers did not share the available data. The EUCAST recommends DD for testing E. coli alone and advices to use MIC method for other Enterobacteriaceae.[16] Until 2018, there was two twofold differences in the MIC between EUCAST and FDA in cut-off defining resistance [Table 2].[15],[16] However, recently in 2019, EUCAST breakpoints are revised and MIC testing is recommended only for E. coli and C. koseri but not for other Enterobacteriaceae with MIC of ≤0.5 μg/ml being defined as susceptible.[17] Since the breakpoint is now lowered in EUCAST 2019 to >0.5 μg/ml as resistant, there is four twofold difference from the FDA cut-off which is ≥8 μg/ml.[17] This challenges interpretation, and also, there is grey zone for isolates with MIC 1–8 μg/ml which might be termed resistant according to EUCAST but susceptible/intermediate susceptible as per the FDA. Furthermore, this questions the true prevalence of tigecycline resistance as reported by various studies when the EUCAST criteria are applied. Since there are no breakpoints for A. baumannii, susceptibility is assessed by determining MIC50 and MIC90 which, however, are not helpful for individual patient care.
Table 2: Interpretative breakpoints for tigecycline susceptibility as proposed by various organisations with newly introduced PK/PD interpretative criteria by European Committee on Antimicrobial Susceptibility Testing

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 ~ Clinical Reporting: Way Forward Top


The elimination of breakpoint recommendation for K. pneumoniae in 2019 by the EUCAST brings in uncertainty.[16] For A. baumannii, EUCAST breakpoints are not available due to insufficient evidence. K. pneumoniae and A. baumannii do not have a species specific breakpoint. At this circumstance, the EUCAST recommended pharmacokinetics/pharmacodynamics (PK/PD) non-species-related breakpoints may be of help.[18] Thus, the EUCAST recommendation suggests dose of 100 mg followed by 50 mg 12 hourly if MIC of the test isolate is ≤0.5 μg/ml in non-critically ill.[17]

For critically ill, high-dose tigecycline of 200 mg loading dose followed by 100 mg every 12 h may be considered in patients infected with pathogens resistant to all other classes of antimicrobials.[18] PK/PD of tigecycline at these high doses predicts that MDR strains with tigecycline MICs of up to 1 mg/L will respond to treatment. This MIC cut-off applies to the wild type of some species of Enterobacteriaceae other than E. coli, most notably for K. pneumoniae and Klebsiella oxytoca.[18]

In summary, BMD is the appropriate method for determining tigecycline susceptibility testing. As there is wide grey area in MIC breakpoints differing by four twofold dilutions between FDA and EUCAST 2019, it is reasonable to use EUCAST PK/PD non-species-related breakpoints for clinical interpretation. However, if the MIC is >1 mg/L, even this PK/PD breakpoint may not be of help.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 ~ References Top

1.
Veeraraghavan B, Pragasam AK, Bakthavatchalam YD, Anandan S, Ramasubramanian V, Swaminathan S, et al. Newer β-lactam/β-lactamase inhibitor for multidrug-resistant gram-negative infections: Challenges, implications and surveillance strategy for India. Indian J Med Microbiol 2018;36:334-43.  Back to cited text no. 1
[PUBMED]  [Full text]  
2.
Shankar C, Nabarro LE, Anandan S, Veeraraghavan B. Minocycline and tigecycline: What is their role in the treatment of carbapenem-resistant gram-negative organisms? Microb Drug Resist 2017;23:437-46.  Back to cited text no. 2
    
3.
Hoban DJ, Reinert RR, Bouchillon SK, Dowzicky MJ. Global in vitro activity of tigecycline and comparator agents: Tigecycline evaluation and surveillance trial 2004-2013. Ann Clin Microbiol Antimicrob 2015;14:27.  Back to cited text no. 3
    
4.
Dowzicky MJ, Chmelařová E. Antimicrobial susceptibility of Gram-negative and Gram-positive bacteria collected from Eastern Europe: Results from the tigecycline evaluation and surveillance trial (TEST), 2011-2016. J Glob Antimicrob Resist 2019;17:44-52.  Back to cited text no. 4
    
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Decousser JW, Woerther PL, Soussy CJ, Fines-Guyon M, Dowzicky MJ. The tigecycline evaluation and surveillance trial; assessment of the activity of tigecycline and other selected antibiotics against gram-positive and gram-negative pathogens from France collected between 2004 and 2016. Antimicrob Resist Infect Control 2018;7:68.  Back to cited text no. 5
    
