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Susceptibility patterns for amoxicillin/clavulanate tests mimicking the licensed formulations and pharmacokinetic relationships: do the MIC obtained with 2:1 ratio testing accurately reflect activity against beta-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis?
Diagn Microbiol Infect Dis. 2005 Nov; 53(3):225-31.DM

Abstract

Amoxicillin/clavulanate has recently undergone formulation changes (XR and ES-600) that represent 14:1 and 16:1 ratios of amoxicillin/clavulanate. These ratios greatly differ from the 2:1 ratio used in initial formulations and in vitro susceptibility testing. The objective of this study was to determine if the reference method using a 2:1 ratio accurately reflects the susceptibility to the various clinically used amoxicillin/clavulanate formulations and their respective serum concentration ratios. A collection of 330 Haemophilus influenzae strains (300 beta-lactamase-positive and 30 beta-lactamase-negative) and 40 Moraxella catarrhalis strains (30 beta-lactamase-positive and 10 beta-lactamase-negative) were tested by the broth microdilution method against eight amoxicillin/clavulanate combinations (4:1, 5:1, 7:1, 9:1, 14:1, and 16:1 ratios; 0.5 and 2 microg/mL fixed clavulanate concentrations) and the minimum inhibitory concentration (MIC) results were compared with those obtained with the reference 2:1 ratio testing. For the beta-lactamase-negative strains of both genera, there was no demonstrable change in the MIC values obtained for all ratios analyzed (2:1 to 16:1). For the beta-lactamase-positive strains of H. influenzae and M. catarrhalis, at ratios >or=4:1 there was a shift in the central tendency of the MIC scatterplot compared with the results of testing 2:1 ratio. As a result, there was a 2-fold dilution increase in the MIC(50) and MIC(90) values, most evident for H. influenzae and BRO-1-producing M. catarrhalis strains. For beta-lactamase-positive strains of H. influenzae, the shift resulted in a change in the interpretive result for 3 isolates (1.0%) from susceptible using the reference method (2:1 ratio) to resistant (8/4 microg/mL; very major error) at the 16:1 ratio. In addition, the number of isolates with MIC values at or 1 dilution lower than the breakpoint (4/2 microg/mL) increased from 5% at 2:1 ratio to 32-33% for ratios 14:1 and 16:1. Our results indicate that, for the beta-lactamase-positive strains of H. influenzae and M. catarrhalis, the results of the amoxicillin/clavulanate reference 2:1 ratio testing do not accurately represent all the currently licensed formulations. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment might be compromised when higher amoxicillin/clavulanate ratios are used clinically. With a better understanding of PK/PD parameters, reevaluation of the amoxicillin/clavulanate in vitro susceptibility testing should be considered by the standardizing authorities to reflect the licensed formulations and accurately predict clinical outcomes.

Authors+Show Affiliations

JMI Laboratories, North Liberty, IA 52317, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16257168

