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  Table of Contents  
Year : 2017  |  Volume : 35  |  Issue : 4  |  Page : 585-587

Dosing strategy based on prevailing aminoglycoside minimum inhibitory concentration in India: Evidence and issues

1 Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Internal Medicine and Infectious Disease, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Medicine, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Microbiology, PD Hinduja Hospital and Medical Research Centre, Bengaluru, Karnataka, India
5 Department of Microbiology, Manipal Hospital, Bengaluru, Karnataka, India
6 Department of Microbiology, The Calcutta Medical Research Institute, Kolkata, West Bengal, India
7 Department of Microbiology, Fortis Hospital, Anandapur, Kolkata, West Bengal, India
8 Department of Microbiology and Immunology, Choithram Hospital, Indore, Madhya Pradesh, India
9 Department of Microbiology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Web Publication1-Feb-2018

Correspondence Address:
Dr. Balaji Veeraraghavan
Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijmm.IJMM_17_386

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 ~ Abstract 

Aminoglycosides are important agents used for treating drug-resistant infections. The current dosing regimen of aminoglycosides does not achieve sufficient serum level concentration for the infected bacterial pathogen interpreted as susceptible based on laboratory testing. Minimum inhibitory concentration was determined for nearly 2000 isolates of Enterobacteriaceae and Pseudomonas aeruginosa by broth microdilution method. Results were interpreted based on CLSI and EUCAST interpretative criteria and the inconsistencies in the susceptibility profile were noted. This study provides insights into the inconsistencies existing in the laboratory interpretation and the corresponding clinical success rates. This urges the need for revising clinical breakpoints for amikacin, to resolve under dosing leading to clinical failure.

Keywords: Aminoglycosides, CLSI, dosing, EUCAST, Minimum Inhibitory Concentration

How to cite this article:
Veeraraghavan B, Pragasam AK, Manesh A, Rupali P, Iyadurai R, Rodrigues C, Joshi S, Roy I, Chaudhuri BN, Chitnis D S, Tapan D. Dosing strategy based on prevailing aminoglycoside minimum inhibitory concentration in India: Evidence and issues. Indian J Med Microbiol 2017;35:585-7

How to cite this URL:
Veeraraghavan B, Pragasam AK, Manesh A, Rupali P, Iyadurai R, Rodrigues C, Joshi S, Roy I, Chaudhuri BN, Chitnis D S, Tapan D. Dosing strategy based on prevailing aminoglycoside minimum inhibitory concentration in India: Evidence and issues. Indian J Med Microbiol [serial online] 2017 [cited 2021 Jan 26];35:585-7. Available from:

 ~ Introduction Top

Aminoglycosides are important classes of agents used for the treatment of drug-resistant pathogens in critically ill patients.[1] Aminoglycosides are used as one of the agents in the empirical therapy, while ototoxicity and nephrotoxicity associated with these agents limit its therapeutic use.[1],[2] These are potent and broad-spectrum agents used for treating life-threatening infections caused by Gram-negative bacteria. According to CDDEP report, among the consumption of several antimicrobials in India between 2000 and 2010, aminoglycosides are the least consumed with <0.5 billion standard units with the minimal increase over the years.[3] However, inappropriate dosage given is a major concern.

Resistance to aminoglycosides is being increasingly reported, which limits its use. Aminoglycoside resistance is mediated by aminoglycoside-modifying enzymes (AME) and/or by 16 S rRNA methyltransferase (16 S RMTases). AME includes as follows: aminoglycoside N-aminoacyltransferases (AAC); Aminoglycoside O-nucleotidyltransferases (ANTs) and aminoglycoside O-phosphotransferases (APHs). AMEs such as AAC, ANT and APH either acetylate, adenylate or phosphorylate aminoglycosides, and thereby inactivating the aminoglycoside.[4] Recently reported 16 S RMTases are capable of conferring high-level resistance to all aminoglycoside agents.[5] However, AMEs are substrate specific conferring resistance to a particular agent among the aminoglycosides.

