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• Management of asymptomatic Mycoplasma genitalium to mitigate the threat of drug resistance
  Peter J White, Joanna Lewis and Paddy J Horner
  Published on: 26 October 2020
• Re: Management of Mycoplasma genitalium infection in general population with low macrolide resistance rates
  Nigel Field
  Published on: 19 August 2020
• Management of Mycoplasma genitalium infection in general population with low macrolide resistance rates
  Luis Piñeiro, Pedro Idigoras and Gustavo Cilla
  Published on: 19 August 2020

• Published on: 26 October 2020

  Management of asymptomatic Mycoplasma genitalium to mitigate the threat of drug resistance

  • Peter J White, Professor of Public Health Modelling Imperial College London
  • Other Contributors:
    • Joanna Lewis, Postdoctoral Research Associate
    • Paddy J Horner, Associate Professor in Sexually Transmitted Infections

  Peter J White, MRC Centre for Outbreak Analysis & Modelling and NIHR Health Protection Research Unit in Modelling and Health Economics, Imperial College London.
  Other Contributors:
  Joanna Lewis, MRC Centre for Outbreak Analysis & Modelling, Imperial College London.
  Paddy J Horner, Population Health Sciences, and NIHR Health Protection Research Unit in Behavioural Science and Evaluation, University of Bristol.

  Pitt et al. commented “asymptomatic patients are not recommended for M. genitalium testing except sexual contacts... The current approach might need rethinking if asymptomatic infections are found to be an important reservoir for AMR and/or a source of infection and disease”.[1]
  Recent analysis of the POPI cohort found 4.9% (95%CrI 0.4%–14.1%) of M. genitalium infections in women progressed to pelvic inflammatory disease, compared with 14.4% (5.9%–24.6%) of Chlamydia trachomatis infections.[2] Combined with its lower prevalence this means that M. genitalium is a much less important cause of disease in women than C. trachomatis.[2]
  There is considerable uncertainty in the natural history and epidemiology of M. genitalium,[3] and we don’t know the importance of asymptomatic infection in transmission. Low bacterial load might limit infectivity but a long duration of infection[2,3] means there may be many potentially-infectious sex-acts. In fact, the BASHH guidelines are motivated by concern about transmission from asymptomatic...

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  Peter J White, MRC Centre for Outbreak Analysis & Modelling and NIHR Health Protection Research Unit in Modelling and Health Economics, Imperial College London.
  Other Contributors:
  Joanna Lewis, MRC Centre for Outbreak Analysis & Modelling, Imperial College London.
  Paddy J Horner, Population Health Sciences, and NIHR Health Protection Research Unit in Behavioural Science and Evaluation, University of Bristol.

  Pitt et al. commented “asymptomatic patients are not recommended for M. genitalium testing except sexual contacts... The current approach might need rethinking if asymptomatic infections are found to be an important reservoir for AMR and/or a source of infection and disease”.[1]
  Recent analysis of the POPI cohort found 4.9% (95%CrI 0.4%–14.1%) of M. genitalium infections in women progressed to pelvic inflammatory disease, compared with 14.4% (5.9%–24.6%) of Chlamydia trachomatis infections.[2] Combined with its lower prevalence this means that M. genitalium is a much less important cause of disease in women than C. trachomatis.[2]
  There is considerable uncertainty in the natural history and epidemiology of M. genitalium,[3] and we don’t know the importance of asymptomatic infection in transmission. Low bacterial load might limit infectivity but a long duration of infection[2,3] means there may be many potentially-infectious sex-acts. In fact, the BASHH guidelines are motivated by concern about transmission from asymptomatic infections. If asymptomatic infections are not treated then one expects a greater average number of transmission events per infection than if they were treated, but those transmitted infections that cause symptoms will tend to be treatable. Alternatively, if asymptomatic infections were treated routinely with current regimens then the short-term effect would be reduced transmission, but at the cost of increased drug resistance – which frequently arises de novo on azithromycin treatment, even after doxycycline pre-treatment – leading to more hard-to-treat (or even untreatable) infections in the future. In 2010–12 16.1% of infections had AMR-conferring mutations,[1] and with widespread use of azithromycin this is likely to have increased since, considering the large and rapid increases in resistance seen elsewhere.
  Ultimately, we need effective regimens and testing for resistance. We agree more modelling is required,[1] and hope a future Natsal survey will provide valuable up-to-date information on M. genitalium prevalence and drug-resistance.

