Edited by: Alessandro Cassini, European Centre for Disease Prevention and Control, Sweden
Reviewed by: Ana Afonso, Universidade de São Paulo, Brazil; Thiago DeSouza-Vieira, National Institute of Allergy and Infectious Diseases (NIAID), United States
This article was submitted to Infectious Diseases - Surveillance, Prevention and Treatment, a section of the journal Frontiers in Medicine
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Recent reports of combined high level resistance to ceftriaxone and azithromycin in
For a number of bacteria, striking ecological correlations have been found between the prevalence of antimicrobial consumption and resistance to that antimicrobial (
Our data came from three sources.
The WHO Global Gonococcal Antimicrobial Surveillance Programme (GASP) is a collaborative global network of regional and subregional reference laboratories that monitors AMR in Ng around the world. WHO GASP data have informed revisions of global, regional and national gonorrhea treatment guidelines, as well as public health strategies and policies developed by WHO and other organizations. The full GASP methodology, including suggested sampling strategy, laboratory techniques, external quality assurance, and internal quality control mechanisms has been published elsewhere (
The total numbers of countries contributing AMR data to GASP increased from 56 in 2009 to 77 in 2014. These are divided into 6 WHO regions (Supplementary Table
Data from Intercontinental Marketing Statistics Health MIDAS (IMS Health, Danbury, CT, USA) were used as a measure of national antimicrobial drug consumption. IMS uses national sample surveys that are performed by pharmaceutical sales distribution channels to estimate antimicrobial consumption from the volume of antibiotics sold in retail and hospital pharmacies. The sales estimates from this sample are projected with use of an algorithm developed by IMS Health to approximate total volumes for sales and consumption. Antimicrobial consumption estimates are reported as the number of standard doses (a dose is classified as a pill, capsule, or ampoule) per 1,000 population per year. Data is available for 63 countries. We used data for the 47 countries that were also represented in the GASP dataset. Data was available from 45 countries in 2000 and 47 in 2008 and 2013.
The Ng incidence by WHO world region were taken from a publication that reported the WHOs estimated Ng incidence and prevalence (
Pearson's correlation was used to assess the association between median antimicrobial consumption (within each WHO Region) in 2008 and the median prevalence of AMR in the year 2009. This was then repeated for antimicrobial consumption in 2013 and AMR in 2014. In the case of ceftriaxone, the AMR data for 2013 was used instead of that of 2014 due to the higher number of data points in 2013 (
We performed linear regression analyses in which the dependent variable was antimicrobial susceptibility (percent resistant) in each country and the independent variable of interest was the prior year antimicrobial consumption rate. The AMR variables used in these regressions were square root transformed to more closely approximate normal distributions.
Stata 13.0 was used for all analyses. A
In both 2009 and 2013, the prevalence of ceftriaxone resistance was highest in the Western Pacific (median percent AMR: 1.3%, interquartile range [IQR] 0.0–20.3). These prevalence estimates, as well as that from South East Asia in 2009 (0.0, IQR 0.0–5.4) were higher than those in Europe at the same times (0.0, IQR 0.0–0.0,
Antimicrobial resistance prevalence by country reported in world regions [median (interquartile range)] Data from GASP.
Ceftriaxone | Europe | 0.0 (0.0–0.0) | 19 | 0.0 (0.0–0.0) | 22 |
SE Asia | 0.0 (0.0–5.4) |
4 | 0.0 (0.0–0.2) | 2 | |
W Pacific | 1.3 (0.0–20.3) |
13 | 1.4 (0.2–4.5) |
10 | |
Americas | 0.0 (0.0–1.3) | 13 | 0.0 (0.0–0.3) | 8 | |
Africa | 0.0 (0.0–0.7) |
3 | 0.0 (0.0–0.0) | 1 | |
