Neisseria gonorrhoeae azithromycin susceptibility in the United States ...

2 downloads 58 Views 1MB Size Report
Dec 1, 2014 - Results: 44,144 N. gonorrhoeae isolates were tested for azithromycin .... San Diego and San Francisco, California; Miami, Florida; Minneapolis,.
AAC Accepts, published online ahead of print on 1 December 2014 Antimicrob. Agents Chemother. doi:10.1128/AAC.04337-14 Copyright © 2014, American Society for Microbiology. All Rights Reserved.

1 2

Neisseria gonorrhoeae azithromycin susceptibility in the United States, the Gonococcal Isolate Surveillance Project: 2005–2013

3 4

Robert D. Kirkcaldy, MD, MPH,a # Olusegun Soge, PhD,b John R. Papp, PhD,a Edward

5

W. Hook, III, MD,c Carlos del Rio, MD,d Grace Kubin, PhD,e Hillard S. Weinstock, MD,

6

MPHa

7 8

Division of STD Prevention, Centers for Disease Control and Prevention, U.S.

9

Department of Health and Human Services, Atlanta, Georgia, USAa; University of

10

Washington, Seattle, Washington, USAb; University of Alabama and Jefferson County

11

Department of Health, Birmingham, Alabama, USAc; Emory University, Atlanta,

12

Georgia, USAd; Texas Department of State Health Services, Austin, Texas, USAe

13

Running Head: N. gonorrhoeae azithromycin susceptibility in the US

14 15

# Address correspondence to Robert D. Kirkcaldy, [email protected]

1

16

Abstract

17

Background: Azithromycin, administered with ceftriaxone, is recommended by CDC for

18

treatment of gonorrhea. Many experts have expressed concern about the ease with

19

which Neisseria gonorrhoeae can acquire macrolide resistance.

20

Objective: We sought to describe gonococcal azithromycin susceptibility in the United

21

States and determine whether azithromycin susceptibility has changed over time.

22

Methods: We analyzed 2005–2013 data from the Gonococcal Isolate Surveillance

23

Project, a CDC-supported sentinel surveillance network that monitors gonococcal

24

antimicrobial susceptibility.

25

Results: 44,144 N. gonorrhoeae isolates were tested for azithromycin susceptibility by

26

agar dilution methods. The overall azithromycin MIC50 was 0.25 µg/ml and the MIC90

27

was 0.5 µg/ml. There were no overall temporal trends in geometric means. Isolates from

28

men who had sex with men had significantly higher geometric mean MICs than isolates

29

from men who have sex exclusively with women. The overall prevalence of reduced

30

azithromycin susceptibility (MIC ≥2 µg/ml) was 0.4% and varied by year from 0.3%

31

(2006 and 2009) to 0.6% (2013).

32

Conclusion: We did not find a clear temporal trend in gonococcal azithromycin MICs in

33

the United States and the prevalence of reduced azithromycin susceptibility remains

34

low. These findings support continued use of azithromycin in the combination therapy

35

regimen for gonorrhea.

2

36

37

Introduction

Gonorrhea is the second most commonly reported notifiable disease in the

38

United States, second only to chlamydia. In 2012, 334,826 gonococcal infections were

39

reported in the United States, representing a continuing gradual increase over the

40

preceding four years.[1] In women, Neisseria gonorrhoeae is a major cause of pelvic

41

inflammatory disease, ectopic pregnancy, and infertility.[2,3] Public health control of

42

gonorrhea relies on prompt detection and effective treatment. However, treatment has

43

been made more challenging because N. gonorrhoeae has successively developed

44

resistance to each antimicrobial recommended for treatment. Penicillinase-producing N.

45

gonorrhoeae and gonococcal fluoroquinolone resistance emerged first in the United

46

States in Hawaii, California and other western states, possibly due to geographic

47

proximity to East Asia and travel, before spreading elsewhere in the United States.[4–6]

48

Fluoroquinolone resistant gonorrhea also initially became prevalent among men who

49

have sex with men (MSM) with gonorrhea before emerging among heterosexuals.[7]

50

Similar epidemiological patterns have been more recently observed for reduced

51

susceptibility to oral cephalosporins: cefixime minimum inhibitory concentrations (MICs)

52

increased sharply in isolates from the western US and from MSM during 2006 and

53

2011.[8,9]

54

Currently, the Centers for Disease Control and Prevention (CDC) recommends

55

only a single first-line regimen for gonorrhea treatment: the combination of ceftriaxone

56

(an injectable cephalosporin) 250 mg as a single intramuscular dose plus either

57

doxycycline 100 mg orally twice daily or azithromycin as a single 1 g oral dose.[9]

3

58

Because of the high prevalence of tetracycline resistance, azithromycin, an azalide

59

macrolide which binds to the bacterial 50S ribosomal subunit and inhibits protein

60

synthesis, is preferred over doxycycline as the second agent. Observational outcome

61

data of pharyngeal gonorrhea also suggest that, compared to the addition of

62

doxycycline, the addition of azithromycin to an oral cephalosporin improves likelihood of

63

cure.[10]

64

Azithromycin has not been recommended for gonorrhea monotherapy because

65

of the reported ease with which N. gonorrhoeae can acquire macrolide resistance.[11]

66

Two mechanisms have been commonly implicated in gonococcal reduced azithromycin

67

susceptibility: overexpression of an efflux pump due to mtrR-coding region mutations

68

[12–15] and decreased antimicrobial affinity due to mutations in genes encoding the

69

23S ribosomal subunit.[15,16] Because of the importance of azithromycin in the

70

currently recommended treatment regimen and risk of macrolide resistance, careful

71

monitoring of azithromycin susceptibility trends is important. We sought to describe

72

gonococcal azithromycin susceptibility in the United States and determine whether

73

gonococcal azithromycin susceptibility has changed over time between 2005 and 2013.

