Treatment efficacy, treatment failures and selection of macrolide resistance in patients with high load of Mycoplasma genitalium during treatment of male urethritis with josamycin

BMC Infectious Diseases

Magnus Unemo³  Mikhail Gomberg¹  Tatiana Rumyantseva²  Pavel Ryzhikh²  Alexander Guschin² 

[1] Moscow Scientific and Practical Center for Dermatovenerology and Cosmetology, Moscow, Russia;Department of Molecular Diagnostics and Epidemiology, Central Research Institute for Epidemiology, Moscow, Russia;Department of Laboratory Medicine, Microbiology, School of Medicine, Örebro University, Örebro, Sweden

关键词: Male urethritis;    Russia;    Macrolides;    Josamycin;    23S rRNA;    Antimicrobial resistance;    Treatment failure;    Treatment efficacy;    Treatment;    Mycoplasma genitalium;   

Others  :  1120410
DOI  :  10.1186/s12879-015-0781-7

 received in 2014-11-03, accepted in 2015-01-23,  发布年份 2015

【 摘 要 】

Background

Azithromycin has been widely used for Mycoplasma genitalium treatment internationally. However, the eradication efficacy has substantially declined recent decade. In Russia, josamycin (another macrolide) is the recommended first-line treatment for M. genitalium infections, however, no data regarding treatment efficacy with josamycin and resistance in M. genitalium infections have been internationally published. We examined the M. genitalium prevalence in males attending an STI clinic in Moscow, Russia from December 2006 to January 2008, investigated treatment efficacy with josamycin in male urethritis, and monitored the M. genitalium DNA eradication dynamics and selection of macrolide resistance in M. genitalium during this treatment.

Methods

Microscopy and real-time PCRs were used to diagnose urethritis and non-viral STIs, respectively, in males (n = 320). M. genitalium positive patients were treated with recommended josamycin regimen and treatment efficacy was monitored using quantitative real-time PCR. Macrolide resistance mutations were identified using sequencing of the 23S rRNA gene.

Results

Forty-seven (14.7%) males were positive for M. genitalium only and most (85.1%) of these had symptoms and signs of urethritis. Forty-six (97.9%) males agreed to participate in the treatment efficacy monitoring. All the pre-treatment M. genitalium specimens had wild-type 23S rRNA. The elimination of M. genitalium DNA was substantially faster in patients with lower pre-treatment M. genitalium load, and the total eradication rate was 43/46 (93.5%). Of the six patients with high pre-treatment M. genitalium load, three (50%) remained positive post-treatment and these positive specimens contained macrolide resistance mutations in the 23S rRNA gene, i.e., A2059G (n = 2) and A2062G (n = 1).

Conclusions

M. genitalium was a frequent cause of male urethritis in Moscow, Russia. The pre-treatment M. genitalium load might be an effective predictor of eradication efficacy with macrolides (and possibly additional antimicrobials) and selection of macrolide resistance. Additional in vivo and in vitro data are crucial to support the recommendation of using josamycin as first-line treatment for M. genitalium infections in Russia. It would be valuable to develop international M. genitalium management guidelines, and quantitative diagnostic PCRs determining also M. genitalium load and resistance mutations (for macrolides and ideally also moxifloxacin) should ideally be recommended.

