Neisseria gonorrhoeae: Situation of antibiotic resistance

Transcription

1 Neisseria gonorrhoeae: Situation of antibiotic resistance Susanne Buder, Peter K. Kohl Konsiliarlaboratorium für Gonokokken Klinik für Dermatologie und Venerologie Vivantes Klinikum Neukölln, Berlin + Therapy of Gonorrhoea and resistance to Antibiotics Marco Cusini STD Clinic Fondazione IRRCS Ca Granda Ospedale Maggiore Milano Glossary NG: Neisseria Gonorrhoeae AMR: antimicrobial resistance ESCs: extended spectrum cephalosporins MDR-NG: multi drug resistant NG XDR-NG: extensively drug resistant NG MIC: Minimal inhibitory concentrations EURO- GASP: European gonococcal antimicrobial surveillance program WHO: World health organization ECDC: European Center for Disease Prevention and Control CDC: Center for Disease Control ISS: Istituto Superiore di Sanità 1

2 History of Gonorrhoea First written mention in Chinese records and old testament Introduction of designation for gonorrhoea by G a l e n u s ( n. Chr.) 1879 Albert N e i s s e r (physician, Breslau) discovered bacteria as the causative agent of gonorrhoea 1882 Cultivation of N. gonorrhoeae by Ernst B u m m (physician, Berlin) Albert Neisser History of Gonorrhoea II, Therapy 16th century: injection of mercury via the urinary meatus on board of the English warship Mary Rose Since the beginning of the 19th century use of silver nitrate, Credé Prophylaxis since discovery of sulphonamide Prontosil, the first commercially available antibiotic by Gerhard D o m a g k (physician, Nobel Prize in Medicine, Brandenburg) 1940/41 first use of Penicillin 2

3 History: Pre antibiotic era: rest, no sex, no alcohol, balsams and urethral irrigations. Prophylactic packets to soldiers during first world war with condoms, calomel ointment and Argyrol History: Sulphonamides: 1935 : 80-90% cure rate. 1950: 90% resistance (chromosomal resistance) Penicillins: 1943: 95% cure rate with 45mg. dose. In 1976 emergence of plasmid mediated resistance (chromosomal and extrachromosomal resistance) Tetracyclines: Chromosomal resistance reproted in 1958, plasmid resistance in the 80 with didfferent plasmids involved Spectinomycin : developed in early 60 chromosomal resistance developed broadly in the 80 Aminoglycosides: few data since these antibiotics are not of wide use (chromosomal resistance) 3

4 History: Macrolides: erithromycin has low efficacy. Azitrhomycin resistance started in Latin America in mid 90 and are now widespread (chromosomal resistance) Quinolones: used for gonorrhoea from mid 80. Clinical resistance started in Asia-Pacific in early 90. In USA and UK resistance is particularly high in MSM ( chromosomal resistance) Cephalosporins: cefixime is the only one with 95% cure rate. Ceftriaxone is the parenteral drug more widely used. The situation seems to mirror the story of penicillin in with progressive decrease suscectibility and appearance of clinical failures. Gonorrhoea and public health Public health control on NG is dependent on effective therapy in the absence of a protective immune response Treatment failures due to AMR, compromise the control of NG and increase the prevalence of associated complications (WHO) Monitoring AMR to maintain effective therapy is essential A first-line treatment change is recommended at 3% (CDC) or 5% (WHO) level of resistance 4

5 Decreasing susceptibility of NG to ESCs may render NG an untreatable disease How to cure NG??????? AMR mechanisms: Chromosomal ( majority): Extra chromosomal (plasmid) Both mechanisms 5