  References
  1. Pitt R, Unemo M, Sonnenberg P, et al. Antimicrobial resistance in Mycoplasma genitalium sampled from the British general population. Sex Transm Infect 2020; 96(6):464-468.
  2. Lewis J, Horner PJ, White PJ. Incidence of Pelvic Inflammatory Disease Associated with Mycoplasma genitalium Infection: Evidence Synthesis of Cohort Study Data. Clin Infect Dis 2020; [online 23 July 2020] doi.org/10.1093/cid/ciaa419
  3. Birger R, Saunders J, Estcourt C, et al. Should we screen for the sexually-transmitted infection Mycoplasma genitalium? Evidence synthesis using a transmission-dynamic model. Sci Rep 2017; 7: 16162.
  Competing interests None declared.
  Disclaimer The views expressed are those of the authors and not necessarily those of the Department of Health and Social Care, MRC, NHS, NIHR, or Public Health England.

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  Conflict of Interest:
  None declared.

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• Published on: 19 August 2020

  Re: Management of Mycoplasma genitalium infection in general population with low macrolide resistance rates

  • Nigel Field, Associate Clinical Professor Director of the Centre for Molecular Epidemiology and Translational Research at the UCL Institute for Global Health

  We thank Piñeiro et al for their interest in our study using data from Britain’s third National Survey of Sexual Attitudes and Lifestyle (Natsal-3).¹ This was a probability sample survey undertaken in 2010-12, with Mycoplasma genitalium testing results from urine available for over 4,500 participants aged 16-44 years.² In this follow-up paper, we reported genotypic data on mutations associated with macrolide and fluoroquinolone resistance.

  We read with interest that Piñeiro et al also found relatively low levels (<20%) of macrolide resistance in a Spanish, mainly general population sample in 2014-17.³ However, the low macrolide resistance (16%) found in our study is probably due not only to the general population sample, but also to the specimens being collected nearly a decade ago. Since 2010-12, there is evidence that macrolide resistance in M. genitalium has rapidly increased globally, and we anticipate finding higher levels of genotypic macrolide resistance in the general population in Britain in 2022 when Natsal-4 is expected to report findings.⁴ These data will be important to inform national and international understanding of incidence and prevalence as well as updated management and infection control strategies.

  We appreciate both the relatively low treatment failure rate in the referenced Spanish study by Piñeiro et al,³ and the treatment strategy...

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  We thank Piñeiro et al for their interest in our study using data from Britain’s third National Survey of Sexual Attitudes and Lifestyle (Natsal-3).¹ This was a probability sample survey undertaken in 2010-12, with Mycoplasma genitalium testing results from urine available for over 4,500 participants aged 16-44 years.² In this follow-up paper, we reported genotypic data on mutations associated with macrolide and fluoroquinolone resistance.

  We read with interest that Piñeiro et al also found relatively low levels (<20%) of macrolide resistance in a Spanish, mainly general population sample in 2014-17.³ However, the low macrolide resistance (16%) found in our study is probably due not only to the general population sample, but also to the specimens being collected nearly a decade ago. Since 2010-12, there is evidence that macrolide resistance in M. genitalium has rapidly increased globally, and we anticipate finding higher levels of genotypic macrolide resistance in the general population in Britain in 2022 when Natsal-4 is expected to report findings.⁴ These data will be important to inform national and international understanding of incidence and prevalence as well as updated management and infection control strategies.

  We appreciate both the relatively low treatment failure rate in the referenced Spanish study by Piñeiro et al,³ and the treatment strategy informed by initial detection of macrolide resistance-associated mutations followed by azithromycin 1.5 g given over 5 days (if no macrolide resistance mutations detected) or moxifloxacin (if macrolide resistance mutations detected). This is in line with the current European guidelines.⁵ A similar but modified regimen using resistance-guided sequential treatment with doxycycline followed by azithromycin 2.5 g given over four days (if no macrolide resistance mutations) or moxifloxacin (if macrolide resistance mutations) is also described by Piñeiro et al, referencing a paper using sitafloxacin instead of moxifloxacin.⁶ Sitafloxacin may be more effective against M. genitalium than moxifloxacin because the doxycycline-sitafloxacin arm in the study clinically failed in only 7.8% of patients despite the observation that 20% of patients had ParC fluoroquinolone resistance-associated mutations.⁶ Furthermore, the cure rate for patients with M. genitalium samples with ParC S83I mutations (a common “fluoroquinolone resistance mutation”), possibly further potentiated by a concomitant GyrA M95I or D99N mutation, has been shown to be significantly higher with sitafloxacin compared to moxifloxacin.⁷ However, Durukan et al⁸ subsequently evaluated the same resistance-guided sequential treatment with doxycycline-moxifloxacin instead of doxycycline-sitafloxacin and found similar high cure rates.