【 授权许可】

   
2015 Guschin et al.; licensee BioMed Central.

【 参考文献 】

• [1]Taylor-Robinson D, Jensen JS: Mycoplasma genitalium: from Chrysalis to multicolored butterfly. Clin Microbiol Rev 2011, 24:498-514.
• [2]Cohen CR, Manhart LE, Bukusi EA, Astete S, Brunham RC, Holmes KK, et al.: Association between Mycoplasma genitalium and acute endometritis. Lancet 2002, 359:765-6.
• [3]Manhart LE, Critchlow CW, Holmes KK, Dutro SM, Eschenbach DA, Stevens CE, et al.: Mucopurulent cervicitis and Mycoplasma genitalium. J Infect Dis 2003, 187:650-7.
• [4]Cohen CR, Mugo NR, Astete SG, Odondo R, Manhart LE, Kiehlbauch JA, et al.: Detection of Mycoplasma genitalium in women with laparoscopically diagnosed acute salpingitis. Sex Transm Infect 2005, 81:463-6.
• [5]Anagrius C, Loré B, Jensen JS: Mycoplasma genitalium: prevalence, clinical significance, and transmission. Sex Transm Infect 2005, 81:458-62.
• [6]Bjartling C, Osser S, Persson K: Mycoplasma genitalium in cervicitis and pelvic inflammatory disease among women at a gynecologic outpatient service. Am J Obstet Gynecol 2012, 206:476-8.
• [7]Andersen B, Sokolowski I, Østergaard L, Kjølseth Møller J, Olesen F, Jensen JS: Mycoplasma genitalium: prevalence and behavioural risk factors in the general population. Sex Transm Infect 2007, 83:237-41.
• [8]Oakeshott P, Aghaizu A, Hay P, Reid F, Kerry S, Atherton H, et al.: Is Mycoplasma genitalium in women the “New Chlamydia?” A community-based prospective cohort study. Clin Infect Dis 2010, 51:1160-6.
• [9]Shahmanesh M, Moi H, Lassau F, Janier M: IUSTI/WHO: European guideline on the management of male non-gonococcal urethritis. Int J STD AIDS 2009, 20:458-64.
• [10]Manhart LE, Gillespie CW, Lowens MS, Khosropour CM, Colombara DV, Golden MR, et al.: Standard treatment regimens for nongonococcal urethritis have similar but declining cure rates: A randomized controlled trial. Clin Infect Dis 2013, 56:934-42.
• [11]Björnelius E, Anagrius C, Bojs G, Carlberg H, Johannisson G, Johansson E, et al.: Antibiotic treatment of symptomatic Mycoplasma genitalium infection in Scandinavia: a controlled clinical trial. Sex Transm Infect 2008, 84:72-6.
• [12]Mena LA, Mroczkowski TF, Nsuami M, Martin DH: A randomized comparison of azithromycin and doxycycline for the treatment of Mycoplasma genitalium-positive urethritis in men. Clin Infect Dis 2009, 48:1649-54.
• [13]Salado-Rasmussen K, Jensen JS: Mycoplasma genitalium testing pattern and macrolide resistance: a Danish nationwide retrospective survey. Clin Infect Dis 2014, 59:24-30.
• [14]Anagrius C, Lore B, Jensen JS: Treatment of Mycoplasma genitalium. Observations from a Swedish STD clinic PLoS ONE 2013, 8:e61481.
• [15]Jernberg E, Moghaddam A, Moi H: Azithromycin and moxifloxacin for microbiological cure of Mycoplasma genitalium infection: an open study. Int J STD AIDS 2008, 19:676-9.
• [16]Schwebke JR, Rompalo A, Taylor S, Seña AC, Martin DH, Lopez LM, et al.: Re-evaluating the treatment of nongonococcal urethritis: emphasizing emerging pathogens - a randomized clinical trial. Clin Infect Dis 2011, 52:163-70.
• [17]Walker J, Fairley CK, Bradshaw CS, Tabrizi SN, Twin J, Chen MY, et al.: Mycoplasma genitalium incidence, organism load, and treatment failure in a cohort of young Australian women. Clin Infect Dis 2013, 56:1094-100.
• [18]Jensen JS, Bradshaw CS, Tabrizi SN, Fairley CK, Hamasuna R: Azithromycin treatment failure in Mycoplasma genitalium-positive patients with nongonococcal urethritis is associated with induced macrolide resistance. Clin Infect Dis 2008, 47:1546-53.
• [19]Couldwell DL, Tagg KA, Jeoffreys NJ, Gilbert GL: Failure of moxifloxacin treatment in Mycoplasma genitalium infections due to macrolide and fluoroquinolone resistance. Int J STD AIDS 2013, 24:822-8.
• [20]Manhart LE, Khosropour CM, Gillespie CW, Lowens MA, Golden MR, Totten PA: Treatment outcomes for persistent Mycoplasma genitalium associated NGU: evidence of moxifloxacin treatment failures. Sex Transm Infect 2013, 89(suppl 1):A29.
• [21]Clinical practice guidelines for management of patients with sexually transmitted infections and reproductive tract infections // Moscow, Russia, 2012. Izdatel'skiy dom Delovoy ekspress. - 112 S (In Russian).
