- Email: [email protected]
Decreased susceptibility to cephalosporins among gonococci? – Authors' reply
Correspondence
4
5
6
Deguchi T, Yasuda M, Ito S. Management of pharyngeal gonorrhea is crucial to prevent the emergence and spread of antibiotic-resistant Neisseria gonorrhoeae. Antimicrob Agents Chemother 2012; 56: 4039–40. Takahashi S, Kurimura Y, Hashimoto J, et al. Pharyngeal Neisseria gonorrhoeae detection in oral-throat wash specimens of male patients with urethritis. J Infect Chemother 2008; 14: 442–44. Chisholm SA, Mouton JW, Lewis DA, Nichols T, Ison CA, Livermore DM. Cephalosporin MIC creep among gonococci: time for a pharmacodynamic rethink? J Antimicrob Chemother 2010; 65: 2141–48.
Antimicrobial resistance in Neisseria gonorrhoeae is a growing problem and without appropriate action gonorrhoea might soon be untreatable in many settings.1 Catherine Ison and colleagues2 describe an association between a change in prescribing practice in 2010 for treatment of gonorrhoea (ceftriaxone plus azithromycin) in England and Wales and a decrease in the prevalence of gonococcal isolates with decreased susceptibility to extendedspectrum cephalosporins in 2011. Although the authors conceded that this change in prevalence could not be unequivocally attributed to the change in prescribing practice, we examined gonococcal antimicrobial resistance data from the Australian Gonococcal Surveillance Programme collected over a similar period to find out whether a similar decrease occurred in Australia. The Australian Gonococcal Surveillance Programme has monitored gonococcal antimicrobial resistance since 1981, and is one of the longest running and most comprehensive programmes of its kind. At present, 2009 Australian Capital Territory New South Wales Northern Territory Queensland
2010
2 (3·1%)
2 (3·6%)
16 (1·7%)
74 (5·6%)
58 (4·4%)
76 (4·5%)
1 (0·2%)
1 (0·25%) 26 (3·2%)
South Australia
9 (5·3%)
19 (11·6%)
Tasmania
0
Western Australia Total (Australia)
2012
2 (6·7%)
10 (1·8%)
Victoria
2011
2 (5·3%)
0
2 (0·4%)
0
18 (2·3%)
17 (2·4%)
1 (0·7%)
1 (0·7%)
0
0
17 (2·2%)
52 (5·7%)
50 (5·3%)
9 (3·1%)
17 (5·2%)
3 (0·7%)
105 (8·4%) 6 (1·2%)
64 (2·0%) 191 (4·8%)
134 (3·2%)
207 (4·4%)
Table: Neisseria gonorrhoeae Isolates with decreased susceptibility to ceftriaxone in states and territories of Australia, 2009–123,5
186
it tests and reports on antimicrobial resistance in 35% of all notified cases of gonorrhoea (about 4000 isolates every year) in Australia.3 Similar to the UK, national rates of gonococci with decreased susceptibility to ceftriaxone dropped from 4·5% in 2010, to 3·2% in 2011 (table; p<0·001), with a reduction reported in almost every state and territory.3 This decrease was not associated with a change to dual therapy, but coincided with an increase in dose of ceftriaxone monotherapy from 250 mg intramuscular injection, to 500 mg intramuscular injection in 2009 due to 250-mg vials of ceftriaxone being unavailable and clinicians’ consciousness of emerging resistance.4 Although some major clinics in Melbourne and Sydney did use ceftriaxone and azithromycin dual therapy, this regimen was not used until 2012, and is not yet in place widely throughout Australia. Hence, it is not plausible that a change to dual therapy could explain the decreases in isolates with reduced susceptibility noted in Australia in 2011. Overall these data suggest that different changes to prescribing practices in England and Wales and Australia were independently associated with falls in the proportion of gonococci with decreased susceptibility to ceftriaxone in 2011. The implication is that broad-scale change to a more optimum treatment might, at least temporarily, reverse emerging cephalosporin resistance. Unfortunately, the reduction in the proportion of isolates with decreased susceptibility to ceftriaxone in Australia seems to have been short-lived, with the proportion increasing to 4·4% in 2012 (table).5 Hence, it seems that increasing the dose of ceftriaxone alone might have only afforded a temporary reprieve. It will be interesting to analyse the effect of dual therapy as it is rolled out, and it is our hope, as Ison and colleagues2 have reported, that the next development in the field of gonorrhoea resistance is a more positive one. MML, BD, and DW’s research of gonorrhoea resistance is supported by an Australian National Health and
Medical Research Council (NHMRC) Project Grant (APP1025517). We declare that we have no conflicts of interest.