  Initiating empirical treatment of patients with, for example, symptomatic non-gonococcal urethritis with doxycycline, before laboratory results are available, currently appears to be the best choice because doxycycline will, (1) cure Chlamydia trachomatis infections, (2) cure 30-40% of M. genitalium infections,⁵ and (3) significantly decrease the M. genitalium load in most cases not achieving cure,⁶ which improves the cure rate of subsequent treatment. As Piñeiro et al mention,³ the adherence and adverse events of treatments are also important. However, the reported adherence to the doxycycline regimen in the studies discussed above was high, i.e. at 90-94%,^6,8 and the adverse events were mainly mild grade 1. In fact, Durukan et al⁸ reported even fewer adverse events with doxycycline compared to azithromycin. Clearly, the adherence to treatment regimens and frequency of adverse events can significantly differ by setting, study population, and study.  

  There are still major gaps in our understanding about the distribution, natural history and pathology of M. genitalium, particularly in different anatomical sites, and about the sequelae of asymptomatic infections. For the moment, the primary focus in clinical practice should be on detecting and treating symptomatic patients (particularly with non-gonococcal urethritis and symptoms and/or signs of pelvic inflammatory disease), even though this may not be effective as a means to reduce population prevalence. We whole-heartedly agree with the need for more M. genitalium research, including on the epidemiology; pathogenesis; serious complications and sequelae; treatment approaches (sequential resistance-guided, ideal azithromycin dose regimen (1.5,^3,5 2.0 g,⁹ 2.5 g,^6,8 or other, and how the total dose should be divided), associations with “fluoroquinolone resistance mutations” and treatment outcomes with different fluoroquinolones, and the pharmacokinetics/pharmacodynamics, compliance and adverse effects of the treatments in different settings), particularly where evaluated using randomised controlled clinical trials; and other mechanisms to manage and control M. genitalium including how to suppress AMR emergence. Ultimately, new antimicrobials and ideally a vaccine are needed for sustainable management and control of M. genitalium infections.

   

  Magnus Unemo¹, Pam Sonnenberg², Nigel Field³

  ¹ WHO Collaborating Centre for Gonorrhoea and Other STIs, National Reference Laboratory for STIs, Department of Laboratory Medicine, Microbiology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden

  ² Centre for Population Research in Sexual Health and HIV, Institute for Global Health, UCL, London, United Kingdom

  ³ Centre for Molecular Epidemiology and Translational Research, Institute for Global Health, UCL, London, United Kingdom

  Correspondence to Dr Nigel Field, Centre for Molecular Epidemiology and Translational Research, Institute for Global Health, UCL, London WC1E 6JB, UK; nigel.field@ucl.ac.uk

  Competing interests None.

  REFERENCES

  1. Pitt R, Unemo M, Sonnenberg P, et al. Antimicrobial resistance in Mycoplasma genitalium sampled from the British general population. Sex Transm Infect 2020. pii: sextrans-2019-054129. doi: 10.1136/sextrans-2019-054129.
  2. Sonnenberg P, Ison CA, Clifton S, et al. Epidemiology of Mycoplasma genitalium in British men and women aged 16–44 years: evidence from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). Int J Epidemiol 2015;44:1982-94.
  3. Piñeiro L, Idigoras P, de la Caba I, et al. Guided antibiotic therapy for Mycoplasma genitalium infections: Analysis of mutations associated with resistance to macrolides and fluoroquinolones. Enferm Infecc Microbiol Clin 2019;37:394-7.
  4. Mercer CH, Clifton S, Prior G, et al. Collecting and exploiting data to understand a nation's sexual health needs: Implications for the British National Surveys of Sexual Attitudes and Lifestyles (Natsal). Sex Transm Infect 2019;95:159–61.
  5. Jensen JS, Cusini M, Gomberg M, et al. 2016 European guideline on Mycoplasma genitalium infections. J Eur Acad Dermatol Venereol 2016;30:1650–6.
  6. Read TRH, Fairley CK, Murray GL, et al. Outcomes of resistance-guided sequential treatment of Mycoplasma genitalium infections: A prospective evaluation. Clin Infect Dis 2019;68:554-60.
  7. Murray GL, Bodiyabadu K, Danielewski J, et al. Moxifloxacin and sitafloxacin treatment failure in Mycoplasma genitalium infection: Association with parC mutation G248T (S83I) and concurrent gyrA mutations. J Infect Dis. 2019;jiz550. doi:10.1093/infdis/jiz550
  8. Durukan D, Read TRH, Murray G, et al. Resistance-guided antimicrobial therapy using doxycycline-moxifloxacin and doxycycline-2.5g azithromycin for the treatment of Mycoplasma genitalium infection: efficacy and tolerability. Clin Infect Dis 2019;ciz1031. doi:10.1093/cid/ciz1031
  9. Soni S, Horner P, Rayment M, et al. British Association for Sexual Health and HIV national guideline for the management of infection with Mycoplasma genitalium (2018). Int J STD AIDS. 2019;30:938–50.