6 Antibiotics in past or present use for NG I - Actually generally recommended: Injectable ESCs: ceftriaxone (cefodizime,cefotaxime,ceftixoxime) Oral ESCs: cefixime (ceftibuten, cefpodoximeproxetil,cefdinir,cefditoren) Spectinomycin II- Less frequently used Penicillins Fluorquinolones Azythromycin Aminoglycosides Carbapenems (proposed) III - Regarded as inappropriate Chloramphenicol and tiamphenicol Tetracyclines Co-trimoxazole Erythromycin Testing-Panel Current Recommendation ß-lactamase/penicillinase activity Ciprofloxacin (breakpoint) Azithromycin (breakpoint) Spectinomycin (breakpoint) Gentamicin (agar dilution/etest) Cefixime (Etest) Ceftriaxone (Etest) Categorize strains: S, I/DS and R Cave! The lowest available Etest MIC range (Minimal Inhibitory Concentration) should be used for Ceftriaxone and Cefixime 6

7 MDR-NG multi drug resistant NG Resistant to one antibiothic class in category I and to two or more in category II (originally emerged in in Western Pacific Region) XDR-NG extensively drug resistant NG Resistant to two ore more in category I and to three ore more in category II (not yet reported) 7

8 Resistance in N. gonorrhoeae Current Situation Global spread of drug-resistant N. gonorrhoeae: threat of multidrug resistant, untreatable gonorrhoea Resistance first developed in WHO West Pacific Region and disseminated globally WHO recommendation: 5% resistant strains is the level at which to consider change of empirical therapy! 8

9 Epidemiology of AMR 9

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11 cefixime ceftriaxone cefixime ceftriaxone Epidemiology in Italy Susceptibility to five antimicrobial agents antibiotic % resistance % suscecti bility %interme diate MIC (mg/l) range ciprofloxacin penicillin tetracycline MIC 90 (mg/l) ceftriaxone spectinomycin

12 Epidemiology in Italy Multi Antigen Sequence Typing of 120 resistant isolates High number of Sequence Types(ST) :48 ST1407 is the most prevalent (35) and is reported to be associated to cefixime resistance High number of STs may be due to a high rate of recombination or to the lack of conditions favouring the spread of a predominant resistant clone Epidemiology in Italy Ciprofloxacin resistance increasing Penicillin resistance decreasing 5% resistant to three drugs 12

13 Development of Resistance in N. gonorrhoeae Penicillin Since 1970 s global spread of high-level plasmid mediated resistance to penicillin (Penicillinase Producing N. gonorrhoeae, PPNG) Number of PPNG in Europe has remained constant at 13% Source: ECDC Surveillance Report, Euro-GASP 2010 Development of Resistance in N. gonorrhoeae Tetracycline and Makrolide Tetracycline Since early 1980 s plasmid mediated Tetracycline resistance detected No current data from Europe, 6% Tetracycline resistant isolates in USA (2004) Tetracycline is often used as co-treatment and as first line empirical therapy due to urethritis with presumed Chlamydia infection Makrolide No apparent trend between 2004 and 2010 Resistance ranged from 0% (Portugal) to 46% (Denmark) with an average of 13% in Europe In Scotland and in Ireland some isolates displayed high-level chromosomal Azithromycin resistance 13

14 Development of Resistance in N. gonorrhoeae Quinolone Dramatic increase of quinolone resistance in the early 2000 years Resistance in 2009 ranged with an average of 70% resistant strains in Europe Ciprofloxacin resistance across Europe is at a level (>5%) that shows this is no longer an appropriate agent for first-line empirical therapy Source: ECDC Surveillance Report, Euro-GASP Development of Resistance in N. gonorrhoeae Cephalosporins Third generation Cephalosporins are amongst the last agents to remain effective Currently recommended as first line therapy in many countries worldwide Reduced susceptibility to the Cephalosporins first emerged in the Western Pacific Region and then disseminated globally Growing concern about multi-drug resistant Neisseria gonorrhoeae (MDR-NG) No new alternatives are currently expected 14

15 Development of Resistance in N. gonorrhoeae Cephalosporins Cefixime Still effective agent Decreased susceptibility in Europe: % % % Ca. 1-3% resistant strains in Western Pacific Region Increasing cases of decreased susceptibility and resistance in Japan, USA, Australia Source: ECDC Euro-Gasp Results Michele Cole 2009: Decreased Susceptibility to Cefixime ( 0.25mg/L) Source: ECDC European response to threat of multidrug resistant gonorrhoea Marita van de Laar, PhD 15