Monica M Lahra, Basil Donovan, David M Whiley [email protected] WHO Collaborating Centre for Sexually Transmitted Diseases, Department of Microbiology, South Eastern Area Laboratory Services, Prince of Wales Hospital, Sydney, NSW, Australia (MML); Kirby Institute, University of New South Wales, Sydney, NSW, Australia (BD); Sydney Sexual Health Centre, Sydney Hospital, Sydney NSW, Australia (BD); and Queensland Paediatric Infectious Diseases Laboratory (DMW), and Queensland Children’s Medical Research Institute (DMW), Royal Children’s Hospital, Brisbane, QLD 4029, Australia 1
2
3
4
5
Whiley DM, Goire N, Lahra MM, et al. The ticking time bomb: escalating antibiotic resistance in Neisseria gonorrhoeae is a public health disaster in waiting. J Antimicrob Chemother 2012; 67: 2059–61 Ison CA, Town K, Obi C, et al; for the GRASP collaborative group. Decreased susceptibility to cephalosporins among gonococci: data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales, 2007–2011. Lancet Infect Dis 2013; 13: 762–68. Lahra MM; for the Australian Gonococcal Surveillance Programme. Annual report of the Australian Gonococcal Surveillance Programme, 2011. Commun Dis Intell Q Rep 2012; 36: E166–73. Tapsall J, Read P, Carmody C, et al. Two cases of failed ceftriaxone treatment in pharyngeal gonorrhoea verified by molecular microbiological methods. J Med Microbiol 2009; 58: 683–87. Lahra MM, for the Australian Gonococcal Surveillance Programme. Australian Gonococcal Surveillance Programme annual report, 2012. Commun Dis Intell 2013; 37: E233—39.
Authors’ reply We read with interest the Correspondence about our Article on decreased susceptibility to cephalosporins among gonococci in England and Wales,1 and welcome the data shared from Australia, France, and Japan. We are encouraged to note that, in Australia, gonococcal isolates with decreased susceptibility to ceftriaxone fell from 2010 to 2011, similar to our findings for susceptibility to cefixime. In both instances, the fall was associated with increased dosage of ceftriaxone; albeit as monotherapy in Australia, whereas dual therapy (in combination with azithromycin) was www.thelancet.com/infection Vol 14 March 2014
Correspondence
used in the UK. The decline cannot be directly attributed to increased dosage of ceftriaxone in either country, but the UK’s switch to dual therapy should mean that an isolate will need to develop resistance to two antimicrobials, rather than to achieve only an increase in minimum inhibitory concentration (MIC) for ceftriaxone, for treatments to fail. The data from France, where there was no apparent decline in susceptibility, is interesting. Guy La Ruche and colleagues used a higher breakpoint (MIC >0·250 mg/L), which has been associated with therapeutic failure. 2 We agree that use of this definition on our dataset would result in fewer isolates with decreased susceptibility. Nevertheless, the purpose of surveillance programmes is to monitor drift towards resistance, in addition to detection of emergence of resistant strains, and so we used a lower breakpoint (MIC ≥0·125 mg/L), which we feel crucial in the absence of new therapeutic drugs for gonorrhoea. Further, there is evidence of failure at MICs of 0·125 mg/L, even with a regimen of 200 mg every 6 h,3 which is pharmacodynamically better than the 400 mg single dose as was previously used in the UK. Our conclusions about trends would be the same, irrespective of the breakpoint chosen, because most of the MICs of 0·125–0·250 mg/L are associated with one clone of gonococcus, circulating in a largely closed sexual network.1,4 We agree with Takashi Deguchi and colleagues about the importance of pharyngeal infection as a reservoir for gonorrhoea, but we did not stress this feature in our analysis because number of pharyngeal isolates in the dataset is low. Our experience is similar to that of Deguchi and La Ruche, in that we also find that pharyngeal isolates are significantly less susceptible to ceftriaxone than are those from anogenital sites (unpublished). However, because the proportion of pharyngeal isolates www.thelancet.com/infection Vol 14 March 2014
