Antimicrobial Resistance & Infections. Clinical Perspectives

Transcription

1 Antimicrobial Resistance & Sexually Transmitted Infections Clinical Perspectives

2 Outline Neisseria gonorrhoeae Global threat of untreatable gonorrhoea Mycoplasma genitalium Rapid loss of treatment options for a new STI Treponema pallidum Limiting treatment options Chlamydia trachomatis Is antimicrobial resistance causing treatment failure?

3 STI treatments fundamentals of clinical practice Treatment for STI should cure 95% (WHO) Single dose treatments, preferably oral Improve completion rates Facilitate contact treatment, eg PDPT Treatment at presentation where possible Follow up may be problematic STI syndromes NGU, cervicitis, PID, epididymo-orchitis no pathogen detected Contact with STI Chlamydia, gonorrhoea, infectious syphilis

4 Treatment factors in N. gonorrhoeae antimicrobial resistance Rapid development of antimicrobial resistance to first-line treatments is driven by: Ability of N. gonorrhoeaeto develop & acquire antibiotic resistance mechanisms Antibiotic misuse treatment with antibiotics that are not fully potent, suppressing symptoms, & leading to resistant strains Antibiotic overuse continual use of one first-line therapy, providing selection pressure for emergence of resistant strains

5 Mechanisms of antibiotic resistance Lewis DA, LukehartSA. Sex Transm Infect 2011 Antimicrobial agent/class Chromosomal mutations Plasmid-mediated resistance Sulphonamides - Thiamphenicol - Penicillins pena, penb, pona,mtrr promoter/genes β-lactamase production Tetracyclines rpsj, penb, mtrr TetM protein production Spectinomycin spc gene - Aminoglycosides kan gene - Macrolides 23sRNA rrl, mtrr/mtrc promoter/genes, ermb, ermc, ermf Quinolones gyra, parc - Cephalosporins Mosaic pena genes pena, penb, pona, mtrr promoter/genes - -

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7 Population drivers of N. gonorrhoeae transmission & antibiotic resistance Core groups Sex workers & their clients (bridging populations) MSM Multiple partners, repeated infections & treatments HIV infection Asymptomatic infections eg, pharyngeal, rectal, cervical Travel D A Lewis. Sex TransmInfect 2013

8 N. gonorrhoeaeresistance Fluoroquinoloneresistant NG First emerged in Western Pacific region Sex work, uncontrolled use of fluoroquinolones Imported then disseminated among MSM in NSW & Victoria Extended spectrum cephalosporin decreased susceptibility First detected in Asia-Pacific (sex work) Spread internationally (MSM) Extensively drug resistant isolates 2010 Japanese sex worker (ceftriaxone MIC 2 mg/l) pena mosaic closely related to previous relatively-resistant strains MSM France, same strain in two MSM in Spain

9 Gonorrhoea WSSHC n=113 Dr Rick Varma

10 Site of infection for MSM Dr Rick Varma Tested for all sites 45 % 95% CI Urethral Anal Pharynx Urethral and anal Urethral and pharynx Anal and pharynx All sites positive Anal gonorrhoea is the most common site of infection among MSM

11 Male anal infection - PCR v Culture Anal positive episodes 35 Both anal PCR and culture done for the same episode Anal PCR positive and culture positive 3 Anal PCR positive and culture negative 21 Anal PCR negative and culture positive 0 Dr Rick Varma 24 All 24 (100%) anal episodes were diagnosed with PCR Only 3/24 (12.5%) of episodes diagnosed with anal culture For pharyngeal infection, all 6 episodes diagnosed with PCR 0/6 diagnosed with pharyngeal culture

12 Case 1 Sam 31 yr-old MSM Many regular & casual male sexual partners Frequent unprotected anal sex, mostly insertive, UPRIOI Contact with STIs+++, visits to SHC Gonorrhoea: 7 episodes (Rx ceftriaxone) 6 urethral, 1 rectal HPV, molluscum contagiosum, pubic lice Chlamydia: 3 episodes urethral NGU: 6 episodes, multiple recurrences (20 doses AZM) M. genitalium urethral infection 2008, persists until Oct 2013 HIV Abneg, syphilis Abneg

