药物敏感实验标准 CLSI MR04-2019

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Romney M. Humphries, PhD, D(ABMM)

Accelerate Diagnostics, Inc.

USA

Ellen N. Kersh, PhD

Centers for Disease Control and Prevention

USA

1 Foreword

The Clinical and Laboratory Standards Institute (CLSI) is a not-for-prot membership organization that brings together the varied

perspectives and expertise of the worldwide laboratory community for the advancement of a common cause: to foster excellence

in laboratory medicine by developing and implementing medical laboratory standards and guidelines that help laboratories fulll

their responsibilities with eﬃciency, eﬀectiveness, and global applicability.

Using the CLSI voluntary consensus process, the Subcommittee on Antimicrobial Susceptibility Testing develops standards that

promote accurate antimicrobial susceptibility testing and appropriate reporting. The subcommittee reviews data from various

sources and studies (eg, in vitro, pharmacokinetic-pharmacodynamic, and clinical studies) to establish antimicrobial susceptibility

test methods, breakpoints, and quality control (QC) ranges.

The details of the necessary and recommended data for selecting appropriate breakpoints and QC ranges, and how the data are

presented for evaluation, are described in CLSI document M23.1 CLSI antibacterial breakpoints are provided in CLSI documents

M1002 and M45.3

Over time, a microorganism’s susceptibility to an antimicrobial agent may decrease, resulting in a lack of clinical eﬃcacy

and/or safety. In addition, microbiological methods, QC parameters, and the manner in which breakpoints are established may be

rened to ensure more accurate results. Because of these types of changes, CLSI continually monitors and updates information

in its documents. Although CLSI standards and guidelines are developed using the most current information available at the time,

the eld of science and medicine is always changing; therefore, standards and guidelines should always be used in conjunction

with clinical judgment, current knowledge, and clinically relevant laboratory test results to guide patient treatment. For more

information, visit www.clsi.org.

This CLSI rationale document is based on CLSI agenda items submitted by the Working Group on Azithromycin.

2 Introduction

Treatment of Neisseria gonorrhoeae infections is a signicant challenge because resistance has emerged to nearly all therapeutic

options. Currently, the Centers for Disease Control and Prevention (CDC) and the World Health Organization recommend dual

therapy with ceftriaxone (250 mg, intramuscular) and azithromycin (1 g, oral) for treatment of uncomplicated gonorrhea.4 This

regimen is hoped to preserve the eﬀectiveness of ceftriaxone because a strain is unlikely to be resistant to both ceftriaxone and

Azithromycin Breakpoint for Neisseria gonorrhoeae

CLSI rationale document MR04

May 2019

Azithromycin Breakpoint for Neisseria gonorrhoeae

azithromycin. N. gonorrhoeae strains with resistance to a single agent may be eﬀectively eradicated when immediately treated

with two drugs, if the strain is susceptible to the second agent. Globally, only isolated case reports from the United Kingdom and

Australia have identied isolates with dual high-level ceftriaxone and azithromycin minimal inhibitory concentrations (MICs) (ie,

resistance).5,6

Susceptibility testing of individual strains to direct treatment choice is not routinely performed because most cases are identied

through use of nucleic acid amplication tests (NAATs), not culture. Culture and susceptibility testing are recommended for all

cases of treatment failure, and surveillance cultures with susceptibility testing are critical to informing international treatment

guidelines. The absence of azithromycin breakpoints precludes the possibility of US Food and Drug Administration (FDA)–cleared

devices to test azithromycin in the medical laboratory, and diﬀering cutoﬀs may be used when surveillance data are evaluated.

Azithromycin is a macrolide. The mechanism of antibacterial action is binding to 23S ribosomal RNA (rRNA), blocking protein

synthesis. Mutations in genes encoding 23S rRNA have been associated with treatment failure during azithromycin monotherapy

for N. gonorrhoeae, particularly when all four alleles of the N. gonorrhoeae 23S rRNA gene are aﬀected. Reports have identied

treatment failures for isolates with MICs of 4 or > 256 µg/mL, associated with the 23S rRNA C2611T and A2059G mutations,

respectively.7,8 Other genetic mutations (eg, meningococcal-like [mosaic] mtrR) can also increase azithromycin MICs, but only to

< 16 µg/mL. The association with treatment failure for these mutations is not established.