tested in the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) rose slightly, from about 4% in 2007, to 7% in 2012, any bias introduced would have tended to lessen the observed downward trend in decreased susceptibility to cefixime. Finally, we share the concern of Monica Lahra and colleagues about whether the decrease might be shortlived, and we too have detected a drift towards decreased susceptibility to ceftriaxone and the emergence of a bimodal population in the 2012 GRASP data.5 Nevertheless the proactive approach of changes to therapy before the recommended WHO level of 5% and the raised awareness that have resulted from action plans has hopefully bought sufficient time to enable new alternative treatments and to develop strategies for gonorrhoea control. The Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) was funded totally (2000–04) and partially (2005–10) by the Department of Health (England) and by Public Health England. DML has received personal fees from Allecra, Discuva; Pfizer, Curetis, Cycle Pharma, Cubist, Alere, Bioversys, Forest, Tetraphase, Wockhardt, Shionogi, and AOP Orphan; grants and personal fees from Achaogen, Adenium, Meiji, and AstraZeneca; grants, personal fees, and other support from GlaxoSmithKline; personal fees and non-financial support from Bruker; grants from VenatoRx, Merck, and Rokitan; and other support from Perkin Elmer. CAI has received funding from Merck for testing alternative antimicrobial agents. All other authors declare that they have no conflicts of interest.
Catherine A Ison, Katy Town, Chinelo Obi, Stephanie Chisholm, Gwenda Hughes, David M Livermore, Catherine M Lowndes [email protected] Sexually Transmitted Bacteria Reference Unit, Microbiological Services (CAI, SC), and HIV/STI Department, Health Protection Services (KT, CO, GH, CML), Public Health England, London NW9 5EQ, UK; and Norwich Medical School, University of East Anglia, Norwich, Norfolk , UK (DML) 1
Ison CA, Town K, Obi C, et al. Decreased susceptibility to cephalosporins among gonococci: data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales, 2007–2011. Lancet Infect Dis. 2013; 13: 762—68.
2
3
4
5
Unemo M, Golparian D, Nicholas R, et al. High level cefixime- and ceftriaxone-resistant N. gonorrhoeae in Europe (France): novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother 2012; 56: 1273–80. Deguchi T, Yasuda M, Yokoi S, et al. Treatment of uncomplicated gonococcal urethritis by double-dosing of 200 mg cefixime at a 6-h interval. J Infect Chemother 2003; 9: 35–39. Chisholm SA, Alexander S, Desouza-Thomas L, et al. Emergence of a Neisseria gonorrhoeae clone showing decreased susceptibility to cefixime in England and Wales. J Antimicrob Chemother. 2011; 66: 2509–12. Health Protection Agency 2013 Gonocococcal Resistance to Antimcrobials Surveillance Programme Action Plan. http://www.hpa. org.uk/webw/HPAweb&HPAwebStandard/ HPAweb_C/1317137983229 (accessed Feb 1, 2014)
Measurement of vaccine confidence using media surveillance system Heidi Larson and colleagues1 aim to develop a new application for surveillance systems that detect and characterise emerging vaccine-related public concerns by monitoring online information such as blogs, website pages, news items, etc. Although the Article is interesting, it is hampered by several major problems. One drawback is lack of application of suitable statistical methods; instead, the authors use simple counts and percentages. The definition of positive and negative or neutral content used is too arbitrary to reach legitimate conclusions, especially when reports could be classified by more than one data category. For example, the finding that the polio vaccine was covered positively and negatively the same number of times in the Nigerian media allows no substantial conclusion. Do the authors mean the report on a genuine but a benign adverse event should be considered as negative content? The authors do not give weight to the scientific content of the articles. It is not known what percentage of articles included in the study had truly scientific, feigned-scientific, or unscientific content. The report does 187
4
5
6
Deguchi T, Yasuda M, Ito S. Management of pharyngeal gonorrhea is crucial to prevent the emergence and spread of antibiotic-resistant Neisseria gonorrhoeae. Antimicrob Agents Chemother 2012; 56: 4039–40. Takahashi S, Kurimura Y, Hashimoto J, et al. Pharyngeal Neisseria gonorrhoeae detection in oral-throat wash specimens of male patients with urethritis. J Infect Chemother 2008; 14: 442–44. Chisholm SA, Mouton JW, Lewis DA, Nichols T, Ison CA, Livermore DM. Cephalosporin MIC creep among gonococci: time for a pharmacodynamic rethink? J Antimicrob Chemother 2010; 65: 2141–48.