Citation

Pottumarthy, Sudha, et al. "Susceptibility Patterns for Amoxicillin/clavulanate Tests Mimicking the Licensed Formulations and Pharmacokinetic Relationships: Do the MIC Obtained With 2:1 Ratio Testing Accurately Reflect Activity Against Beta-lactamase-producing Strains of Haemophilus Influenzae and Moraxella Catarrhalis?" Diagnostic Microbiology and Infectious Disease, vol. 53, no. 3, 2005, pp. 225-31.
Pottumarthy S, Sader HS, Fritsche TR, et al. Susceptibility patterns for amoxicillin/clavulanate tests mimicking the licensed formulations and pharmacokinetic relationships: do the MIC obtained with 2:1 ratio testing accurately reflect activity against beta-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis? Diagn Microbiol Infect Dis. 2005;53(3):225-31.
Pottumarthy, S., Sader, H. S., Fritsche, T. R., & Jones, R. N. (2005). Susceptibility patterns for amoxicillin/clavulanate tests mimicking the licensed formulations and pharmacokinetic relationships: do the MIC obtained with 2:1 ratio testing accurately reflect activity against beta-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis? Diagnostic Microbiology and Infectious Disease, 53(3), 225-31.
Pottumarthy S, et al. Susceptibility Patterns for Amoxicillin/clavulanate Tests Mimicking the Licensed Formulations and Pharmacokinetic Relationships: Do the MIC Obtained With 2:1 Ratio Testing Accurately Reflect Activity Against Beta-lactamase-producing Strains of Haemophilus Influenzae and Moraxella Catarrhalis. Diagn Microbiol Infect Dis. 2005;53(3):225-31. PubMed PMID: 16257168.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Susceptibility patterns for amoxicillin/clavulanate tests mimicking the licensed formulations and pharmacokinetic relationships: do the MIC obtained with 2:1 ratio testing accurately reflect activity against beta-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis? AU - Pottumarthy,Sudha, AU - Sader,Helio S, AU - Fritsche,Thomas R, AU - Jones,Ronald N, Y1 - 2005/10/27/ PY - 2005/04/01/received PY - 2005/05/09/accepted PY - 2005/11/1/pubmed PY - 2006/2/4/medline PY - 2005/11/1/entrez SP - 225 EP - 31 JF - Diagnostic microbiology and infectious disease JO - Diagn Microbiol Infect Dis VL - 53 IS - 3 N2 - Amoxicillin/clavulanate has recently undergone formulation changes (XR and ES-600) that represent 14:1 and 16:1 ratios of amoxicillin/clavulanate. These ratios greatly differ from the 2:1 ratio used in initial formulations and in vitro susceptibility testing. The objective of this study was to determine if the reference method using a 2:1 ratio accurately reflects the susceptibility to the various clinically used amoxicillin/clavulanate formulations and their respective serum concentration ratios. A collection of 330 Haemophilus influenzae strains (300 beta-lactamase-positive and 30 beta-lactamase-negative) and 40 Moraxella catarrhalis strains (30 beta-lactamase-positive and 10 beta-lactamase-negative) were tested by the broth microdilution method against eight amoxicillin/clavulanate combinations (4:1, 5:1, 7:1, 9:1, 14:1, and 16:1 ratios; 0.5 and 2 microg/mL fixed clavulanate concentrations) and the minimum inhibitory concentration (MIC) results were compared with those obtained with the reference 2:1 ratio testing. For the beta-lactamase-negative strains of both genera, there was no demonstrable change in the MIC values obtained for all ratios analyzed (2:1 to 16:1). For the beta-lactamase-positive strains of H. influenzae and M. catarrhalis, at ratios >or=4:1 there was a shift in the central tendency of the MIC scatterplot compared with the results of testing 2:1 ratio. As a result, there was a 2-fold dilution increase in the MIC(50) and MIC(90) values, most evident for H. influenzae and BRO-1-producing M. catarrhalis strains. For beta-lactamase-positive strains of H. influenzae, the shift resulted in a change in the interpretive result for 3 isolates (1.0%) from susceptible using the reference method (2:1 ratio) to resistant (8/4 microg/mL; very major error) at the 16:1 ratio. In addition, the number of isolates with MIC values at or 1 dilution lower than the breakpoint (4/2 microg/mL) increased from 5% at 2:1 ratio to 32-33% for ratios 14:1 and 16:1. Our results indicate that, for the beta-lactamase-positive strains of H. influenzae and M. catarrhalis, the results of the amoxicillin/clavulanate reference 2:1 ratio testing do not accurately represent all the currently licensed formulations. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment might be compromised when higher amoxicillin/clavulanate ratios are used clinically. With a better understanding of PK/PD parameters, reevaluation of the amoxicillin/clavulanate in vitro susceptibility testing should be considered by the standardizing authorities to reflect the licensed formulations and accurately predict clinical outcomes. SN - 0732-8893 UR - https://www.unboundmedicine.com/medline/citation/16257168/Susceptibility_patterns_for_amoxicillin/clavulanate_tests_mimicking_the_licensed_formulations_and_pharmacokinetic_relationships:_do_the_MIC_obtained_with_2:1_ratio_testing_accurately_reflect_activity_against_beta_lactamase_producing_strains_of_Haemophilus_influenzae_and_Moraxella_catarrhalis L2 - https://linkinghub.elsevier.com/retrieve/pii/S0732-8893(05)00115-X DB - PRIME DP - Unbound Medicine ER -