For the current azithromycin breakpoint for N. gonorrhoeae, see Table 1.

gonorrhea.4 This regimen is hoped to preserve the effectiveness of ceftriaxone because a strain

is unlikely to be resistant to both ceftriaxone and azithromycin. N. gonorrhoeae strains with

resistance to a single agent may be effectively eradicated when immediately treated with two

drugs, if the strain is susceptible to the second agent. Globally, only isolated case reports from

the United Kingdom and Australia have identified isolates with dual high-level ceftriaxone and

azithromycin minimal inhibitory concentrations (MICs) (ie, resistance).5,6

Susceptibility testing of individual strains to direct treatment choice is not routinely performed

because most cases are identified through use of nucleic acid amplification tests (NAATs), not

culture. Culture and susceptibility testing are recommended for all cases of treatment failure,

and surveillance cultures with susceptibility testing are critical to informing international

treatment guidelines. The absence of azithromycin breakpoints precludes the possibility of US

Food and Drug Administration (FDA)–cleared devices to test azithromycin in the medical

laboratory, and differing cutoffs may be used when surveillance data are evaluated.

Azithromycin is a macrolide. The mechanism of antibacterial action is binding to 23S ribosomal

RNA (rRNA), blocking protein synthesis. Mutations in genes encoding 23S rRNA have been

associated with treatment failure during azithromycin monotherapy for N. gonorrhoeae,

particularly when all four alleles of the N. gonorrhoeae 23S rRNA gene are affected. Reports

have identified treatment failures for isolates with MICs of 4 or > 256 µg/mL, associated with

the 23S rRNA C2611T and A2059G mutations, respectively.7,8 Other genetic mutations (eg,

meningococcal-like [mosaic] mtrR) can also increase azithromycin MICs, but only to < 16 µg/mL.

The association with treatment failure for these mutations is not established.

For the current azithromycin breakpoint for N. gonorrhoeae, see Table 1.

Table 1. Current CLSI Azithromycin Breakpoint*

Organism Group Antimicrobial Agent

Interpretive Categories and MIC

Breakpoints, µg/mL

SSDD I

N. gonorrhoeae Azithromycin ≤ 1   

* Last reviewed June 2018; first published in CLSI document M100, 29th ed.2

Abbreviations: I, intermediate; MIC, minimal inhibitory concentration; R, resistant; S, susceptible; SDD, susceptible-

dose dependent.

3 Standard Doses and Pharmacokinetic Data

After oral administration, azithromycin rapidly leaves the circulation to enter tissues, achieving

high and prolonged drug concentrations in peripheral sites including genital sites.

A single 500-mg oral dose of azithromycin in healthy adult volunteers is associated with the

pharmacokinetic parameters shown in Table 2.

Table 2. Pharmacokinetic Parameters for 500 mg Azithromycin9

Pharmacokinetic Parameters (Mean)

Total N = 12

Day 1 Day 5

Cmax (µg/mL) 0.41 0.24

Tmax (h) 2.5 3.2

AUC0-24 (µg • h/mL) 2.6 2.1

Cmin (µg/mL) 0.05 0.05

Urinary excretion (% dose) 4.5 6.5

Abbreviations: AUC0-24, area under the concentration time curve from 0 to 24 hours; Cmax, maximum concentration

of drug in serum; Cmin, minimum concentration of drug in serum; h, hours; Tmax, time to maximum serum

concentration.

Median azithromycin exposure (AUC0-288) in polymorphonuclear leukocytes is 800-fold greater

than in serum following a three-day regimen.9

At 19 hours, azithromycin concentration in the cervix is 2.8 µg/g, 70-fold higher than in plasma.

At 10 to 12 and nine to 18 hours, sputum and tonsil azithromycin concentrations are 2.9 µg/mL

and 4.5 µg/g, 30- and > 100-fold greater than in serum or plasma.9

For a single 1-g oral dose of azithromycin in healthy men (N = 10), the median plasma

concentration at two hours was 1.1 µg/mL (0.1 to 1.4 µg/mL), and rectal tissue concentration

peaked between two hours and four days (median 24 hours) with a median Cmax of 132.6 µg/g

(12.7 to 2695.8 µg/g).10,11 For rectal tissue concentration, the estimated AUC0-96 and

AUC0-∞ were 3644 and 13 103 (µg/g) • hr, respectively. Azithromycin elimination was biphasic

with a median initial half-life of 24.2 hours (time zero to 96 hours) and the total median

elimination half-life (time zero to day 14) of 86.6 hours. The elimination rate constant was

0.008/hour.