Total | 0.0 (0–0.016) |
52 | 0.0 (0.0–0.3) |
43 | |
Azithromycin | Europe | 6.7 (2.3–17.3) | 19 | 3.7 (1.8–8.7) | 23 |
SE Asia | 0.0 (0.0–0.0) | 1 | 2.4 (0.2–4.8) | 6 | |
W Pacific | 0.0 (0.0–0.0) |
3 | 1.4 (1.3–5.0) | 9 | |
Americas | 2.9 (0.2–45.6) | 7 | 2.9 (2.5–3.3) | 2 | |
Africa | 1.4 (0.0–2.7) | 2 | 11 (10–83.1) | 3 | |
Total | 3.5 (0.0–12.4) |
32 | 3.45 (1.3–8.7) | 43 | |
Ciprofloxacin | Europe | 67.3 (43.3–79.2) | 19 | 57 (34.7–67.5) | 23 |
SE Asia | 93.2 (83.7–96.7) |
4 | 91.1 (76.4–99.1) |
6 | |
W Pacific | 75.7 (38.8–92.4) | 16 | 82.8 (38.1–95.0) | 10 | |
Americas | 24.0 (6.0–35.0) |
13 | 53.0 (40.0–61.0) | 9 | |
Africa | 5.8 (0.0–53.2) |
3 | 58.0 (53.9–62.0) | 2 | |
Total | 65.1 (32–80) |
52 | 40 (58.3–78) |
50 |
Scatter plots of antimicrobial consumption vs. antimicrobial resistance in the subsequent year for
The prevalence of resistance to azithromycin was highest in Europe in 2009 (6.7, IQR 2.3–17.3) and Africa in 2014 (11.0, IQR 10.0–83.1). The prevalence of azithromycin resistance was lower in Western Pacific (0.0, IQR 0.0–0.0,
Resistance to ciprofloxacin was highest in South East Asia at both time points (2009: 93.2%, IQR 83.7–96.7; 2014: 91.1%, IQR 76.4–99.1). Both these prevalences were higher than those from Europe (2009: 67.3%, IQR 43.3–79.2; 2014: 57.0%, IQR 34.7–67.5; both
In 2000, 2008, and 2009, the consumption of cephalosporins was highest (and increased steadily) in Western Pacific (2000: median standard units/1,000 persons/year- 2000: 2071, IQR 1237–4686; 2008: 2657, IQR 1766–5601; 2013: 3237, IQR 2665–6991; Table
Antimicrobial consumption by country reported in world regions.
Cephalosporins | Europe | 1573 (779–2850) | 22 | 1623 (590–2522) | 22 | 1385 (656–2112) | 22 |
SE Asia | 418 (154–418)* | 3 | 1450 (750–2141) | 4 | 1568 (1132–2707) | 4 | |
W Pacific | 2071 (1237–4686) | 9 | 2657 (1766–5601)* | 10 | 3237 (2665–6991)** | 10 | |
Americas | 1132 (526–1846) | 10 | 1142 (814–2214) | 10 | 1402 (921–2289) | 10 | |
Africa | 769 (769–769) | 1 | 711 (711–711) | 1 | 728 (728–728) | 1 | |
Total | 1644 (814–2522)* | 45 | 1644 (814–2522)* | 47 | 1570 (769–2754)* | 47 | |
Macrolides | Europe | 2299 (1545–3053) | 22 | 2206 (1449–2817) | 22 | 1963 (1236–2390) | 22 |
SE Asia | 559 (266–785)* | 3 | 759 (579–1152)* | 4 | 900 (711–1167)* | 4 | |
W Pacific | 2345 (1128–2855) | 9 | 2042 (1512–2834) | 10 | 2205 (1703–2884) | 10 | |
Americas | 728 (469–1366)** | 10 | 775 (647–1330)** | 10 | 998 (764–1521)** | 10 | |
Africa | 1720 (1720–1720) | 1 | 1743 (1743–1743) | 1 | 1870 (1870–1870) | 1 | |
Total | 1720 (895–2797)** | 45 | 1612 (938–2645)* | 47 | 1626 (1010–2257)* | 47 | |
Fluoroquinolones | Europe | 936 (614–1246) | 22 | 1290 (761–1757) | 22 | 1211 (698–1620) | 22 |
SE Asia | 715 (137–1238) | 3 | 1330 (964–1732) | 4 | 1116 (874–1553) | 4 | |
W Pacific | 590 (365–1110) | 9 | 812 (466–1690) | 10 | 1198 (457–1658) | 10 | |
Americas | 461 (355–943) | 10 | 840 (684–1405) | 10 | 1059 (809–1597) | 10 | |
Africa | 316 (316–316) | 1 | 827 (827–827) | 1 | 881 (881–881) | 1 | |
Total | 741 (383–1150) | 45 | 968 (761–1690) | 47 | 1183 (758–1600) | 47 |
Macrolide consumption was highest in Europe in 2000 (2299, IQR 1545–3053) but this declined by 2008 and 2013. Although macrolide consumption increased in both the Americas and South East Asia between 2000 and 2013, it remained lower at all three times in these two regions than Europe (
Fluoroquinolone consumption increased steadily in all regions between 2000 and 2008 but then declined slightly between 2008 and 2013 in Europe and SE Asia. Consumption was highest in Europe in 2000 but by 2013 was similar in Europe, SE Asia and Western Pacific.
At the level of WHO regions, the prevalence of AMR for the three antimicrobials was positively associated with the consumption rates of those antimicrobials in five out of six assessments (
Pearson's correlation between consumption of antimicrobial and antimicrobial resistance by WHO world region.