13 Case 2 Anthony 44 yrmsm with a history of infectious syphilis 18 months ago Presents in urethral gonorrhoea Unprotected anal sex with multiple partners - calculated risk HIV positive Feb 2011 flu-like illness treated with Tamiflu Jan Serosorting, group sex, IDU ice Rectal Chlamydia x 2 Pharyngeal Chlamydia x 2 Rectal gonorrhoea x 4 Pharyngeal gonorrhoea x 1 Primary syphilis x 2, Early latent syphilis x 1 All episodes gonorrhoea culture negative AZM x 5; ceftriaxone x 6; benzpenicillin x 3; doxycycline x 2

14 Factors in transmission & AMR MSM with multiple sexual partners, HIV, drug use Repeated infections bacterial STI & contact treatment Treatment guidelines change - ceftriaxone MICs Ceftriaxone 250 mg 500 mg 500 mg + AZM 1 g Change in testing practices All N. gonorrhoeae infections diagnosed by culture Anal then pharyngeal N. gonorrhoeae PCR Lapse in use of test-of-cure Case 1: likely undetected pharyngeal infections, cured? Case 2: improved detection but no information on resistance

15 Case 3 difficult-to-treat sites Tapsallet al. J Med Microbiol2009 A 27-year-old MSM presents with urethral discharge and dysuria 1 week after insertive oral sex Diagnosed with urethral & pharyngeal gonorrhoea (culture) FVU negative for C. trachomatis Treated with ceftriaxone 250 mg im After 17 days, re-presented with ur symptoms (no sex) FVU C. trachomatis PCR positive Throat culture again isolated N. gonorrhoeae Treated with AZM 1g, then ceftriaxone 500 mg im

16 Case 3 results Same genotype all 3 gonococcal isolates Ceftriaxone susceptible (MIC 0.03mg 1-1 ) Pen & quinolone resistant (MICs 1 & 16mg 1-1 ) Competitive inhibition of C. trachomatis DNA amplification in presence of high gonococcal load in duplex NAAT C. trachomatisretesting 1 st FVU 2 nd FVU Amplicor NAAT neg pos Monoplex CT NAAT targeting cryptic plasmid pos pos Monoplex PCR to identify strains with 377 bp deletion of Roche assay target site pos pos

17 Case 3 Treatment failure in pharyngeal but not urethral infection despite MIC in susceptible range Increased ceftriaxone MIC (0.03) cfwild-type ( mg 1-1 ) Increased MICs associated with altered PBP2, the main target site for ceftriaxone Mosaic PBP2 has been associated with treatment failure in male urethral gonorrhoea Treatment failure may be more common than realised

18 Case 4 antibiotic misuse A 35 year-old heterosexual man, client of sex worker Urethral discharge, treated with AZM 1 g by his GP Presents to SHC with persistent urethral symptoms Urethral discharge has resolved FVU N. gonorrhoeae PCR+..widespread use of 1 g single-dose azithromycin as a treatment for chlamydial infection contributed to the emergence of azithromycin high level resistance strains of N. gonorrhoeae Lewis DA, Sex Transm Infect 2013

19 Clinical Responses Early detection and treatment Core groups Improved detection NAAT vs culture for diagnosis Contribute to Antibiotic resistance surveillance Culture when NAAT positive Dual therapy ceftriaxone 500 mg im+ AZM 1 g Improve eradication & delay development of resistance Test-of-cure Detect treatment failure International guidelines inconsistent, underused in primary care

20 STIGMA guidelines 2014 Promoting STI testing among MSM

21 Transmission electron micrograph of M. genitalium negatively stained with ammonium molybdate. Mycoplasma genitalium STI cause of NGU, cervicitis, PID 5-25% of nongonococcal urethritis cases Increasing rates of AZM treatment failure 60% in MG+ NGU Manhartet al CID 2013 Associated with 23S rrna gene mutations Selected following AZM treatment Taylor-Robinson D, and Jensen J S Clin. Microbiol. Rev. 2011;24: Transmitted sexually Twin et al, PLoS One 2012 Danish national survey macrolide resistance in 38% Salado-Rasmussen K, Jensen JS. CID 2014 Failure of 2 nd -line treatment moxifloxacin No evaluated alternative antibiotic Infection may clear spontaneously or persist Natural history, sequelae not well understood

22 M. genitalium resistance Couldwell DL, Tagg KA, Jeoffreys NJ, Gilbert GL. Int J STD AIDS 2013 Macrolide resistance mutations 23S rrna gene Sexually transmitted in 20% Emerged following AZM 1 g in 25% with wild-type Associated with microbiological treatment failure (p=0.013) Fluoroquinoloneresistance mutations in parc& gyra Associated with moxifloxacin treatment failure (p=0.005)