4 Minimal Inhibitory Concentration Distribution Data

US national surveillance data from the CDC Gonococcal Isolate Surveillance Project (GISP) were

reviewed for 2014, 2015, and 2016. Figure 1 shows the azithromycin MIC distribution of 15 496

isolates from 2014 to 2016. The mode and MIC50 were 0.25 µg/mL. Notably, in this systematic

sentinel site surveillance method, there were few isolates (2.9%) with azithromycin MICs > 1

µg/mL. The epidemiological cutoff value (ECV) was calculated as 1 µg/mL.

3 Standard Dosages and Pharmacokinetic Data

After oral administration, azithromycin rapidly leaves the circulation to enter tissues, achieving high and prolonged drug

concentrations in peripheral sites including genital sites.

A single 500-mg oral dose of azithromycin in healthy adult volunteers is associated with the pharmacokinetic parameters shown

in Table 2.

Azithromycin Breakpoint for Neisseria gonorrhoeae

Median azithromycin exposure (AUC0-288) in polymorphonuclear leukocytes is 800-fold greater than in serum following a three-

day regimen.9

At 19 hours, azithromycin concentration in the cervix is 2.8 µg/g, 70-fold higher than in plasma. At 10 to 12 and nine to 18 hours,

sputum and tonsil azithromycin concentrations are 2.9 µg/mL and 4.5 µg/g, 30- and > 100-fold greater than in serum or plasma.9

For a single 1-g oral dose of azithromycin in healthy men (N = 10), the median plasma concentration at two hours was 1.1 µg/mL

(0.1 to 1.4 µg/mL), and rectal tissue concentration peaked between two hours and four days (median 24 hours) with a median Cmax

of 132.6 µg/g (12.7 to 2695.8 µg/g).10,11 For rectal tissue concentration, the estimated AUC0-96 and AUC0-∞ were 3644 and 13 103

(µg/g) • hr, respectively. Azithromycin elimination was biphasic with a median initial half-life of 24.2 hours (time zero to 96 hours)

and the total median elimination half-life (time zero to day 14) of 86.6 hours. The elimination rate constant was 0.008/hour.

4 Minimal Inhibitory Concentration Distribution Data

US national surveillance data from the CDC Gonococcal Isolate Surveillance Project (GISP) were reviewed for 2014, 2015, and 2016.

Figure 1 shows the azithromycin MIC distribution of 15 496 isolates from 2014 to 2016. The mode and MIC50 were 0.25 µg/mL.

Notably, in this systematic sentinel site surveillance method, there were few isolates (2.9%) with azithromycin MICs > 1 µg/mL.

The epidemiological cutoﬀ value (ECV) was calculated as 1 µg/mL.

Abbreviations: GISP, Gonococcal Isolate Surveillance Project; MIC, minimal inhibitory concentration.

Figure 1. Azithromycin MIC Distribution for N. gonorrhoeae Isolates Collected by GISP (2014-

2016)

A total of 723 GISP isolates from 2013 to 2015 underwent whole genome sequencing. “High-

level resistance” was defined as an azithromycin MIC >

16 µg/mL. The data are shown in Figure

2. Isolates with A2059G and C2611T were identified. Isolates with four of four alleles harboring

the mutations had MICs ≥

16 µg/mL. Isolates with one to two alleles mutated had MICs of 0.5 or

1 µg/mL.

5.9% 8.4%

21.2%

34.9%

21.30%

5.5%

1.60% 0.70% 0.3% 0.3%

2000

4000

6000

≤0.03 0.06 0.125 0.25 0.5 1 2 4 8 ≥16

N. gonorrhoeae Count

Azithromycin MIC, µg/mL

97.1%

2.9%

A total of 723 GISP isolates from 2013 to 2015 underwent whole genome sequencing. “High-level resistance” was dened as an

azithromycin MIC > 16 µg/mL. The data are shown in Figure 2. Isolates with A2059G and C2611T were identied. Isolates with four

of four alleles harboring the mutations had MICs ≥ 16 µg/mL. Isolates with one to two alleles mutated had MICs of 0.5 or 1 µg/mL.

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摘要：

本页详细介绍了CLSI MR04-2019标准，即由临床与实验室标准协会发布的针对药物敏感实验的权威指南。该标准专注于优化抗菌药物敏感性试验（AST）的方法与质量要求，旨在帮助临床微生物实验室准确检测病原菌对各类抗生素的敏感或耐药性，从而为合理选择抗感染治疗方案提供科学依据。内容涵盖实验操作流程、质控菌株使用、结果判读标准及最新修订要点，特别关注应对日益严峻的全球抗菌药物耐药性问题。无论是从事微生物检测的实验室人员、临床药师，还是关注医院感染控制的专业人员，均可通过本资源获得标准化操作规范和最新

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