Ceftriaxone | 0.88 | 0.94 |
Azithromycin | 0.38 | 0.22 |
Ciprofloxacin | 0.66 | 0.37 |
The association between antimicrobial resistance and consumption at the level of individual countries was positive in six out of six assessments. In four instances the positive associations were statistically significant (cephalosporins 2008: coefficient 0.0005 [95% CI 0.0002–0.0007] and 2013: coefficient 0.0003 [95% CI 0.0002–0.0004]; macrolides 2013: coefficient 0.0005 [95% CI 0.00002–0.001]; fluoroquinolones 2013: coefficient 0.02 [95% CI 0.006–0.031]; Table
Linear regression coefficients for association between antimicrobial consumption (2008 and 2013) and percent antimicrobial resistance for quinolones, macrolides and ceftriaxone (2009 and 2014; coefficient [95% confidence interval]).
Cephalosporins | 0.0005 (0.0002–0.0007) |
40 | 0.0003 (0.0002–0.0004) |
34 |
Macrolides | 0.00008 (−0.0007–0.0009) | 27 | 0.0005 (0.00002–0.001) |
35 |
Fluoroquinolones | 0.0006 (−0.0006–0.002) | 40 | 0.02 (0.006–0.031) |
38 |
At the level of WHO regions, the incidence of Ng was positively associated with the consumption rates of those antimicrobials in 3 out of 6 assessments and (
Pearson's correlation between incidence of gonorrhea in 2012 and (a) antimicrobial resistance in 2014 (b) antimicrobial consumption in 2013 by WHO world region.
a) | ||
Ceftriaxone | 0.90 | 0.38 |
Azithromycin | −0.45 | 0.60 |
Ciprofloxacin | 0.26 | −0.19 |
b) | ||
Ceftriaxone | 0.06 | 0.85 |
Azithromycin | 0.48 | 0.34 |
Ciprofloxacin | −0.63 | 0.28 |
In this ecological analysis, we found that the consumption of cephalosporins was highest in Western Pacific in general and Japan in specific. Furthermore, at the level of regions and countries there was evidence of a positive association between volume of cephalosporin consumption and AMR.
The associations between macrolides/fluoroquinolone consumption and resistance whilst also positive were only statistically significant in 2014. At all three time points fluoroquinolone AMR was highest in South East Asia—the region with the highest or second highest fluoroquinolone consumption in 2000 and 2008. Macrolide AMR was highest/second highest in Europe in 2008/2013, whilst macrolide consumption in Europe was highest or second highest in 2000, 2008, and 2013.
There are a number of possible explanations for these findings. The prevalence of antimicrobials consumed by the general population may be correlated with the antibiotics used to treat Ng-associated STI syndromes and this may be the actual driver of AMR in Ng. This explanation is supported by a large body of evidence that has demonstrated that resistance to a particular antimicrobial in Ng typically follows soon after the introduction of that antimicrobial as recommended therapy for Ng (
This pharmacoecological theory of AMR posits that extensive antimicrobial exposure (including that used for STI treatment) in a population places a selection pressure on circulating Ng to acquire AMR via five mechanisms (
Previous studies evaluating the ecological-level association between antimicrobial consumption and AMR have had divergent findings. In an ecological analysis of county level data from the United States 2005–2013, Kirkcaldy et al. did not find an association between antimicrobial consumption and emergence of AMR in Ng (
A complex interplay between a wide array of factors are likely responsible for the differential emergence and spread of AMR in Ng (
There may be inaccuracies in the AMR and antimicrobial consumption data. The IMS methodology misses non-reporting manufacturer direct sales. This may introduce a bias if this varies between countries (
There has been a large increase in antimicrobial consumption in low and middle-income countries over the last 15 years (
Finally our study further highlights the critical need to strengthen antibiotic stewardship programmes to limit exposure of Ng to antimicrobials and thereby delay the further emergence of resistance in Ng.
Previous studies have found positive ecological associations between antimicrobial consumption and the prevalence of antimicrobial resistance
We used susceptibility data from the WHOs Global Gonococcal Antimicrobial Surveillance Programme and antimicrobial consumption data from the IMS Health MIDAS database to assess if the same was true for
The assessments were carried out for ceftriaxone, azithromycin and ciprofloxacin at two time periods-−2008/9 and 2013/24
In six out of six assessements the association between antimicrobial consumption and resistance was positive
In the case of three assessments these associations were statistically significant.
CK conceptualized the study. CK was responsible for the acquisition, analysis, and interpretation of data. TW provided GASP data. CK, JB, and TW played a role in writing, editing, and approving the final version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The Supplementary Material for this article can be found online at:
Antimicrobial resistance and consumption by country.