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Antimicrobial resistance in Neisseria gonorrhoeae

Antimicrobial resistance in Neisseria gonorrhoeae. David Lewis National Institute for Communicable Diseases National Health Laboratory Service Johannesburg South Africa. NHLS. NHLS. NICD. NICD. The First World War. Gonorrhoea control was based on: - personal hygiene lectures

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Antimicrobial resistance in Neisseria gonorrhoeae

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  1. Antimicrobial resistance in Neisseria gonorrhoeae David Lewis National Institute for Communicable Diseases National Health Laboratory Service Johannesburg South Africa NHLS NHLS NICD NICD

  2. The First World War • Gonorrhoea control was based on: • - personal hygiene lectures • - weekly medical ‘visual’ examination of CSWs • Venereal ablution rooms established in all • barracks (1916) and soldiers at risk were • under order to attend within 24 hours • of potential exposure to N. gonorrhoeae • Self-administered regimen: • - wash genitals with soap and water • - irrigate the urethra with KMnO4 (“pinky panky”) • - apply calomel ointment to the whole area • Prophylactic “packets” (1917) • - calomel ointment to apply to the genitals • - tube of argyrol for the urethra (after coitus) • - condoms

  3. Urethral dilators c. 1900 From Valentine (1900) “The irrigation treatment of gonorrhoea” “Kollmann’s ingeniousness seems to have no limit”

  4. Sulphonamides • Gerhard Domagk reported that Prontosil was • curative against haemolytic streptococci in • animals (1935) - he later usedit with success • in humans • Prontosil released sulphanilamide - easily • manufactured • First studies using sulphanilamide in gonorrhoea • came from Germany, UK and USA (1937) • Cure rates for gonorrhoea rose to 80-90% • By 1944, treatment failures were common

  5. Penicillin • Alexander Fleming published his discovery of penicillin in 1929 • Cecil Paine treated two babies with gonococcal conjunctivitis with crude extract of Penicillium • notatum in 1930 • Penicillin was first used to treat gonococcal urethritis in 1943 (USA) – mainly troops • Cure rates with IM penicillin were >95%

  6. MIC drift for penicillin against Neisseria gonorrhoeae, USA (1955-69) Initial studies in men undertaken to determine the minimal amounts of drug and the shortest treatment period which would produce an acceptable cure rate (20,000 U 3hrly x 6 doses = 72 mg; 15 hours treatment period) 0.05 U = 0.03 μg 0.5 U = 0.3 μg Slyke et al., Am. J. Pub. Health. 1943;33:1392-1394 Martin et al. J. Infect. Dis., 1970:122:459-461 Slide courtesy of David Livermore, Health Protection Agency, UK (modified)

  7. Chromosomally-mediated resistance • By mid 1950s, several reports of decreased susceptibility to penicillin • Chromosomal resistance reported in 1958 Low-level, multiple step resistance penA - 4-8 fold increase in penicillin MICs - lowered affinity for PBP2 - shift to PBP1 target mtr- low level resistance to several Abs (Pen, Ery and Tet) - altered cell envelope with decreased permeability penB- encodes for PorB1-b, porin - 4-fold increase in penicillin and tetracycline MIC with mtr pen A + mtr + penB gives 120-fold increase in penicillin MIC ponA- lowered affinity for PBP-1 penC- efflux/permeability mechanisim (penicillin and tetracyclines)

  8. Plasmid-mediated resistance • First reported independently in UK and USA in 1976 • The 3.2 MDa African and 4.4 MDa Asian plasmids are identical except • for a 2.1 kb deletion • Require the 24.5 MDa conjugative plasmid for transfer • More plasmids were identified from the mid-1980s onwards: • Toronto 3.05 MDa , Rio 2.9 MDa, Nimes 4.0 MDa and New Zealand 6.5 MDa Rise in PPNG prevalence in Cameroon (1985-2005) Manuel de formation des prestataires de soins sur la prise en charge syndromique des IST au Cameroun. Ministry of Public Health, April 2007.

  9. Dutch plasmid American plasmid Tetracycline • Tetracycline was designed by chemical alteration of a microbial product (1952) • Chromosomal resistance soon followed (rpsJ + penB + mtr) • Plasmid-mediated resistance (TRNG), with MIC > 10 mg/L,first appeared in • the Netherlands (1985) and USA (1986) • Dutch and American TRNG strains had different phenotypes • Tetracycline resistance is now unacceptably high in most parts of the world Data from Gauteng Province for 210 N. gonorrhoeae isolates surveyed in 2008 76% 24% STI Reference Centre, National Institute for Communicable Disease, South Africa

  10. Gentamicin • Gentamicin 240 mg i.m. has been used as national anti-gonococcal first-line therapy in Malawi since 1993 • Prescribed together with doxycycline in syndromic management • No standard MIC that defines resistance • Recent surveillance data from Malawi (2007) demonstrate that 100% of isolates tested (n= 100) are susceptible based on agar dilution results (MIC ≤ 4 mg/l) • Injectable agents less liable to abuse Data courtesy of Irving Hoffman, University of North Carolina, USA Malawi surveillance studies have been performed through a collaboration between the University of North Carolina, the Kamuzu Central Hospital’s STI Clinic in Lilongwe and the Malawian Department of Health.