74

Methods

75

The Gonococcal Isolate Surveillance Project (GISP)

76

The Gonococcal Isolate Surveillance Project (GISP) is a US-based national

77

sentinel surveillance system established in 1986 to monitor trends in antimicrobial

78

susceptibility in N. gonorrhoeae and to establish a rational basis for the selection of

79

gonococcal therapies in the US.[17] Sexually transmitted disease (STD) clinics in 25–30 4

80

cities throughout the US participate in GISP as sentinel sites. At each participating STD

81

clinic, urethral N. gonorrhoeae isolates are collected from the first 25 men presenting

82

with symptomatic gonococcal urethritis each month. Isolates are submitted to regional

83

reference laboratories for antimicrobial susceptibility testing by agar dilution according

84

to a common protocol (available at: www.cdc.gov/std/gisp), and results are sent to CDC.

85

GISP also collects de-identified data on patient characteristics and clinical information

86

from clinic medical records.

87

Laboratory methods

88

Gonococcal isolates collected at each sentinel clinic are sub-cultured at the

89

clinic’s local public health laboratory on supplemented chocolate medium and frozen in

90

trypticase soy broth containing 20% glycerol. Isolates are shipped monthly to one of the

91

regional reference laboratories where they are tested for β-lactamase production and

92

susceptibility to azithromycin, penicillin, tetracycline, ciprofloxacin, spectinomycin,

93

cefixime, and ceftriaxone using the agar dilution method. Isolates were inoculated on

94

Difco GC Medium Base supplemented with 1% IsoVitalex Enrichment (Becton-

95

Dickinson Diagnostic Systems, Sparks, Maryland). During 2005–2007, the lowest

96

azithromycin concentration tested was 0.008 µg/ml; this was increased to 0.03 µg/ml in

97

2008. The routine testing range for azithromycin extended to 16.0 µg/ml during 2005–

98

2013. Laboratories were asked to conduct agar dilution testing to identify an endpoint

99

for isolates with MICs ≥ 16.0 µg/ml on the initial testing run; testing to an endpoint was

100

not conducted on three isolates collected during 2005–2013. In the absence of Clinical

101

and Laboratory Standards Institute (CLSI) breakpoints for gonococcal azithromycin

102

susceptibility or resistance,[18] we defined reduced azithromycin susceptibility as MICs 5

103

≥2.0 µg/ml for this analysis. Quality assurance processes are described in detail in the

104

GISP protocol.[19]

105

To ensure accuracy and reproducibility of antimicrobial susceptibility results from

106

the regional reference laboratories, a set of seven control N. gonorrhoeae strains with

107

known MICs of various antimicrobials are included with each susceptibility run. In

108

addition, reference laboratories test a CDC-provided panel of 15 unidentified strains

109

twice yearly to compare results and ensure consistency among laboratories.[19]

110

Results obtained from testing of control strains and CDC-provided panels are used for

111

internal quality assurance.

112

Statistical Analysis

113

Data were limited to sites that continuously participated during the analytic time

114

period: Albuquerque, New Mexico; Atlanta, Georgia; Baltimore, Maryland; Birmingham,

115

Alabama; Chicago, Illinois; Cleveland, Ohio; Dallas, Texas; Denver, Colorado;

116

Greensboro, North Carolina; Honolulu, Hawaii; Las Vegas, Nevada; Los Angeles,

117

Orange County, San Diego and San Francisco, California; Miami, Florida; Minneapolis,

118

Minnesota; New Orleans, Louisiana; Oklahoma City, Oklahoma; Philadelphia,

119

Pennsylvania; Phoenix, Arizona; Portland, Oregon; and Seattle, Washington. Clinical

120

sites were grouped into US census regions. The Northeast and South were combined

121

because of the small number of sites in the Northeast.

122

Azithromycin MIC values ≤0.03 µg/ml were considered to have MICs of 0.03

123

µg/ml for these analyses. Similarly, the four values reported as ≥16.0 µg/ml without

124

reported endpoints were considered to have MICs=16.0 µg/ml for the primary analysis. 6

125

Sensitivity analyses was performed by considering the azithromycin MIC value for these

126

three isolates to be 256.0 µg/ml (the highest azithromycin MIC detected thus far in the

127

United States was ≥256.0 µg/ml [1]). MICs50, geometric means with 95% confidence

128

intervals (CIs), and the percentage of isolates with reduced susceptibility with 95% CIs

129

were calculated. Proportions were compared using chi-square and medians were

130

compared using the Wilcoxon-Mann-Whitney test. Two-sided P values of