Treatment resistant STIs relevant to MSM

Transcription

1 Treatment resistant STIs relevant to MSM David A. Lewis FRCP (UK) PhD Centre for HIV and STIs National Institute for Communicable Diseases (NHLS) Johannesburg, South Africa Regional Director, IUSTI Africa

2 Principles Underlying Choice of Antibiotic for Treatment of STIs Any antimicrobial agent should cure > 95% of urogenital infections Ideal treatment should be (i) oral, (ii) cheap and (iii) single dose Avoid using antibiotics that may induce resistance in other key pathogens (antibiotic stewardship) Use of injectable agents may increase risk of occupational transmission of HIV The regimens used should not (i) deter patients sexual partners from attending for treatment or (ii) deter index patients from returning with subsequent STI episodes Moran & Levine, Clin. Infect. Dis 1995; 20 (suppl 1):S47 S65

3 Neisseria gonorrhoeae Chlamydia trachomatis Trichomonas vaginalis Key STIs associated with resistance issues Mycoplasma genitalium Treponema pallidum Haemophilus ducreyi

4 Neisseria gonorrhoeae

5 Prevalence of Ciprofloxacin Resistant Gonococci in Johannesburg, South Africa ( ) Cefixime (2008) Prevalence of resistance (%) Year data from Esselen Street Clinic, data from Alexandra Health Centre Centre for HIV and STIs (NICD/NHLS)

6 Replacement of Ciprofloxacin by Cefixime as First Line Gonorrhoea Treatment in Southern Africa South Africa Namibia SADC Region

7 Oral Cephalosporins Cefixime is the only oral cephalosporin recommended for the treatment of uncomplicated gonorrhoea Several alternative oral cephalosporins exist but they are not recommended because: they have not met the 95% efficacy criteria in respect of the lower 95% CI they have undocumented or unacceptable efficacy for treating pharyngeal infection there are safety concerns Antimicrobial agent Ano genital Infections Pharyngeal infections Number evaluable % Cured (95% CI) Number evaluable Brown et al. Sex. Transm. Dis.2010; 37: CDC, (April 2004) % Cured (95% CI) Cefixime (400 mg) ( ) ( ) Cefpodoxime proxetil (200mg) ( ) ( ) Ceftibuten (400 mg) ( ) No published data Cefuroxime axetil (1g) ( ) ( )

8 Prevalence of Resistance to Antimicrobial Agents in Central Japan ( ) Gonococcal Phenotype N = N = N = 221 PPNG 1.1% 0.7% 0.5% TRNG (MIC 16mg/l) 2.2% 0.7% 0.5% CMRNG Pen (MIC 2mg/l) 2.2% 59.3% 73.3% CMRNG Tet (MIC 2mg/l) 11.0% 53.7% 68.8% QRNG Levofloxacin (MIC 1mg/l) 27.5% 53.3% 78.3% Cefixime decreased susceptibility (MIC 0.5mg/l) 0% 26.0% 30.3% Ceftriaxone decreased susceptibility (MIC 0.5mg/l) 0% 0% 0.9% Spectinomycin resistance (MIC 128mg/l) 0% 0.7% 0% Ito M et al., Antimicrob. Agents Chemother. 2004;48:

9 Decreased Susceptibility to Cefixime Mosaic pena genes, which encode PBP 2, cause these raised MICs Some of the regions within these mosaic genes show homology to the pena genes of N. perflava (N. sicca), N. cinerea, N. flavescens and N. meningitidis Suggested key mutations include I312M, V316T, N512Y and G545S Ito M et al., Antimicrob. Agents Chemother. 2005;49: ; Tomberg J et al., Biochemistry 2010;49: ; Takahata S et al., Antimicrob. Agents Chemother. 2006; 50:

10 Cefixime MIC (mg/l) and Presence of the Mosaic pena Gene, Japan ( ) No. of gonococcal isolates N = 621 mosaic PenA native PenA MIC (mg/l) Ochiai S et al., J. Clin. Micro. 2008;46:

11 Pharmacokinetic Studies with Cefixime 2 x 200mg Dose (6 hr Apart) MIC (mg/l) No. of isolates (n = 68) Eradicated (n = 60) Persistent (n = 8) MIC 90 = mg/l Mean plasma concentrations of cefixime after administration of the two dose regimen to six healthy Japanese men (mean +/ SD) The MIC 90 for the 61 isolates tested was mg/l Deguchi T et al.,j. Infect. Chemother. 2003;9:35 39 Unknown 7 (died) 0 Microbiological outcome of treatment according to MICs for 68 clinical isolates (68/93 men returned for re examination 3 10 days after treatment) The two dose regimen only worked for isolates with MIC 0.06 mg/l

12 Cephalosporins Pharmacodynamic Issues The clinical efficacy of β lactam antibiotics relates to ft >MIC AfT >MIC of 20 hours is required for efficacy with cephalosporins Note: Simulation of ft >MIC values (h) for various cefixime and ceftriaxone regimens is based on mean pharmacokinetic parameter values Chisholm et al. J. Antimicrob. Chemother.2010;65:

13 Emergence of Clinically Confirmed Cefixime Treatment Failures in Europe

14 Association between Antimicrobial Susceptibility, Gender & Sexual Orientation A. Resistance to ciprofloxacin (MIC 1 mg/l) B. Decreased susceptibility to cefixime (MIC mg/l) Source: Gonococcal Resistance to Antimicrobials Surveillance Programme (GASP), Health Protection Agency, UK

15 Detection of Multi Drug Resistant Gonorrhoea in South Africa CASE A Presumed MSM Lives in Johannesburg Limited details Treated with Azithromycin Lost to follow-up CASE B Known MSM Lives in Johannesburg Recent travel to Japan Failed cefixime treatment x 2 Treated with ceftriaxone 500mg i.m. Needs tests of cure GP involved Both isolates had identical antibiograms (Pen R, Tet R, Cip R, Cefix DS, Azithro DS ) and were identical by NG-MAST typing (ST4822)

16 The World s First Confirmed Gonococcal Isolate Resistant to Ceftriaxone (XDR NG) Gonococcal strain H041 was isolated from the pharynx of a female sex worker in Kyoto, Japan Confirmed as N. gonorrhoeae by 7 tests, NG MAST ST 4220 (new) and MLST ST 7363 MIC to ceftriaxone 2 4 mg/l and to cefixime 8 mg/l Possesses novel mosaic pena allele (pena H041) as well as added mutations in mtrr, penb, pon A (L421P) Resistant to most beta lactams including piperacillin/ tazobactam, fluoroquinolones, macrolides, tetracycline, co trimoxazole, chloramphenicol and nitrofurantoin Susceptible to spectinomycin, gentamicin, imipenem and rifampicin Ohnishi M et al., Emerg. Infect. Dis. 2011;17: Ohnishi M et al., Antimicrob. Agents Chemother. 2011;55:

17 Azithromycin Azalide derived from the macrolide class of antibiotics Compared with erythromycin: better oral absorption better tissue penetration unique pharmacokinetics wider spectrum of activity Tissue levels are up to 50 times higher than plasma levels tissue depletion half life is 2 4 days High concentration in phagocytes resulting in high concentrations being delivered to the site of infection Activity against several bacterial STI pathogens Neisseria gonorrhoeae Chlamydia trachomatis Ureaplasma urealyticum Mycoplasma genitalium Treponema pallidum Haemophilus ducreyi Azithromycin under the microscope Bignell & Garley, Sex. Transm. Infect. 2011;86:

18 Azithromycin Resistance Resistance involves several mechanisms Right shifts in MIC distributions have been observed in both GISP (USA) & GRASP (UK) surveillance programmes Resistance has developed following single dose Azithromycin therapy Clusters of resistance have occurred, e.g. Kansas City ( ) The first high level azithromycin resistant strain (MIC > 2,048 mg/l) was isolated in Argentina in 2001 High level resistance to azithromycin has also been reported in Europe (Scotland, England, Wales & Italy) The English and Welsh isolates had the same NG MAST profile (ST 649) and were linked to the Scottish isolates Galarza et al., Antimicrob. Agents Chemother. 2010;54: , McLean et al., Sex. Transm. Dis. 2004;31:73 78, Chisholm et al., J. Antimicrob. Chemother. 2009;64:

19 Spectinomycin Spectinomycin does not reliably eradicate pharyngeal gonorrhoea important issue for clinical care of MSM and sex workers It is useful in the context of severe penicillin allergy, particularly in pregnancy, where cephalosporins would be contraindicated It remains costly and unavailable in many countries Although most current surveys report that most gonococci are susceptible, this reflects infrequent use of the agent It is likely that resistance will develop should the drug be introduced as first line therapy It could have a role in multi drug therapy

20 Gentamicin Gentamicin 240 mg i.m. has been used as national anti gonococcal first line therapy in Malawi since 1993 (18 years) Global data on susceptibility are scanty Lack of correlation between clinical outcome and laboratory data breakpoints for resistance remain unclear Recent surveillance data from Malawi (2007) demonstrate that all 100 isolates tested were susceptible based on agar dilution results (MIC 4 mg/l) Injectable agents less liable to abuse Brown et al. Sex. Transm. Dis.2010;37:

21 How Can We Maintain Therapeutic Efficacy? Administer cephalosporins at higher doses? Administer I.M. ceftriaxone at the clinic supplemented by extended courses of oral cefixime at home? Use cephalosporins and another effective antimicrobial agent as part of a multi drug therapeutic regimen Use laboratory guided patient individualised treatment where possible on the basis of susceptibility profiles? Rotate antimicrobial agents to create firebreaks? Re introduce bacteriological test of cure to assist with detection of treatment failures and ensure effective treatment is given, particularly for asymptomatic (especially pharyngeal) infections? Bignell & Garley, Sex. Transm. Infect. 2011;86: Riedner et al., N. Engl. J. Med. 2005;353: Hook et al., Sex. Transm. Dis. 2002;29:

22 Multi Drug Therapy Either I.M. ceftriaxone or oral cefixime could be used in combination with another antimicrobial agent capable of treating N. gonorrhoeae infection Ideally this agent should also be active against C. trachomatis and should be prescribed regardless of the presence or absence of this pathogen Azithromycin is the obvious candidate a 2g rather than a 1g dose offers better efficacy but side effects may occur in some patients with the higher dose (these may have been over estimated in early studies) Another approach could be to try a cephalosporin as single first line therapy for gonorrhoea and treat any failures with a multi drug regimen, e.g. spectinomycin 2g i.m. + azithromycin 2g p.o.

23 Antimicrobial Susceptibility Guided Treatment This approach may be appropriate for patients where diagnosis is still made by culture, i.e. endocervical, rectal and pharyngeal infections It has the advantage of still allowing one to prescribe quinolones, which work well in the pharynx It also allows the release from the evolutionary selective pressure of one drug for all Not an option for those countries using the syndromic management approach Not an ethical option for men with visible urethral discharge who require same day treatment

24 Treponema pallidum

25 Azithromycin Resistance in Treponema pallidum Azithromycin treatment failures were reported in MSM in San Francisco in Sequencing of the 23S rrna genes of two T. pallidum strains demonstrated an A2058G mutation in both copies of the gene Retrospective molecular screening of 124 syphilis positive samples from San Francisco (Jan 2000 Dec 2004) identified 46 (37%) azithromycin R strains Mitchell et al. undertook a case control study to identify risk factors all cases were MSM or bisexual 16 (31%) cases were HIV 1 seropositive cases did not appear to be linked by a sexual network cases more often had a history of recent azithromycin use (7/52 cases, 1/72 control) MMWR Morb. Mortal. Wkly. Rep. 2004;53: ; Lukehart S et al., New Engl. J. Med. 2004;351: ; Mitchell S et al., Clin. Infect. Dis. 2006;42:

26 Conclusions Gonorrhoea resistance is worsening globally treatment options are limited MSM are a key population for national public health institutions to monitor for the emergence of antimicrobial resistance For MSM, pharyngeal sampling is required to keep on top of the gonococcal AMR problem and to guide appropriate treatment costly but essential Patients failing cefixime MUST receive high dose ceftriaxone +/ a second agent, e.g. azithromycin We should avoid treating gonorrhoea & syphilis with azithromycin routinely We need to be careful with introducing azithromycin for treatment of other STIs, such as chlamydia Patients with antibiotic resistant STIs should be followed up and contact tracing efforts will require significant enhancement