6.
Fernández-Canigia L, Dowzicky MJ. Susceptibility of important gram-negative pathogens to tigecycline and other antibiotics in Latin America between 2004 and 2010. Ann Clin Microbiol Antimicrob 2012;11:29.  Back to cited text no. 6
    
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Denys GA, Callister SM, Dowzicky MJ. Antimicrobial susceptibility among gram-negative isolates collected in the USA between 2005 and 2011 as part of the tigecycline evaluation and surveillance trial (T.E.S.T.). Ann Clin Microbiol Antimicrob 2013;12:24.  Back to cited text no. 7
    
8.
Veeraraghavan B, Poojary A, Shankar C, Bari AK, Kukreja S, Thukkaram B, et al. In-vitro activity of tigecycline and comparator agents against common pathogens: Indian experience. J Infect Dev Ctries 2019;13:245-50.  Back to cited text no. 8
    
9.
The European Committee on Antimicrobial Susceptibility Testing. Antimicrobial Wild Type Distributions of Microorganisms. Available from: https://mic.eucast.org/Eucast2/SearchController/search.jsp?action=performSearch&BeginIndex=0&Micdif=mic &NumberIndex=50&Antib=345&Specium=-1. [Last accessed on 2019 May 20].  Back to cited text no. 9
    
10.
Torrico M, González N, Giménez MJ, Alou L, Sevillano D, Navarro D, et al. Influence of media and testing methodology on susceptibility to tigecycline of Enterobacteriaceae with reported high tigecycline MIC. J Clin Microbiol 2010;48:2243-6.  Back to cited text no. 10
    
11.
Marchaim D, Pogue JM, Tzuman O, Hayakawa K, Lephart PR, Salimnia H, et al. Major variation in MICs of tigecycline in gram-negative bacilli as a function of testing method. J Clin Microbiol 2014;52:1617-21.  Back to cited text no. 11
    
12.
Zarkotou O, Pournaras S, Altouvas G, Pitiriga V, Tziraki M, Mamali V, et al. Comparative evaluation of tigecycline susceptibility testing methods for expanded-spectrum cephalosporin- and carbapenem-resistant gram-negative pathogens. J Clin Microbiol 2012;50:3747-50.  Back to cited text no. 12
    
13.
Idelevich EA, Büsing M, Mischnik A, Kaase M, Bekeredjian-Ding I, Becker K. False non-susceptible results of tigecycline susceptibility testing against Enterobacteriaceae by an automated system: A multicentre study. J Med Microbiol 2016;65:877-81.  Back to cited text no. 13
    
14.
Huang TD, Berhin C, Bogaerts P, Glupczynski Y.In vitro susceptibility of multidrug-resistant Enterobacteriaceae clinical isolates to tigecycline. J Antimicrob Chemother 2012;67:2696-9.  Back to cited text no. 14
    
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Wyeth Pharmaceuticals Inc. Tygacil Package Insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2005. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021821s016lbl.pdf. [Last accessed on 2019 May 20].  Back to cited text no. 15
    
16.
The European Committee on Antimicrobial Susceptibility Testing. Breakpoint Tables for Interpretation of MICs and Zone Diameters. Version 8.0; 2018. Available from: http://www.eucast.org. [Last accessed on 2019 May 20].  Back to cited text no. 16
    
17.
The European Committee on Antimicrobial Susceptibility Testing. Breakpoint Tables for Interpretation of MICs and Zone Diameters. Version 9.0; 2019. Available from: http://www.eucast.org. [Last accessed on 2019 May 20].  Back to cited text no. 17
    
18.
Guidance Document on Tigecycline Dosing. Available from: http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/General_documents/Tigecycline_Guidance_document_20181223.pdf. [Last accessed on 2019 May 20].  Back to cited text no. 18
    
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Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests. CLSI supplement M100. 29th ed. Wayne, PA: Clinical and Laboratory Standards Institute; 2019.  Back to cited text no. 19
    
20.
BSAC. BSAC Methods for Antimicrobial Susceptibility Testing. Available from: http://www.bsac.org.uk/wp-content/uploads/2012/02/BSAC-disc-susceptibility-testing-methods-Jan-2015.pdf. [Last accessed on 2019 May 20].  Back to cited text no. 20
    


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