16 2010: Decreased Susceptibility to Cefixime ( 0.25mg/L) Source: ECDC European response to threat of multidrug resistant gonorrhoea Marita van de Laar, PhD Development of Resistance in N. gonorrhoeae Cephalosporine Ceftriaxone Last effective agent Upward drift in MIC (Minimal Inhibitory Concentration) In 2010 decreased susceptibility to Ceftriaxone was detected in Europe for the first time Case reports of Ceftriaxone treatment failures in Europe Source: ECDC Surveillance Report, Euro-GASP 2010, Ceftriaxone MIC distribution 16

17 Development of Resistance in N. gonorrhoeae Future Therapy Options? Spectinomycin No decreased susceptibility or resistance to Spectinomycin Known chromosomal resistance Unavailable Gentamicin Successfully used in other parts of the world, notably Africa Breakpoints established in 2010 ( MIC 50 und MIC 90 = 8 mg/l) Future therapy option? Single or combination therapy? Management Guideline (BASHH 2011) Management should now involve First-line: Ceftriaxone 500 mg IM Second-line: Cefixime 400 mg oral (only if IM injection is contra-indicated or refused by patient) Co-treatment: Azithromycin 1g (regardless of Chlamydia result) given at the same time as gonorrhea treatment Test of cure in all patients 17

18 Management Guideline (BASHH2011, CDC) Recommended Regiment Infections of the urethra, cervix, pharynx and rectum in adults and adolescents and pregnant and breast-feeding women Ceftriaxone 500mg-1 g IM single dose plus Co-treatment: Azithromycin 1g single dose Alternative treatment in patients with known b-lactam allergy Azithromycin 2g single dose Disseminated gonococcal infection Ophthalmia Ceftriaxone 1 g IV 1/d or Cefotaxim 1g IV 3 /d for 7days New-borns: Ceftriaxone (25 50 mg/kg ) IV or IM single dose or Cefotaxim (100 mg/kg ) IV for 7 days Adults: Ceftriaxone 1 g/d IV for 5 days EURO-GASP European Gonococcal Antimicrobial Surveillance Programme 21 participating countries in association with European Centre for Disease Prevention and Control (ECDC) and Health Protection Agency (HPA UK) Mission: to monitor emerging, increasing and high-level resistance to inform relevant local, national and European departments on guidelines for therapy to prevent the spread of infection Source: ECDC Surveillance Report, Euro-GASP

19 Control actions Surveillance programs (Euro-GASP) 17 European countries isolates for each country antibiotic susceptibility in 3 labs. Providing longitudinal robust data to inform treatment guidelines Finding new drugs or drugs combination The future Given the proclivity of the gonococcus to become resistant to all previously prescribed antimicrobials, it may be more a matter of when and not if strains emerge that are resistant to also ceftriaxone Vaccine???? 19

20 David A Lewis : Sex Transm Infect 2010 The gonococcus has evolved a number of different resistance determinants over time and multidrugresistant gonococci now exist Gonorrhoea clinical failures after treatment with oral cephalosporins have been reported-these cases are still treatable with high-dose cetriaxone There are no new anti-gonococcal grugs on the horizon and single-dose regimens may need to be replaced with extended regimens or multidrug treatments Public health approaches to gonococcal control need to be enhanced to reduce global burden Gonococcus appears to be winning on points References Tapsall JW, Ndowa F, Lewis DA, Unemo: M. Expert Rev Anti Infect Ther 2009 Lewis DA: Sex Transm Infect 2010 Cole MJ, Unemo M, Hoffmann S, Chisholm SA, Ison CA, van de Laar MJ. Ison CA, Alexander S: Expert Rev Anti Infect Ther 2011 Carannante et al DMID in pub 20

21 Thank you for your attention! Konsiliarlaboratorium für Gonokokken Vivantes-Klinikum Berlin-Neukölln Klinik für Dermatologie und Venerologie Prof. Dr. Peter K. Kohl Rudower Str Berlin Tel.: +49(0) Fax : +49(0) Mail: peter.kohl@vivantes.de 21