  11. Pen Spectinomycin Penicillin Spectinomycin Spectinomycin • Developed and marketed specifically for the treatment of gonorrhoea • Narrow MIC range related to efficacy • Resistance was described in 1973 • and widespread by the early 1980s • Resistance due to mutation in spc • locus - decreases sensitivity of 30S ribosomal subunit to spectinomycin • Major outbreak of spectinomycin • resistant gonorrhoea among US • military in Korea in 1987 after only • 6 years’ use • Still has a key role in selected cases Boslego JW et al., New Eng. J. Med. 1987;317:272-278

  12. Quinolones • Compared to nalidixic acid, fluoroquinolones have 100 x greater activity and broader spectrum by virtue of a fluorine atom at C6 • Clinical failure of single dose 250mg ciprofloxacin was first reported in London in 1990 – failures with the 500mg dose soon followed • Resistance in N. gonorrhoeae is associated with point mutations resulting in amino acid changes in: a) the A subunit (GyrA) of the DNA gyrase b) the parC-encoded subunit of topoisomerase IV • Many countries have now stopped using quinolones to treat gonorrhoea

  13. Rise in ciprofloxacin resistant gonorrhoea WHO Western Pacific Region WHO Western Pacific Region Gonococcal Antimicrobial Surveillance Programme (GASP)

  14. 32% 29% 28% 17% 16% 11% N/D 7% Rise in ciprofloxacin resistant gonorrhoea South Africa (2004-2007) Lewis DA et al., Sex Transm. Infect. 2008;84:352-355 STI Reference Centre, National Institute for Communicable Disease, South Africa

  15. Association between sexual orientation and ciprofloxacin susceptibility profileGRASP and GISP survey data GRASP 2000-2008 GISP 2001-2007 The Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) 2008, Health Protection Agency, UK Gonococcal Isolate Surveillance Project (GISP) Annual Report 2007, CDC, USA

  16. Association between HIV serostatus and ciprofloxacin susceptibility profile2007 surveys in Cape Town and Johannesburg N = 191 N = 75 p = 0.034 Lewis DA et al., Sex Transm. Infect. 2008;84:352-355

  17. Azithomycin • The 2g dose has significant G/I side-effects (better with ER formulation) • Isolates with reduced susceptibility have been identified since 1997 • Emerging resistance involves: • - bacterial efflux systems (mtrRCDE operon, mef genes) • - modification of ribosomal target (erm genes) • - single nucleotide mutation in 23S rRNA gene • A cluster of 6 gonococcal isolates with high-level azithromycin • resistance (MIC 4,096 mg/l) was detected in the UK in 2007 • Heterosexually acquired, patients not previously treated with • azithromycin, identical on NG-MAST typing (ST-649) UK Health Protection Agency Report 2008;2(14);4 April

  18. Shift in GISP Azithomycin MICs (1992-2007) N.B. In 2005, there was a change in medium used in GISP laboratories which resulted in an observational shift in the MIC by one dilution The Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) 2008, Health Protection Agency, UK Gonococcal Isolate Surveillance Project (GISP) Annual Report 2007, CDC, USA

  19. Reliable management options at present • I.M. Cetriaxone 125mg or 250 mg stat. • Oral Cefixime 400mg stat. • Oral Cefpodoxime proxetil 200mg stat. • I.M. Cefuroxime axetil 1g stat. • Oral Cetfibuten 400 mg stat. • Oral Cefdinir 300-600mg stat. • Oral Azithromycin 2g stat. • I.M. Spectinomycin 2g stat.