Antimicrobial resistance in Neisseria gonorrhoeae is a growing problem and without appropriate action gonorrhoea might soon be untreatable in many settings.1 Catherine Ison and colleagues2 describe an association between a change in prescribing practice in 2010 for treatment of gonorrhoea (ceftriaxone plus azithromycin) in England and Wales and a decrease in the prevalence of gonococcal isolates with decreased susceptibility to extendedspectrum cephalosporins in 2011. Although the authors conceded that this change in prevalence could not be unequivocally attributed to the change in prescribing practice, we examined gonococcal antimicrobial resistance data from the Australian Gonococcal Surveillance Programme collected over a similar period to find out whether a similar decrease occurred in Australia. The Australian Gonococcal Surveillance Programme has monitored gonococcal antimicrobial resistance since 1981, and is one of the longest running and most comprehensive programmes of its kind. At present, 2009 Australian Capital Territory New South Wales Northern Territory Queensland
2010
2 (3·1%)
2 (3·6%)
16 (1·7%)
74 (5·6%)
58 (4·4%)
76 (4·5%)
1 (0·2%)
1 (0·25%) 26 (3·2%)
South Australia
9 (5·3%)
19 (11·6%)
Tasmania
0
Western Australia Total (Australia)
2012
2 (6·7%)
10 (1·8%)
Victoria
2011
2 (5·3%)
0
2 (0·4%)
0
18 (2·3%)
17 (2·4%)
1 (0·7%)
1 (0·7%)
0
0
17 (2·2%)
52 (5·7%)
50 (5·3%)
9 (3·1%)
17 (5·2%)
3 (0·7%)
105 (8·4%) 6 (1·2%)
64 (2·0%) 191 (4·8%)
134 (3·2%)
207 (4·4%)
Table: Neisseria gonorrhoeae Isolates with decreased susceptibility to ceftriaxone in states and territories of Australia, 2009–123,5
186
it tests and reports on antimicrobial resistance in 35% of all notified cases of gonorrhoea (about 4000 isolates every year) in Australia.3 Similar to the UK, national rates of gonococci with decreased susceptibility to ceftriaxone dropped from 4·5% in 2010, to 3·2% in 2011 (table; p<0·001), with a reduction reported in almost every state and territory.3 This decrease was not associated with a change to dual therapy, but coincided with an increase in dose of ceftriaxone monotherapy from 250 mg intramuscular injection, to 500 mg intramuscular injection in 2009 due to 250-mg vials of ceftriaxone being unavailable and clinicians’ consciousness of emerging resistance.4 Although some major clinics in Melbourne and Sydney did use ceftriaxone and azithromycin dual therapy, this regimen was not used until 2012, and is not yet in place widely throughout Australia. Hence, it is not plausible that a change to dual therapy could explain the decreases in isolates with reduced susceptibility noted in Australia in 2011. Overall these data suggest that different changes to prescribing practices in England and Wales and Australia were independently associated with falls in the proportion of gonococci with decreased susceptibility to ceftriaxone in 2011. The implication is that broad-scale change to a more optimum treatment might, at least temporarily, reverse emerging cephalosporin resistance. Unfortunately, the reduction in the proportion of isolates with decreased susceptibility to ceftriaxone in Australia seems to have been short-lived, with the proportion increasing to 4·4% in 2012 (table).5 Hence, it seems that increasing the dose of ceftriaxone alone might have only afforded a temporary reprieve. It will be interesting to analyse the effect of dual therapy as it is rolled out, and it is our hope, as Ison and colleagues2 have reported, that the next development in the field of gonorrhoea resistance is a more positive one. MML, BD, and DW’s research of gonorrhoea resistance is supported by an Australian National Health and
Medical Research Council (NHMRC) Project Grant (APP1025517). We declare that we have no conflicts of interest.