   

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  Conflict of Interest:
  None declared.

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• Published on: 19 August 2020

  Management of Mycoplasma genitalium infection in general population with low macrolide resistance rates

  • Luis Piñeiro, Microbiology Department Donostia University Hospital-Biodonostia Health Research Institute
  • Other Contributors:
    • Pedro Idigoras, Microbiology Department
    • Gustavo Cilla, Microbiology Department

  Dear Editor,

  We have read the interesting manuscript “Antimicrobial resistance in Mycoplasma genitalium sampled from the British general population”, from Pitt et al.1 In 56 M. genitalium-positive specimens, macrolide resistance was detected in 9 (16.1%). These results agree with the low rate of resistance (<20%) detected in studies carried out mainly in general population,2 but contrast with the higher rates (>40%) obtained in patients mainly attended in sexually transmitted infections units.3 These two scenarios (general versus core population) could be considered in the management of the M. genitalium infection.
  In our context (80-90% general population), the macrolide resistance rate was 16.3% (43/263).2 After detection of macrolide resistance-associated mutations with rapid techniques, guided antibiotic therapy was prescribed (azithromycin 500 mg day 1 and 250 mg days 2-5, or moxifloxacin) , and sexual partners control and test of cure after 3 weeks recommended. Despite patients adhering to the antibiotic regimen initially indicated, treatment failure was 6%.
  Recently, a resistance-guided sequential treatment with doxycycline followed with azithromycin or moxifloxacin has been proposed.3 In this study the macrolide resistance rate was 68% and the treatment failure 7%. In our opinion, this strategy could be appropriate in populations with high macrolide resistance rate (main conclusion of this study), and healthcare contexts in that guided ther...

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  Dear Editor,

  We have read the interesting manuscript “Antimicrobial resistance in Mycoplasma genitalium sampled from the British general population”, from Pitt et al.1 In 56 M. genitalium-positive specimens, macrolide resistance was detected in 9 (16.1%). These results agree with the low rate of resistance (<20%) detected in studies carried out mainly in general population,2 but contrast with the higher rates (>40%) obtained in patients mainly attended in sexually transmitted infections units.3 These two scenarios (general versus core population) could be considered in the management of the M. genitalium infection.
  In our context (80-90% general population), the macrolide resistance rate was 16.3% (43/263).2 After detection of macrolide resistance-associated mutations with rapid techniques, guided antibiotic therapy was prescribed (azithromycin 500 mg day 1 and 250 mg days 2-5, or moxifloxacin) , and sexual partners control and test of cure after 3 weeks recommended. Despite patients adhering to the antibiotic regimen initially indicated, treatment failure was 6%.
  Recently, a resistance-guided sequential treatment with doxycycline followed with azithromycin or moxifloxacin has been proposed.3 In this study the macrolide resistance rate was 68% and the treatment failure 7%. In our opinion, this strategy could be appropriate in populations with high macrolide resistance rate (main conclusion of this study), and healthcare contexts in that guided therapy could not be rapidly applied. On the other hand, adherence and adverse events associated with antibiotics used should be keeping in mind: 89.9% with doxycycline versus 100% with azithromycin, and 15.2% versus 8.6% , respectively.3 Moreover, other authors have described a lower adherence to doxycycline (100 mg/12h, 7 days) in M. genitalium infections and a clinical response <50%.
  We think sequential resistance-guided therapy results should be more studied in the real medical practice, taking in care the different contexts of the population studied (general population versus core groups with more previous antibiotic treatments), as well as non-compliance and secondary effects due to unnecessary overtreatment with doxycycline in macrolide susceptible infections.

  References
  1. Pitt R, Unemo M, Sonnenberg P, Alexander S, Beddows S, Cole MJ, Clifton S, Mercer CH, Johnson AM, Ison CA, Field N. Antimicrobial resistance in Mycoplasma genitalium sampled from the British general population. Sex Transm Infect. 2020. pii: sextrans-2019-054129. doi: 10.1136/sextrans-2019-054129.
  2. Piñeiro L, Idigoras P, de la Caba I, López-Olaizola M, Cilla G. Guided antibiotic therapy for Mycoplasma genitalium infections: Analysis of mutations associated with resistance to macrolides and fluoroquinolones. Enferm Infecc Microbiol Clin. 2019;37(6):394-7.
  3. Read TRH, Fairley CK, Murray GL, Jensen JS, Danielewski J, Worthington K, Doyle M, Mokany E, Tan L, Chow EPF, Garland SM, Bradshaw CS. Outcomes of Resistance-guided Sequential Treatment of Mycoplasma genitalium Infections: A Prospective Evaluation. Clin Infect Dis. 2019;68(4):554-60.

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  Conflict of Interest:
  None declared.

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