As aminoglycosides exhibit concentration depending killing activity, Cmax/minimum inhibitory concentration (MIC) is an important pharmacodynamic parameter. In critically ill patients, achieving the serum drug concentration of about eight times the MIC of an infected organism determines the therapeutic success.[6] Usage of higher doses to increase Cmax remains uncertain, due to nephro-toxicity and ototoxicity issues associated with increased dosage.

Standard usage and recommendation of aminoglycoside dosing regimens are 3, 6 and 15 mg/kg if the MIC of the infected organism is 1, 2 and 4 μg/ml, respectively. This dosing regimen is being followed for aminoglycosides such as gentamicin, netilmicin and tobramycin. Similarly, for amikacin 15 mg/kg is been preferred for MIC with 1 μg/ml and up to 30 mg/kg for an MIC of 2 μg/ml.[7],[8] However, recommendations for increased dosage is not certain, if the MIC of the infected organism is >2 μg/ml. The objectives of this study were to generate baseline MIC data for amikacin and gentamicin and to compare the in vitro susceptibility data with the current recommendations of dosing.

 ~ Materials and Methods Top

Gram-negative bacilli causing intra-abdominal infections and urinary tract infections that met the criteria of significant pathogen were collected. One isolate per patient was included in this study. Isolates were received from seven hospitals across various regions of India. This includes, Christian Medical College, Vellore, Tamil Nadu; Hinduja Hospital, Mumbai; Manipal hospital, Bangalore, Karnataka; Fortis hospital, Kolkata, West Bengal; The Calcutta Medical Research Institute, Kolkata, West Bengal; Choithram hospital, Indore, Madhya Pradesh; and Sanjay Gandhi Post Graduate Institute of Medical Science, Lucknow, Uttar Pradesh. All the isolates were characterised up to species level by standard biochemical testing methods.[9] MIC were determined using Micro Scan dehydrated Broth Micro Dilution panels and the results were interpreted as per the CLSI and EUCAST guidelines.[10],[11] Amikacin was tested ranging from 4 to 32 μg/ml and gentamicin ranging from 1 to 16 μg/ml. Quality Control (QC) strains such as  Escherichia More Details coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853 were tested in each batch. Readings were taken if the QC range was satisfactory.

 ~ Results and Discussion Top

A total of 2326 Gram-negative bacilli that met with the inclusion criteria were collected during the period of 2013–2016 from seven different hospitals collected across India. For Amikacin, a total of 1957 isolates of Enterobacteriaceae and 228 isolates of P. aeruginosa were included and MIC was determined by broth micro dilution method. For Gentamicin, 62 isolates of Enterobacteriaceae and 79 isolates of non-fermenters were included and MIC was determined by VITEK 2 automated system. The results were interpreted according to CLSI guideline 2017. As per the CLSI guidelines, 79% of Enterobacteriaceae and 61% of P. aeruginosa were interpreted as susceptible to amikacin within MIC of ≤16 μg/ml, respectively. In contrast, as per the EUCAST guidelines, 72% of the Enterobacteriaceae isolates and 54% of the P. aeruginosa were interpreted susceptible with amikacin MIC of ≤8 μg/ml. Seven percent difference in the susceptibility was noted between CLSI and EUCAST interpretative criteria for Enterobacteriaceae and P. aeruginosa. The results discussed here are mentioned in [Table 1]. Notably, the variations were due to the one tube dilution difference in the breakpoint recommended for interpreting susceptibility by CLSI and EUCAST. While, two-fold dilution difference was noticed in the breakpoints for interpreting the isolates as resistant. The clinical breakpoint values are mentioned in [Table 2].
Table 1: In vitro activity of amikacin and gentamicin tested against the clinical isolates

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Table 2: Clinical interpretative breakpoints of CLSI Versus EUCAST 2017 for Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp.