Monica M Lahra, Basil Donovan, David M Whiley [email protected] WHO Collaborating Centre for Sexually Transmitted Diseases, Department of Microbiology, South Eastern Area Laboratory Services, Prince of Wales Hospital, Sydney, NSW, Australia (MML); Kirby Institute, University of New South Wales, Sydney, NSW, Australia (BD); Sydney Sexual Health Centre, Sydney Hospital, Sydney NSW, Australia (BD); and Queensland Paediatric Infectious Diseases Laboratory (DMW), and Queensland Children’s Medical Research Institute (DMW), Royal Children’s Hospital, Brisbane, QLD 4029, Australia 1
2
3
4
5
Whiley DM, Goire N, Lahra MM, et al. The ticking time bomb: escalating antibiotic resistance in Neisseria gonorrhoeae is a public health disaster in waiting. J Antimicrob Chemother 2012; 67: 2059–61 Ison CA, Town K, Obi C, et al; for the GRASP collaborative group. Decreased susceptibility to cephalosporins among gonococci: data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales, 2007–2011. Lancet Infect Dis 2013; 13: 762–68. Lahra MM; for the Australian Gonococcal Surveillance Programme. Annual report of the Australian Gonococcal Surveillance Programme, 2011. Commun Dis Intell Q Rep 2012; 36: E166–73. Tapsall J, Read P, Carmody C, et al. Two cases of failed ceftriaxone treatment in pharyngeal gonorrhoea verified by molecular microbiological methods. J Med Microbiol 2009; 58: 683–87. Lahra MM, for the Australian Gonococcal Surveillance Programme. Australian Gonococcal Surveillance Programme annual report, 2012. Commun Dis Intell 2013; 37: E233—39.
Authors’ reply We read with interest the Correspondence about our Article on decreased susceptibility to cephalosporins among gonococci in England and Wales,1 and welcome the data shared from Australia, France, and Japan. We are encouraged to note that, in Australia, gonococcal isolates with decreased susceptibility to ceftriaxone fell from 2010 to 2011, similar to our findings for susceptibility to cefixime. In both instances, the fall was associated with increased dosage of ceftriaxone; albeit as monotherapy in Australia, whereas dual therapy (in combination with azithromycin) was www.thelancet.com/infection Vol 14 March 2014
Correspondence
used in the UK. The decline cannot be directly attributed to increased dosage of ceftriaxone in either country, but the UK’s switch to dual therapy should mean that an isolate will need to develop resistance to two antimicrobials, rather than to achieve only an increase in minimum inhibitory concentration (MIC) for ceftriaxone, for treatments to fail. The data from France, where there was no apparent decline in susceptibility, is interesting. Guy La Ruche and colleagues used a higher breakpoint (MIC >0·250 mg/L), which has been associated with therapeutic failure. 2 We agree that use of this definition on our dataset would result in fewer isolates with decreased susceptibility. Nevertheless, the purpose of surveillance programmes is to monitor drift towards resistance, in addition to detection of emergence of resistant strains, and so we used a lower breakpoint (MIC ≥0·125 mg/L), which we feel crucial in the absence of new therapeutic drugs for gonorrhoea. Further, there is evidence of failure at MICs of 0·125 mg/L, even with a regimen of 200 mg every 6 h,3 which is pharmacodynamically better than the 400 mg single dose as was previously used in the UK. Our conclusions about trends would be the same, irrespective of the breakpoint chosen, because most of the MICs of 0·125–0·250 mg/L are associated with one clone of gonococcus, circulating in a largely closed sexual network.1,4 We agree with Takashi Deguchi and colleagues about the importance of pharyngeal infection as a reservoir for gonorrhoea, but we did not stress this feature in our analysis because number of pharyngeal isolates in the dataset is low. Our experience is similar to that of Deguchi and La Ruche, in that we also find that pharyngeal isolates are significantly less susceptible to ceftriaxone than are those from anogenital sites (unpublished). However, because the proportion of pharyngeal isolates www.thelancet.com/infection Vol 14 March 2014