• [22]Lanjouw E, Ossewaarde JM, Stary A, Boag F, van der Meijden WI: European guideline for the management of Chlamydia trachomatis infections. Int J STD AIDS 2010, 21:729-37.
• [23]Krausse R, Schubert S: In-vitro activities of tetracyclines, macrolides, fluoroquinolones and clindamycin against Mycoplasma hominis and Ureaplasma ssp. isolated in Germany over 20 years. Clin Microbiol Infect 2010, 16:1649-55.
• [24]Song T, Ye A, Xie X, Huang J, Ruan Z, Kong Y, et al.: Epidemiological investigation and antimicrobial susceptibility analysis of ureaplasma species and Mycoplasma hominis in outpatients with genital manifestations. J Clin Pathol 2014, 67:817-20.
• [25]Renaudin H, Tully JG, Bebear C: In vitro susceptibilities of Mycoplasma genitalium to antibiotics. Antimicrob Agents Chemother 1992, 36:870-2.
• [26]Shipitsyna E, Zolotoverkhaya E, Dohn B, Benkovich A, Savicheva A, Sokolovsky E, et al.: First evaluation of polymerase chain reaction assays used for diagnosis of Mycoplasma genitalium in Russia. J Eur Acad Dermatol Venereol 2009, 23:1164-72.
• [27]Shipitsyna E, Zolotoverkhaya E, Agné-Stadling I, Krysanova A, Savicheva A, Sokolovsky E, et al.: First evaluation of six nucleic acid amplification tests (NAATs) widely used in the diagnosis of Сhlamydia trachomatis in Russia. J Eur Acad Dermatol Venereol 2009, 23:268-76.
• [28]Shipitsyna E, Zolotoverhaya E, Hjelmevoll SO, Maximova A, Savicheva A, Sokolovsky E, et al.: Evaluation of six nucleic acid amplification tests used for diagnosis of Neisseria gonorrhoeae in Russia compared with an international strictly validated real-time porA pseudogene polymerase chain reaction. J Eur Acad Dermatol Venereol 2009, 23:1246-53.
• [29]Shipitsyna E, Zolotoverkhaya E, Chen CY, Chi KH, Grigoryev A, Savicheva A, et al.: Evaluation of polymerase chain reaction assays for the diagnosis of Trichomonas vaginalis infection in Russia. J Eur Acad Dermatol Venereol 2013, 27:e217-23.
• [30]Pond MJ, Nori AV, Witney AA, Lopeman RC, Butcher PD, Sadiq ST: High prevalence of antibiotic-resistant Mycoplasma genitalium in non-gonococcal urethritis: the need for routine testing and the in adequacy of current treatment options. Clin Infect Dis 2014, 58:631-7.
• [31]Tagg KA, Jeoffreys NJ, Couldwell DL, Donald JA, Gilbert GL: Fluoroquinolone and macrolide resistance-associated mutations in Mycoplasma genitalium. J Clin Microbiol 2013, 51:2245-9.
• [32]Lucier TS, Heitzman K, Liu SK, Hu PC: Transition mutations in the 23S rRNA of erythromycin-resistant isolates of Mycoplasma pneumoniae. Antimicrob Agents Chemother 1995, 39:2770-3.
• [33]Furneri PM, Rappazzo G, Musumarra MP, Di Pietro P, Catania LS, Roccasalva LS: Two new point mutations at A2062 associated with resistance to 16-membered macrolide antibiotics in mutant strains of Mycoplasma hominis. Antimicrob Agents Chemother 2001, 45:2958-60.
• [34]Pereyre S, Guyot C, Renaudin H, Charron A, Bébéar C, Bébéar CM: In vitro selection and characterization of resistance to macrolides and related antibiotics in Mycoplasma pneumoniae. Antimicrob Agents Chemother 2004, 48:460-5.
• [35]Garza-Ramos G, Xiong L, Zhong P, Mankin A: Binding site of macrolide antibiotics on the ribosome: new resistance mutation identifies a specific interaction of ketolides with rRNA. J Bacteriol 2001, 183:6898-907.
• [36]Hansen JL, Ippolito JA, Ban N, Nissen P, Moore PB, Steitz TA: The structures of four macrolide antibiotics bound to the large ribosomal subunit. Mol Cell 2002, 10:117-28.
• [37]Depardieu F, Courvalin P: Mutation in 23S rRNA responsible for resistance to 16-membered macrolides and streptogramins in Streptococcus pneumoniae. Antimicrob Agents Chemother 2001, 45:319-23.
• [38]Bissessor M, Tabrizi SN, Twin J, Abdo H, Fairley CK, Chen MY, Vodstrcil LA, Jensen JS, Hocking JS, Garland SM, Bradshaw CS: Macrolide resistance and azithromycin failure in a Mycoplasma genitalium-infected cohort, and response of azithromycin failures to alternative antibiotic regimens. Clin Infect Dis 2014 Dec 23. [Epub ahead of print]