  20. Antimicrobials used to treat GISP patients: 1988-2007 Antimicrobials used to treat GRASP patients: 2000-2008 n=14,647 Antibiotics used to treat GRASP and GISP patients for gonorrhoea Note: GRASP data include antimicrobial agents given simultaneously for chlamydial infection The Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) 2008, Health Protection Agency, UK Gonococcal Isolate Surveillance Project (GISP) Annual Report 2007, CDC, USA

  21. Gonococcal Phenotype 1999-2000 N = 91 2001 N = 150 2002 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% Prevalence of resistance to antimicrobial agents in clinical gonococcal strains isolated in Central Japan, 1999-2002 Ito M et al., Antimicrob. Agents Chemother. 2004;48:3185-3187

  22. Ito M et al., Antimicrob. Agents Chemother. 2005;49:137-143 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 • Recently, another mutation in the ponA gene, which encodes for PBP-1, has been identified in strains exhibiting decreased susceptibility to cefixime (Leu 421 to Pro 421) - less significant than the mosaic penA changes Takahata S et al., Antimicrob. Agents Chemother. 2006;50:3638-3645

  23. Cefixime MIC (mg/l) and presence of the mosaic penA gene, Japan (2002-2005) N = 621 Ochiai S et al., J. Clin. Micro. 2008;46:1804-1810

  24. Critical parameters for β-lactam therapy • β-lactam efficacy depends on duration for which [free drug] exceeds MIC • Penicillin is 70-80% protein bound, so for gonorrhoea, ‘therapeutic time’ is: • Total [penicillin] > 4 x MIC for 7-10 hours • (i.e. more than two-fold dilutions higher) • Data from penicillin-based studies has been extrapolated to cephalosporins • Protein-binding and half-lives of cephalosporins differ • For cephalosporins, a ‘therapeutic time’ for at least 10 hours is required • to eliminate ≥ 95% of N. gonorrhoeae infections Jaffe HW et al., Antimicrob. Agents Chemother. 1979;15:587-591 Deguchi T et al., J. Infect. Chemother. 2003;9:35-39

  25. Cefixime MIC drift, GRASP (2008) MIC (mg/L) MIC (mg/L) Slide courtesy of David Livermore, Health Protection Agency, UK (modified) The Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) 2008, Health Protection Agency, UK

  26. Ceftriaxone MIC drift, GRASP (2008) MIC (mg/L) Slide courtesy of David Livermore, Health Protection Agency, UK The Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) 2008, Health Protection Agency, UK

  27. GRASP - The Gonococcal Resistance to Antimicrobials Surveillance Programme; sentinel data from 24 laboratories and 26 GUM clinics Effect of prescribing cephalosporins on ciprofloxacin resistance (UK) Slide courtesy of Catherine Ison, Health Protection Agency, UK The Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) 2008, Health Protection Agency, UK

  28. Potential solutions • Frapper fort, frapper vite (Ehrlich, 1913) • Cefixime for longer course: 3 days at 400 mg p.o. • Cefixime 800 mg, followed by 2 x 400 mg p.o. • Ceftriaxone 250 mg i.m., followed by 2 days cefixime p.o. • Introduce firebreaks • Rotate cephalosporins / spectinomycin / azithromycin @ 2g • Treat males and females, or index and contacts, differently Slide courtesy of David Livermore, Health Protection Agency, UK (modified)

  29. Multi-drug and extensively drug resistant Neisseria gonorrhoeae (MDR-NG and XDR-NG) • Class I: Antibiotics currently recommended for gonorrhoea • Injectable extended spectrum cephalosporins • Oral extended spectrum cephalosporins • Spectinomycin • Class II: Antibiotics used less frequently, or proposed for more extensive use • Pencillins • Fluoroquinolones • Azithromycin • Aminoglycosides • Carbapenems • Proposed definitions: • MDR-NG: resistant to ≥ 1 class I antibiotic + ≥ 2 class II antibiotics • XDR-NG: resistant to ≥ 2 class I antibiotics + ≥ 3 class II antibiotics Tapsall JW , Ndowa F, Lewis DA, Unemo M (manuscript submitted)

  30. Requirement for an integrated, comprehensive prevention strategy • Enhancement of national and international surveillance systems • Avoid further loss in culturing capability for N. gonorrhoeae • New strategies to prolong the usefulness of existing antimicrobials • Implement screening of high risk individuals • Ensure prompt and efficacious treatment is available • Tighter control on ‘open market’ antibiotic access & quality control of generics • Enhance proportion of sexual partners who receive treatment • Re-vitalise condom promotion and behavioural change strategies • Prioritise research on new therapeutic agents, e.g. anatomical site-specific • clinical efficacy studies, pharmaceutical drug design • Higher priority for sexually transmitted disease control funding

  31. Conclusions • The gonococcus is has repeatedly evolved novel and effective resistance mechanisms • The creeping MICs of N. gonorrhoeae to cephalosporins is a prima facie case of emerging resistance • History repeats itself and human beings have a tendency not to learn • Treatment options are now very limited and we need to reconsider the wisdom of continuing to use single dose therapies • Extended regimens and firebreaks may assist in the short term • Multidrug therapy looks inevitable NHLS NHLS NICD NICD

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