tested in the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) rose slightly, from about 4% in 2007, to 7% in 2012, any bias introduced would have tended to lessen the observed downward trend in decreased susceptibility to cefixime. Finally, we share the concern of Monica Lahra and colleagues about whether the decrease might be shortlived, and we too have detected a drift towards decreased susceptibility to ceftriaxone and the emergence of a bimodal population in the 2012 GRASP data.5 Nevertheless the proactive approach of changes to therapy before the recommended WHO level of 5% and the raised awareness that have resulted from action plans has hopefully bought sufficient time to enable new alternative treatments and to develop strategies for gonorrhoea control. The Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) was funded totally (2000–04) and partially (2005–10) by the Department of Health (England) and by Public Health England. DML has received personal fees from Allecra, Discuva; Pfizer, Curetis, Cycle Pharma, Cubist, Alere, Bioversys, Forest, Tetraphase, Wockhardt, Shionogi, and AOP Orphan; grants and personal fees from Achaogen, Adenium, Meiji, and AstraZeneca; grants, personal fees, and other support from GlaxoSmithKline; personal fees and non-financial support from Bruker; grants from VenatoRx, Merck, and Rokitan; and other support from Perkin Elmer. CAI has received funding from Merck for testing alternative antimicrobial agents. All other authors declare that they have no conflicts of interest.
Catherine A Ison, Katy Town, Chinelo Obi, Stephanie Chisholm, Gwenda Hughes, David M Livermore, Catherine M Lowndes [email protected] Sexually Transmitted Bacteria Reference Unit, Microbiological Services (CAI, SC), and HIV/STI Department, Health Protection Services (KT, CO, GH, CML), Public Health England, London NW9 5EQ, UK; and Norwich Medical School, University of East Anglia, Norwich, Norfolk , UK (DML) 1
Ison CA, Town K, Obi C, et al. Decreased susceptibility to cephalosporins among gonococci: data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales, 2007–2011. Lancet Infect Dis. 2013; 13: 762—68.
2
3
4
5
Unemo M, Golparian D, Nicholas R, et al. High level cefixime- and ceftriaxone-resistant N. gonorrhoeae in Europe (France): novel penA mosaic allele in a successful international clone causes treatment failure. Antimicrob Agents Chemother 2012; 56: 1273–80. Deguchi T, Yasuda M, Yokoi S, et al. Treatment of uncomplicated gonococcal urethritis by double-dosing of 200 mg cefixime at a 6-h interval. J Infect Chemother 2003; 9: 35–39. Chisholm SA, Alexander S, Desouza-Thomas L, et al. Emergence of a Neisseria gonorrhoeae clone showing decreased susceptibility to cefixime in England and Wales. J Antimicrob Chemother. 2011; 66: 2509–12. Health Protection Agency 2013 Gonocococcal Resistance to Antimcrobials Surveillance Programme Action Plan. http://www.hpa. org.uk/webw/HPAweb&HPAwebStandard/ HPAweb_C/1317137983229 (accessed Feb 1, 2014)
Measurement of vaccine confidence using media surveillance system Heidi Larson and colleagues1 aim to develop a new application for surveillance systems that detect and characterise emerging vaccine-related public concerns by monitoring online information such as blogs, website pages, news items, etc. Although the Article is interesting, it is hampered by several major problems. One drawback is lack of application of suitable statistical methods; instead, the authors use simple counts and percentages. The definition of positive and negative or neutral content used is too arbitrary to reach legitimate conclusions, especially when reports could be classified by more than one data category. For example, the finding that the polio vaccine was covered positively and negatively the same number of times in the Nigerian media allows no substantial conclusion. Do the authors mean the report on a genuine but a benign adverse event should be considered as negative content? The authors do not give weight to the scientific content of the articles. It is not known what percentage of articles included in the study had truly scientific, feigned-scientific, or unscientific content. The report does 187