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When comparing in vitro MIC data with CLSI cut-off, for amikacin, 79% of the Enterobacteriaceae isolates were susceptible with MIC of ≤16 μg/ml. However, only 55% were actually treatable with MIC of ≤4 μg/ml as per the current dosing regimen. This is due to the Cmax of the serum drug concentration, which can be effective with MIC of ≤4 μg/ml. Although 24% of the bacterial isolates are clinically susceptible with MIC of 8–16 μg/ml, administration of standard dosing regimen (15 mg/kg) would not achieve sufficient drug concentration in the serum for the bactericidal effect. This leads to the under dosing and likely show a poor clinical outcome if the MIC of an infected organism is 8–16 μg/ml, which is defined as susceptible based on laboratory testing. Similarly, for P. aeruginosa, huge difference was noted in the susceptible isolates with less chance for clinical success. Although 61% of the isolates were susceptible, only 36% of the isolates had an MIC of ≤4 μg/ml, while 25% had an MIC 8–16 μg/ml, respectively.

While with the EUCAST cut-off, 20% difference was noted between the MIC that can be clinically treatable with adequate serum concentration for bacterial isolates MIC within the susceptible range, but likely to show poor clinical response. For aminoglycosides, EUCAST interpretative criteria seem to be a better option than CLSI. However, caution should be exercise that the method followed for aminoglycoside MIC determination is also by the EUCAST. Mismatching of CLSI testing method and EUCAST interpretative criteria must be avoided.

To the best of our knowledge, this is the first study comparing in vitro susceptibility data with the clinical dosing parameters, to substantiate the inadequate serum concentration (Cmax/MIC) resulting in poor clinical outcome. This urges the need for optimising the dose prescribed for amikacin based on the MIC value to improve the clinical response. Moreover, to avoid inappropriate or under dosing that might leads to development of resistance. Further, clinical trials warrants the toxicity issues associated with increased dosage.

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Conflicts of interest

There are no conflicts of interest.

 ~ References Top

Paul M, Silbiger I, Grozinsky S, Soares-Weiser K, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev 2006:CD003344.  Back to cited text no. 1
Kumar A, Safdar N, Kethireddy S, Chateau D. A survival benefit of combination antibiotic therapy for serious infections associated with sepsis and septic shock is contingent only on the risk of death: A meta-analytic/meta-regression study. Crit Care Med 2010;38:1651-64.  Back to cited text no. 2
Laxminarayan R, Chaudhury RR. Antibiotic resistance in India: Drivers and opportunities for action. PLoS Med 2016;13:e1001974.  Back to cited text no. 3
Ramirez MS, Tolmasky ME. Aminoglycoside modifying enzymes. Drug Resist Updat 2010;13:151-71.  Back to cited text no. 4
Doi Y, Wachino JI, Arakawa Y. Aminoglycoside resistance: The emergence of acquired 16S ribosomal RNA methyltransferases. Infect Dis Clin North Am 2016;30:523-37.  Back to cited text no. 5
Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient – Concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev 2014;77:3-11.  Back to cited text no. 6
Inciardi JF, Batra KK. Nonparametric approach to population pharmacokinetics in oncology patients receiving aminoglycoside therapy. Antimicrob Agents Chemother 1993;37:1025-7.  Back to cited text no. 7
Drusano GL, Ambrose PG, Bhavnani SM, Bertino JS, Nafziger AN, Louie A, et al. Back to the future: Using aminoglycosides again and how to dose them optimally. Clin Infect Dis 2007;45:753-60.  Back to cited text no. 8
Versalovic J, Carroll KC, Funke G, Jorgensen JH, Landry ML, Warnock DW, editors. Manual of Clinical Microbiology. 10th ed. Washington, D.C.: American Society for Microbiology; 2011.  Back to cited text no. 9
Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; Twenty seventh Informational Supplement. CLSI document M100-27. Wayne, PA: Clinical and Laboratory Standards Institute; 2017.  Back to cited text no. 10
European Committee on Antimicrobial susceptibility Testing Breakpoint Tables for Interpretation of MICs and Zone Diameters EUCAST; 2015.  Back to cited text no. 11


  [Table 1], [Table 2]


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