23 M. genitalium-case 1 Sam Treated with AZM 1 g for urethritis M. genitaliumpcr + on FVU Persistent urethral symptoms after 3 months Treated with moxifloxacin 400 mg/d for 10d M. genitaliumpcr positive for 5 years Resistance or reinfection? Multiple courses AZM & MXF Asymptomatic sexual contact M. genitaliumpcr + on rectal swab

24 Case 1: Mutation profile Case 1 Contact case1 MG test 1 Pos Pos Mutations test 1 A2058G gyra(met95-ile) Sample not available Treatment 1 AZM AZM MG test 2 Pos Pos Mutations test 2 Treatment 2 MG test 3 Mutations test 3 A2058G gyra (Met95-Ile) MXF Pos A2058G gyra (Met95-Ile) A2058G gyra (Met95-Ile)

25 Future Is Mycoplasma genitaliuman important reproductive tract pathogen? Serious morbidity in women? NGU common in men NGU treatment should be guided by aetiological diagnosis. Salado-Rasmussen & Jensen CID 2014 Introduce routine testing for M.genitaliumin high-risk populations. Detect resistance at the time of initial testing. Rapid high resolution melt analysis assay to detect macrolide resistance mutations Twin et al PLoS One 2012 Need for new treatments

26 Treponema pallidum Mechanisms of AB resistance & treatment Lewis DA, Lukehart SA. Sex Transm Infect 2011 Antimicrobial Resistance mechanisms Treatment Penicillins None Benzathine penicillin Penicillin desensitisation (pregnancy) Neurosyphilis: iv pen Gor procaine pen G + probenecid Tetracyclines None Penicillin allergic patients (except pregnancy) Macrolides Cephalosporins None Chromosomal point mutations in 23S rrna: A2058G, A2059G Caution! Limited experience

27 Azithromycin resistant syphilis Alternative treatment for penicillin-allergic Clinical treatment failure first reported in 2002 Used for PDPT syphilis outbreaks San Francisco Associated with mutation A2058G in 23S ribosome of T. pallidum Selection over time with community use of AZM Real-time selection of spontaneous mutants Resistant strains more likely with recent h/o AZM use Mutation present in 86.6% of samples from in Sydney Jeoffreys NJ 2011 Aust Sex Hlth Conference

28 T. pallidum selective pressure MSM aged 36 yrs Condom breaks during IAI, no sex 5 years Treated for urethritis with AZM 1 g after 1 month AZM 500 mg 3/7 for bronchitis, after 3 months Syphilis Abpositive after 6 months:rpr 1:64 On examination at sexual health clinic Mucous patches glans penis & tongue Ulcerated macular perianal lesions T. pallidum PCR positive perianal lesions, VDRL 1:32 Treated with doxycycline for secondary syphilis

29 Chlamydia trachomatis Is AMR occurring? 100 million new infections each year Persistent/recurrent infection in 10-15% Causes of C. trachomatis treatment failure unknown?re-infection or Resistance Lack of understanding of relationship between results of AMR tests & clinical outcome Case reports of AMR-associatedRx failure SomaniJ, JID 2000 Isolates with macrolide-amr & 23S rrna gene mutation Misyurina OY Antimicrob Agents Chemother 2004 Difficult to study antimicrobial resistance In vitro antimicrobial resistance assay technically complex, method not standardised Wang S JID 2005

30 Chlamydia trachomatis Is AMR occurring? Inflammatory cells may be reservoir of infection Do not support growth in tissue culture Efficacy of Rx of inflammatory cells unknown Heterotypic resistance Subculture of resistant organism results in a population of both resistant & susceptible bacteria Organism may be capable of expressing resistance but only a proportion may do so. Mechanism unknown Isolates with AMR less fit in vitro Homotypic resistance (replication of a homogenous clonal population of resistant organisms) detected in Chlamydia suis?clinical significance (sequelae, transmission)

31 Summary Gonococcal antimicrobial resistance Potential for spread of extensively drug-resistant strains to threaten global health M. genitalium treatment failure Widespread macrolide resistance ~ 40% Fluoroquinolone resistance in ~15% Untreatable infections Lack of guidelines, testing

32 Progress Cases 1 & 2 Sam s M. genitaliuminfection resolved spontaneously (or at least was not detected on testing) after 5 years. He married a woman and has (almost) given up having sex with men. Anthony is taking antiretroviral treatment. He continues his Anthony is taking antiretroviral treatment. He continues his active sexual life and frequently travels for work in Asia and Europe.